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182d3cb85d64b56bc61dee002572654d46f1186a | wikidoc | Big killer | Big killer
In public health, a big killer is a disease or other major cause of loss of human life.
For an alternative list, see List of causes of death by rate
# World Health Organization deaths
## By disease, conditions
- Ischaemic heart disease 7,208,000; 13%
- Cerebrovascular disease 5,509,000; 10%
- Lower respiratory tract infection 3,884,000; 7%
- HIV/AIDS 2,777,000; 5%
- Chronic obstructive pulmonary disease 2,748,000; 5%
- Perinatal conditions (low birthweight, birth asphyxia, birth trauma) 2,462,000; 4%
- Diarrhoeal diseases 1,798,000; 3%
- Tuberculosis 1,566,000; 3%
- Malaria 1,272,000; 2%
- Trachea/bronchus/lung cancers 1,243,000; 2%
- Road traffic accidents 1,192,000; 2%
- Childhood diseases (pertussis, polio, diphtheria, measles, tetanus) 1,124,000; 2%
- Diabetes mellitus 988,000; 2%
- Other unintentional injuries (besides road traffic accidents, poisoning, falls, fires, drowning) 923,000; 2%
- Hypertensive heart disease 911,000; 2%
- Self-inflicted injuries (suicide) 873,000; 2%
- Stomach cancer 850,000; 2%
- Cirrhosis of the liver 786,000; 1%
- Nephritis/nephrosis 677,000; 1%
- Colon/rectal cancer 622,000; 1%
- Liver cancer 618,000; 1%
- Violence 559,000; 1%
- Breast cancer 477,000; 1%
- Esophageal cancer 446,000; 1%
- Inflammatory heart disease 404,000; 1%
- Alzheimer and other dementias 397,000; 1%
- Falls 392,000; 1%
## By category
- Cardiovascular diseases: 16 733 000 27%
- Infectious and parasitic diseases: 10 904 000 19%
- Malignant neoplasms: 7,121,000 13%
- Respiratory infections: 3,963,000 7%
- Respiratory diseases: 3,702,000 7%
- Unintentional injuries: 3,551,000 6%
- Perinatal conditions: 2,462,000 4%
- Digestive diseases: 1,968,000 4%
- Intentional injuries: 1,618,000 3%
- Neuropsychiatric disorders: 1,112,000 2%
- Diabetes mellitus: 988,000 2%
- Diseases of the genitourinary system: 848,000 2%
- Maternal conditions: 510,000 1%
- Congenital abnormalities: 493,000 1%
- Nutritional deficiencies: 485,000 1%
- Nutritional/endocrine disorders: 485,000 1%
Source: The World Health Report - 2004 Annex Table 2 Deaths - World Health Organization | Big killer
Template:Mergeto
In public health, a big killer is a disease or other major cause of loss of human life.
For an alternative list, see List of causes of death by rate
# World Health Organization deaths
2002
## By disease, conditions
- Ischaemic heart disease 7,208,000; 13%
- Cerebrovascular disease 5,509,000; 10%
- Lower respiratory tract infection 3,884,000; 7%
- HIV/AIDS 2,777,000; 5%
- Chronic obstructive pulmonary disease 2,748,000; 5%
- Perinatal conditions (low birthweight, birth asphyxia, birth trauma) 2,462,000; 4%
- Diarrhoeal diseases 1,798,000; 3%
- Tuberculosis 1,566,000; 3%
- Malaria 1,272,000; 2%
- Trachea/bronchus/lung cancers 1,243,000; 2%
- Road traffic accidents 1,192,000; 2%
- Childhood diseases (pertussis, polio, diphtheria, measles, tetanus) 1,124,000; 2%
- Diabetes mellitus 988,000; 2%
- Other unintentional injuries (besides road traffic accidents, poisoning, falls, fires, drowning) 923,000; 2%
- Hypertensive heart disease 911,000; 2%
- Self-inflicted injuries (suicide) 873,000; 2%
- Stomach cancer 850,000; 2%
- Cirrhosis of the liver 786,000; 1%
- Nephritis/nephrosis 677,000; 1%
- Colon/rectal cancer 622,000; 1%
- Liver cancer 618,000; 1%
- Violence 559,000; 1%
- Breast cancer 477,000; 1%
- Esophageal cancer 446,000; 1%
- Inflammatory heart disease 404,000; 1%
- Alzheimer and other dementias 397,000; 1%
- Falls 392,000; 1%
## By category
- Cardiovascular diseases: 16 733 000 27%
- Infectious and parasitic diseases: 10 904 000 19%
- Malignant neoplasms: 7,121,000 13%
- Respiratory infections: 3,963,000 7%
- Respiratory diseases: 3,702,000 7%
- Unintentional injuries: 3,551,000 6%
- Perinatal conditions: 2,462,000 4%
- Digestive diseases: 1,968,000 4%
- Intentional injuries: 1,618,000 3%
- Neuropsychiatric disorders: 1,112,000 2%
- Diabetes mellitus: 988,000 2%
- Diseases of the genitourinary system: 848,000 2%
- Maternal conditions: 510,000 1%
- Congenital abnormalities: 493,000 1%
- Nutritional deficiencies: 485,000 1%
- Nutritional/endocrine disorders: 485,000 1%
Source: The World Health Report - 2004 Annex Table 2 Deaths - World Health Organization | https://www.wikidoc.org/index.php/Big_killer | |
60899b719f4c520569ac3f985d8fb06756a3702a | wikidoc | Bimaristan | Bimaristan
Bimaristan is a middle Persian and modern Persian (بیمارستان bīmārestān) word meaning hospital, with Bimar- meaning "sick" and -stan as location and place.
In the medieval Islamic world, the word "Bimaristan" was used to indicate a hospital in the modern sense, an establishment where the ill were welcomed and cared for by qualified staff. In this way, Muslim physicians were the first to make a distinction between a hospital and other different forms of healing temples, sleep temples, hospices, assylums, lazarets and leper-houses, all of which in ancient times were more concerned with isolating the sick and the mad from society "rather than to offer them any way to a true cure." The medieval Bimaristan hospitals are thus considered "the first hospitals" in the modern sense of the word. The first public hospitals, psychiatric hospitals and medical universities were also introduced by medieval Muslim physicians.
# History
The oldest recorded Bimarestan is of Gundishapur, established in 3rd century by Shapur I the Sasanian emperor, in present day Khuzestan province of Iran. After Sassanian Iran was conquered by Muslim Arab armies in 638, the Bimaristan survived the change of rulers and evolved into a public hospital with medical university and psychiatric facilities over the centuries under Muslim physicians.
During the Muslim conquests themselves, the Muslim armies during the time of Muhammad were reported to have had a moble dispensary following them for the treatment of soldiers on the battlefield.
The first Bimaristan after the Gundishapur was founded in 707 by the Muslim caliph al-Waleed bin Abdel Malek in Damascus. At the time, most Islamic hospitals had doctors that diagnosed and treated all patients, but the Bimaristan was unique in that it had doctors that specialized in certain diseases. Originally, these health centers were specifically for patients with specific afflictions such as pestilence and blindness, and all services were free of charge.
According to Sir John Bagot Glubb:
"By Mamun's time medical schools were extremely active in Baghdad. The first free public hospital was opened in Baghdad during the Caliphate of Haroon-ar-Rashid. As the system developed, physicians and surgeons were appointed who gave lectures to medical students and issued diplomas to those who were considered qualified to practice. The first hospital in Egypt was opened in 872 AD and thereafter public hospitals sprang up all over the empire from Spain and the Maghrib to Persia."
The largest hospital of the Middle Ages and pre-modern era was built in Cairo, Egypt, by Sultan Qalaun al-Mansur in 1285. According to Will Durant, the hospital had a spacious quadrangular enclosure with four buildings around a courtyard "adorned with arcades and cooled with fountains and brooks." The hospital had "separate wards for diverse diseases and for convalescents", and had laboratories, a dispensary, out-patient clinics, kitchens, baths, a library, a religious place of worship, lecture halls, and "pleasant accommodations for the insane." Treatment was given for free to patients of all backgrounds, regardless of gender, ethnicity or income, while convalescents were offered disbursements on their departure so that they wouldn't need to return to work immediately. "The sleepless were provided with soft music, professional story-tellers, and perhaps books of history."
## Organization
The Bimaristans were organized into two sections, one for men and one for women. Within those sections were halls, each for a specific disease and monitored by one or more doctors. Some examples of the specialized halls are the ones for internal diseases, patients that were splinted, delivery, and communicable diseases. The administration of the hospital was based on the employment of health workers that cleaned the hospital and took care of the patients, physicians; and the head doctor, called Al Saoor. The employees took shifts both day and night to ensure they were all well-rested. An extra wing, called Al Sharabkhana, also known as a pharmacy, was added to enable doctors to easily distribute medication. Bimaristans mainly had two goals: the welfare of their patients and to educate new physicians. An excerpt from Ibn Al-Ukhwah’s book, Al-Hisbah reveals how the Bimaristan system made sure their patients were taken care of:
"The physician asks the patient about the cause of his illness and the pain he feels. He prepares syrups and other drugs, then writes a copy of the prescription to the parents attending with the patient. The following day he re-examines the patient and looks at the drugs and asks him how he feels, and accordingly advises the patient. This procedure is repeated every day until the patient is either cured or dies. If the patient is cured, the physician is paid. If the patient dies, his parents go to the chief doctor and present the prescriptions written by the physician. If the chief doctor judges that the physician has performed his job without negligence, he tells the parents that death was natural; if he judges otherwise, he informs them to take the blood money of their relative from the physician as his death was the result of his bad performance and negligence. In this honorable way they were sure that medicine was practiced by experienced, well trained personnel."
Once admitted into a Bimaristan, the patient can stay for as long as she/or he needed; there was no time limit. Once the patient has fully recovered, they were provided, not only with clean clothes, but with pocket money.
## Staff
The earliest recorded hospitals in the medieval Islamic world were more general than previous Bimaristans as they extended their services to the lepers and the invalid and destitute people. All treatment and care was free of charge and there was more than one physician employed in this hospital. Between the 8th and 12th centuries, Muslim hospitals developed a high standard of care. Hospitals built in Baghdad in the ninth and tenth centuries employed up to twenty-five staff physicians and had separate wards for different conditions. Al-Qairawan hospital and mosque, in Tunisia, were built under the Aghlabid rule in 830 CE and was simple but adequately equipped with halls organized into waiting rooms, a mosque, and a special bath.
Another unique feature of medieval Muslim hospitals was the role of female staff, who were rarely employed in ancient and medieval healing temples elsewhere in the world. Medieval Muslim hospitals commonly employed female nurses, including nurses from as far as Sudan, a sign of great breakthrough. Muslim hospitals were also the first to employ female physicians, the most famous being two female physicians from the Banu Zuhr family who served the Almohad ruler Abu Yusuf Ya'qub al-Mansur in the 12th century. This was necessary due to the segregation between male and female patients in Islamic hospitals. Later in the 15th century, female surgeons were illustrated for the first time in Şerafeddin Sabuncuoğlu's Cerrahiyyetu'l-Haniyye (Imperial Surgery).
In addition to regular physicians who attended the sick, there were Fuqaha al-Badan, a kind of religious physio-therapists, group of religious scholars whose medical services included bloodletting, bone setting, and cauterisation. During Ottoman rule, when hospitals reached a particular distinction, Sultan Bayazid II built a mental hospital and medical madrasa in Edirne, and a number of other early hospitals were also built in Turkey. Unlike in Greek temples to healing gods, the clerics working in these facilities employed scientific methodology far beyond that of their contemporaries in their treatment of patients.
## Funding
After the Islamic waqf law (a precursor of the trust law) and madrassah foundations were firmly established by the 10th century, the number of hospitals multiplied throughout throughout Islamic lands. In the 11th century, every Islamic city had at least several hospitals. Córdoba, Spain alone was reported to have had as many as 50 hospitals at the time of Abu al-Qasim al-Zahrawi (Abulcasis).
The waqf trust institutions funded the hospitals for various expenses, including the wages of doctors, ophthalmologists, surgeons, chemists, pharmacists, domestics and all other staff, the purchase of foods and remedies; hospital equipment such as beds, mattresses, bowls and perfumes; and repairs to buildings. The waqf trusts also funded medical schools, and their revenues covered various expenses such as their maintenance and the payment of teachers and students.
# Medical facilities
Muslim physicians set up some of the earliest dedicated hospitals. In the medieval Islamic world, hospitals were built in all major cities; in Cairo for example, the Qalawun Hospital could care for 8,000 patients, and a staff that included physicians, pharmacists, and nurses. One could also access a dispensary, and research facility that led to advances, which included the discovery of the contagious nature of diseases, and research into optics and the mechanisms of the eye. Muslim doctors were removing cataracts with hollow needles over 1000 years before Western physicians dared attempt such a task. Hospitals were built not only for the physically sick, but for the mentally sick also. One of the first ever psychiatric hospitals that cared for the mentally ill was built in Cairo. Hospitals later spread to Europe during the Crusades, inspired by the hospitals in the Middle East. The first hospital in Paris, Les Quinze-vingt, was founded by Louis IX after his return from the Crusade between 1254-1260.
Hospitals in the Islamic world were secular institutions which treated patients of all ethnic backgrounds and financial statuses, including patients who were male and female, civilian and military, child and adult, rich and poor, and Muslims and non-Muslims. Like modern hospitals, medieval Muslim hospitals were often large urban structures which served a variety of different purposes, including its roles as a centre of medical treatment, a home for patients recovering from illness or accidents, an insane asylum for patients suffering from mental illness, a retirement home for the elderly, a medical school for students, and an outpatient clinic dispensing medical drugs.
Muslim hospitals were the first to feature competency tests for doctors, drug purity regulations, nurses and interns, and advanced surgical procedures. As the pathology of contagion was better understood by Muslim physicians, hospitals were created with separate wards for specific illnesses for the first time, so that people with contagious diseases could be kept away from other patients.
## Medical schools and universities
The first medical schools and universities were founded in the medieval Islamic world, where academic degrees and diplomas (ijazah) were issued to students who were qualified to be a practising Doctor of Medicine.
The hospitals and medical schools and universities had systems for the nomination and elections of a head doctor or deans who would have "led the jihad" of teaching the sciences of Islamic medicine, Fiqh, Hadith and Qur'an to medical students.
Al-Nuri hospital in Egypt was a famous teaching hospital built by Nur ad-Din Zanqi, and was where many renowned physicians were taught. The hospital's medical school is said had elegant rooms, and a library which many of its books were donated by Zangi's physician, Abu al-Majid al-Bahili. A number of Muslim physicians and physicists graduated from there. Among the well-known students are Ibn Abi Usaybi'ah (1203-1270) the famous medical historian, and 'Ala ad-Din Ibn al-Nafis (d. 1289) whose discovery of pulmonary circulation and the lesser circulatory system marked a new step in the better understanding of human physiology and was the earliest explanation until William Harvey (1628).
## Psychiatric hospitals
The first psychiatric hospitals and insane asylums were built in the Islamic world as early as the 8th century. The first psychiatric hospitals were built by the Muslim Arabs in Baghdad in 705, Fes in the early 8th century, and Cairo in 800. Other famous psychiatric hospitals were built in Damascus and Aleppo in 1270. Many other Bimaristian hospitals also often had their own wards dedicated to mental health.
One of the features in medieval Muslim hospitals that distinguished them from their contemporaries was their higher standards of medical ethics. Hospitals in the Islamic world treated patients of all religions, ethnicities, and backgrounds, while the hospitals themselves often employed staff from Christian, Jewish and other minority backgrounds. Muslim doctors and physicians were expected to have obligations towards their patients, regardless of their wealth or backgrounds. The ethical standards of Muslim physicians was first laid down in the 9th century by Ishaq bin Ali Rahawi, who wrote the Adab al-Tabib (Conduct of a Physician), the first treatise dedicated to medical ethics. He regarded physicians as "guardians of souls and bodies", and wrote twenty chapters on various topics related to medical ethics, including:
- What the physician must avoid and beware of
- The manners of visitors
- The care of remedies by the physician
- The dignity of the medical profession
- The examination of physicians
- The removal of corruption among physicians
On a professional level, al-Razi (Rhazes) introduced many practical, progressive, medical and psychological ideas in the 10th century. He attacked charlatans and fake doctors who roamed the cities and countryside selling their nostrums and 'cures'. At the same time, he warned that even highly educated doctors did not have the answers to all medical problems and could not cure all sicknesses or heal every disease, which was humanly speaking impossible. To become more useful in their services and truer to their calling, Razi advised practitioners to keep up with advanced knowledge by continually studying medical books and exposing themselves to new information. He made a distinction between curable and incurable diseases. Pertaining to the latter, he commented that in the case of advanced cases of cancer and leprosy the physician should not be blamed when he could not cure them. To add a humorous note, Razi felt great pity for physicians who took care for the well-being of princes, nobility, and women, because they did not obey the doctor's orders to restrict their diet or get medical treatment, thus making it most difficult being their physician. He also wrote the following on medical ethics:
"The doctor's aim is to do good, even to our enemies, so much more to our friends, and my profession forbids us to do harm to our kindred, as it is instituted for the benefit and welfare of the human race, and God imposed on physicians the oath not to compose mortiferous remedies."
## Drugs
The earliest known prohibition of illegal drugs occurred under Islamic law, which prohibited the use of Hashish, a preparation of cannabis, as a recreational drug. Classical jurists in medieval Islamic jurisprudence, however, accepted the use of the Hashish drug for medicinal and therapeutic purposes, and agreed that its "medical use, even if it leads to mental derangement, remains exempt" from punishment. In the 14th century, the Islamic scholar Az-Zarkashi spoke of "the permissibility of its use for medical purposes if it is established that it is beneficial."
According to Mary Lynn Mathre, with "this legal distinction between the intoxicant and the medical uses of cannabis, medieval Muslim theologians were far ahead of present-day American law."
## Neuroethics
Most ancient and medieval societies believed that mental illness was caused by either demonic possession or as punishment from a god, which led to a negative attitude towards mental illness in Judeo-Christian and Greco-Roman societies. On the other hand, Islamic neuroethics and neurotheology held a more sympathetic attitude towards the mentally ill, as exemplified in Sura 4:5 of the Qur'an:
"Do not give your property which God assigned you to manage to the insane: but feed and cloth the insane with this property and tell splendid words to him."
This Quranic verse summarized Islam's attitudes towards the mentally ill, who were considered unfit to manage property but must be treated humanely and be kept under care by a guardian, according to Islamic law. This positive neuroethical understanding of mental health consequently led to the establishment of the first psychiatric hospitals in the medieval Islamic world from the 8th century, and an early scientific understanding of neuroscience and psychology by medieval Muslim physicians and psychologists, who discovered that mental disorders are caused by dysfunctions in the brain.
## Peer review
The first documented description of a peer review process is found in the Ethics of the Physician written by Ishaq bin Ali al-Rahwi (854–931) of al-Raha, Syria, who describes the first medical peer review process. His work, as well as later Arabic medical manuals, state that a visiting physician must always make duplicate notes of a patient's condition on every visit. When the patient was cured or had died, the notes of the physician were examined by a local medical council of other physicians, who would review the practising physician's notes to decide whether his/her performance have met the required standards of medical care. If their reviews were negative, the practicing physician could face a lawsuit from a maltreated patient.
## Public health care
Islamic cities also had an early public health care service. "The extraordinary provision of public bath-houses, complex sanitary systems of drainage (more extensive even than the famous Roman infrastructures), fresh water supplies, and the large and sophisticated urban hospitals, all contributed to the general health of the population." Competency tests were also carried out by medical authorities visiting hospitals and clinics "to regulate, in one way or another, the performance and competency of those providing medical care or active in the medical market-place."
# Notes
- ↑ Micheau, Francoise, "The Scientific Institutions in the Medieval Near East", pp. 991–2 Missing or empty |title= (help).mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}, in Template:Harv
- ↑ Peter Barrett (2004), Science and Theology Since Copernicus: The Search for Understanding, p. 18, Continuum International Publishing Group, ISBN 056708969X.
- ↑ Ibrahim B. Syed PhD, "Islamic Medicine: 1000 years ahead of its times", Journal of the Islamic Medical Association, 2002 (2), p. 2-9 .
- ↑ Jump up to: 4.0 4.1 4.2 Sir Glubb, John Bagot (1969), A Short History of the Arab Peoples, retrieved 2008-01-25
- ↑ Durant, Will (1950), The Story of Civilization IV: The Age of Faith, Simon and Shuster, New York, pp. 330–1
- ↑ al-Hassani, Woodcock and Saoud (2007), 'Muslim heritage in Our World', FSTC Publishing, pp.154-156
- ↑ The Art as a Profession, United States National Library of Medicine
- ↑ G. Bademci (2006), First illustrations of female "Neurosurgeons" in the fifteenth century by Serefeddin Sabuncuoglu, Neurocirugía 17: 162-165.
- ↑ Turkish Contributions to Scientific Work in Islam - Sayili, Aydin, Foundation For Science, Technology and Civilisation, Septermber 2004, Page 9
- ↑ Jump up to: 10.0 10.1 Micheau, Francoise, "The Scientific Institutions in the Medieval Near East", pp. 999–1001 Missing or empty |title= (help), in Template:Harv
- ↑ "Muslim Contribution to Cosmetics". FSTC Limited. 20 May, 2003. Retrieved 2008-01-29. Check date values in: |date= (help)
- ↑ George Sarton, Introduction to the History of Science.(cf. Dr. A. Zahoor and Dr. Z. Haq (1997), Quotations From Famous Historians of Science, Cyberistan.
- ↑ Savage-Smith, Emilie (1996), "Medicine", pp. 933–4 Missing or empty |title= (help), in Template:Harv
- ↑ Michael Woods, Islam, once at forefront of science, fell by wayside, Post-Gazette National Bureau, Sunday, April 11, 2004.
- ↑ Medicine And Health, "Rise and Spread of Islam 622-1500: Science, Technology, Health", World Eras, Thomson Gale.
- ↑ Alatas, Syed Farid, "From Jami`ah to University: Multiculturalism and Christian–Muslim Dialogue", Current Sociology, 54 (1): 112–32
- ↑ Micheau, Francoise, "The Scientific Institutions in the Medieval Near East", pp. 1001–2 Missing or empty |title= (help), in Template:Harv
- ↑ al-Hassani, Woodcock and Saoud(2007),'Muslim Heritage in Our World', FSTC Publishing, p.158-59
- ↑ Ibrahim B. Syed PhD, "Islamic Medicine: 1000 years ahead of its times", Journal of the Islamic Medical Association, 2002 (2), p. 2-9 .
- ↑ Jump up to: 20.0 20.1 Islamic Science, the Scholar and Ethics, Foundation for Science Technology and Civilisation.
- ↑ Mathre, Mary Lynn (1997), Cannabis in Medical Practice: A Legal, Historical and Pharmacological Overview of the Therapeutic Use of Marijuana, McFarland, p. 40, ISBN 0786403616
- ↑ Mathre, Mary Lynn (1997), Cannabis in Medical Practice: A Legal, Historical and Pharmacological Overview of the Therapeutic Use of Marijuana, McFarland, p. 41, ISBN 0786403616
- ↑ Jump up to: 23.0 23.1 A. Vanzan Paladin (1998), "Ethics and neurology in the islamic world: Continuity and change", Italial Journal of Neurological Science 19: 255-258 , Springer-Verlag.
- ↑ Qur'an, Sura 4:5
- ↑ Template:Harv
- ↑ Template:Harv
- ↑ Ray Spier (2002), "The history of the peer-review process", Trends in Biotechnology 20 (8), p. 357-358 .
- ↑ Pormann, Peter E. (2007), Medieval Islamic Medicine, Edinburgh University Press, ISBN 1589011600, retrieved 2008-01-29 Unknown parameter |last-2= ignored (help); |first1= missing |last1= in Authors list (help) | Bimaristan
Bimaristan is a middle Persian and modern Persian (بیمارستان bīmārestān) word meaning hospital, with Bimar- meaning "sick" and -stan as location and place.
In the medieval Islamic world, the word "Bimaristan" was used to indicate a hospital in the modern sense, an establishment where the ill were welcomed and cared for by qualified staff. In this way, Muslim physicians were the first to make a distinction between a hospital and other different forms of healing temples, sleep temples, hospices, assylums, lazarets and leper-houses, all of which in ancient times were more concerned with isolating the sick and the mad from society "rather than to offer them any way to a true cure." The medieval Bimaristan hospitals are thus considered "the first hospitals" in the modern sense of the word.[1] The first public hospitals,[2] psychiatric hospitals[3] and medical universities[4] were also introduced by medieval Muslim physicians.
# History
The oldest recorded Bimarestan is of Gundishapur, established in 3rd century by Shapur I the Sasanian emperor, in present day Khuzestan province of Iran. After Sassanian Iran was conquered by Muslim Arab armies in 638, the Bimaristan survived the change of rulers and evolved into a public hospital with medical university and psychiatric facilities over the centuries under Muslim physicians.
During the Muslim conquests themselves, the Muslim armies during the time of Muhammad were reported to have had a moble dispensary following them for the treatment of soldiers on the battlefield.
The first Bimaristan after the Gundishapur was founded in 707 by the Muslim caliph al-Waleed bin Abdel Malek in Damascus. At the time, most Islamic hospitals had doctors that diagnosed and treated all patients, but the Bimaristan was unique in that it had doctors that specialized in certain diseases. Originally, these health centers were specifically for patients with specific afflictions such as pestilence and blindness, and all services were free of charge.
According to Sir John Bagot Glubb:
"By Mamun's time medical schools were extremely active in Baghdad. The first free public hospital was opened in Baghdad during the Caliphate of Haroon-ar-Rashid. As the system developed, physicians and surgeons were appointed who gave lectures to medical students and issued diplomas to those who were considered qualified to practice. The first hospital in Egypt was opened in 872 AD and thereafter public hospitals sprang up all over the empire from Spain and the Maghrib to Persia."[4]
The largest hospital of the Middle Ages and pre-modern era was built in Cairo, Egypt, by Sultan Qalaun al-Mansur in 1285. According to Will Durant, the hospital had a spacious quadrangular enclosure with four buildings around a courtyard "adorned with arcades and cooled with fountains and brooks." The hospital had "separate wards for diverse diseases and for convalescents", and had laboratories, a dispensary, out-patient clinics, kitchens, baths, a library, a religious place of worship, lecture halls, and "pleasant accommodations for the insane." Treatment was given for free to patients of all backgrounds, regardless of gender, ethnicity or income, while convalescents were offered disbursements on their departure so that they wouldn't need to return to work immediately. "The sleepless were provided with soft music, professional story-tellers, and perhaps books of history."[5]
## Organization
The Bimaristans were organized into two sections, one for men and one for women. Within those sections were halls, each for a specific disease and monitored by one or more doctors. Some examples of the specialized halls are the ones for internal diseases, patients that were splinted, delivery, and communicable diseases. The administration of the hospital was based on the employment of health workers that cleaned the hospital and took care of the patients, physicians; and the head doctor, called Al Saoor. The employees took shifts both day and night to ensure they were all well-rested. An extra wing, called Al Sharabkhana, also known as a pharmacy, was added to enable doctors to easily distribute medication. Bimaristans mainly had two goals: the welfare of their patients and to educate new physicians. An excerpt from Ibn Al-Ukhwah’s book, Al-Hisbah reveals how the Bimaristan system made sure their patients were taken care of:
"The physician asks the patient about the cause of his illness and the pain he feels. He prepares syrups and other drugs, then writes a copy of the prescription to the parents attending with the patient. The following day he re-examines the patient and looks at the drugs and asks him how he feels, and accordingly advises the patient. This procedure is repeated every day until the patient is either cured or dies. If the patient is cured, the physician is paid. If the patient dies, his parents go to the chief doctor and present the prescriptions written by the physician. If the chief doctor judges that the physician has performed his job without negligence, he tells the parents that death was natural; if he judges otherwise, he informs them to take the blood money of their relative from the physician as his death was the result of his bad performance and negligence. In this honorable way they were sure that medicine was practiced by experienced, well trained personnel."
Once admitted into a Bimaristan, the patient can stay for as long as she/or he needed; there was no time limit. Once the patient has fully recovered, they were provided, not only with clean clothes, but with pocket money.
## Staff
The earliest recorded hospitals in the medieval Islamic world were more general than previous Bimaristans as they extended their services to the lepers and the invalid and destitute people. All treatment and care was free of charge and there was more than one physician employed in this hospital.[6] Between the 8th and 12th centuries, Muslim hospitals developed a high standard of care. Hospitals built in Baghdad in the ninth and tenth centuries employed up to twenty-five staff physicians and had separate wards for different conditions. Al-Qairawan hospital and mosque, in Tunisia, were built under the Aghlabid rule in 830 CE and was simple but adequately equipped with halls organized into waiting rooms, a mosque, and a special bath.
Another unique feature of medieval Muslim hospitals was the role of female staff, who were rarely employed in ancient and medieval healing temples elsewhere in the world. Medieval Muslim hospitals commonly employed female nurses, including nurses from as far as Sudan, a sign of great breakthrough. Muslim hospitals were also the first to employ female physicians, the most famous being two female physicians from the Banu Zuhr family who served the Almohad ruler Abu Yusuf Ya'qub al-Mansur in the 12th century.[7] This was necessary due to the segregation between male and female patients in Islamic hospitals. Later in the 15th century, female surgeons were illustrated for the first time in Şerafeddin Sabuncuoğlu's Cerrahiyyetu'l-Haniyye (Imperial Surgery).[8]
In addition to regular physicians who attended the sick, there were Fuqaha al-Badan, a kind of religious physio-therapists, group of religious scholars whose medical services included bloodletting, bone setting, and cauterisation. During Ottoman rule, when hospitals reached a particular distinction, Sultan Bayazid II built a mental hospital and medical madrasa in Edirne, and a number of other early hospitals were also built in Turkey. Unlike in Greek temples to healing gods, the clerics working in these facilities employed scientific methodology far beyond that of their contemporaries in their treatment of patients.[9]
## Funding
After the Islamic waqf law (a precursor of the trust law) and madrassah foundations were firmly established by the 10th century, the number of hospitals multiplied throughout throughout Islamic lands. In the 11th century, every Islamic city had at least several hospitals.[10] Córdoba, Spain alone was reported to have had as many as 50 hospitals at the time of Abu al-Qasim al-Zahrawi (Abulcasis).[11]
The waqf trust institutions funded the hospitals for various expenses, including the wages of doctors, ophthalmologists, surgeons, chemists, pharmacists, domestics and all other staff, the purchase of foods and remedies; hospital equipment such as beds, mattresses, bowls and perfumes; and repairs to buildings. The waqf trusts also funded medical schools, and their revenues covered various expenses such as their maintenance and the payment of teachers and students.[10]
# Medical facilities
Muslim physicians set up some of the earliest dedicated hospitals. In the medieval Islamic world, hospitals were built in all major cities; in Cairo for example, the Qalawun Hospital could care for 8,000 patients, and a staff that included physicians, pharmacists, and nurses. One could also access a dispensary, and research facility that led to advances, which included the discovery of the contagious nature of diseases, and research into optics and the mechanisms of the eye. Muslim doctors were removing cataracts with hollow needles over 1000 years before Western physicians dared attempt such a task. Hospitals were built not only for the physically sick, but for the mentally sick also. One of the first ever psychiatric hospitals that cared for the mentally ill was built in Cairo. Hospitals later spread to Europe during the Crusades, inspired by the hospitals in the Middle East. The first hospital in Paris, Les Quinze-vingt, was founded by Louis IX after his return from the Crusade between 1254-1260.[12]
Hospitals in the Islamic world were secular institutions which treated patients of all ethnic backgrounds and financial statuses, including patients who were male and female, civilian and military, child and adult, rich and poor, and Muslims and non-Muslims. Like modern hospitals, medieval Muslim hospitals were often large urban structures which served a variety of different purposes, including its roles as a centre of medical treatment, a home for patients recovering from illness or accidents, an insane asylum for patients suffering from mental illness, a retirement home for the elderly, a medical school for students, and an outpatient clinic dispensing medical drugs.[13]
Muslim hospitals were the first to feature competency tests for doctors, drug purity regulations, nurses and interns, and advanced surgical procedures.[14] As the pathology of contagion was better understood by Muslim physicians, hospitals were created with separate wards for specific illnesses for the first time, so that people with contagious diseases could be kept away from other patients.[15]
## Medical schools and universities
The first medical schools and universities were founded in the medieval Islamic world, where academic degrees and diplomas (ijazah) were issued to students who were qualified to be a practising Doctor of Medicine.[4][16]
The hospitals and medical schools and universities had systems for the nomination and elections of a head doctor or deans who would have "led the jihad" of teaching the sciences of Islamic medicine, Fiqh, Hadith and Qur'an to medical students.[17]
Al-Nuri hospital in Egypt was a famous teaching hospital built by Nur ad-Din Zanqi, and was where many renowned physicians were taught. The hospital's medical school is said had elegant rooms, and a library which many of its books were donated by Zangi's physician, Abu al-Majid al-Bahili. A number of Muslim physicians and physicists graduated from there. Among the well-known students are Ibn Abi Usaybi'ah (1203-1270) the famous medical historian, and 'Ala ad-Din Ibn al-Nafis (d. 1289) whose discovery of pulmonary circulation and the lesser circulatory system marked a new step in the better understanding of human physiology and was the earliest explanation until William Harvey (1628).[18]
## Psychiatric hospitals
The first psychiatric hospitals and insane asylums were built in the Islamic world as early as the 8th century. The first psychiatric hospitals were built by the Muslim Arabs in Baghdad in 705, Fes in the early 8th century, and Cairo in 800. Other famous psychiatric hospitals were built in Damascus and Aleppo in 1270. Many other Bimaristian hospitals also often had their own wards dedicated to mental health.[19]
One of the features in medieval Muslim hospitals that distinguished them from their contemporaries was their higher standards of medical ethics. Hospitals in the Islamic world treated patients of all religions, ethnicities, and backgrounds, while the hospitals themselves often employed staff from Christian, Jewish and other minority backgrounds. Muslim doctors and physicians were expected to have obligations towards their patients, regardless of their wealth or backgrounds. The ethical standards of Muslim physicians was first laid down in the 9th century by Ishaq bin Ali Rahawi, who wrote the Adab al-Tabib (Conduct of a Physician), the first treatise dedicated to medical ethics. He regarded physicians as "guardians of souls and bodies", and wrote twenty chapters on various topics related to medical ethics, including:[20]
- What the physician must avoid and beware of
- The manners of visitors
- The care of remedies by the physician
- The dignity of the medical profession
- The examination of physicians
- The removal of corruption among physicians
On a professional level, al-Razi (Rhazes) introduced many practical, progressive, medical and psychological ideas in the 10th century. He attacked charlatans and fake doctors who roamed the cities and countryside selling their nostrums and 'cures'. At the same time, he warned that even highly educated doctors did not have the answers to all medical problems and could not cure all sicknesses or heal every disease, which was humanly speaking impossible. To become more useful in their services and truer to their calling, Razi advised practitioners to keep up with advanced knowledge by continually studying medical books and exposing themselves to new information. He made a distinction between curable and incurable diseases. Pertaining to the latter, he commented that in the case of advanced cases of cancer and leprosy the physician should not be blamed when he could not cure them. To add a humorous note, Razi felt great pity for physicians who took care for the well-being of princes, nobility, and women, because they did not obey the doctor's orders to restrict their diet or get medical treatment, thus making it most difficult being their physician. He also wrote the following on medical ethics:
"The doctor's aim is to do good, even to our enemies, so much more to our friends, and my profession forbids us to do harm to our kindred, as it is instituted for the benefit and welfare of the human race, and God imposed on physicians the oath not to compose mortiferous remedies."[20]
## Drugs
The earliest known prohibition of illegal drugs occurred under Islamic law, which prohibited the use of Hashish, a preparation of cannabis, as a recreational drug. Classical jurists in medieval Islamic jurisprudence, however, accepted the use of the Hashish drug for medicinal and therapeutic purposes, and agreed that its "medical use, even if it leads to mental derangement, remains exempt" from punishment. In the 14th century, the Islamic scholar Az-Zarkashi spoke of "the permissibility of its use for medical purposes if it is established that it is beneficial."[21]
According to Mary Lynn Mathre, with "this legal distinction between the intoxicant and the medical uses of cannabis, medieval Muslim theologians were far ahead of present-day American law."[22]
## Neuroethics
Most ancient and medieval societies believed that mental illness was caused by either demonic possession or as punishment from a god, which led to a negative attitude towards mental illness in Judeo-Christian and Greco-Roman societies. On the other hand, Islamic neuroethics and neurotheology held a more sympathetic attitude towards the mentally ill, as exemplified in Sura 4:5 of the Qur'an:[23]
"Do not give your property which God assigned you to manage to the insane: but feed and cloth the insane with this property and tell splendid words to him."[24]
This Quranic verse summarized Islam's attitudes towards the mentally ill, who were considered unfit to manage property but must be treated humanely and be kept under care by a guardian, according to Islamic law.[23] This positive neuroethical understanding of mental health consequently led to the establishment of the first psychiatric hospitals in the medieval Islamic world from the 8th century,[25] and an early scientific understanding of neuroscience and psychology by medieval Muslim physicians and psychologists, who discovered that mental disorders are caused by dysfunctions in the brain.[26]
## Peer review
The first documented description of a peer review process is found in the Ethics of the Physician written by Ishaq bin Ali al-Rahwi (854–931) of al-Raha, Syria, who describes the first medical peer review process. His work, as well as later Arabic medical manuals, state that a visiting physician must always make duplicate notes of a patient's condition on every visit. When the patient was cured or had died, the notes of the physician were examined by a local medical council of other physicians, who would review the practising physician's notes to decide whether his/her performance have met the required standards of medical care. If their reviews were negative, the practicing physician could face a lawsuit from a maltreated patient.[27]
## Public health care
Islamic cities also had an early public health care service. "The extraordinary provision of public bath-houses, complex sanitary systems of drainage (more extensive even than the famous Roman infrastructures), fresh water supplies, and the large and sophisticated urban hospitals, all contributed to the general health of the population." Competency tests were also carried out by medical authorities visiting hospitals and clinics "to regulate, in one way or another, the performance and competency of those providing medical care or active in the medical market-place."[28]
# Notes
- ↑ Micheau, Francoise, "The Scientific Institutions in the Medieval Near East", pp. 991–2 Missing or empty |title= (help).mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}, in Template:Harv
- ↑ Peter Barrett (2004), Science and Theology Since Copernicus: The Search for Understanding, p. 18, Continuum International Publishing Group, ISBN 056708969X.
- ↑ Ibrahim B. Syed PhD, "Islamic Medicine: 1000 years ahead of its times", Journal of the Islamic Medical Association, 2002 (2), p. 2-9 [7-8].
- ↑ Jump up to: 4.0 4.1 4.2 Sir Glubb, John Bagot (1969), A Short History of the Arab Peoples, retrieved 2008-01-25
- ↑ Durant, Will (1950), The Story of Civilization IV: The Age of Faith, Simon and Shuster, New York, pp. 330–1
- ↑ al-Hassani, Woodcock and Saoud (2007), 'Muslim heritage in Our World', FSTC Publishing, pp.154-156
- ↑ The Art as a Profession, United States National Library of Medicine
- ↑ G. Bademci (2006), First illustrations of female "Neurosurgeons" in the fifteenth century by Serefeddin Sabuncuoglu, Neurocirugía 17: 162-165.
- ↑ Turkish Contributions to Scientific Work in Islam - Sayili, Aydin, Foundation For Science, Technology and Civilisation, Septermber 2004, Page 9
- ↑ Jump up to: 10.0 10.1 Micheau, Francoise, "The Scientific Institutions in the Medieval Near East", pp. 999–1001 Missing or empty |title= (help), in Template:Harv
- ↑ "Muslim Contribution to Cosmetics". FSTC Limited. 20 May, 2003. Retrieved 2008-01-29. Check date values in: |date= (help)
- ↑ George Sarton, Introduction to the History of Science.(cf. Dr. A. Zahoor and Dr. Z. Haq (1997), Quotations From Famous Historians of Science, Cyberistan.
- ↑ Savage-Smith, Emilie (1996), "Medicine", pp. 933–4 Missing or empty |title= (help), in Template:Harv
- ↑ Michael Woods, Islam, once at forefront of science, fell by wayside, Post-Gazette National Bureau, Sunday, April 11, 2004.
- ↑ Medicine And Health, "Rise and Spread of Islam 622-1500: Science, Technology, Health", World Eras, Thomson Gale.
- ↑ Alatas, Syed Farid, "From Jami`ah to University: Multiculturalism and Christian–Muslim Dialogue", Current Sociology, 54 (1): 112–32
- ↑ Micheau, Francoise, "The Scientific Institutions in the Medieval Near East", pp. 1001–2 Missing or empty |title= (help), in Template:Harv
- ↑ al-Hassani, Woodcock and Saoud(2007),'Muslim Heritage in Our World', FSTC Publishing, p.158-59
- ↑ Ibrahim B. Syed PhD, "Islamic Medicine: 1000 years ahead of its times", Journal of the Islamic Medical Association, 2002 (2), p. 2-9 [7-8].
- ↑ Jump up to: 20.0 20.1 Islamic Science, the Scholar and Ethics, Foundation for Science Technology and Civilisation.
- ↑ Mathre, Mary Lynn (1997), Cannabis in Medical Practice: A Legal, Historical and Pharmacological Overview of the Therapeutic Use of Marijuana, McFarland, p. 40, ISBN 0786403616
- ↑ Mathre, Mary Lynn (1997), Cannabis in Medical Practice: A Legal, Historical and Pharmacological Overview of the Therapeutic Use of Marijuana, McFarland, p. 41, ISBN 0786403616
- ↑ Jump up to: 23.0 23.1 A. Vanzan Paladin (1998), "Ethics and neurology in the islamic world: Continuity and change", Italial Journal of Neurological Science 19: 255-258 [257], Springer-Verlag.
- ↑ Qur'an, Sura 4:5
- ↑ Template:Harv
- ↑ Template:Harv
- ↑ Ray Spier (2002), "The history of the peer-review process", Trends in Biotechnology 20 (8), p. 357-358 [357].
- ↑ Pormann, Peter E. (2007), Medieval Islamic Medicine, Edinburgh University Press, ISBN 1589011600, retrieved 2008-01-29 Unknown parameter |last-2= ignored (help); |first1= missing |last1= in Authors list (help) | https://www.wikidoc.org/index.php/Bimaristan | |
348b3bb3380ecc5d9572a6be2354cedeb10a5f4b | wikidoc | Biogenesis | Biogenesis
Biogenesis is the process of lifeforms producing other lifeforms, e.g. a spider lays eggs, which develop into spiders.
The term is also used for the assertion that living matter can only be generated by other living matter, in contrast to the hypotheses of abiogenesis which hold that life can arise from non-life under suitable circumstances, although these circumstances still remain unknown.
Until the 19th century, it was commonly believed that life frequently arose from non-life under certain circumstances, a process known as spontaneous generation. This belief was due to the common observation that maggots or mold appeared to arise spontaneously when organic matter was left exposed. It was later discovered that under all these circumstances commonly observed, life only arises from the replication of other living organisms.
A second meaning of biogenesis was given by the French Jesuit priest, scientist and philosopher Pierre Teilhard de Chardin to mean the origin of life itself due to an inherent drive of matter towards higher consciousness, an extension of the now disproven orthogenesis hypothesis.
# Law of biogenesis
Pasteur's (and others) empirical results were summarized in the phrase, Omne vivum ex vivo (or Omne vivum ex ovo), Latin for "all life from egg". This is sometimes called "law of biogenesis" and shows that modern organisms do not spontaneously arise in nature from non-life.
The law of biogenesis is not to be confused with Ernst Haeckel's Biogenetic Law.
No cellular life has ever been observed to arise from non-living matter. The construction of viable viruses capable of infection and evolution from abiotic material has been reported; however, considerable debate still exists regarding if viruses are actually alive. Various other experiments into the possibility and potential mechanisms of abiogenesis have also been reported. | Biogenesis
Biogenesis is the process of lifeforms producing other lifeforms, e.g. a spider lays eggs, which develop into spiders.
The term is also used for the assertion that living matter can only be generated by other living matter, in contrast to the hypotheses of abiogenesis which hold that life can arise from non-life under suitable circumstances, although these circumstances still remain unknown.
Until the 19th century, it was commonly believed that life frequently arose from non-life under certain circumstances, a process known as spontaneous generation. This belief was due to the common observation that maggots or mold appeared to arise spontaneously when organic matter was left exposed. It was later discovered that under all these circumstances commonly observed, life only arises from the replication of other living organisms.
A second meaning of biogenesis was given by the French Jesuit priest, scientist and philosopher Pierre Teilhard de Chardin to mean the origin of life itself due to an inherent drive of matter towards higher consciousness, an extension of the now disproven orthogenesis hypothesis.
# Law of biogenesis
Pasteur's (and others) empirical results were summarized in the phrase, Omne vivum ex vivo (or Omne vivum ex ovo), Latin for "all life [is] from [an] egg". This is sometimes called "law of biogenesis" and shows that modern organisms do not spontaneously arise in nature from non-life.
The law of biogenesis is not to be confused with Ernst Haeckel's Biogenetic Law. [1] [2]
No cellular life has ever been observed to arise from non-living matter. The construction of viable viruses capable of infection and evolution from abiotic material has been reported[1]; however, considerable debate still exists regarding if viruses are actually alive. Various other experiments into the possibility and potential mechanisms of abiogenesis have also been reported. | https://www.wikidoc.org/index.php/Biogenesis | |
ecde6dd8460fdf46e5e90a19a2b62ae19effc74e | wikidoc | Biomimicry | Biomimicry
Biomimicry (from bios, meaning life, and mimesis, meaning to imitate) is a relatively new science that studies nature, its models, systems, processes and elements and then imitates or takes creative inspiration from them to solve human problems sustainably.
In her 1997 book, "Biomimicry: Innovation Inspired by Nature" (ISBN 0-06-053322-6), author Janine M. Benyus introduces biomimicry, presents examples, and explains why the field is important now. She writes, "Our planet-mates (plants, animals and microbes) have been patiently perfecting their wares for more than 3.8 billion years ... turning rock and sea into a life-friendly home. What better models could there be?"
The book lists numerous examples of people who are studying nature's achievements, including photosynthesis, natural selection, and self-sustaining ecosystems, among others. Benyus then explains how those researchers use the inspirations found in nature to emulate "life's genius" for the purpose of improving manufacturing processes, creating new medicines, changing the way people grow food, or harnessing energy.
# Examples
One example is the attempt to learn from and emulate the incredible ability of termites to maintain virtually constant temperature and humidity in their Sub-Saharan Africa homes despite an outside temperature variation from 3 °C to 42 °C (35 °F at night to 104 °F during the day.) Project TERMES (Termite Emulation of Regulatory Mound Environments by Simulation) scanned a termite mound, created 3-D images of the mound structure and provided the first ever glimpse of construction that may likely change the way we build our own buildings. The Eastgate Centre, a mid-rise office complex in Harare, Zimbabwe, (highlighted in this Biomimicry Institute case-study) stays cool without air conditioning and uses only 10% of the energy of a conventional building its size.
Another example is modeling the echolocation of bats in darkness and adapting that functionality into a cane for the visually impaired. Research performed at the University of Leeds (in the UK) led to the UltraCane, a product manufactured, marketed and sold by Sound Foresight Ltd. | Biomimicry
Biomimicry (from bios, meaning life, and mimesis, meaning to imitate) is a relatively new science that studies nature, its models, systems, processes and elements and then imitates or takes creative inspiration from them to solve human problems sustainably.
In her 1997 book, "Biomimicry: Innovation Inspired by Nature" (ISBN 0-06-053322-6), author Janine M. Benyus introduces biomimicry, presents examples, and explains why the field is important now. She writes, "Our planet-mates (plants, animals and microbes) have been patiently perfecting their wares for more than 3.8 billion years ... turning rock and sea into a life-friendly home. What better models could there be?"
The book lists numerous examples of people who are studying nature's achievements, including photosynthesis, natural selection, and self-sustaining ecosystems, among others. Benyus then explains how those researchers use the inspirations found in nature to emulate "life's genius" for the purpose of improving manufacturing processes, creating new medicines, changing the way people grow food, or harnessing energy.
# Examples
One example is the attempt to learn from and emulate the incredible ability of termites to maintain virtually constant temperature and humidity in their Sub-Saharan Africa homes despite an outside temperature variation from 3 °C to 42 °C (35 °F at night to 104 °F during the day.) Project TERMES (Termite Emulation of Regulatory Mound Environments by Simulation) scanned a termite mound, created 3-D images of the mound structure and provided the first ever glimpse of construction that may likely change the way we build our own buildings. The Eastgate Centre, a mid-rise office complex in Harare, Zimbabwe, (highlighted in this Biomimicry Institute case-study) stays cool without air conditioning and uses only 10% of the energy of a conventional building its size.
Another example is modeling the echolocation of bats in darkness and adapting that functionality into a cane for the visually impaired. Research performed at the University of Leeds (in the UK) led to the UltraCane, a product manufactured, marketed and sold by Sound Foresight Ltd. | https://www.wikidoc.org/index.php/Biomimicry | |
41c8da1329636a25ca70bfdc646072d6072d1cf7 | wikidoc | Biophysics | Biophysics
Biophysics (also biological physics) is an interdisciplinary science that employs and develops theories and methods of the physical sciences for the investigation of biological systems. Studies included under the umbrella of biophysics span all levels of biological organization, from the molecular scale to whole organisms and ecosystems. Biophysical research shares significant overlap with biochemistry, nanotechnology, bioengineering and systems biology.
Molecular biophysics typically addresses biological questions that are similar to those in biochemistry and molecular biology, but the questions are approached quantitatively. Scientists in this field conduct research concerned with understanding the interactions between the various systems of a cell, including the interactions between DNA, RNA and protein biosynthesis, as well as how these interactions are regulated. A great variety of techniques are used to answer these questions. For example, through the use of the biophysical and biochemical techniques such as patch-clamp, electrophysiolgy, immunoprecipitation and western blot, the regulation of ion channels can be studied and in turn their cellular and large scale effects can be better understood.
Fluorescent imaging techniques, as well as electron microscopy, x-ray crystallography and atomic force microscopy (AFM) are often used to visualize structures of biological significance. Direct manipulation of molecules using optical tweezers or AFM can also be used to monitor biological events where forces and distances are at the nanoscale. Molecular biophysicists often consider complex biological events as systems of interacting units which can be understood through statistical mechanics, thermodynamics and chemical kinetics. By drawing knowledge and experimental techniques from a wide variety of disciplines, biophysicists are often able to directly observe, model or even manipulate the structures and interactions of individual molecules or complexes of molecules.
In addition to traditional (i.e. molecular) biophysical topics like structural biology or enzyme kinetics, modern biophysics encompasses an extraordinarily broad range of research. It is becoming increasingly common for biophysicists to apply the models and experimental techniques derived from physics, as well as mathematics and statistics, to larger systems such as tissues, organs, populations and ecosystems.
# Focus as a subfield
Biophysics often does not have university-level departments of its own, but have presence as groups across departments within the fields of biology, biochemistry, chemistry, computer science, mathematics, medicine, pharmacology, physiology, physics, and neuroscience. What follows is a list of examples of how each department applies its efforts toward the study of biophysics. This list is hardly all inclusive. Nor does each subject of study belong exclusively to any particular department. Each academic institution makes its own rules and there is much overlap between departments.
- Biology and molecular biology - Almost all forms of biophysics efforts are included in some biology department somewhere. To include some: gene regulation, single protein dynamics, bioenergetics, patch clamping, biomechanics.
- Structural biology - angstrom-resolution structures of proteins, nucleic acids, lipids, carbohydrates, and complexes thereof.
- Biochemistry and chemistry - biomolecular structure, siRNA, nucleic acid structure, structure-activity relationships.
- Computer science - Neural networks, Biomolecular and drug databases.
- Computational chemistry - Molecular dynamics simulation, Molecular docking, Quantum chemistry
- Bioinformatics - sequence alignment, structural alignment, Protein structure prediction
- Mathematics - graph/network theory, population modeling, dynamical systems, phylogenetics.
- Medicine and neuroscience - tackling neural networks experimentally (brain slicing) as well as theoretically (computer models), membrane permitivity, gene therapy, understanding tumors.
- Pharmacology and physiology - channel biology, biomolecular interactions, cellular membranes, polyketides.
- Physics - Biomolecular free energy, stochastic processes, covering dynamics.
Many biophysical techniques are unique to this field. Research efforts in biophysics are often initiated by scientists who were traditional physicists, chemists, and biologists by training.
# Topics in biophysics and related fields
- Animal locomotion
- Bioacoustics
- Biochemical systems theory
- Biofilms
- Biological membranes
- Bioenergetics
- Biomechanics
- Biomineralisation
- Bionics
- Biosensor and Bioelectronics
- Cell division
- Cell membranes
- Cell migration
- Cell signalling
- Channels, receptors and transporters
- Cryobiology
- Dynamical systems
- Electrophysiology
- Enzyme kinetics
- Evolution
- Evolutionarily stable strategy
- Evolutionary algorithms
- Evolutionary computing
- Evolutionary theory
- Game theory
- Gravitational biology
- Mathematical biology
- Metabolic control analysis
- Microscopy
- Molecular biophysics
- Molecular motors
- Muscle and contractility
- Negentropy
- Neural encoding
- Neuroimaging
- Nucleic acids
- Origin of Life
- Phospholipids
- Photobiophysics and biophotonics
- Polysulphur membranes
- Proteins
- Punctuated equilibrium
- Radiobiology
- Sensory systems
- Signaling
- Spectroscopy, imaging, etc.
- Supramolecular assemblies
- Systems biology
- Systems neuroscience
- Tensegrity
- Theoretical biology
# Famous biophysicists
- Luigi Galvani, discoverer of bioelectricity
- Hermann von Helmholtz, first to measure the velocity of nerve impulses; studied hearing and vision
- Alan Hodgkin & Andrew Huxley, mathematical theory of how ion fluxes produce nerve impulses
- Georg von Békésy, research on the human ear
- Bernard Katz, discovered how synapses work
- Hermann J. Muller, discovered that X-rays cause mutations
- Linus Pauling & Robert Corey, co-discoverers of the alpha helix and beta sheet structures in proteins
- J. D. Bernal, X-ray crystallography of plant viruses and proteins
- Rosalind Franklin, Maurice Wilkins, James D. Watson and Francis Crick, pioneers of DNA crystallography and co-discoverers of the structure of DNA. Francis Crick later participated in the Crick, Brenner et al. experiment which established the basis for understanding the genetic code
- Max Perutz & John Kendrew, pioneers of protein crystallography
- Allan Cormack & Godfrey Hounsfield, development of computer assisted tomography
- Paul Lauterbur & Peter Mansfield, development of magnetic resonance imaging
- Seiji Ogawa, development of functional magnetic resonance imaging
# Other notable biophysicists
- Adolf Eugen Fick, responsible for Fick's law of diffusion and a method to determine cardiac output.
- Howard Berg, characterized properties of bacterial chemotaxis
- Steven Block, observed the motions of enzymes such as kinesin and RNA polymerase with optical tweezers
- Carlos Bustamante, known for single-molecule biophysics of molecular motors and biological polymer physics
- Steven Chu, Nobel Laureate who helped develop optical trapping techniques used by many biophysicists
- Friedrich Dessauer, research on radiation, especially X-rays
- Julio Fernandez
- John J. Hopfield, worked on error correction in Transcription and Translation (kinetic proof-reading), and associative memory models (Hopfield net)
- Martin Karplus, research on molecular dynamical simulations of biological macromolecules.
- Franklin Offner, professor emeritus at Northwestern University of professor of biophysics, biomedical engineering and electronics who developed a modern prototype of the electroencephalograph and electrocardiograph called the dynograph
- Benoit Roux
- Mikhail Volkenshtein, Revaz Dogonadze & Zurab Urushadze, authors of the 1st Quantum-Mechanical (Physical) Model of Enzyme Catalysis, supported a theory that enzyme catalysis use quantum-mechanical effects such as tunneling.
- John P. Wikswo, research on biomagnetism
- Douglas Warrick, specializing in bird flight (hummingbirds and pigeons)
- Ernest C. Pollard — founder of the Biophysical Society
- Marvin Makinen, pioneer of the structural basis of enzyme action
- Gopalasamudram Narayana Iyer Ramachandran, developer of the Ramachandran plot and pioneer of the collagen triple-helix structure prediction
- Doug Barrick, repeat protein folding | Biophysics
Editor-in-Chief: Robert G. Schwartz, M.D. [1], Piedmont Physical Medicine and Rehabilitation, P.A.;
Associate Editor-In-Chief: [2]Austin Schwartz, Department of Biophysics, Florida State University, Tallahassee, Florida
Biophysics (also biological physics) is an interdisciplinary science that employs and develops theories and methods of the physical sciences for the investigation of biological systems. Studies included under the umbrella of biophysics span all levels of biological organization, from the molecular scale to whole organisms and ecosystems. Biophysical research shares significant overlap with biochemistry, nanotechnology, bioengineering and systems biology.
Molecular biophysics typically addresses biological questions that are similar to those in biochemistry and molecular biology, but the questions are approached quantitatively. Scientists in this field conduct research concerned with understanding the interactions between the various systems of a cell, including the interactions between DNA, RNA and protein biosynthesis, as well as how these interactions are regulated. A great variety of techniques are used to answer these questions. For example, through the use of the biophysical and biochemical techniques such as patch-clamp, electrophysiolgy, immunoprecipitation and western blot, the regulation of ion channels can be studied and in turn their cellular and large scale effects can be better understood.
Fluorescent imaging techniques, as well as electron microscopy, x-ray crystallography and atomic force microscopy (AFM) are often used to visualize structures of biological significance. Direct manipulation of molecules using optical tweezers or AFM can also be used to monitor biological events where forces and distances are at the nanoscale. Molecular biophysicists often consider complex biological events as systems of interacting units which can be understood through statistical mechanics, thermodynamics and chemical kinetics. By drawing knowledge and experimental techniques from a wide variety of disciplines, biophysicists are often able to directly observe, model or even manipulate the structures and interactions of individual molecules or complexes of molecules.
In addition to traditional (i.e. molecular) biophysical topics like structural biology or enzyme kinetics, modern biophysics encompasses an extraordinarily broad range of research. It is becoming increasingly common for biophysicists to apply the models and experimental techniques derived from physics, as well as mathematics and statistics, to larger systems such as tissues, organs, populations and ecosystems.
# Focus as a subfield
Biophysics often does not have university-level departments of its own, but have presence as groups across departments within the fields of biology, biochemistry, chemistry, computer science, mathematics, medicine, pharmacology, physiology, physics, and neuroscience. What follows is a list of examples of how each department applies its efforts toward the study of biophysics. This list is hardly all inclusive. Nor does each subject of study belong exclusively to any particular department. Each academic institution makes its own rules and there is much overlap between departments.
- Biology and molecular biology - Almost all forms of biophysics efforts are included in some biology department somewhere. To include some: gene regulation, single protein dynamics, bioenergetics, patch clamping, biomechanics.
- Structural biology - angstrom-resolution structures of proteins, nucleic acids, lipids, carbohydrates, and complexes thereof.
- Biochemistry and chemistry - biomolecular structure, siRNA, nucleic acid structure, structure-activity relationships.
- Computer science - Neural networks, Biomolecular and drug databases.
- Computational chemistry - Molecular dynamics simulation, Molecular docking, Quantum chemistry
- Bioinformatics - sequence alignment, structural alignment, Protein structure prediction
- Mathematics - graph/network theory, population modeling, dynamical systems, phylogenetics.
- Medicine and neuroscience - tackling neural networks experimentally (brain slicing) as well as theoretically (computer models), membrane permitivity, gene therapy, understanding tumors.
- Pharmacology and physiology - channel biology, biomolecular interactions, cellular membranes, polyketides.
- Physics - Biomolecular free energy, stochastic processes, covering dynamics.
Many biophysical techniques are unique to this field. Research efforts in biophysics are often initiated by scientists who were traditional physicists, chemists, and biologists by training.
# Topics in biophysics and related fields
- Animal locomotion
- Bioacoustics
- Biochemical systems theory
- Biofilms
- Biological membranes
- Bioenergetics
- Biomechanics
- Biomineralisation
- Bionics
- Biosensor and Bioelectronics
- Cell division
- Cell membranes
- Cell migration
- Cell signalling
- Channels, receptors and transporters
- Cryobiology
- Dynamical systems
- Electrophysiology
- Enzyme kinetics
- Evolution
- Evolutionarily stable strategy
- Evolutionary algorithms
- Evolutionary computing
- Evolutionary theory
- Game theory
- Gravitational biology
- Mathematical biology
- Metabolic control analysis
- Microscopy
- Molecular biophysics
- Molecular motors
- Muscle and contractility
- Negentropy
- Neural encoding
- Neuroimaging
- Nucleic acids
- Origin of Life
- Phospholipids
- Photobiophysics and biophotonics
- Polysulphur membranes
- Proteins
- Punctuated equilibrium
- Radiobiology
- Sensory systems
- Signaling
- Spectroscopy, imaging, etc.
- Supramolecular assemblies
- Systems biology
- Systems neuroscience
- Tensegrity
- Theoretical biology
# Famous biophysicists
- Luigi Galvani, discoverer of bioelectricity
- Hermann von Helmholtz, first to measure the velocity of nerve impulses; studied hearing and vision
- Alan Hodgkin & Andrew Huxley, mathematical theory of how ion fluxes produce nerve impulses
- Georg von Békésy, research on the human ear
- Bernard Katz, discovered how synapses work
- Hermann J. Muller, discovered that X-rays cause mutations
- Linus Pauling & Robert Corey, co-discoverers of the alpha helix and beta sheet structures in proteins
- J. D. Bernal, X-ray crystallography of plant viruses and proteins
- Rosalind Franklin, Maurice Wilkins, James D. Watson and Francis Crick, pioneers of DNA crystallography and co-discoverers of the structure of DNA. Francis Crick later participated in the Crick, Brenner et al. experiment which established the basis for understanding the genetic code
- Max Perutz & John Kendrew, pioneers of protein crystallography
- Allan Cormack & Godfrey Hounsfield, development of computer assisted tomography
- Paul Lauterbur & Peter Mansfield, development of magnetic resonance imaging
- Seiji Ogawa, development of functional magnetic resonance imaging
# Other notable biophysicists
- Adolf Eugen Fick, responsible for Fick's law of diffusion and a method to determine cardiac output.
- Howard Berg, characterized properties of bacterial chemotaxis
- Steven Block, observed the motions of enzymes such as kinesin and RNA polymerase with optical tweezers
- Carlos Bustamante, known for single-molecule biophysics of molecular motors and biological polymer physics
- Steven Chu, Nobel Laureate who helped develop optical trapping techniques used by many biophysicists
- Friedrich Dessauer, research on radiation, especially X-rays
- Julio Fernandez
- John J. Hopfield, worked on error correction in Transcription and Translation (kinetic proof-reading), and associative memory models (Hopfield net)
- Martin Karplus, research on molecular dynamical simulations of biological macromolecules.
- Franklin Offner, professor emeritus at Northwestern University of professor of biophysics, biomedical engineering and electronics who developed a modern prototype of the electroencephalograph and electrocardiograph called the dynograph
- Benoit Roux
- Mikhail Volkenshtein, Revaz Dogonadze & Zurab Urushadze, authors of the 1st Quantum-Mechanical (Physical) Model of Enzyme Catalysis, supported a theory that enzyme catalysis use quantum-mechanical effects such as tunneling.
- John P. Wikswo, research on biomagnetism
- Douglas Warrick, specializing in bird flight (hummingbirds and pigeons)
- Ernest C. Pollard — founder of the Biophysical Society
- Marvin Makinen, pioneer of the structural basis of enzyme action
- Gopalasamudram Narayana Iyer Ramachandran, developer of the Ramachandran plot and pioneer of the collagen triple-helix structure prediction
- Doug Barrick, repeat protein folding | https://www.wikidoc.org/index.php/Biophysical_medicine | |
580bf55618b39bf10b48c0cfdb90eac7ccf0eba5 | wikidoc | Biopolymer | Biopolymer
# Overview
Biopolymers are a class of polymers produced by living organisms.
Starch, proteins and peptides, DNA, and RNA are all examples of biopolymers, in which the monomer units, respectively, are sugars, amino acids, and nucleic acids.
# Biopolymers versus polymers
A major but defining difference between polymers and biopolymers can be found in their structures. Polymers, including biopolymers, are made of repetitive units called monomers. Biopolymers inherently have a well defined structure:
The exact chemical composition and the sequence in which these units are arranged is called the primary structure. Many biopolymers spontaneously fold into characteristic compact shapes (see also "protein folding" as well as secondary structure and tertiary structure), which determine their biological functions and depend in a complicated way on their primary structures. Structural biology is the study of the structural properties of the biopolymers.
In contrast most synthetic polymers have much simpler and more random (or stochastic) structures. This fact leads to a molecular mass distribution that is missing in biopolymers.
In fact, as their synthesis is controlled by a template directed process in most in vivo systems all biopolymers of a type (say one specific protein) are all alike: they all contain the same sequence and number of monomers and thus all have the same mass. This phenomenon is called monodispersity in contrast to the polydispersity encountered in polymers. As a result biopolymers have a polydispersity index of 1.
# Conventions and nomenclature
## Polypeptides
The convention for a polypeptide is to list its constituent amino acid residues as they occur from the amino terminus to the carboxylic acid terminus. The amino acid residues are always joined by peptide bonds. Protein, though used colloquially to refer to any polypeptide, refers to larger or fully functional forms and can consist of several polypeptide chains as well as single chains. Proteins can also be modified to include non-peptide components, such as saccharide chains and lipids.
## Nucleic acids
The convention for a nucleic acid sequence is to list the nucleotides as they occur from the 5' end to the 3' end of the polymer chain, where 5' and 3' refer to the numbering of carbons around the ribose ring which participate in forming the phosphate diester linkages of the chain. Such a sequence is called the primary structure of the biopolymer.
## Sugars
Sugar-based biopolymers are often difficult with regards to convention. Sugar polymers can be linear or branched are typically joined with glycosidic bonds. However, the exact placement of the linkage can vary and the orientation of the linking functional groups is also important, resulting in α- and β-glycosidic bonds with numbering definitive of the linking carbons' location in the ring. In addition, many saccharide units can undergo various chemical modification, such as amination, and can even form parts of other molecules, such as glycoproteins.
# Structural characterization
There are a number of biophysical techniques for determining sequence information. Protein sequence can be determined by Edman degradation, in which the N-terminal residues are hydrolyzed from the chain one at a time, derivatized, and then identified. Mass spectrometer techniques can also be used. Nucleic acid sequence can be determined using gel electrophoresis and capillary electrophoresis. Lastly, mechanical properties of these biopolymers can often be measured using optical tweezers or atomic force microscopy.
# Biopolymers as materials
Some biopolymers- such as polylactic acid, naturally occurring zein, and poly-3-hydroxybutyrate can be used as plastics, replacing the need for polystyrene or polyethylene based plastics.
Some plastics are now referred to as being 'degradable', 'oxy-degradable' or 'UV-degradable'. This means that they break down when exposed to light or air, but these plastics are still primarily (as much as 98 per cent) oil-based and are not currently certified as 'biodegradable' under the European Union directive on Packaging and Packaging Waste (94/62/EC). Biopolymers, however, will break down and some are suitable for domestic composting.
# Biopolymers as Packaging
Biopolymers (also called renewable polymers) are produced from biomass for use in the packaging industry. Biomass comes from crops such as sugar beet, potatoes or wheat: when used to produce biopolymers, these are classified as non food crops. These can be converted in the following pathways:
Sugar beet > Glyconic acid > Polyglonic acid
Starch > (fermentation) > Lactic acid > Polylactic acid (PLA)
Biomass > (fermentation) > Bioethanol > Ethene > Polyethylene
Many types of packaging can be made from biopolymers: food trays, blown starch pellets for shipping fragile goods, thin films for wrapping.
Biopolymers are renewable, sustainable, and can be carbon neutral
Biopolymers are renewable, because they are made from plant materials which can be grown year on year indefinitely. These plant materials come from agricultural non food crops. Therefore, the use of biopolymers would create a sustainable industry. In contrast, the feedstocks for polymers derived from petrochemicals will eventually run out. In addition, biopolymers have the potential to cut carbon emissions and reduce CO2 quantities in the atmosphere: this is because the CO2 released when they degrade can be reabsorbed by crops grown to replace them: this makes them close to carbon neutral.
Biopolymers are biodegradable, and some are also compostable
Some biopolymers are biodegradable: they are broken down into CO2 and water by microorganisms. In addition, some of these biodegradable biopolymers are compostable: they can be put into an industrial composting process and will break down by 90% within 6 months. Biopolymers that do this can be marked with a 'compostable' symbol, under European Standard EN 13432 (2000). Packaging marked with this symbol can be put into industrial composting processes and will break down within 6 months (or less). An example of a compostable polymer is PLA film under 20μm thick: films which are thicker than that do not qualify as compostable, even though they are biodegradable. A home composting logo may soon be established: this will enable consumers to dispose of packaging directly onto their own compost heap. The standards for such a home composting logo have not yet been developed. | Biopolymer
# Overview
Biopolymers are a class of polymers produced by living organisms.
Starch, proteins and peptides, DNA, and RNA are all examples of biopolymers, in which the monomer units, respectively, are sugars, amino acids, and nucleic acids.
# Biopolymers versus polymers
A major but defining difference between polymers and biopolymers can be found in their structures. Polymers, including biopolymers, are made of repetitive units called monomers. Biopolymers inherently have a well defined structure:
The exact chemical composition and the sequence in which these units are arranged is called the primary structure. Many biopolymers spontaneously fold into characteristic compact shapes (see also "protein folding" as well as secondary structure and tertiary structure), which determine their biological functions and depend in a complicated way on their primary structures. Structural biology is the study of the structural properties of the biopolymers.
In contrast most synthetic polymers have much simpler and more random (or stochastic) structures. This fact leads to a molecular mass distribution that is missing in biopolymers.
In fact, as their synthesis is controlled by a template directed process in most in vivo systems all biopolymers of a type (say one specific protein) are all alike: they all contain the same sequence and number of monomers and thus all have the same mass. This phenomenon is called monodispersity in contrast to the polydispersity encountered in polymers. As a result biopolymers have a polydispersity index of 1.
# Conventions and nomenclature
## Polypeptides
The convention for a polypeptide is to list its constituent amino acid residues as they occur from the amino terminus to the carboxylic acid terminus. The amino acid residues are always joined by peptide bonds. Protein, though used colloquially to refer to any polypeptide, refers to larger or fully functional forms and can consist of several polypeptide chains as well as single chains. Proteins can also be modified to include non-peptide components, such as saccharide chains and lipids.
## Nucleic acids
The convention for a nucleic acid sequence is to list the nucleotides as they occur from the 5' end to the 3' end of the polymer chain, where 5' and 3' refer to the numbering of carbons around the ribose ring which participate in forming the phosphate diester linkages of the chain. Such a sequence is called the primary structure of the biopolymer.
## Sugars
Sugar-based biopolymers are often difficult with regards to convention. Sugar polymers can be linear or branched are typically joined with glycosidic bonds. However, the exact placement of the linkage can vary and the orientation of the linking functional groups is also important, resulting in α- and β-glycosidic bonds with numbering definitive of the linking carbons' location in the ring. In addition, many saccharide units can undergo various chemical modification, such as amination, and can even form parts of other molecules, such as glycoproteins.
# Structural characterization
There are a number of biophysical techniques for determining sequence information. Protein sequence can be determined by Edman degradation, in which the N-terminal residues are hydrolyzed from the chain one at a time, derivatized, and then identified. Mass spectrometer techniques can also be used. Nucleic acid sequence can be determined using gel electrophoresis and capillary electrophoresis. Lastly, mechanical properties of these biopolymers can often be measured using optical tweezers or atomic force microscopy.
# Biopolymers as materials
Some biopolymers- such as polylactic acid, naturally occurring zein, and poly-3-hydroxybutyrate can be used as plastics, replacing the need for polystyrene or polyethylene based plastics.
Some plastics are now referred to as being 'degradable', 'oxy-degradable' or 'UV-degradable'. This means that they break down when exposed to light or air, but these plastics are still primarily (as much as 98 per cent) oil-based and are not currently certified as 'biodegradable' under the European Union directive on Packaging and Packaging Waste (94/62/EC). Biopolymers, however, will break down and some are suitable for domestic composting.
# Biopolymers as Packaging
Biopolymers (also called renewable polymers) are produced from biomass for use in the packaging industry. Biomass comes from crops such as sugar beet, potatoes or wheat: when used to produce biopolymers, these are classified as non food crops. These can be converted in the following pathways:
Sugar beet > Glyconic acid > Polyglonic acid
Starch > (fermentation) > Lactic acid > Polylactic acid (PLA)
Biomass > (fermentation) > Bioethanol > Ethene > Polyethylene
Many types of packaging can be made from biopolymers: food trays, blown starch pellets for shipping fragile goods, thin films for wrapping.
Biopolymers are renewable, sustainable, and can be carbon neutral
Biopolymers are renewable, because they are made from plant materials which can be grown year on year indefinitely. These plant materials come from agricultural non food crops. Therefore, the use of biopolymers would create a sustainable industry. In contrast, the feedstocks for polymers derived from petrochemicals will eventually run out. In addition, biopolymers have the potential to cut carbon emissions and reduce CO2 quantities in the atmosphere: this is because the CO2 released when they degrade can be reabsorbed by crops grown to replace them: this makes them close to carbon neutral.
Biopolymers are biodegradable, and some are also compostable
Some biopolymers are biodegradable: they are broken down into CO2 and water by microorganisms. In addition, some of these biodegradable biopolymers are compostable: they can be put into an industrial composting process and will break down by 90% within 6 months. Biopolymers that do this can be marked with a 'compostable' symbol, under European Standard EN 13432 (2000). Packaging marked with this symbol can be put into industrial composting processes and will break down within 6 months (or less). An example of a compostable polymer is PLA film under 20μm thick: films which are thicker than that do not qualify as compostable, even though they are biodegradable. A home composting logo may soon be established: this will enable consumers to dispose of packaging directly onto their own compost heap. The standards for such a home composting logo have not yet been developed. | https://www.wikidoc.org/index.php/Biopolymer | |
4b364a88f54a85e4d677cf0a79414e4ed22016e7 | wikidoc | Biosimilar | Biosimilar
Biosimilars or Follow-on biologics are terms used to describe copies of innovator biopharmaceutical products.
Unlike the more common "small-molecule" drugs, biologics generally exhibit high molecular complexity, and may be quite sensitive to manufacturing process changes. The follow-on manufacturer does not have access to the originator's molecular clone and original cell bank, nor to the exact fermention and purification process. Finally, nearly undetectable differences in impurities and/or breakdown products are known to have serious health implications. This has created a concern that copies of biologics might perform differently than the original branded version of the drug. So copies of biologics are not authorized in the US or the European Union through the simplified procedures allowed for small molecule generics. In the EU a specially-adapted approval procedure has been authorized for certain protein drugs, termed "similar biological medicinal products". This procedure is based on a thorough demonstration of "comparability" of the "similar" product to an existing approved product. In the US the FDA has taken the position that new legislation will be required to address these concerns. Additional Congressional hearings have been held, but no legislation had been approved as of May 2007.
# Background
Cloning of human genetic material and development of in vitro biological production systems has allowed the production of virtually any recombinant DNA based biological substance for eventual development of a drug. Monoclonal antibody technology combined with recombinant DNA technology has paved the way for tailor-made and targeted medicines. Gene- and cell-based therapies are emerging as new approaches.
Recombinant therapeutic proteins are of a complex nature ( composed of a long chain of amino acids, modified amino acids, derivatized by sugar moieties, folded by complex mechanisms). These proteins are made in living cells ( bacteria, yeast, animal or human cell lines). The ultimate characteristics of a drug containing a recombinant therapeutic protein are to a large part determined by the process through which they are produced: choice of the cell type, development of the genetically modified cell for production, production process, purification process, formulation of the therapeutic protein into a drug.
Since the expiry of the patent of the first approved recombinant drugs (e.g. insulin, human growth hormone, interferons, erythropoietin, and more ) ‘copying’ and marketing of these biologics (thus called biosimilars) can be offered by any other biotech company.
However, because no two cell lines, developed independently, can be considered identical, biotech medicines cannot be fully copied. This is recognised by the European Medicines Agency, EMEA, and has resulted in the establishment of the term “biosimilar” in recognition of the fact that, whilst biosimilar products are similar to the original product, they are not exactly the same .
Small distinctions in the cell line, the manufacturing process or the surrounding environment can make a major difference in side effects observed during treatment, i.e. two similar biologics can trigger very different immunogenic response. Therefore, and unlike chemical pharmaceuticals, substitution between biologics, including biosimilars, can have clinical consequences and does create putative health concerns.
Biosimilars are subject to an approval process which requires substantial additional data to that required for chemical generics, although not as comprehensive as for the original biotech medicine. However, the safe application of biologics is also dependent on an informed and appropriate use by healthcare professionals and patients. Introduction of biosimilars also requires a specifically designed pharmacovigilance plan.
Currently ( August 2007), ambiguities concerning naming, regional differences in prescribing practices, regional differences in legally defined rules with respect to substitution are important points that still need to be resolved to ensure a safe use of biosimilars.
# Reference
- ↑ EMEA Guideline on Similar Biological Medicinal Products, CHMP/437/04 London, 30 October 2005
- ↑ US Senate Committee on the Judiciary, Testimony of Dr. Lester Crawford, Acting Commissioner, FDA June 23, 2004
- ↑ [ Hearing: Assessing the Impact of a Safe and Equitable Biosimilar Policy in the United States. Subcommittee on Health
Wednesday, May 2, 2007]
- ↑ EMEA guideline on similar biological medicinal products
- ↑ EMEA guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues
- ↑ EMEA guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues | Biosimilar
Biosimilars or Follow-on biologics are terms used to describe copies of innovator biopharmaceutical products.
Unlike the more common "small-molecule" drugs, biologics generally exhibit high molecular complexity, and may be quite sensitive to manufacturing process changes. The follow-on manufacturer does not have access to the originator's molecular clone and original cell bank, nor to the exact fermention and purification process. Finally, nearly undetectable differences in impurities and/or breakdown products are known to have serious health implications. This has created a concern that copies of biologics might perform differently than the original branded version of the drug. So copies of biologics are not authorized in the US or the European Union through the simplified procedures allowed for small molecule generics. In the EU a specially-adapted approval procedure has been authorized for certain protein drugs, termed "similar biological medicinal products". This procedure is based on a thorough demonstration of "comparability" of the "similar" product to an existing approved product.[1] In the US the FDA has taken the position that new legislation will be required to address these concerns.[2] Additional Congressional hearings have been held,[3] but no legislation had been approved as of May 2007.
# Background
Cloning of human genetic material and development of in vitro biological production systems has allowed the production of virtually any recombinant DNA based biological substance for eventual development of a drug. Monoclonal antibody technology combined with recombinant DNA technology has paved the way for tailor-made and targeted medicines. Gene- and cell-based therapies are emerging as new approaches.
Recombinant therapeutic proteins are of a complex nature ( composed of a long chain of amino acids, modified amino acids, derivatized by sugar moieties, folded by complex mechanisms). These proteins are made in living cells ( bacteria, yeast, animal or human cell lines). The ultimate characteristics of a drug containing a recombinant therapeutic protein are to a large part determined by the process through which they are produced: choice of the cell type, development of the genetically modified cell for production, production process, purification process, formulation of the therapeutic protein into a drug.
Since the expiry of the patent of the first approved recombinant drugs (e.g. insulin, human growth hormone, interferons, erythropoietin, and more ) ‘copying’ and marketing of these biologics (thus called biosimilars) can be offered by any other biotech company.
However, because no two cell lines, developed independently, can be considered identical, biotech medicines cannot be fully copied. This is recognised by the European Medicines Agency, EMEA, and has resulted in the establishment of the term “biosimilar” in recognition of the fact that, whilst biosimilar products are similar to the original product, they are not exactly the same [4].
Small distinctions in the cell line, the manufacturing process or the surrounding environment can make a major difference in side effects observed during treatment, i.e. two similar biologics can trigger very different immunogenic response. Therefore, and unlike chemical pharmaceuticals, substitution between biologics, including biosimilars, can have clinical consequences and does create putative health concerns.
Biosimilars are subject to an approval process [5][6] which requires substantial additional data to that required for chemical generics, although not as comprehensive as for the original biotech medicine. However, the safe application of biologics is also dependent on an informed and appropriate use by healthcare professionals and patients. Introduction of biosimilars also requires a specifically designed pharmacovigilance plan.
Currently ( August 2007), ambiguities concerning naming, regional differences in prescribing practices, regional differences in legally defined rules with respect to substitution are important points that still need to be resolved to ensure a safe use of biosimilars.
# Reference
- ↑ EMEA Guideline on Similar Biological Medicinal Products, CHMP/437/04 London, 30 October 2005
- ↑ US Senate Committee on the Judiciary, Testimony of Dr. Lester Crawford, Acting Commissioner, FDA June 23, 2004
- ↑ [http://energycommerce.house.gov/cmte_mtgs/110-he-hrg.050207.Biosimilar.shtml Hearing: Assessing the Impact of a Safe and Equitable Biosimilar Policy in the United States. Subcommittee on Health
Wednesday, May 2, 2007]
- ↑ EMEA guideline on similar biological medicinal products
- ↑ EMEA guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues
- ↑ EMEA guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Biosimilar | |
dbca9e9febc6732f01d343ec5f37e923a08c63d0 | wikidoc | Bipedalism | Bipedalism
# Overview
Bipedalism is standing, or moving for example by walking, running, or hopping, on two appendages (typically legs). An animal or machine that usually moves in a bipedal manner is known as a biped (/Template:IPA/), meaning "two feet" (Latin bi = two + ped = foot).
# Overview
## Types of bipedal movement
There are a number of states of movement commonly associated with bipedalism.
- Standing. Staying still on both legs. In most bipeds this is an active process, requiring constant adjustment of balance.
- Walking. One foot in front of another, with at least one foot on the ground at any time.
- Running. One foot in front of another, with periods where both feet are off the ground.
- Hopping. Moving by a series of jumps with both feet moving together.
## Bipedal animals
Bipedal movement has evolved a number of times other than in humans, mostly among the vertebrates. The most obvious example of bipedal movement is among the birds and their ancestors the theropod dinosaurs. All dinosaurs are believed to be descended from a fully bipedal ancestor, perhaps similar to Eoraptor. Indeed, among their descendants, the larger flightless birds, the ratites, such as the ostrich, perhaps epitomise the capacity to move bipedally, able to reach speeds of up to 65 km/h. Likewise many theropod dinosaurs, especially the maniraptors, are believed to have been able to move at similar speeds. Bipedal movement also re-evolved in a number of other dinosaur lineages such as the iguanodons. Some extinct members of the crocodilian line, a sister group to the dinosaurs and birds, have also evolved bipedal forms - a crocodile relative from the triassic, Effigia okeeffeae, was believed to be bipedal . Larger birds tend to walk with alternating legs, whereas smaller birds will often hop. Penguins are interesting birds with regard to bipedality as they tend to hold their bodies upright, rather than horizontal as in other birds.
Bipedal movement is less common among mammals, most being quadrupedal. The largest mammalian group using bipedal movement are the kangaroos and their relatives. However these tend to move mostly by hopping, which is quite different from humans and many birds. There are also various groups of hopping rodents, such as the kangaroo rats and springhares. Some primates, such as sifakas and sportive lemurs, also moves by hopping when on the ground. Possibly the only mammals other than humans that commonly move bipedally by an alternating gait rather than hopping are gibbons when on the ground, and giant pangolins.
Limited examples of bipedalism are found in some other mammals. For example the bonobo ape and proboscis monkey, who both live in forests that are often flooded, will wade through water in a bipedal stance. On occasion bonobos and proboscis monkeys, and less frequently some other primates, will also walk or stand bipedely on land. A number of other animals, such as rats, will squat on their hindlegs in order to manipulate food objects. The raccoon often stands erect or squats in water to use its hands to manipulate food and rocks/sticks. Beavers will also move bipedally at times when carrying branches. Some animals, such as the bear, may raise up and move bipedally during physical confrontation, so as to better be able to use their forelegs as weapons. Also a number of mammals, such as ground squirrels or meerkats will stand on their hind legs, but not walk on them, in order to survey their surroundings. Finally, gerenuk antelope are known to stand on their hind legs in order to eat leaves from trees. The extinct giant ground sloth had hip joints whose form indicates that they also did this. Another extinct group, the bizarre rhinoceros/gorilla-like chalicotheres may also have behaved similarly. One unusual form of limited bipedalism is the spotted skunk which when threatened stands on its forelimbs. This allows the skunk, while still facing the attacker, to direct its anal glands towards the attacker. The anal glands can fire an offensively odorous oil.
Bipedalism is unknown among the amphibians. Among the non-archosaur reptiles bipedalism is rare, but it is found in the "reared-up" running of certain lizards. An interesting example is found in at least one genus of basilisk lizard that by this method can run across the surface of water for some distance. Bipedalism in the form of reared-up running can also be found in some insects such as the cockroach. Otherwise bipedal movement is unknown in arthropods. Bipeds are mostly terrestrial animals. However, at least two types of octopus are known to walk bipedally on the sea floor, moving on the tips of two of their arms. According to the study, this form of locomotion may allow them to remain somewhat camouflaged while moving quickly, as the animals are still able to use the remaining six arms for disguise (taking a form like a coconut or seaweed), and as the necessary walking movements are hypothesized to be possible with minimal control from the brain.
## Exceptional cases
Many animals that do not use bipedal locomotion in nature can be trained to walk on their hind legs. Animals missing limbs due to injury or congenital deformity may adapt to bipedal motion, either on two hind legs or on one front and one back leg. For videos of both kinds of bipedal motion in dogs see and . Some unusual individual primates have also been known to be bipedal. There has been one recorded case of a captive macaque, Natasha, switching to bipedal walking completely after recovering from a serious illness , and at least one example of a captive chimp who only walked upright, Oliver. Some animals can also be trained to walk on their front limbs. Humans can learn to walk using solely their arms, see handstand and hand walking.
## Advantages
Bipedalism and associated traits can offer a species several advantages:
- Improved perception. Some evolutionary biologists have suggested that a crucial stage in the evolution of some or all bipeds was the ability to stand, which generally improves the ability to see (and perhaps otherwise detect) distant dangers or resources.
- Free forelimbs. In vertebrate species, for whom evolution of additional limbs would be an enormous genetic change, it can serve to free the front limbs for such other functions as manipulation (in primates), flight (in birds), digging (giant pangolin), or combat (bears).
- Wading. Raccoons and some primates may adopt a bipedal position in water, allowing them to stand or walk in deeper water while still breathing air.
- Faster movement. In animals without a flexible backbone, such as lizards or cockroaches, bipedalism may increase running speed. However the maximum bipedal speed appears less fast than the maximum speed of quadrapedal movement with a flexible backbone - compare the fastest bipeds the ostrich (65 km/h) or the red kangaroo (70 km/h) with the fastest quadruped, the cheetah (103 km/h).
- Greater reach. Gerunuk antelope adopt a bipedal position to browse the leaves from trees.
- Camouflage. It has been speculated that bipedalism in octopuses allows them to move while keeping the rest of their bodies still for camouflage.
- Face attacker while directing anal glands. The defense posture of the spotted skunk, which involves walking on its forelimbs, allows the skunk to face the attacker while simultaneously directing its anal glands at them. The anal glands can squirt an offensive smelling oil.
# Evolution
Bipedalism has a number of adaptive advantages, and has evolved independently in a number of lineages.
## Early reptiles and lizards
The first known biped is the bolosaurid Eudibamus cursoris whose fossils date from 290 million years ago
. Its long hindlegs, short forelegs, and distinctive joints all suggest bipedalism. This may have given increased speed. The species was extinct before the dinosaurs appeared.
Independent of Eudibamus, some modern lizard species have developed the capacity to run on their hind legs for added speed. The praire dog effect where to stand and look around for such thing as predators or food is an evolution adaptation of early human.
## Dinosaurs and birds
Bipedalism also developed independently among the dinosaurs. Dinosaurs diverged from their archosaur ancestors approximately 230 million years ago during the Middle to Late Triassic period, roughly 20 million years after the Permian-Triassic extinction event wiped out an estimated 95% of all life on Earth. Radiometric dating of fossils from the early dinosaur genus Eoraptor establishes its presence in the fossil record at this time. Paleontologists believe Eoraptor resembles the common ancestor of all dinosaurs; if this is true, its traits suggest that the first dinosaurs were small, bipedal predators. The discovery of primitive, dinosaur-like ornithodirans such as Marasuchus and Lagerpeton in Argentinian Middle Triassic strata supports this view; analysis of recovered fossils suggests that these animals were indeed small, bipedal predators.
## Mammals (excluding humans)
A number of mammals will adopt a bipedal stance in specific situations such as for feeding or fighting. A number of groups of extant mammals have independently evolved bipedalism as their main form of locomotion - for example humans, giant pangolins, and macropods. Humans, as their bipedalism has been extensively studied are documented in the next section. Macropods are believed to have evolved bipedal hopping only once in their evolution, at some time no later than 45 million years ago.
## Humans
There are at least twelve distinct hypotheses as to how and why bipedalism evolved in humans, and also some debate as to when. Evidence points to bipedalism evolving before the expansion in human brain size. The different hypotheses are not necessarily mutually exclusive and a number of selective forces may have acted together to lead to human bipedalism.
### Postural feeding hypothesis
The postural feeding hypothesis has been recently supported by Dr. Kevin Hunt, a professor at Indiana University. This theory asserts that chimpanzees were only bipedal when they ate. While on the ground, they would reach up for fruit hanging from small trees and while in trees, bipedalism was utilized by grabbing for an overhead branch. These bipedal movements may have evolved into regular habits because they were so convenient in obtaining food. Also, Hunt theorizes that these movements coevolved with chimpanzee arm-hanging, as this movement was very effective and efficient in harvesting food. When analyzing fossil anatomy, Australopithecus afarensis has very similar features of the hand and shoulder to the chimpanzee, which indicates hanging arms. Also, the Australopithecus hip and hind limb very clearly indicate bipedalism, but these fossils also indicate very inefficient locomotive movement when compared to humans. For this reason, Hunt argues that bipedalism evolved more as a terrestrial feeding posture than as a walking posture. As Hunt says, “A bipedal postural feeding adaptation may have been a preadaptation for the fully realized locomotor bipedalism apparent in Homo erectus.” A related hypothesis is that proto-humans learned upright posture not for picking fruit, as it is argued they would have stayed climbers if plucking fruit were all they were after, rather they learned to keep they head out of the water while searching for water plants, mollusca, and the like.
### Provisioning model
One of the most elaborate theories on the origin of bipedalism is the behavior model presented by C. Owen Lovejoy. Lovejoy theorizes that the evolution of bipedalism was a response to a monogamous society. As hominid males became monogamous, they would leave their families for the day in order to search for food. Once they found food for their family, the hominids would have to bring back the food, and the most effective way of doing this was through bipedalism. Some question whether early hominids really were monogamous though. Some evidence indicates that early hominids, which are proven to be bipedal, were polygamous. Among all monogamous primates, sexual dimorphism is mostly absent, but in Australopithecus afarensis males were found to be nearly twice the weight of females, an attribute scientists would expect in a polygamous species. Lastly, monogamous primates are highly territorial, but fossil evidence indicates that Australopithecus afarensis lived in large groups.
### Other behavioural models
There are a variety of ideas which promote a specific change in behaviour as the key driver for the evolution of hominid bipedalism. For example, Wescott (1967) and later Jablonski & Chaplin (1993) suggest that bipedal threat displays could have been the transitional behaviour which led to some groups of apes beginning to adopt bipedal postures more often. Others (e.g. Dart 1925) have offered the idea that the need for more vigilance against predators could have provided the initial motivation. Dawkins (e.g. 2004) has argued that it could have begun as a kind of fashion that just caught on and then escalated through sexual selection. And it has even been suggested (e.g. Tanner 1981:165) that male phallic display could have been the initial incentive. All these theories lack any observational data, and are in the category of "armchair" theories.
### Thermoregulatory model
The thermoregulatory model explaining the origin of bipedalism is one of the simplest and most fanciful theories on the table, but it is a viable explanation. Dr. Peter Wheeler, a professor of evolutionary biology, proposes that bipedalism raises the amount of body surface area higher above the ground which results in a reduction in heat gain and helps heat dissipation. When a hominid is higher above the ground, the organism accesses more favorable wind speeds and temperatures. During heat seasons, greater wind flow results in a higher heat loss, which makes the organism more comfortable. Also, Wheeler explains that a vertical posture minimizes the direct exposure to the sun whereas quadrupedalism exposes more of the body to direct exposure.
### Carrying models
Charles Darwin wrote that "Man could not have attained his present dominant position in the world without the use of his hands, which are so admirably adapted to the act of obedience of his will" Darwin (1871:52) and many models on bipedal origins are based on this line of thought. Gordon Hewes (1961) suggested that the carrying of meat "over considerable distances" (Hewes 1961:689) was the key factor. Isaac (1978) and Sinclair et al (1986) offered modifications of this idea as indeed did Lovejoy (1981) with his 'provisioning model' described above. Others, such as Nancy Tanner (1981) have suggested that infant carrying was key, whilst others have suggested stone tools and weapons drove the change. The problem with this is that people were bipedal long before they had tools and weapons to carry. Furthermore, it doesn't appear that early proto-humans would have had to carry anything very far, as must of their needs were to be had nearby. It is a common error to attribute to proto-humans the same capacities as modern humans.
### Wading hypothesis
This theory proposes that humans evolved bipedalism as a result of bipedal wading. Mammals that switch from quadrupedalism on land to bipedal wading appear mainly to be found among large primates, especially apes, with relatively few exceptions such as the grizzly bear. Bipedal wading has been observed in the bonobo, chimpanzees, the lowland gorillas, orang utans, baboons and proboscis monkey. Bipedal wading provides the advantage of keeping the head above water for breathing. This theory is a refinement of a general theory of human evolution which often goes by the name of the aquatic ape hypothesis. Kuliukas 2001 argues that the skeletal morphology of the early hominan Australopithecus afarensis is consistent with adaptation for wading in water and that their habitats were probably sufficiently prone to flooding for this behaviour to have been selected for. Furfthermore, all hominid remains have been found deposited in wet conditions, though that's also true of most fossils. The fossil record supports the wading theory. Likewise, all humans still live within walking distance of potable water, having been unable to escape our physiological needs; this being so, Occams Razor suggests that we have never left the water which shaped us.
### Turn-over pulse hypothesis
The theory is part of a general theory of human evolution known as the savanna hypothesis. This theory asserts that a major climate change occurred which induced an onset of drier conditions. These dry conditions severely reduced the amount of wooded habitats in the Pliocene era, about 2.5 million years ago. During this period where the forests became thin, the Australopithecus organisms had to evolve and change their habitats from the forest to grasslands. In order to remain effective in gathering food, the hominids had to travel long distances with food or tools, thus making quadrupedalism extremely inefficient. These hominids evolved into bipeds which made their treks along the grasslands much more efficient. All other theories of bipedalism, aside from the "wading hypothesis" are derivatives of this one. Some of the problems related to this theory have to do with dates. Bipedalism is evident in Australopithecus afarensis a million years before the thinning of the forests in question. It would be a million-and-a-half years or more before these proto-humans would have weapons sufficient to defend themselves or bring down large game. Midden piles from the time suggest a diet rich in turtles. Also, the savannas into which the humans were supposed to have gone, had limited edible vegetation, and an omnivore, like a human, would most likely head for a more diverse food supply, such as the eco-edge between the land and water. The few large apes which have adapted to savanna living have all become dietary specialists surviving on a single plant, the very opposite of an omnivore. None of those apes has developed bipedalism, because as the ones who tried it were eaten, leaving the swift four-legged creatures to survive. On the other hand, if humans developed their bipedalism at the water's edge, they wouldn't have been severely affected by receding forests. | Bipedalism
# Overview
Bipedalism is standing, or moving for example by walking, running, or hopping, on two appendages (typically legs). An animal or machine that usually moves in a bipedal manner is known as a biped (/Template:IPA/), meaning "two feet" (Latin bi = two + ped = foot).
# Overview
## Types of bipedal movement
There are a number of states of movement commonly associated with bipedalism.
- Standing. Staying still on both legs. In most bipeds this is an active process, requiring constant adjustment of balance.
- Walking. One foot in front of another, with at least one foot on the ground at any time.
- Running. One foot in front of another, with periods where both feet are off the ground.
- Hopping. Moving by a series of jumps with both feet moving together.
## Bipedal animals
Bipedal movement has evolved a number of times other than in humans, mostly among the vertebrates. The most obvious example of bipedal movement is among the birds and their ancestors the theropod dinosaurs. All dinosaurs are believed to be descended from a fully bipedal ancestor, perhaps similar to Eoraptor. Indeed, among their descendants, the larger flightless birds, the ratites, such as the ostrich, perhaps epitomise the capacity to move bipedally, able to reach speeds of up to 65 km/h. Likewise many theropod dinosaurs, especially the maniraptors, are believed to have been able to move at similar speeds. Bipedal movement also re-evolved in a number of other dinosaur lineages such as the iguanodons. Some extinct members of the crocodilian line, a sister group to the dinosaurs and birds, have also evolved bipedal forms - a crocodile relative from the triassic, Effigia okeeffeae, was believed to be bipedal [1]. Larger birds tend to walk with alternating legs, whereas smaller birds will often hop. Penguins are interesting birds with regard to bipedality as they tend to hold their bodies upright, rather than horizontal as in other birds.
Bipedal movement is less common among mammals, most being quadrupedal. The largest mammalian group using bipedal movement are the kangaroos and their relatives. However these tend to move mostly by hopping, which is quite different from humans and many birds. There are also various groups of hopping rodents, such as the kangaroo rats and springhares. Some primates, such as sifakas and sportive lemurs, also moves by hopping when on the ground. Possibly the only mammals other than humans that commonly move bipedally by an alternating gait rather than hopping are gibbons when on the ground, and giant pangolins.
Limited examples of bipedalism are found in some other mammals. For example the bonobo ape and proboscis monkey, who both live in forests that are often flooded, will wade through water in a bipedal stance. On occasion bonobos and proboscis monkeys, and less frequently some other primates, will also walk or stand bipedely on land. A number of other animals, such as rats, will squat on their hindlegs in order to manipulate food objects. The raccoon often stands erect or squats in water to use its hands to manipulate food and rocks/sticks. Beavers will also move bipedally at times when carrying branches. Some animals, such as the bear, may raise up and move bipedally during physical confrontation, so as to better be able to use their forelegs as weapons. Also a number of mammals, such as ground squirrels or meerkats will stand on their hind legs, but not walk on them, in order to survey their surroundings. Finally, gerenuk antelope are known to stand on their hind legs in order to eat leaves from trees. The extinct giant ground sloth had hip joints whose form indicates that they also did this. Another extinct group, the bizarre rhinoceros/gorilla-like chalicotheres may also have behaved similarly. One unusual form of limited bipedalism is the spotted skunk which when threatened stands on its forelimbs. This allows the skunk, while still facing the attacker, to direct its anal glands towards the attacker. The anal glands can fire an offensively odorous oil.
Bipedalism is unknown among the amphibians. Among the non-archosaur reptiles bipedalism is rare, but it is found in the "reared-up" running of certain lizards. An interesting example is found in at least one genus of basilisk lizard that by this method can run across the surface of water for some distance. Bipedalism in the form of reared-up running can also be found in some insects such as the cockroach. Otherwise bipedal movement is unknown in arthropods. Bipeds are mostly terrestrial animals. However, at least two types of octopus are known to walk bipedally [2] on the sea floor, moving on the tips of two of their arms. According to the study, this form of locomotion may allow them to remain somewhat camouflaged while moving quickly, as the animals are still able to use the remaining six arms for disguise (taking a form like a coconut or seaweed), and as the necessary walking movements are hypothesized to be possible with minimal control from the brain.
## Exceptional cases
Many animals that do not use bipedal locomotion in nature can be trained to walk on their hind legs. Animals missing limbs due to injury or congenital deformity may adapt to bipedal motion, either on two hind legs or on one front and one back leg. For videos of both kinds of bipedal motion in dogs see [3] and [4]. Some unusual individual primates have also been known to be bipedal. There has been one recorded case of a captive macaque, Natasha, switching to bipedal walking completely after recovering from a serious illness [5], and at least one example of a captive chimp who only walked upright, Oliver. Some animals can also be trained to walk on their front limbs. Humans can learn to walk using solely their arms, see handstand and hand walking.
## Advantages
Bipedalism and associated traits can offer a species several advantages:
- Improved perception. Some evolutionary biologists have suggested that a crucial stage in the evolution of some or all bipeds was the ability to stand, which generally improves the ability to see (and perhaps otherwise detect) distant dangers or resources.
- Free forelimbs. In vertebrate species, for whom evolution of additional limbs would be an enormous genetic change, it can serve to free the front limbs for such other functions as manipulation (in primates), flight (in birds), digging (giant pangolin), or combat (bears).
- Wading. Raccoons and some primates may adopt a bipedal position in water, allowing them to stand or walk in deeper water while still breathing air.
- Faster movement. In animals without a flexible backbone, such as lizards or cockroaches, bipedalism may increase running speed. However the maximum bipedal speed appears less fast than the maximum speed of quadrapedal movement with a flexible backbone - compare the fastest bipeds the ostrich (65 km/h) or the red kangaroo (70 km/h) with the fastest quadruped, the cheetah (103 km/h).
- Greater reach. Gerunuk antelope adopt a bipedal position to browse the leaves from trees.
- Camouflage. It has been speculated that bipedalism in octopuses allows them to move while keeping the rest of their bodies still for camouflage.
- Face attacker while directing anal glands. The defense posture of the spotted skunk, which involves walking on its forelimbs, allows the skunk to face the attacker while simultaneously directing its anal glands at them. The anal glands can squirt an offensive smelling oil.
# Evolution
Bipedalism has a number of adaptive advantages, and has evolved independently in a number of lineages.
## Early reptiles and lizards
The first known biped is the bolosaurid Eudibamus cursoris whose fossils date from 290 million years ago [6]
[1]. Its long hindlegs, short forelegs, and distinctive joints all suggest bipedalism. This may have given increased speed. The species was extinct before the dinosaurs appeared.
Independent of Eudibamus, some modern lizard species have developed the capacity to run on their hind legs for added speed. The praire dog effect where to stand and look around for such thing as predators or food is an evolution adaptation of early human.
## Dinosaurs and birds
Bipedalism also developed independently among the dinosaurs. Dinosaurs diverged from their archosaur ancestors approximately 230 million years ago during the Middle to Late Triassic period, roughly 20 million years after the Permian-Triassic extinction event wiped out an estimated 95% of all life on Earth.[2][3] Radiometric dating of fossils from the early dinosaur genus Eoraptor establishes its presence in the fossil record at this time. Paleontologists believe Eoraptor resembles the common ancestor of all dinosaurs;[4] if this is true, its traits suggest that the first dinosaurs were small, bipedal predators.[5] The discovery of primitive, dinosaur-like ornithodirans such as Marasuchus and Lagerpeton in Argentinian Middle Triassic strata supports this view; analysis of recovered fossils suggests that these animals were indeed small, bipedal predators.
## Mammals (excluding humans)
A number of mammals will adopt a bipedal stance in specific situations such as for feeding or fighting. A number of groups of extant mammals have independently evolved bipedalism as their main form of locomotion - for example humans, giant pangolins, and macropods. Humans, as their bipedalism has been extensively studied are documented in the next section. Macropods are believed to have evolved bipedal hopping only once in their evolution, at some time no later than 45 million years ago.[6]
## Humans
There are at least twelve distinct hypotheses as to how and why bipedalism evolved in humans, and also some debate as to when. Evidence points to bipedalism evolving before the expansion in human brain size. The different hypotheses are not necessarily mutually exclusive and a number of selective forces may have acted together to lead to human bipedalism.
### Postural feeding hypothesis
The postural feeding hypothesis has been recently supported by Dr. Kevin Hunt, a professor at Indiana University. This theory asserts that chimpanzees were only bipedal when they ate. While on the ground, they would reach up for fruit hanging from small trees and while in trees, bipedalism was utilized by grabbing for an overhead branch. These bipedal movements may have evolved into regular habits because they were so convenient in obtaining food. Also, Hunt theorizes that these movements coevolved with chimpanzee arm-hanging, as this movement was very effective and efficient in harvesting food. When analyzing fossil anatomy, Australopithecus afarensis has very similar features of the hand and shoulder to the chimpanzee, which indicates hanging arms. Also, the Australopithecus hip and hind limb very clearly indicate bipedalism, but these fossils also indicate very inefficient locomotive movement when compared to humans. For this reason, Hunt argues that bipedalism evolved more as a terrestrial feeding posture than as a walking posture. As Hunt says, “A bipedal postural feeding adaptation may have been a preadaptation for the fully realized locomotor bipedalism apparent in Homo erectus.” A related hypothesis is that proto-humans learned upright posture not for picking fruit, as it is argued they would have stayed climbers if plucking fruit were all they were after, rather they learned to keep they head out of the water while searching for water plants, mollusca, and the like.
### Provisioning model
One of the most elaborate theories on the origin of bipedalism is the behavior model presented by C. Owen Lovejoy. Lovejoy theorizes that the evolution of bipedalism was a response to a monogamous society. As hominid males became monogamous, they would leave their families for the day in order to search for food. Once they found food for their family, the hominids would have to bring back the food, and the most effective way of doing this was through bipedalism. Some question whether early hominids really were monogamous though. Some evidence indicates that early hominids, which are proven to be bipedal, were polygamous. Among all monogamous primates, sexual dimorphism is mostly absent, but in Australopithecus afarensis males were found to be nearly twice the weight of females, an attribute scientists would expect in a polygamous species. Lastly, monogamous primates are highly territorial, but fossil evidence indicates that Australopithecus afarensis lived in large groups.
### Other behavioural models
There are a variety of ideas which promote a specific change in behaviour as the key driver for the evolution of hominid bipedalism. For example, Wescott (1967) and later Jablonski & Chaplin (1993) suggest that bipedal threat displays could have been the transitional behaviour which led to some groups of apes beginning to adopt bipedal postures more often. Others (e.g. Dart 1925) have offered the idea that the need for more vigilance against predators could have provided the initial motivation. Dawkins (e.g. 2004) has argued that it could have begun as a kind of fashion that just caught on and then escalated through sexual selection. And it has even been suggested (e.g. Tanner 1981:165) that male phallic display could have been the initial incentive. All these theories lack any observational data, and are in the category of "armchair" theories.
### Thermoregulatory model
The thermoregulatory model explaining the origin of bipedalism is one of the simplest and most fanciful theories on the table, but it is a viable explanation. Dr. Peter Wheeler, a professor of evolutionary biology, proposes that bipedalism raises the amount of body surface area higher above the ground which results in a reduction in heat gain and helps heat dissipation. When a hominid is higher above the ground, the organism accesses more favorable wind speeds and temperatures. During heat seasons, greater wind flow results in a higher heat loss, which makes the organism more comfortable. Also, Wheeler explains that a vertical posture minimizes the direct exposure to the sun whereas quadrupedalism exposes more of the body to direct exposure.
### Carrying models
Charles Darwin wrote that "Man could not have attained his present dominant position in the world without the use of his hands, which are so admirably adapted to the act of obedience of his will" Darwin (1871:52) and many models on bipedal origins are based on this line of thought. Gordon Hewes (1961) suggested that the carrying of meat "over considerable distances" (Hewes 1961:689) was the key factor. Isaac (1978) and Sinclair et al (1986) offered modifications of this idea as indeed did Lovejoy (1981) with his 'provisioning model' described above. Others, such as Nancy Tanner (1981) have suggested that infant carrying was key, whilst others have suggested stone tools and weapons drove the change. The problem with this is that people were bipedal long before they had tools and weapons to carry. Furthermore, it doesn't appear that early proto-humans would have had to carry anything very far, as must of their needs were to be had nearby. It is a common error to attribute to proto-humans the same capacities as modern humans.
### Wading hypothesis
This theory proposes that humans evolved bipedalism as a result of bipedal wading. Mammals that switch from quadrupedalism on land to bipedal wading appear mainly to be found among large primates, especially apes, with relatively few exceptions such as the grizzly bear. Bipedal wading has been observed in the bonobo, chimpanzees, the lowland gorillas, orang utans, baboons and proboscis monkey. Bipedal wading provides the advantage of keeping the head above water for breathing. This theory is a refinement of a general theory of human evolution which often goes by the name of the aquatic ape hypothesis. Kuliukas 2001 argues that the skeletal morphology of the early hominan Australopithecus afarensis is consistent with adaptation for wading in water and that their habitats were probably sufficiently prone to flooding for this behaviour to have been selected for. Furfthermore, all hominid remains have been found deposited in wet conditions, though that's also true of most fossils. The fossil record supports the wading theory. Likewise, all humans still live within walking distance of potable water, having been unable to escape our physiological needs; this being so, Occams Razor suggests that we have never left the water which shaped us.
### Turn-over pulse hypothesis
The theory is part of a general theory of human evolution known as the savanna hypothesis. This theory asserts that a major climate change occurred which induced an onset of drier conditions. These dry conditions severely reduced the amount of wooded habitats in the Pliocene era, about 2.5 million years ago. During this period where the forests became thin, the Australopithecus organisms had to evolve and change their habitats from the forest to grasslands. In order to remain effective in gathering food, the hominids had to travel long distances with food or tools, thus making quadrupedalism extremely inefficient. These hominids evolved into bipeds which made their treks along the grasslands much more efficient. All other theories of bipedalism, aside from the "wading hypothesis" are derivatives of this one. Some of the problems related to this theory have to do with dates. Bipedalism is evident in Australopithecus afarensis a million years before the thinning of the forests in question. It would be a million-and-a-half years or more before these proto-humans would have weapons sufficient to defend themselves or bring down large game. Midden piles from the time suggest a diet rich in turtles. Also, the savannas into which the humans were supposed to have gone, had limited edible vegetation, and an omnivore, like a human, would most likely head for a more diverse food supply, such as the eco-edge between the land and water. The few large apes which have adapted to savanna living have all become dietary specialists surviving on a single plant, the very opposite of an omnivore. None of those apes has developed bipedalism, because as the ones who tried it were eaten, leaving the swift four-legged creatures to survive. On the other hand, if humans developed their bipedalism at the water's edge, they wouldn't have been severely affected by receding forests. | https://www.wikidoc.org/index.php/Bipedalism | |
e23f715ff9da5c2cb5cca8e3132cb13cf903bc58 | wikidoc | Bipyridine | Bipyridine
# Overview
Bipyridines form a family of chemical compounds with the formula (C5H4N)2. They are derived by the coupling of two pyridine rings. Six isomers of bipyridine exist. Two isomers are prominent: 2,2'-bipyridine is a popular ligand in coordination chemistry and 4,4'-bipyridine is a precursor to the herbicide paraquat. The bipyridines are colourless solids, which are soluble in organic solvents and slightly soluble in water.
Inamrinone and Milrinone are used occasionally for short term. They inhibit phosphodiesterase by increasing cAMP, exerting positive inotropy and causing vasodilation. Amrinone causes thrombocytopenia; Milrinone decreases survival in heart failure.
# 2,2'-Bipyridine
2,2'-Bipyridine is a chelating ligand that forms complexes with most transition metal ions. Many of these complexes have distinctive optical properties and some are of interest for analysis. Also see bipyridyl.
2,2'-Bipyridine is used in the manufacture of Diquat. Diquat's toxicity is due to a similar mechanism to paraquat.
# 4,4'-Bipyridine
4,4'-Bipyridine (4,4'-bipy) is mainly used as a precursor to N,N'-dimethyl-4,4'-bipyridinium 2+, known as paraquat. This species is electroactive, and its toxicity arises from the ability of this dication to interrupt biological electron transfer. Because of its structure, 4,4'-bipyridine can bridge between metal centres to give coordination polymers.
de:Bipyridine | Bipyridine
# Overview
Bipyridines form a family of chemical compounds with the formula (C5H4N)2. They are derived by the coupling of two pyridine rings. Six isomers of bipyridine exist. Two isomers are prominent: 2,2'-bipyridine is a popular ligand in coordination chemistry and 4,4'-bipyridine is a precursor to the herbicide paraquat. The bipyridines are colourless solids, which are soluble in organic solvents and slightly soluble in water.
Inamrinone and Milrinone are used occasionally for short term. They inhibit phosphodiesterase by increasing cAMP, exerting positive inotropy and causing vasodilation. Amrinone causes thrombocytopenia; Milrinone decreases survival in heart failure.
# 2,2'-Bipyridine
2,2'-Bipyridine is a chelating ligand that forms complexes with most transition metal ions. Many of these complexes have distinctive optical properties and some are of interest for analysis. Also see bipyridyl.
2,2'-Bipyridine is used in the manufacture of Diquat. Diquat's toxicity is due to a similar mechanism to paraquat.
# 4,4'-Bipyridine
4,4'-Bipyridine (4,4'-bipy) is mainly used as a precursor to N,N'-dimethyl-4,4'-bipyridinium [(C5H4NCH3)2]2+, known as paraquat. This species is electroactive, and its toxicity arises from the ability of this dication to interrupt biological electron transfer. Because of its structure, 4,4'-bipyridine can bridge between metal centres to give coordination polymers.
de:Bipyridine
Template:WH
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028f69d0ca47ea5795b524c2f84cadcf11a580c6 | wikidoc | Birth mass | Birth mass
# Overview
Birth mass is the mass of a baby at its birth. It has direct links with the gestational age at which the child was born and can be estimated during the pregnancy by measuring fundal height. A baby born within the normal range of mass for that gestational age is known as appropriate for gestational age (AGA). Those born above or below that range have often had an unusual rate of development – this often indicates complications with the pregnancy that may affect the baby or its mother.
The incidence of birth mass being outside of the AGA is influenced by the parents in numerous ways, including:
- Genetics
- The health of the mother, particularly during the pregnancy
- Environmental factors, including exposure of the mother to secondhand smoke, pp. 198–205
- Other factors, like multiple births, where each baby is likely to be outside the AGA, one more so than the other
There have been numerous studies that have attempted, with varying degrees of success, to show links between birth mass and later-life conditions, including diabetes, obesity, tobacco smoking and intelligence.
# Conditions
Associated conditions include:
- Large for gestational age
- Small for gestational age
# Influence on adult life
Studies have been conducted to investigate how a person's birth mass can influence aspects of their future life. This includes theorised links with obesity, diabetes and intelligence.
## Obesity
A baby born small or large for gestational age (either of the two extremes) is thought to have an increased risk of obesity in later life.
GH therapy at a certain dose induced catch-up of lean body mass (LBM). However percentage body fat decreased in the GH-treated subjects. Bone mineral density SDS measured by DEXA increased significantly in the GH-treated group compared to the untreated subjects, though there is much debate over whether or not SGA (small for gestational age) is significantly adverse to children to warrant inducing catch-up.
## Diabetes
Babies that have a low birth mass are thought to have an increased risk of developing type 2 diabetes in later life.
## Intelligence
Some studies have shown a direct link between an increased birth mass and an increased intelligence quotient. | Birth mass
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Birth mass is the mass of a baby at its birth. It has direct links with the gestational age at which the child was born and can be estimated during the pregnancy by measuring fundal height. A baby born within the normal range of mass for that gestational age is known as appropriate for gestational age (AGA). Those born above or below that range have often had an unusual rate of development – this often indicates complications with the pregnancy that may affect the baby or its mother.
The incidence of birth mass being outside of the AGA is influenced by the parents in numerous ways, including:
- Genetics
- The health of the mother, particularly during the pregnancy
- Environmental factors, including exposure of the mother to secondhand smoke[1], pp. 198–205
- Other factors, like multiple births, where each baby is likely to be outside the AGA, one more so than the other
There have been numerous studies that have attempted, with varying degrees of success, to show links between birth mass and later-life conditions, including diabetes, obesity, tobacco smoking and intelligence.
# Conditions
Associated conditions include:
- Large for gestational age
- Small for gestational age
# Influence on adult life
Studies have been conducted to investigate how a person's birth mass can influence aspects of their future life. This includes theorised links with obesity, diabetes and intelligence.
## Obesity
A baby born small or large for gestational age (either of the two extremes) is thought to have an increased risk of obesity in later life.[2][3][4]
GH therapy at a certain dose induced catch-up of lean body mass (LBM). However percentage body fat decreased in the GH-treated subjects. Bone mineral density SDS measured by DEXA increased significantly in the GH-treated group compared to the untreated subjects, though there is much debate over whether or not SGA (small for gestational age) is significantly adverse to children to warrant inducing catch-up.[5]
## Diabetes
Babies that have a low birth mass are thought to have an increased risk of developing type 2 diabetes in later life.[6][7][8]
## Intelligence
Some studies have shown a direct link between an increased birth mass and an increased intelligence quotient.[9][10][11] | https://www.wikidoc.org/index.php/Birth_mass | |
90ef8fd5179afb7a2349d2b0e97258057afc687e | wikidoc | Birth rate | Birth rate
In demography, natality, or rather the crude birth rate (CBR) of a population is the number of childbirths per 1,000 people per year. It can be mathematically represented by CBR = \frac{n}{p}{1000} where n is the number of childbirths in that year, and p is the current population. This figure is combined with the crude death rate to produce the rate of natural population growth (natural in that it does not take into account net migration).
Another indicator of fertility is frequently used: the total fertility rate — average number of children born to each woman over the course of her life. In general, the total fertility rate is a better indicator of (current) fertility rates because unlike the crude birth rate it is not affected by the age distribution of the population.
Fertility rates tend to be higher in less economically developed countries and lower in more economically developed countries.
# Other methods of measuring birth rate
General fertility rate (GFR) – This measures the number of births per 1,000 women aged 15 to 45.
Standardised birth rate (SBR) – This compares the age-sex structure to a hypothetical standard population.
Total fertility rate (TFR) – The mean number of children a woman is expected to bear during her child-bearing years. It is also independent of the age-sex structure of the population.
# Factors affecting birth rate
- Pro-natalist policies and Anti-natalist policies from government
- Abortion rates
- Existing age-sex structure
- Social and religious beliefs - especially in relation to contraception
- Female literacy levels
- Economic prosperity (although in theory when the economy is doing well families can afford to have more children in practice the higher the economic prosperity the lower the birth rate).
- Poverty levels – children can be seen as an economic resource in developing countries as they can earn money.
- Infant Mortality Rate – a family may have more children if a country's IMR is high as it is likely some of those children will die.
- Urbanization
- Homosexuality - homosexual men and women most commonly do not become mothers and fathers, decreasing the number of births per year.
- Typical age of marriage
- Pension availability
- Conflict | Birth rate
In demography, natality, or rather the crude birth rate (CBR) of a population is the number of childbirths per 1,000 people per year. It can be mathematically represented by <math>CBR = \frac{n}{p}{1000}</math> where n is the number of childbirths in that year, and p is the current population. This figure is combined with the crude death rate to produce the rate of natural population growth (natural in that it does not take into account net migration).
Another indicator of fertility is frequently used: the total fertility rate — average number of children born to each woman over the course of her life. In general, the total fertility rate is a better indicator of (current) fertility rates because unlike the crude birth rate it is not affected by the age distribution of the population.
Fertility rates tend to be higher in less economically developed countries and lower in more economically developed countries.
# Other methods of measuring birth rate
General fertility rate (GFR) – This measures the number of births per 1,000 women aged 15 to 45.
Standardised birth rate (SBR) – This compares the age-sex structure to a hypothetical standard population.
Total fertility rate (TFR) – The mean number of children a woman is expected to bear during her child-bearing years. It is also independent of the age-sex structure of the population.
# Factors affecting birth rate
- Pro-natalist policies and Anti-natalist policies from government
- Abortion rates
- Existing age-sex structure
- Social and religious beliefs - especially in relation to contraception
- Female literacy levels
- Economic prosperity (although in theory when the economy is doing well families can afford to have more children in practice the higher the economic prosperity the lower the birth rate).
- Poverty levels – children can be seen as an economic resource in developing countries as they can earn money.
- Infant Mortality Rate – a family may have more children if a country's IMR is high as it is likely some of those children will die.
- Urbanization
- Homosexuality - homosexual men and women most commonly do not become mothers and fathers, decreasing the number of births per year.
- Typical age of marriage
- Pension availability
- Conflict | https://www.wikidoc.org/index.php/Birth_rate | |
6d0931490978a3838cb46823f72c7e7def1cf196 | wikidoc | Bisoprolol | Bisoprolol
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Bisoprolol is a beta-adrenergic blocker that is FDA approved for the treatment of hypertension. Common adverse reactions include diarrhea, headache, rhinitis, upper respiratory infection, fatigue.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
The dose of bisoprolol fumarate must be individualized to the needs of the patient. The usual starting dose is 5 mg once daily. In some patients, 2.5 mg may be an appropriate starting dose. If the antihypertensive effect of 5 mg is inadequate, the dose may be increased to 10 mg and then, if necessary, to 20 mg once daily.
In patients with hepatic impairment (hepatitis or cirrhosis) or renal dysfunction (creatinine clearance less than 40 mL/min), the initial daily dose should be 2.5 mg and caution should be used in dose-titration. Since limited data suggest that bisoprolol fumarate is not dialyzable, drug replacement is not necessary in patients undergoing dialysis.
It is not necessary to adjust the dose in the elderly, unless there is also significant renal dysfunction or hepatic dysfunction.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Bisoprolol in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- 5 mg to 10 mg (no significant difference in the decrese of non-ST segment depression between both dosages was demonstrated).
- Dosing Information
- Initiate with 1.25 mg/day and increase according to tolerance to a maximum dose of 10 mg/day (gradually).
- Dosing Information
- 5 mg/day.
- Dosing information
- 5 to 10 mg/day.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is no pediatric experience with bisoprolol fumarate.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Bisoprolol in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Bisoprolol in pediatric patients.
# Contraindications
- Cardiogenic shock
- Overt cardiac failure
- Second degree AV block
- Third degree AV block
- Marked sinus bradycardia
# Warnings
Sympathetic stimulation is a vital component supporting circulatory function in the setting of congestive heart failure, and beta-blockade may result in further depression of myocardial contractility and precipitate more severe failure. In general, beta-blocking agents should be avoided in patients with overt congestive heart failure. However, in some patients with compensated cardiac failure it may be necessary to utilize them. In such a situation, they must be used cautiously.
Continued depression of the myocardium with beta-blockers can, in some patients, precipitate cardiac failure. At the first signs or symptoms of heart failure, discontinuation of bisoprolol fumarate should be considered. In some cases, beta-blocker therapy can be continued while heart failure is treated with other drugs.
Exacerbation of angina pectoris, and, in some instances, myocardial infarction or ventricular arrhythmia, have been observed in patients with coronary artery disease following abrupt cessation of therapy with beta-blockers. Such patients should, therefore, be cautioned against interruption or discontinuation of therapy without the physician‘s advice. Even in patients without overt coronary artery disease, it may be advisable to taper therapy with bisoprolol fumarate over approximately one week with the patient under careful observation. If withdrawal symptoms occur, bisoprolol fumarate therapy should be reinstituted, at least temporarily.
Beta-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease. Caution should be exercised in such individuals.
PATIENTS WITH BRONCHOSPASTIC DISEASE SHOULD, IN GENERAL, NOT RECEIVE BETA-BLOCKERS. Because of its relative beta1-selectivity, however, bisoprolol fumarate may be used with caution in patients with bronchospastic disease who do not respond to, or who cannot tolerate other antihypertensive treatment. Since beta1-selectivity is not absolute, the lowest possible dose of bisoprolol fumarate should be used, with therapy starting at 2.5 mg. A beta2 agonist (bronchodilator) should be made available.
Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery; however, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures.
Beta-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia. Nonselective beta-blockers may potentiate insulin-induced hypoglycemia and delay recovery of serum glucose levels. Because of its beta1-selectivity, this is less likely with bisoprolol fumarate. However, patients subject to spontaneous hypoglycemia, or diabetic patients receiving insulin or oral hypoglycemic agents, should be cautioned about these possibilities and bisoprolol fumarate should be used with caution.
Beta-adrenergic blockade may mask clinical signs of hyperthyroidism, such as tachycardia. Abrupt withdrawal of beta-blockade may be followed by an exacerbation of the symptoms of hyperthyroidism or may precipitate thyroid storm.
While taking beta-blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions.
# Adverse Reactions
## Clinical Trials Experience
Safety data are available in more than 30,000 patients or volunteers. Frequency estimates and rates of withdrawal of therapy for adverse events were derived from two U.S. placebo-controlled studies.
In Study A, doses of 5, 10, and 20 mg bisoprolol fumarate were administered for 4 weeks. In Study B, doses of 2.5, 10, and 40 mg of bisoprolol fumarate were administered for 12 weeks. A total of 273 patients were treated with 5 to 20 mg of bisoprolol fumarate; 132 received placebo.
Withdrawal of therapy for adverse events was 3.3% for patients receiving bisoprolol fumarate and 6.8% for patients on placebo. Withdrawals were less than 1% for either bradycardia or fatigue/lack of energy.
The following table presents adverse experiences, whether or not considered drug related, reported in at least 1% of patients in these studies, for all patients studied in placebo-controlled clinical trials (2.5 to 40 mg), as well as for a subgroup that was treated with doses within the recommended dosage range (5 to 20 mg). Of the adverse events listed in the table, bradycardia, diarrhea, asthenia, fatigue, and sinusitis appear to be dose related.
- Central Nervous System: Dizziness, unsteadiness, headache, paresthesia, hypoaesthesia, hyperesthesia, somnolence, anxiety/restlessness, decreased concentration/memory.
- Autonomic Nervous System: Dry mouth.
- Cardiovascular: Bradycardia, palpitations and other rhythm disturbances, cold extremities, claudication, hypotension, orthostatic hypotension, chest pain, congestive heart failure, dyspnea on exertion.
- Psychiatric: Vivid dreams, insomnia, depression.
- Gastrointestinal: Gastric/epigastric/abdominal pain, gastritis, dyspepsia, nausea, vomiting, diarrhea, constipation, peptic ulcer.
- Musculoskeletal: Muscle/joint pain, back/neck pain, muscle cramps, twitching/tremor.
- Skin: Rash, acne, eczema, skin irritation, pruritus, flushing, sweating, alopecia, cutaneous vasculitis.
- Special Senses: Visual disturbances, ocular pain/pressure, abnormal lacrimation, tinnitus, earache, taste abnormalities.
- Metabolic: Gout.
- Respiratory: Asthma/bronchospasm, bronchitis, coughing, dyspnea, pharyngitis, rhinitis, sinusitis, URI.
- Genitourinary: Decreased libido/impotence, cystitis, renal colic, polyuria.
- Hematologic: Purpura.
- General: Fatigue, asthenia, chest pain, malaise, edema, weight gain, angioedema.
In addition, a variety of adverse effects have been reported with other beta-adrenergic blocking agents and should be considered potential adverse effects of bisoprolol fumarate:
- Central Nervous System: Reversible mental depression progressing to catatonia, hallucinations, an acute reversible syndrome characterized by disorientation to time and place, emotional lability, slightly clouded sensorium.
- Allergic: Fever, combined with aching and sore throat, laryngospasm, respiratory distress.
- Hematologic: Agranulocytosis, thrombocytopenia, thrombocytopenic purpura.
- Gastrointestinal: Mesenteric arterial thrombosis, ischemic colitis.
- Miscellaneous: The oculomucocutaneous syndrome associated with the beta-blocker practolol has not been reported with bisoprolol fumarate during investigational use or extensive foreign marketing experience.
In clinical trials, the most frequently reported laboratory change was an increase in serum triglycerides, but this was not a consistent finding.
Sporadic liver test abnormalities have been reported. In the U.S. controlled trials experience with bisoprolol fumarate treatment for 4 to 12 weeks, the incidence of concomitant elevations in SGOT and SGPT from 1 to 2 times normal was 3.9%, compared to 2.5% for placebo. No patient had concomitant elevations greater than twice normal.
In the long-term, uncontrolled experience with bisoprolol fumarate treatment for 6 to 18 months, the incidence of one or more concomitant elevations in SGOT and SGPT from 1 to 2 times normal was 6.2%. The incidence of multiple occurrences was 1.9%. For concomitant elevations in SGOT and SGPT of greater than twice normal, the incidence was 1.5%. The incidence of multiple occurrences was 0.3%. In many cases these elevations were attributed to underlying disorders, or resolved during continued treatment with bisoprolol fumarate.
Other laboratory changes included small increases in uric acid, creatinine, BUN, serum potassium, glucose, and phosphorus and decreases in WBC and platelets. These were generally not of clinical importance and rarely resulted in discontinuation of bisoprolol fumarate.
As with other beta-blockers, ANA conversions have also been reported on bisoprolol fumarate. About 15% of patients in long-term studies converted to a positive titer, although about one-third of these patients subsequently reconverted to a negative titer while on continued therapy.
## Postmarketing Experience
- Central Nervous System: Vertigo, syncope, sleep disturbances.
- Musculoskeletal: Arthralgia.
- Skin: Psoriasis, dermatitis, angioedema, exfoliative dermatitis.
- Special Senses: Decreased hearing.
- Genitourinary: Peyronie‘s disease.
# Drug Interactions
- Bisoprolol fumarate should not be combined with other beta-blocking agents.
- Patients receiving catecholamine-depleting drugs, such as reserpine or guanethidine, should be closely monitored, because the added beta-adrenergic blocking action of bisoprolol fumarate may produce excessive reduction of sympathetic activity.
- In patients receiving concurrent therapy with clonidine, if therapy is to be discontinued, it is suggested that bisoprolol fumarate be discontinued for several days before the withdrawal of clonidine.
- Bisoprolol fumarate should be used with care when myocardial depressants or inhibitors of AV conduction, such as certain calcium channel blockers (particularly of the phenylalkylamine verapamil and benzothiazepine diltiazem classes), or antiarrhythmic agents, such as disopyramide, are used concurrently.
- Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia.
- Concurrent use of rifampin increases the metabolic clearance of bisoprolol fumarate, resulting in a shortened elimination half-life of bisoprolol fumarate. However, initial dose modification is generally not necessary.
- Pharmacokinetic studies document no clinically relevant interactions with other agents given concomitantly, including thiazide diuretics and cimetidine.
- There was no effect of bisoprolol fumarate on prothrombin time in patients on stable doses of warfarin.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
In rats, bisoprolol fumarate was not teratogenic at doses up to 150 mg/kg/day which is 375 and 77 times the MRHD on the basis of body weight and body surface area, respectively. Bisoprolol fumarate was fetotoxic (increased late resorptions) at 50 mg/kg/day and maternotoxic (decreased food intake and body weight gain) at 150 mg/kg/day. The fetotoxicity in rats occurred at 125 times the MRHD on a body weight basis and 26 times the MRHD on the basis of body surface area. The maternotoxicity occurred at 375 times the MRHD on a body weight basis and 77 times the MRHD on the basis of body surface area. In rabbits, bisoprolol fumarate was not teratogenic at doses up to 12.5 mg/kg/day, which is 31 and 12 times the MRHD based on body weight and body surface area, respectively, but was embryolethal (increased early resorptions) at 12.5 mg/kg/day.
There are no adequate and well-controlled studies in pregnant women. Bisoprolol fumarate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Bisoprolol in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Bisoprolol during labor and delivery.
### Nursing Mothers
Small amounts of bisoprolol fumarate (<2% of the dose) have been detected in the milk of lactating rats. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk caution should be exercised when bisoprolol fumarate is administered to nursing women.
### Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
Bisoprolol fumarate has been used in elderly patients with hypertension. Response rates and mean decreases in systolic blood pressure and diastolic blood pressure were similar to the decreases in younger patients in the U.S. clinical studies. Although no dose response study was conducted in elderly patients, there was a tendency for older patients to be maintained on higher doses of bisoprolol fumarate.
Observed reductions in heart rate were slightly greater in the elderly than in the young and tended to increase with increasing dose. In general, no disparity in adverse experience reports or dropouts for safety reasons was observed between older and younger patients. Dose adjustment based on age is not necessary.
### Gender
There is no FDA guidance on the use of Bisoprolol with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Bisoprolol with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Bisoprolol in patients with renal impairment.
### Hepatic Impairment
Use caution in adjusting the dose of bisoprolol fumarate in patients with renal or hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Bisoprolol in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Bisoprolol in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Oral
### Monitoring
There is limited information regarding Bisoprolol Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Bisoprolol and IV administrations.
# Overdosage
The most common signs expected with overdosage of a beta-blocker are bradycardia, hypotension, congestive heart failure, bronchospasm, and hypoglycemia. To date, a few cases of overdose (maximum: 2000 mg) with bisoprolol fumarate have been reported. Bradycardia and/or hypotension were noted. Sympathomimetic agents were given in some cases, and all patients recovered.
In general, if overdose occurs, bisoprolol fumarate therapy should be stopped and supportive and symptomatic treatment should be provided. Limited data suggest that bisoprolol fumarate is not dialyzable. Based on the expected pharmacologic actions and recommendations for other beta-blockers, the following general measures should be considered when clinically warranted:
- Bradycardia: Administer IV atropine. If the response is inadequate, isoproterenol or another agent with positive chronotropic properties may be given cautiously. Under some circumstances, transvenous pacemaker insertion may be necessary.
- Hypotension: IV fluids and vasopressors should be administered. Intravenous glucagon may be useful.
- Heart Block (second or third degree): Patients should be carefully monitored and treated with isoproterenol infusion or transvenous cardiac pacemaker insertion, as appropriate.
- Congestive Heart Failure: Initiate conventional therapy (i.e., digitalis, diuretics, inotropic agents, vasodilating agents).
- Bronchospasm: Administer bronchodilator therapy such as isoproterenol and/or aminophylline.
- Hypoglycemia: Administer IV glucose.
# Pharmacology
## Mechanism of Action
The mechanism of action of its antihypertensive effects has not been completely established. Factors which may be involved include:
- Decreased cardiac output,
- Inhibition of renin release by the kidneys,
- Diminution of tonic sympathetic outflow from the vasomotor centers in the brain.
## Structure
Bisoprolol fumarate is a synthetic, beta1-selective (cardioselective) adrenoceptor blocking agent. The chemical name for bisoprolol fumarate is (±)-1-methyl)phenoxy)-3--2-propanol(E)-2-butenedioate (2:1) (salt). It possesses an asymmetric carbon atom in its structure and is provided as a racemic mixture. The S(-) enantiomer is responsible for most of the beta-blocking activity. Its molecular formula is (C18H31NO4)2C4H4O4 and its structure is:
Bisoprolol fumarate has a molecular weight of 766.97. It is a white crystalline powder which is approximately equally hydrophilic and lipophilic, and is readily soluble in water, methanol, ethanol, and chloroform.
Bisoprolol fumarate is available as 5 and 10 mg tablets for oral administration.
Inactive ingredients include microcrystalline cellulose, anhydrous dibasic calcium phosphate, crospovidone, colloidal silicon dioxide, magnesium stearate, hypromellose, polyethylene glycol, polysorbate 80, and titanium dioxide. The 5 mg tablets also contain red and yellow iron oxide.
## Pharmacodynamics
Bisoprolol fumarate is a beta1-selective (cardioselective) adrenoceptor blocking agent without significant membrane stabilizing activity or intrinsic sympathomimetic activity in its therapeutic dosage range. Cardioselectivity is not absolute, however, and at higher doses (≥20 mg) bisoprolol fumarate also inhibits beta2-adrenoceptors, chiefly located in the bronchial and vascular musculature; to retain selectivity it is therefore important to use the lowest effective dose.
The most prominent effect of bisoprolol fumarate is the negative chronotropic effect, resulting in a reduction in resting and exercise heart rate. There is a fall in resting and exercise cardiac output with little observed change in stroke volume, and only a small increase in right atrial pressure, or pulmonary capillary wedge pressure at rest or during exercise.
Findings in short-term clinical hemodynamics studies with bisoprolol fumarate are similar to those observed with other beta-blocking agents.
In normal volunteers, bisoprolol fumarate therapy resulted in a reduction of exercise- and isoproterenol-induced tachycardia. The maximal effect occurred within 1 to 4 hours post-dosing. Effects persisted for 24 hours at doses equal to or greater than 5 mg.
Electrophysiology studies in man have demonstrated that bisoprolol fumarate significantly decreases heart rate, increases sinus node recovery time, prolongs AV node refractory periods, and, with rapid atrial stimulation, prolongs AV nodal conduction.
Beta1-selectivity of bisoprolol fumarate has been demonstrated in both animal and human studies. No effects at therapeutic doses on beta2-adrenoceptor density have been observed. Pulmonary function tests have been conducted in healthy volunteers, asthmatics, and patients with chronic obstructive pulmonary disease (COPD). Doses of bisoprolol fumarate ranged from 5 to 60 mg, atenolol from 50 to 200 mg, metoprolol from 100 to 200 mg, and propranolol from 40 to 80 mg. In some studies, slight, asymptomatic increases in airways resistance (AWR) and decreases in forced expiratory volume (FEV1) were observed with doses of bisoprolol fumarate 20 mg and higher, similar to the small increases in AWR also noted with the other cardioselective beta-blockers. The changes induced by beta-blockade with all agents were reversed by bronchodilator therapy.
Bisoprolol fumarate had minimal effect on serum lipids during antihypertensive studies. In U.S. placebo-controlled trials, changes in total cholesterol averaged +0.8% for bisoprolol fumarate-treated patients, and +0.7% for placebo. Changes in triglycerides averaged +19% for bisoprolol fumarate-treated patients, and +17% for placebo.
Bisoprolol fumarate has also been given concomitantly with thiazide diuretics. Even very low doses of hydrochlorothiazide (6.25 mg) were found to be additive with bisoprolol fumarate in lowering blood pressure in patients with mild-to-moderate hypertension.
## Pharmacokinetics
The absolute bioavailability after a 10 mg oral dose of bisoprolol fumarate is about 80%. Absorption is not affected by the presence of food. The first pass metabolism of bisoprolol fumarate is about 20%.
Binding to serum proteins is approximately 30%. Peak plasma concentrations occur within 2 to 4 hours of dosing with 5 to 20 mg, and mean peak values range from 16 ng/mL at 5 mg to 70 ng/mL at 20 mg. Once daily dosing with bisoprolol fumarate results in less than twofold intersubject variation in peak plasma levels. The plasma elimination half-life is 9 to 12 hours and is slightly longer in elderly patients, in part because of decreased renal function in that population. Steady state is attained within 5 days of once daily dosing. In both young and elderly populations, plasma accumulation is low; the accumulation factor ranges from 1.1 to 1.3, and is what would be expected from the first order kinetics and once daily dosing. Plasma concentrations are proportional to the administered dose in the range of 5 to 20 mg. Pharmacokinetic characteristics of the two enantiomers are similar.
Bisoprolol fumarate is eliminated equally by renal and non-renal pathways with about 50% of the dose appearing unchanged in the urine and the remainder appearing in the form of inactive metabolites. In humans, the known metabolites are labile or have no known pharmacologic activity. Less than 2% of the dose is excreted in the feces. Bisoprolol fumarate is not metabolized by cytochrome P450 II D6 (debrisoquin hydroxylase).
In subjects with creatinine clearance less than 40 mL/min, the plasma half-life is increased approximately threefold compared to healthy subjects.
In patients with cirrhosis of the liver, the elimination of bisoprolol fumarate is more variable in rate and significantly slower than that in healthy subjects, with plasma half-life ranging from 8.3 to 21.7 hours.
## Nonclinical Toxicology
Long-term studies were conducted with oral bisoprolol fumarate administered in the feed of mice (20 and 24 months) and rats (26 months). No evidence of carcinogenic potential was seen in mice dosed up to 250 mg/kg/day or rats dosed up to 125 mg/kg/day. On a body weight basis, these doses are 625 and 312 times, respectively, the maximum recommended human dose (MRHD) of 20 mg, (or 0.4 mg/kg/day based on a 50 kg individual); on a body surface area basis, these doses are 59 times (mice) and 64 times (rats) the MRHD. The mutagenic potential of bisoprolol fumarate was evaluated in the microbial mutagenicity (Ames) test, the point mutation and chromosome aberration assays in Chinese hamster V79 cells, the unscheduled DNA synthesis test, the micronucleus test in mice, and the cytogenetics assay in rats. There was no evidence of mutagenic potential in these in vitro and in vivo assays.
Reproduction studies in rats did not show any impairment of fertility at doses up to 150 mg/kg/day of bisoprolol fumarate, or 375 and 77 times the MRHD on the basis of body weight and body surface area, respectively.
# Clinical Studies
In two randomized double-blind placebo-controlled trials conducted in the U.S., reductions in systolic blood pressure and diastolic blood pressure and heart rate 24 hours after dosing in patients with mild-to-moderate hypertension are shown below. In both studies, mean systolic blood pressures/diastolic blood pressures at baseline were approximately 150/100 mm Hg, and mean heart rate was 76 bpm. Drug effect is calculated by subtracting the placebo effect from the overall change in blood pressure and heart rate.
Blood pressure responses were seen within one week of treatment and changed little thereafter. They were sustained for 12 weeks and for over a year in studies of longer duration. Blood pressure returned to baseline when bisoprolol fumarate was tapered over two weeks in a long-term study.
Overall, significantly greater blood pressure reductions were observed on bisoprolol fumarate than on placebo regardless of race, age, or gender. There were no significant differences in response between black and nonblack patients.
# How Supplied
ZEBETA® (bisoprolol fumarate) is supplied as 5 mg and 10 mg tablets:
- The 5 mg tablet is pink, heart-shaped, biconvex, film-coated, vertically scored in half on both sides, with an engraved stylized b/stylized b on one side and 6/0 on the reverse side, supplied as follows: 30 Unit-of-use (NDC 51285-060-01)
- The 10 mg tablet is white, heart-shaped, biconvex, film-coated, with an engraved stylized b on one side and 61 on the reverse side, supplied as follows: 30 Unit-of-use (NDC 51285-061-01)
## Storage
- Store at 20o to 25o C (68o to 77oF).
- Protect from moisture.
- Dispense in tight containers.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Patients, especially those with coronary artery disease, should be warned about discontinuing use of bisoprolol fumarate without a physician‘s supervision. Patients should also be advised to consult a physician if any difficulty in breathing occurs, or if they develop signs or symptoms of congestive heart failure or excessive bradycardia.
Patients subject to spontaneous hypoglycemia, or diabetic patients receiving insulin or oral hypoglycemic agents, should be cautioned that beta-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia, and bisoprolol fumarate should be used with caution.
Patients should know how they react to this medicine before they operate automobiles and machinery or engage in other tasks requiring alertness.
# Precautions with Alcohol
Alcohol-Bisoprolol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Zebeta
# Look-Alike Drug Names
- Zebeta - Diabeta
- Zebeta - Zetia
# Drug Shortage Status
Drug Shortage
# Price | Bisoprolol
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alonso Alvarado, M.D. [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Bisoprolol is a beta-adrenergic blocker that is FDA approved for the treatment of hypertension. Common adverse reactions include diarrhea, headache, rhinitis, upper respiratory infection, fatigue.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
The dose of bisoprolol fumarate must be individualized to the needs of the patient. The usual starting dose is 5 mg once daily. In some patients, 2.5 mg may be an appropriate starting dose. If the antihypertensive effect of 5 mg is inadequate, the dose may be increased to 10 mg and then, if necessary, to 20 mg once daily.
In patients with hepatic impairment (hepatitis or cirrhosis) or renal dysfunction (creatinine clearance less than 40 mL/min), the initial daily dose should be 2.5 mg and caution should be used in dose-titration. Since limited data suggest that bisoprolol fumarate is not dialyzable, drug replacement is not necessary in patients undergoing dialysis.
It is not necessary to adjust the dose in the elderly, unless there is also significant renal dysfunction or hepatic dysfunction.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Bisoprolol in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- 5 mg to 10 mg (no significant difference in the decrese of non-ST segment depression between both dosages was demonstrated).[1]
- Dosing Information
- Initiate with 1.25 mg/day and increase according to tolerance to a maximum dose of 10 mg/day (gradually).[2]
- Dosing Information
- 5 mg/day.[3]
- Dosing information
- 5 to 10 mg/day.[4]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is no pediatric experience with bisoprolol fumarate.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Bisoprolol in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Bisoprolol in pediatric patients.
# Contraindications
- Cardiogenic shock
- Overt cardiac failure
- Second degree AV block
- Third degree AV block
- Marked sinus bradycardia
# Warnings
Sympathetic stimulation is a vital component supporting circulatory function in the setting of congestive heart failure, and beta-blockade may result in further depression of myocardial contractility and precipitate more severe failure. In general, beta-blocking agents should be avoided in patients with overt congestive heart failure. However, in some patients with compensated cardiac failure it may be necessary to utilize them. In such a situation, they must be used cautiously.
Continued depression of the myocardium with beta-blockers can, in some patients, precipitate cardiac failure. At the first signs or symptoms of heart failure, discontinuation of bisoprolol fumarate should be considered. In some cases, beta-blocker therapy can be continued while heart failure is treated with other drugs.
Exacerbation of angina pectoris, and, in some instances, myocardial infarction or ventricular arrhythmia, have been observed in patients with coronary artery disease following abrupt cessation of therapy with beta-blockers. Such patients should, therefore, be cautioned against interruption or discontinuation of therapy without the physician‘s advice. Even in patients without overt coronary artery disease, it may be advisable to taper therapy with bisoprolol fumarate over approximately one week with the patient under careful observation. If withdrawal symptoms occur, bisoprolol fumarate therapy should be reinstituted, at least temporarily.
Beta-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease. Caution should be exercised in such individuals.
PATIENTS WITH BRONCHOSPASTIC DISEASE SHOULD, IN GENERAL, NOT RECEIVE BETA-BLOCKERS. Because of its relative beta1-selectivity, however, bisoprolol fumarate may be used with caution in patients with bronchospastic disease who do not respond to, or who cannot tolerate other antihypertensive treatment. Since beta1-selectivity is not absolute, the lowest possible dose of bisoprolol fumarate should be used, with therapy starting at 2.5 mg. A beta2 agonist (bronchodilator) should be made available.
Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery; however, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures.
Beta-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia. Nonselective beta-blockers may potentiate insulin-induced hypoglycemia and delay recovery of serum glucose levels. Because of its beta1-selectivity, this is less likely with bisoprolol fumarate. However, patients subject to spontaneous hypoglycemia, or diabetic patients receiving insulin or oral hypoglycemic agents, should be cautioned about these possibilities and bisoprolol fumarate should be used with caution.
Beta-adrenergic blockade may mask clinical signs of hyperthyroidism, such as tachycardia. Abrupt withdrawal of beta-blockade may be followed by an exacerbation of the symptoms of hyperthyroidism or may precipitate thyroid storm.
While taking beta-blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions.
# Adverse Reactions
## Clinical Trials Experience
Safety data are available in more than 30,000 patients or volunteers. Frequency estimates and rates of withdrawal of therapy for adverse events were derived from two U.S. placebo-controlled studies.
In Study A, doses of 5, 10, and 20 mg bisoprolol fumarate were administered for 4 weeks. In Study B, doses of 2.5, 10, and 40 mg of bisoprolol fumarate were administered for 12 weeks. A total of 273 patients were treated with 5 to 20 mg of bisoprolol fumarate; 132 received placebo.
Withdrawal of therapy for adverse events was 3.3% for patients receiving bisoprolol fumarate and 6.8% for patients on placebo. Withdrawals were less than 1% for either bradycardia or fatigue/lack of energy.
The following table presents adverse experiences, whether or not considered drug related, reported in at least 1% of patients in these studies, for all patients studied in placebo-controlled clinical trials (2.5 to 40 mg), as well as for a subgroup that was treated with doses within the recommended dosage range (5 to 20 mg). Of the adverse events listed in the table, bradycardia, diarrhea, asthenia, fatigue, and sinusitis appear to be dose related.
- Central Nervous System: Dizziness, unsteadiness, headache, paresthesia, hypoaesthesia, hyperesthesia, somnolence, anxiety/restlessness, decreased concentration/memory.
- Autonomic Nervous System: Dry mouth.
- Cardiovascular: Bradycardia, palpitations and other rhythm disturbances, cold extremities, claudication, hypotension, orthostatic hypotension, chest pain, congestive heart failure, dyspnea on exertion.
- Psychiatric: Vivid dreams, insomnia, depression.
- Gastrointestinal: Gastric/epigastric/abdominal pain, gastritis, dyspepsia, nausea, vomiting, diarrhea, constipation, peptic ulcer.
- Musculoskeletal: Muscle/joint pain, back/neck pain, muscle cramps, twitching/tremor.
- Skin: Rash, acne, eczema, skin irritation, pruritus, flushing, sweating, alopecia, cutaneous vasculitis.
- Special Senses: Visual disturbances, ocular pain/pressure, abnormal lacrimation, tinnitus, earache, taste abnormalities.
- Metabolic: Gout.
- Respiratory: Asthma/bronchospasm, bronchitis, coughing, dyspnea, pharyngitis, rhinitis, sinusitis, URI.
- Genitourinary: Decreased libido/impotence, cystitis, renal colic, polyuria.
- Hematologic: Purpura.
- General: Fatigue, asthenia, chest pain, malaise, edema, weight gain, angioedema.
In addition, a variety of adverse effects have been reported with other beta-adrenergic blocking agents and should be considered potential adverse effects of bisoprolol fumarate:
- Central Nervous System: Reversible mental depression progressing to catatonia, hallucinations, an acute reversible syndrome characterized by disorientation to time and place, emotional lability, slightly clouded sensorium.
- Allergic: Fever, combined with aching and sore throat, laryngospasm, respiratory distress.
- Hematologic: Agranulocytosis, thrombocytopenia, thrombocytopenic purpura.
- Gastrointestinal: Mesenteric arterial thrombosis, ischemic colitis.
- Miscellaneous: The oculomucocutaneous syndrome associated with the beta-blocker practolol has not been reported with bisoprolol fumarate during investigational use or extensive foreign marketing experience.
In clinical trials, the most frequently reported laboratory change was an increase in serum triglycerides, but this was not a consistent finding.
Sporadic liver test abnormalities have been reported. In the U.S. controlled trials experience with bisoprolol fumarate treatment for 4 to 12 weeks, the incidence of concomitant elevations in SGOT and SGPT from 1 to 2 times normal was 3.9%, compared to 2.5% for placebo. No patient had concomitant elevations greater than twice normal.
In the long-term, uncontrolled experience with bisoprolol fumarate treatment for 6 to 18 months, the incidence of one or more concomitant elevations in SGOT and SGPT from 1 to 2 times normal was 6.2%. The incidence of multiple occurrences was 1.9%. For concomitant elevations in SGOT and SGPT of greater than twice normal, the incidence was 1.5%. The incidence of multiple occurrences was 0.3%. In many cases these elevations were attributed to underlying disorders, or resolved during continued treatment with bisoprolol fumarate.
Other laboratory changes included small increases in uric acid, creatinine, BUN, serum potassium, glucose, and phosphorus and decreases in WBC and platelets. These were generally not of clinical importance and rarely resulted in discontinuation of bisoprolol fumarate.
As with other beta-blockers, ANA conversions have also been reported on bisoprolol fumarate. About 15% of patients in long-term studies converted to a positive titer, although about one-third of these patients subsequently reconverted to a negative titer while on continued therapy.
## Postmarketing Experience
- Central Nervous System: Vertigo, syncope, sleep disturbances.
- Musculoskeletal: Arthralgia.
- Skin: Psoriasis, dermatitis, angioedema, exfoliative dermatitis.
- Special Senses: Decreased hearing.
- Genitourinary: Peyronie‘s disease.
# Drug Interactions
- Bisoprolol fumarate should not be combined with other beta-blocking agents.
- Patients receiving catecholamine-depleting drugs, such as reserpine or guanethidine, should be closely monitored, because the added beta-adrenergic blocking action of bisoprolol fumarate may produce excessive reduction of sympathetic activity.
- In patients receiving concurrent therapy with clonidine, if therapy is to be discontinued, it is suggested that bisoprolol fumarate be discontinued for several days before the withdrawal of clonidine.
- Bisoprolol fumarate should be used with care when myocardial depressants or inhibitors of AV conduction, such as certain calcium channel blockers (particularly of the phenylalkylamine verapamil and benzothiazepine diltiazem classes), or antiarrhythmic agents, such as disopyramide, are used concurrently.
- Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia.
- Concurrent use of rifampin increases the metabolic clearance of bisoprolol fumarate, resulting in a shortened elimination half-life of bisoprolol fumarate. However, initial dose modification is generally not necessary.
- Pharmacokinetic studies document no clinically relevant interactions with other agents given concomitantly, including thiazide diuretics and cimetidine.
- There was no effect of bisoprolol fumarate on prothrombin time in patients on stable doses of warfarin.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
In rats, bisoprolol fumarate was not teratogenic at doses up to 150 mg/kg/day which is 375 and 77 times the MRHD on the basis of body weight and body surface area, respectively. Bisoprolol fumarate was fetotoxic (increased late resorptions) at 50 mg/kg/day and maternotoxic (decreased food intake and body weight gain) at 150 mg/kg/day. The fetotoxicity in rats occurred at 125 times the MRHD on a body weight basis and 26 times the MRHD on the basis of body surface area. The maternotoxicity occurred at 375 times the MRHD on a body weight basis and 77 times the MRHD on the basis of body surface area. In rabbits, bisoprolol fumarate was not teratogenic at doses up to 12.5 mg/kg/day, which is 31 and 12 times the MRHD based on body weight and body surface area, respectively, but was embryolethal (increased early resorptions) at 12.5 mg/kg/day.
There are no adequate and well-controlled studies in pregnant women. Bisoprolol fumarate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Bisoprolol in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Bisoprolol during labor and delivery.
### Nursing Mothers
Small amounts of bisoprolol fumarate (<2% of the dose) have been detected in the milk of lactating rats. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk caution should be exercised when bisoprolol fumarate is administered to nursing women.
### Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
Bisoprolol fumarate has been used in elderly patients with hypertension. Response rates and mean decreases in systolic blood pressure and diastolic blood pressure were similar to the decreases in younger patients in the U.S. clinical studies. Although no dose response study was conducted in elderly patients, there was a tendency for older patients to be maintained on higher doses of bisoprolol fumarate.
Observed reductions in heart rate were slightly greater in the elderly than in the young and tended to increase with increasing dose. In general, no disparity in adverse experience reports or dropouts for safety reasons was observed between older and younger patients. Dose adjustment based on age is not necessary.
### Gender
There is no FDA guidance on the use of Bisoprolol with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Bisoprolol with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Bisoprolol in patients with renal impairment.
### Hepatic Impairment
Use caution in adjusting the dose of bisoprolol fumarate in patients with renal or hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Bisoprolol in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Bisoprolol in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Oral
### Monitoring
There is limited information regarding Bisoprolol Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Bisoprolol and IV administrations.
# Overdosage
The most common signs expected with overdosage of a beta-blocker are bradycardia, hypotension, congestive heart failure, bronchospasm, and hypoglycemia. To date, a few cases of overdose (maximum: 2000 mg) with bisoprolol fumarate have been reported. Bradycardia and/or hypotension were noted. Sympathomimetic agents were given in some cases, and all patients recovered.
In general, if overdose occurs, bisoprolol fumarate therapy should be stopped and supportive and symptomatic treatment should be provided. Limited data suggest that bisoprolol fumarate is not dialyzable. Based on the expected pharmacologic actions and recommendations for other beta-blockers, the following general measures should be considered when clinically warranted:
- Bradycardia: Administer IV atropine. If the response is inadequate, isoproterenol or another agent with positive chronotropic properties may be given cautiously. Under some circumstances, transvenous pacemaker insertion may be necessary.
- Hypotension: IV fluids and vasopressors should be administered. Intravenous glucagon may be useful.
- Heart Block (second or third degree): Patients should be carefully monitored and treated with isoproterenol infusion or transvenous cardiac pacemaker insertion, as appropriate.
- Congestive Heart Failure: Initiate conventional therapy (i.e., digitalis, diuretics, inotropic agents, vasodilating agents).
- Bronchospasm: Administer bronchodilator therapy such as isoproterenol and/or aminophylline.
- Hypoglycemia: Administer IV glucose.
# Pharmacology
## Mechanism of Action
The mechanism of action of its antihypertensive effects has not been completely established. Factors which may be involved include:
- Decreased cardiac output,
- Inhibition of renin release by the kidneys,
- Diminution of tonic sympathetic outflow from the vasomotor centers in the brain.
## Structure
Bisoprolol fumarate is a synthetic, beta1-selective (cardioselective) adrenoceptor blocking agent. The chemical name for bisoprolol fumarate is (±)-1-[4-((2-(1-Methylethoxy)ethoxy]methyl)phenoxy)-3-[(1-methylethyl)amino]-2-propanol(E)-2-butenedioate (2:1) (salt). It possesses an asymmetric carbon atom in its structure and is provided as a racemic mixture. The S(-) enantiomer is responsible for most of the beta-blocking activity. Its molecular formula is (C18H31NO4)2•C4H4O4 and its structure is:
Bisoprolol fumarate has a molecular weight of 766.97. It is a white crystalline powder which is approximately equally hydrophilic and lipophilic, and is readily soluble in water, methanol, ethanol, and chloroform.
Bisoprolol fumarate is available as 5 and 10 mg tablets for oral administration.
Inactive ingredients include microcrystalline cellulose, anhydrous dibasic calcium phosphate, crospovidone, colloidal silicon dioxide, magnesium stearate, hypromellose, polyethylene glycol, polysorbate 80, and titanium dioxide. The 5 mg tablets also contain red and yellow iron oxide.
## Pharmacodynamics
Bisoprolol fumarate is a beta1-selective (cardioselective) adrenoceptor blocking agent without significant membrane stabilizing activity or intrinsic sympathomimetic activity in its therapeutic dosage range. Cardioselectivity is not absolute, however, and at higher doses (≥20 mg) bisoprolol fumarate also inhibits beta2-adrenoceptors, chiefly located in the bronchial and vascular musculature; to retain selectivity it is therefore important to use the lowest effective dose.
The most prominent effect of bisoprolol fumarate is the negative chronotropic effect, resulting in a reduction in resting and exercise heart rate. There is a fall in resting and exercise cardiac output with little observed change in stroke volume, and only a small increase in right atrial pressure, or pulmonary capillary wedge pressure at rest or during exercise.
Findings in short-term clinical hemodynamics studies with bisoprolol fumarate are similar to those observed with other beta-blocking agents.
In normal volunteers, bisoprolol fumarate therapy resulted in a reduction of exercise- and isoproterenol-induced tachycardia. The maximal effect occurred within 1 to 4 hours post-dosing. Effects persisted for 24 hours at doses equal to or greater than 5 mg.
Electrophysiology studies in man have demonstrated that bisoprolol fumarate significantly decreases heart rate, increases sinus node recovery time, prolongs AV node refractory periods, and, with rapid atrial stimulation, prolongs AV nodal conduction.
Beta1-selectivity of bisoprolol fumarate has been demonstrated in both animal and human studies. No effects at therapeutic doses on beta2-adrenoceptor density have been observed. Pulmonary function tests have been conducted in healthy volunteers, asthmatics, and patients with chronic obstructive pulmonary disease (COPD). Doses of bisoprolol fumarate ranged from 5 to 60 mg, atenolol from 50 to 200 mg, metoprolol from 100 to 200 mg, and propranolol from 40 to 80 mg. In some studies, slight, asymptomatic increases in airways resistance (AWR) and decreases in forced expiratory volume (FEV1) were observed with doses of bisoprolol fumarate 20 mg and higher, similar to the small increases in AWR also noted with the other cardioselective beta-blockers. The changes induced by beta-blockade with all agents were reversed by bronchodilator therapy.
Bisoprolol fumarate had minimal effect on serum lipids during antihypertensive studies. In U.S. placebo-controlled trials, changes in total cholesterol averaged +0.8% for bisoprolol fumarate-treated patients, and +0.7% for placebo. Changes in triglycerides averaged +19% for bisoprolol fumarate-treated patients, and +17% for placebo.
Bisoprolol fumarate has also been given concomitantly with thiazide diuretics. Even very low doses of hydrochlorothiazide (6.25 mg) were found to be additive with bisoprolol fumarate in lowering blood pressure in patients with mild-to-moderate hypertension.
## Pharmacokinetics
The absolute bioavailability after a 10 mg oral dose of bisoprolol fumarate is about 80%. Absorption is not affected by the presence of food. The first pass metabolism of bisoprolol fumarate is about 20%.
Binding to serum proteins is approximately 30%. Peak plasma concentrations occur within 2 to 4 hours of dosing with 5 to 20 mg, and mean peak values range from 16 ng/mL at 5 mg to 70 ng/mL at 20 mg. Once daily dosing with bisoprolol fumarate results in less than twofold intersubject variation in peak plasma levels. The plasma elimination half-life is 9 to 12 hours and is slightly longer in elderly patients, in part because of decreased renal function in that population. Steady state is attained within 5 days of once daily dosing. In both young and elderly populations, plasma accumulation is low; the accumulation factor ranges from 1.1 to 1.3, and is what would be expected from the first order kinetics and once daily dosing. Plasma concentrations are proportional to the administered dose in the range of 5 to 20 mg. Pharmacokinetic characteristics of the two enantiomers are similar.
Bisoprolol fumarate is eliminated equally by renal and non-renal pathways with about 50% of the dose appearing unchanged in the urine and the remainder appearing in the form of inactive metabolites. In humans, the known metabolites are labile or have no known pharmacologic activity. Less than 2% of the dose is excreted in the feces. Bisoprolol fumarate is not metabolized by cytochrome P450 II D6 (debrisoquin hydroxylase).
In subjects with creatinine clearance less than 40 mL/min, the plasma half-life is increased approximately threefold compared to healthy subjects.
In patients with cirrhosis of the liver, the elimination of bisoprolol fumarate is more variable in rate and significantly slower than that in healthy subjects, with plasma half-life ranging from 8.3 to 21.7 hours.
## Nonclinical Toxicology
Long-term studies were conducted with oral bisoprolol fumarate administered in the feed of mice (20 and 24 months) and rats (26 months). No evidence of carcinogenic potential was seen in mice dosed up to 250 mg/kg/day or rats dosed up to 125 mg/kg/day. On a body weight basis, these doses are 625 and 312 times, respectively, the maximum recommended human dose (MRHD) of 20 mg, (or 0.4 mg/kg/day based on a 50 kg individual); on a body surface area basis, these doses are 59 times (mice) and 64 times (rats) the MRHD. The mutagenic potential of bisoprolol fumarate was evaluated in the microbial mutagenicity (Ames) test, the point mutation and chromosome aberration assays in Chinese hamster V79 cells, the unscheduled DNA synthesis test, the micronucleus test in mice, and the cytogenetics assay in rats. There was no evidence of mutagenic potential in these in vitro and in vivo assays.
Reproduction studies in rats did not show any impairment of fertility at doses up to 150 mg/kg/day of bisoprolol fumarate, or 375 and 77 times the MRHD on the basis of body weight and body surface area, respectively.
# Clinical Studies
In two randomized double-blind placebo-controlled trials conducted in the U.S., reductions in systolic blood pressure and diastolic blood pressure and heart rate 24 hours after dosing in patients with mild-to-moderate hypertension are shown below. In both studies, mean systolic blood pressures/diastolic blood pressures at baseline were approximately 150/100 mm Hg, and mean heart rate was 76 bpm. Drug effect is calculated by subtracting the placebo effect from the overall change in blood pressure and heart rate.
Blood pressure responses were seen within one week of treatment and changed little thereafter. They were sustained for 12 weeks and for over a year in studies of longer duration. Blood pressure returned to baseline when bisoprolol fumarate was tapered over two weeks in a long-term study.
Overall, significantly greater blood pressure reductions were observed on bisoprolol fumarate than on placebo regardless of race, age, or gender. There were no significant differences in response between black and nonblack patients.
# How Supplied
ZEBETA® (bisoprolol fumarate) is supplied as 5 mg and 10 mg tablets:
- The 5 mg tablet is pink, heart-shaped, biconvex, film-coated, vertically scored in half on both sides, with an engraved stylized b/stylized b on one side and 6/0 on the reverse side, supplied as follows: 30 Unit-of-use (NDC 51285-060-01)
- The 10 mg tablet is white, heart-shaped, biconvex, film-coated, with an engraved stylized b on one side and 61 on the reverse side, supplied as follows: 30 Unit-of-use (NDC 51285-061-01)
## Storage
- Store at 20o to 25o C (68o to 77oF).
- Protect from moisture.
- Dispense in tight containers.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Patients, especially those with coronary artery disease, should be warned about discontinuing use of bisoprolol fumarate without a physician‘s supervision. Patients should also be advised to consult a physician if any difficulty in breathing occurs, or if they develop signs or symptoms of congestive heart failure or excessive bradycardia.
Patients subject to spontaneous hypoglycemia, or diabetic patients receiving insulin or oral hypoglycemic agents, should be cautioned that beta-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia, and bisoprolol fumarate should be used with caution.
Patients should know how they react to this medicine before they operate automobiles and machinery or engage in other tasks requiring alertness.
# Precautions with Alcohol
Alcohol-Bisoprolol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Zebeta
# Look-Alike Drug Names
- Zebeta - Diabeta
- Zebeta - Zetia
# Drug Shortage Status
Drug Shortage
# Price | https://www.wikidoc.org/index.php/Bisoprolol | |
0e0cbf2b088648e24b84397a1105521640243a84 | wikidoc | Bitolterol | Bitolterol
# Overview
Bitolterol mesylate (Tornalate) is a β2-adrenergic receptor agonist used for the relief of bronchospasm in conditions such as asthma and COPD. In these disorders there is a narrowing of the airways (bronchi and their ramifications) that carry air to the lungs. Muscle spasm and inflammation within the bronchi get worse this narrowing. Bitolterol relaxes the smooth muscles present continuously around the bronchi and bronchioles facilitating the flow of air through them.
Bitolterol has a rapid onset of action (2–5 minutes) and may last up to 6–8 hours.
The drug, alone or in co-administration with theophylline, doesn't show cardiotoxic effect.
The USA Food and Drug Administration (FDA) approved bitolterol in December 1984. The drug was withdrawn from the market by Élan Pharmaceuticals in 2001. | Bitolterol
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Bitolterol mesylate (Tornalate) is a β2-adrenergic receptor agonist used for the relief of bronchospasm in conditions such as asthma[1][2] and COPD.[3][4][5] In these disorders there is a narrowing of the airways (bronchi and their ramifications) that carry air to the lungs. Muscle spasm and inflammation within the bronchi get worse this narrowing. Bitolterol relaxes the smooth muscles present continuously around the bronchi and bronchioles facilitating the flow of air through them.
Bitolterol has a rapid onset of action (2–5 minutes) and may last up to 6–8 hours.[6]
The drug, alone or in co-administration with theophylline, doesn't show cardiotoxic effect.[7]
The USA Food and Drug Administration (FDA) approved bitolterol in December 1984. The drug was withdrawn from the market by Élan Pharmaceuticals in 2001. | https://www.wikidoc.org/index.php/Bitolterol | |
0a2554f94f3d5c7755d9905843eed33f8e01021a | wikidoc | Black body | Black body
In physics, a black body is an idealized object that absorbs all electromagnetic radiation that falls on it. No electromagnetic radiation passes through it and none is reflected. Because no light (visible electromagnetic radiation) is reflected or transmitted, the object appears black when it is cold. However, a black body emits a temperature-dependent spectrum of light. This thermal radiation from a black body is termed black-body radiation.
At room temperature, black bodies emit mostly infrared light, but as the temperature increases past a few hundred degrees Celsius, black bodies start to emit visible wavelengths, from red, through orange, yellow, and white before ending up at blue, beyond which the emission includes increasing amounts of ultraviolet.
The term "black body" was introduced by Gustav Kirchhoff in 1860.
Black-body emission gives insight into the thermal equilibrium state of a continuous field. In classical physics, each different Fourier mode in thermal equilibrium should have the same energy, leading to the theory of ultraviolet catastrophe that there would be an infinite amount of energy in any continuous field. Black bodies could test the properties of thermal equilibrium because they emit radiation which is distributed thermally. Studying the laws of the black body historically led to quantum mechanics.
# Explanation
In the laboratory, black-body radiation is approximated by the radiation from a small hole entrance to a large cavity, a hohlraum. (this technique leads to the alternative term cavity radiation) Any light entering the hole would have to reflect off the walls of the cavity multiple times before it escaped, in which process it is nearly certain to be absorbed. This occurs regardless of the wavelength of the radiation entering (as long as it is small compared to the hole). The hole, then, is a close approximation of a theoretical black body and, if the cavity is heated, the spectrum of the hole's radiation (i.e., the amount of light emitted from the hole at each wavelength) will be continuous, and will not depend on the material in the cavity (compare with emission spectrum). By a theorem proved by Kirchhoff, this curve depends only on the temperature of the cavity walls.
Calculating this curve was a major challenge in theoretical physics during the late nineteenth century. The problem was finally solved in 1901 by Max Planck as Planck's law of black-body radiation.
By making changes to Wien's radiation law (not to be confused with Wien's displacement law) consistent with thermodynamics and electromagnetism, he found a mathematical formula fitting the experimental data in a satisfactory way. To find a physical interpretation for this formula, Planck had then to assume that the energy of the oscillators in the cavity was quantized (i.e., integer multiples of some quantity). Einstein built on this idea and proposed the quantization of electromagnetic radiation itself in 1905 to explain the photoelectric effect. These theoretical advances eventually resulted in the superseding of classical electromagnetism by quantum electrodynamics. Today, these quanta are called photons and the black-body cavity may be thought of as containing a gas of photons. In addition, it led to the development of quantum probability distributions, called Fermi-Dirac statistics and Bose-Einstein statistics, each applicable to a different class of particle, which are used in quantum mechanics instead of the classical distributions. See also fermion and boson.
The wavelength at which the radiation is strongest is given by Wien's displacement law, and the overall power emitted per unit area is given by the Stefan-Boltzmann law. So, as temperature increases, the glow color changes from red to yellow to white to blue. Even as the peak wavelength moves into the ultra-violet, enough radiation continues to be emitted in the blue wavelengths that the body will continue to appear blue. It will never become invisible — indeed, the radiation of visible light increases monotonically with temperature.
The radiance or observed intensity is not a function of direction. Therefore a black body is a perfect Lambertian radiator.
Real objects never behave as full-ideal black bodies, and instead the emitted radiation at a given frequency is a fraction of what the ideal emission would be. The emissivity of a material specifies how well a real body radiates energy as compared with a black body. This emissivity depends on factors such as temperature, emission angle, and wavelength. However, it is typical in engineering to assume that a surface's spectral emissivity and absorptivity do not depend on wavelength, so that the emissivity is a constant. This is known as the grey body assumption.
Due to the rapid fall-off of emitted photons with decreasing energy, a black body at room temperature (300 K) with 1 m² of surface area emits a visible photon every thousand years or so, which is negligible for most purposes.
When dealing with non-black surfaces, the deviations from ideal black-body behavior are determined by both the geometrical structure and the chemical composition, and follow Kirchhoff's Law: emissivity equals absorptivity, so that an object that does not absorb all incident light will also emit less radiation than an ideal black body.
In astronomy, objects such as stars are frequently regarded as black bodies, though this is often a poor approximation. An almost perfect black-body spectrum is exhibited by the cosmic microwave background radiation. Hawking radiation is the hypothetical black-body radiation emitted by black holes.
## Black body simulators
Although a black body is a theoretical object (i.e. emissivity (e) = 1.0), common applications define a source of infrared radiation as a black body when the object approaches an emissivity of 1.0, (typically e = .99 or better). A source of infrared radiation less than .99 is referred to as a greybody. Applications for black body simulators typically include the testing and calibration of infrared systems and infrared sensor equipment.
Super black is an example of such a material, made from a nickel-phosphorus alloy. More recently, a team of Japanese scientists discovered a material even closer to a black body, based on single-walled carbon nanotubes (SWNTs), which absorbs between 97% and 99% of the wavelengths of the light that hits it.
# Equations governing black bodies
## Planck's law of black-body radiation
where
- I(\nu,T)d\nu \, is the amount of energy per unit surface area per unit time per unit solid angle emitted in the frequency range between ν and ν+dν by a black body at temperature T;
- h \, is Planck's constant;
- c \, is the speed of light; and
- k \, is Boltzmann's constant.
## Wien's displacement law
The relationship between the temperature T of a black body, and wavelength \lambda_{max} at which the intensity of the radiation it produces is at a maximum is
- T \lambda_\mathrm{max} = 2.898... \times 10^6 \ \mathrm{nm \ K}. \,
The nanometer is a convenient unit of measure for optical wavelengths. Note that 1 nanometer is equivalent to 10−9 meters.
## Stefan–Boltzmann law
This law states that amount of thermal radiations emitted per second per unit area of the surface of a black body is directly proportional to the fourth power of its absolute temperature.
The total energy radiated per unit area per unit time j^{\star} (in watts per square meter) by a black body is related to its temperature T (in kelvins) and the Stefan–Boltzmann constant \sigma=5.67 x 10^{-8}Wm^{-2}K^{-4} as follows:
# Radiation emitted by a human body
Black-body laws can be applied to human beings. For example, some of a person's energy is radiated away in the form of electromagnetic radiation, most of which is infrared.
The net power radiated is the difference between the power emitted and the power absorbed:
Applying the Stefan–Boltzmann law,
The total surface area of an adult is about 2 m², and the mid- and far-infrared emissivity of skin and most clothing is near unity, as it is for most nonmetallic surfaces. Skin temperature is about 33°C, but clothing reduces the surface temperature to about 28°C when the ambient temperature is 20°C. Hence, the net radiative heat loss is about
The total energy radiated in one day is about 9 MJ (Mega joules), or 2000 kcal (food calories). Basal metabolic rate for a 40-year-old male is about 35 kcal/(m²·h), which is equivalent to 1700 kcal per day assuming the same 2 m² area. However, the mean metabolic rate of sedentary adults is about 50% to 70% greater than their basal rate.
There are other important thermal loss mechanisms, including convection and evaporation. Conduction is negligible since the Nusselt number is much greater than unity. Evaporation (perspiration) is only required if radiation and convection are insufficient to maintain a steady state temperature. Free convection rates are comparable, albeit somewhat lower, than radiative rates. Thus, radiation accounts for about 2/3 of thermal energy loss in cool, still air. Given the approximate nature of many of the assumptions, this can only be taken as a crude estimate. Ambient air motion, causing forced convection, or evaporation reduces the relative importance of radiation as a thermal loss mechanism.
Also, applying Wien's Law to humans, one finds that the peak wavelength of light emitted by a person is
This is why thermal imaging devices designed for human subjects are most sensitive to 7000–14000 nanometers wavelength.
# Temperature relation between a planet and its star
Here is an application of black-body laws to determine the black body temperature of a planet. The surface may be warmer due to the greenhouse effect.
## Factors
The temperature of a planet depends on a few factors:
- Incident radiation (from the Sun, for example)
- Emitted radiation (for example Earth's infrared glow)
- The albedo effect (the fraction of light a planet reflects)
- The greenhouse effect (for planets with an atmosphere)
- Energy generated internally by a planet itself (due to radioactive decay, tidal heating and adiabatic contraction due to cooling).
For the inner planets, incident and emitted radiation have the most significant impact on temperature. This derivation is concerned mainly with that.
## Assumptions
If we assume the following:
- The Sun and the Earth both radiate as spherical black bodies.
- The Earth is in thermal equilibrium.
then we can derive a formula for the relationship between the Earth's temperature and the Sun's surface temperature.
## Derivation
To begin, we use the Stefan–Boltzmann law to find the total power (energy/second) the Sun is emitting:
The Sun emits that power equally in all directions. Because of this, the Earth is hit with only a tiny fraction of it. This is the power from the Sun that the Earth absorbs:
Even though the earth only absorbs as a circular area \pi R^2, it emits equally in all directions as a sphere:
Now, our second assumption was that the earth is in thermal equilibrium, so the power absorbed must equal the power emitted:
Many factors cancel from both sides and this equation can be greatly simplified.
## The result
After canceling of factors, the final result is
In other words, given the assumptions made, the temperature of Earth depends only on the surface temperature of the Sun, the radius of the Sun, the distance between Earth and the Sun and the albedo of Earth.
## Temperature of Earth
If we substitute in the measured values for the Sun,
we'll find the effective temperature of the Earth to be
This is the black body temperature that would cause the same amount of energy emission, as measured from space, while the surface temperature is higher due to the greenhouse effect.
Estimates of the Earth's average albedo vary in the range 0.3–0.4, resulting in different estimated effective temperatures. Estimates are often based on the solar constant (total insolation power density) rather than the temperature, size, and distance of the sun. For example, using 0.4 for albedo, and an insolation of 1400 Wm-2), one obtains an effective temperature of about 245 K.
Similarly using albedo 0.3 and solar constant of 1372 Wm-2), one obtains an effective temperature of 255 K.
# Doppler effect for a moving black body
The Doppler effect is the well known phenomenon describing how observed frequencies of light are "shifted" when a light source is moving relative to the observer. If f is the emitted frequency of a monochromatic light source, it will appear to have frequency f' if it is moving relative to the observer :
where v is the velocity of the source in the observer's rest frame, θ is the angle between the velocity vector and the observer-source direction, and c is the speed of light. This is the fully relativistic formula, and can be simplified for the special cases of objects moving directly towards ( θ = π) or away ( θ = 0) from the observer, and for speeds much less than c.
To calculate the spectrum of a moving black body, then, it seems straightforward to simply apply this formula to each frequency of the blackbody spectrum. However, simply scaling each frequency like this is not enough. We also have to account for the finite size of the viewing aperture, because the solid angle receiving the light also undergoes a Lorentz transformation. (We can subsequently allow the aperture to be arbitrarily small, and the source arbitrarily far, but this cannot be ignored at the outset.) When this effect is included, it is found that a black body at temperature T that is receding with velocity v appears to have a spectrum identical to a stationary black body at temperature T' , given by:
For the case of a source moving directly towards or away from the observer, this reduces to
Here v > 0 indicates a receding source, and v < 0 indicates an approaching source.
This is an important effect in astronomy, where the velocities of stars and galaxies can reach significant fractions of c. An example is found in the cosmic microwave background radiation, which exhibits a dipole anisotropy from the Earth's motion relative to this blackbody radiation field. | Black body
In physics, a black body is an idealized object that absorbs all electromagnetic radiation that falls on it. No electromagnetic radiation passes through it and none is reflected. Because no light (visible electromagnetic radiation) is reflected or transmitted, the object appears black when it is cold. However, a black body emits a temperature-dependent spectrum of light. This thermal radiation from a black body is termed black-body radiation.[1]
At room temperature, black bodies emit mostly infrared light, but as the temperature increases past a few hundred degrees Celsius, black bodies start to emit visible wavelengths, from red, through orange, yellow, and white before ending up at blue, beyond which the emission includes increasing amounts of ultraviolet.
The term "black body" was introduced by Gustav Kirchhoff in 1860.
Black-body emission gives insight into the thermal equilibrium state of a continuous field. In classical physics, each different Fourier mode in thermal equilibrium should have the same energy, leading to the theory of ultraviolet catastrophe that there would be an infinite amount of energy in any continuous field. Black bodies could test the properties of thermal equilibrium because they emit radiation which is distributed thermally. Studying the laws of the black body historically led to quantum mechanics.
# Explanation
In the laboratory, black-body radiation is approximated by the radiation from a small hole entrance to a large cavity, a hohlraum. (this technique leads to the alternative term cavity radiation) Any light entering the hole would have to reflect off the walls of the cavity multiple times before it escaped, in which process it is nearly certain to be absorbed. This occurs regardless of the wavelength of the radiation entering (as long as it is small compared to the hole). The hole, then, is a close approximation of a theoretical black body and, if the cavity is heated, the spectrum of the hole's radiation (i.e., the amount of light emitted from the hole at each wavelength) will be continuous, and will not depend on the material in the cavity (compare with emission spectrum). By a theorem proved by Kirchhoff, this curve depends only on the temperature of the cavity walls.[2]
Calculating this curve was a major challenge in theoretical physics during the late nineteenth century. The problem was finally solved in 1901 by Max Planck as Planck's law of black-body radiation.[3]
By making changes to Wien's radiation law (not to be confused with Wien's displacement law) consistent with thermodynamics and electromagnetism, he found a mathematical formula fitting the experimental data in a satisfactory way. To find a physical interpretation for this formula, Planck had then to assume that the energy of the oscillators in the cavity was quantized (i.e., integer multiples of some quantity). Einstein built on this idea and proposed the quantization of electromagnetic radiation itself in 1905 to explain the photoelectric effect. These theoretical advances eventually resulted in the superseding of classical electromagnetism by quantum electrodynamics. Today, these quanta are called photons and the black-body cavity may be thought of as containing a gas of photons. In addition, it led to the development of quantum probability distributions, called Fermi-Dirac statistics and Bose-Einstein statistics, each applicable to a different class of particle, which are used in quantum mechanics instead of the classical distributions. See also fermion and boson.
The wavelength at which the radiation is strongest is given by Wien's displacement law, and the overall power emitted per unit area is given by the Stefan-Boltzmann law. So, as temperature increases, the glow color changes from red to yellow to white to blue. Even as the peak wavelength moves into the ultra-violet, enough radiation continues to be emitted in the blue wavelengths that the body will continue to appear blue. It will never become invisible — indeed, the radiation of visible light increases monotonically with temperature.[4]
The radiance or observed intensity is not a function of direction. Therefore a black body is a perfect Lambertian radiator.
Real objects never behave as full-ideal black bodies, and instead the emitted radiation at a given frequency is a fraction of what the ideal emission would be. The emissivity of a material specifies how well a real body radiates energy as compared with a black body. This emissivity depends on factors such as temperature, emission angle, and wavelength. However, it is typical in engineering to assume that a surface's spectral emissivity and absorptivity do not depend on wavelength, so that the emissivity is a constant. This is known as the grey body assumption.
Due to the rapid fall-off of emitted photons with decreasing energy, a black body at room temperature (300 K) with 1 m² of surface area emits a visible photon every thousand years or so, which is negligible for most purposes.
When dealing with non-black surfaces, the deviations from ideal black-body behavior are determined by both the geometrical structure and the chemical composition, and follow Kirchhoff's Law: emissivity equals absorptivity, so that an object that does not absorb all incident light will also emit less radiation than an ideal black body.
In astronomy, objects such as stars are frequently regarded as black bodies, though this is often a poor approximation. An almost perfect black-body spectrum is exhibited by the cosmic microwave background radiation. Hawking radiation is the hypothetical black-body radiation emitted by black holes.
## Black body simulators
Although a black body is a theoretical object (i.e. emissivity (e) = 1.0), common applications define a source of infrared radiation as a black body when the object approaches an emissivity of 1.0, (typically e = .99 or better). A source of infrared radiation less than .99 is referred to as a greybody.[5] Applications for black body simulators typically include the testing and calibration of infrared systems and infrared sensor equipment.
Super black is an example of such a material, made from a nickel-phosphorus alloy. More recently, a team of Japanese scientists discovered a material even closer to a black body, based on single-walled carbon nanotubes (SWNTs), which absorbs between 97% and 99% of the wavelengths of the light that hits it.[6]
# Equations governing black bodies
## Planck's law of black-body radiation
where
- <math>I(\nu,T)d\nu \,</math> is the amount of energy per unit surface area per unit time per unit solid angle emitted in the frequency range between ν and ν+dν by a black body at temperature T;
- <math>h \,</math> is Planck's constant;
- <math>c \,</math> is the speed of light; and
- <math>k \,</math> is Boltzmann's constant.
## Wien's displacement law
The relationship between the temperature T of a black body, and wavelength <math>\lambda_{max}</math> at which the intensity of the radiation it produces is at a maximum is
- <math>T \lambda_\mathrm{max} = 2.898... \times 10^6 \ \mathrm{nm \ K}. \,</math>
The nanometer is a convenient unit of measure for optical wavelengths. Note that 1 nanometer is equivalent to 10−9 meters.
## Stefan–Boltzmann law
This law states that amount of thermal radiations emitted per second per unit area of the surface of a black body is directly proportional to the fourth power of its absolute temperature.
The total energy radiated per unit area per unit time <math>j^{\star}</math> (in watts per square meter) by a black body is related to its temperature T (in kelvins) and the Stefan–Boltzmann constant <math>\sigma=5.67 x 10^{-8}Wm^{-2}K^{-4}</math> as follows:
# Radiation emitted by a human body
Black-body laws can be applied to human beings. For example, some of a person's energy is radiated away in the form of electromagnetic radiation, most of which is infrared.
The net power radiated is the difference between the power emitted and the power absorbed:
Applying the Stefan–Boltzmann law,
The total surface area of an adult is about 2 m², and the mid- and far-infrared emissivity of skin and most clothing is near unity, as it is for most nonmetallic surfaces.[7][8] Skin temperature is about 33°C,[9] but clothing reduces the surface temperature to about 28°C when the ambient temperature is 20°C.[10] Hence, the net radiative heat loss is about
The total energy radiated in one day is about 9 MJ (Mega joules), or 2000 kcal (food calories). Basal metabolic rate for a 40-year-old male is about 35 kcal/(m²·h),[11] which is equivalent to 1700 kcal per day assuming the same 2 m² area. However, the mean metabolic rate of sedentary adults is about 50% to 70% greater than their basal rate.[12]
There are other important thermal loss mechanisms, including convection and evaporation. Conduction is negligible since the Nusselt number is much greater than unity. Evaporation (perspiration) is only required if radiation and convection are insufficient to maintain a steady state temperature. Free convection rates are comparable, albeit somewhat lower, than radiative rates.[13] Thus, radiation accounts for about 2/3 of thermal energy loss in cool, still air. Given the approximate nature of many of the assumptions, this can only be taken as a crude estimate. Ambient air motion, causing forced convection, or evaporation reduces the relative importance of radiation as a thermal loss mechanism.
Also, applying Wien's Law to humans, one finds that the peak wavelength of light emitted by a person is
This is why thermal imaging devices designed for human subjects are most sensitive to 7000–14000 nanometers wavelength.
# Temperature relation between a planet and its star
Here is an application of black-body laws to determine the black body temperature of a planet. The surface may be warmer due to the greenhouse effect.[14]
## Factors
The temperature of a planet depends on a few factors:
- Incident radiation (from the Sun, for example)
- Emitted radiation (for example Earth's infrared glow)
- The albedo effect (the fraction of light a planet reflects)
- The greenhouse effect (for planets with an atmosphere)
- Energy generated internally by a planet itself (due to radioactive decay, tidal heating and adiabatic contraction due to cooling).
For the inner planets, incident and emitted radiation have the most significant impact on temperature. This derivation is concerned mainly with that.
## Assumptions
If we assume the following:
- The Sun and the Earth both radiate as spherical black bodies.
- The Earth is in thermal equilibrium.
then we can derive a formula for the relationship between the Earth's temperature and the Sun's surface temperature.
## Derivation
To begin, we use the Stefan–Boltzmann law to find the total power (energy/second) the Sun is emitting:
The Sun emits that power equally in all directions. Because of this, the Earth is hit with only a tiny fraction of it. This is the power from the Sun that the Earth absorbs:
Even though the earth only absorbs as a circular area <math>\pi R^2</math>, it emits equally in all directions as a sphere:
Now, our second assumption was that the earth is in thermal equilibrium, so the power absorbed must equal the power emitted:
Many factors cancel from both sides and this equation can be greatly simplified.
## The result
After canceling of factors, the final result is
In other words, given the assumptions made, the temperature of Earth depends only on the surface temperature of the Sun, the radius of the Sun, the distance between Earth and the Sun and the albedo of Earth.
## Temperature of Earth
If we substitute in the measured values for the Sun,[citation needed]
we'll find the effective temperature of the Earth to be
This is the black body temperature that would cause the same amount of energy emission, as measured from space, while the surface temperature is higher due to the greenhouse effect.
Estimates of the Earth's average albedo vary in the range 0.3–0.4, resulting in different estimated effective temperatures. Estimates are often based on the solar constant (total insolation power density) rather than the temperature, size, and distance of the sun. For example, using 0.4 for albedo, and an insolation of 1400 Wm-2), one obtains an effective temperature of about 245 K.[15]
Similarly using albedo 0.3 and solar constant of 1372 Wm-2), one obtains an effective temperature of 255 K. [16][17]
# Doppler effect for a moving black body
The Doppler effect is the well known phenomenon describing how observed frequencies of light are "shifted" when a light source is moving relative to the observer. If f is the emitted frequency of a monochromatic light source, it will appear to have frequency f' if it is moving relative to the observer :
where v is the velocity of the source in the observer's rest frame, θ is the angle between the velocity vector and the observer-source direction, and c is the speed of light.[18] This is the fully relativistic formula, and can be simplified for the special cases of objects moving directly towards ( θ = π) or away ( θ = 0) from the observer, and for speeds much less than c.
To calculate the spectrum of a moving black body, then, it seems straightforward to simply apply this formula to each frequency of the blackbody spectrum. However, simply scaling each frequency like this is not enough. We also have to account for the finite size of the viewing aperture, because the solid angle receiving the light also undergoes a Lorentz transformation. (We can subsequently allow the aperture to be arbitrarily small, and the source arbitrarily far, but this cannot be ignored at the outset.) When this effect is included, it is found that a black body at temperature T that is receding with velocity v appears to have a spectrum identical to a stationary black body at temperature T' , given by:[19]
For the case of a source moving directly towards or away from the observer, this reduces to
Here v > 0 indicates a receding source, and v < 0 indicates an approaching source.
This is an important effect in astronomy, where the velocities of stars and galaxies can reach significant fractions of c. An example is found in the cosmic microwave background radiation, which exhibits a dipole anisotropy from the Earth's motion relative to this blackbody radiation field. | https://www.wikidoc.org/index.php/Black_body | |
c2eb7f9eee2ab868709b9616cf16db640f4d0872 | wikidoc | Blindsight | Blindsight
# Overview
Blindsight is a phenomenon in which people who are perceptually blind in a certain area of their visual field demonstrate some response to visual stimuli, without any qualitative experience ('qualia'). In Type 1 blindsight subjects have no awareness whatsoever of any stimuli, but yet are able to predict, at levels significantly above chance, aspects of a visual stimulus, such as location, or type of movement, often in a forced-response or guessing situation. Type 2 blindsight is when subjects have some awareness of, for example, movement within the blind area, but no visual percept, or quale. This may be caused by, for example, the person being aware of their eyes' tracking motion which will function normally. Blindsight is caused by injury to the part of the brain responsible for vision.
# Pathophysiology
Visual processing in the brain goes through a series of stages. Destruction of the first visual cortical area, primary visual cortex (or V1 or striate cortex) leads to blindness in the part of the visual field that corresponds to the damaged cortical representation. The area of blindness - known as a scotoma - is in the visual field opposite the damaged hemisphere and can vary from a small area up to the entire hemifield.
Although individuals with damage to V1 are not consciously aware of stimuli presented in their blind field, Lawrence Weiskrantz and colleagues showed in the early 1970s that if forced to guess about whether a stimulus is present in their blind field, some observers do better than chance. This ability to detect stimuli that the observer is not conscious of can extend to discrimination of the type of stimulus (for example, whether an 'X' or 'O' has been presented in the blind field). This general phenomenon has been dubbed "blindsight".
It is unsurprising from a neurological viewpoint that damage to V1 leads to reports of blindness. Visual processing occurs in the brain in a hierarchical series of stages (with much crosstalk and feedback between areas). As V1 is the first cortical area in this hierarchy, any damage to V1 severely limits visual information passing from the retina, via the LGN and then V1, to higher cortical areas. However, the route from the retina through V1 is not the only visual pathway into the cortex, though it is by far the largest; it is commonly thought that the residual performance of people exhibiting blindsight is due to preserved pathways into the extrastriate cortex that bypass V1. What is surprising is that activity in these extrastriate areas is apparently insufficient to support visual awareness in the absence of V1.
Blindsight may be thought of as a converse of the form of anosognosia known as Anton's syndrome, in which there is full cortical blindness along with the confabulation of visual experience.
Notable medical fiction authors including Robin Cook write extensively on this condition . Other medical fiction authors include Tess Gerritsen; Brett Chatz; Patricia Cornwell and Michael Palmer.Template:ClarifymeTemplate:Specify | Blindsight
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Blindsight is a phenomenon in which people who are perceptually blind in a certain area of their visual field demonstrate some response to visual stimuli, without any qualitative experience ('qualia'). In Type 1 blindsight subjects have no awareness whatsoever of any stimuli, but yet are able to predict, at levels significantly above chance, aspects of a visual stimulus, such as location, or type of movement, often in a forced-response or guessing situation. Type 2 blindsight is when subjects have some awareness of, for example, movement within the blind area, but no visual percept, or quale. This may be caused by, for example, the person being aware of their eyes' tracking motion which will function normally. Blindsight is caused by injury to the part of the brain responsible for vision.
# Pathophysiology
Visual processing in the brain goes through a series of stages. Destruction of the first visual cortical area, primary visual cortex (or V1 or striate cortex) leads to blindness in the part of the visual field that corresponds to the damaged cortical representation. The area of blindness - known as a scotoma - is in the visual field opposite the damaged hemisphere and can vary from a small area up to the entire hemifield.
Although individuals with damage to V1 are not consciously aware of stimuli presented in their blind field, Lawrence Weiskrantz and colleagues showed in the early 1970s that if forced to guess about whether a stimulus is present in their blind field, some observers do better than chance. This ability to detect stimuli that the observer is not conscious of can extend to discrimination of the type of stimulus (for example, whether an 'X' or 'O' has been presented in the blind field). This general phenomenon has been dubbed "blindsight".
It is unsurprising from a neurological viewpoint that damage to V1 leads to reports of blindness. Visual processing occurs in the brain in a hierarchical series of stages (with much crosstalk and feedback between areas). As V1 is the first cortical area in this hierarchy, any damage to V1 severely limits visual information passing from the retina, via the LGN and then V1, to higher cortical areas. However, the route from the retina through V1 is not the only visual pathway into the cortex, though it is by far the largest; it is commonly thought that the residual performance of people exhibiting blindsight is due to preserved pathways into the extrastriate cortex that bypass V1. What is surprising is that activity in these extrastriate areas is apparently insufficient to support visual awareness in the absence of V1.
Blindsight may be thought of as a converse of the form of anosognosia known as Anton's syndrome, in which there is full cortical blindness along with the confabulation of visual experience.
Notable medical fiction authors including Robin Cook write extensively on this condition <cite: Blindsight>. Other medical fiction authors include Tess Gerritsen; Brett Chatz; Patricia Cornwell and Michael Palmer.Template:ClarifymeTemplate:Specify | https://www.wikidoc.org/index.php/Blindsight | |
26875e379260e232085e340ad106ea2506dbf210 | wikidoc | Blood bank | Blood bank
A blood bank is a cache or bank of blood or blood components, gathered as a result of blood donation, stored and preserved for later use in blood transfusions.
An early development leading to the establishment of blood banks occurred in 1915, when Richard Lewison of Mount Sinai Hospital, New York initiated the use of sodium citrate as an anticoagulant. This discovery transformed the blood transfusion procedure from direct (vein-to-vein) to indirect. In the same year, Richard Weil demonstrated the feasibility of refrigerated storage of anticoagulated blood. The introduction of a citrate-glucose solution by Francis Peyton Rous and JR Turner two years later permitted storage of blood in containers for several days, thus opening the way for the first "blood depot" established in Britain during World War I. Oswald Hope Robertson, a medical researcher and U.S. Army officer who established the depots, is now recognized as the creator of the first blood bank.
By the mid-1930s, the Soviet Union had set up a system of at least sixty large blood centers and more than 500 subsidiary ones, all storing "canned" blood and shipping it to all corners of the country. News of the Soviet experience traveled to America, where in 1937 Bernard Fantus, director of therapeutics at the Cook County Hospital in Chicago, established the first hospital blood bank in the United States. In creating a hospital laboratory that preserved and stored donor blood, Fantus originated the term "blood bank." Within a few years, hospital and community blood banks were established across the United States. Willem Johan Kolff organised the first blood bank in Europe (in 1940).
An important breakthrough came in 1939-40 when Karl Landsteiner, Alex Wiener, Philip Levine, and R.E. Stetson discovered the Rh blood group system, which was found to be the cause of the majority of transfusion reactions up to that time. Three years later, the introduction by J.F. Loutit and Patrick L. Mollison of acid-citrate-dextrose (ACD) solution, which reduces the volume of anticoagulant, permitted transfusions of greater volumes of blood and allowed longer term storage.
Carl Walter and W.P. Murphy, Jr., introduced the plastic bag for blood collection in 1950. Replacing breakable glass bottles with durable plastic bags allowed for the evolution of a collection system capable of safe and easy preparation of multiple blood components from a single unit of Whole Blood.
Further extending the shelf life of stored blood was an anticoagulant preservative, CPDA-1, introduced in 1979. It increased the blood supply and facilitated resource sharing among blood banks. Newer solutions contain adenine and extend the shelf life of red cells to 42 days.
Freezing of Red Blood Cells is done by combining them with a solution of glycerol to prevent ice crystal formation, and frozen Red Blood Cells have a stated shelf life of ten years. The process is expensive and time-consuming, and very few blood banks maintain a stock of frozen Red Blood Cells.
Plasma, usually Fresh Frozen Plasma (FFP), can be stored for up to a year if kept frozen. Platelets are typically stored for only five days since they are stored at room temperature and are considered to be at high risk for bacterial contamination. Experimental protocols involving bacteriological screening exist to extend the shelf life to seven days. The AABB, formerly the American Association of Blood Banks, maintains a Circular of Information which details the use and other important information regarding blood products.(Available in PDF format here) | Blood bank
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
A blood bank is a cache or bank of blood or blood components, gathered as a result of blood donation, stored and preserved for later use in blood transfusions.
An early development leading to the establishment of blood banks occurred in 1915, when Richard Lewison of Mount Sinai Hospital, New York initiated the use of sodium citrate as an anticoagulant. This discovery transformed the blood transfusion procedure from direct (vein-to-vein) to indirect. In the same year, Richard Weil demonstrated the feasibility of refrigerated storage of anticoagulated blood. The introduction of a citrate-glucose solution by Francis Peyton Rous and JR Turner two years later permitted storage of blood in containers for several days, thus opening the way for the first "blood depot" established in Britain during World War I. Oswald Hope Robertson, a medical researcher and U.S. Army officer who established the depots, is now recognized as the creator of the first blood bank.
By the mid-1930s, the Soviet Union had set up a system of at least sixty large blood centers and more than 500 subsidiary ones, all storing "canned" blood and shipping it to all corners of the country. News of the Soviet experience traveled to America, where in 1937 Bernard Fantus, director of therapeutics at the Cook County Hospital in Chicago, established the first hospital blood bank in the United States. In creating a hospital laboratory that preserved and stored donor blood, Fantus originated the term "blood bank." Within a few years, hospital and community blood banks were established across the United States. Willem Johan Kolff organised the first blood bank in Europe (in 1940).
An important breakthrough came in 1939-40 when Karl Landsteiner, Alex Wiener, Philip Levine, and R.E. Stetson discovered the Rh blood group system, which was found to be the cause of the majority of transfusion reactions up to that time. Three years later, the introduction by J.F. Loutit and Patrick L. Mollison of acid-citrate-dextrose (ACD) solution, which reduces the volume of anticoagulant, permitted transfusions of greater volumes of blood and allowed longer term storage.
Carl Walter and W.P. Murphy, Jr., introduced the plastic bag for blood collection in 1950. Replacing breakable glass bottles with durable plastic bags allowed for the evolution of a collection system capable of safe and easy preparation of multiple blood components from a single unit of Whole Blood.
Further extending the shelf life of stored blood was an anticoagulant preservative, CPDA-1, introduced in 1979. It increased the blood supply and facilitated resource sharing among blood banks. Newer solutions contain adenine and extend the shelf life of red cells to 42 days.
Freezing of Red Blood Cells is done by combining them with a solution of glycerol to prevent ice crystal formation, and frozen Red Blood Cells have a stated shelf life of ten years. The process is expensive and time-consuming, and very few blood banks maintain a stock of frozen Red Blood Cells.
Plasma, usually Fresh Frozen Plasma (FFP), can be stored for up to a year if kept frozen.[1] Platelets are typically stored for only five days since they are stored at room temperature and are considered to be at high risk for bacterial contamination. Experimental protocols involving bacteriological screening exist to extend the shelf life to seven days. The AABB, formerly the American Association of Blood Banks, maintains a Circular of Information which details the use and other important information regarding blood products.(Available in PDF format here) | https://www.wikidoc.org/index.php/Blood_bank | |
b992cb1cab44eb648921a54232cd612589986164 | wikidoc | Blood cell | Blood cell
# Overview
A blood cell (also called blood corpuscle) is any cell of any type normally found in blood. In mammals, these fall into three general categories:
- Red blood cells
- White blood cells
- Platelets
Together, these three kinds of blood cells sum up for a total 45% of blood tissue (55% is plasma).
# Disorders
A decrease in number of blood cells is called cytopenia. An increase, on the other hand, is called polycythemia. | Blood cell
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
A blood cell (also called blood corpuscle) is any cell of any type normally found in blood. In mammals, these fall into three general categories:
- Red blood cells
- White blood cells
- Platelets
Together, these three kinds of blood cells sum up for a total 45% of blood tissue (55% is plasma).
# Disorders
A decrease in number of blood cells is called cytopenia. An increase, on the other hand, is called polycythemia.[1] | https://www.wikidoc.org/index.php/Blood_cell | |
f7e8a3d15d033055c8d40ff9d921a1e07e562ff3 | wikidoc | Hematology | Hematology
# Overview
Hematology (American English) or haematology (British English) is the branch of biology (physiology), pathology, clinical laboratory, internal medicine, and pediatrics that is concerned with the study of blood, the blood-forming organs, and blood diseases. Hematology includes the study of etiology, diagnosis, treatment, prognosis, and prevention of blood diseases. The lab work that goes into the study of blood is performed by a Medical Technologist.
Blood diseases affect the production of blood and its components, such as blood cells, haemoglobin, blood proteins, the mechanism of coagulation, etc.
# Hematologists and Hematopathologists
Physicians specialized in hematology are known as hematologists. Their routine work mainly includes the care and treatment of patients with hematological diseases, although some may also work at the hematology laboratory viewing blood films and bone marrow slides under the microscope, interpreting various hematological test results. In some institutions, hematologists also manage the hematology laboratory. Physicians who mainly work in hematology laboratories, and most commonly manage it, are pathologists specialized in the diagnosis of hematological diseases, referred to as hematopathologists. Hematologists and hematopathologists generally work in conjunction to formulate a diagnosis and deliver the most appropiate therapy if needed. Hematology is a distinct subspecialty of internal medicine, separate from but overlapping with the subspecialty of medical oncology. Hematologists may specialise further or have special interests, for example in:
- treating bleeding disorders such as hemophilia and idiopathic thrombocytopenic purpura
- treating hematological malignacies such as lymphoma and leukemia (onco hematology)
- treating hemoglobinopathies
- in the science of blood transfusion and the work of a blood bank
(Hema- comes from the Greek word "`'aima" meaning "blood", -logy comes from the Greek "logos" meaning word. [referring to the first root word, as in biology, with bio- meaning life and, of course
# Common basic clinical hematology tests
In a clinical laboratory the hematology department performs numerous different tests on blood. The most commonly performed test is the complete blood count (CBC) also called full blood count (FBC), which includes; white blood cell count, platelet count, hemoglobin level and several parameters of red blood cells. Coagulation is a sub-speciality of hematology; basic general coagulation tests are the prothrombin time (PT) and partial thromboplastin time (PTT). Another common hematology test in the erythrocyte sedimentation rate (ESR).
In a blood bank the Coombs test is the most commonly performed test.
(Images shown below are courtesy of Melih Aktan MD, Istanbul Medical Faculty - Turkey, and Kyoto University - Japan, and Hospital Universitario La Fe Servicio Hematologia)
- Normal bone marrow
- Normal bone marrow
- Normal peripheral blood cells
- Normal spleen
- Monocyte
- Monocyte
- Monocyte TEM
- Myeloblast
- Neutrophil
- Neutrophil and monocyte
- Neutrophil granulocyte and lymphocyte
- Neutrophil granulocytes
- Lymphocyte and erytrocyte
- Lymphocytes and Thrombocytes
- Neutrophil granulocytes
- Neutrophil granulocytes
- Neutrophil, basophil and active lymphocyte
- Spherocyte
- Spherocyte
- Spherocyte
- Elliptocyte
- Elliptocyte
- Echinocyte
- Eosinophil
- Eosinophil and lymphocyte
- Erythroblast
- Erythrocyte rouleaux formation
- Erythrocyte rouleaux formation
- Erytrocytes
- Erytrocytes
- Erytrocytes
- Erytrocytes
- Erytrocytes
- Fragmentated erytrocytes
- Granulocyte and metamyelocyte
# Hematology as basic medical science
- Blood
Venous blood
Venipuncture
Hemopoiesis
Blood tests
Cord blood
- Venous blood
- Venipuncture
- Hemopoiesis
- Blood tests
- Cord blood
- Red blood cells
Erythropoiesis
Erythropoietin
Iron metabolism
Hemoglobin
Glycolysis
Pentose phosphate pathway
- Erythropoiesis
- Erythropoietin
- Iron metabolism
- Hemoglobin
- Glycolysis
- Pentose phosphate pathway
- Reticuloendothelial system
Bone marrow
Spleen
Liver
- Bone marrow
- Spleen
- Liver
- Lymphatic system
- Blood transfusion
Blood plasma
Blood bank
Blood donors
Blood groups
- Blood plasma
- Blood bank
- Blood donors
- Blood groups
- Haemostasis
Coagulation
Vitamin K
- Coagulation
- Vitamin K
- Complement system
Immunoglobulins
- Immunoglobulins
# Classification of hematologic diseases
- Hemoglobinopathies (congenital abnormality of the hemoglobin molecule or of the rate of hemoglobin synthesis)
Sickle-cell disease
Thalassemia
Methemoglobinemia
- Sickle-cell disease
- Thalassemia
- Methemoglobinemia
- Anemias (lack of red blood cells or hemoglobin)
Iron deficiency anemia
Megaloblastic anemia
Vitamin B12 deficiency
Pernicious anemia
Folate deficiency
Hemolytic anemias (destruction of red blood cells)
Genetic disorders of RBC membrane
Hereditary spherocytosis
Hereditary elliptocytosis
Genetic disorders of RBC metabolism
Glucose-6-phosphate dehydrogenase deficiency (G6PD)
Pyruvate kinase deficiency
Immune mediated hemolytic anaemia (direct Coombs test is positive)
Autoimmune hemolytic anemia
Warm antibody autoimmune hemolytic anemia
Idiopathic
Systemic lupus erythematosus (SLE)
Evans' syndrome (antiplatelet antibodies and haemolytic antibodies)
Cold antibody autoimmune hemolytic anemia
Idiopathic cold hemagglutinin syndrome
Infectious mononucleosis
Paroxysmal cold hemoglobinuria (rare)
Alloimmune hemolytic anemia
Hemolytic disease of the newborn (HDN)
Rh disease (Rh D)
ABO hemolytic disease of the newborn
Anti-Kell hemolytic disease of the newborn
Rhesus c hemolytic disease of the newborn
Rhesus E hemolytic disease of the newborn
Other blood group incompatibility (RhC, Rhe, Kid, Duffy, MN, P and others)
Drug induced immune mediated hemolytic anaemia
Penicillin (high dose)
Methyldopa
Hemoglobinopathies (where these is an unstable or crystalline hemoglobin)
Paroxysmal nocturnal hemoglobinuria (rare acquired clonal disorder of red blood cell surface proteins)
Direct physical damage to RBCs
Microangiopathic hemolytic anemia
Secondary to artificial heart valve(s)
Aplastic anemia
Fanconi anemia
Diamond-Blackfan anemia
Acquired pure red cell aplasia
- Iron deficiency anemia
- Megaloblastic anemia
Vitamin B12 deficiency
Pernicious anemia
Folate deficiency
- Vitamin B12 deficiency
Pernicious anemia
- Pernicious anemia
- Folate deficiency
- Hemolytic anemias (destruction of red blood cells)
Genetic disorders of RBC membrane
Hereditary spherocytosis
Hereditary elliptocytosis
Genetic disorders of RBC metabolism
Glucose-6-phosphate dehydrogenase deficiency (G6PD)
Pyruvate kinase deficiency
Immune mediated hemolytic anaemia (direct Coombs test is positive)
Autoimmune hemolytic anemia
Warm antibody autoimmune hemolytic anemia
Idiopathic
Systemic lupus erythematosus (SLE)
Evans' syndrome (antiplatelet antibodies and haemolytic antibodies)
Cold antibody autoimmune hemolytic anemia
Idiopathic cold hemagglutinin syndrome
Infectious mononucleosis
Paroxysmal cold hemoglobinuria (rare)
Alloimmune hemolytic anemia
Hemolytic disease of the newborn (HDN)
Rh disease (Rh D)
ABO hemolytic disease of the newborn
Anti-Kell hemolytic disease of the newborn
Rhesus c hemolytic disease of the newborn
Rhesus E hemolytic disease of the newborn
Other blood group incompatibility (RhC, Rhe, Kid, Duffy, MN, P and others)
Drug induced immune mediated hemolytic anaemia
Penicillin (high dose)
Methyldopa
Hemoglobinopathies (where these is an unstable or crystalline hemoglobin)
Paroxysmal nocturnal hemoglobinuria (rare acquired clonal disorder of red blood cell surface proteins)
Direct physical damage to RBCs
Microangiopathic hemolytic anemia
Secondary to artificial heart valve(s)
- Genetic disorders of RBC membrane
Hereditary spherocytosis
Hereditary elliptocytosis
- Hereditary spherocytosis
- Hereditary elliptocytosis
- Genetic disorders of RBC metabolism
Glucose-6-phosphate dehydrogenase deficiency (G6PD)
Pyruvate kinase deficiency
- Glucose-6-phosphate dehydrogenase deficiency (G6PD)
- Pyruvate kinase deficiency
- Immune mediated hemolytic anaemia (direct Coombs test is positive)
Autoimmune hemolytic anemia
Warm antibody autoimmune hemolytic anemia
Idiopathic
Systemic lupus erythematosus (SLE)
Evans' syndrome (antiplatelet antibodies and haemolytic antibodies)
Cold antibody autoimmune hemolytic anemia
Idiopathic cold hemagglutinin syndrome
Infectious mononucleosis
Paroxysmal cold hemoglobinuria (rare)
Alloimmune hemolytic anemia
Hemolytic disease of the newborn (HDN)
Rh disease (Rh D)
ABO hemolytic disease of the newborn
Anti-Kell hemolytic disease of the newborn
Rhesus c hemolytic disease of the newborn
Rhesus E hemolytic disease of the newborn
Other blood group incompatibility (RhC, Rhe, Kid, Duffy, MN, P and others)
Drug induced immune mediated hemolytic anaemia
Penicillin (high dose)
Methyldopa
- Autoimmune hemolytic anemia
Warm antibody autoimmune hemolytic anemia
Idiopathic
Systemic lupus erythematosus (SLE)
Evans' syndrome (antiplatelet antibodies and haemolytic antibodies)
Cold antibody autoimmune hemolytic anemia
Idiopathic cold hemagglutinin syndrome
Infectious mononucleosis
Paroxysmal cold hemoglobinuria (rare)
- Warm antibody autoimmune hemolytic anemia
Idiopathic
Systemic lupus erythematosus (SLE)
Evans' syndrome (antiplatelet antibodies and haemolytic antibodies)
- Idiopathic
- Systemic lupus erythematosus (SLE)
- Evans' syndrome (antiplatelet antibodies and haemolytic antibodies)
- Cold antibody autoimmune hemolytic anemia
Idiopathic cold hemagglutinin syndrome
Infectious mononucleosis
Paroxysmal cold hemoglobinuria (rare)
- Idiopathic cold hemagglutinin syndrome
- Infectious mononucleosis
- Paroxysmal cold hemoglobinuria (rare)
- Alloimmune hemolytic anemia
Hemolytic disease of the newborn (HDN)
Rh disease (Rh D)
ABO hemolytic disease of the newborn
Anti-Kell hemolytic disease of the newborn
Rhesus c hemolytic disease of the newborn
Rhesus E hemolytic disease of the newborn
Other blood group incompatibility (RhC, Rhe, Kid, Duffy, MN, P and others)
- Hemolytic disease of the newborn (HDN)
Rh disease (Rh D)
ABO hemolytic disease of the newborn
Anti-Kell hemolytic disease of the newborn
Rhesus c hemolytic disease of the newborn
Rhesus E hemolytic disease of the newborn
Other blood group incompatibility (RhC, Rhe, Kid, Duffy, MN, P and others)
- Rh disease (Rh D)
- ABO hemolytic disease of the newborn
- Anti-Kell hemolytic disease of the newborn
- Rhesus c hemolytic disease of the newborn
- Rhesus E hemolytic disease of the newborn
- Other blood group incompatibility (RhC, Rhe, Kid, Duffy, MN, P and others)
- Drug induced immune mediated hemolytic anaemia
Penicillin (high dose)
Methyldopa
- Penicillin (high dose)
- Methyldopa
- Hemoglobinopathies (where these is an unstable or crystalline hemoglobin)
- Paroxysmal nocturnal hemoglobinuria (rare acquired clonal disorder of red blood cell surface proteins)
- Direct physical damage to RBCs
Microangiopathic hemolytic anemia
Secondary to artificial heart valve(s)
- Microangiopathic hemolytic anemia
- Secondary to artificial heart valve(s)
- Aplastic anemia
Fanconi anemia
Diamond-Blackfan anemia
Acquired pure red cell aplasia
- Fanconi anemia
- Diamond-Blackfan anemia
- Acquired pure red cell aplasia
- Decreased numbers of cells
Myelodysplastic syndrome
Myelofibrosis
Neutropenia (decrease in the number of neutrophils)
Agranulocytosis
Glanzmann's thrombasthenia
Thrombocytopenia (decrease in the number of platelets)
Idiopathic thrombocytopenic purpura (ITP)
Thrombotic thrombocytopenic purpura (TTP)
Heparin-induced thrombocytopenia (HIT)
- Myelodysplastic syndrome
- Myelofibrosis
- Neutropenia (decrease in the number of neutrophils)
- Agranulocytosis
- Glanzmann's thrombasthenia
- Thrombocytopenia (decrease in the number of platelets)
Idiopathic thrombocytopenic purpura (ITP)
Thrombotic thrombocytopenic purpura (TTP)
Heparin-induced thrombocytopenia (HIT)
- Idiopathic thrombocytopenic purpura (ITP)
- Thrombotic thrombocytopenic purpura (TTP)
- Heparin-induced thrombocytopenia (HIT)
- Myeloproliferative disorders (Increased numbers of cells)
Polycythemia vera (increase in the number of cells in general)
Leukocytosis (increase in the number of white blood cells)
Thrombocytosis (increase in the number of platelets)
Myeloproliferative disorder
- Polycythemia vera (increase in the number of cells in general)
- Leukocytosis (increase in the number of white blood cells)
- Thrombocytosis (increase in the number of platelets)
- Myeloproliferative disorder
- Hematological malignancies
Lymphomas
Hodgkin's disease
Non-Hodgkin's lymphoma{includes the next eight entries}
Burkitt's lymphoma
Anaplastic large cell lymphoma
Splenic marginal zone lymphoma
Hepatosplenic T-cell lymphoma
Angioimmunoblastic T-cell lymphoma (AILT)
Myelomas
Multiple myeloma
Waldenström macroglobulinemia
Plasmacytoma
Leukemias
Acute lymphocytic leukemia (ALL)
Chronic lymphocytic leukemia (CLL){now included in theCLL/SCLL type NHL}
Acute myelogenous leukemia (AML)
Chronic myelogenous leukemia (CML)
T-cell prolymphocytic leukemia (T-PLL)
B-cell prolymphocytic leukemia (B-PLL)
Chronic neutrophilic leukemia (CNL)
Hairy cell leukemia (HCL)
T-cell large granular lymphocyte leukemia (T-LGL)
Aggressive NK-cell leukemia
- Lymphomas
Hodgkin's disease
Non-Hodgkin's lymphoma{includes the next eight entries}
Burkitt's lymphoma
Anaplastic large cell lymphoma
Splenic marginal zone lymphoma
Hepatosplenic T-cell lymphoma
Angioimmunoblastic T-cell lymphoma (AILT)
- Hodgkin's disease
- Non-Hodgkin's lymphoma{includes the next eight entries}
- Burkitt's lymphoma
- Anaplastic large cell lymphoma
- Splenic marginal zone lymphoma
- Hepatosplenic T-cell lymphoma
- Angioimmunoblastic T-cell lymphoma (AILT)
- Myelomas
Multiple myeloma
Waldenström macroglobulinemia
- Multiple myeloma
- Waldenström macroglobulinemia
- Plasmacytoma
- Leukemias
Acute lymphocytic leukemia (ALL)
Chronic lymphocytic leukemia (CLL){now included in theCLL/SCLL type NHL}
Acute myelogenous leukemia (AML)
Chronic myelogenous leukemia (CML)
T-cell prolymphocytic leukemia (T-PLL)
B-cell prolymphocytic leukemia (B-PLL)
Chronic neutrophilic leukemia (CNL)
Hairy cell leukemia (HCL)
T-cell large granular lymphocyte leukemia (T-LGL)
Aggressive NK-cell leukemia
- Acute lymphocytic leukemia (ALL)
- Chronic lymphocytic leukemia (CLL){now included in theCLL/SCLL type NHL}
- Acute myelogenous leukemia (AML)
- Chronic myelogenous leukemia (CML)
- T-cell prolymphocytic leukemia (T-PLL)
- B-cell prolymphocytic leukemia (B-PLL)
- Chronic neutrophilic leukemia (CNL)
- Hairy cell leukemia (HCL)
- T-cell large granular lymphocyte leukemia (T-LGL)
- Aggressive NK-cell leukemia
- Coagulopathies (disorders of bleeding and coagulation)
Thrombocytosis
Recurrent thrombosis
Disseminated intravascular coagulation
Disorders of clotting proteins
Hemophilia
Hemophilia A
Hemophilia B (also known as Christmas disease)
Hemophilia C
Von Willebrand disease
Disseminated intravascular coagulation
Protein S deficiency
Antiphospholipid syndrome
Disorders of platelets
Thrombocytopenia
Glanzmann's thrombasthenia
Wiskott-Aldrich syndrome
- Thrombocytosis
- Recurrent thrombosis
- Disseminated intravascular coagulation
- Disorders of clotting proteins
Hemophilia
Hemophilia A
Hemophilia B (also known as Christmas disease)
Hemophilia C
Von Willebrand disease
Disseminated intravascular coagulation
Protein S deficiency
Antiphospholipid syndrome
- Hemophilia
Hemophilia A
Hemophilia B (also known as Christmas disease)
Hemophilia C
- Hemophilia A
- Hemophilia B (also known as Christmas disease)
- Hemophilia C
- Von Willebrand disease
- Disseminated intravascular coagulation
- Protein S deficiency
- Antiphospholipid syndrome
- Disorders of platelets
Thrombocytopenia
Glanzmann's thrombasthenia
Wiskott-Aldrich syndrome
- Thrombocytopenia
- Glanzmann's thrombasthenia
- Wiskott-Aldrich syndrome
- Miscellaneous
Haemochromatosis
Asplenia
Hypersplenism
Gauchers disease
Monoclonal gammopathy of undetermined significance
- Haemochromatosis
- Asplenia
- Hypersplenism
Gauchers disease
- Gauchers disease
- Monoclonal gammopathy of undetermined significance
- Hematological changes secondary to non-hematological disorders
Anemia of chronic disease
Infectious mononucleosis
AIDS
Malaria
Leishmaniasis
- Anemia of chronic disease
- Infectious mononucleosis
- AIDS
- Malaria
- Leishmaniasis
# Tests
Tests used in the investigation of hematological problems include:
- Full blood count
- Erythrocyte sedimentation rate (ESR)
- Blood film
- Bone marrow examination
- Coombs test
- Diascopy
- serum Ferritin level
- Vitamin B12 and Folate levels
- Prothrombin time
- Partial thromboplastin time
- Protein electrophoresis
- Hemoglobin electrophoresis
- D-dimer
# Treatments
Treatments include:
- Diet advice
- Oral medication - tablets or liquid medicines
- Anticoagulation therapy
- Intramuscular injections (for example, Vitamin B12 injections)
- Blood transfusion (for anemia)
- Venesection (for iron overload or polycythemia)
- Bone marrow transplant (for example, for leukemia)
- Chemotherapy (for example, for leukemia)
- Radiotherapy (in decline, for example, for leukemia) | Hematology
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Editor-In-Chief: Robert Killeen, MD
Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2]
# Overview
Hematology (American English) or haematology (British English) is the branch of biology (physiology), pathology, clinical laboratory, internal medicine, and pediatrics that is concerned with the study of blood, the blood-forming organs, and blood diseases. Hematology includes the study of etiology, diagnosis, treatment, prognosis, and prevention of blood diseases. The lab work that goes into the study of blood is performed by a Medical Technologist.
Blood diseases affect the production of blood and its components, such as blood cells, haemoglobin, blood proteins, the mechanism of coagulation, etc.
# Hematologists and Hematopathologists
Physicians specialized in hematology are known as hematologists. Their routine work mainly includes the care and treatment of patients with hematological diseases, although some may also work at the hematology laboratory viewing blood films and bone marrow slides under the microscope, interpreting various hematological test results. In some institutions, hematologists also manage the hematology laboratory. Physicians who mainly work in hematology laboratories, and most commonly manage it, are pathologists specialized in the diagnosis of hematological diseases, referred to as hematopathologists. Hematologists and hematopathologists generally work in conjunction to formulate a diagnosis and deliver the most appropiate therapy if needed. Hematology is a distinct subspecialty of internal medicine, separate from but overlapping with the subspecialty of medical oncology. Hematologists may specialise further or have special interests, for example in:
- treating bleeding disorders such as hemophilia and idiopathic thrombocytopenic purpura
- treating hematological malignacies such as lymphoma and leukemia (onco hematology)
- treating hemoglobinopathies
- in the science of blood transfusion and the work of a blood bank
(Hema- comes from the Greek word "`'aima" meaning "blood", -logy comes from the Greek "logos" meaning word. [referring to the first root word, as in biology, with bio- meaning life and, of course
# Common basic clinical hematology tests
In a clinical laboratory the hematology department performs numerous different tests on blood. The most commonly performed test is the complete blood count (CBC) also called full blood count (FBC), which includes; white blood cell count, platelet count, hemoglobin level and several parameters of red blood cells. Coagulation is a sub-speciality of hematology; basic general coagulation tests are the prothrombin time (PT) and partial thromboplastin time (PTT). Another common hematology test in the erythrocyte sedimentation rate (ESR).
In a blood bank the Coombs test is the most commonly performed test.
(Images shown below are courtesy of Melih Aktan MD, Istanbul Medical Faculty - Turkey, and Kyoto University - Japan, and Hospital Universitario La Fe Servicio Hematologia)
- Normal bone marrow
- Normal bone marrow
- Normal peripheral blood cells
- Normal spleen
- Monocyte
- Monocyte
- Monocyte TEM
- Myeloblast
- Neutrophil
- Neutrophil and monocyte
- Neutrophil granulocyte and lymphocyte
- Neutrophil granulocytes
- Lymphocyte and erytrocyte
- Lymphocytes and Thrombocytes
- Neutrophil granulocytes
- Neutrophil granulocytes
- Neutrophil, basophil and active lymphocyte
- Spherocyte
- Spherocyte
- Spherocyte
- Elliptocyte
- Elliptocyte
- Echinocyte
- Eosinophil
- Eosinophil and lymphocyte
- Erythroblast
- Erythrocyte rouleaux formation
- Erythrocyte rouleaux formation
- Erytrocytes
- Erytrocytes
- Erytrocytes
- Erytrocytes
- Erytrocytes
- Fragmentated erytrocytes
- Granulocyte and metamyelocyte
# Hematology as basic medical science
- Blood
Venous blood
Venipuncture
Hemopoiesis
Blood tests
Cord blood
- Venous blood
- Venipuncture
- Hemopoiesis
- Blood tests
- Cord blood
- Red blood cells
Erythropoiesis
Erythropoietin
Iron metabolism
Hemoglobin
Glycolysis
Pentose phosphate pathway
- Erythropoiesis
- Erythropoietin
- Iron metabolism
- Hemoglobin
- Glycolysis
- Pentose phosphate pathway
- Reticuloendothelial system
Bone marrow
Spleen
Liver
- Bone marrow
- Spleen
- Liver
- Lymphatic system
- Blood transfusion
Blood plasma
Blood bank
Blood donors
Blood groups
- Blood plasma
- Blood bank
- Blood donors
- Blood groups
- Haemostasis
Coagulation
Vitamin K
- Coagulation
- Vitamin K
- Complement system
Immunoglobulins
- Immunoglobulins
# Classification of hematologic diseases
- Hemoglobinopathies (congenital abnormality of the hemoglobin molecule or of the rate of hemoglobin synthesis)
Sickle-cell disease
Thalassemia
Methemoglobinemia
- Sickle-cell disease
- Thalassemia
- Methemoglobinemia
- Anemias (lack of red blood cells or hemoglobin)
Iron deficiency anemia
Megaloblastic anemia
Vitamin B12 deficiency
Pernicious anemia
Folate deficiency
Hemolytic anemias (destruction of red blood cells)
Genetic disorders of RBC membrane
Hereditary spherocytosis
Hereditary elliptocytosis
Genetic disorders of RBC metabolism
Glucose-6-phosphate dehydrogenase deficiency (G6PD)
Pyruvate kinase deficiency
Immune mediated hemolytic anaemia (direct Coombs test is positive)
Autoimmune hemolytic anemia
Warm antibody autoimmune hemolytic anemia
Idiopathic
Systemic lupus erythematosus (SLE)
Evans' syndrome (antiplatelet antibodies and haemolytic antibodies)
Cold antibody autoimmune hemolytic anemia
Idiopathic cold hemagglutinin syndrome
Infectious mononucleosis
Paroxysmal cold hemoglobinuria (rare)
Alloimmune hemolytic anemia
Hemolytic disease of the newborn (HDN)
Rh disease (Rh D)
ABO hemolytic disease of the newborn
Anti-Kell hemolytic disease of the newborn
Rhesus c hemolytic disease of the newborn
Rhesus E hemolytic disease of the newborn
Other blood group incompatibility (RhC, Rhe, Kid, Duffy, MN, P and others)
Drug induced immune mediated hemolytic anaemia
Penicillin (high dose)
Methyldopa
Hemoglobinopathies (where these is an unstable or crystalline hemoglobin)
Paroxysmal nocturnal hemoglobinuria (rare acquired clonal disorder of red blood cell surface proteins)
Direct physical damage to RBCs
Microangiopathic hemolytic anemia
Secondary to artificial heart valve(s)
Aplastic anemia
Fanconi anemia
Diamond-Blackfan anemia
Acquired pure red cell aplasia
- Iron deficiency anemia
- Megaloblastic anemia
Vitamin B12 deficiency
Pernicious anemia
Folate deficiency
- Vitamin B12 deficiency
Pernicious anemia
- Pernicious anemia
- Folate deficiency
- Hemolytic anemias (destruction of red blood cells)
Genetic disorders of RBC membrane
Hereditary spherocytosis
Hereditary elliptocytosis
Genetic disorders of RBC metabolism
Glucose-6-phosphate dehydrogenase deficiency (G6PD)
Pyruvate kinase deficiency
Immune mediated hemolytic anaemia (direct Coombs test is positive)
Autoimmune hemolytic anemia
Warm antibody autoimmune hemolytic anemia
Idiopathic
Systemic lupus erythematosus (SLE)
Evans' syndrome (antiplatelet antibodies and haemolytic antibodies)
Cold antibody autoimmune hemolytic anemia
Idiopathic cold hemagglutinin syndrome
Infectious mononucleosis
Paroxysmal cold hemoglobinuria (rare)
Alloimmune hemolytic anemia
Hemolytic disease of the newborn (HDN)
Rh disease (Rh D)
ABO hemolytic disease of the newborn
Anti-Kell hemolytic disease of the newborn
Rhesus c hemolytic disease of the newborn
Rhesus E hemolytic disease of the newborn
Other blood group incompatibility (RhC, Rhe, Kid, Duffy, MN, P and others)
Drug induced immune mediated hemolytic anaemia
Penicillin (high dose)
Methyldopa
Hemoglobinopathies (where these is an unstable or crystalline hemoglobin)
Paroxysmal nocturnal hemoglobinuria (rare acquired clonal disorder of red blood cell surface proteins)
Direct physical damage to RBCs
Microangiopathic hemolytic anemia
Secondary to artificial heart valve(s)
- Genetic disorders of RBC membrane
Hereditary spherocytosis
Hereditary elliptocytosis
- Hereditary spherocytosis
- Hereditary elliptocytosis
- Genetic disorders of RBC metabolism
Glucose-6-phosphate dehydrogenase deficiency (G6PD)
Pyruvate kinase deficiency
- Glucose-6-phosphate dehydrogenase deficiency (G6PD)
- Pyruvate kinase deficiency
- Immune mediated hemolytic anaemia (direct Coombs test is positive)
Autoimmune hemolytic anemia
Warm antibody autoimmune hemolytic anemia
Idiopathic
Systemic lupus erythematosus (SLE)
Evans' syndrome (antiplatelet antibodies and haemolytic antibodies)
Cold antibody autoimmune hemolytic anemia
Idiopathic cold hemagglutinin syndrome
Infectious mononucleosis
Paroxysmal cold hemoglobinuria (rare)
Alloimmune hemolytic anemia
Hemolytic disease of the newborn (HDN)
Rh disease (Rh D)
ABO hemolytic disease of the newborn
Anti-Kell hemolytic disease of the newborn
Rhesus c hemolytic disease of the newborn
Rhesus E hemolytic disease of the newborn
Other blood group incompatibility (RhC, Rhe, Kid, Duffy, MN, P and others)
Drug induced immune mediated hemolytic anaemia
Penicillin (high dose)
Methyldopa
- Autoimmune hemolytic anemia
Warm antibody autoimmune hemolytic anemia
Idiopathic
Systemic lupus erythematosus (SLE)
Evans' syndrome (antiplatelet antibodies and haemolytic antibodies)
Cold antibody autoimmune hemolytic anemia
Idiopathic cold hemagglutinin syndrome
Infectious mononucleosis
Paroxysmal cold hemoglobinuria (rare)
- Warm antibody autoimmune hemolytic anemia
Idiopathic
Systemic lupus erythematosus (SLE)
Evans' syndrome (antiplatelet antibodies and haemolytic antibodies)
- Idiopathic
- Systemic lupus erythematosus (SLE)
- Evans' syndrome (antiplatelet antibodies and haemolytic antibodies)
- Cold antibody autoimmune hemolytic anemia
Idiopathic cold hemagglutinin syndrome
Infectious mononucleosis
Paroxysmal cold hemoglobinuria (rare)
- Idiopathic cold hemagglutinin syndrome
- Infectious mononucleosis
- Paroxysmal cold hemoglobinuria (rare)
- Alloimmune hemolytic anemia
Hemolytic disease of the newborn (HDN)
Rh disease (Rh D)
ABO hemolytic disease of the newborn
Anti-Kell hemolytic disease of the newborn
Rhesus c hemolytic disease of the newborn
Rhesus E hemolytic disease of the newborn
Other blood group incompatibility (RhC, Rhe, Kid, Duffy, MN, P and others)
- Hemolytic disease of the newborn (HDN)
Rh disease (Rh D)
ABO hemolytic disease of the newborn
Anti-Kell hemolytic disease of the newborn
Rhesus c hemolytic disease of the newborn
Rhesus E hemolytic disease of the newborn
Other blood group incompatibility (RhC, Rhe, Kid, Duffy, MN, P and others)
- Rh disease (Rh D)
- ABO hemolytic disease of the newborn
- Anti-Kell hemolytic disease of the newborn
- Rhesus c hemolytic disease of the newborn
- Rhesus E hemolytic disease of the newborn
- Other blood group incompatibility (RhC, Rhe, Kid, Duffy, MN, P and others)
- Drug induced immune mediated hemolytic anaemia
Penicillin (high dose)
Methyldopa
- Penicillin (high dose)
- Methyldopa
- Hemoglobinopathies (where these is an unstable or crystalline hemoglobin)
- Paroxysmal nocturnal hemoglobinuria (rare acquired clonal disorder of red blood cell surface proteins)
- Direct physical damage to RBCs
Microangiopathic hemolytic anemia
Secondary to artificial heart valve(s)
- Microangiopathic hemolytic anemia
- Secondary to artificial heart valve(s)
- Aplastic anemia
Fanconi anemia
Diamond-Blackfan anemia
Acquired pure red cell aplasia
- Fanconi anemia
- Diamond-Blackfan anemia
- Acquired pure red cell aplasia
- Decreased numbers of cells
Myelodysplastic syndrome
Myelofibrosis
Neutropenia (decrease in the number of neutrophils)
Agranulocytosis
Glanzmann's thrombasthenia
Thrombocytopenia (decrease in the number of platelets)
Idiopathic thrombocytopenic purpura (ITP)
Thrombotic thrombocytopenic purpura (TTP)
Heparin-induced thrombocytopenia (HIT)
- Myelodysplastic syndrome
- Myelofibrosis
- Neutropenia (decrease in the number of neutrophils)
- Agranulocytosis
- Glanzmann's thrombasthenia
- Thrombocytopenia (decrease in the number of platelets)
Idiopathic thrombocytopenic purpura (ITP)
Thrombotic thrombocytopenic purpura (TTP)
Heparin-induced thrombocytopenia (HIT)
- Idiopathic thrombocytopenic purpura (ITP)
- Thrombotic thrombocytopenic purpura (TTP)
- Heparin-induced thrombocytopenia (HIT)
- Myeloproliferative disorders (Increased numbers of cells)
Polycythemia vera (increase in the number of cells in general)
Leukocytosis (increase in the number of white blood cells)
Thrombocytosis (increase in the number of platelets)
Myeloproliferative disorder
- Polycythemia vera (increase in the number of cells in general)
- Leukocytosis (increase in the number of white blood cells)
- Thrombocytosis (increase in the number of platelets)
- Myeloproliferative disorder
- Hematological malignancies
Lymphomas
Hodgkin's disease
Non-Hodgkin's lymphoma{includes the next eight entries}
Burkitt's lymphoma
Anaplastic large cell lymphoma
Splenic marginal zone lymphoma
Hepatosplenic T-cell lymphoma
Angioimmunoblastic T-cell lymphoma (AILT)
Myelomas
Multiple myeloma
Waldenström macroglobulinemia
Plasmacytoma
Leukemias
Acute lymphocytic leukemia (ALL)
Chronic lymphocytic leukemia (CLL){now included in theCLL/SCLL type NHL}
Acute myelogenous leukemia (AML)
Chronic myelogenous leukemia (CML)
T-cell prolymphocytic leukemia (T-PLL)
B-cell prolymphocytic leukemia (B-PLL)
Chronic neutrophilic leukemia (CNL)
Hairy cell leukemia (HCL)
T-cell large granular lymphocyte leukemia (T-LGL)
Aggressive NK-cell leukemia
- Lymphomas
Hodgkin's disease
Non-Hodgkin's lymphoma{includes the next eight entries}
Burkitt's lymphoma
Anaplastic large cell lymphoma
Splenic marginal zone lymphoma
Hepatosplenic T-cell lymphoma
Angioimmunoblastic T-cell lymphoma (AILT)
- Hodgkin's disease
- Non-Hodgkin's lymphoma{includes the next eight entries}
- Burkitt's lymphoma
- Anaplastic large cell lymphoma
- Splenic marginal zone lymphoma
- Hepatosplenic T-cell lymphoma
- Angioimmunoblastic T-cell lymphoma (AILT)
- Myelomas
Multiple myeloma
Waldenström macroglobulinemia
- Multiple myeloma
- Waldenström macroglobulinemia
- Plasmacytoma
- Leukemias
Acute lymphocytic leukemia (ALL)
Chronic lymphocytic leukemia (CLL){now included in theCLL/SCLL type NHL}
Acute myelogenous leukemia (AML)
Chronic myelogenous leukemia (CML)
T-cell prolymphocytic leukemia (T-PLL)
B-cell prolymphocytic leukemia (B-PLL)
Chronic neutrophilic leukemia (CNL)
Hairy cell leukemia (HCL)
T-cell large granular lymphocyte leukemia (T-LGL)
Aggressive NK-cell leukemia
- Acute lymphocytic leukemia (ALL)
- Chronic lymphocytic leukemia (CLL){now included in theCLL/SCLL type NHL}
- Acute myelogenous leukemia (AML)
- Chronic myelogenous leukemia (CML)
- T-cell prolymphocytic leukemia (T-PLL)
- B-cell prolymphocytic leukemia (B-PLL)
- Chronic neutrophilic leukemia (CNL)
- Hairy cell leukemia (HCL)
- T-cell large granular lymphocyte leukemia (T-LGL)
- Aggressive NK-cell leukemia
- Coagulopathies (disorders of bleeding and coagulation)
Thrombocytosis
Recurrent thrombosis
Disseminated intravascular coagulation
Disorders of clotting proteins
Hemophilia
Hemophilia A
Hemophilia B (also known as Christmas disease)
Hemophilia C
Von Willebrand disease
Disseminated intravascular coagulation
Protein S deficiency
Antiphospholipid syndrome
Disorders of platelets
Thrombocytopenia
Glanzmann's thrombasthenia
Wiskott-Aldrich syndrome
- Thrombocytosis
- Recurrent thrombosis
- Disseminated intravascular coagulation
- Disorders of clotting proteins
Hemophilia
Hemophilia A
Hemophilia B (also known as Christmas disease)
Hemophilia C
Von Willebrand disease
Disseminated intravascular coagulation
Protein S deficiency
Antiphospholipid syndrome
- Hemophilia
Hemophilia A
Hemophilia B (also known as Christmas disease)
Hemophilia C
- Hemophilia A
- Hemophilia B (also known as Christmas disease)
- Hemophilia C
- Von Willebrand disease
- Disseminated intravascular coagulation
- Protein S deficiency
- Antiphospholipid syndrome
- Disorders of platelets
Thrombocytopenia
Glanzmann's thrombasthenia
Wiskott-Aldrich syndrome
- Thrombocytopenia
- Glanzmann's thrombasthenia
- Wiskott-Aldrich syndrome
- Miscellaneous
Haemochromatosis
Asplenia
Hypersplenism
Gauchers disease
Monoclonal gammopathy of undetermined significance
- Haemochromatosis
- Asplenia
- Hypersplenism
Gauchers disease
- Gauchers disease
- Monoclonal gammopathy of undetermined significance
- Hematological changes secondary to non-hematological disorders
Anemia of chronic disease
Infectious mononucleosis
AIDS
Malaria
Leishmaniasis
- Anemia of chronic disease
- Infectious mononucleosis
- AIDS
- Malaria
- Leishmaniasis
# Tests
Tests used in the investigation of hematological problems include:
- Full blood count
- Erythrocyte sedimentation rate (ESR)
- Blood film
- Bone marrow examination
- Coombs test
- Diascopy
- serum Ferritin level
- Vitamin B12 and Folate levels
- Prothrombin time
- Partial thromboplastin time
- Protein electrophoresis
- Hemoglobin electrophoresis
- D-dimer
# Treatments
Treatments include:
- Diet advice
- Oral medication - tablets or liquid medicines
- Anticoagulation therapy
- Intramuscular injections (for example, Vitamin B12 injections)
- Blood transfusion (for anemia)
- Venesection (for iron overload or polycythemia)
- Bone marrow transplant (for example, for leukemia)
- Chemotherapy (for example, for leukemia)
- Radiotherapy (in decline, for example, for leukemia)
# External links
- American Society of Hematology
- BloodLine
- Major milestones in history of hematology (PDF)
- Multilingual index
- Extensive Hematology Slide Collection
# Additional Resources
- Hematologists
- Blood disorders
- Hematology topics
Template:Hematology
af:Hematologie
bn:রক্তবিদ্যা
bg:Хематология
ca:Hematologia
de:Hämatologie
eo:Hematologio
eu:Hematologia
fa:خونشناسی
gl:Hematoloxía
id:Hematologi
is:Blóðfræði
he:המטולוגיה
lt:Hematologija
nl:Hematologie
nds:Hämatologie
sq:Hematologjia
sk:Hematológia
fi:Hematologia
sv:Hematologi
th:โลหิตวิทยา
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Blood_disease | |
4fd278cf0bd7d7a247712c395f03902ede68a582 | wikidoc | Blood film | Blood film
A blood film or peripheral blood smear is a slide made from a drop of blood, that allows the cells to be examined microscopically. Blood films are usually done to investigate hematological problems (disorders of the blood itself) and, occasionally, to look for parasites within the blood such as malaria and filaria.
# Preparation
Blood films are made by placing a drop of blood on one end of a slide, and using a spreader slide to disperse the blood over the slide's length. The aim is to get a region where the cells are spaced far enough apart to be counted and differentiated.
The slide is left to air dry, after which the blood is fixed to the slide by immersing it briefly in methanol. The fixative is essential for good staining and presentation of cellular detail. After fixation, the slide is stained to distinguish the cells from each other.
## Common blood film staining methods
- Romanowsky stain
Giemsa stain
Wright's stain
Jenner's stain
Leishman stain
Field's stain
- Giemsa stain
- Wright's stain
- Jenner's stain
- Leishman stain
- Field's stain
# Interpretation
## Routine examination
A blood film will help identify circulating blood cells. Apart from counting the cells, morphology of cells can provide a wealth of information and assist in making a diagnosis.
Cellular components of blood are:
- Red blood cells (erythrocytes)
- White blood cells (leukocytes)
- Platelets (thrombocytes)
Normal blood films are typically full of red blood cells, with occasional white blood cells and minuscule platelets, which are harder to notice due to their size.
## Disorders
Characteristic red blood cell abnormalities are anemia, sickle cell anemia and spherocytosis. Sometimes the microscopic investigation of the red cells can be essential to the diagnosis of life-threatening disease (e.g. TTP).
White blood cells are classified according to their propensity to stain with particular substances, the shape of the nuclei and the granular inclusions.
- Neutrophil granulocytes usually make up close to 80% of the white count. They have multilobulated nuclei and lightly staining granules. They assist in destruction of foreign particles by the immune system by phagocytosis and intracellular killing.
- Eosinophil granulocytes have granules that stain with eosin and play a role in allergy and parasitic disease. Eo's have a multilobulated nucleus.
- Basophil granulocytes are only seen occasionally. They are polymorphonuceated and their granules stain dark with alkaline stains, such as haematoxylin. They are further characterised by the fact that the granula seem to overlie the nucleus. Basophils are similar if not identicle in cell lineage to mast cells although no conclusive evidence to this end has been shown. Mast cells are "tissue basophils" and mediate certain immune reactions to allergens. - Lymphocytes have very little cytoplasm and a large nucleus (high NC ratio) and are responsible for antigen-specific immune functions, either by antibodies (B cell) or by direct cytotoxicity (T cell). The distinction between B and T cells cannot be made by light microscopy.
- Plasma cells are mature B lymphocytes that engage in the production of one specific antibody. They are characterised by light basophilic staining and a very ecentric nucleus.
- Other cells are white cell precursors. When these are very abundant it can be a feature of infection or leukemia, although the most common types of leukemia (CML and CLL) are characterised by mature cells, and have more of an abnormal appearance on light microscopy (it should be noted that additional tests can aid the diagnosis).
# Use in diagnosing malaria
The preferred and most reliable diagnosis of malaria is microscopic examination of blood films, because each of the four major parasite species has distinguishing characteristics. Two sorts of blood film are traditionally used. Thin films are similar to usual blood films and allow species identification, because the parasite's appearance is best preserved in this preparation. Thick films allow the microscopist to screen a larger volume of blood and are about eleven times more sensitive than the thin film, so picking up low levels of infection is easier on the thick film, but the appearance of the parasite is much more distorted and therefore distinguishing between the different species can be much more difficult. From the thick film, an experienced microscopist can detect parasite levels down to as low as 0.0000001%. Microscopic diagnosis can be difficult because the early trophozoites ("ring form") of all four species look identical and it is never possible to diagnose species on the basis of a single ring form; species identification is always based on several trophozoites. Please refer to the chapters on each parasite for their microscopic appearances: P. falciparum, P. vivax, P. ovale, P. malariae.
The biggest pitfall in most laboratories in developed countries is leaving too great a delay between taking the blood sample and making the blood films. As blood cools to room temperature, male gametocytes will divide and release microgametes: these are long sinuous filamentous structures that can be mistaken for organisms such as Borrelia. If the blood is kept at warmer temperatures, schizonts will rupture and merozoites invading erythrocytes will mistakenly give the appearance of the accolé form of P. falciparum. If P. vivax or P. ovale is left for several hours in EDTA, the build up of acid in the sample will cause the parasitised erythrocytes to shrink and the parasite will roll up, simulating the appearance of P. malariae. This problem is made worse if anticoagulants such as heparin or citrate are used. The anticoagulant that causes the least problems is EDTA. Romanovski's stain or a variant stain is usually used. Some laboratories mistakenly use the same stain as they do for routine haematology blood films (pH 7.2): malaria blood films must be stained at pH 6.8, or Schüffner's dots and James's dots will not be seen. | Blood film
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
A blood film or peripheral blood smear is a slide made from a drop of blood, that allows the cells to be examined microscopically. Blood films are usually done to investigate hematological problems (disorders of the blood itself) and, occasionally, to look for parasites within the blood such as malaria and filaria.
# Preparation
Blood films are made by placing a drop of blood on one end of a slide, and using a spreader slide to disperse the blood over the slide's length. The aim is to get a region where the cells are spaced far enough apart to be counted and differentiated.
The slide is left to air dry, after which the blood is fixed to the slide by immersing it briefly in methanol. The fixative is essential for good staining and presentation of cellular detail. After fixation, the slide is stained to distinguish the cells from each other.
## Common blood film staining methods
- Romanowsky stain
Giemsa stain
Wright's stain
Jenner's stain
Leishman stain
Field's stain
- Giemsa stain
- Wright's stain
- Jenner's stain
- Leishman stain
- Field's stain
# Interpretation
## Routine examination
A blood film will help identify circulating blood cells. Apart from counting the cells, morphology of cells can provide a wealth of information and assist in making a diagnosis.[1]
Cellular components of blood are:
- Red blood cells (erythrocytes)
- White blood cells (leukocytes)
- Platelets (thrombocytes)
Normal blood films are typically full of red blood cells, with occasional white blood cells and minuscule platelets, which are harder to notice due to their size.
## Disorders
Characteristic red blood cell abnormalities are anemia, sickle cell anemia and spherocytosis. Sometimes the microscopic investigation of the red cells can be essential to the diagnosis of life-threatening disease (e.g. TTP).
White blood cells are classified according to their propensity to stain with particular substances, the shape of the nuclei and the granular inclusions.
- Neutrophil granulocytes usually make up close to 80% of the white count. They have multilobulated nuclei and lightly staining granules. They assist in destruction of foreign particles by the immune system by phagocytosis and intracellular killing.
- Eosinophil granulocytes have granules that stain with eosin and play a role in allergy and parasitic disease. Eo's have a multilobulated nucleus.
- Basophil granulocytes are only seen occasionally. They are polymorphonuceated and their granules stain dark with alkaline stains, such as haematoxylin. They are further characterised by the fact that the granula seem to overlie the nucleus. Basophils are similar if not identicle in cell lineage to mast cells although no conclusive evidence to this end has been shown. Mast cells are "tissue basophils" and mediate certain immune reactions to allergens. * Lymphocytes have very little cytoplasm and a large nucleus (high NC ratio) and are responsible for antigen-specific immune functions, either by antibodies (B cell) or by direct cytotoxicity (T cell). The distinction between B and T cells cannot be made by light microscopy.
- Plasma cells are mature B lymphocytes that engage in the production of one specific antibody. They are characterised by light basophilic staining and a very ecentric nucleus.
- Other cells are white cell precursors. When these are very abundant it can be a feature of infection or leukemia, although the most common types of leukemia (CML and CLL) are characterised by mature cells, and have more of an abnormal appearance on light microscopy (it should be noted that additional tests can aid the diagnosis).
# Use in diagnosing malaria
The preferred and most reliable diagnosis of malaria is microscopic examination of blood films, because each of the four major parasite species has distinguishing characteristics. Two sorts of blood film are traditionally used. Thin films are similar to usual blood films and allow species identification, because the parasite's appearance is best preserved in this preparation. Thick films allow the microscopist to screen a larger volume of blood and are about eleven times more sensitive than the thin film, so picking up low levels of infection is easier on the thick film, but the appearance of the parasite is much more distorted and therefore distinguishing between the different species can be much more difficult.[2] From the thick film, an experienced microscopist can detect parasite levels down to as low as 0.0000001%. Microscopic diagnosis can be difficult because the early trophozoites ("ring form") of all four species look identical and it is never possible to diagnose species on the basis of a single ring form; species identification is always based on several trophozoites. Please refer to the chapters on each parasite for their microscopic appearances: P. falciparum, P. vivax, P. ovale, P. malariae.
The biggest pitfall in most laboratories in developed countries is leaving too great a delay between taking the blood sample and making the blood films. As blood cools to room temperature, male gametocytes will divide and release microgametes: these are long sinuous filamentous structures that can be mistaken for organisms such as Borrelia. If the blood is kept at warmer temperatures, schizonts will rupture and merozoites invading erythrocytes will mistakenly give the appearance of the accolé form of P. falciparum. If P. vivax or P. ovale is left for several hours in EDTA, the build up of acid in the sample will cause the parasitised erythrocytes to shrink and the parasite will roll up, simulating the appearance of P. malariae. This problem is made worse if anticoagulants such as heparin or citrate are used. The anticoagulant that causes the least problems is EDTA. Romanovski's stain or a variant stain is usually used. Some laboratories mistakenly use the same stain as they do for routine haematology blood films (pH 7.2): malaria blood films must be stained at pH 6.8, or Schüffner's dots and James's dots will not be seen. | https://www.wikidoc.org/index.php/Blood_film | |
6f88c9670747c946edef7181d60b6db00788f427 | wikidoc | Blood flow | Blood flow
# Overview
- Blood flow is the flow of blood in the cardiovascular system.
- The discovery that blood flows is attributed to William Harvey.
- The flow in healthy vessels is generally laminar, however in diseased (e.g. atherosclerotic) arteries the flow may be transitional or turbulent.
# Factors Affecting the Blood Flow
- Blood flows from one site to another proportionally to the difference of pressures between these sites and inversely proportionally to the resistance of conduits (which are the vessels) in which blood is circulating.
- This is the same concept of Ohm's law and it can be illustrated in the following formula:
Flow = Difference in Pressure/Resistance
Difference in pressure= Pressure at the first site - Pressure at the second site
Resistance= 8 x viscosity of blood x length of vessels/ Pi x radius of vessels^4
- Flow = Difference in Pressure/Resistance
- Difference in pressure= Pressure at the first site - Pressure at the second site
- Resistance= 8 x viscosity of blood x length of vessels/ Pi x radius of vessels^4
- Circulation is influenced by the resistance of the vascular bed against which the heart is pumping.
Pulmonary Vascular Resistance (PVR) is created by the pulmonary bed on the right side of the heart.
Systemic Vascular Resistance (SVR) is created by the systemic vascular bed on the left side of the heart.
- Pulmonary Vascular Resistance (PVR) is created by the pulmonary bed on the right side of the heart.
- Systemic Vascular Resistance (SVR) is created by the systemic vascular bed on the left side of the heart.
## The radius of the blood vessels:
- The vessels actively change diameter under the influence of physiology or therapy:
Vasoconstrictors decrease vessel radius and increase resistance and hence decrease the blood flow.
Vasodilators increase vessel radius and decrease resistance and hence increase the blood flow.
- Vasoconstrictors decrease vessel radius and increase resistance and hence decrease the blood flow.
- Vasodilators increase vessel radius and decrease resistance and hence increase the blood flow.
- It is important to note that resistance to flow changes dramatically with respect to the radius of the tube. This is important in angioplasty, as it enables the increase of blood flow with balloon catheter to the deprived organ significantly with only a small increase in radius of a vessel.
## Blood viscosity:
- Blood viscosity affects blood resistance and hence alters blood flow:
Blood is an inhomogeneous medium consisting mainly of plasma and a suspension of red blood cells.
Red cells tend to coagulate when the flow shear rates are low, while increasing shear rates break these formations apart, thus reducing blood viscosity.
This results in two non-Newtonian blood properties, shear thinning and yield stress.
In healthy large arteries blood can be successfully approximated as a homogeneous, Newtonian fluid since the vessel size is much greater than the size of particles and shear rates are sufficiently high that particle interactions may have a negligible effect on the flow.
In smaller vessels, however, non-Newtonian blood behavior should be taken into account.
- Blood is an inhomogeneous medium consisting mainly of plasma and a suspension of red blood cells.
- Red cells tend to coagulate when the flow shear rates are low, while increasing shear rates break these formations apart, thus reducing blood viscosity.
- This results in two non-Newtonian blood properties, shear thinning and yield stress.
In healthy large arteries blood can be successfully approximated as a homogeneous, Newtonian fluid since the vessel size is much greater than the size of particles and shear rates are sufficiently high that particle interactions may have a negligible effect on the flow.
In smaller vessels, however, non-Newtonian blood behavior should be taken into account.
- In healthy large arteries blood can be successfully approximated as a homogeneous, Newtonian fluid since the vessel size is much greater than the size of particles and shear rates are sufficiently high that particle interactions may have a negligible effect on the flow.
- In smaller vessels, however, non-Newtonian blood behavior should be taken into account. | Blood flow
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Assistant Editor(s)-in-Chief: Rim Halaby
# Overview
- Blood flow is the flow of blood in the cardiovascular system.
- The discovery that blood flows is attributed to William Harvey.
- The flow in healthy vessels is generally laminar, however in diseased (e.g. atherosclerotic) arteries the flow may be transitional or turbulent.
# Factors Affecting the Blood Flow
- Blood flows from one site to another proportionally to the difference of pressures between these sites and inversely proportionally to the resistance of conduits (which are the vessels) in which blood is circulating.
- This is the same concept of Ohm's law and it can be illustrated in the following formula:
Flow = Difference in Pressure/Resistance
Difference in pressure= Pressure at the first site - Pressure at the second site
Resistance= 8 x viscosity of blood x length of vessels/ Pi x radius of vessels^4
- Flow = Difference in Pressure/Resistance
- Difference in pressure= Pressure at the first site - Pressure at the second site
- Resistance= 8 x viscosity of blood x length of vessels/ Pi x radius of vessels^4
- Circulation is influenced by the resistance of the vascular bed against which the heart is pumping.
Pulmonary Vascular Resistance (PVR) is created by the pulmonary bed on the right side of the heart.
Systemic Vascular Resistance (SVR) is created by the systemic vascular bed on the left side of the heart.
- Pulmonary Vascular Resistance (PVR) is created by the pulmonary bed on the right side of the heart.
- Systemic Vascular Resistance (SVR) is created by the systemic vascular bed on the left side of the heart.
## The radius of the blood vessels:
- The vessels actively change diameter under the influence of physiology or therapy:
Vasoconstrictors decrease vessel radius and increase resistance and hence decrease the blood flow.
Vasodilators increase vessel radius and decrease resistance and hence increase the blood flow.
- Vasoconstrictors decrease vessel radius and increase resistance and hence decrease the blood flow.
- Vasodilators increase vessel radius and decrease resistance and hence increase the blood flow.
- It is important to note that resistance to flow changes dramatically with respect to the radius of the tube. This is important in angioplasty, as it enables the increase of blood flow with balloon catheter to the deprived organ significantly with only a small increase in radius of a vessel.
## Blood viscosity:
- Blood viscosity affects blood resistance and hence alters blood flow:
Blood is an inhomogeneous medium consisting mainly of plasma and a suspension of red blood cells.
Red cells tend to coagulate when the flow shear rates are low, while increasing shear rates break these formations apart, thus reducing blood viscosity.
This results in two non-Newtonian blood properties, shear thinning and yield stress.
In healthy large arteries blood can be successfully approximated as a homogeneous, Newtonian fluid since the vessel size is much greater than the size of particles and shear rates are sufficiently high that particle interactions may have a negligible effect on the flow.
In smaller vessels, however, non-Newtonian blood behavior should be taken into account.
- Blood is an inhomogeneous medium consisting mainly of plasma and a suspension of red blood cells.
- Red cells tend to coagulate when the flow shear rates are low, while increasing shear rates break these formations apart, thus reducing blood viscosity.
- This results in two non-Newtonian blood properties, shear thinning and yield stress.
In healthy large arteries blood can be successfully approximated as a homogeneous, Newtonian fluid since the vessel size is much greater than the size of particles and shear rates are sufficiently high that particle interactions may have a negligible effect on the flow.
In smaller vessels, however, non-Newtonian blood behavior should be taken into account.
- In healthy large arteries blood can be successfully approximated as a homogeneous, Newtonian fluid since the vessel size is much greater than the size of particles and shear rates are sufficiently high that particle interactions may have a negligible effect on the flow.
- In smaller vessels, however, non-Newtonian blood behavior should be taken into account. | https://www.wikidoc.org/index.php/Blood_flow | |
d0434b06d7c53be155e4847f3f0c9cb5eee81487 | wikidoc | Blood type | Blood type
A blood type (also called a blood group) is a classification of blood based on the presence or absence of inherited antigenic substances on the surface of red blood cells (RBCs). These antigens may be proteins, carbohydrates, glycoproteins or glycolipids, depending on the blood group system, and some of these antigens are also present on the surface of other types of cells of various tissues.
Several of these red blood cell surface antigens, that stem from one allele (or very closely linked genes), collectively form a blood group system.
Immunological effects of mismatched blood transfusions are much more likely to involve components of the ABO blood group system or the RhD antigen (also known as the Rhesus factor or Rhesus D antigen) of the Rhesus blood group system than components of any of the other blood group systems; hence, in the routine preparation of blood for transfusion in a blood bank, the presence or absence the immunogenic blood group antigens, the A antigen, the B antigen and the RhD antigen are always determined for all recipient and donor blood. This identifies the ABO blood group and the RhD antigen status, which are both stated in the common terminology A positive, O negative, etc., where a capital letter (A, B or O) refers to the ABO blood group, and positive or negative refers to the presence or absence of the RhD antigen of the Rhesus blood group system. In the routine preparation and selection of donor blood for blood transfusion, it is not necessary to determine the status of any other blood group antigens or antibodies, because antibody screening and cross-matching (or computer aided simulated cross-matching) prior to transfusion detects if there are any other blood group incompatibilities between potential donor blood and intended recipients.
If an individual is exposed to a blood group antigen that is not recognised as self, the immune system will produce antibodies that can specifically bind to that particular blood group antigen and an immunological memory against that antigen is formed. The individual will have become sensitized to that blood group antigen. These antibodies can bind to antigens on the surface of transfused red blood cells (or other tissue cells) often leading to destruction of the cells by recruitment of other components of the immune system. When IgM antibodies bind to the transfused cells, the transfused cells can clump. It is vital that compatible blood is selected for transfusions and that compatible tissue is selected for organ transplantation. Transfusion reactions involving minor antigens or weak antibodies may lead to minor problems. However, more serious incompatibilities can lead to a more vigorous immune response with massive RBC destruction, low blood pressure, and even death.
Blood types are inherited and represent contributions from both parents. Often, pregnant women carry a fetus with a different blood type from their own, and sometimes the mother forms antibodies against the red blood cells of the fetus, which causes hemolysis of fetal RBCs, and which in turn can lead to low fetal blood counts, a condition known as hemolytic disease of the newborn. Some blood types are associated with inheritance of other diseases; for example, the Kell antigen is associated with McLeod syndrome. Certain blood types may affect susceptibility to infections, an example being the resistance to specific malaria species seen in individuals lacking the Duffy antigen. The Duffy antigen, presumedly as a result of natural selection, is less common in ethnic groups from areas with a high incidence of malaria.
The two most significant blood group systems were discovered during early experiments with blood transfusion: the ABO group in 1901 and the Rhesus group in 1937. Development of the Coombs test in 1945, the advent of transfusion medicine, and the understanding of hemolytic disease of the newborn led to discovery of more blood groups. Today, a total of 29 human blood group systems are recognized by the International Society of Blood Transfusion (ISBT). A complete blood type would describe a full set of 29 substances on the surface of RBCs, and an individual's blood type is one of the many possible combinations of blood group antigens. Across the 29 blood groups, over 600 different blood group antigens have been found, but many of these are very rare or are mainly found in certain ethnic groups. Almost always, an individual has the same blood group for life; but very rarely, an individual's blood type changes through addition or suppression of an antigen in infection, malignancy or autoimmune disease. Blood types have been used in forensic science and in paternity testing, but both of these uses are being replaced by DNA analysis, which provides greater certitude.
# Blood group systems
## ABO blood group system
The ABO system is the most important blood group system in human blood transfusion. The associated anti-A antibodies and anti-B antibodies are usually "Immunoglobulin M", abbreviated IgM, antibodies. ABO IgM antibodies are produced in the first years of life by sensitization to environmental substances such as food, bacteria and viruses. The "O" in ABO is often called "0" (zero/null) in other languages.
## Rhesus blood group system
The Rhesus system is the second most significant blood group system in human blood transfusion. The most significant Rhesus antigen is the RhD antigen because it is the most immunogenic of the five main rhesus antigens. It is common for RhD negative individuals not to have any anti-RhD IgG or IgM antibodies, because anti-RhD antibodies are not usually produced by sensitization against environmental substances. However, RhD negative individuals can produce IgG anti-RhD antibodies following a sensitizing event: possibly a fetomaternal transfusion of blood from a fetus in pregnancy or occasionally a blood transfusion with RhD positive RBCs.
### ABO and Rh distribution by nation
## Other blood group systems
The International Society of Blood Transfusion currently recognizes 29 blood group systems (including the ABO and Rh systems). Thus, in addition to the ABO antigens and Rhesus antigens, many other antigens are expressed on the RBC surface membrane. For example, an individual can be AB RhD positive, and at the same time M and N positive (MNS system), K positive (Kell system), Lea or Leb negative (Lewis system), and so on, being positive or negative for each blood group system antigen. Many of the blood group systems were named after the patients in whom the corresponding antibodies were initially encountered.
# Clinical significance
## Blood transfusion
Transfusion medicine is a specialized branch of hematology that is concerned with the study of blood groups, along with the work of a blood bank to provide a transfusion service for blood and other blood products. Across the world, blood products must be prescribed by a medical doctor (licensed physician or surgeon) in a similar way as medicines. In the USA, blood products are tightly regulated by the Food and Drug Administration.
Much of the routine work of a blood bank involves testing blood from both donors and recipients to ensure that every individual recipient is given blood that is compatible and is as safe as possible. If a unit of incompatible blood is transfused between a donor and recipient, a severe acute immunological reaction, hemolysis (RBC destruction), renal failure and shock are likely to occur, and death is a possibility. Antibodies can be highly active and can attack RBCs and bind components of the complement system to cause massive hemolysis of the transfused blood.
Patients should ideally receive their own blood or type-specific blood products to minimize the chance of a transfusion reaction. Risks can be further reduced by cross-matching blood, but this may be skipped when blood is required for an emergency. Cross-matching involves mixing a sample of the recipient's blood with a sample of the donor's blood and checking to see if the mixture agglutinates, or forms clumps. If agglutination is not obvious by direct vision, blood bank technicians usually check for agglutination with a microscope. If agglutination occurs, that particular donor's blood cannot be transfused to that particular recipient. In a blood bank it is vital that all blood specimens are correctly identified, so labeling has been standardized using a barcode system known as ISBT 128.
The blood group may be included on identification tags or on tattoos worn by military personnel, in case they should need an emergency blood transfusion. Frontline German Waffen-SS had such tattoos during World War II. Ironically, this was an easy form of SS identification.
Rare blood types can cause supply problems for blood banks and hospitals. For example Duffy-negative blood occurs much more frequently in people of African origin, and the rarity of this blood type in the rest of the population can result in a shortage of Duffy-negative blood for patients of African ethnicity. Similarly for RhD negative people, there is a risk associated with travelling to parts of the world where supplies of RhD negative blood are rare, particularly East Asia, where blood services may endeavor to encourage Westerners to donate blood.
## Hemolytic disease of the newborn (HDN)
A pregnant woman can make IgG blood group antibodies if her fetus has a blood group antigen that she does not have. This can happen if some of the fetus' blood cells pass into the mother's blood circulation (e.g. a small fetomaternal hemorrhage at the time of childbirth or obstetric intervention), or sometimes after a therapeutic blood transfusion. This can cause Rh disease or other forms of hemolytic disease of the newborn (HDN) in the current pregnancy and/or subsequent pregnancies. If a pregnant woman is known to have anti-RhD antibodies, the RhD blood type of a fetus can be tested by analysis of fetal DNA in maternal plasma to assess the risk to the fetus of Rh disease. Antibodies associated with some blood groups can cause severe HDN, others can only cause mild HDN and others are not known to cause HDN.
# Compatibility
## Blood products
In order to provide maximum benefit from each blood donation and to extend shelf-life, blood banks fractionate some whole blood into several products. The most common of these products are packed RBCs, plasma, platelets, cryoprecipitate, and fresh frozen plasma (FFP). FFP is quick-frozen to retain the labile clotting factors V and VIII, which are usually administered to patients who have a potentially fatal clotting problem caused by a condition such as advanced liver disease, overdose of anticoagulant, or disseminated intravascular coagulation (DIC).
Units of packed red cells are made by removing as much of the plasma as possible from whole blood units.
Clotting factors synthesized by modern recombinant methods are now in routine clinical use for hemophilia, as the risks of infection transmission that occur with pooled blood products are avoided.
## Red blood cell compatibility
- Blood group AB individuals have both A and B antigens on the surface of their RBCs, and their blood serum does not contain any antibodies against either A or B antigen. Therefore, an individual with type AB blood can receive blood from any group (with AB being preferable), but can donate blood only to another group AB individual.
- Blood group A individuals have the A antigen on the surface of their RBCs, and blood serum containing IgM antibodies against the B antigen. Therefore, a group A individual can receive blood only from individuals of groups A or O (with A being preferable), and can donate blood to individuals of groups A or AB.
- Blood group B individuals have the B antigen on the surface of their RBCs, and blood serum containing IgM antibodies against the A antigen. Therefore, a group B individual can receive blood only from individuals of groups B or O (with B being preferable), and can donate blood to individuals of groups B or AB.
- Blood group O (or blood group zero in some countries) individuals do not have either A or B antigens on the surface of their RBCs, but their blood serum contains IgM anti-A antibodies and anti-B antibodies against the A and B blood group antigens. Therefore, a group O individual can receive blood only from a group O individual, but can donate blood to individuals of any ABO blood group (ie A, B, O or AB). If anyone needs a blood transfusion in a dire emergency, and if the time taken to process the recipient's blood would cause a detrimental delay, O Negative blood can be issued.
Table note
1. Assumes absence of atypical antibodies that would cause an incompatibility between donor and recipient blood, as is usual for blood selected by cross matching.
A RhD negative patient who does not have any anti-RhD antibodies (never being previously sensitized to RhD positive RBCs) can receive a transfusion of RhD positive blood once, but this would cause sensitization to the RhD antigen, and a female patient would become at risk for hemolytic disease of the newborn. If a RhD negative patient has developed anti-RhD antibodies, a subsequent exposure to RhD positive blood would lead to a potentially dangerous transfusion reaction. RhD positive blood should never be given to RhD negative women of childbearing age or to patients with RhD antibodies, so blood banks must conserve Rhesus negative blood for these patients. In extreme circumstances, such as for a major bleed when stocks of RhD negative blood units are very low at the blood bank, RhD positive blood might be given to RhD negative females above child-bearing age or to Rh negative males, providing that they did not have anti-RhD antibodies, to conserve RhD negative blood stock in the blood bank.
The converse is not true; RhD positive patients do not react to RhD negative blood.
## Plasma compatibility
Donor-recipient compatibility for blood plasma is the converse of that of RBCs. Plasma extracted from type AB blood can be transfused to individuals of any blood group, but type O plasma can be used only by type O recipients.
Table note
1. Assumes absence of strong atypical antibodies in donor plasma
Rhesus D antibodies are uncommon, so generally neither RhD negative nor RhD positive blood contain anti-RhD antibodies. If a potential donor is found to have anti-RhD antibodies or any strong atypical blood group antibody by antibody screening in the blood bank, they would not be accepted as a donor (or in some blood banks the blood would be drawn the product would be appropriately labeled); therefore, donor blood plasma issued by a blood bank can be selected to be free of RhD antibodies and free of other atypical antibodies, and such donor plasma issued from a blood bank would be suitable for a recipient who may be RhD positive or RhD negative, as long as blood plasma and the recipient are ABO compatible.
## Universal donors and universal recipients
With regard to transfusions of whole blood or packed red blood cells, individuals with type O negative blood are often called universal donors, and those with type AB positive blood are called universal recipients (Strictly speaking this is not true and individuals with Bombay blood group or Hh antigen system are the universal donors). Although blood donors with particularly strong anti-A, anti-B or any atypical blood group antibody are excluded from blood donation, the terms universal donor and universal recipient are an over-simplification, because they only consider possible reactions of the recipient's anti-A and anti-B antibodies to transfused red blood cells, and also possible sensitisation to RhD antigens. The possible reactions of anti-A and anti-B antibodies present in the transfused blood to the recipients RBCs are not considered, because a relatively small volume of plasma containing antibodies is transfused.
By way of example; considering the transfusion of O RhD negative blood (universal donor blood) into a recipient of blood group A RhD positive, an immune reaction between the recipient's anti-B antibodies and the transfused RBCs is not anticipated. However, the relatively small amount of plasma in the transfused blood contains anti-A antibodies, which could react with the A antigens on the surface of the recipients RBCs, but a significant reaction is unlikely because of the dilution factors. Rhesus D sensitisization is not anticipated.
Additionally, red blood cell surface antigens other than A, B and Rh D, might cause adverse reactions and sensitization, if they can bind to the corresponding antibodies to generate an immune response. Transfusions are further complicated because platelets and white blood cells (WBCs) have their own systems of surface antigens, and sensitization to platelet or WBC antigens can occur as a result of transfusion.
With regard to transfusions of plasma, this situation is reversed. Type O plasma can be given only to O recipients, while AB plasma (which does not contain anti-A or anti-B antibodies) can be given to patients of any ABO blood group.
## Conversion
In April 2007, a method was discovered to convert blood types A, B, and AB to O, using enzymes. This method is still experimental and the resulting blood has yet to undergo human trials. The method specifically removes or converts antigens on the red blood cells, so other antigens and antibodies would remain. This does not help plasma compatibility, but that is a lesser concern since plasma has much more limited clinical utility in transfusion and is much easier to preserve.
# Popular use
The Japanese blood type theory of personality is a popular belief that a person's ABO blood type is predictive of their personality, character, and compatibility with others, according to books by Masahiko Nomi. This belief has carried over to a certain extent in other parts of East Asia such as South Korea and Taiwan. In Japan, asking someone their blood type is considered as normal as asking their astrological sign. It is also common for Japanese-made video games (especially role-playing games) and manga series to include blood type with character descriptions. This belief is completely dismissed by scientists.
The blood type diet is an American system whereby people seek improved health by modifying their food intake and lifestyle according to their ABO blood group and secretor status. This system includes some reference to differences in personality, but not to the extent of the Japanese theory. | Blood type
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]
A blood type (also called a blood group) is a classification of blood based on the presence or absence of inherited antigenic substances on the surface of red blood cells (RBCs). These antigens may be proteins, carbohydrates, glycoproteins or glycolipids, depending on the blood group system, and some of these antigens are also present on the surface of other types of cells of various tissues.
Several of these red blood cell surface antigens, that stem from one allele (or very closely linked genes), collectively form a blood group system.
Immunological effects of mismatched blood transfusions are much more likely to involve components of the ABO blood group system or the RhD antigen (also known as the Rhesus factor or Rhesus D antigen) of the Rhesus blood group system than components of any of the other blood group systems; hence, in the routine preparation of blood for transfusion in a blood bank, the presence or absence the immunogenic blood group antigens, the A antigen, the B antigen and the RhD antigen are always determined for all recipient and donor blood. This identifies the ABO blood group and the RhD antigen status, which are both stated in the common terminology A positive, O negative, etc., where a capital letter (A, B or O) refers to the ABO blood group, and positive or negative refers to the presence or absence of the RhD antigen of the Rhesus blood group system. In the routine preparation and selection of donor blood for blood transfusion, it is not necessary to determine the status of any other blood group antigens or antibodies, because antibody screening and cross-matching (or computer aided simulated cross-matching) prior to transfusion detects if there are any other blood group incompatibilities between potential donor blood and intended recipients.
If an individual is exposed to a blood group antigen that is not recognised as self, the immune system will produce antibodies that can specifically bind to that particular blood group antigen and an immunological memory against that antigen is formed. The individual will have become sensitized to that blood group antigen. These antibodies can bind to antigens on the surface of transfused red blood cells (or other tissue cells) often leading to destruction of the cells by recruitment of other components of the immune system. When IgM antibodies bind to the transfused cells, the transfused cells can clump. It is vital that compatible blood is selected for transfusions and that compatible tissue is selected for organ transplantation. Transfusion reactions involving minor antigens or weak antibodies may lead to minor problems. However, more serious incompatibilities can lead to a more vigorous immune response with massive RBC destruction, low blood pressure, and even death.
Blood types are inherited and represent contributions from both parents. Often, pregnant women carry a fetus with a different blood type from their own, and sometimes the mother forms antibodies against the red blood cells of the fetus, which causes hemolysis of fetal RBCs, and which in turn can lead to low fetal blood counts, a condition known as hemolytic disease of the newborn. Some blood types are associated with inheritance of other diseases; for example, the Kell antigen is associated with McLeod syndrome.[1] Certain blood types may affect susceptibility to infections, an example being the resistance to specific malaria species seen in individuals lacking the Duffy antigen.[2] The Duffy antigen, presumedly as a result of natural selection, is less common in ethnic groups from areas with a high incidence of malaria.[3]
The two most significant blood group systems were discovered during early experiments with blood transfusion: the ABO group in 1901[4] and the Rhesus group in 1937.[5] Development of the Coombs test in 1945,[6] the advent of transfusion medicine, and the understanding of hemolytic disease of the newborn led to discovery of more blood groups. Today, a total of 29 human blood group systems are recognized by the International Society of Blood Transfusion (ISBT).[7] A complete blood type would describe a full set of 29 substances on the surface of RBCs, and an individual's blood type is one of the many possible combinations of blood group antigens. Across the 29 blood groups, over 600 different blood group antigens have been found,[8] but many of these are very rare or are mainly found in certain ethnic groups. Almost always, an individual has the same blood group for life; but very rarely, an individual's blood type changes through addition or suppression of an antigen in infection, malignancy or autoimmune disease.[9] Blood types have been used in forensic science and in paternity testing, but both of these uses are being replaced by DNA analysis, which provides greater certitude.
# Blood group systems
## ABO blood group system
The ABO system is the most important blood group system in human blood transfusion. The associated anti-A antibodies and anti-B antibodies are usually "Immunoglobulin M", abbreviated IgM, antibodies. ABO IgM antibodies are produced in the first years of life by sensitization to environmental substances such as food, bacteria and viruses. The "O" in ABO is often called "0" (zero/null) in other languages.[10]
## Rhesus blood group system
The Rhesus system is the second most significant blood group system in human blood transfusion. The most significant Rhesus antigen is the RhD antigen because it is the most immunogenic of the five main rhesus antigens. It is common for RhD negative individuals not to have any anti-RhD IgG or IgM antibodies, because anti-RhD antibodies are not usually produced by sensitization against environmental substances. However, RhD negative individuals can produce IgG anti-RhD antibodies following a sensitizing event: possibly a fetomaternal transfusion of blood from a fetus in pregnancy or occasionally a blood transfusion with RhD positive RBCs.
### ABO and Rh distribution by nation
## Other blood group systems
The International Society of Blood Transfusion currently recognizes 29 blood group systems (including the ABO and Rh systems).[7] Thus, in addition to the ABO antigens and Rhesus antigens, many other antigens are expressed on the RBC surface membrane. For example, an individual can be AB RhD positive, and at the same time M and N positive (MNS system), K positive (Kell system), Lea or Leb negative (Lewis system), and so on, being positive or negative for each blood group system antigen. Many of the blood group systems were named after the patients in whom the corresponding antibodies were initially encountered.
# Clinical significance
## Blood transfusion
Transfusion medicine is a specialized branch of hematology that is concerned with the study of blood groups, along with the work of a blood bank to provide a transfusion service for blood and other blood products. Across the world, blood products must be prescribed by a medical doctor (licensed physician or surgeon) in a similar way as medicines. In the USA, blood products are tightly regulated by the Food and Drug Administration.
Much of the routine work of a blood bank involves testing blood from both donors and recipients to ensure that every individual recipient is given blood that is compatible and is as safe as possible. If a unit of incompatible blood is transfused between a donor and recipient, a severe acute immunological reaction, hemolysis (RBC destruction), renal failure and shock are likely to occur, and death is a possibility. Antibodies can be highly active and can attack RBCs and bind components of the complement system to cause massive hemolysis of the transfused blood.
Patients should ideally receive their own blood or type-specific blood products to minimize the chance of a transfusion reaction. Risks can be further reduced by cross-matching blood, but this may be skipped when blood is required for an emergency. Cross-matching involves mixing a sample of the recipient's blood with a sample of the donor's blood and checking to see if the mixture agglutinates, or forms clumps. If agglutination is not obvious by direct vision, blood bank technicians usually check for agglutination with a microscope. If agglutination occurs, that particular donor's blood cannot be transfused to that particular recipient. In a blood bank it is vital that all blood specimens are correctly identified, so labeling has been standardized using a barcode system known as ISBT 128.
The blood group may be included on identification tags or on tattoos worn by military personnel, in case they should need an emergency blood transfusion. Frontline German Waffen-SS had such tattoos during World War II. Ironically, this was an easy form of SS identification.[25]
Rare blood types can cause supply problems for blood banks and hospitals. For example Duffy-negative blood occurs much more frequently in people of African origin,[26] and the rarity of this blood type in the rest of the population can result in a shortage of Duffy-negative blood for patients of African ethnicity. Similarly for RhD negative people, there is a risk associated with travelling to parts of the world where supplies of RhD negative blood are rare, particularly East Asia, where blood services may endeavor to encourage Westerners to donate blood.[27]
## Hemolytic disease of the newborn (HDN)
A pregnant woman can make IgG blood group antibodies if her fetus has a blood group antigen that she does not have. This can happen if some of the fetus' blood cells pass into the mother's blood circulation (e.g. a small fetomaternal hemorrhage at the time of childbirth or obstetric intervention), or sometimes after a therapeutic blood transfusion. This can cause Rh disease or other forms of hemolytic disease of the newborn (HDN) in the current pregnancy and/or subsequent pregnancies. If a pregnant woman is known to have anti-RhD antibodies, the RhD blood type of a fetus can be tested by analysis of fetal DNA in maternal plasma to assess the risk to the fetus of Rh disease.[28] Antibodies associated with some blood groups can cause severe HDN, others can only cause mild HDN and others are not known to cause HDN.
# Compatibility
## Blood products
In order to provide maximum benefit from each blood donation and to extend shelf-life, blood banks fractionate some whole blood into several products. The most common of these products are packed RBCs, plasma, platelets, cryoprecipitate, and fresh frozen plasma (FFP). FFP is quick-frozen to retain the labile clotting factors V and VIII, which are usually administered to patients who have a potentially fatal clotting problem caused by a condition such as advanced liver disease, overdose of anticoagulant, or disseminated intravascular coagulation (DIC).
Units of packed red cells are made by removing as much of the plasma as possible from whole blood units.
Clotting factors synthesized by modern recombinant methods are now in routine clinical use for hemophilia, as the risks of infection transmission that occur with pooled blood products are avoided.
## Red blood cell compatibility
- Blood group AB individuals have both A and B antigens on the surface of their RBCs, and their blood serum does not contain any antibodies against either A or B antigen. Therefore, an individual with type AB blood can receive blood from any group (with AB being preferable), but can donate blood only to another group AB individual.
- Blood group A individuals have the A antigen on the surface of their RBCs, and blood serum containing IgM antibodies against the B antigen. Therefore, a group A individual can receive blood only from individuals of groups A or O (with A being preferable), and can donate blood to individuals of groups A or AB.
- Blood group B individuals have the B antigen on the surface of their RBCs, and blood serum containing IgM antibodies against the A antigen. Therefore, a group B individual can receive blood only from individuals of groups B or O (with B being preferable), and can donate blood to individuals of groups B or AB.
- Blood group O (or blood group zero in some countries) individuals do not have either A or B antigens on the surface of their RBCs, but their blood serum contains IgM anti-A antibodies and anti-B antibodies against the A and B blood group antigens. Therefore, a group O individual can receive blood only from a group O individual, but can donate blood to individuals of any ABO blood group (ie A, B, O or AB). If anyone needs a blood transfusion in a dire emergency, and if the time taken to process the recipient's blood would cause a detrimental delay, O Negative blood can be issued.
Table note
1. Assumes absence of atypical antibodies that would cause an incompatibility between donor and recipient blood, as is usual for blood selected by cross matching.
A RhD negative patient who does not have any anti-RhD antibodies (never being previously sensitized to RhD positive RBCs) can receive a transfusion of RhD positive blood once, but this would cause sensitization to the RhD antigen, and a female patient would become at risk for hemolytic disease of the newborn. If a RhD negative patient has developed anti-RhD antibodies, a subsequent exposure to RhD positive blood would lead to a potentially dangerous transfusion reaction. RhD positive blood should never be given to RhD negative women of childbearing age or to patients with RhD antibodies, so blood banks must conserve Rhesus negative blood for these patients. In extreme circumstances, such as for a major bleed when stocks of RhD negative blood units are very low at the blood bank, RhD positive blood might be given to RhD negative females above child-bearing age or to Rh negative males, providing that they did not have anti-RhD antibodies, to conserve RhD negative blood stock in the blood bank.
The converse is not true; RhD positive patients do not react to RhD negative blood.
## Plasma compatibility
Donor-recipient compatibility for blood plasma is the converse of that of RBCs. Plasma extracted from type AB blood can be transfused to individuals of any blood group, but type O plasma can be used only by type O recipients.
Table note
1. Assumes absence of strong atypical antibodies in donor plasma
Rhesus D antibodies are uncommon, so generally neither RhD negative nor RhD positive blood contain anti-RhD antibodies. If a potential donor is found to have anti-RhD antibodies or any strong atypical blood group antibody by antibody screening in the blood bank, they would not be accepted as a donor (or in some blood banks the blood would be drawn the product would be appropriately labeled); therefore, donor blood plasma issued by a blood bank can be selected to be free of RhD antibodies and free of other atypical antibodies, and such donor plasma issued from a blood bank would be suitable for a recipient who may be RhD positive or RhD negative, as long as blood plasma and the recipient are ABO compatible.
## Universal donors and universal recipients
With regard to transfusions of whole blood or packed red blood cells, individuals with type O negative blood are often called universal donors, and those with type AB positive blood are called universal recipients (Strictly speaking this is not true and individuals with Bombay blood group or Hh antigen system are the universal donors). Although blood donors with particularly strong anti-A, anti-B or any atypical blood group antibody are excluded from blood donation, the terms universal donor and universal recipient are an over-simplification, because they only consider possible reactions of the recipient's anti-A and anti-B antibodies to transfused red blood cells, and also possible sensitisation to RhD antigens. The possible reactions of anti-A and anti-B antibodies present in the transfused blood to the recipients RBCs are not considered, because a relatively small volume of plasma containing antibodies is transfused.
By way of example; considering the transfusion of O RhD negative blood (universal donor blood) into a recipient of blood group A RhD positive, an immune reaction between the recipient's anti-B antibodies and the transfused RBCs is not anticipated. However, the relatively small amount of plasma in the transfused blood contains anti-A antibodies, which could react with the A antigens on the surface of the recipients RBCs, but a significant reaction is unlikely because of the dilution factors. Rhesus D sensitisization is not anticipated.
Additionally, red blood cell surface antigens other than A, B and Rh D, might cause adverse reactions and sensitization, if they can bind to the corresponding antibodies to generate an immune response. Transfusions are further complicated because platelets and white blood cells (WBCs) have their own systems of surface antigens, and sensitization to platelet or WBC antigens can occur as a result of transfusion.
With regard to transfusions of plasma, this situation is reversed. Type O plasma can be given only to O recipients, while AB plasma (which does not contain anti-A or anti-B antibodies) can be given to patients of any ABO blood group.
## Conversion
In April 2007, a method was discovered to convert blood types A, B, and AB to O, using enzymes. This method is still experimental and the resulting blood has yet to undergo human trials.[31][32] The method specifically removes or converts antigens on the red blood cells, so other antigens and antibodies would remain. This does not help plasma compatibility, but that is a lesser concern since plasma has much more limited clinical utility in transfusion and is much easier to preserve.
# Popular use
The Japanese blood type theory of personality is a popular belief that a person's ABO blood type is predictive of their personality, character, and compatibility with others, according to books by Masahiko Nomi. This belief has carried over to a certain extent in other parts of East Asia such as South Korea and Taiwan. In Japan, asking someone their blood type is considered as normal as asking their astrological sign. It is also common for Japanese-made video games (especially role-playing games) and manga series to include blood type with character descriptions. This belief is completely dismissed by scientists.
The blood type diet is an American system whereby people seek improved health by modifying their food intake and lifestyle according to their ABO blood group and secretor status.[33] This system includes some reference to differences in personality, but not to the extent of the Japanese theory. | https://www.wikidoc.org/index.php/Blood_group | |
20a08eff3385af6a122dacd2ea27ebfd08459aed | wikidoc | Blood test | Blood test
# Overview
Blood tests are laboratory tests done on blood to gain an appreciation of disease states and the function of organs. Since blood flows throughout the body, acting as a medium for providing oxygen and other nutrients, and drawing waste products back to the excretory systems for disposal, the state of the bloodstream affects, or is affected by, many medical conditions. For these reasons, blood tests are the most commonly performed medical tests. Blood is obtained from one of the patient's veins by venipuncture or fingerprick, except for tests such as Arterial blood gas.
Blood is useful as it is a relatively non-invasive way to obtain cells, and extracellular fluid (plasma), from the body to check on its health. Although the term blood test is used, most routine tests (except for most haematology) are done on plasma or serum.
The list below includes both specific tests, and general techniques.
# Blood chemistry tests
A basic metabolic panel measures sodium, potassium, chloride, bicarbonate, blood urea nitrogen (BUN), magnesium, creatinine, and glucose. It also sometimes includes calcium.
While the regular glucose test is taken at a certain point in time, the glucose tolerance test involves repeated testing to determine the rate at which glucose is processed by the body.
While the above tests are all taken from venous blood, by contrast the arterial blood gas test is, as its name would suggest, taken from arterial blood, and is therefore more dangerous and uncomfortable.
# Large organic molecules
## Proteins
- Protein electrophoresis (general technique -- not a specific test)
- Western blot (general technique -- not a specific test)
- Liver function tests
## Antibody Proteins
- Serology (general technique -- not a specific test)
Wassermann test (for syphilis)
- Wassermann test (for syphilis)
- ELISA test
- Coombs test
## Other
- Polymerase chain reaction (DNA). DNA testing is today possible with even very small quantities of blood: this is commonly used in forensic science, but is now also part of the diagnostic process of many disorders.
- Northern blot (RNA)
# Cells
- Full blood count (or "complete blood count")
- Hematocrit and MCV ("mean corpuscular volume")
- Erythrocyte sedimentation rate (ESR)
- Cross-matching. Determination of blood type for blood transfusion or transplants
- Blood cultures are commonly taken if infection is suspected. Positive cultures and resulting sensitivity results are often useful in guiding medical treatment. | Blood test
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Blood tests are laboratory tests done on blood to gain an appreciation of disease states and the function of organs. Since blood flows throughout the body, acting as a medium for providing oxygen and other nutrients, and drawing waste products back to the excretory systems for disposal, the state of the bloodstream affects, or is affected by, many medical conditions. For these reasons, blood tests are the most commonly performed medical tests. Blood is obtained from one of the patient's veins by venipuncture or fingerprick, except for tests such as Arterial blood gas.
Blood is useful as it is a relatively non-invasive way to obtain cells, and extracellular fluid (plasma), from the body to check on its health. Although the term blood test is used, most routine tests (except for most haematology) are done on plasma or serum.
The list below includes both specific tests, and general techniques.
# Blood chemistry tests
A basic metabolic panel measures sodium, potassium, chloride, bicarbonate, blood urea nitrogen (BUN), magnesium, creatinine, and glucose. It also sometimes includes calcium.
While the regular glucose test is taken at a certain point in time, the glucose tolerance test involves repeated testing to determine the rate at which glucose is processed by the body.
While the above tests are all taken from venous blood, by contrast the arterial blood gas test is, as its name would suggest, taken from arterial blood, and is therefore more dangerous and uncomfortable.
# Large organic molecules
## Proteins
- Protein electrophoresis (general technique -- not a specific test)
- Western blot (general technique -- not a specific test)
- Liver function tests
## Antibody Proteins
- Serology (general technique -- not a specific test)
Wassermann test (for syphilis)
- Wassermann test (for syphilis)
- ELISA test
- Coombs test
## Other
- Polymerase chain reaction (DNA). DNA testing is today possible with even very small quantities of blood: this is commonly used in forensic science, but is now also part of the diagnostic process of many disorders.
- Northern blot (RNA)
# Cells
- Full blood count (or "complete blood count")
- Hematocrit and MCV ("mean corpuscular volume")
- Erythrocyte sedimentation rate (ESR)
- Cross-matching. Determination of blood type for blood transfusion or transplants
- Blood cultures are commonly taken if infection is suspected. Positive cultures and resulting sensitivity results are often useful in guiding medical treatment.
# External links
- Cold autoantibody webpage on "health a to z" | https://www.wikidoc.org/index.php/Blood_test | |
e915747ad2d926e0815abd6d215262c64bbabce8 | wikidoc | Boceprevir | Boceprevir
# Disclaimer
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# Overview
Boceprevir is an antiviral and protease inhibitor that is FDA approved for the treatment of chronic hepatitis C genotype 1 infection, in combination with peginterferon alfa and ribavirin, in adult patients with compensated liver disease, including cirrhosis, who are previously untreated or who have failed previous interferon and ribavirin therapy, including prior null responders, partial responders, and relapsers. Common adverse reactions include fatigue, anemia, nausea, headache and dysgeusia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Boceprevir must be administered in combination with peginterferon alfa and ribavirin. The dose of Boceprevir is 800 mg (four 200-mg capsules) three times daily (every 7 to 9 hours) with food (a meal or light snack). Refer to the prescribing information for peginterferon alfa and ribavirin for instructions on dosing.
- The following dosing recommendations differ for some subgroups from the dosing studied in the Phase 3 trials. Response-Guided Therapy (RGT) is recommended for most individuals, but longer dosing is recommended in targeted subgroups (e.g., patients with cirrhosis).
### Boceprevir/Peginterferon alfa/Ribavirin Combination Therapy: Patients Without Cirrhosis Who Are Previously Untreated or Who Previously Failed Interferon and Ribavirin Therapy
- Initiate therapy with peginterferon alfa and ribavirin for 4 weeks (Treatment Weeks 1вАУ4).
- Add Boceprevir 800 mg (four 200-mg capsules) orally three times daily (every 7 to 9 hours) to peginterferon alfa and ribavirin regimen after 4 weeks of treatment. Based on the patient's HCV-RNA levels at Treatment Week (TW) 8, TW12 and TW24, use the following guidelines to determine duration of treatment (see TABLE 1).
- Consideration should be given to treating previously untreated patients who are poorly interferon responsive (as determined at TW4) with 4 weeks peginterferon alfa and ribavirin followed by 44 weeks of Boceprevir 800 mg orally three times daily (every 7 to 9 hours) in combination with peginterferon alfa and ribavirin in order to maximize rates of SVR.
### Boceprevir/Peginterferon alfa/Ribavirin Combination Therapy: Patients with Cirrhosis
- Prior to initiating therapy in patients with compensated cirrhosis, see use in specific populations for additional information.
- Patients with compensated cirrhosis should receive 4 weeks peginterferon alfa and ribavirin followed by 44 weeks Boceprevir 800 mg (four 200-mg capsules) three times daily (every 7 to 9 hours) in combination with peginterferon alfa and ribavirin.
### Dose Modification
- Dose reduction of Boceprevir is not recommended.
- If a patient has a serious adverse reaction potentially related to peginterferon alfa and/or ribavirin, the peginterferon alfa and/or ribavirin dose should be reduced or discontinued. Refer to the prescribing information for peginterferon alfa and ribavirin for additional information about how to reduce and/or discontinue the peginterferon alfa and/or ribavirin dose. Boceprevir must not be administered in the absence of peginterferon alfa and ribavirin. If peginterferon alfa or ribavirin is permanently discontinued, Boceprevir must also be discontinued.
### Discontinuation of Dosing Based on Treatment Futility
- Discontinuation of therapy is recommended in all patients with 1) HCV-RNA levels of greater than or equal to 1000 IU per mL at TW8; or 2) HCV-RNA levels of greater than or equal to 100 IU per mL at TW12; or 3) confirmed detectable HCV-RNA levels at TW24.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Boceprevir in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Boceprevir in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Boceprevir FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Boceprevir in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Boceprevir in pediatric patients.
# Contraindications
- Contraindications to peginterferon alfa and ribavirin also apply to Boceprevir combination treatment. Refer to the respective prescribing information for a list of the contraindications for peginterferon alfa and ribavirin.
- Boceprevir in combination with peginterferon alfa and ribavirin is contraindicated in:
- Pregnant women and men whose female partners are pregnant because of the risks for birth defects and fetal death associated with ribavirin.
- Patients with a history of a hypersensitivity reaction to boceprevir.
- Coadministration with drugs that are highly dependent on CYP3A4/CYP3A5 for clearance, and for which elevated plasma concentrations are associated with serious and/or life-threatening events, including those in TABLE 2, is contraindicated.
- Coadministration with potent CYP3A4/CYP3A5 inducers, where significantly reduced boceprevir plasma concentrations may be associated with reduced efficacy, including those in TABLE 2, is contraindicated.
# Warnings
## Embryofetal Toxicity (Use with Ribavirin and Peginterferon Alfa)
- Ribavirin may cause birth defects and/or death of the exposed fetus. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Ribavirin therapy should not be started unless a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. Refer to the prescribing information for ribavirin for additional information.
- Women of childbearing potential and men must use at least two forms of effective contraception during treatment and for at least 6 months after treatment has concluded. One of these forms of contraception can be a combined oral contraceptive product containing at least 1 mg of norethindrone. Oral contraceptives containing lower doses of norethindrone and other forms of hormonal contraception have not been studied or are contraindicated. Routine monthly pregnancy tests must be performed during this time.
## Anemia (Use with Ribavirin and Peginterferon Alfa)
- Anemia has been reported with peginterferon alfa and ribavirin therapy. The addition of Boceprevir to peginterferon alfa and ] is associated with an additional decrease in hemoglobin concentrations. Complete blood counts (with white blood cell differential counts) should be obtained pretreatment, and at Treatment Weeks 2, 4, 8, and 12, and should be monitored closely at other time points, as clinically appropriate. If hemoglobin is less than 10 g per dL, a decrease in dosage of ribavirin is recommended; and if hemoglobin is less than 8.5 g per dL, discontinuation of ribavirin is recommended. If ribavirin is permanently discontinued for management of anemia, then peginterferon alfa and Boceprevir must also be discontinued. Refer to the prescribing information for ribavirin for additional information regarding dose reduction and/or discontinuation.
- In clinical trials with Boceprevir the proportion of subjects who experienced hemoglobin values less than 10 g per dL and less than 8.5 g per dL was higher in subjects treated with the combination of Boceprevir with Peginterferon alfa 2a®/Ribavirin® than in those treated with Peginterferon alfa 2a/Ribavirin alone (see TABLE 4). With the interventions used for anemia management in the clinical trials, the average additional decrease of hemoglobin was approximately 1 g per dL.
- In clinical trials, the median time to onset of hemoglobin less than 10 g per dL from the initiation of therapy was similar among subjects treated with the combination of Boceprevir and Peginterferon alfa 2a/Ribavirin (71 days with a range of 15-337 days), compared to those who received Peginterferon alfa 2a/Ribavirin (71 days with a range of 8-337 days). Certain adverse reactions consistent with symptoms of anemia, such as dyspnea, exertional dyspnea, dizziness and syncope were reported more frequently in subjects who received the combination of Boceprevir with Peginterferon alfa 2a/Ribavirin than in those treated with Peginterferon alfa 2a/Ribavirin alone.
- In clinical trials with Boceprevir, dose modifications (generally of Peginterferon alfa 2a/Ribavirin) due to anemia occurred twice as often in subjects treated with the combination of Boceprevir with Peginterferon alfa 2a/Ribavirin (26%) compared to Peginterferon alfa 2a/Ribavirin (13%). The proportion of subjects who discontinued study drug due to anemia was 1% in subjects treated with the combination of Boceprevir with Peginterferon alfa 2a/Ribavirin and 1% in subjects who received Peginterferon alfa 2a/Ribavirin. The use of erythropoiesis stimulating agents (ESAs) was permitted for management of anemia, at the investigator's discretion, with or without ribavirin dose reduction in the Phase 2 and 3 clinical trials. The proportion of subjects who received an ESA was 43% in those treated with the combination of Boceprevir with Peginterferon alfa 2a/Ribavirin compared to 24% in those treated with Peginterferon alfa 2a/Ribavirin alone. The proportion of subjects who received a transfusion for the management of anemia was 3% of subjects treated with the combination of Boceprevir with Peginterferon alfa 2a/Ribavirin compared to less than 1% in subjects who received Peginterferon alfa 2a/Ribavirin alone.
- Thromboembolic events have been associated with ESA use in other disease states; and have also been reported with peginterferon alfa use in hepatitis C patients. Thromboembolic events were reported in clinical trials with Boceprevir among subjects receiving the combination of Boceprevir with Peginterferon alfa 2a/Ribavirin, and among those receiving Peginterferon alfa 2a/Ribavirin alone, regardless of ESA use. No definite causality assessment or benefit risk assessment could be made for these events due to the presence of confounding factors and lack of randomization of ESA use.
- A randomized, parallel-arm, open-label clinical trial was conducted in previously untreated CHC subjects with genotype 1 infection to compare use of an ESA versus ribavirin dose reduction for initial management of anemia during therapy with Boceprevir in combination with peginterferon alfa-2b and ribavirin. Similar SVR rates were reported in subjects who were randomized to receive ribavirin dose reduction compared to subjects who were randomized to receive an ESA. In this trial, use of ESAs was associated with an increased risk of thromboembolic events including pulmonary embolism, acute myocardial infarction, cerebrovascular accident, and deep vein thrombosis compared to ribavirin dose reduction alone. The treatment discontinuation rate due to anemia was similar in subjects randomized to receive ribavirin dose reduction compared to subjects randomized to receive ESA (2% in each group). The transfusion rate was 4% in subjects randomized to receive ribavirin dose reduction and 2% in subjects randomized to receive ESA. Ribavirin dose reduction is recommended for the initial management of anemia.
## Neutropenia (Use with Ribavirin and Peginterferon Alfa)
- In Phase 2 and 3 clinical trials, seven percent of subjects receiving the combination of Boceprevir with Peginterferon alfa 2a/Ribavirin had neutrophil counts of less than 0.5 × 109 per L compared to 4% of subjects receiving Peginterferon alfa 2a/Ribavirin alone (see TABLE 4). Three subjects experienced severe or life-threatening infections associated with neutropenia, and two subjects experienced life-threatening neutropenia while receiving the combination of Boceprevir with Peginterferon alfa 2a/Ribavirin. Complete blood counts (with white blood cell differential counts) should be obtained at pretreatment, and at Treatment Weeks 2, 4, 8, and 12, and should be monitored closely at other time points, as clinically appropriate. Decreases in neutrophil counts may require dose reduction or discontinuation of peginterferon alfa and ribavirin. If peginterferon alfa and ribavirin are permanently discontinued, then Boceprevir must also be discontinued. Refer to the prescribing information for peginterferon alfa and ribavirin for additional information regarding dose reduction or discontinuation.
## Pancytopenia (Use with Ribavirin and Peginterferon Alfa)
- Serious cases of pancytopenia have been reported postmarketing in patients receiving Boceprevir in combination with peginterferon alfa and ribavirin. Complete blood counts (with white blood cell differential counts) should be obtained at pretreatment, and at Treatment Weeks 2, 4, 8, and 12, and should be monitored closely at other time points, as clinically appropriate. Refer to the prescribing information for ribavirin and peginterferon alfa for guidelines for discontinuation of therapy based on laboratory parameters.
## Hypersensitivity
- Serious acute hypersensitivity reactions (e.g., urticaria, angioedema) have been observed during combination therapy with Boceprevir, peginterferon alfa and ribavirin. If such an acute reaction occurs, combination therapy should be discontinued and appropriate medical therapy immediately instituted.
## Drug Interactions
- See TABLE 2 for a listing of drugs that are contraindicated for use with Boceprevir due to potentially life-threatening adverse events, significant drug interactions or loss of virologic activity. Please refer to TABLE 5 for established and other potentially significant drug interactions.
## Laboratory Tests
- HCV-RNA levels should be monitored at Treatment Weeks 4, 8, 12, and 24, at the end of treatment, during treatment follow-up, and for other time points as clinically indicated. Use of a sensitive real-time reverse-transcription polymerase chain reaction (RT-PCR) assay for monitoring HCV-RNA levels during treatment is recommended. The assay should have a lower limit of HCV-RNA quantification of equal to or less than 25 IU per mL, and a limit of HCV-RNA detection of approximately 10 to 15 IU per mL. For the purposes of assessing Response-Guided Therapy milestones, a confirmed "detectable but below limit of quantification" HCV-RNA result should not be considered equivalent to an "undetectable" HCV-RNA result (reported as "Target Not Detected" or "HCV-RNA Not Detected"). Complete blood count (with white blood cell differential counts) should be obtained at pretreatment, and at Treatment Weeks 2, 4, 8, and 12, and should be monitored closely at other time points, as clinically appropriate.
- Refer to the prescribing information for peginterferon alfa and ribavirin for pre-treatment, on-treatment and post-treatment laboratory testing recommendations including hematology, biochemistry (including hepatic function tests), and pregnancy testing requirements.
# Adverse Reactions
## Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of Boceprevir cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The following serious and otherwise important adverse drug reactions (ADRs) are discussed in detail in another section of the labeling:
- Anemia
- Neutropenia
- Pancytopenia
- Hypersensitivity
The most commonly reported adverse reactions (more than 35% of subjects regardless of investigator's causality assessment) in adult subjects were fatigue, anemia, nausea, headache, and dysgeusia when Boceprevir was used in combination with Peginterferon alfa 2a and Ribavirin.
- The safety of the combination of Boceprevir 800 mg three times daily with Peginterferon alfa 2a/Ribavirin was assessed in 2095 subjects with chronic hepatitis C in one Phase 2, open-label trial and two Phase 3, randomized, double-blind, placebo-controlled clinical trials. SPRINT-1 (subjects who were previously untreated) evaluated the use of Boceprevir in combination with Peginterferon alfa 2a/Ribavirin with or without a four-week lead-in period with Peginterferon alfa 2a/Ribavirin compared to Peginterferon alfa 2a/Ribavirin alone. SPRINT-2 (subjects who were previously untreated) and RESPOND-2 (subjects who had failed previous therapy) evaluated the use of Boceprevir 800 mg three times daily in combination with Peginterferon alfa 2a/Ribavirin with a four-week lead-in period with Peginterferon alfa 2a/Ribavirin compared to Peginterferon alfa 2a/Ribavirin alone. The population studied had a mean age of 49 years (3% of subjects were older than 65 years of age), 39% were female, 82% were white and 15% were black.
- During the four week lead-in period with Peginterferon alfa 2a/Ribavirin in subjects treated with the combination of Boceprevir with Peginterferon alfa 2a/Ribavirin, 28/1263 (2%) subjects experienced adverse reactions leading to discontinuation of treatment. During the entire course of treatment, the proportion of subjects who discontinued treatment due to adverse reactions was 13% for subjects receiving the combination of Boceprevir with Peginterferon alfa 2a/Ribavirin and 12% for subjects receiving Peginterferon alfa 2a/Ribavirin alone. Events resulting in discontinuation were similar to those seen in previous studies with Peginterferon alfa 2a/Ribavirin. Only anemia and fatigue were reported as events that led to discontinuation in more than 1% of subjects in any arm.
- Adverse reactions that led to dose modifications of any drug (primarily Peginterferon alfa 2a and Ribavirin) occurred in 39% of subjects receiving the combination of Boceprevir with Peginterferon alfa 2a/Ribavirin compared to 24% of subjects receiving Peginterferon alfa 2a/Ribavirin alone. The most common reason for dose reduction was anemia, which occurred more frequently in subjects receiving the combination of Boceprevir with Peginterferon alfa 2a/Ribavirin than in subjects receiving Peginterferon alfa 2a/Ribavirin alone.
- Serious adverse events were reported in 11% of subjects receiving the combination of Boceprevir with Peginterferon alfa 2a/Ribavirin and in 8% of subjects receiving Peginterferon alfa 2a/Ribavirin.
- Adverse events (regardless of investigator's causality assessment) reported in greater than or equal to 10% of subjects receiving the combination of Boceprevir with Peginterferon alfa 2a/Ribavirin and reported at a rate of greater than or equal to 5% than Peginterferon alfa 2a/Ribavirin alone in SPRINT-1, SPRINT-2, and RESPOND-2 are presented in TABLE 3.
## Other Important Adverse Reactions Reported in Clinical Trials
- Among subjects (previously untreated subjects or those who failed previous therapy) who received Boceprevir in combination with peginterferon alfa and ribavirin, the following adverse drug reactions were reported. These events are notable because of their seriousness, severity, or increased frequency in subjects who received Boceprevir in combination with peginterferon alfa and ribavirin compared with subjects who received only peginterferon alfa and ribavirin.
- Dysgeusia (alteration of taste) was an adverse event reported at an increased frequency in subjects receiving Boceprevir in combination with peginterferon alfa and ribavirin compared with subjects receiving peginterferon alfa and ribavirin alone. Adverse events such as dry mouth, nausea, vomiting and diarrhea were also reported at an increased frequency in subjects receiving Boceprevir in combination with peginterferon alfa and ribavirin.
- Changes in selected hematological parameters during treatment of adult subjects with the combination of Boceprevir with Peginterferon alfa 2a and Ribavirin are described in TABLE 4.
- Decreases in hemoglobin may require a decrease in dosage or discontinuation of ribavirin. If ribavirin is permanently discontinued, then peginterferon alfa and Boceprevir must also be discontinued.
- The proportion of subjects with decreased neutrophil and platelet counts was higher in subjects treated with Boceprevir in combination with Peginterferon alfa 2a/Ribavirin compared to subjects receiving Peginterferon alfa 2a/Ribavirin alone. Three percent of subjects receiving the combination of Boceprevir with Peginterferon alfa 2a/Ribavirin had platelet counts of less than 50 × 109 per L compared to 1% of subjects receiving Peginterferon alfa 2a/Ribavirin alone. Decreases in neutrophils or platelets may require a decrease in dosage or interruption of peginterferon alfa, or discontinuation of therapy. If peginterferon alfa is permanently discontinued, then ribavirin and Boceprevir must also be discontinued.
## Postmarketing Experience
The following adverse reactions have been identified during post-approval use of Boceprevir in combination with peginterferon alfa and ribavirin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- Blood and Lymphatic System Disorders: agranulocytosis, pancytopenia, thrombocytopenia.
- Gastrointestinal Disorders: mouth ulceration, stomatitis.
- Infections and Infestations: pneumonia, sepsis.
- Skin and Subcutaneous Tissue Disorders: angioedema, urticaria; drug rash with eosinophilia and systemic symptoms (DRESS) syndrome, exfoliative rash, exfoliative dermatitis, Stevens-Johnson syndrome, toxic skin eruption, toxicoderma.
# Drug Interactions
### Potential for Boceprevir to Affect Other Drugs
- Boceprevir is a strong inhibitor of CYP3A4/CYP3A5. Drugs metabolized primarily by CYP3A4/CYP3A5 may have increased exposure when administered with Boceprevir which could increase or prolong their therapeutic and adverse effects. Boceprevir does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP2E1 in vitro. In addition, boceprevir does not induce CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or CYP3A4/5 in vitro.
- Boceprevir is a potential inhibitor of p-glycoprotein (P-gp) based on in vitro studies. In a drug interaction trial conducted with digoxin, Boceprevir had limited p-glycoprotein inhibitory potential at clinically relevant concentrations.
### Potential for Other Drugs to Affect Boceprevir
- Boceprevir is primarily metabolized by aldo-ketoreductase (AKR). In drug interaction trials conducted with AKR inhibitors diflunisal and ibuprofen, boceprevir exposure did not increase to a clinically significant extent. Boceprevir may be coadministered with AKR inhibitors.
- Boceprevir is partly metabolized by CYP3A4/CYP3A5. It is also a substrate for p-glycoprotein. Coadministration of Boceprevir with drugs that induce or inhibit CYP3A4/CYP3A5 could decrease or increase exposure to boceprevir.
### Established and Other Potential Significant Drug Interactions
- TABLE 5 provides recommendations based on established or potentially clinically significant drug interactions. Boceprevir is contraindicated with drugs that are potent inducers of CYP3A4/CYP3A5 and drugs that are highly dependent on CYP3A4/CYP3A5 for clearance, and for which elevated plasma concentrations are associated with serious and/or life-threatening events.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
- Boceprevir must be administered in combination with peginterferon alfa and ribavirin
- Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin; and therefore ribavirin is contraindicated in women who are pregnant and in the male partners of women who are pregnant. Interferons have abortifacient effects in animals and should be assumed to have abortifacient potential in humans.
- Extreme caution must be taken to avoid pregnancy in female patients and female partners of male patients while taking this combination. Women of childbearing potential and their male partners should not receive ribavirin unless they are using effective contraception (two reliable forms) during treatment with ribavirin and for 6 months after treatment. One of these reliable forms of contraception can be a combined oral contraceptive product containing at least 1 mg of norethindrone. Oral contraceptives containing lower doses of norethindrone and other forms of hormonal contraception have not been studied or are contraindicated.
- In case of exposure during pregnancy, a Ribavirin Pregnancy Registry has been established to monitor maternal-fetal outcomes of pregnancies in female patients and female partners of male patients exposed to ribavirin during treatment and for 6 months following cessation of treatment. Physicians and patients are encouraged to report such cases by calling 1-800-593-2214.
- Boceprevir must not be used as a monotherapy. There are no adequate and well-controlled studies with Boceprevir in pregnant women. No effects on fetal development have been observed in rats and rabbits at boceprevir AUC exposures approximately 11.8- and 2.0-fold higher, respectively, than those in humans at the recommended dose of 800 mg three times daily.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Boceprevir in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Boceprevir during labor and delivery.
### Nursing Mothers
- It is not known whether Boceprevir is excreted into human breast milk. Levels of boceprevir and/or metabolites in the milk of lactating rats were slightly higher than levels observed in maternal blood. Peak blood concentrations of boceprevir and/or metabolites in nursing pups were less than 1% of those of maternal blood concentrations. Because of the potential for adverse reactions from the drug in nursing infants, a decision must be made whether to discontinue nursing or discontinue treatment with Boceprevir, taking into account the importance of the therapy to the mother.
### Pediatric Use
- The safety, efficacy, and pharmacokinetic profile of Boceprevir in pediatric patients have not been studied.
### Geriatic Use
- Clinical studies of Boceprevir did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration and monitoring of Boceprevir in geriatric patients due to the greater frequency of decreased hepatic function, concomitant diseases and other drug therapy.
### Gender
There is no FDA guidance on the use of Boceprevir with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Boceprevir with respect to specific racial populations.
### Renal Impairment
- No dosage adjustment of Boceprevir is required for patients with any degree of renal impairment.
### Hepatic Impairment
- No dose adjustment of Boceprevir is required for patients with mild, moderate or severe hepatic impairment. Safety and efficacy of Boceprevir have not been studied in patients with decompensated cirrhosis.
- In published observational studies of patients with compensated cirrhosis treated with first generation HCV protease inhibitors, including boceprevir, in combination with peginterferon alfa and ribavirin, platelet count < 100,000/mm3 and serum albumin < 3.5 g/dL were baseline characteristics that were identified as predictors of death or serious complications (severe infection or hepatic decompensation) during therapy.
- The potential risks and benefits of Boceprevir in combination with peginterferon alfa and ribavirin should be carefully considered before initiating therapy in patients with compensated cirrhosis who have platelet count < 100,000/mm3 and serum albumin < 3.5 g/dL at baseline. If therapy is initiated, close monitoring for signs of infections and worsening liver function is warranted.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Boceprevir in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Boceprevir in patients who are immunocompromised.
### Organ Transplantation
- The safety and efficacy of Boceprevir alone or in combination with peginterferon alfa and ribavirin for the treatment of chronic hepatitis C genotype 1 infection in liver or other organ transplant recipients have not been studied.
# Administration and Monitoring
### Administration
There is limited information regarding Boceprevir Administration in the drug label.
### Monitoring
There is limited information regarding Boceprevir Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Boceprevir and IV administrations.
# Overdosage
- Daily doses of 3600 mg have been taken by healthy volunteers for 5 days without untoward symptomatic effects.
- There is no specific antidote for overdose with Boceprevir. Treatment of overdosage with Boceprevir should consist of general supportive measures, including monitoring of vital signs, and observation of the patient's clinical status.
# Pharmacology
## Mechanism of Action
- Boceprevir is a direct acting antiviral drug against the hepatitis C virus
## Structure
- Boceprevir has the following chemical name: (1R,5S)-N-3-Amino-1-(cyclobutylmethyl)-2,3-dioxopropyl-3-carbonylamino-3,3-dimethyl-1-oxobutyl-6,6-dimethyl-3-azabicyclo3.1.0hexan-2(S)-carboxamide. The molecular formula is C27H45N5O5 and its molecular weight is 519.7. Boceprevir has the following structural formula:
## Pharmacodynamics
- The effect of boceprevir 800 mg and 1200 mg on QTc interval was evaluated in a randomized, multiple-dose, placebo-, and active-controlled (moxifloxacin 400 mg) 4-way crossover thorough QT study in 36 healthy subjects. In the study with demonstrated ability to detect small effects, the upper bound of the one-sided 95% confidence interval for the largest placebo-adjusted, baseline-corrected QTc based on individual correction method (QTcI) was below 10 ms, the threshold for regulatory concern. The dose of 1200 mg yields a boceprevir maximum exposure increase of approximately 15% which may not cover exposures due to coadministration with strong CYP3A4 inhibitors or use in patients with severe hepatic impairment. However, at the doses studied in the thorough QT study, no apparent concentration-QT relationship was identified. Thus, there is no expectation of a QTc effect under a higher exposure scenario.
## Pharmacokinetics
- Boceprevir capsules contain a 1:1 mixture of two diastereomers, SCH534128 and SCH534129. In plasma the diastereomer ratio changes to 2:1, favoring the active diastereomer, SCH534128. Plasma concentrations of boceprevir described below consist of both diastereomers SCH534128 and SCH534129, unless otherwise specified.
- In healthy subjects who received 800 mg three times daily alone, boceprevir drug exposure was characterized by AUC(т) of 5408 ng × hr per mL (n=71), Cmax of 1723 ng per mL (n=71), and Cmin of 88 ng per mL (n=71). Pharmacokinetic results were similar between healthy subjects and HCV-infected subjects.
### Absorption
- Boceprevir was absorbed following oral administration with a median Tmax of 2 hours. Steady state AUC, Cmax, and Cmin increased in a less-than-dose-proportional manner and individual exposures overlapped substantially at 800 mg and 1200 mg, suggesting diminished absorption at higher doses. Accumulation is minimal (0.8- to 1.5-fold) and pharmacokinetic steady state is achieved after approximately 1 day of three times daily dosing. The absolute bioavailability of boceprevir has not been studied.
- Effects of Food on Oral Absorption: Boceprevir should be administered with food. Food enhanced the exposure of boceprevir by up to 65% at the 800 mg three times daily dose, relative to the fasting state. The bioavailability of boceprevir was similar regardless of meal type (e.g., high-fat vs. low-fat) or whether taken 5 minutes prior to eating, during a meal, or immediately following completion of the meal. Therefore, Boceprevir may be taken without regard to either meal type or timing of the meal.
### Distribution
- Boceprevir has a mean apparent volume of distribution (Vd/F) of approximately 772 L at steady state in healthy subjects. Human plasma protein binding is approximately 75% following a single dose of boceprevir 800 mg. Boceprevir is administered as an approximately equal mixture of two diastereomers, SCH534128 and SCH534129, which rapidly interconvert in plasma. The predominant diastereomer, SCH534128, is pharmacologically active and the other diastereomer is inactive.
### Metabolism
- Studies in vitro indicate that boceprevir primarily undergoes metabolism through the aldo-keto reductase (AKR)-mediated pathway to ketone-reduced metabolites that are inactive against HCV. After a single 800-mg oral dose of 14C-boceprevir, the most abundant circulating metabolites were a diastereomeric mixture of ketone-reduced metabolites with a mean exposure approximately 4-fold greater than that of boceprevir. Boceprevir also undergoes, to a lesser extent, oxidative metabolism mediated by CYP3A4/5.
### Drug Interactions
- Drug interaction studies were performed with boceprevir and drugs likely to be coadministered or drugs commonly used as probes for pharmacokinetic interactions. The effects of coadministration of boceprevir on AUC, Cmax and Cmin are summarized in TABLE 6 (effects of coadministered drugs on boceprevir) and TABLE 7 (effects of boceprevir on coadministered drugs).
### Elimination
- Boceprevir is eliminated with a mean plasma half-life (t½) of approximately 3.4 hours. Boceprevir has a mean total body clearance (CL/F) of approximately 161 L per hr. Following a single 800 mg oral dose of 14C-boceprevir, approximately 79% and 9% of the dose was excreted in feces and urine, respectively, with approximately 8% and 3% of the dosed radiocarbon eliminated as boceprevir in feces and urine. The data indicate that boceprevir is eliminated primarily by the liver.
## Nonclinical Toxicology
### Carcinogenesis and Mutagenesis
- Use with Ribavirin and Peginterferon alfa: Ribavirin is genotoxic in in vitro and in vivo assays. Ribavirin was not oncogenic in mouse and rat carcinogenicity studies at doses less than the maximum recommended daily human dose. Please refer to the prescribing information for ribavirin for additional information.
- Two-year carcinogenicity studies in mice and rats were conducted with boceprevir. Mice were administered doses of up to 500 mg per kg in males and 650 mg per kg in females, and rats were administered doses of up to 125 mg per kg in males and 100 mg per kg in females. In mice, no significant increases in the incidence of drug-related neoplasms were observed at the highest doses tested resulting in boceprevir AUC exposures approximately 2.3- and 6.0-fold higher in males and females, respectively, than those in humans at the recommended dose of 800 mg three times daily. In rats, no increases in the incidence of drug-related neoplasms were observed at the highest doses tested resulting in boceprevir AUC exposures similar to those in humans at the recommended dose of 800 mg three times daily.
- Boceprevir was not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity, chromosomal aberration in human peripheral blood lymphocytes and mouse micronucleus assays.
### Impairment of Fertility
- Use with Ribavirin and Peginterferon alfa: In fertility studies in male animals, ribavirin induced reversible testicular toxicity; while peginterferon alfa may impair fertility in females. Please refer to the prescribing information for ribavirin and peginterferon alfa for additional information.
- Boceprevir-induced reversible effects on fertility and early embryonic development in female rats, with no effects observed at a 75 mg per kg dose level. At this dose, boceprevir AUC exposures are approximately 1.3-fold higher than those in humans at the recommended dose of 800 mg three times daily. Decreased fertility was also observed in male rats, most likely as a consequence of testicular degeneration. No testicular degeneration was observed at a 15 mg per kg dose level resulting in boceprevir AUC exposures of less than those in humans at the recommended dose of 800 mg three times daily. Testicular degeneration was not observed in mice or monkeys administered boceprevir for 3 months at doses of up to 900 or 1000 mg per kg, respectively. At these doses, boceprevir AUC exposures are approximately 6.8- and 4.4-fold higher in mice and monkeys, respectively, than those in humans at the recommended dose of 800 mg three times daily. Additionally, limited clinical monitoring has revealed no evidence of testicular toxicity in human subjects.
# Clinical Studies
The efficacy of Boceprevir as a treatment for chronic hepatitis C (genotype 1) infection was assessed in approximately 1500 adult subjects who were previously untreated (SPRINT-2) or who had failed previous peginterferon alfa and ribavirin therapy (RESPOND-2) in Phase 3 clinical studies.
## Previously Untreated Subjects
- SPRINT-2 was a randomized, double-blind, placebo-controlled study comparing two therapeutic regimens of Boceprevir 800 mg orally three times daily in combination with PR Peginterferon alfa 2a 1.5 micrograms per kg per week subcutaneously and weight-based dosing with Ribavirin (600вАУ1400 mg per day orally divided twice daily)] to PR alone in adult subjects who had chronic hepatitis C (HCV genotype 1) infection with detectable levels of HCV-RNA and were not previously treated with interferon alfa therapy. Subjects were randomized in a 1:1:1 ratio within two separate cohorts (Cohort 1/non-Black and Cohort 2/Black) and were stratified by HCV genotype (1a or 1b) and by HCV-RNA viral load (less than or equal to 400,000 IU per mL vs. more than 400,000 IU per mL) to one of the following three treatment arms:
- Peginterferon alfa 2a + Ribavirin for 48 weeks (PR48).
- Peginterferon alfa 2a + Ribavirin for four weeks followed by Boceprevir 800 mg three times daily + Peginterferon alfa 2a + Ribavirin for 24 weeks. The subjects were then continued on different regimens based on Treatment Week (TW) 8 through TW24 response-guided therapy (boceprevir-RGT). All subjects in this treatment arm were limited to 24 weeks of therapy with Boceprevir.
Subjects with undetectable HCV-RNA (Target Not Detected) at TW8 (early responders) and remained undetectable through TW24 discontinued therapy and entered follow-up at the TW28 visit.
Subjects with detectable HCV-RNA at TW8 or any subsequent treatment week but subsequently achieving undetectable HCV-RNA (Target Not Detected) at TW24 (late responders) were changed in a blinded fashion to placebo at the TW28 visit and continued therapy with Peginterferon alfa 2a + Ribavirin for an additional 20 weeks, for a total treatment duration of 48 weeks.
- Subjects with undetectable HCV-RNA (Target Not Detected) at TW8 (early responders) and remained undetectable through TW24 discontinued therapy and entered follow-up at the TW28 visit.
- Subjects with detectable HCV-RNA at TW8 or any subsequent treatment week but subsequently achieving undetectable HCV-RNA (Target Not Detected) at TW24 (late responders) were changed in a blinded fashion to placebo at the TW28 visit and continued therapy with Peginterferon alfa 2a + Ribavirin for an additional 20 weeks, for a total treatment duration of 48 weeks.
- Peginterferon alfa 2a + Ribavirin for four weeks followed by Boceprevir 800 mg three times daily + Peginterferon alfa 2a + Ribavirin for 44 weeks (boceprevir-PR48).
All subjects with detectable HCV-RNA in plasma at TW24 were discontinued from treatment. Sustained Virologic Response (SVR) was defined as plasma HCV-RNA less than 25 IU/mL at Follow-up Week 24. Plasma HCV-RNA results at Follow-up Week 12 were used if plasma HCV-RNA results at Follow-up Week 24 were missing.
Mean age of subjects randomized was 49 years. The racial distribution of subjects was as follows: 82% White, 14% Black, and 4% others. The distribution of subjects by gender was 60% men and 40% women.
The addition of Boceprevir to Peginterferon alfa 2a and Ribavirin significantly increased the SVR rates compared to Peginterferon alfa 2a and Ribavirin alone in the combined cohort (63% to 66% in arms containing Boceprevir vs. 38% PR48 control) for randomized subjects who received at least one dose of any study medication (Full-Analysis-Set population). SVR rates for Blacks who received the combination of Boceprevir with Peginterferon alfa 2a and Ribavirin were 42% to 53% in a predefined analysis (see TABLE 10).
- In subjects with cirrhosis at baseline, sustained virologic response was higher in those who received treatment with the combination of Boceprevir with Peginterferon alfa 2a and Ribavirin for 44 weeks after lead-in therapy with Peginterferon alfa 2a and Ribavirin (10/24, 42%) compared to those who received RGT (5/16 , 31%).
### Sustained Virologic Response (SVR) Based on TW8 HCV-RNA Results
- TABLE 11 presents sustained virologic response based on TW8 HCV-RNA results in previously untreated subjects. Fifty-seven percent (208/368) of subjects in the boceprevir-RGT arm and 56% (204/366) of subjects in the boceprevir-PR48 arm had undetectable HCV-RNA (Target Not Detected) at TW8 (early responders) compared with 17% (60/363) of subjects in the PR48 arm.
- Among subjects with detectable HCV-RNA at TW8 who had attained undetectable HCV-RNA (Target Not Detected) at TW24 and completed at least 28 weeks of treatment, the SVR rates were 66% (45/68) in boceprevir-RGT arm (4 weeks of Peginterferon alfa 2a and Ribavirin then 24 weeks of Boceprevir with Peginterferon alfa 2a and Ribavirin followed by 20 weeks of Peginterferon alfa 2a and Ribavirin alone) and 75% (55/73) in boceprevir-PR48 arms (4 weeks of Peginterferon alfa 2a and Ribavirin then 44 weeks of Boceprevir with Peginterferon alfa 2a and Ribavirin).
### Previous Partial Responders and Relapsers to Interferon and Ribavirin Therapy
- RESPOND-2 was a randomized, parallel-group, double-blind study comparing two therapeutic regimens of Boceprevir 800 mg orally three times daily in combination with PR ] 1.5 micrograms per kg per week subcutaneously and weight-based ribavirin (600вАУ1400 mg per day orally divided twice daily)] compared to PR alone in adult subjects with chronic hepatitis C (HCV genotype 1) infection with demonstrated interferon responsiveness (as defined historically by a decrease in HCV-RNA viral load greater than or equal to 2-log10 by Week 12, but never achieved SVR partial responders or undetectable HCV-RNA at end of prior treatment with a subsequent detectable HCV-RNA in plasma ). Subjects with less than 2-log10 decrease in HCV-RNA by week 12 of previous treatment (prior null responders) were not eligible for enrollment in this trial. Subjects were randomized in a 1:2:2 ratio and stratified based on response to their previous qualifying regimen (relapsers vs. partial responders) and by HCV subtype (1a vs. 1b) to one of the following treatment arms:
- Peginterferon alfa 2a + Ribavirin for 48 weeks (PR48)
- Peginterferon alfa 2a + Ribavirin for 4 weeks followed by Boceprevir 800 mg three times daily + Peginterferon alfa 2a + Ribavirin for 32 weeks. The subjects were then continued on different treatment regimens based on TW8 and TW12 response-guided therapy (boceprevir-RGT). All subjects in this treatment arm were limited to 32 weeks of Boceprevir.
Subjects with undetectable HCV-RNA (Target Not Detected) at TW8 (early responders) and TW12 completed therapy at TW36 visit.
Subjects with a detectable HCV-RNA at TW8 but subsequently undetectable (Target Not Detected) at TW12 (late responders) were changed in a blinded fashion to placebo at the TW36 visit and continued treatment with Peginterferon alfa 2a + Ribavirin for an additional 12 weeks, for a total treatment duration of 48 weeks.
- Subjects with undetectable HCV-RNA (Target Not Detected) at TW8 (early responders) and TW12 completed therapy at TW36 visit.
- Subjects with a detectable HCV-RNA at TW8 but subsequently undetectable (Target Not Detected) at TW12 (late responders) were changed in a blinded fashion to placebo at the TW36 visit and continued treatment with Peginterferon alfa 2a + Ribavirin for an additional 12 weeks, for a total treatment duration of 48 weeks.
- Peginterferon alfa 2a + Ribavirin for 4 weeks followed by Boceprevir 800 mg three times daily + Peginterferon alfa 2a + Ribavirin for 44 weeks (boceprevir-PR48).
- All subjects with detectable HCV-RNA in plasma at TW12 were discontinued from treatment. Sustained Virologic Response (SVR) was defined as plasma HCV-RNA less than 25 IU/mL at Follow-up Week 24. Plasma HCV-RNA results at Follow-up Week 12 were used if plasma HCV-RNA results at Follow-up Week 24 were missing.
- Mean age of subjects randomized was 53 years. The racial distribution of subjects was as follows: 85% White, 12% Black, and 3% others. The distribution of subjects by gender was 67% men and 33% women.
- The addition of Boceprevir to the Peginterferon alfa 2a and Ribavirin therapy significantly increased the SVR rates compared to Peginterferon alfa 2a/Ribavirin alone (59% to 66% in arms containing Boceprevir vs. 23% PR48 control) for randomized subjects who received at least one dose of any study medication (Full-Analysis-Set population) (see TABLE 12).
- In subjects with cirrhosis at baseline, sustained virologic response was higher in those who received treatment with the combination of Boceprevir with Peginterferon alfa 2a and Ribavirin for 44 weeks after 4 weeks of lead-in therapy with Peginterferon alfa 2a and Ribavirin (17/22, 77%) compared to those who received RGT (6/17, 35%).
### Sustained Virologic Response (SVR) Based on TW8 HCV-RNA Results
- TABLE 13 presents sustained virologic response based on TW8 HCV-RNA results in subjects who were relapsers or partial responders to previous interferon and ribavirin therapy. Forty-six percent (74/162) of subjects in the boceprevir-RGT arm and 52% (84/161) in the boceprevir-PR48 had undetectable HCV-RNA (Target Not Detected) at TW8 (early responders) compared with 9% (7/80) in the PR48 arm.
- Among subjects with detectable HCV-RNA at TW8 who attained an undetectable HCV-RNA (Target Not Detected) at TW12 and completed at least 36 weeks of treatment, the SVR rates were 79% (27/34) in boceprevir-RGT arm (4 weeks of Peginterferon alfa 2a and Ribavirin then 32 weeks of Boceprevir with Peginterferon alfa 2a and Ribavirin followed by 12 weeks of Peginterferon alfa 2a and Ribavirin alone) and 72% (29/40) in boceprevir-PR48 arm (4 weeks of Peginterferon alfa 2a and Ribavirin then 44 weeks of Boceprevir with Peginterferon alfa 2a and Ribavirin).
## Interferon Responsiveness during Lead-In Therapy with Peginterferon alfa and Ribavirin
## Previously Untreated Subjects
- In previously untreated subjects evaluated in SPRINT-2, interferon-responsiveness (defined as greater than or equal to 1-log10 decline in viral load at TW4) was predictive of SVR. Subjects treated with Boceprevir who demonstrated interferon responsiveness at TW4 achieved SVR rates of 81% (203/252) in boceprevir-RGT arm and 79% (200/254) in boceprevir-PR48 arm, compared to 52% (134/260) in subjects treated with Peginterferon alfa 2a/Ribavirin.
- Subjects treated with Boceprevir who demonstrated poor interferon responsiveness (defined as less than 1-log10 decline in viral load at TW4), achieved SVR rates of 28% (27/97) in boceprevir-RGT arm and 38% (36/95) in boceprevir-PR48 arm, compared to 4% (3/83) in subjects treated with Peginterferon alfa 2a/Ribavirin. Subjects with less than a 0.5-log10 decline in viral load at TW4 achieved SVR rates of 28% (13/47) in boceprevir-RGT arm and 30% (11/37) in boceprevir-PR48 arm, compared to 0% (0/25) in subjects treated with Peginterferon alfa 2a/Ribavirin. Subjects with less than a 0.5-log10 decline in viral load at TW4 with peginterferon alfa plus ribavirin therapy alone are predicted to have a null response (less than 2-log10 viral load decline at TW12) to peginterferon alfa and ribavirin.
## Previous Partial Responders and Relapsers to Interferon and Ribavirin Therapy
- In subjects who were previous relapsers and partial responders evaluated in RESPOND-2, interferon-responsiveness (defined as greater than or equal to 1-log10 decline in viral load at TW4) was predictive of SVR. Subjects treated with Boceprevir who demonstrated interferon responsiveness at TW4 achieved SVR rates of 74% (81/110) in boceprevir-RGT arm and 79% (90/114) in boceprevir-PR48 arm, compared to 27% (18/67) in subjects treated with Peginterferon alfa 2a/Ribavirin. Subjects treated with Boceprevir who demonstrated poor interferon responsiveness (defined as less than 1-log10 decline in viral load at TW4) achieved SVR rates of 33% (15/46) in boceprevir-RGT arm and 34% (15/44) in boceprevir-PR48 arm, compared to 0% (0/12) in subjects treated with Peginterferon alfa 2a/Ribavirin.
## Prior Null Responders to Interferon and Ribavirin Therapy
- PROVIDE was an open-label, single-arm trial of Boceprevir 800 mg orally three times daily in combination with peginterferon alfa-2b 1.5 micrograms per kg per week subcutaneously and weight-based ribavirin (600 вАУ 1,400 mg per day orally divided twice daily) in adult subjects with chronic hepatitis C (HCV) genotype 1 infection who did not achieve SVR while in the peginterferon alfa/ribavirin control arms of previous Phase 2 and 3 trials of combination therapy with Boceprevir Subjects who enrolled in PROVIDE within 2 weeks after the last dose of peginterferon alfa/ribavirin in the prior trial received Boceprevir 800 mg three times daily + peginterferon alfa-2b + ribavirin for 44 weeks. Subjects who were not able to enroll in this trial within 2 weeks received Peginterferon alfa 2a/Ribavirin lead-in for 4 weeks followed by Boceprevir 800 mg three times daily + peginterferon alfa-2b + ribavirin for 44 weeks.
Among subjects who were null responders in the peginterferon alfa/ribavirin control arm of the prior trial, SVR (reported as plasma HCV-RNA <25 IU/mL at follow-up week 24) was 38% (20/52) and the relapse rate was 13% (3/23).
## Use of Ribavirin Dose Reduction versus Erythropoiesis Stimulating Agent (ESA) in the Management of Anemia in Previously Untreated Subjects
- A randomized, parallel-arm, open-label study was conducted to compare two strategies for the management of anemia (use of ESA versus ribavirin dose reduction) in 687 subjects with previously untreated CHC genotype 1 infection who became anemic during therapy with Boceprevir 800 mg orally three times daily plus peginterferon alfa-2b 1.5 micrograms per kg per week subcutaneously and weight-based ribavirin (600 вАУ 1,400 mg orally per day divided twice daily). The study enrolled subjects with serum hemoglobin concentrations of less than 15 g per dL. Subjects were treated for 4 weeks with peginterferon alfa-2b and ribavirin followed by up to 44 weeks of Boceprevir plus peginterferon alfa-2b and ribavirin. If a subject became anemic (serum hemoglobin of approximately less than or equal to 10 g per dL within the treatment period), the subject was randomized in a 1:1 ratio to either ribavirin dose reduction (N=249) or use of erythropoietin 40,000 units subcutaneously once weekly for the management of the anemia (N=251). If serum hemoglobin concentrations continued to decrease to less than or equal to 8.5 g per dL, subjects could be treated with additional anemia interventions, including the addition of erythropoietin (18% of those in the ribavirin dose reduction arm) or ribavirin dose reduction (37% of those in the ESA arm).
- Mean age of subjects randomized was 49 years. The racial distribution of subjects was as follows: 77% White, 19% Black, and 4% other. The distribution of subjects by gender was 37% men and 63% women.
- The overall intent-to-treat SVR rate for all enrolled subjects (including those subjects who were not randomized to RBV dose reduction or ESA for the management of anemia) was 63% (431/687). The SVR rate in subjects randomized who received ribavirin dose reduction was 71% (178/249), similar to the SVR rate of 71% (178/251) in subjects randomized to receive an ESA. The relapse rates in subjects randomized to receive ribavirin dose reduction or an ESA were 10% (19/196) and 10% (19/197), respectively.
# How Supplied
- Boceprevir 200 mg capsules are comprised of a red-colored cap with the Merck logo printed in yellow ink, and a yellow-colored body with "314" printed in red ink. The capsules are packaged into a carton with 28 bottles containing 12 capsules (NDC 0085-0314-02).
## Storage
- Boceprevir Capsules should be refrigerated at 2вАУ8°C (36вАУ46°F) until dispensed. Avoid exposure to excessive heat. For patient use, refrigerated capsules of Boceprevir can remain stable until the expiration date printed on the label. Boceprevir can also be stored at room temperature up to 25°C (77°F) for 3 months. Keep container tightly closed.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Boceprevir Patient Counseling Information in the drug label.
# Precautions with Alcohol
- Alcohol-Boceprevir interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Victrelis
# Look-Alike Drug Names
There is limited information regarding Boceprevir Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Boceprevir
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alberto Plate [2]
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# Overview
Boceprevir is an antiviral and protease inhibitor that is FDA approved for the treatment of chronic hepatitis C genotype 1 infection, in combination with peginterferon alfa and ribavirin, in adult patients with compensated liver disease, including cirrhosis, who are previously untreated or who have failed previous interferon and ribavirin therapy, including prior null responders, partial responders, and relapsers. Common adverse reactions include fatigue, anemia, nausea, headache and dysgeusia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Boceprevir must be administered in combination with peginterferon alfa and ribavirin. The dose of Boceprevir is 800 mg (four 200-mg capsules) three times daily (every 7 to 9 hours) with food (a meal or light snack). Refer to the prescribing information for peginterferon alfa and ribavirin for instructions on dosing.
- The following dosing recommendations differ for some subgroups from the dosing studied in the Phase 3 trials. Response-Guided Therapy (RGT) is recommended for most individuals, but longer dosing is recommended in targeted subgroups (e.g., patients with cirrhosis).
### Boceprevir/Peginterferon alfa/Ribavirin Combination Therapy: Patients Without Cirrhosis Who Are Previously Untreated or Who Previously Failed Interferon and Ribavirin Therapy
- Initiate therapy with peginterferon alfa and ribavirin for 4 weeks (Treatment Weeks 1вАУ4).
- Add Boceprevir 800 mg (four 200-mg capsules) orally three times daily (every 7 to 9 hours) to peginterferon alfa and ribavirin regimen after 4 weeks of treatment. Based on the patient's HCV-RNA levels at Treatment Week (TW) 8, TW12 and TW24, use the following guidelines to determine duration of treatment (see TABLE 1).
- Consideration should be given to treating previously untreated patients who are poorly interferon responsive (as determined at TW4) with 4 weeks peginterferon alfa and ribavirin followed by 44 weeks of Boceprevir 800 mg orally three times daily (every 7 to 9 hours) in combination with peginterferon alfa and ribavirin in order to maximize rates of SVR.
### Boceprevir/Peginterferon alfa/Ribavirin Combination Therapy: Patients with Cirrhosis
- Prior to initiating therapy in patients with compensated cirrhosis, see use in specific populations for additional information.
- Patients with compensated cirrhosis should receive 4 weeks peginterferon alfa and ribavirin followed by 44 weeks Boceprevir 800 mg (four 200-mg capsules) three times daily (every 7 to 9 hours) in combination with peginterferon alfa and ribavirin.
### Dose Modification
- Dose reduction of Boceprevir is not recommended.
- If a patient has a serious adverse reaction potentially related to peginterferon alfa and/or ribavirin, the peginterferon alfa and/or ribavirin dose should be reduced or discontinued. Refer to the prescribing information for peginterferon alfa and ribavirin for additional information about how to reduce and/or discontinue the peginterferon alfa and/or ribavirin dose. Boceprevir must not be administered in the absence of peginterferon alfa and ribavirin. If peginterferon alfa or ribavirin is permanently discontinued, Boceprevir must also be discontinued.
### Discontinuation of Dosing Based on Treatment Futility
- Discontinuation of therapy is recommended in all patients with 1) HCV-RNA levels of greater than or equal to 1000 IU per mL at TW8; or 2) HCV-RNA levels of greater than or equal to 100 IU per mL at TW12; or 3) confirmed detectable HCV-RNA levels at TW24.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Boceprevir in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Boceprevir in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Boceprevir FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Boceprevir in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Boceprevir in pediatric patients.
# Contraindications
- Contraindications to peginterferon alfa and ribavirin also apply to Boceprevir combination treatment. Refer to the respective prescribing information for a list of the contraindications for peginterferon alfa and ribavirin.
- Boceprevir in combination with peginterferon alfa and ribavirin is contraindicated in:
- Pregnant women and men whose female partners are pregnant because of the risks for birth defects and fetal death associated with ribavirin.
- Patients with a history of a hypersensitivity reaction to boceprevir.
- Coadministration with drugs that are highly dependent on CYP3A4/CYP3A5 for clearance, and for which elevated plasma concentrations are associated with serious and/or life-threatening events, including those in TABLE 2, is contraindicated.
- Coadministration with potent CYP3A4/CYP3A5 inducers, where significantly reduced boceprevir plasma concentrations may be associated with reduced efficacy, including those in TABLE 2, is contraindicated.
# Warnings
## Embryofetal Toxicity (Use with Ribavirin and Peginterferon Alfa)
- Ribavirin may cause birth defects and/or death of the exposed fetus. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Ribavirin therapy should not be started unless a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. Refer to the prescribing information for ribavirin for additional information.
- Women of childbearing potential and men must use at least two forms of effective contraception during treatment and for at least 6 months after treatment has concluded. One of these forms of contraception can be a combined oral contraceptive product containing at least 1 mg of norethindrone. Oral contraceptives containing lower doses of norethindrone and other forms of hormonal contraception have not been studied or are contraindicated. Routine monthly pregnancy tests must be performed during this time.
## Anemia (Use with Ribavirin and Peginterferon Alfa)
- Anemia has been reported with peginterferon alfa and ribavirin therapy. The addition of Boceprevir to peginterferon alfa and [ribavirin]] is associated with an additional decrease in hemoglobin concentrations. Complete blood counts (with white blood cell differential counts) should be obtained pretreatment, and at Treatment Weeks 2, 4, 8, and 12, and should be monitored closely at other time points, as clinically appropriate. If hemoglobin is less than 10 g per dL, a decrease in dosage of ribavirin is recommended; and if hemoglobin is less than 8.5 g per dL, discontinuation of ribavirin is recommended. If ribavirin is permanently discontinued for management of anemia, then peginterferon alfa and Boceprevir must also be discontinued. Refer to the prescribing information for ribavirin for additional information regarding dose reduction and/or discontinuation.
- In clinical trials with Boceprevir the proportion of subjects who experienced hemoglobin values less than 10 g per dL and less than 8.5 g per dL was higher in subjects treated with the combination of Boceprevir with Peginterferon alfa 2a®/Ribavirin® than in those treated with Peginterferon alfa 2a/Ribavirin alone (see TABLE 4). With the interventions used for anemia management in the clinical trials, the average additional decrease of hemoglobin was approximately 1 g per dL.
- In clinical trials, the median time to onset of hemoglobin less than 10 g per dL from the initiation of therapy was similar among subjects treated with the combination of Boceprevir and Peginterferon alfa 2a/Ribavirin (71 days with a range of 15-337 days), compared to those who received Peginterferon alfa 2a/Ribavirin (71 days with a range of 8-337 days). Certain adverse reactions consistent with symptoms of anemia, such as dyspnea, exertional dyspnea, dizziness and syncope were reported more frequently in subjects who received the combination of Boceprevir with Peginterferon alfa 2a/Ribavirin than in those treated with Peginterferon alfa 2a/Ribavirin alone.
- In clinical trials with Boceprevir, dose modifications (generally of Peginterferon alfa 2a/Ribavirin) due to anemia occurred twice as often in subjects treated with the combination of Boceprevir with Peginterferon alfa 2a/Ribavirin (26%) compared to Peginterferon alfa 2a/Ribavirin (13%). The proportion of subjects who discontinued study drug due to anemia was 1% in subjects treated with the combination of Boceprevir with Peginterferon alfa 2a/Ribavirin and 1% in subjects who received Peginterferon alfa 2a/Ribavirin. The use of erythropoiesis stimulating agents (ESAs) was permitted for management of anemia, at the investigator's discretion, with or without ribavirin dose reduction in the Phase 2 and 3 clinical trials. The proportion of subjects who received an ESA was 43% in those treated with the combination of Boceprevir with Peginterferon alfa 2a/Ribavirin compared to 24% in those treated with Peginterferon alfa 2a/Ribavirin alone. The proportion of subjects who received a transfusion for the management of anemia was 3% of subjects treated with the combination of Boceprevir with Peginterferon alfa 2a/Ribavirin compared to less than 1% in subjects who received Peginterferon alfa 2a/Ribavirin alone.
- Thromboembolic events have been associated with ESA use in other disease states; and have also been reported with peginterferon alfa use in hepatitis C patients. Thromboembolic events were reported in clinical trials with Boceprevir among subjects receiving the combination of Boceprevir with Peginterferon alfa 2a/Ribavirin, and among those receiving Peginterferon alfa 2a/Ribavirin alone, regardless of ESA use. No definite causality assessment or benefit risk assessment could be made for these events due to the presence of confounding factors and lack of randomization of ESA use.
- A randomized, parallel-arm, open-label clinical trial was conducted in previously untreated CHC subjects with genotype 1 infection to compare use of an ESA versus ribavirin dose reduction for initial management of anemia during therapy with Boceprevir in combination with peginterferon alfa-2b and ribavirin. Similar SVR rates were reported in subjects who were randomized to receive ribavirin dose reduction compared to subjects who were randomized to receive an ESA. In this trial, use of ESAs was associated with an increased risk of thromboembolic events including pulmonary embolism, acute myocardial infarction, cerebrovascular accident, and deep vein thrombosis compared to ribavirin dose reduction alone. The treatment discontinuation rate due to anemia was similar in subjects randomized to receive ribavirin dose reduction compared to subjects randomized to receive ESA (2% in each group). The transfusion rate was 4% in subjects randomized to receive ribavirin dose reduction and 2% in subjects randomized to receive ESA. Ribavirin dose reduction is recommended for the initial management of anemia.
## Neutropenia (Use with Ribavirin and Peginterferon Alfa)
- In Phase 2 and 3 clinical trials, seven percent of subjects receiving the combination of Boceprevir with Peginterferon alfa 2a/Ribavirin had neutrophil counts of less than 0.5 × 109 per L compared to 4% of subjects receiving Peginterferon alfa 2a/Ribavirin alone (see TABLE 4). Three subjects experienced severe or life-threatening infections associated with neutropenia, and two subjects experienced life-threatening neutropenia while receiving the combination of Boceprevir with Peginterferon alfa 2a/Ribavirin. Complete blood counts (with white blood cell differential counts) should be obtained at pretreatment, and at Treatment Weeks 2, 4, 8, and 12, and should be monitored closely at other time points, as clinically appropriate. Decreases in neutrophil counts may require dose reduction or discontinuation of peginterferon alfa and ribavirin. If peginterferon alfa and ribavirin are permanently discontinued, then Boceprevir must also be discontinued. Refer to the prescribing information for peginterferon alfa and ribavirin for additional information regarding dose reduction or discontinuation.
## Pancytopenia (Use with Ribavirin and Peginterferon Alfa)
- Serious cases of pancytopenia have been reported postmarketing in patients receiving Boceprevir in combination with peginterferon alfa and ribavirin. Complete blood counts (with white blood cell differential counts) should be obtained at pretreatment, and at Treatment Weeks 2, 4, 8, and 12, and should be monitored closely at other time points, as clinically appropriate. Refer to the prescribing information for ribavirin and peginterferon alfa for guidelines for discontinuation of therapy based on laboratory parameters.
## Hypersensitivity
- Serious acute hypersensitivity reactions (e.g., urticaria, angioedema) have been observed during combination therapy with Boceprevir, peginterferon alfa and ribavirin. If such an acute reaction occurs, combination therapy should be discontinued and appropriate medical therapy immediately instituted.
## Drug Interactions
- See TABLE 2 for a listing of drugs that are contraindicated for use with Boceprevir due to potentially life-threatening adverse events, significant drug interactions or loss of virologic activity. Please refer to TABLE 5 for established and other potentially significant drug interactions.
## Laboratory Tests
- HCV-RNA levels should be monitored at Treatment Weeks 4, 8, 12, and 24, at the end of treatment, during treatment follow-up, and for other time points as clinically indicated. Use of a sensitive real-time reverse-transcription polymerase chain reaction (RT-PCR) assay for monitoring HCV-RNA levels during treatment is recommended. The assay should have a lower limit of HCV-RNA quantification of equal to or less than 25 IU per mL, and a limit of HCV-RNA detection of approximately 10 to 15 IU per mL. For the purposes of assessing Response-Guided Therapy milestones, a confirmed "detectable but below limit of quantification" HCV-RNA result should not be considered equivalent to an "undetectable" HCV-RNA result (reported as "Target Not Detected" or "HCV-RNA Not Detected"). Complete blood count (with white blood cell differential counts) should be obtained at pretreatment, and at Treatment Weeks 2, 4, 8, and 12, and should be monitored closely at other time points, as clinically appropriate.
- Refer to the prescribing information for peginterferon alfa and ribavirin for pre-treatment, on-treatment and post-treatment laboratory testing recommendations including hematology, biochemistry (including hepatic function tests), and pregnancy testing requirements.
# Adverse Reactions
## Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of Boceprevir cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The following serious and otherwise important adverse drug reactions (ADRs) are discussed in detail in another section of the labeling:
- Anemia
- Neutropenia
- Pancytopenia
- Hypersensitivity
The most commonly reported adverse reactions (more than 35% of subjects regardless of investigator's causality assessment) in adult subjects were fatigue, anemia, nausea, headache, and dysgeusia when Boceprevir was used in combination with Peginterferon alfa 2a and Ribavirin.
- The safety of the combination of Boceprevir 800 mg three times daily with Peginterferon alfa 2a/Ribavirin was assessed in 2095 subjects with chronic hepatitis C in one Phase 2, open-label trial and two Phase 3, randomized, double-blind, placebo-controlled clinical trials. SPRINT-1 (subjects who were previously untreated) evaluated the use of Boceprevir in combination with Peginterferon alfa 2a/Ribavirin with or without a four-week lead-in period with Peginterferon alfa 2a/Ribavirin compared to Peginterferon alfa 2a/Ribavirin alone. SPRINT-2 (subjects who were previously untreated) and RESPOND-2 (subjects who had failed previous therapy) evaluated the use of Boceprevir 800 mg three times daily in combination with Peginterferon alfa 2a/Ribavirin with a four-week lead-in period with Peginterferon alfa 2a/Ribavirin compared to Peginterferon alfa 2a/Ribavirin alone. The population studied had a mean age of 49 years (3% of subjects were older than 65 years of age), 39% were female, 82% were white and 15% were black.
- During the four week lead-in period with Peginterferon alfa 2a/Ribavirin in subjects treated with the combination of Boceprevir with Peginterferon alfa 2a/Ribavirin, 28/1263 (2%) subjects experienced adverse reactions leading to discontinuation of treatment. During the entire course of treatment, the proportion of subjects who discontinued treatment due to adverse reactions was 13% for subjects receiving the combination of Boceprevir with Peginterferon alfa 2a/Ribavirin and 12% for subjects receiving Peginterferon alfa 2a/Ribavirin alone. Events resulting in discontinuation were similar to those seen in previous studies with Peginterferon alfa 2a/Ribavirin. Only anemia and fatigue were reported as events that led to discontinuation in more than 1% of subjects in any arm.
- Adverse reactions that led to dose modifications of any drug (primarily Peginterferon alfa 2a and Ribavirin) occurred in 39% of subjects receiving the combination of Boceprevir with Peginterferon alfa 2a/Ribavirin compared to 24% of subjects receiving Peginterferon alfa 2a/Ribavirin alone. The most common reason for dose reduction was anemia, which occurred more frequently in subjects receiving the combination of Boceprevir with Peginterferon alfa 2a/Ribavirin than in subjects receiving Peginterferon alfa 2a/Ribavirin alone.
- Serious adverse events were reported in 11% of subjects receiving the combination of Boceprevir with Peginterferon alfa 2a/Ribavirin and in 8% of subjects receiving Peginterferon alfa 2a/Ribavirin.
- Adverse events (regardless of investigator's causality assessment) reported in greater than or equal to 10% of subjects receiving the combination of Boceprevir with Peginterferon alfa 2a/Ribavirin and reported at a rate of greater than or equal to 5% than Peginterferon alfa 2a/Ribavirin alone in SPRINT-1, SPRINT-2, and RESPOND-2 are presented in TABLE 3.
## Other Important Adverse Reactions Reported in Clinical Trials
- Among subjects (previously untreated subjects or those who failed previous therapy) who received Boceprevir in combination with peginterferon alfa and ribavirin, the following adverse drug reactions were reported. These events are notable because of their seriousness, severity, or increased frequency in subjects who received Boceprevir in combination with peginterferon alfa and ribavirin compared with subjects who received only peginterferon alfa and ribavirin.
- Dysgeusia (alteration of taste) was an adverse event reported at an increased frequency in subjects receiving Boceprevir in combination with peginterferon alfa and ribavirin compared with subjects receiving peginterferon alfa and ribavirin alone. Adverse events such as dry mouth, nausea, vomiting and diarrhea were also reported at an increased frequency in subjects receiving Boceprevir in combination with peginterferon alfa and ribavirin.
- Changes in selected hematological parameters during treatment of adult subjects with the combination of Boceprevir with Peginterferon alfa 2a and Ribavirin are described in TABLE 4.
- Decreases in hemoglobin may require a decrease in dosage or discontinuation of ribavirin. If ribavirin is permanently discontinued, then peginterferon alfa and Boceprevir must also be discontinued.
- The proportion of subjects with decreased neutrophil and platelet counts was higher in subjects treated with Boceprevir in combination with Peginterferon alfa 2a/Ribavirin compared to subjects receiving Peginterferon alfa 2a/Ribavirin alone. Three percent of subjects receiving the combination of Boceprevir with Peginterferon alfa 2a/Ribavirin had platelet counts of less than 50 × 109 per L compared to 1% of subjects receiving Peginterferon alfa 2a/Ribavirin alone. Decreases in neutrophils or platelets may require a decrease in dosage or interruption of peginterferon alfa, or discontinuation of therapy. If peginterferon alfa is permanently discontinued, then ribavirin and Boceprevir must also be discontinued.
## Postmarketing Experience
The following adverse reactions have been identified during post-approval use of Boceprevir in combination with peginterferon alfa and ribavirin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- Blood and Lymphatic System Disorders: agranulocytosis, pancytopenia, thrombocytopenia.
- Gastrointestinal Disorders: mouth ulceration, stomatitis.
- Infections and Infestations: pneumonia, sepsis.
- Skin and Subcutaneous Tissue Disorders: angioedema, urticaria; drug rash with eosinophilia and systemic symptoms (DRESS) syndrome, exfoliative rash, exfoliative dermatitis, Stevens-Johnson syndrome, toxic skin eruption, toxicoderma.
# Drug Interactions
### Potential for Boceprevir to Affect Other Drugs
- Boceprevir is a strong inhibitor of CYP3A4/CYP3A5. Drugs metabolized primarily by CYP3A4/CYP3A5 may have increased exposure when administered with Boceprevir which could increase or prolong their therapeutic and adverse effects. Boceprevir does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP2E1 in vitro. In addition, boceprevir does not induce CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or CYP3A4/5 in vitro.
- Boceprevir is a potential inhibitor of p-glycoprotein (P-gp) based on in vitro studies. In a drug interaction trial conducted with digoxin, Boceprevir had limited p-glycoprotein inhibitory potential at clinically relevant concentrations.
### Potential for Other Drugs to Affect Boceprevir
- Boceprevir is primarily metabolized by aldo-ketoreductase (AKR). In drug interaction trials conducted with AKR inhibitors diflunisal and ibuprofen, boceprevir exposure did not increase to a clinically significant extent. Boceprevir may be coadministered with AKR inhibitors.
- Boceprevir is partly metabolized by CYP3A4/CYP3A5. It is also a substrate for p-glycoprotein. Coadministration of Boceprevir with drugs that induce or inhibit CYP3A4/CYP3A5 could decrease or increase exposure to boceprevir.
### Established and Other Potential Significant Drug Interactions
- TABLE 5 provides recommendations based on established or potentially clinically significant drug interactions. Boceprevir is contraindicated with drugs that are potent inducers of CYP3A4/CYP3A5 and drugs that are highly dependent on CYP3A4/CYP3A5 for clearance, and for which elevated plasma concentrations are associated with serious and/or life-threatening events.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
- Boceprevir must be administered in combination with peginterferon alfa and ribavirin
- Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin; and therefore ribavirin is contraindicated in women who are pregnant and in the male partners of women who are pregnant. Interferons have abortifacient effects in animals and should be assumed to have abortifacient potential in humans.
- Extreme caution must be taken to avoid pregnancy in female patients and female partners of male patients while taking this combination. Women of childbearing potential and their male partners should not receive ribavirin unless they are using effective contraception (two reliable forms) during treatment with ribavirin and for 6 months after treatment. One of these reliable forms of contraception can be a combined oral contraceptive product containing at least 1 mg of norethindrone. Oral contraceptives containing lower doses of norethindrone and other forms of hormonal contraception have not been studied or are contraindicated.
- In case of exposure during pregnancy, a Ribavirin Pregnancy Registry has been established to monitor maternal-fetal outcomes of pregnancies in female patients and female partners of male patients exposed to ribavirin during treatment and for 6 months following cessation of treatment. Physicians and patients are encouraged to report such cases by calling 1-800-593-2214.
- Boceprevir must not be used as a monotherapy. There are no adequate and well-controlled studies with Boceprevir in pregnant women. No effects on fetal development have been observed in rats and rabbits at boceprevir AUC exposures approximately 11.8- and 2.0-fold higher, respectively, than those in humans at the recommended dose of 800 mg three times daily.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Boceprevir in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Boceprevir during labor and delivery.
### Nursing Mothers
- It is not known whether Boceprevir is excreted into human breast milk. Levels of boceprevir and/or metabolites in the milk of lactating rats were slightly higher than levels observed in maternal blood. Peak blood concentrations of boceprevir and/or metabolites in nursing pups were less than 1% of those of maternal blood concentrations. Because of the potential for adverse reactions from the drug in nursing infants, a decision must be made whether to discontinue nursing or discontinue treatment with Boceprevir, taking into account the importance of the therapy to the mother.
### Pediatric Use
- The safety, efficacy, and pharmacokinetic profile of Boceprevir in pediatric patients have not been studied.
### Geriatic Use
- Clinical studies of Boceprevir did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration and monitoring of Boceprevir in geriatric patients due to the greater frequency of decreased hepatic function, concomitant diseases and other drug therapy.
### Gender
There is no FDA guidance on the use of Boceprevir with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Boceprevir with respect to specific racial populations.
### Renal Impairment
- No dosage adjustment of Boceprevir is required for patients with any degree of renal impairment.
### Hepatic Impairment
- No dose adjustment of Boceprevir is required for patients with mild, moderate or severe hepatic impairment. Safety and efficacy of Boceprevir have not been studied in patients with decompensated cirrhosis.
- In published observational studies of patients with compensated cirrhosis treated with first generation HCV protease inhibitors, including boceprevir, in combination with peginterferon alfa and ribavirin, platelet count < 100,000/mm3 and serum albumin < 3.5 g/dL were baseline characteristics that were identified as predictors of death or serious complications (severe infection or hepatic decompensation) during therapy.
- The potential risks and benefits of Boceprevir in combination with peginterferon alfa and ribavirin should be carefully considered before initiating therapy in patients with compensated cirrhosis who have platelet count < 100,000/mm3 and serum albumin < 3.5 g/dL at baseline. If therapy is initiated, close monitoring for signs of infections and worsening liver function is warranted.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Boceprevir in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Boceprevir in patients who are immunocompromised.
### Organ Transplantation
- The safety and efficacy of Boceprevir alone or in combination with peginterferon alfa and ribavirin for the treatment of chronic hepatitis C genotype 1 infection in liver or other organ transplant recipients have not been studied.
# Administration and Monitoring
### Administration
There is limited information regarding Boceprevir Administration in the drug label.
### Monitoring
There is limited information regarding Boceprevir Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Boceprevir and IV administrations.
# Overdosage
- Daily doses of 3600 mg have been taken by healthy volunteers for 5 days without untoward symptomatic effects.
- There is no specific antidote for overdose with Boceprevir. Treatment of overdosage with Boceprevir should consist of general supportive measures, including monitoring of vital signs, and observation of the patient's clinical status.
# Pharmacology
## Mechanism of Action
- Boceprevir is a direct acting antiviral drug against the hepatitis C virus
## Structure
- Boceprevir has the following chemical name: (1R,5S)-N-3-Amino-1-(cyclobutylmethyl)-2,3-dioxopropyl-3-[2(S)-(1,1-dimethylethyl)amino]carbonylamino-3,3-dimethyl-1-oxobutyl-6,6-dimethyl-3-azabicyclo3.1.0hexan-2(S)-carboxamide. The molecular formula is C27H45N5O5 and its molecular weight is 519.7. Boceprevir has the following structural formula:
## Pharmacodynamics
- The effect of boceprevir 800 mg and 1200 mg on QTc interval was evaluated in a randomized, multiple-dose, placebo-, and active-controlled (moxifloxacin 400 mg) 4-way crossover thorough QT study in 36 healthy subjects. In the study with demonstrated ability to detect small effects, the upper bound of the one-sided 95% confidence interval for the largest placebo-adjusted, baseline-corrected QTc based on individual correction method (QTcI) was below 10 ms, the threshold for regulatory concern. The dose of 1200 mg yields a boceprevir maximum exposure increase of approximately 15% which may not cover exposures due to coadministration with strong CYP3A4 inhibitors or use in patients with severe hepatic impairment. However, at the doses studied in the thorough QT study, no apparent concentration-QT relationship was identified. Thus, there is no expectation of a QTc effect under a higher exposure scenario.
## Pharmacokinetics
- Boceprevir capsules contain a 1:1 mixture of two diastereomers, SCH534128 and SCH534129. In plasma the diastereomer ratio changes to 2:1, favoring the active diastereomer, SCH534128. Plasma concentrations of boceprevir described below consist of both diastereomers SCH534128 and SCH534129, unless otherwise specified.
- In healthy subjects who received 800 mg three times daily alone, boceprevir drug exposure was characterized by AUC(т) of 5408 ng × hr per mL (n=71), Cmax of 1723 ng per mL (n=71), and Cmin of 88 ng per mL (n=71). Pharmacokinetic results were similar between healthy subjects and HCV-infected subjects.
### Absorption
- Boceprevir was absorbed following oral administration with a median Tmax of 2 hours. Steady state AUC, Cmax, and Cmin increased in a less-than-dose-proportional manner and individual exposures overlapped substantially at 800 mg and 1200 mg, suggesting diminished absorption at higher doses. Accumulation is minimal (0.8- to 1.5-fold) and pharmacokinetic steady state is achieved after approximately 1 day of three times daily dosing. The absolute bioavailability of boceprevir has not been studied.
- Effects of Food on Oral Absorption: Boceprevir should be administered with food. Food enhanced the exposure of boceprevir by up to 65% at the 800 mg three times daily dose, relative to the fasting state. The bioavailability of boceprevir was similar regardless of meal type (e.g., high-fat vs. low-fat) or whether taken 5 minutes prior to eating, during a meal, or immediately following completion of the meal. Therefore, Boceprevir may be taken without regard to either meal type or timing of the meal.
### Distribution
- Boceprevir has a mean apparent volume of distribution (Vd/F) of approximately 772 L at steady state in healthy subjects. Human plasma protein binding is approximately 75% following a single dose of boceprevir 800 mg. Boceprevir is administered as an approximately equal mixture of two diastereomers, SCH534128 and SCH534129, which rapidly interconvert in plasma. The predominant diastereomer, SCH534128, is pharmacologically active and the other diastereomer is inactive.
### Metabolism
- Studies in vitro indicate that boceprevir primarily undergoes metabolism through the aldo-keto reductase (AKR)-mediated pathway to ketone-reduced metabolites that are inactive against HCV. After a single 800-mg oral dose of 14C-boceprevir, the most abundant circulating metabolites were a diastereomeric mixture of ketone-reduced metabolites with a mean exposure approximately 4-fold greater than that of boceprevir. Boceprevir also undergoes, to a lesser extent, oxidative metabolism mediated by CYP3A4/5.
### Drug Interactions
- Drug interaction studies were performed with boceprevir and drugs likely to be coadministered or drugs commonly used as probes for pharmacokinetic interactions. The effects of coadministration of boceprevir on AUC, Cmax and Cmin are summarized in TABLE 6 (effects of coadministered drugs on boceprevir) and TABLE 7 (effects of boceprevir on coadministered drugs).
### Elimination
- Boceprevir is eliminated with a mean plasma half-life (t½) of approximately 3.4 hours. Boceprevir has a mean total body clearance (CL/F) of approximately 161 L per hr. Following a single 800 mg oral dose of 14C-boceprevir, approximately 79% and 9% of the dose was excreted in feces and urine, respectively, with approximately 8% and 3% of the dosed radiocarbon eliminated as boceprevir in feces and urine. The data indicate that boceprevir is eliminated primarily by the liver.
## Nonclinical Toxicology
### Carcinogenesis and Mutagenesis
- Use with Ribavirin and Peginterferon alfa: Ribavirin is genotoxic in in vitro and in vivo assays. Ribavirin was not oncogenic in mouse and rat carcinogenicity studies at doses less than the maximum recommended daily human dose. Please refer to the prescribing information for ribavirin for additional information.
- Two-year carcinogenicity studies in mice and rats were conducted with boceprevir. Mice were administered doses of up to 500 mg per kg in males and 650 mg per kg in females, and rats were administered doses of up to 125 mg per kg in males and 100 mg per kg in females. In mice, no significant increases in the incidence of drug-related neoplasms were observed at the highest doses tested resulting in boceprevir AUC exposures approximately 2.3- and 6.0-fold higher in males and females, respectively, than those in humans at the recommended dose of 800 mg three times daily. In rats, no increases in the incidence of drug-related neoplasms were observed at the highest doses tested resulting in boceprevir AUC exposures similar to those in humans at the recommended dose of 800 mg three times daily.
- Boceprevir was not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity, chromosomal aberration in human peripheral blood lymphocytes and mouse micronucleus assays.
### Impairment of Fertility
- Use with Ribavirin and Peginterferon alfa: In fertility studies in male animals, ribavirin induced reversible testicular toxicity; while peginterferon alfa may impair fertility in females. Please refer to the prescribing information for ribavirin and peginterferon alfa for additional information.
- Boceprevir-induced reversible effects on fertility and early embryonic development in female rats, with no effects observed at a 75 mg per kg dose level. At this dose, boceprevir AUC exposures are approximately 1.3-fold higher than those in humans at the recommended dose of 800 mg three times daily. Decreased fertility was also observed in male rats, most likely as a consequence of testicular degeneration. No testicular degeneration was observed at a 15 mg per kg dose level resulting in boceprevir AUC exposures of less than those in humans at the recommended dose of 800 mg three times daily. Testicular degeneration was not observed in mice or monkeys administered boceprevir for 3 months at doses of up to 900 or 1000 mg per kg, respectively. At these doses, boceprevir AUC exposures are approximately 6.8- and 4.4-fold higher in mice and monkeys, respectively, than those in humans at the recommended dose of 800 mg three times daily. Additionally, limited clinical monitoring has revealed no evidence of testicular toxicity in human subjects.
# Clinical Studies
The efficacy of Boceprevir as a treatment for chronic hepatitis C (genotype 1) infection was assessed in approximately 1500 adult subjects who were previously untreated (SPRINT-2) or who had failed previous peginterferon alfa and ribavirin therapy (RESPOND-2) in Phase 3 clinical studies.
## Previously Untreated Subjects
- SPRINT-2 was a randomized, double-blind, placebo-controlled study comparing two therapeutic regimens of Boceprevir 800 mg orally three times daily in combination with PR Peginterferon alfa 2a 1.5 micrograms per kg per week subcutaneously and weight-based dosing with Ribavirin (600вАУ1400 mg per day orally divided twice daily)] to PR alone in adult subjects who had chronic hepatitis C (HCV genotype 1) infection with detectable levels of HCV-RNA and were not previously treated with interferon alfa therapy. Subjects were randomized in a 1:1:1 ratio within two separate cohorts (Cohort 1/non-Black and Cohort 2/Black) and were stratified by HCV genotype (1a or 1b) and by HCV-RNA viral load (less than or equal to 400,000 IU per mL vs. more than 400,000 IU per mL) to one of the following three treatment arms:
- Peginterferon alfa 2a + Ribavirin for 48 weeks (PR48).
- Peginterferon alfa 2a + Ribavirin for four weeks followed by Boceprevir 800 mg three times daily + Peginterferon alfa 2a + Ribavirin for 24 weeks. The subjects were then continued on different regimens based on Treatment Week (TW) 8 through TW24 response-guided therapy (boceprevir-RGT). All subjects in this treatment arm were limited to 24 weeks of therapy with Boceprevir.
Subjects with undetectable HCV-RNA (Target Not Detected) at TW8 (early responders) and remained undetectable through TW24 discontinued therapy and entered follow-up at the TW28 visit.
Subjects with detectable HCV-RNA at TW8 or any subsequent treatment week but subsequently achieving undetectable HCV-RNA (Target Not Detected) at TW24 (late responders) were changed in a blinded fashion to placebo at the TW28 visit and continued therapy with Peginterferon alfa 2a + Ribavirin for an additional 20 weeks, for a total treatment duration of 48 weeks.
- Subjects with undetectable HCV-RNA (Target Not Detected) at TW8 (early responders) and remained undetectable through TW24 discontinued therapy and entered follow-up at the TW28 visit.
- Subjects with detectable HCV-RNA at TW8 or any subsequent treatment week but subsequently achieving undetectable HCV-RNA (Target Not Detected) at TW24 (late responders) were changed in a blinded fashion to placebo at the TW28 visit and continued therapy with Peginterferon alfa 2a + Ribavirin for an additional 20 weeks, for a total treatment duration of 48 weeks.
- Peginterferon alfa 2a + Ribavirin for four weeks followed by Boceprevir 800 mg three times daily + Peginterferon alfa 2a + Ribavirin for 44 weeks (boceprevir-PR48).
All subjects with detectable HCV-RNA in plasma at TW24 were discontinued from treatment. Sustained Virologic Response (SVR) was defined as plasma HCV-RNA less than 25 IU/mL at Follow-up Week 24. Plasma HCV-RNA results at Follow-up Week 12 were used if plasma HCV-RNA results at Follow-up Week 24 were missing.
Mean age of subjects randomized was 49 years. The racial distribution of subjects was as follows: 82% White, 14% Black, and 4% others. The distribution of subjects by gender was 60% men and 40% women.
The addition of Boceprevir to Peginterferon alfa 2a and Ribavirin significantly increased the SVR rates compared to Peginterferon alfa 2a and Ribavirin alone in the combined cohort (63% to 66% in arms containing Boceprevir vs. 38% PR48 control) for randomized subjects who received at least one dose of any study medication (Full-Analysis-Set population). SVR rates for Blacks who received the combination of Boceprevir with Peginterferon alfa 2a and Ribavirin were 42% to 53% in a predefined analysis (see TABLE 10).
- In subjects with cirrhosis at baseline, sustained virologic response was higher in those who received treatment with the combination of Boceprevir with Peginterferon alfa 2a and Ribavirin for 44 weeks after lead-in therapy with Peginterferon alfa 2a and Ribavirin (10/24, 42%) compared to those who received RGT (5/16 , 31%).
### Sustained Virologic Response (SVR) Based on TW8 HCV-RNA Results
- TABLE 11 presents sustained virologic response based on TW8 HCV-RNA results in previously untreated subjects. Fifty-seven percent (208/368) of subjects in the boceprevir-RGT arm and 56% (204/366) of subjects in the boceprevir-PR48 arm had undetectable HCV-RNA (Target Not Detected) at TW8 (early responders) compared with 17% (60/363) of subjects in the PR48 arm.
- Among subjects with detectable HCV-RNA at TW8 who had attained undetectable HCV-RNA (Target Not Detected) at TW24 and completed at least 28 weeks of treatment, the SVR rates were 66% (45/68) in boceprevir-RGT arm (4 weeks of Peginterferon alfa 2a and Ribavirin then 24 weeks of Boceprevir with Peginterferon alfa 2a and Ribavirin followed by 20 weeks of Peginterferon alfa 2a and Ribavirin alone) and 75% (55/73) in boceprevir-PR48 arms (4 weeks of Peginterferon alfa 2a and Ribavirin then 44 weeks of Boceprevir with Peginterferon alfa 2a and Ribavirin).
### Previous Partial Responders and Relapsers to Interferon and Ribavirin Therapy
- RESPOND-2 was a randomized, parallel-group, double-blind study comparing two therapeutic regimens of Boceprevir 800 mg orally three times daily in combination with PR [[[Peginterferon alfa 2a]] 1.5 micrograms per kg per week subcutaneously and weight-based ribavirin (600вАУ1400 mg per day orally divided twice daily)] compared to PR alone in adult subjects with chronic hepatitis C (HCV genotype 1) infection with demonstrated interferon responsiveness (as defined historically by a decrease in HCV-RNA viral load greater than or equal to 2-log10 by Week 12, but never achieved SVR partial responders or undetectable HCV-RNA at end of prior treatment with a subsequent detectable HCV-RNA in plasma [relapsers]). Subjects with less than 2-log10 decrease in HCV-RNA by week 12 of previous treatment (prior null responders) were not eligible for enrollment in this trial. Subjects were randomized in a 1:2:2 ratio and stratified based on response to their previous qualifying regimen (relapsers vs. partial responders) and by HCV subtype (1a vs. 1b) to one of the following treatment arms:
- Peginterferon alfa 2a + Ribavirin for 48 weeks (PR48)
- Peginterferon alfa 2a + Ribavirin for 4 weeks followed by Boceprevir 800 mg three times daily + Peginterferon alfa 2a + Ribavirin for 32 weeks. The subjects were then continued on different treatment regimens based on TW8 and TW12 response-guided therapy (boceprevir-RGT). All subjects in this treatment arm were limited to 32 weeks of Boceprevir.
Subjects with undetectable HCV-RNA (Target Not Detected) at TW8 (early responders) and TW12 completed therapy at TW36 visit.
Subjects with a detectable HCV-RNA at TW8 but subsequently undetectable (Target Not Detected) at TW12 (late responders) were changed in a blinded fashion to placebo at the TW36 visit and continued treatment with Peginterferon alfa 2a + Ribavirin for an additional 12 weeks, for a total treatment duration of 48 weeks.
- Subjects with undetectable HCV-RNA (Target Not Detected) at TW8 (early responders) and TW12 completed therapy at TW36 visit.
- Subjects with a detectable HCV-RNA at TW8 but subsequently undetectable (Target Not Detected) at TW12 (late responders) were changed in a blinded fashion to placebo at the TW36 visit and continued treatment with Peginterferon alfa 2a + Ribavirin for an additional 12 weeks, for a total treatment duration of 48 weeks.
- Peginterferon alfa 2a + Ribavirin for 4 weeks followed by Boceprevir 800 mg three times daily + Peginterferon alfa 2a + Ribavirin for 44 weeks (boceprevir-PR48).
- All subjects with detectable HCV-RNA in plasma at TW12 were discontinued from treatment. Sustained Virologic Response (SVR) was defined as plasma HCV-RNA less than 25 IU/mL at Follow-up Week 24. Plasma HCV-RNA results at Follow-up Week 12 were used if plasma HCV-RNA results at Follow-up Week 24 were missing.
- Mean age of subjects randomized was 53 years. The racial distribution of subjects was as follows: 85% White, 12% Black, and 3% others. The distribution of subjects by gender was 67% men and 33% women.
- The addition of Boceprevir to the Peginterferon alfa 2a and Ribavirin therapy significantly increased the SVR rates compared to Peginterferon alfa 2a/Ribavirin alone (59% to 66% in arms containing Boceprevir vs. 23% PR48 control) for randomized subjects who received at least one dose of any study medication (Full-Analysis-Set population) (see TABLE 12).
- In subjects with cirrhosis at baseline, sustained virologic response was higher in those who received treatment with the combination of Boceprevir with Peginterferon alfa 2a and Ribavirin for 44 weeks after 4 weeks of lead-in therapy with Peginterferon alfa 2a and Ribavirin (17/22, 77%) compared to those who received RGT (6/17, 35%).
### Sustained Virologic Response (SVR) Based on TW8 HCV-RNA Results
- TABLE 13 presents sustained virologic response based on TW8 HCV-RNA results in subjects who were relapsers or partial responders to previous interferon and ribavirin therapy. Forty-six percent (74/162) of subjects in the boceprevir-RGT arm and 52% (84/161) in the boceprevir-PR48 had undetectable HCV-RNA (Target Not Detected) at TW8 (early responders) compared with 9% (7/80) in the PR48 arm.
- Among subjects with detectable HCV-RNA at TW8 who attained an undetectable HCV-RNA (Target Not Detected) at TW12 and completed at least 36 weeks of treatment, the SVR rates were 79% (27/34) in boceprevir-RGT arm (4 weeks of Peginterferon alfa 2a and Ribavirin then 32 weeks of Boceprevir with Peginterferon alfa 2a and Ribavirin followed by 12 weeks of Peginterferon alfa 2a and Ribavirin alone) and 72% (29/40) in boceprevir-PR48 arm (4 weeks of Peginterferon alfa 2a and Ribavirin then 44 weeks of Boceprevir with Peginterferon alfa 2a and Ribavirin).
## Interferon Responsiveness during Lead-In Therapy with Peginterferon alfa and Ribavirin
## Previously Untreated Subjects
- In previously untreated subjects evaluated in SPRINT-2, interferon-responsiveness (defined as greater than or equal to 1-log10 decline in viral load at TW4) was predictive of SVR. Subjects treated with Boceprevir who demonstrated interferon responsiveness at TW4 achieved SVR rates of 81% (203/252) in boceprevir-RGT arm and 79% (200/254) in boceprevir-PR48 arm, compared to 52% (134/260) in subjects treated with Peginterferon alfa 2a/Ribavirin.
- Subjects treated with Boceprevir who demonstrated poor interferon responsiveness (defined as less than 1-log10 decline in viral load at TW4), achieved SVR rates of 28% (27/97) in boceprevir-RGT arm and 38% (36/95) in boceprevir-PR48 arm, compared to 4% (3/83) in subjects treated with Peginterferon alfa 2a/Ribavirin. Subjects with less than a 0.5-log10 decline in viral load at TW4 achieved SVR rates of 28% (13/47) in boceprevir-RGT arm and 30% (11/37) in boceprevir-PR48 arm, compared to 0% (0/25) in subjects treated with Peginterferon alfa 2a/Ribavirin. Subjects with less than a 0.5-log10 decline in viral load at TW4 with peginterferon alfa plus ribavirin therapy alone are predicted to have a null response (less than 2-log10 viral load decline at TW12) to peginterferon alfa and ribavirin.
## Previous Partial Responders and Relapsers to Interferon and Ribavirin Therapy
- In subjects who were previous relapsers and partial responders evaluated in RESPOND-2, interferon-responsiveness (defined as greater than or equal to 1-log10 decline in viral load at TW4) was predictive of SVR. Subjects treated with Boceprevir who demonstrated interferon responsiveness at TW4 achieved SVR rates of 74% (81/110) in boceprevir-RGT arm and 79% (90/114) in boceprevir-PR48 arm, compared to 27% (18/67) in subjects treated with Peginterferon alfa 2a/Ribavirin. Subjects treated with Boceprevir who demonstrated poor interferon responsiveness (defined as less than 1-log10 decline in viral load at TW4) achieved SVR rates of 33% (15/46) in boceprevir-RGT arm and 34% (15/44) in boceprevir-PR48 arm, compared to 0% (0/12) in subjects treated with Peginterferon alfa 2a/Ribavirin.
## Prior Null Responders to Interferon and Ribavirin Therapy
- PROVIDE was an open-label, single-arm trial of Boceprevir 800 mg orally three times daily in combination with peginterferon alfa-2b 1.5 micrograms per kg per week subcutaneously and weight-based ribavirin (600 вАУ 1,400 mg per day orally divided twice daily) in adult subjects with chronic hepatitis C (HCV) genotype 1 infection who did not achieve SVR while in the peginterferon alfa/ribavirin control arms of previous Phase 2 and 3 trials of combination therapy with Boceprevir Subjects who enrolled in PROVIDE within 2 weeks after the last dose of peginterferon alfa/ribavirin in the prior trial received Boceprevir 800 mg three times daily + peginterferon alfa-2b + ribavirin for 44 weeks. Subjects who were not able to enroll in this trial within 2 weeks received Peginterferon alfa 2a/Ribavirin lead-in for 4 weeks followed by Boceprevir 800 mg three times daily + peginterferon alfa-2b + ribavirin for 44 weeks.
Among subjects who were null responders in the peginterferon alfa/ribavirin control arm of the prior trial, SVR (reported as plasma HCV-RNA <25 IU/mL at follow-up week 24) was 38% (20/52) and the relapse rate was 13% (3/23).
## Use of Ribavirin Dose Reduction versus Erythropoiesis Stimulating Agent (ESA) in the Management of Anemia in Previously Untreated Subjects
- A randomized, parallel-arm, open-label study was conducted to compare two strategies for the management of anemia (use of ESA versus ribavirin dose reduction) in 687 subjects with previously untreated CHC genotype 1 infection who became anemic during therapy with Boceprevir 800 mg orally three times daily plus peginterferon alfa-2b 1.5 micrograms per kg per week subcutaneously and weight-based ribavirin (600 вАУ 1,400 mg orally per day divided twice daily). The study enrolled subjects with serum hemoglobin concentrations of less than 15 g per dL. Subjects were treated for 4 weeks with peginterferon alfa-2b and ribavirin followed by up to 44 weeks of Boceprevir plus peginterferon alfa-2b and ribavirin. If a subject became anemic (serum hemoglobin of approximately less than or equal to 10 g per dL within the treatment period), the subject was randomized in a 1:1 ratio to either ribavirin dose reduction (N=249) or use of erythropoietin 40,000 units subcutaneously once weekly for the management of the anemia (N=251). If serum hemoglobin concentrations continued to decrease to less than or equal to 8.5 g per dL, subjects could be treated with additional anemia interventions, including the addition of erythropoietin (18% of those in the ribavirin dose reduction arm) or ribavirin dose reduction (37% of those in the ESA arm).
- Mean age of subjects randomized was 49 years. The racial distribution of subjects was as follows: 77% White, 19% Black, and 4% other. The distribution of subjects by gender was 37% men and 63% women.
- The overall intent-to-treat SVR rate for all enrolled subjects (including those subjects who were not randomized to RBV dose reduction or ESA for the management of anemia) was 63% (431/687). The SVR rate in subjects randomized who received ribavirin dose reduction was 71% (178/249), similar to the SVR rate of 71% (178/251) in subjects randomized to receive an ESA. The relapse rates in subjects randomized to receive ribavirin dose reduction or an ESA were 10% (19/196) and 10% (19/197), respectively.
# How Supplied
- Boceprevir 200 mg capsules are comprised of a red-colored cap with the Merck logo printed in yellow ink, and a yellow-colored body with "314" printed in red ink. The capsules are packaged into a carton with 28 bottles containing 12 capsules (NDC 0085-0314-02).
## Storage
- Boceprevir Capsules should be refrigerated at 2вАУ8°C (36вАУ46°F) until dispensed. Avoid exposure to excessive heat. For patient use, refrigerated capsules of Boceprevir can remain stable until the expiration date printed on the label. Boceprevir can also be stored at room temperature up to 25°C (77°F) for 3 months. Keep container tightly closed.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Boceprevir Patient Counseling Information in the drug label.
# Precautions with Alcohol
- Alcohol-Boceprevir interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Victrelis
# Look-Alike Drug Names
There is limited information regarding Boceprevir Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Boceprevir | |
1cca35542f419423e2401c189997c48cb7b2ad5d | wikidoc | Human body | Human body
# Overview
The human body is the entire physical structure of a human organism. The human body consists of a head, neck, torso, two arms and two legs. The average height of an adult human is about 1.6 m (5 to 6 feet) tall. This size is largely determined by genes. Body type and body composition are influenced by postnatal factors such as diet and exercise.
The human body is often called a "body". The body of a dead person is called a "corpse" or "cadaver".
The human body consists of systems, organs,
tissues and cells. Human anatomy studies structures and systems of the human body. The study of the workings of the human body is called physiology. Ecology focuses on the distribution and abundance of the bodies and how the distribution and abundance are affected by interactions between bodies and its environment.
Combination of individual atoms, molecules, polypeptides, cells in human body, is a source of emergence.
# Social psychology
The human body can be used for communication. Many people, consciously or unconsciously, send and receive non-verbal signals all the time. Body language forms part of paralanguage. | Human body
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
The human body is the entire physical structure of a human organism. The human body consists of a head, neck, torso, two arms and two legs. The average height of an adult human is about 1.6 m (5 to 6 feet) tall. This size is largely determined by genes. Body type and body composition are influenced by postnatal factors such as diet and exercise.
The human body is often called a "body". The body of a dead person is called a "corpse" or "cadaver".
The human body consists of systems, organs,
tissues and cells. Human anatomy studies structures and systems of the human body. The study of the workings of the human body is called physiology. Ecology focuses on the distribution and abundance of the bodies and how the distribution and abundance are affected by interactions between bodies and its environment.
Combination of individual atoms, molecules, polypeptides, cells in human body, is a source of emergence.
# Social psychology
The human body can be used for communication. Many people, consciously or unconsciously, send and receive non-verbal signals all the time. Body language forms part of paralanguage. | https://www.wikidoc.org/index.php/Body | |
5a2303836a65f5ab1b812f4ddbc69a8078cac96a | wikidoc | Body image | Body image
Body image is a term which may refer to our perceptions of our own physical appearance, or our internal sense of having a body which is constructed by the brain.
Essentially a person's body image is how they perceive their exterior to look, and in many cases this can be dramatically different to how they actually appear to others. Negative feelings towards a person's body can in some cases lead to mental disorders such as depression or eating disorders, though there can be a variety of different reasons why these disorders can occur.
Within the media industry there have recently been popular debates focusing on how Size Zero models can negatively influence young people into feeling insecure about their own body image. It has been suggested that size zero models be banned from cat walks. Many celebrities are targeted by the media due to their often drastic weight loss and slender frames, examples of such personalities would be member of the Spice Girls and wife of L.A Galaxy Footballer David Beckham, Victoria Beckham, famous socialite and daughter of Lionel Richie, Nicole Richie and ex Destiny's Child member turned solo singer and Actress Beyonce. Other controversial thin celebrities include British Super Model Kate Moss. Some examples of celebrity men targeted in a similar fashion can be found, but the media seems to focus principally on the effect that the Size Zero phenomenon has on young women.
# Body Image and Physical Appearance
## Recent Research
Body image is often measured by asking the subject to rate their current and ideal body shape using a series of depictions. The difference between these two values is the amount of body dissatisfaction.
Monteath and McCabe found that 44% of women express negative feelings about both individual body parts and their bodies as a whole.
Psychology Today found that 56% of the women and about 40% of the men who responded to their survey in 1997 were dissatisfied with their overall appearance.
The desire to lose weight is highly correlated with poor body image, which typically means that more women have a poor body image than men. Susan Kashubeck-West, Laurie B. Mintz, and Ingrid Weigold report that the sex differences in body image disappear when we consider only those people who are trying to lose weight.
Our life orientation also shapes how we feel about our bodies. Women who self-identify as feminists view their body more positively than those who do not consider themselves feminists, even though there was no difference between the groups in average body weight. Exercise habits, sexual experiences, and mood also influence the feelings people have toward their bodies.
Men's body image is a topic of increasing interest in both academic articles and in the popular press. Current research indicates many men wish to become more muscular than they currently perceive themselves to be, often desiring up to 26 pounds of additional muscle mass.
The desire for additional muscle has been linked to many men's concepts about masculinity. A variety of research has indicated a relationship between men's endorsement of traditionally masculine ideas and characteristics, and his desire for additional muscle. Some research has suggested this relationship between muscle and masculinity may begin early in life, as boys' action figures are often depicted as super-muscular, often beyond the actual limits of human physiology.
This desire for additional muscle has been given various nicknames, including "The Adonis Complex", "Bigorexia", "Reverse Anorexia", and "Muscle dysmorphia". Muscle dissatisfaction has been linked to low self esteem, personality disorder and is related to the use of muscle-building supplements and anabolic steroids. As such, men's body image dissatisfaction represents a substantial concern to public health researchers.
# Body Image and the Brain
## Definition and Origin
According to Vilayanur S. Ramachandran of the University of California, San Diego, the nature of self has five defining characteristics. One of them is the sense of embodiment and ownership of a body. Although we do in fact have a body, the brain is responsible for the construction of a "body-image," a term introduced in the writings of neurologist Henry Head (which also has been used interchangeably with the term body-schema.) Your sense of having a body involves the visual system, the vestibular system, and proprioception; the sense of body position and movement (a term coined by Charles Scott Sherrington in his published work entitled, The Integrated Action of the Nervous System.) Proprioception correlates with dynamic body maps in the somatosensory, motor, and parietal cortices. Most notable is the primary somatosensory receiving area (S1) in the somatosensory cortex, where the sensory homunculus or "little man" resides. The neurons in this region are responsible for cutaneous (skin), visceral (organ), and proprioceptive sensation, as they fire to represent each part of your body--from the genitalia to the internal organs--with the help of sensory input that travels from peripheral nerves, through the spinal cord, and into the brain.
## Neurological Phenomenon
Ablation of those sensory nerves that carry sensory input from proprioceptors to the brain, results in a loss of proprioception. A person may experience such a loss in certain limbs, or throughout their entire body. In Oliver Sacks book, The Man Who Mistook His Wife for a Hat, he describes a patient named Christina who suffered from a selective neuritis--an infection in her spinal fluid that disconnected her entire body from the parietal cortices in her brain, causing a total loss of proprioception--and thereby a sense of disembodiment. Christina would flail and overshoot her limbs. Her body flopped around like a rag doll. Standing or sitting straight was nearly impossible for her.
Many amputees who have lost limbs, continue to sense the presence of them, as the body-image remains intact. Even those born without arms or legs, experience such phantoms. Often, the presence of these phantoms are so convincing, patients may step out of bed onto phantom legs or feet, or pick up cups with a phantom hand (Ronald Melzack, 1992-2006).
A phantom limb is integral to wearing a prosthetic, in which the phantom fits like a glove. The body-image of the missing limb must be present, otherwise a prosthetic cannot be used effectively.
There are many types of phantoms. Some are paralyzed; frozen in unusual positions. Many phantoms are like photocopies; exact replicas of the missing limbs. Others are grossly distorted and disproportioned--they may even be disconnected from the rest of the body and dangle in mid-air. Some disappear, only to be resurrected decades later. Interestingly, a women may have a phantom penis with phantom erections. While the overall sex of a human being is determined by DNA, it is possible that the sex of the brain itself is determined by the hormones an embryo is exposed to while in the womb. Nonetheless, a man may have a female brain, and a woman may have a male brain. This phenomenon may explain transsexualism.
The somatosensory system has been known to be involved in phantom limb syndrome. According to V.S. Ramachandran, motor signals contribute to phantom limb phenomenon as well. The motor cortex is primarily responsible for voluntary movement. But when motor signals are sent to muscles, a duplicate signal is sent to the parietal lobes as well in a feedback loop, thereby eliciting a sense of proprioception in the missing limbs.
The body-image also emerges from the convergence of multiple senses (i.e. proprioception and vision) in the angular gyrus and supramarginal gyrus. The body-image can detach from the physical body, and take on a phantom existence. Note that electrical stimulation of the angular gyrus causes an out-of-body experience, a decoupling of vision and proprioceptive sensory experience.
Also, some patients with anosognosia, usually left-side hemiplegics who have suffered from a stroke, experience a disassociation with their paralyzed limbs. Some may be convinced that their paralyzed leg for example, is not really theirs--perhaps the leg of a stranger. They will assert that their real leg has disappeared, and in this conclusion, attempt to shove or kick their own leg out of bed. This kind of anosognosia involves lesions on the right side of the brain--notably the somatosensory and parietal cortices. | Body image
Body image is a term which may refer to our perceptions of our own physical appearance, or our internal sense of having a body which is constructed by the brain.
Essentially a person's body image is how they perceive their exterior to look, and in many cases this can be dramatically different to how they actually appear to others. Negative feelings towards a person's body can in some cases lead to mental disorders such as depression or eating disorders, though there can be a variety of different reasons why these disorders can occur.
Within the media industry there have recently been popular debates focusing on how Size Zero models can negatively influence young people into feeling insecure about their own body image. It has been suggested that size zero models be banned from cat walks. Many celebrities are targeted by the media due to their often drastic weight loss and slender frames, examples of such personalities would be member of the Spice Girls and wife of L.A Galaxy Footballer David Beckham, Victoria Beckham, famous socialite and daughter of Lionel Richie, Nicole Richie and ex Destiny's Child member turned solo singer and Actress Beyonce. Other controversial thin celebrities include British Super Model Kate Moss. Some examples of celebrity men targeted in a similar fashion can be found, but the media seems to focus principally on the effect that the Size Zero phenomenon has on young women.
# Body Image and Physical Appearance
## Recent Research
Body image is often measured by asking the subject to rate their current and ideal body shape using a series of depictions. The difference between these two values is the amount of body dissatisfaction.
Monteath and McCabe found that 44%[1] of women express negative feelings about both individual body parts and their bodies as a whole.
Psychology Today found that 56% of the women and about 40% of the men who responded to their survey in 1997 were dissatisfied with their overall appearance.[2]
The desire to lose weight is highly correlated with poor body image, which typically means that more women have a poor body image than men. Susan Kashubeck-West, Laurie B. Mintz, and Ingrid Weigold report that the sex differences in body image disappear when we consider only those people who are trying to lose weight.[3]
Our life orientation also shapes how we feel about our bodies. Women who self-identify as feminists view their body more positively than those who do not consider themselves feminists, even though there was no difference between the groups in average body weight.[4] Exercise habits, sexual experiences, and mood also influence the feelings people have toward their bodies.
Men's body image is a topic of increasing interest in both academic articles and in the popular press. Current research indicates many men wish to become more muscular than they currently perceive themselves to be, often desiring up to 26 pounds of additional muscle mass.[5]
The desire for additional muscle has been linked to many men's concepts about masculinity. A variety of research has indicated a relationship between men's endorsement of traditionally masculine ideas and characteristics, and his desire for additional muscle[6]. Some research has suggested this relationship between muscle and masculinity may begin early in life, as boys' action figures are often depicted as super-muscular, often beyond the actual limits of human physiology. [7]
This desire for additional muscle has been given various nicknames, including "The Adonis Complex", "Bigorexia", "Reverse Anorexia", and "Muscle dysmorphia". Muscle dissatisfaction has been linked to low self esteem,[8] personality disorder [9] and is related to the use of muscle-building supplements and anabolic steroids. [10] [11] As such, men's body image dissatisfaction represents a substantial concern to public health researchers.
# Body Image and the Brain
## Definition and Origin
According to Vilayanur S. Ramachandran of the University of California, San Diego, the nature of self has five defining characteristics. One of them is the sense of embodiment and ownership of a body. Although we do in fact have a body, the brain is responsible for the construction of a "body-image," a term introduced in the writings of neurologist Henry Head (which also has been used interchangeably with the term body-schema.) Your sense of having a body involves the visual system, the vestibular system, and proprioception; the sense of body position and movement (a term coined by Charles Scott Sherrington in his published work entitled, The Integrated Action of the Nervous System.) Proprioception correlates with dynamic body maps in the somatosensory, motor, and parietal cortices. Most notable is the primary somatosensory receiving area (S1) in the somatosensory cortex, where the sensory homunculus or "little man" resides. The neurons in this region are responsible for cutaneous (skin), visceral (organ), and proprioceptive sensation, as they fire to represent each part of your body--from the genitalia to the internal organs--with the help of sensory input that travels from peripheral nerves, through the spinal cord, and into the brain.
## Neurological Phenomenon
Ablation of those sensory nerves that carry sensory input from proprioceptors to the brain, results in a loss of proprioception. A person may experience such a loss in certain limbs, or throughout their entire body. In Oliver Sacks book, The Man Who Mistook His Wife for a Hat, he describes a patient named Christina who suffered from a selective neuritis--an infection in her spinal fluid that disconnected her entire body from the parietal cortices in her brain, causing a total loss of proprioception--and thereby a sense of disembodiment. Christina would flail and overshoot her limbs. Her body flopped around like a rag doll. Standing or sitting straight was nearly impossible for her.
Many amputees who have lost limbs, continue to sense the presence of them, as the body-image remains intact. Even those born without arms or legs, experience such phantoms. Often, the presence of these phantoms are so convincing, patients may step out of bed onto phantom legs or feet, or pick up cups with a phantom hand (Ronald Melzack, 1992-2006).
A phantom limb is integral to wearing a prosthetic, in which the phantom fits like a glove. The body-image of the missing limb must be present, otherwise a prosthetic cannot be used effectively.
There are many types of phantoms. Some are paralyzed; frozen in unusual positions. Many phantoms are like photocopies; exact replicas of the missing limbs. Others are grossly distorted and disproportioned--they may even be disconnected from the rest of the body and dangle in mid-air. Some disappear, only to be resurrected decades later. Interestingly, a women may have a phantom penis with phantom erections. While the overall sex of a human being is determined by DNA, it is possible that the sex of the brain itself is determined by the hormones an embryo is exposed to while in the womb. Nonetheless, a man may have a female brain, and a woman may have a male brain. This phenomenon may explain transsexualism.
The somatosensory system has been known to be involved in phantom limb syndrome. According to V.S. Ramachandran, motor signals contribute to phantom limb phenomenon as well. The motor cortex is primarily responsible for voluntary movement. But when motor signals are sent to muscles, a duplicate signal is sent to the parietal lobes as well in a feedback loop, thereby eliciting a sense of proprioception in the missing limbs.
The body-image also emerges from the convergence of multiple senses (i.e. proprioception and vision) in the angular gyrus and supramarginal gyrus.[12] The body-image can detach from the physical body, and take on a phantom existence. Note that electrical stimulation of the angular gyrus causes an out-of-body experience, a decoupling of vision and proprioceptive sensory experience.
Also, some patients with anosognosia, usually left-side hemiplegics who have suffered from a stroke, experience a disassociation with their paralyzed limbs. Some may be convinced that their paralyzed leg for example, is not really theirs--perhaps the leg of a stranger. They will assert that their real leg has disappeared, and in this conclusion, attempt to shove or kick their own leg out of bed. This kind of anosognosia involves lesions on the right side of the brain--notably the somatosensory and parietal cortices. | https://www.wikidoc.org/index.php/Body_image | |
255ee1f8f66f9a558682c525bf37c991a330e667 | wikidoc | Body water | Body water
A significant fraction of the human body is water. This body water is distributed in different compartments in the body. Lean muscle tissue contains about 75% water. Blood contains 83% water, body fat contains 25% water and bone has 22% water.
In diseased states where body water is affected, the compartment or compartments that have changed can give clues to the nature of the problem.
Body water is regulated by hormones, including anti-diuretic hormone (ADH), aldosterone and atrial natriuretic peptide.
There are many methods that can be used to determine body water. One way to get a simple estimate is by calculation.
# Calculation of body water
In individuals of normal weight, water is abundant in most parts of the body, except in adipose tissue (fat). These calculations are for adults of average build, and are inappropriate for obese or overly muscular people. These proportions are very simplified and use round numbers for quick calculation.
In men about 69% of the body mass is water. This value is about 55% in women due to a higher proportion of body fat. This is the total body water.
Body water is broken down into the following compartments:
- Intracellular fluid (2/3 of Body Water)
- Extracellular fluid (1/3 of Body Water)
Plasma (1/4 of Extracellular fluid)
Interstitial fluid (3/4 of Extracellular fluid)
Transcellular fluid (normally ignored in calculations)
Contained inside organs, such as the gastrointestinal, cerebrospinal, and ocular fluids.
- Plasma (1/4 of Extracellular fluid)
- Interstitial fluid (3/4 of Extracellular fluid)
- Transcellular fluid (normally ignored in calculations)
Contained inside organs, such as the gastrointestinal, cerebrospinal, and ocular fluids.
- Contained inside organs, such as the gastrointestinal, cerebrospinal, and ocular fluids.
# Measurement of body water
## Dilution and equilibration
Total body water can be determined using Flowing afterglow mass spectrometry FA-MS
measurement of deuterium abundance in breath samples from individuals. A known dose of deuterated water (Heavy water, D2O) is ingested and allowed to equilibrate within the body water. The FA-MS instrument then measures the deuterium-to-hydrogen (D:H) ratio in the exhaled breath water vapour. The total body water is then accurately measured from the increase in breath deuterium content in relation to the volume of D2O ingested.
Different substances can be used to measure different fluid compartments:
- total body water: tritiated water or deuterium
- extracellular fluid: inulin
- blood plasma: Evans blue
## Bioelectrical impedance analysis
Another method of determining total body water percentage (TBW%) is via Bioelectrical Impedance Analysis (BIA). In the traditional BIA method, a person lies on a cot and spot electrodes are placed on the hands and bare feet. Electrolyte gel is applied first, and then a current of 50 kHz is introduced. BIA has emerged as a promising technique because of its simplicity, low cost, high reproducibility and noninvasiveness. BIA prediction equations can be either generalized or population-specific, allowing this method to be potentially very accurate. Selecting the appropriate equation is important to determining the quality of the results.
For clinical purposes, scientists are developing a multi-frequency BIA method that may further improve the method's ability to predict a person's hydration level. New segmental BIA equipment that uses more electrodes may lead to more precise measurements of specific parts of the body.
Ingesting pure water has been proven to cause unrepeatable and erroneous results with the BIA system. This is according to RJL Systems
# Conditions associated with abnormal body water
- Renal failure
- Obesity
- Third Spacing | Body water
A significant fraction of the human body is water. This body water is distributed in different compartments in the body. Lean muscle tissue contains about 75% water. Blood contains 83% water, body fat contains 25% water and bone has 22% water.
In diseased states where body water is affected, the compartment or compartments that have changed can give clues to the nature of the problem.
Body water is regulated by hormones, including anti-diuretic hormone (ADH), aldosterone and atrial natriuretic peptide.
There are many methods that can be used to determine body water. One way to get a simple estimate is by calculation.
# Calculation of body water
In individuals of normal weight, water is abundant in most parts of the body, except in adipose tissue (fat). These calculations are for adults of average build, and are inappropriate for obese or overly muscular people. These proportions are very simplified and use round numbers for quick calculation.
In men about 69% of the body mass is water. This value is about 55% in women due to a higher proportion of body fat. This is the total body water.
Body water is broken down into the following compartments:[1]
- Intracellular fluid (2/3 of Body Water)
- Extracellular fluid (1/3 of Body Water)
Plasma (1/4 of Extracellular fluid)
Interstitial fluid (3/4 of Extracellular fluid)
Transcellular fluid (normally ignored in calculations)
Contained inside organs, such as the gastrointestinal, cerebrospinal, and ocular fluids.
- Plasma (1/4 of Extracellular fluid)
- Interstitial fluid (3/4 of Extracellular fluid)
- Transcellular fluid (normally ignored in calculations)
Contained inside organs, such as the gastrointestinal, cerebrospinal, and ocular fluids.
- Contained inside organs, such as the gastrointestinal, cerebrospinal, and ocular fluids.
# Measurement of body water
## Dilution and equilibration
Total body water can be determined using Flowing afterglow mass spectrometry FA-MS
measurement of deuterium abundance in breath samples from individuals. A known dose of deuterated water (Heavy water, D2O) is ingested and allowed to equilibrate within the body water. The FA-MS instrument then measures the deuterium-to-hydrogen (D:H) ratio in the exhaled breath water vapour. The total body water is then accurately measured from the increase in breath deuterium content in relation to the volume of D2O ingested.
Different substances can be used to measure different fluid compartments:[2]
- total body water: tritiated water or deuterium
- extracellular fluid: inulin
- blood plasma: Evans blue
## Bioelectrical impedance analysis
Another method of determining total body water percentage (TBW%) is via Bioelectrical Impedance Analysis (BIA). In the traditional BIA method, a person lies on a cot and spot electrodes are placed on the hands and bare feet. Electrolyte gel is applied first, and then a current of 50 kHz is introduced. BIA has emerged as a promising technique because of its simplicity, low cost, high reproducibility and noninvasiveness. BIA prediction equations can be either generalized or population-specific, allowing this method to be potentially very accurate. Selecting the appropriate equation is important to determining the quality of the results.
For clinical purposes, scientists are developing a multi-frequency BIA method that may further improve the method's ability to predict a person's hydration level. New segmental BIA equipment that uses more electrodes may lead to more precise measurements of specific parts of the body.
Ingesting pure water has been proven to cause unrepeatable and erroneous results with the BIA system. This is according to RJL Systems http://www.rjlsystems.com
# Conditions associated with abnormal body water
- Renal failure
- Obesity
- Third Spacing | https://www.wikidoc.org/index.php/Body_water | |
6fe401b171beb120cfab86ac3ef0ca671e41cba2 | wikidoc | Bohr model | Bohr model
In atomic physics, the Bohr model created by Niels Bohr depicts the atom as a small, positively charged nucleus surrounded by electrons that travel in circular orbits around the nucleus — similar in structure to the solar system, but with electrostatic forces providing attraction, rather than gravity. This was an improvement on the earlier cubic model (1902), the plum-pudding model (1904), the Saturnian model (1904), and the Rutherford model (1911). Since the Bohr model is a quantum physics-based modification of the Rutherford model, many sources combine the two, referring to the Rutherford-Bohr model.
Introduced by Niels Bohr in 1913, the model's key success lay in explaining the Rydberg formula for the spectral emission lines of atomic hydrogen; while the Rydberg formula had been known experimentally, it did not gain a theoretical underpinning until the Bohr model was introduced. Not only did the Bohr model explain the reason for the structure of the Rydberg formula, but it provided a justification for its empirical results in terms of fundamental physical constants.
The Bohr model is a primitive model of the hydrogen atom. As a theory, it can be derived as a first-order approximation of the hydrogen atom using the broader and much more accurate quantum mechanics, and thus may be considered to be an obsolete scientific theory. However, because of its simplicity, and its correct results for selected systems (see below for application), the Bohr model is still commonly taught to introduce students to quantum mechanics, before moving on to the more accurate but more complex valence shell atom. A related model was originally proposed by Arthur Erich Haas in 1910, but was rejected. The quantum theory of the period between Planck's discovery of the quantum (1900) and the advent of a full-blown quantum mechanics (1925) is often referred to as the `Old quantum theory'.
# History
In the early 20th century, experiments by Ernest Rutherford established that atoms consisted of a diffuse cloud of negatively charged electrons surrounding a small, dense, positively charged nucleus. Given this experimental data, it was quite natural for Rutherford to consider a planetary model for the atom, the Rutherford model of 1911, with electrons orbiting a sun-like nucleus. However, the planetary model for the atom has a difficulty. The laws of classical mechanics, specifically the Larmor formula, predict that the electron will release electromagnetic radiation as it orbits a nucleus. Because the electron would be losing energy, it would gradually spiral inwards and collapse into the nucleus. This is a disaster, because it predicts that all matter is unstable.
Also, as the electron spirals inward, the emission would gradually increase in frequency as the orbit got smaller and faster. This would produce a continuous smear, in frequency, of electromagnetic radiation. However, late 19th century experiments with electric discharges through various low-pressure gasses in evacuated glass tubes had shown that atoms will only emit light (that is, electromagnetic radiation) at certain discrete frequencies.
To overcome this difficulty, Niels Bohr proposed, in 1913, what is now called the Bohr model of the atom. He suggested that electrons could only have certain classical motions:
- The electrons travel in circular orbits that have discrete (quantized) angular momenta, and therefore quantized energies. That is, not every circular orbit is possible but only certain specific ones, at certain specific distances from the nucleus and having specific energies.
- The electrons do not continuously lose energy as they travel. They can only gain and lose energy by jumping from one allowed orbit to another, absorbing or emitting electromagnetic radiation at frequency \nu determined by the energy difference \Delta E = E_2 - E_1 of the levels according to Bohr's formula
The significance of the Bohr model is that the laws of classical mechanics apply to the motion of the electron about the nucleus only in a sense restricted by quantum rules like that for angular momentum L, restricting its value to
where n = 1,2,3,… and is called the principal quantum number. The lowest value of n is 1. This corresponds to a smallest possible radius of 0.0529 nm. This is known as the Bohr radius. Once an electron is in this lowest orbit, it can get no closer to the proton. Starting from the angular momentum quantum rule Bohr was able to calculate the energies of the allowed orbits of the hydrogen atom and other hydrogenlike atoms and ions.
Other points are:
- Analogously to Einstein's theory of the Photoelectric effect it is assumed in Bohr's formula that on a quantum jump a discrete amount of energy is radiated. However, contrary to Einstein did Bohr stick to the classical Maxwell theory of the electromagnetic field. Quantization of the electromagnetic field was explained by the discreteness of the atomic energy levels; Bohr did not believe in the existence of photons.
- According to the Maxwell theory the frequency \nu of the radiation is equal to the rotation frequency \nu_{rot} of the electron in its orbit. This result is obtained to a good approximation from the Bohr model for jumps between energy levels E_{n+1} and E_{n} for sufficiently large values of n (so-called Rydberg states), the two orbits involved in emission for large values of n having nearly the same rotation frequency. However, in general the radiation frequencies are different from the rotation frequencies. This marks the birth of the correspondence principle, requiring quantum theory to yield agreement with the classical theory only in the limit of large quantum numbers.
- The Bohr-Kramers-Slater (BKS) theory is an attempt to extend the Bohr model so as to account for conservation of energy and momentum in quantum jumps.
Bohr's condition, that the angular momentum is an integer multiple of \scriptstyle\hbar was later reinterpreted by DeBroglie as a standing wave condition: the electron is described by a wave and a whole number of wavelengths must fit along the circumference of the electron's orbit:
Substituting DeBroglie's wavelength reproduces Bohr's rule. Bohr justified his rule by appealing to the correspondence principle, without providing a wave interpretation.
In 1925 rather a new kind of mechanics was proposed, viz. quantum mechanics in which Bohr's model of electrons traveling in quantized orbits was extended into a more accurate model of electron motion. The new theory was proposed by Werner Heisenberg. Another form of the same theory, modern quantum mechanics, was discovered by the Austrian physicist Erwin Schrödinger independently and by different reasoning.
# Electron energy levels
The Bohr model gives almost exact results only for a system where two charged points orbit each other at speeds much less than that of light. This not only includes one-electron systems such as the hydrogen atom, singly-ionized helium, doubly ionized lithium, but it includes positronium and Rydberg states of any atom where one electron is far away from everything else. It can be used for K-line X-ray transition calculations if other assumptions are added (see Moseley's law below). In high energy physics,
it can be used to calculate the masses of heavy quark mesons.
To calculate the orbits requires two assumptions:
1. Classical mechanics
2. Quantum rule
The combination of natural constants in the energy formula is called the Rydberg energy R_E:
This expression is clarified by interpreting it in combinations which form more natural units:
For nuclei with Z protons, the energy levels are:
When Z is approximately 137 (about 1/α), the motion becomes highly relativistic. Then the Z^2 cancels the \alpha^2 in R, so the orbit energy begins to be comparable to rest energy. Sufficiently large nuclei, if they were stable, would reduce their charge by creating a bound electron from the vacuum, ejecting the positron to infinity. This is the theoretical phenomenon of electromagnetic charge screening which predicts a maximum nuclear charge. Emission of such positrons has been observed in the collisions of heavy ions to create temporary super-heavy nuclei.
For positronium, the formula uses the reduced mass. For any value of the radius, the electron and the positron are each moving at half the speed around their common center of mass, and each has only one fourth the kinetic energy. The total kinetic energy is half what it would be for a single electron moving around a heavy nucleus.
# Rydberg formula
The Rydberg formula, which was known empirically before Bohr's formula, is now in Bohr's theory seen as describing the energies of transitions or quantum jumps between one orbital energy level, and another. Bohr's formula gives the numerical value of the already-known and measured Rydberg's constant, but now in terms of more fundamental constants of nature, including the electron's charge and Planck's constant.
When the electron moves from one energy level to another, a photon is emitted. Using the derived formula for the different 'energy' levels of hydrogen one may determine the 'wavelengths' of light that a hydrogen atom can emit.
The energy of a photon emitted by a hydrogen atom is given by the difference of two hydrogen energy levels:
where nf is the final energy level, and ni is the initial energy level.
Since the energy of a photon is
the wavelength of the photon given off is given by
This is known as the Rydberg formula, and the Rydberg constant R is R_E/hc, or R_E/2\pi in natural units. This formula was known in the nineteenth century to scientists studying spectroscopy, but there was no theoretical explanation for this form or a theoretical prediction for the value of R, until Bohr. In fact, Bohr's derivation of the Rydberg constant, as well as the concomitant agreement of Bohr's formula with experimentally observed spectral lines of the Lyman (n_f = 1), Balmer (n_f = 2), and Paschen (n_f = 3) series, and successful theoretical prediction of other lines not yet observed, was one reason that his model was immediately accepted.
# Shell model of the atom
Bohr extended the model of Hydrogen to give an approximate model for heavier atoms. This gave a physical picture which reproduced many known atomic properties for the first time.
Heavier atoms have more protons in the nucleus, and more electrons to cancel the charge. Bohr's idea was that each discrete orbit could only hold a certain number of electrons. After that orbit is full, the next level would have to be used. This gives the atom a shell structure, in which each shell corresponds to a Bohr orbit.
This model is even more approximate than the model of hydrogen, because it treats the electrons in each shell as non-interacting. But the repulsions of electrons is taken into account somewhat by the phenomenon of screening. The electrons in outer orbits do not only orbit the nucleus, but they also orbit the inner electrons, so the effective charge Z that they see is reduced by the number of the electrons in the inner orbit.
For example, the lithium atom has two electrons in the lowest 1S orbit, and these orbit at Z=2. Each one sees the nuclear charge of Z=3 minus the screening effect of the other, which crudely reduces the nuclear charge by 1 unit. This means that the innermost electrons orbit at approximately 1/4th the Bohr radius. The outermost electron in lithium orbits at roughly Z=1, since the two inner electrons reduce the nuclear charge by 2. This outer electron should be at nearly one Bohr radius from the nucleus. Because the electrons strongly repel each other, the effective charge description is very approximate, the effective charge Z doesn't usually come out to be an integer. But Moseley's law experimentally probes the innermost pair of electrons, and shows that they do see a nuclear charge of approximately Z-1, while the outermost electron in an atom or ion with only one electron in the outermost shell orbits a core with effective charge Z-k where k is the total number of electrons in the inner shells.
The shell model was able to qualitatively explain many of the mysterious properties of atoms which became codified in the late 19th century in the periodic table of the elements. One property was the size of atoms, which could be determined approximately by measuring the viscosity of gasses and density of pure crystaline solids. Atoms tend to get smaller as you move to the right in the periodic table, becoming much bigger at the next line of the table. Atoms to the right of the table tend to gain electrons, while atoms to the left tend to lose them. Every element on the last column of the table is chemically inert (noble gas).
In the shell model, this phenomenon is explained by shell-filling. Successive atoms get smaller because they are filling orbits of the same size, until the orbit is full, at which point the next atom in the table has a loosely bound outer electron, causing it to expand. The first Bohr orbit is filled when it has two electrons, and this explains why helium is inert. The second orbit allows eight electrons, and when it is full the atom is neon, again inert. The third orbital contains eight again, except that in the more correct Sommerfeld treatment (reproduced in modern quantum mechanics) there are extra "d" electrons. The third orbit may hold an extra 10 d electrons, but these positions are not filled until a few more orbitals from the next level are filled (Filling the n=3 d orbitals produces the 10 transition elements). The irregular filling pattern is an effect of interactions between electrons, which are not taken into account in either the Bohr or Sommerfeld models, and which are difficult to calculate even in the modern treatment.
# Moseley's law and calculation of K-alpha X-ray emission lines
Niels Bohr said in 1962, "You see actually the Rutherford work was not taken seriously. We cannot understand today, but it was not taken seriously at all. There was no mention of it any place. The great change came from Moseley."
In 1913 Henry Moseley found an empirical relationship between the strongest X-ray line emitted by atoms under electron bombardment (then known as the K-alpha line), and their atomic number Z. Moseley's empiric formula was found to be derivable from Rydberg and Bohr's formula (Moseley actually mentions only Ernest Rutherford and Antonius Van den Broek in terms of models). The two additional assumptions that this X-ray line came from a transition between energy levels with quantum numbers 1 and 2, and , that the atomic number Z when used in the formula for atoms heavier than hydrogen, should be diminished by 1, to (Z-1)².
Moseley wrote to Bohr, puzzled about his results, but Bohr was not able to help. At that time, he thought that the postulated innermost "K" shell of electrons should have at least four electrons, not the two which would have neatly explained the result. So Moseley published his results without a theoretical explanation.
Later, people realized that the effect was caused by charge screening, with an inner shell containing only 2 electrons. In the experiment, one of the innermost electrons in the atom is knocked out, leaving a vacancy in the lowest Bohr orbit, which contains a single remaining electron. This vacancy is then filled by electrons in the next orbit, which has n=2. But the n=2 electrons see an effective charge of Z-1, which is the value appropriate for the charge of the nucleus, when a single electron remains in the lowest Bohr orbit to screen the nuclear charge +Z, and lower it by -1 (due to the electron's negative charge screening the nuclear positive charge). The energy gained by an electron dropping from the second shell to the first gives Moseley's law for K-alpha lines:
-r
Here, Rv is the Rydberg constant given in terms of frequency, or RE/h = 3.28 x 1015 Hz. This latter relationship had been empirically derived by Moseley, in a simple plot of the square root of X-ray frequency against atomic number. Moseley's law not only established the objective meaning of atomic number (see Henry Moseley for detail) but, as Bohr noted, it also did more than the Rydberg derivation to establish the validity of the Rutherford/Van den Broek/Bohr nuclear model of the atom, with atomic number as nuclear charge.
The K-alpha line of Moseley's time is now known to be a pair of close lines, written as (Kα1 and Kα2) in Siegbahn notation.
# Shortcomings
The Bohr model gives an incorrect value \scriptstyle \mathbf{L} = \hbar for the ground state orbital angular momentum. The angular momentum in the true ground state is known to be zero. Although mental pictures fail somewhat at these levels of scale, an electron in the lowest modern "orbital" with no orbital momentum, may be thought of as not to rotate "around" the nucleus at all, but merely to go tightly around it in an ellipse with zero area (this may be pictured as "back and forth", without striking or interacting with the nucleus). This is only reproduced in a more sophisticated semiclassical treatment like Sommerfeld's, but even in that case, the model fails to explain the empirically spherical nature of the orbital which represents the behavior of electrons with zero angular momentum.
In modern quantum mechanics, the electron in hydrogen is a spherical cloud of probability which grows more dense near the nucleus. The rate-constant of probability-decay in hydrogen is equal to the inverse of the Bohr radius, but since Bohr worked with circular orbits, not zero area ellipses, the fact that these two numbers exactly agree, is considered a "coincidence." (Though many such coincidenal agreements are found between the semi-classical vs. full quantum mechanial treatment of the atom; these include identical energy levels in the hydrogen atom, and the derivation of a fine structure constant, which arises from the relativistic Bohr-Sommerfield model (see below), and which happens to be equal to an entirely different concept, in full modern quantum mechanics).
The Bohr model also has difficulty with, or else fails to explain:
- Much of the spectra of larger atoms. At best, it can make predictions about the K-alpha and some L-alpha X-ray emission spectra for larger atoms, if two additional ad hoc assumptions are made (see Moseley's law above). Emission spectra for atoms with a single outer-shell electron (atoms in the lithium group) can also be approximately predicted. Also, if the empiric electron-nuclear screening factors for many atoms are known, many other spectral lines can be deduced from the information, in similar atoms of differing elements, via the Ritz-Rydberg combination principles (see Rydberg formula). All these techniques essentially make use of Bohr's Newtonian energy-potential picture of the atom.
- The relative intensities of spectral lines; although in some simple cases, Bohr's formula or modifications of it, was able to provide reasonable estimates (for example, calculations by Kramers for the Stark effect).
- The existence of fine structure and hyperfine structure in spectral lines, which are known to be due to a variety of relativistic and subtle effects, as well as complications from electron spin.
- The Zeeman effect - changes in spectral lines due to external magnetic fields; these are also due to more complicated quantum principles interacting with electron spin and orbital magnetic fields.
# Refinements
Several enhancements to the Bohr model were proposed; most notably the Sommerfeld model or Bohr-Sommerfeld model, which suggested that electrons travel in elliptical orbits around a nucleus instead of the Bohr model's circular orbits. This model supplemented the quantized angular momentum condition of the Bohr model with an additional radial quantization condition, the Sommerfeld-Wilson quantization condition
\int_0^T p_r dq_r = n h
where p_r is the radial momentum canonically conjugate to the coordinate q which is the radial position and T is one full orbital period. The integral is the action of action-angle coordinates. This condition, suggested by the correspondence principle, is the only one possible, since the quantum numbers are adiabatic invariants.
The Bohr-Sommerfeld model was fundamentally inconsistent and led to many paradoxes. The azimuthal quantum number measured the tilt of the orbital plane relative to the x-y plane, and it could only take a few discrete values. This contradicted the obvious fact that an atom could be turned this way and that relative to the coordinates without restriction. The Sommerfeld quantization can be performed in different canonical coordinates, and sometimes gives answers which are different. The incorporation of radiation corrections was difficult, because it required finding action-angle coordinates for a combined radiation/atom system, which is difficult when the radiation is allowed to escape. The whole theory did not extend to non-integrable motions, which meant that many systems could not be treated even in principle. In the end, the model was replaced the modern quantum mechanical treatment of the hydrogen atom, which was first given by Wolfgang Pauli in 1925, using Heisenberg's matrix mechanics. The current picture of the hydrogen atom is based on the atomic orbitals of wave mechanics which Erwin Schrodinger developed in 1926.
However, this is not to say that the Bohr model was without its successes. Calculations based on the Bohr-Sommerfeld model were able to accurately explain a number of more complex atomic spectral effects. For example, up to first-order perturbations, the Bohr model and quantum mechanics make the same predictions for the spectral line splitting in the Stark effect. At higher-order perturbations, however, the Bohr model and quantum mechanics differ, and measurements of the Stark effect under high field strengths helped confirm the correctness of quantum mechanics over the Bohr model. The prevailing theory behind this difference lies in the shapes of the orbitals of the electrons, which vary according to the energy state of the electron.
The Bohr-Sommerfeld quantization conditions lead to questions in modern mathematics. Consistent semiclassical quantization condition requires a certain type of structure on the phase space, which places topological limitations on the types of symplectic manifolds which can be quantized. In particular, the symplectic form should be the curvature form of a connection of a Hermitian line bundle, which is called a prequantization. | Bohr model
In atomic physics, the Bohr model created by Niels Bohr depicts the atom as a small, positively charged nucleus surrounded by electrons that travel in circular orbits around the nucleus — similar in structure to the solar system, but with electrostatic forces providing attraction, rather than gravity. This was an improvement on the earlier cubic model (1902), the plum-pudding model (1904), the Saturnian model (1904), and the Rutherford model (1911). Since the Bohr model is a quantum physics-based modification of the Rutherford model, many sources combine the two, referring to the Rutherford-Bohr model.
Introduced by Niels Bohr in 1913, the model's key success lay in explaining the Rydberg formula for the spectral emission lines of atomic hydrogen; while the Rydberg formula had been known experimentally, it did not gain a theoretical underpinning until the Bohr model was introduced. Not only did the Bohr model explain the reason for the structure of the Rydberg formula, but it provided a justification for its empirical results in terms of fundamental physical constants.
The Bohr model is a primitive model of the hydrogen atom. As a theory, it can be derived as a first-order approximation of the hydrogen atom using the broader and much more accurate quantum mechanics, and thus may be considered to be an obsolete scientific theory. However, because of its simplicity, and its correct results for selected systems (see below for application), the Bohr model is still commonly taught to introduce students to quantum mechanics, before moving on to the more accurate but more complex valence shell atom. A related model was originally proposed by Arthur Erich Haas in 1910, but was rejected. The quantum theory of the period between Planck's discovery of the quantum (1900) and the advent of a full-blown quantum mechanics (1925) is often referred to as the `Old quantum theory'.
# History
In the early 20th century, experiments by Ernest Rutherford established that atoms consisted of a diffuse cloud of negatively charged electrons surrounding a small, dense, positively charged nucleus. Given this experimental data, it was quite natural for Rutherford to consider a planetary model for the atom, the Rutherford model of 1911, with electrons orbiting a sun-like nucleus. However, the planetary model for the atom has a difficulty. The laws of classical mechanics, specifically the Larmor formula, predict that the electron will release electromagnetic radiation as it orbits a nucleus. Because the electron would be losing energy, it would gradually spiral inwards and collapse into the nucleus. This is a disaster, because it predicts that all matter is unstable.
Also, as the electron spirals inward, the emission would gradually increase in frequency as the orbit got smaller and faster. This would produce a continuous smear, in frequency, of electromagnetic radiation. However, late 19th century experiments with electric discharges through various low-pressure gasses in evacuated glass tubes had shown that atoms will only emit light (that is, electromagnetic radiation) at certain discrete frequencies.
To overcome this difficulty, Niels Bohr proposed, in 1913, what is now called the Bohr model of the atom. He suggested that electrons could only have certain classical motions:
- The electrons travel in circular orbits that have discrete (quantized) angular momenta, and therefore quantized energies. That is, not every circular orbit is possible but only certain specific ones, at certain specific distances from the nucleus and having specific energies.
- The electrons do not continuously lose energy as they travel. They can only gain and lose energy by jumping from one allowed orbit to another, absorbing or emitting electromagnetic radiation at frequency <math>\nu</math> determined by the energy difference <math>\Delta E = E_2 - E_1</math> of the levels according to Bohr's formula
The significance of the Bohr model is that the laws of classical mechanics apply to the motion of the electron about the nucleus only in a sense restricted by quantum rules like that for angular momentum L, restricting its value to
where n = 1,2,3,… and is called the principal quantum number. The lowest value of n is 1. This corresponds to a smallest possible radius of 0.0529 nm. This is known as the Bohr radius. Once an electron is in this lowest orbit, it can get no closer to the proton. Starting from the angular momentum quantum rule Bohr[1] was able to calculate the energies of the allowed orbits of the hydrogen atom and other hydrogenlike atoms and ions.
Other points are:
- Analogously to Einstein's theory of the Photoelectric effect it is assumed in Bohr's formula that on a quantum jump a discrete amount of energy is radiated. However, contrary to Einstein did Bohr stick to the classical Maxwell theory of the electromagnetic field. Quantization of the electromagnetic field was explained by the discreteness of the atomic energy levels; Bohr did not believe in the existence of photons.
- According to the Maxwell theory the frequency <math>\nu</math> of the radiation is equal to the rotation frequency <math>\nu_{rot}</math> of the electron in its orbit. This result is obtained to a good approximation from the Bohr model for jumps between energy levels <math>E_{n+1}</math> and <math>E_{n}</math> for sufficiently large values of <math>n</math> (so-called Rydberg states), the two orbits involved in emission for large values of <math>n</math> having nearly the same rotation frequency. However, in general the radiation frequencies are different from the rotation frequencies. This marks the birth of the correspondence principle, requiring quantum theory to yield agreement with the classical theory only in the limit of large quantum numbers.
- The Bohr-Kramers-Slater (BKS) theory is an attempt to extend the Bohr model so as to account for conservation of energy and momentum in quantum jumps.
Bohr's condition, that the angular momentum is an integer multiple of <math>\scriptstyle\hbar</math> was later reinterpreted by DeBroglie as a standing wave condition: the electron is described by a wave and a whole number of wavelengths must fit along the circumference of the electron's orbit:
Substituting DeBroglie's wavelength reproduces Bohr's rule. Bohr justified his rule by appealing to the correspondence principle, without providing a wave interpretation.
In 1925 rather a new kind of mechanics was proposed, viz. quantum mechanics in which Bohr's model of electrons traveling in quantized orbits was extended into a more accurate model of electron motion. The new theory was proposed by Werner Heisenberg. Another form of the same theory, modern quantum mechanics, was discovered by the Austrian physicist Erwin Schrödinger independently and by different reasoning.
# Electron energy levels
The Bohr model gives almost exact results only for a system where two charged points orbit each other at speeds much less than that of light. This not only includes one-electron systems such as the hydrogen atom, singly-ionized helium, doubly ionized lithium, but it includes positronium and Rydberg states of any atom where one electron is far away from everything else. It can be used for K-line X-ray transition calculations if other assumptions are added (see Moseley's law below). In high energy physics,
it can be used to calculate the masses of heavy quark mesons.
To calculate the orbits requires two assumptions:
1. Classical mechanics
2. Quantum rule
The combination of natural constants in the energy formula is called the Rydberg energy <math>R_E</math>:
This expression is clarified by interpreting it in combinations which form more natural units:
For nuclei with Z protons, the energy levels are:
When Z is approximately 137 (about 1/α), the motion becomes highly relativistic. Then the <math>Z^2</math> cancels the <math>\alpha^2</math> in R, so the orbit energy begins to be comparable to rest energy. Sufficiently large nuclei, if they were stable, would reduce their charge by creating a bound electron from the vacuum, ejecting the positron to infinity. This is the theoretical phenomenon of electromagnetic charge screening which predicts a maximum nuclear charge. Emission of such positrons has been observed in the collisions of heavy ions to create temporary super-heavy nuclei.
For positronium, the formula uses the reduced mass. For any value of the radius, the electron and the positron are each moving at half the speed around their common center of mass, and each has only one fourth the kinetic energy. The total kinetic energy is half what it would be for a single electron moving around a heavy nucleus.
# Rydberg formula
The Rydberg formula, which was known empirically before Bohr's formula, is now in Bohr's theory seen as describing the energies of transitions or quantum jumps between one orbital energy level, and another. Bohr's formula gives the numerical value of the already-known and measured Rydberg's constant, but now in terms of more fundamental constants of nature, including the electron's charge and Planck's constant.
When the electron moves from one energy level to another, a photon is emitted. Using the derived formula for the different 'energy' levels of hydrogen one may determine the 'wavelengths' of light that a hydrogen atom can emit.
The energy of a photon emitted by a hydrogen atom is given by the difference of two hydrogen energy levels:
where nf is the final energy level, and ni is the initial energy level.
Since the energy of a photon is
the wavelength of the photon given off is given by
This is known as the Rydberg formula, and the Rydberg constant R is <math>R_E/hc</math>, or <math>R_E/2\pi</math> in natural units. This formula was known in the nineteenth century to scientists studying spectroscopy, but there was no theoretical explanation for this form or a theoretical prediction for the value of R, until Bohr. In fact, Bohr's derivation of the Rydberg constant, as well as the concomitant agreement of Bohr's formula with experimentally observed spectral lines of the Lyman (<math>n_f = 1</math>), Balmer (<math>n_f = 2</math>), and Paschen (<math>n_f = 3</math>) series, and successful theoretical prediction of other lines not yet observed, was one reason that his model was immediately accepted.
# Shell model of the atom
Bohr extended the model of Hydrogen to give an approximate model for heavier atoms. This gave a physical picture which reproduced many known atomic properties for the first time.
Heavier atoms have more protons in the nucleus, and more electrons to cancel the charge. Bohr's idea was that each discrete orbit could only hold a certain number of electrons. After that orbit is full, the next level would have to be used. This gives the atom a shell structure, in which each shell corresponds to a Bohr orbit.
This model is even more approximate than the model of hydrogen, because it treats the electrons in each shell as non-interacting. But the repulsions of electrons is taken into account somewhat by the phenomenon of screening. The electrons in outer orbits do not only orbit the nucleus, but they also orbit the inner electrons, so the effective charge Z that they see is reduced by the number of the electrons in the inner orbit.
For example, the lithium atom has two electrons in the lowest 1S orbit, and these orbit at Z=2. Each one sees the nuclear charge of Z=3 minus the screening effect of the other, which crudely reduces the nuclear charge by 1 unit. This means that the innermost electrons orbit at approximately 1/4th the Bohr radius. The outermost electron in lithium orbits at roughly Z=1, since the two inner electrons reduce the nuclear charge by 2. This outer electron should be at nearly one Bohr radius from the nucleus. Because the electrons strongly repel each other, the effective charge description is very approximate, the effective charge Z doesn't usually come out to be an integer. But Moseley's law experimentally probes the innermost pair of electrons, and shows that they do see a nuclear charge of approximately Z-1, while the outermost electron in an atom or ion with only one electron in the outermost shell orbits a core with effective charge Z-k where k is the total number of electrons in the inner shells.
The shell model was able to qualitatively explain many of the mysterious properties of atoms which became codified in the late 19th century in the periodic table of the elements. One property was the size of atoms, which could be determined approximately by measuring the viscosity of gasses and density of pure crystaline solids. Atoms tend to get smaller as you move to the right in the periodic table, becoming much bigger at the next line of the table. Atoms to the right of the table tend to gain electrons, while atoms to the left tend to lose them. Every element on the last column of the table is chemically inert (noble gas).
In the shell model, this phenomenon is explained by shell-filling. Successive atoms get smaller because they are filling orbits of the same size, until the orbit is full, at which point the next atom in the table has a loosely bound outer electron, causing it to expand. The first Bohr orbit is filled when it has two electrons, and this explains why helium is inert. The second orbit allows eight electrons, and when it is full the atom is neon, again inert. The third orbital contains eight again, except that in the more correct Sommerfeld treatment (reproduced in modern quantum mechanics) there are extra "d" electrons. The third orbit may hold an extra 10 d electrons, but these positions are not filled until a few more orbitals from the next level are filled (Filling the n=3 d orbitals produces the 10 transition elements). The irregular filling pattern is an effect of interactions between electrons, which are not taken into account in either the Bohr or Sommerfeld models, and which are difficult to calculate even in the modern treatment.
# Moseley's law and calculation of K-alpha X-ray emission lines
Niels Bohr said in 1962, "You see actually the Rutherford work [the nuclear atom] was not taken seriously. We cannot understand today, but it was not taken seriously at all. There was no mention of it any place. The great change came from Moseley."
In 1913 Henry Moseley found an empirical relationship between the strongest X-ray line emitted by atoms under electron bombardment (then known as the K-alpha line), and their atomic number Z. Moseley's empiric formula was found to be derivable from Rydberg and Bohr's formula (Moseley actually mentions only Ernest Rutherford and Antonius Van den Broek in terms of models). The two additional assumptions that [1] this X-ray line came from a transition between energy levels with quantum numbers 1 and 2, and [2], that the atomic number Z when used in the formula for atoms heavier than hydrogen, should be diminished by 1, to (Z-1)².
Moseley wrote to Bohr, puzzled about his results, but Bohr was not able to help. At that time, he thought that the postulated innermost "K" shell of electrons should have at least four electrons, not the two which would have neatly explained the result. So Moseley published his results without a theoretical explanation.
Later, people realized that the effect was caused by charge screening, with an inner shell containing only 2 electrons. In the experiment, one of the innermost electrons in the atom is knocked out, leaving a vacancy in the lowest Bohr orbit, which contains a single remaining electron. This vacancy is then filled by electrons in the next orbit, which has n=2. But the n=2 electrons see an effective charge of Z-1, which is the value appropriate for the charge of the nucleus, when a single electron remains in the lowest Bohr orbit to screen the nuclear charge +Z, and lower it by -1 (due to the electron's negative charge screening the nuclear positive charge). The energy gained by an electron dropping from the second shell to the first gives Moseley's law for K-alpha lines:
or
Here, Rv is the Rydberg constant given in terms of frequency, or RE/h = 3.28 x 1015 Hz. This latter relationship had been empirically derived by Moseley, in a simple plot of the square root of X-ray frequency against atomic number. Moseley's law not only established the objective meaning of atomic number (see Henry Moseley for detail) but, as Bohr noted, it also did more than the Rydberg derivation to establish the validity of the Rutherford/Van den Broek/Bohr nuclear model of the atom, with atomic number as nuclear charge.
The K-alpha line of Moseley's time is now known to be a pair of close lines, written as (Kα1 and Kα2) in Siegbahn notation.
# Shortcomings
The Bohr model gives an incorrect value <math>\scriptstyle \mathbf{L} = \hbar </math> for the ground state orbital angular momentum. The angular momentum in the true ground state is known to be zero. Although mental pictures fail somewhat at these levels of scale, an electron in the lowest modern "orbital" with no orbital momentum, may be thought of as not to rotate "around" the nucleus at all, but merely to go tightly around it in an ellipse with zero area (this may be pictured as "back and forth", without striking or interacting with the nucleus). This is only reproduced in a more sophisticated semiclassical treatment like Sommerfeld's, but even in that case, the model fails to explain the empirically spherical nature of the orbital which represents the behavior of electrons with zero angular momentum.
In modern quantum mechanics, the electron in hydrogen is a spherical cloud of probability which grows more dense near the nucleus. The rate-constant of probability-decay in hydrogen is equal to the inverse of the Bohr radius, but since Bohr worked with circular orbits, not zero area ellipses, the fact that these two numbers exactly agree, is considered a "coincidence." (Though many such coincidenal agreements are found between the semi-classical vs. full quantum mechanial treatment of the atom; these include identical energy levels in the hydrogen atom, and the derivation of a fine structure constant, which arises from the relativistic Bohr-Sommerfield model (see below), and which happens to be equal to an entirely different concept, in full modern quantum mechanics).
The Bohr model also has difficulty with, or else fails to explain:
- Much of the spectra of larger atoms. At best, it can make predictions about the K-alpha and some L-alpha X-ray emission spectra for larger atoms, if two additional ad hoc assumptions are made (see Moseley's law above). Emission spectra for atoms with a single outer-shell electron (atoms in the lithium group) can also be approximately predicted. Also, if the empiric electron-nuclear screening factors for many atoms are known, many other spectral lines can be deduced from the information, in similar atoms of differing elements, via the Ritz-Rydberg combination principles (see Rydberg formula). All these techniques essentially make use of Bohr's Newtonian energy-potential picture of the atom.
- The relative intensities of spectral lines; although in some simple cases, Bohr's formula or modifications of it, was able to provide reasonable estimates (for example, calculations by Kramers for the Stark effect).
- The existence of fine structure and hyperfine structure in spectral lines, which are known to be due to a variety of relativistic and subtle effects, as well as complications from electron spin.
- The Zeeman effect - changes in spectral lines due to external magnetic fields; these are also due to more complicated quantum principles interacting with electron spin and orbital magnetic fields.
# Refinements
Several enhancements to the Bohr model were proposed; most notably the Sommerfeld model or Bohr-Sommerfeld model, which suggested that electrons travel in elliptical orbits around a nucleus instead of the Bohr model's circular orbits. This model supplemented the quantized angular momentum condition of the Bohr model with an additional radial quantization condition, the Sommerfeld-Wilson quantization condition
\int_0^T p_r dq_r = n h
\,</math>
where p_r is the radial momentum canonically conjugate to the coordinate q which is the radial position and T is one full orbital period. The integral is the action of action-angle coordinates. This condition, suggested by the correspondence principle, is the only one possible, since the quantum numbers are adiabatic invariants.
The Bohr-Sommerfeld model was fundamentally inconsistent and led to many paradoxes. The azimuthal quantum number measured the tilt of the orbital plane relative to the x-y plane, and it could only take a few discrete values. This contradicted the obvious fact that an atom could be turned this way and that relative to the coordinates without restriction. The Sommerfeld quantization can be performed in different canonical coordinates, and sometimes gives answers which are different. The incorporation of radiation corrections was difficult, because it required finding action-angle coordinates for a combined radiation/atom system, which is difficult when the radiation is allowed to escape. The whole theory did not extend to non-integrable motions, which meant that many systems could not be treated even in principle. In the end, the model was replaced the modern quantum mechanical treatment of the hydrogen atom, which was first given by Wolfgang Pauli in 1925, using Heisenberg's matrix mechanics. The current picture of the hydrogen atom is based on the atomic orbitals of wave mechanics which Erwin Schrodinger developed in 1926.
However, this is not to say that the Bohr model was without its successes. Calculations based on the Bohr-Sommerfeld model were able to accurately explain a number of more complex atomic spectral effects. For example, up to first-order perturbations, the Bohr model and quantum mechanics make the same predictions for the spectral line splitting in the Stark effect. At higher-order perturbations, however, the Bohr model and quantum mechanics differ, and measurements of the Stark effect under high field strengths helped confirm the correctness of quantum mechanics over the Bohr model. The prevailing theory behind this difference lies in the shapes of the orbitals of the electrons, which vary according to the energy state of the electron.
The Bohr-Sommerfeld quantization conditions lead to questions in modern mathematics. Consistent semiclassical quantization condition requires a certain type of structure on the phase space, which places topological limitations on the types of symplectic manifolds which can be quantized. In particular, the symplectic form should be the curvature form of a connection of a Hermitian line bundle, which is called a prequantization. | https://www.wikidoc.org/index.php/Bohr_model | |
4030a56c9724b4ab241febcf086660ebb79b6949 | wikidoc | Bonesetter | Bonesetter
A bonesetter is a practitioner of joint manipulation. Before the advent of chiropractors, osteopaths and physical therapists, bonesetters were the main providers of this type of treatment in the world. Bonesetters would also reduce joint dislocations and 're-set' bone fractures.
The original spinal adjustment was a variation of a procedure known today as spinal manipulation. This form of treatment has documented use as far back as Hippocrates, the ancient Egyptians and Asian Cultures and was carried through the ages by families of bonesetters. The modern form of spinal manipulation techniques have charactersitic biomechanical features, and are usually associated with an audible "popping" sound.
In some older Eastern families and communities bonesetting was learned in conjunction with acupressure / acupuncture as the main healing art and treatment for the remote location and family members. For many years this type of training was normal practice in these families and communities being passed on from generation to generation. These teachings and uses could be easily found in regular use in the Samurai culture of Japan. This type of ancient formal training has almost completely vanished due to the modern chiropractic / medical boards and certifications. However you can still find a small number classicaly trained martial arts practitioners practicing this art in traditional ways today.
Other "Lay" bonesetters still practice in some parts of the world.
# Present day bonesetting in the United Kingdom
Bonesetting involves the bonesetter adjusting the position of the bones in relation to another without the use of anaesthetics.
## The Profession
Bonesetters practice in the United Kingdom and are listed with Unified Bonesetters Ltd. The practicing title of Bonesetter in the United Kingdom is protected. All members are subject to a continuing peer review system to assess fitness to practice. This is carried out in the practitoner's own practice.
## Therapeutic Principles
Bonesetters accept the general principles that relief of pain and restoration of function through manipulation of the bones will allow the body as a whole to improve its function of both nerves and arteries.
## Treatments
Bonesetters treat pain and dysfunction and include in the treatment plan patient review and self management. | Bonesetter
A bonesetter is a practitioner of joint manipulation. Before the advent of chiropractors, osteopaths and physical therapists, bonesetters were the main providers of this type of treatment in the world. Bonesetters would also reduce joint dislocations and 're-set' bone fractures.
The original spinal adjustment was a variation of a procedure known today as spinal manipulation. This form of treatment has documented use as far back as Hippocrates, the ancient Egyptians and Asian Cultures and was carried through the ages by families of bonesetters. The modern form of spinal manipulation techniques have charactersitic biomechanical features, and are usually associated with an audible "popping" sound.
In some older Eastern families and communities bonesetting was learned in conjunction with acupressure / acupuncture as the main healing art and treatment for the remote location and family members. For many years this type of training was normal practice in these families and communities being passed on from generation to generation. These teachings and uses could be easily found in regular use in the Samurai culture of Japan. This type of ancient formal training has almost completely vanished due to the modern chiropractic / medical boards and certifications. However you can still find a small number classicaly trained martial arts practitioners practicing this art in traditional ways today.
Other "Lay" bonesetters still practice in some parts of the world.[1] [2]
# Present day bonesetting in the United Kingdom
Bonesetting involves the bonesetter adjusting the position of the bones in relation to another without the use of anaesthetics.
## The Profession
Bonesetters practice in the United Kingdom and are listed with Unified Bonesetters Ltd. The practicing title of Bonesetter in the United Kingdom is protected. All members are subject to a continuing peer review system to assess fitness to practice. This is carried out in the practitoner's own practice.
## Therapeutic Principles
Bonesetters accept the general principles that relief of pain and restoration of function through manipulation of the bones will allow the body as a whole to improve its function of both nerves and arteries.
## Treatments
Bonesetters treat pain and dysfunction and include in the treatment plan patient review and self management. | https://www.wikidoc.org/index.php/Bonesetter | |
00f6172d9fd0512a07519fb5e8505f08b0acd765 | wikidoc | Borg score | Borg score
Synonyms and keywords: Borg Rating of Perceived Exertion; rating of perceived exertion; RPE
# Overview
The Borg score is a way of measuring physical activity intensity level. Perceived exertion is how hard you feel like your body is working. It is based on the physical sensations a person experiences during physical activity, including increased heart rate, increased respiration or breathing rate, increased sweating, and muscle fatigue. Although this is a subjective measure, a person's exertion rating may provide a fairly good estimate of the actual heart rate during physical activity- (Borg, 1998).
# Borg Score
- Practitioners generally agree that perceived exertion ratings between 12 to 14 on the Borg Scale suggests that physical activity is being performed at a moderate level of intensity. During activity, use the Borg Scale to assign numbers to how you feel. Self-monitoring how hard your body is working can help you adjust the intensity of the activity by speeding up or slowing down your movements.
- Through experience of monitoring how your body feels, it will become easier to know when to adjust your intensity. For example, a walker who wants to engage in moderate-intensity activity would aim for a Borg Scale level of "somewhat hard" (12-14). If he describes his muscle fatigue and breathing as "very light" (9 on the Borg Scale) he would want to increase his intensity. On the other hand, if he felt his exertion was "extremely hard" (19 on the Borg Scale) he would need to slow down his movements to achieve the moderate-intensity range.
- A high correlation exists between a person's perceived exertion rating times 10 and the actual heart rate during physical activity; so a person's exertion rating may provide a fairly good estimate of the actual heart rate during activity. For example, if a person's rating of perceived exertion (RPE) is 12, then 12 x 10 = 120; so the heart rate should be approximately 120 beats per minute. Note that this calculation is only an approximation of heart rate, and the actual heart rate can vary quite a bit depending on age and physical condition. The Borg Rating of Perceived Exertion is also the preferred method to assess intensity among those individuals who take medications that affect heart rate or pulse.
# Instructions for Borg Score
While doing physical activity, we want you to rate your perception of exertion. This feeling should reflect how heavy and strenuous the exercise feels to you, combining all sensations and feelings of physical stress, effort, and fatigue. Do not concern yourself with any one factor such as leg pain or shortness of breath, but try to focus on your total feeling of exertion.
Look at the rating scale below while you are engaging in an activity; it ranges from 6 to 20, where 6 means "no exertion at all" and 20 means "maximal exertion." Choose the number from below that best describes your level of exertion. This will give you a good idea of the intensity level of your activity, and you can use this information to speed up or slow down your movements to reach your desired range.
Try to appraise your feeling of exertion as honestly as possible, without thinking about what the actual physical load is. Your own feeling of effort and exertion is important, not how it compares to other people's. Look at the scales and the expressions and then give a number.
The following are different numbers of the Borg score and their interpretation:
- 6: No exertion at all
- 7.5: Extremely light
- 9: It corresponds to "very light" exercise. For a healthy person, it is like walking slowly at his or her own pace for some minutes.
- 11: Light
- 13: It corresponds to "somewhat hard" exercise, but it still feels OK to continue.
- 15: Hard (heavy)
- 17: It corresponds to "very hard" is very strenuous. A healthy person can still go on, but he or she really has to push him- or herself. It feels very heavy, and the person is very tired.
- 19: This is an extremely strenuous exercise level. For most people this is the most strenuous exercise they have ever experienced.
- 20: Maximal exertion | Borg score
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Synonyms and keywords: Borg Rating of Perceived Exertion; rating of perceived exertion; RPE
# Overview
The Borg score is a way of measuring physical activity intensity level. Perceived exertion is how hard you feel like your body is working. It is based on the physical sensations a person experiences during physical activity, including increased heart rate, increased respiration or breathing rate, increased sweating, and muscle fatigue. Although this is a subjective measure, a person's exertion rating may provide a fairly good estimate of the actual heart rate during physical activity* (Borg, 1998).
# Borg Score
- Practitioners generally agree that perceived exertion ratings between 12 to 14 on the Borg Scale suggests that physical activity is being performed at a moderate level of intensity. During activity, use the Borg Scale to assign numbers to how you feel. Self-monitoring how hard your body is working can help you adjust the intensity of the activity by speeding up or slowing down your movements.
- Through experience of monitoring how your body feels, it will become easier to know when to adjust your intensity. For example, a walker who wants to engage in moderate-intensity activity would aim for a Borg Scale level of "somewhat hard" (12-14). If he describes his muscle fatigue and breathing as "very light" (9 on the Borg Scale) he would want to increase his intensity. On the other hand, if he felt his exertion was "extremely hard" (19 on the Borg Scale) he would need to slow down his movements to achieve the moderate-intensity range.
- A high correlation exists between a person's perceived exertion rating times 10 and the actual heart rate during physical activity; so a person's exertion rating may provide a fairly good estimate of the actual heart rate during activity. For example, if a person's rating of perceived exertion (RPE) is 12, then 12 x 10 = 120; so the heart rate should be approximately 120 beats per minute. Note that this calculation is only an approximation of heart rate, and the actual heart rate can vary quite a bit depending on age and physical condition. The Borg Rating of Perceived Exertion is also the preferred method to assess intensity among those individuals who take medications that affect heart rate or pulse.
# Instructions for Borg Score
While doing physical activity, we want you to rate your perception of exertion. This feeling should reflect how heavy and strenuous the exercise feels to you, combining all sensations and feelings of physical stress, effort, and fatigue. Do not concern yourself with any one factor such as leg pain or shortness of breath, but try to focus on your total feeling of exertion.
Look at the rating scale below while you are engaging in an activity; it ranges from 6 to 20, where 6 means "no exertion at all" and 20 means "maximal exertion." Choose the number from below that best describes your level of exertion. This will give you a good idea of the intensity level of your activity, and you can use this information to speed up or slow down your movements to reach your desired range.
Try to appraise your feeling of exertion as honestly as possible, without thinking about what the actual physical load is. Your own feeling of effort and exertion is important, not how it compares to other people's. Look at the scales and the expressions and then give a number.
The following are different numbers of the Borg score and their interpretation:
- 6: No exertion at all
- 7
- 7.5: Extremely light
- 8
- 9: It corresponds to "very light" exercise. For a healthy person, it is like walking slowly at his or her own pace for some minutes.
- 10
- 11: Light
- 12
- 13: It corresponds to "somewhat hard" exercise, but it still feels OK to continue.
- 14
- 15: Hard (heavy)
- 16
- 17: It corresponds to "very hard" is very strenuous. A healthy person can still go on, but he or she really has to push him- or herself. It feels very heavy, and the person is very tired.
- 18
- 19: This is an extremely strenuous exercise level. For most people this is the most strenuous exercise they have ever experienced.
- 20: Maximal exertion | https://www.wikidoc.org/index.php/Borg_Rating_of_Perceived_Exertion | |
c25b4c3a76c6877ebb5960da850703d068f077a0 | wikidoc | Boric acid | Boric acid
# Overview
Boric acid, also called boracic acid or orthoboric acid or Acidum Boricum, is a mild acid often used as an antiseptic, insecticide, flame retardant, in nuclear power plants to control the fission rate of uranium, and as a precursor of other chemical compounds. It exists in the form of colorless crystals or a white powder and dissolves in water. It has the chemical formula H3BO3, sometimes written B(OH)3. When occurring as a mineral, it is called sassolite.
# Preparation
Boric acid is produced mainly from borate minerals by the reaction with sulfuric acid. The largest source of borates in the world is an open-pit mine in Boron, California, USA.
# Properties
Boric acid was first prepared by Wilhelm Homberg (1652-1715) from borax, by the action of mineral acids, and was given the name sal sedativum Hombergi ("sedative salt of Homberg"). The presence of boric acid or its salts has been noted in sea-water. It is also said to exist in plants and especially in almost all fruits (A. H. Allen, Analyst, 1904, 301). The free acid is found native in certain volcanic districts such as Tuscany, the Lipari Islands and Nevada, issuing mixed with steam from fissures in the ground; it is also found as a constituent of many minerals (borax, boracite, boronatrocaicite and colemanite).Boric acid is soluble in boiling water. When heated above 170°C it dehydrates, forming metaboric acid HBO2. Metaboric acid is a white, cubic crystalline solid and is only slightly soluble in water. It melts at about 236°C, and when heated above about 300°C further dehydrates, forming tetraboric acid or pyroboric acid, H2B4O7. Boric acid can refer to any of these compounds. Further heating leads to boron trioxide.
Boric acid does not dissociate in aqueous solution, but is acidic due to its interaction with water molecules:
Polyborate anions are formed at pH 7–10 if the boron concentration is higher than about 0.025 mol/L. The best known of these is the tetraborate ion, found in the mineral borax:
# Crystal structure
Crystalline boric acid consists of layers of B(OH)3 molecules held together by hydrogen bonds. The distance between two adjacent layers is 318 pm.
# Toxicology
While strictly speaking, Boric Acid is poisonous if taken internally or inhaled, it is generally not considered to be much more toxic than table salt (based on its mammal LD50 rating of 2660mg/kg body mass).. The Thirteenth Edition of the Merck Index indicates that the LD50 of boric acid is 5.14 g/kg for oral dosages given to rats, and that 5 to 20 g/kg has produced death in adult humans. The LD50 of sodium chloride is reported to be 3.75 g/kg in rats according to the Merk Index.
According to the Dutch Health Council(1998/19) Boric Acid should be regarded as if it impairs fertility in humans (R60).
However, it is toxic to unborn infants, and on the testicles of boys. Also, it has been associated with low birth weight, eye malformations and problems with the nervous system.
# Uses
## Medicinal uses
It can be used as an antiseptic for minor burns or cuts and is sometimes used in dressings or salves or is applied in a very dilute solution as an eye wash. (1.5% solution or 1 tbsp per quart of boiled water has been suggested for the latter.) As an anti-bacterial compound, boric acid can also be used as an acne treatment. Boric acid can be used to treat yeast and fungal infections such as candidiasis (vaginal yeast infections) by inserting a vaginal suppository containing 600 mg of boric acid daily for 14 days (PMID 10865926). It is also used as prevention of athlete's foot, by inserting powder in the socks or stockings, and in solution can be used to treat some kinds of otitis externa (ear infection) in both humans and animals. The preservative in urine sample bottles (red cap) in the UK is boric acid.
Boric acid has the distinction of being the only known acid that is actually beneficial (rather than harmful) to the eyes, and as such is used by ophthalmologists and in some commercial eye drops.
## Insecticidal use
Boric acid was first registered as an insecticide in 1948 by the EPA for control of cockroaches, termites, fire ants, fleas, silverfish, and many other insects. It acts as a stomach poison affecting the insects' metabolism, and the dry powder is abrasive to the insects' exoskeleton.
Boric acid may be used either in an insect bait formulation containing a feed attractant or as a dry powder. The powder may be injected into cracks and crevices, where it forms a fine layer of dust. Insects travel through the boric acid dust, which adheres to their legs. When the insects groom themselves, they then ingest the poison, which causes death three to ten days later of starvation and dehydration.
## Preservative Use
In combination with its use as an insecticide it also prevents and destroys existing wet and dry rot in timbers. It can be used in combination with an ethylene glycol carrier to treat external wood against fungal and insect attack. It is possible to buy Borate impregnated rods for insertion into wood via drill holes where damp and moisture is known to collect and sit. It is available in a gel form and injectable paste form for treating rot affected wood without the need to replace the timber.
You can buy concentrates of Borate based timber treatments which can be sprayed or dipped. Surface treatments prevent slime, mycelium and algae growth even in marine environments. There is a wide range of manufacturers of wood preservers based on boric acid/ borate mineral salts.
## Industrial uses
Boric acid is used in nuclear power plants to slow down the rate at which fission is occurring. Fission chain reactions are generally driven by the amount of neutrons present (as products from previous fissions). Natural Boron is 20% Boron-10 and about 80% Boron-11. Boron-10 has a high cross-section for absorption of low energy (thermal) neutrons. By adding more boric acid to the reactor coolant which circulates through the reactor, the probability that a neutron can survive to cause fission is reduced. Therefore, boric acid concentration changes effectively regulate the rate of fissions taking place in the reactor. This is only done in Pressurized Water Reactors (PWR's). Boron is also dissolved into the spent fuel pools containing used uranium rods. The concentration is high enough to keep fissions at a minimum.
In the jewelry industry, boric acid is often used in combination with denatured alcohol to reduce surface oxidation and firescale from forming on metals during annealing and soldering operations.
It is also used in the manufacturing of remming mass, a fine silica-containing powder used for producing induction furnace linings and ceramics.
## Miscellaneous uses
Borates including boric acid have been used since the time of the Greeks for cleaning, preserving food, and other activities.
Silly Putty was originally made by adding boric acid to silicone oil. Now name-brand Silly Putty also contains significant amounts of elemental silicon (silicon binds to the silicone and allows the material to bounce 20% higher).
Lithium borate is the lithium salt of boric acid and is used in the laboratory as buffer for gel. TBE buffer is widely used for the electrophoresis of nucleic acids and has a higher buffer capacity than a TAE Buffer. It can be used for DNA and RNA polyacrylamide and agarose gel electrophoresis.
It is used in pyrotechnics to prevent the amide-forming reaction between aluminum and nitrates. A small amount of boric acid is added to the composition to neutralize alkaline amides that can react with the aluminum.
Boric acid is popularly used among fire jugglers and fire spinners dissolved in methanol to give a deep green flame.
It is also used in India and across the world to dust down Carrom boards to decrease friction and increase speed of play.
Boric acid is also used in special effects. When Boric Acid is combined with an alcohol (usually ethanol), it produces a green flame when burned. | Boric acid
Template:Chembox new
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Boric acid, also called boracic acid or orthoboric acid or Acidum Boricum, is a mild acid often used as an antiseptic, insecticide, flame retardant, in nuclear power plants to control the fission rate of uranium, and as a precursor of other chemical compounds. It exists in the form of colorless crystals or a white powder and dissolves in water. It has the chemical formula H3BO3, sometimes written B(OH)3. When occurring as a mineral, it is called sassolite.
# Preparation
Boric acid is produced mainly from borate minerals by the reaction with sulfuric acid. The largest source of borates in the world is an open-pit mine in Boron, California, USA.
# Properties
Boric acid was first prepared by Wilhelm Homberg (1652-1715) from borax, by the action of mineral acids, and was given the name sal sedativum Hombergi ("sedative salt of Homberg"). The presence of boric acid or its salts has been noted in sea-water. It is also said to exist in plants and especially in almost all fruits (A. H. Allen, Analyst, 1904, 301). The free acid is found native in certain volcanic districts such as Tuscany, the Lipari Islands and Nevada, issuing mixed with steam from fissures in the ground; it is also found as a constituent of many minerals (borax, boracite, boronatrocaicite and colemanite).Boric acid is soluble in boiling water. When heated above 170°C it dehydrates, forming metaboric acid HBO2. Metaboric acid is a white, cubic crystalline solid and is only slightly soluble in water. It melts at about 236°C, and when heated above about 300°C further dehydrates, forming tetraboric acid or pyroboric acid, H2B4O7. Boric acid can refer to any of these compounds. Further heating leads to boron trioxide.
Boric acid does not dissociate in aqueous solution, but is acidic due to its interaction with water molecules:
Polyborate anions are formed at pH 7–10 if the boron concentration is higher than about 0.025 mol/L. The best known of these is the tetraborate ion, found in the mineral borax:
# Crystal structure
Crystalline boric acid consists of layers of B(OH)3 molecules held together by hydrogen bonds. The distance between two adjacent layers is 318 pm.
# Toxicology
While strictly speaking, Boric Acid is poisonous if taken internally or inhaled, it is generally not considered to be much more toxic than table salt (based on its mammal LD50 rating of 2660mg/kg body mass).[2]. The Thirteenth Edition of the Merck Index indicates that the LD50 of boric acid is 5.14 g/kg for oral dosages given to rats, and that 5 to 20 g/kg has produced death in adult humans. The LD50 of sodium chloride is reported to be 3.75 g/kg in rats according to the Merk Index.
According to the Dutch Health Council(1998/19) Boric Acid should be regarded as if it impairs fertility in humans (R60).
However, it is toxic to unborn infants, and on the testicles of boys. Also, it has been associated with low birth weight, eye malformations and problems with the nervous system.
# Uses
## Medicinal uses
It can be used as an antiseptic for minor burns or cuts and is sometimes used in dressings or salves or is applied in a very dilute solution as an eye wash. (1.5% solution or 1 tbsp per quart of boiled water has been suggested for the latter.) As an anti-bacterial compound, boric acid can also be used as an acne treatment. Boric acid can be used to treat yeast and fungal infections such as candidiasis (vaginal yeast infections) by inserting a vaginal suppository containing 600 mg of boric acid daily for 14 days (PMID 10865926). It is also used as prevention of athlete's foot, by inserting powder in the socks or stockings, and in solution can be used to treat some kinds of otitis externa (ear infection) in both humans and animals. The preservative in urine sample bottles (red cap) in the UK is boric acid.
Boric acid has the distinction of being the only known acid that is actually beneficial (rather than harmful) to the eyes, and as such is used by ophthalmologists and in some commercial eye drops.
## Insecticidal use
Boric acid was first registered as an insecticide in 1948 by the EPA for control of cockroaches, termites, fire ants, fleas, silverfish, and many other insects. [3] It acts as a stomach poison affecting the insects' metabolism, and the dry powder is abrasive to the insects' exoskeleton.
Boric acid may be used either in an insect bait formulation containing a feed attractant or as a dry powder. The powder may be injected into cracks and crevices, where it forms a fine layer of dust. Insects travel through the boric acid dust, which adheres to their legs. When the insects groom themselves, they then ingest the poison, which causes death three to ten days later of starvation and dehydration.
## Preservative Use
In combination with its use as an insecticide it also prevents and destroys existing wet and dry rot in timbers. It can be used in combination with an ethylene glycol carrier to treat external wood against fungal and insect attack. It is possible to buy Borate impregnated rods for insertion into wood via drill holes where damp and moisture is known to collect and sit. It is available in a gel form and injectable paste form for treating rot affected wood without the need to replace the timber.
You can buy concentrates of Borate based timber treatments which can be sprayed or dipped. Surface treatments prevent slime, mycelium and algae growth even in marine environments. There is a wide range of manufacturers of wood preservers based on boric acid/ borate mineral salts.
## Industrial uses
Boric acid is used in nuclear power plants to slow down the rate at which fission is occurring. Fission chain reactions are generally driven by the amount of neutrons present (as products from previous fissions). Natural Boron is 20% Boron-10 and about 80% Boron-11. Boron-10 has a high cross-section for absorption of low energy (thermal) neutrons. By adding more boric acid to the reactor coolant which circulates through the reactor, the probability that a neutron can survive to cause fission is reduced. Therefore, boric acid concentration changes effectively regulate the rate of fissions taking place in the reactor. This is only done in Pressurized Water Reactors (PWR's). Boron is also dissolved into the spent fuel pools containing used uranium rods. The concentration is high enough to keep fissions at a minimum.
In the jewelry industry, boric acid is often used in combination with denatured alcohol to reduce surface oxidation and firescale from forming on metals during annealing and soldering operations.
It is also used in the manufacturing of remming mass, a fine silica-containing powder used for producing induction furnace linings and ceramics.
## Miscellaneous uses
Borates including boric acid have been used since the time of the Greeks for cleaning, preserving food, and other activities.
Silly Putty was originally made by adding boric acid to silicone oil. Now name-brand Silly Putty also contains significant amounts of elemental silicon (silicon binds to the silicone and allows the material to bounce 20% higher).
Lithium borate is the lithium salt of boric acid and is used in the laboratory as buffer for gel. TBE buffer is widely used for the electrophoresis of nucleic acids and has a higher buffer capacity than a TAE Buffer. It can be used for DNA and RNA polyacrylamide and agarose gel electrophoresis.
It is used in pyrotechnics to prevent the amide-forming reaction between aluminum and nitrates. A small amount of boric acid is added to the composition to neutralize alkaline amides that can react with the aluminum.
Boric acid is popularly used among fire jugglers and fire spinners dissolved in methanol to give a deep green flame.
It is also used in India and across the world to dust down Carrom boards to decrease friction and increase speed of play.
Boric acid is also used in special effects. When Boric Acid is combined with an alcohol (usually ethanol), it produces a green flame when burned. | https://www.wikidoc.org/index.php/Boric_Acid | |
53227da9d6de7f7f5fec5c5be1aab8571f91e142 | wikidoc | Bortezomib | Bortezomib
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# Overview
Bortezomib is a Proteasome Inhibitor that is FDA approved for the treatment of Multiple Myeloma, Mantle Cell Lymphoma. Common adverse reactions include hypotension, rash, constipation, decrease in appetite, diarrhea, nausea, vomiting, anemia, arthralgia, bone pain, cramp, myalgia, asthenia, dizziness, dysesthesia, headache, insomnia, paresthesia , peripheral neuropathy, mental disorder, cough, dyspnea, lower respiratory tract infection, fever.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### General Dosing Guidelines
- Recommended starting dosage: 1.3 mg/m2.
- Administered intravenously at a concentration of 1 mg/mL
- Administered subcutaneously at a concentration of 2.5 mg/mL.
- When administered intravenously, Bortezomib is administered as a 3 to 5 second bolus intravenous injection. Bortezomib is for intravenous or subcutaneous use only. Bortezomib should not be administered by any other route.
- Because each route of administration has a different reconstituted concentration, caution should be used when calculating the volume to be administered.
### Dosage in Previously Untreated Multiple Myeloma
- Bortezomib is administered in combination with oral melphalan and oral prednisone for nine 6-week treatment cycles as shown in Table 1. In Cycles 1-4, Bortezomib is administered twice weekly (days 1, 4, 8, 11, 22, 25, 29 and 32). In Cycles 5-9, Bortezomib is administered once weekly (days 1, 8, 22 and 29). At least 72 hours should elapse between consecutive doses of Bortezomib.
### Dose Modification Guidelines for Bortezomib When Given in Combination with melphalan and prednisone
- Prior to initiating any cycle of therapy with Bortezomib in combination with melphalan and prednisone:
- Platelet count should be at least 70 × 109/L and the absolute neutrophil count (ANC) should be at least 1.0 × 109/L
- Non-hematological toxicities should have resolved to Grade 1 or baseline
### Dosage and Dose Modifications for Relapsed Multiple Myeloma and Mantle Cell Lymphoma
- Bortezomib (1.3 mg/m2/dose) is administered twice weekly for 2 weeks (Days 1, 4, 8, and 11) followed by a 10-day rest period (Days 12-21). For extended therapy of more than 8 cycles, Bortezomib may be administered on the standard schedule or on a maintenance schedule of once weekly for 4 weeks (Days 1, 8, 15, and 22) followed by a 13-day rest period (Days 23 to 35) . At least 72 hours should elapse between consecutive doses of Bortezomib.
- Bortezomib therapy should be withheld at the onset of any Grade 3 non-hematological or Grade 4 hematological toxicities excluding neuropathy as discussed below . Once the symptoms of the toxicity have resolved, Bortezomib therapy may be reinitiated at a 25% reduced dose (1.3 mg/m2/dose reduced to 1 mg/m2/dose; 1 mg/m2/dose reduced to 0.7 mg/m2/dose).
- For dose modifications guidelines for peripheral neuropathy .
### Dosage in Patients with Hepatic Impairment
Patients with mild hepatic impairment do not require a starting dose adjustment and should be treated per the recommended Bortezomib dose. Patients with moderate or severe hepatic impairment should be started on Bortezomib at a reduced dose of 0.7 mg/m2 per injection during the first cycle, and a subsequent dose escalation to 1.0 mg/m2 or further dose reduction to 0.5 mg/m2 may be considered based on patient tolerance (see Table 4)
### Administration Precautions
- The drug quantity contained in one vial (3.5 mg) may exceed the usual dose required. Caution should be used in calculating the dose to prevent overdose.
- When administered subcutaneously, sites for each injection (thigh or abdomen) should be rotated. New injections should be given at least one inch from an old site and never into areas where the site is tender, bruised, erythematous, or indurated.
- If local injection site reactions occur following Bortezomib administration subcutaneously, a less concentrated Bortezomib solution (1 mg/mL instead of 2.5 mg/mL) may be administered subcutaneously. Alternatively, the intravenous route of administration should be considered
Dose must be individualized to prevent overdosage. After determining patient body surface area (BSA) in square meters, use the following equations to calculate the total volume (mL) of reconstituted Bortezomib to be administered:
- Intravenous Administration
- Subcutaneous Administration
Stickers that indicate the route of administration are provided with each Bortezomib vial. These stickers should be placed directly on the syringe of Bortezomib once Bortezomib is prepared to help alert practitioners of the correct route of administration for Bortezomib.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. If any discoloration or particulate matter is observed, the reconstituted product should not be used.
Stability: Unopened vials of Bortezomib are stable until the date indicated on the package when stored in the original package protected from light.
Bortezomib contains no antimicrobial preservative. Reconstituted Bortezomib should be administered within 8 hours of preparation. When reconstituted as directed, Bortezomib may be stored at 25°C (77°F). The reconstituted material may be stored in the original vial and/or the syringe prior to administration. The product may be stored for up to 8 hours in a syringe; however, total storage time for the reconstituted material must not exceed 8 hours when exposed to normal indoor lighting.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Bortezomib in adult patients.
### Non–Guideline-Supported Use
### Waldenström macroglobulinemia
- Dosing information
- 1.3 mg/m(2) on days 1, 4, 8, and 11. Treatment was repeated every 21 days (median number of cycles, 6; range, 2 to 39 cycles) until 2 cycles beyond stable PR or a minimum of 4 cycles
- 1.6 mg/m(2) IV on days 1, 8, and 15 (repeated every 28 days)
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
The safety and effectiveness of Bortezomib in children have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Bortezomib in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Bortezomib in pediatric patients.
# Contraindications
Bortezomib is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol. Reactions have included anaphylactic reactions.
Bortezomib is contraindicated for intrathecal administration. Fatal events have occurred with intrathecal administration of Bortezomib.
# Warnings
### Peripheral Neuropathy
Bortezomib treatment causes a peripheral neuropathy that is predominantly sensory; however, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥ Grade 3) during treatment with Bortezomib. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. In the Phase 3 relapsed multiple myeloma trial comparing Bortezomib subcutaneous versus intravenous the incidence of Grade ≥ 2 peripheral neuropathy was 24% for subcutaneous and 39% for intravenous. Grade ≥ 3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 15% in the intravenous treatment group. Starting Bortezomib subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy.
Patients experiencing new or worsening peripheral neuropathy during Bortezomib therapy may require a decrease in the dose and/or a less dose-intense schedule. In the Bortezomib versus dexamethasone phase 3 relapsed multiple myeloma study, improvement in or resolution of peripheral neuropathy was reported in 48% of patients with ≥ Grade 2 peripheral neuropathy following dose adjustment or interruption. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥ Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies . The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma.
### Hypotension
The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 8%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics .
### Cardiac Toxicity
Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have occurred during Bortezomib therapy, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart disease should be closely monitored. In the relapsed multiple myeloma study of Bortezomib versus dexamethasone, the incidence of any treatment-related cardiac disorder was 8% and 5% in the Bortezomib and dexamethasone groups, respectively. The incidence of adverse reactions suggestive of heart failure (acute pulmonary edema, pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock) was ≤ 1% for each individual reaction in the Bortezomib group. In the dexamethasone group the incidence was ≤ 1% for cardiac failure and congestive cardiac failure; there were no reported reactions of acute pulmonary edema, pulmonary edema, or cardiogenic shock. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established.
### Pulmonary Toxicity
Acute Respiratory Distress Syndrome (ARDS) and acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration have occurred in patients receiving Bortezomib. Some of these events have been fatal.
In a clinical trial, the first two patients given high-dose cytarabine (2g/m2 per day) by continuous infusion with daunorubicin and Bortezomib for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy.
There have been reports of pulmonary hypertension associated with Bortezomib administration in the absence of left heart failure or significant pulmonary disease.
In the event of new or worsening cardiopulmonary symptoms, consider interrupting Bortezomib until a prompt and comprehensive diagnostic evaluation is conducted.
### Posterior Reversible Encephalopathy Syndrome (PRES)
Posterior Reversible Encephalopathy Syndrome (PRES; formerly termed Reversible Posterior Leukoencephalopathy Syndrome (RPLS)) has occurred in patients receiving Bortezomib. PRES is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing PRES, discontinue Bortezomib. The safety of reinitiating Bortezomib therapy in patients previously experiencing PRES is not known.
### Gastrointestinal Toxicity
Bortezomib treatment can cause nausea, diarrhea, constipation, and vomiting. sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration. Interrupt Bortezomib for severe symptoms.
### Thrombocytopenia/Neutropenia
Bortezomib is associated with thrombocytopenia and neutropenia that follow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia related to pretreatment platelet count is shown in Table 6. In the relapsed multiple myeloma study of Bortezomib versus dexamethasone, the incidence of bleeding (≥ Grade 3) was 2% on the Bortezomib arm and was < 1% in the dexamethasone arm. Complete blood counts (CBC) should be monitored frequently during treatment with Bortezomib. Platelet count should be monitored prior to each dose of Bortezomib. Patients experiencing thrombocytopenia may require change in the dose and schedule of Bortezomib . Gastrointestinal and intracerebral hemorrhage has been reported in association with Bortezomib. Transfusions may be considered.
### Tumor Lysis Syndrome
Tumor lysis syndrome has been reported with Bortezomib therapy. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. Monitor patients closely and take appropriate precautions.
### Hepatic Toxicity
Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic reactions include hepatitis, increases in liver enzymes, and hyperbilirubinemia. Interrupt Bortezomib therapy to assess reversibility. There is limited re-challenge information in these patients.
### Embryo-fetal Risk
Women of reproductive potential should avoid becoming pregnant while being treated with Bortezomib. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses
# Adverse Reactions
## Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
Summary of Clinical Trial in Patients with Previously Untreated Multiple Myeloma
Table 7 describes safety data from 340 patients with previously untreated multiple myeloma who received Bortezomib (1.3 mg/m2) administered intravenously in combination with melphalan (9 mg/m2) and prednisone (60 mg/m2) in a prospective randomized study.
The safety profile of Bortezomib in combination with melphalan/prednisone is consistent with the known safety profiles of both Bortezomib and melphalan/prednisone.
‘’‘Relapsed multiple myeloma Randomized Study of Bortezomib versus dexamethasone’‘’
The safety data described below and in Table 8 reflect exposure to either Bortezomib (n=331) or dexamethasone (n=332) in a study of patients with relapsed multiple myeloma. Bortezomib was administered intravenously at doses of 1.3 mg/m2 twice weekly for 2 out of 3 weeks (21-day cycle). After eight 21-day cycles patients continued therapy for three 35-day cycles on a weekly schedule. Duration of treatment was up to 11 cycles (9 months) with a median duration of 6 cycles (4.1 months). For inclusion in the trial, patients must have had measurable disease and 1 to 3 prior therapies. There was no upper age limit for entry. Creatinine clearance could be as low as 20 mL/min and bilirubin levels as high as 1.5 times the upper limit of normal. The overall frequency of adverse reactions was similar in men and women, and in patients < 65 and ≥ 65 years of age. Most patients were Caucasian .
Among the 331 Bortezomib-treated patients, the most commonly reported (> 20%) adverse reactions overall were nausea (52%), diarrhea (52%), fatigue (39%), peripheral neuropathies NEC (35%), thrombocytopenia (33%), constipation (30%), vomiting (29%), and anorexia (21%). The most commonly reported (> 20%) adverse reaction reported among the 332 patients in the dexamethasone group was fatigue (25%). Eight percent (8%) of patients in the Bortezomib-treated arm experienced a Grade 4 adverse reaction; the most common reactions were thrombocytopenia (4%) and neutropenia (2%). Nine percent (9%) of dexamethasone-treated patients experienced a Grade 4 adverse reaction. All individual dexamethasone-related Grade 4 adverse reactions were less than 1%.
Serious Adverse Reactions and Adverse Reactions Leading to Treatment Discontinuation in the Relapsed multiple myeloma Study of Bortezomib versus dexamethasone
Serious adverse reactions are defined as any reaction that results in death, is life-threatening, requires hospitalization or prolongs a current hospitalization, results in a significant disability, or is deemed to be an important medical event. A total of 80 (24%) patients from the Bortezomib treatment arm experienced a serious adverse reaction during the study, as did 83 (25%) dexamethasone-treated patients. The most commonly reported serious adverse reactions in the Bortezomib treatment arm were diarrhea (3%), dehydration, herpes zoster, pyrexia, nausea, vomiting, dyspnea, and thrombocytopenia (2% each). In the dexamethasone treatment group, the most commonly reported serious adverse reactions were pneumonia (4%), hyperglycemia (3%), pyrexia, and psychotic disorder (2% each).
A total of 145 patients, including 84 (25%) of 331 patients in the Bortezomib treatment group and 61 (18%) of 332 patients in the dexamethasone treatment group were discontinued from treatment due to adverse reactions. Among the 331 Bortezomib treated patients, the most commonly reported adverse reaction leading to discontinuation was peripheral neuropathy (8%). Among the 332 patients in the dexamethasone group, the most commonly reported adverse reactions leading to treatment discontinuation were psychotic disorder and hyperglycemia (2% each).
Four deaths were considered to be Bortezomib-related in this relapsed multiple myeloma study: 1 case each of cardiogenic shock, respiratory insufficiency, congestive heart failure and cardiac arrest. Four deaths were considered dexamethasone-related: 2 cases of sepsis, 1 case of bacterial meningitis, and 1 case of sudden death at home.
Most Commonly Reported Adverse Reactions in the Relapsed multiple myeloma Study of Bortezomib versus dexamethasone
The most common adverse reactions from the relapsed multiple myeloma study are shown in Table 8. All adverse reactions with incidence ≥ 10% in the Bortezomib arm are included.
In general, safety data were similar for the subcutaneous and intravenous treatment groups. Differences were observed in the rates of some Grade ≥ 3 adverse reactions. Differences of ≥ 5% were reported in neuralgia (3% subcutaneous versus 9% intravenous), peripheral neuropathies NEC (6% subcutaneous versus 15% intravenous), neutropenia (13% subcutaneous versus 18% intravenous), and thrombocytopenia (8% subcutaneous versus 16% intravenous).
A local reaction was reported in 6% of patients in the subcutaneous group, mostly redness. Only 2 (1%) patients were reported as having severe reactions, 1 case of pruritus and 1 case of redness. Local reactions led to reduction in injection concentration in one patient and drug discontinuation in one patient. Local reactions resolved in a median of 6 days.
Dose reductions occurred due to adverse reactions in 31% of patients in the subcutaneous treatment group compared with 43% of the intravenously-treated patients. The most common adverse reactions leading to a dose reduction included peripheral sensory neuropathy (17% in the subcutaneous treatment group compared with 31% in the intravenous treatment group); and neuralgia (11% in the subcutaneous treatment group compared with 19% in the intravenous treatment group).
Serious Adverse Reactions and Adverse Reactions Leading to Treatment Discontinuation in the Relapsed multiple myeloma Study of Bortezomib Subcutaneous versus Intravenous
The incidence of serious adverse reactions was similar for the subcutaneous treatment group (20%) and the intravenous treatment group (19%). The most commonly reported serious adverse reactions in the subcutaneous treatment arm were pneumonia and pyrexia (2% each). In the intravenous treatment group, the most commonly reported serious adverse reactions were pneumonia, diarrhea, and peripheral sensory neuropathy (3% each).
In the subcutaneous treatment group, 27 patients (18%) discontinued study treatment due to an adverse reaction compared with 17 patients (23%) in the intravenous treatment group. Among the 147 subcutaneously-treated patients, the most commonly reported adverse reactions leading to discontinuation were peripheral sensory neuropathy (5%) and neuralgia (5%). Among the 74 patients in the intravenous treatment group, the most commonly reported adverse reactions leading to treatment discontinuation were peripheral sensory neuropathy (9%) and neuralgia (9%).
Two patients (1%) in the subcutaneous treatment group and 1 (1%) patient in the intravenous treatment group died due to an adverse reaction during treatment. In the subcutaneous group the causes of death were one case of pneumonia and one case of sudden death. In the intravenous group the cause of death was coronary artery insufficiency.
Integrated Summary of Safety (Relapsed multiple myeloma and Mantle Cell Lymphoma)
Safety data from phase 2 and 3 studies of single agent Bortezomib 1.3 mg/m2/dose twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously-treated multiple myeloma (N=1008) and previously-treated mantle cell lymphoma (N=155) were integrated and tabulated. This analysis does not include data from the Phase 3 Open-Label Study of Bortezomib subcutaneous versus intravenous in relapsed multiple myeloma. In the integrated studies, the safety profile of Bortezomib was similar in patients with multiple myeloma and mantle cell lymphoma.
In the integrated analysis, the most commonly reported (> 20%) adverse reactions were nausea (49%), diarrhea (46%), asthenic conditions including fatigue (41%) and weakness (11%), peripheral neuropathies NEC (38%), thrombocytopenia (32%), vomiting (28%), constipation (25%), and pyrexia (21%). Eleven percent (11%) of patients experienced at least 1 episode of ≥ Grade 4 toxicity, most commonly thrombocytopenia (4%) and neutropenia (2%).
In the Phase 2 relapsed multiple myeloma clinical trials of Bortezomib administered intravenously, local skin irritation was reported in 5% of patients, but extravasation of Bortezomib was not associated with tissue damage.
Serious Adverse Reactions and Adverse Reactions Leading to Treatment Discontinuation in the Integrated Summary of Safety
A total of 26% of patients experienced a serious adverse reaction during the studies. The most commonly reported serious adverse reactions included diarrhea, vomiting and pyrexia (3% each), nausea, dehydration, and thrombocytopenia (2% each) and pneumonia, dyspnea, peripheral neuropathies NEC, and herpes zoster (1% each).
Adverse reactions leading to discontinuation occurred in 22% of patients. The reasons for discontinuation included peripheral neuropathy (8%), and fatigue, thrombocytopenia, and diarrhea (2% each).
In total, 2% of the patients died and the cause of death was considered by the investigator to be possibly related to study drug: including reports of cardiac arrest, congestive heart failure, respiratory failure, renal failure, pneumonia and sepsis.
Most Commonly Reported Adverse Reactions in the Integrated Summary of Safety
The most common adverse reactions are shown in Table 10. All adverse reactions occurring at ≥ 10% are included. In the absence of a randomized comparator arm, it is often not possible to distinguish between adverse events that are drug-caused and those that reflect the patient's underlying disease. Please see the discussion of specific adverse reactions that follows.
Safety Experience from the Phase 2 Open-Label Extension Study in Relapsed multiple myeloma
In the phase 2 extension study of 63 patients, no new cumulative or new long-term toxicities were observed with prolonged Bortezomib treatment. These patients were treated for a total of 5.3 to 23 months, including time on Bortezomib in the prior Bortezomib study .
Safety Experience from the Phase 3 Open-Label Study of Bortezomib Subcutaneous versus Intravenous in Relapsed multiple myeloma
The safety and efficacy of Bortezomib administered subcutaneously were evaluated in one Phase 3 study at the recommended dose of 1.3 mg/m2. This was a randomized, comparative study of Bortezomib subcutaneous versus intravenous in 222 patients with relapsed multiple myeloma. The safety data described below and in Table 9 reflect exposure to either Bortezomib subcutaneous (n=147) or Bortezomib intravenous (n=74)
In general, safety data were similar for the subcutaneous and intravenous treatment groups. Differences were observed in the rates of some Grade ≥ 3 adverse reactions. Differences of ≥ 5% were reported in neuralgia (3% subcutaneous versus 9% intravenous), peripheral neuropathies NEC (6% subcutaneous versus 15% intravenous), neutropenia (13% subcutaneous versus 18% intravenous), and thrombocytopenia (8% subcutaneous versus 16% intravenous).
A local reaction was reported in 6% of patients in the subcutaneous group, mostly redness. Only 2 (1%) patients were reported as having severe reactions, 1 case of pruritus and 1 case of redness. Local reactions led to reduction in injection concentration in one patient and drug discontinuation in one patient. Local reactions resolved in a median of 6 days.
Dose reductions occurred due to adverse reactions in 31% of patients in the subcutaneous treatment group compared with 43% of the intravenously-treated patients. The most common adverse reactions leading to a dose reduction included peripheral sensory neuropathy (17% in the subcutaneous treatment group compared with 31% in the intravenous treatment group); and neuralgia (11% in the subcutaneous treatment group compared with 19% in the intravenous treatment group).
Serious Adverse Reactions and Adverse Reactions Leading to Treatment Discontinuation in the Relapsed multiple myeloma Study of Bortezomib Subcutaneous versus Intravenous
The incidence of serious adverse reactions was similar for the subcutaneous treatment group (20%) and the intravenous treatment group (19%). The most commonly reported serious adverse reactions in the subcutaneous treatment arm were pneumonia and pyrexia (2% each). In the intravenous treatment group, the most commonly reported serious adverse reactions were pneumonia, diarrhea, and peripheral sensory neuropathy (3% each).
In the subcutaneous treatment group, 27 patients (18%) discontinued study treatment due to an adverse reaction compared with 17 patients (23%) in the intravenous treatment group. Among the 147 subcutaneously-treated patients, the most commonly reported adverse reactions leading to discontinuation were |peripheral sensory neuropathy (5%) and neuralgia (5%). Among the 74 patients in the intravenous treatment group, the most commonly reported adverse reactions leading to treatment discontinuation were |peripheral sensory neuropathy (9%) and neuralgia (9%).
Two patients (1%) in the subcutaneous treatment group and 1 (1%) patient in the intravenous treatment group died due to an adverse reaction during treatment. In the subcutaneous group the causes of death were one case of pneumonia and one case of sudden death. In the intravenous group the cause of death was coronary artery insufficiency.
Integrated Summary of Safety (Relapsed multiple myeloma and Mantle Cell Lymphoma)
Safety data from phase 2 and 3 studies of single agent Bortezomib 1.3 mg/m2/dose twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously-treated multiple myeloma (N=1008) and previously-treated mantle cell lymphoma (N=155) were integrated and tabulated. This analysis does not include data from the Phase 3 Open-Label Study of Bortezomib subcutaneous versus intravenous in relapsed multiple myeloma. In the integrated studies, the safety profile of Bortezomib was similar in patients with multiple myeloma and mantle cell lymphoma.
In the integrated analysis, the most commonly reported (> 20%) adverse reactions were nausea (49%), diarrhea (46%), asthenic conditions including fatigue (41%) and weakness (11%), peripheral neuropathies NEC (38%), thrombocytopenia (32%), vomiting (28%), constipation (25%), and pyrexia (21%). Eleven percent (11%) of patients experienced at least 1 episode of ≥ Grade 4 toxicity, most commonly thrombocytopenia (4%) and neutropenia (2%).
In the Phase 2 relapsed multiple myeloma clinical trials of Bortezomib administered intravenously, local skin irritation was reported in 5% of patients, but extravasation of Bortezomib was not associated with tissue damage.
Serious Adverse Reactions and Adverse Reactions Leading to Treatment Discontinuation in the Integrated Summary of Safety
A total of 26% of patients experienced a serious adverse reaction during the studies. The most commonly reported serious adverse reactions included diarrhea, vomiting and pyrexia (3% each), nausea, dehydration, and thrombocytopenia (2% each) and pneumonia, dyspnea, peripheral neuropathies NEC, and herpes zoster (1% each).
Adverse reactions leading to discontinuation occurred in 22% of patients. The reasons for discontinuation included peripheral neuropathy (8%), and fatigue, thrombocytopenia, and diarrhea (2% each).
In total, 2% of the patients died and the cause of death was considered by the investigator to be possibly related to study drug: including reports of cardiac arrest, congestive heart failure, respiratory failure, renal failure, pneumonia and sepsis.
Most Commonly Reported Adverse Reactions in the Integrated Summary of Safety
The most common adverse reactions are shown in Table 10. All adverse reactions occurring at ≥ 10% are included. In the absence of a randomized comparator arm, it is often not possible to distinguish between adverse events that are drug-caused and those that reflect the patient's underlying disease. Please see the discussion of specific adverse reactions that follows.
Description of Selected Adverse Reactions from the Integrated Phase 2 and 3 Relapsed multiple myeloma and Phase 2 Mantle Cell Lymphoma Studies
Gastrointestinal Toxicity
A total of 75% of patients experienced at least one gastrointestinal disorder. The most common gastrointestinal disorders included nausea, diarrhea, constipation, vomiting, and appetite decreased. Other gastrointestinal disorders included dyspepsia and dysgeusia. Grade 3 adverse reactions occurred in 14% of patients; ≥ Grade 4 adverse reactions were ≤ 1%. Gastrointestinal adverse reactions were considered serious in 7% of patients. Four percent (4%) of patients discontinued due to a gastrointestinal adverse reaction. nausea was reported more often in patients with multiple myeloma (51%) compared to patients with mantle cell lymphoma (36%).
Thrombocytopenia
Across the studies, Bortezomib-associated thrombocytopenia was characterized by a decrease in platelet count during the dosing period (days 1 to 11) and a return toward baseline during the 10-day rest period during each treatment cycle. Overall, thrombocytopenia was reported in 32% of patients. thrombocytopenia was Grade 3 in 22%, ≥ Grade 4 in 4%, and serious in 2% of patients, and the reaction resulted in Bortezomib discontinuation in 2% of patients. thrombocytopenia was reported more often in patients with multiple myeloma (34%) compared to patients with mantle cell lymphoma (16%). The incidence of ≥ Grade 3 thrombocytopenia also was higher in patients with multiple myeloma (28%) compared to patients with mantle cell lymphoma (8%).
Peripheral Neuropathy
Overall, peripheral neuropathies NEC occurred in 38% of patients. peripheral neuropathy was Grade 3 for 11% of patients and ≥ Grade 4 for < 1% of patients. Eight percent (8%) of patients discontinued Bortezomib due to peripheral neuropathy. The incidence of peripheral neuropathy was higher among patients with mantle cell lymphoma (54%) compared to patients with multiple myeloma (36%).
In the Bortezomib versus dexamethasone phase 3 relapsed multiple myeloma study, among the 62 Bortezomib-treated patients who experienced ≥ Grade 2 peripheral neuropathy and had dose adjustments, 48% had improved or resolved with a median of 3.8 months from first onset.
In the phase 2 relapsed multiple myeloma studies, among the 30 patients who experienced Grade 2 peripheral neuropathy resulting in discontinuation or who experienced ≥ Grade 3 peripheral neuropathy, 73% reported improvement or resolution with a median time of 47 days to improvement of one Grade or more from the last dose of Bortezomib.
Hypotension
The incidence of hypotension (postural, orthostatic and hypotension NOS) was 8% in patients treated with Bortezomib. hypotension was Grade 1 or 2 in the majority of patients and Grade 3 in 2% and ≥ Grade 4 in < 1%. Two percent (2%) of patients had hypotension reported as a serious adverse reaction, and 1% discontinued due to hypotension. The incidence of hypotension was similar in patients with multiple myeloma (8%) and those with mantle cell lymphoma (9%). In addition, < 1% of patients experienced hypotension associated with a syncopal reaction.
Neutropenia
Neutrophil counts decreased during the Bortezomib dosing period (days 1 to 11) and returned toward baseline during the 10-day rest period during each treatment cycle. Overall, neutropenia occurred in 15% of patients and was Grade 3 in 8% of patients and ≥ Grade 4 in 2%. Neutropenia was reported as a serious adverse reaction in < 1% of patients and < 1% of patients discontinued due to neutropenia. The incidence of neutropenia was higher in patients with multiple myeloma (16%) compared to patients with mantle cell lymphoma (5%). The incidence of ≥ Grade 3 neutropenia also was higher in patients with multiple myeloma (12%) compared to patients with mantle cell lymphoma (3%).
Asthenic conditions (fatigue, Malaise, Weakness, Asthenia)
Asthenic conditions were reported in 54% of patients. fatigue was reported as Grade 3 in 7% and ≥ Grade 4 in < 1% of patients. Asthenia was reported as Grade 3 in 2% and ≥ Grade 4 in < 1% of patients. Two percent (2%) of patients discontinued treatment due to fatigue and < 1% due to weakness and asthenia. Asthenic conditions were reported in 53% of patients with multiple myeloma and 59% of patients with mantle cell lymphoma.
Pyrexia
pyrexia (> 38ºC) was reported as an adverse reaction for 21% of patients. The reaction was Grade 3 in 1% and ≥ Grade 4 in < 1%. pyrexia was reported as a serious adverse reaction in 3% of patients and led to Bortezomib discontinuation in < 1% of patients. The incidence of pyrexia was higher among patients with multiple myeloma (23%) compared to patients with mantle cell lymphoma (10%). The incidence of ≥ Grade 3 pyrexia was 1% in patients with multiple myeloma and < 1% in patients with mantle cell lymphoma
Herpes Virus Infection
Consider using antiviral prophylaxis in subjects being treated with Bortezomib. In the randomized studies in previously untreated and relapsed multiple myeloma, herpes zoster reactivation was more common in subjects treated with Bortezomib (ranging between 6-11%) than in the control groups (3-4%). Herpes simplex was seen in 1-3% in subjects treated with Bortezomib and 1-3% in the control groups. In the previously untreated multiple myeloma study, herpes zoster virus reactivation in the Bortezomib, melphalan and prednisone arm was less common in subjects receiving prophylactic antiviral therapy (3%) than in subjects who did not receive prophylactic antiviral therapy (17%).
Additional Adverse Reactions from Clinical Studies
The following clinically important serious adverse reactions that are not described above have been reported in clinical trials in patients treated with Bortezomib administered as monotherapy or in combination with other chemotherapeutics. These studies were conducted in patients with hematological malignancies and in solid tumors.
Blood and lymphatic system disorders: Anemia, disseminated intravascular coagulation, febrile neutropenia, lymphopenia, leukopenia
Cardiac disorders: Angina pectoris, atrial fibrillation aggravated, atrial flutter, bradycardia, sinus arrest, cardiac amyloidosis, complete atrioventricular block, myocardial ischemia, myocardial infarction, pericarditis, pericardial effusion, Torsades de pointes, ventricular tachycardia
Ear and labyrinth disorders: Hearing impaired, vertigo
Eye disorders: Diplopia and blurred vision, conjunctival infection, irritation
Gastrointestinal disorders: Abdominal pain, ascites, dysphagia, fecal impaction, gastroenteritis, gastritis hemorrhagic, hematemesis, hemorrhagic duodenitis, ileus paralytic, large intestinal obstruction, paralytic intestinal obstruction, peritonitis, small intestinal obstruction, large intestinal perforation, stomatitis, melena, pancreatitis acute, oral mucosal petechiae, gastroesophageal reflux
General disorders and administration site conditions: Chills, edema, edema peripheral, injection site erythema, neuralgia, injection site pain, irritation, malaise, phlebitis
Hepatobiliary disorders: Cholestasis, hepatic hemorrhage, hyperbilirubinemia, portal vein thrombosis, hepatitis, liver failure
Immune system disorders: Anaphylactic reaction, drug hypersensitivity, immune complex mediated hypersensitivity, angioedema, laryngeal edema
Infections and infestations: Aspergillosis, bacteremia, bronchitis, urinary tract infection, herpes viral infection, listeriosis, nasopharyngitis, pneumonia, respiratory tract infection, septic shock, toxoplasmosis, oral candidiasis, sinusitis, catheter related infection
Injury, poisoning and procedural complications: Catheter related complication, skeletal fracture, subdural hematoma
Investigations: Weight decreased
Metabolism and nutrition disorders: dehydration, hypocalcemia, hyperuricemia, hypokalemia, hyperkalemia, hyponatremia, hypernatremia
Musculoskeletal and connective tissue disorders: Arthralgia, back pain, bone pain, myalgia, pain in extremity
Nervous system disorders: Ataxia, coma, dizziness, dysarthria, dysesthesia, dysautonomia, encephalopathy, cranial palsy, grand mal convulsion, headache, hemorrhagic stroke, motor dysfunction, neuralgia, spinal cord compression, paralysis, postherpetic neuralgia, transient ischemic attack
Psychiatric disorders: Agitation, anxiety, confusion, insomnia, mental status change, psychotic disorder, suicidal ideation
Renal and urinary disorders: Calculus renal, bilateral hydronephrosis, bladder spasm, hematuria, hemorrhagic cystitis, urinary incontinence, urinary retention, renal failure (acute and chronic), glomerular nephritis proliferative
Respiratory, thoracic and mediastinal disorders: Acute respiratory distress syndrome, aspiration pneumonia, atelectasis, chronic obstructive airways disease exacerbated, cough, dysphagia, dyspnea, dyspnea exertional, epistaxis, hemoptysis, hypoxia, lung infiltration, pleural effusion, pneumonitis, respiratory distress, pulmonary hypertension
Skin and subcutaneous tissue disorders: Urticaria, face edema, rash (which may be pruritic), leukocytoclastic vasculitis, pruritus.
Vascular disorders: Cerebrovascular accident, cerebral hemorrhage, deep venous thrombosis, hypertension, peripheral embolism, pulmonary embolism, pulmonary hypertension
## Postmarketing Experience
The following adverse reactions have been identified from the worldwide postmarketing experience with Bortezomib. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: atrioventricular block complete, cardiac tamponade, ischemic colitis, encephalopathy, dysautonomia, deafness bilateral, disseminated intravascular coagulation, hepatitis, acute pancreatitis, progressive multifocal leukoencephalopathy (PML), acute diffuse infiltrative pulmonary disease, PRES (formerly RPLS), toxic epidermal necrolysis, acute febrile neutrophilic dermatosis (Sweet's syndrome), herpes meningoencephalitis, optic neuropathy, blindness and ophthalmic herpes.
# Drug Interactions
Bortezomib is a substrate of cytochrome P450 enzyme 3A4, 2C19 and 1A2.
### CYP3A4 inhibitors
Co-administration of ketoconazole, a strong CYP3A4 inhibitor, increased the exposure of bortezomib by 35% in 12 patients. Monitor patients for signs of bortezomib toxicity and consider a bortezomib dose reduction if bortezomib must be given in combination with strong CYP3A4 inhibitors (e.g. ketoconazole, ritonavir).
### CYP2C19 inhibitors
Co-administration of omeprazole, a strong inhibitor of CYP2C19, had no effect on the exposure of bortezomib in 17 patients.
### CYP3A4 inducers
Co-administration of rifampin, a strong CYP3A4 inducer, is expected to decrease the exposure of bortezomib by at least 45%. Because the drug interaction study (n=6) was not designed to exert the maximum effect of rifampin on bortezomib PK, decreases greater than 45% may occur.
Efficacy may be reduced when Bortezomib is used in combination with strong CYP3A4 inducers; therefore, concomitant use of strong CYP3A4 inducers is not recommended in patients receiving Bortezomib.
St. John's Wort (Hypericum perforatum) may decrease bortezomib exposure unpredictably and should be avoided.
### dexamethasone
Co-administration of dexamethasone, a weak CYP3A4 inducer, had no effect on the exposure of bortezomib in 7 patients.
### melphalan-prednisone
Co-administration of melphalan-prednisone increased the exposure of bortezomib by 17% in 21 patients. However, this increase is unlikely to be clinically relevant.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
Bortezomib was not teratogenic in nonclinical developmental toxicity studies in rats and rabbits at the highest dose tested (0.075 mg/kg; 0.5 mg/m2 in the rat and 0.05 mg/kg; 0.6 mg/m2 in the rabbit) when administered during organogenesis. These dosages are approximately half the clinical dose of 1.3 mg/m2 based on body surface area.
Pregnant rabbits given bortezomib during organogenesis at a dose of 0.05mg/kg (0.6 mg/m2) experienced significant post-implantation loss and decreased number of live fetuses. Live fetuses from these litters also showed significant decreases in fetal weight. The dose is approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area.
There are no adequate and well-controlled studies in pregnant women. If Bortezomib is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Bortezomib in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Bortezomib during labor and delivery.
### Nursing Mothers
It is not known whether bortezomib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Bortezomib, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
The safety and effectiveness of Bortezomib in children have not been established.
### Geriatic Use
Of the 669 patients enrolled in the relapsed multiple myeloma study, 245 (37%) were 65 years of age or older: 125 (38%) on the Bortezomib arm and 120 (36%) on the dexamethasone arm. Median time to progression and median duration of response for patients ≥ 65 were longer on Bortezomib compared to dexamethasone . On the Bortezomib arm, 40% (n=46) of evaluable patients aged ≥ 65 experienced response (CR+PR) versus 18% (n=21) on the dexamethasone arm. The incidence of Grade 3 and 4 events was 64%, 78% and 75% for Bortezomib patients ≤ 50, 51-64 and ≥ 65 years old, respectively.
No overall differences in safety or effectiveness were observed between patients ≥ age 65 and younger patients receiving Bortezomib; but greater sensitivity of some older individuals cannot be ruled out.
### Gender
There is no FDA guidance on the use of Bortezomib with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Bortezomib with respect to specific racial populations.
### Renal Impairment
The exposure of bortezomib is increased in patients with moderate (bilirubin ≥ 1.5 – 3× ULN) and severe (bilirubin > 3 × ULN) hepatic impairment. Starting dose should be reduced in those patients
### Hepatic Impairment
The exposure of bortezomib is increased in patients with moderate (bilirubin ≥ 1.5 – 3× ULN) and severe (bilirubin > 3 × ULN) hepatic impairment. Starting dose should be reduced in those patients
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Bortezomib in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Bortezomib in patients who are immunocompromised.
### Patients with Diabetes
During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral anti-diabetic agents receiving Bortezomib treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their anti-diabetic medication.
# Administration and Monitoring
### Administration
intravenous injection or subcutaneous
### Monitoring
FDA Package Insert for Bortezomib contains no information regarding drug monitoring.
# IV Compatibility
There is limited information about the IV Compatibility.
# Overdosage
There is no known specific antidote for Bortezomib overdosage. In humans, fatal outcomes following the administration of more than twice the recommended therapeutic dose have been reported, which were associated with the acute onset of symptomatic hypotension and thrombocytopenia . In the event of an overdosage, the patient's vital signs should be monitored and appropriate supportive care given.
Studies in monkeys and dogs showed that intravenous bortezomib doses as low as 2 times the recommended clinical dose on a mg/m2 basis were associated with increases in heart rate, decreases in contractility, hypotension, and death. In dog studies, a slight increase in the corrected QT interval was observed at doses resulting in death. In monkeys, doses of 3.0 mg/m2 and greater (approximately twice the recommended clinical dose) resulted in hypotension starting at 1 hour post-administration, with progression to death in 12 to 14 hours following drug administration.
# Pharmacology
## Mechanism of Action
Bortezomib is a reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome in mammalian cells. The 26S proteasome is a large protein complex that degrades ubiquitinated proteins. The ubiquitin-proteasome pathway plays an essential role in regulating the intracellular concentration of specific proteins, thereby maintaining homeostasis within cells. Inhibition of the 26S proteasome prevents this targeted proteolysis, which can affect multiple signaling cascades within the cell. This disruption of normal homeostatic mechanisms can lead to cell death. Experiments have demonstrated that bortezomib is cytotoxic to a variety of cancer cell types in vitro. Bortezomib causes a delay in tumor growth in vivo in nonclinical tumor models, including multiple myeloma.
## Structure
Bortezomib® (bortezomib) for Injection is an antineoplastic agent available for intravenous injection or subcutaneous use. Each single use vial contains 3.5 mg of bortezomib as a sterile lyophilized powder. Inactive ingredient: 35 mg mannitol, USP.
Bortezomib is a modified dipeptidyl boronic acid. The product is provided as a mannitol boronic ester which, in reconstituted form, consists of the mannitol ester in equilibrium with its hydrolysis product, the monomeric boronic acid. The drug substance exists in its cyclic anhydride form as a trimeric boroxine.
The chemical name for bortezomib, the monomeric boronic acid, is propyl]amino]butyl] boronic acid.
Bortezomib has the following chemical structure:
The molecular weight is 384.24. The molecular formula is C19H25BN4O4. The solubility of bortezomib, as the monomeric boronic acid, in water is 3.3 to 3.8 mg/mL in a pH range of 2 to 6.5.
## Pharmacodynamics
FDA Package Insert for Bortezomib contains no information regarding Adverse Reactions.
## Pharmacokinetics
Following intravenous administration of 1 mg/m2 and 1.3 mg/m2 doses to 24 patients with multiple myeloma (n=12, per each dose level), the mean maximum plasma concentrations of bortezomib (Cmax) after the first dose (Day 1) were 57 and 112 ng/mL, respectively. In subsequent doses, when administered twice weekly, the mean maximum observed plasma concentrations ranged from 67 to 106 ng/mL for the 1 mg/m2 dose and 89 to 120 ng/mL for the 1.3 mg/m2 dose. The mean elimination half-life of bortezomib upon multiple dosing ranged from 40 to 193 hours after the 1 mg/m2 dose and 76 to 108 hours after the 1.3mg/m2 dose. The mean total body clearances was 102 and 112 L/h following the first dose for doses of 1 mg/m2 and 1.3 mg/m2, respectively, and ranged from 15 to 32 L/h following subsequent doses for doses of 1 and 1.3 mg/m2, respectively.
Following an intravenous bolus or subcutaneous injection of a 1.3 mg/m2 dose to patients (n = 14 for intravenous, n = 17 for subcutaneous) with multiple myeloma, the total systemic exposure after repeat dose administration (AUClast) was equivalent for subcutaneous and intravenous administration. The Cmax after subcutaneous administration (20.4 ng/mL) was lower than intravenous (223 ng/mL). The AUClast geometric mean ratio was 0.99 and 90% confidence intervals were 80.18% - 122.80%.
Distribution: The mean distribution volume of bortezomib ranged from approximately 498 to 1884 L/m2 following single- or repeat-dose administration of 1 mg/m2 or 1.3mg/m2 to patients with multiple myeloma. This suggests bortezomib distributes widely to peripheral tissues. The binding of bortezomib to human plasma proteins averaged 83% over the concentration range of 100 to 1000 ng/mL.
Metabolism: In vitro studies with human liver microsomes and human cDNA-expressed cytochrome P450 isozymes indicate that bortezomib is primarily oxidatively metabolized via cytochrome P450 enzymes 3A4, 2C19, and 1A2. Bortezomib metabolism by CYP 2D6 and 2C9 enzymes is minor. The major metabolic pathway is deboronation to form 2 deboronated metabolites that subsequently undergo hydroxylation to several metabolites. Deboronated bortezomib metabolites are inactive as 26S proteasome inhibitors. Pooled plasma data from 8 patients at 10 min and 30 min after dosing indicate that the plasma levels of metabolites are low compared to the parent drug.
Elimination: The pathways of elimination of bortezomib have not been characterized in humans.
Age: Analyses of data after the first dose of Cycle 1 (Day 1) in 39 multiple myeloma patients who had received intravenous doses of 1 mg/m2 and 1.3 mg/m2 showed that both dose-normalized AUC and Cmax tend to be less in younger patients. Patients < 65 years of age (n=26) had about 25% lower mean dose-normalized AUC and Cmax than those ≥ 65 years of age (n=13).
Gender: Mean dose-normalized AUC and Cmax values were comparable between male (n=22) and female (n=17) patients after the first dose of Cycle 1 for the 1 and 1.3 mg/m2 doses.
Race: The effect of race on exposure to bortezomib could not be assessed as most of the patients were Caucasian.
Hepatic Impairment: The effect of hepatic impairment (see Table 4 for definition of hepatic impairment) on the pharmacokinetics of bortezomib was assessed in 60 patients with cancer at bortezomib doses ranging from 0.5 to 1.3 mg/m2. When compared to patients with normal hepatic function, mild hepatic impairment did not alter dose-normalized bortezomib AUC. However, the dose-normalized mean AUC values were increased by approximately 60% in patients with moderate or severe hepatic impairment. A lower starting dose is recommended in patients with moderate or severe hepatic impairment, and those patients should be monitored closely .
Renal Impairment: A pharmacokinetic study was conducted in patients with various degrees of renal impairment who were classified according to their creatinine clearance values (CrCl) into the following groups: Normal (CrCl ≥60 mL/min/1.73 m2, N=12), Mild (CrCl=40-59 mL/min/1.73 m2, N=10), Moderate (CrCl=20-39 mL/min/1.73 m2, N=9), and Severe (CrCl < 20 mL/min/1.73 m2, N=3). A group of dialysis patients who were dosed after dialysis was also included in the study (N=8). Patients were administered intravenous doses of 0.7 to 1.3 mg/m2 of bortezomib twice weekly. Exposure of bortezomib (dose-normalized AUC and Cmax) was comparable among all the groups .
Pediatric: There are no pharmacokinetic data in pediatric patients.
Cytochrome P450: Bortezomib is a poor inhibitor of human liver microsome cytochrome P450 1A2, 2C9, 2D6, and 3A4, with IC50 values of > 30µM (> 11.5µg/mL). Bortezomib may inhibit 2C19 activity (IC50 = 18 µM, 6.9 µg/mL) and increase exposure to drugs that are substrates for this enzyme. Bortezomib did not induce the activities of cytochrome P450 3A4 and 1A2 in primary cultured human hepatocytes.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies have not been conducted with bortezomib.
Bortezomib showed clastogenic activity (structural chromosomal aberrations) in the in vitro chromosomal aberration assay using Chinese hamster ovary cells. Bortezomib was not genotoxic when tested in the in vitro mutagenicity assay (Ames test) and in vivo micronucleus assay in mice.
Fertility studies with bortezomib were not performed but evaluation of reproductive tissues has been performed in the general toxicity studies. In the 6-month rat toxicity study, degenerative effects in the ovary were observed at doses ≥ 0.3 mg/m2 (one-fourth of the recommended clinical dose), and degenerative changes in the testes occurred at 1.2 mg/m2. Bortezomib could have a potential effect on either male or female fertility.
### Animal Toxicology and/or Pharmacology
Cardiovascular Toxicity: Studies in monkeys showed that administration of dosages approximately twice the recommended clinical dose resulted in heart rate elevations, followed by profound progressive hypotension, bradycardia, and death 12 to 14 hours post dose. Doses ≥ 1.2 mg/m2 induced dose-proportional changes in cardiac parameters. Bortezomib has been shown to distribute to most tissues in the body, including the myocardium. In a repeated dosing toxicity study in the monkey, myocardial hemorrhage, inflammation, and necrosis were also observed.
Chronic Administration: In animal studies at a dose and schedule similar to that recommended for patients (twice weekly dosing for 2 weeks followed by 1-week rest), toxicities observed included severe anemia and thrombocytopenia, and gastrointestinal, neurological and lymphoid system toxicities. Neurotoxic effects of bortezomib in animal studies included axonal swelling and degeneration in peripheral nerves, dorsal spinal roots, and tracts of the spinal cord. Additionally, multifocal hemorrhage and necrosis in the brain, eye, and heart were observed.
# Clinical Studies
### multiple myeloma
Randomized, Open-Label Clinical Study in Patients with Previously Untreated multiple myeloma:
A prospective, international, randomized (1:1), open-label clinical study of 682 patients was conducted to determine whether Bortezomib administered intravenously (1.3 mg/m2) in combination with melphalan (9 mg/m2) and prednisone (60 mg/m2) resulted in improvement in time to progression (TTP) when compared to melphalan (9 mg/m2) and prednisone (60 mg/m2) in patients with previously untreated multiple myeloma. Treatment was administered for a maximum of 9 cycles (approximately 54 weeks) and was discontinued early for disease progression or unacceptable toxicity. Antiviral prophylaxis was recommended for patients on the Bortezomib study arm.
The median age of the patients in the study was 71 years (48;91), 50% were male, 88% were Caucasian and the median Karnofsky performance status score for the patients was 80 (60;100). Patients had IgG/IgA/Light chain myeloma in 63%/25%/8% instances, a median hemoglobin of 105 g/L (64;165), and a median platelet count of 221,500 /microliter (33,000;587,000).
Efficacy results for the trial are presented in Table 11. At a pre-specified interim analysis (with median follow-up of 16.3 months), the combination of Bortezomib, melphalan and prednisone therapy resulted in significantly superior results for time to progression, progression-free survival, overall survival and response rate. Further enrollment was halted, and patients receiving melphalan and prednisone were offered Bortezomib in addition. A later, pre-specified analysis of overall survival (with median follow-up of 36.7 months with a hazard ratio of 0.65, 95% CI: 0.51, 0.84) resulted in a statistically significant survival benefit for the Bortezomib, melphalan and prednisone treatment arm despite subsequent therapies including Bortezomib based regimens. In an updated analysis of overall survival based on 387 deaths (median follow-up 60.1 months), the median overall survival for the Bortezomib, melphalan and prednisone treatment arm was 56.4 months and for the melphalan and prednisone treatment arm was 43.1 months, with a hazard ratio of 0.695 (95% CI: 0.57, 0.85).
TTP was statistically significantly longer on the Bortezomib, melphalan and prednisone arm (see Figure 1). (median follow-up 16.3 months)
Overall survival was statistically significantly longer on the Bortezomib, melphalan and prednisone arm (see Figure 2). (median follow-up 60.1 months)
Randomized, Clinical Study in Relapsed multiple myeloma of Bortezomib versus dexamethasone
A prospective phase 3, international, randomized (1:1), stratified, open-label clinical study enrolling 669 patients was designed to determine whether Bortezomib resulted in improvement in time to progression (TTP) compared to high-dose dexamethasone in patients with progressive multiple myeloma following 1 to 3 prior therapies. Patients considered to be refractory to prior high-dose dexamethasone were excluded as were those with baseline Grade ≥ 2 peripheral neuropathy or platelet counts < 50,000/µL. A total of 627 patients were evaluable for response.
Stratification factors were based on the number of lines of prior therapy the patient had previously received (1 previous line versus more than 1 line of therapy), time of progression relative to prior treatment (progression during or within 6 months of stopping their most recent therapy versus relapse > 6 months after receiving their most recent therapy), and screening beta2-microglobulin levels (≤ 2.5 mg/L versus > 2.5 mg/L).
Baseline patient and disease characteristics are summarized in Table 12.
Patients in the Bortezomib treatment group were to receive eight 3-week treatment cycles followed by three 5-week treatment cycles of Bortezomib. Patients achieving a CR were treated for 4 cycles beyond first evidence of CR. Within each 3-week treatment cycle, Bortezomib 1.3 mg/m2/dose alone was administered by intravenous bolus twice weekly for 2 weeks on Days 1, 4, 8, and 11 followed by a 10-day rest period (Days 12 to 21). Within each 5-week treatment cycle, Bortezomib 1.3 mg/m2/dose alone was administered by intravenous bolus once weekly for 4 weeks on Days 1, 8, 15, and 22 followed by a 13-day rest period (Days 23 to 35).
Patients in the dexamethasone treatment group were to receive four 5-week treatment cycles followed by five 4-week treatment cycles. Within each 5-week treatment cycle, dexamethasone 40 mg/day PO was administered once daily on Days 1 to 4, 9 to 12, and 17 to 20 followed by a 15-day rest period (Days 21-35). Within each 4-week treatment cycle, dexamethasone 40 mg/day PO was administered once daily on Days 1 to 4 followed by a 24-day rest period (Days 5 to 28). Patients with documented progressive disease on dexamethasone were offered Bortezomib at a standard dose and schedule on a companion study. Following a preplanned interim analysis of time to progression, the dexamethasone arm was halted and all patients randomized to dexamethasone were offered Bortezomib, regardless of disease status.
In the Bortezomib arm, 34% of patients received at least one Bortezomib dose in all 8 of the 3-week cycles of therapy, and 13% received at least one dose in all 11 cycles. The average number of Bortezomib doses during the study was 22, with a range of 1 to 44. In the dexamethasone arm, 40% of patients received at least one dose in all 4 of the 5-week treatment cycles of therapy, and 6% received at least one dose in all 9 cycles.
The time to event analyses and response rates from the relapsed multiple myeloma study are presented in Table 13. Response and progression were assessed using the European Group for Blood and Marrow Transplantation (EBMT) criteria. Complete response (CR) required < 5% plasma cells in the marrow, 100% reduction in M-protein, and a negative immunofixation test (IF-). Partial response (PR) requires ≥ 50% reduction in serum myeloma protein and ≥ 90% reduction of urine myeloma protein on at least 2 occasions for a minimum of at least 6 weeks along with stable bone disease and normal calcium. Near complete response (nCR) was defined as meeting all the criteria for complete response including 100% reduction in M-protein by protein electrophoresis; however, M-protein was still detectable by immunofixation (IF+).
TTP was statistically significantly longer on the Bortezomib arm (see Figure 3).
As shown in Figure 4 Bortezomib had a significant survival advantage relative to dexamethasone (p < 0.05). The median follow-up was 8.3 months.
For the 121 patients achieving a response (CR or PR) on the Bortezomib arm, the median duration was 8.0 months (95% CI: 6.9, 11.5 months) compared to 5.6 months (95% CI: 4.8, 9.2 months) for the 56 responders on the dexamethasone arm. The response rate was significantly higher on the Bortezomib arm regardless of beta2-microglobulin levels at baseline.
Randomized, Open-Label Clinical Study of Bortezomib Subcutaneous versus Intravenous in Relapsed multiple myeloma
An open-label, randomized, phase 3 non-inferiority study compared the efficacy and safety of the subcutaneous administration of Bortezomib versus the intravenous administration. This study included 222 bortezomib naïve patients with relapsed multiple myeloma, who were randomized in a 2:1 ratio to receive 1.3 mg/m2 of Bortezomib by either the subcutaneous (n=148) or intravenous (n=74) route for 8 cycles. Patients who did not obtain an optimal response (less than Complete Response (CR)) to therapy with Bortezomib alone after 4 cycles were allowed to receive oral dexamethasone 20 mg daily on the day of and after Bortezomib administration (82 patients in subcutaneous treatment group and 39 patients in the intravenous treatment group). Patients with baseline Grade ≥ 2 peripheral neuropathy or neuropathic pain, or platelet counts < 50,000/µL were excluded. A total of 218 patients were evaluable for response.
Stratification factors were based on the number of lines of prior therapy the patient had received (1 previous line versus more than 1 line of therapy), and international staging system (ISS) stage (incorporating beta2-microglobulin and albumin levels; Stages I, II, or III).
The baseline demographic and others characteristics of the two treatment groups are summarized as follows: the median age of the patient population was approximately 64 years of age (range 38-88 years), primarily male (subcutaneous: 50%, intravenous: 64%); the primary type of myeloma is IgG (subcutaneous: 65% IgG, 26% IgA, 8% light chain; intravenous: 72% IgG, 19% IgA, 8% light chain), ISS staging I/II/III (%) was 27, 41, 32 for both subcutaneous and intravenous, Karnofsky performance status score was ≤ 70% in 22% of subcutaneous and 16% of intravenous, creatinine clearance was 67.5 mL/min in subcutaneous and 73 mL/min in intravenous, the median years from diagnosis was 2.68 and 2.93 in subcutaneous and intravenous respectively and the proportion of patients with more than one prior line of therapy was 38% in subcutaneous and 35% in intravenous.
This study met its primary (non-inferiority) objective that single agent subcutaneous Bortezomib retains at least 60% of the overall response rate after 4 cycles relative to single agent intravenous Bortezomib. The results are provided in Table 14.
A Randomized Phase 2 Dose-Response Study in Relapsed multiple myeloma
An open-label, multicenter study randomized 54 patients with multiple myeloma who had progressed or relapsed on or after front-line therapy to receive Bortezomib 1 mg/m2 or 1.3 mg/m2 intravenous bolus twice weekly for 2 weeks on Days 1, 4, 8, and 11 followed by a 10-day rest period (Days 12 to 21). The median duration of time between diagnosis of multiple myeloma and first dose of Bortezomib on this trial was 2.0 years, and patients had received a median of 1 prior line of treatment (median of 3 prior therapies). A single complete response was seen at each dose. The overall response rates (CR + PR) were 30% (8/27) at 1 mg/m2 and 38% (10/26) at 1.3 mg/m2.
A Phase 2 Open-Label Extension Study in Relapsed multiple myeloma
Patients from the two phase 2 studies, who in the investigators' opinion would experience additional clinical benefit, continued to receive Bortezomib beyond 8 cycles on an extension study. Sixty-three (63) patients from the phase 2 multiple myeloma studies were enrolled and received a median of 7 additional cycles of Bortezomib therapy for a total median of 14 cycles (range 7 to 32). The overall median dosing intensity was the same in both the parent protocol and extension study. Sixty-seven percent (67%) of patients initiated the extension study at the same or higher dose intensity at which they completed the parent protocol, and 89% of patients maintained the standard 3-week dosing schedule during the extension study. No new cumulative or new long-term toxicities were observed with prolonged Bortezomib treatment .
### Mantle Cell Lymphoma
A Phase 2 Single-arm Clinical Study in Relapsed Mantle Cell Lymphoma After Prior Therapy
The safety and efficacy of Bortezomib in relapsed or refractory mantle cell lymphoma were evaluated in an open-label, single-arm, multicenter study of 155 patients with progressive disease who had received at least 1 prior therapy. The median age of the patients was 65 years (42, 89), 81% were male, and 92% were Caucasian. Of the total, 75% had one or more extra-nodal sites of disease, and 77% were stage 4. In 91% of the patients, prior therapy included all of the following: an anthracycline or mitoxantrone, cyclophosphamide, and rituximab. A total of thirty seven percent (37%) of patients were refractory to their last prior therapy. An intravenous bolus injection of Bortezomib 1.3 mg/m2/dose was administered twice weekly for 2 weeks on Days 1, 4, 8, and 11 followed by a 10-day rest period (Days 12 to 21) for a maximum of 17 treatment cycles. Patients achieving a CR or CRu were treated for 4 cycles beyond first evidence of CR or CRu. The study employed dose modifications for toxicity.
Responses to Bortezomib are shown in Table 15. Response rates to Bortezomib were determined according to the International Workshop Response Criteria (IWRC) based on independent radiologic review of CT scans. The median number of cycles administered across all patients was 4; in responding patients the median number of cycles was 8. The median time to response was 40 days (range 31 to 204 days). The median duration of follow-up was more than 13 months.
# How Supplied
Bortezomib® (bortezomib) for Injection is supplied as individually cartoned 10 mL vials containing 3.5 mg of bortezomib as a white to off-white cake or powder.
NDC 63020-049-01
3.5 mg single use vial
## Storage
Unopened vials may be stored at controlled room temperature 25°C (77°F); excursions permitted from 15 to 30°C (59 to 86°F) . Retain in original package to protect from light.
Consider handling and disposal of Bortezomib according to guidelines issued for cytotoxic drugs, including the use of gloves and other protective clothing to prevent skin contact1.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Physicians are advised to discuss the following with patients prior to treatment with Bortezomib:
Ability to Drive or Operate Machinery or Impairment of Mental Ability: Bortezomib may cause fatigue, dizziness, syncope, orthostatic/postural hypotension. Advise patients not to drive or operate machinery if they experience any of these symptoms.
dehydration/hypotension: Patients receiving Bortezomib therapy may experience vomiting and/or diarrhea. Advise patients how to avoid dehydration. Instruct patients to seek medical advice if they experience symptoms of dizziness, light headedness or fainting spells.
Pregnancy/Nursing: Advise patients to use effective contraceptive measures to prevent pregnancy during treatment with Bortezomib. Instruct patients to report pregnancy to their physicians immediately. Advise patients that they should not receive Bortezomib while pregnant or breast-feeding. If a patient wishes to restart breastfeeding after treatment, she should be advised to discuss the appropriate timing with her physician.
Concomitant Medications: Advise patients to speak with their physicians about any other medication they are currently taking.
Diabetic Patients: Advise patients to check their blood sugar frequently if using an oral antidiabetic medication and to notify their physicians of any changes in blood sugar level.
peripheral neuropathy: Advise patients to contact their physicians if they experience new or worsening symptoms of peripheral neuropathy such as tingling, numbness, pain, a burning feeling in the feet or hands, or weakness in the arms or legs.
Other: Instruct patients to contact their physicians if they develop a rash, experience shortness of breath, cough, or swelling of the feet, ankles, or legs, convulsion, persistent headache, reduced eyesight, an increase in blood pressure or blurred vision.
Distributed and Marketed by:
Millennium Pharmaceuticals, Inc.
40 Landsdowne Street
Cambridge, MA 02139
# Precautions with Alcohol
Alcohol-Bortezomib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
VELCADE
# Look-Alike Drug Names
There is limited information regarding Bortezomib Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Bortezomib
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2]; Aparna Vuppala, M.B.B.S. [3]
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# Overview
Bortezomib is a Proteasome Inhibitor that is FDA approved for the treatment of Multiple Myeloma, Mantle Cell Lymphoma. Common adverse reactions include hypotension, rash, constipation, decrease in appetite, diarrhea, nausea, vomiting, anemia, arthralgia, bone pain, cramp, myalgia, asthenia, dizziness, dysesthesia, headache, insomnia, paresthesia , peripheral neuropathy, mental disorder, cough, dyspnea, lower respiratory tract infection, fever.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### General Dosing Guidelines
- Recommended starting dosage: 1.3 mg/m2.
- Administered intravenously at a concentration of 1 mg/mL
- Administered subcutaneously at a concentration of 2.5 mg/mL.
- When administered intravenously, Bortezomib is administered as a 3 to 5 second bolus intravenous injection. Bortezomib is for intravenous or subcutaneous use only. Bortezomib should not be administered by any other route.
- Because each route of administration has a different reconstituted concentration, caution should be used when calculating the volume to be administered.
### Dosage in Previously Untreated Multiple Myeloma
- Bortezomib is administered in combination with oral melphalan and oral prednisone for nine 6-week treatment cycles as shown in Table 1. In Cycles 1-4, Bortezomib is administered twice weekly (days 1, 4, 8, 11, 22, 25, 29 and 32). In Cycles 5-9, Bortezomib is administered once weekly (days 1, 8, 22 and 29). At least 72 hours should elapse between consecutive doses of Bortezomib.
### Dose Modification Guidelines for Bortezomib When Given in Combination with melphalan and prednisone
- Prior to initiating any cycle of therapy with Bortezomib in combination with melphalan and prednisone:
- Platelet count should be at least 70 × 109/L and the absolute neutrophil count (ANC) should be at least 1.0 × 109/L
- Non-hematological toxicities should have resolved to Grade 1 or baseline
### Dosage and Dose Modifications for Relapsed Multiple Myeloma and Mantle Cell Lymphoma
- Bortezomib (1.3 mg/m2/dose) is administered twice weekly for 2 weeks (Days 1, 4, 8, and 11) followed by a 10-day rest period (Days 12-21). For extended therapy of more than 8 cycles, Bortezomib may be administered on the standard schedule or on a maintenance schedule of once weekly for 4 weeks (Days 1, 8, 15, and 22) followed by a 13-day rest period (Days 23 to 35) . At least 72 hours should elapse between consecutive doses of Bortezomib.
- Bortezomib therapy should be withheld at the onset of any Grade 3 non-hematological or Grade 4 hematological toxicities excluding neuropathy as discussed below . Once the symptoms of the toxicity have resolved, Bortezomib therapy may be reinitiated at a 25% reduced dose (1.3 mg/m2/dose reduced to 1 mg/m2/dose; 1 mg/m2/dose reduced to 0.7 mg/m2/dose).
- For dose modifications guidelines for peripheral neuropathy .
### Dosage in Patients with Hepatic Impairment
Patients with mild hepatic impairment do not require a starting dose adjustment and should be treated per the recommended Bortezomib dose. Patients with moderate or severe hepatic impairment should be started on Bortezomib at a reduced dose of 0.7 mg/m2 per injection during the first cycle, and a subsequent dose escalation to 1.0 mg/m2 or further dose reduction to 0.5 mg/m2 may be considered based on patient tolerance (see Table 4)
### Administration Precautions
- The drug quantity contained in one vial (3.5 mg) may exceed the usual dose required. Caution should be used in calculating the dose to prevent overdose.
- When administered subcutaneously, sites for each injection (thigh or abdomen) should be rotated. New injections should be given at least one inch from an old site and never into areas where the site is tender, bruised, erythematous, or indurated.
- If local injection site reactions occur following Bortezomib administration subcutaneously, a less concentrated Bortezomib solution (1 mg/mL instead of 2.5 mg/mL) may be administered subcutaneously. Alternatively, the intravenous route of administration should be considered
Dose must be individualized to prevent overdosage. After determining patient body surface area (BSA) in square meters, use the following equations to calculate the total volume (mL) of reconstituted Bortezomib to be administered:
- Intravenous Administration [1 mg/mL concentration]
- Subcutaneous Administration [2.5 mg/mL concentration]
Stickers that indicate the route of administration are provided with each Bortezomib vial. These stickers should be placed directly on the syringe of Bortezomib once Bortezomib is prepared to help alert practitioners of the correct route of administration for Bortezomib.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. If any discoloration or particulate matter is observed, the reconstituted product should not be used.
Stability: Unopened vials of Bortezomib are stable until the date indicated on the package when stored in the original package protected from light.
Bortezomib contains no antimicrobial preservative. Reconstituted Bortezomib should be administered within 8 hours of preparation. When reconstituted as directed, Bortezomib may be stored at 25°C (77°F). The reconstituted material may be stored in the original vial and/or the syringe prior to administration. The product may be stored for up to 8 hours in a syringe; however, total storage time for the reconstituted material must not exceed 8 hours when exposed to normal indoor lighting.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Bortezomib in adult patients.
### Non–Guideline-Supported Use
### Waldenström macroglobulinemia
- Dosing information
- 1.3 mg/m(2) on days 1, 4, 8, and 11. Treatment was repeated every 21 days (median number of cycles, 6; range, 2 to 39 cycles) until 2 cycles beyond stable PR or a minimum of 4 cycles
- 1.6 mg/m(2) IV on days 1, 8, and 15 (repeated every 28 days)[1]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
The safety and effectiveness of Bortezomib in children have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Bortezomib in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Bortezomib in pediatric patients.
# Contraindications
Bortezomib is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol. Reactions have included anaphylactic reactions.
Bortezomib is contraindicated for intrathecal administration. Fatal events have occurred with intrathecal administration of Bortezomib.
# Warnings
### Peripheral Neuropathy
Bortezomib treatment causes a peripheral neuropathy that is predominantly sensory; however, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥ Grade 3) during treatment with Bortezomib. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. In the Phase 3 relapsed multiple myeloma trial comparing Bortezomib subcutaneous versus intravenous the incidence of Grade ≥ 2 peripheral neuropathy was 24% for subcutaneous and 39% for intravenous. Grade ≥ 3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 15% in the intravenous treatment group. Starting Bortezomib subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy.
Patients experiencing new or worsening peripheral neuropathy during Bortezomib therapy may require a decrease in the dose and/or a less dose-intense schedule. In the Bortezomib versus dexamethasone phase 3 relapsed multiple myeloma study, improvement in or resolution of peripheral neuropathy was reported in 48% of patients with ≥ Grade 2 peripheral neuropathy following dose adjustment or interruption. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥ Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies . The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma.
### Hypotension
The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 8%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics .
### Cardiac Toxicity
Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have occurred during Bortezomib therapy, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart disease should be closely monitored. In the relapsed multiple myeloma study of Bortezomib versus dexamethasone, the incidence of any treatment-related cardiac disorder was 8% and 5% in the Bortezomib and dexamethasone groups, respectively. The incidence of adverse reactions suggestive of heart failure (acute pulmonary edema, pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock) was ≤ 1% for each individual reaction in the Bortezomib group. In the dexamethasone group the incidence was ≤ 1% for cardiac failure and congestive cardiac failure; there were no reported reactions of acute pulmonary edema, pulmonary edema, or cardiogenic shock. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established.
### Pulmonary Toxicity
Acute Respiratory Distress Syndrome (ARDS) and acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration have occurred in patients receiving Bortezomib. Some of these events have been fatal.
In a clinical trial, the first two patients given high-dose cytarabine (2g/m2 per day) by continuous infusion with daunorubicin and Bortezomib for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy.
There have been reports of pulmonary hypertension associated with Bortezomib administration in the absence of left heart failure or significant pulmonary disease.
In the event of new or worsening cardiopulmonary symptoms, consider interrupting Bortezomib until a prompt and comprehensive diagnostic evaluation is conducted.
### Posterior Reversible Encephalopathy Syndrome (PRES)
Posterior Reversible Encephalopathy Syndrome (PRES; formerly termed Reversible Posterior Leukoencephalopathy Syndrome (RPLS)) has occurred in patients receiving Bortezomib. PRES is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing PRES, discontinue Bortezomib. The safety of reinitiating Bortezomib therapy in patients previously experiencing PRES is not known.
### Gastrointestinal Toxicity
Bortezomib treatment can cause nausea, diarrhea, constipation, and vomiting. sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration. Interrupt Bortezomib for severe symptoms.
### Thrombocytopenia/Neutropenia
Bortezomib is associated with thrombocytopenia and neutropenia that follow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia related to pretreatment platelet count is shown in Table 6. In the relapsed multiple myeloma study of Bortezomib versus dexamethasone, the incidence of bleeding (≥ Grade 3) was 2% on the Bortezomib arm and was < 1% in the dexamethasone arm. Complete blood counts (CBC) should be monitored frequently during treatment with Bortezomib. Platelet count should be monitored prior to each dose of Bortezomib. Patients experiencing thrombocytopenia may require change in the dose and schedule of Bortezomib . Gastrointestinal and intracerebral hemorrhage has been reported in association with Bortezomib. Transfusions may be considered.
### Tumor Lysis Syndrome
Tumor lysis syndrome has been reported with Bortezomib therapy. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. Monitor patients closely and take appropriate precautions.
### Hepatic Toxicity
Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic reactions include hepatitis, increases in liver enzymes, and hyperbilirubinemia. Interrupt Bortezomib therapy to assess reversibility. There is limited re-challenge information in these patients.
### Embryo-fetal Risk
Women of reproductive potential should avoid becoming pregnant while being treated with Bortezomib. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses
# Adverse Reactions
## Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
Summary of Clinical Trial in Patients with Previously Untreated Multiple Myeloma
Table 7 describes safety data from 340 patients with previously untreated multiple myeloma who received Bortezomib (1.3 mg/m2) administered intravenously in combination with melphalan (9 mg/m2) and prednisone (60 mg/m2) in a prospective randomized study.
The safety profile of Bortezomib in combination with melphalan/prednisone is consistent with the known safety profiles of both Bortezomib and melphalan/prednisone.
‘’‘Relapsed multiple myeloma Randomized Study of Bortezomib versus dexamethasone’‘’
The safety data described below and in Table 8 reflect exposure to either Bortezomib (n=331) or dexamethasone (n=332) in a study of patients with relapsed multiple myeloma. Bortezomib was administered intravenously at doses of 1.3 mg/m2 twice weekly for 2 out of 3 weeks (21-day cycle). After eight 21-day cycles patients continued therapy for three 35-day cycles on a weekly schedule. Duration of treatment was up to 11 cycles (9 months) with a median duration of 6 cycles (4.1 months). For inclusion in the trial, patients must have had measurable disease and 1 to 3 prior therapies. There was no upper age limit for entry. Creatinine clearance could be as low as 20 mL/min and bilirubin levels as high as 1.5 times the upper limit of normal. The overall frequency of adverse reactions was similar in men and women, and in patients < 65 and ≥ 65 years of age. Most patients were Caucasian .
Among the 331 Bortezomib-treated patients, the most commonly reported (> 20%) adverse reactions overall were nausea (52%), diarrhea (52%), fatigue (39%), peripheral neuropathies NEC (35%), thrombocytopenia (33%), constipation (30%), vomiting (29%), and anorexia (21%). The most commonly reported (> 20%) adverse reaction reported among the 332 patients in the dexamethasone group was fatigue (25%). Eight percent (8%) of patients in the Bortezomib-treated arm experienced a Grade 4 adverse reaction; the most common reactions were thrombocytopenia (4%) and neutropenia (2%). Nine percent (9%) of dexamethasone-treated patients experienced a Grade 4 adverse reaction. All individual dexamethasone-related Grade 4 adverse reactions were less than 1%.
Serious Adverse Reactions and Adverse Reactions Leading to Treatment Discontinuation in the Relapsed multiple myeloma Study of Bortezomib versus dexamethasone
Serious adverse reactions are defined as any reaction that results in death, is life-threatening, requires hospitalization or prolongs a current hospitalization, results in a significant disability, or is deemed to be an important medical event. A total of 80 (24%) patients from the Bortezomib treatment arm experienced a serious adverse reaction during the study, as did 83 (25%) dexamethasone-treated patients. The most commonly reported serious adverse reactions in the Bortezomib treatment arm were diarrhea (3%), dehydration, herpes zoster, pyrexia, nausea, vomiting, dyspnea, and thrombocytopenia (2% each). In the dexamethasone treatment group, the most commonly reported serious adverse reactions were pneumonia (4%), hyperglycemia (3%), pyrexia, and psychotic disorder (2% each).
A total of 145 patients, including 84 (25%) of 331 patients in the Bortezomib treatment group and 61 (18%) of 332 patients in the dexamethasone treatment group were discontinued from treatment due to adverse reactions. Among the 331 Bortezomib treated patients, the most commonly reported adverse reaction leading to discontinuation was peripheral neuropathy (8%). Among the 332 patients in the dexamethasone group, the most commonly reported adverse reactions leading to treatment discontinuation were psychotic disorder and hyperglycemia (2% each).
Four deaths were considered to be Bortezomib-related in this relapsed multiple myeloma study: 1 case each of cardiogenic shock, respiratory insufficiency, congestive heart failure and cardiac arrest. Four deaths were considered dexamethasone-related: 2 cases of sepsis, 1 case of bacterial meningitis, and 1 case of sudden death at home.
Most Commonly Reported Adverse Reactions in the Relapsed multiple myeloma Study of Bortezomib versus dexamethasone
The most common adverse reactions from the relapsed multiple myeloma study are shown in Table 8. All adverse reactions with incidence ≥ 10% in the Bortezomib arm are included.
In general, safety data were similar for the subcutaneous and intravenous treatment groups. Differences were observed in the rates of some Grade ≥ 3 adverse reactions. Differences of ≥ 5% were reported in neuralgia (3% subcutaneous versus 9% intravenous), peripheral neuropathies NEC (6% subcutaneous versus 15% intravenous), neutropenia (13% subcutaneous versus 18% intravenous), and thrombocytopenia (8% subcutaneous versus 16% intravenous).
A local reaction was reported in 6% of patients in the subcutaneous group, mostly redness. Only 2 (1%) patients were reported as having severe reactions, 1 case of pruritus and 1 case of redness. Local reactions led to reduction in injection concentration in one patient and drug discontinuation in one patient. Local reactions resolved in a median of 6 days.
Dose reductions occurred due to adverse reactions in 31% of patients in the subcutaneous treatment group compared with 43% of the intravenously-treated patients. The most common adverse reactions leading to a dose reduction included peripheral sensory neuropathy (17% in the subcutaneous treatment group compared with 31% in the intravenous treatment group); and neuralgia (11% in the subcutaneous treatment group compared with 19% in the intravenous treatment group).
Serious Adverse Reactions and Adverse Reactions Leading to Treatment Discontinuation in the Relapsed multiple myeloma Study of Bortezomib Subcutaneous versus Intravenous
The incidence of serious adverse reactions was similar for the subcutaneous treatment group (20%) and the intravenous treatment group (19%). The most commonly reported serious adverse reactions in the subcutaneous treatment arm were pneumonia and pyrexia (2% each). In the intravenous treatment group, the most commonly reported serious adverse reactions were pneumonia, diarrhea, and peripheral sensory neuropathy (3% each).
In the subcutaneous treatment group, 27 patients (18%) discontinued study treatment due to an adverse reaction compared with 17 patients (23%) in the intravenous treatment group. Among the 147 subcutaneously-treated patients, the most commonly reported adverse reactions leading to discontinuation were peripheral sensory neuropathy (5%) and neuralgia (5%). Among the 74 patients in the intravenous treatment group, the most commonly reported adverse reactions leading to treatment discontinuation were peripheral sensory neuropathy (9%) and neuralgia (9%).
Two patients (1%) in the subcutaneous treatment group and 1 (1%) patient in the intravenous treatment group died due to an adverse reaction during treatment. In the subcutaneous group the causes of death were one case of pneumonia and one case of sudden death. In the intravenous group the cause of death was coronary artery insufficiency.
Integrated Summary of Safety (Relapsed multiple myeloma and Mantle Cell Lymphoma)
Safety data from phase 2 and 3 studies of single agent Bortezomib 1.3 mg/m2/dose twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously-treated multiple myeloma (N=1008) and previously-treated mantle cell lymphoma (N=155) were integrated and tabulated. This analysis does not include data from the Phase 3 Open-Label Study of Bortezomib subcutaneous versus intravenous in relapsed multiple myeloma. In the integrated studies, the safety profile of Bortezomib was similar in patients with multiple myeloma and mantle cell lymphoma.
In the integrated analysis, the most commonly reported (> 20%) adverse reactions were nausea (49%), diarrhea (46%), asthenic conditions including fatigue (41%) and weakness (11%), peripheral neuropathies NEC (38%), thrombocytopenia (32%), vomiting (28%), constipation (25%), and pyrexia (21%). Eleven percent (11%) of patients experienced at least 1 episode of ≥ Grade 4 toxicity, most commonly thrombocytopenia (4%) and neutropenia (2%).
In the Phase 2 relapsed multiple myeloma clinical trials of Bortezomib administered intravenously, local skin irritation was reported in 5% of patients, but extravasation of Bortezomib was not associated with tissue damage.
Serious Adverse Reactions and Adverse Reactions Leading to Treatment Discontinuation in the Integrated Summary of Safety
A total of 26% of patients experienced a serious adverse reaction during the studies. The most commonly reported serious adverse reactions included diarrhea, vomiting and pyrexia (3% each), nausea, dehydration, and thrombocytopenia (2% each) and pneumonia, dyspnea, peripheral neuropathies NEC, and herpes zoster (1% each).
Adverse reactions leading to discontinuation occurred in 22% of patients. The reasons for discontinuation included peripheral neuropathy (8%), and fatigue, thrombocytopenia, and diarrhea (2% each).
In total, 2% of the patients died and the cause of death was considered by the investigator to be possibly related to study drug: including reports of cardiac arrest, congestive heart failure, respiratory failure, renal failure, pneumonia and sepsis.
Most Commonly Reported Adverse Reactions in the Integrated Summary of Safety
The most common adverse reactions are shown in Table 10. All adverse reactions occurring at ≥ 10% are included. In the absence of a randomized comparator arm, it is often not possible to distinguish between adverse events that are drug-caused and those that reflect the patient's underlying disease. Please see the discussion of specific adverse reactions that follows.
Safety Experience from the Phase 2 Open-Label Extension Study in Relapsed multiple myeloma
In the phase 2 extension study of 63 patients, no new cumulative or new long-term toxicities were observed with prolonged Bortezomib treatment. These patients were treated for a total of 5.3 to 23 months, including time on Bortezomib in the prior Bortezomib study .
Safety Experience from the Phase 3 Open-Label Study of Bortezomib Subcutaneous versus Intravenous in Relapsed multiple myeloma
The safety and efficacy of Bortezomib administered subcutaneously were evaluated in one Phase 3 study at the recommended dose of 1.3 mg/m2. This was a randomized, comparative study of Bortezomib subcutaneous versus intravenous in 222 patients with relapsed multiple myeloma. The safety data described below and in Table 9 reflect exposure to either Bortezomib subcutaneous (n=147) or Bortezomib intravenous (n=74)
In general, safety data were similar for the subcutaneous and intravenous treatment groups. Differences were observed in the rates of some Grade ≥ 3 adverse reactions. Differences of ≥ 5% were reported in neuralgia (3% subcutaneous versus 9% intravenous), peripheral neuropathies NEC (6% subcutaneous versus 15% intravenous), neutropenia (13% subcutaneous versus 18% intravenous), and thrombocytopenia (8% subcutaneous versus 16% intravenous).
A local reaction was reported in 6% of patients in the subcutaneous group, mostly redness. Only 2 (1%) patients were reported as having severe reactions, 1 case of pruritus and 1 case of redness. Local reactions led to reduction in injection concentration in one patient and drug discontinuation in one patient. Local reactions resolved in a median of 6 days.
Dose reductions occurred due to adverse reactions in 31% of patients in the subcutaneous treatment group compared with 43% of the intravenously-treated patients. The most common adverse reactions leading to a dose reduction included peripheral sensory neuropathy (17% in the subcutaneous treatment group compared with 31% in the intravenous treatment group); and neuralgia (11% in the subcutaneous treatment group compared with 19% in the intravenous treatment group).
Serious Adverse Reactions and Adverse Reactions Leading to Treatment Discontinuation in the Relapsed multiple myeloma Study of Bortezomib Subcutaneous versus Intravenous
The incidence of serious adverse reactions was similar for the subcutaneous treatment group (20%) and the intravenous treatment group (19%). The most commonly reported serious adverse reactions in the subcutaneous treatment arm were pneumonia and pyrexia (2% each). In the intravenous treatment group, the most commonly reported serious adverse reactions were pneumonia, diarrhea, and peripheral sensory neuropathy (3% each).
In the subcutaneous treatment group, 27 patients (18%) discontinued study treatment due to an adverse reaction compared with 17 patients (23%) in the intravenous treatment group. Among the 147 subcutaneously-treated patients, the most commonly reported adverse reactions leading to discontinuation were |peripheral sensory neuropathy (5%) and neuralgia (5%). Among the 74 patients in the intravenous treatment group, the most commonly reported adverse reactions leading to treatment discontinuation were |peripheral sensory neuropathy (9%) and neuralgia (9%).
Two patients (1%) in the subcutaneous treatment group and 1 (1%) patient in the intravenous treatment group died due to an adverse reaction during treatment. In the subcutaneous group the causes of death were one case of pneumonia and one case of sudden death. In the intravenous group the cause of death was coronary artery insufficiency.
Integrated Summary of Safety (Relapsed multiple myeloma and Mantle Cell Lymphoma)
Safety data from phase 2 and 3 studies of single agent Bortezomib 1.3 mg/m2/dose twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously-treated multiple myeloma (N=1008) and previously-treated mantle cell lymphoma (N=155) were integrated and tabulated. This analysis does not include data from the Phase 3 Open-Label Study of Bortezomib subcutaneous versus intravenous in relapsed multiple myeloma. In the integrated studies, the safety profile of Bortezomib was similar in patients with multiple myeloma and mantle cell lymphoma.
In the integrated analysis, the most commonly reported (> 20%) adverse reactions were nausea (49%), diarrhea (46%), asthenic conditions including fatigue (41%) and weakness (11%), peripheral neuropathies NEC (38%), thrombocytopenia (32%), vomiting (28%), constipation (25%), and pyrexia (21%). Eleven percent (11%) of patients experienced at least 1 episode of ≥ Grade 4 toxicity, most commonly thrombocytopenia (4%) and neutropenia (2%).
In the Phase 2 relapsed multiple myeloma clinical trials of Bortezomib administered intravenously, local skin irritation was reported in 5% of patients, but extravasation of Bortezomib was not associated with tissue damage.
Serious Adverse Reactions and Adverse Reactions Leading to Treatment Discontinuation in the Integrated Summary of Safety
A total of 26% of patients experienced a serious adverse reaction during the studies. The most commonly reported serious adverse reactions included diarrhea, vomiting and pyrexia (3% each), nausea, dehydration, and thrombocytopenia (2% each) and pneumonia, dyspnea, peripheral neuropathies NEC, and herpes zoster (1% each).
Adverse reactions leading to discontinuation occurred in 22% of patients. The reasons for discontinuation included peripheral neuropathy (8%), and fatigue, thrombocytopenia, and diarrhea (2% each).
In total, 2% of the patients died and the cause of death was considered by the investigator to be possibly related to study drug: including reports of cardiac arrest, congestive heart failure, respiratory failure, renal failure, pneumonia and sepsis.
Most Commonly Reported Adverse Reactions in the Integrated Summary of Safety
The most common adverse reactions are shown in Table 10. All adverse reactions occurring at ≥ 10% are included. In the absence of a randomized comparator arm, it is often not possible to distinguish between adverse events that are drug-caused and those that reflect the patient's underlying disease. Please see the discussion of specific adverse reactions that follows.
Description of Selected Adverse Reactions from the Integrated Phase 2 and 3 Relapsed multiple myeloma and Phase 2 Mantle Cell Lymphoma Studies
Gastrointestinal Toxicity
A total of 75% of patients experienced at least one gastrointestinal disorder. The most common gastrointestinal disorders included nausea, diarrhea, constipation, vomiting, and appetite decreased. Other gastrointestinal disorders included dyspepsia and dysgeusia. Grade 3 adverse reactions occurred in 14% of patients; ≥ Grade 4 adverse reactions were ≤ 1%. Gastrointestinal adverse reactions were considered serious in 7% of patients. Four percent (4%) of patients discontinued due to a gastrointestinal adverse reaction. nausea was reported more often in patients with multiple myeloma (51%) compared to patients with mantle cell lymphoma (36%).
Thrombocytopenia
Across the studies, Bortezomib-associated thrombocytopenia was characterized by a decrease in platelet count during the dosing period (days 1 to 11) and a return toward baseline during the 10-day rest period during each treatment cycle. Overall, thrombocytopenia was reported in 32% of patients. thrombocytopenia was Grade 3 in 22%, ≥ Grade 4 in 4%, and serious in 2% of patients, and the reaction resulted in Bortezomib discontinuation in 2% of patients. thrombocytopenia was reported more often in patients with multiple myeloma (34%) compared to patients with mantle cell lymphoma (16%). The incidence of ≥ Grade 3 thrombocytopenia also was higher in patients with multiple myeloma (28%) compared to patients with mantle cell lymphoma (8%).
Peripheral Neuropathy
Overall, peripheral neuropathies NEC occurred in 38% of patients. peripheral neuropathy was Grade 3 for 11% of patients and ≥ Grade 4 for < 1% of patients. Eight percent (8%) of patients discontinued Bortezomib due to peripheral neuropathy. The incidence of peripheral neuropathy was higher among patients with mantle cell lymphoma (54%) compared to patients with multiple myeloma (36%).
In the Bortezomib versus dexamethasone phase 3 relapsed multiple myeloma study, among the 62 Bortezomib-treated patients who experienced ≥ Grade 2 peripheral neuropathy and had dose adjustments, 48% had improved or resolved with a median of 3.8 months from first onset.
In the phase 2 relapsed multiple myeloma studies, among the 30 patients who experienced Grade 2 peripheral neuropathy resulting in discontinuation or who experienced ≥ Grade 3 peripheral neuropathy, 73% reported improvement or resolution with a median time of 47 days to improvement of one Grade or more from the last dose of Bortezomib.
Hypotension
The incidence of hypotension (postural, orthostatic and hypotension NOS) was 8% in patients treated with Bortezomib. hypotension was Grade 1 or 2 in the majority of patients and Grade 3 in 2% and ≥ Grade 4 in < 1%. Two percent (2%) of patients had hypotension reported as a serious adverse reaction, and 1% discontinued due to hypotension. The incidence of hypotension was similar in patients with multiple myeloma (8%) and those with mantle cell lymphoma (9%). In addition, < 1% of patients experienced hypotension associated with a syncopal reaction.
Neutropenia
Neutrophil counts decreased during the Bortezomib dosing period (days 1 to 11) and returned toward baseline during the 10-day rest period during each treatment cycle. Overall, neutropenia occurred in 15% of patients and was Grade 3 in 8% of patients and ≥ Grade 4 in 2%. Neutropenia was reported as a serious adverse reaction in < 1% of patients and < 1% of patients discontinued due to neutropenia. The incidence of neutropenia was higher in patients with multiple myeloma (16%) compared to patients with mantle cell lymphoma (5%). The incidence of ≥ Grade 3 neutropenia also was higher in patients with multiple myeloma (12%) compared to patients with mantle cell lymphoma (3%).
Asthenic conditions (fatigue, Malaise, Weakness, Asthenia)
Asthenic conditions were reported in 54% of patients. fatigue was reported as Grade 3 in 7% and ≥ Grade 4 in < 1% of patients. Asthenia was reported as Grade 3 in 2% and ≥ Grade 4 in < 1% of patients. Two percent (2%) of patients discontinued treatment due to fatigue and < 1% due to weakness and asthenia. Asthenic conditions were reported in 53% of patients with multiple myeloma and 59% of patients with mantle cell lymphoma.
Pyrexia
pyrexia (> 38ºC) was reported as an adverse reaction for 21% of patients. The reaction was Grade 3 in 1% and ≥ Grade 4 in < 1%. pyrexia was reported as a serious adverse reaction in 3% of patients and led to Bortezomib discontinuation in < 1% of patients. The incidence of pyrexia was higher among patients with multiple myeloma (23%) compared to patients with mantle cell lymphoma (10%). The incidence of ≥ Grade 3 pyrexia was 1% in patients with multiple myeloma and < 1% in patients with mantle cell lymphoma
Herpes Virus Infection
Consider using antiviral prophylaxis in subjects being treated with Bortezomib. In the randomized studies in previously untreated and relapsed multiple myeloma, herpes zoster reactivation was more common in subjects treated with Bortezomib (ranging between 6-11%) than in the control groups (3-4%). Herpes simplex was seen in 1-3% in subjects treated with Bortezomib and 1-3% in the control groups. In the previously untreated multiple myeloma study, herpes zoster virus reactivation in the Bortezomib, melphalan and prednisone arm was less common in subjects receiving prophylactic antiviral therapy (3%) than in subjects who did not receive prophylactic antiviral therapy (17%).
Additional Adverse Reactions from Clinical Studies
The following clinically important serious adverse reactions that are not described above have been reported in clinical trials in patients treated with Bortezomib administered as monotherapy or in combination with other chemotherapeutics. These studies were conducted in patients with hematological malignancies and in solid tumors.
Blood and lymphatic system disorders: Anemia, disseminated intravascular coagulation, febrile neutropenia, lymphopenia, leukopenia
Cardiac disorders: Angina pectoris, atrial fibrillation aggravated, atrial flutter, bradycardia, sinus arrest, cardiac amyloidosis, complete atrioventricular block, myocardial ischemia, myocardial infarction, pericarditis, pericardial effusion, Torsades de pointes, ventricular tachycardia
Ear and labyrinth disorders: Hearing impaired, vertigo
Eye disorders: Diplopia and blurred vision, conjunctival infection, irritation
Gastrointestinal disorders: Abdominal pain, ascites, dysphagia, fecal impaction, gastroenteritis, gastritis hemorrhagic, hematemesis, hemorrhagic duodenitis, ileus paralytic, large intestinal obstruction, paralytic intestinal obstruction, peritonitis, small intestinal obstruction, large intestinal perforation, stomatitis, melena, pancreatitis acute, oral mucosal petechiae, gastroesophageal reflux
General disorders and administration site conditions: Chills, edema, edema peripheral, injection site erythema, neuralgia, injection site pain, irritation, malaise, phlebitis
Hepatobiliary disorders: Cholestasis, hepatic hemorrhage, hyperbilirubinemia, portal vein thrombosis, hepatitis, liver failure
Immune system disorders: Anaphylactic reaction, drug hypersensitivity, immune complex mediated hypersensitivity, angioedema, laryngeal edema
Infections and infestations: Aspergillosis, bacteremia, bronchitis, urinary tract infection, herpes viral infection, listeriosis, nasopharyngitis, pneumonia, respiratory tract infection, septic shock, toxoplasmosis, oral candidiasis, sinusitis, catheter related infection
Injury, poisoning and procedural complications: Catheter related complication, skeletal fracture, subdural hematoma
Investigations: Weight decreased
Metabolism and nutrition disorders: dehydration, hypocalcemia, hyperuricemia, hypokalemia, hyperkalemia, hyponatremia, hypernatremia
Musculoskeletal and connective tissue disorders: Arthralgia, back pain, bone pain, myalgia, pain in extremity
Nervous system disorders: Ataxia, coma, dizziness, dysarthria, dysesthesia, dysautonomia, encephalopathy, cranial palsy, grand mal convulsion, headache, hemorrhagic stroke, motor dysfunction, neuralgia, spinal cord compression, paralysis, postherpetic neuralgia, transient ischemic attack
Psychiatric disorders: Agitation, anxiety, confusion, insomnia, mental status change, psychotic disorder, suicidal ideation
Renal and urinary disorders: Calculus renal, bilateral hydronephrosis, bladder spasm, hematuria, hemorrhagic cystitis, urinary incontinence, urinary retention, renal failure (acute and chronic), glomerular nephritis proliferative
Respiratory, thoracic and mediastinal disorders: Acute respiratory distress syndrome, aspiration pneumonia, atelectasis, chronic obstructive airways disease exacerbated, cough, dysphagia, dyspnea, dyspnea exertional, epistaxis, hemoptysis, hypoxia, lung infiltration, pleural effusion, pneumonitis, respiratory distress, pulmonary hypertension
Skin and subcutaneous tissue disorders: Urticaria, face edema, rash (which may be pruritic), leukocytoclastic vasculitis, pruritus.
Vascular disorders: Cerebrovascular accident, cerebral hemorrhage, deep venous thrombosis, hypertension, peripheral embolism, pulmonary embolism, pulmonary hypertension
## Postmarketing Experience
The following adverse reactions have been identified from the worldwide postmarketing experience with Bortezomib. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: atrioventricular block complete, cardiac tamponade, ischemic colitis, encephalopathy, dysautonomia, deafness bilateral, disseminated intravascular coagulation, hepatitis, acute pancreatitis, progressive multifocal leukoencephalopathy (PML), acute diffuse infiltrative pulmonary disease, PRES (formerly RPLS), toxic epidermal necrolysis, acute febrile neutrophilic dermatosis (Sweet's syndrome), herpes meningoencephalitis, optic neuropathy, blindness and ophthalmic herpes.
# Drug Interactions
Bortezomib is a substrate of cytochrome P450 enzyme 3A4, 2C19 and 1A2.
### CYP3A4 inhibitors
Co-administration of ketoconazole, a strong CYP3A4 inhibitor, increased the exposure of bortezomib by 35% in 12 patients. Monitor patients for signs of bortezomib toxicity and consider a bortezomib dose reduction if bortezomib must be given in combination with strong CYP3A4 inhibitors (e.g. ketoconazole, ritonavir).
### CYP2C19 inhibitors
Co-administration of omeprazole, a strong inhibitor of CYP2C19, had no effect on the exposure of bortezomib in 17 patients.
### CYP3A4 inducers
Co-administration of rifampin, a strong CYP3A4 inducer, is expected to decrease the exposure of bortezomib by at least 45%. Because the drug interaction study (n=6) was not designed to exert the maximum effect of rifampin on bortezomib PK, decreases greater than 45% may occur.
Efficacy may be reduced when Bortezomib is used in combination with strong CYP3A4 inducers; therefore, concomitant use of strong CYP3A4 inducers is not recommended in patients receiving Bortezomib.
St. John's Wort (Hypericum perforatum) may decrease bortezomib exposure unpredictably and should be avoided.
### dexamethasone
Co-administration of dexamethasone, a weak CYP3A4 inducer, had no effect on the exposure of bortezomib in 7 patients.
### melphalan-prednisone
Co-administration of melphalan-prednisone increased the exposure of bortezomib by 17% in 21 patients. However, this increase is unlikely to be clinically relevant.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
Bortezomib was not teratogenic in nonclinical developmental toxicity studies in rats and rabbits at the highest dose tested (0.075 mg/kg; 0.5 mg/m2 in the rat and 0.05 mg/kg; 0.6 mg/m2 in the rabbit) when administered during organogenesis. These dosages are approximately half the clinical dose of 1.3 mg/m2 based on body surface area.
Pregnant rabbits given bortezomib during organogenesis at a dose of 0.05mg/kg (0.6 mg/m2) experienced significant post-implantation loss and decreased number of live fetuses. Live fetuses from these litters also showed significant decreases in fetal weight. The dose is approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area.
There are no adequate and well-controlled studies in pregnant women. If Bortezomib is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Bortezomib in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Bortezomib during labor and delivery.
### Nursing Mothers
It is not known whether bortezomib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Bortezomib, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
The safety and effectiveness of Bortezomib in children have not been established.
### Geriatic Use
Of the 669 patients enrolled in the relapsed multiple myeloma study, 245 (37%) were 65 years of age or older: 125 (38%) on the Bortezomib arm and 120 (36%) on the dexamethasone arm. Median time to progression and median duration of response for patients ≥ 65 were longer on Bortezomib compared to dexamethasone [5.5 mo versus 4.3 mo, and 8.0 mo versus 4.9 mo, respectively]. On the Bortezomib arm, 40% (n=46) of evaluable patients aged ≥ 65 experienced response (CR+PR) versus 18% (n=21) on the dexamethasone arm. The incidence of Grade 3 and 4 events was 64%, 78% and 75% for Bortezomib patients ≤ 50, 51-64 and ≥ 65 years old, respectively.
No overall differences in safety or effectiveness were observed between patients ≥ age 65 and younger patients receiving Bortezomib; but greater sensitivity of some older individuals cannot be ruled out.
### Gender
There is no FDA guidance on the use of Bortezomib with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Bortezomib with respect to specific racial populations.
### Renal Impairment
The exposure of bortezomib is increased in patients with moderate (bilirubin ≥ 1.5 – 3× ULN) and severe (bilirubin > 3 × ULN) hepatic impairment. Starting dose should be reduced in those patients
### Hepatic Impairment
The exposure of bortezomib is increased in patients with moderate (bilirubin ≥ 1.5 – 3× ULN) and severe (bilirubin > 3 × ULN) hepatic impairment. Starting dose should be reduced in those patients
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Bortezomib in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Bortezomib in patients who are immunocompromised.
### Patients with Diabetes
During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral anti-diabetic agents receiving Bortezomib treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their anti-diabetic medication.
# Administration and Monitoring
### Administration
intravenous injection or subcutaneous
### Monitoring
FDA Package Insert for Bortezomib contains no information regarding drug monitoring.
# IV Compatibility
There is limited information about the IV Compatibility.
# Overdosage
There is no known specific antidote for Bortezomib overdosage. In humans, fatal outcomes following the administration of more than twice the recommended therapeutic dose have been reported, which were associated with the acute onset of symptomatic hypotension and thrombocytopenia . In the event of an overdosage, the patient's vital signs should be monitored and appropriate supportive care given.
Studies in monkeys and dogs showed that intravenous bortezomib doses as low as 2 times the recommended clinical dose on a mg/m2 basis were associated with increases in heart rate, decreases in contractility, hypotension, and death. In dog studies, a slight increase in the corrected QT interval was observed at doses resulting in death. In monkeys, doses of 3.0 mg/m2 and greater (approximately twice the recommended clinical dose) resulted in hypotension starting at 1 hour post-administration, with progression to death in 12 to 14 hours following drug administration.
# Pharmacology
## Mechanism of Action
Bortezomib is a reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome in mammalian cells. The 26S proteasome is a large protein complex that degrades ubiquitinated proteins. The ubiquitin-proteasome pathway plays an essential role in regulating the intracellular concentration of specific proteins, thereby maintaining homeostasis within cells. Inhibition of the 26S proteasome prevents this targeted proteolysis, which can affect multiple signaling cascades within the cell. This disruption of normal homeostatic mechanisms can lead to cell death. Experiments have demonstrated that bortezomib is cytotoxic to a variety of cancer cell types in vitro. Bortezomib causes a delay in tumor growth in vivo in nonclinical tumor models, including multiple myeloma.
## Structure
Bortezomib® (bortezomib) for Injection is an antineoplastic agent available for intravenous injection or subcutaneous use. Each single use vial contains 3.5 mg of bortezomib as a sterile lyophilized powder. Inactive ingredient: 35 mg mannitol, USP.
Bortezomib is a modified dipeptidyl boronic acid. The product is provided as a mannitol boronic ester which, in reconstituted form, consists of the mannitol ester in equilibrium with its hydrolysis product, the monomeric boronic acid. The drug substance exists in its cyclic anhydride form as a trimeric boroxine.
The chemical name for bortezomib, the monomeric boronic acid, is [(1R)-3-methyl-1-[ [(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl) amino]propyl]amino]butyl] boronic acid.
Bortezomib has the following chemical structure:
The molecular weight is 384.24. The molecular formula is C19H25BN4O4. The solubility of bortezomib, as the monomeric boronic acid, in water is 3.3 to 3.8 mg/mL in a pH range of 2 to 6.5.
## Pharmacodynamics
FDA Package Insert for Bortezomib contains no information regarding Adverse Reactions.
## Pharmacokinetics
Following intravenous administration of 1 mg/m2 and 1.3 mg/m2 doses to 24 patients with multiple myeloma (n=12, per each dose level), the mean maximum plasma concentrations of bortezomib (Cmax) after the first dose (Day 1) were 57 and 112 ng/mL, respectively. In subsequent doses, when administered twice weekly, the mean maximum observed plasma concentrations ranged from 67 to 106 ng/mL for the 1 mg/m2 dose and 89 to 120 ng/mL for the 1.3 mg/m2 dose. The mean elimination half-life of bortezomib upon multiple dosing ranged from 40 to 193 hours after the 1 mg/m2 dose and 76 to 108 hours after the 1.3mg/m2 dose. The mean total body clearances was 102 and 112 L/h following the first dose for doses of 1 mg/m2 and 1.3 mg/m2, respectively, and ranged from 15 to 32 L/h following subsequent doses for doses of 1 and 1.3 mg/m2, respectively.
Following an intravenous bolus or subcutaneous injection of a 1.3 mg/m2 dose to patients (n = 14 for intravenous, n = 17 for subcutaneous) with multiple myeloma, the total systemic exposure after repeat dose administration (AUClast) was equivalent for subcutaneous and intravenous administration. The Cmax after subcutaneous administration (20.4 ng/mL) was lower than intravenous (223 ng/mL). The AUClast geometric mean ratio was 0.99 and 90% confidence intervals were 80.18% - 122.80%.
Distribution: The mean distribution volume of bortezomib ranged from approximately 498 to 1884 L/m2 following single- or repeat-dose administration of 1 mg/m2 or 1.3mg/m2 to patients with multiple myeloma. This suggests bortezomib distributes widely to peripheral tissues. The binding of bortezomib to human plasma proteins averaged 83% over the concentration range of 100 to 1000 ng/mL.
Metabolism: In vitro studies with human liver microsomes and human cDNA-expressed cytochrome P450 isozymes indicate that bortezomib is primarily oxidatively metabolized via cytochrome P450 enzymes 3A4, 2C19, and 1A2. Bortezomib metabolism by CYP 2D6 and 2C9 enzymes is minor. The major metabolic pathway is deboronation to form 2 deboronated metabolites that subsequently undergo hydroxylation to several metabolites. Deboronated bortezomib metabolites are inactive as 26S proteasome inhibitors. Pooled plasma data from 8 patients at 10 min and 30 min after dosing indicate that the plasma levels of metabolites are low compared to the parent drug.
Elimination: The pathways of elimination of bortezomib have not been characterized in humans.
Age: Analyses of data after the first dose of Cycle 1 (Day 1) in 39 multiple myeloma patients who had received intravenous doses of 1 mg/m2 and 1.3 mg/m2 showed that both dose-normalized AUC and Cmax tend to be less in younger patients. Patients < 65 years of age (n=26) had about 25% lower mean dose-normalized AUC and Cmax than those ≥ 65 years of age (n=13).
Gender: Mean dose-normalized AUC and Cmax values were comparable between male (n=22) and female (n=17) patients after the first dose of Cycle 1 for the 1 and 1.3 mg/m2 doses.
Race: The effect of race on exposure to bortezomib could not be assessed as most of the patients were Caucasian.
Hepatic Impairment: The effect of hepatic impairment (see Table 4 for definition of hepatic impairment) on the pharmacokinetics of bortezomib was assessed in 60 patients with cancer at bortezomib doses ranging from 0.5 to 1.3 mg/m2. When compared to patients with normal hepatic function, mild hepatic impairment did not alter dose-normalized bortezomib AUC. However, the dose-normalized mean AUC values were increased by approximately 60% in patients with moderate or severe hepatic impairment. A lower starting dose is recommended in patients with moderate or severe hepatic impairment, and those patients should be monitored closely .
Renal Impairment: A pharmacokinetic study was conducted in patients with various degrees of renal impairment who were classified according to their creatinine clearance values (CrCl) into the following groups: Normal (CrCl ≥60 mL/min/1.73 m2, N=12), Mild (CrCl=40-59 mL/min/1.73 m2, N=10), Moderate (CrCl=20-39 mL/min/1.73 m2, N=9), and Severe (CrCl < 20 mL/min/1.73 m2, N=3). A group of dialysis patients who were dosed after dialysis was also included in the study (N=8). Patients were administered intravenous doses of 0.7 to 1.3 mg/m2 of bortezomib twice weekly. Exposure of bortezomib (dose-normalized AUC and Cmax) was comparable among all the groups .
Pediatric: There are no pharmacokinetic data in pediatric patients.
Cytochrome P450: Bortezomib is a poor inhibitor of human liver microsome cytochrome P450 1A2, 2C9, 2D6, and 3A4, with IC50 values of > 30µM (> 11.5µg/mL). Bortezomib may inhibit 2C19 activity (IC50 = 18 µM, 6.9 µg/mL) and increase exposure to drugs that are substrates for this enzyme. Bortezomib did not induce the activities of cytochrome P450 3A4 and 1A2 in primary cultured human hepatocytes.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies have not been conducted with bortezomib.
Bortezomib showed clastogenic activity (structural chromosomal aberrations) in the in vitro chromosomal aberration assay using Chinese hamster ovary cells. Bortezomib was not genotoxic when tested in the in vitro mutagenicity assay (Ames test) and in vivo micronucleus assay in mice.
Fertility studies with bortezomib were not performed but evaluation of reproductive tissues has been performed in the general toxicity studies. In the 6-month rat toxicity study, degenerative effects in the ovary were observed at doses ≥ 0.3 mg/m2 (one-fourth of the recommended clinical dose), and degenerative changes in the testes occurred at 1.2 mg/m2. Bortezomib could have a potential effect on either male or female fertility.
### Animal Toxicology and/or Pharmacology
Cardiovascular Toxicity: Studies in monkeys showed that administration of dosages approximately twice the recommended clinical dose resulted in heart rate elevations, followed by profound progressive hypotension, bradycardia, and death 12 to 14 hours post dose. Doses ≥ 1.2 mg/m2 induced dose-proportional changes in cardiac parameters. Bortezomib has been shown to distribute to most tissues in the body, including the myocardium. In a repeated dosing toxicity study in the monkey, myocardial hemorrhage, inflammation, and necrosis were also observed.
Chronic Administration: In animal studies at a dose and schedule similar to that recommended for patients (twice weekly dosing for 2 weeks followed by 1-week rest), toxicities observed included severe anemia and thrombocytopenia, and gastrointestinal, neurological and lymphoid system toxicities. Neurotoxic effects of bortezomib in animal studies included axonal swelling and degeneration in peripheral nerves, dorsal spinal roots, and tracts of the spinal cord. Additionally, multifocal hemorrhage and necrosis in the brain, eye, and heart were observed.
# Clinical Studies
### multiple myeloma
Randomized, Open-Label Clinical Study in Patients with Previously Untreated multiple myeloma:
A prospective, international, randomized (1:1), open-label clinical study of 682 patients was conducted to determine whether Bortezomib administered intravenously (1.3 mg/m2) in combination with melphalan (9 mg/m2) and prednisone (60 mg/m2) resulted in improvement in time to progression (TTP) when compared to melphalan (9 mg/m2) and prednisone (60 mg/m2) in patients with previously untreated multiple myeloma. Treatment was administered for a maximum of 9 cycles (approximately 54 weeks) and was discontinued early for disease progression or unacceptable toxicity. Antiviral prophylaxis was recommended for patients on the Bortezomib study arm.
The median age of the patients in the study was 71 years (48;91), 50% were male, 88% were Caucasian and the median Karnofsky performance status score for the patients was 80 (60;100). Patients had IgG/IgA/Light chain myeloma in 63%/25%/8% instances, a median hemoglobin of 105 g/L (64;165), and a median platelet count of 221,500 /microliter (33,000;587,000).
Efficacy results for the trial are presented in Table 11. At a pre-specified interim analysis (with median follow-up of 16.3 months), the combination of Bortezomib, melphalan and prednisone therapy resulted in significantly superior results for time to progression, progression-free survival, overall survival and response rate. Further enrollment was halted, and patients receiving melphalan and prednisone were offered Bortezomib in addition. A later, pre-specified analysis of overall survival (with median follow-up of 36.7 months with a hazard ratio of 0.65, 95% CI: 0.51, 0.84) resulted in a statistically significant survival benefit for the Bortezomib, melphalan and prednisone treatment arm despite subsequent therapies including Bortezomib based regimens. In an updated analysis of overall survival based on 387 deaths (median follow-up 60.1 months), the median overall survival for the Bortezomib, melphalan and prednisone treatment arm was 56.4 months and for the melphalan and prednisone treatment arm was 43.1 months, with a hazard ratio of 0.695 (95% CI: 0.57, 0.85).
TTP was statistically significantly longer on the Bortezomib, melphalan and prednisone arm (see Figure 1). (median follow-up 16.3 months)
Overall survival was statistically significantly longer on the Bortezomib, melphalan and prednisone arm (see Figure 2). (median follow-up 60.1 months)
Randomized, Clinical Study in Relapsed multiple myeloma of Bortezomib versus dexamethasone
A prospective phase 3, international, randomized (1:1), stratified, open-label clinical study enrolling 669 patients was designed to determine whether Bortezomib resulted in improvement in time to progression (TTP) compared to high-dose dexamethasone in patients with progressive multiple myeloma following 1 to 3 prior therapies. Patients considered to be refractory to prior high-dose dexamethasone were excluded as were those with baseline Grade ≥ 2 peripheral neuropathy or platelet counts < 50,000/µL. A total of 627 patients were evaluable for response.
Stratification factors were based on the number of lines of prior therapy the patient had previously received (1 previous line versus more than 1 line of therapy), time of progression relative to prior treatment (progression during or within 6 months of stopping their most recent therapy versus relapse > 6 months after receiving their most recent therapy), and screening beta2-microglobulin levels (≤ 2.5 mg/L versus > 2.5 mg/L).
Baseline patient and disease characteristics are summarized in Table 12.
Patients in the Bortezomib treatment group were to receive eight 3-week treatment cycles followed by three 5-week treatment cycles of Bortezomib. Patients achieving a CR were treated for 4 cycles beyond first evidence of CR. Within each 3-week treatment cycle, Bortezomib 1.3 mg/m2/dose alone was administered by intravenous bolus twice weekly for 2 weeks on Days 1, 4, 8, and 11 followed by a 10-day rest period (Days 12 to 21). Within each 5-week treatment cycle, Bortezomib 1.3 mg/m2/dose alone was administered by intravenous bolus once weekly for 4 weeks on Days 1, 8, 15, and 22 followed by a 13-day rest period (Days 23 to 35).
Patients in the dexamethasone treatment group were to receive four 5-week treatment cycles followed by five 4-week treatment cycles. Within each 5-week treatment cycle, dexamethasone 40 mg/day PO was administered once daily on Days 1 to 4, 9 to 12, and 17 to 20 followed by a 15-day rest period (Days 21-35). Within each 4-week treatment cycle, dexamethasone 40 mg/day PO was administered once daily on Days 1 to 4 followed by a 24-day rest period (Days 5 to 28). Patients with documented progressive disease on dexamethasone were offered Bortezomib at a standard dose and schedule on a companion study. Following a preplanned interim analysis of time to progression, the dexamethasone arm was halted and all patients randomized to dexamethasone were offered Bortezomib, regardless of disease status.
In the Bortezomib arm, 34% of patients received at least one Bortezomib dose in all 8 of the 3-week cycles of therapy, and 13% received at least one dose in all 11 cycles. The average number of Bortezomib doses during the study was 22, with a range of 1 to 44. In the dexamethasone arm, 40% of patients received at least one dose in all 4 of the 5-week treatment cycles of therapy, and 6% received at least one dose in all 9 cycles.
The time to event analyses and response rates from the relapsed multiple myeloma study are presented in Table 13. Response and progression were assessed using the European Group for Blood and Marrow Transplantation (EBMT) criteria. Complete response (CR) required < 5% plasma cells in the marrow, 100% reduction in M-protein, and a negative immunofixation test (IF-). Partial response (PR) requires ≥ 50% reduction in serum myeloma protein and ≥ 90% reduction of urine myeloma protein on at least 2 occasions for a minimum of at least 6 weeks along with stable bone disease and normal calcium. Near complete response (nCR) was defined as meeting all the criteria for complete response including 100% reduction in M-protein by protein electrophoresis; however, M-protein was still detectable by immunofixation (IF+).
TTP was statistically significantly longer on the Bortezomib arm (see Figure 3).
As shown in Figure 4 Bortezomib had a significant survival advantage relative to dexamethasone (p < 0.05). The median follow-up was 8.3 months.
For the 121 patients achieving a response (CR or PR) on the Bortezomib arm, the median duration was 8.0 months (95% CI: 6.9, 11.5 months) compared to 5.6 months (95% CI: 4.8, 9.2 months) for the 56 responders on the dexamethasone arm. The response rate was significantly higher on the Bortezomib arm regardless of beta2-microglobulin levels at baseline.
Randomized, Open-Label Clinical Study of Bortezomib Subcutaneous versus Intravenous in Relapsed multiple myeloma
An open-label, randomized, phase 3 non-inferiority study compared the efficacy and safety of the subcutaneous administration of Bortezomib versus the intravenous administration. This study included 222 bortezomib naïve patients with relapsed multiple myeloma, who were randomized in a 2:1 ratio to receive 1.3 mg/m2 of Bortezomib by either the subcutaneous (n=148) or intravenous (n=74) route for 8 cycles. Patients who did not obtain an optimal response (less than Complete Response (CR)) to therapy with Bortezomib alone after 4 cycles were allowed to receive oral dexamethasone 20 mg daily on the day of and after Bortezomib administration (82 patients in subcutaneous treatment group and 39 patients in the intravenous treatment group). Patients with baseline Grade ≥ 2 peripheral neuropathy or neuropathic pain, or platelet counts < 50,000/µL were excluded. A total of 218 patients were evaluable for response.
Stratification factors were based on the number of lines of prior therapy the patient had received (1 previous line versus more than 1 line of therapy), and international staging system (ISS) stage (incorporating beta2-microglobulin and albumin levels; Stages I, II, or III).
The baseline demographic and others characteristics of the two treatment groups are summarized as follows: the median age of the patient population was approximately 64 years of age (range 38-88 years), primarily male (subcutaneous: 50%, intravenous: 64%); the primary type of myeloma is IgG (subcutaneous: 65% IgG, 26% IgA, 8% light chain; intravenous: 72% IgG, 19% IgA, 8% light chain), ISS staging I/II/III (%) was 27, 41, 32 for both subcutaneous and intravenous, Karnofsky performance status score was ≤ 70% in 22% of subcutaneous and 16% of intravenous, creatinine clearance was 67.5 mL/min in subcutaneous and 73 mL/min in intravenous, the median years from diagnosis was 2.68 and 2.93 in subcutaneous and intravenous respectively and the proportion of patients with more than one prior line of therapy was 38% in subcutaneous and 35% in intravenous.
This study met its primary (non-inferiority) objective that single agent subcutaneous Bortezomib retains at least 60% of the overall response rate after 4 cycles relative to single agent intravenous Bortezomib. The results are provided in Table 14.
A Randomized Phase 2 Dose-Response Study in Relapsed multiple myeloma
An open-label, multicenter study randomized 54 patients with multiple myeloma who had progressed or relapsed on or after front-line therapy to receive Bortezomib 1 mg/m2 or 1.3 mg/m2 intravenous bolus twice weekly for 2 weeks on Days 1, 4, 8, and 11 followed by a 10-day rest period (Days 12 to 21). The median duration of time between diagnosis of multiple myeloma and first dose of Bortezomib on this trial was 2.0 years, and patients had received a median of 1 prior line of treatment (median of 3 prior therapies). A single complete response was seen at each dose. The overall response rates (CR + PR) were 30% (8/27) at 1 mg/m2 and 38% (10/26) at 1.3 mg/m2.
A Phase 2 Open-Label Extension Study in Relapsed multiple myeloma
Patients from the two phase 2 studies, who in the investigators' opinion would experience additional clinical benefit, continued to receive Bortezomib beyond 8 cycles on an extension study. Sixty-three (63) patients from the phase 2 multiple myeloma studies were enrolled and received a median of 7 additional cycles of Bortezomib therapy for a total median of 14 cycles (range 7 to 32). The overall median dosing intensity was the same in both the parent protocol and extension study. Sixty-seven percent (67%) of patients initiated the extension study at the same or higher dose intensity at which they completed the parent protocol, and 89% of patients maintained the standard 3-week dosing schedule during the extension study. No new cumulative or new long-term toxicities were observed with prolonged Bortezomib treatment .
### Mantle Cell Lymphoma
A Phase 2 Single-arm Clinical Study in Relapsed Mantle Cell Lymphoma After Prior Therapy
The safety and efficacy of Bortezomib in relapsed or refractory mantle cell lymphoma were evaluated in an open-label, single-arm, multicenter study of 155 patients with progressive disease who had received at least 1 prior therapy. The median age of the patients was 65 years (42, 89), 81% were male, and 92% were Caucasian. Of the total, 75% had one or more extra-nodal sites of disease, and 77% were stage 4. In 91% of the patients, prior therapy included all of the following: an anthracycline or mitoxantrone, cyclophosphamide, and rituximab. A total of thirty seven percent (37%) of patients were refractory to their last prior therapy. An intravenous bolus injection of Bortezomib 1.3 mg/m2/dose was administered twice weekly for 2 weeks on Days 1, 4, 8, and 11 followed by a 10-day rest period (Days 12 to 21) for a maximum of 17 treatment cycles. Patients achieving a CR or CRu were treated for 4 cycles beyond first evidence of CR or CRu. The study employed dose modifications for toxicity.
Responses to Bortezomib are shown in Table 15. Response rates to Bortezomib were determined according to the International Workshop Response Criteria (IWRC) based on independent radiologic review of CT scans. The median number of cycles administered across all patients was 4; in responding patients the median number of cycles was 8. The median time to response was 40 days (range 31 to 204 days). The median duration of follow-up was more than 13 months.
# How Supplied
Bortezomib® (bortezomib) for Injection is supplied as individually cartoned 10 mL vials containing 3.5 mg of bortezomib as a white to off-white cake or powder.
NDC 63020-049-01
3.5 mg single use vial
## Storage
Unopened vials may be stored at controlled room temperature 25°C (77°F); excursions permitted from 15 to 30°C (59 to 86°F) . Retain in original package to protect from light.
Consider handling and disposal of Bortezomib according to guidelines issued for cytotoxic drugs, including the use of gloves and other protective clothing to prevent skin contact1.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Physicians are advised to discuss the following with patients prior to treatment with Bortezomib:
Ability to Drive or Operate Machinery or Impairment of Mental Ability: Bortezomib may cause fatigue, dizziness, syncope, orthostatic/postural hypotension. Advise patients not to drive or operate machinery if they experience any of these symptoms.
dehydration/hypotension: Patients receiving Bortezomib therapy may experience vomiting and/or diarrhea. Advise patients how to avoid dehydration. Instruct patients to seek medical advice if they experience symptoms of dizziness, light headedness or fainting spells.
Pregnancy/Nursing: Advise patients to use effective contraceptive measures to prevent pregnancy during treatment with Bortezomib. Instruct patients to report pregnancy to their physicians immediately. Advise patients that they should not receive Bortezomib while pregnant or breast-feeding. If a patient wishes to restart breastfeeding after treatment, she should be advised to discuss the appropriate timing with her physician.
Concomitant Medications: Advise patients to speak with their physicians about any other medication they are currently taking.
Diabetic Patients: Advise patients to check their blood sugar frequently if using an oral antidiabetic medication and to notify their physicians of any changes in blood sugar level.
peripheral neuropathy: Advise patients to contact their physicians if they experience new or worsening symptoms of peripheral neuropathy such as tingling, numbness, pain, a burning feeling in the feet or hands, or weakness in the arms or legs.
Other: Instruct patients to contact their physicians if they develop a rash, experience shortness of breath, cough, or swelling of the feet, ankles, or legs, convulsion, persistent headache, reduced eyesight, an increase in blood pressure or blurred vision.
Distributed and Marketed by:
Millennium Pharmaceuticals, Inc.
40 Landsdowne Street
Cambridge, MA 02139
# Precautions with Alcohol
Alcohol-Bortezomib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
VELCADE
# Look-Alike Drug Names
There is limited information regarding Bortezomib Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Bortezomib | |
d57f202fff1ff9e832191a9d927a36bd7bc54f04 | wikidoc | Defecation | Defecation
# Overview
Defecation is the act or process by which organisms eliminate solid or semisolid waste material (feces) from the digestive tract via the anus. Humans expel feces with a frequency varying from a few times daily to a few times weekly; sloths can go a week without expelling. Waves of muscular contraction known as peristalsis in the walls of the colon move fecal matter through the digestive tract towards the rectum. Undigested food may also be expelled this way; this process is called egestion.
The rectum ampulla (anatomically also: ampulla recti) acts as a temporary storage facility for the unneeded material. As the rectal walls expand due to the material filling it, stretch receptors from the nervous system located in the rectal walls stimulate the desire to defecate. If the urge is not acted upon, the material in the rectum is often returned to the colon where more water is absorbed. If defecation is delayed for a prolonged period the fecal matter may harden, resulting in constipation.
When the rectum is full, an increase in intrarectal pressure forces the walls of the anal canal apart allowing the fecal matter to enter the canal. The rectum shortens as material is forced into the anal canal and peristaltic waves push the feces out of the rectum. The internal and external anal sphincters allow the feces to be passed by muscles pulling the anus up over the exiting feces.
During defecation the chest muscles, diaphragm, abdominal wall muscles, and pelvic diaphragm all exert pressure on the digestive tract and ventilation temporarily ceases as the lungs push the chest diaphragm down in order to exert pressure. Blood pressure rises throughout the body and the amount of blood pumped by the heart decreases. During this time, the body is effectively undergoing similar stresses to that of a valsalva maneuver. Death has been known to occur in cases where defecation causes the blood pressure to rise enough to cause the rupture of an aneurysm or to dislodge blood clots (see thrombosis).
Humans must consciously relax the external sphincter muscles to expel waste. The anal and urethal sphincter muscles are closely linked, and experiments by Dr. Harrison Weed at the Ohio State University Medical Center have shown that they can only be contracted together, not individually, and that they both show relaxation during urination. This explains why defecation is frequently accompanied with urination.
Defecation may be involuntary or under voluntary control. Young children learn voluntary control through the process of toilet training. Once trained, loss of control causing fecal incontinence may be caused by physical injury (such as damage to the anal sphincter that may result from an episiotomy), intense fright, inflammatory bowel disease, impaired water absorption in the colon (see diarrhea), and psychological or neurological factors.
The positions and modalities of defecation are culture-dependent. In some regions of the world, such as South Asia, East Asia and rural parts of the Middle East, it is customary to squat (typically using squat toilets), while in most of the Western World sit-down toilets are used.
The anus and buttocks may be cleansed with toilet paper or similar paper products. In some cultures water is also used (e.g. as with a bidet). In Japan, some toilets known as washlets are designed to wash and dry the anus of the user after defecation. | Defecation
# Overview
Defecation is the act or process by which organisms eliminate solid or semisolid waste material (feces) from the digestive tract via the anus. Humans expel feces with a frequency varying from a few times daily to a few times weekly; sloths can go a week without expelling. Waves of muscular contraction known as peristalsis in the walls of the colon move fecal matter through the digestive tract towards the rectum. Undigested food may also be expelled this way; this process is called egestion.
The rectum ampulla (anatomically also: ampulla recti) acts as a temporary storage facility for the unneeded material. As the rectal walls expand due to the material filling it, stretch receptors from the nervous system located in the rectal walls stimulate the desire to defecate. If the urge is not acted upon, the material in the rectum is often returned to the colon where more water is absorbed. If defecation is delayed for a prolonged period the fecal matter may harden, resulting in constipation.
When the rectum is full, an increase in intrarectal pressure forces the walls of the anal canal apart allowing the fecal matter to enter the canal. The rectum shortens as material is forced into the anal canal and peristaltic waves push the feces out of the rectum. The internal and external anal sphincters allow the feces to be passed by muscles pulling the anus up over the exiting feces.
During defecation the chest muscles, diaphragm, abdominal wall muscles, and pelvic diaphragm all exert pressure on the digestive tract and ventilation temporarily ceases as the lungs push the chest diaphragm down in order to exert pressure. Blood pressure rises throughout the body and the amount of blood pumped by the heart decreases. During this time, the body is effectively undergoing similar stresses to that of a valsalva maneuver. Death has been known to occur in cases where defecation causes the blood pressure to rise enough to cause the rupture of an aneurysm or to dislodge blood clots (see thrombosis).
Humans must consciously relax the external sphincter muscles to expel waste. The anal and urethal sphincter muscles are closely linked, and experiments by Dr. Harrison Weed at the Ohio State University Medical Center have shown that they can only be contracted together, not individually, and that they both show relaxation during urination. This explains why defecation is frequently accompanied with urination.
Defecation may be involuntary or under voluntary control. Young children learn voluntary control through the process of toilet training. Once trained, loss of control causing fecal incontinence may be caused by physical injury (such as damage to the anal sphincter that may result from an episiotomy), intense fright, inflammatory bowel disease, impaired water absorption in the colon (see diarrhea), and psychological or neurological factors.
The positions and modalities of defecation are culture-dependent. In some regions of the world, such as South Asia, East Asia and rural parts of the Middle East, it is customary to squat (typically using squat toilets), while in most of the Western World sit-down toilets are used.
The anus and buttocks may be cleansed with toilet paper or similar paper products. In some cultures water is also used (e.g. as with a bidet). In Japan, some toilets known as washlets are designed to wash and dry the anus of the user after defecation. | https://www.wikidoc.org/index.php/Bowel_movement | |
ed2ddd9b2e9c4cf3a043df9e0dd0dac4f094c55f | wikidoc | Brad Cohen | Brad Cohen
Brad Cohen is a motivational speaker and an award-winning teacher and author. He has a severe case of Tourette syndrome, described in his book, Front of the Class: How Tourette Syndrome Made Me the Teacher I Never Had. During his childhood, he was accused of being a troublemaker in school and was unfairly punished by his teachers. He decided to "become the teacher that he never had". After he graduated and received his certificate in teaching, twenty-four elementary schools rejected him before he finally got a job at Mountain View Elementary School in Cobb County, Georgia. As a new teacher, he won Teacher of the Year Award for the State of Georgia. Brad Cohen married Nancy Lazarus of Charleston, South Carolina on June 25 2006.
# Early life
Brad grew up in St. Louis, Missouri in a Jewish family. His parents divorced during his early childhood. His mother was compassionate towards him, but his father did not understand Tourette syndrome. He often got frustrated with his son, and he would yell at him for making noises or physical convulsions. When his father moved away, they drifted apart.
# School years
Teachers did not understand Brad because they thought he was a mischievous student, due to the noises (tics) caused by his Tourette syndrome. His 5th grade teacher forced him to walk to the front of the classroom to apologize for the noises he made and promise that he would never do them again. He felt humiliated and decided that he would become the teacher he never had. He said, "I wanted to be the teacher who looked at strengths, not weaknesses."
In the beginning of his eighth grade year, his principal decided to let Brad speak to the school about his Tourette syndrome. Brad continued to speak in front of people about his Tourette syndrome, increasing his confidence and speaking skills.
# College life
Cohen attended Bradley University in Peoria, Illinois, majoring in teacher education. He was discriminated against while attending Bradley, when he was kicked out of a local fast food restaurant due to his vocal tics. After his peers boycotted the restaurant, the manager anxiously apologized to Brad. Brad graduated cum laude with many academic honors.
# Career
Cohen moved to Atlanta, Georgia, in the 1990s to seek employment. He
applied to numerous elementary schools for a teaching position. He interviewed with administrators, but his interviews were always punctuated by his tics. He was rejected twenty-four times befor Mountain View Elementary school hired him to teach second and third grades. He was awarded the Sallie Mae First Class Teacher of the Year in 1997.
Cohen is currently teaching second grade at Tritt Elementary School in the suburbs of Atlanta. At the beginning of each year, he teaches the students about his Tourette syndrome.
# Accomplishments
Brad has been active in several organizations. He has been featured in a public service announcement for the Tourette Syndrome Association. He also serves as the Vice President for the Tourette Syndrome Association of Georgia. He was a chairman of Relay for Life, a Little League coach, a MLB mascot, and has been recognized for his community involvement.
Cohen's book, Front of the Class: How Tourette Syndrome Made Me the Teacher I Never Had was published in 2005 with Lisa Wysocky.
His book won the Independent Publisher Book Award for Best Education Book of 2005. Brad appeared on The Oprah Winfrey Show on May 26, 2006.
# Notes
- ↑ VanderWyk & Burnham Authors. Brad Cohen. Accessed 4 June 2006.
- ↑ Tourette Syndrome Association. Brad Cohen PSA (PDF). Accessed 4 January 2007.
- ↑ Tourette Syndrome Association. Front of the Class wins independent publisher award. Accessed 4 January 2007.
- ↑ The Oprah Winfrey Show. Against All Odds. Accessed 3 June 2006. | Brad Cohen
Brad Cohen is a motivational speaker and an award-winning teacher and author. He has a severe case of Tourette syndrome, described in his book, Front of the Class: How Tourette Syndrome Made Me the Teacher I Never Had. During his childhood, he was accused of being a troublemaker in school and was unfairly punished by his teachers. He decided to "become the teacher that he never had". After he graduated and received his certificate in teaching, twenty-four elementary schools rejected him before he finally got a job at Mountain View Elementary School in Cobb County, Georgia. As a new teacher, he won Teacher of the Year Award for the State of Georgia. Brad Cohen married Nancy Lazarus of Charleston, South Carolina on June 25 2006.
# Early life
Brad grew up in St. Louis, Missouri in a Jewish family. His parents divorced during his early childhood. His mother was compassionate towards him, but his father did not understand Tourette syndrome. He often got frustrated with his son, and he would yell at him for making noises or physical convulsions. When his father moved away, they drifted apart.
# School years
Teachers did not understand Brad because they thought he was a mischievous student, due to the noises (tics) caused by his Tourette syndrome. His 5th grade teacher forced him to walk to the front of the classroom to apologize for the noises he made and promise that he would never do them again. He felt humiliated and decided that he would become the teacher he never had. He said, "I wanted to be the teacher who looked at strengths, not weaknesses."
In the beginning of his eighth grade year, his principal decided to let Brad speak to the school about his Tourette syndrome. Brad continued to speak in front of people about his Tourette syndrome, increasing his confidence and speaking skills.
# College life
Cohen attended Bradley University in Peoria, Illinois, majoring in teacher education. He was discriminated against while attending Bradley, when he was kicked out of a local fast food restaurant due to his vocal tics. After his peers boycotted the restaurant, the manager anxiously apologized to Brad. Brad graduated cum laude with many academic honors.[1]
# Career
Cohen moved to Atlanta, Georgia, in the 1990s to seek employment. He
applied to numerous elementary schools for a teaching position. He interviewed with administrators, but his interviews were always punctuated by his tics. He was rejected twenty-four times befor Mountain View Elementary school hired him to teach second and third grades. He was awarded the Sallie Mae First Class Teacher of the Year in 1997.
Cohen is currently teaching second grade at Tritt Elementary School in the suburbs of Atlanta. At the beginning of each year, he teaches the students about his Tourette syndrome.
# Accomplishments
Brad has been active in several organizations. He has been featured in a public service announcement for the Tourette Syndrome Association.[2] He also serves as the Vice President for the Tourette Syndrome Association of Georgia. He was a chairman of Relay for Life, a Little League coach, a MLB mascot, and has been recognized for his community involvement.
Cohen's book, Front of the Class: How Tourette Syndrome Made Me the Teacher I Never Had was published in 2005 with Lisa Wysocky.
His book won the Independent Publisher Book Award for Best Education Book of 2005.[3] Brad appeared on The Oprah Winfrey Show on May 26, 2006.[4]
# Notes
- ↑ VanderWyk & Burnham Authors. Brad Cohen. Accessed 4 June 2006.
- ↑ Tourette Syndrome Association. Brad Cohen PSA (PDF). Accessed 4 January 2007.
- ↑ Tourette Syndrome Association. Front of the Class wins independent publisher award. Accessed 4 January 2007.
- ↑ The Oprah Winfrey Show. Against All Odds. Accessed 3 June 2006.
# External links
- Front of the Class - the official website of Brad Cohen's book.
- A short biography of Cohen.
- Video clip from The Oprah Winfrey Show
Template:Topics related to Tourette syndrome | https://www.wikidoc.org/index.php/Brad_Cohen | |
7d35bdaea75c03590076e935d15f41d632271562 | wikidoc | Bradykinin | Bradykinin
Bradykinin is an inflammatory mediator. It is a peptide that causes blood vessels to dilate (enlarge), and therefore causes blood pressure to fall. A class of drugs called ACE inhibitors, which are used to lower blood pressure, increase bradykinin (by inhibiting its degradation), further lowering blood pressure. Bradykinin dilates blood vessels via the release of prostacyclin, nitric oxide, and Endothelium-Derived Hyperpolarizing Factor.
Bradykinin is a physiologically and pharmacologically active peptide of the kinin group of proteins, consisting of nine amino acids.
# Structure
Bradykinin is a 9-amino acid peptide chain. The amino acid sequence of bradykinin is: Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg (RPPGFSPFR). Its empirical formula is therefore C50H73N15O11.
# Synthesis
The kinin-kallikrein system makes bradykinin by proteolytic cleavage of its kininogen precursor, high-molecular-weight kininogen (HMWK or HK), by the enzyme kallikrein. Moreover, there is compelling evidence that plasmin, a fibrinolytic enzyme, is able to generate bradykinin after HMWK cleavage.
# Metabolism
In humans, bradykinin is broken down by three kininases: angiotensin-converting enzyme (ACE), aminopeptidase P (APP), and carboxypeptidase N (CPN), which cleave the 7-8, 1-2, and 8-9 positions, respectively.
# Physiological role (function)
## Effects
Bradykinin is a potent endothelium-dependent vasodilator, leading to a drop in blood pressure. It also causes contraction of non-vascular smooth muscle in the bronchus and gut, increases vascular permeability and is also involved in the mechanism of pain. Bradykinin also causes natriuresis, contributing to the drop in blood pressure.
Bradykinin raises internal calcium levels in neocortical astrocytes causing them to release glutamate, though this finding has only been confirmed in-vitro.
Bradykinin is also thought to be the cause of the dry cough in some patients on widely-prescribed angiotensin-converting enzyme (ACE) inhibitor drugs. It is thought that bradykinin is converted to inactive metabolites by ACE, therefore inhibition of this enzyme leads to increased levels of bradykinin, which causes a dry cough via bronchoconstriction. In severe cases, the elevation of bradykinin may result in angioedema, a medical emergency. People of African descent have up to 5x increased risk of ACE inhibitor induced angioedema due to hereditary predisposing risk factors such as hereditary angioedema. This refractory cough is a common cause for stopping ACE inhibitor therapy, in which case angiotensin II receptor antagonists (ARBs) are the next line of treatment.
Overactivation of bradykinin is thought to play a role in a rare disease called hereditary angioedema, formerly known as hereditary angio-neurotic edema.
Initial secretion of bradykinin post-natally causes constriction and eventual atrophy of the ductus arteriosus, forming the ligamentum arteriosum between the pulmonary trunk and aortic arch. It also plays a role in the constriction and eventual occlusion of a number of other fetal vessels, including the umbilical arteries and vein. The differential vasoconstriction of these fetal vessels compared to the vasodilator response of other vessels suggest that the walls of these fetal vessels are different than other vessels.
## Receptors
- The B1 receptor (also called bradykinin receptor B1) is expressed only as a result of tissue injury, and is presumed to play a role in chronic pain. This receptor has been also described to play a role in inflammation. Most recently, it has been shown that the kinin B1 receptor recruits neutrophil via the chemokine CXCL5 production. Moreover, endothelial cells have been described as a potential source for this B1 receptor-CXCL5 pathway.
- The B2 receptor is constitutively expressed and participates in bradykinin's vasodilatory role.
The kinin B1 and B2 receptors belong to G protein coupled receptor (GPCR) family.
# History
Bradykinin was discovered in 1948 by three Brazilian physiologists and pharmacologists working at the Instituto Biológico, in São Paulo, Brazil, led by Dr. Maurício Rocha e Silva. Together with colleagues Wilson Teixeira Beraldo and Gastão Rosenfeld, they discovered the powerful hypotensive effects of bradykinin in animal preparations. Bradykinin was detected in the blood plasma of animals after the addition of venom extracted from the Bothrops jararaca (Brazilian lancehead snake), brought by Rosenfeld from the Butantan Institute. The discovery was part of a continuing study on circulatory shock and proteolytic enzymes related to the toxicology of snake bites, started by Rocha e Silva as early as 1939. Bradykinin was to prove a new autopharmacological principle, i.e., a substance that is released in the body by a metabolic modification from precursors, which are pharmacologically active. According to B.J. Hagwood, Rocha e Silva's biographer, "The discovery of bradykinin has led to a new understanding of many physiological and pathological phenomena including circulatory shock induced by venoms and toxins." Etymology: brady slow, kinin kīn(eîn) to move, set in motion, ? from the effect of snake venom on intestinal smooth muscle, which was noted to slowly contract.
# Therapeutic implications
The practical importance of the discovery of bradykinin became apparent when one of his collaborators at the Medical School of Ribeirão Preto at the University of São Paulo, Dr. Sérgio Henrique Ferreira, discovered a bradykinin-potentiating factor (BPF) in the bothropic venom, which increases powerfully both the duration and magnitude of its effects on vasodilation and the consequent fall in blood pressure. On the basis of this finding, Squibb scientists developed the first of a new generation of highly-effective anti-hypertensive drugs, the so-called ACE inhibitors, such as captopril (trademarked Capoten).
Currently, bradykinin inhibitors (antagonists) are being developed as potential therapies for hereditary angioedema. Icatibant is one such inhibitor. Additional bradykinin inhibitors exist. It has long been known in animal studies that bromelain, a substance obtained from the stems and leaves of the pineapple plant, suppresses trauma-induced swelling caused by the release of bradykinin into the bloodstream and tissues. Other substances that act as bradykinin inhibitors include aloe and polyphenols, substances found in red wine and green tea.
# Role in carcinogenesis and progression
Bradykinins have been implicated in a number of cancer progression processes.. Increased levels of bradykinins resulting from ACE inhibitor use have been associated with increased lung cancer risks Bradykinins have been implicated in cell proliferation and migration in gastric cancers, and bradykinin antagonists have been investigated as anti-cancer agents. | Bradykinin
Bradykinin is an inflammatory mediator. It is a peptide that causes blood vessels to dilate (enlarge), and therefore causes blood pressure to fall. A class of drugs called ACE inhibitors, which are used to lower blood pressure, increase bradykinin (by inhibiting its degradation), further lowering blood pressure. Bradykinin dilates blood vessels via the release of prostacyclin, nitric oxide, and Endothelium-Derived Hyperpolarizing Factor.
Bradykinin is a physiologically and pharmacologically active peptide of the kinin group of proteins, consisting of nine amino acids.
# Structure
Bradykinin is a 9-amino acid peptide chain. The amino acid sequence of bradykinin is: Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg (RPPGFSPFR). Its empirical formula is therefore C50H73N15O11.
# Synthesis
The kinin-kallikrein system makes bradykinin by proteolytic cleavage of its kininogen precursor, high-molecular-weight kininogen (HMWK or HK), by the enzyme kallikrein. Moreover, there is compelling evidence that plasmin, a fibrinolytic enzyme, is able to generate bradykinin after HMWK cleavage.[1]
# Metabolism
In humans, bradykinin is broken down by three kininases: angiotensin-converting enzyme (ACE), aminopeptidase P (APP), and carboxypeptidase N (CPN), which cleave the 7-8, 1-2, and 8-9 positions, respectively.[2][3]
# Physiological role (function)
## Effects
Bradykinin is a potent endothelium-dependent vasodilator, leading to a drop in blood pressure. It also causes contraction of non-vascular smooth muscle in the bronchus and gut, increases vascular permeability and is also involved in the mechanism of pain.[4] Bradykinin also causes natriuresis, contributing to the drop in blood pressure.
Bradykinin raises internal calcium levels in neocortical astrocytes causing them to release glutamate, though this finding has only been confirmed in-vitro.[5]
Bradykinin is also thought to be the cause of the dry cough in some patients on widely-prescribed angiotensin-converting enzyme (ACE) inhibitor drugs[6]. It is thought that bradykinin is converted to inactive metabolites by ACE, therefore inhibition of this enzyme leads to increased levels of bradykinin, which causes a dry cough via bronchoconstriction. In severe cases, the elevation of bradykinin may result in angioedema, a medical emergency.[7] People of African descent have up to 5x increased risk of ACE inhibitor induced angioedema due to hereditary predisposing risk factors such as hereditary angioedema.[8] This refractory cough is a common cause for stopping ACE inhibitor therapy, in which case angiotensin II receptor antagonists (ARBs) are the next line of treatment.
Overactivation of bradykinin is thought to play a role in a rare disease called hereditary angioedema, formerly known as hereditary angio-neurotic edema.[9]
Initial secretion of bradykinin post-natally causes constriction and eventual atrophy of the ductus arteriosus, forming the ligamentum arteriosum between the pulmonary trunk and aortic arch. It also plays a role in the constriction and eventual occlusion of a number of other fetal vessels, including the umbilical arteries and vein. The differential vasoconstriction of these fetal vessels compared to the vasodilator response of other vessels suggest that the walls of these fetal vessels are different than other vessels.[10]
## Receptors
- The B1 receptor (also called bradykinin receptor B1) is expressed only as a result of tissue injury, and is presumed to play a role in chronic pain. This receptor has been also described to play a role in inflammation.[11] Most recently, it has been shown that the kinin B1 receptor recruits neutrophil via the chemokine CXCL5 production. Moreover, endothelial cells have been described as a potential source for this B1 receptor-CXCL5 pathway.[12]
- The B2 receptor is constitutively expressed and participates in bradykinin's vasodilatory role.
The kinin B1 and B2 receptors belong to G protein coupled receptor (GPCR) family.
# History
Bradykinin was discovered in 1948 by three Brazilian physiologists and pharmacologists working at the Instituto Biológico, in São Paulo, Brazil, led by Dr. Maurício Rocha e Silva. Together with colleagues Wilson Teixeira Beraldo and Gastão Rosenfeld, they discovered the powerful hypotensive effects of bradykinin in animal preparations. Bradykinin was detected in the blood plasma of animals after the addition of venom extracted from the Bothrops jararaca (Brazilian lancehead snake), brought by Rosenfeld from the Butantan Institute. The discovery was part of a continuing study on circulatory shock and proteolytic enzymes related to the toxicology of snake bites, started by Rocha e Silva as early as 1939. Bradykinin was to prove a new autopharmacological principle, i.e., a substance that is released in the body by a metabolic modification from precursors, which are pharmacologically active. According to B.J. Hagwood, Rocha e Silva's biographer, "The discovery of bradykinin has led to a new understanding of many physiological and pathological phenomena including circulatory shock induced by venoms and toxins." Etymology: brady [Gk] slow, kinin [Gk ] kīn(eîn) to move, set in motion, ? from the effect of snake venom on intestinal smooth muscle, which was noted to slowly contract.[citation needed]
# Therapeutic implications
The practical importance of the discovery of bradykinin became apparent when one of his collaborators at the Medical School of Ribeirão Preto at the University of São Paulo, Dr. Sérgio Henrique Ferreira, discovered a bradykinin-potentiating factor (BPF) in the bothropic venom, which increases powerfully both the duration and magnitude of its effects on vasodilation and the consequent fall in blood pressure. On the basis of this finding, Squibb scientists developed the first of a new generation of highly-effective anti-hypertensive drugs, the so-called ACE inhibitors, such as captopril (trademarked Capoten).
Currently, bradykinin inhibitors (antagonists) are being developed as potential therapies for hereditary angioedema. Icatibant is one such inhibitor. Additional bradykinin inhibitors exist. It has long been known in animal studies that bromelain, a substance obtained from the stems and leaves of the pineapple plant, suppresses trauma-induced swelling caused by the release of bradykinin into the bloodstream and tissues.[13] Other substances that act as bradykinin inhibitors include aloe[14][15] and polyphenols, substances found in red wine and green tea.[16]
# Role in carcinogenesis and progression
Bradykinins have been implicated in a number of cancer progression processes.[17]. Increased levels of bradykinins resulting from ACE inhibitor use have been associated with increased lung cancer risks[18] Bradykinins have been implicated in cell proliferation and migration in gastric cancers,[19] and bradykinin antagonists have been investigated as anti-cancer agents[20]. | https://www.wikidoc.org/index.php/Bradykinin | |
ea799aff2f81d78009f04445ef0a9e40f4309b20 | wikidoc | Bragg peak | Bragg peak
# Overview
The Bragg curve plots the energy loss of ionizing radiation during its travel through matter. For protons, α-rays, and other ion rays, there is a pronounced peak in the curve immediately before the particles come to rest. This is called Bragg peak, for William Henry Bragg who discovered it in 1903.
When a fast charged particle moves through matter, it ionizes particles and deposits a dose along its path. A peak occurs because the interaction cross section increases as the charged particle's energy decreases. In the figure to the right, it is the narrow peak of the native proton beam curve which is produced by a particle accelerator of 250 MeV.
The figure also shows the absorption of a beam of energetic photons which is entirely different in nature; the curve is mainly exponential.
The phenomenon is exploited in particle therapy of cancer, to concentrate the effect of light ion beams on the tumor being treated while minimizing the effect on the surrounding healthy tissue. The blue curve in the figure ("modified proton beam") shows how the originally monoenergetic proton beam with the sharp peak is widened by increasing the range of energies, so that a larger range of depths can be treated. This is typically achieved by using variable thickness attenuators: spinning wedges are often used.
de:Bragg-Kurve | Bragg peak
# Overview
The Bragg curve plots the energy loss of ionizing radiation during its travel through matter. For protons, α-rays, and other ion rays, there is a pronounced peak in the curve immediately before the particles come to rest. This is called Bragg peak, for William Henry Bragg who discovered it in 1903.
When a fast charged particle moves through matter, it ionizes particles and deposits a dose along its path. A peak occurs because the interaction cross section increases as the charged particle's energy decreases. In the figure to the right, it is the narrow peak of the native proton beam curve which is produced by a particle accelerator of 250 MeV.
The figure also shows the absorption of a beam of energetic photons which is entirely different in nature; the curve is mainly exponential.
The phenomenon is exploited in particle therapy of cancer, to concentrate the effect of light ion beams on the tumor being treated while minimizing the effect on the surrounding healthy tissue. The blue curve in the figure ("modified proton beam") shows how the originally monoenergetic proton beam with the sharp peak is widened by increasing the range of energies, so that a larger range of depths can be treated. This is typically achieved by using variable thickness attenuators: spinning wedges are often used.
de:Bragg-Kurve
Template:WS | https://www.wikidoc.org/index.php/Bragg_peak | |
72361c5e734cdfca7f2d0dc14f7efe546d68fe2a | wikidoc | Bretazenil | Bretazenil
Bretazenil is an anxiolytic drug which is derived from the benzodiazepine family, and was invented in 1988. It is most closely related in structure to the benzodiazepine antagonist flumazenil, although its effects are somewhat different.
Bretazenil was originally developed as an anti-anxiety drug, but never commercialised. It is a partial agonist for GABAA receptors in the brain. David Nutt from the University of Bristol has suggested bretazenil as a possible base from which to make a better social drug, as it displays several of the positive effects of alcohol intoxication such as relaxation and sociability, but without the bad effects such as aggression, amnesia, nausea, loss of coordination, liver disease and brain damage. The effects of bretazenil can also be quickly reversed by the action of flumazenil, which is used as an antidote to benzodiazepine overdose, in contrast to alcohol for which there is no effective and reliable antidote.
However, while less addictive than benzodiazepine full agonists such as diazepam, long-term use of bretazenil would still be expected to result in dependence and addiction. Bretazenil, were it to be made commercially available, would thus most likely be classed as a controlled substance, e.g. Schedule III or Schedule IV in the USA, and so is unlikely to ever be commercialised for recreational use in that country. More liberal jurisdictions however might potentially permit the sale of bretazenil as a recreational alternative to alcohol, especially in countries such as Russia where liver and brain damage from chronic alcohol abuse place a severe burden on the health service and so the potential advantages of a less toxic alternative drug might outweigh the complications of introducing a new recreational drug to the market. | Bretazenil
Bretazenil is an anxiolytic drug which is derived from the benzodiazepine family, and was invented in 1988. It is most closely related in structure to the benzodiazepine antagonist flumazenil, although its effects are somewhat different.
Bretazenil was originally developed as an anti-anxiety drug, but never commercialised. It is a partial agonist for GABAA receptors in the brain. David Nutt from the University of Bristol has suggested bretazenil as a possible base from which to make a better social drug, as it displays several of the positive effects of alcohol intoxication such as relaxation and sociability, but without the bad effects such as aggression, amnesia, nausea, loss of coordination, liver disease and brain damage. The effects of bretazenil can also be quickly reversed by the action of flumazenil, which is used as an antidote to benzodiazepine overdose,[1] in contrast to alcohol for which there is no effective and reliable antidote.
However, while less addictive than benzodiazepine full agonists such as diazepam[2], long-term use of bretazenil would still be expected to result in dependence and addiction. Bretazenil, were it to be made commercially available, would thus most likely be classed as a controlled substance, e.g. Schedule III or Schedule IV in the USA, and so is unlikely to ever be commercialised for recreational use in that country. More liberal jurisdictions however might potentially permit the sale of bretazenil as a recreational alternative to alcohol, especially in countries such as Russia where liver and brain damage from chronic alcohol abuse place a severe burden on the health service and so the potential advantages of a less toxic alternative drug might outweigh the complications of introducing a new recreational drug to the market. | https://www.wikidoc.org/index.php/Bretazenil | |
942a91ee449f7fa144cd8c497b99567420de80e1 | wikidoc | Brevetoxin | Brevetoxin
Brevetoxin, or brevetoxins, are a suite of cyclic polyether compounds produced naturally by a species of dinoflagellate known as Karenia brevis. Brevetoxins are neurotoxins that bind to voltage-gated sodium channels in nerve cells, leading to disruption of normal neurological processes and causing the illness clinically described as Neurotoxic Shellfish Poisoning (NSP).
Other Brevetoxins:
- Brevetoxin-5 (PbTx-5): like PbTx-3, but acetylated hydroxyl group in position 38.
- Brevetoxin-6 (PbTx-6): like PbTx-2, but double bond 27-28 is epoxidated.
Brevetoxin-2 was synthesized in 1995 by K.C. Nicolau and coworkers in 123 steps with 91% average yield (final yield ~9·10-6). | Brevetoxin
Brevetoxin, or brevetoxins, are a suite of cyclic polyether compounds produced naturally by a species of dinoflagellate known as Karenia brevis. Brevetoxins are neurotoxins that bind to voltage-gated sodium channels in nerve cells, leading to disruption of normal neurological processes and causing the illness clinically described as Neurotoxic Shellfish Poisoning (NSP).
Other Brevetoxins:
- Brevetoxin-5 (PbTx-5): like PbTx-3, but acetylated hydroxyl group in position 38.
- Brevetoxin-6 (PbTx-6): like PbTx-2, but double bond 27-28 is epoxidated.
Brevetoxin-2 was synthesized in 1995 by K.C. Nicolau and coworkers in 123 steps with 91% average yield (final yield ~9·10-6).[1] | https://www.wikidoc.org/index.php/Brevetoxin | |
5fcd2a2c67692ceb6ac7f819d2c2faa70e0e8ace | wikidoc | Brigatinib | Brigatinib
# Disclaimer
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# Overview
Brigatinib is a kinase inhibitor that is FDA approved for the treatment of anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) that has progressed on or is intolerant to crizotinib. Common adverse reactions include nausea, diarrhea, fatigue, cough, and headache.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Brigatinib is indicated for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib.
- This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
- The recommended dosing regimen for brigatinib is:
- 90 mg orally once daily for the first 7 days;
- If 90 mg is tolerated during the first 7 days, increase the dose to 180 mg orally once daily.
- Administer brigatinib until disease progression or unacceptable toxicity.
- If brigatinib is interrupted for 14 days or longer for reasons other than adverse reactions, resume treatment at 90 mg once daily for 7 days before increasing to the previously tolerated dose.
- Brigatinib may be taken with or without food. Instruct patients to swallow tablets whole. Do not crush or chew tablets.
- If a dose of brigatinib is missed or vomiting occurs after taking a dose, do not administer an additional dose and take the next dose of brigatinib at the scheduled time.
- Brigatinib dose modification levels are summarized in Table 1.
- Once reduced for adverse reactions, do not subsequently increase the dose of brigatinib. Permanently discontinue brigatinib if patients are unable to tolerate the 60 mg once daily dose.
- Recommendations for dose modifications of brigatinib for the management of adverse reactions are provided in Table 2.
- Avoid concomitant use of strong CYP3A inhibitors during treatment with brigatinib. If concomitant use of a strong CYP3A inhibitor cannot be avoided, reduce the brigatinib once daily dose by approximately 50% (i.e., from 180 mg to 90 mg, or from 90 mg to 60 mg). After discontinuation of a strong CYP3A inhibitor, resume the brigatinib dose that was tolerated prior to initiating the strong CYP3A inhibitor.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding brigatinib Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding brigatinib Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Brigatinib FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding brigatinib Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding brigatinib Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
- None
# Warnings
- Severe, life-threatening, and fatal pulmonary adverse reactions consistent with interstitial lung disease (ILD)/pneumonitis have occurred with brigatinib.
- In Trial ALTA (ALTA), ILD/pneumonitis occurred in 3.7% of patients in the 90 mg group (90 mg once daily) and 9.1% of patients in the 90→180 mg group (180 mg once daily with 7-day lead-in at 90 mg once daily).
- Adverse reactions consistent with possible ILD/pneumonitis occurred early (within 9 days of initiation of brigatinib; median onset was 2 days) in 6.4% of patients, with Grade 3 to 4 reactions occurring in 2.7%.
- Monitor for new or worsening respiratory symptoms (e.g., dyspnea, cough, etc.), particularly during the first week of initiating brigatinib. Withhold brigatinib in any patient with new or worsening respiratory symptoms, and promptly evaluate for ILD/pneumonitis or other causes of respiratory symptoms (e.g., pulmonary embolism, tumor progression, and infectious pneumonia). For Grade 1 or 2 ILD/pneumonitis, either resume brigatinib with dose reduction according to Table 1 after recovery to baseline or permanently discontinue brigatinib. Permanently discontinue brigatinib for Grade 3 or 4 ILD/pneumonitis or recurrence of Grade 1 or 2 ILD/pneumonitis.
- In ALTA, hypertension was reported in 11% of patients in the 90 mg group who received brigatinib and 21% of patients in the 90→180 mg group. Grade 3 hypertension occurred in 5.9% of patients overall.
- Control blood pressure prior to treatment with brigatinib. Monitor blood pressure after 2 weeks and at least monthly thereafter during treatment with brigatinib. Withhold brigatinib for Grade 3 hypertension despite optimal antihypertensive therapy. Upon resolution or improvement to Grade 1 severity, resume brigatinib at a reduced dose. Consider permanent discontinuation of treatment with brigatinib for Grade 4 hypertension or recurrence of Grade 3 hypertension.
- Use caution when administering brigatinib in combination with antihypertensive agents that cause bradycardia.
- Bradycardia can occur with brigatinib. In ALTA, heart rates less than 50 beats per minute (bpm) occurred in 5.7% of patients in the 90 mg group and 7.6% of patients in the 90→180 mg group. Grade 2 bradycardia occurred in 1 (0.9%) patient in the 90 mg group.
- Monitor heart rate and blood pressure during treatment with brigatinib. Monitor patients more frequently if concomitant use of drug known to cause bradycardia cannot be avoided.
- For symptomatic bradycardia, withhold brigatinib and review concomitant medications for those known to cause bradycardia. If a concomitant medication known to cause bradycardia is identified and discontinued or dose adjusted, resume brigatinib at the same dose following resolution of symptomatic bradycardia; otherwise, reduce the dose of brigatinib following resolution of symptomatic bradycardia. Discontinue brigatinib for life-threatening bradycardia if no contributing concomitant medication is identified.
- In ALTA, adverse reactions leading to visual disturbance including blurred vision, diplopia, and reduced visual acuity, were reported in 7.3% of patients receiving brigatinib in the 90 mg group and 10% of patients in the 90→180 mg group. Grade 3 macular edema and cataract occurred in one patient each in the 90→180 mg group.
- Advise patients to report any visual symptoms. Withhold brigatinib and obtain an ophthalmologic evaluation in patients with new or worsening visual symptoms of Grade 2 or greater severity. Upon recovery of Grade 2 or Grade 3 visual disturbances to Grade 1 severity or baseline, resume brigatinib at a reduced dose. Permanently discontinue treatment with brigatinib for Grade 4 visual disturbances.
- In ALTA, creatine phosphokinase (CPK) elevation occurred in 27% of patients receiving brigatinib in the 90 mg group and 48% of patients in the 90 mg→180 mg group. The incidence of Grade 3-4 CPK elevation was 2.8% in the 90 mg group and 12% in the 90→180 mg group.
- Dose reduction for CPK elevation occurred in 1.8% of patients in the 90 mg group and 4.5% in the 90→180 mg group.
- Advise patients to report any unexplained muscle pain, tenderness, or weakness. Monitor CPK levels during brigatinib treatment. Withhold brigatinib for Grade 3 or 4 CPK elevation. Upon resolution or recovery to Grade 1 or baseline, resume brigatinib at the same dose or at a reduced dose as described in Table 2.
- In ALTA, amylase elevation occurred in 27% of patients in the 90 mg group and 39% of patients in the 90→180 mg group. Lipase elevations occurred in 21% of patients in the 90 mg group and 45% of patients in the 90→180 mg group. Grade 3 or 4 amylase elevation occurred in 3.7% of patients in the 90 mg group and 2.7% of patients in the 90→180 mg group. Grade 3 or 4 lipase elevation occurred in 4.6% of patients in the 90 mg group and 5.5% of patients in the 90→180 mg group.
- Monitor lipase and amylase during treatment with brigatinib. Withhold brigatinib for Grade 3 or 4 pancreatic enzyme elevation. Upon resolution or recovery to Grade 1 or baseline, resume brigatinib at the same dose or at a reduced dose as described in Table 2.
- In ALTA, 43% of patients who received brigatinib experienced new or worsening hyperglycemia. Grade 3 hyperglycemia, based on laboratory assessment of serum fasting glucose levels, occurred in 3.7% of patients. Two of 20 (10%) patients with diabetes or glucose intolerance at baseline required initiation of insulin while receiving brigatinib.
- Assess fasting serum glucose prior to initiation of brigatinib and monitor periodically thereafter. Initiate or optimize anti-hyperglycemic medications as needed. If adequate hyperglycemic control cannot be achieved with optimal medical management, withhold brigatinib until adequate hyperglycemic control is achieved and consider reducing the dose of brigatinib as described in Table 1 or permanently discontinuing brigatinib.
- Based on its mechanism of action and findings in animals, brigatinib can cause fetal harm when administered to pregnant women. There are no clinical data on the use of brigatinib in pregnant women. Administration of brigatinib to pregnant rats during the period of organogenesis resulted in dose-related skeletal anomalies at doses as low as 12.5 mg/kg/day (approximately 0.7 times the human exposure by AUC at 180 mg once daily) as well as increased post implantation loss, malformations, and decreased fetal body weight at doses of 25 mg/kg/day (approximately 1.26 times the human exposure at 180 mg once daily) or higher.
- Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with brigatinib and for at least 4 months following the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment and for at least 3 months after the last dose of brigatinib.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- The safety of brigatinib was evaluated in 219 patients with locally advanced or metastatic ALK-positive non-small cell lung cancer (NSCLC) who received at least one dose of brigatinib in ALTA after experiencing disease progression on crizotinib. Patients received brigatinib 90 mg once daily continuously (90 mg group) or 90 mg once daily for 7 days followed by 180 mg once daily (90→180 mg group). The median duration of treatment was 7.5 months in the 90 mg group and 7.8 months in the 90→180 mg group. A total of 150 (68%) patients were exposed to brigatinib for greater than or equal to 6 months and 42 (19%) patients were exposed for greater than or equal to one year.
- The study population characteristics were: median age 54 years (range: 18 to 82), age less than 65 years (77%), female (57%), White (67%), Asian (31%), Stage IV disease (98%), NSCLC adenocarcinoma histology (97%), never or former smoker (95%), ECOG Performance Status (PS) 0 or 1 (93%), and brain metastases at baseline (69%).
- Serious adverse reactions occurred in 38% of patients in the 90 mg group and 40% of patients in the 90→180 mg group. The most common serious adverse reactions were pneumonia (5.5% overall, 3.7% in the 90 mg group, and 7.3% in the 90→180 mg group) and ILD/pneumonitis (4.6% overall, 1.8% in the 90 mg group and 7.3% in the 90→180 mg group). Fatal adverse reactions occurred in 3.7% of patients and consisted of pneumonia (2 patients), sudden death, dyspnea, respiratory failure, pulmonary embolism, bacterial meningitis and urosepsis (1 patient each).
- In ALTA, 2.8% of patients in the 90 mg group and 8.2% of patients in the 90→180 mg group permanently discontinued brigatinib for adverse reactions. The most frequent adverse reactions that led to discontinuation were ILD/pneumonitis (0.9% in the 90 mg group and 1.8% in the 90→180 mg group) and pneumonia (1.8% in the 90→180 mg group only).
- In ALTA, 14% of patients required a dose reduction due to adverse reactions (7.3% in the 90 mg group and 20% in the 90→180 mg group). The most common adverse reaction that led to dose reduction was increased creatine phosphokinase for both regimens (1.8% in the 90 mg group and 4.5% in the 90→180 mg group).
- Table 3 and Table 4 summarize the common adverse reactions and laboratory abnormalities observed in ALTA.
## Postmarketing Experience
There is limited information regarding Brigatinib Postmarketing Experience in the drug label.
# Drug Interactions
- Drugs That May Increase Brigatinib Plasma Concentrations (Strong CYP3A Inhibitors)
- Drugs That May Decrease Brigatinib Plasma Concentrations (Strong CYP3A Inducers)
- Drugs That May Have Their Plasma Concentrations Altered by Brigatinib (CYP3A Substrates)
- Coadministration of itraconazole, a strong CYP3A inhibitor, increased brigatinib plasma concentrations and may result in increased adverse reactions. Avoid the concomitant use of strong CYP3A inhibitors with brigatinib, including but not limited to certain antivirals (e.g., boceprevir, cobicistat, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir), macrolide antibiotics (e.g., clarithromycin), antifungals (e.g., itraconazole, ketoconazole, posaconazole, voriconazole), and conivaptan. Avoid grapefruit or grapefruit juice as it may also increase plasma concentrations of brigatinib. If concomitant use of a strong CYP3A inhibitor cannot be avoided, reduce the dose of brigatinib by approximately 50%.
- Coadministration of brigatinib with rifampin, a strong CYP3A inducer, decreased brigatinib plasma concentrations and may result in decreased efficacy. Avoid the concomitant use of strong CYP3A inducers with brigatinib, including but not limited to rifampin, carbamazepine, phenytoin, and St. John's Wort.
- Brigatinib induces CYP3A in vitro and may decrease concentrations of CYP3A substrates. Coadministration of brigatinib with CYP3A substrates, including hormonal contraceptives, can result in decreased concentrations and loss of efficacy of CYP3A substrates.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
### Risk Summary
- Based on its mechanism of action and findings in animals, brigatinib can cause fetal harm when administered to a pregnant woman. There are no clinical data on the use of brigatinib in pregnant women. Administration of brigatinib to pregnant rats during the period of organogenesis resulted in dose-related skeletal anomalies at doses as low as 12.5 mg/kg/day (approximately 0.7 times the human exposure by AUC at 180 mg once daily) as well as increased post-implantation loss, malformations, and decreased fetal body weight at doses of 25 mg/kg/day (approximately 1.26 times the human exposure at 180 mg once daily) or greater. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the potential risk to a fetus.
- In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
### Data (Animal)
- In an embryo-fetal development study in which pregnant rats were administered daily doses of brigatinib during organogenesis, dose-related skeletal (incomplete ossification, small incisors) and visceral anomalies were observed at doses as low as 12.5 mg/kg/day (approximately 0.7 times the human exposure by AUC at 180 mg once daily). Malformations observed at 25 mg/kg/day (approximately 1.26 times the human AUC at 180 mg once daily) included anasarca (generalized subcutaneous edema), anophthalmia (absent eyes), forelimb hyperflexion, small, short and/or bent limbs, multiple fused ribs, bent scapulae, omphalocele (intestine protruding into umbilicus), and gastroschisis (intestines protruding through a defect in the abdominal wall) along with visceral findings of moderate bilateral dilatation of the lateral ventricles.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Brigatinib in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Brigatinib during labor and delivery.
### Nursing Mothers
- There are no data regarding the secretion of brigatinib in human milk or its effects on the breastfed infant or milk production. Because of the potential for adverse reactions in breastfed infants, advise lactating women not to breastfeed during treatment with brigatinib and for 1 week following the final dose.
### Pediatric Use
- The safety and efficacy of brigatinib in pediatric patients have not been established.
### Geriatic Use
- Clinical studies of brigatinib did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients. Of the 222 patients in ALTA, 19.4% were 65-74 years and 4.1% were 75 years or older. No clinically relevant differences in safety or efficacy were observed between patients ≥65 years and younger patients.
### Gender
There is no FDA guidance on the use of Brigatinib with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Brigatinib with respect to specific racial populations.
### Renal Impairment
- No dose adjustment is recommended for patients with mild and moderate renal impairment . The pharmacokinetics and safety of brigatinib in patients with severe renal impairment (CLcr 15 to 29 mL/min estimated by Cockcroft-Gault) have not been studied.
### Hepatic Impairment
- No dose adjustment is recommended for patients with mild hepatic impairment (total bilirubin within upper limit of normal and AST greater than ULN or total bilirubin greater than 1 and up to 1.5 times ULN and any AST). The pharmacokinetics and safety of brigatinib in patients with moderate or severe hepatic impairment have not been studied.
### Females of Reproductive Potential and Males
Contraception (Females)
- Advise females of reproductive potential to use effective non-hormonal contraception during treatment with brigatinib and for at least 4 months after the final dose. Counsel patients to use a non-hormonal method of contraception since brigatinib can render some hormonal contraceptives ineffective.
Infertility (Males)
- Because of the potential for genotoxicity, advise males with female partners of reproductive potential to use effective contraception during treatment with brigatinib and for at least 3 months after the final dose.
- Based on findings in male reproductive organs in animals, brigatinib may cause reduced fertility in males.
### Immunocompromised Patients
There is no FDA guidance one the use of Brigatinib in patients who are immunocompromised.
# Administration and Monitoring
### Administration
### Oral
- May be taken with or without food.
- Swallow tablets whole; do not crush or chew.
- Missed dose: If a dose is missed or vomiting occurs after taking a dose, do not administer an additional dose; take the next dose at its scheduled time.
### Monitoring
- Tumor response may indicate efficacy.
- Creatine phosphokinase (CPK) levels: Regularly during treatment.
- Lipase and amylase levels: Regularly during treatment.
- Fasting serum glucose: Prior to initiation and regularly during treatment.
- New or worsening respiratory symptoms (eg, dyspnea, cough): Especially during the first week of treatment.
- Blood pressure: 2 weeks after initiation and at least monthly thereafter during use.
- Heart rate: Regularly throughout treatment, and more frequently in patients requiring concomitant therapy known to cause bradycardia.
- Ophthalmologic evaluation: Upon patient report of new or worsening visual disturbance.
# IV Compatibility
There is limited information regarding the compatibility of Brigatinib and IV administrations.
# Overdosage
There is limited information regarding Brigatinib overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
- Brigatinib is a tyrosine kinase inhibitor with in vitro activity at clinically achievable concentrations against multiple kinases including ALK, ROS1, insulin-like growth factor-1 receptor (IGF-1R), and FLT-3 as well as EGFR deletion and point mutations. Brigatinib inhibited autophosphorylation of ALK and ALK-mediated phosphorylation of the downstream signaling proteins STAT3, AKT, ERK1/2, and S6 in in vitro and in vivo assays. Brigatinib also inhibited the in vitro proliferation of cell lines expressing EML4-ALK and NPM-ALK fusion proteins and demonstrated dose-dependent inhibition of EML4-ALK-positive NSCLC xenograft growth in mice.
- At clinically achievable concentrations (≤ 500 nM), brigatinib inhibited the in vitro viability of cells expressing EML4-ALK and 17 mutant forms associated with resistance to ALK inhibitors including crizotinib, as well as EGFR-Del (E746-A750), ROS1-L2026M, FLT3-F691L, and FLT3-D835Y. Brigatinib exhibited in vivo anti-tumor activity against 4 mutant forms of EML4-ALK, including G1202R and L1196M mutants identified in NSCLC tumors in patients who have progressed on crizotinib. Brigatinib also reduced tumor burden and prolonged survival in mice implanted intracranially with an ALK-driven tumor cell line.
## Structure
## Pharmacodynamics
- Brigatinib exposure-response relationships and the time course of the pharmacodynamic response are unknown.
### Cardiac Electrophysiology
- The QT interval prolongation potential of brigatinib was assessed in 123 patients following once daily brigatinib doses of 30 mg (1/6th of the approved 180 mg dose) to 240 mg (1.3 times the approved 180 mg dose). Brigatinib did not prolong the QT interval to a clinically relevant extent.
## Pharmacokinetics
- The geometric mean (CV%) steady-state maximum concentration (Cmax) of brigatinib at brigatinib doses of 90 mg and 180 mg once daily was 552 (65%) ng/mL and 1452 (60%) ng/mL, respectively, and the corresponding area under the concentration-time curve (AUC0-Tau) was 8165 (57%) ng∙h/mL and 20276 (56%) ng∙h/mL. After a single dose and repeat dosing of brigatinib, systemic exposure of brigatinib was dose proportional over the dose range of 60 mg (0.3 times the approved 180 mg dose) to 240 mg (1.3 times the approved 180 mg dose) once daily. The mean accumulation ratio after repeat dosing was 1.9 to 2.4.
### Absorption
- Following administration of single oral doses of brigatinib of 30 to 240 mg, the median time to peak concentration (Tmax) ranged from 1 to 4 hours.
Effect of Food
- Brigatinib Cmax was reduced by 13% with no effect on AUC in healthy subjects administered brigatinib after a high fat meal (approximately 920 calories, 58 grams carbohydrate, 59 grams fat and 40 grams protein) compared to the Cmax and AUC after overnight fasting.
### Distribution
- Brigatinib is 66% bound to human plasma proteins and the binding is not concentration-dependent in vitro. The blood-to-plasma concentration ratio is 0.69. Following oral administration of brigatinib 180 mg once daily, the mean apparent volume of distribution (Vz/F) of brigatinib at steady-state was 153 L.
### Elimination
- Following oral administration of brigatinib 180 mg once daily, the mean apparent oral clearance (CL/F) of brigatinib at steady-state is 12.7 L/h and the mean plasma elimination half-life is 25 hours.
Metabolism
- Brigatinib is primarily metabolized by CYP2C8 and CYP3A4 in vitro. Following oral administration of a single 180 mg dose of radiolabeled brigatinib to healthy subjects, N-demethylation and cysteine conjugation were the two major metabolic pathways. Unchanged brigatinib (92%) and its primary metabolite, AP26123 (3.5%), were the major circulating radioactive components. The steady-state AUC of AP26123 was less than 10% of AUC of brigatinib exposure in patients. The metabolite, AP26123, inhibited ALK with approximately 3-fold lower potency than brigatinib in vitro.
Excretion
- Following oral administration of a single 180 mg dose of radiolabeled brigatinib to healthy subjects, 65% of the administered dose was recovered in feces and 25% of the administered dose was recovered in urine. Unchanged brigatinib represented 41% and 86% of the total radioactivity in feces and urine, respectively.
### Specific Populations
- Age, race, sex, body weight, and albumin concentration have no clinically meaningful effect on the pharmacokinetics of brigatinib.
Hepatic Impairment
- As hepatic elimination is a major route of excretion for brigatinib, hepatic impairment may result in increased plasma brigatinib concentrations. Based on a population pharmacokinetic analysis, brigatinib exposures were similar between 49 subjects with mild hepatic impairment (total bilirubin within upper limit of normal and AST greater than ULN or total bilirubin greater than 1 and up to 1.5 times ULN and any AST) and 377 subjects with normal hepatic function (total bilirubin and AST within ULN). The pharmacokinetics of brigatinib in patients with moderate (total bilirubin greater than 1.5 and up to 3.0 times ULN and any AST) to severe (total bilirubin greater than 3.0 times ULN and any AST) hepatic impairment has not been studied.
Renal Impairment
Based on a population pharmacokinetic analysis, brigatinib exposures were similar among 125 subjects with mild renal impairment (CLcr 60 to less than 90 mL/min), 34 subjects with moderate renal impairment (CLcr 30 to less than 60 mL/min) and 270 subjects with normal renal function (CLcr greater than or equal to 90 mL/min), suggesting that no dose adjustment is necessary in patients with mild to moderate renal impairment. Patients with severe renal impairment (CLcr less than 30 mL/min) were not included in clinical trials.
### Drug Interactions
Effects of Other Drugs on Brigatinib
- Strong CYP3A Inhibitors: Coadministration of 200 mg twice daily doses of itraconazole (a strong CYP3A inhibitor) with a single 90 mg dose of brigatinib increased brigatinib Cmax by 21% and AUC0-INF by 101%, relative to a 90 mg dose of brigatinib administered alone.
- Strong CYP2C8 Inhibitors: Coadministration of 600 mg twice daily doses of gemfibrozil (a strong CYP2C8 inhibitor) with a single 90 mg dose of brigatinib decreased brigatinib Cmax by 41% and AUC0-INF by 12%, relative to a 90 mg dose of brigatinib administered alone. The effect of gemfibrozil on the pharmacokinetics of brigatinib is not clinically meaningful and the underlying mechanism for the decreased exposure of brigatinib is unknown.
- Strong CYP3A Inducers: Coadministration of 600 mg daily doses of rifampin (a strong CYP3A inducer) with a single 180 mg dose of brigatinib decreased brigatinib Cmax by 60% and AUC0-INF by 80%, relative to a 180 mg dose of brigatinib administered alone.
- P-gp and BCRP Inhibitors: In vitro studies suggest that brigatinib is a substrate of the efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Given that brigatinib exhibits high solubility and high permeability in vitro, P-gp and BCRP inhibitors are unlikely to increase plasma concentrations of brigatinib.
- Other Transporters: Brigatinib is not a substrate of organic anion transporting polypeptide (OATP1B1, OATP1B3), organic anion transporter (OAT1, OAT3), organic cation transporter (OCT1, OCT2), multidrug and toxin extrusion protein (MATE1, MATE2K), or bile salt export pump (BSEP).
Effects of Brigatinib on Other Drugs
- Transporter Substrates: Brigatinib is an inhibitor of P-gp, BCRP, OCT1, MATE1, and MATE2K in vitro. Therefore, brigatinib may have the potential to increase concentrations of coadministered substrates of these transporters. Brigatinib at clinically relevant concentrations did not inhibit OATP1B1, OATP1B3, OAT1, OAT3, OCT2 or BSEP.
- CYP Substrates: Brigatinib and its primary metabolite, AP26123, did not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4/5 at clinically relevant concentrations.
- Brigatinib, at clinically relevant plasma concentrations, induced CYP3A via activation of the pregnane X receptor (PXR). Brigatinib may also induce CYP2C enzymes via the same mechanism at clinically relevant concentrations.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
- Carcinogenicity studies have not been performed with brigatinib.
- Treatment with brigatinib resulted in chromosomal damage in an in vivo mammalian erythrocyte micronucleus in the rat, but was not mutagenic in the Ames or in vitro mammalian chromosome aberration tests.
- Dedicated animal fertility studies were not conducted with brigatinib. Testicular toxicity was observed in repeat-dose animal studies at doses resulting in exposure as low as 0.2 times the exposure in patients at the 180 mg dose. In rats, findings included lower weight of testes, seminal vesicles and prostate gland, and testicular tubular degeneration; these effects were not reversible during the 2-month recovery period. In monkeys, findings included reduced size of testes along with microscopic evidence of hypospermatogenesis; these effects were reversible during the recovery period.
# Clinical Studies
- The efficacy of brigatinib was demonstrated in a two-arm, open-label, multicenter trial (ALTA, NCT02094573) in adult patients with locally advanced or metastatic ALK-positive non-small cell lung cancer (NSCLC) who had progressed on crizotinib. The study required patients to have a documented ALK rearrangement based on an FDA-approved test or a different test with adequate archival tissue to confirm ALK arrangement by the Vysis® ALK Break-Apart fluorescence in situ hybridization (FISH) Probe Kit test. Key eligibility criteria included an ECOG Performance Status of 0-2 and progression on crizotinib. Neurologically stable patients with central nervous system (CNS) metastases were permitted to enroll. Patients with a history of interstitial lung disease or drug-related pneumonitis or who had received crizotinib within 3 days of the first dose of brigatinib were excluded. The major efficacy outcome measure was confirmed overall response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) as evaluated by an Independent Review Committee (IRC). Additional efficacy outcome measures included Investigator-assessed ORR, duration of response (DOR), intracranial ORR, and intracranial DOR.
- A total of 222 patients were randomized to receive brigatinib either 90 mg once daily (90 mg arm; n=112) or 180 mg once daily following a 7-day lead-in at 90 mg once daily (90→180 mg arm; n=110). Randomization was stratified by brain metastases (present versus absent) and best prior response to crizotinib (complete or partial response versus any other response/unevaluable).
- Baseline demographic characteristics of the overall study population were: median age 54 years (range 18 to 82, 23% 65 and over), 67% White and 31% Asian, 57% female, 36% ECOG PS 0 and 57% ECOG PS 1, and 95% never or former smokers. The disease characteristics of the overall study population were: Stage IV disease in 98%, adenocarcinoma histology in 97%, prior systemic chemotherapy in 74%, metastatic disease to the brain in 69% (61% had received prior radiation to the brain), bone metastases in 39%, and liver metastases in 26% of patients. Sixty-four percent of patients had an objective response to prior crizotinib.
- The median duration of follow-up was 8 months (range: 0.1-20.2). Efficacy results from ALTA are summarized in Table 5.
- IRC assessment of intracranial ORR and intracranial DOR according to RECIST v1.1 in the subgroup of 44 patients with measurable brain metastases (≥10 mm in longest diameter) at baseline are summarized in Table 6. Duration of intracranial response was measured from date of first intracranial response until intracranial disease progression (new lesions, intracranial target lesion diameter growth ≥20% from nadir, or unequivocal progression of intracranial non-target lesions) or death.
- Among the 23 patients who exhibited an intracranial response, 78% of patients in the 90 mg arm and 68% of patients in the 90→180 mg arm maintained a response for at least 4 months.
# How Supplied
- 30 mg tablets: round, white to off-white film-coated tablet with "U3" debossed on one side and plain on the other side; available in:
- Bottles of 21 tablets (NDC 76189-113-21)
- Bottles of 180 tablets (NDC 76189-113-18)
- 90 mg tablets: oval, white to off-white film-coated tablet with "U7" debossed on one side and plain on the other side; available in:
- Bottles of 7 tablets (NDC 76189-119-07)
- Bottles of 30 tablets (NDC 76189-119-30)
## Storage
- Store at controlled room temperature 20°C to 25°C (68°F to 77°F); excursion permitted between 15°C to 30°C (59°F to 86°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
### Interstitial Lung Disease (ILD)/Pneumonitis
- Inform patients of the symptoms and risks of serious pulmonary adverse reactions such as ILD/pneumonitis. Advise patients to immediately report any new or worsening respiratory symptoms
### Hypertension
- Advise patients of risks of hypertension and to promptly report signs or symptoms of hypertension.
### Bradycardia
- Advise patients to report any symptoms of bradycardia and to inform their healthcare provider about the use of heart and blood pressure medications.
### Visual Disturbance
- Advise patients to inform their healthcare provider of any new or worsening vision symptoms.
### Creatine Phosphokinase (CPK) Elevation
- Inform patients of the signs and symptoms of creatinine phosphokinase (CPK) elevation and the need for monitoring during treatment. Advise patients to inform their healthcare provider of any new or worsening symptoms of unexplained muscle pain, tenderness, or weakness.
### Pancreatic Enzyme Elevation
- Inform patients of the signs and symptoms of pancreatitis and the need to monitor for amylase and lipase elevations during treatment.
### Hyperglycemia
- Inform patients of the risks of new or worsening hyperglycemia and the need to periodically monitor glucose levels. Advise patients with diabetes mellitus or glucose intolerance that anti-hyperglycemic medications may need to be adjusted during treatment with brigatinib.
### Females and Males of Reproductive Potential
Embryo-Fetal Toxicity
- Advise females and males of reproductive potential that brigatinib can cause fetal harm.
- Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy and to use effective non-hormonal contraception during treatment with brigatinib and for at least 4 months after the final dose.
- Advise males with female partners of reproductive potential to use effective contraception during treatment with brigatinib and for at least 3 months after the final dose.
Lactation
- Advise females not to breastfeed during treatment with brigatinib and for at least 1 week following the final dose.
Infertility
- Advise males of reproductive potential of the potential for reduced fertility from brigatinib.
### Drug Interactions
- Advise patients to inform their health care provider of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products. Inform patients to avoid grapefruit or grapefruit juice while taking brigatinib.
### Dosing and Administration
- Instruct patients to start with 90 mg of brigatinib once daily for the first 7 days and if tolerated, increase the dose to 180 mg once daily. Advise patients to take brigatinib with or without food.
### Missed Dose
- Advise patients that if a dose of brigatinib is missed or if the patient vomits after taking a dose of brigatinib, not to take an extra dose, but to take the next dose at the regular time.
# Precautions with Alcohol
Alcohol-Brigatinib interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
- Alunbrig
# Look-Alike Drug Names
There is limited information regarding Brigatinib Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | Brigatinib
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yashasvi Aryaputra[2], Anmol Pitliya, M.B.B.S. M.D.[3]
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# Overview
Brigatinib is a kinase inhibitor that is FDA approved for the treatment of anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) that has progressed on or is intolerant to crizotinib. Common adverse reactions include nausea, diarrhea, fatigue, cough, and headache.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Brigatinib is indicated for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib.
- This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
- The recommended dosing regimen for brigatinib is:
- 90 mg orally once daily for the first 7 days;
- If 90 mg is tolerated during the first 7 days, increase the dose to 180 mg orally once daily.
- Administer brigatinib until disease progression or unacceptable toxicity.
- If brigatinib is interrupted for 14 days or longer for reasons other than adverse reactions, resume treatment at 90 mg once daily for 7 days before increasing to the previously tolerated dose.
- Brigatinib may be taken with or without food. Instruct patients to swallow tablets whole. Do not crush or chew tablets.
- If a dose of brigatinib is missed or vomiting occurs after taking a dose, do not administer an additional dose and take the next dose of brigatinib at the scheduled time.
- Brigatinib dose modification levels are summarized in Table 1.
- Once reduced for adverse reactions, do not subsequently increase the dose of brigatinib. Permanently discontinue brigatinib if patients are unable to tolerate the 60 mg once daily dose.
- Recommendations for dose modifications of brigatinib for the management of adverse reactions are provided in Table 2.
- Avoid concomitant use of strong CYP3A inhibitors during treatment with brigatinib. If concomitant use of a strong CYP3A inhibitor cannot be avoided, reduce the brigatinib once daily dose by approximately 50% (i.e., from 180 mg to 90 mg, or from 90 mg to 60 mg). After discontinuation of a strong CYP3A inhibitor, resume the brigatinib dose that was tolerated prior to initiating the strong CYP3A inhibitor.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding brigatinib Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding brigatinib Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Brigatinib FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding brigatinib Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding brigatinib Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
- None
# Warnings
- Severe, life-threatening, and fatal pulmonary adverse reactions consistent with interstitial lung disease (ILD)/pneumonitis have occurred with brigatinib.
- In Trial ALTA (ALTA), ILD/pneumonitis occurred in 3.7% of patients in the 90 mg group (90 mg once daily) and 9.1% of patients in the 90→180 mg group (180 mg once daily with 7-day lead-in at 90 mg once daily).
- Adverse reactions consistent with possible ILD/pneumonitis occurred early (within 9 days of initiation of brigatinib; median onset was 2 days) in 6.4% of patients, with Grade 3 to 4 reactions occurring in 2.7%.
- Monitor for new or worsening respiratory symptoms (e.g., dyspnea, cough, etc.), particularly during the first week of initiating brigatinib. Withhold brigatinib in any patient with new or worsening respiratory symptoms, and promptly evaluate for ILD/pneumonitis or other causes of respiratory symptoms (e.g., pulmonary embolism, tumor progression, and infectious pneumonia). For Grade 1 or 2 ILD/pneumonitis, either resume brigatinib with dose reduction according to Table 1 after recovery to baseline or permanently discontinue brigatinib. Permanently discontinue brigatinib for Grade 3 or 4 ILD/pneumonitis or recurrence of Grade 1 or 2 ILD/pneumonitis.
- In ALTA, hypertension was reported in 11% of patients in the 90 mg group who received brigatinib and 21% of patients in the 90→180 mg group. Grade 3 hypertension occurred in 5.9% of patients overall.
- Control blood pressure prior to treatment with brigatinib. Monitor blood pressure after 2 weeks and at least monthly thereafter during treatment with brigatinib. Withhold brigatinib for Grade 3 hypertension despite optimal antihypertensive therapy. Upon resolution or improvement to Grade 1 severity, resume brigatinib at a reduced dose. Consider permanent discontinuation of treatment with brigatinib for Grade 4 hypertension or recurrence of Grade 3 hypertension.
- Use caution when administering brigatinib in combination with antihypertensive agents that cause bradycardia.
- Bradycardia can occur with brigatinib. In ALTA, heart rates less than 50 beats per minute (bpm) occurred in 5.7% of patients in the 90 mg group and 7.6% of patients in the 90→180 mg group. Grade 2 bradycardia occurred in 1 (0.9%) patient in the 90 mg group.
- Monitor heart rate and blood pressure during treatment with brigatinib. Monitor patients more frequently if concomitant use of drug known to cause bradycardia cannot be avoided.
- For symptomatic bradycardia, withhold brigatinib and review concomitant medications for those known to cause bradycardia. If a concomitant medication known to cause bradycardia is identified and discontinued or dose adjusted, resume brigatinib at the same dose following resolution of symptomatic bradycardia; otherwise, reduce the dose of brigatinib following resolution of symptomatic bradycardia. Discontinue brigatinib for life-threatening bradycardia if no contributing concomitant medication is identified.
- In ALTA, adverse reactions leading to visual disturbance including blurred vision, diplopia, and reduced visual acuity, were reported in 7.3% of patients receiving brigatinib in the 90 mg group and 10% of patients in the 90→180 mg group. Grade 3 macular edema and cataract occurred in one patient each in the 90→180 mg group.
- Advise patients to report any visual symptoms. Withhold brigatinib and obtain an ophthalmologic evaluation in patients with new or worsening visual symptoms of Grade 2 or greater severity. Upon recovery of Grade 2 or Grade 3 visual disturbances to Grade 1 severity or baseline, resume brigatinib at a reduced dose. Permanently discontinue treatment with brigatinib for Grade 4 visual disturbances.
- In ALTA, creatine phosphokinase (CPK) elevation occurred in 27% of patients receiving brigatinib in the 90 mg group and 48% of patients in the 90 mg→180 mg group. The incidence of Grade 3-4 CPK elevation was 2.8% in the 90 mg group and 12% in the 90→180 mg group.
- Dose reduction for CPK elevation occurred in 1.8% of patients in the 90 mg group and 4.5% in the 90→180 mg group.
- Advise patients to report any unexplained muscle pain, tenderness, or weakness. Monitor CPK levels during brigatinib treatment. Withhold brigatinib for Grade 3 or 4 CPK elevation. Upon resolution or recovery to Grade 1 or baseline, resume brigatinib at the same dose or at a reduced dose as described in Table 2.
- In ALTA, amylase elevation occurred in 27% of patients in the 90 mg group and 39% of patients in the 90→180 mg group. Lipase elevations occurred in 21% of patients in the 90 mg group and 45% of patients in the 90→180 mg group. Grade 3 or 4 amylase elevation occurred in 3.7% of patients in the 90 mg group and 2.7% of patients in the 90→180 mg group. Grade 3 or 4 lipase elevation occurred in 4.6% of patients in the 90 mg group and 5.5% of patients in the 90→180 mg group.
- Monitor lipase and amylase during treatment with brigatinib. Withhold brigatinib for Grade 3 or 4 pancreatic enzyme elevation. Upon resolution or recovery to Grade 1 or baseline, resume brigatinib at the same dose or at a reduced dose as described in Table 2.
- In ALTA, 43% of patients who received brigatinib experienced new or worsening hyperglycemia. Grade 3 hyperglycemia, based on laboratory assessment of serum fasting glucose levels, occurred in 3.7% of patients. Two of 20 (10%) patients with diabetes or glucose intolerance at baseline required initiation of insulin while receiving brigatinib.
- Assess fasting serum glucose prior to initiation of brigatinib and monitor periodically thereafter. Initiate or optimize anti-hyperglycemic medications as needed. If adequate hyperglycemic control cannot be achieved with optimal medical management, withhold brigatinib until adequate hyperglycemic control is achieved and consider reducing the dose of brigatinib as described in Table 1 or permanently discontinuing brigatinib.
- Based on its mechanism of action and findings in animals, brigatinib can cause fetal harm when administered to pregnant women. There are no clinical data on the use of brigatinib in pregnant women. Administration of brigatinib to pregnant rats during the period of organogenesis resulted in dose-related skeletal anomalies at doses as low as 12.5 mg/kg/day (approximately 0.7 times the human exposure by AUC at 180 mg once daily) as well as increased post implantation loss, malformations, and decreased fetal body weight at doses of 25 mg/kg/day (approximately 1.26 times the human exposure at 180 mg once daily) or higher.
- Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with brigatinib and for at least 4 months following the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment and for at least 3 months after the last dose of brigatinib.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- The safety of brigatinib was evaluated in 219 patients with locally advanced or metastatic ALK-positive non-small cell lung cancer (NSCLC) who received at least one dose of brigatinib in ALTA after experiencing disease progression on crizotinib. Patients received brigatinib 90 mg once daily continuously (90 mg group) or 90 mg once daily for 7 days followed by 180 mg once daily (90→180 mg group). The median duration of treatment was 7.5 months in the 90 mg group and 7.8 months in the 90→180 mg group. A total of 150 (68%) patients were exposed to brigatinib for greater than or equal to 6 months and 42 (19%) patients were exposed for greater than or equal to one year.
- The study population characteristics were: median age 54 years (range: 18 to 82), age less than 65 years (77%), female (57%), White (67%), Asian (31%), Stage IV disease (98%), NSCLC adenocarcinoma histology (97%), never or former smoker (95%), ECOG Performance Status (PS) 0 or 1 (93%), and brain metastases at baseline (69%).
- Serious adverse reactions occurred in 38% of patients in the 90 mg group and 40% of patients in the 90→180 mg group. The most common serious adverse reactions were pneumonia (5.5% overall, 3.7% in the 90 mg group, and 7.3% in the 90→180 mg group) and ILD/pneumonitis (4.6% overall, 1.8% in the 90 mg group and 7.3% in the 90→180 mg group). Fatal adverse reactions occurred in 3.7% of patients and consisted of pneumonia (2 patients), sudden death, dyspnea, respiratory failure, pulmonary embolism, bacterial meningitis and urosepsis (1 patient each).
- In ALTA, 2.8% of patients in the 90 mg group and 8.2% of patients in the 90→180 mg group permanently discontinued brigatinib for adverse reactions. The most frequent adverse reactions that led to discontinuation were ILD/pneumonitis (0.9% in the 90 mg group and 1.8% in the 90→180 mg group) and pneumonia (1.8% in the 90→180 mg group only).
- In ALTA, 14% of patients required a dose reduction due to adverse reactions (7.3% in the 90 mg group and 20% in the 90→180 mg group). The most common adverse reaction that led to dose reduction was increased creatine phosphokinase for both regimens (1.8% in the 90 mg group and 4.5% in the 90→180 mg group).
- Table 3 and Table 4 summarize the common adverse reactions and laboratory abnormalities observed in ALTA.
## Postmarketing Experience
There is limited information regarding Brigatinib Postmarketing Experience in the drug label.
# Drug Interactions
- Drugs That May Increase Brigatinib Plasma Concentrations (Strong CYP3A Inhibitors)
- Drugs That May Decrease Brigatinib Plasma Concentrations (Strong CYP3A Inducers)
- Drugs That May Have Their Plasma Concentrations Altered by Brigatinib (CYP3A Substrates)
- Coadministration of itraconazole, a strong CYP3A inhibitor, increased brigatinib plasma concentrations and may result in increased adverse reactions. Avoid the concomitant use of strong CYP3A inhibitors with brigatinib, including but not limited to certain antivirals (e.g., boceprevir, cobicistat, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir), macrolide antibiotics (e.g., clarithromycin), antifungals (e.g., itraconazole, ketoconazole, posaconazole, voriconazole), and conivaptan. Avoid grapefruit or grapefruit juice as it may also increase plasma concentrations of brigatinib. If concomitant use of a strong CYP3A inhibitor cannot be avoided, reduce the dose of brigatinib by approximately 50%.
- Coadministration of brigatinib with rifampin, a strong CYP3A inducer, decreased brigatinib plasma concentrations and may result in decreased efficacy. Avoid the concomitant use of strong CYP3A inducers with brigatinib, including but not limited to rifampin, carbamazepine, phenytoin, and St. John's Wort.
- Brigatinib induces CYP3A in vitro and may decrease concentrations of CYP3A substrates. Coadministration of brigatinib with CYP3A substrates, including hormonal contraceptives, can result in decreased concentrations and loss of efficacy of CYP3A substrates.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
### Risk Summary
- Based on its mechanism of action and findings in animals, brigatinib can cause fetal harm when administered to a pregnant woman. There are no clinical data on the use of brigatinib in pregnant women. Administration of brigatinib to pregnant rats during the period of organogenesis resulted in dose-related skeletal anomalies at doses as low as 12.5 mg/kg/day (approximately 0.7 times the human exposure by AUC at 180 mg once daily) as well as increased post-implantation loss, malformations, and decreased fetal body weight at doses of 25 mg/kg/day (approximately 1.26 times the human exposure at 180 mg once daily) or greater. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the potential risk to a fetus.
- In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
### Data (Animal)
- In an embryo-fetal development study in which pregnant rats were administered daily doses of brigatinib during organogenesis, dose-related skeletal (incomplete ossification, small incisors) and visceral anomalies were observed at doses as low as 12.5 mg/kg/day (approximately 0.7 times the human exposure by AUC at 180 mg once daily). Malformations observed at 25 mg/kg/day (approximately 1.26 times the human AUC at 180 mg once daily) included anasarca (generalized subcutaneous edema), anophthalmia (absent eyes), forelimb hyperflexion, small, short and/or bent limbs, multiple fused ribs, bent scapulae, omphalocele (intestine protruding into umbilicus), and gastroschisis (intestines protruding through a defect in the abdominal wall) along with visceral findings of moderate bilateral dilatation of the lateral ventricles.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Brigatinib in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Brigatinib during labor and delivery.
### Nursing Mothers
- There are no data regarding the secretion of brigatinib in human milk or its effects on the breastfed infant or milk production. Because of the potential for adverse reactions in breastfed infants, advise lactating women not to breastfeed during treatment with brigatinib and for 1 week following the final dose.
### Pediatric Use
- The safety and efficacy of brigatinib in pediatric patients have not been established.
### Geriatic Use
- Clinical studies of brigatinib did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients. Of the 222 patients in ALTA, 19.4% were 65-74 years and 4.1% were 75 years or older. No clinically relevant differences in safety or efficacy were observed between patients ≥65 years and younger patients.
### Gender
There is no FDA guidance on the use of Brigatinib with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Brigatinib with respect to specific racial populations.
### Renal Impairment
- No dose adjustment is recommended for patients with mild and moderate renal impairment [creatinine clearance (CLcr) 30 to 89 mL/min estimated by Cockcroft-Gault)]. The pharmacokinetics and safety of brigatinib in patients with severe renal impairment (CLcr 15 to 29 mL/min estimated by Cockcroft-Gault) have not been studied.
### Hepatic Impairment
- No dose adjustment is recommended for patients with mild hepatic impairment (total bilirubin within upper limit of normal [ULN] and AST greater than ULN or total bilirubin greater than 1 and up to 1.5 times ULN and any AST). The pharmacokinetics and safety of brigatinib in patients with moderate or severe hepatic impairment have not been studied.
### Females of Reproductive Potential and Males
Contraception (Females)
- Advise females of reproductive potential to use effective non-hormonal contraception during treatment with brigatinib and for at least 4 months after the final dose. Counsel patients to use a non-hormonal method of contraception since brigatinib can render some hormonal contraceptives ineffective.
Infertility (Males)
- Because of the potential for genotoxicity, advise males with female partners of reproductive potential to use effective contraception during treatment with brigatinib and for at least 3 months after the final dose.
- Based on findings in male reproductive organs in animals, brigatinib may cause reduced fertility in males.
### Immunocompromised Patients
There is no FDA guidance one the use of Brigatinib in patients who are immunocompromised.
# Administration and Monitoring
### Administration
### Oral
- May be taken with or without food.
- Swallow tablets whole; do not crush or chew.
- Missed dose: If a dose is missed or vomiting occurs after taking a dose, do not administer an additional dose; take the next dose at its scheduled time.
### Monitoring
- Tumor response may indicate efficacy.
- Creatine phosphokinase (CPK) levels: Regularly during treatment.
- Lipase and amylase levels: Regularly during treatment.
- Fasting serum glucose: Prior to initiation and regularly during treatment.
- New or worsening respiratory symptoms (eg, dyspnea, cough): Especially during the first week of treatment.
- Blood pressure: 2 weeks after initiation and at least monthly thereafter during use.
- Heart rate: Regularly throughout treatment, and more frequently in patients requiring concomitant therapy known to cause bradycardia.
- Ophthalmologic evaluation: Upon patient report of new or worsening visual disturbance.
# IV Compatibility
There is limited information regarding the compatibility of Brigatinib and IV administrations.
# Overdosage
There is limited information regarding Brigatinib overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
- Brigatinib is a tyrosine kinase inhibitor with in vitro activity at clinically achievable concentrations against multiple kinases including ALK, ROS1, insulin-like growth factor-1 receptor (IGF-1R), and FLT-3 as well as EGFR deletion and point mutations. Brigatinib inhibited autophosphorylation of ALK and ALK-mediated phosphorylation of the downstream signaling proteins STAT3, AKT, ERK1/2, and S6 in in vitro and in vivo assays. Brigatinib also inhibited the in vitro proliferation of cell lines expressing EML4-ALK and NPM-ALK fusion proteins and demonstrated dose-dependent inhibition of EML4-ALK-positive NSCLC xenograft growth in mice.
- At clinically achievable concentrations (≤ 500 nM), brigatinib inhibited the in vitro viability of cells expressing EML4-ALK and 17 mutant forms associated with resistance to ALK inhibitors including crizotinib, as well as EGFR-Del (E746-A750), ROS1-L2026M, FLT3-F691L, and FLT3-D835Y. Brigatinib exhibited in vivo anti-tumor activity against 4 mutant forms of EML4-ALK, including G1202R and L1196M mutants identified in NSCLC tumors in patients who have progressed on crizotinib. Brigatinib also reduced tumor burden and prolonged survival in mice implanted intracranially with an ALK-driven tumor cell line.
## Structure
## Pharmacodynamics
- Brigatinib exposure-response relationships and the time course of the pharmacodynamic response are unknown.
### Cardiac Electrophysiology
- The QT interval prolongation potential of brigatinib was assessed in 123 patients following once daily brigatinib doses of 30 mg (1/6th of the approved 180 mg dose) to 240 mg (1.3 times the approved 180 mg dose). Brigatinib did not prolong the QT interval to a clinically relevant extent.
## Pharmacokinetics
- The geometric mean (CV%) steady-state maximum concentration (Cmax) of brigatinib at brigatinib doses of 90 mg and 180 mg once daily was 552 (65%) ng/mL and 1452 (60%) ng/mL, respectively, and the corresponding area under the concentration-time curve (AUC0-Tau) was 8165 (57%) ng∙h/mL and 20276 (56%) ng∙h/mL. After a single dose and repeat dosing of brigatinib, systemic exposure of brigatinib was dose proportional over the dose range of 60 mg (0.3 times the approved 180 mg dose) to 240 mg (1.3 times the approved 180 mg dose) once daily. The mean accumulation ratio after repeat dosing was 1.9 to 2.4.
### Absorption
- Following administration of single oral doses of brigatinib of 30 to 240 mg, the median time to peak concentration (Tmax) ranged from 1 to 4 hours.
Effect of Food
- Brigatinib Cmax was reduced by 13% with no effect on AUC in healthy subjects administered brigatinib after a high fat meal (approximately 920 calories, 58 grams carbohydrate, 59 grams fat and 40 grams protein) compared to the Cmax and AUC after overnight fasting.
### Distribution
- Brigatinib is 66% bound to human plasma proteins and the binding is not concentration-dependent in vitro. The blood-to-plasma concentration ratio is 0.69. Following oral administration of brigatinib 180 mg once daily, the mean apparent volume of distribution (Vz/F) of brigatinib at steady-state was 153 L.
### Elimination
- Following oral administration of brigatinib 180 mg once daily, the mean apparent oral clearance (CL/F) of brigatinib at steady-state is 12.7 L/h and the mean plasma elimination half-life is 25 hours.
Metabolism
- Brigatinib is primarily metabolized by CYP2C8 and CYP3A4 in vitro. Following oral administration of a single 180 mg dose of radiolabeled brigatinib to healthy subjects, N-demethylation and cysteine conjugation were the two major metabolic pathways. Unchanged brigatinib (92%) and its primary metabolite, AP26123 (3.5%), were the major circulating radioactive components. The steady-state AUC of AP26123 was less than 10% of AUC of brigatinib exposure in patients. The metabolite, AP26123, inhibited ALK with approximately 3-fold lower potency than brigatinib in vitro.
Excretion
- Following oral administration of a single 180 mg dose of radiolabeled brigatinib to healthy subjects, 65% of the administered dose was recovered in feces and 25% of the administered dose was recovered in urine. Unchanged brigatinib represented 41% and 86% of the total radioactivity in feces and urine, respectively.
### Specific Populations
- Age, race, sex, body weight, and albumin concentration have no clinically meaningful effect on the pharmacokinetics of brigatinib.
Hepatic Impairment
- As hepatic elimination is a major route of excretion for brigatinib, hepatic impairment may result in increased plasma brigatinib concentrations. Based on a population pharmacokinetic analysis, brigatinib exposures were similar between 49 subjects with mild hepatic impairment (total bilirubin within upper limit of normal [ULN] and AST greater than ULN or total bilirubin greater than 1 and up to 1.5 times ULN and any AST) and 377 subjects with normal hepatic function (total bilirubin and AST within ULN). The pharmacokinetics of brigatinib in patients with moderate (total bilirubin greater than 1.5 and up to 3.0 times ULN and any AST) to severe (total bilirubin greater than 3.0 times ULN and any AST) hepatic impairment has not been studied.
Renal Impairment
Based on a population pharmacokinetic analysis, brigatinib exposures were similar among 125 subjects with mild renal impairment (CLcr 60 to less than 90 mL/min), 34 subjects with moderate renal impairment (CLcr 30 to less than 60 mL/min) and 270 subjects with normal renal function (CLcr greater than or equal to 90 mL/min), suggesting that no dose adjustment is necessary in patients with mild to moderate renal impairment. Patients with severe renal impairment (CLcr less than 30 mL/min) were not included in clinical trials.
### Drug Interactions
Effects of Other Drugs on Brigatinib
- Strong CYP3A Inhibitors: Coadministration of 200 mg twice daily doses of itraconazole (a strong CYP3A inhibitor) with a single 90 mg dose of brigatinib increased brigatinib Cmax by 21% and AUC0-INF by 101%, relative to a 90 mg dose of brigatinib administered alone.
- Strong CYP2C8 Inhibitors: Coadministration of 600 mg twice daily doses of gemfibrozil (a strong CYP2C8 inhibitor) with a single 90 mg dose of brigatinib decreased brigatinib Cmax by 41% and AUC0-INF by 12%, relative to a 90 mg dose of brigatinib administered alone. The effect of gemfibrozil on the pharmacokinetics of brigatinib is not clinically meaningful and the underlying mechanism for the decreased exposure of brigatinib is unknown.
- Strong CYP3A Inducers: Coadministration of 600 mg daily doses of rifampin (a strong CYP3A inducer) with a single 180 mg dose of brigatinib decreased brigatinib Cmax by 60% and AUC0-INF by 80%, relative to a 180 mg dose of brigatinib administered alone.
- P-gp and BCRP Inhibitors: In vitro studies suggest that brigatinib is a substrate of the efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Given that brigatinib exhibits high solubility and high permeability in vitro, P-gp and BCRP inhibitors are unlikely to increase plasma concentrations of brigatinib.
- Other Transporters: Brigatinib is not a substrate of organic anion transporting polypeptide (OATP1B1, OATP1B3), organic anion transporter (OAT1, OAT3), organic cation transporter (OCT1, OCT2), multidrug and toxin extrusion protein (MATE1, MATE2K), or bile salt export pump (BSEP).
Effects of Brigatinib on Other Drugs
- Transporter Substrates: Brigatinib is an inhibitor of P-gp, BCRP, OCT1, MATE1, and MATE2K in vitro. Therefore, brigatinib may have the potential to increase concentrations of coadministered substrates of these transporters. Brigatinib at clinically relevant concentrations did not inhibit OATP1B1, OATP1B3, OAT1, OAT3, OCT2 or BSEP.
- CYP Substrates: Brigatinib and its primary metabolite, AP26123, did not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4/5 at clinically relevant concentrations.
- Brigatinib, at clinically relevant plasma concentrations, induced CYP3A via activation of the pregnane X receptor (PXR). Brigatinib may also induce CYP2C enzymes via the same mechanism at clinically relevant concentrations.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
- Carcinogenicity studies have not been performed with brigatinib.
- Treatment with brigatinib resulted in chromosomal damage in an in vivo mammalian erythrocyte micronucleus in the rat, but was not mutagenic in the Ames or in vitro mammalian chromosome aberration tests.
- Dedicated animal fertility studies were not conducted with brigatinib. Testicular toxicity was observed in repeat-dose animal studies at doses resulting in exposure as low as 0.2 times the exposure in patients at the 180 mg dose. In rats, findings included lower weight of testes, seminal vesicles and prostate gland, and testicular tubular degeneration; these effects were not reversible during the 2-month recovery period. In monkeys, findings included reduced size of testes along with microscopic evidence of hypospermatogenesis; these effects were reversible during the recovery period.
# Clinical Studies
- The efficacy of brigatinib was demonstrated in a two-arm, open-label, multicenter trial (ALTA, NCT02094573) in adult patients with locally advanced or metastatic ALK-positive non-small cell lung cancer (NSCLC) who had progressed on crizotinib. The study required patients to have a documented ALK rearrangement based on an FDA-approved test or a different test with adequate archival tissue to confirm ALK arrangement by the Vysis® ALK Break-Apart fluorescence in situ hybridization (FISH) Probe Kit test. Key eligibility criteria included an ECOG Performance Status of 0-2 and progression on crizotinib. Neurologically stable patients with central nervous system (CNS) metastases were permitted to enroll. Patients with a history of interstitial lung disease or drug-related pneumonitis or who had received crizotinib within 3 days of the first dose of brigatinib were excluded. The major efficacy outcome measure was confirmed overall response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) as evaluated by an Independent Review Committee (IRC). Additional efficacy outcome measures included Investigator-assessed ORR, duration of response (DOR), intracranial ORR, and intracranial DOR.
- A total of 222 patients were randomized to receive brigatinib either 90 mg once daily (90 mg arm; n=112) or 180 mg once daily following a 7-day lead-in at 90 mg once daily (90→180 mg arm; n=110). Randomization was stratified by brain metastases (present versus absent) and best prior response to crizotinib (complete or partial response versus any other response/unevaluable).
- Baseline demographic characteristics of the overall study population were: median age 54 years (range 18 to 82, 23% 65 and over), 67% White and 31% Asian, 57% female, 36% ECOG PS 0 and 57% ECOG PS 1, and 95% never or former smokers. The disease characteristics of the overall study population were: Stage IV disease in 98%, adenocarcinoma histology in 97%, prior systemic chemotherapy in 74%, metastatic disease to the brain in 69% (61% had received prior radiation to the brain), bone metastases in 39%, and liver metastases in 26% of patients. Sixty-four percent of patients had an objective response to prior crizotinib.
- The median duration of follow-up was 8 months (range: 0.1-20.2). Efficacy results from ALTA are summarized in Table 5.
- IRC assessment of intracranial ORR and intracranial DOR according to RECIST v1.1 in the subgroup of 44 patients with measurable brain metastases (≥10 mm in longest diameter) at baseline are summarized in Table 6. Duration of intracranial response was measured from date of first intracranial response until intracranial disease progression (new lesions, intracranial target lesion diameter growth ≥20% from nadir, or unequivocal progression of intracranial non-target lesions) or death.
- Among the 23 patients who exhibited an intracranial response, 78% of patients in the 90 mg arm and 68% of patients in the 90→180 mg arm maintained a response for at least 4 months.
# How Supplied
- 30 mg tablets: round, white to off-white film-coated tablet with "U3" debossed on one side and plain on the other side; available in:
- Bottles of 21 tablets (NDC 76189-113-21)
- Bottles of 180 tablets (NDC 76189-113-18)
- 90 mg tablets: oval, white to off-white film-coated tablet with "U7" debossed on one side and plain on the other side; available in:
- Bottles of 7 tablets (NDC 76189-119-07)
- Bottles of 30 tablets (NDC 76189-119-30)
## Storage
- Store at controlled room temperature 20°C to 25°C (68°F to 77°F); excursion permitted between 15°C to 30°C (59°F to 86°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
### Interstitial Lung Disease (ILD)/Pneumonitis
- Inform patients of the symptoms and risks of serious pulmonary adverse reactions such as ILD/pneumonitis. Advise patients to immediately report any new or worsening respiratory symptoms
### Hypertension
- Advise patients of risks of hypertension and to promptly report signs or symptoms of hypertension.
### Bradycardia
- Advise patients to report any symptoms of bradycardia and to inform their healthcare provider about the use of heart and blood pressure medications.
### Visual Disturbance
- Advise patients to inform their healthcare provider of any new or worsening vision symptoms.
### Creatine Phosphokinase (CPK) Elevation
- Inform patients of the signs and symptoms of creatinine phosphokinase (CPK) elevation and the need for monitoring during treatment. Advise patients to inform their healthcare provider of any new or worsening symptoms of unexplained muscle pain, tenderness, or weakness.
### Pancreatic Enzyme Elevation
- Inform patients of the signs and symptoms of pancreatitis and the need to monitor for amylase and lipase elevations during treatment.
### Hyperglycemia
- Inform patients of the risks of new or worsening hyperglycemia and the need to periodically monitor glucose levels. Advise patients with diabetes mellitus or glucose intolerance that anti-hyperglycemic medications may need to be adjusted during treatment with brigatinib.
### Females and Males of Reproductive Potential
Embryo-Fetal Toxicity
- Advise females and males of reproductive potential that brigatinib can cause fetal harm.
- Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy and to use effective non-hormonal contraception during treatment with brigatinib and for at least 4 months after the final dose.
- Advise males with female partners of reproductive potential to use effective contraception during treatment with brigatinib and for at least 3 months after the final dose.
Lactation
- Advise females not to breastfeed during treatment with brigatinib and for at least 1 week following the final dose.
Infertility
- Advise males of reproductive potential of the potential for reduced fertility from brigatinib.
### Drug Interactions
- Advise patients to inform their health care provider of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products. Inform patients to avoid grapefruit or grapefruit juice while taking brigatinib.
### Dosing and Administration
- Instruct patients to start with 90 mg of brigatinib once daily for the first 7 days and if tolerated, increase the dose to 180 mg once daily. Advise patients to take brigatinib with or without food.
### Missed Dose
- Advise patients that if a dose of brigatinib is missed or if the patient vomits after taking a dose of brigatinib, not to take an extra dose, but to take the next dose at the regular time.
# Precautions with Alcohol
Alcohol-Brigatinib interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
- Alunbrig
# Look-Alike Drug Names
There is limited information regarding Brigatinib Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | https://www.wikidoc.org/index.php/Brigatinib | |
0d8fd90bdf968d2ee56f96d40f69b83a1515086b | wikidoc | Ticagrelor | Ticagrelor
Synonyms / Brand Names: Brilinta
# Disclaimer
WikiDoc Drug Project is a constellation of drug information for healthcare providers and patients vigorously vetted on the basis of FDA package insert, MedlinePlus, Practice Guidelines, Scientific Statements, and scholarly medical literature. The information provided is not a medical advice or treatment. WikiDoc does not promote any medication or off-label use of drugs. Please read our full disclaimer here.
# Black Box Warning
FDA Package Insert for Ticagrelor contains no information regarding Black Box Warning.
# Overview
Ticagrelor is a ADP-induced aggregation inhibitor, platelet aggregation inhibitor that is FDA approved for the treatment of acute coronary syndromes, There is a Black Box Warning for this drug as shown here. Common adverse reactions include bleeding, major and minor, headache, serum creatinine raised, cough, dyspnea.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- Initial dose: “Brilinta 180 mg PO once” with aspirin (325 mg) once.
- Maintenance dose: “Brilinta 90 mg PO bid” with aspirin 75-100 mg PO qd.
- Not recommended when aspirin maintenance dose is above 100 mg.
- Dosing Information
- Loading dose: “Brilinta 180 mg PO” with aspirin (325 mg), once.
- Maintenance: “ticagrelor 90 mg PO bid” with aspirin 75-100 mg qd.
- Use of aspirin maintenance dose above 100 mg is not recommended.
- Consider carefully the continuation of therapy beyond 12 months (for drug-eluting stents).
## Off-Label Use and Dosage (Adult)
There is limited information about Off-Label Use and Dosage of Ticagrelor tablet in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information about FDA-Labeled Indications and Dosageof Ticagrelor tablet in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information about Off-Label Use and Dosage of Ticagrelor tablet in pediatric patients.
# Contraindications
- History of intracranial hemorrhage
- Active pathological bleeding
- Severe hepatic impairment
- Hypersensitivity to ticagrelor or any component of the product
# Warnings
- Like other antiplatelet agents, ticagrelor increases the risk of bleeding.
- In PLATO, use of ticagrelor with maintenance doses of aspirin above 100 mg decreased the effectiveness of ticagrelor.
- Moderate Hepatic Impairment: Consider the risks and benefits of treatment, noting the probable increase in exposure to ticagrelor.
- Dyspnea: Dyspnea was reported more frequently with ticagrelor than with clopidogrel. Dyspnea resulting from ticagrelor is self-limiting. Rule out other causes.
- Discontinuation of ticagrelor: Premature discontinuation increases the risk of myocardial infarction, stent thrombosis, and death.
# Adverse Reactions
## Clinical Trials Experience
The following adverse reactions are also discussed elsewhere in the labeling:
Warnings
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
ticagrelor has been evaluated for safety in more than 10000 patients, including more than 3000 patients treated for more than 1 year.
Bleeding
PLATO used the following bleeding severity categorization:
- Major bleed – fatal/life-threatening. Any one of the following: fatal; intracranial; intrapericardial bleed with cardiac tamponade; hypovolemic shock or severe hypotension due to bleeding and requiring pressors or surgery; clinically overt or apparent bleeding associated with a decrease in hemoglobin (Hb) of more than 5 g/dL; transfusion of 4 or more units (whole blood or packed red blood cells (PRBCs)) for bleeding.
- Major bleed – other. Any one of the following: significantly disabling (e.g., intraocular with permanent vision loss); clinically overt or apparent bleeding associated with a decrease in Hb of 3 g/dL; transfusion of 2-3 units (whole blood or PRBCs) for bleeding.
- Minor bleed. Requires medical intervention to stop or treat bleeding (e.g., epistaxis requiring visit to medical facility for packing).
- Minimal bleed. All others (e.g., bruising, bleeding gums, oozing from injection sites, etc.) not requiring intervention or treatment.
Figure 1 shows major bleeding events over time. Many events are early, at a time of coronary angiography, PCI, CABG, and other procedures, but the risk persists during later use of antiplatelet therapy.
Figure 1- Kaplan-Meier estimate of time to first PLATO-defined ‘Total Major’ bleeding event
Annualized rates of bleeding are summarized in Table 1 below. About half of the bleeding events were in the first 30 days.
As shown in Table 1, Ticagrelor was associated with a somewhat greater risk of non- CABG bleeding than was Clopidogrel. No baseline demographic factor altered the relative risk of bleeding with Ticagrelor compared to Clopidogrel.
In PLATO, 1584 patients underwent CABG surgery. The percentages of those patients who bled are shown in Table 2. Rates were very high but similar for Ticagrelor and Clopidogrel.
Although the platelet inhibition effect of Ticagrelor has a faster offset than Clopidogrel in in vitro tests and Ticagrelor is a reversibly binding P2Y12 inhibitor, PLATO did not show an advantage of Ticagrelor compared to Clopidogrel for CABG-related bleeding. When antiplatelet therapy was stopped 5 days before CABG, major bleeding occurred in 75% of Ticagrelor treated patients and 79% on Clopidogrel.
No data exist with Ticagrelor regarding a hemostatic benefit of platelet transfusions.
Drug Discontinuation
In PLATO, the rate of study drug discontinuation attributed to adverse reactions was 7.4% for Ticagrelor and 5.4% for Clopidogrel. Bleeding caused permanent discontinuation of study drug in 2.3% of Ticagrelor patients and 1.0% of Clopidogrel patients. Dyspnea led to study drug discontinuation in 0.9% of Ticagrelor and 0.1% of Clopidogrel patients.
Common Adverse Events
A variety of non-hemorrhagic adverse events occurred in PLATO at rates of 3% or more. These are shown in Table 3. In the absence of a placebo control, whether these are drug related cannot be determined in most cases, except where they are more common on Ticagrelor or clearly related to the drug’s pharmacologic effect (dyspnea).
Bradycardia
In clinical studies Ticagrelor has been shown to increase the occurrence of Holter-detected bradyarrhythmias (including ventricular pauses). PLATO excluded patients at increased risk of bradycardic events (e.g., patients who have sick sinus syndrome, 2nd or 3rd degree AV block, or bradycardic-related syncope and not protected with a pacemaker). In PLATO, syncope, pre-syncope and loss of consciousness were reported by 1.7% and 1.5% of ticagrelor and Clopidogrel patients, respectively.
In a Holter substudy of about 3000 patients in PLATO, more patients had ventricular pauses with Ticagrelor (6.0%) than with Clopidogrel (3.5%) in the acute phase; rates were 2.2% and 1.6% respectively after 1 month.
Gynecomastia
In PLATO, gynecomastia was reported by 0.23% of men on ticagrelor and 0.05% on Clopidogrel.
Other sex-hormonal adverse reactions, including sex organ malignancies, did not differ between the two treatment groups in PLATO.
Lab abnormalities
Serum Uric Acid:
Serum uric acid levels increased approximately 0.6 mg/dL from baseline on Ticagrelor and approximately 0.2 mg/dL on Clopidogrel in PLATO. The difference disappeared within 30 days of discontinuing treatment. Reports of gout did not differ between treatment groups in PLATO (0.6% in each group).
Serum Creatinine:
In PLATO, a >50% increase in serum creatinine levels was observed in 7.4% of patients receiving Ticagrelor compared to 5.9% of patients receiving Clopidogrel. The increases typically did not progress with ongoing treatment and often decreased with continued therapy. Evidence of reversibility upon discontinuation was observed even in those with the greatest on treatment increases. Treatment groups in PLATO did not differ for renal-related serious adverse events such as acute renal failure, chronic renal failure, toxic nephropathy, or oliguria.
Immune system disorders – Hypersensitivity reactions including angioedema. See Contraindications.
## Postmarketing Experience
There is limited information about Postmarketing Experience of Ticagrelor tablet in pediatric patients.
# Drug Interactions
Effects of other drugs
Ticagrelor is predominantly metabolized by CYP3A4 and to a lesser extent by CYP3A5. Ticagrelor is also a p-glycoprotein (P-gp) substrate.
- CYP3A inhibitors
- Avoid use of strong inhibitors of CYP3A (e.g., ketoconazole, itraconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir and telithromycin). See Warnings and Pharmacology.
- CYP3A inducers
- Avoid use with potent inducers of CYP3A (e.g., rifampin, dexamethasone, phenytoin, carbamazepine and phenobarbital) See Contraindications, Pharmacology and Warnings.
- Aspirin
- See Pharmacology and Warnings.
Effect of ticagrelor on other drugs.
Ticagrelor is an inhibitor of CYP3A4/5 and the P-glycoprotein transporter.
- Simvastatin, lovastatin
- Ticagrelor will result in higher serum concentrations of simvastatin and lovastatin because these drugs are metabolized by CYP3A4. Avoid simvastatin and lovastatin doses greater than 40 mg. See Pharmacology.
- Digoxin
- Digoxin: Because of inhibition of the P-glycoprotein transporter, monitor digoxin levels with initiation of or any change in ticagrelor therapy. See Pharmacology
- Other Concomitant Therapy
- Ticagrelor can be administered with unfractionated or low-molecular-weight heparin, GPIIb/IIIa inhibitors, proton pump inhibitors, beta-blockers, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers.
# Use in Specific Populations
### Pregnancy
- Pregnancy Category (FDA): C
- Pregnancy Category (AUS): Ticagrelor is not included in Australian Drug Evaluation Committee (ADEC) Pregnancy Categories.
- There are no adequate and well-controlled studies of ticagrelor use in pregnant women. In animal studies, ticagrelor caused structural abnormalities at maternal doses about 5 to 7 times the maximum recommended human dose (MRHD) based on body surface area. ticagrelor should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- In reproductive toxicology studies, pregnant rats received ticagrelor during organogenesis at doses from 20 to 300 mg/kg/day. The lowest dose was approximately the same as the MRHD of 90 mg twice daily for a 60 kg human on a mg/m2 basis. Adverse outcomes in offspring occurred at doses of 300 mg/kg/day (16.5 times the MRHD on a mg/m2 basis) and included supernumerary liver lobe and ribs, incomplete ossification of sternebrae, displaced articulation of pelvis, and misshapen/misaligned sternebrae. When pregnant rabbits received ticagrelor during organogenesis at doses from 21 to 63 mg/kg/day, fetuses exposed to the highest maternal dose of 63 mg/kg/day (6.8 times the MRHD on a mg/m2 basis) had delayed gall bladder development and incomplete ossification of the hyoid, pubis and sternebrae occurred.
- In a prenatal/postnatal study, pregnant rats received ticagrelor at doses of 10 to 180 mg/kg/day during late gestation and lactation. Pup death and effects on pup growth were observed at 180 mg/kg/day (approximately 10 times the MRHD on a mg/m2 basis). Relatively minor effects such as delays in pinna unfolding and eye opening occurred at doses of 10 and 60 mg/kg (approximately one-half and 3.2 times the MRHD on a mg/m2 basis).
### Labor and Delivery
There is limited information about Labor and Delivery of Ticagrelor tablet in patients.
### Nursing Mothers
There is limited information about Nursing Mothers of Ticagrelor tablet in patients.
### Pediatric Use
The safety and effectiveness of ticagrelor in pediatric patients have not been established.
### Geriatric Use
- In PLATO, 43% of patients were ≥65 years of age and 15% were ≥75 years of age. The relative risk of bleeding was similar in both treatment and age groups.
- No overall differences in safety or effectiveness were observed between these patients and younger patients. While this clinical experience has not identified differences in responses between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out.
Clinical Pharmacology.
### Gender
There is no FDA guidance on the use of Ticagrelor with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ticagrelor with respect to specific racial populations.
### Renal Impairment
No dosage adjustment is needed in patients with renal impairment. Patients receiving dialysis have not been studied [see Clinical Pharmacology.
### Hepatic Impairment
- Ticagrelor has not been studied in the patients with moderate or severe hepatic impairment. Ticagrelor is metabolized by the liver and impaired hepatic function can increase risks for bleeding and other adverse events. Hence, ticagrelor is contraindicated for use in patients with severe hepatic impairment and its use should be considered carefully in patients with moderate hepatic impairment. No dosage adjustment is needed in patients with mild hepatic impairment [see Contraindications, Warnings and Precautions (5.3) and Clinical Pharmacology.
### Immunocompromised Patients
There is no FDA guidance one the use of Ticagrelor in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- [[Orall.
- Initiate ticagrelor treatment with a 180 mg (two 90 mg tablets) loading dose and continue treatment with 90 mg twice daily.
- After the initial loading dose of aspirin (usually 325 mg), use ticagrelor with a daily maintenance dose of aspirin of 75-100 mg.
- ACS patients who have received a loading dose of clopidogrel may be started on ticagrelor.
- ticagrelor can be administered with or without food.
- A patient who misses a dose of ticagrelor should take one 90 mg tablet (their next dose) at its scheduled time.
### Monitoring
# IV Compatibility
# Overdosage
# Pharmacology
## Mechanism of Action
- Ticagrelor and its major metabolite reversibly interact with the platelet P2Y12 ADP-receptor to prevent signal transduction and platelet activation. Ticagrelor and its active metabolite are approximately equipotent.
- The inhibition of platelet aggregation (IPA) by ticagrelor and clopidogrel was compared in a 6 week study examining both acute and chronic platelet inhibition effects in response to 20 μM ADP as the platelet aggregation agonist.
- The onset of IPA was evaluated on Day 1 of the study following loading doses of 180 mg ticagrelor or 600 mg clopidogrel. As shown in Figure 2, IPA was higher in the ticagrelor group at all time points. The maximum IPA effect of ticagrelor was reached at around 2 hours, and was maintained for at least 8 hours.
- The offset of IPA was examined after 6 weeks on ticagrelor 90 mg twice daily or clopidogrel 75 mg daily, again in response to 20 μM ADP.
- As shown in Figure 3, mean maximum IPA following the last dose of ticagrelor was 88% and 62% for clopidogrel. The insert in Figure 3 shows that after 24 hours, IPA in the ticagrelor group (58%) was similar to IPA in clopidogrel group (52%), indicating that patients who miss a dose of ticagrelor would still maintain IPA similar to the trough IPA of patients treated with clopidogrel. After 5 days, IPA in the ticagrelor group was similar to IPA in the placebo group. It is not known how either bleeding risk or thrombotic risk track with IPA, for either ticagrelor or clopidogrel.
Figure 2 - Mean inhibition of platelet aggregation (±SE) following single oral doses of placebo, 180 mg ticagrelor or 600 mg clopidogrel
- Transitioning from clopidogrel to ticagrelor resulted in an absolute IPA increase of 26.4% and from ticagrelor to clopidogrel resulted in an absolute IPA decrease of 24.5%. Patients can be transitioned from clopidogrel to ticagrelor without interruption of antiplatelet effect [see dosage and Administration (2) .
## Structure
- Ticagrelor cyclopentyltriazolopyrimidine, inhibitor of platelet activation and aggregation mediated by the P2Y12 ADP-receptor. Chemically it is (1S,2S,3R,5S)-3-amino}-5-(propylthio)-3H--triazolopyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol. The empirical formula of ticagrelor is C23H28F2N6O4S and its molecular weight is 522.57. The chemical structure of ticagrelor is:
- Ticagrelor is a crystalline powder with an aqueous solubility of approximately 10 μg/mL at room temperature.
- Ticagrelor tablets for oral administration contain 90 mg of ticagrelor and the following ingredients: mannitol, dibasic calcium phosphate, sodium starch glycolate, hydroxypropyl cellulose, magnesium stearate, hydroxypropyl methylcellulose, titanium dioxide, talc, polyethylene glycol 400, and ferric oxide yellow.
## Pharmacodynamics
- The inhibition of platelet aggregation (IPA) by ticagrelor and clopidogrel was compared in a 6 week study examining both acute and chronic platelet inhibition effects in response to 20 μM ADP as the platelet aggregation agonist.
- The onset of IPA was evaluated on Day 1 of the study following loading doses of 180 mg ticagrelor or 600 mg clopidogrel. As shown in Figure 2, IPA was higher in the ticagrelor group at all time points. The maximum IPA effect of ticagrelor was reached at around 2 hours, and was maintained for at least 8 hours.
- The offset of IPA was examined after 6 weeks on ticagrelor 90 mg twice daily or clopidogrel 75 mg daily, again in response to 20 μM ADP.
- As shown in Figure 3, mean maximum IPA following the last dose of ticagrelor was 88% and 62% for clopidogrel. The insert in Figure 3 shows that after 24 hours, IPA in the ticagrelor group (58%) was similar to IPA in clopidogrel group (52%), indicating that patients who miss a dose of ticagrelor would still maintain IPA similar to the trough IPA of patients treated with clopidogrel. After 5 days, IPA in the ticagrelor group was similar to IPA in the placebo group. It is not known how either bleeding risk or thrombotic risk track with IPA, for either ticagrelor or clopidogrel.
Figure 2 - Mean inhibition of platelet aggregation (±SE) following single oral doses of placebo, 180 mg ticagrelor or 600 mg clopidogrel
- Transitioning from clopidogrel to ticagrelor resulted in an absolute IPA increase of 26.4% and from ticagrelor to clopidogrel resulted in an absolute IPA decrease of 24.5%. Patients can be transitioned from clopidogrel to ticagrelor without interruption of antiplatelet effect [see dosage and Administration (2) .
## Pharmacokinetics
- Ticagrelor demonstrates dose proportional pharmacokinetics, which are similar in patients and healthy volunteers.
Absorption
- Absorption of ticagrelor occurs with a median tmax of 1.5 h (range 1.0–4.0). The formation of the major circulating metabolite AR-C124910XX (active) from ticagrelor occurs with a median tmax of 2.5 h (range 1.5-5.0).
- The mean absolute bioavailability of ticagrelor is about 36%, (range 30%-42%). Ingestion of a high-fat meal had no effect on ticagrelor Cmax, but resulted in a 21% increase in AUC. The Cmax of its major metabolite was decreased by 22% with no change in AUC. Ticagrelor can be taken with or without food.
Distribution
- The steady state volume of distribution of ticagrelor is 88 L. Ticagrelor and the active metabolite are extensively bound to human plasma proteins (>99%).
Metabolism
- CYP3A4 is the major enzyme responsible for ticagrelor metabolism and the formation of its major active metabolite. Ticagrelor and its major active metabolite are weak P-glycoprotein substrates and inhibitors. The systemic exposure to the active metabolite is approximately 30-40% of the exposure of ticagrelor.
Excretion
- The primary route of ticagrelor elimination is hepatic metabolism. When radiolabeled ticagrelor is administered, the mean recovery of radioactivity is approximately 84% (58% in feces, 26% in urine). Recoveries of ticagrelor and the active metabolite in urine were both less than 1% of the dose. The primary route of elimination for the major metabolite of ticagrelor is most likely to be biliary secretion. The mean t1/2 is approximately 7 hours for ticagrelor and 9 hours for the active metabolite.
Special Populations
- The effects of age, gender, ethnicity, renal impairment and mild hepatic impairment on the pharmacokinetics of ticagrelor are presented in Figure 4. Effects are modest and do not require dose adjustment.
- Figure 4 - Impact of intrinsic factors on the pharmacokinetics of ticagrelor
Pediatric
- Ticagrelor has not been evaluated in a pediatric population .
Body Weight
- No dose adjustment is necessary for ticagrelor based on weight.
Smoking
- Habitual smoking increased population mean clearance of ticagrelor by approximately 22% when compared to non-smokers. No dose adjustment is necessary for ticagrelor based on smoking status.
Effects of Other Drugs on Ticagrelor
- CYP3A4 is the major enzyme responsible for ticagrelor metabolism and the formation of its major active metabolite. The effects of other drugs on the pharmacokinetics of ticagrelor are presented in Figure 5 as change relative to ticagrelor given alone (test/reference). Strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, and clarithromycin) substantially increase ticagrelor exposure. Moderate CYP3A inhibitors have lesser effects (e.g., diltiazem). CYP3A inducers (e.g., rifampin) substantially reduce ticagrelor blood levels. P-gp inhibitors (e.g. cyclosporine) increase ticagrelor exposure.
Effects of Brilinta on Other Drugs
- In vitro metabolism studies demonstrate that ticagrelor and its major active metabolite are weak inhibitors of CYP3A4, potential activators of CYP3A5 and inhibitors of the P-gp transporter. Ticagrelor and AR-C124910XX were shown to have no inhibitory effect on human CYP1A2, CYP2C19, and CYP2E1 activity. For specific in vivo effects on the pharmacokinetics of simvastatin, atorvastatin, ethinyl estradiol, levonorgesterol, tolbutamide, digoxin and cyclosporine, see Figure 6.
## Nonclinical Toxicology
Carcinogenesis
- Ticagrelor was not carcinogenic in the mouse at doses up to 250 mg/kg/day or in the male rat at doses up to 120 mg/kg/day (19 and 15 times the MRHD of 90 mg twice daily on the basis of AUC, respectively). Uterine carcinomas, uterine adenocarcinomas and hepatocellular adenomas were seen in female rats at doses of 180 mg/kg/day (29-fold the maximally recommended dose of 90 mg twice daily on the basis of AUC), whereas 60 mg/kg/day (8-fold the MRHD based on AUC) was not carcinogenic in female rats.
Mutagenesis
- Ticagrelor did not demonstrate genotoxicity when tested in the Ames bacterial mutagenicity test, mouse lymphoma assay and the rat micronucleus test. The active O-demethylated metabolite did not demonstrate genotoxicity in the Ames assay and mouse lymphoma assay.
Impairment of Fertility
- Ticagrelor had no effect on male fertility at doses up to 180 mg/kg/day or on female fertility at doses up to 200 mg/kg/day (>15-fold the MRHD on the basis of AUC). Doses of ≥10 mg/kg/day given to female rats caused an increased incidence of irregular duration estrus cycles (1.5-fold the MRHD based on AUC).
# Clinical Studies
- The clinical evidence for the effectiveness of Brilinta is derived from PLATO, a randomized double-blind study comparing Brilinta (N=9333) to clopidogrel (N=9291), both given in combination with aspirin and other standard therapy, in patients with acute coronary syndromes (ACS). Patients were treated for at least 6 months and for up to 12 months. Study endpoints were obtained until the study was complete, even if drug was discontinued.
- Patients who presented within 24 hours of onset of the most recent episode of chest pain or symptoms were randomized to receive Brilinta or clopidogrel. Patients who had already been treated with clopidogrel could be enrolled and randomized to either study treatment. Patients could be included whether there was intent to manage the ACS medically or invasively, but patient randomization was not stratified by this intent. Subjects in the clopidogrel arm were treated with an initial loading dose of clopidogrel 300 mg, if previous clopidogrel therapy had not been given prior to randomization. Patients undergoing PCI could receive an additional 300 mg of clopidogrel at investigator discretion. All subjects randomized to Brilinta received a loading dose of 180 mg followed by a maintenance dose of 90 mg twice daily. Concomitant aspirin was recommended at a loading dose of 160-500 mg. A daily maintenance dose of aspirin 75-100 mg was recommended, but higher maintenance doses of aspirin were allowed according to local judgment.
- Because of ticagrelor’s metabolism by CYP3A enzymes, the protocol recommended limiting the maximum dosage of simvastatin and lovastatin to 40 mg in both study arms. - Because of an increased bleeding risk, the study excluded patients with previous intracranial hemorrhage, a gastrointestinal bleed within the past 6 months, or other factors that predispose to bleeding.
- PLATO patients were predominantly male (72%) and Caucasian (92%). About 43% of patients were >65 years and 15% were >75 years.
- The study’s primary endpoint was the composite of first occurrence of cardiovascular death, non-fatal MI (excluding silent MI), or non-fatal stroke. The components were assessed as secondary endpoints.
- Median exposure to study drug was 277 days. About half of the patients received pre-study clopidogrel and about 99% of the patients received aspirin at some time during PLATO. About 35% of patients were receiving a statin at baseline and 93% received a statin sometime during PLATO.
- Table 4 shows the study results for the primary composite endpoint and the contribution of each component to the primary endpoint. Separate secondary endpoint analyses are shown for the overall occurrence of CV death, MI, and stroke and overall mortality.
- The difference between treatments on the composite resulted from effects on CV death and MI; each was statistically significant when considered as a secondary endpoint and there was no beneficial effect on strokes. For all-cause mortality the benefit was also statistically significant (p = 0.0003) with a hazard ratio of 0.78.
- Among 11289 patients with PCI receiving any stent during PLATO, there was a lower risk of stent thrombosis (1.3% for adjudicated “definite”) than with clopidogrel (1.9%) (HR 0.67, 95% CI 0.50-0.91; p=0.0091). The results were similar for drug-eluting and bare metal stents.
The Kaplan-Meier curve (Figure 7) shows time to first occurrence of the primary composite endpoint of CV death, non-fatal MI or non-fatal stroke in the overall study.
Figure 7 - Time to First Occurrence of CV death, MI, or Stroke in PLATO
- The curves separate by 30 days (RRR 12%) and continue to diverge throughout the 12 month treatment period (RRR 16%).
- A wide range of demographic, concurrent baseline medications, and other treatment differences were examined for their influence on outcome. Many of these are shown in Figure 8. Such analyses must be interpreted cautiously, as differences can reflect the play of chance among a large number of analyses. Most of the analyses show effects consistent with the overall results, but there are two marked exceptions: a finding of heterogeneity by region and a strong influence of the maintenance dose of aspirin. - These are considered further below.
- Most of the characteristics shown are baseline characteristics, but some reflect post-randomization determinations (e.g., final diagnosis, aspirin maintenance dose, use of PCI). Patients were not stratified by initial diagnosis, but the effect in the unstable angina subset (determined after randomization) appeared smaller than the effect in the NSTEMI and STEMI subsets. The results in the subsets based on final diagnosis (STEMI, NSTEMI and unstable angina) are also presented in Figure 8.
Figure 8 - Subgroup analyses of PLATO
Regional Differences
- Results in the rest of the world compared to effects in North America (US and Canada) show a smaller effect in North America, numerically inferior to the control and driven by the US subset. The statistical test for the US/non-US comparison is statistically significant (p=0.009), and the same trend is present for both CV death and non-fatal MI. The individual results and nominal p-values, like all subset analyses, need cautious interpretation, and they could represent chance findings. The consistency of the differences in both the CV mortality and non-fatal MI components, however, supports the possibility that the finding is reliable.
- A wide variety of baseline and procedural differences between the US and non-US (including intended invasive vs. planned medical management, use of GPIIb/IIIa inhibitors, use of drug eluting vs. bare-metal stents) were examined to see if they could account for regional differences, but with one exception, aspirin maintenance dose, these differences did not appear to lead to differences in outcome.
aspirin Dose
- The PLATO protocol left the choice of aspirin maintenance dose up to the investigator and use patterns were very different in the US and elsewhere, with about 8% of non-US investigators using aspirin doses above 100 mg, and about 2% using doses above 300 mg, in contrast with US practice, where 57% of patients received doses above 100 mg and 54% received doses above 300 mg. Overall results favored Brilinta when used with low maintenance doses (≤ 100 mg) of aspirin, and results analyzed by aspirin dose were similar in the US and elsewhere. Figure 8 shows overall results by median aspirin dose. Table 5 shows results by region and dose.
Table 5 - PLATO: CV Death, MI, Stroke by maintenance aspirin dose in the US and outside the US
- Like any unplanned subset analysis, especially one where the characteristic is not a true baseline characteristic (but may be determined by usual investigator practice), the above analyses must be treated with caution. It is notable, however, that aspirin dose predicts outcome in both regions with a similar pattern, and that the pattern is similar for the two major components of the primary endpoint, CV death and non-fatal MI.
Despite the need to treat such results cautiously, there appears to be good reason to restrict aspirin maintenance dosage accompanying ticagrelor to 100 mg. Higher doses do not have an established benefit in the ACS setting, and there is a strong suggestion that use of such doses reduces the effectiveness of Brilinta.
Pharmacogenetics
- In a genetic substudy of PLATO (n=10,285), the effects of Brilinta compared to clopidogrel on thrombotic events and bleeding were not significantly affected by CYP2C19 genotype.
# How Supplied
- Brilinta (ticagrelor) 90 mg is supplied as a round, biconvex, yellow, film-coated tablet marked with a “90” above “T” on one side.
- Bottles of 14 – NDC 0186-0777-28.
- Bottles of 60 – NDC 0186-0777-60.
- Bottles of 180 – NDC 0186-0777-18.
- 100 count Hospital Unit Dose – NDC 0186-0777-39.
- Store at 25°C (77°F); excursions permitted to 15°-30°C (59°- 86°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Information
For patient information about ticagrelor, click here.
# Precautions with Alcohol
Alcohol-Ticagrelor interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
Brilinta®
# Look-Alike Drug Names
# Drug Shortage Status
# Price | Ticagrelor
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2]; Ammu Susheela, M.D. [3]
Synonyms / Brand Names: Brilinta
# Disclaimer
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# Black Box Warning
FDA Package Insert for Ticagrelor contains no information regarding Black Box Warning.
# Overview
Ticagrelor is a ADP-induced aggregation inhibitor, platelet aggregation inhibitor that is FDA approved for the treatment of acute coronary syndromes, There is a Black Box Warning for this drug as shown here. Common adverse reactions include bleeding, major and minor, headache, serum creatinine raised, cough, dyspnea.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- Initial dose: “Brilinta 180 mg PO once” with aspirin (325 mg) once.
- Maintenance dose: “Brilinta 90 mg PO bid” with aspirin 75-100 mg PO qd.
- Not recommended when aspirin maintenance dose is above 100 mg.
- Dosing Information
- Loading dose: “Brilinta 180 mg PO” with aspirin (325 mg), once.
- Maintenance: “ticagrelor 90 mg PO bid” with aspirin 75-100 mg qd.
- Use of aspirin maintenance dose above 100 mg is not recommended.
- Consider carefully the continuation of therapy beyond 12 months (for drug-eluting stents).
## Off-Label Use and Dosage (Adult)
There is limited information about Off-Label Use and Dosage of Ticagrelor tablet in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information about FDA-Labeled Indications and Dosageof Ticagrelor tablet in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information about Off-Label Use and Dosage of Ticagrelor tablet in pediatric patients.
# Contraindications
- History of intracranial hemorrhage
- Active pathological bleeding
- Severe hepatic impairment
- Hypersensitivity to ticagrelor or any component of the product
# Warnings
- Like other antiplatelet agents, ticagrelor increases the risk of bleeding.
- In PLATO, use of ticagrelor with maintenance doses of aspirin above 100 mg decreased the effectiveness of ticagrelor.
- Moderate Hepatic Impairment: Consider the risks and benefits of treatment, noting the probable increase in exposure to ticagrelor.
- Dyspnea: Dyspnea was reported more frequently with ticagrelor than with clopidogrel. Dyspnea resulting from ticagrelor is self-limiting. Rule out other causes.
- Discontinuation of ticagrelor: Premature discontinuation increases the risk of myocardial infarction, stent thrombosis, and death.
# Adverse Reactions
## Clinical Trials Experience
The following adverse reactions are also discussed elsewhere in the labeling:
Warnings
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
ticagrelor has been evaluated for safety in more than 10000 patients, including more than 3000 patients treated for more than 1 year.
Bleeding
PLATO used the following bleeding severity categorization:
- Major bleed – fatal/life-threatening. Any one of the following: fatal; intracranial; intrapericardial bleed with cardiac tamponade; hypovolemic shock or severe hypotension due to bleeding and requiring pressors or surgery; clinically overt or apparent bleeding associated with a decrease in hemoglobin (Hb) of more than 5 g/dL; transfusion of 4 or more units (whole blood or packed red blood cells (PRBCs)) for bleeding.
- Major bleed – other. Any one of the following: significantly disabling (e.g., intraocular with permanent vision loss); clinically overt or apparent bleeding associated with a decrease in Hb of 3 g/dL; transfusion of 2-3 units (whole blood or PRBCs) for bleeding.
- Minor bleed. Requires medical intervention to stop or treat bleeding (e.g., epistaxis requiring visit to medical facility for packing).
- Minimal bleed. All others (e.g., bruising, bleeding gums, oozing from injection sites, etc.) not requiring intervention or treatment.
Figure 1 shows major bleeding events over time. Many events are early, at a time of coronary angiography, PCI, CABG, and other procedures, but the risk persists during later use of antiplatelet therapy.
Figure 1- Kaplan-Meier estimate of time to first PLATO-defined ‘Total Major’ bleeding event
Annualized rates of bleeding are summarized in Table 1 below. About half of the bleeding events were in the first 30 days.
As shown in Table 1, Ticagrelor was associated with a somewhat greater risk of non- CABG bleeding than was Clopidogrel. No baseline demographic factor altered the relative risk of bleeding with Ticagrelor compared to Clopidogrel.
In PLATO, 1584 patients underwent CABG surgery. The percentages of those patients who bled are shown in Table 2. Rates were very high but similar for Ticagrelor and Clopidogrel.
Although the platelet inhibition effect of Ticagrelor has a faster offset than Clopidogrel in in vitro tests and Ticagrelor is a reversibly binding P2Y12 inhibitor, PLATO did not show an advantage of Ticagrelor compared to Clopidogrel for CABG-related bleeding. When antiplatelet therapy was stopped 5 days before CABG, major bleeding occurred in 75% of Ticagrelor treated patients and 79% on Clopidogrel.
No data exist with Ticagrelor regarding a hemostatic benefit of platelet transfusions.
Drug Discontinuation
In PLATO, the rate of study drug discontinuation attributed to adverse reactions was 7.4% for Ticagrelor and 5.4% for Clopidogrel. Bleeding caused permanent discontinuation of study drug in 2.3% of Ticagrelor patients and 1.0% of Clopidogrel patients. Dyspnea led to study drug discontinuation in 0.9% of Ticagrelor and 0.1% of Clopidogrel patients.
Common Adverse Events
A variety of non-hemorrhagic adverse events occurred in PLATO at rates of 3% or more. These are shown in Table 3. In the absence of a placebo control, whether these are drug related cannot be determined in most cases, except where they are more common on Ticagrelor or clearly related to the drug’s pharmacologic effect (dyspnea).
Bradycardia
In clinical studies Ticagrelor has been shown to increase the occurrence of Holter-detected bradyarrhythmias (including ventricular pauses). PLATO excluded patients at increased risk of bradycardic events (e.g., patients who have sick sinus syndrome, 2nd or 3rd degree AV block, or bradycardic-related syncope and not protected with a pacemaker). In PLATO, syncope, pre-syncope and loss of consciousness were reported by 1.7% and 1.5% of ticagrelor and Clopidogrel patients, respectively.
In a Holter substudy of about 3000 patients in PLATO, more patients had ventricular pauses with Ticagrelor (6.0%) than with Clopidogrel (3.5%) in the acute phase; rates were 2.2% and 1.6% respectively after 1 month.
Gynecomastia
In PLATO, gynecomastia was reported by 0.23% of men on ticagrelor and 0.05% on Clopidogrel.
Other sex-hormonal adverse reactions, including sex organ malignancies, did not differ between the two treatment groups in PLATO.
Lab abnormalities
Serum Uric Acid:
Serum uric acid levels increased approximately 0.6 mg/dL from baseline on Ticagrelor and approximately 0.2 mg/dL on Clopidogrel in PLATO. The difference disappeared within 30 days of discontinuing treatment. Reports of gout did not differ between treatment groups in PLATO (0.6% in each group).
Serum Creatinine:
In PLATO, a >50% increase in serum creatinine levels was observed in 7.4% of patients receiving Ticagrelor compared to 5.9% of patients receiving Clopidogrel. The increases typically did not progress with ongoing treatment and often decreased with continued therapy. Evidence of reversibility upon discontinuation was observed even in those with the greatest on treatment increases. Treatment groups in PLATO did not differ for renal-related serious adverse events such as acute renal failure, chronic renal failure, toxic nephropathy, or oliguria.
Immune system disorders – Hypersensitivity reactions including angioedema. See Contraindications.
## Postmarketing Experience
There is limited information about Postmarketing Experience of Ticagrelor tablet in pediatric patients.
# Drug Interactions
Effects of other drugs
Ticagrelor is predominantly metabolized by CYP3A4 and to a lesser extent by CYP3A5. Ticagrelor is also a p-glycoprotein (P-gp) substrate.
- CYP3A inhibitors
- Avoid use of strong inhibitors of CYP3A (e.g., ketoconazole, itraconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir and telithromycin). See Warnings and Pharmacology.
- CYP3A inducers
- Avoid use with potent inducers of CYP3A (e.g., rifampin, dexamethasone, phenytoin, carbamazepine and phenobarbital) See Contraindications, Pharmacology and Warnings.
- Aspirin
- See Pharmacology and Warnings.
Effect of ticagrelor on other drugs.
Ticagrelor is an inhibitor of CYP3A4/5 and the P-glycoprotein transporter.
- Simvastatin, lovastatin
- Ticagrelor will result in higher serum concentrations of simvastatin and lovastatin because these drugs are metabolized by CYP3A4. Avoid simvastatin and lovastatin doses greater than 40 mg. See Pharmacology.
- Digoxin
- Digoxin: Because of inhibition of the P-glycoprotein transporter, monitor digoxin levels with initiation of or any change in ticagrelor therapy. See Pharmacology
- Other Concomitant Therapy
- Ticagrelor can be administered with unfractionated or low-molecular-weight heparin, GPIIb/IIIa inhibitors, proton pump inhibitors, beta-blockers, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers.
# Use in Specific Populations
### Pregnancy
- Pregnancy Category (FDA): C
- Pregnancy Category (AUS): Ticagrelor is not included in Australian Drug Evaluation Committee (ADEC) Pregnancy Categories.
- There are no adequate and well-controlled studies of ticagrelor use in pregnant women. In animal studies, ticagrelor caused structural abnormalities at maternal doses about 5 to 7 times the maximum recommended human dose (MRHD) based on body surface area. ticagrelor should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- In reproductive toxicology studies, pregnant rats received ticagrelor during organogenesis at doses from 20 to 300 mg/kg/day. The lowest dose was approximately the same as the MRHD of 90 mg twice daily for a 60 kg human on a mg/m2 basis. Adverse outcomes in offspring occurred at doses of 300 mg/kg/day (16.5 times the MRHD on a mg/m2 basis) and included supernumerary liver lobe and ribs, incomplete ossification of sternebrae, displaced articulation of pelvis, and misshapen/misaligned sternebrae. When pregnant rabbits received ticagrelor during organogenesis at doses from 21 to 63 mg/kg/day, fetuses exposed to the highest maternal dose of 63 mg/kg/day (6.8 times the MRHD on a mg/m2 basis) had delayed gall bladder development and incomplete ossification of the hyoid, pubis and sternebrae occurred.
- In a prenatal/postnatal study, pregnant rats received ticagrelor at doses of 10 to 180 mg/kg/day during late gestation and lactation. Pup death and effects on pup growth were observed at 180 mg/kg/day (approximately 10 times the MRHD on a mg/m2 basis). Relatively minor effects such as delays in pinna unfolding and eye opening occurred at doses of 10 and 60 mg/kg (approximately one-half and 3.2 times the MRHD on a mg/m2 basis).
### Labor and Delivery
There is limited information about Labor and Delivery of Ticagrelor tablet in patients.
### Nursing Mothers
There is limited information about Nursing Mothers of Ticagrelor tablet in patients.
### Pediatric Use
The safety and effectiveness of ticagrelor in pediatric patients have not been established.
### Geriatric Use
- In PLATO, 43% of patients were ≥65 years of age and 15% were ≥75 years of age. The relative risk of bleeding was similar in both treatment and age groups.
- No overall differences in safety or effectiveness were observed between these patients and younger patients. While this clinical experience has not identified differences in responses between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out.
Clinical Pharmacology.
### Gender
There is no FDA guidance on the use of Ticagrelor with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ticagrelor with respect to specific racial populations.
### Renal Impairment
No dosage adjustment is needed in patients with renal impairment. Patients receiving dialysis have not been studied [see Clinical Pharmacology.
### Hepatic Impairment
- Ticagrelor has not been studied in the patients with moderate or severe hepatic impairment. Ticagrelor is metabolized by the liver and impaired hepatic function can increase risks for bleeding and other adverse events. Hence, ticagrelor is contraindicated for use in patients with severe hepatic impairment and its use should be considered carefully in patients with moderate hepatic impairment. No dosage adjustment is needed in patients with mild hepatic impairment [see Contraindications, Warnings and Precautions (5.3) and Clinical Pharmacology.
### Immunocompromised Patients
There is no FDA guidance one the use of Ticagrelor in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- [[Orall.
- Initiate ticagrelor treatment with a 180 mg (two 90 mg tablets) loading dose and continue treatment with 90 mg twice daily.
- After the initial loading dose of aspirin (usually 325 mg), use ticagrelor with a daily maintenance dose of aspirin of 75-100 mg.
- ACS patients who have received a loading dose of clopidogrel may be started on ticagrelor.
- ticagrelor can be administered with or without food.
- A patient who misses a dose of ticagrelor should take one 90 mg tablet (their next dose) at its scheduled time.
### Monitoring
# IV Compatibility
# Overdosage
# Pharmacology
## Mechanism of Action
- Ticagrelor and its major metabolite reversibly interact with the platelet P2Y12 ADP-receptor to prevent signal transduction and platelet activation. Ticagrelor and its active metabolite are approximately equipotent.
- The inhibition of platelet aggregation (IPA) by ticagrelor and clopidogrel was compared in a 6 week study examining both acute and chronic platelet inhibition effects in response to 20 μM ADP as the platelet aggregation agonist.
- The onset of IPA was evaluated on Day 1 of the study following loading doses of 180 mg ticagrelor or 600 mg clopidogrel. As shown in Figure 2, IPA was higher in the ticagrelor group at all time points. The maximum IPA effect of ticagrelor was reached at around 2 hours, and was maintained for at least 8 hours.
- The offset of IPA was examined after 6 weeks on ticagrelor 90 mg twice daily or clopidogrel 75 mg daily, again in response to 20 μM ADP.
- As shown in Figure 3, mean maximum IPA following the last dose of ticagrelor was 88% and 62% for clopidogrel. The insert in Figure 3 shows that after 24 hours, IPA in the ticagrelor group (58%) was similar to IPA in clopidogrel group (52%), indicating that patients who miss a dose of ticagrelor would still maintain IPA similar to the trough IPA of patients treated with clopidogrel. After 5 days, IPA in the ticagrelor group was similar to IPA in the placebo group. It is not known how either bleeding risk or thrombotic risk track with IPA, for either ticagrelor or clopidogrel.
Figure 2 - Mean inhibition of platelet aggregation (±SE) following single oral doses of placebo, 180 mg ticagrelor or 600 mg clopidogrel
- Transitioning from clopidogrel to ticagrelor resulted in an absolute IPA increase of 26.4% and from ticagrelor to clopidogrel resulted in an absolute IPA decrease of 24.5%. Patients can be transitioned from clopidogrel to ticagrelor without interruption of antiplatelet effect [see dosage and Administration (2) .
## Structure
- Ticagrelor cyclopentyltriazolopyrimidine, inhibitor of platelet activation and aggregation mediated by the P2Y12 ADP-receptor. Chemically it is (1S,2S,3R,5S)-3-[7-{[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H-[1,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol. The empirical formula of ticagrelor is C23H28F2N6O4S and its molecular weight is 522.57. The chemical structure of ticagrelor is:
- Ticagrelor is a crystalline powder with an aqueous solubility of approximately 10 μg/mL at room temperature.
- Ticagrelor tablets for oral administration contain 90 mg of ticagrelor and the following ingredients: mannitol, dibasic calcium phosphate, sodium starch glycolate, hydroxypropyl cellulose, magnesium stearate, hydroxypropyl methylcellulose, titanium dioxide, talc, polyethylene glycol 400, and ferric oxide yellow.
## Pharmacodynamics
- The inhibition of platelet aggregation (IPA) by ticagrelor and clopidogrel was compared in a 6 week study examining both acute and chronic platelet inhibition effects in response to 20 μM ADP as the platelet aggregation agonist.
- The onset of IPA was evaluated on Day 1 of the study following loading doses of 180 mg ticagrelor or 600 mg clopidogrel. As shown in Figure 2, IPA was higher in the ticagrelor group at all time points. The maximum IPA effect of ticagrelor was reached at around 2 hours, and was maintained for at least 8 hours.
- The offset of IPA was examined after 6 weeks on ticagrelor 90 mg twice daily or clopidogrel 75 mg daily, again in response to 20 μM ADP.
- As shown in Figure 3, mean maximum IPA following the last dose of ticagrelor was 88% and 62% for clopidogrel. The insert in Figure 3 shows that after 24 hours, IPA in the ticagrelor group (58%) was similar to IPA in clopidogrel group (52%), indicating that patients who miss a dose of ticagrelor would still maintain IPA similar to the trough IPA of patients treated with clopidogrel. After 5 days, IPA in the ticagrelor group was similar to IPA in the placebo group. It is not known how either bleeding risk or thrombotic risk track with IPA, for either ticagrelor or clopidogrel.
Figure 2 - Mean inhibition of platelet aggregation (±SE) following single oral doses of placebo, 180 mg ticagrelor or 600 mg clopidogrel
- Transitioning from clopidogrel to ticagrelor resulted in an absolute IPA increase of 26.4% and from ticagrelor to clopidogrel resulted in an absolute IPA decrease of 24.5%. Patients can be transitioned from clopidogrel to ticagrelor without interruption of antiplatelet effect [see dosage and Administration (2) .
## Pharmacokinetics
- Ticagrelor demonstrates dose proportional pharmacokinetics, which are similar in patients and healthy volunteers.
Absorption
- Absorption of ticagrelor occurs with a median tmax of 1.5 h (range 1.0–4.0). The formation of the major circulating metabolite AR-C124910XX (active) from ticagrelor occurs with a median tmax of 2.5 h (range 1.5-5.0).
- The mean absolute bioavailability of ticagrelor is about 36%, (range 30%-42%). Ingestion of a high-fat meal had no effect on ticagrelor Cmax, but resulted in a 21% increase in AUC. The Cmax of its major metabolite was decreased by 22% with no change in AUC. Ticagrelor can be taken with or without food.
Distribution
- The steady state volume of distribution of ticagrelor is 88 L. Ticagrelor and the active metabolite are extensively bound to human plasma proteins (>99%).
Metabolism
- CYP3A4 is the major enzyme responsible for ticagrelor metabolism and the formation of its major active metabolite. Ticagrelor and its major active metabolite are weak P-glycoprotein substrates and inhibitors. The systemic exposure to the active metabolite is approximately 30-40% of the exposure of ticagrelor.
Excretion
- The primary route of ticagrelor elimination is hepatic metabolism. When radiolabeled ticagrelor is administered, the mean recovery of radioactivity is approximately 84% (58% in feces, 26% in urine). Recoveries of ticagrelor and the active metabolite in urine were both less than 1% of the dose. The primary route of elimination for the major metabolite of ticagrelor is most likely to be biliary secretion. The mean t1/2 is approximately 7 hours for ticagrelor and 9 hours for the active metabolite.
Special Populations
- The effects of age, gender, ethnicity, renal impairment and mild hepatic impairment on the pharmacokinetics of ticagrelor are presented in Figure 4. Effects are modest and do not require dose adjustment.
- Figure 4 - Impact of intrinsic factors on the pharmacokinetics of ticagrelor
Pediatric
- Ticagrelor has not been evaluated in a pediatric population [see Use in Specific Populations (8.4)].
Body Weight
- No dose adjustment is necessary for ticagrelor based on weight.
Smoking
- Habitual smoking increased population mean clearance of ticagrelor by approximately 22% when compared to non-smokers. No dose adjustment is necessary for ticagrelor based on smoking status.
Effects of Other Drugs on Ticagrelor
- CYP3A4 is the major enzyme responsible for ticagrelor metabolism and the formation of its major active metabolite. The effects of other drugs on the pharmacokinetics of ticagrelor are presented in Figure 5 as change relative to ticagrelor given alone (test/reference). Strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, and clarithromycin) substantially increase ticagrelor exposure. Moderate CYP3A inhibitors have lesser effects (e.g., diltiazem). CYP3A inducers (e.g., rifampin) substantially reduce ticagrelor blood levels. P-gp inhibitors (e.g. cyclosporine) increase ticagrelor exposure.
Effects of Brilinta on Other Drugs
- In vitro metabolism studies demonstrate that ticagrelor and its major active metabolite are weak inhibitors of CYP3A4, potential activators of CYP3A5 and inhibitors of the P-gp transporter. Ticagrelor and AR-C124910XX were shown to have no inhibitory effect on human CYP1A2, CYP2C19, and CYP2E1 activity. For specific in vivo effects on the pharmacokinetics of simvastatin, atorvastatin, ethinyl estradiol, levonorgesterol, tolbutamide, digoxin and cyclosporine, see Figure 6.
## Nonclinical Toxicology
Carcinogenesis
- Ticagrelor was not carcinogenic in the mouse at doses up to 250 mg/kg/day or in the male rat at doses up to 120 mg/kg/day (19 and 15 times the MRHD of 90 mg twice daily on the basis of AUC, respectively). Uterine carcinomas, uterine adenocarcinomas and hepatocellular adenomas were seen in female rats at doses of 180 mg/kg/day (29-fold the maximally recommended dose of 90 mg twice daily on the basis of AUC), whereas 60 mg/kg/day (8-fold the MRHD based on AUC) was not carcinogenic in female rats.
Mutagenesis
- Ticagrelor did not demonstrate genotoxicity when tested in the Ames bacterial mutagenicity test, mouse lymphoma assay and the rat micronucleus test. The active O-demethylated metabolite did not demonstrate genotoxicity in the Ames assay and mouse lymphoma assay.
Impairment of Fertility
- Ticagrelor had no effect on male fertility at doses up to 180 mg/kg/day or on female fertility at doses up to 200 mg/kg/day (>15-fold the MRHD on the basis of AUC). Doses of ≥10 mg/kg/day given to female rats caused an increased incidence of irregular duration estrus cycles (1.5-fold the MRHD based on AUC).
# Clinical Studies
- The clinical evidence for the effectiveness of Brilinta is derived from PLATO, a randomized double-blind study comparing Brilinta (N=9333) to clopidogrel (N=9291), both given in combination with aspirin and other standard therapy, in patients with acute coronary syndromes (ACS). Patients were treated for at least 6 months and for up to 12 months. Study endpoints were obtained until the study was complete, even if drug was discontinued.
- Patients who presented within 24 hours of onset of the most recent episode of chest pain or symptoms were randomized to receive Brilinta or clopidogrel. Patients who had already been treated with clopidogrel could be enrolled and randomized to either study treatment. Patients could be included whether there was intent to manage the ACS medically or invasively, but patient randomization was not stratified by this intent. Subjects in the clopidogrel arm were treated with an initial loading dose of clopidogrel 300 mg, if previous clopidogrel therapy had not been given prior to randomization. Patients undergoing PCI could receive an additional 300 mg of clopidogrel at investigator discretion. All subjects randomized to Brilinta received a loading dose of 180 mg followed by a maintenance dose of 90 mg twice daily. Concomitant aspirin was recommended at a loading dose of 160-500 mg. A daily maintenance dose of aspirin 75-100 mg was recommended, but higher maintenance doses of aspirin were allowed according to local judgment.
- Because of ticagrelor’s metabolism by CYP3A enzymes, the protocol recommended limiting the maximum dosage of simvastatin and lovastatin to 40 mg in both study arms. * Because of an increased bleeding risk, the study excluded patients with previous intracranial hemorrhage, a gastrointestinal bleed within the past 6 months, or other factors that predispose to bleeding.
- PLATO patients were predominantly male (72%) and Caucasian (92%). About 43% of patients were >65 years and 15% were >75 years.
- The study’s primary endpoint was the composite of first occurrence of cardiovascular death, non-fatal MI (excluding silent MI), or non-fatal stroke. The components were assessed as secondary endpoints.
- Median exposure to study drug was 277 days. About half of the patients received pre-study clopidogrel and about 99% of the patients received aspirin at some time during PLATO. About 35% of patients were receiving a statin at baseline and 93% received a statin sometime during PLATO.
- Table 4 shows the study results for the primary composite endpoint and the contribution of each component to the primary endpoint. Separate secondary endpoint analyses are shown for the overall occurrence of CV death, MI, and stroke and overall mortality.
- The difference between treatments on the composite resulted from effects on CV death and MI; each was statistically significant when considered as a secondary endpoint and there was no beneficial effect on strokes. For all-cause mortality the benefit was also statistically significant (p = 0.0003) with a hazard ratio of 0.78.
- Among 11289 patients with PCI receiving any stent during PLATO, there was a lower risk of stent thrombosis (1.3% for adjudicated “definite”) than with clopidogrel (1.9%) (HR 0.67, 95% CI 0.50-0.91; p=0.0091). The results were similar for drug-eluting and bare metal stents.
The Kaplan-Meier curve (Figure 7) shows time to first occurrence of the primary composite endpoint of CV death, non-fatal MI or non-fatal stroke in the overall study.
Figure 7 - Time to First Occurrence of CV death, MI, or Stroke in PLATO
- The curves separate by 30 days (RRR 12%) and continue to diverge throughout the 12 month treatment period (RRR 16%).
- A wide range of demographic, concurrent baseline medications, and other treatment differences were examined for their influence on outcome. Many of these are shown in Figure 8. Such analyses must be interpreted cautiously, as differences can reflect the play of chance among a large number of analyses. Most of the analyses show effects consistent with the overall results, but there are two marked exceptions: a finding of heterogeneity by region and a strong influence of the maintenance dose of aspirin. * These are considered further below.
- Most of the characteristics shown are baseline characteristics, but some reflect post-randomization determinations (e.g., final diagnosis, aspirin maintenance dose, use of PCI). Patients were not stratified by initial diagnosis, but the effect in the unstable angina subset (determined after randomization) appeared smaller than the effect in the NSTEMI and STEMI subsets. The results in the subsets based on final diagnosis (STEMI, NSTEMI and unstable angina) are also presented in Figure 8.
Figure 8 - Subgroup analyses of PLATO
Regional Differences
- Results in the rest of the world compared to effects in North America (US and Canada) show a smaller effect in North America, numerically inferior to the control and driven by the US subset. The statistical test for the US/non-US comparison is statistically significant (p=0.009), and the same trend is present for both CV death and non-fatal MI. The individual results and nominal p-values, like all subset analyses, need cautious interpretation, and they could represent chance findings. The consistency of the differences in both the CV mortality and non-fatal MI components, however, supports the possibility that the finding is reliable.
- A wide variety of baseline and procedural differences between the US and non-US (including intended invasive vs. planned medical management, use of GPIIb/IIIa inhibitors, use of drug eluting vs. bare-metal stents) were examined to see if they could account for regional differences, but with one exception, aspirin maintenance dose, these differences did not appear to lead to differences in outcome.
aspirin Dose
- The PLATO protocol left the choice of aspirin maintenance dose up to the investigator and use patterns were very different in the US and elsewhere, with about 8% of non-US investigators using aspirin doses above 100 mg, and about 2% using doses above 300 mg, in contrast with US practice, where 57% of patients received doses above 100 mg and 54% received doses above 300 mg. Overall results favored Brilinta when used with low maintenance doses (≤ 100 mg) of aspirin, and results analyzed by aspirin dose were similar in the US and elsewhere. Figure 8 shows overall results by median aspirin dose. Table 5 shows results by region and dose.
Table 5 - PLATO: CV Death, MI, Stroke by maintenance aspirin dose in the US and outside the US
- Like any unplanned subset analysis, especially one where the characteristic is not a true baseline characteristic (but may be determined by usual investigator practice), the above analyses must be treated with caution. It is notable, however, that aspirin dose predicts outcome in both regions with a similar pattern, and that the pattern is similar for the two major components of the primary endpoint, CV death and non-fatal MI.
Despite the need to treat such results cautiously, there appears to be good reason to restrict aspirin maintenance dosage accompanying ticagrelor to 100 mg. Higher doses do not have an established benefit in the ACS setting, and there is a strong suggestion that use of such doses reduces the effectiveness of Brilinta.
Pharmacogenetics
- In a genetic substudy of PLATO (n=10,285), the effects of Brilinta compared to clopidogrel on thrombotic events and bleeding were not significantly affected by CYP2C19 genotype.
# How Supplied
- Brilinta (ticagrelor) 90 mg is supplied as a round, biconvex, yellow, film-coated tablet marked with a “90” above “T” on one side.
- Bottles of 14 – NDC 0186-0777-28.
- Bottles of 60 – NDC 0186-0777-60.
- Bottles of 180 – NDC 0186-0777-18.
- 100 count Hospital Unit Dose – NDC 0186-0777-39.
- Store at 25°C (77°F); excursions permitted to 15°-30°C (59°- 86°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Information
For patient information about ticagrelor, click here.
# Precautions with Alcohol
Alcohol-Ticagrelor interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
Brilinta®
# Look-Alike Drug Names
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Brilinta | |
2bacb2a2ff2a96979dc7d375151b1c4dadc5c551 | wikidoc | Vicia faba | Vicia faba
# Overview
Vicia faba, the broad bean, fava bean, faba bean, horse bean, field bean, tic bean is a species of bean (Fabaceae) native to north Africa and southwest Asia, and extensively cultivated elsewhere. Although usually classified in the same genus Vicia as the vetches, some botanists treat it in a separate monotypic genus as Faba sativa Moench.
It is a rigid, erect plant 0.5-1.7 m tall, with stout stems with a square cross-section. The leaves are 10-25 cm long, pinnate with 2-7 leaflets, and of a distinct glaucous grey-green colour; unlike most other vetches, the leaves do not have tendrils for climbing over other vegetation. The flowers are 1-2.5 cm long, with five petals, the standard petal white, the wing petals white with a black spot (true black, not deep purple or blue as is the case in many "black" colourings ), and the keel petals white. The fruit is a broad leathery pod, green maturing blackish-brown, with a densely downy surface; in the wild species, the pods are 5-10 cm long and 1 cm diameter, but many modern cultivars developed for food use have pods 15-25 cm long and 2-3 cm thick. Each pod contains 3-8 seeds; round to oval and 5-10 mm diameter in the wild plant, usually flattened and up to 20-25 mm long, 15 mm broad and 5-10 mm thick in food cultivars. Vicia faba has a diploid (2n) chromosome number of 12, meaning that each cell in the plant has 12 chromosomes (6 homologous pairs). Five pairs are acrocentric chromosomes and 1 pair is metacentric.
# Cultivation and uses
Broad beans have a long tradition of cultivation in Old World agriculture, being among the most ancient plants in cultivation and also among the easiest to grow. It is believed that along with lentils, peas, and chickpeas, they became part of the eastern Mediterranean diet in around 6000 BC or earlier. They are still often grown as a cover crop to prevent erosion because they can over-winter and because as a legume, they fix nitrogen in the soil. These commonly cultivated plants can be attacked by fungal diseases, such as Rust (Uromyces viciae-fabae) and Chocolate Spot (Botrytis fabae).
In much of the Anglophone world, the name broad bean is used for the large-seeded cultivars grown for human food, while horse bean and field bean refer to cultivars with smaller, harder seeds (more like the wild species) used for animal feed, though their stronger flavour is preferred in some human food recipes, such as falafel. The term fava bean (from the Italian fava, meaning "bean") is its most common name in the United States, with Broad Bean being the most common name in the UK.
# Culinary uses
Broad beans are eaten while still young and tender, enabling harvesting to begin as early as the middle of spring for plants started under glass or over-wintered in a protected location, but even the maincrop sown in early spring will be ready from mid to late summer. Horse beans, left to mature fully, are usually harvested in the late autumn.
The beans can be fried, causing the skin to split open, and then salted and/or spiced to produce a savory crunchy snack. These are popular in China, Peru (habas saladas), Mexico (habas con chile) and in Thailand (where their name means "open-mouth nut").
In the Sichuan cuisine of China, broad beans are combined with soybeans and chili peppers to produce a spicy fermented bean paste called doubanjiang.
In most Arab countries the fava bean is used for a breakfast meal called ful medames. Ful medames is usually crushed fava beans in a sauce although the Fava beans do not have to be crushed.
# Health issues
Broad beans are rich in tyramine, and thus should be avoided by those taking monoamine oxidase (MAOI) inhibitors.
Raw broad beans contain vicine, isouramil and convicine, which can induce hemolytic anemia in patients with the hereditary condition glucose-6-phosphate dehydrogenase deficiency (G6PD). This potentially fatal condition is called "favism" after the fava bean.
Broad beans are rich in L-dopa, a substance used medically in the treatment of Parkinson's disease. L-dopa is also a natriuretic agent, which might help in controlling hypertension. Some also use fava beans as a natural alternative to drugs like Viagra, citing a link between L-dopa production and the human libido.
The Broad beans is widely cultivated in district Kech and Panjgur of Balochistan Province of Pakistan and eastern province of Iran. In Balochi language it is called Bakalaink and Baqala in Persian The elders generally restrict the young children from eating it raw(when unmatured)because it can cause constipation and jaundice like symptoms.
# Other uses
- In ancient Greece and Rome, beans were used in voting; a white bean being used to cast a yes vote, and a black bean for no.
- In Ubykh culture, throwing beans on the ground and interpreting the pattern in which they fall was a common method of divination (favomancy), and the word for "bean-thrower" in that language has become a generic term for seers and soothsayers in general.
- In Italy, broad beans are traditionally sown on November 2, All Souls Day. Small cakes made in the shape of broad beans (though not of them) are known as fave dei morti or "beans of the dead". According to tradition, Sicily once experienced a failure of all crops other than the beans; the beans kept the population from starvation, and thanks were given to Saint Joseph. Broad beans subsequently became traditional on Saint Joseph's Day altars in many Italian communities. Some people carry a broad bean for good luck; some believe that if one carries a broad bean, one will never be without the essentials of life. In Rome, on the first of May Roman families traditionally eat fresh fava beans with Pecorino Romano cheese during a daily excursion in the Campagna.
- In Portugal a Christmas Cake called Bolo Rei is baked with a "Fava" bean inside.
- In ancient Greece and Rome, beans were used as a food for the dead, such as during the annual Lemuria festival. In some folk legends, such as in Estonia and the common Jack and the Beanstalk story, magical beans grow tall enough to bring the hero to the clouds. The Grimm Brothers collected a story in which a bean splits its sides laughing at the failure of others. Dreaming of a bean is sometimes said to be a sign of impending conflict, though others said that they caused bad dreams. Pliny claimed that they acted as a laxative. European folklore also claims that planting beans on Good Friday or during the night brings good luck.
# Cultural references
- The name and modern term Fabian derives from this bean.
- In the 1992 videogame OutRunners, an anthropomorphic broad bean character is featured on billboards and the start of the game called "Broad Bean," a parody of Bibendum (the Michelin man), presumably the mascot of the fictional company sponsoring the race, Sam Spree.
- In the film The Silence of the Lambs, Hannibal Lecter mentions that he once ate the liver of a census taker "with some fava beans and a nice Chianti." | Vicia faba
# Overview
Vicia faba, the broad bean, fava bean, faba bean, horse bean, field bean, tic bean is a species of bean (Fabaceae) native to north Africa and southwest Asia, and extensively cultivated elsewhere. Although usually classified in the same genus Vicia as the vetches, some botanists treat it in a separate monotypic genus as Faba sativa Moench.
It is a rigid, erect plant 0.5-1.7 m tall, with stout stems with a square cross-section. The leaves are 10-25 cm long, pinnate with 2-7 leaflets, and of a distinct glaucous grey-green colour; unlike most other vetches, the leaves do not have tendrils for climbing over other vegetation. The flowers are 1-2.5 cm long, with five petals, the standard petal white, the wing petals white with a black spot (true black, not deep purple or blue as is the case in many "black" colourings [1]), and the keel petals white. The fruit is a broad leathery pod, green maturing blackish-brown, with a densely downy surface; in the wild species, the pods are 5-10 cm long and 1 cm diameter, but many modern cultivars developed for food use have pods 15-25 cm long and 2-3 cm thick. Each pod contains 3-8 seeds; round to oval and 5-10 mm diameter in the wild plant, usually flattened and up to 20-25 mm long, 15 mm broad and 5-10 mm thick in food cultivars. Vicia faba has a diploid (2n) chromosome number of 12, meaning that each cell in the plant has 12 chromosomes (6 homologous pairs). Five pairs are acrocentric chromosomes and 1 pair is metacentric.
# Cultivation and uses
Broad beans have a long tradition of cultivation in Old World agriculture, being among the most ancient plants in cultivation and also among the easiest to grow. It is believed that along with lentils, peas, and chickpeas, they became part of the eastern Mediterranean diet in around 6000 BC or earlier. They are still often grown as a cover crop to prevent erosion because they can over-winter and because as a legume, they fix nitrogen in the soil. These commonly cultivated plants can be attacked by fungal diseases, such as Rust (Uromyces viciae-fabae) and Chocolate Spot (Botrytis fabae).
In much of the Anglophone world, the name broad bean is used for the large-seeded cultivars grown for human food, while horse bean and field bean refer to cultivars with smaller, harder seeds (more like the wild species) used for animal feed, though their stronger flavour is preferred in some human food recipes, such as falafel. The term fava bean (from the Italian fava, meaning "bean") is its most common name in the United States, with Broad Bean being the most common name in the UK.
# Culinary uses
Broad beans are eaten while still young and tender, enabling harvesting to begin as early as the middle of spring for plants started under glass or over-wintered in a protected location, but even the maincrop sown in early spring will be ready from mid to late summer. Horse beans, left to mature fully, are usually harvested in the late autumn.
The beans can be fried, causing the skin to split open, and then salted and/or spiced to produce a savory crunchy snack. These are popular in China, Peru (habas saladas), Mexico (habas con chile) and in Thailand (where their name means "open-mouth nut").
In the Sichuan cuisine of China, broad beans are combined with soybeans and chili peppers to produce a spicy fermented bean paste called doubanjiang.
In most Arab countries the fava bean is used for a breakfast meal called ful medames. Ful medames is usually crushed fava beans in a sauce although the Fava beans do not have to be crushed.
# Health issues
Broad beans are rich in tyramine, and thus should be avoided by those taking monoamine oxidase (MAOI) inhibitors.
Raw broad beans contain vicine, isouramil and convicine, which can induce hemolytic anemia in patients with the hereditary condition glucose-6-phosphate dehydrogenase deficiency (G6PD). This potentially fatal condition is called "favism" after the fava bean.[1][2]
Broad beans are rich in L-dopa, a substance used medically in the treatment of Parkinson's disease. L-dopa is also a natriuretic agent, which might help in controlling hypertension.[3] Some also use fava beans as a natural alternative to drugs like Viagra, citing a link between L-dopa production and the human libido.[4]
The Broad beans is widely cultivated in district Kech and Panjgur of Balochistan Province of Pakistan and eastern province of Iran. In Balochi language it is called Bakalaink and Baqala in Persian The elders generally restrict the young children from eating it raw(when unmatured)because it can cause constipation and jaundice like symptoms.
# Other uses
- In ancient Greece and Rome, beans were used in voting; a white bean being used to cast a yes vote, and a black bean for no.
- In Ubykh culture, throwing beans on the ground and interpreting the pattern in which they fall was a common method of divination (favomancy), and the word for "bean-thrower" in that language has become a generic term for seers and soothsayers in general.
- In Italy, broad beans are traditionally sown on November 2, All Souls Day. Small cakes made in the shape of broad beans (though not of them) are known as fave dei morti or "beans of the dead". According to tradition, Sicily once experienced a failure of all crops other than the beans; the beans kept the population from starvation, and thanks were given to Saint Joseph. Broad beans subsequently became traditional on Saint Joseph's Day altars in many Italian communities. Some people carry a broad bean for good luck; some believe that if one carries a broad bean, one will never be without the essentials of life. In Rome, on the first of May Roman families traditionally eat fresh fava beans with Pecorino Romano cheese during a daily excursion in the Campagna.
- In Portugal a Christmas Cake called Bolo Rei is baked with a "Fava" bean inside.
- In ancient Greece and Rome, beans were used as a food for the dead, such as during the annual Lemuria festival. In some folk legends, such as in Estonia and the common Jack and the Beanstalk story, magical beans grow tall enough to bring the hero to the clouds. The Grimm Brothers collected a story in which a bean splits its sides laughing at the failure of others. Dreaming of a bean is sometimes said to be a sign of impending conflict, though others said that they caused bad dreams. Pliny claimed that they acted as a laxative. European folklore also claims that planting beans on Good Friday or during the night brings good luck.
# Cultural references
- The name and modern term Fabian derives from this bean.
- In the 1992 videogame OutRunners, an anthropomorphic broad bean character is featured on billboards and the start of the game called "Broad Bean," a parody of Bibendum (the Michelin man), presumably the mascot of the fictional company sponsoring the race, Sam Spree.
- In the film The Silence of the Lambs, Hannibal Lecter mentions that he once ate the liver of a census taker "with some fava beans and a nice Chianti." | https://www.wikidoc.org/index.php/Broad_bean | |
9bb8f245c9fabeda457cc4f43f1e9247f2c27e13 | wikidoc | Brodalumab | Brodalumab
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# Black Box Warning
# Overview
Brodalumab is a human interleukin-17 receptor A (IL-17RA) antagonist that is FDA approved for the treatment of moderate to severe plaque psoriasis in adult patients who are candidates for systemic therapy or phototherapy and have failed to respond or have lost response to other systemic therapies. There is a Black Box Warning for this drug as shown here. Common adverse reactions include arthralgia, headache, fatigue, diarrhea, oropharyngeal pain, nausea, myalgia, injection site reactions, influenza, neutropenia, and tinea infections.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Brodalumab is indicated for the treatment of moderate to severe plaque psoriasis in adult patients who are candidates for systemic therapy or phototherapy and have failed to respond or have lost response to other systemic therapies.
- The recommended brodalumab dose is 210 mg administered by subcutaneous injection at Weeks 0, 1, and 2 followed by 210 mg every 2 weeks.
- If an adequate response has not been achieved after 12 to 16 weeks of treatment with brodalumab, consider discontinuing therapy. Continued treatment beyond 16 weeks in patients who have not achieved an adequate response is not likely to result in greater success.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding brodalumab Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding brodalumab Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Brodalumab FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding brodalumab Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding brodalumab Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
- Brodalumab is contraindicated in patients with Crohn’s disease because brodalumab may cause worsening of disease.
# Warnings
- Suicidal ideation and behavior, including 4 completed suicides, occurred in subjects treated with brodalumab in the psoriasis clinical trials. There were no completed suicides in the 12-week placebo-controlled portion of the trials. Brodalumab users with a history of suicidality or depression had an increased incidence of suicidal ideation and behavior as compared to users without such a history. A causal association between treatment with brodalumab and increased risk of suicidal ideation and behavior has not been established.
- Prescribers should weigh the potential risks and benefits before using brodalumab in patients with a history of depression or suicidality. Patients with new or worsening symptoms of depression or suicidality should be referred to a mental health professional, as appropriate. Advise patients and caregivers to seek medical attention for manifestations of suicidal ideation and behavior, new onset or worsening depression, anxiety, or other mood changes. Prescribers should also re-evaluate the risks and benefits of continuing treatment with brodalumab if such events occur.
- Because of the observed suicidal ideation and behavior in subjects treated with brodalumab, if an adequate response to brodalumab has not been achieved within 12 to 16 weeks, consider discontinuing therapy.
- Brodalumab is available only through a restricted program under a REMS.
- Brodalumab is available only through a restricted program under a REMS called the brodalumab REMS Program because of the observed suicidal ideation and behavior in subjects treated with brodalumab.
- Notable requirements of the brodalumab REMS Program include the following:
- Prescribers must be certified with the program.
- Patients must sign a Patient-Prescriber Agreement Form.
- Pharmacies must be certified with the program and must only dispense to patients who are authorized to receive brodalumab.
- Further information, including a list of qualified pharmacies, is available at www.SILIQREMS.com or by calling the brodalumab REMS Program Call Center at 855-511-6135.
- Brodalumab may increase the risk of infections. In clinical trials, subjects treated with brodalumab had a higher rate of serious infections than subjects treated with placebo (0.5% versus 0.2%) and higher rates of fungal infections (2.4% versus 0.9%). One case of cryptococcal meningitis occurred in a subject treated with brodalumab during the 12-week randomized treatment period and led to discontinuation of therapy.
- During the course of clinical trials for plaque psoriasis, the exposure-adjusted rates for infections and serious infections were similar in the subjects treated with brodalumab and those treated with ustekinumab.
- In patients with a chronic infection or a history of recurrent infection, consider the risks and benefits prior to prescribing brodalumab. Instruct patients to seek medical help if signs or symptoms of clinically important chronic or acute infection occur. If a patient develops a serious infection or is not responding to standard therapy for the infection, monitor the patient closely and discontinue brodalumab therapy until the infection resolves.
- Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with brodalumab. Do not administer brodalumab to patients with active TB infection. Initiate treatment for latent TB prior to administering brodalumab.
- Consider anti-TB therapy prior to initiation of brodalumab in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed. Closely monitor patients receiving brodalumab for signs and symptoms of active TB during and after treatment.
- In psoriasis trials, which excluded subjects with active Crohn’s disease, Crohn’s disease occurred in one subject during treatment with brodalumab and led to discontinuation of therapy. In other trials, exacerbation of Crohn’s disease was observed with brodalumab use.
- Brodalumab is contraindicated in patients with Crohn’s disease.
- Discontinue brodalumab if the patient develops Crohn’s disease while taking brodalumab.
- Avoid use of live vaccines in patients treated with brodalumab. No data are available on the ability of live or inactive vaccines to elicit an immune response in patients being treated with brodalumab.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- The overall safety population included 4558 subjects (3066 brodalumab, 613 ustekinumab, 879 placebo) in controlled clinical trials and open-label extension studies. The majority of subjects were male (69%), white (91%), and aged 40-64 years old (58%). One-third of subjects reported previous biologic use prior to enrollment. Across the clinical development program, 4464 subjects received at least one dose of brodalumab; 3755 subjects were exposed to brodalumab for at least 1 year.
- Data from one multicenter, randomized, placebo-controlled trial (Trial 1), two multicenter, randomized, placebo- and active-controlled trials (Trials 2 and 3), and one dose-finding trial (Trial 4) in plaque psoriasis were pooled to evaluate the safety of brodalumab (210 mg weekly at Weeks 0, 1, and 2, followed by treatments every 2 weeks ) compared to placebo for up to 12 weeks after treatment initiation.
- During the 12-week, randomized treatment period, about 1% of the subjects in the treatment groups (brodalumab, ustekinumab and placebo) discontinued treatment because of adverse events. Adverse events leading to discontinuation of brodalumab included neutropenia, arthralgia, and urticaria. The proportion of subjects who developed serious adverse events was similar among the brodalumab, ustekinumab, and placebo groups.
- TABLE 1 summarizes the adverse reactions that occurred at a rate of at least 1% and at a higher rate in the brodalumab 210 mg Q2W group than in the placebo group during the 12-week randomized treatment period of the pooled trials.
- Adverse reactions that occurred in less than 1% of subjects in the brodalumab group through Week 12 were conjunctivitis and candida infections (including oral , genital , and esophageal versus none in the placebo group).
- Through Week 52, exposure-adjusted rates of serious adverse events were similar between subjects treated with brodalumab and those treated with ustekinumab. Through the end of the trial, the exposure-adjusted rates of treatment-emergent serious adverse events were similar to those seen in the 52-week period in the subjects treated with brodalumab.
Suicidal Ideation and Behavior
- During the 12-week randomized treatment period in the pooled trials, one subject in the brodalumab group attempted suicide and none in the placebo or ustekinumab groups. From initiation through Week 52 of the trials, suicidal ideation or behavior occurred in 7 of 4019 subjects (0.2 per 100 subject-years) treated with brodalumab and in 2 of 613 subjects (0.4 per 100 subject-years) treated with ustekinumab.
- During the course of the clinical trials for plaque psoriasis, suicidal ideation or behavior occurred in 34 of 4464 subjects treated with brodalumab (0.37 per 100 subject-years). Eight of the 10 subjects who attempted or completed suicide had a history of depression and/or suicidal ideation or behavior.
Infections
- During the 12-week randomized treatment period, infections occurred in 25.4% of the brodalumab group compared to 23.4% of the placebo group. The majority of infections consisted of nasopharyngitis, upper respiratory tract infection, pharyngitis, urinary tract infections, bronchitis, and influenza, and did not necessitate treatment discontinuation. The brodalumab group had a higher rate of fungal infections compared to the placebo group (1.8% vs 0.9%). The fungal infections were primarily non-serious skin and mucosal candida infections.
Neutropenia
- During the 12-week randomized treatment period, neutropenia occurred in 0.7% of subjects in the brodalumab group. Most adverse reactions of neutropenia were transient. In subjects with normal absolute neutrophil count (ANC) at baseline, a reduction in ANC occurred in 6.8% of subjects in the brodalumab group, compared to 3.3% in the ustekinumab group, and 3.6% in the placebo group. Neutropenia ≥ Grade 3 (< 1000/mm3) occurred in 0.5% of subjects in the brodalumab group compared to 0.2% of subjects in the ustekinumab group and none in the placebo group. From Week 0 to end of trial, the exposure-adjusted rate of treatment-emergent neutropenia was 0.4 per 100 subject-years (0.1 per 100 subject-years were ≥ Grade 3). No serious infections were associated with cases of neutropenia.
### Immunogenicity
- As with all therapeutic proteins, there is potential for immunogenicity with brodalumab. Approximately 3% of subjects treated with brodalumab developed antibodies to brodalumab through the 52-week treatment period. Of the subjects who developed antibodies to brodalumab, none had antibodies that were classified as neutralizing. However, the assay to test for neutralizing antibodies had limitations detecting neutralizing antibodies in the presence of brodalumab; therefore, the incidence of neutralizing antibody development could be underestimated.
- The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to brodalumab with the incidence of antibodies to other products may be misleading.
## Postmarketing Experience
There is limited information regarding Brodalumab Postmarketing Experience in the drug label.
# Drug Interactions
- Live Vaccinations
- CYP450 Substrates
- Avoid use of live vaccines in patients treated with brodalumab.
- The formation of CYP450 enzymes can be altered by increased levels of certain cytokines (e.g., IL-1, IL-6, IL-10, TNFα, IFN) during chronic inflammation. Treatment with brodalumab may modulate serum levels of some cytokines.
- Therefore, upon initiation or discontinuation of brodalumab in patients who are receiving concomitant drugs which are CYP450 substrates, particularly those with a narrow therapeutic index, consider monitoring for effect (e.g., for warfarin) or drug concentration (e.g., for cyclosporine) and consider dosage modification of the CYP450 substrate.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- There are no human data on brodalumab use in pregnant women to inform a drug associated risk. Human IgG antibodies are known to cross the placental barrier; therefore, brodalumab may be transmitted from the mother to the developing fetus. In a combined embryofetal development and pre- and post-natal development study, no adverse developmental effects were observed in infants born to pregnant monkeys after subcutaneous administration of brodalumab during organogenesis through parturition at doses up to 26 times the maximum recommended human dose (MRHD).
- The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
- A combined embryofetal development and pre- and post-natal development study was conducted in cynomolgus monkeys administered brodalumab. No brodalumab-related effects on embryofetal toxicity or malformations, or on morphological, functional or immunological development were observed in infants from pregnant monkeys administered weekly subcutaneous doses of brodalumab up to 26 times the MRHD from the beginning of organogenesis to parturition (on a mg/kg basis of 90 mg/kg/week).
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Brodalumab in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Brodalumab during labor and delivery.
### Nursing Mothers
- There are no data on the presence of brodalumab in human milk, the effects on the breastfed infant, or the effects on milk production. Brodalumab was detected in the milk of lactating cynomolgus monkeys. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for brodalumab and any potential adverse effects on the breastfed infant from brodalumab or from the underlying maternal condition.
### Pediatric Use
- The safety and effectiveness of brodalumab have not been evaluated in pediatric patients.
### Geriatic Use
- Of the 3066 plaque psoriasis subjects initially randomized to brodalumab in clinical trials, 192 (6%) were ≥ 65 years old and no subjects were ≥ 75 years old. Although no differences in safety or efficacy were observed between older and younger subjects, the number of subjects aged 65 years and older was not sufficient to determine whether they responded differently from younger subjects.
### Gender
There is no FDA guidance on the use of Brodalumab with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Brodalumab with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Brodalumab in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Brodalumab in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Brodalumab in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Brodalumab in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with brodalumab.
- Administer brodalumab subcutaneously. Each prefilled syringe is for single-dose only.
- Instruct patients to review the Medication Guide before use. Brodalumab is intended for use under the guidance and supervision of a healthcare professional. Patients may self-inject brodalumab when deemed appropriate by a healthcare professional and after proper training in subcutaneous injection technique using the prefilled syringe.
- Advise patients who are self-administering to inject the full dose and to read the Instructions for Use before administration (see Instructions for Use).
- Do not inject brodalumab into areas where the skin is tender, bruised, red, hard, thick, scaly, or affected by psoriasis.
- Allow brodalumab prefilled syringe to reach room temperature (approximately 30 minutes) before injecting. Do not warm in any other way. Do not remove the gray needle cap on the prefilled syringe while allowing it to reach room temperature.
- Visually inspect brodalumab for particles and discoloration prior to administration. brodalumab is a clear to slightly opalescent, colorless to slightly yellow solution. A few translucent to white, amorphous proteinaceous particles may be present. Do not use brodalumab if it is cloudy or discolored or if foreign matter is present.
- Instruct patients to use the prefilled syringe and to inject the full amount (1.5 mL), which provides 210 mg of brodalumab, according to the directions provided in the Instructions for Use.
### Monitoring
- Reductions in the fraction of body surface area affected, the nature and severity of psoriatic induration, erythema, and scaling are indicative of efficacy.
- TB; prior to and during therapy.
- Manifestations of suicidal ideation and behavior, new onset or worsening depression, anxiety, or other mood changes.
# IV Compatibility
There is limited information regarding the compatibility of Brodalumab and IV administrations.
# Overdosage
There is limited information regarding Brodalumab overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
- Brodalumab is a human monoclonal IgG2 antibody that selectively binds to human IL-17RA and inhibits its interactions with cytokines IL-17A, IL-17F, IL-17C, IL-17A/F heterodimer and IL-25. IL-17RA is a protein expressed on the cell surface and is a required component of receptor complexes utilized by multiple IL-17 family cytokines. Blocking IL-17RA inhibits IL-17 cytokine-induced responses including the release of pro-inflammatory cytokines and chemokines.
## Structure
There is limited information regarding Brodalumab Structure in the drug label.
## Pharmacodynamics
- Elevated levels of IL-17A, IL-17C and IL-17F are found in psoriatic plaques. Serum IL-17A levels, measured at Weeks 12, 24, and 48 of brodalumab 210 mg every 2 weeks of treatment, were higher than the baseline levels in subjects with moderate to severe plaque psoriasis. The relationship between the pharmacodynamic activity and the mechanism(s) by which brodalumab exerts its clinical effects is unknown.
## Pharmacokinetics
- Following a single subcutaneous dose of 210 mg in subjects with plaque psoriasis, brodalumab reached peak mean (±SD) serum concentration (Cmax) of 13.4±7.3 mcg/mL by approximately 3 days post dose. The mean (±SD) area-under-the-concentration-time curve (AUC) of brodalumab was 111±64 mcgday/mL.
- Following multiple subcutaneous doses of 210 mg every 2 weeks, steady-state was achieved by Week 4. The mean (±SD) Cmax was 20.6±14.6 mcg/mL and the mean (±SD) AUC over the two week dosing interval was 227±167 mcgday/mL.
- Following subcutaneous administration, brodalumab bioavailability was approximately 55%.
- Following a single subcutaneous administration of brodalumab 210 mg in subjects with plaque psoriasis, the mean (±SD) apparent volume of distribution (Vz/F) of brodalumab was 8.9±9.4 L.
- The metabolic pathway of brodalumab has not been characterized. As a human monoclonal IgG2 antibody, brodalumab is expected to be degraded into small peptides and amino acids via catabolic pathways in a manner similar to endogenous IgG.
- Following a single subcutaneous administration of brodalumab 210 mg in subjects with plaque psoriasis, the mean (±SD) apparent total clearance (CL/F) was 3.0±3.5 L/day. The clearance of brodalumab increased with decreasing doses due to nonlinear elimination.
- Brodalumab exhibited non-linear pharmacokinetics with exposures that increased greater than dose-proportionally over a dose range from 140 mg (approximately 0.67 times the recommended dose) to 350 mg (approximately 1.67 times the recommended dose) following subcutaneous administrations in subjects with plaque psoriasis.
- Brodalumab trough concentrations were lower in subjects with higher body weight.
Hepatic or Renal Impairment
- No trials were conducted to assess the effect of hepatic or renal impairment on the pharmacokinetics of brodalumab.
Age: Geriatric Population
- Population pharmacokinetic analysis indicated that age did not significantly influence the clearance of brodalumab in subjects with plaque psoriasis. Subjects who were 65 years or older had a similar brodalumab clearance as compared to subjects less than 65 years old.
- In subjects with plaque psoriasis, one week following a single subcutaneous administration of 210 mg brodalumab, the exposure of midazolam (CYP3A4 substrate) was increased by 24%.
## Nonclinical Toxicology
- Animal studies have not been conducted to evaluate the carcinogenic or mutagenic potential of brodalumab. The published literature is mixed on the potential effects on malignancy risk due to the inhibition of the IL-17RA, the pharmacological action of brodalumab. Some published literature suggests that IL-17A directly promotes cancer cell invasion, which suggests a potential beneficial effect of brodalumab. However, other reports indicate IL-17A promotes T-cell mediated tumor rejection, which suggests a potential adverse effect by brodalumab. However, inhibition of the IL-17RA with brodalumab has not been studied in these models. Therefore, the relevance of experimental findings in these models for malignancy risk in humans is unknown.
- In cynomolgus monkeys, there were no effects on fertility parameters such as changes in reproductive organs or sperm analysis following subcutaneous administration of brodalumab at dose levels up to 90 mg/kg/week for six months (26 times the MRHD on a mg/kg basis). The monkeys were not mated in this study to evaluate effects on fertility.
# Clinical Studies
- Three multicenter, randomized, double-blind, controlled trials (Trials 1, 2, and 3) enrolled a total of 4373 subjects 18 years of age and older with at least a 6-month history of moderate to severe plaque psoriasis, defined as having a minimum affected body surface area (BSA) of 10%, a Psoriasis Area and Severity Index (PASI) score ≥ 12, a static Physician’s Global Assessment (sPGA) score ≥3 in the overall assessment (plaque thickness/induration, erythema, and scaling) of psoriasis on a severity scale of 0 to 5, and who were candidates for systemic therapy or phototherapy. In all three trials, subjects were randomized to subcutaneous treatment with placebo or brodalumab 210 mg at Weeks 0, 1, and 2, followed by treatments every 2 weeks through Week 12. In the two active comparator trials (Trials 2 and 3), subjects randomized to ustekinumab received a 45 mg dose if their weight was less than or equal to 100 kg and a 90 mg dose if their weight was greater than 100 kg at Weeks 0, 4, and 16, followed by the same dose every 12 weeks.
- All three trials assessed the change from baseline to Week 12 compared to placebo in the two co-primary endpoints: 1) PASI 75, the proportion of subjects who achieved at least a 75% reduction in the PASI composite score that takes into consideration both the percentage of body surface area affected and the nature and severity of psoriatic changes (induration, erythema, and scaling) within the affected region, and 2) the proportion of subjects with an sPGA of 0 (clear) or 1 (almost clear), and at least a 2-point improvement from baseline. In Trials 2 and 3, comparisons were also made to ustekinumab for the primary endpoint of the proportion of subjects who achieved a reduction in PASI score of 100% (PASI 100) from baseline at Week 12.
- Other evaluated outcomes included the proportion of subjects who achieved an sPGA of 0 (clear) at Week 12, and the proportion of subjects who achieved a Psoriasis Symptom Inventory (PSI) score of 0 (not at all) or 1 (mild) on every item (itch, redness, scaling, burning, stinging, cracking, flaking, and pain) at Week 12. Baseline demographics and disease characteristics were generally consistent across all treatment groups in all three trials. Subjects were predominantly men (69%) and white (91%), with a mean age of 45 years. The mean baseline body weight was 90.5 kg and 28% of subjects had body weight greater than 100 kg. The baseline PASI score ranged from 9.4 to 72 (median: 17.4) and the baseline affected BSA ranged from 10 to 97% (median: 21%). Baseline sPGA scores ranged from “3 (moderate)” (58%) to “5 (very severe)” (5%).
- Approximately 21% of subjects had a history of psoriatic arthritis. Approximately 30% of subjects had previously received a biologic therapy and 12% of subjects had failed previous biologic therapy.
- The results of Trials 1, 2, and 3 are presented in TABLE 2.
- Examination of age, gender, race, use of prior systemic or phototherapy, and use of prior biologics did not identify differences in response to brodalumab among these subgroups.
- At Week 12, compared to subjects in the placebo group, a greater proportion of subjects in brodalumab 210 mg Q2W group achieved a Psoriasis Symptom Inventory (PSI) score of 0 (not at all) or 1 (mild) on every item (itch, redness, scaling, burning, stinging, cracking, flaking, pain).
- In Trial 1, subjects randomized to receive brodalumab and who were responders at Week 12 (i.e., sPGA of 0 or 1) were re-randomized to receive either placebo or brodalumab. Among responders at Week 12, 83% (69/83) of subjects re-randomized to continued treatment with brodalumab 210 mg Q2W maintained this response (sPGA of 0 or 1) at Week 52 compared to none (0/84) who were re-randomized to placebo and withdrawn from brodalumab. In addition, 87% (72/83) of subjects re-randomized to continued treatment with brodalumab 210 mg Q2W achieved PASI 75 response at Week 52 compared to none (0/84) who were re-randomized to placebo and withdrawn from brodalumab.
- Trials 2 and 3 included a re-randomized phase during which subjects originally randomized to receive brodalumab during the first 12 weeks were re-randomized to one of four brodalumab regimens at the Week 12 visit and placebo subjects were crossed over to receive brodalumab 210 mg Q2W. Subjects receiving ustekinumab continued the same treatment until crossed over at Week 52 to brodalumab 210 mg Q2W. For sPGA 0 or 1 responders at Week 12, the percentage of subjects who maintained this response at Week 52 was 79% for subjects treated with brodalumab 210 mg Q2W. For PASI 100 responders at Week 12, 72% of the subjects who continued on brodalumab 210 mg Q2W maintained the response at Week 52.
# How Supplied
- Brodalumab (brodalumab) Injection is available in a single-dose prefilled syringe containing a sterile, preservative-free clear to slightly opalescent, colorless to slightly yellow solution that may contain a few translucent to white, amorphous particles.
- NDC 0187-0004-02: Carton of two 210 mg/1.5 mL single-dose prefilled syringes.
## Storage
- Store refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light and physical damage during storage.
- When necessary, prefilled syringes can be stored at room temperature up to a maximum of 77°F (25°C) in the original carton for a maximum single period of 14 days with protection from light and sources of heat. Once the prefilled syringe has reached room temperature, do not place back into the refrigerator. Discard after 14 days at room temperature.
- Do not freeze.
- Do not shake.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Instruct patients and their caregivers to monitor for the emergence of suicidal thoughts and behavior and promptly seek medical attention if the patient experiences suicidal thoughts, new or worsening depression, anxiety, or other mood changes.
- Instruct patients to carry the wallet card provided and to call the National Suicide Prevention Lifeline at 1-800-273-8255 if they experience suicidal thoughts.
- Because of the observed suicidal thoughts and behavior in subjects treated with brodalumab, brodalumab is available only through a restricted program called the brodalumab REMS Program. Inform the patient of the following:
- Patients must enroll in the program.
- Patients will be given a brodalumab Patient Wallet Card that they should carry with them at all times. This card describes symptoms which, if experienced, should prompt the patient to immediately seek medical evaluation. Advise the patient to show the brodalumab Patient Wallet Card to other treating healthcare providers.
- Brodalumab is available only from certified pharmacies participating in the program. Therefore, provide patients with the telephone number and website for information on how to obtain the product.
- Inform patients that brodalumab may lower the ability of their immune system to fight infections. Instruct patients of the importance of communicating any history of infections to their healthcare providers and to contact their healthcare providers if they develop any signs or symptoms of infection.
- Instruct patients to seek medical advice if they develop signs and symptoms of Crohn’s disease.
- Instruct the patient to perform the first self-injection under the guidance and supervision of a qualified healthcare professional for proper training in subcutaneous injection technique.
- Instruct patients who are self-administering to inject the full dose of brodalumab.
- Instruct patients or caregivers in the technique of proper syringe and needle disposal.
# Precautions with Alcohol
Alcohol-Brodalumab interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
- Siliq
# Look-Alike Drug Names
There is limited information regarding Brodalumab Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | Brodalumab
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yashasvi Aryaputra[2], Anmol Pitliya, M.B.B.S. M.D.[3]
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# Black Box Warning
# Overview
Brodalumab is a human interleukin-17 receptor A (IL-17RA) antagonist that is FDA approved for the treatment of moderate to severe plaque psoriasis in adult patients who are candidates for systemic therapy or phototherapy and have failed to respond or have lost response to other systemic therapies. There is a Black Box Warning for this drug as shown here. Common adverse reactions include arthralgia, headache, fatigue, diarrhea, oropharyngeal pain, nausea, myalgia, injection site reactions, influenza, neutropenia, and tinea infections.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Brodalumab is indicated for the treatment of moderate to severe plaque psoriasis in adult patients who are candidates for systemic therapy or phototherapy and have failed to respond or have lost response to other systemic therapies.
- The recommended brodalumab dose is 210 mg administered by subcutaneous injection at Weeks 0, 1, and 2 followed by 210 mg every 2 weeks.
- If an adequate response has not been achieved after 12 to 16 weeks of treatment with brodalumab, consider discontinuing therapy. Continued treatment beyond 16 weeks in patients who have not achieved an adequate response is not likely to result in greater success.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding brodalumab Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding brodalumab Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Brodalumab FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding brodalumab Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding brodalumab Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
- Brodalumab is contraindicated in patients with Crohn’s disease because brodalumab may cause worsening of disease.
# Warnings
- Suicidal ideation and behavior, including 4 completed suicides, occurred in subjects treated with brodalumab in the psoriasis clinical trials. There were no completed suicides in the 12-week placebo-controlled portion of the trials. Brodalumab users with a history of suicidality or depression had an increased incidence of suicidal ideation and behavior as compared to users without such a history. A causal association between treatment with brodalumab and increased risk of suicidal ideation and behavior has not been established.
- Prescribers should weigh the potential risks and benefits before using brodalumab in patients with a history of depression or suicidality. Patients with new or worsening symptoms of depression or suicidality should be referred to a mental health professional, as appropriate. Advise patients and caregivers to seek medical attention for manifestations of suicidal ideation and behavior, new onset or worsening depression, anxiety, or other mood changes. Prescribers should also re-evaluate the risks and benefits of continuing treatment with brodalumab if such events occur.
- Because of the observed suicidal ideation and behavior in subjects treated with brodalumab, if an adequate response to brodalumab has not been achieved within 12 to 16 weeks, consider discontinuing therapy.
- Brodalumab is available only through a restricted program under a REMS.
- Brodalumab is available only through a restricted program under a REMS called the brodalumab REMS Program because of the observed suicidal ideation and behavior in subjects treated with brodalumab.
- Notable requirements of the brodalumab REMS Program include the following:
- Prescribers must be certified with the program.
- Patients must sign a Patient-Prescriber Agreement Form.
- Pharmacies must be certified with the program and must only dispense to patients who are authorized to receive brodalumab.
- Further information, including a list of qualified pharmacies, is available at www.SILIQREMS.com or by calling the brodalumab REMS Program Call Center at 855-511-6135.
- Brodalumab may increase the risk of infections. In clinical trials, subjects treated with brodalumab had a higher rate of serious infections than subjects treated with placebo (0.5% versus 0.2%) and higher rates of fungal infections (2.4% versus 0.9%). One case of cryptococcal meningitis occurred in a subject treated with brodalumab during the 12-week randomized treatment period and led to discontinuation of therapy.
- During the course of clinical trials for plaque psoriasis, the exposure-adjusted rates for infections and serious infections were similar in the subjects treated with brodalumab and those treated with ustekinumab.
- In patients with a chronic infection or a history of recurrent infection, consider the risks and benefits prior to prescribing brodalumab. Instruct patients to seek medical help if signs or symptoms of clinically important chronic or acute infection occur. If a patient develops a serious infection or is not responding to standard therapy for the infection, monitor the patient closely and discontinue brodalumab therapy until the infection resolves.
- Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with brodalumab. Do not administer brodalumab to patients with active TB infection. Initiate treatment for latent TB prior to administering brodalumab.
- Consider anti-TB therapy prior to initiation of brodalumab in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed. Closely monitor patients receiving brodalumab for signs and symptoms of active TB during and after treatment.
- In psoriasis trials, which excluded subjects with active Crohn’s disease, Crohn’s disease occurred in one subject during treatment with brodalumab and led to discontinuation of therapy. In other trials, exacerbation of Crohn’s disease was observed with brodalumab use.
- Brodalumab is contraindicated in patients with Crohn’s disease.
- Discontinue brodalumab if the patient develops Crohn’s disease while taking brodalumab.
- Avoid use of live vaccines in patients treated with brodalumab. No data are available on the ability of live or inactive vaccines to elicit an immune response in patients being treated with brodalumab.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- The overall safety population included 4558 subjects (3066 brodalumab, 613 ustekinumab, 879 placebo) in controlled clinical trials and open-label extension studies. The majority of subjects were male (69%), white (91%), and aged 40-64 years old (58%). One-third of subjects reported previous biologic use prior to enrollment. Across the clinical development program, 4464 subjects received at least one dose of brodalumab; 3755 subjects were exposed to brodalumab for at least 1 year.
- Data from one multicenter, randomized, placebo-controlled trial (Trial 1), two multicenter, randomized, placebo- and active-controlled trials (Trials 2 and 3), and one dose-finding trial (Trial 4) in plaque psoriasis were pooled to evaluate the safety of brodalumab (210 mg weekly at Weeks 0, 1, and 2, followed by treatments every 2 weeks [Q2W]) compared to placebo for up to 12 weeks after treatment initiation.
- During the 12-week, randomized treatment period, about 1% of the subjects in the treatment groups (brodalumab, ustekinumab and placebo) discontinued treatment because of adverse events. Adverse events leading to discontinuation of brodalumab included neutropenia, arthralgia, and urticaria. The proportion of subjects who developed serious adverse events was similar among the brodalumab, ustekinumab, and placebo groups.
- TABLE 1 summarizes the adverse reactions that occurred at a rate of at least 1% and at a higher rate in the brodalumab 210 mg Q2W group than in the placebo group during the 12-week randomized treatment period of the pooled trials.
- Adverse reactions that occurred in less than 1% of subjects in the brodalumab group through Week 12 were conjunctivitis and candida infections (including oral [0.2%], genital [0.1%], and esophageal [0.1%] versus none in the placebo group).
- Through Week 52, exposure-adjusted rates of serious adverse events were similar between subjects treated with brodalumab and those treated with ustekinumab. Through the end of the trial, the exposure-adjusted rates of treatment-emergent serious adverse events were similar to those seen in the 52-week period in the subjects treated with brodalumab.
Suicidal Ideation and Behavior
- During the 12-week randomized treatment period in the pooled trials, one subject in the brodalumab group attempted suicide and none in the placebo or ustekinumab groups. From initiation through Week 52 of the trials, suicidal ideation or behavior occurred in 7 of 4019 subjects (0.2 per 100 subject-years) treated with brodalumab and in 2 of 613 subjects (0.4 per 100 subject-years) treated with ustekinumab.
- During the course of the clinical trials for plaque psoriasis, suicidal ideation or behavior occurred in 34 of 4464 subjects treated with brodalumab (0.37 per 100 subject-years). Eight of the 10 subjects who attempted or completed suicide had a history of depression and/or suicidal ideation or behavior.
Infections
- During the 12-week randomized treatment period, infections occurred in 25.4% of the brodalumab group compared to 23.4% of the placebo group. The majority of infections consisted of nasopharyngitis, upper respiratory tract infection, pharyngitis, urinary tract infections, bronchitis, and influenza, and did not necessitate treatment discontinuation. The brodalumab group had a higher rate of fungal infections compared to the placebo group (1.8% vs 0.9%). The fungal infections were primarily non-serious skin and mucosal candida infections.
Neutropenia
- During the 12-week randomized treatment period, neutropenia occurred in 0.7% of subjects in the brodalumab group. Most adverse reactions of neutropenia were transient. In subjects with normal absolute neutrophil count (ANC) at baseline, a reduction in ANC occurred in 6.8% of subjects in the brodalumab group, compared to 3.3% in the ustekinumab group, and 3.6% in the placebo group. Neutropenia ≥ Grade 3 (< 1000/mm3) occurred in 0.5% of subjects in the brodalumab group compared to 0.2% of subjects in the ustekinumab group and none in the placebo group. From Week 0 to end of trial, the exposure-adjusted rate of treatment-emergent neutropenia was 0.4 per 100 subject-years (0.1 per 100 subject-years were ≥ Grade 3). No serious infections were associated with cases of neutropenia.
### Immunogenicity
- As with all therapeutic proteins, there is potential for immunogenicity with brodalumab. Approximately 3% of subjects treated with brodalumab developed antibodies to brodalumab through the 52-week treatment period. Of the subjects who developed antibodies to brodalumab, none had antibodies that were classified as neutralizing. However, the assay to test for neutralizing antibodies had limitations detecting neutralizing antibodies in the presence of brodalumab; therefore, the incidence of neutralizing antibody development could be underestimated.
- The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to brodalumab with the incidence of antibodies to other products may be misleading.
## Postmarketing Experience
There is limited information regarding Brodalumab Postmarketing Experience in the drug label.
# Drug Interactions
- Live Vaccinations
- CYP450 Substrates
- Avoid use of live vaccines in patients treated with brodalumab.
- The formation of CYP450 enzymes can be altered by increased levels of certain cytokines (e.g., IL-1, IL-6, IL-10, TNFα, IFN) during chronic inflammation. Treatment with brodalumab may modulate serum levels of some cytokines.
- Therefore, upon initiation or discontinuation of brodalumab in patients who are receiving concomitant drugs which are CYP450 substrates, particularly those with a narrow therapeutic index, consider monitoring for effect (e.g., for warfarin) or drug concentration (e.g., for cyclosporine) and consider dosage modification of the CYP450 substrate.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- There are no human data on brodalumab use in pregnant women to inform a drug associated risk. Human IgG antibodies are known to cross the placental barrier; therefore, brodalumab may be transmitted from the mother to the developing fetus. In a combined embryofetal development and pre- and post-natal development study, no adverse developmental effects were observed in infants born to pregnant monkeys after subcutaneous administration of brodalumab during organogenesis through parturition at doses up to 26 times the maximum recommended human dose (MRHD).
- The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
- A combined embryofetal development and pre- and post-natal development study was conducted in cynomolgus monkeys administered brodalumab. No brodalumab-related effects on embryofetal toxicity or malformations, or on morphological, functional or immunological development were observed in infants from pregnant monkeys administered weekly subcutaneous doses of brodalumab up to 26 times the MRHD from the beginning of organogenesis to parturition (on a mg/kg basis of 90 mg/kg/week).
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Brodalumab in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Brodalumab during labor and delivery.
### Nursing Mothers
- There are no data on the presence of brodalumab in human milk, the effects on the breastfed infant, or the effects on milk production. Brodalumab was detected in the milk of lactating cynomolgus monkeys. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for brodalumab and any potential adverse effects on the breastfed infant from brodalumab or from the underlying maternal condition.
### Pediatric Use
- The safety and effectiveness of brodalumab have not been evaluated in pediatric patients.
### Geriatic Use
- Of the 3066 plaque psoriasis subjects initially randomized to brodalumab in clinical trials, 192 (6%) were ≥ 65 years old and no subjects were ≥ 75 years old. Although no differences in safety or efficacy were observed between older and younger subjects, the number of subjects aged 65 years and older was not sufficient to determine whether they responded differently from younger subjects.
### Gender
There is no FDA guidance on the use of Brodalumab with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Brodalumab with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Brodalumab in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Brodalumab in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Brodalumab in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Brodalumab in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with brodalumab.
- Administer brodalumab subcutaneously. Each prefilled syringe is for single-dose only.
- Instruct patients to review the Medication Guide before use. Brodalumab is intended for use under the guidance and supervision of a healthcare professional. Patients may self-inject brodalumab when deemed appropriate by a healthcare professional and after proper training in subcutaneous injection technique using the prefilled syringe.
- Advise patients who are self-administering to inject the full dose and to read the Instructions for Use before administration (see Instructions for Use).
- Do not inject brodalumab into areas where the skin is tender, bruised, red, hard, thick, scaly, or affected by psoriasis.
- Allow brodalumab prefilled syringe to reach room temperature (approximately 30 minutes) before injecting. Do not warm in any other way. Do not remove the gray needle cap on the prefilled syringe while allowing it to reach room temperature.
- Visually inspect brodalumab for particles and discoloration prior to administration. brodalumab is a clear to slightly opalescent, colorless to slightly yellow solution. A few translucent to white, amorphous proteinaceous particles may be present. Do not use brodalumab if it is cloudy or discolored or if foreign matter is present.
- Instruct patients to use the prefilled syringe and to inject the full amount (1.5 mL), which provides 210 mg of brodalumab, according to the directions provided in the Instructions for Use.
### Monitoring
- Reductions in the fraction of body surface area affected, the nature and severity of psoriatic induration, erythema, and scaling are indicative of efficacy.
- TB; prior to and during therapy.
- Manifestations of suicidal ideation and behavior, new onset or worsening depression, anxiety, or other mood changes.
# IV Compatibility
There is limited information regarding the compatibility of Brodalumab and IV administrations.
# Overdosage
There is limited information regarding Brodalumab overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
- Brodalumab is a human monoclonal IgG2 antibody that selectively binds to human IL-17RA and inhibits its interactions with cytokines IL-17A, IL-17F, IL-17C, IL-17A/F heterodimer and IL-25. IL-17RA is a protein expressed on the cell surface and is a required component of receptor complexes utilized by multiple IL-17 family cytokines. Blocking IL-17RA inhibits IL-17 cytokine-induced responses including the release of pro-inflammatory cytokines and chemokines.
## Structure
There is limited information regarding Brodalumab Structure in the drug label.
## Pharmacodynamics
- Elevated levels of IL-17A, IL-17C and IL-17F are found in psoriatic plaques. Serum IL-17A levels, measured at Weeks 12, 24, and 48 of brodalumab 210 mg every 2 weeks of treatment, were higher than the baseline levels in subjects with moderate to severe plaque psoriasis. The relationship between the pharmacodynamic activity and the mechanism(s) by which brodalumab exerts its clinical effects is unknown.
## Pharmacokinetics
- Following a single subcutaneous dose of 210 mg in subjects with plaque psoriasis, brodalumab reached peak mean (±SD) serum concentration (Cmax) of 13.4±7.3 mcg/mL by approximately 3 days post dose. The mean (±SD) area-under-the-concentration-time curve (AUC) of brodalumab was 111±64 mcg•day/mL.
- Following multiple subcutaneous doses of 210 mg every 2 weeks, steady-state was achieved by Week 4. The mean (±SD) Cmax was 20.6±14.6 mcg/mL and the mean (±SD) AUC over the two week dosing interval was 227±167 mcg•day/mL.
- Following subcutaneous administration, brodalumab bioavailability was approximately 55%.
- Following a single subcutaneous administration of brodalumab 210 mg in subjects with plaque psoriasis, the mean (±SD) apparent volume of distribution (Vz/F) of brodalumab was 8.9±9.4 L.
- The metabolic pathway of brodalumab has not been characterized. As a human monoclonal IgG2 antibody, brodalumab is expected to be degraded into small peptides and amino acids via catabolic pathways in a manner similar to endogenous IgG.
- Following a single subcutaneous administration of brodalumab 210 mg in subjects with plaque psoriasis, the mean (±SD) apparent total clearance (CL/F) was 3.0±3.5 L/day. The clearance of brodalumab increased with decreasing doses due to nonlinear elimination.
- Brodalumab exhibited non-linear pharmacokinetics with exposures that increased greater than dose-proportionally over a dose range from 140 mg (approximately 0.67 times the recommended dose) to 350 mg (approximately 1.67 times the recommended dose) following subcutaneous administrations in subjects with plaque psoriasis.
- Brodalumab trough concentrations were lower in subjects with higher body weight.
Hepatic or Renal Impairment
- No trials were conducted to assess the effect of hepatic or renal impairment on the pharmacokinetics of brodalumab.
Age: Geriatric Population
- Population pharmacokinetic analysis indicated that age did not significantly influence the clearance of brodalumab in subjects with plaque psoriasis. Subjects who were 65 years or older had a similar brodalumab clearance as compared to subjects less than 65 years old.
- In subjects with plaque psoriasis, one week following a single subcutaneous administration of 210 mg brodalumab, the exposure of midazolam (CYP3A4 substrate) was increased by 24%.
## Nonclinical Toxicology
- Animal studies have not been conducted to evaluate the carcinogenic or mutagenic potential of brodalumab. The published literature is mixed on the potential effects on malignancy risk due to the inhibition of the IL-17RA, the pharmacological action of brodalumab. Some published literature suggests that IL-17A directly promotes cancer cell invasion, which suggests a potential beneficial effect of brodalumab. However, other reports indicate IL-17A promotes T-cell mediated tumor rejection, which suggests a potential adverse effect by brodalumab. However, inhibition of the IL-17RA with brodalumab has not been studied in these models. Therefore, the relevance of experimental findings in these models for malignancy risk in humans is unknown.
- In cynomolgus monkeys, there were no effects on fertility parameters such as changes in reproductive organs or sperm analysis following subcutaneous administration of brodalumab at dose levels up to 90 mg/kg/week for six months (26 times the MRHD on a mg/kg basis). The monkeys were not mated in this study to evaluate effects on fertility.
# Clinical Studies
- Three multicenter, randomized, double-blind, controlled trials (Trials 1, 2, and 3) enrolled a total of 4373 subjects 18 years of age and older with at least a 6-month history of moderate to severe plaque psoriasis, defined as having a minimum affected body surface area (BSA) of 10%, a Psoriasis Area and Severity Index (PASI) score ≥ 12, a static Physician’s Global Assessment (sPGA) score ≥3 in the overall assessment (plaque thickness/induration, erythema, and scaling) of psoriasis on a severity scale of 0 to 5, and who were candidates for systemic therapy or phototherapy. In all three trials, subjects were randomized to subcutaneous treatment with placebo or brodalumab 210 mg at Weeks 0, 1, and 2, followed by treatments every 2 weeks [Q2W] through Week 12. In the two active comparator trials (Trials 2 and 3), subjects randomized to ustekinumab received a 45 mg dose if their weight was less than or equal to 100 kg and a 90 mg dose if their weight was greater than 100 kg at Weeks 0, 4, and 16, followed by the same dose every 12 weeks.
- All three trials assessed the change from baseline to Week 12 compared to placebo in the two co-primary endpoints: 1) PASI 75, the proportion of subjects who achieved at least a 75% reduction in the PASI composite score that takes into consideration both the percentage of body surface area affected and the nature and severity of psoriatic changes (induration, erythema, and scaling) within the affected region, and 2) the proportion of subjects with an sPGA of 0 (clear) or 1 (almost clear), and at least a 2-point improvement from baseline. In Trials 2 and 3, comparisons were also made to ustekinumab for the primary endpoint of the proportion of subjects who achieved a reduction in PASI score of 100% (PASI 100) from baseline at Week 12.
- Other evaluated outcomes included the proportion of subjects who achieved an sPGA of 0 (clear) at Week 12, and the proportion of subjects who achieved a Psoriasis Symptom Inventory (PSI) score of 0 (not at all) or 1 (mild) on every item (itch, redness, scaling, burning, stinging, cracking, flaking, and pain) at Week 12. Baseline demographics and disease characteristics were generally consistent across all treatment groups in all three trials. Subjects were predominantly men (69%) and white (91%), with a mean age of 45 years. The mean baseline body weight was 90.5 kg and 28% of subjects had body weight greater than 100 kg. The baseline PASI score ranged from 9.4 to 72 (median: 17.4) and the baseline affected BSA ranged from 10 to 97% (median: 21%). Baseline sPGA scores ranged from “3 (moderate)” (58%) to “5 (very severe)” (5%).
- Approximately 21% of subjects had a history of psoriatic arthritis. Approximately 30% of subjects had previously received a biologic therapy and 12% of subjects had failed previous biologic therapy.
- The results of Trials 1, 2, and 3 are presented in TABLE 2.
- Examination of age, gender, race, use of prior systemic or phototherapy, and use of prior biologics did not identify differences in response to brodalumab among these subgroups.
- At Week 12, compared to subjects in the placebo group, a greater proportion of subjects in brodalumab 210 mg Q2W group achieved a Psoriasis Symptom Inventory (PSI) score of 0 (not at all) or 1 (mild) on every item (itch, redness, scaling, burning, stinging, cracking, flaking, pain).
- In Trial 1, subjects randomized to receive brodalumab and who were responders at Week 12 (i.e., sPGA of 0 or 1) were re-randomized to receive either placebo or brodalumab. Among responders at Week 12, 83% (69/83) of subjects re-randomized to continued treatment with brodalumab 210 mg Q2W maintained this response (sPGA of 0 or 1) at Week 52 compared to none (0/84) who were re-randomized to placebo and withdrawn from brodalumab. In addition, 87% (72/83) of subjects re-randomized to continued treatment with brodalumab 210 mg Q2W achieved PASI 75 response at Week 52 compared to none (0/84) who were re-randomized to placebo and withdrawn from brodalumab.
- Trials 2 and 3 included a re-randomized phase during which subjects originally randomized to receive brodalumab during the first 12 weeks were re-randomized to one of four brodalumab regimens at the Week 12 visit and placebo subjects were crossed over to receive brodalumab 210 mg Q2W. Subjects receiving ustekinumab continued the same treatment until crossed over at Week 52 to brodalumab 210 mg Q2W. For sPGA 0 or 1 responders at Week 12, the percentage of subjects who maintained this response at Week 52 was 79% for subjects treated with brodalumab 210 mg Q2W. For PASI 100 responders at Week 12, 72% of the subjects who continued on brodalumab 210 mg Q2W maintained the response at Week 52.
# How Supplied
- Brodalumab (brodalumab) Injection is available in a single-dose prefilled syringe containing a sterile, preservative-free clear to slightly opalescent, colorless to slightly yellow solution that may contain a few translucent to white, amorphous particles.
- NDC 0187-0004-02: Carton of two 210 mg/1.5 mL single-dose prefilled syringes.
## Storage
- Store refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light and physical damage during storage.
- When necessary, prefilled syringes can be stored at room temperature up to a maximum of 77°F (25°C) in the original carton for a maximum single period of 14 days with protection from light and sources of heat. Once the prefilled syringe has reached room temperature, do not place back into the refrigerator. Discard after 14 days at room temperature.
- Do not freeze.
- Do not shake.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Instruct patients and their caregivers to monitor for the emergence of suicidal thoughts and behavior and promptly seek medical attention if the patient experiences suicidal thoughts, new or worsening depression, anxiety, or other mood changes.
- Instruct patients to carry the wallet card provided and to call the National Suicide Prevention Lifeline at 1-800-273-8255 if they experience suicidal thoughts.
- Because of the observed suicidal thoughts and behavior in subjects treated with brodalumab, brodalumab is available only through a restricted program called the brodalumab REMS Program. Inform the patient of the following:
- Patients must enroll in the program.
- Patients will be given a brodalumab Patient Wallet Card that they should carry with them at all times. This card describes symptoms which, if experienced, should prompt the patient to immediately seek medical evaluation. Advise the patient to show the brodalumab Patient Wallet Card to other treating healthcare providers.
- Brodalumab is available only from certified pharmacies participating in the program. Therefore, provide patients with the telephone number and website for information on how to obtain the product.
- Inform patients that brodalumab may lower the ability of their immune system to fight infections. Instruct patients of the importance of communicating any history of infections to their healthcare providers and to contact their healthcare providers if they develop any signs or symptoms of infection.
- Instruct patients to seek medical advice if they develop signs and symptoms of Crohn’s disease.
- Instruct the patient to perform the first self-injection under the guidance and supervision of a qualified healthcare professional for proper training in subcutaneous injection technique.
- Instruct patients who are self-administering to inject the full dose of brodalumab.
- Instruct patients or caregivers in the technique of proper syringe and needle disposal.
# Precautions with Alcohol
Alcohol-Brodalumab interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
- Siliq
# Look-Alike Drug Names
There is limited information regarding Brodalumab Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | https://www.wikidoc.org/index.php/Brodalumab | |
25742f438b7ea480fd46081c7f0eb7be293c63bf | wikidoc | Bromazepam | Bromazepam
# Overview
Bromazepam (marketed under brand names Calmepam, Compendium, Creosedin, Durazanil, Lectopam, Lexaurin, Lexilium, Lexomil, Lexotan, Lexotanil, Normoc, Novepam, Somalium) is a drug which is a benzodiazepine derivative. It has sedative, hypnotic, anxiolytic and skeletal muscle relaxant properties.
# Pharmacology
Its molecular structure is composed of a diazepine connected to a benzene ring and a pyridine ring, the benzene ring having a bromine atom attached to it. It is a 1,4-benzodiazepine, which means that the nitrogens on the seven-sided diazepine ring are in the 1 and 4 positions.
Bromazepam binds to the GABA receptor GABAA, causing a conformational change and increasing inhibitory effects of GABA. Other neurotransmitters are not influenced. Bromazepam is intermediate-short acting benzodiazepine and is lipophilic, is metabolised hepatically via oxidative pathways. It does not possess any antidepressant qualities. Bromazepam shares with other benzodiazepines the risk of abuse, misuse, psychological and/or physical dependence. According to many psychiatric experts Bromazepam has a greater abuse potential than other benzodiazepines because of fast resorption and rapid onset of action. Due to its relatively short halflife and duration of action (8 to 12 hours), withdrawal symptoms may be more severe and more frequently encountered than with long acting benzodiazepines.
Bromazepam is reported to be metabolized by a hepatic enzyme belonging to the Cytochrome P450 family of enzymes. In 2003, a team led by Dr. Oda Manami at Oita Medical University reported that CYP3A4 was not the responsible enzyme, seeing as itraconazole, a known inhibitor of CYP3A4, did not effect its metabolism. In 1995, J. van Harten at Solvay Duphar B.V.'s Department of Clinical Pharmacology in Weesp reported that fluvoxamine, which is a potent inhibitor of CYP1A2, a less potent CYP3A4 inhibitor, and a negligible inhibitor of CYP2D6, does inhibit its metabolism.
The active metabolite of bromazepam is hydroxybromazepam.
# Indications
- Short-term treatment of insomnia
- Short-term treatment of anxiety or panic attacks, if a benzodiazepine is required
- Alleviation of the symptoms of alcohol- and opiate-withdrawal, under close clinical supervision
## Availability
Bromazepam is available as a generic in Belgium(as Lexotan), Bosnia, Bulgaria, Canada, Chile, Denmark (as Bromam), France, Germany,Israel (Lenitin, by Teva), Italy, Kosovo, Macedonia, The Netherlands (as Lexotanil), Poland, Portugal and Switzerland.
It is also available as Lexotanil in Bangladesh, Colombia, Greece, Pakistan, United Arab Emirates and Venezuela.
It is available as Leoxotan and Somalium in Australia, Brazil, Portugal and Singapore.
It is available as Lexilium in Macedonia and Serbia.
# Dosage
Usually, 3mg to 6mg at bedtime, with additional 1.5mg to 3mg during the next day if needed. Malnourished patients, patients with compromised cardiovascular, liver or renal function, and elderly patients should receive lower doses. In hospitalized patients with severe agitation and/or anxiety, daily doses of up to 24mg have been given and tolerated for a limited period of time. A 3mg dose of bromazepam is equivalent to a 5mg dose of diazepam.
# Side-effects
All common side-effects of benzodiazepines have been noted. Consult the article under Diazepam. Euphoria, leading to a high abuse potential, is quite often reported.
Up to 30% treated on a long-term basis develop a form of dependence known as 'low-dose-dependence', i.e. these patients do not need increasing doses to experience the feeling of 'well-being' caused by the drug.
Leukopenia and liver-damage of the cholostatic type with or without jaundice (icterus) have additionally been seen; the original manufacturer Roche recommends regular laboratory examinations to be performed routinely.
Ambulatory patients should be warned that Bromazepam may impair the ability to drive vehicles and to operate machinery. The impairment is worsened by consumption of alcohol, because both act as central nervous system depressants. During the course of therapy, tolerance to the sedative effect usually develops.
# Contraindications
The general contraindications for benzodiazepines apply. Consult the section under Diazepam.
## Special Populations
In 1987, a team of scientists lead by Ochs reported that the elimination half-life, peak serum concentration, and serum free fraction are significantly elevated and the oral clearance and volume of distribution significantly lowered in elderly subjects. The clinical consequence is that the elderly should be treated with lower doses than younger patients.
# Legal Status
Bromazepam is a Schedule IV drug under the Convention on Psychotropic Substances. | Bromazepam
# Overview
Bromazepam (marketed under brand names Calmepam, Compendium, Creosedin, Durazanil, Lectopam, Lexaurin, Lexilium, Lexomil, Lexotan, Lexotanil, Normoc, Novepam, Somalium)[1] is a drug which is a benzodiazepine derivative. It has sedative, hypnotic, anxiolytic and skeletal muscle relaxant properties.
# Pharmacology
Its molecular structure is composed of a diazepine connected to a benzene ring and a pyridine ring, the benzene ring having a bromine atom attached to it.[2] It is a 1,4-benzodiazepine, which means that the nitrogens on the seven-sided diazepine ring are in the 1 and 4 positions.
Bromazepam binds to the GABA receptor GABAA, causing a conformational change and increasing inhibitory effects of GABA. Other neurotransmitters are not influenced. Bromazepam is intermediate-short acting benzodiazepine and is lipophilic, is metabolised hepatically via oxidative pathways.[3] It does not possess any antidepressant qualities. Bromazepam shares with other benzodiazepines the risk of abuse, misuse, psychological and/or physical dependence. According to many psychiatric experts Bromazepam has a greater abuse potential than other benzodiazepines because of fast resorption and rapid onset of action. Due to its relatively short halflife and duration of action (8 to 12 hours), withdrawal symptoms may be more severe and more frequently encountered than with long acting benzodiazepines.
Bromazepam is reported to be metabolized by a hepatic enzyme belonging to the Cytochrome P450 family of enzymes. In 2003, a team led by Dr. Oda Manami at Oita Medical University reported that CYP3A4 was not the responsible enzyme, seeing as itraconazole, a known inhibitor of CYP3A4, did not effect its metabolism.[4] In 1995, J. van Harten at Solvay Duphar B.V.'s Department of Clinical Pharmacology in Weesp reported that fluvoxamine, which is a potent inhibitor of CYP1A2, a less potent CYP3A4 inhibitor, and a negligible inhibitor of CYP2D6, does inhibit its metabolism.[5]
The active metabolite of bromazepam is hydroxybromazepam.
# Indications
- Short-term treatment of insomnia
- Short-term treatment of anxiety or panic attacks, if a benzodiazepine is required
- Alleviation of the symptoms of alcohol- and opiate-withdrawal, under close clinical supervision
## Availability
Bromazepam is available as a generic in Belgium(as Lexotan), Bosnia, Bulgaria, Canada, Chile, Denmark (as Bromam), France, Germany,Israel (Lenitin, by Teva), Italy, Kosovo, Macedonia, The Netherlands (as Lexotanil), Poland, Portugal and Switzerland.
It is also available as Lexotanil in Bangladesh, Colombia, Greece, Pakistan, United Arab Emirates and Venezuela.
It is available as Leoxotan and Somalium in Australia, Brazil, Portugal and Singapore.
It is available as Lexilium in Macedonia and Serbia.
# Dosage
Usually, 3mg to 6mg at bedtime, with additional 1.5mg to 3mg during the next day if needed. Malnourished patients, patients with compromised cardiovascular, liver or renal function, and elderly patients should receive lower doses. In hospitalized patients with severe agitation and/or anxiety, daily doses of up to 24mg have been given and tolerated for a limited period of time. A 3mg dose of bromazepam is equivalent to a 5mg dose of diazepam.
# Side-effects
All common side-effects of benzodiazepines have been noted. Consult the article under Diazepam. Euphoria, leading to a high abuse potential, is quite often reported.
Up to 30% treated on a long-term basis develop a form of dependence known as 'low-dose-dependence', i.e. these patients do not need increasing doses to experience the feeling of 'well-being' caused by the drug.
Leukopenia and liver-damage of the cholostatic type with or without jaundice (icterus) have additionally been seen; the original manufacturer Roche recommends regular laboratory examinations to be performed routinely.
Ambulatory patients should be warned that Bromazepam may impair the ability to drive vehicles and to operate machinery. The impairment is worsened by consumption of alcohol, because both act as central nervous system depressants. During the course of therapy, tolerance to the sedative effect usually develops.
# Contraindications
The general contraindications for benzodiazepines apply. Consult the section under Diazepam.
## Special Populations
In 1987, a team of scientists lead by Ochs reported that the elimination half-life, peak serum concentration, and serum free fraction are significantly elevated and the oral clearance and volume of distribution significantly lowered in elderly subjects.[6] The clinical consequence is that the elderly should be treated with lower doses than younger patients.
# Legal Status
Bromazepam is a Schedule IV drug under the Convention on Psychotropic Substances.[7] | https://www.wikidoc.org/index.php/Bromazepam | |
0d7b432801dfc47f366f2f3a218d1d6db669dddb | wikidoc | Bromhexine | Bromhexine
# Overview
Bromhexine is a mucolytic (expectorant) agent used in the treatment of respiratory disorders associated with viscid or excessive mucus. In addition, bromhexine has antioxidant properties.
# Function
Bromhexine is intended to support the body's mechanisms for clearing mucus from the respiratory tract.
It is secretolytic, increasing the production of serous mucus in the respiratory tract and makes the phlegm thinner and less viscous. This contributes to a secretomotoric effect by helping the cilia transport the phlegm out of the lungs. For this reason it is often added to cough syrups.
Bromhexine is a synthetic derivative of the herbal active ingredient vasicine. It has been shown to increase the proportion of serous bronchial secretion, making it more easily expectorated. It is indicated as "secretolytic therapy in bronchopulmonary diseases associated with abnormal mucus secretion and impaired mucus transport".
Bromhexine is contained in various formulations, high and low strength syrups 8 mg/5 ml, 4 mg/5 ml, tablets and soluble tablets (both with 8 mg bromhexine) and solution for oral use 10 mg/5 ml, adapted to the need of the patients. The posology varies with the age and weight, but there are products for all age groups from infant on. Bromhexine is well established and tolerated.
Sometimes it is replaced by its metabolite ambroxol, as in Mucosolvan or Mucoangin.
# Brand names
- Bisolvon
- Paxirasol
- Barkacin
- Bromhexin
- Vasican
- Bisolex
- Robitussin Chesty/Forte
- Duro-Tuss Chesty
- Benadryl Chesty/Forte
- Movex
- Bromex
- Solvex
- Mucolyte
- Brofentol
- Brofentol Plus
- Dysolvon
- Flegamina | Bromhexine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Bromhexine is a mucolytic (expectorant) agent used in the treatment of respiratory disorders associated with viscid or excessive mucus. In addition, bromhexine has antioxidant properties.[1]
# Function
Bromhexine is intended to support the body's mechanisms for clearing mucus from the respiratory tract.
It is secretolytic, increasing the production of serous mucus in the respiratory tract and makes the phlegm thinner and less viscous. This contributes to a secretomotoric effect by helping the cilia transport the phlegm out of the lungs. For this reason it is often added to cough syrups.
Bromhexine is a synthetic derivative of the herbal active ingredient vasicine. It has been shown to increase the proportion of serous bronchial secretion, making it more easily expectorated. It is indicated as "secretolytic therapy in bronchopulmonary diseases associated with abnormal mucus secretion and impaired mucus transport".
Bromhexine is contained in various formulations, high and low strength syrups 8 mg/5 ml, 4 mg/5 ml, tablets and soluble tablets (both with 8 mg bromhexine) and solution for oral use 10 mg/5 ml, adapted to the need of the patients. The posology varies with the age and weight, but there are products for all age groups from infant on. Bromhexine is well established and tolerated.
Sometimes it is replaced by its metabolite ambroxol, as in Mucosolvan or Mucoangin.
# Brand names
- Bisolvon
- Paxirasol
- Barkacin
- Bromhexin
- Vasican
- Bisolex
- Robitussin Chesty/Forte
- Duro-Tuss Chesty
- Benadryl Chesty/Forte
- Movex
- Bromex
- Solvex
- Mucolyte
- Brofentol
- Brofentol Plus
- Dysolvon
- Flegamina | https://www.wikidoc.org/index.php/Bromhexine | |
4f4eb61eb81b9dcd03f311e56a2e503877100b2a | wikidoc | Bromopride | Bromopride
# Overview
Bromopride (INN) is a dopamine antagonist with prokinetic properties widely used as an antiemetic, closely related to metoclopramide. It is not available in the United States.
Bromopride appears to be safe and effective for use in pregnancy.
# Indications
Bromopride is indicated in the treatment of nausea and vomiting, including postoperative nausea and vomiting (PONV); gastroesophageal reflux disease (GERD/GORD); and as preparation for endoscopy and radiographic studies of the gastrointestinal tract. The manufacturer also claims it is valuable in, among other indications, hiccups and gastrointestinal adverse effects of radiation therapy.
# Adverse effects
Bromopride is generally well tolerated; the most common adverse effects of its use are somnolence and fatigue. Bromopride may rarely cause extrapyramidal symptoms and, as with metoclopramide, may increase prolactin levels.
# Chemistry
Bromopride is a substituted benzamide, closely related to metoclopramide. It is identical to metoclopramide except for the presence of a bromine atom where metoclopramide has a chlorine substituent.
# Availability
Bromopride is not available in the United States or the United Kingdom. It is marketed in Brazil by Sanofi-Synthélabo under the trade name 'Digesan, by LIBBS under the name Plamet, and as a generic drug. | Bromopride
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Bromopride (INN) is a dopamine antagonist with prokinetic properties widely used as an antiemetic, closely related to metoclopramide. It is not available in the United States.
Bromopride appears to be safe and effective for use in pregnancy.[1]
# Indications
Bromopride is indicated in the treatment of nausea and vomiting, including postoperative nausea and vomiting (PONV); gastroesophageal reflux disease (GERD/GORD); and as preparation for endoscopy and radiographic studies of the gastrointestinal tract. The manufacturer also claims it is valuable in, among other indications, hiccups and gastrointestinal adverse effects of radiation therapy.
# Adverse effects
Bromopride is generally well tolerated; the most common adverse effects of its use are somnolence and fatigue. Bromopride may rarely cause extrapyramidal symptoms and, as with metoclopramide, may increase prolactin levels.[2]
# Chemistry
Bromopride is a substituted benzamide, closely related to metoclopramide.[3] It is identical to metoclopramide except for the presence of a bromine atom where metoclopramide has a chlorine substituent.
# Availability
Bromopride is not available in the United States or the United Kingdom. It is marketed in Brazil by Sanofi-Synthélabo under the trade name 'Digesan, by LIBBS under the name Plamet, and as a generic drug. | https://www.wikidoc.org/index.php/Bromopride | |
c66e32aec9b521e3eae1f7081569911cd7160acf | wikidoc | Bronchiole | Bronchiole
# Overview
The bronchioles are the first airway branches that no longer contain cartilage. They are branches of the bronchi, and are smaller than one millimeter in diameter.
There are no glands or cartilage in any of the bronchioles, and the epithelial cells become more cuboidal in shape.
The bronchioles terminate by entering the circular sacs called alveoli.
Control of airflow resistance and air distrubution in the lungs is controlled by the bronchioles.
# Pathology
Bronchospasm, a life-threatening situation, occurs when the smooth muscular tissue of the bronchioles constricts, severely narrowing their diameter. Bronchospasm is commonly treated by oxygen therapy and bronchodilators.
The medical condition of inflammation of the bronchioles is termed bronchiolitis. Diseases of the bronchioles include asthma, bronchiolitis obliterans, respiratory syncytial virus infection, and influenza.
# Additional images
- Cross sectional cut of primary bronchiole
- Bronchi, bronchial tree, and lungs
- 1. Trachea2. Mainstem bronchus3. Lobar bronchus4. Segmental bronchus5. Bronchiole6. Alveolar duct7. Alveolus | Bronchiole
Template:Infobox Anatomy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
The bronchioles are the first airway branches that no longer contain cartilage. They are branches of the bronchi, and are smaller than one millimeter in diameter.
There are no glands or cartilage in any of the bronchioles, and the epithelial cells become more cuboidal in shape.
The bronchioles terminate by entering the circular sacs called alveoli.
Control of airflow resistance and air distrubution in the lungs is controlled by the bronchioles.
# Pathology
Bronchospasm, a life-threatening situation, occurs when the smooth muscular tissue of the bronchioles constricts, severely narrowing their diameter. Bronchospasm is commonly treated by oxygen therapy and bronchodilators.
The medical condition of inflammation of the bronchioles is termed bronchiolitis. Diseases of the bronchioles include asthma, bronchiolitis obliterans, respiratory syncytial virus infection, and influenza.
# Additional images
- Cross sectional cut of primary bronchiole
- Bronchi, bronchial tree, and lungs
- 1. Trachea2. Mainstem bronchus3. Lobar bronchus4. Segmental bronchus5. Bronchiole6. Alveolar duct7. Alveolus
Template:Lung
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Bronchia | |
99bed9b8b9ba1a27bb5f5fd42581f676a61dd49c | wikidoc | Brotizolam | Brotizolam
# Overview
Brotizolam (marketed under brand name Lendormin) is a drug which is thienobenzodiazepine (a benzodiazepine derivative). It possesses anxiolytic, anticonvulsant, sedative and skeletal muscle relaxant properties, and is considered to be similar in effect to short-acting benzodiazepines such as triazolam. It is used in the short term treatment of insomnia although due to its short half life it is considered to have relatively high abuse potential and so would not be a first-line treatment. Brotizolam is a potent drug with a dosage of between 0.5 and 1.5 milligrams, but is rapidly eliminated with an average half life of 4.4 hours (range 3.6 - 7.9 hours).
Brotizolam is not approved for sale in the UK, United States or Canada.
# Pharmacology
Brotizolam induces impairment of motor function and has hypnotic properties.
Brotizolam increases the slow wave light sleep (SWLS) in a dose-dependent manner whilst suppressing deep sleep stages. Less time is spent in stages 3 and 4 which are the deep sleep stages when benzodiazepines such as brotizolam are used. Benzodiazepines are therefore not good hypnotics in the treatment of insomnia. The suppression of deep sleep stages by benzodiazepines may be especially problematic to the elderly as they naturally spend less time in the deep sleep stage.
# Indications
Insomnia. Brotizolam is prescribed for the short term treatment, 2 - 4 weeks only of severe insomnia. Insomnia can be described as a difficulty falling asleep, frequent awakening, early awakenings or a combination of each. Brotizolam is a short-intermediate acting benzodiazepine and is sometimes used in patients who have difficulty in maintaining sleep or getting to sleep. Hypnotics should only be used on a short term basis or in those with chronic insomnia on an occasional basis. | Brotizolam
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Brotizolam (marketed under brand name Lendormin) is a drug which is thienobenzodiazepine (a benzodiazepine derivative). It possesses anxiolytic, anticonvulsant, sedative and skeletal muscle relaxant properties, and is considered to be similar in effect to short-acting benzodiazepines such as triazolam. It is used in the short term treatment of insomnia although due to its short half life it is considered to have relatively high abuse potential and so would not be a first-line treatment. Brotizolam is a potent drug with a dosage of between 0.5 and 1.5 milligrams, but is rapidly eliminated with an average half life of 4.4 hours (range 3.6 - 7.9 hours).
Brotizolam is not approved for sale in the UK, United States or Canada.
# Pharmacology
Brotizolam induces impairment of motor function and has hypnotic properties.[1]
Brotizolam increases the slow wave light sleep (SWLS) in a dose-dependent manner whilst suppressing deep sleep stages. Less time is spent in stages 3 and 4 which are the deep sleep stages when benzodiazepines such as brotizolam are used. Benzodiazepines are therefore not good hypnotics in the treatment of insomnia. The suppression of deep sleep stages by benzodiazepines may be especially problematic to the elderly as they naturally spend less time in the deep sleep stage.[2]
# Indications
Insomnia. Brotizolam is prescribed for the short term treatment, 2 - 4 weeks only of severe insomnia. Insomnia can be described as a difficulty falling asleep, frequent awakening, early awakenings or a combination of each. Brotizolam is a short-intermediate acting benzodiazepine and is sometimes used in patients who have difficulty in maintaining sleep or getting to sleep. Hypnotics should only be used on a short term basis or in those with chronic insomnia on an occasional basis.[3] | https://www.wikidoc.org/index.php/Brotizolam | |
194b3b713df8bd23501967bc86eab4d4be4297ea | wikidoc | BrownBoost | BrownBoost
BrownBoost is a boosting algorithm that is robust to noisy datasets. BrownBoost is an adaptive version of the boost by majority algorithm. As is true for all boosting algorithms, BrownBoost is used in conjunction with other machine learning methods. BrownBoost was introduced by Yoav Freund.
# Motivation
AdaBoost performs well on a variety of datasets; however, it can be shown that AdaBoost does not perform well on noisy data sets. This is a result of AdaBoost's focus on examples that are repeatedly misclassified. In contrast, BrownBoost effectively "gives up" on examples that are repeatedly misclassified.
The user of the algorithm can set the amount of error to be tolerated in the training set. Thus, if the training set is noisy (say 10% of all examples are assumed to be mislabeled), the booster can be told to accept a 10% error rate. Since the noisy examples may be ignored, only the true examples will contribute to the learning process.
# BrownBoost Learning Algorithm
BrownBoost is unique in that it uses a non-convex potential loss function, thus it does not fit into the AnyBoost framework. The non-convex optimization provides a method to avoid overfitting data sets. AdaBoost has one parameter to set: the number of rounds of boosting. BrownBoost has an analogue parameter referred to as the amount of time the booster runs. This paramter is referred to as c.
Input: m training examples (x_{1},y_{1}),\ldots,(x_{m},y_{m}) where x_{y} \in X,\, y_{j} \in Y = \{-1, +1\}
Initialise: s=c, r_1(x_j) = 0 \forall j.
While s > 0:
- Set the weights of each example: W_{i}(x_j) = e^{- \frac{(r_i(x_j)+s)^2}{c}}, where r_i(x_j) is the margin of example x_j
- Find a classifier h_i : X \to \{-1,+1\} such that \sum_j W_i(x_j) h_i(x_j) y_j > 0
- Find values \alpha^*, t^- that satisfy the differential equation: \frac{dt}{d\alpha} = \sum_j e^{-\frac{(r_i(x_j)+\alpha h_i(x_j) y_j + s - t)^2}{c}} = 0. (Note this is similar to the condition E_{W_{i+1}}=0 set forth by Schapire and Singer)
This update is subject to the constraint
\sum
\left(\Phi\left(r_i(x_j) + \alpha h(x_j) y_j + s - t\right) -
\Phi\left( r_i(x_j) + s \right)
, where
\Phi(z) = 1-erf(z/\sqrt{c})
is the potential loss for a point with margin r_i(x_j)
- Update the margins for each example: r_{i+1}(x_j) = r_i(x_j) + \alpha h(x_j) y_j
- Update the time remaining: s = s - t
Output: H(x) = \textrm{sign}\left( \sum_i \alpha_{i} h_{i}(x) \right)
# Empirical Results
In preliminary experimental results with noisy datasets, BrownBoost outperformed AdaBoost's generalization error; however, LogitBoost performed as well as BrownBoost. An implementation of BrownBoost can be found in the open source software JBoost. | BrownBoost
BrownBoost is a boosting algorithm that is robust to noisy datasets. BrownBoost is an adaptive version of the boost by majority algorithm. As is true for all boosting algorithms, BrownBoost is used in conjunction with other machine learning methods. BrownBoost was introduced by Yoav Freund.[1]
# Motivation
AdaBoost performs well on a variety of datasets; however, it can be shown that AdaBoost does not perform well on noisy data sets.[2] This is a result of AdaBoost's focus on examples that are repeatedly misclassified. In contrast, BrownBoost effectively "gives up" on examples that are repeatedly misclassified.
The user of the algorithm can set the amount of error to be tolerated in the training set. Thus, if the training set is noisy (say 10% of all examples are assumed to be mislabeled), the booster can be told to accept a 10% error rate. Since the noisy examples may be ignored, only the true examples will contribute to the learning process.
# BrownBoost Learning Algorithm
BrownBoost is unique in that it uses a non-convex potential loss function, thus it does not fit into the AnyBoost framework. The non-convex optimization provides a method to avoid overfitting data sets. AdaBoost has one parameter to set: the number of rounds of boosting. BrownBoost has an analogue parameter referred to as the amount of time the booster runs. This paramter is referred to as <math>c</math>.
Input: <math>m</math> training examples <math>(x_{1},y_{1}),\ldots,(x_{m},y_{m})</math> where <math>x_{y} \in X,\, y_{j} \in Y = \{-1, +1\}</math>
Initialise: <math>s=c</math>, <math>r_1(x_j) = 0 \forall j</math>.
While <math>s > 0</math>:
- Set the weights of each example: <math>W_{i}(x_j) = e^{- \frac{(r_i(x_j)+s)^2}{c}}</math>, where <math>r_i(x_j)</math> is the margin of example <math>x_j</math>
- Find a classifier <math>h_i : X \to \{-1,+1\}</math> such that <math>\sum_j W_i(x_j) h_i(x_j) y_j > 0</math>
- Find values <math>\alpha^*, t^*</math> that satisfy the differential equation: <math>\frac{dt}{d\alpha} = \sum_j e^{-\frac{(r_i(x_j)+\alpha h_i(x_j) y_j + s - t)^2}{c}} = 0</math>. (Note this is similar to the condition <math>E_{W_{i+1}}[h_i(x_j) y_j]=0</math> set forth by Schapire and Singer[3])
This update is subject to the constraint
<math>
\sum
\left(\Phi\left(r_i(x_j) + \alpha h(x_j) y_j + s - t\right) -
\Phi\left( r_i(x_j) + s \right)
</math>, where
<math>
\Phi(z) = 1-erf(z/\sqrt{c})
</math> is the potential loss for a point with margin <math>r_i(x_j)</math>
- Update the margins for each example: <math>r_{i+1}(x_j) = r_i(x_j) + \alpha h(x_j) y_j</math>
- Update the time remaining: <math>s = s - t</math>
Output: <math>H(x) = \textrm{sign}\left( \sum_i \alpha_{i} h_{i}(x) \right)</math>
# Empirical Results
In preliminary experimental results with noisy datasets, BrownBoost outperformed AdaBoost's generalization error; however, LogitBoost performed as well as BrownBoost.[4] An implementation of BrownBoost can be found in the open source software JBoost. | https://www.wikidoc.org/index.php/BrownBoost | |
71d0320f5cdfabb968dfd487d00a64f4914b7f1f | wikidoc | Brugmansia | Brugmansia
Brugmansia is a genus of six species of flowering plants in the family Solanaceae, native to subtropical regions of South America, along the Andes from Colombia to northern Chile, and also in southeastern Brazil. They are known as Angel's Trumpets, sharing that name with the closely related genus Datura. The genus differs from Datura in being perennial and woody (Datura species are herbaceous), and in having pendulous (not erect) flowers.
Brugmansia are large shrubs or small trees, reaching heights of 3–11 m, with tan, slightly rough bark. The leaves are alternate, generally large, 10–30 cm long and 4–18 cm broad, with an entire or coarsely toothed margin, and are covered with fine hairs.
The name Angel's Trumpet refers to the large, very dramatic, pendulous trumpet-shaped flowers, 14–50 cm long and 10–35 cm across at the wide end. They are white, yellow, pink, orange or red, and have a delicate, attractive scent with light, lemony overtones, most noticeable in early evening.
- Brugmansia arborea. Andes (Ecuador to northern Chile).
- Brugmansia aurea. Andes (Colombia to Ecuador).
- Brugmansia sanguinea. Andes (Colombia to Peru and Bolivia).
- Brugmansia suaveolens. Southeast Brazil west to Bolivia and Peru.
- Brugmansia versicolor. Ecuador.
- Brugmansia vulcanicola. Colombia.
# Cultivation
Brugmansia are easily grown in a moist, fertile, well-drained soil, in full sun to part shade, in frost-free climates. They begin to flower in mid to late spring in warm climates and continue into the fall, often continuing as late as early winter in warm conditions. In cool winters, outdoor plants need protection, but the roots are hardy and will resprout in April or May. The species from the higher elevations, B. sanguinea and B. vulcanicola, prefer moderate temperatures and cool nights, and may not flower if temperatures are very hot. Most Brugmansias may be propagated easily by rooting 10–20 cm cuttings taken from the end of a branch during the summer.
Several hybrids and numerous cultivars have been developed for use as ornamental plants. B. × candida is a hybrid between B. aurea and B. versicolor, while B. × insignis is a hybrid between B. suaveolens and B. versicolor. Some cultivars of B. × candida produce white, yellow, pale orange or pink flowers; B. × insignis produces white or peach flowers; B. versicolor flowers start off white and turn salmon pink. There are cultivars producing double flowers, and some with variegated leaves.
# Uses
As with Datura, all parts of Brugmansia are highly toxic. The plants are sometimes ingested for recreational or shamanic intoxication as the plant contains the tropane alkaloids scopolamine and atropine; however because the potency of the toxic compounds in the plant is variable, the degree of intoxication is unpredictable and can be fatal.
Ritualized Brugmansia consumption is an important aspect of the shamanic complexes noted among many Indigenous peoples of western Amazonia, such as the Jivaroan speaking peoples. Likewise, it is a central component in the cosmology and shamanic practices of the Urarina peoples of Loreto, Peru.
# Plant Registration
ABADS (American Brugmansia & Datura Society, Inc., is designated in the 2004 edition of the International Code of Nomenclature for Cultivated Plants as the official International Cultivar Registration Authority in 2002.
# References and external links
- "American Brugmansia & Datura Society, Inc"
- Germplasm Resources Information Network: Brugmansia
- Erowid Brugmansia Vault
- Lockwood, T. E. (1973). Generic recognition of Brugmansia. Bot. Mus. Leafl. 23: 273–283.
- Huxley, A. (1992). The New RHS Dictionary of Gardening. Macmillan.
- A recently opened Brugmansia flower
A recently opened Brugmansia flower
- Flower detail
Flower detail
- Man holding a Brugmansia flower
Man holding a Brugmansia flower
da:Engletrompet
de:Engelstrompeten
nl:Brugmansia
qu:Wantuq
sv:Änglatrumpeter
to:Talupite ʻangelo | Brugmansia
Brugmansia is a genus of six species of flowering plants in the family Solanaceae, native to subtropical regions of South America, along the Andes from Colombia to northern Chile, and also in southeastern Brazil. They are known as Angel's Trumpets, sharing that name with the closely related genus Datura. The genus differs from Datura in being perennial and woody (Datura species are herbaceous), and in having pendulous (not erect) flowers.
Brugmansia are large shrubs or small trees, reaching heights of 3–11 m, with tan, slightly rough bark. The leaves are alternate, generally large, 10–30 cm long and 4–18 cm broad, with an entire or coarsely toothed margin, and are covered with fine hairs.
The name Angel's Trumpet refers to the large, very dramatic, pendulous trumpet-shaped flowers, 14–50 cm long and 10–35 cm across at the wide end. They are white, yellow, pink, orange or red, and have a delicate, attractive scent with light, lemony overtones, most noticeable in early evening.
- Brugmansia arborea. Andes (Ecuador to northern Chile).
- Brugmansia aurea. Andes (Colombia to Ecuador).
- Brugmansia sanguinea. Andes (Colombia to Peru and Bolivia).
- Brugmansia suaveolens. Southeast Brazil west to Bolivia and Peru.
- Brugmansia versicolor. Ecuador.
- Brugmansia vulcanicola. Colombia.
# Cultivation
Brugmansia are easily grown in a moist, fertile, well-drained soil, in full sun to part shade, in frost-free climates. They begin to flower in mid to late spring in warm climates and continue into the fall, often continuing as late as early winter in warm conditions. In cool winters, outdoor plants need protection, but the roots are hardy and will resprout in April or May. The species from the higher elevations, B. sanguinea and B. vulcanicola, prefer moderate temperatures and cool nights, and may not flower if temperatures are very hot. Most Brugmansias may be propagated easily by rooting 10–20 cm cuttings taken from the end of a branch during the summer.
Several hybrids and numerous cultivars have been developed for use as ornamental plants. B. × candida is a hybrid between B. aurea and B. versicolor, while B. × insignis is a hybrid between B. suaveolens and B. versicolor. Some cultivars of B. × candida produce white, yellow, pale orange or pink flowers; B. × insignis produces white or peach flowers; B. versicolor flowers start off white and turn salmon pink. There are cultivars producing double flowers, and some with variegated leaves.
# Uses
As with Datura, all parts of Brugmansia are highly toxic. The plants are sometimes ingested for recreational or shamanic intoxication as the plant contains the tropane alkaloids scopolamine and atropine; however because the potency of the toxic compounds in the plant is variable, the degree of intoxication is unpredictable and can be fatal.
Ritualized Brugmansia consumption is an important aspect of the shamanic complexes noted among many Indigenous peoples of western Amazonia, such as the Jivaroan speaking peoples. Likewise, it is a central component in the cosmology and shamanic practices of the Urarina peoples of Loreto, Peru.
# Plant Registration
ABADS (American Brugmansia & Datura Society, Inc., is designated in the 2004 edition of the International Code of Nomenclature for Cultivated Plants [the 2004 Code] as the official International Cultivar Registration Authority [ICRA} for Brugmansia and Datura (Solanaceae). This role was delegated to ABADS by the International Society for Horticultural Science [ISHS] in 2002.
# References and external links
- "American Brugmansia & Datura Society, Inc"
- Germplasm Resources Information Network: Brugmansia
- Erowid Brugmansia Vault
- Lockwood, T. E. (1973). Generic recognition of Brugmansia. Bot. Mus. Leafl. 23: 273–283.
- Huxley, A. (1992). The New RHS Dictionary of Gardening. Macmillan.
- A recently opened Brugmansia flower
A recently opened Brugmansia flower
- Flower detail
Flower detail
- Man holding a Brugmansia flower
Man holding a Brugmansia flower
da:Engletrompet
de:Engelstrompeten
nl:Brugmansia
qu:Wantuq
sv:Änglatrumpeter
to:Talupite ʻangelo | https://www.wikidoc.org/index.php/Brugmansia | |
9735b741df0839622dbac0246605e203e9749b06 | wikidoc | Bryostatin | Bryostatin
# Overview
Bryostatins are a group of macrocyclic lactones first discovered in the late 1960s in a species of bryozoan, Bugula neritina. Believed to be produced by symbiont bacteria to protect the bryozoan larva from predation, they have cytotoxic properties and are under investigation as anti-cancer agents and as a memory enhancement agent.
In vitro trials have shown bryostatins to act synergistically with other anti-cancer drugs and to modulate protein kinase C (PKC) activity, with a potent antileukemic effect and action against lung, prostate and non-Hodgkin's lymphoma tumor cells.
Human clinical trials have been less promising, but suggest bryostatins to have a potentially useful synergistic action with other chemotherapeutic agents.
The low concentration in bryozoans (to extract one gram of bryostatin, roughly one tonne of the raw bryozoans is needed) makes extraction unviable for large scale production. Due to the structural complexity, synthesis has proved difficult, with only a few total syntheses reported so far. However, structurally simpler synthetic analogs have been prepared which exhibit similar biological profile and in some cases greater potency, which may provide a practical supply for clinical use. | Bryostatin
# Overview
Bryostatins are a group of macrocyclic lactones first discovered in the late 1960s in a species of bryozoan, Bugula neritina. Believed to be produced by symbiont bacteria to protect the bryozoan larva from predation, they have cytotoxic properties and are under investigation as anti-cancer agents and as a memory enhancement agent.
In vitro trials have shown bryostatins to act synergistically with other anti-cancer drugs and to modulate protein kinase C (PKC) activity, with a potent antileukemic effect and action against lung, prostate and non-Hodgkin's lymphoma tumor cells.
Human clinical trials have been less promising, but suggest bryostatins to have a potentially useful synergistic action with other chemotherapeutic agents.
The low concentration in bryozoans (to extract one gram of bryostatin, roughly one tonne of the raw bryozoans is needed) makes extraction unviable for large scale production. Due to the structural complexity, synthesis has proved difficult, with only a few total syntheses reported so far. However, structurally simpler synthetic analogs have been prepared which exhibit similar biological profile and in some cases greater potency, which may provide a practical supply for clinical use. [1]
# External links
- Drugs from the seas – current status and microbiological implications, Proksch P, Edrada RA, Ebel R, Appl Microbiol Biotechnol. 2002 Jul;59(2-3):125-34.
- Bryostatin 1 Aphios report
- Bryostatins 1-3 QXHealth summary
- ^ "The Practical Synthesis of a Novel and Highly Potent Analogue of Bryostatin." P. A. Wender, J. L. Baryza, C. E. Bennett, F. C. Bi, S. E. Brenner, M. O. Clarke, J. C. Horan, C. Kan, E. Lacote, B. Lippa, P. G. Nell, T. M. Turner, Journal of the American Chemical Society, 2002, vol. 124, pp. 13648-13649.
Template:WS | https://www.wikidoc.org/index.php/Bryostatin | |
2b3df0147480ccd10f4f00b554e43525af119808 | wikidoc | Bufanolide | Bufanolide
Bufanolides (bū-fan′ō-līd) are a type of steroids. Bufanolides are found mostly as cardiac glycoside aglycones, meaning that bufanolides are bound with sugars to form glycosides (specifically, cardiac glycosides). Bufanolides are toxic, both as steroids and glycoside aglycones.
# Etymology
Supposedly, the term derives from the toad genus Bufo. Derivatives are named replacing the suffix -anolide with -enolide, -adienolide etc.
# Classification
According to MeSH, bufanolides are classified as fallows;
- Polycyclic compounds
- Steroids
- Cardanolides
- Cardenolides
- Cardiac glycosides
- Bufanolides
- Bufenolides
- Bufadienolides
- Proscillaridin
- Daigremontianin
- Cardenolides
Note that cardenolides have been classified under cardanolides as well as cardiac glycosides in this classification. | Bufanolide
Bufanolides (bū-fan′ō-līd) are a type of steroids. Bufanolides are found mostly as cardiac glycoside aglycones, meaning that bufanolides are bound with sugars to form glycosides (specifically, cardiac glycosides). Bufanolides are toxic, both as steroids and glycoside aglycones.
# Etymology
Supposedly, the term derives from the toad genus Bufo. Derivatives are named replacing the suffix -anolide with -enolide, -adienolide etc.
# Classification
According to MeSH, bufanolides are classified as fallows;
- Polycyclic compounds
- Steroids
- Cardanolides
- Cardenolides
- Cardiac glycosides
- Bufanolides
- Bufenolides
- Bufadienolides
- Proscillaridin
- Daigremontianin
- Cardenolides
Note that cardenolides have been classified under cardanolides as well as cardiac glycosides in this classification. | https://www.wikidoc.org/index.php/Bufadienolide | |
46826ca36dc7242deaca7ee205f97369b54fb53e | wikidoc | Buffy coat | Buffy coat
The buffy coat is the fraction of an anticoagulated blood sample after centrifugation that contains most of the white blood cells.
# Description
After centrifugation, one can distinguish a layer of clear fluid (the plasma), a layer of red fluid containing most of the red blood cells, and a thin layer in between, making up less than 1% of the total volume of the blood sample, the buffy coat (so-called because it is usually buff in hue), with most of the white blood cells and platelets. The buffy coat is used, for example, to extract DNA from the blood of mammals (since mammalian red blood cells are anucleate and do not contain DNA).
The buffy coat is usually whitish in color but sometimes green, if the blood sample contains large amounts of neutrophils, which are high in green myeloperoxidase.
# Diagnostic Uses of the Buffy Coat
- Quantitative Buffy Coat (QBC) is a laboratory test to detect infection with malaria or other blood parasites: the blood is taken in a QBC capillary tube which is coated with acridine orange (a fluorescent dye) and centrifuged; the fluorescing parasites can then be observed under ultraviolet light at the interface between red blood cells and buffy coat. This test is more sensitive than the conventional thick smear and in >90% of cases, the species of parasite can also be identified.
- In cases of extremely low white blood cell count, it may be difficult to perform a manual differential of the various types of white cells, and it may be virtually impossible to obtain an automated differential. In such cases the medical technologist may obtain a buffy coat, from which a blood smear is made. This smear contains a much higher number of white blood cells than whole blood. | Buffy coat
Template:WikiDoc Cardiology News
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
The buffy coat is the fraction of an anticoagulated blood sample after centrifugation that contains most of the white blood cells.
# Description
After centrifugation, one can distinguish a layer of clear fluid (the plasma), a layer of red fluid containing most of the red blood cells, and a thin layer in between, making up less than 1% of the total volume of the blood sample, the buffy coat (so-called because it is usually buff in hue), with most of the white blood cells and platelets. The buffy coat is used, for example, to extract DNA from the blood of mammals (since mammalian red blood cells are anucleate and do not contain DNA).
The buffy coat is usually whitish in color but sometimes green, if the blood sample contains large amounts of neutrophils, which are high in green myeloperoxidase.
# Diagnostic Uses of the Buffy Coat
- Quantitative Buffy Coat (QBC) is a laboratory test to detect infection with malaria or other blood parasites: the blood is taken in a QBC capillary tube which is coated with acridine orange (a fluorescent dye) and centrifuged; the fluorescing parasites can then be observed under ultraviolet light at the interface between red blood cells and buffy coat. This test is more sensitive than the conventional thick smear and in >90% of cases, the species of parasite can also be identified.
- In cases of extremely low white blood cell count, it may be difficult to perform a manual differential of the various types of white cells, and it may be virtually impossible to obtain an automated differential. In such cases the medical technologist may obtain a buffy coat, from which a blood smear is made. This smear contains a much higher number of white blood cells than whole blood. | https://www.wikidoc.org/index.php/Buffy_coat | |
01906cc64c7e2a7f0907c6f6ef5177cf31f8ee4e | wikidoc | Bupranolol | Bupranolol
# Overview
Bupranolol is a non-selective beta blocker without intrinsic sympathomimetic activity (ISA), but with strong membrane stabilizing activity. Its potency is similar to propranolol.
# Uses and Dosage
Like other beta blockers, oral bupranolol can be used to treat hypertension and tachycardia. The initial dose is 50 mg two times a day. It can be increased to 100 mg four times a day. Bupranolol eye drops (0.05%-0.5%) are used against glaucoma.
# Pharmacology
Bupranolol is quickly and completely absorbed from the gut. Over 90% undergo first-pass metabolism. Bupranolol has a plasma half life of about two to four hours, with levels never reaching 1 µg/l in therapeutic doses. The main metabolite is carboxybupranolol, 4-chloro-3-benzoic acid – that is, the methyl group at the benzene ring is oxidized to a carboxyl group –, of which 88% are eliminated renally within 24 hours.
# Adverse Effects, Contraindications, Interactions
Adverse effects, contraindications and interactions are similar to other beta blockers. | Bupranolol
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Bupranolol is a non-selective beta blocker without intrinsic sympathomimetic activity (ISA), but with strong membrane stabilizing activity. Its potency is similar to propranolol.
# Uses and Dosage
Like other beta blockers, oral bupranolol can be used to treat hypertension and tachycardia. The initial dose is 50 mg two times a day. It can be increased to 100 mg four times a day. Bupranolol eye drops (0.05%-0.5%) are used against glaucoma.
# Pharmacology
Bupranolol is quickly and completely absorbed from the gut. Over 90% undergo first-pass metabolism. Bupranolol has a plasma half life of about two to four hours, with levels never reaching 1 µg/l in therapeutic doses. The main metabolite is carboxybupranolol, 4-chloro-3-[3-(1,1-dimethylethylamino)-2-hydroxy-propyloxy]benzoic acid – that is, the methyl group at the benzene ring is oxidized to a carboxyl group –, of which 88% are eliminated renally within 24 hours.
# Adverse Effects, Contraindications, Interactions
Adverse effects, contraindications and interactions are similar to other beta blockers. | https://www.wikidoc.org/index.php/Bupranolol | |
2370b7f6d7d9655439613472eec5562d93bf54c7 | wikidoc | Lesser sac | Lesser sac
The lesser sac, also known as the omental bursa, is the cavity in the abdomen that is formed by the lesser and greater omentum. Usually found in mammals, it is connected with the greater sac via the epiploic foramen (also known as the Foramen of Winslow). In mammals, it is not uncommon for the lesser sac to contain considerable amounts of fat.
In human anatomy, the wall of the stomach, pancreas and splenic artery are a part of the wall of the lesser sac. If these structures rupture they may leak into the lesser sac. For the stomach, which lies anterior to the omental bursa, the rupture must be on the posterior side, as if it were anteriorly located, the leak would collect in the greater sac.
The lesser sac is embryologically formed from an infolding of the greater omentum. The open end of the infolding, known as the epiploic foramen, is usually proximal to the stomach.
# Additional images
- Upper part of celom of human embryo of 6.8 mm., seen from behind.
- Schematic figure of the bursa omentalis, etc. Human embryo of eight weeks.
- Diagrams to illustrate the development of the greater omentum and transverse mesocolon. | Lesser sac
Template:Infobox Anatomy
The lesser sac, also known as the omental bursa, is the cavity in the abdomen that is formed by the lesser and greater omentum. Usually found in mammals, it is connected with the greater sac via the epiploic foramen (also known as the Foramen of Winslow). In mammals, it is not uncommon for the lesser sac to contain considerable amounts of fat.
In human anatomy, the wall of the stomach, pancreas and splenic artery[1] are a part of the wall of the lesser sac. If these structures rupture they may leak into the lesser sac. For the stomach, which lies anterior to the omental bursa, the rupture must be on the posterior side, as if it were anteriorly located, the leak would collect in the greater sac.
The lesser sac is embryologically formed from an infolding of the greater omentum. The open end of the infolding, known as the epiploic foramen, is usually proximal to the stomach.
# Additional images
- Upper part of celom of human embryo of 6.8 mm., seen from behind.
- Schematic figure of the bursa omentalis, etc. Human embryo of eight weeks.
- Diagrams to illustrate the development of the greater omentum and transverse mesocolon. | https://www.wikidoc.org/index.php/Bursa_omentalis | |
1d4b77f169bca90238cad0a1a7fcdb0806961cc6 | wikidoc | Butalbital | Butalbital
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Butalbital is a combination that is FDA approved for the treatment of for the relief of the symptom complex of tension (or muscle contraction) headache. Common adverse reactions include lightheadedness and gastrointestinal disturbances including nausea, vomiting, and flatulence, toxic epidermal necrolysis and erythema multiforme.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Butalbital, aspirin, and caffeine tablets are indicated for the relief of the symptom complex of tension (or muscle contraction) headache.
- Evidence supporting the efficacy and safety of butalbital, aspirin, and caffeine in the treatment of multiple recurrent headaches is unavailable. Caution in this regard is required because butalbital is habit-forming and potentially abusable.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Butalbital in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Butalbital in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Butalbital in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Butalbital in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Butalbital in pediatric patients.
# Contraindications
- Hypersensitivity to aspirin, caffeine, or barbiturates. Patients with porphyria.
# Warnings
- Prolonged use of barbiturates can produce drug dependence, characterized by psychic dependence, and less frequently, physical dependence and tolerance. The abuse liability of butalbital, aspirin, and caffeine is similar to that of other barbiturate-containing drug combinations. Caution should be exercised when prescribing medication for patients with a known propensity for taking excessive quantities of drugs, which is not uncommon in patients with chronic tension headache.
- Butalbital, aspirin, and caffeine may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a car or operating machinery. The patient should be cautioned accordingly. Central Nervous System depressant effects of butalbital may be additive with those of other CNS depressants. Concurrent use with other sedative-hypnotics or alcohol should be avoided. When such combined therapy is necessary, the dose of one or more agents may need to be reduced.
- Salicylates should be used with extreme caution in the presence of peptic ulcer or coagulation abnormalities.
# Adverse Reactions
## Clinical Trials Experience
- The most frequent adverse reactions are drowsiness and dizziness. Less frequent adverse reactions are lightheadedness and gastrointestinal disturbances including nausea, vomiting, and flatulence. A single incidence of bone marrow suppression has been reported with the use of butalbital, aspirin, and caffeine. Several cases of dermatological reactions including toxic epidermal necrolysis and erythema multiforme have been reported.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Butalbital in the drug label.
# Drug Interactions
There is limited information regarding Butalbital Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Adequate studies have not been performed in animals to determine whether this drug affects fertility in males or females, has teratogenic potential, or has other adverse effects on the fetus. While there are no well-controlled studies in pregnant women, over twenty years of marketing and clinical experience does not include any positive evidence of adverse effects on the fetus. Although there is no clearly defined risk, such experience cannot exclude the possibility of infrequent or subtle damage to the human fetus. Butalbital, aspirin, and caffeine should be used in pregnant women only when clearly needed.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Butalbital in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Butalbital during labor and delivery.
### Nursing Mothers
- The effects of butalbital, aspirin, and caffeine on infants of nursing mothers are not known. Salicylates and barbiturates are excreted in the breast milk of nursing mothers. The serum levels in infants are believed to be insignificant with therapeutic doses.
### Pediatric Use
- Safety and effectiveness in pediatric patients below the age of 12 have not been established.
### Geriatic Use
There is no FDA guidance on the use of Butalbital with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Butalbital with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Butalbital with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Butalbital in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Butalbital in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Butalbital in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Butalbital in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Butalbital in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Butalbital in the drug label.
# Overdosage
- The toxic effects of acute overdosage of butalbital, aspirin, and caffeine are attributable mainly to its barbiturate component, and, to a lesser extent, aspirin. Because toxic effects of caffeine occur in very high dosages only, the possibility of significant caffeine toxicity from butalbital, aspirin, and caffeine overdosage is unlikely. Symptoms attributable to acute barbiturate poisoning include drowsiness, confusion, and coma; respiratory depression; hypotension; shock. Symptoms attributable to acute aspirin poisoning include hyperpnea; acid-base disturbances with development of metabolic acidosis; vomiting and abdominal pain; tinnitus; hyperthermia; hypoprothrombinemia; restlessness; delirium; convulsions. Acute caffeine poisoning may cause insomnia, restlessness, tremor, and delirium; tachycardia and extrasystoles. Treatment consists primarily of management of barbiturate intoxication and the correction of the acid-base imbalance due to salicylism. Vomiting should be induced mechanically or with emetics in the conscious patient. Gastric lavage may be used if the pharyngeal and laryngeal reflexes are present and if less than 4 hours have elapsed since ingestion. A cuffed endotracheal tube should be inserted before gastric lavage of the unconscious patient and when necessary to provide assisted respiration. Diuresis, alkalinization of the urine, and correction of electrolyte disturbances should be accomplished through administration of intravenous fluids such as 1% sodium bicarbonate in 5% dextrose in water. Meticulous attention should be given to maintaining adequate pulmonary ventilation. Correction of hypotension may require the administration of levartherenol bitartrate or phenylephrine hydrochloride by intravenous infusion . In severe cases of intoxication, peritoneal dialysis, hemodialysis, or exchange transfusion may be lifesaving. Hypoprothrombinemia should be treated with Vitamin K, intravenously.
There is limited information regarding Chronic Overdose of Butalbital in the drug label.
# Pharmacology
There is limited information regarding Butalbital Pharmacology in the drug label.
## Mechanism of Action
- Pharmacologically, butalbital, aspirin, and caffeine combines the analgesic properties of aspirin with the anxiolytic and muscle relaxant properties of butalbital.
The clinical effectiveness of butalbital, aspirin, and caffeine in tension headache has been established in double-blind, placebo-controlled, multi-clinic trials. A factorial design study compared butalbital, aspirin, and caffeine with each of its major components. This study demonstrated that each component contributes to the efficacy of butalbital, aspirin, and caffeine in the treatment of the target symptoms of tension headache (headache pain, psychic tension, and muscle contraction in the head, neck, and shoulder region). For each symptom and the symptom complex as a whole, butalbital, aspirin, and caffeine was shown to have significantly superior clinical effects to either component alone.
## Structure
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Butalbital in the drug label.
## Pharmacokinetics
- The behavior of the individual components is described below.
- The systemic availability of aspirin after an oral dose is highly dependent on the dosage form, the presence of food, the gastric emptying time, gastric pH, antacids, buffering agents, and particle size. These factors affect not necessarily the extent of absorption of total salicylates but more the stability of aspirin prior to absorption.
- During the absorption process and after absorption, aspirin mainly hydrolyzed to salicylic acid and distributed to all body tissues and fluids, including fetal tissues, breast milk, and the central nervous system (CNS). Highest concentrations are found in plasma, liver, renal cortex, heart, and lung. In plasma, about 50%-80% of the salicylic acid and its metabolites are loosely bound to plasma proteins.
- The clearance of total salicylates is subject to saturable kinetics; however, first-order elimination kinetics are still a good approximation for doses up to 650 mg. The plasma half-life for aspirin is about 12 minutes and for salicylic acid and/or total salicylates is about 3.0 hours.
- The elimination of therapeutic doses is through the kidneys either as salicylic acid or other biotransformation products. The renal clearance is greatly augmented by an alkaline urine as is produced by concurrent administration of sodium bicarbonate or potassium citrate.
- The biotransformation of aspirin occurs primarily in the hepatocytes. The major metabolites are salicyluric acid (75%), the phenolic and acyl glucuronides of salicylate (15%), and gentisic and gentisuric acid (1%). The bioavailability of the aspirin component butalbital, aspirin, and caffeine is equivalent to that of a solution except for a slower rate of absorption. A peak concentration of 8.80 mcg/mL was obtained at 40 minutes after a 650 mg dose.
- Butalbital is well absorbed from the gastrointestinal tract and is expected to distribute to most of the tissues in the body. Barbiturates, in general, may appear in breast milk and readily cross the placental barrier. They are bound to plasma and tissue proteins to a varying degree and binding increases directly as a function of lipid solubility.
- Elimination of butalbital is primarily via the kidney (59%-88% of the dose) as unchanged drug or metabolites. The plasma half-life is about 35 hours. Urinary excretion products included parent drug (about 3.6% of the dose), 5-isobutyl-5-(2,3-dihydroxypropyl) barbituric acid (about 24% of the dose), 5-allyl-5(3-hydroxy-2-methyl-1-propyl) barbituric acid (about 4.8% of the dose), products with the barbituric acid ring hydrolyzed with excretion of urea (about 14% of the dose), as well as unidentified materials. Of the material excreted in the urine, 32% was conjugated.
- The bioavailability of the butalbital component of butalbital, aspirin, and caffeine is equivalent to that of a solution except for a decrease in the rate of absorption. A peak concentration of 2020 ng/mL is obtained at about 1.5 hours after a 100 mg dose.
- The in vitro plasma protein binding of butalbital is 45% over the concentration range of 0.5 to 20 mcg/mL. This falls within the range of plasma protein binding (20% to 45%) reported with other barbiturates such as phenobarbital, pentobarbital, and secobarbital sodium. The plasma-to-blood concentration ratio was almost unity indicating that there is no preferential distribution of butalbital into either plasma or blood cells. (see OVERDOSAGE for toxicity information).
- Like most xanthines, caffeine is rapidly absorbed and distributed in all body tissues and fluids, including the CNS, fetal tissues, and breast milk.
- Caffeine is cleared rapidly through metabolism and excretion in the urine. The plasma half-life is about 3.0 hours. Hepatic biotransformation prior to excretion results in about equal amounts of 1-methyl-xanthine and 1-methyluric acid. Of the 70% of the dose that has been recovered in the urine, only 3% was unchanged drug.
- The bioavailability of the caffeine component for butalbital, aspirin, and caffeine is equivalent to that of a solution except for a slightly longer time to peak. A peak concentration of 1660 ng/mL was obtained in less than an hour for an 80 mg dose
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Butalbital in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Butalbital in the drug label.
# How Supplied
- Butalbital, Aspirin, and Caffeine Tablets, USP 50 mg/325 mg/40 mg are White, Round, Unscored Compressed Tablets Imprinted “West-ward 785”.
Bottles of 30 tablets
Bottles of 50 tablets
Bottles of 100 tablets
Bottles of 500 tablets
Bottles of 1000 tablets
Unit Dose Boxes of 100 tablets
- Store at 20-25oC (68-77oF) . Protect from light and moisture.
- Dispense in tight, light-resistant container as defined in the USP using a child-resistant closure.
## Storage
There is limited information regarding Butalbital Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Butalbital in the drug label.
# Precautions with Alcohol
- Alcohol-Butalbital interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
There is limited information regarding Butalbital Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Butalbital Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Butalbital
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aparna Vuppala, M.B.B.S. [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Butalbital is a combination that is FDA approved for the treatment of for the relief of the symptom complex of tension (or muscle contraction) headache. Common adverse reactions include lightheadedness and gastrointestinal disturbances including nausea, vomiting, and flatulence, toxic epidermal necrolysis and erythema multiforme.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Butalbital, aspirin, and caffeine tablets are indicated for the relief of the symptom complex of tension (or muscle contraction) headache.
- Evidence supporting the efficacy and safety of butalbital, aspirin, and caffeine in the treatment of multiple recurrent headaches is unavailable. Caution in this regard is required because butalbital is habit-forming and potentially abusable.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Butalbital in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Butalbital in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Butalbital in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Butalbital in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Butalbital in pediatric patients.
# Contraindications
- Hypersensitivity to aspirin, caffeine, or barbiturates. Patients with porphyria.
# Warnings
- Prolonged use of barbiturates can produce drug dependence, characterized by psychic dependence, and less frequently, physical dependence and tolerance. The abuse liability of butalbital, aspirin, and caffeine is similar to that of other barbiturate-containing drug combinations. Caution should be exercised when prescribing medication for patients with a known propensity for taking excessive quantities of drugs, which is not uncommon in patients with chronic tension headache.
- Butalbital, aspirin, and caffeine may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a car or operating machinery. The patient should be cautioned accordingly. Central Nervous System depressant effects of butalbital may be additive with those of other CNS depressants. Concurrent use with other sedative-hypnotics or alcohol should be avoided. When such combined therapy is necessary, the dose of one or more agents may need to be reduced.
- Salicylates should be used with extreme caution in the presence of peptic ulcer or coagulation abnormalities.
# Adverse Reactions
## Clinical Trials Experience
- The most frequent adverse reactions are drowsiness and dizziness. Less frequent adverse reactions are lightheadedness and gastrointestinal disturbances including nausea, vomiting, and flatulence. A single incidence of bone marrow suppression has been reported with the use of butalbital, aspirin, and caffeine. Several cases of dermatological reactions including toxic epidermal necrolysis and erythema multiforme have been reported.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Butalbital in the drug label.
# Drug Interactions
There is limited information regarding Butalbital Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Adequate studies have not been performed in animals to determine whether this drug affects fertility in males or females, has teratogenic potential, or has other adverse effects on the fetus. While there are no well-controlled studies in pregnant women, over twenty years of marketing and clinical experience does not include any positive evidence of adverse effects on the fetus. Although there is no clearly defined risk, such experience cannot exclude the possibility of infrequent or subtle damage to the human fetus. Butalbital, aspirin, and caffeine should be used in pregnant women only when clearly needed.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Butalbital in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Butalbital during labor and delivery.
### Nursing Mothers
- The effects of butalbital, aspirin, and caffeine on infants of nursing mothers are not known. Salicylates and barbiturates are excreted in the breast milk of nursing mothers. The serum levels in infants are believed to be insignificant with therapeutic doses.
### Pediatric Use
- Safety and effectiveness in pediatric patients below the age of 12 have not been established.
### Geriatic Use
There is no FDA guidance on the use of Butalbital with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Butalbital with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Butalbital with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Butalbital in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Butalbital in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Butalbital in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Butalbital in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Butalbital in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Butalbital in the drug label.
# Overdosage
- The toxic effects of acute overdosage of butalbital, aspirin, and caffeine are attributable mainly to its barbiturate component, and, to a lesser extent, aspirin. Because toxic effects of caffeine occur in very high dosages only, the possibility of significant caffeine toxicity from butalbital, aspirin, and caffeine overdosage is unlikely. Symptoms attributable to acute barbiturate poisoning include drowsiness, confusion, and coma; respiratory depression; hypotension; shock. Symptoms attributable to acute aspirin poisoning include hyperpnea; acid-base disturbances with development of metabolic acidosis; vomiting and abdominal pain; tinnitus; hyperthermia; hypoprothrombinemia; restlessness; delirium; convulsions. Acute caffeine poisoning may cause insomnia, restlessness, tremor, and delirium; tachycardia and extrasystoles. Treatment consists primarily of management of barbiturate intoxication and the correction of the acid-base imbalance due to salicylism. Vomiting should be induced mechanically or with emetics in the conscious patient. Gastric lavage may be used if the pharyngeal and laryngeal reflexes are present and if less than 4 hours have elapsed since ingestion. A cuffed endotracheal tube should be inserted before gastric lavage of the unconscious patient and when necessary to provide assisted respiration. Diuresis, alkalinization of the urine, and correction of electrolyte disturbances should be accomplished through administration of intravenous fluids such as 1% sodium bicarbonate in 5% dextrose in water. Meticulous attention should be given to maintaining adequate pulmonary ventilation. Correction of hypotension may require the administration of levartherenol bitartrate or phenylephrine hydrochloride by intravenous infusion . In severe cases of intoxication, peritoneal dialysis, hemodialysis, or exchange transfusion may be lifesaving. Hypoprothrombinemia should be treated with Vitamin K, intravenously.
There is limited information regarding Chronic Overdose of Butalbital in the drug label.
# Pharmacology
There is limited information regarding Butalbital Pharmacology in the drug label.
## Mechanism of Action
- Pharmacologically, butalbital, aspirin, and caffeine combines the analgesic properties of aspirin with the anxiolytic and muscle relaxant properties of butalbital.
The clinical effectiveness of butalbital, aspirin, and caffeine in tension headache has been established in double-blind, placebo-controlled, multi-clinic trials. A factorial design study compared butalbital, aspirin, and caffeine with each of its major components. This study demonstrated that each component contributes to the efficacy of butalbital, aspirin, and caffeine in the treatment of the target symptoms of tension headache (headache pain, psychic tension, and muscle contraction in the head, neck, and shoulder region). For each symptom and the symptom complex as a whole, butalbital, aspirin, and caffeine was shown to have significantly superior clinical effects to either component alone.
## Structure
-
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Butalbital in the drug label.
## Pharmacokinetics
- The behavior of the individual components is described below.
- The systemic availability of aspirin after an oral dose is highly dependent on the dosage form, the presence of food, the gastric emptying time, gastric pH, antacids, buffering agents, and particle size. These factors affect not necessarily the extent of absorption of total salicylates but more the stability of aspirin prior to absorption.
- During the absorption process and after absorption, aspirin mainly hydrolyzed to salicylic acid and distributed to all body tissues and fluids, including fetal tissues, breast milk, and the central nervous system (CNS). Highest concentrations are found in plasma, liver, renal cortex, heart, and lung. In plasma, about 50%-80% of the salicylic acid and its metabolites are loosely bound to plasma proteins.
- The clearance of total salicylates is subject to saturable kinetics; however, first-order elimination kinetics are still a good approximation for doses up to 650 mg. The plasma half-life for aspirin is about 12 minutes and for salicylic acid and/or total salicylates is about 3.0 hours.
- The elimination of therapeutic doses is through the kidneys either as salicylic acid or other biotransformation products. The renal clearance is greatly augmented by an alkaline urine as is produced by concurrent administration of sodium bicarbonate or potassium citrate.
- The biotransformation of aspirin occurs primarily in the hepatocytes. The major metabolites are salicyluric acid (75%), the phenolic and acyl glucuronides of salicylate (15%), and gentisic and gentisuric acid (1%). The bioavailability of the aspirin component butalbital, aspirin, and caffeine is equivalent to that of a solution except for a slower rate of absorption. A peak concentration of 8.80 mcg/mL was obtained at 40 minutes after a 650 mg dose.
- Butalbital is well absorbed from the gastrointestinal tract and is expected to distribute to most of the tissues in the body. Barbiturates, in general, may appear in breast milk and readily cross the placental barrier. They are bound to plasma and tissue proteins to a varying degree and binding increases directly as a function of lipid solubility.
- Elimination of butalbital is primarily via the kidney (59%-88% of the dose) as unchanged drug or metabolites. The plasma half-life is about 35 hours. Urinary excretion products included parent drug (about 3.6% of the dose), 5-isobutyl-5-(2,3-dihydroxypropyl) barbituric acid (about 24% of the dose), 5-allyl-5(3-hydroxy-2-methyl-1-propyl) barbituric acid (about 4.8% of the dose), products with the barbituric acid ring hydrolyzed with excretion of urea (about 14% of the dose), as well as unidentified materials. Of the material excreted in the urine, 32% was conjugated.
- The bioavailability of the butalbital component of butalbital, aspirin, and caffeine is equivalent to that of a solution except for a decrease in the rate of absorption. A peak concentration of 2020 ng/mL is obtained at about 1.5 hours after a 100 mg dose.
- The in vitro plasma protein binding of butalbital is 45% over the concentration range of 0.5 to 20 mcg/mL. This falls within the range of plasma protein binding (20% to 45%) reported with other barbiturates such as phenobarbital, pentobarbital, and secobarbital sodium. The plasma-to-blood concentration ratio was almost unity indicating that there is no preferential distribution of butalbital into either plasma or blood cells. (see OVERDOSAGE for toxicity information).
- Like most xanthines, caffeine is rapidly absorbed and distributed in all body tissues and fluids, including the CNS, fetal tissues, and breast milk.
- Caffeine is cleared rapidly through metabolism and excretion in the urine. The plasma half-life is about 3.0 hours. Hepatic biotransformation prior to excretion results in about equal amounts of 1-methyl-xanthine and 1-methyluric acid. Of the 70% of the dose that has been recovered in the urine, only 3% was unchanged drug.
- The bioavailability of the caffeine component for butalbital, aspirin, and caffeine is equivalent to that of a solution except for a slightly longer time to peak. A peak concentration of 1660 ng/mL was obtained in less than an hour for an 80 mg dose
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Butalbital in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Butalbital in the drug label.
# How Supplied
- Butalbital, Aspirin, and Caffeine Tablets, USP 50 mg/325 mg/40 mg are White, Round, Unscored Compressed Tablets Imprinted “West-ward 785”.
Bottles of 30 tablets
Bottles of 50 tablets
Bottles of 100 tablets
Bottles of 500 tablets
Bottles of 1000 tablets
Unit Dose Boxes of 100 tablets
- Store at 20-25oC (68-77oF) [See USP Controlled Room Temperature]. Protect from light and moisture.
- Dispense in tight, light-resistant container as defined in the USP using a child-resistant closure.
## Storage
There is limited information regarding Butalbital Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Butalbital in the drug label.
# Precautions with Alcohol
- Alcohol-Butalbital interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
There is limited information regarding Butalbital Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Butalbital Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Butalbital | |
be1c5d5c894ff6cee938457588a490873a6a3722 | wikidoc | Butenafine | Butenafine
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Butenafine is an antifungal that is FDA approved for the treatment of dermatologic infection, tinea (pityriasis) versicolor due to M. furfur (formerly P. orbiculare). Common adverse reactions include contact dermatitis, erythema, itching, skin irritation.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Butenafine HCl Cream, 1% is indicated for the topical treatment of the dermatologic infection, tinea (pityriasis) versicolor due to M. furfur (formerly P. orbiculare). Butenafine HCl cream was not studied in immunocompromised patients.
- Patients with tinea (pityriasis) versicolor should apply Mentax® Cream, 1%, once daily for two weeks. Sufficient Mentax® Cream should be applied to cover affected areas and immediately surrounding skin of patients with tinea versicolor. If a patient shows no clinical improvement after the treatment period, the diagnosis and therapy should be reviewed.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Butenafine in adult patients.
### Non–Guideline-Supported Use
- Onychomycosis due to dermatophyte
- Seborrheic dermatitis
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Butenafine FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Butenafine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Butenafine in pediatric patients.
# Contraindications
- Butenafine Cream, 1%, is contraindicated in individuals who have known or suspected sensitivity to Mentax® Cream, 1%, or any of its components.
# Warnings
- Butenafine Cream, 1%, is not for ophthalmic, oral, or intravaginal use.
# Adverse Reactions
## Clinical Trials Experience
There is limited information regarding Clinical Trial Experience of Butenafine in the drug label.
## Postmarketing Experience
- In controlled clinical trials, 9 (approximately 1%) of 815 patients treated with Mentax® Cream, 1%, reported adverse events related to the skin. These included burning/stinging, itching and worsening of the condition. No patient treated with Mentax® Cream, 1%, discontinued treatment due to an adverse event. In the vehicle-treated patients, 2 of 718 patients discontinued because of treatment site adverse events, one of which was severe burning/stinging and itching at the site of application.
- In uncontrolled clinical trials, the most frequently reported adverse events in patients treated with Mentax® Cream, 1%, were: contact dermatitis, erythema, irritation, and itching, each occurring in less than 2% of patients.
- In provocative testing in over 200 subjects, there was no evidence of allergic-contact sensitization for either cream or vehicle base for Mentax® Cream, 1%.
# Drug Interactions
There is limited information regarding Butenafine Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Subcutaneous doses of butenafine (dose levels up to 25 mg/kg/day administered during organogenesis) (equivalent to 0.5 times the maximum recommended dose in humans for tinea versicolor based on body surface area comparisons) were not teratogenic in rats. In an oral embryofetal development study in rabbits (dose levels up to 400 mg butenafine HCl/kg/day administered during organogenesis) (equivalent to 16 times the maximum recommended dose in humans for tinea versicolor based on body surface area comparisons), no treatment-related external, visceral, skeletal malformations or variations were observed.
In an oral peri- and post-natal developmental study in rats (dose levels up to 125 mg butenafine HCl/kg/day) (equivalent to 2.5 times the maximum recommended dose in humans for tinea versicolor based on body surface area comparisons), no treatment-related effects on postnatal survival, development of the F1 generation or their subsequent maturation and fertility were observed.
There are, however, no adequate and well-controlled studies that have been conducted with topically applied butenafine in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Butenafine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Butenafine during labor and delivery.
### Nursing Mothers
It is not known if butenafine HCl is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised in prescribing Mentax® Cream, 1%, to a nursing woman.
### Pediatric Use
Safety and efficacy in pediatric patients below the age of 12 years have not been studied since tinea versicolor is uncommon in patients below the age of 12 years.
### Geriatic Use
There is no FDA guidance on the use of Butenafine with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Butenafine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Butenafine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Butenafine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Butenafine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Butenafine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Butenafine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Topical
### Monitoring
There is limited information regarding Butenafine Monitoring in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Butenafine in the drug label.
# Overdosage
- Overdosage of butenafine HCl in humans has not been reported to date.
# Pharmacology
There is limited information regarding Butenafine Pharmacology in the drug label.
## Mechanism of Action
## Structure
- Mentax® Cream, 1%, contains the synthetic antifungal agent, butenafine hydrochloride. Butenafine is a member of the class of antifungal compounds known as benzylamines which are structurally related to the allylamines.
- Butenafine HCl is designated chemically as N-4-tert-butylbenzyl-N-methyl-1-naphthalenemethylamine hydrochloride. The compound has the molecular formula C23H27NHCl, a molecular weight of 353.93, and the following structural formula:
- Butenafine HCl is a white, odorless, crystalline powder. It is freely soluble in methanol, ethanol, and chloroform, and slightly soluble in water. Each gram of Mentax® Cream, 1%, contains 10 mg of butenafine HCl in a white cream base of purified water USP, propylene glycol dicaprylate, glycerin USP, cetyl alcohol NF, glyceryl monostearate SE, white petrolatum USP, stearic acid NF, polyoxyethylene (23) cetyl ether, benzyl alcohol NF, diethanolamine NF, and sodium benzoate NF.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Butenafine in the drug label.
## Pharmacokinetics
- In one study conducted in healthy subjects for 14 days, 6 grams of Mentax® Cream, 1%, was applied once daily to the dorsal skin (3,000 cm2) of 7 subjects, and 20 grams of the cream was applied once daily to the arms, trunk and groin areas (10,000 cm2) of another 12 subjects. After 14 days of topical applications, the 6-gram dose group yielded a mean peak plasma butenafine HCl concentration, Cmax of 1.4 ± 0.8 ng/mL, occurring at a mean time to the peak plasma concentration, Tmax, of 15 ± 8 hours, and a mean area under the plasma concentration-time curve, AUC0-24 hrs of 23.9 ± 11.3 ng-hr/mL. For the 20-gram dose group, the mean Cmax was 5.0 ± 2.0 ng/mL, occurring at a mean Tmax of 6 ± 6 hours, and the mean AUC0-24 hrs was 87.8 ± 45.3 ng-hr/mL. A biphasic decline of plasma butenafine HCl concentrations was observed with the half-lives estimated to be 35 hours and > 150 hours, respectively.
- At 72 hours after the last dose application, the mean plasma concentrations decreased to 0.3 ± 0.2 ng/mL for the 6-gram dose group and 1.1 ± 0.9 ng/mL for the 20-gram dose group. Low levels of butenafine HCl remained in the plasma 7 days after the last dose application (mean: 0.1 ± 0.2 ng/mL for the 6-gram dose group, and 0.7 ± 0.5 ng/mL for the 20-gram dose group). The total amount (or % dose) of butenafine HCl absorbed through the skin into the systemic circulation has not been quantitated. It was determined that the primary metabolite in urine was formed through hydroxylation at the terminal t-butyl side-chain.
- In 11 patients with tinea pedis, butenafine HCl cream, 1%, was applied by the patients to cover the affected and immediately surrounding skin area once daily for 4 weeks, and a single blood sample was collected between 10 and 20 hours following dosing at 1, 2 and 4 weeks after treatment. The plasma butenafine HCl concentration ranged from undetectable to 0.3 ng/mL.
- In 24 patients with tinea cruris, butenafine HCl cream, 1%, was applied by the patients to cover the affected and immediately surrounding skin area once daily for 2 weeks (mean average daily dose: 1.3 ± 0.2 g). A single blood sample was collected between 0.5 and 65 hours after the last dose, and the plasma butenafine HCl concentration ranged from undetectable to 2.52 ng/mL (mean ± SD: 0.91 ± 0.15 ng/mL). Four weeks after cessation of treatment, the plasma butenafine HCl concentration ranged from undetectable to 0.28 ng/mL.
- Butenafine HCl is a benzylamine derivative with a mode of action similar to that of the allylamine class of antifungal drugs. Butenafine HCl is hypothesized to act by inhibiting the epoxidation of squalene, thus blocking the biosynthesis of ergosterol, an essential component of fungal cell membranes. The benzylamine derivatives, like the allylamines, act at an earlier step in the ergosterol biosynthesis pathway than the azole class of antifungal drugs. Depending on the concentration of the drug and the fungal species tested, butenafine HCl may be fungicidal or fungistatic in vitro. However, the clinical significance of these in vitro data are unknown.
- Butenafine HCl has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section:
- Epidermophyton floccosum
- Trichophyton rubrum
- Malassezia furfur
- Trichophyton tonsurans
- Trichophyton mentagrophytes
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Butenafine in the drug label.
# Clinical Studies
- In the following data presentations, patients with tinea (pityriasis) versicolor were studied. The term “Negative Mycology” is defined as absence of hyphae in a KOH preparation of skin scrapings, i.e., no fungal forms seen or the presence of yeast cells (blastospores) only. The term “Effective Treatment” is defined as Negative Mycology plus total signs and symptoms score (on a scale from zero to three) for erythema, scaling, and pruritus equal to or less than 1 at Week 8. The term “Complete Cure” refers to patients who had Negative Mycology plus sign/symptoms score of zero for erythema, scaling, and pruritus.
- Two separate studies compared Mentax® Cream to vehicle applied once daily for 2 weeks in the treatment of tinea (pityriasis) versicolor. Patients were treated for 2 weeks and were evaluated at the following weeks post-treatment: 2 (Week 4) and 6 (Week 8). All subjects with a positive baseline KOH and who were dispensed medications were included in the “intent-to-treat” analysis shown in the table below. Statistical significance (Mentax® vs. vehicle) was achieved for Effective Treatment, but not Complete Cure at 6 weeks post-treatment in Study 31. Marginal statistical significance (p = 0.051) (Mentax® vs. vehicle) was achieved for Effective Treatment, but not Complete Cure at 6 weeks post-treatment in Study 32. Data from these two controlled studies are presented in the table below.
- Tinea (pityriasis) versicolor is a superficial, chronically recurring infection of the glabrous skin caused by Malassezia furfur (formerly Pityrosporum orbiculare). The commensal organism is part of the normal skin flora. In susceptible individuals, the condition may give rise to hyperpigmented or hypopigmented patches on the trunk which may extend to the neck, arms, and upper thighs.
- Treatment of the infection may not immediately result in restoration of pigment of the affected sites. Normalization of pigment following successful therapy is variable and may take months, depending upon individual skin type and incidental sun exposure. The rate of recurrence of infection is variable.
# How Supplied
- Butenafine Cream, 1%, is supplied in tubes in the following sizes:
- 15-gram tube (NDC 0378-6151-46)
- 30-gram tube (NDC 0378-6151-49)
## Storage
- STORE BETWEEN 5° and 30°C (41° and 86°F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Butenafine in the drug label.
# Precautions with Alcohol
- Alcohol-Butenafine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- MENTAX®
# Look-Alike Drug Names
There is limited information regarding Butenafine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Butenafine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Butenafine is an antifungal that is FDA approved for the treatment of dermatologic infection, tinea (pityriasis) versicolor due to M. furfur (formerly P. orbiculare). Common adverse reactions include contact dermatitis, erythema, itching, skin irritation.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Butenafine HCl Cream, 1% is indicated for the topical treatment of the dermatologic infection, tinea (pityriasis) versicolor due to M. furfur (formerly P. orbiculare). Butenafine HCl cream was not studied in immunocompromised patients.
- Patients with tinea (pityriasis) versicolor should apply Mentax® Cream, 1%, once daily for two weeks. Sufficient Mentax® Cream should be applied to cover affected areas and immediately surrounding skin of patients with tinea versicolor. If a patient shows no clinical improvement after the treatment period, the diagnosis and therapy should be reviewed.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Butenafine in adult patients.
### Non–Guideline-Supported Use
- Onychomycosis due to dermatophyte[1]
- Seborrheic dermatitis
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Butenafine FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Butenafine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Butenafine in pediatric patients.
# Contraindications
- Butenafine Cream, 1%, is contraindicated in individuals who have known or suspected sensitivity to Mentax® Cream, 1%, or any of its components.
# Warnings
- Butenafine Cream, 1%, is not for ophthalmic, oral, or intravaginal use.
# Adverse Reactions
## Clinical Trials Experience
There is limited information regarding Clinical Trial Experience of Butenafine in the drug label.
## Postmarketing Experience
- In controlled clinical trials, 9 (approximately 1%) of 815 patients treated with Mentax® Cream, 1%, reported adverse events related to the skin. These included burning/stinging, itching and worsening of the condition. No patient treated with Mentax® Cream, 1%, discontinued treatment due to an adverse event. In the vehicle-treated patients, 2 of 718 patients discontinued because of treatment site adverse events, one of which was severe burning/stinging and itching at the site of application.
- In uncontrolled clinical trials, the most frequently reported adverse events in patients treated with Mentax® Cream, 1%, were: contact dermatitis, erythema, irritation, and itching, each occurring in less than 2% of patients.
- In provocative testing in over 200 subjects, there was no evidence of allergic-contact sensitization for either cream or vehicle base for Mentax® Cream, 1%.
# Drug Interactions
There is limited information regarding Butenafine Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Subcutaneous doses of butenafine (dose levels up to 25 mg/kg/day administered during organogenesis) (equivalent to 0.5 times the maximum recommended dose in humans for tinea versicolor based on body surface area comparisons) were not teratogenic in rats. In an oral embryofetal development study in rabbits (dose levels up to 400 mg butenafine HCl/kg/day administered during organogenesis) (equivalent to 16 times the maximum recommended dose in humans for tinea versicolor based on body surface area comparisons), no treatment-related external, visceral, skeletal malformations or variations were observed.
In an oral peri- and post-natal developmental study in rats (dose levels up to 125 mg butenafine HCl/kg/day) (equivalent to 2.5 times the maximum recommended dose in humans for tinea versicolor based on body surface area comparisons), no treatment-related effects on postnatal survival, development of the F1 generation or their subsequent maturation and fertility were observed.
There are, however, no adequate and well-controlled studies that have been conducted with topically applied butenafine in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Butenafine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Butenafine during labor and delivery.
### Nursing Mothers
It is not known if butenafine HCl is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised in prescribing Mentax® Cream, 1%, to a nursing woman.
### Pediatric Use
Safety and efficacy in pediatric patients below the age of 12 years have not been studied since tinea versicolor is uncommon in patients below the age of 12 years.
### Geriatic Use
There is no FDA guidance on the use of Butenafine with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Butenafine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Butenafine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Butenafine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Butenafine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Butenafine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Butenafine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Topical
### Monitoring
There is limited information regarding Butenafine Monitoring in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Butenafine in the drug label.
# Overdosage
- Overdosage of butenafine HCl in humans has not been reported to date.
# Pharmacology
There is limited information regarding Butenafine Pharmacology in the drug label.
## Mechanism of Action
-
## Structure
- Mentax® Cream, 1%, contains the synthetic antifungal agent, butenafine hydrochloride. Butenafine is a member of the class of antifungal compounds known as benzylamines which are structurally related to the allylamines.
- Butenafine HCl is designated chemically as N-4-tert-butylbenzyl-N-methyl-1-naphthalenemethylamine hydrochloride. The compound has the molecular formula C23H27N•HCl, a molecular weight of 353.93, and the following structural formula:
- Butenafine HCl is a white, odorless, crystalline powder. It is freely soluble in methanol, ethanol, and chloroform, and slightly soluble in water. Each gram of Mentax® Cream, 1%, contains 10 mg of butenafine HCl in a white cream base of purified water USP, propylene glycol dicaprylate, glycerin USP, cetyl alcohol NF, glyceryl monostearate SE, white petrolatum USP, stearic acid NF, polyoxyethylene (23) cetyl ether, benzyl alcohol NF, diethanolamine NF, and sodium benzoate NF.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Butenafine in the drug label.
## Pharmacokinetics
- In one study conducted in healthy subjects for 14 days, 6 grams of Mentax® Cream, 1%, was applied once daily to the dorsal skin (3,000 cm2) of 7 subjects, and 20 grams of the cream was applied once daily to the arms, trunk and groin areas (10,000 cm2) of another 12 subjects. After 14 days of topical applications, the 6-gram dose group yielded a mean peak plasma butenafine HCl concentration, Cmax of 1.4 ± 0.8 ng/mL, occurring at a mean time to the peak plasma concentration, Tmax, of 15 ± 8 hours, and a mean area under the plasma concentration-time curve, AUC0-24 hrs of 23.9 ± 11.3 ng-hr/mL. For the 20-gram dose group, the mean Cmax was 5.0 ± 2.0 ng/mL, occurring at a mean Tmax of 6 ± 6 hours, and the mean AUC0-24 hrs was 87.8 ± 45.3 ng-hr/mL. A biphasic decline of plasma butenafine HCl concentrations was observed with the half-lives estimated to be 35 hours and > 150 hours, respectively.
- At 72 hours after the last dose application, the mean plasma concentrations decreased to 0.3 ± 0.2 ng/mL for the 6-gram dose group and 1.1 ± 0.9 ng/mL for the 20-gram dose group. Low levels of butenafine HCl remained in the plasma 7 days after the last dose application (mean: 0.1 ± 0.2 ng/mL for the 6-gram dose group, and 0.7 ± 0.5 ng/mL for the 20-gram dose group). The total amount (or % dose) of butenafine HCl absorbed through the skin into the systemic circulation has not been quantitated. It was determined that the primary metabolite in urine was formed through hydroxylation at the terminal t-butyl side-chain.
- In 11 patients with tinea pedis, butenafine HCl cream, 1%, was applied by the patients to cover the affected and immediately surrounding skin area once daily for 4 weeks, and a single blood sample was collected between 10 and 20 hours following dosing at 1, 2 and 4 weeks after treatment. The plasma butenafine HCl concentration ranged from undetectable to 0.3 ng/mL.
- In 24 patients with tinea cruris, butenafine HCl cream, 1%, was applied by the patients to cover the affected and immediately surrounding skin area once daily for 2 weeks (mean average daily dose: 1.3 ± 0.2 g). A single blood sample was collected between 0.5 and 65 hours after the last dose, and the plasma butenafine HCl concentration ranged from undetectable to 2.52 ng/mL (mean ± SD: 0.91 ± 0.15 ng/mL). Four weeks after cessation of treatment, the plasma butenafine HCl concentration ranged from undetectable to 0.28 ng/mL.
- Butenafine HCl is a benzylamine derivative with a mode of action similar to that of the allylamine class of antifungal drugs. Butenafine HCl is hypothesized to act by inhibiting the epoxidation of squalene, thus blocking the biosynthesis of ergosterol, an essential component of fungal cell membranes. The benzylamine derivatives, like the allylamines, act at an earlier step in the ergosterol biosynthesis pathway than the azole class of antifungal drugs. Depending on the concentration of the drug and the fungal species tested, butenafine HCl may be fungicidal or fungistatic in vitro. However, the clinical significance of these in vitro data are unknown.
- Butenafine HCl has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section:
- Epidermophyton floccosum
- Trichophyton rubrum
- Malassezia furfur
- Trichophyton tonsurans
- Trichophyton mentagrophytes
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Butenafine in the drug label.
# Clinical Studies
- In the following data presentations, patients with tinea (pityriasis) versicolor were studied. The term “Negative Mycology” is defined as absence of hyphae in a KOH preparation of skin scrapings, i.e., no fungal forms seen or the presence of yeast cells (blastospores) only. The term “Effective Treatment” is defined as Negative Mycology plus total signs and symptoms score (on a scale from zero to three) for erythema, scaling, and pruritus equal to or less than 1 at Week 8. The term “Complete Cure” refers to patients who had Negative Mycology plus sign/symptoms score of zero for erythema, scaling, and pruritus.
- Two separate studies compared Mentax® Cream to vehicle applied once daily for 2 weeks in the treatment of tinea (pityriasis) versicolor. Patients were treated for 2 weeks and were evaluated at the following weeks post-treatment: 2 (Week 4) and 6 (Week 8). All subjects with a positive baseline KOH and who were dispensed medications were included in the “intent-to-treat” analysis shown in the table below. Statistical significance (Mentax® vs. vehicle) was achieved for Effective Treatment, but not Complete Cure at 6 weeks post-treatment in Study 31. Marginal statistical significance (p = 0.051) (Mentax® vs. vehicle) was achieved for Effective Treatment, but not Complete Cure at 6 weeks post-treatment in Study 32. Data from these two controlled studies are presented in the table below.
- Tinea (pityriasis) versicolor is a superficial, chronically recurring infection of the glabrous skin caused by Malassezia furfur (formerly Pityrosporum orbiculare). The commensal organism is part of the normal skin flora. In susceptible individuals, the condition may give rise to hyperpigmented or hypopigmented patches on the trunk which may extend to the neck, arms, and upper thighs.
- Treatment of the infection may not immediately result in restoration of pigment of the affected sites. Normalization of pigment following successful therapy is variable and may take months, depending upon individual skin type and incidental sun exposure. The rate of recurrence of infection is variable.
# How Supplied
- Butenafine Cream, 1%, is supplied in tubes in the following sizes:
- 15-gram tube (NDC 0378-6151-46)
- 30-gram tube (NDC 0378-6151-49)
## Storage
- STORE BETWEEN 5° and 30°C (41° and 86°F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Butenafine in the drug label.
# Precautions with Alcohol
- Alcohol-Butenafine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- MENTAX®[2]
# Look-Alike Drug Names
There is limited information regarding Butenafine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Butenafine | |
66c104a20fe2012390d324e1e9ee29d5938322fd | wikidoc | Malar rash | Malar rash
Malar rash, also called butterfly rash, is a medical sign consisting of a characteristic form of facial rash. It is often seen in Lupus erythematosus. Malar is the Latin for "cheek".
The malar rash of lupus is red or purplish and mildly scaly. Characteristically, it has the shape of a butterfly and involves the bridge of the nose.
# Epidemiology and Demographics
A malar rash is present in approximately 46-65% of lupus sufferers and varies between different populations.
# Diagnosis
## Common Causes
There are numerous other conditions which can cause rashes with a similar appearance. Where lupus is suspected further medical tests (usually an ANA) and a detailed history are necessary to differentiate it from other conditions. | Malar rash
Template:Search infobox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Malar rash, also called butterfly rash, is a medical sign consisting of a characteristic form of facial rash. It is often seen in Lupus erythematosus. Malar is the Latin for "cheek".
The malar rash of lupus is red or purplish and mildly scaly. Characteristically, it has the shape of a butterfly and involves the bridge of the nose.
# Epidemiology and Demographics
A malar rash is present in approximately 46-65% of lupus sufferers and varies between different populations.[1][2][3]
# Diagnosis
## Common Causes
There are numerous other conditions which can cause rashes with a similar appearance. Where lupus is suspected further medical tests (usually an ANA) and a detailed history are necessary to differentiate it from other conditions. | https://www.wikidoc.org/index.php/Butterfly_rash | |
4653632622b083fb8212383443323344767b07f4 | wikidoc | By-product | By-product
A by-product is a secondary or incidental product deriving from a manufacturing process, a chemical reaction or a biochemical pathway, and is not the primary product or service being produced. A by-product can be useful and marketable, or it can have severe ecological consequences.
# Major by-products
## Animal sources
- dried blood and blood meal - from slaughterhouse operations
- chicken by-product meal - clean parts of the carcass of slaughtered chicken, such as necks, feet, undeveloped eggs, and intestines.
- chrome shavings - from a stage of leather manufacture
- collagen and gelatin - from the boiled skin and other parts of slaughtered livestock
- feathers - from poultry processing
- lanolin - from the cleaning of wool
- manure - from animal husbandry
- meat and bone meal - from the rendering of animal bones and offal
- poultry byproduct and poultry meal - made from unmarketable poultry bones and offal
- poultry litter - swept from the floors of chicken coops]
- whey - from cheese manufacturing
- fetal pigs
## Vegetation
- acidulated soap stock - from the refining of vegetable oil
- bran and germ - from the milling of whole grains into refined grains
- brewer's yeast - from ethanol fermentation
- corn stover - residual plant matter after harvesting of cereals
- distillers grains - from ethanol fermentation
- glycerol - from the production of biodiesel
- grape seed oil - recovered from leftovers of the winemaking process
- molasses - from sugar refining
- orange oil and other citrus oils - recovered from the peels of processed fruit
- pectin - recovered from the remains of processed fruit
- sawdust and bark- from the processing of logs into lumber
- straw- from grain harvesting
## Minerals and petro chemicals
- asphalt - from the refining of crude oil
- fly ash - from the combustion of coal
- slag - from ore refining
- gypsum - from Flue gas desulfurization
- ash and smoke - from the combustion of fuel
- mineral oil - from refining crude oil to produce gasoline
- salt - from desalination
## Other
- sludge - from wastewater treatment | By-product
A by-product is a secondary or incidental product deriving from a manufacturing process, a chemical reaction or a biochemical pathway, and is not the primary product or service being produced. A by-product can be useful and marketable, or it can have severe ecological consequences.
# Major by-products
## Animal sources
- dried blood and blood meal - from slaughterhouse operations
- chicken by-product meal - clean parts of the carcass of slaughtered chicken, such as necks, feet, undeveloped eggs, and intestines.
- chrome shavings - from a stage of leather manufacture
- collagen and gelatin - from the boiled skin and other parts of slaughtered livestock
- feathers - from poultry processing
- lanolin - from the cleaning of wool
- manure - from animal husbandry
- meat and bone meal - from the rendering of animal bones and offal
- poultry byproduct and poultry meal - made from unmarketable poultry bones and offal
- poultry litter - swept from the floors of chicken coops]
- whey - from cheese manufacturing
- fetal pigs
## Vegetation
- acidulated soap stock - from the refining of vegetable oil
- bran and germ - from the milling of whole grains into refined grains
- brewer's yeast - from ethanol fermentation
- corn stover - residual plant matter after harvesting of cereals
- distillers grains - from ethanol fermentation
- glycerol - from the production of biodiesel
- grape seed oil - recovered from leftovers of the winemaking process
- molasses - from sugar refining
- orange oil and other citrus oils - recovered from the peels of processed fruit
- pectin - recovered from the remains of processed fruit
- sawdust and bark- from the processing of logs into lumber
- straw- from grain harvesting
## Minerals and petro chemicals
- asphalt - from the refining of crude oil
- fly ash - from the combustion of coal
- slag - from ore refining
- gypsum - from Flue gas desulfurization
- ash and smoke - from the combustion of fuel
- mineral oil - from refining crude oil to produce gasoline
- salt - from desalination
## Other
- sludge - from wastewater treatment | https://www.wikidoc.org/index.php/By-product | |
987d6830340cc29ec7c8f4dae3d0792dd87f2cbb | wikidoc | C-terminus | C-terminus
The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal end, or COOH-terminus) of a protein or polypeptide is the end of the amino acid chain terminated by a free carboxyl group (-COOH). The convention for writing peptide sequences is to put the C-terminal end on the right and write the sequence from N- to C-terminus.
# Chemistry
Each amino acid has a carboxyl group and an amine group, and amino acids link to one another to form a chain by a dehydration reaction by joining the amine group of one amino acid to the carboxyl group of the next. Thus polypeptide chains have an end with an unbound carboxyl group, the C-terminus, and an end with an amine group, the N-terminus. Proteins are synthesized starting from the N-terminus and ending at the C-terminus.
# Function
## C-terminal retention signals
While the N-terminus of a protein often contains targeting signals, the C-terminus can contain retention signals for protein sorting. The most common ER retention signal is the amino acid sequence -KDEL (or -HDEL) at the C-terminus, which keeps the protein in the endoplasmic reticulum and prevents it from entering the secretory pathway.
## C-terminal modifications
The C-terminus of proteins can be modified posttranslationally, most commonly by the addition of a lipid anchor to the C-terminus that allows the protein to be inserted into a membrane without having a transmembrane domain.
- Prenylation
One form of C-terminal modification is prenylation. During prenylation, a farnesyl- or geranylgeranyl-isoprenoid membrane anchor is added to a cysteine residue near the C-terminus. Small, membrane-bound G proteins are often modified this way.
- GPI anchors
Another form of C-terminal modification is the addition of a phosphoglycan, glycosylphosphatidylinositol (GPI), as a membrane anchor. The GPI anchor is attached to the C-terminus after proteolytic cleavage of a C-terminal propeptide. The most prominent example for this type of modification is the prion protein.
## C-terminal domain
The C-terminal domain (CTD) of some proteins has specialized functions.
- CTD of RNA polymerase
The carboxy-terminal domain of RNA polymerase II typically consists of up to 52 repeats of the sequence Tyr-Ser-Pro-Thr-Ser-Pro-Ser . Other proteins often bind the C-terminal domain of RNA polymerase in order to activate polymerase activity. It is the protein domain which is involved in the initiation of DNA transcription, the capping of the RNA transcript, and attachment to the spliceosome for RNA splicing. | C-terminus
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal end, or COOH-terminus) of a protein or polypeptide is the end of the amino acid chain terminated by a free carboxyl group (-COOH). The convention for writing peptide sequences is to put the C-terminal end on the right and write the sequence from N- to C-terminus.
# Chemistry
Each amino acid has a carboxyl group and an amine group, and amino acids link to one another to form a chain by a dehydration reaction by joining the amine group of one amino acid to the carboxyl group of the next. Thus polypeptide chains have an end with an unbound carboxyl group, the C-terminus, and an end with an amine group, the N-terminus. Proteins are synthesized starting from the N-terminus and ending at the C-terminus.
# Function
## C-terminal retention signals
While the N-terminus of a protein often contains targeting signals, the C-terminus can contain retention signals for protein sorting. The most common ER retention signal is the amino acid sequence -KDEL (or -HDEL) at the C-terminus, which keeps the protein in the endoplasmic reticulum and prevents it from entering the secretory pathway.
## C-terminal modifications
The C-terminus of proteins can be modified posttranslationally, most commonly by the addition of a lipid anchor to the C-terminus that allows the protein to be inserted into a membrane without having a transmembrane domain.
- Prenylation
One form of C-terminal modification is prenylation. During prenylation, a farnesyl- or geranylgeranyl-isoprenoid membrane anchor is added to a cysteine residue near the C-terminus. Small, membrane-bound G proteins are often modified this way.
- GPI anchors
Another form of C-terminal modification is the addition of a phosphoglycan, glycosylphosphatidylinositol (GPI), as a membrane anchor. The GPI anchor is attached to the C-terminus after proteolytic cleavage of a C-terminal propeptide. The most prominent example for this type of modification is the prion protein.
## C-terminal domain
The C-terminal domain (CTD) of some proteins has specialized functions.
- CTD of RNA polymerase
The carboxy-terminal domain of RNA polymerase II typically consists of up to 52 repeats of the sequence Tyr-Ser-Pro-Thr-Ser-Pro-Ser [1]. Other proteins often bind the C-terminal domain of RNA polymerase in order to activate polymerase activity. It is the protein domain which is involved in the initiation of DNA transcription, the capping of the RNA transcript, and attachment to the spliceosome for RNA splicing[2]. | https://www.wikidoc.org/index.php/C-terminal | |
3239292dce0c2d3479e18da10a53701a85e3d106 | wikidoc | C. R. Bard | C. R. Bard
C. R. Bard, Inc. (Template:Nyse) is one of the large S&P 500 companies of the United States, a surgical specialties and hospital medical device manufacturer in Murray Hill, New Jersey. It is named after its founder, who sold the company within only a few years of its founding. In later decades it grew to its current size largely through many small acquisitions.
# History
C. R. Bard, Inc. was founded in 1923 by Charles Russell Bard.
In 1926, Bard sold the company to John F. Willits and Edson L.Outwin for US$18,000.
In 1934, the Bard company began to produce the Foley Catheter, a landmark product.
In 1948, Bard moved the company headquarters from New York City to Summit, New Jersey. That year, Net sales revenue exceeded US$1 million.
In 1963, C. R. Bard, Inc. becomes a publicly-traded company. The company had already been paying a cash dividend since 1960, and it has continued every year since.
In 1968 Bard became listed on the New York Stock Exchange, with the ticker symbol BCR. It began manufacturing operations at a plant in Murray Hill, New Jersey.
In 1974 it went international, with plants in South America and Japan.
In 1981, Bard opened manufacturing facilities in Puerto Rico and Ireland.
Bard peformed well through the long bear market of the 1970s. Its stock rose, from the low early in that decade, to up by seven-fold times by its 1983 peak. It split three-for-two in 1982.
By 1986, Bard had become listed in the S&P 500 among the largest 500 publicly-traded companies in the United States. Annual earnings by 1986 were over US$40 million. In 1986 the stock split again, two-for-one.
By the late 1980s, the stock had again split two-for-one.
In 1990, Bard formed the divisions Bard Electrophysiology, Bard Interventional Products, Bard Peripheral Technologies, and Specialty Access Products Business Group.
In 1994, net sales revenue reached over the US$1 billion milestone for the first time.
In 1995, Bard formed the division Bard Corporate Healthcare Services. By the end of the year, earnings were almost US$90 million, more than double from the decade earlier.
In 1996 Bard's new division Bard Medical Products was formed from the groups Davol, Bard Urological and Bard Patient Care.
In 1998 Bard did some significant divestments of businesses, as it sold the Coronary Cath Lab division to Arterial Vascular Engineering, and sold the Diagnostic Sciences division to Polymedco, and sold Global Intra-Aortic Balloon Products division to Arrow International, Inc.
In 1999, Bard continued its divestment plan, as it sold its Cardiopulmonary division to LifeStream.
In 2004 Bard sold some of its Endoscopic Technologies division to CONMED.
# Acquisitions
- 1966, Bard acquired USCI, with which it had an association dating back to 1941.
- 1975, Bard acquired William Harvey Research Corp.
- 1980, Bard acquired Davol Inc.
- 1986, Bard acquired American Endoscopy, Inc.
- 1989, Bard acquired Catheter Technology Corporation, which in 1991 became Bard Access Systems, Inc.
Angiomed AG
Cardial S.A.
Vas-Cath, Inc.
- Angiomed AG
- Cardial S.A.
- Vas-Cath, Inc.
MedChem Products, Inc.
American Hydrosurgical
GESCO.
- MedChem Products, Inc.
- American Hydrosurgical
- GESCO.
IMPRA, Inc.
Cardiac Assist Division of St. Jude Medical
X-Trode S.r.l.
- IMPRA, Inc.
- Cardiac Assist Division of St. Jude Medical
- X-Trode S.r.l.
- 1998, Dymax of Pittsburgh, Pennsylvania
Surgical Sense, Inc. assets
Mill-Rose Laboratories, Inc. assets
- Surgical Sense, Inc. assets
- Mill-Rose Laboratories, Inc. assets
Source Tech Medical, L.L.C. assets
Biomedical Instruments and Products GmbH technology
- Source Tech Medical, L.L.C. assets
- Biomedical Instruments and Products GmbH technology
ONUX Medical assets
Bridger Biomed, Inc.
Sorenson Medical product line
- ONUX Medical assets
- Bridger Biomed, Inc.
- Sorenson Medical product line
- 2005, GENYX Medical, Inc. assets
PST, LLC assets
Venetec International, Inc.
- PST, LLC assets
- Venetec International, Inc. | C. R. Bard
Template:Infobox Company
C. R. Bard, Inc. (Template:Nyse) is one of the large S&P 500 companies of the United States, a surgical specialties and hospital medical device manufacturer in Murray Hill, New Jersey. It is named after its founder, who sold the company within only a few years of its founding. In later decades it grew to its current size largely through many small acquisitions.
# History
C. R. Bard, Inc. was founded in 1923 by Charles Russell Bard.[1]
In 1926, Bard sold the company to John F. Willits and Edson L.Outwin for US$18,000.[1]
In 1934, the Bard company began to produce the Foley Catheter, a landmark product.[1]
In 1948, Bard moved the company headquarters from New York City to Summit, New Jersey. That year, Net sales revenue exceeded US$1 million.[1]
In 1963, C. R. Bard, Inc. becomes a publicly-traded company.[1] The company had already been paying a cash dividend since 1960, and it has continued every year since.[2]
In 1968 Bard became listed on the New York Stock Exchange, with the ticker symbol BCR. It began manufacturing operations at a plant in Murray Hill, New Jersey.[1]
In 1974 it went international, with plants in South America and Japan.[1]
In 1981, Bard opened manufacturing facilities in Puerto Rico and Ireland.[1]
Bard peformed well through the long bear market of the 1970s. Its stock rose, from the low early in that decade, to up by seven-fold times by its 1983 peak. It split three-for-two in 1982.[2]
By 1986, Bard had become listed in the S&P 500 among the largest 500 publicly-traded companies in the United States. Annual earnings by 1986 were over US$40 million. In 1986 the stock split again, two-for-one.[2]
By the late 1980s, the stock had again split two-for-one.[2]
In 1990, Bard formed the divisions Bard Electrophysiology, Bard Interventional Products, Bard Peripheral Technologies, and Specialty Access Products Business Group.[1]
In 1994, net sales revenue reached over the US$1 billion milestone for the first time.[1]
In 1995, Bard formed the division Bard Corporate Healthcare Services. [1] By the end of the year, earnings were almost US$90 million, more than double from the decade earlier.[2]
In 1996 Bard's new division Bard Medical Products was formed from the groups Davol, Bard Urological and Bard Patient Care.[1]
In 1998 Bard did some significant divestments of businesses, as it sold the Coronary Cath Lab division to Arterial Vascular Engineering, and sold the Diagnostic Sciences division to Polymedco, and sold Global Intra-Aortic Balloon Products division to Arrow International, Inc.[1]
In 1999, Bard continued its divestment plan, as it sold its Cardiopulmonary division to LifeStream.[1]
In 2004 Bard sold some of its Endoscopic Technologies division to CONMED.[1]
# Acquisitions
- 1966, Bard acquired USCI, with which it had an association dating back to 1941.[1]
- 1975, Bard acquired William Harvey Research Corp.
- 1980, Bard acquired Davol Inc.
- 1986, Bard acquired American Endoscopy, Inc.
- 1989, Bard acquired Catheter Technology Corporation, which in 1991 became Bard Access Systems, Inc.[1]
- 1994
Angiomed AG
Cardial S.A.
Vas-Cath, Inc.
- Angiomed AG
- Cardial S.A.
- Vas-Cath, Inc.
- 1995
MedChem Products, Inc.
American Hydrosurgical
GESCO.
- MedChem Products, Inc.
- American Hydrosurgical
- GESCO.
- 1996
IMPRA, Inc.
Cardiac Assist Division of St. Jude Medical
X-Trode S.r.l.
- IMPRA, Inc.
- Cardiac Assist Division of St. Jude Medical
- X-Trode S.r.l.
- 1998, Dymax of Pittsburgh, Pennsylvania
- 2000
Surgical Sense, Inc. assets
Mill-Rose Laboratories, Inc. assets
- Surgical Sense, Inc. assets
- Mill-Rose Laboratories, Inc. assets
- 2003
Source Tech Medical, L.L.C. assets
Biomedical Instruments and Products GmbH technology
- Source Tech Medical, L.L.C. assets
- Biomedical Instruments and Products GmbH technology
- 2004
ONUX Medical assets
Bridger Biomed, Inc.
Sorenson Medical product line
- ONUX Medical assets
- Bridger Biomed, Inc.
- Sorenson Medical product line
- 2005, GENYX Medical, Inc. assets
- 2006
PST, LLC assets
Venetec International, Inc.
- PST, LLC assets
- Venetec International, Inc.
# External links
- C. R. Bard official web site.
- Yahoo! - C. R. Bard Company Profile.
- C. R. Bard - Hoover's Profile | https://www.wikidoc.org/index.php/C._R._Bard | |
c50588cd4e88a0c72dfda691284070898f1552ae | wikidoc | C8 complex | C8 complex
Complement component 8 is a protein involved in the complement system. It is part of the membrane attack complex (MAC).
A hereditary deficiency of C8 can result in increased susceptibility to Neisseria infections, such as meningitis and gonorrhea.
# Structure
C8 is a heterotrimer; it consists of three different subunits. These are called C8 alpha, beta and gamma chains, encoded by the genes C8A, C8B and C8G respectively. | C8 complex
Complement component 8 is a protein involved in the complement system. It is part of the membrane attack complex (MAC).
A hereditary deficiency of C8 can result in increased susceptibility to Neisseria infections, such as meningitis and gonorrhea.
# Structure
C8 is a heterotrimer; it consists of three different subunits. These are called C8 alpha, beta and gamma chains, encoded by the genes C8A, C8B and C8G respectively. | https://www.wikidoc.org/index.php/C8_complex | |
a3016e0e8114fc225d94678ae380e13b44b90a6f | wikidoc | CA1 (gene) | CA1 (gene)
Carbonic anhydrase 1 is an enzyme that in humans is encoded by the CA1 gene.
Carbonic anhydrases (CAs) are a large family of zinc metalloenzymes that catalyze the reversible hydration of carbon dioxide. They participate in a variety of biological processes, including cellular respiration, calcification, acid-base balance, bone resorption, and the formation of aqueous humor, cerebrospinal fluid, saliva, and gastric acid.
They show extensive diversity in tissue distribution and in their subcellular localization. CA1 is closely linked to CA2 and CA3 genes on chromosome 8, and it encodes a cytosolic protein which is found at the highest level in erythrocytes. Transcript variants of CA1 utilizing alternative polyA_sites have been described in literature.
# Structure
The human CA1 protein contains an N-terminus active site, zinc binding site, and substrate-binding site. The crystal structure of the human CA1-bicarbonate anion complex reveals the geometry of two H-bonds between the Glu106-Thr199 pair and the Glu117-His119 pair, and one pi H-bond between a water molecule and the phenyl ring of the Tyr114 residue. The product inhibition of CA1 via bicarbonate anions is correlated to the proton localization change on His119. So the Glu117-His119 H-bond is considered to regulate the ionicity of the zinc ion and the binding strength of the bicarbonate anion.
# Mechanism
The reaction catalyzed by CA1 is the same as other carbonic anhydrase family proteins:
(in tissues - high CO2 concentration)
The CA1-catalyzed reaction has a relatively low reaction affinity (Km) of 4.0 mM for CO2, turnover number (Kcat) of 7005200000000000000♠2×105 s−1, and catalytic efficiency (Kcat/Km) of 7007500000000000000♠5×107 M−1s−1 comparing to other isozymes of the α-CA family of carbonic anhydrases. The turnover rate and catalytic rate of CA1 are only about 10% that of CA2 (Kcat: 7006140000000000000♠1.4×106 s−1, Kcat/Km: 7008150000000000000♠1.5×108 M−1s−1).
# Function
Carbonic anhydrase 1 belongs to α-CA sub-family and is localized in the cytosol of red blood cell, GI tract, cardiac tissues and other organs or tissues. Transmembrane transport of CA-produced bicarbonate contributes significantly to cellular pH regulation.
In a human zinc-activated variant of CA1, the Michigan Variant, a single point mutation changes His 67 to Arg in a critical region of the active site. This variant of the zinc metalloenzyme appears to be unique in that it possesses esterase activity that is specifically enhanced by added free zinc ions.
# Clinical significance
CA1 activation is associated with worsened pathological remodeling in human ischemic diabetic cardiomyopathy. In diabetic mellitus type 2 patients with postinfarct heart failure who were undergoing surgical coronary revascularization, myocardial levels of CA1 were sixfold higher than nondiabetic patients. Elevated CA1 expression was mainly localized in the cardiac interstitium and endothelial cells. Furthermore, high glucose-induced elevation of CA1 hampers endothelial cell permeability and determines endothelial cell apoptosis in vitro.
CA1 also mediates hemorrhagic retinal and cerebral vascular permeability through prekallikrein activation and serine protease factor XIIa generation. These phenomena induce proliferative diabetic retinopathy and diabetic macular edema disease progression, which represent leading causes of vision loss.
As CA1 is an important therapeutic target, development of its inhibitors will contribute to disease treatment. Compared to other CA family members, CA1 has relatively low affinity to common CA inhibitors. Nonetheless, it has medium affinity for CA inhibitor sulfonamides.
# Interactions
CA1 has been shown to interact with:
- TFCP2
- HSD17B7
- MAPK6
These interactions have been confirmed using the high throughput method (one hit) | CA1 (gene)
Carbonic anhydrase 1 is an enzyme that in humans is encoded by the CA1 gene.[1][2]
Carbonic anhydrases (CAs) are a large family of zinc metalloenzymes that catalyze the reversible hydration of carbon dioxide. They participate in a variety of biological processes, including cellular respiration, calcification, acid-base balance, bone resorption, and the formation of aqueous humor, cerebrospinal fluid, saliva, and gastric acid.
They show extensive diversity in tissue distribution and in their subcellular localization. CA1 is closely linked to CA2 and CA3 genes on chromosome 8, and it encodes a cytosolic protein which is found at the highest level in erythrocytes. Transcript variants of CA1 utilizing alternative polyA_sites have been described in literature.[2]
# Structure
The human CA1 protein contains an N-terminus active site, zinc binding site, and substrate-binding site.[3] The crystal structure of the human CA1-bicarbonate anion complex reveals the geometry of two H-bonds between the Glu106-Thr199 pair and the Glu117-His119 pair, and one pi H-bond between a water molecule and the phenyl ring of the Tyr114 residue. The product inhibition of CA1 via bicarbonate anions is correlated to the proton localization change on His119. So the Glu117-His119 H-bond is considered to regulate the ionicity of the zinc ion and the binding strength of the bicarbonate anion.[4]
# Mechanism
The reaction catalyzed by CA1 is the same as other carbonic anhydrase family proteins:
(in tissues - high CO2 concentration)[5]
The CA1-catalyzed reaction has a relatively low reaction affinity (Km) of 4.0 mM for CO2,[3][6] turnover number (Kcat) of 7005200000000000000♠2×105 s−1, and catalytic efficiency (Kcat/Km) of 7007500000000000000♠5×107 M−1s−1 comparing to other isozymes of the α-CA family of carbonic anhydrases. The turnover rate and catalytic rate of CA1 are only about 10% that of CA2 (Kcat: 7006140000000000000♠1.4×106 s−1, Kcat/Km: 7008150000000000000♠1.5×108 M−1s−1).[7]
# Function
Carbonic anhydrase 1 belongs to α-CA sub-family and is localized in the cytosol of red blood cell, GI tract, cardiac tissues and other organs or tissues.[8] Transmembrane transport of CA-produced bicarbonate contributes significantly to cellular pH regulation.[9]
In a human zinc-activated variant of CA1, the Michigan Variant, a single point mutation changes His 67 to Arg in a critical region of the active site. This variant of the zinc metalloenzyme appears to be unique in that it possesses esterase activity that is specifically enhanced by added free zinc ions.[10]
# Clinical significance
CA1 activation is associated with worsened pathological remodeling in human ischemic diabetic cardiomyopathy.[8] In diabetic mellitus type 2 patients with postinfarct heart failure who were undergoing surgical coronary revascularization, myocardial levels of CA1 were sixfold higher than nondiabetic patients. Elevated CA1 expression was mainly localized in the cardiac interstitium and endothelial cells. Furthermore, high glucose-induced elevation of CA1 hampers endothelial cell permeability and determines endothelial cell apoptosis in vitro.[8]
CA1 also mediates hemorrhagic retinal and cerebral vascular permeability through prekallikrein activation and serine protease factor XIIa generation. These phenomena induce proliferative diabetic retinopathy and diabetic macular edema disease progression, which represent leading causes of vision loss.[11]
As CA1 is an important therapeutic target, development of its inhibitors will contribute to disease treatment. Compared to other CA family members, CA1 has relatively low affinity to common CA inhibitors.[12] Nonetheless, it has medium affinity for CA inhibitor sulfonamides.[13]
# Interactions
CA1 has been shown to interact with:
- TFCP2[14]
- HSD17B7[15]
- MAPK6[16]
These interactions have been confirmed using the high throughput method (one hit) | https://www.wikidoc.org/index.php/CA1_(gene) | |
feca0e6b63f0ba9396bd0f8b0a04b8e269be0f7f | wikidoc | CARE Trial | CARE Trial
# Objective
To assess if pravastatin would reduce the sum of fatal coronary artery disease (CAD) and nonfatal myocardial infarction (MI) in patients who had a previous MI and a total cholesterol value < 240 mg/dl.
# Methods
Cholesterol and Recurrent Events trial was a double blinded, randomized study wherein 4159 patients with a history of a myocardial infarction in the previous two years who had a total cholesterol value < 240 mg/dl were enrolled and treated with either 40 mg pravastatin or a placebo.
# Results
The following results were obtained after a median follow-up time of 5 years:
- Reduced combined end point of coronary death and nonfatal MI (10.2 versus 13.2 percent)
- Reduced need for revascularization with CABG or PTCA (14.1 versus 18.8 percent)
- Reduced frequency of stroke (2.6 versus 3.8 percent) and of stroke plus transient ischemic attacks (4.4 versus 6.0 percent) | CARE Trial
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Click here to download slides for CARE Trial.
# Objective
To assess if pravastatin would reduce the sum of fatal coronary artery disease (CAD) and nonfatal myocardial infarction (MI) in patients who had a previous MI and a total cholesterol value < 240 mg/dl.
# Methods
Cholesterol and Recurrent Events trial was a double blinded, randomized study wherein 4159 patients with a history of a myocardial infarction in the previous two years who had a total cholesterol value < 240 mg/dl were enrolled and treated with either 40 mg pravastatin or a placebo.
# Results
The following results were obtained after a median follow-up time of 5 years:
- Reduced combined end point of coronary death and nonfatal MI (10.2 versus 13.2 percent)
- Reduced need for revascularization with CABG or PTCA (14.1 versus 18.8 percent)
- Reduced frequency of stroke (2.6 versus 3.8 percent) and of stroke plus transient ischemic attacks (4.4 versus 6.0 percent)[1][2] | https://www.wikidoc.org/index.php/CARE_Trial | |
e90d15d690b81df38d841ae5e917ac3fe6d463bd | wikidoc | Caspase 10 | Caspase 10
Caspase-10 is an enzyme that, in humans, is encoded by the CASP10 gene.
This gene encodes a protein that is a member of the cysteine-aspartic acid protease (caspase) family. Sequential activation of caspases plays a central role in the execution-phase of cell apoptosis. Caspases exist as inactive proenzymes that undergo proteolytic processing at conserved aspartic residues to produce two subunits, large and small, that dimerize to form the active enzyme. This protein cleaves and activates caspases 3 and 7, and the protein itself is processed by caspase 8. Mutations in this gene are associated with apoptosis defects seen in type II autoimmune lymphoproliferative syndrome. Three alternatively spliced transcript variants encoding different isoforms have been described for this gene.
# Interactions
Caspase 10 has been shown to interact with FADD, CFLAR, Caspase 8, Fas receptor, RYBP, TNFRSF1A and TNFRSF10B. | Caspase 10
Caspase-10 is an enzyme that, in humans, is encoded by the CASP10 gene.[1]
This gene encodes a protein that is a member of the cysteine-aspartic acid protease (caspase) family. Sequential activation of caspases plays a central role in the execution-phase of cell apoptosis. Caspases exist as inactive proenzymes that undergo proteolytic processing at conserved aspartic residues to produce two subunits, large and small, that dimerize to form the active enzyme. This protein cleaves and activates caspases 3 and 7, and the protein itself is processed by caspase 8. Mutations in this gene are associated with apoptosis defects seen in type II autoimmune lymphoproliferative syndrome. Three alternatively spliced transcript variants encoding different isoforms have been described for this gene.[2]
# Interactions
Caspase 10 has been shown to interact with FADD,[3][4][5][6] CFLAR,[5][7][8] Caspase 8,[3][7][9][10] Fas receptor,[3][4][11] RYBP,[12] TNFRSF1A[3][4] and TNFRSF10B.[3][11] | https://www.wikidoc.org/index.php/CASP10 | |
539e5111bf79a46dd89cc988c7c29a6f27b3c9d8 | wikidoc | Caveolin 1 | Caveolin 1
Caveolin-1 is a protein that in humans is encoded by the CAV1 gene.
# Function
The scaffolding protein encoded by this gene is the main component of the caveolae plasma membranes found in most cell types. The protein links integrin subunits to the tyrosine kinase FYN, an initiating step in coupling integrins to the Ras-ERK pathway and promoting cell cycle progression. The gene is a tumor suppressor gene candidate and a negative regulator of the Ras-p42/44 MAP kinase cascade. CAV1 and CAV2 are located next to each other on chromosome 7 and express colocalizing proteins that form a stable hetero-oligomeric complex. By using alternative initiation codons in the same reading frame, two isoforms (alpha and beta) are encoded by a single transcript from this gene.
# Interactions
Caveolin 1 has been shown to interact with heterotrimeric G proteins,
Src tyrosine kinases (Src, Lyn) and H-Ras,
cholesterol,
TGF beta receptor 1,
endothelial NOS,
androgen receptor,
amyloid precursor protein,
gap junction protein, alpha 1,
nitric oxide synthase 2A, epidermal growth factor receptor, endothelin receptor type B, PDGFRB, PDGFRA, PTGS2, TRAF2, estrogen receptor alpha, caveolin 2, PLD2, Bruton's tyrosine kinase and SCP2. All these interactions are through a caveolin-scaffolding domain (CSD) within caveolin-1 molecule. Molecules that interact with caveolin-1 contain caveolin-binding motifs (CBM). | Caveolin 1
Caveolin-1 is a protein that in humans is encoded by the CAV1 gene.[1]
# Function
The scaffolding protein encoded by this gene is the main component of the caveolae plasma membranes found in most cell types. The protein links integrin subunits to the tyrosine kinase FYN, an initiating step in coupling integrins to the Ras-ERK pathway and promoting cell cycle progression. The gene is a tumor suppressor gene candidate and a negative regulator of the Ras-p42/44 MAP kinase cascade. CAV1 and CAV2 are located next to each other on chromosome 7 and express colocalizing proteins that form a stable hetero-oligomeric complex. By using alternative initiation codons in the same reading frame, two isoforms (alpha and beta) are encoded by a single transcript from this gene.[2]
# Interactions
Caveolin 1 has been shown to interact with heterotrimeric G proteins,[3]
Src tyrosine kinases (Src, Lyn) and H-Ras,[4]
cholesterol,[5]
TGF beta receptor 1,[6]
endothelial NOS,[7]
androgen receptor,[8]
amyloid precursor protein,[9]
gap junction protein, alpha 1,[10]
nitric oxide synthase 2A,[11] epidermal growth factor receptor,[12] endothelin receptor type B,[13] PDGFRB,[14] PDGFRA,[14] PTGS2,[15] TRAF2,[16][17] estrogen receptor alpha,[18] caveolin 2,[19][20] PLD2,[21][22] Bruton's tyrosine kinase[23] and SCP2.[24] All these interactions are through a caveolin-scaffolding domain (CSD) within caveolin-1 molecule.[4] Molecules that interact with caveolin-1 contain caveolin-binding motifs (CBM).[25] | https://www.wikidoc.org/index.php/CAV1 | |
b64e7e50b42a5f35ba2ab25a49d8b09df854307b | wikidoc | CBL (gene) | CBL (gene)
Cbl (named after Casitas B-lineage Lymphoma) is a mammalian gene encoding the protein CBL which is an E3 ubiquitin-protein ligase involved in cell signalling and protein ubiquitination. Mutations to this gene have been implicated in a number of human cancers, particularly acute myeloid leukaemia.
# Discovery
In 1989 a virally encoded portion of the chromosomal mouse Cbl gene was the first member of the Cbl family to be discovered and was named v-Cbl to distinguish it from normal mouse c-Cbl. The virus used in the experiment was a retrovirus known as Cas-Br-M, and was found to have excised approximately a third of the original c-Cbl gene from mice it was injected into. Sequencing revealed that the portion carried by the retrovirus encoded a tyrosine kinase binding domain, and that this was the oncogenic form as retroviruses carrying full-length c-Cbl did not induce tumour formation. The resultant transformed retrovirus was found to consistently induce a type of pre-B lymphoma, known as Casitas B-lineage lymphoma, in infected mice.
# Structure
Full length c-Cbl has been found to consist of several regions encoding for functionally distinct protein domains:
- N-terminal tyrosine kinase binding domain (TKB domain): determines the protein which it can bind to
- RING finger domain motif: recruits enzymes involved in ubiquitination
- Proline-rich region: the site of interaction between Cbl and cytosolic proteins involved in Cbl's adaptor functions
- C-terminal ubiquitin-associated domain (UBA domain): the site of ubiquitin binding
This domain structure and the tyrosine and serine-rich content of the protein product is typical of an "adaptor molecule" used in cell signalling pathways.
# Homologues
Three mammalian homologues have been characterized, which all differ in their ability to function as adaptor proteins due to the differing lengths of their C-terminal UBA domains:
- c-Cbl: ubiquitously expressed, 906 and 913 amino acids in length in humans and mice respectively
- Cbl-b: ubiquitously expressed, 982 amino acids long.
- Cbl-c: lacks the UBA domain and is therefore only 474 amino acids in length. It is primarily expressed in epithelial cells however its function is poorly understood.
Both c-Cbl and Cbl-b have orthologues in D. melanogaster (D-Cbl) and C. elegans (Sli-1), hinting at a long evolutionary path for these proteins.
# Function
## Ubiquitin ligase
Ubiquitination is the process of chemically attaching ubiquitin monomers to a protein, thereby targeting it for degradation. As this is a multi-step process, several different enzymes are involved, the final one being a member of the E3 family of ligases. Cbl functions as an E3 ligase, and therefore is able to catalyse the formation of a covalent bond between ubiquitin and Cbl's protein substrate - typically a receptor tyrosine kinase. The RING-finger domain mediates this transfer, however like other E3 ligases of the RING type no intermediate covalent bond is formed between ubiquitin and the RING-finger domain. The stepwise attachment of ubiquitin to the substrate receptor tyrosine kinase can lead to its removal from the plasma membrane and subsequent trafficking to the lysosome for degradation.
# Interactions
Cbl gene has been shown to interact with:
- Abl gene,
- ARHGEF7,
- C-Met,
- CD2AP,
- CSF1R.
- CRK,
- CRKL,
- EGFR,<
- FRS2,
- FYN,
- Grb2,
- HCK,
- IGF1R,
- LCP2;,
- NCK1,
- PDGFRA,
- PIK3R1,
- PIK3R2,
- PLCG1,
- PTK2B,
- PTPN11,
- SH2B2,
- SH3KBP1
- SHC1,
- SLA2,
- SORBS1,
- SORBS2,
- SPRY2,
- Syk,
- UBE2L3,
- VAV1,
- YWHAB,
- YWHAQ, and
- ZAP-70, | CBL (gene)
Cbl (named after Casitas B-lineage Lymphoma) is a mammalian gene encoding the protein CBL which is an E3 ubiquitin-protein ligase involved in cell signalling and protein ubiquitination. Mutations to this gene have been implicated in a number of human cancers, particularly acute myeloid leukaemia.[1]
# Discovery
In 1989 a virally encoded portion of the chromosomal mouse Cbl gene was the first member of the Cbl family to be discovered[2] and was named v-Cbl to distinguish it from normal mouse c-Cbl. The virus used in the experiment was a retrovirus known as Cas-Br-M, and was found to have excised approximately a third of the original c-Cbl gene from mice it was injected into. Sequencing revealed that the portion carried by the retrovirus encoded a tyrosine kinase binding domain, and that this was the oncogenic form as retroviruses carrying full-length c-Cbl did not induce tumour formation. The resultant transformed retrovirus was found to consistently induce a type of pre-B lymphoma, known as Casitas B-lineage lymphoma, in infected mice.
# Structure
Full length c-Cbl has been found to consist of several regions encoding for functionally distinct protein domains:
- N-terminal tyrosine kinase binding domain (TKB domain): determines the protein which it can bind to
- RING finger domain motif: recruits enzymes involved in ubiquitination
- Proline-rich region: the site of interaction between Cbl and cytosolic proteins involved in Cbl's adaptor functions
- C-terminal ubiquitin-associated domain (UBA domain): the site of ubiquitin binding
This domain structure and the tyrosine and serine-rich content of the protein product is typical of an "adaptor molecule" used in cell signalling pathways.[3]
# Homologues
Three mammalian homologues have been characterized, which all differ in their ability to function as adaptor proteins due to the differing lengths of their C-terminal UBA domains:
- c-Cbl: ubiquitously expressed, 906 and 913 amino acids in length in humans and mice respectively
- Cbl-b: ubiquitously expressed, 982 amino acids long.
- Cbl-c: lacks the UBA domain and is therefore only 474 amino acids in length. It is primarily expressed in epithelial cells however its function is poorly understood.
Both c-Cbl and Cbl-b have orthologues in D. melanogaster (D-Cbl) and C. elegans (Sli-1), hinting at a long evolutionary path for these proteins.[3]
# Function
## Ubiquitin ligase
Ubiquitination is the process of chemically attaching ubiquitin monomers to a protein, thereby targeting it for degradation. As this is a multi-step process, several different enzymes are involved, the final one being a member of the E3 family of ligases. Cbl functions as an E3 ligase, and therefore is able to catalyse the formation of a covalent bond between ubiquitin and Cbl's protein substrate - typically a receptor tyrosine kinase. The RING-finger domain mediates this transfer, however like other E3 ligases of the RING type no intermediate covalent bond is formed between ubiquitin and the RING-finger domain. The stepwise attachment of ubiquitin to the substrate receptor tyrosine kinase can lead to its removal from the plasma membrane and subsequent trafficking to the lysosome for degradation.
# Interactions
Cbl gene has been shown to interact with:
- Abl gene,[4][5]
- ARHGEF7,[6]
- C-Met,[7][8]
- CD2AP,[9][10][11]
- CSF1R.[12]
- CRK,[13][14]
- CRKL,[15][16][17][18][19][20][21][22]
- EGFR,[7]<[23][24]
- FRS2,[25]
- FYN,[19][26]
- Grb2,[7][13][14][15][25][27][28][29][30][31][32][33][34]
- HCK,[35][36]
- IGF1R,[37]
- LCP2;,[15][38]
- NCK1,[4][15]
- PDGFRA,[39]
- PIK3R1,[13][40][41]
- PIK3R2,[16][42]
- PLCG1,[23][43]
- PTK2B,[9][44]
- PTPN11,[45]
- SH2B2,[7][46]
- SH3KBP1[8][47][48][49][50]
- SHC1,[13][27]
- SLA2,[51]
- SORBS1,[9][52]
- SORBS2,[5][9]
- SPRY2,[7][53][54]
- Syk,[55][56][57]
- UBE2L3,[53][58][59]
- VAV1,[56][60]
- YWHAB,[31]
- YWHAQ,[61][62] and
- ZAP-70,[63][64] | https://www.wikidoc.org/index.php/CBL_(gene) | |
52abcf2513d6ec25eec5f58a58f19d3a7ea26e29 | wikidoc | CCS (gene) | CCS (gene)
Copper chaperone for superoxide dismutase is a metalloprotein that is responsible for the delivery of Cu to superoxide dismutase (SOD1). CCS is a 54kDa protein that is present in mammals and most eukaryotes including yeast. The structure of CCS is composed of three distinct domains that are necessary for its function. Although CCS is important for many organisms, there are CCS independent pathways for SOD1, and many species lack CCS all together, such as C. elegans. In humans the protein is encoded by the CCS gene.
# Structure and function
CCS is composed of three domains. Domain I is located on the N-terminus and contains the MXCXXC Cu binding sequence. It has been determined to be necessary for function of CCS but its specific role is currently unknown. The structure of domain II greatly resembles that of SOD1 which allows it to perform the function of binding to SOD1. Domain III contains a CXC Cu binding motif and performs the Cu insertion and subsequent disulfide oxidation of SOD1.
When CCS docks to SOD1, cysteine 244 of CCS and 57 of SOD1 form a disulfide linkage. This disulfide bond is then transferred to form a disulfide bridge between cysteine 57 and 146 of SOD1. CCS's catalytic oxidation of SOD1's disulfide bridge can only be performed in the presence of oxygen. Furthermore, the disulfide linkage of SOD1 can be performed without the presence of CCS but requires oxygen and is much slower. Additionally, CCS is proposed to help the proper folding of SOD1 by binding in the apo-state.
As well as SOD1, CCS (gene) has been shown to interact with APBA1.
# Localization
CCS is localized in the nucleus, cytosol, and mitochondrial intermembrane space. CCS is imported to the mitochondria by Mia40 and Erv1 disulfide relay system. The cysteine 64 of CCS Domain I generates a disulfide intermediate with Mia40. This disulfide bond is transferred to link cysteine 64 and 27 of CCS, stabilizing the protein in the mitochondrial intermembrane space where it delivers Cu to the Cu-less apo-SOD1.
# Role in copper homeostasis
In mammals cellular Cu levels are regulated by CCS's interaction with the 26S proteasome. During times of Cu excess CCS delivers Cu to XIAP and primes the complex for auto-ubiquitination and subsequent degradation. Expression of SOD1 is not modified by Cu availability but by CCS ability to deliver Cu. Knockouts of CCS (Δccs) show 70-90% decrease in SOD1 activity as well as increased expression of Cu binding proteins, namely, MT-I, MT-II, ATOX1, COX17, ATP7A to, presumably, reduce the amount of free Cu.
Cells with CCS mutants have been shown to display ALS like symptoms. Moreover, SOD1 mutants that have altered interactions with CCS have been shown to display misfolding and aggregation. | CCS (gene)
Copper chaperone for superoxide dismutase is a metalloprotein that is responsible for the delivery of Cu to superoxide dismutase (SOD1).[1] CCS is a 54kDa protein that is present in mammals and most eukaryotes including yeast. The structure of CCS is composed of three distinct domains that are necessary for its function.[2][3] Although CCS is important for many organisms, there are CCS independent pathways for SOD1, and many species lack CCS all together, such as C. elegans.[3] In humans the protein is encoded by the CCS gene.[4][5]
# Structure and function
CCS is composed of three domains.[1] Domain I is located on the N-terminus and contains the MXCXXC Cu binding sequence.[1] It has been determined to be necessary for function of CCS but its specific role is currently unknown.[1] The structure of domain II greatly resembles that of SOD1 which allows it to perform the function of binding to SOD1.[1] Domain III contains a CXC Cu binding motif and performs the Cu insertion and subsequent disulfide oxidation of SOD1.[1]
When CCS docks to SOD1, cysteine 244 of CCS and 57 of SOD1 form a disulfide linkage.[2] This disulfide bond is then transferred to form a disulfide bridge between cysteine 57 and 146 of SOD1.[2] CCS's catalytic oxidation of SOD1's disulfide bridge can only be performed in the presence of oxygen.[2] Furthermore, the disulfide linkage of SOD1 can be performed without the presence of CCS but requires oxygen and is much slower.[2] Additionally, CCS is proposed to help the proper folding of SOD1 by binding in the apo-state.[2]
As well as SOD1, CCS (gene) has been shown to interact with APBA1.[6]
# Localization
CCS is localized in the nucleus, cytosol, and mitochondrial intermembrane space.[3] CCS is imported to the mitochondria by Mia40 and Erv1 disulfide relay system.[3] The cysteine 64 of CCS Domain I generates a disulfide intermediate with Mia40.[3] This disulfide bond is transferred to link cysteine 64 and 27 of CCS, stabilizing the protein in the mitochondrial intermembrane space where it delivers Cu to the Cu-less apo-SOD1.[2][3]
# Role in copper homeostasis
In mammals cellular Cu levels are regulated by CCS's interaction with the 26S proteasome.[3] During times of Cu excess CCS delivers Cu to XIAP and primes the complex for auto-ubiquitination and subsequent degradation.[3] Expression of SOD1 is not modified by Cu availability but by CCS ability to deliver Cu.[3] Knockouts of CCS (Δccs) show 70-90% decrease in SOD1 activity as well as increased expression of Cu binding proteins, namely, MT-I, MT-II, ATOX1, COX17, ATP7A to, presumably, reduce the amount of free Cu.[3]
Cells with CCS mutants have been shown to display ALS like symptoms.[2] Moreover, SOD1 mutants that have altered interactions with CCS have been shown to display misfolding and aggregation.[2] | https://www.wikidoc.org/index.php/CCS_(gene) | |
fe620d883b28644b945a521a1220c8520371df86 | wikidoc | Neprilysin | Neprilysin
Neprilysin (/ˌnɛprɪˈlaɪsɪn/), also known as membrane metallo-endopeptidase (MME), neutral endopeptidase (NEP), cluster of differentiation 10 (CD10), and common acute lymphoblastic leukemia antigen (CALLA) is an enzyme that in humans is encoded by the MME gene. Neprilysin is a zinc-dependent metalloprotease that cleaves peptides at the amino side of hydrophobic residues and inactivates several peptide hormones including glucagon, enkephalins, substance P, neurotensin, oxytocin, and bradykinin. It also degrades the amyloid beta peptide whose abnormal misfolding and aggregation in neural tissue has been implicated as a cause of Alzheimer's disease. Synthesized as a membrane-bound protein, the neprilysin ectodomain is released into the extracellular domain after it has been transported from the Golgi apparatus to the cell surface.
Neprilysin is expressed in a wide variety of tissues and is particularly abundant in kidney. It is also a common acute lymphocytic leukemia antigen that is an important cell surface marker in the diagnosis of human acute lymphocytic leukemia (ALL). This protein is present on leukemic cells of pre-B phenotype, which represent 85% of cases of ALL.
Hematopoetic progenitors expressing CD10 are considered "common lymphoid progenitors", which means they can differentiate into T, B or natural killer cells. CD10 is of use in hematological diagnosis since it is expressed by early B, pro-B and pre-B lymphocytes, and by lymph node germinal centers. Hematologic diseases in which it is positive include ALL, angioimmunoblastic T cell lymphoma, Burkitt lymphoma, chronic myelogenous leukemia in blast crisis (90%), diffuse large B-cell lymphoma (variable), follicular center cells (70%), hairy cell leukemia (10%), and myeloma (some). It tends to be negative in acute myeloid leukemia, chronic lymphocytic leukemia, mantle cell lymphoma, and marginal zone lymphoma. CD10 is found on non-T ALL cells, which derive from pre-B lymphocytes, and in germinal center-related non-Hodgkin lymphoma such as Burkitt lymphoma and follicular lymphoma, but not on leukemia cells or lymphomas, which originate in more mature B cells.
# Amyloid beta regulation
Neprilysin-deficient knockout mice show both Alzheimer's-like behavioral impairment and amyloid-beta deposition in the brain, providing strong evidence for the protein's association with the Alzheimer's disease process. Because neprilysin is thought to be the rate-limiting step in amyloid beta degradation, it has been considered a potential therapeutic target; compounds such as the peptide hormone somatostatin have been identified that increase the enzyme's activity level. One hypothesis for the strong dependence of Alzheimer's incidence on age focuses on the declining production of somatostatin in the brains of elderly people, which thus depresses the activity of neprilysin and promotes aggregation of unprocessed amyloid beta. Declining neprilysin activity with increasing age may also be explained by oxidative damage, known to be a causative factor in Alzheimer's disease; higher levels of inappropriately oxidized neprilysin have been found in Alzheimer's patients compared to cognitively normal elderly people.
# Signaling peptides
Neprilysin is also associated with other biochemical processes, and is particularly highly expressed in kidney and lung tissues. Inhibitors have been designed with the aim of developing analgesic and antihypertensive agents that act by preventing neprilysin's activity against signaling peptides such as enkephalins, substance P, endothelin, and atrial natriuretic peptide.
Associations have been observed between neprilysin expression and various types of cancer; however, the relationship between neprilysin expression and carcinogenesis remains obscure. In cancer biomarker studies, the neprilysin gene is often referred to as CD10 or CALLA. In some types of cancer, such as metastatic carcinoma and some advanced melanomas, neprilysin is overexpressed; in other types, most notably lung cancers, neprilysin is downregulated, and thus unable to modulate the pro-growth autocrine signaling of cancer cells via secreted peptides such as mammalian homologs related to bombesin.
Some plant extracts (methanol extracts of Ceropegia rupicola, Kniphofia sumarae, Plectranthus cf barbatus, and an aqueous extract of Pavetta longiflora) were found able to inhibit the enzymatic activity of neutral endopeptidase.
# Inhibitors
Inhibitors have been designed with the aim of developing analgesic and antihypertensive agents that act by preventing neprilysin's activity against signaling peptides such as enkephalins, substance P, endothelin, and atrial natriuretic peptide.
Some are intended to treat heart failure.
- Sacubitril/valsartan (Entresto/LCZ696), which has been tested against enalapril in patients with heart failure.
- Sacubitril (AHU-377), a prodrug which is a component of sacubitril/valsartan
- Sacubitrilat (LBQ657), the active form of sacubitril
- RB-101, an enkephalinase inhibitor, used in scientific research.
- UK-414,495
- Omapatrilat (dual inhibitor of NEP and angiotensin-converting enzyme) developed by BMS did not receive FDA approval due to angioedema safety concerns.
- Ecadotril
Other dual inhibitors of NEP with ACE/angiotensin receptor are (in 2003) being developed by pharmaceutical companies.
# Immunochemistry
CD10 is used in clinical pathology for diagnostic purpose.
## In lymphomas and leukemias
- Acute lymphoblastic leukemia (ALL) cells are CD10+.
- Follicular lymphoma (follicle centre cell lymphoma) are CD10+.
- Burkitt Lymphoma cells are CD10+.
- CD10+ diffuse large B cell lymphoma (CD10+ DLBLC)
Marker for germinal center phenotype (CD10, HGAL, BCL6, CD38) are considered a favorable prognostic factor, but CD10+, BCL2+ tumors could have poorer survival. For some authors, CD10 expression in DLBCL does not influence survival.
- Marker for germinal center phenotype (CD10, HGAL, BCL6, CD38) are considered a favorable prognostic factor, but CD10+, BCL2+ tumors could have poorer survival. For some authors, CD10 expression in DLBCL does not influence survival.
- Angioimmunoblastic T cell lymphoma (AITL) are CD10+ and distinguishes AITL from other T cell lymphomas (CD10−)
Some benign T cells can be CD10+
- Some benign T cells can be CD10+
## In epithelial tumors
- Clear cell renal cell carcinoma (Clear cell RCC)
CD10+ distinguishes renal cell carcinoma, conventional type with eosinophilic morphology from its mimickers. Chromophobe carcinoma and oncocytoma are CD10−.
- CD10+ distinguishes renal cell carcinoma, conventional type with eosinophilic morphology from its mimickers. Chromophobe carcinoma and oncocytoma are CD10−.
- Pancreatic tumors
Solid pseudopapillary tumours are CD10+.
CD10+ differentiates mucinous cystic neoplasms (CD10+/CK20+) from intraductal papillary mucinous neoplasm of branch duct type (CD10−/CK20-).
- Solid pseudopapillary tumours are CD10+.
- CD10+ differentiates mucinous cystic neoplasms (CD10+/CK20+) from intraductal papillary mucinous neoplasm of branch duct type (CD10−/CK20-).
- Cutaneous tumors
CD10 may differentiate basal cell carcinoma (CD10 epithelial staining) from trichoblastoma (CD10 peritumoral stromal staining), basal cell carcinoma with follicular differentiation (CD10 stromal and epithelial staining) and squamous cell carcinoma (strong stromal staining).
CD10 differentiates CD10+ atypical fibroxanthoma from CD10− spindle cell melanoma and sarcomatoid squamous cell carcinoma.
- CD10 may differentiate basal cell carcinoma (CD10 epithelial staining) from trichoblastoma (CD10 peritumoral stromal staining), basal cell carcinoma with follicular differentiation (CD10 stromal and epithelial staining) and squamous cell carcinoma (strong stromal staining).
- CD10 differentiates CD10+ atypical fibroxanthoma from CD10− spindle cell melanoma and sarcomatoid squamous cell carcinoma.
- Urothelial tumors express CD10 (42-67%).
CD10 expression is strongly correlated with high tumor grade and stage in urothelial carcinoma of the bladder. CD10 may be associated with tumor progression in bladder cancer pathogenesis.
- CD10 expression is strongly correlated with high tumor grade and stage in urothelial carcinoma of the bladder. CD10 may be associated with tumor progression in bladder cancer pathogenesis.
## In other tumors
- CD10 expression might be one of the characteristics of müllerian system-derived neoplastic mesenchymal cells.
Normal endometrial stroma
Endometrial stromal sarcoma (ESS) are CD10+ (Smooth muscle tumors are usually CD10−, but can be CD10+
Malignant müllerian mixed tumor (MMMT)
Müllerian adenosarcoma
Uterine high-grade leiomyosarcoma
Uterine rhabdomyosarcoma
- Normal endometrial stroma
- Endometrial stromal sarcoma (ESS) are CD10+ (Smooth muscle tumors are usually CD10−, but can be CD10+
- Malignant müllerian mixed tumor (MMMT)
- Müllerian adenosarcoma
- Uterine high-grade leiomyosarcoma
- Uterine rhabdomyosarcoma
- Vascular tumors
Epithelioid hemangioendothelioma are mostly CD10+.
Hemangioblastoma is usually CD10− (metastatic renal cell carcinoma is CD10+)
- Epithelioid hemangioendothelioma are mostly CD10+.
- Hemangioblastoma is usually CD10− (metastatic renal cell carcinoma is CD10+) | Neprilysin
Neprilysin (/ˌnɛprɪˈlaɪsɪn/), also known as membrane metallo-endopeptidase (MME), neutral endopeptidase (NEP), cluster of differentiation 10 (CD10), and common acute lymphoblastic leukemia antigen (CALLA) is an enzyme that in humans is encoded by the MME gene. Neprilysin is a zinc-dependent metalloprotease that cleaves peptides at the amino side of hydrophobic residues and inactivates several peptide hormones including glucagon, enkephalins, substance P, neurotensin, oxytocin, and bradykinin.[1] It also degrades the amyloid beta peptide whose abnormal misfolding and aggregation in neural tissue has been implicated as a cause of Alzheimer's disease. Synthesized as a membrane-bound protein, the neprilysin ectodomain is released into the extracellular domain after it has been transported from the Golgi apparatus to the cell surface.
Neprilysin is expressed in a wide variety of tissues and is particularly abundant in kidney. It is also a common acute lymphocytic leukemia antigen that is an important cell surface marker in the diagnosis of human acute lymphocytic leukemia (ALL). This protein is present on leukemic cells of pre-B phenotype, which represent 85% of cases of ALL.[1]
Hematopoetic progenitors expressing CD10 are considered "common lymphoid progenitors", which means they can differentiate into T, B or natural killer cells.[2] CD10 is of use in hematological diagnosis since it is expressed by early B, pro-B and pre-B lymphocytes, and by lymph node germinal centers.[3] Hematologic diseases in which it is positive include ALL, angioimmunoblastic T cell lymphoma, Burkitt lymphoma, chronic myelogenous leukemia in blast crisis (90%), diffuse large B-cell lymphoma (variable), follicular center cells (70%), hairy cell leukemia (10%), and myeloma (some). It tends to be negative in acute myeloid leukemia, chronic lymphocytic leukemia, mantle cell lymphoma, and marginal zone lymphoma. CD10 is found on non-T ALL cells, which derive from pre-B lymphocytes, and in germinal center-related non-Hodgkin lymphoma such as Burkitt lymphoma and follicular lymphoma, but not on leukemia cells or lymphomas, which originate in more mature B cells.[4]
# Amyloid beta regulation
Neprilysin-deficient knockout mice show both Alzheimer's-like behavioral impairment and amyloid-beta deposition in the brain,[5] providing strong evidence for the protein's association with the Alzheimer's disease process. Because neprilysin is thought to be the rate-limiting step in amyloid beta degradation,[6] it has been considered a potential therapeutic target; compounds such as the peptide hormone somatostatin have been identified that increase the enzyme's activity level.[7] One hypothesis for the strong dependence of Alzheimer's incidence on age focuses on the declining production of somatostatin in the brains of elderly people, which thus depresses the activity of neprilysin and promotes aggregation of unprocessed amyloid beta.[8] Declining neprilysin activity with increasing age may also be explained by oxidative damage, known to be a causative factor in Alzheimer's disease; higher levels of inappropriately oxidized neprilysin have been found in Alzheimer's patients compared to cognitively normal elderly people.[9]
# Signaling peptides
Neprilysin is also associated with other biochemical processes, and is particularly highly expressed in kidney and lung tissues. Inhibitors have been designed with the aim of developing analgesic and antihypertensive agents that act by preventing neprilysin's activity against signaling peptides such as enkephalins, substance P, endothelin, and atrial natriuretic peptide.[10][11]
Associations have been observed between neprilysin expression and various types of cancer; however, the relationship between neprilysin expression and carcinogenesis remains obscure. In cancer biomarker studies, the neprilysin gene is often referred to as CD10 or CALLA. In some types of cancer, such as metastatic carcinoma and some advanced melanomas, neprilysin is overexpressed;[12] in other types, most notably lung cancers, neprilysin is downregulated, and thus unable to modulate the pro-growth autocrine signaling of cancer cells via secreted peptides such as mammalian homologs related to bombesin.[13]
Some plant extracts (methanol extracts of Ceropegia rupicola, Kniphofia sumarae, Plectranthus cf barbatus, and an aqueous extract of Pavetta longiflora) were found able to inhibit the enzymatic activity of neutral endopeptidase.[14]
# Inhibitors
Inhibitors have been designed with the aim of developing analgesic and antihypertensive agents that act by preventing neprilysin's activity against signaling peptides such as enkephalins, substance P, endothelin, and atrial natriuretic peptide.[10][11]
Some are intended to treat heart failure.[15]
- Sacubitril/valsartan (Entresto/LCZ696), which has been tested against enalapril in patients with heart failure.[15]
- Sacubitril (AHU-377), a prodrug which is a component of sacubitril/valsartan
- Sacubitrilat (LBQ657), the active form of sacubitril
- RB-101, an enkephalinase inhibitor, used in scientific research.
- UK-414,495
- Omapatrilat (dual inhibitor of NEP and angiotensin-converting enzyme) developed by BMS did not receive FDA approval due to angioedema safety concerns.
- Ecadotril
Other dual inhibitors of NEP with ACE/angiotensin receptor are (in 2003) being developed by pharmaceutical companies.[16]
# Immunochemistry
CD10 is used in clinical pathology for diagnostic purpose.
## In lymphomas and leukemias
- Acute lymphoblastic leukemia (ALL) cells are CD10+.
- Follicular lymphoma (follicle centre cell lymphoma) are CD10+.
- Burkitt Lymphoma cells are CD10+.
- CD10+ diffuse large B cell lymphoma (CD10+ DLBLC)[17]
Marker for germinal center phenotype (CD10, HGAL, BCL6, CD38) are considered a favorable prognostic factor,[18][19] but CD10+, BCL2+ tumors could have poorer survival.[20] For some authors, CD10 expression in DLBCL does not influence survival.[21]
- Marker for germinal center phenotype (CD10, HGAL, BCL6, CD38) are considered a favorable prognostic factor,[18][19] but CD10+, BCL2+ tumors could have poorer survival.[20] For some authors, CD10 expression in DLBCL does not influence survival.[21]
- Angioimmunoblastic T cell lymphoma (AITL) are CD10+[22][23] and distinguishes AITL from other T cell lymphomas (CD10−)[24]
Some benign T cells can be CD10+[25]
- Some benign T cells can be CD10+[25]
## In epithelial tumors
- Clear cell renal cell carcinoma (Clear cell RCC)
CD10+ distinguishes renal cell carcinoma, conventional type with eosinophilic morphology from its mimickers. Chromophobe carcinoma and oncocytoma are CD10−.[26]
- CD10+ distinguishes renal cell carcinoma, conventional type with eosinophilic morphology from its mimickers. Chromophobe carcinoma and oncocytoma are CD10−.[26]
- Pancreatic tumors
Solid pseudopapillary tumours are CD10+.[27]
CD10+ differentiates mucinous cystic neoplasms (CD10+/CK20+) from intraductal papillary mucinous neoplasm of branch duct type (CD10−/CK20-).[27]
- Solid pseudopapillary tumours are CD10+.[27]
- CD10+ differentiates mucinous cystic neoplasms (CD10+/CK20+) from intraductal papillary mucinous neoplasm of branch duct type (CD10−/CK20-).[27]
- Cutaneous tumors
CD10 may differentiate basal cell carcinoma (CD10 epithelial staining) from trichoblastoma (CD10 peritumoral stromal staining), basal cell carcinoma with follicular differentiation (CD10 stromal and epithelial staining)[28] and squamous cell carcinoma (strong stromal staining).[29]
CD10 differentiates CD10+ atypical fibroxanthoma from CD10− spindle cell melanoma and sarcomatoid squamous cell carcinoma.
- CD10 may differentiate basal cell carcinoma (CD10 epithelial staining) from trichoblastoma (CD10 peritumoral stromal staining), basal cell carcinoma with follicular differentiation (CD10 stromal and epithelial staining)[28] and squamous cell carcinoma (strong stromal staining).[29]
- CD10 differentiates CD10+ atypical fibroxanthoma from CD10− spindle cell melanoma and sarcomatoid squamous cell carcinoma.
- Urothelial tumors express CD10 (42-67%).[30]
CD10 expression is strongly correlated with high tumor grade and stage in urothelial carcinoma of the bladder. CD10 may be associated with tumor progression in bladder cancer pathogenesis.[31]
- CD10 expression is strongly correlated with high tumor grade and stage in urothelial carcinoma of the bladder. CD10 may be associated with tumor progression in bladder cancer pathogenesis.[31]
## In other tumors
- CD10 expression might be one of the characteristics of müllerian system-derived neoplastic mesenchymal cells.[32]
Normal endometrial stroma[33]
Endometrial stromal sarcoma (ESS) are CD10+ (Smooth muscle tumors are usually CD10−,[34] but can be CD10+ [32]
Malignant müllerian mixed tumor (MMMT)
Müllerian adenosarcoma
Uterine high-grade leiomyosarcoma
Uterine rhabdomyosarcoma
- Normal endometrial stroma[33]
- Endometrial stromal sarcoma (ESS) are CD10+ (Smooth muscle tumors are usually CD10−,[34] but can be CD10+ [32]
- Malignant müllerian mixed tumor (MMMT)
- Müllerian adenosarcoma
- Uterine high-grade leiomyosarcoma
- Uterine rhabdomyosarcoma
- Vascular tumors
Epithelioid hemangioendothelioma are mostly CD10+.[35]
Hemangioblastoma is usually CD10− (metastatic renal cell carcinoma is CD10+)[36][37]
- Epithelioid hemangioendothelioma are mostly CD10+.[35]
- Hemangioblastoma is usually CD10− (metastatic renal cell carcinoma is CD10+)[36][37] | https://www.wikidoc.org/index.php/CD10 | |
90c4d661ec86ed6d263df972feb5ef0f86568515 | wikidoc | Syndecan 1 | Syndecan 1
Syndecan 1 is a protein which in humans is encoded by the SDC1 gene.
# Function
The protein encoded by this gene is a transmembrane (type I) heparan sulfate proteoglycan and is a member of the syndecan proteoglycan family. The syndecans mediate cell binding, cell signaling, and cytoskeletal organization and syndecan receptors are required for internalization of the HIV-1 tat protein. The syndecan-1 protein functions as an integral membrane protein and participates in cell proliferation, cell migration and cell-matrix interactions via its receptor for extracellular matrix proteins. Syndecan-1 is a sponge for growth factors, with binding largely via heparan sulfate chains.
An exception is the prosecretory mitogen lacritin that binds syndecan-1 only after heparanase modification. Binding utilizes an enzyme-regulated 'off-on' switch in which active epithelial heparanase (HPSE) cleaves off heparan sulfate to expose a binding site in the N-terminal region of syndecan-1's core protein. Three SDC1 elements are required. (1) The heparanase-exposed hydrophobic sequence GAGAL that promotes the alpha helicity of lacritin's C-terminal amphipathic alpha helix form and likely binds to the hydrophobic face. (2) Heparanase-cleaved heparan sulfate that is 3-O sulfated. This likely interacts with the cationic face of lacritin's C-terminal amphipathic alpha helix. (3) An N-terminal chondroitin sulfate chain that also likely binds to the cationic face. Point mutagenesis of lacritin has narrowed the ligation site.
While several transcript variants may exist for this gene, the full-length natures of only two have been described to date. These two represent the major variants of this gene and encode the same protein.
# Clinical significance
Altered syndecan-1 expression has been detected in several different tumor types.
It is a specific antigen on multiple myeloma cells.
Indatuximab ravtansine targets this protein.
# Application
It is a useful marker for plasma cells, but only if the cells tested are already known to be derived from blood. | Syndecan 1
Syndecan 1 is a protein which in humans is encoded by the SDC1 gene.[1][2]
# Function
The protein encoded by this gene is a transmembrane (type I) heparan sulfate proteoglycan and is a member of the syndecan proteoglycan family. The syndecans mediate cell binding, cell signaling, and cytoskeletal organization and syndecan receptors are required for internalization of the HIV-1 tat protein. The syndecan-1 protein functions as an integral membrane protein and participates in cell proliferation, cell migration and cell-matrix interactions via its receptor for extracellular matrix proteins. Syndecan-1 is a sponge for growth factors, with binding largely via heparan sulfate chains.
An exception is the prosecretory mitogen lacritin that binds syndecan-1 only after heparanase modification.[3][4] Binding utilizes an enzyme-regulated 'off-on' switch in which active epithelial heparanase (HPSE) cleaves off heparan sulfate to expose a binding site in the N-terminal region of syndecan-1's core protein.[3] Three SDC1 elements are required. (1) The heparanase-exposed hydrophobic sequence GAGAL that promotes the alpha helicity of lacritin's C-terminal amphipathic alpha helix form and likely binds to the hydrophobic face. (2) Heparanase-cleaved heparan sulfate that is 3-O sulfated.[4] This likely interacts with the cationic face of lacritin's C-terminal amphipathic alpha helix. (3) An N-terminal chondroitin sulfate chain that also likely binds to the cationic face. Point mutagenesis of lacritin has narrowed the ligation site.[4]
While several transcript variants may exist for this gene, the full-length natures of only two have been described to date. These two represent the major variants of this gene and encode the same protein.[5]
# Clinical significance
Altered syndecan-1 expression has been detected in several different tumor types.
It is a specific antigen on multiple myeloma cells.[6]
Indatuximab ravtansine targets this protein.
# Application
It is a useful marker for plasma cells,[7] but only if the cells tested are already known to be derived from blood.[8] | https://www.wikidoc.org/index.php/CD138 | |
ca62ac7514fa7097558121eccb09d7fc66e69f56 | wikidoc | Fas ligand | Fas ligand
Fas ligand (FasL or CD95L) is a type-II transmembrane protein that belongs to the tumor necrosis factor (TNF) family. Its binding with its receptor induces apoptosis. Fas ligand/receptor interactions play an important role in the regulation of the immune system and the progression of cancer.
# Structure
Fas ligand or FasL is a homotrimeric type II transmembrane protein expressed on cytotoxic T lymphocytes. It signals through trimerization of FasR, which spans the membrane of the "target" cell. This trimerization usually leads to apoptosis, or cell death.
Soluble Fas ligand is generated by cleaving membrane-bound FasL at a conserved cleavage site by the external matrix metalloproteinase MMP-7.
# Receptors
- FasR: The Fas receptor (FasR), or CD95, is the most intensely studied member of the death receptor family. The gene is situated on chromosome 10 in humans and 19 in mice. Previous reports have identified as many as eight splice variants, which are translated into seven isoforms of the protein. Many of these isoforms are rare haplotypes that are usually associated with a state of disease. Apoptosis-inducing Fas receptor is dubbed isoform 1 and is a type 1 transmembrane protein. It consists of three cysteine-rich pseudorepeats, a transmembrane domain, and an intracellular death domain.
- DcR3: Decoy receptor 3 (DcR3) is a recently discovered decoy receptor of the tumor necrosis factor superfamily that binds to FasL, LIGHT, and TL1A. DcR3 is a soluble receptor that has no signal transduction capabilities (hence a "decoy") and functions to prevent FasR-FasL interactions by competitively binding to membrane-bound Fas ligand and rendering them inactive.
# Cell signaling
Fas forms the death-inducing signaling complex (DISC) upon ligand binding. Membrane-anchored Fas ligand trimer on the surface of an adjacent cell causes trimerization of Fas receptor. This event is also mimicked by binding of an agonistic Fas antibody, though some evidence suggests that the apoptotic signal induced by the antibody is unreliable in the study of Fas signaling. To this end, several clever ways of trimerizing the antibody for in vitro research have been employed.
Upon ensuing death domain (DD) aggregation, the receptor complex is internalized via the cellular endosomal machinery. This allows the adaptor molecule Fas-associated death domain (FADD) to bind the death domain of Fas through its own death domain. FADD also contains a death effector domain (DED) near its amino terminus, which facilitates binding to the DED of FADD-like ICE (FLICE), more commonly referred to as caspase-8. FLICE can then self-activate through proteolytic cleavage into p10 and p18 subunits, of which two form the active heterotetramer enzyme. Active caspase-8 is then released from the DISC into the cytosol, where it cleaves other effector caspases, eventually leading to DNA degradation, membrane blebbing, and other hallmarks of apoptosis.
Some reports have suggested that the extrinsic Fas pathway is sufficient to induce complete apoptosis in certain cell types through DISC assembly and subsequent caspase-8 activation. These cells are dubbed Type 1 cells and are characterized by the inability of anti-apoptotic members of the Bcl-2 family (namely Bcl-2 and Bcl-xL) to protect from Fas-mediated apoptosis. Characterized Type 1 cells include H9, CH1, SKW6.4, and SW480, all of which are lymphocyte lineages except the latter, which is of the colon adenocarcinoma lineage.
Evidence for crosstalk between the extrinsic and intrinsic pathways exists in the Fas signal cascade. In most cell types, caspase-8 catalyzes the cleavage of the pro-apoptotic BH3-only protein Bid into its truncated form, tBid. BH-3 only members of the Bcl-2 family engage exclusively anti-apoptotic members of the family (Bcl-2, Bcl-xL), allowing Bak and Bax to translocate to the outer mitochondrial membrane, thus permeabilizing it and facilitating release of pro-apoptotic proteins such as cytochrome c and Smac/DIABLO, an antagonist of inhibitors of apoptosis proteins (IAPs).
Soluble FasL is less active than its membrane-bound counterpart and does not induce receptor trimerization and DISC formation.
# Functions
Apoptosis triggered by Fas-Fas ligand binding plays a fundamental role in the regulation of the immune system. Its functions include:
- T-cell homeostasis: the activation of T-cells leads to their expression of the Fas ligand. T cells are initially resistant to Fas-mediated apoptosis during clonal expansion, but become progressively more sensitive the longer they are activated, ultimately resulting in activation-induced cell death (AICD). This process is needed to prevent an excessive immune response and eliminate autoreactive T-cells. Humans and mice with deleterious mutations of Fas or Fas ligand develop an accumulation of aberrant T-cells, leading to lymphadenopathy, splenomegaly, and lupus erythematosus.
- Cytotoxic T-cell activity: Fas-induced apoptosis and the perforin pathway are the two main mechanisms by which cytotoxic T lymphocytes induce cell death in cells expressing foreign antigens.
- Immune privilege: Cells in immune privileged areas such as the cornea or testes express Fas ligand and induce the apoptosis of infiltrating lymphocytes. It is one of many mechanisms the body employs in the establishment and maintenance of immune privilege.
- Maternal tolerance: Fas ligand may be instrumental in the prevention of leukocyte trafficking between the mother and the fetus, although no pregnancy defects have yet been attributed to a faulty Fas-Fas ligand system.
- Tumor counterattack: Tumors may over-express Fas ligand and induce the apoptosis of infiltrating lymphocytes, allowing the tumor to escape the effects of an immune response. The up-regulation of Fas ligand often occurs following chemotherapy, from which the tumor cells have attained apoptosis resistance.
# Role in disease
Defective Fas-mediated apoptosis may lead to oncogenesis as well as drug resistance in existing tumors. Germline mutation of Fas is associated with autoimmune lymphoproliferative syndrome (ALPS), a childhood disorder of apoptosis.
# Interactions
Fas ligand has been shown to interact with:
- CASP8,
- EZR,
- FADD,
- FNBP1,
- FYN,
- FAS,
- Grb2,
- PACSIN2, and
- TNFRSF6B. | Fas ligand
Fas ligand (FasL or CD95L) is a type-II transmembrane protein that belongs to the tumor necrosis factor (TNF) family. Its binding with its receptor induces apoptosis. Fas ligand/receptor interactions play an important role in the regulation of the immune system and the progression of cancer.
# Structure
Fas ligand or FasL is a homotrimeric type II transmembrane protein expressed on cytotoxic T lymphocytes. It signals through trimerization of FasR, which spans the membrane of the "target" cell. This trimerization usually leads to apoptosis, or cell death.
Soluble Fas ligand is generated by cleaving membrane-bound FasL at a conserved cleavage site by the external matrix metalloproteinase MMP-7.
# Receptors
- FasR: The Fas receptor (FasR), or CD95, is the most intensely studied member of the death receptor family. The gene is situated on chromosome 10 in humans and 19 in mice. Previous reports have identified as many as eight splice variants, which are translated into seven isoforms of the protein. Many of these isoforms are rare haplotypes that are usually associated with a state of disease. Apoptosis-inducing Fas receptor is dubbed isoform 1 and is a type 1 transmembrane protein. It consists of three cysteine-rich pseudorepeats, a transmembrane domain, and an intracellular death domain.
- DcR3: Decoy receptor 3 (DcR3) is a recently discovered decoy receptor of the tumor necrosis factor superfamily that binds to FasL, LIGHT, and TL1A. DcR3 is a soluble receptor that has no signal transduction capabilities (hence a "decoy") and functions to prevent FasR-FasL interactions by competitively binding to membrane-bound Fas ligand and rendering them inactive.[1]
# Cell signaling
Fas forms the death-inducing signaling complex (DISC) upon ligand binding. Membrane-anchored Fas ligand trimer on the surface of an adjacent cell causes trimerization of Fas receptor. This event is also mimicked by binding of an agonistic Fas antibody, though some evidence suggests that the apoptotic signal induced by the antibody is unreliable in the study of Fas signaling. To this end, several clever ways of trimerizing the antibody for in vitro research have been employed.
Upon ensuing death domain (DD) aggregation, the receptor complex is internalized via the cellular endosomal machinery. This allows the adaptor molecule Fas-associated death domain (FADD) to bind the death domain of Fas through its own death domain. FADD also contains a death effector domain (DED) near its amino terminus, which facilitates binding to the DED of FADD-like ICE (FLICE), more commonly referred to as caspase-8. FLICE can then self-activate through proteolytic cleavage into p10 and p18 subunits, of which two form the active heterotetramer enzyme. Active caspase-8 is then released from the DISC into the cytosol, where it cleaves other effector caspases, eventually leading to DNA degradation, membrane blebbing, and other hallmarks of apoptosis.
Some reports have suggested that the extrinsic Fas pathway is sufficient to induce complete apoptosis in certain cell types through DISC assembly and subsequent caspase-8 activation. These cells are dubbed Type 1 cells and are characterized by the inability of anti-apoptotic members of the Bcl-2 family (namely Bcl-2 and Bcl-xL) to protect from Fas-mediated apoptosis. Characterized Type 1 cells include H9, CH1, SKW6.4, and SW480, all of which are lymphocyte lineages except the latter, which is of the colon adenocarcinoma lineage.
Evidence for crosstalk between the extrinsic and intrinsic pathways exists in the Fas signal cascade. In most cell types, caspase-8 catalyzes the cleavage of the pro-apoptotic BH3-only protein Bid into its truncated form, tBid. BH-3 only members of the Bcl-2 family engage exclusively anti-apoptotic members of the family (Bcl-2, Bcl-xL), allowing Bak and Bax to translocate to the outer mitochondrial membrane, thus permeabilizing it and facilitating release of pro-apoptotic proteins such as cytochrome c and Smac/DIABLO, an antagonist of inhibitors of apoptosis proteins (IAPs).
Soluble FasL is less active than its membrane-bound counterpart and does not induce receptor trimerization and DISC formation.
# Functions
Apoptosis triggered by Fas-Fas ligand binding plays a fundamental role in the regulation of the immune system. Its functions include:
- T-cell homeostasis: the activation of T-cells leads to their expression of the Fas ligand. T cells are initially resistant to Fas-mediated apoptosis during clonal expansion, but become progressively more sensitive the longer they are activated, ultimately resulting in activation-induced cell death (AICD). This process is needed to prevent an excessive immune response and eliminate autoreactive T-cells. Humans and mice with deleterious mutations of Fas or Fas ligand develop an accumulation of aberrant T-cells, leading to lymphadenopathy, splenomegaly, and lupus erythematosus.
- Cytotoxic T-cell activity: Fas-induced apoptosis and the perforin pathway are the two main mechanisms by which cytotoxic T lymphocytes induce cell death in cells expressing foreign antigens.[2]
- Immune privilege: Cells in immune privileged areas such as the cornea or testes express Fas ligand and induce the apoptosis of infiltrating lymphocytes. It is one of many mechanisms the body employs in the establishment and maintenance of immune privilege.
- Maternal tolerance: Fas ligand may be instrumental in the prevention of leukocyte trafficking between the mother and the fetus, although no pregnancy defects have yet been attributed to a faulty Fas-Fas ligand system.
- Tumor counterattack: Tumors may over-express Fas ligand and induce the apoptosis of infiltrating lymphocytes, allowing the tumor to escape the effects of an immune response.[3] The up-regulation of Fas ligand often occurs following chemotherapy, from which the tumor cells have attained apoptosis resistance.
# Role in disease
Defective Fas-mediated apoptosis may lead to oncogenesis as well as drug resistance in existing tumors. Germline mutation of Fas is associated with autoimmune lymphoproliferative syndrome (ALPS), a childhood disorder of apoptosis.
# Interactions
Fas ligand has been shown to interact with:
- CASP8,[4][5]
- EZR,[4][6]
- FADD,[4][5]
- FNBP1,[7]
- FYN,[8][9]
- FAS,[4][5][10][11]
- Grb2,[7][8]
- PACSIN2,[7] and
- TNFRSF6B.[12][13][14] | https://www.wikidoc.org/index.php/CD95_antigen | |
9efca01665c6e637f45a9443f903cccdea6ea338 | wikidoc | Citicoline | Citicoline
# Overview
Citicoline (INN), also known as cytidine diphosphate-choline (CDP-Choline) & cytidine 5'-diphosphocholine is a psychostimulant/nootropic. It is an intermediate in the generation of phosphatidylcholine from choline.
Studies suggest that CDP-choline supplements increase dopamine receptor densities, and suggest that CDP-choline supplementation helps prevent memory impairment resulting from poor environmental conditions. Preliminary research has found that citicoline supplements help improve focus and mental energy and may possibly be useful in the treatment of attention deficit disorder. Citicoline has also been shown to elevate ACTH independently from CRH levels and to amplify the release of other HPA axis hormones such as LH, FSH, GH and TSH in response to hypothalamic releasing factors.
These effects on HPA hormone levels may be beneficial for some individuals but may have undesirable effects in those with medical conditions featuring ACTH or cortisol hypersecretion including, but not limited to, PCOS, type II diabetes and major depressive disorder.
# Medical uses
Citicoline is available as a supplement online and in stores. It is sold in over 70 countries under a variety of brand names: Ceraxon, Cognizin, NeurAxon, Somazina, Synapsine, etc. When taken as a supplement citicoline is hydrolyzed into choline and cytidine in the intestine. Once these cross the blood–brain barrier it is reformed into citicoline by the rate-limiting enzyme in phosphatidylcholine synthesis, CTP-phosphocholine cytidylyltransferase.
## Memory disorders
In the hippocampi of rats with induced Alzheimer’s Disease, citicoline counteracts neuronal degeneration and reduces the number of apoptotic cells present. Citicoline supplementation also improves memory retention.
## Ischemic stroke
Citicoline is approved for treatment in cases of head trauma, stroke, and neurodegenerative disease in Japan and Europe. Citicoline improves the clinical outcome following an ischemic stroke, as evidenced by the reduction in size of lesions caused by ischemic strokes after supplementation. It has been claimed that citicoline reduces rates of death and disability following an ischemic stroke.
However, the largest trial to date, a randomised, placebo-controlled, sequential trial in patients with moderate-to-severe acute ischaemic stroke in Europe, enrolling 2298 patients, found no benefit of administering citicoline on survival or recovery from stroke.
It should be noted that Citicoline is the only substance that ever showed any significant neuroprotective effect at least in patients with less severe stroke events.
## Vision
Citicoline improves visual function in patients with glaucoma, amblyopia, and non-arteritic ischaemic optic neuropathy.
## Satiety
Cocaine dependence is associated with depleted dopamine levels in the central nervous system. In cocaine-dependent individuals citicoline increases brain dopamine levels and reduces cravings. In the general population citicoline increases brain responses to food stimuli, specifically in the amygdala, insula, and lateral orbitofrontal cortex, which correlate with decreased appetite.
# Mechanism of action
## Neuroprotective effects
The neuroprotective effects exhibited by citicoline may be due to its preservation of cardiolipin and sphingomyelin, preservation of arachidonic acid content of phosphatidylcholine and phosphatidylethanolamine, partial restoration of phosphatidylcholine levels, and stimulation of glutathione synthesis and glutathione reductase activity. Citicoline’s effects may also be explained by the reduction of phospholipase A2 activity.
Citicoline increases phosphatidylcholine synthesis. The mechanism for this may be:
- By converting 1, 2-diacylglycerol into phosphatidylcholine
- Stimulating the synthesis of SAMe, which aids in membrane stabilization and reduces levels of arachidonic acid. This is especially important after an ischemia, when arachidonic acid levels are elevated.
## Neuronal membrane
The brain prefers to use choline to synthesize acetylcholine. This limits the amount of choline available to synthesize phosphatidylcholine. When the availability of choline is low or the need for acetylcholine increases, phospholipids containing choline can be catabolized from neuronal membranes. These phospholipids include sphingomyelin and phosphatidylcholine. Supplementation with citicoline can increase the amount of choline available for acetylcholine synthesis and aid in rebuilding membrane phospholipid stores after depletion.
Citicoline decreases phospholipase stimulation. This can lower levels of hydroxyl radicals produced after an ischemia and prevent cardiolipin from being catabolized by phospholipase A2. It can also work to restore cardiolipin levels in the inner mitochondrial membrane.
## Cell signalling
Citicoline enhances cellular communication by increasing the availability of neurotransmitters, including acetylcholine, norepinephrine, and dopamine.
## Blood flow
Citicoline increases glucose metabolism in the brain and cerebral blood flow.
## Inflammation and stress
Citicoline reduces oxidative stress. It also prevents excessive inflammatory response in the brain by inhibiting the release of free fatty acids and decreasing blood–brain barrier breakdown.
## Glutamate transport
Citicoline lowers increased glutamate concentrations and raises decreased ATP concentrations induced by ischemia. Citicoline also increases glutamate uptake by increasing expression of EAAT2, a glutamate transporter, in vitro in rat astrocytes. It is suggested that the neuroprotective effects of citicoline after a stroke are due in part to citicoline’s ability to decrease levels of glutamate in the brain.
# Pharmacokinetics
Citicoline is water-soluble, with more than 90% oral bioavailability. Plasma levels peak one hour after oral ingestion, and a majority of the citicoline is excreted as CO2 in respiration, and again 24 hours after ingestion, where the remaining citicoline is excreted through urine.
## Side effects
Citicoline has a very low toxicity profile in animals and humans. Clinically, doses of 2000 mg per day have been observed and approved. Minor transient adverse effects are rare and most commonly include stomach pain and diarrhea.
# Synthesis
## In vivo
phosphatidylcholine is a major phospholipid in eukaryotic cell membranes. Close regulation of its biosynthesis, degradation, and distribution is essential to proper cell function. phosphatidylcholine is synthesized in vivo by two pathways
- The Kennedy pathway, which includes the transformation of choline to citicoline, by way of phosphorylcholine, to produce phosphatidylcholine when condensed with diacylglycerol.
- Phosphatidylcholine can also be produced by the methylation pathway, where phosphatidylethanolamine is sequentially methylated. | Citicoline
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Citicoline (INN), also known as cytidine diphosphate-choline (CDP-Choline) & cytidine 5'-diphosphocholine is a psychostimulant/nootropic. It is an intermediate in the generation of phosphatidylcholine from choline.
Studies suggest that CDP-choline supplements increase dopamine receptor densities,[1] and suggest that CDP-choline supplementation helps prevent memory impairment resulting from poor environmental conditions.[2] Preliminary research has found that citicoline supplements help improve focus and mental energy and may possibly be useful in the treatment of attention deficit disorder.[3][4] Citicoline has also been shown to elevate ACTH independently from CRH levels and to amplify the release of other HPA axis hormones such as LH, FSH, GH and TSH in response to hypothalamic releasing factors.[5]
These effects on HPA hormone levels may be beneficial for some individuals but may have undesirable effects in those with medical conditions featuring ACTH or cortisol hypersecretion including, but not limited to, PCOS, type II diabetes and major depressive disorder.[6][7]
# Medical uses
Citicoline is available as a supplement online and in stores. It is sold in over 70 countries under a variety of brand names: Ceraxon, Cognizin, NeurAxon, Somazina, Synapsine, etc. When taken as a supplement citicoline is hydrolyzed into choline and cytidine in the intestine.[8] Once these cross the blood–brain barrier it is reformed into citicoline by the rate-limiting enzyme in phosphatidylcholine synthesis, CTP-phosphocholine cytidylyltransferase.[9][10]
## Memory disorders
In the hippocampi of rats with induced Alzheimer’s Disease, citicoline counteracts neuronal degeneration and reduces the number of apoptotic cells present. Citicoline supplementation also improves memory retention.[9]
## Ischemic stroke
Citicoline is approved for treatment in cases of head trauma, stroke, and neurodegenerative disease in Japan and Europe. Citicoline improves the clinical outcome following an ischemic stroke, as evidenced by the reduction in size of lesions caused by ischemic strokes after supplementation.[11] It has been claimed that citicoline reduces rates of death and disability following an ischemic stroke.[12]
However, the largest trial to date, a randomised, placebo-controlled, sequential trial in patients with moderate-to-severe acute ischaemic stroke in Europe, enrolling 2298 patients, found no benefit of administering citicoline on survival or recovery from stroke.[13]
It should be noted that Citicoline is the only substance that ever showed any significant neuroprotective effect at least in patients with less severe stroke events.[14]
## Vision
Citicoline improves visual function in patients with glaucoma, amblyopia, and non-arteritic ischaemic optic neuropathy.[15][16]
## Satiety
Cocaine dependence is associated with depleted dopamine levels in the central nervous system. In cocaine-dependent individuals citicoline increases brain dopamine levels and reduces cravings.[17] In the general population citicoline increases brain responses to food stimuli, specifically in the amygdala, insula, and lateral orbitofrontal cortex, which correlate with decreased appetite.[18]
# Mechanism of action
## Neuroprotective effects
The neuroprotective effects exhibited by citicoline may be due to its preservation of cardiolipin and sphingomyelin, preservation of arachidonic acid content of phosphatidylcholine and phosphatidylethanolamine, partial restoration of phosphatidylcholine levels, and stimulation of glutathione synthesis and glutathione reductase activity. Citicoline’s effects may also be explained by the reduction of phospholipase A2 activity.[19]
Citicoline increases phosphatidylcholine synthesis.[20][21][22] The mechanism for this may be:
- By converting 1, 2-diacylglycerol into phosphatidylcholine
- Stimulating the synthesis of SAMe, which aids in membrane stabilization and reduces levels of arachidonic acid. This is especially important after an ischemia, when arachidonic acid levels are elevated.[23]
## Neuronal membrane
The brain prefers to use choline to synthesize acetylcholine. This limits the amount of choline available to synthesize phosphatidylcholine. When the availability of choline is low or the need for acetylcholine increases, phospholipids containing choline can be catabolized from neuronal membranes. These phospholipids include sphingomyelin and phosphatidylcholine.[19] Supplementation with citicoline can increase the amount of choline available for acetylcholine synthesis and aid in rebuilding membrane phospholipid stores after depletion.[24]
Citicoline decreases phospholipase stimulation. This can lower levels of hydroxyl radicals produced after an ischemia and prevent cardiolipin from being catabolized by phospholipase A2.[25][26] It can also work to restore cardiolipin levels in the inner mitochondrial membrane.[25]
## Cell signalling
Citicoline enhances cellular communication by increasing the availability of neurotransmitters, including acetylcholine, norepinephrine, and dopamine.[27]
## Blood flow
Citicoline increases glucose metabolism in the brain and cerebral blood flow.[28]
## Inflammation and stress
Citicoline reduces oxidative stress. It also prevents excessive inflammatory response in the brain by inhibiting the release of free fatty acids and decreasing blood–brain barrier breakdown.[21]
## Glutamate transport
Citicoline lowers increased glutamate concentrations and raises decreased ATP concentrations induced by ischemia. Citicoline also increases glutamate uptake by increasing expression of EAAT2, a glutamate transporter, in vitro in rat astrocytes. It is suggested that the neuroprotective effects of citicoline after a stroke are due in part to citicoline’s ability to decrease levels of glutamate in the brain.[29]
# Pharmacokinetics
Citicoline is water-soluble, with more than 90% oral bioavailability.[24] Plasma levels peak one hour after oral ingestion, and a majority of the citicoline is excreted as CO2 in respiration, and again 24 hours after ingestion, where the remaining citicoline is excreted through urine.[30]
## Side effects
Citicoline has a very low toxicity profile in animals and humans. Clinically, doses of 2000 mg per day have been observed and approved. Minor transient adverse effects are rare and most commonly include stomach pain and diarrhea.[21]
# Synthesis
## In vivo
phosphatidylcholine is a major phospholipid in eukaryotic cell membranes. Close regulation of its biosynthesis, degradation, and distribution is essential to proper cell function. phosphatidylcholine is synthesized in vivo by two pathways
- The Kennedy pathway, which includes the transformation of choline to citicoline, by way of phosphorylcholine, to produce phosphatidylcholine when condensed with diacylglycerol.
- Phosphatidylcholine can also be produced by the methylation pathway, where phosphatidylethanolamine is sequentially methylated.[31] | https://www.wikidoc.org/index.php/CDP-Choline | |
83fb66881ed4161b2520b71a21fd536a72c2a733 | wikidoc | Chimerin 1 | Chimerin 1
Chimerin 1, (CHN1) also known as alpha-1-chimerin, n-chimerin is a protein which in humans is encoded by the CHN1 gene.
Chimerin 1 is a GTPase activating protein specific for RAC GTP-binding proteins. It is expressed primarily in the brain and may be involved in signal transduction.
This gene encodes GTPase-activating protein for p21-rac and a phorbol ester receptor. It plays an important role in ocular motor axon pathfinding.
# Function
CHN1 is a three-domain protein with the N-terminal SH2 domain, the C-terminal RhoGAP domain and the central C1 domain similar to protein kinase C. When lipid diacylglycerol (DAG) binds to the C1 domain, CHN1 is transferred to the plasma membrane and negatively regulates Rho-family small GTPases RAC1 and CDC42, thus causing the morphological change of axons by pruning the ends of axon dendrites.
Mutational analysis suggests that un-overlapping residues of the RhoGAP domain are involved in RAC1-binding and the RAC1-GAP activity. Regulation of the RhoGAP activity of CHN1 by phorbol esters, natural compounds mimic of the lipid second messenger DAG, presents a possible way of designing agents for therapeutics.
# Clinical significance
Heterozygous missense mutations in this gene cause Duane's retraction syndrome 2 (DURS2). | Chimerin 1
Chimerin 1, (CHN1) also known as alpha-1-chimerin, n-chimerin is a protein which in humans is encoded by the CHN1 gene.[2][3]
Chimerin 1 is a GTPase activating protein specific for RAC GTP-binding proteins. It is expressed primarily in the brain and may be involved in signal transduction.
This gene encodes GTPase-activating protein for p21-rac and a phorbol ester receptor. It plays an important role in ocular motor axon pathfinding.
# Function
CHN1 is a three-domain protein with the N-terminal SH2 domain, the C-terminal RhoGAP domain and the central C1 domain similar to protein kinase C. When lipid diacylglycerol (DAG) binds to the C1 domain, CHN1 is transferred to the plasma membrane and negatively regulates Rho-family small GTPases RAC1 and CDC42, thus causing the morphological change of axons by pruning the ends of axon dendrites.[4][5]
Mutational analysis suggests that un-overlapping residues of the RhoGAP domain are involved in RAC1-binding and the RAC1-GAP activity. Regulation of the RhoGAP activity of CHN1 by phorbol esters, natural compounds mimic of the lipid second messenger DAG, presents a possible way of designing agents for therapeutics.[6]
# Clinical significance
Heterozygous missense mutations in this gene cause Duane's retraction syndrome 2 (DURS2).[7] | https://www.wikidoc.org/index.php/CHN1_gene | |
a3a47c4259c4743114e47316afc7899c791ef219 | wikidoc | CKB (gene) | CKB (gene)
Brain-type creatine kinase also known as CK-BB is a creatine kinase that in humans is encoded by the CKB gene.
# Function
The protein encoded by this gene, CK-BB, consists of a homodimer of two identical brain-type CK-B subunits. BB-CK is a cytoplasmic enzyme involved in cellular energy homeostasis, with certain fractions of the enzyme being bound to cell membranes, ATPases, and a variety of ATP-requiring enzymes in the cell. There, CK-BB forms tightly coupled microcompartments for in situ regeneration of ATP that has been used up. The encoded protein reversibly catalyzes the transfer of "energy-rich" phosphate between ATP and creatine or between phospho-creatine (PCr) and ADP. Its functional entity is a homodimer (CK-BB) in brain and smooth muscle as well as in other tissues and cells such as neuronal cells, retina, kidney, bone, etc. In heart, a heterodimer (CK-MB) shahil consisting of one CK-B brain-type CK subunit and one CK-M muscle-type CK subunit is prominently expressed. The encoded CK-BB and CK-MB proteins are members of the ATP:guanido phosphotransferase protein family.
# Ectopic expression
Ectopic expression (CKBE) of the B (brain) type of creatine kinase (CK-BB) in red cells and platelets is a rare, benign anomaly detected during a newborn screening program for Duchenne muscular dystrophy. | CKB (gene)
Brain-type creatine kinase also known as CK-BB is a creatine kinase that in humans is encoded by the CKB gene.[1]
# Function
The protein encoded by this gene, CK-BB, consists of a homodimer of two identical brain-type CK-B subunits. BB-CK is a cytoplasmic enzyme involved in cellular energy homeostasis, with certain fractions of the enzyme being bound to cell membranes, ATPases, and a variety of ATP-requiring enzymes in the cell. There, CK-BB forms tightly coupled microcompartments for in situ regeneration of ATP that has been used up. The encoded protein reversibly catalyzes the transfer of "energy-rich" phosphate between ATP and creatine or between phospho-creatine (PCr) and ADP. Its functional entity is a homodimer (CK-BB) in brain and smooth muscle as well as in other tissues and cells such as neuronal cells, retina, kidney, bone, etc. In heart, a heterodimer (CK-MB) shahil consisting of one CK-B brain-type CK subunit and one CK-M muscle-type CK subunit is prominently expressed. The encoded CK-BB and CK-MB proteins are members of the ATP:guanido phosphotransferase protein family.[2]
# Ectopic expression
Ectopic expression (CKBE) of the B (brain) type of creatine kinase (CK-BB) in red cells and platelets is a rare, benign anomaly detected during a newborn screening program for Duchenne muscular dystrophy.[3][4] | https://www.wikidoc.org/index.php/CKBE | |
115a45c72b7a8b0e76877672008175f2074ac87a | wikidoc | CKM (gene) | CKM (gene)
Creatine kinase, muscle also known as CKM is a creatine kinase that in humans is encoded by the CKM gene.
# Structure
In the figure to the right, the crystal structure of the muscle-type M-CK monomer is shown. In vivo, two such monomers arrange symmetrically to form the active MM-CK enzyme.
# Function
The protein encoded by this gene is a cytoplasmic enzyme involved in cellular energy homeostasis. The encoded protein reversibly catalyzes the transfer of "energy-rich" phosphate between ATP and creatine and between phospho-creatine and ADP. Its functional entity is a MM-CK homodimer in striated (sarcomeric) skeletal and cardiac muscle.
# Clinical significance
In heart, in addition to the MM-CK homodimer, also the heterodimer MB-CK consisting of one muscle (M-CK) and one brain-type (B-CK) subunit is expressed. The latter may be an important serum marker for myocardial infarction, if released from damaged myocardial cells into the blood where it can be detected by clinical chemistry. | CKM (gene)
Creatine kinase, muscle also known as CKM is a creatine kinase that in humans is encoded by the CKM gene.[1]
# Structure
In the figure to the right, the crystal structure of the muscle-type M-CK monomer is shown. In vivo, two such monomers arrange symmetrically to form the active MM-CK enzyme.
# Function
The protein encoded by this gene is a cytoplasmic enzyme involved in cellular energy homeostasis. The encoded protein reversibly catalyzes the transfer of "energy-rich" phosphate between ATP and creatine and between phospho-creatine and ADP. Its functional entity is a MM-CK homodimer in striated (sarcomeric) skeletal and cardiac muscle.
# Clinical significance
In heart, in addition to the MM-CK homodimer, also the heterodimer MB-CK consisting of one muscle (M-CK) and one brain-type (B-CK) subunit is expressed. The latter may be an important serum marker for myocardial infarction, if released from damaged myocardial cells into the blood where it can be detected by clinical chemistry. | https://www.wikidoc.org/index.php/CKM_(gene) | |
5bbbfc230033f2f5f5bac7b35c3552b80be88289 | wikidoc | CLAS Trial | CLAS Trial
# Objective
To determine whether combined therapy with the lipid lowering agents colestipol hydrochloride (30g daily) plus niacin (3-12g daily) would produce significant change in coronary, carotid, and femoral artery atherosclerosis and coronary bypass graft lesions as determined by angiography. Also, to determine possible correlations between lesion changes and plasma lipid and lipoprotein cholesterol levels and to explore interrelationships of atherosclerosis change in femoral, coronary, and carotid arteries.
# Methods
CLAS (Cholesterol Lowering Atherosclerosis Study) was a randomized, selectively blinded study wherein 188 men, with known previous coronary artery bypass grafts, were randomized to diet plus placebo or diet plus combined lipid lowering therapy consisting of colestipol and niacin and followed up at 2 years and 4 years.
# Results
The following results were noted:
- Treatment group had a 37% raise in HDL-C levels and a 43% reduction in LDL-C levels.
- Regression of atherosclerosis, as measured by angiography, was greater with combined drug treatment at 2 years and at 4 years.
- Reduction in the percentage of subjects with new atheroma formation in native coronary arteries.
- Significantly reduced percentage of subjects with new lesions or any adverse change in bypass grafts.
- Atherosclerosis regression occurred in 16.2% of colestipol-niacin treated vs 2.4% placebo treated
# Conclusion
The benefit of combined nicotinic acid and colestipol therapy was most prominent in patients with baseline plasma cholesterol levels above 240 mg/dL. | CLAS Trial
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Objective
To determine whether combined therapy with the lipid lowering agents colestipol hydrochloride (30g daily) plus niacin (3-12g daily) would produce significant change in coronary, carotid, and femoral artery atherosclerosis and coronary bypass graft lesions as determined by angiography. Also, to determine possible correlations between lesion changes and plasma lipid and lipoprotein cholesterol levels and to explore interrelationships of atherosclerosis change in femoral, coronary, and carotid arteries.
# Methods
CLAS (Cholesterol Lowering Atherosclerosis Study) was a randomized, selectively blinded study wherein 188 men, with known previous coronary artery bypass grafts, were randomized to diet plus placebo or diet plus combined lipid lowering therapy consisting of colestipol and niacin and followed up at 2 years and 4 years.
# Results
The following results were noted:[1]
- Treatment group had a 37% raise in HDL-C levels and a 43% reduction in LDL-C levels.
- Regression of atherosclerosis, as measured by angiography, was greater with combined drug treatment at 2 years and at 4 years.
- Reduction in the percentage of subjects with new atheroma formation in native coronary arteries.
- Significantly reduced percentage of subjects with new lesions or any adverse change in bypass grafts.
- Atherosclerosis regression occurred in 16.2% of colestipol-niacin treated vs 2.4% placebo treated
# Conclusion
The benefit of combined nicotinic acid and colestipol therapy was most prominent in patients with baseline plasma cholesterol levels above 240 mg/dL.[2][3][4][5] | https://www.wikidoc.org/index.php/CLAS_Trial | |
a93beb203a5478b749540bba1b249ada11768663 | wikidoc | Calponin 2 | Calponin 2
Calponin 2 is a protein that in humans is encoded by the CNN2 gene.
The CNN2 gene is located at 19p13.3 in the human chromosomal genome, encoding the protein calponin 2. Calponin 2 is one of the three isoforms of calponin and an actin filament-associated regulatory protein with wide tissue distributions. Human calponin 2 is a 33.7-kDa protein consisting of 309 amino acids with an isoelectric point (pI) of 7.23. Accordingly, it is also known as neutral calponin.
# Evolution
Calponin isoforms are conserved proteins whereas calponin 2 has diverged from calponin 1 and calponin 3 mainly in the C-terminal variable region. Phylogenetic lineage of calponin 2 showed that calponin 2 is conserved among mammalian species but more diverged among amphibian, reptile and fish species (Fig 1).
# Tissue distribution
CNN2 is expressed in a broader range of tissue and cell types, including developing and remodeling smooth muscle as well as adult mature smooth muscle, epidermal keratinocytes, fibroblasts, lung alveolar cells, endothelial cells, myeloid white blood cells, platelet, B lymphocyte, and myoblasts. These cell types can be classified as a) cells that are physiologically under high mechanical tension (e.g., smooth muscle in the wall of hollow organs, epithelial and endothelial cells), b) cells that have high rates of proliferation (e.g., myoblasts), and c) cells that are actively migrating (e.g., fibroblasts and macrophages). Therefore, the tissue distributions of calponin 2 imply its potential role in regulating cytoskeleton functions and cell motility.
# Interaction with other proteins
In vitro protein binding studies have demonstrated that calponin binds actin and cross-links actin filaments. Calponin also binds tropomyosin, tubulin, desmin, Ca2+-calmodulin, Ca2+-S100, myosin, and phospholipids. Calponin also interacts with caldesmon and a-actinin, which however may only reflect their co-localization on actin filaments. The variable C-terminal segment regulates actin-binding affinity, and calponin 2 is shown to have the lowest affinity for F-actin among the three isoforms.
# Function
## Cell proliferation
Significant amounts of calponin 2 are found in growing smooth muscle tissues such as embryonic stomach and urinary bladder as well as the uterus during early pregnancy. The expression of calponin 2 decreases to lower levels in quiescent adult smooth muscle cells while the expression of calponin 1 is up-regulated. Transfective over-expression of calponin 2 inhibited cell proliferation. A hypothesis is that higher level of calponin 2 is required in fast proliferating cells to maintain the dynamic equilibrium of the actin cytoskeleton.
## Cell motility
Primary fibroblasts and peritoneal macrophages isolated from Cnn2 knockout mice migrate faster than that of wild type control cells. Calponin 2 may affect cell migration differently in different cell types and in different biological processes. A study showed that forced expression of calponin 2 in endothelial cells enhanced angiogenic cell migration in vivo and anti-sense calponin 2 RNA reduced chemotaxis of human umbilical vein endothelial cells in culture. A hypothesis is that a proper level of calponin 2 may be required to maintain the physiological motility of different cell types in different biological processes. Calponin 2’s regulation of cell motility is based on inhibition of actin activated myosin motor function, as fibroblasts isolated from Cnn2 knockout mice showed increased cell traction force generated by myosin II motors.
## Cell adhesion
A significant level of calponin 2 is found in human and mouse platelets. Platelet adhesion is a critical step in blood coagulation and thrombosis. In a microfluidic flow-based thrombosis assay, the time to initiation of rapid platelet/thrombus accumulation was significantly longer in blood samples from Cnn2 knockout versus wild type mice. The effect of calponin 2 on facilitating the velocity of cell adhesion was also shown with prostate cancer cells expression high or low levels of calponin 2.
## Immune cells
Significant amounts of calponin 2 are found in blood cells of myeloid lineage. Monocytes derived from Cnn2 gene knockout mice proliferated faster than wild type control cells. Calponin 2-null macrophages migrated faster and exhibit enhanced phagocytosis. In global as well as myeloid cell-specific Cnn2 knockout mice, the development of inflammatory arthritis induced by anti-glucose-6-phosphate isomerase serum was significantly attenuated as compared with that in wild type mice . Deletion of calponin 2 in macrophages also significantly attenuated the development of atherosclerosis lesions in apolipoprotein E knockout (ApoE-/-) mice
# Regulation by mechanical tension
## Gene expression
The expression of calponin 2 is significantly increased in cells cultured on hard versus soft gel substrates that produce high or low traction force and cytoskeleton tension. The expression of calponin 2 in NIH/3T3 cells was decreased when cytoskeleton tension was reduced after blebbstatin inhibition of myosin II motors. To demonstrate the Cnn2 promoter-specific regulation, transfective expression of calponin 2 using a cytomegalovirus promoter was independent of the stiffness of culture substrate.
A binding site for transcriptional factor HES-1 (hairy and enhancer of split 1) has been identified in the 5’-upstream region of mouse Cnn2 promoter, responsible for the mechanical regulation. HES-1 is known to function downstream of the Notch-RBP J signaling pathway, which has been suggested to mediate cellular mechanoregulations. Deletion or mutation of the HES-1 site abolished the mechanical regulation and resulted in a substrate stiffness independent high level of transcription. Therefore, the regulatory mechanism is a low tension-induced repression. Corresponding to the down-regulation of Cnn2 gene expression, the level of HES-1 increased in cells cultured on soft gel substrate in comparison with that in cells cultured on hard substrates.
## Degradation
Calponin 2 is also regulated by mechanical tension at the protein level. A rapid and selective degradation of calponin 2 occurs in lung tissues after a short period of deflation. This low cytoskeleton tension-induced degradation of calponin 2 in collapsed lung was completely prevented in post mortem mouse lung simply by air inflation to maintain tension applied to the alveolae. The cytoskeleton tension-dependent stability of calponin 2 was further confirmed in monolayer cells cultured on expanded elastic membrane by its rapid degradation after a reduction of the dimension of the cultural substrate to acutely reduce cytoskeleton tension.
# Notes | Calponin 2
Calponin 2 is a protein that in humans is encoded by the CNN2 gene.
The CNN2 gene is located at 19p13.3 in the human chromosomal genome,[1] encoding the protein calponin 2. Calponin 2 is one of the three isoforms of calponin and an actin filament-associated regulatory protein with wide tissue distributions. Human calponin 2 is a 33.7-kDa protein consisting of 309 amino acids with an isoelectric point (pI) of 7.23. Accordingly, it is also known as neutral calponin.
# Evolution
Calponin isoforms are conserved proteins whereas calponin 2 has diverged from calponin 1 and calponin 3 mainly in the C-terminal variable region. Phylogenetic lineage of calponin 2 showed that calponin 2 is conserved among mammalian species but more diverged among amphibian, reptile and fish species (Fig 1).
# Tissue distribution
CNN2 is expressed in a broader range of tissue and cell types, including developing and remodeling smooth muscle as well as adult mature smooth muscle,[2] epidermal keratinocytes,[3] fibroblasts,[4] lung alveolar cells,[5] endothelial cells,[6] myeloid white blood cells,[7] platelet,[8] B lymphocyte,[9][10] and myoblasts.[11] These cell types can be classified as a) cells that are physiologically under high mechanical tension (e.g., smooth muscle in the wall of hollow organs, epithelial and endothelial cells), b) cells that have high rates of proliferation (e.g., myoblasts), and c) cells that are actively migrating (e.g., fibroblasts and macrophages). Therefore, the tissue distributions of calponin 2 imply its potential role in regulating cytoskeleton functions and cell motility.[12]
# Interaction with other proteins
In vitro protein binding studies have demonstrated that calponin binds actin[13] and cross-links actin filaments.[14] Calponin also binds tropomyosin,[15][16] tubulin,[17] desmin,[18][19] Ca2+-calmodulin,[13] Ca2+-S100,[20] myosin,[21] and phospholipids.[22] Calponin also interacts with caldesmon[23] and a-actinin,[24] which however may only reflect their co-localization on actin filaments.[14][25] The variable C-terminal segment regulates actin-binding affinity, and calponin 2 is shown to have the lowest affinity for F-actin among the three isoforms.[26]
# Function
## Cell proliferation
Significant amounts of calponin 2 are found in growing smooth muscle tissues such as embryonic stomach and urinary bladder as well as the uterus during early pregnancy.[2] The expression of calponin 2 decreases to lower levels in quiescent adult smooth muscle cells while the expression of calponin 1 is up-regulated.[2] Transfective over-expression of calponin 2 inhibited cell proliferation.[2][10] A hypothesis is that higher level of calponin 2 is required in fast proliferating cells to maintain the dynamic equilibrium of the actin cytoskeleton.
## Cell motility
Primary fibroblasts and peritoneal macrophages isolated from Cnn2 knockout mice migrate faster than that of wild type control cells.[7] Calponin 2 may affect cell migration differently in different cell types and in different biological processes. A study showed that forced expression of calponin 2 in endothelial cells enhanced angiogenic cell migration in vivo and anti-sense calponin 2 RNA reduced chemotaxis of human umbilical vein endothelial cells in culture.[6] A hypothesis is that a proper level of calponin 2 may be required to maintain the physiological motility of different cell types in different biological processes. Calponin 2’s regulation of cell motility is based on inhibition of actin activated myosin motor function, as fibroblasts isolated from Cnn2 knockout mice showed increased cell traction force generated by myosin II motors.
## Cell adhesion
A significant level of calponin 2 is found in human and mouse platelets.[8] Platelet adhesion is a critical step in blood coagulation and thrombosis. In a microfluidic flow-based thrombosis assay, the time to initiation of rapid platelet/thrombus accumulation was significantly longer in blood samples from Cnn2 knockout versus wild type mice.[8] The effect of calponin 2 on facilitating the velocity of cell adhesion was also shown with prostate cancer cells expression high or low levels of calponin 2.[6]
## Immune cells
Significant amounts of calponin 2 are found in blood cells of myeloid lineage. Monocytes derived from Cnn2 gene knockout mice proliferated faster than wild type control cells. Calponin 2-null macrophages migrated faster and exhibit enhanced phagocytosis.[7] In global as well as myeloid cell-specific Cnn2 knockout mice, the development of inflammatory arthritis induced by anti-glucose-6-phosphate isomerase serum was significantly attenuated as compared with that in wild type mice . Deletion of calponin 2 in macrophages also significantly attenuated the development of atherosclerosis lesions in apolipoprotein E knockout (ApoE-/-) mice[12]
# Regulation by mechanical tension
## Gene expression
The expression of calponin 2 is significantly increased in cells cultured on hard versus soft gel substrates that produce high or low traction force and cytoskeleton tension.[4] The expression of calponin 2 in NIH/3T3 cells was decreased when cytoskeleton tension was reduced after blebbstatin inhibition of myosin II motors.[5] To demonstrate the Cnn2 promoter-specific regulation, transfective expression of calponin 2 using a cytomegalovirus promoter was independent of the stiffness of culture substrate.[4]
A binding site for transcriptional factor HES-1 (hairy and enhancer of split 1) has been identified in the 5’-upstream region of mouse Cnn2 promoter, responsible for the mechanical regulation.[11] HES-1 is known to function downstream of the Notch-RBP J signaling pathway,[27] which has been suggested to mediate cellular mechanoregulations.[28][29] Deletion or mutation of the HES-1 site abolished the mechanical regulation and resulted in a substrate stiffness independent high level of transcription. Therefore, the regulatory mechanism is a low tension-induced repression. Corresponding to the down-regulation of Cnn2 gene expression, the level of HES-1 increased in cells cultured on soft gel substrate in comparison with that in cells cultured on hard substrates.[11]
## Degradation
Calponin 2 is also regulated by mechanical tension at the protein level. A rapid and selective degradation of calponin 2 occurs in lung tissues after a short period of deflation.[5] This low cytoskeleton tension-induced degradation of calponin 2 in collapsed lung was completely prevented in post mortem mouse lung simply by air inflation to maintain tension applied to the alveolae.[5] The cytoskeleton tension-dependent stability of calponin 2 was further confirmed in monolayer cells cultured on expanded elastic membrane by its rapid degradation after a reduction of the dimension of the cultural substrate to acutely reduce cytoskeleton tension.[5]
# Notes | https://www.wikidoc.org/index.php/CNN2 | |
85e7404de09f161cb07bdbcf9b11b822bd5ecebc | wikidoc | CNO (gene) | CNO (gene)
Protein cappuccino homolog is a protein that in humans is encoded by the CNO gene.
This intronless gene encodes a protein that may play a role in organelle biogenesis associated with melanosomes, platelet dense granules, and lysosomes. A similar protein in mouse is a component of a protein complex termed biogenesis of lysosome-related organelles complex 1 (BLOC-1), and is a model for Hermansky–Pudlak syndrome. The encoded protein may play a role in intracellular vesicular trafficking.
# Interactions
CNO (gene) has been shown to interact with BLOC1S2 and PLDN. | CNO (gene)
Protein cappuccino homolog is a protein that in humans is encoded by the CNO gene.[1][2][3]
This intronless gene encodes a protein that may play a role in organelle biogenesis associated with melanosomes, platelet dense granules, and lysosomes. A similar protein in mouse is a component of a protein complex termed biogenesis of lysosome-related organelles complex 1 (BLOC-1), and is a model for Hermansky–Pudlak syndrome. The encoded protein may play a role in intracellular vesicular trafficking.[3]
# Interactions
CNO (gene) has been shown to interact with BLOC1S2[4] and PLDN.[4] | https://www.wikidoc.org/index.php/CNO_(gene) | |
da3fd3c776c45375bebf99544389c09d16502368 | wikidoc | Depressant | Depressant
# Overview
A depressant, referred to in slang as a "downer," is a chemical agent that diminishes the function or activity of a specific part of the body (see also sedative). The term is especially used with regard to the central nervous system (CNS). Alcohol (consumed in alcoholic beverages) is the most obvious example of a depressant. Although some drugs act on the CNS by targeting or involving receptors such as the NMDA receptor, the mu-opioid receptor, and the CB1 cannabinoid receptor, many depressants impact the CNS by increasing the activity of a particular neurotransmitter known as gamma-aminobutyric acid (GABA),
GABA's role is to calm the CNS and promote sleep. Drugs that stimulate the activity of this amino acid slow brain function and result in a drowsy or calm feeling. These characteristics account for the prescription of depressants to relieve symptoms of anxiety or insomnia. Internal systems regulate the body's production of GABA, but when substances that stimulate GABA action are ingested, it is possible to induce hazardously high levels of the amino acid, which can slow breathing and heart rates dangerously, and may result in death.
CNS depressants require a period of adaptation. Typically, initial side effects include slurred speech, dizziness, and loss of coordination, effects commonly associated with alcohol consumption.
# Medical Uses
The most common medically used depressants generally fall into two classes, namely barbiturates and benzodiazepines. Other depressants include alcohol, narcotics (opiate derivatives), sedative-hypnotics, first-generation antihistamines (such as diphenhydramine,) and some anaesthetics (such as ketamine and phencyclidine).
Barbituates
While barbiturates are effective in relieving the conditions they are designed to address, they are readily abused, physically addictive, and have serious potential for overdose. In the late 1960s, when it became clear that the social cost of barbiturates was beginning to outweigh their medical benefits, a serious search began for a replacement drug (see Methaqualone). Most people still using barbiturates today do so to prevent seizures or use mild forms to relieve the symptoms of migraines.
Benzodiazepines
Benzodiazepines mediate many of the same symptoms as barbiturates, but are far less toxic and have a greatly reduced risk of overdose. However, benzodiazepines carry their own risks; where barbiturates pose a greater "front-end" danger in that overdose or drug/alcohol interactions may result in fatality, benzodiazepines pose a greater "back-end" risk with their higher potential for addiction, dependence, and serious physical and psychological withdrawal symptoms. Sudden cessation of long-term benzodiazepine use instead of tapering can be dangerous and have serious results.
Combining multiple depressants is very dangerous as CNS-depressive properties often increase multiplicatively rather than linearly. This characteristic makes depressants a common choice for deliberate overdoses (in the case of suicide). In the case of those addicted to opiates, the ingestion of alcohol or benzodizepines along with a normal dose of heroin (average daily dose of 300-500 mg) often results in death.
# Depressants/Downers
- antipsychotic drugs
- alcohol
- barbiturates
- benzodiazepines
- carisoprodol (Soma®)
- chloral hydrate (Noctec®)
- dextromethorphan
- diphenhydramine (Benadryl®)
- eszopiclone (Lunesta®)
- diethyl ether
- ethchlorvynol (Placidyl®)
- ethanol - any kind of alcoholic beverage
- gamma-hydroxybutyrate (Liquid X®)
- glutethimide (Doriden®)
- ketamine (Ketaset®)
- meprobamate (Miltown®)
- methaqualone (Quaalude®)
- methyprylon (Noludar®)
- nitrous oxide
- Suvorexant
- tiletamine (Telazol®)
- zaleplon (Sonata®)
- zolpidem (Ambien®)
- zopiclone (Imovane®) | Depressant
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
A depressant, referred to in slang as a "downer," is a chemical agent that diminishes the function or activity of a specific part of the body (see also sedative). The term is especially used with regard to the central nervous system (CNS). Alcohol (consumed in alcoholic beverages) is the most obvious example of a depressant. Although some drugs act on the CNS by targeting or involving receptors such as the NMDA receptor, the mu-opioid receptor, and the CB1 cannabinoid receptor, many depressants impact the CNS by increasing the activity of a particular neurotransmitter known as gamma-aminobutyric acid (GABA),
GABA's role is to calm the CNS and promote sleep. Drugs that stimulate the activity of this amino acid slow brain function and result in a drowsy or calm feeling. These characteristics account for the prescription of depressants to relieve symptoms of anxiety or insomnia. Internal systems regulate the body's production of GABA, but when substances that stimulate GABA action are ingested, it is possible to induce hazardously high levels of the amino acid, which can slow breathing and heart rates dangerously, and may result in death.
CNS depressants require a period of adaptation. Typically, initial side effects include slurred speech, dizziness, and loss of coordination, effects commonly associated with alcohol consumption.
# Medical Uses
The most common medically used depressants generally fall into two classes, namely barbiturates and benzodiazepines. Other depressants include alcohol, narcotics (opiate derivatives), sedative-hypnotics, first-generation antihistamines (such as diphenhydramine,) and some anaesthetics (such as ketamine and phencyclidine).
Barbituates
While barbiturates are effective in relieving the conditions they are designed to address, they are readily abused, physically addictive, and have serious potential for overdose. In the late 1960s, when it became clear that the social cost of barbiturates was beginning to outweigh their medical benefits, a serious search began for a replacement drug (see Methaqualone). Most people still using barbiturates today do so to prevent seizures or use mild forms to relieve the symptoms of migraines.
Benzodiazepines
Benzodiazepines mediate many of the same symptoms as barbiturates, but are far less toxic and have a greatly reduced risk of overdose. However, benzodiazepines carry their own risks; where barbiturates pose a greater "front-end" danger in that overdose or drug/alcohol interactions may result in fatality, benzodiazepines pose a greater "back-end" risk with their higher potential for addiction, dependence, and serious physical and psychological withdrawal symptoms. Sudden cessation of long-term benzodiazepine use instead of tapering can be dangerous and have serious results.
Combining multiple depressants is very dangerous as CNS-depressive properties often increase multiplicatively rather than linearly. This characteristic makes depressants a common choice for deliberate overdoses (in the case of suicide). In the case of those addicted to opiates, the ingestion of alcohol or benzodizepines along with a normal dose of heroin (average daily dose of 300-500 mg) often results in death.
# Depressants/Downers
- antipsychotic drugs
- alcohol
- barbiturates
- benzodiazepines
- carisoprodol (Soma®)
- chloral hydrate (Noctec®)
- dextromethorphan
- diphenhydramine (Benadryl®)
- eszopiclone (Lunesta®)
- diethyl ether
- ethchlorvynol (Placidyl®)
- ethanol - any kind of alcoholic beverage
- gamma-hydroxybutyrate (Liquid X®)
- glutethimide (Doriden®)
- ketamine (Ketaset®)
- meprobamate (Miltown®)
- methaqualone (Quaalude®)
- methyprylon (Noludar®)
- nitrous oxide
- Suvorexant
- tiletamine (Telazol®)
- zaleplon (Sonata®)
- zolpidem (Ambien®)
- zopiclone (Imovane®)
# External links
- Painfully Obvious - A Community Resource
- Fact sheets and Harm Reduction Strategies About Depressants and Other Recreational Drugs
- U.S. Department of Human and Health Services: Drug Categories for Substances of Abuse
- About Psychotropic Medications: Quick Reference to Medications Used in Mental Health
Template:WH
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/CNS_depressant | |
eea160d79d12cb3231e82ddecace46404e92e716 | wikidoc | CO2 sensor | CO2 sensor
# Overview
A CO2 sensor is an instrument for the measurement of carbon dioxide gas. The most common principles for CO2 sensors are infrared gas sensors (NDIR) and chemical gas sensors.
# Nondispersive Infrared (NDIR) CO2 Sensors
NDIR sensors are the simplest of the spectroscopic sensors. The key components are an infrared source, a light tube, an interference (wavelength) filter, and an infrared detector. The gas is pumped or diffuses into the light tube, and the electronics measures the absorption of the characteristic wavelength of light. NDIR sensors are most often used for measuring carbon dioxide. The best of these have sensitivities of 20-50 PPM. Typical NDIR sensors are still in the (US) $100 to $1000 range. Most are used for carbon dioxide, because no other sensing method works reliably for this gas. New developments include using MEMS to bring down the costs of this sensor and to create smaller devices (for example for use in air conditioning applications).
# Chemical CO2 Sensors
Chemical CO2 gas sensors with sensitive layers based on polymer- or heteropolysiloxane have the principal advantage of a very low energy consumption and can be reduced in size to fit into microelectronic-based systems. On the downside, short- and long term drift effects as well as a rather low overall lifetime are major obstacles when compared with the NDIR measurement principle. | CO2 sensor
# Overview
A CO2 sensor is an instrument for the measurement of carbon dioxide gas. The most common principles for CO2 sensors are infrared gas sensors (NDIR) and chemical gas sensors.
# Nondispersive Infrared (NDIR) CO2 Sensors
NDIR sensors are the simplest of the spectroscopic sensors.[citation needed] The key components are an infrared source, a light tube, an interference (wavelength) filter, and an infrared detector. The gas is pumped or diffuses into the light tube, and the electronics measures the absorption of the characteristic wavelength of light. NDIR sensors are most often used for measuring carbon dioxide.[1] The best of these have sensitivities of 20-50 PPM.[1] Typical NDIR sensors are still in the (US) $100 to $1000 range. Most are used for carbon dioxide, because no other sensing method works reliably for this gas. New developments include using MEMS to bring down the costs of this sensor and to create smaller devices (for example for use in air conditioning applications).
# Chemical CO2 Sensors
Chemical CO2 gas sensors with sensitive layers based on polymer- or heteropolysiloxane have the principal advantage of a very low energy consumption and can be reduced in size to fit into microelectronic-based systems. On the downside, short- and long term drift effects as well as a rather low overall lifetime are major obstacles when compared with the NDIR measurement principle[2]. | https://www.wikidoc.org/index.php/CO2_sensor | |
5cdbc014d5b934112a0de3c7bcddcb0b9739a548 | wikidoc | Calcinosis | Calcinosis
Calcinosis is the formation of calcium deposits in any soft tissue.
# Types
## Dystrophic calcification
The most common type of calcinosis is dystrophic calcification. This type of calcification can occur as a response to any soft tissue damage, including that involved in implantation of medical devices.
## Metastatic calcification
Metastatic calcification involves a systemic calcium-phosphate mineral imbalance, which can be caused by renal failure, milk-alkali syndrome, or other etiologies.
## Tumoral calcinosis
The etiology of the rare condition of tumoral calcinosis is not entirely understood. It is generally characterized by large, globular calcifications near joints.
Hyperphosphatemic familial tumoral calcinosis (HFTC) is a rare autosomal recessive metabolic disorder. Its principal clinical features are represented by ectopic periarticular calcifications associated with elevated levels of serum phosphate. HFTC is characterized by extensive phenotypic and genetic heterogeneity. HFTC has been shown to result from mutations in two genes: GALNT3 and FGF23. All GALNT3 mutations reported up to March 2006 were identified in patients of either Middle Eastern or African-American extraction. The secretion of FGF23 requires O-glycosylation, which is selectively directed by GALNT3, to block processing of FGF23. | Calcinosis
Calcinosis is the formation of calcium deposits in any soft tissue.
# Types
## Dystrophic calcification
The most common type of calcinosis is dystrophic calcification. This type of calcification can occur as a response to any soft tissue damage, including that involved in implantation of medical devices.
## Metastatic calcification
Metastatic calcification involves a systemic calcium-phosphate mineral imbalance, which can be caused by renal failure, milk-alkali syndrome, or other etiologies.
## Tumoral calcinosis
The etiology of the rare condition of tumoral calcinosis is not entirely understood. It is generally characterized by large, globular calcifications near joints.
Hyperphosphatemic familial tumoral calcinosis (HFTC) is a rare autosomal recessive metabolic disorder.[1] Its principal clinical features are represented by ectopic periarticular calcifications associated with elevated levels of serum phosphate.[1] HFTC is characterized by extensive phenotypic and genetic heterogeneity.[2] HFTC has been shown to result from mutations in two genes: GALNT3 and FGF23.[2] All GALNT3 mutations reported up to March 2006 were identified in patients of either Middle Eastern or African-American extraction.[2] The secretion of FGF23 requires O-glycosylation, which is selectively directed by GALNT3, to block processing of FGF23.[3] | https://www.wikidoc.org/index.php/Calcinosis | |
1ff772b525b59e7381b325719a4777f8290cb6d0 | wikidoc | Calcitonin | Calcitonin
Calcitonin (also known as thyrocalcitonin) is a 32-amino acid linear polypeptide hormone that is produced
in humans primarily by the parafollicular cells (also known as C-cells) of the thyroid gland, and in many other animals in the ultimopharyngeal body. It acts to reduce blood calcium (Ca2+), opposing the effects of parathyroid hormone (PTH).
Calcitonin has been found in fish, reptiles, birds, and mammals. Its importance in humans has not been as well established as its importance in other animals, as its function is usually not significant in the regulation of normal calcium homeostasis. It belongs to the calcitonin-like protein family.
# Biosynthesis and regulation
Calcitonin is formed by the proteolytic cleavage of a larger prepropeptide, which is the product of the CALC1 gene (CALCA). It is functionally an antagonist with PTH and Vitamin D3.The CALC1 gene belongs to a superfamily of related protein hormone precursors including islet amyloid precursor protein, calcitonin gene-related peptide, and the precursor of adrenomedullin.
Secretion of calcitonin is stimulated by:
- an increase in serum
- gastrin and pentagastrin.
# Function
The hormone participates in calcium (Ca2+) and phosphorus metabolism. In many ways, calcitonin counteracts parathyroid hormone (PTH) and vitamin D
More specifically, calcitonin lowers blood Ca2+ levels in two ways:
- Major effect: Inhibits osteoclast activity in bones
- Minor effect: Inhibits renal tubular cell reabsorption of Ca2+ and phosphate, allowing them to be excreted in the urine
High concentrations of calcitonin may be able to increase urinary excretion of calcium and phosphate via the renal tubules. leading to marked hypocalcemia. However, this is a minor effect with no physiological significance in humans. It is also a short-lived effect because the kidneys become resistant to calcitonin, as demonstrated by the kidney's unaffected excretion of calcium in patients with thyroid tumors that secrete excessive calcitonin.
In its skeleton-preserving actions, calcitonin protects against calcium loss from skeleton during periods of calcium mobilization, such as pregnancy and, especially, lactation. The protective mechanisms include the direct inhibition of bone resorption and the indirect effect through the inhibition of the release of prolactin from the pituitary gland. The reason provided is that prolactin induces the release of PTH related peptide which enhances bone resorption, but is still under investigation.,
Other effects are in preventing postprandial hypercalcemia resulting from absorption of Ca2+. Also, calcitonin inhibits food intake in rats and monkeys, and may have CNS action involving the regulation of feeding and appetite.
Calcitonin lowers blood calcium and phosphorus mainly through its inhibition of osteoclasts. Osteoblasts do not have calcitonin receptors and are therefore not directly affected by calcitonin levels. However, since bone resorption and bone formation are coupled processes, eventually calcitonin's inhibition of osteoclastic activity leads to increased osteoblastic activity (as an indirect effect).
# Receptor
The calcitonin receptor, localized to osteoclasts, the kidney, and regions of the brain, is a G protein-coupled receptor. It is coupled by Gs to adenylate cyclase, and thereby to the generation of cAMP in target cells. It may also affect the ovaries in women and the testes in men.
# Discovery
Calcitonin was purified in 1962 by Copp and Cheney. While it was initially considered a secretion of the parathyroid glands, it was later identified as the secretion of the C-cells of the thyroid gland.
# Medical Significance
Calcitonin assay is used in identifying patients with nodular thyroid diseases. It is helpful in making an early diagnosis of medullary carcinoma of thyroid. A malignancy of the parafollicular cells, i.e. Medullary thyroid cancer, typically produces an elevated serum calcitonin level. Prognosis of MTC depends on early detection and treatment.
# Pharmacology
Salmon calcitonin is used for the treatment of:
- Postmenopausal osteoporosis
- Hypercalcaemia
- Paget's disease
- Bone metastases
- Phantom limb pain
It has been investigated as a possible non-operative treatment for spinal stenosis.
The following information is from the UK Electronic Medicines Compendium
## General characteristics of the active substance
Salmon calcitonin is rapidly absorbed and eliminated. Peak plasma concentrations are attained within the first hour of administration.
Animal studies have shown that calcitonin is primarily metabolised via proteolysis in the kidney following parenteral administration. The metabolites lack the specific biological activity of calcitonin. Bioavailability following subcutaneous and intramuscular injection in humans is high and similar for the two routes of administration (71% and 66%, respectively).
Calcitonin has short absorption and elimination half-lives of 10–15 minutes and 50–80 minutes, respectively. Salmon calcitonin is primarily and almost exclusively degraded in the kidneys, forming pharmacologically inactive fragments of the molecule. Therefore, the metabolic clearance is much lower in patients with end-stage renal failure than in healthy subjects. However, the clinical relevance of this finding is not known. Plasma protein binding is 30% to 40%.
## Characteristics in patients
There is a relationship between the subcutaneous dose of calcitonin and peak plasma concentrations. Following parenteral administration of 100 IU calcitonin, peak plasma concentration lies between about 200 and 400 pg/ml. Higher blood levels may be associated with increased incidence of nausea, vomiting, and secretory diarrhea.
## Preclinical safety data
Conventional long-term toxicity, reproduction, mutagenicity, and carcinogenicity studies have been performed in laboratory animals. Salmon calcitonin is devoid of embryotoxic, teratogenic, and mutagenic potential.
An increased incidence of pituitary adenomas has been reported in rats given synthetic salmon calcitonin for 1 year. This is considered a species-specific effect and of no clinical relevance. Salmon calcitonin does not cross the placental barrier.
In lactating animals given calcitonin, suppression of milk production has been observed. Calcitonin is secreted into the milk.
# Pharmaceutical manufacture
Calcitonin was extracted from the ultimobranchial glands (thyroid-like glands) of fish, particularly salmon. Salmon calcitonin resembles human calcitonin, but is more active. At present, it is produced either by recombinant DNA technology or by chemical peptide synthesis. The pharmacological properties of the synthetic and recombinant peptides have been demonstrated to be qualitatively and quantitatively equivalent.
# Uses of calcitonin
## Treatments
Calcitonin can be used therapeutically for the treatment of hypercalcemia or osteoporosis.
In a recent clinical study, subcutaneous injections of calcitonin have reduced the incidence of fractures and reduced the decrease in bone mass in women with type 2 diabetes complicated with osteoporosis.
Subcutaneous injections of calcitonin in patients suffering from mania resulted in significant decreases in irritability, euphoria and hyperactivity and hence calcitonin holds promise for treating bipolar disorder. However no further work on this potential application of calcitonin has been reported.
## Diagnostics
It may be used diagnostically as a tumor marker for medullary thyroid cancer, in which high calcitonin levels may be present and elevated levels after surgery may indicate recurrence. It may even be used on biopsy samples from suspicious lesions (e.g., lymph nodes that are swollen) to establish whether they are metastases of the original cancer.
Cutoffs for calcitonin to distinguish cases with medullary thyroid cancer have been suggested to be as follows, with a higher value increasing the suspicion of medullary thyroid cancer:
- females: 5 ng/L or pg/mL
- males: 12 ng/L or pg/mL
- children under 6 months of age: 40 ng/L or pg/mL
- children between 6 months and 3 years of age: 15 ng/L or pg/mL
When over 3 years of age, adult cutoffs may be used
Increased levels of calcitonin have also been reported for various other conditions. They include: C-cell hyperplasia, nonthyroidal oat cell carcinoma, nonthyroidal small cell carcinoma and other nonthyroidal malignancies, acute and chronic renal failure, hypercalcemia, hypergastrinemia and other gastrointestinal disorders, and pulmonary disease.
## Structure
Calcitonin is a polypeptide hormone of 32 amino acids, with a molecular weight of 3454.93 daltons. Its structure comprises a single alpha helix. Alternative splicing of the gene coding for calcitonin produces a distantly related peptide of 37 amino acids, called calcitonin gene-related peptide (CGRP), beta type.
The following are the amino acid sequences of salmon and human calcitonin:
- salmon:
- human:
Compared to salmon calcitonin, human calcitonin differs at 16 residues. | Calcitonin
Calcitonin (also known as thyrocalcitonin) is a 32-amino acid linear polypeptide hormone that is produced
in humans primarily by the parafollicular cells (also known as C-cells) of the thyroid gland, and in many other animals in the ultimopharyngeal body.[1] It acts to reduce blood calcium (Ca2+), opposing the effects of parathyroid hormone (PTH).[2]
Calcitonin has been found in fish, reptiles, birds, and mammals. Its importance in humans has not been as well established as its importance in other animals, as its function is usually not significant in the regulation of normal calcium homeostasis.[3] It belongs to the calcitonin-like protein family.
# Biosynthesis and regulation
Calcitonin is formed by the proteolytic cleavage of a larger prepropeptide, which is the product of the CALC1 gene (CALCA). It is functionally an antagonist with PTH and Vitamin D3.The CALC1 gene belongs to a superfamily of related protein hormone precursors including islet amyloid precursor protein, calcitonin gene-related peptide, and the precursor of adrenomedullin.
Secretion of calcitonin is stimulated by:
- an increase in serum [Ca2+][4]
- gastrin and pentagastrin.[5]
# Function
The hormone participates in calcium (Ca2+) and phosphorus metabolism. In many ways, calcitonin counteracts parathyroid hormone (PTH) and vitamin D
More specifically, calcitonin lowers blood Ca2+ levels in two ways:
- Major effect: Inhibits osteoclast activity in bones[6]
- Minor effect: Inhibits renal tubular cell reabsorption of Ca2+ and phosphate, allowing them to be excreted in the urine[7][8]
High concentrations of calcitonin may be able to increase urinary excretion of calcium and phosphate via the renal tubules.[9] leading to marked hypocalcemia. However, this is a minor effect with no physiological significance in humans. It is also a short-lived effect because the kidneys become resistant to calcitonin, as demonstrated by the kidney's unaffected excretion of calcium in patients with thyroid tumors that secrete excessive calcitonin.[10]
In its skeleton-preserving actions, calcitonin protects against calcium loss from skeleton during periods of calcium mobilization, such as pregnancy and, especially, lactation. The protective mechanisms include the direct inhibition of bone resorption and the indirect effect through the inhibition of the release of prolactin from the pituitary gland. The reason provided is that prolactin induces the release of PTH related peptide which enhances bone resorption, but is still under investigation.,[11][12][13]
Other effects are in preventing postprandial hypercalcemia resulting from absorption of Ca2+. Also, calcitonin inhibits food intake in rats and monkeys, and may have CNS action involving the regulation of feeding and appetite.
Calcitonin lowers blood calcium and phosphorus mainly through its inhibition of osteoclasts. Osteoblasts do not have calcitonin receptors and are therefore not directly affected by calcitonin levels. However, since bone resorption and bone formation are coupled processes, eventually calcitonin's inhibition of osteoclastic activity leads to increased osteoblastic activity (as an indirect effect).[10]
# Receptor
The calcitonin receptor, localized to osteoclasts,[14] the kidney, and regions of the brain, is a G protein-coupled receptor. It is coupled by Gs to adenylate cyclase, and thereby to the generation of cAMP in target cells. It may also affect the ovaries in women and the testes in men.
# Discovery
Calcitonin was purified in 1962 by Copp and Cheney.[15] While it was initially considered a secretion of the parathyroid glands, it was later identified as the secretion of the C-cells of the thyroid gland.[16]
# Medical Significance
Calcitonin assay is used in identifying patients with nodular thyroid diseases. It is helpful in making an early diagnosis of medullary carcinoma of thyroid. A malignancy of the parafollicular cells, i.e. Medullary thyroid cancer, typically produces an elevated serum calcitonin level. Prognosis of MTC depends on early detection and treatment.
# Pharmacology
Salmon calcitonin is used for the treatment of:
- Postmenopausal osteoporosis
- Hypercalcaemia
- Paget's disease
- Bone metastases
- Phantom limb pain[17]
It has been investigated as a possible non-operative treatment for spinal stenosis.[18]
The following information is from the UK Electronic Medicines Compendium[19]
## General characteristics of the active substance
Salmon calcitonin is rapidly absorbed and eliminated. Peak plasma concentrations are attained within the first hour of administration.
Animal studies have shown that calcitonin is primarily metabolised via proteolysis in the kidney following parenteral administration. The metabolites lack the specific biological activity of calcitonin. Bioavailability following subcutaneous and intramuscular injection in humans is high and similar for the two routes of administration (71% and 66%, respectively).
Calcitonin has short absorption and elimination half-lives of 10–15 minutes and 50–80 minutes, respectively. Salmon calcitonin is primarily and almost exclusively degraded in the kidneys, forming pharmacologically inactive fragments of the molecule. Therefore, the metabolic clearance is much lower in patients with end-stage renal failure than in healthy subjects. However, the clinical relevance of this finding is not known. Plasma protein binding is 30% to 40%.
## Characteristics in patients
There is a relationship between the subcutaneous dose of calcitonin and peak plasma concentrations. Following parenteral administration of 100 IU calcitonin, peak plasma concentration lies between about 200 and 400 pg/ml. Higher blood levels may be associated with increased incidence of nausea, vomiting, and secretory diarrhea.
## Preclinical safety data
Conventional long-term toxicity, reproduction, mutagenicity, and carcinogenicity studies have been performed in laboratory animals. Salmon calcitonin is devoid of embryotoxic, teratogenic, and mutagenic potential.
An increased incidence of pituitary adenomas has been reported in rats given synthetic salmon calcitonin for 1 year. This is considered a species-specific effect and of no clinical relevance.[20] Salmon calcitonin does not cross the placental barrier.
In lactating animals given calcitonin, suppression of milk production has been observed. Calcitonin is secreted into the milk.
# Pharmaceutical manufacture
Calcitonin was extracted from the ultimobranchial glands (thyroid-like glands) of fish, particularly salmon. Salmon calcitonin resembles human calcitonin, but is more active. At present, it is produced either by recombinant DNA technology or by chemical peptide synthesis. The pharmacological properties of the synthetic and recombinant peptides have been demonstrated to be qualitatively and quantitatively equivalent.[19]
# Uses of calcitonin
## Treatments
Calcitonin can be used therapeutically for the treatment of hypercalcemia or osteoporosis.[21]
In a recent clinical study, subcutaneous injections of calcitonin have reduced the incidence of fractures and reduced the decrease in bone mass in women with type 2 diabetes complicated with osteoporosis.[22]
Subcutaneous injections of calcitonin in patients suffering from mania resulted in significant decreases in irritability, euphoria and hyperactivity and hence calcitonin holds promise for treating bipolar disorder.[23] However no further work on this potential application of calcitonin has been reported.
## Diagnostics
It may be used diagnostically as a tumor marker for medullary thyroid cancer, in which high calcitonin levels may be present and elevated levels after surgery may indicate recurrence. It may even be used on biopsy samples from suspicious lesions (e.g., lymph nodes that are swollen) to establish whether they are metastases of the original cancer.
Cutoffs for calcitonin to distinguish cases with medullary thyroid cancer have been suggested to be as follows, with a higher value increasing the suspicion of medullary thyroid cancer:[24]
- females: 5 ng/L or pg/mL
- males: 12 ng/L or pg/mL
- children under 6 months of age: 40 ng/L or pg/mL
- children between 6 months and 3 years of age: 15 ng/L or pg/mL
When over 3 years of age, adult cutoffs may be used
Increased levels of calcitonin have also been reported for various other conditions. They include: C-cell hyperplasia, nonthyroidal oat cell carcinoma, nonthyroidal small cell carcinoma and other nonthyroidal malignancies, acute and chronic renal failure, hypercalcemia, hypergastrinemia and other gastrointestinal disorders, and pulmonary disease.[25]
## Structure
Calcitonin is a polypeptide hormone of 32 amino acids, with a molecular weight of 3454.93 daltons. Its structure comprises a single alpha helix.[26] Alternative splicing of the gene coding for calcitonin produces a distantly related peptide of 37 amino acids, called calcitonin gene-related peptide (CGRP), beta type.[27]
The following are the amino acid sequences of salmon and human calcitonin:[citation needed]
- salmon:
- human:
Compared to salmon calcitonin, human calcitonin differs at 16 residues. | https://www.wikidoc.org/index.php/Calcitonin | |
c2646ce000679c9775335a478527e09d8ae56780 | wikidoc | Calfactant | Calfactant
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Calfactant is a Lung Surfactant that is FDA approved for the prevention of of respiratory distress syndrome(RDS) in premature infants at high risk for RDS and for the treatment (“rescue”) of premature infants who develop RDS. Common adverse reactions include cyanosis, airway obstruction, bradycardia, reflux of surfactant into the endotracheal tube, requirement for manual ventilation, and reintubation.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Calfactant is indicated for the prevention of Respiratory Distress Syndrome (RDS) in premature infants at high risk for RDS and for the treatment (“rescue”) of premature infants who develop RDS. Calfactant decreases the incidence of RDS, mortality due to RDS, and air leaks associated with RDS.
- Prophylaxis therapy at birth with Calfactant is indicated for premature infants less than 29 weeks of gestational age at significant risk for RDS. Calfactant prophylaxis should be administered as soon as possible, preferably within 30 minutes after birth.
- Calfactant therapy is indicated for infants less than or equal to 72 hours of age with RDS (confirmed by clinical and radiologic findings) and requiring endotracheal intubation.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Calfactant in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Calfactant in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Calfactant in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Calfactant in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Calfactant in pediatric patients.
# Contraindications
None
# Warnings
- Calfactant is intended for intratracheal use only.
- THE ADMINISTRATION OF EXOGENOUS SURFACTANTS, INCLUDING Calfactant, OFTEN RAPIDLY IMPROVES OXY GENATION AND LUNG COMPLIANCE. Following administration of Calfactant, patients should be carefully monitored so that oxygen therapy and ventilatory support can be modified in response to changes in respiratory status. Calfactant therapy is not a substitute for neonatal intensive care. Optimal care of premature infants at risk for RDS and new born infants with RDS who need endotracheal intubation requires an acute care unit organized, staffed, equipped, and experienced with intubation, ventilator management, and general care of these patients.
- TRANSIENT EPISODES OF REFLUX OF Calfactant INTO THE ENDOTRACHEAL TUBE, CYANOSIS, BRADYCARDIA, OR AIRWAY OBSTRUCTION HAVE OCCURRED DURING THE DOSING PROCEDURES. These events require stopping Calfactant administration and taking appropriate measures to alleviate the condition. After the patient is stable, dosing can proceed with appropriate monitoring.
### Precautions
- DescriptionWhen repeat dosing was given at fixed 12-hour intervals in the Calfactant vs. Exosurf Neonatal® trials, transient episodes of cyanosis, bradycardia, reflux of surfactant into the endotracheal tube, and airway obstruction were observed more frequently among infants in the Calfactant-treated group.
- An increased proportion of patients with both intraventricular hemorrhage (IVH) and periventricular leukomalacia (PVL) was observed in Calfactant-treated infants in the Calfactant-Exosurf Neonatal® controlled trials. These observations were not associated with increased mortality.
- No data are available on the use of Calfactant in conjunction with experimental therapies of RDS, e.g., high-frequency ventilation. Data from controlled trials on the efficacy of Calfactant are limited to doses of approximately 100 mg phospholipid/kg body weight and up to a total of 4 doses.
# Adverse Reactions
## Clinical Trials Experience
- The most common adverse reactions associated with Calfactant dosing procedures in the controlled trials were cyanosis (65%), airway obstruction (39%), bradycardia (34%), reflux of surfactant into the endotracheal tube (21%), requirement for manual ventilation (16%), and reintubation (3%). These events were generally transient and not associated with serious complications or death. The incidence of common complications of prematurity and RDS in the four controlled Calfactant trials are presented in Table3.Prophylaxis and treatment study results for each surfactant are combined.
- Follow-up Evaluations
- Two-year follow-up data of neurodevelopmental outcomes in 415 infants enrolled in 5 centers that participated in the Calfactant vs Exosurf Neonatal® controlled trials demonstrated significant developmental delays in equal percentages of Calfactant and Exosurf Neonatal® patients.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Calfactant in the drug label.
# Drug Interactions
There is limited information regarding Calfactant Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Calfactant in women who are pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Calfactant in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Calfactant during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Calfactant with respect to nursing mothers.
### Pediatric Use
There is no FDA guidance on the use of Calfactant with respect to pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of Calfactant with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Calfactant with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Calfactant with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Calfactant in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Calfactant in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Calfactant in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Calfactant in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intrathecal
### Monitoring
There is limited information regarding Monitoring of Calfactant in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Calfactant in the drug label.
# Overdosage
- There have been no reports of overdosage with Calfactant. While there are no known adverse effects of excess lung surfactant, overdosage would result in overloading the lungs with an isotonic solution. Ventilation should be supported until clearance of the liquid is accomplished.
# Pharmacology
There is limited information regarding Calfactant Pharmacology in the drug label.
## Mechanism of Action
- Endogenous lung surfactant is essential for effective ventilation because it modifies alveolar surface tension thereby stabilizing the alveoli. Lung surfactant deficiency is the cause of Respiratory Distress Syndrome (RDS) in premature infants. Calfactant restores surface activity to the lungs of these infants.
## Structure
- Calfactant® (calfactant) Intratracheal Suspension is a sterile, non-pyrogenic lung surfactant intended for intratracheal instillation only. It is an extract of natural surfactant from calf lungs which includes phospholipids, neutral lipids, and hydrophobic surfactant-associated proteins B and C (SP-B and SP-C). It contains no preservatives.
- Calfactant is an off-white suspension of calfactant in 0.9% aqueous sodium chloride solution. It has a pH of 5.0 - 6.2 (target pH 5.7). Each milliliter of Calfactant contains 35 mg total phospholipids (including 26 mg phosphatidylcholine of which 16 mg is disaturated phosphatidylcholine) and 0.7 mg proteins including 0.26 mg of SP-B.
## Pharmacodynamics
- Calfactant adsorbs rapidly to the surface of the air:liquid interface and modifies surface tension similarly to natural lung surfactant. A minimum surface tension of less than or equal to 3 mN/m is produced in vitro by Calfactant as measured on a pulsating bubble surfactometer. Ex vivo, Calfactant restores the pressure volume mechanics and compliance of surfactant-deficient rat lungs. In vivo, Calfactant improves lung compliance, respiratory gas exchange, and survival in preterm lambs with profound surfactant deficiency
## Pharmacokinetics
- Animal Metabolism: Calfactant is administered directly to the lung lumen surface, its site of action. No human studies of absorption, biotransformation, or excretion of Calfactant have been performed. The administration of Calfactant with radiolabeled phospholipids into the lungs of adult rabbits results in the persistence of 50% of radioactivity in the lung alveolar lining and25% of radioactivity in the lung tissue 24 hours later. Less than 5% of the radioactivity is found in other organs. In premature lambs with lethal surfactant deficiency, less than 30% of instilled Calfactant is present in the lung lining after 24 hours.
## Nonclinical Toxicology
- Carcinogenesis studies and animal reproduction studies have not been performed with Calfactant. A single mutagenicity study (Ames assay) was negative.
# Clinical Studies
- Clinical Studies: The efficacy of Calfactant was demonstrated in two multiple-dose controlled clinical trials involving approximately 2,000 infants treated with Calfactant (approximately 100 mg phospholipid/kg) or Exosurf Neonatal®. In addition, two controlled trials of Calfactant versus Survanta®, and four uncontrolled trials were conducted that involved approximately 15,500 patients treated with Calfactant.
- Treatment Trial
- A total of 1,126 infants less than or equal to 72 hours of age with RDS who required endotracheal intubation and had an a/A PO2 less than 0.22 were enrolled into a multiple-dose, randomized, double-blind treatment trial comparing Calfactant (3 mL/kg) and Exosurf Neonatal® (5 mL/kg). Patients were given an initial dose and one repeat dose 12 hours later if intubation was still required. The dose was instilled in two aliquots through a side port adapter into the proximal end of the endotracheal tube. Each aliquot was given in small bursts over 20-30 inspiratory cycles. After each aliquot was instilled, the infant was positioned with either the right or the left side dependent. Results for efficacy parameters evaluated at 28 days or to discharge for all treated patients from this treatment trial are shown in Table 1.
- Prophylaxis Trial
- A total of 853 infants less than 29 weeks gestation were enrolled into a multiple-dose, randomized, double-blind prophylaxis trial comparing Calfactant (3 mL/kg) and Exosurf Neonatal® (5 mL/kg). The initial dose was administered within 30 minutes of birth. Repeat doses were administered at 12 and 24 hours if the patient remained intubated. Each dose was administered divided in 2 equal aliquots, and given through a side port adapter into the proximal end of the endotra cheal tube. Each aliquot was given in small bursts over 20-30 inspiratory cycles. After each aliquot was instilled, the infant was positioned with either the right or the left side dependent. Results for efficacy parameters evaluated to day 28 or to discharge for all treated patients from this prophylaxis trial are shown in Table 2.
- Treatment Trial
- A total of 662 infants with RDS who required endotracheal intubation and had an a/A PO2 less than 0.22 were enrolled into a multiple-dose, randomized, double-blind treatment trial comparing Calfactant (4 mL/kg of a formulation that contained 25 mg of phospholipids/mL rather than the 35 mg/mL in the marketed formulation) and Survanta® (4 mL/kg). Repeat doses were allowed Greater than or equal to 6 hours following the previous treatment (for up to three doses before 96 hours of age) if the patient required Greater than or equal to 30% oxygen. The surfactant was given through a 5 French feeding catheter inserted into the endo tracheal tube. The total dose was instilled in four equal aliquots with the catheter removed between each of the instillations and mechanical ventilation resumed for 0.5 to 2 minutes. Each of the aliquots was administered with the patient in one of four different positions (prone, supine, right, and left lateral) to facilitate even distribution of the surfactant. Results for the major efficacy parameters evaluated at 28 days or to discharge (incidence of air leaks, death due to respiratory causes or to any cause, BPD, or treatment failure) for all treated patients from this treatment trial were not significantly different between Calfactant and Survanta®.
- Prophylaxis Trial
- A total of 457 infants less than or equal to 30 weeks gestation and less than 1251 grams birth weight were enrolled into a multiple-dose, randomized, double-blind trial comparing Calfactant (4 mL/kg of a formulation that contained 25 mg of phospholipids/mL rather than the 35 mg/mL in the marketed formulation) and Survanta® (4 mL/kg). The initial dose was administered within15 minutes of birth and repeat doses were allowed Greater than or equal to 6 hours following the previous treatment (for up to three doses before 96 hours of age) if the patient required Greater than or equal to 30% oxygen. The surfactant was given through a 5 French feeding catheter inserted into the endotracheal tube. The total dose was instilled in four equal aliquots with the catheter removed between each of the instillations and mechanical ventilation resumed for 0.5 to 2 minutes. Each of the aliquots was administered with the patient in one of four different positions (prone, supine, right, and left lateral). Results for efficacy endpoints evaluated at 28 days or to discharge for all treated patients from this prophylaxis trial showed an increase in mortality from any cause at 28 days (p=0.03) and in death due to respiratory causes (p=0.005) in Calfactant-treated infants. For evaluable patients (patients who met the protocol-defined entry criteria), mortality from any cause and mortality due to respiratory causes were also higher in the Calfactant group (p = 0.07 and 0.03, respectively). However, these observations have not been replicated in other adequate and well-controlled trials and their relevance to the intended population is unknown. All other efficacy outcomes (incidence of RDS, air leaks, BPD, and treatment failure) were not significantly different between Calfactant and Survanta® when analyzed for all treated patients and for evaluable patients.
- Acute Clinical Effects: As with other surfactants, marked improvements in oxygenation and lung compliance may occur shortly after the administration of Calfactant. All controlled clinical trials with Calfactant demonstrated significant improvements in fraction of inspired oxygen (FiO2) and mean airway pressure (MAP) during the first 24 to 48 hours following initiation of Calfactant therapy.
# How Supplied
- Calfactant Intratracheal Suspension is supplied sterile in single-use, rubber-stoppered glass vials containing 3 mL (NDC 61938-456-03) and 6 mL (NDC 61938-456-06) off-white suspension.
## Storage
- Store Calfactant (calfactant) Intratracheal Suspension at refrigerated temperature 2° to 8°C (36° to 46°F) and protect from light. THE 3mL VIAL MUST BE STORED UPRIGHT. Vials are for single use only. After opening, discard unused drug.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Calfactant in the drug label.
# Precautions with Alcohol
- Alcohol-Calfactant interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Calfactant
# Look-Alike Drug Names
There is limited information regarding Calfactant Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Calfactant
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aparna Vuppala, M.B.B.S. [2]
# Disclaimer
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# Overview
Calfactant is a Lung Surfactant that is FDA approved for the prevention of of respiratory distress syndrome(RDS) in premature infants at high risk for RDS and for the treatment (“rescue”) of premature infants who develop RDS. Common adverse reactions include cyanosis, airway obstruction, bradycardia, reflux of surfactant into the endotracheal tube, requirement for manual ventilation, and reintubation.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Calfactant is indicated for the prevention of Respiratory Distress Syndrome (RDS) in premature infants at high risk for RDS and for the treatment (“rescue”) of premature infants who develop RDS. Calfactant decreases the incidence of RDS, mortality due to RDS, and air leaks associated with RDS.
- Prophylaxis therapy at birth with Calfactant is indicated for premature infants less than 29 weeks of gestational age at significant risk for RDS. Calfactant prophylaxis should be administered as soon as possible, preferably within 30 minutes after birth.
- Calfactant therapy is indicated for infants less than or equal to 72 hours of age with RDS (confirmed by clinical and radiologic findings) and requiring endotracheal intubation.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Calfactant in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Calfactant in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Calfactant in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Calfactant in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Calfactant in pediatric patients.
# Contraindications
None
# Warnings
- Calfactant is intended for intratracheal use only.
- THE ADMINISTRATION OF EXOGENOUS SURFACTANTS, INCLUDING Calfactant, OFTEN RAPIDLY IMPROVES OXY GENATION AND LUNG COMPLIANCE. Following administration of Calfactant, patients should be carefully monitored so that oxygen therapy and ventilatory support can be modified in response to changes in respiratory status. Calfactant therapy is not a substitute for neonatal intensive care. Optimal care of premature infants at risk for RDS and new born infants with RDS who need endotracheal intubation requires an acute care unit organized, staffed, equipped, and experienced with intubation, ventilator management, and general care of these patients.
- TRANSIENT EPISODES OF REFLUX OF Calfactant INTO THE ENDOTRACHEAL TUBE, CYANOSIS, BRADYCARDIA, OR AIRWAY OBSTRUCTION HAVE OCCURRED DURING THE DOSING PROCEDURES. These events require stopping Calfactant administration and taking appropriate measures to alleviate the condition. After the patient is stable, dosing can proceed with appropriate monitoring.
### Precautions
- DescriptionWhen repeat dosing was given at fixed 12-hour intervals in the Calfactant vs. Exosurf Neonatal® trials, transient episodes of cyanosis, bradycardia, reflux of surfactant into the endotracheal tube, and airway obstruction were observed more frequently among infants in the Calfactant-treated group.
- An increased proportion of patients with both intraventricular hemorrhage (IVH) and periventricular leukomalacia (PVL) was observed in Calfactant-treated infants in the Calfactant-Exosurf Neonatal® controlled trials. These observations were not associated with increased mortality.
- No data are available on the use of Calfactant in conjunction with experimental therapies of RDS, e.g., high-frequency ventilation. Data from controlled trials on the efficacy of Calfactant are limited to doses of approximately 100 mg phospholipid/kg body weight and up to a total of 4 doses.
# Adverse Reactions
## Clinical Trials Experience
- The most common adverse reactions associated with Calfactant dosing procedures in the controlled trials were cyanosis (65%), airway obstruction (39%), bradycardia (34%), reflux of surfactant into the endotracheal tube (21%), requirement for manual ventilation (16%), and reintubation (3%). These events were generally transient and not associated with serious complications or death. The incidence of common complications of prematurity and RDS in the four controlled Calfactant trials are presented in Table3.Prophylaxis and treatment study results for each surfactant are combined.
- Follow-up Evaluations
- Two-year follow-up data of neurodevelopmental outcomes in 415 infants enrolled in 5 centers that participated in the Calfactant vs Exosurf Neonatal® controlled trials demonstrated significant developmental delays in equal percentages of Calfactant and Exosurf Neonatal® patients.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Calfactant in the drug label.
# Drug Interactions
There is limited information regarding Calfactant Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Calfactant in women who are pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Calfactant in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Calfactant during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Calfactant with respect to nursing mothers.
### Pediatric Use
There is no FDA guidance on the use of Calfactant with respect to pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of Calfactant with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Calfactant with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Calfactant with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Calfactant in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Calfactant in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Calfactant in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Calfactant in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intrathecal
### Monitoring
There is limited information regarding Monitoring of Calfactant in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Calfactant in the drug label.
# Overdosage
- There have been no reports of overdosage with Calfactant. While there are no known adverse effects of excess lung surfactant, overdosage would result in overloading the lungs with an isotonic solution. Ventilation should be supported until clearance of the liquid is accomplished.
# Pharmacology
There is limited information regarding Calfactant Pharmacology in the drug label.
## Mechanism of Action
- Endogenous lung surfactant is essential for effective ventilation because it modifies alveolar surface tension thereby stabilizing the alveoli. Lung surfactant deficiency is the cause of Respiratory Distress Syndrome (RDS) in premature infants. Calfactant restores surface activity to the lungs of these infants.
## Structure
- Calfactant® (calfactant) Intratracheal Suspension is a sterile, non-pyrogenic lung surfactant intended for intratracheal instillation only. It is an extract of natural surfactant from calf lungs which includes phospholipids, neutral lipids, and hydrophobic surfactant-associated proteins B and C (SP-B and SP-C). It contains no preservatives.
- Calfactant is an off-white suspension of calfactant in 0.9% aqueous sodium chloride solution. It has a pH of 5.0 - 6.2 (target pH 5.7). Each milliliter of Calfactant contains 35 mg total phospholipids (including 26 mg phosphatidylcholine of which 16 mg is disaturated phosphatidylcholine) and 0.7 mg proteins including 0.26 mg of SP-B.
## Pharmacodynamics
- Calfactant adsorbs rapidly to the surface of the air:liquid interface and modifies surface tension similarly to natural lung surfactant. A minimum surface tension of less than or equal to 3 mN/m is produced in vitro by Calfactant as measured on a pulsating bubble surfactometer. Ex vivo, Calfactant restores the pressure volume mechanics and compliance of surfactant-deficient rat lungs. In vivo, Calfactant improves lung compliance, respiratory gas exchange, and survival in preterm lambs with profound surfactant deficiency
## Pharmacokinetics
- Animal Metabolism: Calfactant is administered directly to the lung lumen surface, its site of action. No human studies of absorption, biotransformation, or excretion of Calfactant have been performed. The administration of Calfactant with radiolabeled phospholipids into the lungs of adult rabbits results in the persistence of 50% of radioactivity in the lung alveolar lining and25% of radioactivity in the lung tissue 24 hours later. Less than 5% of the radioactivity is found in other organs. In premature lambs with lethal surfactant deficiency, less than 30% of instilled Calfactant is present in the lung lining after 24 hours.
## Nonclinical Toxicology
- Carcinogenesis studies and animal reproduction studies have not been performed with Calfactant. A single mutagenicity study (Ames assay) was negative.
# Clinical Studies
- Clinical Studies: The efficacy of Calfactant was demonstrated in two multiple-dose controlled clinical trials involving approximately 2,000 infants treated with Calfactant (approximately 100 mg phospholipid/kg) or Exosurf Neonatal®. In addition, two controlled trials of Calfactant versus Survanta®, and four uncontrolled trials were conducted that involved approximately 15,500 patients treated with Calfactant.
- Treatment Trial
- A total of 1,126 infants less than or equal to 72 hours of age with RDS who required endotracheal intubation and had an a/A PO2 less than 0.22 were enrolled into a multiple-dose, randomized, double-blind treatment trial comparing Calfactant (3 mL/kg) and Exosurf Neonatal® (5 mL/kg). Patients were given an initial dose and one repeat dose 12 hours later if intubation was still required. The dose was instilled in two aliquots through a side port adapter into the proximal end of the endotracheal tube. Each aliquot was given in small bursts over 20-30 inspiratory cycles. After each aliquot was instilled, the infant was positioned with either the right or the left side dependent. Results for efficacy parameters evaluated at 28 days or to discharge for all treated patients from this treatment trial are shown in Table 1.
- Prophylaxis Trial
- A total of 853 infants less than 29 weeks gestation were enrolled into a multiple-dose, randomized, double-blind prophylaxis trial comparing Calfactant (3 mL/kg) and Exosurf Neonatal® (5 mL/kg). The initial dose was administered within 30 minutes of birth. Repeat doses were administered at 12 and 24 hours if the patient remained intubated. Each dose was administered divided in 2 equal aliquots, and given through a side port adapter into the proximal end of the endotra cheal tube. Each aliquot was given in small bursts over 20-30 inspiratory cycles. After each aliquot was instilled, the infant was positioned with either the right or the left side dependent. Results for efficacy parameters evaluated to day 28 or to discharge for all treated patients from this prophylaxis trial are shown in Table 2.
- Treatment Trial
- A total of 662 infants with RDS who required endotracheal intubation and had an a/A PO2 less than 0.22 were enrolled into a multiple-dose, randomized, double-blind treatment trial comparing Calfactant (4 mL/kg of a formulation that contained 25 mg of phospholipids/mL rather than the 35 mg/mL in the marketed formulation) and Survanta® (4 mL/kg). Repeat doses were allowed Greater than or equal to 6 hours following the previous treatment (for up to three doses before 96 hours of age) if the patient required Greater than or equal to 30% oxygen. The surfactant was given through a 5 French feeding catheter inserted into the endo tracheal tube. The total dose was instilled in four equal aliquots with the catheter removed between each of the instillations and mechanical ventilation resumed for 0.5 to 2 minutes. Each of the aliquots was administered with the patient in one of four different positions (prone, supine, right, and left lateral) to facilitate even distribution of the surfactant. Results for the major efficacy parameters evaluated at 28 days or to discharge (incidence of air leaks, death due to respiratory causes or to any cause, BPD, or treatment failure) for all treated patients from this treatment trial were not significantly different between Calfactant and Survanta®.
- Prophylaxis Trial
- A total of 457 infants less than or equal to 30 weeks gestation and less than 1251 grams birth weight were enrolled into a multiple-dose, randomized, double-blind trial comparing Calfactant (4 mL/kg of a formulation that contained 25 mg of phospholipids/mL rather than the 35 mg/mL in the marketed formulation) and Survanta® (4 mL/kg). The initial dose was administered within15 minutes of birth and repeat doses were allowed Greater than or equal to 6 hours following the previous treatment (for up to three doses before 96 hours of age) if the patient required Greater than or equal to 30% oxygen. The surfactant was given through a 5 French feeding catheter inserted into the endotracheal tube. The total dose was instilled in four equal aliquots with the catheter removed between each of the instillations and mechanical ventilation resumed for 0.5 to 2 minutes. Each of the aliquots was administered with the patient in one of four different positions (prone, supine, right, and left lateral). Results for efficacy endpoints evaluated at 28 days or to discharge for all treated patients from this prophylaxis trial showed an increase in mortality from any cause at 28 days (p=0.03) and in death due to respiratory causes (p=0.005) in Calfactant-treated infants. For evaluable patients (patients who met the protocol-defined entry criteria), mortality from any cause and mortality due to respiratory causes were also higher in the Calfactant group (p = 0.07 and 0.03, respectively). However, these observations have not been replicated in other adequate and well-controlled trials and their relevance to the intended population is unknown. All other efficacy outcomes (incidence of RDS, air leaks, BPD, and treatment failure) were not significantly different between Calfactant and Survanta® when analyzed for all treated patients and for evaluable patients.
- Acute Clinical Effects: As with other surfactants, marked improvements in oxygenation and lung compliance may occur shortly after the administration of Calfactant. All controlled clinical trials with Calfactant demonstrated significant improvements in fraction of inspired oxygen (FiO2) and mean airway pressure (MAP) during the first 24 to 48 hours following initiation of Calfactant therapy.
# How Supplied
- Calfactant Intratracheal Suspension is supplied sterile in single-use, rubber-stoppered glass vials containing 3 mL (NDC 61938-456-03) and 6 mL (NDC 61938-456-06) off-white suspension.
## Storage
- Store Calfactant (calfactant) Intratracheal Suspension at refrigerated temperature 2° to 8°C (36° to 46°F) and protect from light. THE 3mL VIAL MUST BE STORED UPRIGHT. Vials are for single use only. After opening, discard unused drug.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Calfactant in the drug label.
# Precautions with Alcohol
- Alcohol-Calfactant interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Calfactant
# Look-Alike Drug Names
There is limited information regarding Calfactant Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Calfactant | |
9078f0cd021e5cde93ea706d7aa8a6cf258f0736 | wikidoc | Calixarene | Calixarene
# Overview
A calixarene is a macrocycle or cyclic oligomer based on a hydroxyalkylation product of a phenol and an aldehyde . The word calixarene is derived from calix or chalice because this type of molecule resembles a vase and from the word arene that refers to the aromatic building block. Calixarenes have hydrophobic cavities that can hold smaller molecules or ions and belong to the class of cavitands known in Host-guest chemistry. Calixarene nomenclature is straightforward and involves counting the number of repeating units in the ring and include it in the name. A calixarene has 4 units in the ring and a calixarene has 6. A substituent in the meso position Rb is added to the name with a prefix C- as in C-methylcalixarene.
# Synthesis
The aromatic components are derived from phenol, resorcinol or pyrogallol, For phenol, the aldehyde most often used is simply formaldehyde, while larger aldehydes (acetaldehyde, or larger) are generally required in condensation reactions with resorcinol and pyrogallol. The chemical reaction ranks under electrophilic aromatic substitutions followed by an elimination of water and then a second aromatic substitution. The reaction is acid catalysed or base catalysed. Calixarenes are difficult to produce because it is all too easy to end up with complex mixtures of linear and cyclic oligomers with different numbers of repeating units. With finely tuned starting materials and reaction conditions synthesis can also be surprisingly easy. In 2005, research produced a pyrogallolarene by simply mixing a solvent-free dispersion of isovaleraldehyde with pyrogallol and a catalytic amount of p-toluenesulfonic acid in a mortar and pestle . Calixarenes as parent compounds are sparingly soluble and are high melting crystalline solids .
# Structure
Calixarenes are characterised by a three-dimensional basket, cup or bucket shape. In calixarenes the internal volume is around 10 cubic nanometers. Calixarenes are characterised by a wide upper rim and a narrow lower rim and a central annulus. With phenol as a starting material the 4 hydroxyl groups are intrannular on the lower rim. In a resorcinarene 8 hydroxyl groups are placed extraannular on the upper ring. Calixarenes exist in different chemical conformations because rotation around the methylene bridge is not difficult. In calixarene 4 up-down conformations exist: cone ( point group C2v,C4v), partial cone Cs, 1,2 alternate C2h and 1,3 alternate D2d. The 4 hydroxyl groups interact by hydrogen bonding and stabilize the cone conformation. This conformation is in dymamic equilibrium with the other conformations. Conformations can be locked in place with proper substituents replacing the hydroxyl groups which increase the rotational barrier. Alternatively placing a bulky substituent on the upper rim also locks a conformation. The calixarene based on p-tert-butyl phenol is also a cone .
# History
Adolf von Baeyer pioneered the chemistry of calixarenes although he was unable to determine its structure and did not realise its potential (he was pursuing dyes). In 1872 he mixed benzaldehyde with pyrogallol and a strong acid and noted a red-brown resin with a marked viscosity increase. He also used resorcinol and formaldehyde which he had to prepare from iodoform himself because a commercial grade of formaldehyde at that time had not been realised yet. In 1894 the Lederer-Manasse hydroxyalkylation was invented as a synthetic tool for the preparation of hydroxylmethyl phenols, bringing calixarenes one step closer. In 1902 Leo Baekeland made phenol formaldehyde resins a commercial success under the trade name Bakelite. In these resins phenol and formaldehyde are exhaustively condensed with each other to form heavily cross-linked polymers. The first attempt to control the reaction was made by Alois Zinke and Erich Ziegler in 1942. They employed para substituted phenols which inhibits crosslinking and should result in a linear polymer with formaldehyde. So in 1944 p-tert-butyl phenol with formaldehyde and sodium hydroxide in linseed oil as a solvent produced for the first time a crystalline solid with a high melting point rather than a resin. In the same year another duo by the names of Niederl and Vogel did something similar with a para substituted resorcinol and they were the first to postulate a cyclic tetramer. In these days structure elucidation was limited to determination of molar mass by freezing-point depression and functional group analysis.
John Cornforth was in 1955 the first to realize the potential of calixarenes as a basket analogue to enzymes and repeated the work done by Zinke. He obtained a mixture of products and elicited the services of Dorothy Crowfoot Hodgkin for structure elucidation by X-ray crystallography but with limited success. First commercial success came to calixarenes in the nineteen fifties when the company Petrolite started a range of calixarene products as demulsifiers user in the oil industry.
The word calixarene was coined by David Gutsche in 1975 who was also interested in this type of compound as biomimetic, since the molecule resembled the calyx krater vases of ancient Greece. It was by then established that unmodified calixarenes exhibit extensive conformational mobility so that the basket was not much of a basket after all. Donald J. Cram fixed this shortcoming by inventing a way of immobilizing calixarenes. He was able to freeze in a conformation by so called lower rim functionalization, replacing the hydroxyl groups by larger substituents. The acetate calixarene fixates the molecule as a partial cone, whereas the carbonate ester yields the full cone.
# Host guest interactions
Calixarenes are efficient sodium ionophores and are applied as such in chemical sensors. With the right chemistry these molecules exhibit great selectivity towards other cations. Calixarenes are used in commercial applications as sodium selective electrodes for the measurement of sodium levels in blood. Calixarenes also form complexes with cadmium, lead, lanthanides and actinides. Calixarene and the C70 fullerene in p-xylene form a ball-and-socket supramolecular complex. calixarenes also form exo-calix ammonium salts with aliphatic amines such as piperidine.
See Host-guest chemistry.
# Molecular self-assembly
Molecular self-assembly of resorcinarenes and pyrogallolarenes lead to larger supramolecular assemblies . Both in the crystalline state and in solution, they are known to form hexamers that are akin to certain Archimedean solids with an internal volume of around one cubic nanometer (nanocapsules). (Isobutylpyrogallolarene)6 is held together by 48 intermolecular hydrogen bonds. The remaining 24 hydrogen bonds are intramolecular. The cavity is filled by a number of solvent molecules.
# Applications
Calixarenes are applied in enzyme mimetics, ion sensitive electrodes or sensors, selective membrames, non-linear optics and in HPLC stationary phase . In addition, in nanotechnology calixarenes are used as negative resist for high-resolution electron beam lithography .
A tetrathiaarene is found to mimic aquaporin proteins . This calixarene adopts a 1,3-alternate conformation (methoxy groups populate the lower ring) and water is not contained in the basket but grabbed by two opposing tert-butyl groups on the outer rim in a pincer. The nonporous and hydrophobic crystals are soaked in water for 8 hours in which time the calixarene:water ratio nevertheless acquires the value of one.
Calixarenes are able to accelerate reactions taking place inside the concavity by a combination of local concentration effect and polar stabilization of the transition state. An extended resorcinarene cavitand is found to accelerate the reaction rate of a Menshutkin reaction between quinuclidine and butylbromide by a factor of 1600 .
In heterocalixarenes the phenolic units are replaced by heterocycles , for instance by furans in calixfuranes and by pyridines in calixpyridines. Calixarenes have been used as the macrocycle portion of a rotaxane and two calixarene molecules covalently joined together by the lower rims form carcerands. | Calixarene
Editor-In-Chief: Henry A. Hoff
# Overview
A calixarene is a macrocycle or cyclic oligomer based on a hydroxyalkylation product of a phenol and an aldehyde [1]. The word calixarene is derived from calix or chalice because this type of molecule resembles a vase and from the word arene that refers to the aromatic building block. Calixarenes have hydrophobic cavities that can hold smaller molecules or ions and belong to the class of cavitands known in Host-guest chemistry. Calixarene nomenclature is straightforward and involves counting the number of repeating units in the ring and include it in the name. A calix[4]arene has 4 units in the ring and a calix[6]arene has 6. A substituent in the meso position Rb is added to the name with a prefix C- as in C-methylcalix[6]arene.
# Synthesis
The aromatic components are derived from phenol, resorcinol or pyrogallol, For phenol, the aldehyde most often used is simply formaldehyde, while larger aldehydes (acetaldehyde, or larger) are generally required in condensation reactions with resorcinol and pyrogallol. The chemical reaction ranks under electrophilic aromatic substitutions followed by an elimination of water and then a second aromatic substitution. The reaction is acid catalysed or base catalysed. Calixarenes are difficult to produce because it is all too easy to end up with complex mixtures of linear and cyclic oligomers with different numbers of repeating units. With finely tuned starting materials and reaction conditions synthesis can also be surprisingly easy. In 2005, research produced a pyrogallol[4]arene by simply mixing a solvent-free dispersion of isovaleraldehyde with pyrogallol and a catalytic amount of p-toluenesulfonic acid in a mortar and pestle [2]. Calixarenes as parent compounds are sparingly soluble and are high melting crystalline solids [3].
# Structure
Calixarenes are characterised by a three-dimensional basket, cup or bucket shape. In calix[4]arenes the internal volume is around 10 cubic nanometers. Calixarenes are characterised by a wide upper rim and a narrow lower rim and a central annulus. With phenol as a starting material the 4 hydroxyl groups are intrannular on the lower rim. In a resorcin[4]arene 8 hydroxyl groups are placed extraannular on the upper ring. Calixarenes exist in different chemical conformations because rotation around the methylene bridge is not difficult. In calix[4]arene 4 up-down conformations exist: cone ( point group C2v,C4v), partial cone Cs, 1,2 alternate C2h and 1,3 alternate D2d. The 4 hydroxyl groups interact by hydrogen bonding and stabilize the cone conformation. This conformation is in dymamic equilibrium with the other conformations. Conformations can be locked in place with proper substituents replacing the hydroxyl groups which increase the rotational barrier. Alternatively placing a bulky substituent on the upper rim also locks a conformation. The calixarene based on p-tert-butyl phenol is also a cone [1].
# History
Adolf von Baeyer pioneered the chemistry of calixarenes although he was unable to determine its structure and did not realise its potential (he was pursuing dyes). In 1872 he mixed benzaldehyde with pyrogallol and a strong acid and noted a red-brown resin with a marked viscosity increase. He also used resorcinol and formaldehyde which he had to prepare from iodoform himself because a commercial grade of formaldehyde at that time had not been realised yet. In 1894 the Lederer-Manasse hydroxyalkylation was invented as a synthetic tool for the preparation of hydroxylmethyl phenols, bringing calixarenes one step closer. In 1902 Leo Baekeland made phenol formaldehyde resins a commercial success under the trade name Bakelite. In these resins phenol and formaldehyde are exhaustively condensed with each other to form heavily cross-linked polymers. The first attempt to control the reaction was made by Alois Zinke and Erich Ziegler in 1942. They employed para substituted phenols which inhibits crosslinking and should result in a linear polymer with formaldehyde. So in 1944 p-tert-butyl phenol with formaldehyde and sodium hydroxide in linseed oil as a solvent produced for the first time a crystalline solid with a high melting point rather than a resin. In the same year another duo by the names of Niederl and Vogel did something similar with a para substituted resorcinol and they were the first to postulate a cyclic tetramer. In these days structure elucidation was limited to determination of molar mass by freezing-point depression and functional group analysis.
John Cornforth was in 1955 the first to realize the potential of calixarenes as a basket analogue to enzymes and repeated the work done by Zinke. He obtained a mixture of products and elicited the services of Dorothy Crowfoot Hodgkin for structure elucidation by X-ray crystallography but with limited success. First commercial success came to calixarenes in the nineteen fifties when the company Petrolite started a range of calixarene products as demulsifiers user in the oil industry.
The word calixarene was coined by David Gutsche [2] in 1975 who was also interested in this type of compound as biomimetic, since the molecule resembled the calyx krater vases of ancient Greece. It was by then established that unmodified calixarenes exhibit extensive conformational mobility so that the basket was not much of a basket after all. Donald J. Cram fixed this shortcoming by inventing a way of immobilizing calixarenes. He was able to freeze in a conformation by so called lower rim functionalization, replacing the hydroxyl groups by larger substituents. The acetate calixarene fixates the molecule as a partial cone, whereas the carbonate ester yields the full cone.
# Host guest interactions
Calixarenes are efficient sodium ionophores and are applied as such in chemical sensors. With the right chemistry these molecules exhibit great selectivity towards other cations. Calixarenes are used in commercial applications as sodium selective electrodes for the measurement of sodium levels in blood. Calixarenes also form complexes with cadmium, lead, lanthanides and actinides. [3] Calix[5]arene and the C70 fullerene in p-xylene form a ball-and-socket supramolecular complex. [4] calixarenes also form exo-calix ammonium salts with aliphatic amines such as piperidine. [4]
See Host-guest chemistry.
# Molecular self-assembly
Molecular self-assembly of resorcinarenes and pyrogallolarenes lead to larger supramolecular assemblies [5]. Both in the crystalline state and in solution, they are known to form hexamers that are akin to certain Archimedean solids with an internal volume of around one cubic nanometer (nanocapsules). (Isobutylpyrogallol[4]arene)6 is held together by 48 intermolecular hydrogen bonds. The remaining 24 hydrogen bonds are intramolecular. The cavity is filled by a number of solvent molecules. [5]
# Applications
Calixarenes are applied in enzyme mimetics, ion sensitive electrodes or sensors, selective membrames, non-linear optics [6] and in HPLC stationary phase [7]. In addition, in nanotechnology calixarenes are used as negative resist for high-resolution electron beam lithography [8].
A tetrathia[4]arene is found to mimic aquaporin proteins [6]. This calixarene adopts a 1,3-alternate conformation (methoxy groups populate the lower ring) and water is not contained in the basket but grabbed by two opposing tert-butyl groups on the outer rim in a pincer. The nonporous and hydrophobic crystals are soaked in water for 8 hours in which time the calixarene:water ratio nevertheless acquires the value of one.
Calixarenes are able to accelerate reactions taking place inside the concavity by a combination of local concentration effect and polar stabilization of the transition state. An extended resorcin[4]arene cavitand is found to accelerate the reaction rate of a Menshutkin reaction between quinuclidine and butylbromide by a factor of 1600 [7].
In heterocalixarenes the phenolic units are replaced by heterocycles [8], for instance by furans in calix[n]furanes and by pyridines in calix[n]pyridines. Calixarenes have been used as the macrocycle portion of a rotaxane and two calixarene molecules covalently joined together by the lower rims form carcerands. | https://www.wikidoc.org/index.php/Calixarene | |
904ed8e23174150fa739706699e3d26ff78790df | wikidoc | Calmodulin | Calmodulin
# Overview
Calmodulin (CaM) (an abbreviation for CALcium MODULated proteIN) is a calcium-binding protein expressed in all eukaryotic cells. It can bind to and regulate a number of different protein targets, thereby affecting many different cellular functions.
# Function
CaM mediates processes such as inflammation, metabolism, apoptosis, muscle contraction, intracellular movement, short-term and long-term memory, nerve growth and the immune response. CaM is expressed in many cell types and can have different subcellular locations, including the cytoplasm, within organelles, or associated with the plasma or organelle membranes. Many of the proteins that CaM binds are unable to bind calcium themselves, and as such use CaM as a calcium sensor and signal transducer. CaM can also make use of the calcium stores in the endoplasmic reticulum, and the sarcoplasmic reticulum. CaM undergoes a conformational change upon binding to calcium, which enables it to bind to specific proteins for a specific response. CaM can bind up to four calcium ions, and can undergo post-translational modifications, such as phosphorylation, acetylation, methylation and proteolytic cleavage, each of which can potentially modulate its actions. Calmodulin can also bind to edema factor toxin from the anthrax bacteria.
# Structure
Calmodulin is a small, acidic protein approximately 148 amino acids long (16706 Dalton) and, as such, is a favorite for testing protein simulation software. It contains four EF-hand "motifs", each of which binds a Ca2+ ion. The protein has two approximately symmetrical domains, separated by a flexible "hinge" region.
# Mechanism
Calcium is bound via the use of the EF hand motif, which supplies an electronegative environment for ion coordination. After calcium binding, hydrophobic methyl groups from methionine residues become exposed on the protein via conformational change. This presents hydrophobic surfaces, which can in turn bind to Basic Amphiphilic Helices (BAA helices) on the target protein. These helices contain complementary hydrophobic regions. The flexibilily of Calmodulin's hinged region allows the molecule to "wrap around" its target. This property allows it to tightly bind to a wide range of different target proteins.
# Family members
- Calmodulin 1 (CALM1)
- Calmodulin 2 (CALM2)
- Calmodulin 3 (CALM3)
- Calmodulin-like 1 (CALML1)
- Calmodulin-like 3 (CALML3)
- Calmodulin-like 4 (CALML4)
- Calmodulin-like 5 (CALML5)
- Calmodulin-like 6 (CALML6)
# Other calcium-binding proteins
Calmodulin belongs to one of the two main groups of calcium-binding proteins, called EF hand proteins. The other group, called annexins, bind calcium and phospholipid (e.g., lipocortin). Many other proteins bind calcium, although binding calcium may not be considered their principal function in the cell. | Calmodulin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Calmodulin (CaM) (an abbreviation for CALcium MODULated proteIN) is a calcium-binding protein expressed in all eukaryotic cells. It can bind to and regulate a number of different protein targets, thereby affecting many different cellular functions.[1][2]
# Function
CaM mediates processes such as inflammation, metabolism, apoptosis, muscle contraction, intracellular movement, short-term and long-term memory, nerve growth and the immune response. CaM is expressed in many cell types and can have different subcellular locations, including the cytoplasm, within organelles, or associated with the plasma or organelle membranes. Many of the proteins that CaM binds are unable to bind calcium themselves, and as such use CaM as a calcium sensor and signal transducer. CaM can also make use of the calcium stores in the endoplasmic reticulum, and the sarcoplasmic reticulum. CaM undergoes a conformational change upon binding to calcium, which enables it to bind to specific proteins for a specific response. CaM can bind up to four calcium ions, and can undergo post-translational modifications, such as phosphorylation, acetylation, methylation and proteolytic cleavage, each of which can potentially modulate its actions. Calmodulin can also bind to edema factor toxin from the anthrax bacteria.
# Structure
Calmodulin is a small, acidic protein approximately 148 amino acids long (16706 Dalton) and, as such, is a favorite for testing protein simulation software. It contains four EF-hand "motifs", each of which binds a Ca2+ ion. The protein has two approximately symmetrical domains, separated by a flexible "hinge" region.
# Mechanism
Calcium is bound via the use of the EF hand motif, which supplies an electronegative environment for ion coordination. After calcium binding, hydrophobic methyl groups from methionine residues become exposed on the protein via conformational change. This presents hydrophobic surfaces, which can in turn bind to Basic Amphiphilic Helices (BAA helices) on the target protein. These helices contain complementary hydrophobic regions. The flexibilily of Calmodulin's hinged region allows the molecule to "wrap around" its target. This property allows it to tightly bind to a wide range of different target proteins.
# Family members
- Calmodulin 1 (CALM1)
- Calmodulin 2 (CALM2)
- Calmodulin 3 (CALM3)
- Calmodulin-like 1 (CALML1)
- Calmodulin-like 3 (CALML3)
- Calmodulin-like 4 (CALML4)
- Calmodulin-like 5 (CALML5)
- Calmodulin-like 6 (CALML6)
# Other calcium-binding proteins
Calmodulin belongs to one of the two main groups of calcium-binding proteins, called EF hand proteins. The other group, called annexins, bind calcium and phospholipid (e.g., lipocortin). Many other proteins bind calcium, although binding calcium may not be considered their principal function in the cell. | https://www.wikidoc.org/index.php/Calmodulin | |
48b83e27c61b04060028f62e328c4a4a54c6968a | wikidoc | Calponin 1 | Calponin 1
Calponin 1 is a basic smooth muscle protein that in humans is encoded by the CNN1 gene.
The CNN1 gene is located at 19p13.2-p13.1 in the human chromosomal genome and contains 7 exons, encoding the protein calponin 1, an actin filament-associated regulatory protein. Human calponin 1 is a 33.2-KDa protein consists of 297 amino acids with an isoelectric point of 9.1, thus calponin 1 is also known as basic calponin.
# Evolution
Three homologous genes, Cnn1, Cnn2 and Cnn3, have evolved in vertebrates, encoding three isoforms of calponin: calponin 1, calponin 2, calponin 3, respectively. Protein sequence alignment shows that calponin 1 is highly conserved in mammals but more diverged among lower vertebrates.
# Smooth muscle-specific expression
The expression of CNN1 is specific to differentiated mature smooth muscle cells, suggesting a role in contractile functions. Calponin 1 is up-regulated in smooth muscle tissues during postnatal development with a higher content in phasic smooth muscle of the digestive tract.
# Structure-function relationship
The majority of structure-function relationship studies of calponin were with experiments using chicken calponin 1. Primary structure of calponin consists of a conserved N-terminal calponin homology (CH) domain, a conserved middle region containing two actin-binding sites, and a C-terminal variable region that contributes to the differences among there isoforms.
## The CH domain
The CH domain was found in a number of actin-binding proteins (such as α-actinin, spectrin, and filamin) to form the actin-binding region or serve as a regulatory structure. However, the CH domain in calponin is not the binding site for actin nor does it regulate the modes of calponin-F-actin binding. Nonetheless, CH domain in calponin was found to bind to extra-cellular regulated kinase (ERK) for calponin to play a possible role as an adaptor protein in the ERK signaling cascades.
## Actin-binding sites
Calponin binds actin to promote and sustain polymerization. The binding of calponin to F-actin inhibits the MgATPase activity of smooth muscle myosin. Calponin binds F-actin through two sites at residues 144-162 and 171-188 in chicken calponin 1. The two actin-binding sites are conserved in the three calponin isoforms.
There are three repeating sequence motifs in calponin next to the C-terminal region. This repeating structure is conserved in all three isoforms and across species. Outlined in Fig. 2, the first repeating motif overlaps with the second actin-binding site and contains protein kinase C (PKC) phosphorylation sites Ser175 and Thr184 that are not present in the first actin-binding site. This feature is consistent with the hypothesis that the second actin-binding site plays a regulatory role in the binding of calponin to the actin filament. Similar sequences as well as potential phosphorylation sites are present in repeats 2 and 3 whereas their function is unknown.
## C-terminal variable region
The C-terminal segment of calponin has diverged significantly among the three isoforms. The variable lengths and amino acid sequences of the C-terminal segment produce the size and charge differences among the calponin isoforms. The corresponding charge features rendered calponin 1, 2 and 3 the names of basic, neutral and acidic calponins.
The C-terminal segment of calponin has an effect on weakening the binding of calponin to F-actin. Deletion of the C-terminal tail strongly enhanced the actin-binding and bundling activities of all three isoforms of calponin. The C-terminal tail regulates the interaction with F-actin by altering the function of the second actin-bing site of calponin.
# Regulation of smooth muscle contractility
Numerous in vitro experimental data indicate that calponin 1 functions as an inhibitory regulator of smooth muscle contractility through inhibiting actomyosin interactions. In this regulation, binding of Ca2+-calmodulin and PKC phosphorylation dissociate calponin 1 from the actin filament and facilitate smooth muscle contraction.
In vivo data also support the role of calponin 1 as regulator of smooth muscle contractility. While aortic smooth muscle of adult Wistar Kyoto rats, which naturally lacks calponin 1, is fully contractile, it has a decreased sensitivity to norepinephrine activation. Matrix metalloproteinase-2 proteolysis of calponin 1 resulted in vascular hypocontractility to phenylephrine. Vas deferens smooth muscle from calponin 1 knockout mice showed faster maximum shortening velocity. Calponin 1 knockout mice exhibited blunted MAP response to phenylephrine administration.
# Phosphorylation regulation
There is a large collection of in vitro evidences demonstrating the phosphorylation regulation of calponin. The primary phosphorylation sites are Ser175 and Thr184 in the second actin-binding site (Fig. 2). Experimental data showed that Ser175 and Thr184 in calponin 1 are phosphorylated by PKC in vitro. Direct association was found between calponin 1 and PKCα and PKCε. Calmodulin-dependent kinase II and Rho-kinase are also found to phosphorylate calponin at Ser175 and Thr184 in vitro. Of these two residues, the main site of regulatory phosphorylation by calmodulin-dependent kinase II and Rho-kinase is Ser175. Dephosphorylation of calponin is catalyzed by type 2B protein phosphatase
Unphosphorylated calponin binds to actin and inhibits actomyosin MgATPase. Ser175 phosphorylation alters the molecular conformation of calponin and dissociates calponin from F-actin. The consequence is to release the inhibition of actomyosin MgATPase and increase the production of force.
Despite the overwhelming evidence for the phosphorylation regulation of calponin obtained from in vitro studies, phosphorylated calponin is not readily detectable in vivo or in living cells under physiological conditions. Based on the observation that PKC phosphorylation of calponin 1 weakens the binding affinity for the actin filaments, the phosphorylated calponin may not be stable in the actin cytoskeleton thus be degraded in the cell.
# Notes | Calponin 1
Calponin 1 is a basic smooth muscle protein that in humans is encoded by the CNN1 gene.[1]
The CNN1 gene is located at 19p13.2-p13.1 in the human chromosomal genome and contains 7 exons, encoding the protein calponin 1, an actin filament-associated regulatory protein.[2] Human calponin 1 is a 33.2-KDa protein consists of 297 amino acids with an isoelectric point of 9.1,[3] thus calponin 1 is also known as basic calponin.
# Evolution
Three homologous genes, Cnn1, Cnn2 and Cnn3, have evolved in vertebrates, encoding three isoforms of calponin: calponin 1,[3][4] calponin 2,[5] calponin 3,[6] respectively. Protein sequence alignment shows that calponin 1 is highly conserved in mammals but more diverged among lower vertebrates.
# Smooth muscle-specific expression
The expression of CNN1 is specific to differentiated mature smooth muscle cells, suggesting a role in contractile functions. Calponin 1 is up-regulated in smooth muscle tissues during postnatal development[7] with a higher content in phasic smooth muscle of the digestive tract.[8]
# Structure-function relationship
The majority of structure-function relationship studies of calponin were with experiments using chicken calponin 1. Primary structure of calponin consists of a conserved N-terminal calponin homology (CH) domain, a conserved middle region containing two actin-binding sites, and a C-terminal variable region that contributes to the differences among there isoforms.
## The CH domain
The CH domain was found in a number of actin-binding proteins (such as α-actinin, spectrin, and filamin) to form the actin-binding region or serve as a regulatory structure.[9] However, the CH domain in calponin is not the binding site for actin nor does it regulate the modes of calponin-F-actin binding.[10] Nonetheless, CH domain in calponin was found to bind to extra-cellular regulated kinase (ERK) for calponin to play a possible role as an adaptor protein in the ERK signaling cascades.[11]
## Actin-binding sites
Calponin binds actin to promote and sustain polymerization. The binding of calponin to F-actin inhibits the MgATPase activity of smooth muscle myosin.[12][13][12][14] Calponin binds F-actin through two sites at residues 144-162 and 171-188 in chicken calponin 1. The two actin-binding sites are conserved in the three calponin isoforms.
There are three repeating sequence motifs in calponin next to the C-terminal region. This repeating structure is conserved in all three isoforms and across species. Outlined in Fig. 2, the first repeating motif overlaps with the second actin-binding site and contains protein kinase C (PKC) phosphorylation sites Ser175 and Thr184 that are not present in the first actin-binding site. This feature is consistent with the hypothesis that the second actin-binding site plays a regulatory role in the binding of calponin to the actin filament. Similar sequences as well as potential phosphorylation sites are present in repeats 2 and 3 whereas their function is unknown.
## C-terminal variable region
The C-terminal segment of calponin has diverged significantly among the three isoforms. The variable lengths and amino acid sequences of the C-terminal segment produce the size and charge differences among the calponin isoforms. The corresponding charge features rendered calponin 1, 2 and 3 the names of basic, neutral and acidic calponins.[15][16][17]
The C-terminal segment of calponin has an effect on weakening the binding of calponin to F-actin. Deletion of the C-terminal tail strongly enhanced the actin-binding and bundling activities of all three isoforms of calponin.[18][19] The C-terminal tail regulates the interaction with F-actin by altering the function of the second actin-bing site of calponin.[20]
# Regulation of smooth muscle contractility
Numerous in vitro experimental data indicate that calponin 1 functions as an inhibitory regulator of smooth muscle contractility through inhibiting actomyosin interactions.[2][21][22] In this regulation, binding of Ca2+-calmodulin and PKC phosphorylation dissociate calponin 1 from the actin filament and facilitate smooth muscle contraction.[23]
In vivo data also support the role of calponin 1 as regulator of smooth muscle contractility. While aortic smooth muscle of adult Wistar Kyoto rats, which naturally lacks calponin 1, is fully contractile, it has a decreased sensitivity to norepinephrine activation.[24][25] Matrix metalloproteinase-2 proteolysis of calponin 1 resulted in vascular hypocontractility to phenylephrine.[26] Vas deferens smooth muscle from calponin 1 knockout mice showed faster maximum shortening velocity.[27] Calponin 1 knockout mice exhibited blunted MAP response to phenylephrine administration.[28]
# Phosphorylation regulation
There is a large collection of in vitro evidences demonstrating the phosphorylation regulation of calponin. The primary phosphorylation sites are Ser175 and Thr184 in the second actin-binding site (Fig. 2). Experimental data showed that Ser175 and Thr184 in calponin 1 are phosphorylated by PKC in vitro.[23] Direct association was found between calponin 1 and PKCα[29] and PKCε.[11] Calmodulin-dependent kinase II and Rho-kinase are also found to phosphorylate calponin at Ser175 and Thr184 in vitro.[30][31] Of these two residues, the main site of regulatory phosphorylation by calmodulin-dependent kinase II and Rho-kinase is Ser175. Dephosphorylation of calponin is catalyzed by type 2B protein phosphatase[32][33]
Unphosphorylated calponin binds to actin and inhibits actomyosin MgATPase. Ser175 phosphorylation alters the molecular conformation of calponin and dissociates calponin from F-actin.[34] The consequence is to release the inhibition of actomyosin MgATPase and increase the production of force.[14][35][36]
Despite the overwhelming evidence for the phosphorylation regulation of calponin obtained from in vitro studies, phosphorylated calponin is not readily detectable in vivo or in living cells under physiological conditions.[37][38] Based on the observation that PKC phosphorylation of calponin 1 weakens the binding affinity for the actin filaments,[34] the phosphorylated calponin may not be stable in the actin cytoskeleton thus be degraded in the cell.
# Notes | https://www.wikidoc.org/index.php/Calponin_1 | |
3cb1ee724868ef1d0eaf22457cb7cdf66e88fb7c | wikidoc | Calretinin | Calretinin
Calretinin also known as 29 kDa calbindin is a calcium-binding protein involved in calcium signaling. In humans, the calretinin protein is encoded by the CALB2 gene.
# Function
This gene encodes an intracellular calcium-binding protein belonging to the troponin C superfamily. Members of this protein family have six EF-hand domains which bind calcium. This protein plays a role in diverse cellular functions, including message targeting and intracellular calcium buffering.
Calretinin is abundantly expressed in neurons including retina (which gave it the name) and cortical interneurons. Expression was found in different neurons than that of the similar vitamin D-dependent calcium-binding protein, calbindin-28kDa.
Calretinin has an important role as a modulator of neuronal excitability including the induction of long-term potentiation. Loss of expression of calretinin in hippocampal interneurons has been suggested to be relevant in temporal lobe epilepsy.
It is expressed in a number of other locations including hair follicles.
# Clinical significance
Calretinin is a diagnostic marker for some human diseases, including Hirschsprung disease and some cancers.
## Mesothelioma
Using immunohistochemistry, calretinin can be demonstrated in both benign mesothelium and in malignant mesothelioma and can be used to help differentiate different lung tumours. Antibodies to calretinin can also be used to distinguish between different types of brain tumour, demonstrating only those with neuronal rather than glial, differentiation. Furthermore, the essential function of calretinin in mesothelioma cell lines has been demonstrated in vitro and may be an interesting target for therapeutical approaches.
## Hirschsprung disease
In Hirschsprung disease, calretinin immunohistochemistry offers additional diagnostic value in specimens with inadequate amount of submucosa and rarely seen ganglion cells. The presence of ganglion cells consistently correlated with calretinin-positive thin nerve fibrils in the lamina propria, muscularis mucosae and superficial submucosa. These calretinin-positive thin neurofibrils are absent in the aganglionic segments of bowel and in the areas without ganglion cells from the junction of normal with diseased rectum. Calretinin is strongly expressed in the submucosal and subserosal nerve trunks in the ganglionic segment. No calretinin expression is seen in the nerve trunks in the rest of the aganglionic segment. It has faint expression in the thick nerve trunks from the areas without ganglion cells. Faint positivity of the thick submucosal and subserosal nerves in the absence of ganglion cells and calretinin positive nerve fibrils, is characteristic of the junction of the aganglionic-to-normal rectum. | Calretinin
Calretinin also known as 29 kDa calbindin is a calcium-binding protein involved in calcium signaling.[1] In humans, the calretinin protein is encoded by the CALB2 gene.[2][3]
# Function
This gene encodes an intracellular calcium-binding protein belonging to the troponin C superfamily. Members of this protein family have six EF-hand domains which bind calcium. This protein plays a role in diverse cellular functions, including message targeting and intracellular calcium buffering.[2]
Calretinin is abundantly expressed in neurons including retina (which gave it the name)[1] and cortical interneurons.[4] Expression was found in different neurons than that of the similar vitamin D-dependent calcium-binding protein, calbindin-28kDa.[1]
Calretinin has an important role as a modulator of neuronal excitability including the induction of long-term potentiation.[5] Loss of expression of calretinin in hippocampal interneurons has been suggested to be relevant in temporal lobe epilepsy.[6]
It is expressed in a number of other locations including hair follicles.[7]
# Clinical significance
Calretinin is a diagnostic marker for some human diseases, including Hirschsprung disease and some cancers.
## Mesothelioma
Using immunohistochemistry, calretinin can be demonstrated in both benign mesothelium and in malignant mesothelioma[8][9] and can be used to help differentiate different lung tumours.[10] Antibodies to calretinin can also be used to distinguish between different types of brain tumour, demonstrating only those with neuronal rather than glial, differentiation.[11] Furthermore, the essential function of calretinin in mesothelioma cell lines has been demonstrated in vitro and may be an interesting target for therapeutical approaches.[12]
## Hirschsprung disease
In Hirschsprung disease, calretinin immunohistochemistry offers additional diagnostic value in specimens with inadequate amount of submucosa and rarely seen ganglion cells. The presence of ganglion cells consistently correlated with calretinin-positive thin nerve fibrils in the lamina propria, muscularis mucosae and superficial submucosa. These calretinin-positive thin neurofibrils are absent in the aganglionic segments of bowel and in the areas without ganglion cells from the junction of normal with diseased rectum. Calretinin is strongly expressed in the submucosal and subserosal nerve trunks in the ganglionic segment. No calretinin expression is seen in the nerve trunks in the rest of the aganglionic segment. It has faint expression in the thick nerve trunks from the areas without ganglion cells. Faint positivity of the thick submucosal and subserosal nerves in the absence of ganglion cells and calretinin positive nerve fibrils, is characteristic of the junction of the aganglionic-to-normal rectum.[13] | https://www.wikidoc.org/index.php/Calretinin | |
a748e8b62aa663df6954ee6a0ae7d2355c6f4c83 | wikidoc | Camouflage | Camouflage
Camouflage is a method of cryptic or concealing coloration that allows an otherwise visible organism or object to remain indiscernible from the surrounding environment through deception. Examples include a tiger's stripes and the battledress of a modern soldier. The theory of camouflage covers various strategies which are used.
# Cryptic coloration in nature
Cryptic coloration is the most common form of camouflage, found to some extent in the majority of species. The simplest way is for an animal to be of a color similar to its surroundings. Examples include the "earth tones" of deer, squirrels, or moles (to match trees or dirt), or the combination of blue skin and white underbelly of sharks via countershading (which makes them difficult to detect from both above and below). More complex patterns can be seen in animals such as flounder, moths, and frogs, among many others.
The type of camouflage a species will develop depends on several factors:
- The environment in which it lives. This is usually the most important factor.
- The physiology and behavior of an animal. Animals with fur need different camouflage than those with feathers or scales. Likewise, animals who live in groups use different camouflage techniques than those that are solitary.
- If the animal is preyed upon, then the behavior or characteristics of its predator can influence how the camouflage develops. For example, if the predator has achromatic vision, then the animal will not need to match the color of its surroundings.
Animals produce colors in two ways:
- Biochromes — natural microscopic pigments that absorb certain wavelengths of light and reflect others, creating a visible color that is targeted towards its primary predator.
- Microscopic physical structures, which act like prisms to reflect and scatter light to produce a color that is different from the skin, such as the translucent fur of the Polar Bear, which actually has black skin.
Cryptic coloration can change as well. This can be due to just a changing of the seasons, or it can be in response to more rapid environmental changes. For example, the Arctic fox has a white coat in winter, and a brown coat in summer. Mammals and birds require a new fur coat and new set of feathers respectively, but some animals, such as cuttlefish, have deeper-level pigment cells, called chromatophores, that they can control. Other animals such as certain fish species or the nudibranch can actually change their skin coloration by changing their diet. However, the most well-known creature that changes color, the chameleon, usually does not do so for camouflage purposes, but instead to express its mood.
Beyond colors, skin patterns are often helpful in cryptic coloration as well. The Craik-O'Brien-Cornsweet illusion describes visual perception as occurring through contrasts of outlines. One recognizes a dog, for example, not by its color as much as by its shape. Often what matters most for good cryptic coloration is to break up the outline of a creature's body. This can be seen in common domestic pets such as tabby cats, but striping overall in other animals such as tigers and zebras help them blend into their environment, the jungle and the grasslands respectively. The latter two provide an interesting example, as one's initial impression might be that their coloration does not match their surroundings at all, but tigers' prey are usually color blind to a certain extent such that they cannot tell the difference between orange and green, and zebras' main predators, lions, are color blind. In the case of zebras, the stripes also blend together so that a herd of zebras looks like one large mass, making it difficult for a lion to pick out any individual zebra. This same concept is used by many striped fish species as well. Among birds, the white "chinstraps" of Canada geese make a flock in tall grass appear more like sticks and less like birds' heads.
In nature, there is a strong evolutionary pressure for animals to blend into their environment or conceal their shape; for prey animals to avoid predators and for predators to be able to sneak up on prey. Natural camouflage is one method that animals use to meet these. There are a number of methods of doing so. One is for the animal to blend in with its surroundings, while another is for the animal to disguise itself as something uninteresting or something dangerous.
There is a permanent co-evolution of the sensory abilities of animals for whom it is beneficial to be able to detect the camouflaged animal, and the cryptic characteristics of the concealing species. Different aspects of crypsis and sensory abilities may be more or less pronounced in given predator-prey pairs of species.
Some cryptic animals also simulate natural movement, e.g., of a leaf in the wind. This is called procryptic behaviour or habit. Other animals attach or attract natural materials to their body for concealment.
A few animals have chromatic response, changing color in changing environments, either seasonally (ermine, snowshoe hare) or far more rapidly with chromatophores in their integument (the cephalopod family).
Some animals, notably in aquatic environments, also take steps to camouflage the odours they create that may attract predators.
Some herd animals adopt a similar pattern to make it difficult to distinguish a single animal. Examples include stripes on zebras and the reflective scales on fish.
# Military camouflage
Camouflage was not in wide use in early western civilization based warfare. 19th century armies tended to use bright colors and bold, impressive designs. These were intended to daunt the enemy, attract recruits, foster unit cohesion, or allow easier identification of units in the fog of war. Another very important reason for the brightly colored uniforms was that before the invention of gunpowder which did not emit such huge amounts of smoke, it was very hard to decide which unit someone belonged to by looking at their uniforms; furthermore, even in the best of circumstances, the colors tended to be covered by soot after the shooting had gone on for a while. All the dust that the marching units stirred up had a similar effect.
Smaller, irregular units of scouts in the 18th century were the first to adopt colors in drab shades of brown and green. Major armies retained their color until convinced otherwise. The British in India in 1857 were forced by casualties to dye their red tunics to neutral tones, initially a muddy tan called khaki (from the Urdu word for 'dusty' as the tan matched the local dust). White tropical uniforms were dyed by the simple expedient of soaking them in tea. This was only a temporary measure. It became standard in Indian service in the 1880s, but it was not until the Second Boer War that, in 1902, the uniforms of the entire British army were standardized on this dun tone for battledress. Other armies, such as the United States, Russia, Italy, and Germany followed suit either with khaki, or with other colors more suitable for their environments.
Camouflage netting, natural materials, disruptive color patterns, and paint with special infrared, thermal, and radar qualities have also been used on military vehicles, ships, aircraft, installations and buildings. A striking example of this is the dazzle camouflage used on ships during WW I.
# Other human uses of cryptic coloration
Hunters often use camouflage clothing that is visually tailored to the game they are hunting. The most striking example if this is the blaze orange camouflage, which relies on the fact that most large game animals, such as deer, are dichromats, and perceive the orange as a dull color. On the other hand, ultraviolet dyes commonly used in laundry detergents to make the laundered items appear brighter are visible to many game animals, and using these will cause what appears to the human eye to be cryptically colored clothing to stand out against the background when viewed by an animal with ultraviolet sensitive eyes. | Camouflage
Template:Otheruses1
Camouflage is a method of cryptic or concealing coloration that allows an otherwise visible organism or object to remain indiscernible from the surrounding environment through deception. Examples include a tiger's stripes and the battledress of a modern soldier. The theory of camouflage covers various strategies which are used.
# Cryptic coloration in nature
Cryptic coloration is the most common form of camouflage, found to some extent in the majority of species. The simplest way is for an animal to be of a color similar to its surroundings. Examples include the "earth tones" of deer, squirrels, or moles (to match trees or dirt), or the combination of blue skin and white underbelly of sharks via countershading (which makes them difficult to detect from both above and below). More complex patterns can be seen in animals such as flounder, moths, and frogs, among many others.
The type of camouflage a species will develop depends on several factors:
- The environment in which it lives. This is usually the most important factor.
- The physiology and behavior of an animal. Animals with fur need different camouflage than those with feathers or scales. Likewise, animals who live in groups use different camouflage techniques than those that are solitary.
- If the animal is preyed upon, then the behavior or characteristics of its predator can influence how the camouflage develops. For example, if the predator has achromatic vision, then the animal will not need to match the color of its surroundings.
Animals produce colors in two ways:
- Biochromes — natural microscopic pigments that absorb certain wavelengths of light and reflect others, creating a visible color that is targeted towards its primary predator.
- Microscopic physical structures, which act like prisms to reflect and scatter light to produce a color that is different from the skin, such as the translucent fur of the Polar Bear, which actually has black skin.
Cryptic coloration can change as well. This can be due to just a changing of the seasons, or it can be in response to more rapid environmental changes. For example, the Arctic fox has a white coat in winter, and a brown coat in summer. Mammals and birds require a new fur coat and new set of feathers respectively, but some animals, such as cuttlefish, have deeper-level pigment cells, called chromatophores, that they can control. Other animals such as certain fish species or the nudibranch can actually change their skin coloration by changing their diet. However, the most well-known creature that changes color, the chameleon, usually does not do so for camouflage purposes, but instead to express its mood.
Beyond colors, skin patterns are often helpful in cryptic coloration as well. The Craik-O'Brien-Cornsweet illusion describes visual perception as occurring through contrasts of outlines. One recognizes a dog, for example, not by its color as much as by its shape. Often what matters most for good cryptic coloration is to break up the outline of a creature's body. This can be seen in common domestic pets such as tabby cats, but striping overall in other animals such as tigers and zebras help them blend into their environment, the jungle and the grasslands respectively. The latter two provide an interesting example, as one's initial impression might be that their coloration does not match their surroundings at all, but tigers' prey are usually color blind to a certain extent such that they cannot tell the difference between orange and green, and zebras' main predators, lions, are color blind. In the case of zebras, the stripes also blend together so that a herd of zebras looks like one large mass, making it difficult for a lion to pick out any individual zebra. This same concept is used by many striped fish species as well. Among birds, the white "chinstraps" of Canada geese make a flock in tall grass appear more like sticks and less like birds' heads.
In nature, there is a strong evolutionary pressure for animals to blend into their environment or conceal their shape; for prey animals to avoid predators and for predators to be able to sneak up on prey. Natural camouflage is one method that animals use to meet these. There are a number of methods of doing so. One is for the animal to blend in with its surroundings, while another is for the animal to disguise itself as something uninteresting or something dangerous.
There is a permanent co-evolution of the sensory abilities of animals for whom it is beneficial to be able to detect the camouflaged animal, and the cryptic characteristics of the concealing species. Different aspects of crypsis and sensory abilities may be more or less pronounced in given predator-prey pairs of species.
Some cryptic animals also simulate natural movement, e.g., of a leaf in the wind. This is called procryptic behaviour or habit. Other animals attach or attract natural materials to their body for concealment.
A few animals have chromatic response, changing color in changing environments, either seasonally (ermine, snowshoe hare) or far more rapidly with chromatophores in their integument (the cephalopod family).
Some animals, notably in aquatic environments, also take steps to camouflage the odours they create that may attract predators.[citation needed]
Some herd animals adopt a similar pattern to make it difficult to distinguish a single animal. Examples include stripes on zebras and the reflective scales on fish.
# Military camouflage
Camouflage was not in wide use in early western civilization based warfare. 19th century armies tended to use bright colors and bold, impressive designs. These were intended to daunt the enemy, attract recruits, foster unit cohesion, or allow easier identification of units in the fog of war. Another very important reason for the brightly colored uniforms was that before the invention of gunpowder which did not emit such huge amounts of smoke, it was very hard to decide which unit someone belonged to by looking at their uniforms; furthermore, even in the best of circumstances, the colors tended to be covered by soot after the shooting had gone on for a while. All the dust that the marching units stirred up had a similar effect.
Smaller, irregular units of scouts in the 18th century were the first to adopt colors in drab shades of brown and green. Major armies retained their color until convinced otherwise. The British in India in 1857 were forced by casualties to dye their red tunics to neutral tones, initially a muddy tan called khaki (from the Urdu word for 'dusty' as the tan matched the local dust). White tropical uniforms were dyed by the simple expedient of soaking them in tea. This was only a temporary measure. It became standard in Indian service in the 1880s, but it was not until the Second Boer War that, in 1902, the uniforms of the entire British army were standardized on this dun tone for battledress. Other armies, such as the United States, Russia, Italy, and Germany followed suit either with khaki, or with other colors more suitable for their environments.
Camouflage netting, natural materials, disruptive color patterns, and paint with special infrared, thermal, and radar qualities have also been used on military vehicles, ships, aircraft, installations and buildings. A striking example of this is the dazzle camouflage used on ships during WW I.
# Other human uses of cryptic coloration
Hunters often use camouflage clothing that is visually tailored to the game they are hunting. The most striking example if this is the blaze orange camouflage, which relies on the fact that most large game animals, such as deer, are dichromats, and perceive the orange as a dull color. On the other hand, ultraviolet dyes commonly used in laundry detergents to make the laundered items appear brighter are visible to many game animals, and using these will cause what appears to the human eye to be cryptically colored clothing to stand out against the background when viewed by an animal with ultraviolet sensitive eyes.[1] | https://www.wikidoc.org/index.php/Camouflage | |
96e1162f557584d21f8a5047b861585f0965a345 | wikidoc | Intertrigo | Intertrigo
An intertrigo is an inflammation (rash) of the body folds (adjacent areas of skin).
An intertrigo sometimes refers to a bacterial, fungal, or viral infection that has developed at the site of broken skin due to such inflammation.
An intertrigo usually develops from the chafing of warm, moist skin in the areas of the inner thighs and genitalia, the armpits, under the breasts, the underside of the belly, behind the ears, and the web spaces between the toes and fingers. An intertrigo usually appears red and raw-looking, and may also itch, ooze, and be sore. Intertrigos occur more often among overweight individuals, those with diabetes, those restricted to bed rest or diaper use, and those who use medical devices, like artificial limbs, that trap moisture against the skin. Also, there are several skin diseases that can cause an intertrigo to develop, such as dermatitis or inverse psoriasis.
# Differentiating intertrigo from other diseases
Intertrigo should be differentiated from other diseases causing papulosquamous or erythmatosquamous rash. The differentials include:
# Treatments
In general, treatment for all skin rashes, less is more, and consult a dermatologist if it persists for more than a week. Infections can be treated with a topical and/or oral medication(s). The most common treatment being a baby diaper rash ointment such as a topical zinc oxide cream. Some commonly available over the counter brand names: Sudocrem, Desitin, Butt Paste, and Balmex. There are also many other generic diaper rash creams that may work. Also for a persistent intertrigo infection it is common for an anti-fungal cream, most commonly clotrimazole 1%, to be used in conjunction with a diaper rash ointment.
It is suggested to use a paper towel to apply the zinc oxide cream and/or anti-fungal ointment(s) to avoid excessive hand washing, as it is very difficult to wash zinc oxide ointment from the hands because it resists water. Other ingredients in baby rash ointments that are beneficial to relief of intertrigo is cod liver oil and shark liver oil. These oils are also available in pill forms that may also help the infection (see links).
Hydrocortisone available at drug stores and over the counter in low dosages is beneficial in relieving the pain and symptoms of the infection but does not cure the infection.
Keeping the area of the intertrigo dry and exposed to the air can help prevent recurrences. If the individual is overweight, losing weight can help. Using antibacterial soap, surrounding the skin with absorbent cotton or a band of cotton fabric, and treating the skin with absorbent body powders and even antiperspirants will all help prevent future occurrences. Relapses of intertrigos are common, however, and require periodic care from a dermatologist.
# Prescription Medicines
These prescriptions are very dangerous and are usually only prescribed by a doctor for extreme cases.
- Grifulvin V
- Griseofulvin | Intertrigo
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
An intertrigo is an inflammation (rash) of the body folds (adjacent areas of skin).
An intertrigo sometimes refers to a bacterial, fungal, or viral infection that has developed at the site of broken skin due to such inflammation.
An intertrigo usually develops from the chafing of warm, moist skin in the areas of the inner thighs and genitalia, the armpits, under the breasts, the underside of the belly, behind the ears, and the web spaces between the toes and fingers. An intertrigo usually appears red and raw-looking, and may also itch, ooze, and be sore. Intertrigos occur more often among overweight individuals, those with diabetes, those restricted to bed rest or diaper use, and those who use medical devices, like artificial limbs, that trap moisture against the skin. Also, there are several skin diseases that can cause an intertrigo to develop, such as dermatitis or inverse psoriasis.
# Differentiating intertrigo from other diseases
Intertrigo should be differentiated from other diseases causing papulosquamous or erythmatosquamous rash. The differentials include:
# Treatments
In general, treatment for all skin rashes, less is more, and consult a dermatologist if it persists for more than a week. Infections can be treated with a topical and/or oral medication(s). The most common treatment being a baby diaper rash ointment such as a topical zinc oxide cream. Some commonly available over the counter brand names: Sudocrem, Desitin, Butt Paste, and Balmex. There are also many other generic diaper rash creams that may work. Also for a persistent intertrigo infection it is common for an anti-fungal cream, most commonly clotrimazole 1%, to be used in conjunction with a diaper rash ointment.
It is suggested to use a paper towel to apply the zinc oxide cream and/or anti-fungal ointment(s) to avoid excessive hand washing, as it is very difficult to wash zinc oxide ointment from the hands because it resists water. Other ingredients in baby rash ointments that are beneficial to relief of intertrigo is cod liver oil and shark liver oil. These oils are also available in pill forms that may also help the infection (see links).
Hydrocortisone available at drug stores and over the counter in low dosages is beneficial in relieving the pain and symptoms of the infection but does not cure the infection.
Keeping the area of the intertrigo dry and exposed to the air can help prevent recurrences. If the individual is overweight, losing weight can help. Using antibacterial soap, surrounding the skin with absorbent cotton or a band of cotton fabric, and treating the skin with absorbent body powders and even antiperspirants will all help prevent future occurrences. Relapses of intertrigos are common, however, and require periodic care from a dermatologist.
# Prescription Medicines
These prescriptions are very dangerous and are usually only prescribed by a doctor for extreme cases.
- Grifulvin V
- Griseofulvin | https://www.wikidoc.org/index.php/Candida_Intertrigo | |
e47fbabf047e4e1fa89a576d28dcc9b9ddc395f0 | wikidoc | Captodiame | Captodiame
# Overview
Captodiame (INN), also known as captodiamine, is an antihistamine sold under the trade names Covatine, Covatix, and Suvren which is used as a sedative and anxiolytic. It is a derivative of diphenhydramine.
A 2004 study suggested captodiame may be helpful in preventing benzodiazepine withdrawal syndrome in people discontinuing benzodiazepine treatment.
In addition to its actions as an antihistamine, captodiamine has been found to act as a 5-HT2C receptor antagonist and σ1 receptor and D3 receptor agonist. It produces antidepressant-like effects in rats. However, captodiamine is unique among antidepressant-like drugs in that it increases brain-derived neurotrophic factor (BDNF) levels in the hypothalamus but not in the frontal cortex or hippocampus. This unique action may be related to its ability to attenuate stress-induced anhedonia and corticotropin-releasing factor (CRF) signaling in the hypothalamus. | Captodiame
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Captodiame (INN), also known as captodiamine, is an antihistamine sold under the trade names Covatine, Covatix, and Suvren which is used as a sedative and anxiolytic. It is a derivative of diphenhydramine.[1]
A 2004 study suggested captodiame may be helpful in preventing benzodiazepine withdrawal syndrome in people discontinuing benzodiazepine treatment.[1]
In addition to its actions as an antihistamine, captodiamine has been found to act as a 5-HT2C receptor antagonist and σ1 receptor and D3 receptor agonist.[2] It produces antidepressant-like effects in rats.[2] However, captodiamine is unique among antidepressant-like drugs in that it increases brain-derived neurotrophic factor (BDNF) levels in the hypothalamus but not in the frontal cortex or hippocampus.[2] This unique action may be related to its ability to attenuate stress-induced anhedonia and corticotropin-releasing factor (CRF) signaling in the hypothalamus.[2] | https://www.wikidoc.org/index.php/Captodiame | |
12157f640b093833e800359250279d48e301c16f | wikidoc | Sucralfate | Sucralfate
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Sucralfate is an antiulcer agent that is FDA approved for the {{{indicationType}}} of active duodenal ulcer. Common adverse reactions include constipation, hyperglycemia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- The recommended adult oral dosage for duodenal ulcer is 1 g (10 mL/2 teaspoons) four times per day. CARAFATE should be administered on an empty stomach.
- Antacids may be prescribed as needed for relief of pain but should not be taken within one-half hour before or after sucralfate.
- While healing with sucralfate may occur during the first week or two, treatment should be continued for 4 to 8 weeks unless healing has been demonstrated by x-ray or endoscopic examination.
- Elderly: In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Sucralfate in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- Topical sucralfate lowered healing times in burn patients.
- Dosing Information
- Combination therapy with sucralfate 1 gram 3 times daily plus ranitidine 300 milligrams (mg) at bedtime.
- Dosing Information
- Sucralfate was given as 12 grams (60 milliliters) through the nasogastric tube.
- Dosing Information
- 1 gram sucralfate for 475 milligrams aluminum hydroxide.
- Dosing Information
- Sucralfate enemas twice daily for 14 to 23 days .
- Dosing Information
- Nasogastric sucralfate (1 grams every 6 hours).
- Dosing Information
- Sucralfate rectal retention enema therapy for 6 to 8 weeks.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Sucralfate in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Sucralfate in pediatric patients.
### Non–Guideline-Supported Use
- Dosing Information
- Suspension prepared with sucralfate powder to oral mucosa (especially blisters) 4 times a day.
# Contraindications
- CARAFATE is contraindicated for patients with known hypersensitivity reactions to the active substance or to any of the excipients.
# Warnings
### Precautions
- The physician should read the "PRECAUTIONS" section when considering the use of CARAFATE in pregnant or pediatric patients, or patients of childbearing potential.
- Duodenal ulcer is a chronic, recurrent disease. While short-term treatment with sucralfate can result in complete healing of the ulcer, a successful course of treatment with sucralfate should not be expected to alter the post healing frequency or severity of duodenal ulceration.
- Episodes of hyperglycemia have been reported in diabetic patients. Close monitoring of glycemia in diabetic patients treated with sucralfate suspension is recommended. Adjustment of the anti-diabetic treatment dose during the use of sucralfate suspension might be necessary.
- Special Populations: Chronic Renal Failure and Dialysis Patients
- When sucralfate is administered orally, small amounts of aluminum are absorbed from the gastrointestinal tract. Concomitant use of sucralfate with other products that contain aluminum, such as aluminum-containing antacids, may increase the total body burden of aluminum. Patients with normal renal function receiving the recommended doses of sucralfate and aluminum-containing products adequately excrete aluminum in the urine. Patients with chronic renal failure or those receiving dialysis have impaired excretion of absorbed aluminum. In addition, aluminum does not cross dialysis membranes because it is bound to albumin and transferrin plasma proteins. Aluminum accumulation and toxicity (aluminum osteodystrophy, osteomalacia, encephalopathy) have been described in patients with renal impairment. Sucralfate should be used with caution in patients with chronic renal failure.
- Drug Interactions
- Some studies have shown that simultaneous sucralfate administration in healthy volunteers reduced the extent of absorption (bioavailability) of single doses of the following: cimetidine, digoxin, fluoroquinolone antibiotics, ketoconazole, l-thyroxine, phenytoin, quinidine, ranitidine, tetracycline, and theophylline. Subtherapeutic prothrombin times with concomitant warfarin and sucralfate therapy have been reported in spontaneous and published case reports. However, two clinical studies have demonstrated no change in either serum warfarin concentration or prothrombin time with the addition of sucralfate to chronic warfarin therapy.
- The mechanism of these interactions appears to be nonsystemic in nature, presumably resulting from sucralfate binding to the concomitant agent in the gastrointestinal tract. In all cases studied to date (cimetidine, ciprofloxacin, digoxin, norfloxacin, ofloxacin, and ranitidine), dosing the concomitant medication 2 hours before sucralfate eliminated the interaction. Due to CARAFATE's potential to alter the absorption of some drugs, CARAFATE should be administered separately from other drugs when alterations in bioavailability are felt to be critical. In these cases, patients should be monitored appropriately.
# Adverse Reactions
## Clinical Trials Experience
- Adverse reactions to sucralfate tablets in clinical trials were minor and only rarely led to discontinuation of the drug. In studies involving over 2700 patients treated with sucralfate, adverse effects were reported in 129 (4.7%).
- Constipation was the most frequent complaint (2%). Other adverse effects reported in less than 0.5% of the patients are listed below by body system:
- Gastrointestinal: diarrhea, dry mouth, flatulence, gastric discomfort, indigestion, nausea, vomiting
- Dermatological: pruritus, rash
- Nervous System: dizziness, insomnia, sleepiness, vertigo
- Other: back pain, headache
## Postmarketing Experience
- Post-marketing cases of hypersensitivity have been reported with the use of sucralfate suspension, including anaphylactic reactions, dyspnea, lip swelling, edema of the mouth, pharyngeal edema, pruritus, rash, swelling of the face and urticaria.
- Cases of bronchospasm, laryngeal edema and respiratory tract edema have been reported with an unknown oral formulation of sucralfate.
- Cases of hyperglycemia have been reported with sucralfate
- Bezoars have been reported in patients treated with sucralfate. The majority of patients had underlying medical conditions that may predispose to bezoar formation (such as delayed gastric emptying) or were receiving concomitant enteral tube feedings.
- Inadvertent injection of insoluble sucralfate and its insoluble excipients has led to fatal complications, including pulmonary and cerebral emboli. Sucralfate is not intended for intravenous administration.
# Drug Interactions
- Some studies have shown that simultaneous sucralfate administration in healthy volunteers reduced the extent of absorption (bioavailability) of single doses of the following: cimetidine, digoxin, fluoroquinolone antibiotics, ketoconazole, l-thyroxine, phenytoin, quinidine, ranitidine, tetracycline, and theophylline. Subtherapeutic prothrombin times with concomitant warfarin and sucralfate therapy have been reported in spontaneous and published case reports. However, two clinical studies have demonstrated no change in either serum warfarin concentration or prothrombin time with the addition of sucralfate to chronic warfarin therapy.
- The mechanism of these interactions appears to be nonsystemic in nature, presumably resulting from sucralfate binding to the concomitant agent in the gastrointestinal tract. In all cases studied to date (cimetidine, ciprofloxacin, digoxin, norfloxacin, ofloxacin, and ranitidine), dosing the concomitant medication 2 hours before sucralfate eliminated the interaction. Due to CARAFATE's potential to alter the absorption of some drugs, CARAFATE should be administered separately from other drugs when alterations in bioavailability are felt to be critical. In these cases, patients should be monitored appropriately.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category B
- Teratogenicity studies have been performed in mice, rats, and rabbits at doses up to 50 times the human dose and have revealed no evidence of harm to the fetus due to sucralfate. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Sucralfate in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Sucralfate during labor and delivery.
### Nursing Mothers
- It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when sucralfate is administered to a nursing woman.
### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
- Clinical studies of CARAFATE Suspension did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
- This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
### Gender
There is no FDA guidance on the use of Sucralfate with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Sucralfate with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Sucralfate in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Sucralfate in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Sucralfate in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Sucralfate in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Close monitoring of glycemia in diabetic patients treated with sucralfate suspension is recommended.
# IV Compatibility
There is limited information regarding IV Compatibility of Sucralfate in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Acute oral studies in animals, however, using doses up to 12 g/kg body weight, could not find a lethal dose. Sucralfate is only minimally absorbed from the gastrointestinal tract. Risks associated with acute overdosage should, therefore, be minimal. In rare reports describing sucralfate overdose, most patients remained asymptomatic. Those few reports where adverse events were described included symptoms of dyspepsia, abdominal pain, nausea, and vomiting.
### Management
- Due to limited experience in humans with overdosage of sucralfate, no specific treatment recommendations can be given.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Sucralfate in the drug label.
# Pharmacology
## Mechanism of Action
- Sucralfate is only minimally absorbed from the gastrointestinal tract. The small amounts of the sulfated disaccharide that are absorbed are excreted primarily in the urine.
- Although the mechanism of sucralfate’s ability to accelerate healing of duodenal ulcers remains to be fully defined, it is known that it exerts its effect through a local, rather than systemic, action. The following observations also appear pertinent:
- Studies in human subjects and with animal models of ulcer disease have shown that sucralfate forms an ulcer-adherent complex with proteinaceous exudate at the ulcer site.
- In vitro, a sucralfate-albumin film provides a barrier to diffusion of hydrogen ions.
- In human subjects, sucralfate given in doses recommended for ulcer therapy inhibits pepsin activity in gastric juice by 32%.
- In vitro, sucralfate adsorbs bile salts.
- These observations suggest that sucralfate’s antiulcer activity is the result of formation of an ulcer-adherent complex that covers the ulcer site and protects it against further attack by acid, pepsin, and bile salts. There are approximately 14 to 16 mEq of acid-neutralizing capacity per 1 g dose of sucralfate.
## Structure
- CARAFATE Suspension contains sucralfate and sucralfate is an α-D-glucopyranoside, β-D-fructofuranosyl-, octakis-(hydrogen sulfate), aluminum complex.
- CARAFATE Suspension for oral administration contains 1 g of sucralfate per 10 mL.
- CARAFATE Suspension also contains: colloidal silicon dioxide NF, FD&C Red #40, flavor, glycerin USP, methylcellulose USP, methylparaben NF, microcrystalline cellulose NF, purified water USP, simethicone USP, and sorbitol solution USP. Therapeutic category: antiulcer.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Sucralfate in the drug label.
## Pharmacokinetics
There is limited information regarding Pharmacokinetics of Sucralfate in the drug label.
## Nonclinical Toxicology
- Chronic oral toxicity studies of 24 months’ duration were conducted in mice and rats at doses up to 1 g/kg (12 times the human dose).
- There was no evidence of drug-related tumorigenicity. A reproduction study in rats at doses up to 38 times the human dose did not reveal any indication of fertility impairment. Mutagenicity studies were not conducted.
# Clinical Studies
- In a multicenter, double-blind, placebo-controlled study of CARAFATE Suspension, a dosage regimen of 1 g (10 mL) four times daily was demonstrated to be superior to placebo in ulcer healing.
- Equivalence of sucralfate suspension to sucralfate tablets has not been demonstrated.
# How Supplied
- CARAFATE (sucralfate) Suspension 1 g/10 mL is a pink suspension supplied in bottles of 14 fl oz (NDC 58914-170-14).
- SHAKE WELL BEFORE USING. AVOID FREEZING.
- Store at controlled room temperature 20-25°C (68-77°F).
## Storage
There is limited information regarding Sucralfate Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Sucralfate in the drug label.
# Precautions with Alcohol
- Alcohol-Sucralfate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Carafate®
# Look-Alike Drug Names
There is limited information regarding Sucralfate Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Sucralfate
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Sucralfate is an antiulcer agent that is FDA approved for the {{{indicationType}}} of active duodenal ulcer. Common adverse reactions include constipation, hyperglycemia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- The recommended adult oral dosage for duodenal ulcer is 1 g (10 mL/2 teaspoons) four times per day. CARAFATE should be administered on an empty stomach.
- Antacids may be prescribed as needed for relief of pain but should not be taken within one-half hour before or after sucralfate.
- While healing with sucralfate may occur during the first week or two, treatment should be continued for 4 to 8 weeks unless healing has been demonstrated by x-ray or endoscopic examination.
- Elderly: In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Sucralfate in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- Topical sucralfate lowered healing times in burn patients.
- Dosing Information
- Combination therapy with sucralfate 1 gram 3 times daily plus ranitidine 300 milligrams (mg) at bedtime.
- Dosing Information
- Sucralfate was given as 12 grams (60 milliliters) through the nasogastric tube.
- Dosing Information
- 1 gram sucralfate for 475 milligrams aluminum hydroxide.
- Dosing Information
- Sucralfate enemas twice daily for 14 to 23 days .
- Dosing Information
- Nasogastric sucralfate (1 grams every 6 hours).
- Dosing Information
- Sucralfate rectal retention enema therapy for 6 to 8 weeks.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Sucralfate in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Sucralfate in pediatric patients.
### Non–Guideline-Supported Use
- Dosing Information
- Suspension prepared with sucralfate powder to oral mucosa (especially blisters) 4 times a day.
# Contraindications
- CARAFATE is contraindicated for patients with known hypersensitivity reactions to the active substance or to any of the excipients.
# Warnings
### Precautions
- The physician should read the "PRECAUTIONS" section when considering the use of CARAFATE in pregnant or pediatric patients, or patients of childbearing potential.
- Duodenal ulcer is a chronic, recurrent disease. While short-term treatment with sucralfate can result in complete healing of the ulcer, a successful course of treatment with sucralfate should not be expected to alter the post healing frequency or severity of duodenal ulceration.
- Episodes of hyperglycemia have been reported in diabetic patients. Close monitoring of glycemia in diabetic patients treated with sucralfate suspension is recommended. Adjustment of the anti-diabetic treatment dose during the use of sucralfate suspension might be necessary.
- Special Populations: Chronic Renal Failure and Dialysis Patients
- When sucralfate is administered orally, small amounts of aluminum are absorbed from the gastrointestinal tract. Concomitant use of sucralfate with other products that contain aluminum, such as aluminum-containing antacids, may increase the total body burden of aluminum. Patients with normal renal function receiving the recommended doses of sucralfate and aluminum-containing products adequately excrete aluminum in the urine. Patients with chronic renal failure or those receiving dialysis have impaired excretion of absorbed aluminum. In addition, aluminum does not cross dialysis membranes because it is bound to albumin and transferrin plasma proteins. Aluminum accumulation and toxicity (aluminum osteodystrophy, osteomalacia, encephalopathy) have been described in patients with renal impairment. Sucralfate should be used with caution in patients with chronic renal failure.
- Drug Interactions
- Some studies have shown that simultaneous sucralfate administration in healthy volunteers reduced the extent of absorption (bioavailability) of single doses of the following: cimetidine, digoxin, fluoroquinolone antibiotics, ketoconazole, l-thyroxine, phenytoin, quinidine, ranitidine, tetracycline, and theophylline. Subtherapeutic prothrombin times with concomitant warfarin and sucralfate therapy have been reported in spontaneous and published case reports. However, two clinical studies have demonstrated no change in either serum warfarin concentration or prothrombin time with the addition of sucralfate to chronic warfarin therapy.
- The mechanism of these interactions appears to be nonsystemic in nature, presumably resulting from sucralfate binding to the concomitant agent in the gastrointestinal tract. In all cases studied to date (cimetidine, ciprofloxacin, digoxin, norfloxacin, ofloxacin, and ranitidine), dosing the concomitant medication 2 hours before sucralfate eliminated the interaction. Due to CARAFATE's potential to alter the absorption of some drugs, CARAFATE should be administered separately from other drugs when alterations in bioavailability are felt to be critical. In these cases, patients should be monitored appropriately.
# Adverse Reactions
## Clinical Trials Experience
- Adverse reactions to sucralfate tablets in clinical trials were minor and only rarely led to discontinuation of the drug. In studies involving over 2700 patients treated with sucralfate, adverse effects were reported in 129 (4.7%).
- Constipation was the most frequent complaint (2%). Other adverse effects reported in less than 0.5% of the patients are listed below by body system:
- Gastrointestinal: diarrhea, dry mouth, flatulence, gastric discomfort, indigestion, nausea, vomiting
- Dermatological: pruritus, rash
- Nervous System: dizziness, insomnia, sleepiness, vertigo
- Other: back pain, headache
## Postmarketing Experience
- Post-marketing cases of hypersensitivity have been reported with the use of sucralfate suspension, including anaphylactic reactions, dyspnea, lip swelling, edema of the mouth, pharyngeal edema, pruritus, rash, swelling of the face and urticaria.
- Cases of bronchospasm, laryngeal edema and respiratory tract edema have been reported with an unknown oral formulation of sucralfate.
- Cases of hyperglycemia have been reported with sucralfate
- Bezoars have been reported in patients treated with sucralfate. The majority of patients had underlying medical conditions that may predispose to bezoar formation (such as delayed gastric emptying) or were receiving concomitant enteral tube feedings.
- Inadvertent injection of insoluble sucralfate and its insoluble excipients has led to fatal complications, including pulmonary and cerebral emboli. Sucralfate is not intended for intravenous administration.
# Drug Interactions
- Some studies have shown that simultaneous sucralfate administration in healthy volunteers reduced the extent of absorption (bioavailability) of single doses of the following: cimetidine, digoxin, fluoroquinolone antibiotics, ketoconazole, l-thyroxine, phenytoin, quinidine, ranitidine, tetracycline, and theophylline. Subtherapeutic prothrombin times with concomitant warfarin and sucralfate therapy have been reported in spontaneous and published case reports. However, two clinical studies have demonstrated no change in either serum warfarin concentration or prothrombin time with the addition of sucralfate to chronic warfarin therapy.
- The mechanism of these interactions appears to be nonsystemic in nature, presumably resulting from sucralfate binding to the concomitant agent in the gastrointestinal tract. In all cases studied to date (cimetidine, ciprofloxacin, digoxin, norfloxacin, ofloxacin, and ranitidine), dosing the concomitant medication 2 hours before sucralfate eliminated the interaction. Due to CARAFATE's potential to alter the absorption of some drugs, CARAFATE should be administered separately from other drugs when alterations in bioavailability are felt to be critical. In these cases, patients should be monitored appropriately.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category B
- Teratogenicity studies have been performed in mice, rats, and rabbits at doses up to 50 times the human dose and have revealed no evidence of harm to the fetus due to sucralfate. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Sucralfate in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Sucralfate during labor and delivery.
### Nursing Mothers
- It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when sucralfate is administered to a nursing woman.
### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
- Clinical studies of CARAFATE Suspension did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
- This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
### Gender
There is no FDA guidance on the use of Sucralfate with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Sucralfate with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Sucralfate in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Sucralfate in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Sucralfate in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Sucralfate in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Close monitoring of glycemia in diabetic patients treated with sucralfate suspension is recommended.
# IV Compatibility
There is limited information regarding IV Compatibility of Sucralfate in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Acute oral studies in animals, however, using doses up to 12 g/kg body weight, could not find a lethal dose. Sucralfate is only minimally absorbed from the gastrointestinal tract. Risks associated with acute overdosage should, therefore, be minimal. In rare reports describing sucralfate overdose, most patients remained asymptomatic. Those few reports where adverse events were described included symptoms of dyspepsia, abdominal pain, nausea, and vomiting.
### Management
- Due to limited experience in humans with overdosage of sucralfate, no specific treatment recommendations can be given.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Sucralfate in the drug label.
# Pharmacology
## Mechanism of Action
- Sucralfate is only minimally absorbed from the gastrointestinal tract. The small amounts of the sulfated disaccharide that are absorbed are excreted primarily in the urine.
- Although the mechanism of sucralfate’s ability to accelerate healing of duodenal ulcers remains to be fully defined, it is known that it exerts its effect through a local, rather than systemic, action. The following observations also appear pertinent:
- Studies in human subjects and with animal models of ulcer disease have shown that sucralfate forms an ulcer-adherent complex with proteinaceous exudate at the ulcer site.
- In vitro, a sucralfate-albumin film provides a barrier to diffusion of hydrogen ions.
- In human subjects, sucralfate given in doses recommended for ulcer therapy inhibits pepsin activity in gastric juice by 32%.
- In vitro, sucralfate adsorbs bile salts.
- These observations suggest that sucralfate’s antiulcer activity is the result of formation of an ulcer-adherent complex that covers the ulcer site and protects it against further attack by acid, pepsin, and bile salts. There are approximately 14 to 16 mEq of acid-neutralizing capacity per 1 g dose of sucralfate.
## Structure
- CARAFATE Suspension contains sucralfate and sucralfate is an α-D-glucopyranoside, β-D-fructofuranosyl-, octakis-(hydrogen sulfate), aluminum complex.
- CARAFATE Suspension for oral administration contains 1 g of sucralfate per 10 mL.
- CARAFATE Suspension also contains: colloidal silicon dioxide NF, FD&C Red #40, flavor, glycerin USP, methylcellulose USP, methylparaben NF, microcrystalline cellulose NF, purified water USP, simethicone USP, and sorbitol solution USP. Therapeutic category: antiulcer.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Sucralfate in the drug label.
## Pharmacokinetics
There is limited information regarding Pharmacokinetics of Sucralfate in the drug label.
## Nonclinical Toxicology
- Chronic oral toxicity studies of 24 months’ duration were conducted in mice and rats at doses up to 1 g/kg (12 times the human dose).
- There was no evidence of drug-related tumorigenicity. A reproduction study in rats at doses up to 38 times the human dose did not reveal any indication of fertility impairment. Mutagenicity studies were not conducted.
# Clinical Studies
- In a multicenter, double-blind, placebo-controlled study of CARAFATE Suspension, a dosage regimen of 1 g (10 mL) four times daily was demonstrated to be superior to placebo in ulcer healing.
- Equivalence of sucralfate suspension to sucralfate tablets has not been demonstrated.
# How Supplied
- CARAFATE (sucralfate) Suspension 1 g/10 mL is a pink suspension supplied in bottles of 14 fl oz (NDC 58914-170-14).
- SHAKE WELL BEFORE USING. AVOID FREEZING.
- Store at controlled room temperature 20-25°C (68-77°F).
## Storage
There is limited information regarding Sucralfate Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Sucralfate in the drug label.
# Precautions with Alcohol
- Alcohol-Sucralfate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Carafate®[2]
# Look-Alike Drug Names
There is limited information regarding Sucralfate Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Carafate | |
018206d235c97d99ffca84ac200f0e4e20a83447 | wikidoc | Carbapenem | Carbapenem
Carbapenems are a class of beta-lactam antibiotics with a broad spectrum of antibacterial activity, and have a structure which renders them highly resistant to beta-lactamases. Carbapenem antibiotics were originally developed from thienamycin, a naturally-derived product of Streptomyces cattleya.
The following drugs belong to the carbapenem class:
- Imipenem (often given as part of Imipenem/cilastatin)
Imipenem can be hydrolysed in the mammalian kidney by a dehydropeptidase enzyme, and so is given with a dehydropeptidase inhibitor, cilastatin
- Imipenem can be hydrolysed in the mammalian kidney by a dehydropeptidase enzyme, and so is given with a dehydropeptidase inhibitor, cilastatin
- Meropenem
- Ertapenem
- Faropenem
- Doripenem
- Panipenem/betamipron
These agents have the broadest antibacterial spectrum compared to other beta-lactam classes such as penicillins and cephalosporins. Additionally they are generally resistant to the typical bacterial beta-lactamase enzymes which are one of the principal resistance mechanisms of bacteria. They are active against both Gram positive and gram negative bacteria, with the exception of intracellular bacteria, such as the Chlamydiae.
The carbapenems are structurally very similar to the penicillins, but the sulfur atom in position 1 of the structure has been replaced with a carbon atom, and hence the name of the group, the carbapenems.
Due to their expanded spectra, the desire to avoid generation of resistance and the fact that they have generally poor oral bioavailability, they are administered intravenously in hospital settings for more serious infections. However, research is underway to develop an effective oral carbapenem. | Carbapenem
Carbapenems are a class of beta-lactam antibiotics with a broad spectrum of antibacterial activity, and have a structure which renders them highly resistant to beta-lactamases. Carbapenem antibiotics were originally developed from thienamycin, a naturally-derived product of Streptomyces cattleya.[1]
The following drugs belong to the carbapenem class:
- Imipenem (often given as part of Imipenem/cilastatin)
Imipenem can be hydrolysed in the mammalian kidney by a dehydropeptidase enzyme, and so is given with a dehydropeptidase inhibitor, cilastatin
- Imipenem can be hydrolysed in the mammalian kidney by a dehydropeptidase enzyme, and so is given with a dehydropeptidase inhibitor, cilastatin
- Meropenem
- Ertapenem
- Faropenem
- Doripenem
- Panipenem/betamipron
These agents have the broadest antibacterial spectrum compared to other beta-lactam classes such as penicillins and cephalosporins. Additionally they are generally resistant to the typical bacterial beta-lactamase enzymes which are one of the principal resistance mechanisms of bacteria. They are active against both Gram positive and gram negative bacteria, with the exception of intracellular bacteria, such as the Chlamydiae.
The carbapenems are structurally very similar to the penicillins, but the sulfur atom in position 1 of the structure has been replaced with a carbon atom, and hence the name of the group, the carbapenems.
Due to their expanded spectra, the desire to avoid generation of resistance and the fact that they have generally poor oral bioavailability, they are administered intravenously in hospital settings for more serious infections. However, research is underway to develop an effective oral carbapenem.[2] | https://www.wikidoc.org/index.php/Carbapenem | |
eb71a43a158f2d9a6ecd19789a63cd5d1319b042 | wikidoc | Carbetocin | Carbetocin
# Overview
Carbetocin (trade names Duratocin, Pabal, Lonactene) is an obstetric drug used to control postpartum hemorrhage and bleeding after giving birth, particularly following Cesarean section. It is an eight amino acid long analogue of oxytocin (a nonapeptide) and thus has a similar action. Carbetocin primarily agonizes peripherally expressed oxytocin receptors. Carbetocin is manufactured by Ferring Pharmaceuticals and is available in Canada and the United Kingdom, but not in the United States.
# Medical uses
Carbetocin works as an oxytocic, antihemorrhagic and uterotonic drug in the peripheral nervous system. The most common causes of postpartum hemorrhage are lack of tone in the uterus from overstretching or the use of an anesthetic. Carbetocin has been approved for use immediately following an elective Cesarean section when a local or spinal anesthesia has been administered. Since the uterus cannot contract on its own following incision during a Cesarean section, exogenous administration of oxytocin or an analog is necessary to restore uterine tone and prevent hemorrhage.
Safety of carbetocin following vaginal births and emergency Cesarean sections has not been established, though studies have suggested efficacy following vaginal births to that following Cesarean sections. Some studies have shown that a 10-70 ug dose following vaginal delivery caused contractions and no adverse side effects. Carbetocin has also been shown to increase uterine involution (the return of the uterus to its contracted state after the birth of the baby) in humans, horses and cows.
Carbetocin has also been shown to stimulate milk letdown through its action on the oxytocin receptors on the myoepithelial cells and there was not a significant amount of carbetocin in breastmilk.
Each dose of Duratocin contains 100 micrograms of carbetocin, 9 mg sodium chloride and ascetic acid. pH is 3.8 and peptide content is greater than 85 percent.
# Pharmacokinetics
Carbetocin is to be used in the hospital by prescription only. It can be administered intravenously or intramuscularly, resulting in different pharmacokinetic action. In both cases, the recommended dose for an average adult female is 100 ug, administered slowly over a minute. Contractile effects of the uterus are apparent within two minutes and can be observed for approximately one hour, though maximum binding occurs about 30 minutes after intramuscular injection. Administration is performed immediately following parturition to minimize risk of postpartum hemorrhage by inducing uterine contractions, increasing muscle tone and thickening the blood. Administration can be performed only once; further administration would prove risky. If further uterine stimulation is needed, treatment with other forms of oxytocic uterotonic drugs should be used.
Endogenous and synthetic oxytocin has a half-life of approximately 3.5 minutes. Carbetocin, in comparison, has a much longer half-life ranging from 85–100 minutes. The bioavailable dose is around 80%. The elimination half-life following intravenous administration is around 40 minutes, though the elimination mechanism is not entirely known. Studies have shown that elimination is only minimally renal (0.7%), but may occur at least partially through enzymatic degradation of peptides, primarily on the C-terminal end. Both elimination and volume of distribution are not dose dependent.
# Mechanism of action
Carbetocin functions as an agonist at peripheral oxytocin receptors, particularly in the myometrium, with lesser affinity for myopepithelial cells. Oxytocin receptors are G-Protein coupled and their mechanism of action involves second messengers and the production of inositol phosphates. Carbetocin mimics this mechanism. Binding for carbetocin and other oxytocin agonists has been shown to be nonselective at the extracellular N-terminus and loops E2 and E3. While the oxytocin receptor shows equal affinity for oxytocin and carbetocin, the biological effect of carbetocin is almost 50% that of endogenous or exogenous oxytocin. Carbetocin has a much longer lasting effect than oxytocin, necessitating only a single dose. Carbetocin inhibits endogenous oxytocin release, interrupting the uterine feedback loop with the hypothalamus and decreasing both central and peripheral release of oxytocin.
During pregnancy, the synthesis of oxytocin receptors in the uterus greatly increases, reaching a peak during labor and delivery. Consequently, the administration of carbetocin or another oxytocin analog during or immediately following birth will have increased uterotonic and contractile effect. The application of carbetocin does not affect a non-pregnant uterus with lower oxytocin receptor expression. Carbetocin also functions to thicken the blood, further preventing post-partum hemorrhage. Carbetocin should not be used to induce or augment labor since it could cause cardiac or respiratory distress to mother or infant.
# Interactions with other drugs and neurotransmitter systems
Due to oxytocin’s close sequence homology with vasopressin, oxytocin analogs often bind with much lower affinity to vasopressin receptors V1, in the uterine lining, and V2, in the kidneys and may consequently interact with or disrupt the vasopressin circuitry and feedback loops.
Carbetocin may work synergistically with drugs such as Dinoprostone and Misoprostol that ripen the cervix. Concurrent use of these drugs can be risky, particularly during pregnancy and prenatal care, possibly causing premature labor or abortion.
# Adverse effects
Ten to forty percent of patients will experience nausea, vomiting, abdominal pain, itching skin, increased body temperature, trembling and weakness. One to five percent of patients may experience back and chest pain, dizziness, anemia, chills and sweating, metallic taste, tachycardia and respiratory distress.
Contraindications for the use of carbetocin include inappropriate timing during labor and delivery (such as before parturition or to induce labor) or allergic reactions to carbetocin or other oxytocin homologues. Additionally, carbetocin should not be used if a patient has high blood pressure or cardiovascular problems. Overdosage or repeated use of carbetocin, particularly if used during pregnancy, could cause hyper-excitation of the oxytocin receptors resulting in excessive and prolonged stimulation of uterine contractions, increasing risk of uterine rupture, placental abruption, fetal respiratory distress and postpartum hemorrhage.
# Comparison with other drugs
Due to carbetocin's considerably longer half-life, its effects are longer lasting than other oxytocin homologs such as Pitocin or barusiban. A single carbetocin administration compared to a placebo or an eight hour intravenous drip of oxytocin in a randomized blind study, necessitated significantly less additional oxytocin therapy following a Cesarean section. Oxytocin receptor antagonists, such as Barusiban or atosiban have the opposite effect of depressing oxytocin receptor activity and can be used to stop premature labor and uterine contractions.
# Legal approval
Carbetocin has been approved for use under the following three brand names in 23 countries, not including the United States: Duratocin (Argentina, Australia, Bahrain, Canada, China, Hong Kong, Italy, Malaysia, Singapore, New Zealand), Lonactene (Mexico), and Pabal (Austria, Belgium, Switzerland, Germany, Estonia, France, UK, Hungary, Lithuania, Luxembourg). Duratocin has also been approved for veterinary use in Poland, Germany, Italy, Belgium, Luxembourg, France and the Netherlands. | Carbetocin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Carbetocin (trade names Duratocin, Pabal, Lonactene) is an obstetric drug used to control postpartum hemorrhage and bleeding after giving birth, particularly following Cesarean section.[1] It is an eight amino acid long analogue of oxytocin (a nonapeptide) and thus has a similar action.[2][3] Carbetocin primarily agonizes peripherally expressed oxytocin receptors. Carbetocin is manufactured by Ferring Pharmaceuticals and is available in Canada and the United Kingdom, but not in the United States.
# Medical uses
Carbetocin works as an oxytocic, antihemorrhagic and uterotonic drug in the peripheral nervous system. The most common causes of postpartum hemorrhage are lack of tone in the uterus from overstretching or the use of an anesthetic.[4] Carbetocin has been approved for use immediately following an elective Cesarean section when a local or spinal anesthesia has been administered.[5] Since the uterus cannot contract on its own following incision during a Cesarean section, exogenous administration of oxytocin or an analog is necessary to restore uterine tone and prevent hemorrhage.[5][6]
Safety of carbetocin following vaginal births and emergency Cesarean sections has not been established, though studies have suggested efficacy following vaginal births to that following Cesarean sections. Some studies have shown that a 10-70 ug dose following vaginal delivery caused contractions and no adverse side effects.[7] Carbetocin has also been shown to increase uterine involution (the return of the uterus to its contracted state after the birth of the baby) in humans, horses and cows.[8][9]
Carbetocin has also been shown to stimulate milk letdown through its action on the oxytocin receptors on the myoepithelial cells and there was not a significant amount of carbetocin in breastmilk.[7]
Each dose of Duratocin contains 100 micrograms of carbetocin, 9 mg sodium chloride and ascetic acid. pH is 3.8 and peptide content is greater than 85 percent.
# Pharmacokinetics
Carbetocin is to be used in the hospital by prescription only. It can be administered intravenously or intramuscularly, resulting in different pharmacokinetic action. In both cases, the recommended dose for an average adult female is 100 ug, administered slowly over a minute. Contractile effects of the uterus are apparent within two minutes and can be observed for approximately one hour,[10] though maximum binding occurs about 30 minutes after intramuscular injection. Administration is performed immediately following parturition to minimize risk of postpartum hemorrhage by inducing uterine contractions, increasing muscle tone and thickening the blood. Administration can be performed only once; further administration would prove risky. If further uterine stimulation is needed, treatment with other forms of oxytocic uterotonic drugs should be used.[10]
Endogenous and synthetic oxytocin has a half-life of approximately 3.5 minutes.[6][11] Carbetocin, in comparison, has a much longer half-life ranging from 85–100 minutes.[6][11] The bioavailable dose is around 80%.[7] The elimination half-life following intravenous administration is around 40 minutes, though the elimination mechanism is not entirely known.[10] Studies have shown that elimination is only minimally renal (0.7%), but may occur at least partially through enzymatic degradation of peptides, primarily on the C-terminal end.[11] Both elimination and volume of distribution are not dose dependent.[10]
# Mechanism of action
Carbetocin functions as an agonist at peripheral oxytocin receptors, particularly in the myometrium, with lesser affinity for myopepithelial cells. Oxytocin receptors are G-Protein coupled[12] and their mechanism of action involves second messengers and the production of inositol phosphates.[13] Carbetocin mimics this mechanism.[11] Binding for carbetocin and other oxytocin agonists has been shown to be nonselective at the extracellular N-terminus and loops E2 and E3.[13] While the oxytocin receptor shows equal affinity for oxytocin and carbetocin, the biological effect of carbetocin is almost 50% that of endogenous or exogenous oxytocin.[11][13] Carbetocin has a much longer lasting effect than oxytocin, necessitating only a single dose. Carbetocin inhibits endogenous oxytocin release, interrupting the uterine feedback loop with the hypothalamus and decreasing both central and peripheral release of oxytocin.[12]
During pregnancy, the synthesis of oxytocin receptors in the uterus greatly increases, reaching a peak during labor and delivery. Consequently, the administration of carbetocin or another oxytocin analog during or immediately following birth will have increased uterotonic and contractile effect. The application of carbetocin does not affect a non-pregnant uterus with lower oxytocin receptor expression.[6] Carbetocin also functions to thicken the blood, further preventing post-partum hemorrhage.[14] Carbetocin should not be used to induce or augment labor since it could cause cardiac or respiratory distress to mother or infant.[5][6]
# Interactions with other drugs and neurotransmitter systems
Due to oxytocin’s close sequence homology with vasopressin, oxytocin analogs often bind with much lower affinity to vasopressin receptors V1, in the uterine lining, and V2, in the kidneys[15] and may consequently interact with or disrupt the vasopressin circuitry and feedback loops.
Carbetocin may work synergistically with drugs such as Dinoprostone and Misoprostol that ripen the cervix. Concurrent use of these drugs can be risky, particularly during pregnancy and prenatal care, possibly causing premature labor or abortion.
# Adverse effects
Ten to forty percent of patients will experience nausea, vomiting, abdominal pain, itching skin, increased body temperature, trembling and weakness. One to five percent of patients may experience back and chest pain, dizziness, anemia, chills and sweating, metallic taste, tachycardia and respiratory distress.[10][14][15]
Contraindications for the use of carbetocin include inappropriate timing during labor and delivery (such as before parturition or to induce labor) or allergic reactions to carbetocin or other oxytocin homologues.[10] Additionally, carbetocin should not be used if a patient has high blood pressure or cardiovascular problems. Overdosage or repeated use of carbetocin, particularly if used during pregnancy, could cause hyper-excitation of the oxytocin receptors resulting in excessive and prolonged stimulation of uterine contractions, increasing risk of uterine rupture, placental abruption, fetal respiratory distress and postpartum hemorrhage.[10]
# Comparison with other drugs
Due to carbetocin's considerably longer half-life, its effects are longer lasting than other oxytocin homologs such as Pitocin or barusiban.[13] A single carbetocin administration compared to a placebo or an eight hour intravenous drip of oxytocin in a randomized blind study, necessitated significantly less additional oxytocin therapy following a Cesarean section. Oxytocin receptor antagonists, such as Barusiban or atosiban have the opposite effect of depressing oxytocin receptor activity and can be used to stop premature labor and uterine contractions.[13]
# Legal approval
Carbetocin has been approved for use under the following three brand names in 23 countries, not including the United States: Duratocin (Argentina, Australia, Bahrain, Canada, China, Hong Kong, Italy, Malaysia, Singapore, New Zealand), Lonactene (Mexico), and Pabal (Austria, Belgium, Switzerland, Germany, Estonia, France, UK, Hungary, Lithuania, Luxembourg). Duratocin has also been approved for veterinary use in Poland, Germany, Italy, Belgium, Luxembourg, France and the Netherlands.[14] | https://www.wikidoc.org/index.php/Carbetocin | |
60d44ca69ed365ed3a8a229008c684975eb50058 | wikidoc | Carboprost | Carboprost
For patient information regarding Carboprost tromethamine, click here.
# Disclaimer
# Black Box Warning
# Overview
Carboprost is a Endocrine metabolic agent and prostaglandin that is FDA approved for the treatment of postpartum hemorrhage due to uterine atony, and aborting pregnancy related to second trimester. There is a Black Box Warning for this drug as shown here. Common adverse reactions include flushing, diarrhea, nausea, vomiting and leukocytosis.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Carboprost tromethamine Sterile Solution is indicated for aborting pregnancy between the 13th and 20th weeks of gestation as calculated from the first day of the last normal menstrual period and in the following conditions related to second trimester abortion:
- Failure of expulsion of the fetus during the course of treatment by another method
- Premature rupture of membranes in intrauterine methods with loss of drug and insufficient or absent uterine activity
- Requirement of a repeat intrauterine instillation of drug for expulsion of the fetus
- Inadvertent or spontaneous rupture of membranes in the presence of a previable fetus and absence of adequate activity for expulsion.
- Carboprost tromethamine is indicated for the treatment of postpartum hemorrhage due to uterine atony which has not responded to conventional methods of management. Prior treatment should include the use of intravenously administered oxytocin, manipulative techniques such as uterine massage and, unless contraindicated, intramuscular ergot preparations. Studies have shown that in such cases, the use of Carboprost tromethamine has resulted in satisfactory control of hemorrhage, although it is unclear whether or not ongoing or delayed effects of previously administered ecbolic agents have contributed to the outcome. In a high proportion of cases, Carboprost tromethamine used in this manner has resulted in the cessation of life threatening bleeding and the avoidance of emergency surgical intervention.
### Dosing information
- An initial dose of 1 mL of Carboprost tromethamine Sterile Solution (containing the equivalent of 250 micrograms of carboprost) is to be administered deep in the muscle with a tuberculin syringe. Subsequent doses of 250 micrograms should be administered at 1½ to 3½ hour intervals depending on uterine response.
- An optional test dose of 100 micrograms (0.4 mL) may be administered initially. The dose may be increased to 500 micrograms (2 mL) if uterine contractility is judged to be inadequate after several doses of 250 micrograms (1 mL).
- he total dose administered of carboprost tromethamine should not exceed 12 milligrams and continuous administration of the drug for more than two days is not recommended.
- An initial dose of 250 micrograms of Carboprost tromethamine Sterile Solution (1 mL of Carboprost tromethamine) is to be given deep, intramuscularly. In clinical trials it was found that the majority of successful cases (73%) responded to single injections. In some selected cases, however, multiple dosing at intervals of 15 to 90 minutes was carried out with successful outcome. The need for additional injections and the interval at which these should be given can be determined only by the attending physicians as dictated by the course of clinical events. The total dose of Carboprost tromethamine should not exceed 2 milligrams (8 doses).
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Carboprost in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Carboprost in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Carboprost in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Carboprost in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Carboprost in pediatric patients.
# Contraindications
- Hypersensitivity (including anaphylaxis and angioedema) to Carboprost tromethamine Sterile Solution
- Acute pelvic inflammatory disease
- Patients with active cardiac, pulmonary, renal or hepatic disease
# Warnings
- Carboprost tromethamine does not appear to directly affect the fetoplacental unit. Therefore, the possibility does exist that the previable fetus aborted by Carboprost tromethamine could exhibit transient life signs. Carboprost tromethamine is not indicated if the fetus in utero has reached the stage of viability. Carboprost tromethamine should not be considered a feticidal agent.
- Evidence from animal studies has suggested that certain other prostaglandins have some teratogenic potential. Although these studies do not indicate that Carboprost tromethamine is teratogenic, any pregnancy termination with Carboprost tromethamine that fails should be completed by some other means.
- This product contains benzyl alcohol. Benzyl alcohol has been reported to be associated with a fatal "Gasping Syndrome" in premature infants.
### PRECAUTIONS
- Animal studies lasting several weeks at high doses have shown that prostaglandins of the E and F series can induce proliferation of bone. Such effects have also been noted in newborn infants who have received prostaglandin E1 during prolonged treatment. There is no evidence that short term administration of Carboprost tromethamine Sterile Solution can cause similar bone effects.
- In patients with a history of asthma, hypo- or hypertension, cardiovascular, renal, or hepatic disease, anemia, jaundice, diabetes, or epilepsy, Carboprost tromethamine should be used cautiously.
- As with any oxytocic agent, Carboprost tromethamine should be used with caution in patients with compromised (scarred) uteri.
- As with spontaneous abortion, a process which is sometimes incomplete, abortion induced by Carboprost tromethamine may be expected to be incomplete in about 20% of cases.
- Although the incidence of cervical trauma is extremely small, the cervix should always be carefully examined immediately post-abortion.
- Use of Carboprost tromethamine is associated with transient pyrexia that may be due to its effect on hypothalamic thermoregulation. Temperature elevations exceeding 2° F (1.1° C) were observed in approximately one-eighth of the patients who received the recommended dosage regimen. In all cases, temperature returned to normal when therapy ended. Differentiation of post-abortion endometritis from drug-induced temperature elevations is difficult, but with increasing clinical experience, the distinctions become more obvious and are summarized below:
TABLE
- Increased blood pressure. In the postpartum hemorrhage series, 5/115 (4%) of patients had an increase of blood pressure reported as a side effect. The degree of hypertension was moderate and it is not certain as to whether this was in fact due to a direct effect of Carboprost tromethamine or a return to a status of pregnancy associated hypertension manifest by the correction of hypovolemic shock. In any event the cases reported did not require specific therapy for the elevated blood pressure.
- Use in patients with chorioamnionitis. During the clinical trials with Carboprost tromethamine, chorioamnionitis was identified as a complication contributing to postpartum uterine atony and hemorrhage in 8/115 (7%) of cases, 3 of which failed to respond to Carboprost tromethamine. This complication during labor may have an inhibitory effect on the uterine response to Carboprost tromethamine similar to what has been reported for other oxytocic agents.1
- Duff, Sanders, and Gibbs; The course of labor in term patients with chorioamnionitis; Am. J. Obstet. Gynecol.; vol. 147, no. 4, October 15, 1983 pp 391–395.
# Adverse Reactions
## Clinical Trials Experience
- The adverse effects of Carboprost tromethamine Sterile Solution are generally transient and reversible when therapy ends. The most frequent adverse reactions observed are related to its contractile effect on smooth muscle.
- In patients studied, approximately two-thirds experienced vomiting and diarrhea, approximately one-third had nausea, one-eighth had a temperature increase greater than 2° F, and one-fourteenth experienced flushing.
- The pretreatment or concurrent administration of antiemetic and antidiarrheal drugs decreases considerably the very high incidence of gastrointestinal effects common with all prostaglandins used for abortion. Their use should be considered an integral part of the management of patients undergoing abortion with Carboprost tromethamine.
- Of those patients experiencing a temperature elevation, approximately one-sixteenth had a clinical diagnosis of endometritis. The remaining temperature elevations returned to normal within several hours after the last injection.
- Adverse effects observed during the use of Carboprost tromethamine for abortion and for hemorrhage, not all of which are clearly drug related, in decreasing order of frequency include:
TABLE
- The most common complications when Carboprost tromethamine was utilized for abortion requiring additional treatment after discharge from the hospital were endometritis, retained placental fragments, and excessive uterine bleeding, occurring in about one in every 50 patients.
## Postmarketing Experience
- Hypersensitivity reactions (e.g. Anaphylactic reaction, Anaphylactic shock, Anaphylactoid reaction, Angioedema).
# Drug Interactions
- Carboprost tromethamine may augment the activity of other oxytocic agents. Concomitant use with other oxytocic agents is not recommended.
# Use in Specific Populations
### Pregnancy
- Animal studies do not indicate that Carboprost tromethamine is teratogenic, however, it has been shown to be embryotoxic in rats and rabbits and any dose which produces increased uterine tone could put the embryo or fetus at risk.
### Labor and Delivery
There is no FDA guidance on use of Carboprost during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Carboprost with respect to nursing mothers.
### Pediatric Use
There is no FDA guidance on the use of Carboprost with respect to pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of Carboprost with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Carboprost with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Carboprost with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Carboprost in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Carboprost in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Carboprost in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Carboprost in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intramuscular
### Monitoring
There is limited information regarding Monitoring of Carboprost in the drug label.
- Description
# Overdosage
There is limited information regarding Chronic Overdose of Carboprost in the drug label.
# Pharmacology
## Mechanism of Action
- Carboprost tromethamine administered intramuscularly stimulates in the gravid uterus myometrial contractions similar to labor contractions at the end of a full term pregnancy. Whether or not these contractions result from a direct effect of carboprost on the myometrium has not been determined. Nonetheless, they evacuate the products of conception from the uterus in most cases.
- Postpartum, the resultant myometrial contractions provide hemostasis at the site of placentation.
## Structure
- Carboprost tromethamine Sterile Solution, an oxytocic, contains the tromethamine salt of the (15S)-15 methyl analogue of naturally occurring prostaglandin F2α in a solution suitable for intramuscular injection.
Carboprost tromethamine is the established name for the active ingredient in Carboprost tromethamine. Four other chemical names are:
1. (15S)-15-methyl prostaglandin F2α tromethamine salt
2. 7-(3α,5α-dihydroxy-2ß--1α-cyclopentyl]-cis-5-heptenoic acid compound with 2-amino-2-(hydroxymethyl)-1,3-propanediol
3. (15S)-9α,11α,15-trihydroxy-15-methylprosta-cis-5, trans-13-dienoic acid tromethamine salt
4. (15S)-15-methyl PGF2α-THAM
The structural formula is represented below:
## Pharmacodynamics
- Carboprost tromethamine also stimulates the smooth muscle of the human gastrointestinal tract. This activity may produce the vomiting or diarrhea or both that is common when carboprost tromethamine is used to terminate pregnancy and for use postpartum. In laboratory animals and also in humans carboprost tromethamine can elevate body temperature. With the clinical doses of carboprost tromethamine used for the termination of pregnancy, and for use postpartum, some patients do experience transient temperature increases.
- In laboratory animals and in humans large doses of carboprost tromethamine can raise blood pressure, probably by contracting the vascular smooth muscle. With the doses of carboprost tromethamine used for terminating pregnancy, this effect has not been clinically significant. In laboratory animals and also in humans carboprost tromethamine can elevate body temperature. With the clinical doses of carboprost tromethamine used for the termination of pregnancy, some patients do experience temperature increases. In some patients, carboprost tromethamine may cause transient bronchoconstriction.
## Pharmacokinetics
- Drug plasma concentrations were determined by radioimmunoassay in peripheral blood samples collected by different investigators from 10 patients undergoing abortion. The patients had been injected intramuscularly with 250 micrograms of carboprost at two hour intervals. Blood levels of drug peaked at an average of 2060 picograms/mL one-half hour after the first injection then declined to an average concentration of 770 picograms/mL two hours after the first injection just before the second injection. The average plasma concentration one-half hour after the second injection was slightly higher (2663 picograms/mL) than that after the first injection and decreased again to an average of 1047 picograms/mL by two hours after the second injection. Plasma samples were collected from 5 of these 10 patients following additional injections of the prostaglandin. The average peak concentrations of drug were slightly higher following each successive injection of the prostaglandin, but always decreased to levels less than the preceding peak values by two hours after each injection.
- Five women who had delivery spontaneously at term were treated immediately postpartum with a single injection of 250 micrograms of carboprost tromethamine. Peripheral blood samples were collected at several times during the four hours following treatment and carboprost tromethamine levels were determined by radioimmunoassay. The highest concentration of carboprost tromethamine was observed at 15 minutes in two patients (3009 and 2916 picograms/mL), at 30 minutes in two patients (3097 and 2792 picograms/mL), and at 60 minutes in one patient (2718 picograms/mL).
## Nonclinical Toxicology
- Carcinogenic bioassay studies have not been conducted in animals with Carboprost tromethamine due to the limited indications for use and short duration of administration. No evidence of mutagenicity was observed in the Micronucleus Test or Ames Assay.
# Clinical Studies
There is limited information regarding Clinical Studies of Carboprost in the drug label.
# How Supplied
N/A
# Images
## Package and Label Display Panel
NDC 0009-0856-08
Contains 10 of NDC 0009-0856-05
Rx only
10–1 mL Single-Dose Ampoules
Hemabate®
carboprost tromethamine
injection, USP
250 mcg*
FOR INTRAMUSCULAR USE ONLY
Pfizer Injectables
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Carboprost in the drug label.
# Precautions with Alcohol
- Alcohol-Carboprost interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- HEMABATE®
# Look-Alike Drug Names
N/A
# Drug Shortage Status | Carboprost
For patient information regarding Carboprost tromethamine, click here.
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Adeel Jamil, M.D. [2]
# Disclaimer
# Black Box Warning
# Overview
Carboprost is a Endocrine metabolic agent and prostaglandin that is FDA approved for the treatment of postpartum hemorrhage due to uterine atony, and aborting pregnancy related to second trimester. There is a Black Box Warning for this drug as shown here. Common adverse reactions include flushing, diarrhea, nausea, vomiting and leukocytosis.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Carboprost tromethamine Sterile Solution is indicated for aborting pregnancy between the 13th and 20th weeks of gestation as calculated from the first day of the last normal menstrual period and in the following conditions related to second trimester abortion:
- Failure of expulsion of the fetus during the course of treatment by another method
- Premature rupture of membranes in intrauterine methods with loss of drug and insufficient or absent uterine activity
- Requirement of a repeat intrauterine instillation of drug for expulsion of the fetus
- Inadvertent or spontaneous rupture of membranes in the presence of a previable fetus and absence of adequate activity for expulsion.
- Carboprost tromethamine is indicated for the treatment of postpartum hemorrhage due to uterine atony which has not responded to conventional methods of management. Prior treatment should include the use of intravenously administered oxytocin, manipulative techniques such as uterine massage and, unless contraindicated, intramuscular ergot preparations. Studies have shown that in such cases, the use of Carboprost tromethamine has resulted in satisfactory control of hemorrhage, although it is unclear whether or not ongoing or delayed effects of previously administered ecbolic agents have contributed to the outcome. In a high proportion of cases, Carboprost tromethamine used in this manner has resulted in the cessation of life threatening bleeding and the avoidance of emergency surgical intervention.
### Dosing information
- An initial dose of 1 mL of Carboprost tromethamine Sterile Solution (containing the equivalent of 250 micrograms of carboprost) is to be administered deep in the muscle with a tuberculin syringe. Subsequent doses of 250 micrograms should be administered at 1½ to 3½ hour intervals depending on uterine response.
- An optional test dose of 100 micrograms (0.4 mL) may be administered initially. The dose may be increased to 500 micrograms (2 mL) if uterine contractility is judged to be inadequate after several doses of 250 micrograms (1 mL).
- he total dose administered of carboprost tromethamine should not exceed 12 milligrams and continuous administration of the drug for more than two days is not recommended.
- An initial dose of 250 micrograms of Carboprost tromethamine Sterile Solution (1 mL of Carboprost tromethamine) is to be given deep, intramuscularly. In clinical trials it was found that the majority of successful cases (73%) responded to single injections. In some selected cases, however, multiple dosing at intervals of 15 to 90 minutes was carried out with successful outcome. The need for additional injections and the interval at which these should be given can be determined only by the attending physicians as dictated by the course of clinical events. The total dose of Carboprost tromethamine should not exceed 2 milligrams (8 doses).
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Carboprost in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Carboprost in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Carboprost in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Carboprost in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Carboprost in pediatric patients.
# Contraindications
- Hypersensitivity (including anaphylaxis and angioedema) to Carboprost tromethamine Sterile Solution
- Acute pelvic inflammatory disease
- Patients with active cardiac, pulmonary, renal or hepatic disease
# Warnings
- Carboprost tromethamine does not appear to directly affect the fetoplacental unit. Therefore, the possibility does exist that the previable fetus aborted by Carboprost tromethamine could exhibit transient life signs. Carboprost tromethamine is not indicated if the fetus in utero has reached the stage of viability. Carboprost tromethamine should not be considered a feticidal agent.
- Evidence from animal studies has suggested that certain other prostaglandins have some teratogenic potential. Although these studies do not indicate that Carboprost tromethamine is teratogenic, any pregnancy termination with Carboprost tromethamine that fails should be completed by some other means.
- This product contains benzyl alcohol. Benzyl alcohol has been reported to be associated with a fatal "Gasping Syndrome" in premature infants.
### PRECAUTIONS
- Animal studies lasting several weeks at high doses have shown that prostaglandins of the E and F series can induce proliferation of bone. Such effects have also been noted in newborn infants who have received prostaglandin E1 during prolonged treatment. There is no evidence that short term administration of Carboprost tromethamine Sterile Solution can cause similar bone effects.
- In patients with a history of asthma, hypo- or hypertension, cardiovascular, renal, or hepatic disease, anemia, jaundice, diabetes, or epilepsy, Carboprost tromethamine should be used cautiously.
- As with any oxytocic agent, Carboprost tromethamine should be used with caution in patients with compromised (scarred) uteri.
- As with spontaneous abortion, a process which is sometimes incomplete, abortion induced by Carboprost tromethamine may be expected to be incomplete in about 20% of cases.
- Although the incidence of cervical trauma is extremely small, the cervix should always be carefully examined immediately post-abortion.
- Use of Carboprost tromethamine is associated with transient pyrexia that may be due to its effect on hypothalamic thermoregulation. Temperature elevations exceeding 2° F (1.1° C) were observed in approximately one-eighth of the patients who received the recommended dosage regimen. In all cases, temperature returned to normal when therapy ended. Differentiation of post-abortion endometritis from drug-induced temperature elevations is difficult, but with increasing clinical experience, the distinctions become more obvious and are summarized below:
TABLE
- Increased blood pressure. In the postpartum hemorrhage series, 5/115 (4%) of patients had an increase of blood pressure reported as a side effect. The degree of hypertension was moderate and it is not certain as to whether this was in fact due to a direct effect of Carboprost tromethamine or a return to a status of pregnancy associated hypertension manifest by the correction of hypovolemic shock. In any event the cases reported did not require specific therapy for the elevated blood pressure.
- Use in patients with chorioamnionitis. During the clinical trials with Carboprost tromethamine, chorioamnionitis was identified as a complication contributing to postpartum uterine atony and hemorrhage in 8/115 (7%) of cases, 3 of which failed to respond to Carboprost tromethamine. This complication during labor may have an inhibitory effect on the uterine response to Carboprost tromethamine similar to what has been reported for other oxytocic agents.1
- Duff, Sanders, and Gibbs; The course of labor in term patients with chorioamnionitis; Am. J. Obstet. Gynecol.; vol. 147, no. 4, October 15, 1983 pp 391–395.
# Adverse Reactions
## Clinical Trials Experience
- The adverse effects of Carboprost tromethamine Sterile Solution are generally transient and reversible when therapy ends. The most frequent adverse reactions observed are related to its contractile effect on smooth muscle.
- In patients studied, approximately two-thirds experienced vomiting and diarrhea, approximately one-third had nausea, one-eighth had a temperature increase greater than 2° F, and one-fourteenth experienced flushing.
- The pretreatment or concurrent administration of antiemetic and antidiarrheal drugs decreases considerably the very high incidence of gastrointestinal effects common with all prostaglandins used for abortion. Their use should be considered an integral part of the management of patients undergoing abortion with Carboprost tromethamine.
- Of those patients experiencing a temperature elevation, approximately one-sixteenth had a clinical diagnosis of endometritis. The remaining temperature elevations returned to normal within several hours after the last injection.
- Adverse effects observed during the use of Carboprost tromethamine for abortion and for hemorrhage, not all of which are clearly drug related, in decreasing order of frequency include:
TABLE
- The most common complications when Carboprost tromethamine was utilized for abortion requiring additional treatment after discharge from the hospital were endometritis, retained placental fragments, and excessive uterine bleeding, occurring in about one in every 50 patients.
## Postmarketing Experience
- Hypersensitivity reactions (e.g. Anaphylactic reaction, Anaphylactic shock, Anaphylactoid reaction, Angioedema).
# Drug Interactions
- Carboprost tromethamine may augment the activity of other oxytocic agents. Concomitant use with other oxytocic agents is not recommended.
# Use in Specific Populations
### Pregnancy
- Animal studies do not indicate that Carboprost tromethamine is teratogenic, however, it has been shown to be embryotoxic in rats and rabbits and any dose which produces increased uterine tone could put the embryo or fetus at risk.
### Labor and Delivery
There is no FDA guidance on use of Carboprost during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Carboprost with respect to nursing mothers.
### Pediatric Use
There is no FDA guidance on the use of Carboprost with respect to pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of Carboprost with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Carboprost with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Carboprost with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Carboprost in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Carboprost in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Carboprost in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Carboprost in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intramuscular
### Monitoring
There is limited information regarding Monitoring of Carboprost in the drug label.
- Description
# Overdosage
There is limited information regarding Chronic Overdose of Carboprost in the drug label.
# Pharmacology
## Mechanism of Action
- Carboprost tromethamine administered intramuscularly stimulates in the gravid uterus myometrial contractions similar to labor contractions at the end of a full term pregnancy. Whether or not these contractions result from a direct effect of carboprost on the myometrium has not been determined. Nonetheless, they evacuate the products of conception from the uterus in most cases.
- Postpartum, the resultant myometrial contractions provide hemostasis at the site of placentation.
## Structure
- Carboprost tromethamine Sterile Solution, an oxytocic, contains the tromethamine salt of the (15S)-15 methyl analogue of naturally occurring prostaglandin F2α in a solution suitable for intramuscular injection.
Carboprost tromethamine is the established name for the active ingredient in Carboprost tromethamine. Four other chemical names are:
1. (15S)-15-methyl prostaglandin F2α tromethamine salt
2. 7-(3α,5α-dihydroxy-2ß-[(3S)-3-hydroxy-3-methyl-trans-1-octenyl]-1α-cyclopentyl]-cis-5-heptenoic acid compound with 2-amino-2-(hydroxymethyl)-1,3-propanediol
3. (15S)-9α,11α,15-trihydroxy-15-methylprosta-cis-5, trans-13-dienoic acid tromethamine salt
4. (15S)-15-methyl PGF2α-THAM
The structural formula is represented below:
## Pharmacodynamics
- Carboprost tromethamine also stimulates the smooth muscle of the human gastrointestinal tract. This activity may produce the vomiting or diarrhea or both that is common when carboprost tromethamine is used to terminate pregnancy and for use postpartum. In laboratory animals and also in humans carboprost tromethamine can elevate body temperature. With the clinical doses of carboprost tromethamine used for the termination of pregnancy, and for use postpartum, some patients do experience transient temperature increases.
- In laboratory animals and in humans large doses of carboprost tromethamine can raise blood pressure, probably by contracting the vascular smooth muscle. With the doses of carboprost tromethamine used for terminating pregnancy, this effect has not been clinically significant. In laboratory animals and also in humans carboprost tromethamine can elevate body temperature. With the clinical doses of carboprost tromethamine used for the termination of pregnancy, some patients do experience temperature increases. In some patients, carboprost tromethamine may cause transient bronchoconstriction.
## Pharmacokinetics
- Drug plasma concentrations were determined by radioimmunoassay in peripheral blood samples collected by different investigators from 10 patients undergoing abortion. The patients had been injected intramuscularly with 250 micrograms of carboprost at two hour intervals. Blood levels of drug peaked at an average of 2060 picograms/mL one-half hour after the first injection then declined to an average concentration of 770 picograms/mL two hours after the first injection just before the second injection. The average plasma concentration one-half hour after the second injection was slightly higher (2663 picograms/mL) than that after the first injection and decreased again to an average of 1047 picograms/mL by two hours after the second injection. Plasma samples were collected from 5 of these 10 patients following additional injections of the prostaglandin. The average peak concentrations of drug were slightly higher following each successive injection of the prostaglandin, but always decreased to levels less than the preceding peak values by two hours after each injection.
- Five women who had delivery spontaneously at term were treated immediately postpartum with a single injection of 250 micrograms of carboprost tromethamine. Peripheral blood samples were collected at several times during the four hours following treatment and carboprost tromethamine levels were determined by radioimmunoassay. The highest concentration of carboprost tromethamine was observed at 15 minutes in two patients (3009 and 2916 picograms/mL), at 30 minutes in two patients (3097 and 2792 picograms/mL), and at 60 minutes in one patient (2718 picograms/mL).
## Nonclinical Toxicology
- Carcinogenic bioassay studies have not been conducted in animals with Carboprost tromethamine due to the limited indications for use and short duration of administration. No evidence of mutagenicity was observed in the Micronucleus Test or Ames Assay.
# Clinical Studies
There is limited information regarding Clinical Studies of Carboprost in the drug label.
# How Supplied
N/A
# Images
## Package and Label Display Panel
NDC 0009-0856-08
Contains 10 of NDC 0009-0856-05
Rx only
10–1 mL Single-Dose Ampoules
Hemabate®
carboprost tromethamine
injection, USP
250 mcg*
FOR INTRAMUSCULAR USE ONLY
Pfizer Injectables
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Carboprost in the drug label.
# Precautions with Alcohol
- Alcohol-Carboprost interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- HEMABATE®
# Look-Alike Drug Names
N/A
# Drug Shortage Status | https://www.wikidoc.org/index.php/Carboprost | |
b3f22676b599660590c8c49fe2f1b6783804b2df | wikidoc | Carcinogen | Carcinogen
# Overview
The term carcinogen refers to any substance, radionuclide or radiation which is an agent directly involved in the promotion of cancer or in the facilitation of its propagation. This may be due to genomic instability or to the disruption of cellular metabolic processes. Several radioactive substances are considered carcinogens, but their carcinogenic activity is attributed to the radiation, for example gamma rays or alpha particles, which they emit. Common examples of carcinogens are inhaled asbestos and tobacco smoke.
Cancer is a disease where damaged cells of the patient's body do not undergo programmed cell death, but their growth is no longer controlled and their metabolism is altered. Carcinogens may increase the risk of getting cancer by altering cellular metabolism or damaging DNA directly in cells, which interferes with biological processes, and induces the uncontrolled, malignant division ultimately leading to the formation of tumors. Usually DNA damage, if too severe to repair, leads to programmed cell death, but if the programmed cell death pathway is damaged, then the cell cannot prevent itself from becoming a cancer cell.
There are many natural carcinogens. Aflatoxin B1, which is produced by the fungus Aspergillus flavus growing on stored grains, nuts and peanut butter, is an example of a potent, naturally-occurring microbial carcinogen. Certain viruses such as Hepatitis B and human papilloma viruses have been found to cause cancer in humans. The first one shown to cause cancer in animals was Rous sarcoma virus, discovered in 1910 by Peyton Rous.
Benzene, kepone, EDB, asbestos, and the waste rock of oil shale mining have all been classified as carcinogenic.As far back as the 1930s]], industrial and tobacco smoke were identified as sources of dozens of carcinogens, including benzopyrene, tobacco-specific nitrosamines such as nitrosonornicotine, and reactive aldehydes such as formaldehyde — which is also a hazard in embalming and making plastics. Vinyl chloride, from which PVC is manufactured, is a carcinogen and thus a hazard in PVC production.
Co-carcinogens are chemicals which do not separately cause cancer, but do so in specific combinations.
After the carcinogen enters the body, the body makes an attempt to eliminate it through a process called biotransformation. The purpose of these reactions is to make the carcinogen more water-soluble so that it can be removed from the body. But these reactions can also convert a less toxic carcinogen into a more toxic one.
DNA is nucleophilic, therefore soluble carbon electrophiles are carcinogenic, because DNA attacks them. For example, some alkenes are toxicated by human enzymes to produce an electrophilic epoxide. DNA attacks the epoxide, and is bound permanently to it. This is the mechanism behind the carcinogenity of benzopyrene in tobacco smoke, other aromatics, aflatoxin and mustard gas.
# Radiation
CERCLA identifies all radionuclides as carcinogens, although the nature of the emitted radiation (alpha, beta, or gamma, and the energy), its consequent capacity to cause ionization in tissues, and the magnitude of radiation exposure, determine the potential hazard. For example, Thorotrast, a (incidentally-radioactive) suspension previously used as a contrast medium in x-ray diagnostics, is thought to be the most potent human carcinogen known because of its retention within various organs and persistent emission of alpha particles. Marie Curie, one of the pioneers of radioactivity, died of cancer caused by radiation exposure during her experiments.
Not all types of electromagnetic radiation are carcinogenic. Low-energy waves on the electromagnetic spectrum are generally not, including radio waves, microwave radiation, infrared radiation, and visible light. Higher-energy radiation, including ultraviolet radiation (present in sunlight), x-rays, and gamma radiation, generally is carcinogenic, if received in sufficient doses.
Substances or foods irradiated with electrons or electromagnetic radiation (such as microwave, X-ray or gamma) are not carcinogenic. No "radiation" remains, just like no light remains in a lens. (In contrast, non-electromagnetic neutron radiation produced inside nuclear reactors can make substances radioactive.)
# Carcinogens in prepared food
Cooking food at high temperatures, for example broiling or barbecuing meats, can lead to the formation of minute quantities of many potent carcinogens that are comparable to those found in cigarette smoke (i.e., benzopyrene). Charring of food resembles coking and tobacco pyrolysis and produces similar carcinogens. There are several carcinogenic pyrolysis products, such as polynuclear aromatic hydrocarbons, which are converted by human enzymes into epoxides, which attach permanently to DNA. Pre-cooking meats in a microwave oven for 2-3 minutes before broiling shortens the time on the hot pan, which can help minimize the formation of these carcinogens.
Recent reports have found that the known animal carcinogen acrylamide is generated in fried or overheated carbohydrate foods (such as french fries and potato chips). Studies are underway at the US Food and Drug Administration and Europe an regulatory agencies to assess its potential risk to humans. The charred residue on barbecued meats has been identified as a carcinogen, along with many other tars.
Nevertheless, the fact that the food contains minute quantities doesn't necessarily mean that there is a significant hazard. The gastrointestinal tract sheds its outer layer continuously to protect itself from carcinomas, and has a high activity of detoxifying enzymes. The lungs are not protected in this manner, therefore smoking is much more hazardous.
# Classification of carcinogens
Carcinogens can be classified as genotoxic or nongenotoxic. Genotoxins cause irreversible genetic damage or mutations by binding to DNA. Genotoxins include chemical agents like N-Nitroso-N-Methylurea (MNU) or non-chemical agents such as ultraviolet light and ionizing radiation. Certain viruses can also act as carcinogens by interacting with DNA.
Nongenotoxins do not directly affect DNA but act in other ways to promote growth. These include hormones and some organic compounds.
# IARC classification of carcinogens
- Group 1: the agent (mixture) is definitely carcinogenic to humans. The exposure circumstance entails exposures that are carcinogenic to humans.
- Group 2A: the agent (mixture) is probably carcinogenic to humans. The exposure circumstance entails exposures that are probably carcinogenic to humans.
- Group 2B: the agent (mixture) is possibly carcinogenic to humans. The exposure circumstance entails exposures that are possibly carcinogenic to humans.
- Group 3: the agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans.
- Group 4: the agent (mixture) is probably not carcinogenic to humans.
Further details can be found in the IARC Monographs.
# Notes
- ↑ Wei Zheng, Deborah R Gustafson, Rashmi Sinha, James R Cerhan, et al. "Well-done meat intake and the risk of breast cancer." Journal of the National Cancer Institute. Oxford: Nov 18, 1998.Vol. 90, Iss. 22; pg. 1724, 6 pgs.
- ↑ "The Gale Encyclopedia of Cancer: A guide to Cancer and its Treatments, Second Edition. Page no. 137"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} | Carcinogen
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
The term carcinogen refers to any substance, radionuclide or radiation which is an agent directly involved in the promotion of cancer or in the facilitation of its propagation. This may be due to genomic instability or to the disruption of cellular metabolic processes. Several radioactive substances are considered carcinogens, but their carcinogenic activity is attributed to the radiation, for example gamma rays or alpha particles, which they emit. Common examples of carcinogens are inhaled asbestos and tobacco smoke.
Cancer is a disease where damaged cells of the patient's body do not undergo programmed cell death, but their growth is no longer controlled and their metabolism is altered. Carcinogens may increase the risk of getting cancer by altering cellular metabolism or damaging DNA directly in cells, which interferes with biological processes, and induces the uncontrolled, malignant division ultimately leading to the formation of tumors. Usually DNA damage, if too severe to repair, leads to programmed cell death, but if the programmed cell death pathway is damaged, then the cell cannot prevent itself from becoming a cancer cell.
There are many natural carcinogens. Aflatoxin B1, which is produced by the fungus Aspergillus flavus growing on stored grains, nuts and peanut butter, is an example of a potent, naturally-occurring microbial carcinogen. Certain viruses such as Hepatitis B and human papilloma viruses have been found to cause cancer in humans. The first one shown to cause cancer in animals was Rous sarcoma virus, discovered in 1910 by Peyton Rous.
Benzene, kepone, EDB, asbestos, and the waste rock of oil shale mining have all been classified as carcinogenic.As far back as the 1930s]], industrial and tobacco smoke were identified as sources of dozens of carcinogens, including benzopyrene, tobacco-specific nitrosamines such as nitrosonornicotine, and reactive aldehydes such as formaldehyde — which is also a hazard in embalming and making plastics. Vinyl chloride, from which PVC is manufactured, is a carcinogen and thus a hazard in PVC production.
Co-carcinogens are chemicals which do not separately cause cancer, but do so in specific combinations.
After the carcinogen enters the body, the body makes an attempt to eliminate it through a process called biotransformation. The purpose of these reactions is to make the carcinogen more water-soluble so that it can be removed from the body. But these reactions can also convert a less toxic carcinogen into a more toxic one.
DNA is nucleophilic, therefore soluble carbon electrophiles are carcinogenic, because DNA attacks them. For example, some alkenes are toxicated by human enzymes to produce an electrophilic epoxide. DNA attacks the epoxide, and is bound permanently to it. This is the mechanism behind the carcinogenity of benzopyrene in tobacco smoke, other aromatics, aflatoxin and mustard gas.
# Radiation
CERCLA identifies all radionuclides as carcinogens, although the nature of the emitted radiation (alpha, beta, or gamma, and the energy), its consequent capacity to cause ionization in tissues, and the magnitude of radiation exposure, determine the potential hazard. For example, Thorotrast, a (incidentally-radioactive) suspension previously used as a contrast medium in x-ray diagnostics, is thought to be the most potent human carcinogen known because of its retention within various organs and persistent emission of alpha particles. Marie Curie, one of the pioneers of radioactivity, died of cancer caused by radiation exposure during her experiments.
Not all types of electromagnetic radiation are carcinogenic. Low-energy waves on the electromagnetic spectrum are generally not, including radio waves, microwave radiation, infrared radiation, and visible light. Higher-energy radiation, including ultraviolet radiation (present in sunlight), x-rays, and gamma radiation, generally is carcinogenic, if received in sufficient doses.
Substances or foods irradiated with electrons or electromagnetic radiation (such as microwave, X-ray or gamma) are not carcinogenic. No "radiation" remains, just like no light remains in a lens. (In contrast, non-electromagnetic neutron radiation produced inside nuclear reactors can make substances radioactive.)
# Carcinogens in prepared food
Cooking food at high temperatures, for example broiling or barbecuing meats, can lead to the formation of minute quantities of many potent carcinogens that are comparable to those found in cigarette smoke (i.e., benzopyrene).[1] Charring of food resembles coking and tobacco pyrolysis and produces similar carcinogens. There are several carcinogenic pyrolysis products, such as polynuclear aromatic hydrocarbons, which are converted by human enzymes into epoxides, which attach permanently to DNA. Pre-cooking meats in a microwave oven for 2-3 minutes before broiling shortens the time on the hot pan, which can help minimize the formation of these carcinogens.
Recent reports have found that the known animal carcinogen acrylamide is generated in fried or overheated carbohydrate foods (such as french fries and potato chips). Studies are underway at the US Food and Drug Administration and Europe an regulatory agencies to assess its potential risk to humans. The charred residue on barbecued meats has been identified as a carcinogen, along with many other tars.
Nevertheless, the fact that the food contains minute quantities doesn't necessarily mean that there is a significant hazard. The gastrointestinal tract sheds its outer layer continuously to protect itself from carcinomas, and has a high activity of detoxifying enzymes. The lungs are not protected in this manner, therefore smoking is much more hazardous.
# Classification of carcinogens
Carcinogens can be classified as genotoxic or nongenotoxic. Genotoxins cause irreversible genetic damage or mutations by binding to DNA. Genotoxins include chemical agents like N-Nitroso-N-Methylurea (MNU) or non-chemical agents such as ultraviolet light and ionizing radiation. Certain viruses can also act as carcinogens by interacting with DNA.
Nongenotoxins do not directly affect DNA but act in other ways to promote growth. These include hormones and some organic compounds.[2]
# IARC classification of carcinogens
- Group 1: the agent (mixture) is definitely carcinogenic to humans. The exposure circumstance entails exposures that are carcinogenic to humans.
- Group 2A: the agent (mixture) is probably carcinogenic to humans. The exposure circumstance entails exposures that are probably carcinogenic to humans.
- Group 2B: the agent (mixture) is possibly carcinogenic to humans. The exposure circumstance entails exposures that are possibly carcinogenic to humans.
- Group 3: the agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans.
- Group 4: the agent (mixture) is probably not carcinogenic to humans.
Further details can be found in the IARC Monographs.
# Notes
- ↑ Wei Zheng, Deborah R Gustafson, Rashmi Sinha, James R Cerhan, et al. "Well-done meat intake and the risk of breast cancer." Journal of the National Cancer Institute. Oxford: Nov 18, 1998.Vol. 90, Iss. 22; pg. 1724, 6 pgs.
- ↑ "The Gale Encyclopedia of Cancer: A guide to Cancer and its Treatments, Second Edition. Page no. 137"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} | https://www.wikidoc.org/index.php/Carcinogen | |
94532cd4b3a6c7be8c78bac379910525b3cdeb17 | wikidoc | Carol Cass | Carol Cass
# Overview
Carol Cass is an Canadian research scientist. She is internationally recognized as an expert on nucleosides, an important class of anti-cancer drugs. Her research has led to the more effective use of nucleoside drugs and the development of new treatments for patients with acute and chronic leukemias, lymphomas, and cancers of the lung, bladder, breast and pancreas.
She determined that nucleoside-based drugs are able to cross cell membranes by binding to specialized transporter proteins. The drugs are able to enter and directly attack cancer cells during the binding process.
Since 2003, Cass has been director of Alberta’s Cross Cancer Institute. She is Canada research chair in oncology at the University of Alberta.
# Awards
- 2006, awarded the Robert L. Noble Prize by the National Cancer Institute of Canada for her contributions to cancer research. | Carol Cass
# Overview
Carol Cass is an Canadian research scientist. She is internationally recognized as an expert on nucleosides, an important class of anti-cancer drugs. Her research has led to the more effective use of nucleoside drugs and the development of new treatments for patients with acute and chronic leukemias, lymphomas, and cancers of the lung, bladder, breast and pancreas.
She determined that nucleoside-based drugs are able to cross cell membranes by binding to specialized transporter proteins. The drugs are able to enter and directly attack cancer cells during the binding process.
Since 2003, Cass has been director of Alberta’s Cross Cancer Institute. She is Canada research chair in oncology at the University of Alberta.
# Awards
- 2006, awarded the Robert L. Noble Prize by the National Cancer Institute of Canada for her contributions to cancer research.
# External links
- Robert L. Noble Prize
Template:WS | https://www.wikidoc.org/index.php/Carol_Cass | |
14524d52cf1ca1fbb0cf6dd0d4cb831ad017b6dd | wikidoc | Carotenoid | Carotenoid
# Overview
Carotenoids are organic pigments that are naturally occurring in plants and some other photosynthetic organisms like algae, some types of fungus and some bacteria.
There are over 600 known carotenoids; they are split into two classes, xanthophylls and carotenes. They absorb blue light.
# Properties
Carotenoids belong to the category of tetraterpenoids (i.e. they contain 40 carbon atoms). Structurally they are in the form of a polyene chain which is sometimes terminated by rings.
- Carotenoids with molecules containing oxygen, such as lutein and zeaxanthin, are known as xanthophylls.
- The unoxygenated (oxygen free) carotenoids such as alpha-carotene, beta-carotene and lycopene are known as carotenes. Carotenes typically contain only carbon and hydrogen.
Probably the most well-known carotenoid is the one that gives this second group its name, carotene, found in carrots and responsible for their bright orange colour. Crude palm oil, however, is the richest source of carotenoids in nature.
Their colour, ranging from pale yellow through bright orange to deep red, is directly linked to their structure. Xanthophylls are often yellow, hence their class name. The double carbon-carbon bonds interact with each other in a process called conjugation, which allows electrons in the molecule to move freely across these areas of the molecule. As the number of double bonds increases, electrons associated with conjugated systems have more room to move, and require less energy to change states. This causes the range of energies of light absorbed by the molecule to decrease. As more frequencies of light are absorbed from the short end of the visible spectrum, the compounds acquire an increasingly red appearance.
# Physiological effects
In photosynthetic organisms, carotenoids play a vital role in the photosynthetic reaction centre. They either participate in the energy-transfer process, or protect the reaction center from auto-oxidation. In non-photosynthesizing organisms, carotenoids have been linked to oxidation-preventing mechanisms.
Carotenoids have many physiological functions. Given their structure (above) carotenoids are efficient free-radical scavengers, and they enhance the vertebrate immune system. Consequently, epidemiological studies have shown that people with high beta-carotene intake and high plasma levels of beta-carotene have a significantly reduced risk of lung cancer. But studies of supplementation with large doses of beta-carotene in smokers have shown an increase in cancer risk (possibly because excessive beta-carotene results in breakdown products that reduce plasma vitamin A and worsen the lung cell proliferation induced by smoke). Similar results have been found in other animals.
Animals are incapable of synthesizing carotenoids, and must obtain them through their diet, yet they are common and often in ornamental features. For example, the pink colour of flamingos and salmon, and the red colouring of lobsters are due to carotenoids. It has been proposed that carotenoids are used in ornamental traits because, given their physiological and chemical properties, they can be used as honest indicators of individual health, and hence they can be used by animals when selecting potential mates.
The most common carotenoids include lycopene and the vitamin A precursor β-carotene. In plants, the xanthophyll lutein is the most abundant carotenoid and its role in preventing age-related eye disease is currently under investigation. Lutein and the other carotenoid pigments found in leaves are not obvious because of the presence of other pigments such as chlorophyll.
# Aroma chemicals
Products of carotenoid degradation such as ionones, damascones, and damascenones are also important fragrance chemicals that are used extensively in the perfumes and fragrance industry. Both beta-damascenone and beta-ionone although low in concentration in rose distillates are the key odour-contributing compounds in flowers. In fact, the sweet floral smells present in black tea, aged tobacco, grape, and many fruits are due to the aromatics compounds resulting from carotenoid breakdown. | Carotenoid
# Overview
Carotenoids are organic pigments that are naturally occurring in plants and some other photosynthetic organisms like algae, some types of fungus and some bacteria.
There are over 600 known carotenoids; they are split into two classes, xanthophylls and carotenes. They absorb blue light.
# Properties
Carotenoids belong to the category of tetraterpenoids (i.e. they contain 40 carbon atoms). Structurally they are in the form of a polyene chain which is sometimes terminated by rings.
- Carotenoids with molecules containing oxygen, such as lutein and zeaxanthin, are known as xanthophylls.
- The unoxygenated (oxygen free) carotenoids such as alpha-carotene, beta-carotene and lycopene are known as carotenes. Carotenes typically contain only carbon and hydrogen.
Probably the most well-known carotenoid is the one that gives this second group its name, carotene, found in carrots and responsible for their bright orange colour. Crude palm oil, however, is the richest source of carotenoids in nature.
Their colour, ranging from pale yellow through bright orange to deep red, is directly linked to their structure. Xanthophylls are often yellow, hence their class name. The double carbon-carbon bonds interact with each other in a process called conjugation, which allows electrons in the molecule to move freely across these areas of the molecule. As the number of double bonds increases, electrons associated with conjugated systems have more room to move, and require less energy to change states. This causes the range of energies of light absorbed by the molecule to decrease. As more frequencies of light are absorbed from the short end of the visible spectrum, the compounds acquire an increasingly red appearance.
# Physiological effects
In photosynthetic organisms, carotenoids play a vital role in the photosynthetic reaction centre. They either participate in the energy-transfer process, or protect the reaction center from auto-oxidation. In non-photosynthesizing organisms, carotenoids have been linked to oxidation-preventing mechanisms.
Carotenoids have many physiological functions. Given their structure (above) carotenoids are efficient free-radical scavengers, and they enhance the vertebrate immune system. Consequently, epidemiological studies have shown that people with high beta-carotene intake and high plasma levels of beta-carotene have a significantly reduced risk of lung cancer. But studies of supplementation with large doses of beta-carotene in smokers have shown an increase in cancer risk (possibly because excessive beta-carotene results in breakdown products that reduce plasma vitamin A and worsen the lung cell proliferation induced by smoke). Similar results have been found in other animals.
Animals are incapable of synthesizing carotenoids, and must obtain them through their diet, yet they are common and often in ornamental features. For example, the pink colour of flamingos and salmon, and the red colouring of lobsters are due to carotenoids. It has been proposed that carotenoids are used in ornamental traits because, given their physiological and chemical properties, they can be used as honest indicators of individual health, and hence they can be used by animals when selecting potential mates.
The most common carotenoids include lycopene and the vitamin A precursor β-carotene. In plants, the xanthophyll lutein is the most abundant carotenoid and its role in preventing age-related eye disease is currently under investigation. Lutein and the other carotenoid pigments found in leaves are not obvious because of the presence of other pigments such as chlorophyll.
# Aroma chemicals
Products of carotenoid degradation such as ionones, damascones, and damascenones are also important fragrance chemicals that are used extensively in the perfumes and fragrance industry. Both beta-damascenone and beta-ionone although low in concentration in rose distillates are the key odour-contributing compounds in flowers. In fact, the sweet floral smells present in black tea, aged tobacco, grape, and many fruits are due to the aromatics compounds resulting from carotenoid breakdown. | https://www.wikidoc.org/index.php/Carotenoid | |
d1be429ddc86c63191ed982ffa2977b50f8961f4 | wikidoc | Carr index | Carr index
The Carr index is an indication of the compressibility of a powder. It is calculated by the formula C=100\frac{V_B-V_T}{V_B}, where V_B is the freely settled volume of a given mass of powder, and V_T is the tapped density of the same mass of powder. It can also be expressed as C=100\times(1-\frac{\rho_B}{\rho_T}), where \rho_B is the freely settled bulk density of the powder, and \rho_T is the tapped density of the powder.
The Carr index is frequently used in pharmaceutics as an indication of the flowability of a powder. A Carr index greater than 25% is considered to be an indication of poor flowability, and below 15%, of good flowability.
The Carr index is related to the Hausner ratio, another indication of flowability, by the formula C=100\times(H-1). | Carr index
The Carr index is an indication of the compressibility of a powder. It is calculated by the formula <math>C=100\frac{V_B-V_T}{V_B}</math>, where <math>V_B</math> is the freely settled volume of a given mass of powder, and <math>V_T</math> is the tapped density of the same mass of powder. It can also be expressed as <math>C=100\times(1-\frac{\rho_B}{\rho_T})</math>, where <math>\rho_B</math> is the freely settled bulk density of the powder, and <math>\rho_T</math> is the tapped density of the powder.
The Carr index is frequently used in pharmaceutics as an indication of the flowability of a powder. A Carr index greater than 25% is considered to be an indication of poor flowability, and below 15%, of good flowability.[1]
The Carr index is related to the Hausner ratio, another indication of flowability, by the formula <math>C=100\times(H-1)</math>. | https://www.wikidoc.org/index.php/Carr_index | |
86a37be600562e74659cc4c9e553eea44d8ffa6f | wikidoc | Carvedilol | Carvedilol
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# Overview
Carvedilol is an alpha-adrenergic blocker, beta-adrenergic blocker that is FDA approved for the {{{indicationType}}} of heart failure, left ventricular dysfunction following myocardial infarction, hypertension. Common adverse reactions include bradyarrhythmia, hypotension, peripheral edema, abnormal weight gain, hyperglycemia, dizziness, fatigue..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- DOSAGE MUST BE INDIVIDUALIZED AND CLOSELY MONITORED BY A PHYSICIAN DURING UP‑TITRATION. Prior to initiation of carvedilol, it is recommended that fluid retention be minimized. The recommended starting dose of carvedilol is 10 mg once daily for 2 weeks. Patients who tolerate a dose of 10 mg once daily may have their dose increased to 20, 40, and 80 mg over successive intervals of at least 2 weeks. Patients should be maintained on lower doses if higher doses are not tolerated.
- Patients should be advised that initiation of treatment and (to a lesser extent) dosage increases may be associated with transient symptoms of dizziness or lightheadedness (and rarely syncope) within the first hour after dosing. Thus, during these periods, they should avoid situations such as driving or hazardous tasks, where symptoms could result in injury. Vasodilatory symptoms often do not require treatment, but it may be useful to separate the time of dosing of carvedilol from that of the ACE inhibitor or to reduce temporarily the dose of the ACE inhibitor. The dose of carvedilol should not be increased until symptoms of worsening heart failure or vasodilation have been stabilized.
- Fluid retention (with or without transient worsening heart failure symptoms) should be treated by an increase in the dose of diuretics.
The dose of carvedilol should be reduced if patients experience bradycardia (heart rate <55 beats/minute).
Episodes of dizziness or fluid retention during initiation of carvedilol can generally be managed without discontinuation of treatment and do not preclude subsequent successful titration of, or a favorable response to, carvedilol.
- Dosing information
- DOSAGE MUST BE INDIVIDUALIZED AND MONITORED DURING UP‑TITRATION. Treatment with carvedilol may be started as an inpatient or outpatient and should be started after the patient is hemodynamically stable and fluid retention has been minimized. It is recommended that carvedilol be started at 20 mg once daily and increased after 3 to 10 days, based on tolerability, to 40 mg once daily, then again to the target dose of 80 mg once daily. A lower starting dose may be used (10 mg once daily) and/or the rate of up‑titration may be slowed if clinically indicated (e.g., due to low blood pressure or heart rate, or fluid retention). Patients should be maintained on lower doses if higher doses are not tolerated. The recommended dosing regimen need not be altered in patients who received treatment with an IV or oral β‑blocker during the acute phase of the myocardial infarction.
- Dosing information
- DOSAGE MUST BE INDIVIDUALIZED. The recommended starting dose of carvedilol is 20 mg once daily. If this dose is tolerated, using standing systolic pressure measured about 1 hour after dosing as a guide, the dose should be maintained for 7 to 14 days, and then increased to 40 mg once daily if needed, based on trough blood pressure, again using standing systolic pressure 1 hour after dosing as a guide for tolerance. This dose should also be maintained for 7 to 14 days and can then be adjusted upward to 80 mg once daily if tolerated and needed. Although not specifically studied, it is anticipated the full antihypertensive effect of carvedilol would be seen within 7 to 14 days as had been demonstrated with immediate‑release carvedilol. Total daily dose should not exceed 80 mg.
- Concomitant administration with a diuretic can be expected to produce additive effects and exaggerate the orthostatic component of carvedilol action.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Dosing information
- 6.25 mg bid, then titrated to a maximum of 25 mg bid
### Non–Guideline-Supported Use
- Dosing information
- 25 to 50 mg twice daily
- Dosing information
- Titrate to a maximum dosage of 25 mg bid, 50 mg for patient >85 kg
- Dosing information
- 6.25 mg bid, then titrated to 25-50 mg bid
- Dosing information
- 3.125 mg bid, then titrated every 2 weeks to a maximum of 25 mg bid
- Dosing information
- 2.5 to 20 mg daily
- Dosing information
- 12.5 to 25 mg daily
- Dosing information
- 6.25 mg daily, then titrated to 12.5 mg daily
- Dosing information
- 3.125 mg bid, titrate to 25 mg bid
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Carvedilol FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Carvedilol in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Carvedilol in pediatric patients.
# Contraindications
Carvedilol is contraindicated in the following conditions:
- Bronchial asthma or related bronchospastic conditions. Deaths from status asthmaticus have been reported following single doses of COREG.
- AV block (Second- or third-degree)
- Sick sinus syndrome
- Severe bradycardia (unless a permanent pacemaker is in place).
- Cardiogenic shock or who have decompensated heart failure requiring the use of intravenous inotropic therapy. Such patients should first be weaned from intravenous therapy before initiating COREG
- Severe hepatic impairment
- Serious hypersensitivity reaction (e.g., Stevens-Johnson syndrome, anaphylactic reaction, angioedema) to any component of this medication or other medications containing carvedilol.
# Warnings
- Acute exacerbation of coronary artery disease upon cessation of therapy: Do not abruptly discontinue.
- Bradycardia, hypotension, fluid retention may occur. Reduce the dose as needed.
- Non-allergic bronchospasm (e.g., chronic bronchitis and emphysema): Avoid β-blockers.
- However, if deemed necessary, use with caution and at lowest effective dose.
Diabetes: Monitor glucose as β-blockers may mask symptoms of hypoglycemia or worsen hyperglycemia.
Patients with coronary artery disease, who are being treated with carvedilol, should be advised against abrupt discontinuation of therapy. Severe exacerbation of angina and the occurrence of myocardial infarction and ventricular arrhythmias have been reported in angina patients following the abrupt discontinuation of therapy with β-blockers. The last 2 complications may occur with or without preceding exacerbation of the angina pectoris. As with other β-blockers, when discontinuation of carvedilol is planned, the patients should be carefully observed and advised to limit physical activity to a minimum. carvedilol should be discontinued over 1 to 2 weeks whenever possible. If the angina worsens or acute coronary insufficiency develops, it is recommended that carvedilol be promptly reinstituted, at least temporarily. Because coronary artery disease is common and may be unrecognized, it may be prudent not to discontinue therapy with carvedilol abruptly even in patients treated only for hypertension or heart failure.
## Bradycardia
In clinical trials, carvedilol causedbradycardia in about 2% of hypertensive subjects, 9% of heart failure subjects, and 6.5% of myocardial infarction subjects with left ventricular dysfunction. If pulse rate drops below 55 beats/minute, the dosage should be reduced.
In clinical trials of primarily mild‑to‑moderate heart failure, hypotension and postural hypotension occurred in 9.7% and syncope in 3.4% of subjects receiving carvedilol compared with 3.6% and 2.5% of placebo subjects, respectively. The risk for these events was highest during the first 30 days of dosing, corresponding to the up‑titration period and was a cause for discontinuation of therapy in 0.7% of subjects receiving carvedilol, compared with 0.4% of placebo subjects. In a long‑term, placebo‑controlled trial in severe heart failure (COPERNICUS), hypotension and postural hypotension occurred in 15.1% and syncope in 2.9% of heart failure subjects receiving carvedilol compared with 8.7% and 2.3% of placebo subjects, respectively. These events were a cause for discontinuation of therapy in 1.1% of subjects receiving carvedilol, compared with 0.8% of placebo subjects.
Postural hypotension occurred in 1.8% and syncope in 0.1% of hypertensive subjects, primarily following the initial dose or at the time of dose increase and was a cause for discontinuation of therapy in 1% of subjects.
In the CAPRICORN trial of survivors of an acutemyocardial infarction, hypotension or postural hypotension occurred in 20.2% of subjects receiving carvedilol compared with 12.6% of placebo subjects. Syncope was reported in 3.9% and 1.9% of subjects, respectively. These events were a cause for discontinuation of therapy in 2.5% of subjects receiving carvedilol, compared with 0.2% of placebo subjects.
Starting with a low dose, administration with food, and gradual up-titration should decrease the likelihood of syncope or excessive hypotension . During initiation of therapy, the patient should be cautioned to avoid situations such as driving or hazardous tasks, where injury could result should syncope occur.
Worsening heart failure or fluid retention may occur during up-titration of carvedilol. If such symptoms occur, diuretics should be increased and the carvedilol dose should not be advanced until clinical stability resumes . Occasionally it is necessary to lower the carvedilol dose or temporarily discontinue it. Such episodes do not preclude subsequent successful titration of, or a favorable response to, carvedilol. In a placebo-controlled trial of subjects with severe heart failure, worsening heart failure during the first 3 months was reported to a similar degree with carvedilol and with placebo. When treatment was maintained beyond 3 months, worsening heart failure was reported less frequently in subjects treated with carvedilol than with placebo. Worsening heart failure observed during long-term therapy is more likely to be related to the patients’ underlying disease than to treatment with carvedilol.
Patients with bronchospastic disease (e.g., chronic bronchitis and emphysema) should, in general, not receive β-blockers. carvedilol may be used with caution, however, in patients who do not respond to, or cannot tolerate, other antihypertensive agents. It is prudent, if carvedilol is used, to use the smallest effective dose, so that inhibition of endogenous or exogenous β-agonists is minimized.
In clinical trials of subjects with heart failure, subjects with bronchospastic disease were enrolled if they did not require oral or inhaled medication to treat their bronchospastic disease. In such patients, it is recommended that carvedilol be used with caution. The dosing recommendations should be followed closely and the dose should be lowered if any evidence of bronchospasm is observed during up-titration.
In general, β-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia. Nonselective β-blockers may potentiate insulin-induced hypoglycemia and delay recovery of serum glucose levels. Patients subject to spontaneous hypoglycemia, or diabetic patients receiving insulin or oral hypoglycemic agents, should be cautioned about these possibilities.
In heart failure patients with diabetes, carvedilol therapy may lead to worsening hyperglycemia, which responds to intensification of hypoglycemic therapy. It is recommended that blood glucose be monitored when carvedilol dosing is initiated, adjusted, or discontinued. Trials designed to examine the effects of carvedilol on glycemic control in patients with diabetes and heart failure have not been conducted.
In a trial designed to examine the effects of carvedilol on glycemic control in a population with mild-to-moderate hypertension and well-controlled type 2diabetes mellitus, carvedilol had no adverse effect on glycemic control, based on HbA1c measurements [see Carvidilol clinical studies
# Adverse Reactions
## Clinical Trials Experience
Carvedilol has been evaluated for safety in subjects with heart failure (mild, moderate, and severe), in subjects with left ventricular dysfunction following myocardial infarction, and in hypertensive subjects. The observed adverse event profile was consistent with the pharmacology of the drug and the health status of the subjects in the clinical trials. Adverse events reported for each of these populations reflecting the use of either carvedilol or immediate-release carvedilol are provided below. Excluded are adverse events considered too general to be informative, and those not reasonably associated with the use of the drug because they were associated with the condition being treated or are very common in the treated population. Rates of adverse events were generally similar across demographic subsets (men and women, elderly and non‑elderly, blacks and non‑blacks). Carvedilol has been evaluated for safety in a 4-week (2 weeks of immediate-release carvedilol and 2 weeks of COREG CR) clinical trial (n = 187) which included 157 subjects with stable mild, moderate, or severe chronic heart failure and 30 subjects with left ventricular dysfunction following acute myocardial infarction. The profile of adverse events observed with carvedilol in this small, short-term trial was generally similar to that observed with immediate-release carvedilol. Differences in safety would not be expected based on the similarity in plasma levels for carvedilol and immediate-release carvedilol.
Heart Failure
The following information describes the safety experience in heart failure with immediate-release carvedilol.
Carvedilol has been evaluated for safety in heart failure in more than 4,500 subjects worldwide of whom more than 2,100 participated in placebo‑controlled clinical trials. Approximately 60% of the total treated population in placebo‑controlled clinical trials received carvedilol for at least 6 months and 30% received carvedilol for at least 12 months. In the COMET trial, 1,511 subjects with mild‑to‑moderate heart failure were treated with carvedilol for up to 5.9 years (mean: 4.8 years). Both in US clinical trials in mild‑to‑moderate heart failure that compared carvedilol in daily doses up to 100 mg (n = 765) with placebo (n = 437), and in a multinational clinical trial in severe heart failure (COPERNICUS) that compared carvedilol in daily doses up to 50 mg (n = 1,156) with placebo (n = 1,133), discontinuation rates for adverse experiences were similar in carvedilol and placebo subjects. In placebo‑controlled clinical trials, the only cause of discontinuation >1%, and occurring more often on carvedilol was dizziness (1.3% on carvedilol, 0.6% on placebo in the COPERNICUS trial).
The table below shows adverse events reported in subjects with mild‑to‑moderate heart failure enrolled in US placebo‑controlled clinical trials, and with severe heart failure enrolled in the COPERNICUS trial. Shown are adverse events that occurred more frequently in drug‑treated subjects than placebo‑treated subjects with an incidence of >3% in subjects treated with carvedilol regardless of causality. Median trial medication exposure was 6.3 months for both carvedilol and placebo subjects in the trials of mild‑to‑moderate heart failure, and 10.4 months in the trial of subjects with severe heart failure. The adverse event profile of carvedilol observed in the long-term COMET trial was generally similar to that observed in the US Heart Failure Trials.
Cardiac failure and dyspnea were also reported in these trials, but the rates were equal or greater in subjects who received placebo.
The following adverse events were reported with a frequency of >1% but ≤3% and more frequently with carvedilol in either the US placebo-controlled trials in subjects with mild-to-moderate heart failure, or in subjects with severe heart failure in the COPERNICUS trial.
Incidence >1% to ≤3%
- Body as a Whole: Allergy, malaise, hypovolemia, fever, leg edema.
- Cardiovascular: Fluid overload, orthostatic hypotension, aggravated angina pectoris, AV block, palpitation, hypertension.
- Central and Peripheral Nervous System: Hypesthesia, vertigo, paresthesia.
- Gastrointestinal: Melena, periodontitis.
- Liver and Biliary System: SGPT increased, SGOT increased.
- Metabolic and Nutritional: Hyperuricemia, hypoglycemia, hyponatremia, increased alkaline phosphatase, glycosuria, hypervolemia, diabetes mellitus, GGT increased, weight loss, hyperkalemia, creatinine increased.
- Musculoskeletal: Muscle cramps.
- Platelet, Bleeding, and Clotting: Prothrombin decreased, purpura, thrombocytopenia.
- Psychiatric: Somnolence.
- Reproductive, male: Impotence.
- Special Senses: Blurred vision.
- Urinary System: Renal insufficiency, albuminuria, hematuria.
Left Ventricular Dysfunction Following Myocardial Infarction
The following information describes the safety experience in left ventricular dysfunction following acute myocardial infarction with immediate-release carvedilol.
Carvedilol has been evaluated for safety in survivors of an acute myocardial infarction with left ventricular dysfunction in the CAPRICORN trial which involved 969 subjects who received carvedilol and 980 who received placebo. Approximately 75% of the subjects received carvedilol for at least 6 months and 53% received carvedilol for at least 12 months. Subjects were treated for an average of 12.9 months and 12.8 months with carvedilol and placebo, respectively.
The most common adverse events reported with carvedilol in the CAPRICORN trial were consistent with the profile of the drug in the US heart failure trials and the COPERNICUS trial. The only additional adverse events reported in CAPRICORN in >3% of the subjects and more commonly on carvedilol were dyspnea, anemia, and lung edema. The following adverse events were reported with a frequency of >1% but ≤3% and more frequently with carvedilol: flu syndrome, cerebrovascular accident, peripheral vascular disorder, hypotonia, depression, gastrointestinal pain, arthritis, and gout. The overall rates of discontinuations due to adverse events were similar in both groups of subjects. In this database, the only cause of discontinuation >1%, and occurring more often on carvedilol was hypotension (1.5% on carvedilol, 0.2% on placebo).
Hypertension
Carvedilol was evaluated for safety in an 8-week double-blind trial in 337 subjects with essential hypertension. The profile of adverse events observed with carvedilol was generally similar to that observed with immediate-release carvedilol. The overall rates of discontinuations due to adverse events were similar between carvedilol and placebo.
The following information describes the safety experience in hypertension with immediate-release carvedilol.
Carvedilol has been evaluated for safety in hypertension in more than 2,193 subjects in US clinical trials and in 2,976 subjects in international clinical trials. Approximately 36% of the total treated population received carvedilol for at least 6 months. In general, carvedilol was well tolerated at doses up to 50 mg daily. Most adverse events reported during carvedilol therapy were of mild to moderate severity. In US controlled clinical trials directly comparing carvedilol monotherapy in doses up to 50 mg (n = 1,142) with placebo (n = 462), 4.9% of carvedilol subjects discontinued for adverse events versus 5.2% of placebo subjects. Although there was no overall difference in discontinuation rates, discontinuations were more common in the carvedilol group for orthostatic hypotension (1% versus 0). The overall incidence of adverse events in US placebo‑controlled trials was found to increase with increasing dose of carvedilol. For individual adverse events this could only be distinguished for dizziness, which increased in frequency from 2% to 5% as total daily dose increased from 6.25 mg to 50 mg as single or divided doses.
The table below shows adverse events in US placebo‑controlled clinical trials for hypertension that occurred with an incidence of ≥1% regardless of causality, and that were more frequent in drug‑treated subjects than placebo‑treated subjects.
Dyspnea and fatigue were also reported in these trials, but the rates were equal or greater in subjects who received placebo.
The following adverse events not described above were reported as possibly or probably related to carvedilol in worldwide open or controlled trials with carvedilol in subjects with hypertension or heart failure.
Incidence >0.1% to ≤1%
- Cardiovascular: Peripheral ischemia, tachycardia.
- Central and Peripheral Nervous System: Hypokinesia.
- Gastrointestinal: Bilirubinemia, increased hepatic enzymes (0.2% of hypertension patients and 0.4% of heart failure patients were discontinued from therapy because of increases in hepatic enzymes).
Psychiatric: Nervousness, sleep disorder, aggravated depression, impaired concentration, abnormal thinking, paroniria, emotional lability.
- Respiratory System: Asthma.
- Reproductive, male: Decreased libido.
- Skin and Appendages: Pruritus, rash erythematous, rash maculopapular, rash psoriaform, photosensitivity reaction.
- Special Senses: Tinnitus.
- Urinary System: Micturition frequency increased.
- Autonomic Nervous System: Dry mouth, sweating increased.
- Metabolic and Nutritional: Hypokalemia, hypertriglyceridemia.
- Hematologic: Anemia, leukopenia.
The following events were reported in ≤0.1% of subjects and are potentially important: complete AV block, bundle branch block, myocardial ischemia, cerebrovascular disorder, seizures, migraine, neuralgia, paresis, anaphylactoid reaction, alopecia, exfoliative dermatitis, amnesia, GI hemorrhage, bronchospasm, pulmonary edema, decreased hearing, respiratory alkalosis, increased BUN, decreased HDL, pancytopenia, and atypical lymphocytes.
Reversible elevations in serum transaminases (ALT or AST) have been observed during treatment with carvedilol. Rates of transaminase elevations (2 to 3 times the upper limit of normal) observed during controlled clinical trials have generally been similar between subjects treated with carvedilol and those treated with placebo. However, transaminase elevations, confirmed by rechallenge, have been observed with carvedilol. In a long-term, placebo-controlled trial in severe heart failure, subjects treated with carvedilol had lower values for hepatic transaminases than subjects treated with placebo, possibly because carvedilol-induced improvements in cardiac function led to less hepatic congestion and/or improved hepatic blood flow.
Carvedilol therapy has not been associated with clinically significant changes in serum potassium, total triglycerides, total cholesterol, HDL cholesterol, uric acid, blood urea nitrogen, or creatinine. No clinically relevant changes were noted in fasting serum glucose in hypertensive subjects; fasting serum glucose was not evaluated in the heart failure clinical trials.
## Postmarketing Experience
The following adverse reactions have been identified during post-approval use of carvedilol. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Blood and Lymphatic System Disorders: Aplastic anemia.
Immune System Disorders: Hypersensitivity (e.g., anaphylactic reactions, angioedema, urticaria).
Renal and Urinary Disorders: Urinary incontinence.
Respiratory, Thoracic and Mediastinal Disorders: Interstitial pneumonitis.
Skin and Subcutaneous Tissue Disorders: Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme.
# Drug Interactions
Interactions of carvedilol with potent inhibitors of CYP2D6 isoenzyme (such as quinidine, fluoxetine, paroxetine, and propafenone) have not been studied, but these drugs would be expected to increase blood levels of the R(+) enantiomer of carvedilol. Retrospective analysis of side effects in clinical trials showed that poor 2D6 metabolizers had a higher rate of dizziness during up-titration, presumably resulting from vasodilating effects of the higher concentrations of the α‑blocking R(+) enantiomer.
Patients taking both agents with β‑blocking properties and a drug that can deplete catecholamines (e.g., reserpine and monoamine oxidase inhibitors) should be observed closely for signs of hypotension and/or severe bradycardia.
Concomitant administration of clonidine with agents with β‑blocking properties may potentiate blood pressure and heart rate lowering effects. When concomitant treatment with agents with β‑blocking properties and clonidine is to be terminated, the β‑blocking agent should be discontinued first. Clonidine therapy can then be discontinued several days later by gradually decreasing the dosage.
Modest increases in mean trough cyclosporine concentrations were observed following initiation of carvedilol treatment in 21 renal transplant subjects suffering from chronic vascular rejection. In about 30% of subjects, the dose of cyclosporine had to be reduced in order to maintain cyclosporine concentrations within the therapeutic range, while in the remainder no adjustment was needed. On the average for the group, the dose of cyclosporine was reduced about 20% in these subjects. Due to wide interindividual variability in the dose adjustment required, it is recommended that cyclosporine concentrations be monitored closely after initiation of carvedilol therapy and that the dose of cyclosporine be adjusted as appropriate.
Both digitalis glycosides and β‑blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia. Digoxin concentrations are increased by about 15% when digoxin and carvedilol are administered concomitantly. Therefore, increased monitoring of digoxin is recommended when initiating, adjusting, or discontinuing carvedilol.
Rifampin reduced plasma concentrations of carvedilol by about 70%. Cimetidine increased area under the curve (AUC) by about 30% but caused no change in Cmax.
Amiodarone, and its metabolite desethyl amiodarone, inhibitors of CYP2C9 and P-glycoprotein, increased concentrations of the S(-) enantiomer of carvedilol by at least 2-fold. The concomitant administration of amiodarone or other CYP2C9 inhibitors such as fluconazole with carvedilol may enhance the β‑blocking properties of carvedilol resulting in further slowing of the heart rate or cardiac conduction. Patients should be observed for signs of bradycardia or heart block, particularly when one agent is added to pre-existing treatment with the other.
Conduction disturbance (rarely with hemodynamic compromise) has been observed when carvedilol is coadministered with diltiazem. As with other agents with β‑blocking properties, if carvedilol is to be administered orally with calcium channel blockers of the verapamil or diltiazem type, it is recommended that ECG and blood pressure be monitored.
Agents with β‑blocking properties may enhance the blood‑sugar‑reducing effect of insulin and oral hypoglycemics. Therefore, in patients taking insulin or oral hypoglycemics, regular monitoring of blood glucose is recommended.
There is no clinically meaningful increase in AUC and Cmax with concomitant administration of carvedilol extended‑release capsules with pantoprazole.
If treatment with carvedilol is to be continued perioperatively, particular care should be taken when anesthetic agents which depress myocardial function, such as ether, cyclopropane, and trichloroethylene, are used.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
Studies performed in pregnant rats and rabbits given carvedilol revealed increased post-implantation loss in rats at doses of 300 mg/kg/day (50 times the maximum recommended human dose as mg/m2) and in rabbits at doses of 75 mg/kg/day (25 times the MRHD as mg/m2). In the rats, there was also a decrease in fetal body weight at the maternally toxic dose of 300 mg/kg/day (50 times the MRHD as mg/m2), which was accompanied by an elevation in the frequency of fetuses with delayed skeletal development (missing or stunted 13th rib). In rats the no-observed-effect level for developmental toxicity was 60 mg/kg/day (10 times the MRHD as mg/m2); in rabbits it was 15 mg/kg/day (5 times the MRHD as mg/m2). There are no adequate and well-controlled studies in pregnant women. Carvedilol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Carvedilol in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Carvedilol during labor and delivery.
### Nursing Mothers
It is not known whether this drug is excreted in human milk. Studies in rats have shown that carvedilol and/or its metabolites (as well as other β-blockers) cross the placental barrier and are excreted in breast milk. There was increased mortality at one week post-partum in neonates from rats treated with 60 mg/kg/day (10 times the MRHD as mg/m2) and above during the last trimester through day 22 of lactation. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from β-blockers, especially bradycardia, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. The effects of other α- and β-blocking agents have included perinatal and neonatal distress.
### Pediatric Use
Effectiveness of carvedilol in patients younger than 18 years has not been established.
In a double-blind trial, 161 children (mean age: 6 years, range: 2 months to 17 years; 45% younger than 2 years) with chronic heart failure who were receiving standard background treatment were randomized to placebo or to 2 dose levels of carvedilol. These dose levels produced placebo-corrected heart rate reduction of 4 to 6 heart beats per minute, indicative of β-blockade activity. Exposure appeared to be lower in pediatric subjects than adults. After 8 months of follow-up, there was no significant effect of treatment on clinical outcomes. Adverse reactions in this trial that occurred in greater than 10% of subjects treated with carvedilol and at twice the rate of placebo-treated subjects included chest pain (17% versus 6%), dizziness (13% versus 2%), and dyspnea (11% versus 0%).
### Geriatic Use
The initial clinical trials of COREG CR in subjects with hypertension, heart failure, and left ventricular dysfunction following myocardial infarction did not include sufficient numbers of subjects 65 years of age or older to determine whether they respond differently from younger patients.
A randomized trial (n = 405) comparing subjects with mild to severe heart failure switched to carvedilol or maintained on immediate-release carvedilol included 220 subjects who were 65 years of age or older. In this elderly subgroup, the combined incidence of dizziness, hypotension, or syncope was 24% (18/75) in subjects switched from the highest dose of immediate-release carvedilol (25 mg twice daily) to the highest dose of carvedilol (80 mg once daily) compared with 11% (4/36) in subjects maintained on immediate-release carvedilol (25 mg twice daily). When switching from the higher doses of immediate-release carvedilol to carvedilol, a lower starting dose is recommended for elderly patients.
The following information is available for trials with immediate-release carvedilol. Of the 765 subjects with heart failure randomized to carvedilol in US clinical trials, 31% (235) were 65 years of age or older, and 7.3% (56) were 75 years of age or older. Of the 1,156 subjects randomized to carvedilol in a long‑term, placebo‑controlled trial in severe heart failure, 47% (547) were 65 years of age or older, and 15% (174) were 75 years of age or older. Of 3,025 subjects receiving carvedilol in heart failure trials worldwide, 42% were 65 years of age or older. Of the 975 subjects with myocardial infarction randomized to carvedilol in the CAPRICORN trial, 48% (468) were 65 years of age or older, and 11% (111) were 75 years of age or older. Of the 2,065 hypertensive subjects in US clinical trials of efficacy or safety who were treated with carvedilol, 21% (436) were 65 years of age or older. Of 3,722 subjects receiving immediate-release carvedilol in hypertension clinical trials conducted worldwide, 24% were 65 years of age or older.
With the exception of dizziness in hypertensive subjects (incidence 8.8% in the elderly versus 6% in younger subjects), no overall differences in the safety or effectiveness were observed between the older subjects and younger subjects in each of these populations. Similarly, other reported clinical experience has not identified differences in responses between the elderly and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.
### Gender
There is no FDA guidance on the use of Carvedilol with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Carvedilol with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Carvedilol in patients with renal impairment.
### Hepatic Impairment
Carvedilol is contraindicated in patients with severe liver impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Carvedilol in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Carvedilol in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Oral
### Monitoring
DOSAGE MUST BE INDIVIDUALIZED AND CLOSELY MONITORED BY A PHYSICIAN DURING UP‑TITRATION.
# IV Compatibility
There is limited information regarding the compatibility of Carvedilol and IV administrations.
# Overdosage
Overdosage may cause severe hypotension, bradycardia, cardiac insufficiency, cardiogenic shock, and cardiac arrest. Respiratory problems, bronchospasms, vomiting, lapses of consciousness, and generalized seizures may also occur.
The patient should be placed in a supine position and, where necessary, kept under observation and treated under intensive-care conditions. Gastric lavage or pharmacologically induced emesis may be used shortly after ingestion. The following agents may be administered:
- For excessive bradycardia: atropine, 2 mg IV.
- To support cardiovascular function: glucagon, 5 to 10 mg IV rapidly over 30 seconds, followed by a continuous infusion of 5 mg/hour; sympathomimetics (dobutamine, isoprenaline, adrenaline) at doses according to body weight and effect.
If peripheral vasodilation dominates, it may be necessary to administer adrenaline or noradrenaline with continuous monitoring of circulatory conditions. For therapy-resistant bradycardia, pacemaker therapy should be performed. For bronchospasm, β‑sympathomimetics (as aerosol or IV) or aminophylline IV should be given. In the event of seizures, slow IV injection of diazepam or clonazepam is recommended.
NOTE: In the event of severe intoxication where there are symptoms of shock, treatment with antidotes must be continued for a sufficiently long period of time consistent with the 7- to 10-hour half-life of carvedilol.
There is no experience of overdosage with carvedilol. Cases of overdosage with carvedilol alone or in combination with other drugs have been reported. Quantities ingested in some cases exceeded 1,000 milligrams. Symptoms experienced included low blood pressure and heart rate. Standard supportive treatment was provided and individuals recovered.
# Pharmacology
## Mechanism of Action
Carvedilol is a racemic mixture in which nonselective β‑adrenoreceptor blocking activity is present in the S(-) enantiomer and α1‑adrenergic blocking activity is present in both R(+) and S(-) enantiomers at equal potency. Carvedilol has no intrinsic sympathomimetic activity.
## Structure
Carvedilol phosphate is a nonselective β‑adrenergic blocking agent with α1-blocking activity. It is (2RS)-1-(9H-Carbazol-4-yloxy)-3-((2-(2-methoxyphenoxy)ethyl)amino)propan-2-ol phosphate salt (1:1) hemihydrate. It is a racemic mixture with the following structure:
Carvedilol phosphate is a white to almost white solid with a molecular weight of 513.5 (406.5 carvedilol free base) and a molecular formula of C24H26N2O4H3PO41/2 H2O.
COREG CR is available for once-a-day administration as controlled-release oral capsules containing 10, 20, 40, or 80 mg carvedilol phosphate. Carvedilol hard gelatin capsules are filled with carvedilol phosphate immediate-release and controlled-release microparticles that are drug-layered and then coated with methacrylic acid copolymers. Inactive ingredients include crospovidone, hydrogenated castor oil, hydrogenated vegetable oil, magnesium stearate, methacrylic acid copolymers, microcrystalline cellulose, and povidone.
## Pharmacodynamics
The basis for the beneficial effects of carvedilol in patients with heart failure and in patients with left ventricular dysfunction following an acute myocardial infarction is not known. The concentration-response relationship for β1‑blockade following administration of carvedilol is equivalent (±20%) to immediate-release carvedilol tablets.
The mechanism by which β‑blockade produces an antihypertensive effect has not been established.
β‑adrenoreceptor blocking activity has been demonstrated in animal and human studies showing that carvedilol (1) reduces cardiac output in normal subjects; (2) reduces exercise- and/or isoproterenol-induced tachycardia; and (3) reduces reflex orthostatic tachycardia. Significant β‑adrenoreceptor blocking effect is usually seen within 1 hour of drug administration.
α1‑adrenoreceptor blocking activity has been demonstrated in human and animal studies, showing that carvedilol (1) attenuates the pressor effects of phenylephrine; (2) causes vasodilation; and (3) reduces peripheral vascular resistance. These effects contribute to the reduction of blood pressure and usually are seen within 30 minutes of drug administration.
Due to the α1‑receptor blocking activity of carvedilol, blood pressure is lowered more in the standing than in the supine position, and symptoms of orthostatic hypotension (1.8%), including rare instances of syncope, can occur. Following oral administration, when postural hypotension has occurred, it has been transient and is uncommon when immediate-release carvedilol is administered with food at the recommended starting dose and titration increments are closely followed.
In a randomized, double-blind, placebo-controlled trial, the β1‑blocking effect of carvedilol, as measured by heart rate response to submaximal bicycle ergometry, was shown to be equivalent to that observed with immediate-release carvedilol at steady state in adult subjects with essential hypertension.
In hypertensive subjects with normal renal function, therapeutic doses of carvedilol decreased renal vascular resistance with no change in glomerular filtration rate or renal plasma flow. Changes in excretion of sodium, potassium, uric acid, and phosphorus in hypertensive patients with normal renal function were similar after carvedilol and placebo.
Carvedilol has little effect on plasma catecholamines, plasma aldosterone, or electrolyte levels, but it does significantly reduce plasma renin activity when given for at least 4 weeks. It also increases levels of atrial natriuretic peptide.
## Pharmacokinetics
Carvedilol is rapidly and extensively absorbed following oral administration of immediate-release carvedilol tablets, with an absolute bioavailability of approximately 25% to 35% due to a significant degree of first-pass metabolism. Carvedilol extended-release capsules have approximately 85% of the bioavailability of immediate-release carvedilol tablets. For corresponding dosages, the exposure (AUC, Cmax, trough concentration) of carvedilol as carvedilol extended-release capsules is equivalent to those of immediate-release carvedilol tablets when both are administered with food. The absorption of carvedilol from carvedilol is slower and more prolonged compared with the immediate-release carvedilol tablet with peak concentrations achieved approximately 5 hours after administration. Plasma concentrations of carvedilol increase in a dose-proportional manner over the dosage range of carvedilol 10 to 80 mg. Within-subject and between-subject variability for AUC and Cmax is similar for carvedilol and immediate-release carvedilol.
Effect of Food
Administration of carvedilol with a high-fat meal resulted in increases (~20%) in AUC and Cmax compared with carvedilol administered with a standard meal. Decreases in AUC (27%) and Cmax (43%) were observed when carvedilol was administered in the fasted state compared with administration after a standard meal. Carvedilol should be taken with food.
In a trial with adult subjects, sprinkling the contents of the carvedilol capsule on applesauce did not appear to have a significant effect on overall exposure (AUC) compared with administration of the intact capsule following a standard meal but did result in a decrease in Cmax (18%).
Carvedilol is more than 98% bound to plasma proteins, primarily with albumin. The plasma protein binding is independent of concentration over the therapeutic range. Carvedilol is a basic, lipophilic compound with a steady-state volume of distribution of approximately 115 L, indicating substantial distribution into extravascular tissues.
Carvedilol is extensively metabolized. Following oral administration of radiolabelled carvedilol to healthy volunteers, carvedilol accounted for only about 7% of the total radioactivity in plasma as measured by AUC. Less than 2% of the dose was excreted unchanged in the urine. Carvedilol is metabolized primarily by aromatic ring oxidation and glucuronidation. The oxidative metabolites are further metabolized by conjugation via glucuronidation and sulfation. The metabolites of carvedilol are excreted primarily via the bile into the feces. Demethylation and hydroxylation at the phenol ring produce 3 active metabolites with β‑receptor blocking activity. Based on preclinical studies, the 4'-hydroxyphenyl metabolite is approximately 13 times more potent than carvedilol for β‑blockade.
Compared with carvedilol, the 3 active metabolites exhibit weak vasodilating activity. Plasma concentrations of the active metabolites are about one-tenth of those observed for carvedilol and have pharmacokinetics similar to the parent.
Carvedilol undergoes stereoselective first-pass metabolism with plasma levels of R(+)-carvedilol approximately 2 to 3 times higher than S(-)-carvedilol following oral administration of carvedilol in healthy subjects. Apparent clearance is 90 L/h and 213 L/h for R(+)- and S(-)-carvedilol, respectively.
The primary P450 enzymes responsible for the metabolism of both R(+) and S(-)-carvedilol in human liver microsomes were CYP2D6 and CYP2C9 and to a lesser extent CYP3A4, 2C19, 1A2, and 2E1. CYP2D6 is thought to be the major enzyme in the 4’- and 5’-hydroxylation of carvedilol, with a potential contribution from 3A4. CYP2C9 is thought to be of primary importance in the O-methylation pathway of S(-)-carvedilol.
Carvedilol is subject to the effects of genetic polymorphism with poor metabolizers of debrisoquin (a marker for cytochrome P450 2D6) exhibiting 2- to 3-fold higher plasma concentrations of R(+)-carvedilol compared with extensive metabolizers. In contrast, plasma levels of S(-)-carvedilol are increased only about 20% to 25% in poor metabolizers, indicating this enantiomer is metabolized to a lesser extent by cytochrome P450 2D6 than R(+)-carvedilol. The pharmacokinetics of carvedilol do not appear to be different in poor metabolizers of S-mephenytoin (patients deficient in cytochrome P450 2C19).
Heart Failure
Following administration of immediate-release carvedilol tablets, steady‑state plasma concentrations of carvedilol and its enantiomers increased proportionally over the dose range in subjects with heart failure. Compared with healthy subjects, subjects with heart failure had increased mean AUC and Cmax values for carvedilol and its enantiomers, with up to 50% to 100% higher values observed in 6 subjects with NYHA class IV heart failure. The mean apparent terminal elimination half‑life for carvedilol was similar to that observed in healthy subjects.
For corresponding dose levels, the steady-state pharmacokinetics of carvedilol (AUC, Cmax, trough concentrations) observed after administration of carvedilol to subjects with chronic heart failure (mild, moderate, and severe) were similar to those observed after administration of immediate-release carvedilol tablets.
Hypertension
For corresponding dose levels, the pharmacokinetics (AUC, Cmax, and trough concentrations) observed with administration of carvedilol were equivalent (±20%) to those observed with immediate-release carvedilol tablets following repeat dosing in subjects with essential hypertension.
Geriatric
Plasma levels of carvedilol average about 50% higher in the elderly compared with young subjects after administration of immediate-release carvedilol.
Hepatic Impairment
No trials have been performed with carvedilol in subjects with hepatic impairment. Compared with healthy subjects, subjects with severe hepatic impairment (cirrhosis) exhibit a 4- to 7-fold increase in carvedilol levels. Carvedilol is contraindicated in patients with severe liver impairment.
Renal Impairment
No trials have been performed with carvedilol in subjects with renal impairment. Although carvedilol is metabolized primarily by the liver, plasma concentrations of carvedilol have been reported to be increased in patients with renal impairment after dosing with immediate-release carvedilol. Based on mean AUC data, approximately 40% to 50% higher plasma concentrations of carvedilol were observed in hypertensive subjects with moderate to severe renal impairment compared with a control group of hypertensive subjects with normal renal function. However, the ranges of AUC values were similar for both groups. Changes in mean peak plasma levels were less pronounced, approximately 12% to 26% higher in subjects with impaired renal function.
Consistent with its high degree of plasma protein binding, carvedilol does not appear to be cleared significantly by hemodialysis.
## Nonclinical Toxicology
In 2-year studies conducted in rats given carvedilol at doses up to 75 mg/kg/day (12 times the MRHD when compared on a mg/m2 basis) or in mice given up to 200 mg/kg/day (16 times the MRHD on a mg/m2 basis), carvedilol had no carcinogenic effect.
Carvedilol was negative when tested in a battery of genotoxicity assays, including the Ames and the CHO/HGPRT assays for mutagenicity and the in vitro hamster micronucleus and in vivo human lymphocyte cell tests for clastogenicity.
At doses ≥200 mg/kg/day (≥32 times the MRHD as mg/m2) carvedilol was toxic to adult rats (sedation, reduced weight gain) and was associated with a reduced number of successful matings, prolonged mating time, significantly fewer corpora lutea and implants per dam, and complete resorption of 18% of the litters. The no-observed-effect dose level for overt toxicity and impairment of fertility was 60 mg/kg/day (10 times the MRHD as mg/m2).
# Clinical Studies
A total of 6,975 subjects with mild-to-severe heart failure were evaluated in placebo-controlled and active-controlled trials of immediate-release carvedilol.
Mild-to-Moderate Heart Failure
Carvedilol was studied in 5 multicenter, placebo‑controlled trials, and in 1 active-controlled trial (COMET trial) involving subjects with mild-to-moderate heart failure.
Four US multicenter, double‑blind, placebo‑controlled trials enrolled 1,094 subjects (696 randomized to carvedilol) with NYHA class II‑III heart failure and ejection fraction ≤0.35. The vast majority were on digitalis, diuretics, and an ACE inhibitor at trial entry. Subjects were assigned to the trials based upon exercise ability. An Australia‑New Zealand double‑blind, placebo‑controlled trial enrolled 415 subjects (half randomized to immediate‑release carvedilol) with less severe heart failure. All protocols excluded subjects expected to undergo cardiac transplantation during the 7.5 to 15 months of double‑blind follow‑up. All randomized subjects had tolerated a 2‑week course on immediate‑release carvedilol 6.25 mg twice daily.
In each trial, there was a primary end point, either progression of heart failure (1 US trial) or exercise tolerance (2 US trials meeting enrollment goals and the Australia‑New Zealand trial). There were many secondary end points specified in these trials, including NYHA classification, patient and physician global assessments, and cardiovascular hospitalization. Other analyses not prospectively planned included the sum of deaths and total cardiovascular hospitalizations. In situations where the primary end points of a trial do not show a significant benefit of treatment, assignment of significance values to the other results is complex, and such values need to be interpreted cautiously.
The results of the US and Australia‑New Zealand trials were as follows:
- Slowing Progression of Heart Failure: One US multicenter trial (366 subjects) had as its primary end point the sum of cardiovascular mortality, cardiovascular hospitalization, and sustained increase in heart failure medications. Heart failure progression was reduced, during an average follow‑up of 7 months, by 48% (P = 0.008).
In the Australia‑New Zealand trial, death and total hospitalizations were reduced by about 25% over 18 to 24 months. In the 3 largest US trials, death and total hospitalizations were reduced by 19%, 39%, and 49%, nominally statistically significant in the last 2 trials. The Australia‑New Zealand results were statistically borderline.
- Functional Measures: None of the multicenter trials had NYHA classification as a primary end point, but all such trials had it as a secondary end point. There was at least a trend toward improvement in NYHA class in all trials. Exercise tolerance was the primary end point in 3 trials; in none was a statistically significant effect found.
- Subjective Measures: Health-related quality of life, as measured with a standard questionnaire (a primary end point in 1 trial), was unaffected by carvedilol. However, patients’ and investigators’ global assessments showed significant improvement in most trials.
- Mortality: Death was not a pre-specified end point in any trial, but was analyzed in all trials. Overall, in these 4 US trials, mortality was reduced, nominally significantly so in 2 trials.
The COMET Trial
In this double-blind trial, 3,029 subjects with NYHA class II-IV heart failure (left ventricular ejection fraction ≤35%) were randomized to receive either carvedilol (target dose: 25 mg twice daily) or immediate-release metoprolol tartrate (target dose: 50 mg twice daily). The mean age of the subjects was approximately 62 years, 80% were males, and the mean left ventricular ejection fraction at baseline was 26%. Approximately 96% of the subjects had NYHA class II or III heart failure. Concomitant treatment included diuretics (99%), ACE inhibitors (91%), digitalis (59%), aldosterone antagonists (11%), and “statin” lipid-lowering agents (21%). The mean duration of follow-up was 4.8 years. The mean dose of carvedilol was 42 mg per day.
The trial had 2 primary end points: all-cause mortality and the composite of death plus hospitalization for any reason. The results of COMET are presented in Table 5 below. All-cause mortality carried most of the statistical weight and was the primary determinant of the trial size. All-cause mortality was 34% in the subjects treated with carvedilol and was 40% in the immediate-release metoprolol group (P = 0.0017; hazard ratio = 0.83, 95% CI: 0.74 to 0.93). The effect on mortality was primarily due to a reduction in cardiovascular death. The difference between the 2 groups with respect to the composite end point was not significant (P = 0.122). The estimated mean survival was 8.0 years with carvedilol and 6.6 years with immediate-release metoprolol.
It is not known whether this formulation of metoprolol at any dose or this low dose of metoprolol in any formulation has any effect on survival or hospitalization in patients with heart failure. Thus, this trial extends the time over which carvedilol manifests benefits on survival in heart failure, but it is not evidence that carvedilol improves outcome over the formulation of metoprolol with benefits in heart failure.
Severe Heart Failure (COPERNICUS)
In a double-blind trial, 2,289 subjects with heart failure at rest or with minimal exertion and left ventricular ejection fraction <25% (mean 20%), despite digitalis (66%), diuretics (99%), and ACE inhibitors (89%) were randomized to placebo or carvedilol. Carvedilol was titrated from a starting dose of 3.125 mg twice daily to the maximum tolerated dose or up to 25 mg twice daily over a minimum of 6 weeks. Most subjects achieved the target dose of 25 mg. The trial was conducted in Eastern and Western Europe, the United States, Israel, and Canada. Similar numbers of subjects per group (about 100) withdrew during the titration period.
The primary end point of the trial was all‑cause mortality, but cause‑specific mortality and the risk of death or hospitalization (total, cardiovascular , or heart failure ) were also examined. The developing trial data were followed by a data monitoring committee, and mortality analyses were adjusted for these multiple looks. The trial was stopped after a median follow‑up of 10 months because of an observed 35% reduction in mortality (from 19.7% per patient-year on placebo to 12.8% on carvedilol, hazard ratio 0.65, 95% CI: 0.52 to 0.81, P = 0.0014, adjusted). The results of COPERNICUS are shown in the table below.
Cardiovascular = CV; Heart failure = HF.
Figure. Survival Analysis for COPERNICUS (Intent-to-Treat)
The effect on mortality was principally the result of a reduction in the rate of sudden death among subjects without worsening heart failure.
Patients' global assessments, in which carvedilol‑treated subjects were compared with placebo, were based on pre-specified, periodic patient self-assessments regarding whether clinical status post-treatment showed improvement, worsening, or no change compared with baseline. Subjects treated with carvedilol showed significant improvements in global assessments compared with those treated with placebo in COPERNICUS.
The protocol also specified that hospitalizations would be assessed. Fewer subjects on immediate‑release carvedilol than on placebo were hospitalized for any reason (372 versus 432, P= 0.0029), for cardiovascular reasons (246 versus 314, P = 0.0003), or for worsening heart failure (198 versus 268, P = 0.0001).
Immediate‑release carvedilol had a consistent and beneficial effect on all‑cause mortality as well as the combined end points of all‑cause mortality plus hospitalization (total, CV, or for heart failure) in the overall trial population and in all subgroups examined, including men and women, elderly and non‑elderly, blacks and non‑blacks, and diabetics and non-diabetics (see Figure 2).
Figure. Effects on Mortality for Subgroups in COPERNICUS
Although the clinical trials used twice-daily dosing, clinical pharmacologic and pharmacokinetic data provide a reasonable basis for concluding that once-daily dosing with COREG CR should be adequate in the treatment of heart failure.
CAPRICORN was a double‑blind trial comparing carvedilol and placebo in 1,959 subjects with a recent myocardial infarction (within 21 days) and left ventricular ejection fraction of ≤40%, with (47%) or without symptoms of heart failure. Subjects given carvedilol received 6.25 mg twice daily, titrated as tolerated to 25 mg twice daily. Subjects had to have a systolic blood pressure >90 mm Hg, a sitting heart rate >60 beats/minute, and no contraindication to β‑blocker use. Treatment of the index infarction included aspirin (85%), IV or oral β‑blockers (37%), nitrates (73%), heparin (64%), thrombolytics (40%), and acute angioplasty (12%). Background treatment included ACE inhibitors or angiotensin receptor blockers (97%), anticoagulants (20%), lipid‑lowering agents (23%), and diuretics (34%). Baseline population characteristics included an average age of 63 years, 74% male, 95% Caucasian, mean blood pressure 121/74 mm Hg, 22% with diabetes, and 54% with a history of hypertension. Mean dosage achieved of carvedilol was 20 mg twice daily; mean duration of follow‑up was 15 months.
All‑cause mortality was 15% in the placebo group and 12% in the carvedilol group, indicating a 23% risk reduction in subjects treated with carvedilol (95% CI: 2% to 40%,P = 0.03), as shown in Figure 3. The effects on mortality in various subgroups are shown in Figure 4. Nearly all deaths were cardiovascular (which were reduced by 25% by carvedilol), and most of these deaths were sudden or related to pump failure (both types of death were reduced by carvedilol). Another trial end point, total mortality and all-cause hospitalization, did not show a significant improvement.
There was also a significant 40% reduction in fatal or non-fatal myocardial infarction observed in the group treated with carvedilol (95% CI: 11% to 60%, P = 0.01). A similar reduction in the risk of myocardial infarction was also observed in a meta-analysis of placebo-controlled trials of carvedilol in heart failure.
Figure. Survival Analysis for CAPRICORN (Intent-to-Treat)
Figure. Effects on Mortality for Subgroups in CAPRICORN
Although the clinical trials used twice-daily dosing, clinical pharmacologic and pharmacokinetic data provide a reasonable basis for concluding that once-daily dosing with COREG CR should be adequate in the treatment of left ventricular dysfunction following myocardial infarction.
A double-blind, randomized, placebo-controlled, 8-week trial evaluated the blood pressure lowering effects of COREG CR 20 mg, 40 mg, and 80 mg once daily in 338 subjects with essential hypertension (sitting diastolic blood pressure ≥90 and ≤109 mm Hg). Of 337 evaluable subjects, a total of 273 subjects (81%) completed the trial. Of the 64 (19%) subjects withdrawn from the trial, 10 (3%) were due to adverse events, 10 (3%) were due to lack of efficacy; the remaining 44 (13%) withdrew for other reasons. The mean age of the subjects was approximately 53 years, 66% were male, and the mean sitting systolic blood pressure (SBP) and DBP at baseline were 150 mm Hg and 99 mm Hg, respectively. Dose titration occurred at 2‑week intervals.
Statistically significant reductions in blood pressure as measured by 24‑hour ambulatory blood pressure monitoring (ABPM) were observed with each dose of COREG CR compared with placebo. Placebo-subtracted mean changes from baseline in mean SBP/DBP were ‑6.1/‑4.0 mm Hg, ‑9.4/‑7.6 mm Hg, and ‑11.8/‑9.2 mm Hg for COREG CR 20 mg, 40 mg, and 80 mg, respectively. Placebo-subtracted mean changes from baseline in mean trough (average of hours 20 to 24) SBP/DBP were ‑3.3/‑2.8 mm Hg, ‑4.9/‑5.2 mm Hg, and ‑8.4/‑7.4 mm Hg for COREG CR 20 mg, 40 mg, and 80 mg, respectively. The placebo-corrected trough to peak (3 to 7 h) ratio was approximately 0.6 for COREG CR 80 mg. In this trial, assessments of 24‑hour ABPM monitoring demonstrated statistically significant blood pressure reductions with COREG CR throughout the dosing period.
Figure. Changes from Baseline in Systolic Blood Pressure and Diastolic Blood Pressure Measured by 24-Hour ABPM
Immediate‑release carvedilol was studied in 2 placebo‑controlled trials that utilized twice‑daily dosing, at total daily doses of 12.5 to 50 mg. In these and other trials, the starting dose did not exceed 12.5 mg. At 50 mg/day, COREG reduced sitting trough (12‑hour) blood pressure by about 9/5.5 mm Hg; at 25 mg/day the effect was about 7.5/3.5 mm Hg. Comparisons of trough‑to‑peak blood pressure showed a trough‑to‑peak ratio for blood pressure response of about 65%. Heart rate fell by about 7.5 beats/minute at 50 mg/day. In general, as is true for other β‑blockers, responses were smaller in black than non‑black subjects. There were no age‑ or gender‑related differences in response. The dose‑related blood pressure response was accompanied by a dose‑related increase in adverse effects.
In a double-blind trial (GEMINI), carvedilol, added to an ACE inhibitor or angiotensin receptor blocker, was evaluated in a population with mild‑to‑moderate hypertension and well-controlled type 2 diabetes mellitus. The mean HbA1c at baseline was 7.2%. COREG was titrated to a mean dose of 17.5 mg twice daily and maintained for 5 months. COREG had no adverse effect on glycemic control, based on HbA1c measurements (mean change from baseline of 0.02%, 95% CI: ‑0.06 to 0.10, P = NS).
# How Supplied
The hard gelatin capsules are available in the following strengths:
- 10 mg – white and green capsule shell printed with “GSK COREG CR” and “10 mg”
- 20 mg – white and yellow capsule shell printed with “GSK COREG CR” and “20 mg”
- 40 mg – yellow and green capsule shell printed with “GSK COREG CR” and “40 mg”
- 80 mg – white capsule shell printed with “GSK COREG CR” and “80 mg”
- 10 mg 30’s: NDC 0007-3370-13
- 20 mg 30’s: NDC 0007-3371-13
- 40 mg 30’s: NDC 0007-3372-13
- 80 mg 30’s: NDC 0007-3373-13
## Storage
Store at 25°C (77°F); excursions 15° to 30°C (59° to 86°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
COREG CR is a prescription medicine that belongs to a group of medicines called “beta-blockers”. COREG CR is used, often with other medicines, for the following conditions:
- to treat patients with certain types of heart failure
- to treat patients who had a heart attack that worsened how well the heart pumps
- to treat patients with high blood pressure (hypertension)
COREG CR is not approved for use in children under 18 years of age.
Do not take carvedilol if you:
- Have severe heart failure and require certain intravenous medicines that help support circulation.
- Have asthma or other breathing problems.
- Have a slow heartbeat or certain conditions that cause your heart to skip a beat (irregular heartbeat).
- Have liver problems.
- Are allergic to any of the ingredients in carvedilol. See “What are the ingredients in carvedilol?”
Tell your doctor about all of your medical conditions, including if you:
- Have asthma or other lung problems (such as bronchitis or emphysema).
- Have problems with blood flow in your feet and legs (peripheral vascular disease). Carvedilol can make some of your symptoms worse.
- Have diabetes.
- Have thyroid problems.
- Have a condition called pheochromocytoma.
- Have had severe allergic reactions.
- Are scheduled for surgery and will be given anesthetic agents.
- Are scheduled for cataract surgery and have taken or are currently taking carvedilol.
- Are pregnant or trying to become pregnant. It is not known if carvedilol is safe for your unborn baby. You and your doctor should talk about the best way to control your high blood pressure during pregnancy.
- Are breastfeeding. It is not known if carvedilol passes into your breast milk. You should not breastfeed while using carvedilol.
Tell your doctor about all of the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. Carvedilol and certain other medicines can affect each other and cause serious side effects. Carvedilol may affect the way other medicines work. Also, other medicines may affect how well carvedilol works.
Know the medicines you take. Keep a list of your medicines and show it to your doctor and pharmacist before you start a new medicine.
- Take carvedilol exactly as prescribed. Take carvedilol one time each day with food. It is important that you take carvedilol only one time each day. To lessen possible side effects, your doctor might begin with a low dose and then slowly increase the dose.
- Swallow carvedilol capsules whole. Do not chew or crush carvedilol capsules.
- If you have trouble swallowing carvedilol whole:
- The capsule may be carefully opened and the beads sprinkled over a spoonful of applesauce which should be eaten right away. The applesauce should not be warm.
- Do not sprinkle beads on foods other than applesauce.
- Do not stop taking carvedilol and do not change the amount of carvedilol you take without talking to your doctor.
- If you miss a dose of carvedilol, take your dose as soon as you remember, unless it is time to take your next dose. Take your next dose at the usual time. Do not take 2 doses at the same time.
- If you take too much carvedilol, call your doctor or poison control center right away.
Carvedilol can cause you to feel dizzy, tired, or faint. Do not drive a car, use machinery, or do anything that needs you to be alert if you have these symptoms.
Serious side effects of carvedilol include:
- Chest pain and heart attack if you suddenly stop taking carvedilol.
- Slow heart beat.
- Low blood pressure (which may cause dizziness or fainting when you stand up). If these happen, sit or lie down, and tell your doctor right away.
- Worsening heart failure. Tell your doctor right away if you have signs and symptoms that your heart failure may be worse, such as weight gain or increased shortness of breath.
- Changes in your blood sugar. If you have diabetes, tell your doctor if you have any changes in your blood sugar levels.
- Masking (hiding) the symptoms of low blood sugar, especially a fast heartbeat.
- New or worsening symptoms of peripheral vascular disease.
- Leg pain that happens when you walk, but goes away when you rest.
- No feeling (numbness) in your legs or feet while you are resting.
- Cold legs or feet.
- Masking the symptoms of hyperthyroidism (overactive thyroid), such as a fast heartbeat.
- Worsening of severe allergic reactions. Medicines to treat a severe allergic reaction may not work as well while you are taking carvedilol.
- Rare but serious allergic reactions (including hives or swelling of the face, lips, tongue, and/or throat that may cause difficulty in breathing or swallowing) have happened in patients who were on carvedilol. These reactions can be life-threatening.
Common side effects of carvedilol include shortness of breath, weight gain, diarrhea, and tiredness. If you wear contact lenses, you may have fewer tears or dry eyes that can become bothersome.
Call your doctor if you have any side effects that bother you or don’t go away.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
- Store carvedilol at less than 86°F (30°C).
- Safely throw away carvedilol that is out of date or no longer needed.
- Keep carvedilol and all medicines out of the reach of children.
Medicines are sometimes prescribed for conditions other than those described in patient information leaflets. Do not use carvedilol for a condition for which it was not prescribed. Do not give carvedilol to other people, even if they have the same symptoms you have. It may harm them.
This leaflet summarizes the most important information about carvedilol. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about carvedilol that is written for healthcare professionals.
Active ingredient: carvedilol phosphate
Inactive ingredients: crospovidone, hydrogenated castor oil, hydrogenated vegetable oil, magnesium stearate, methacrylic acid copolymers, microcrystalline cellulose, and povidone
COREG CR capsules come in the following strengths: 10 mg, 20 mg, 40 mg, 80 mg.
Blood pressure is the force of blood in your blood vessels when your heart beats and when your heart rests. You have high blood pressure when the force is too much. High blood pressure makes the heart work harder to pump blood through the body and causes damage to blood vessels. carvedilol can help your blood vessels relax so your blood pressure is lower. Medicines that lower blood pressure may lower your chance of having a stroke or heart attack.
# Precautions with Alcohol
Alcohol-Carvedilol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
Coreg
# Look-Alike Drug Names
Carvedilol - Captopril
# Drug Shortage Status
# Price | Carvedilol
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alonso Alvarado, M.D. [2]
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# Overview
Carvedilol is an alpha-adrenergic blocker, beta-adrenergic blocker that is FDA approved for the {{{indicationType}}} of heart failure, left ventricular dysfunction following myocardial infarction, hypertension. Common adverse reactions include bradyarrhythmia, hypotension, peripheral edema, abnormal weight gain, hyperglycemia, dizziness, fatigue..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- DOSAGE MUST BE INDIVIDUALIZED AND CLOSELY MONITORED BY A PHYSICIAN DURING UP‑TITRATION. Prior to initiation of carvedilol, it is recommended that fluid retention be minimized. The recommended starting dose of carvedilol is 10 mg once daily for 2 weeks. Patients who tolerate a dose of 10 mg once daily may have their dose increased to 20, 40, and 80 mg over successive intervals of at least 2 weeks. Patients should be maintained on lower doses if higher doses are not tolerated.
- Patients should be advised that initiation of treatment and (to a lesser extent) dosage increases may be associated with transient symptoms of dizziness or lightheadedness (and rarely syncope) within the first hour after dosing. Thus, during these periods, they should avoid situations such as driving or hazardous tasks, where symptoms could result in injury. Vasodilatory symptoms often do not require treatment, but it may be useful to separate the time of dosing of carvedilol from that of the ACE inhibitor or to reduce temporarily the dose of the ACE inhibitor. The dose of carvedilol should not be increased until symptoms of worsening heart failure or vasodilation have been stabilized.
- Fluid retention (with or without transient worsening heart failure symptoms) should be treated by an increase in the dose of diuretics.
The dose of carvedilol should be reduced if patients experience bradycardia (heart rate <55 beats/minute).
Episodes of dizziness or fluid retention during initiation of carvedilol can generally be managed without discontinuation of treatment and do not preclude subsequent successful titration of, or a favorable response to, carvedilol.
- Dosing information
- DOSAGE MUST BE INDIVIDUALIZED AND MONITORED DURING UP‑TITRATION. Treatment with carvedilol may be started as an inpatient or outpatient and should be started after the patient is hemodynamically stable and fluid retention has been minimized. It is recommended that carvedilol be started at 20 mg once daily and increased after 3 to 10 days, based on tolerability, to 40 mg once daily, then again to the target dose of 80 mg once daily. A lower starting dose may be used (10 mg once daily) and/or the rate of up‑titration may be slowed if clinically indicated (e.g., due to low blood pressure or heart rate, or fluid retention). Patients should be maintained on lower doses if higher doses are not tolerated. The recommended dosing regimen need not be altered in patients who received treatment with an IV or oral β‑blocker during the acute phase of the myocardial infarction.
- Dosing information
- DOSAGE MUST BE INDIVIDUALIZED. The recommended starting dose of carvedilol is 20 mg once daily. If this dose is tolerated, using standing systolic pressure measured about 1 hour after dosing as a guide, the dose should be maintained for 7 to 14 days, and then increased to 40 mg once daily if needed, based on trough blood pressure, again using standing systolic pressure 1 hour after dosing as a guide for tolerance. This dose should also be maintained for 7 to 14 days and can then be adjusted upward to 80 mg once daily if tolerated and needed. Although not specifically studied, it is anticipated the full antihypertensive effect of carvedilol would be seen within 7 to 14 days as had been demonstrated with immediate‑release carvedilol. Total daily dose should not exceed 80 mg.
- Concomitant administration with a diuretic can be expected to produce additive effects and exaggerate the orthostatic component of carvedilol action.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Dosing information
- 6.25 mg bid, then titrated to a maximum of 25 mg bid[1]
### Non–Guideline-Supported Use
- Dosing information
- 25 to 50 mg twice daily[2]
- Dosing information
- Titrate to a maximum dosage of 25 mg bid, 50 mg for patient >85 kg[3]
- Dosing information
- 6.25 mg bid, then titrated to 25-50 mg bid[4]
- Dosing information
- 3.125 mg bid, then titrated every 2 weeks to a maximum of 25 mg bid[5]
- Dosing information
- 2.5 to 20 mg daily
- Dosing information
- 12.5 to 25 mg daily[6]
- Dosing information
- 6.25 mg daily, then titrated to 12.5 mg daily[7]
- Dosing information
- 3.125 mg bid, titrate to 25 mg bid[8]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Carvedilol FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Carvedilol in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Carvedilol in pediatric patients.
# Contraindications
Carvedilol is contraindicated in the following conditions:
- Bronchial asthma or related bronchospastic conditions. Deaths from status asthmaticus have been reported following single doses of COREG.
- AV block (Second- or third-degree)
- Sick sinus syndrome
- Severe bradycardia (unless a permanent pacemaker is in place).
- Cardiogenic shock or who have decompensated heart failure requiring the use of intravenous inotropic therapy. Such patients should first be weaned from intravenous therapy before initiating COREG
- Severe hepatic impairment
- Serious hypersensitivity reaction (e.g., Stevens-Johnson syndrome, anaphylactic reaction, angioedema) to any component of this medication or other medications containing carvedilol.
# Warnings
- Acute exacerbation of coronary artery disease upon cessation of therapy: Do not abruptly discontinue.
- Bradycardia, hypotension, fluid retention may occur. Reduce the dose as needed.
- Non-allergic bronchospasm (e.g., chronic bronchitis and emphysema): Avoid β-blockers.
- However, if deemed necessary, use with caution and at lowest effective dose.
Diabetes: Monitor glucose as β-blockers may mask symptoms of hypoglycemia or worsen hyperglycemia.
Patients with coronary artery disease, who are being treated with carvedilol, should be advised against abrupt discontinuation of therapy. Severe exacerbation of angina and the occurrence of myocardial infarction and ventricular arrhythmias have been reported in angina patients following the abrupt discontinuation of therapy with β-blockers. The last 2 complications may occur with or without preceding exacerbation of the angina pectoris. As with other β-blockers, when discontinuation of carvedilol is planned, the patients should be carefully observed and advised to limit physical activity to a minimum. carvedilol should be discontinued over 1 to 2 weeks whenever possible. If the angina worsens or acute coronary insufficiency develops, it is recommended that carvedilol be promptly reinstituted, at least temporarily. Because coronary artery disease is common and may be unrecognized, it may be prudent not to discontinue therapy with carvedilol abruptly even in patients treated only for hypertension or heart failure.
## Bradycardia
In clinical trials, carvedilol causedbradycardia in about 2% of hypertensive subjects, 9% of heart failure subjects, and 6.5% of myocardial infarction subjects with left ventricular dysfunction. If pulse rate drops below 55 beats/minute, the dosage should be reduced.
In clinical trials of primarily mild‑to‑moderate heart failure, hypotension and postural hypotension occurred in 9.7% and syncope in 3.4% of subjects receiving carvedilol compared with 3.6% and 2.5% of placebo subjects, respectively. The risk for these events was highest during the first 30 days of dosing, corresponding to the up‑titration period and was a cause for discontinuation of therapy in 0.7% of subjects receiving carvedilol, compared with 0.4% of placebo subjects. In a long‑term, placebo‑controlled trial in severe heart failure (COPERNICUS), hypotension and postural hypotension occurred in 15.1% and syncope in 2.9% of heart failure subjects receiving carvedilol compared with 8.7% and 2.3% of placebo subjects, respectively. These events were a cause for discontinuation of therapy in 1.1% of subjects receiving carvedilol, compared with 0.8% of placebo subjects.
Postural hypotension occurred in 1.8% and syncope in 0.1% of hypertensive subjects, primarily following the initial dose or at the time of dose increase and was a cause for discontinuation of therapy in 1% of subjects.
In the CAPRICORN trial of survivors of an acutemyocardial infarction, hypotension or postural hypotension occurred in 20.2% of subjects receiving carvedilol compared with 12.6% of placebo subjects. Syncope was reported in 3.9% and 1.9% of subjects, respectively. These events were a cause for discontinuation of therapy in 2.5% of subjects receiving carvedilol, compared with 0.2% of placebo subjects.
Starting with a low dose, administration with food, and gradual up-titration should decrease the likelihood of syncope or excessive hypotension [see Dosage and Administration ]. During initiation of therapy, the patient should be cautioned to avoid situations such as driving or hazardous tasks, where injury could result should syncope occur.
Worsening heart failure or fluid retention may occur during up-titration of carvedilol. If such symptoms occur, diuretics should be increased and the carvedilol dose should not be advanced until clinical stability resumes [see Dosage and Administration (2)]. Occasionally it is necessary to lower the carvedilol dose or temporarily discontinue it. Such episodes do not preclude subsequent successful titration of, or a favorable response to, carvedilol. In a placebo-controlled trial of subjects with severe heart failure, worsening heart failure during the first 3 months was reported to a similar degree with carvedilol and with placebo. When treatment was maintained beyond 3 months, worsening heart failure was reported less frequently in subjects treated with carvedilol than with placebo. Worsening heart failure observed during long-term therapy is more likely to be related to the patients’ underlying disease than to treatment with carvedilol.
Patients with bronchospastic disease (e.g., chronic bronchitis and emphysema) should, in general, not receive β-blockers. carvedilol may be used with caution, however, in patients who do not respond to, or cannot tolerate, other antihypertensive agents. It is prudent, if carvedilol is used, to use the smallest effective dose, so that inhibition of endogenous or exogenous β-agonists is minimized.
In clinical trials of subjects with heart failure, subjects with bronchospastic disease were enrolled if they did not require oral or inhaled medication to treat their bronchospastic disease. In such patients, it is recommended that carvedilol be used with caution. The dosing recommendations should be followed closely and the dose should be lowered if any evidence of bronchospasm is observed during up-titration.
In general, β-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia. Nonselective β-blockers may potentiate insulin-induced hypoglycemia and delay recovery of serum glucose levels. Patients subject to spontaneous hypoglycemia, or diabetic patients receiving insulin or oral hypoglycemic agents, should be cautioned about these possibilities.
In heart failure patients with diabetes, carvedilol therapy may lead to worsening hyperglycemia, which responds to intensification of hypoglycemic therapy. It is recommended that blood glucose be monitored when carvedilol dosing is initiated, adjusted, or discontinued. Trials designed to examine the effects of carvedilol on glycemic control in patients with diabetes and heart failure have not been conducted.
In a trial designed to examine the effects of carvedilol on glycemic control in a population with mild-to-moderate hypertension and well-controlled type 2diabetes mellitus, carvedilol had no adverse effect on glycemic control, based on HbA1c measurements [see Carvidilol clinical studies
# Adverse Reactions
## Clinical Trials Experience
Carvedilol has been evaluated for safety in subjects with heart failure (mild, moderate, and severe), in subjects with left ventricular dysfunction following myocardial infarction, and in hypertensive subjects. The observed adverse event profile was consistent with the pharmacology of the drug and the health status of the subjects in the clinical trials. Adverse events reported for each of these populations reflecting the use of either carvedilol or immediate-release carvedilol are provided below. Excluded are adverse events considered too general to be informative, and those not reasonably associated with the use of the drug because they were associated with the condition being treated or are very common in the treated population. Rates of adverse events were generally similar across demographic subsets (men and women, elderly and non‑elderly, blacks and non‑blacks). Carvedilol has been evaluated for safety in a 4-week (2 weeks of immediate-release carvedilol and 2 weeks of COREG CR) clinical trial (n = 187) which included 157 subjects with stable mild, moderate, or severe chronic heart failure and 30 subjects with left ventricular dysfunction following acute myocardial infarction. The profile of adverse events observed with carvedilol in this small, short-term trial was generally similar to that observed with immediate-release carvedilol. Differences in safety would not be expected based on the similarity in plasma levels for carvedilol and immediate-release carvedilol.
Heart Failure
The following information describes the safety experience in heart failure with immediate-release carvedilol.
Carvedilol has been evaluated for safety in heart failure in more than 4,500 subjects worldwide of whom more than 2,100 participated in placebo‑controlled clinical trials. Approximately 60% of the total treated population in placebo‑controlled clinical trials received carvedilol for at least 6 months and 30% received carvedilol for at least 12 months. In the COMET trial, 1,511 subjects with mild‑to‑moderate heart failure were treated with carvedilol for up to 5.9 years (mean: 4.8 years). Both in US clinical trials in mild‑to‑moderate heart failure that compared carvedilol in daily doses up to 100 mg (n = 765) with placebo (n = 437), and in a multinational clinical trial in severe heart failure (COPERNICUS) that compared carvedilol in daily doses up to 50 mg (n = 1,156) with placebo (n = 1,133), discontinuation rates for adverse experiences were similar in carvedilol and placebo subjects. In placebo‑controlled clinical trials, the only cause of discontinuation >1%, and occurring more often on carvedilol was dizziness (1.3% on carvedilol, 0.6% on placebo in the COPERNICUS trial).
The table below shows adverse events reported in subjects with mild‑to‑moderate heart failure enrolled in US placebo‑controlled clinical trials, and with severe heart failure enrolled in the COPERNICUS trial. Shown are adverse events that occurred more frequently in drug‑treated subjects than placebo‑treated subjects with an incidence of >3% in subjects treated with carvedilol regardless of causality. Median trial medication exposure was 6.3 months for both carvedilol and placebo subjects in the trials of mild‑to‑moderate heart failure, and 10.4 months in the trial of subjects with severe heart failure. The adverse event profile of carvedilol observed in the long-term COMET trial was generally similar to that observed in the US Heart Failure Trials.
Cardiac failure and dyspnea were also reported in these trials, but the rates were equal or greater in subjects who received placebo.
The following adverse events were reported with a frequency of >1% but ≤3% and more frequently with carvedilol in either the US placebo-controlled trials in subjects with mild-to-moderate heart failure, or in subjects with severe heart failure in the COPERNICUS trial.
Incidence >1% to ≤3%
- Body as a Whole: Allergy, malaise, hypovolemia, fever, leg edema.
- Cardiovascular: Fluid overload, orthostatic hypotension, aggravated angina pectoris, AV block, palpitation, hypertension.
- Central and Peripheral Nervous System: Hypesthesia, vertigo, paresthesia.
- Gastrointestinal: Melena, periodontitis.
- Liver and Biliary System: SGPT increased, SGOT increased.
- Metabolic and Nutritional: Hyperuricemia, hypoglycemia, hyponatremia, increased alkaline phosphatase, glycosuria, hypervolemia, diabetes mellitus, GGT increased, weight loss, hyperkalemia, creatinine increased.
- Musculoskeletal: Muscle cramps.
- Platelet, Bleeding, and Clotting: Prothrombin decreased, purpura, thrombocytopenia.
- Psychiatric: Somnolence.
- Reproductive, male: Impotence.
- Special Senses: Blurred vision.
- Urinary System: Renal insufficiency, albuminuria, hematuria.
Left Ventricular Dysfunction Following Myocardial Infarction
The following information describes the safety experience in left ventricular dysfunction following acute myocardial infarction with immediate-release carvedilol.
Carvedilol has been evaluated for safety in survivors of an acute myocardial infarction with left ventricular dysfunction in the CAPRICORN trial which involved 969 subjects who received carvedilol and 980 who received placebo. Approximately 75% of the subjects received carvedilol for at least 6 months and 53% received carvedilol for at least 12 months. Subjects were treated for an average of 12.9 months and 12.8 months with carvedilol and placebo, respectively.
The most common adverse events reported with carvedilol in the CAPRICORN trial were consistent with the profile of the drug in the US heart failure trials and the COPERNICUS trial. The only additional adverse events reported in CAPRICORN in >3% of the subjects and more commonly on carvedilol were dyspnea, anemia, and lung edema. The following adverse events were reported with a frequency of >1% but ≤3% and more frequently with carvedilol: flu syndrome, cerebrovascular accident, peripheral vascular disorder, hypotonia, depression, gastrointestinal pain, arthritis, and gout. The overall rates of discontinuations due to adverse events were similar in both groups of subjects. In this database, the only cause of discontinuation >1%, and occurring more often on carvedilol was hypotension (1.5% on carvedilol, 0.2% on placebo).
Hypertension
Carvedilol was evaluated for safety in an 8-week double-blind trial in 337 subjects with essential hypertension. The profile of adverse events observed with carvedilol was generally similar to that observed with immediate-release carvedilol. The overall rates of discontinuations due to adverse events were similar between carvedilol and placebo.
The following information describes the safety experience in hypertension with immediate-release carvedilol.
Carvedilol has been evaluated for safety in hypertension in more than 2,193 subjects in US clinical trials and in 2,976 subjects in international clinical trials. Approximately 36% of the total treated population received carvedilol for at least 6 months. In general, carvedilol was well tolerated at doses up to 50 mg daily. Most adverse events reported during carvedilol therapy were of mild to moderate severity. In US controlled clinical trials directly comparing carvedilol monotherapy in doses up to 50 mg (n = 1,142) with placebo (n = 462), 4.9% of carvedilol subjects discontinued for adverse events versus 5.2% of placebo subjects. Although there was no overall difference in discontinuation rates, discontinuations were more common in the carvedilol group for orthostatic hypotension (1% versus 0). The overall incidence of adverse events in US placebo‑controlled trials was found to increase with increasing dose of carvedilol. For individual adverse events this could only be distinguished for dizziness, which increased in frequency from 2% to 5% as total daily dose increased from 6.25 mg to 50 mg as single or divided doses.
The table below shows adverse events in US placebo‑controlled clinical trials for hypertension that occurred with an incidence of ≥1% regardless of causality, and that were more frequent in drug‑treated subjects than placebo‑treated subjects.
Dyspnea and fatigue were also reported in these trials, but the rates were equal or greater in subjects who received placebo.
The following adverse events not described above were reported as possibly or probably related to carvedilol in worldwide open or controlled trials with carvedilol in subjects with hypertension or heart failure.
Incidence >0.1% to ≤1%
- Cardiovascular: Peripheral ischemia, tachycardia.
- Central and Peripheral Nervous System: Hypokinesia.
- Gastrointestinal: Bilirubinemia, increased hepatic enzymes (0.2% of hypertension patients and 0.4% of heart failure patients were discontinued from therapy because of increases in hepatic enzymes).
Psychiatric: Nervousness, sleep disorder, aggravated depression, impaired concentration, abnormal thinking, paroniria, emotional lability.
- Respiratory System: Asthma.
- Reproductive, male: Decreased libido.
- Skin and Appendages: Pruritus, rash erythematous, rash maculopapular, rash psoriaform, photosensitivity reaction.
- Special Senses: Tinnitus.
- Urinary System: Micturition frequency increased.
- Autonomic Nervous System: Dry mouth, sweating increased.
- Metabolic and Nutritional: Hypokalemia, hypertriglyceridemia.
- Hematologic: Anemia, leukopenia.
The following events were reported in ≤0.1% of subjects and are potentially important: complete AV block, bundle branch block, myocardial ischemia, cerebrovascular disorder, seizures, migraine, neuralgia, paresis, anaphylactoid reaction, alopecia, exfoliative dermatitis, amnesia, GI hemorrhage, bronchospasm, pulmonary edema, decreased hearing, respiratory alkalosis, increased BUN, decreased HDL, pancytopenia, and atypical lymphocytes.
Reversible elevations in serum transaminases (ALT or AST) have been observed during treatment with carvedilol. Rates of transaminase elevations (2 to 3 times the upper limit of normal) observed during controlled clinical trials have generally been similar between subjects treated with carvedilol and those treated with placebo. However, transaminase elevations, confirmed by rechallenge, have been observed with carvedilol. In a long-term, placebo-controlled trial in severe heart failure, subjects treated with carvedilol had lower values for hepatic transaminases than subjects treated with placebo, possibly because carvedilol-induced improvements in cardiac function led to less hepatic congestion and/or improved hepatic blood flow.
Carvedilol therapy has not been associated with clinically significant changes in serum potassium, total triglycerides, total cholesterol, HDL cholesterol, uric acid, blood urea nitrogen, or creatinine. No clinically relevant changes were noted in fasting serum glucose in hypertensive subjects; fasting serum glucose was not evaluated in the heart failure clinical trials.
## Postmarketing Experience
The following adverse reactions have been identified during post-approval use of carvedilol. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Blood and Lymphatic System Disorders: Aplastic anemia.
Immune System Disorders: Hypersensitivity (e.g., anaphylactic reactions, angioedema, urticaria).
Renal and Urinary Disorders: Urinary incontinence.
Respiratory, Thoracic and Mediastinal Disorders: Interstitial pneumonitis.
Skin and Subcutaneous Tissue Disorders: Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme.
# Drug Interactions
Interactions of carvedilol with potent inhibitors of CYP2D6 isoenzyme (such as quinidine, fluoxetine, paroxetine, and propafenone) have not been studied, but these drugs would be expected to increase blood levels of the R(+) enantiomer of carvedilol. Retrospective analysis of side effects in clinical trials showed that poor 2D6 metabolizers had a higher rate of dizziness during up-titration, presumably resulting from vasodilating effects of the higher concentrations of the α‑blocking R(+) enantiomer.
Patients taking both agents with β‑blocking properties and a drug that can deplete catecholamines (e.g., reserpine and monoamine oxidase inhibitors) should be observed closely for signs of hypotension and/or severe bradycardia.
Concomitant administration of clonidine with agents with β‑blocking properties may potentiate blood pressure and heart rate lowering effects. When concomitant treatment with agents with β‑blocking properties and clonidine is to be terminated, the β‑blocking agent should be discontinued first. Clonidine therapy can then be discontinued several days later by gradually decreasing the dosage.
Modest increases in mean trough cyclosporine concentrations were observed following initiation of carvedilol treatment in 21 renal transplant subjects suffering from chronic vascular rejection. In about 30% of subjects, the dose of cyclosporine had to be reduced in order to maintain cyclosporine concentrations within the therapeutic range, while in the remainder no adjustment was needed. On the average for the group, the dose of cyclosporine was reduced about 20% in these subjects. Due to wide interindividual variability in the dose adjustment required, it is recommended that cyclosporine concentrations be monitored closely after initiation of carvedilol therapy and that the dose of cyclosporine be adjusted as appropriate.
Both digitalis glycosides and β‑blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia. Digoxin concentrations are increased by about 15% when digoxin and carvedilol are administered concomitantly. Therefore, increased monitoring of digoxin is recommended when initiating, adjusting, or discontinuing carvedilol.
Rifampin reduced plasma concentrations of carvedilol by about 70%. Cimetidine increased area under the curve (AUC) by about 30% but caused no change in Cmax.
Amiodarone, and its metabolite desethyl amiodarone, inhibitors of CYP2C9 and P-glycoprotein, increased concentrations of the S(-) enantiomer of carvedilol by at least 2-fold. The concomitant administration of amiodarone or other CYP2C9 inhibitors such as fluconazole with carvedilol may enhance the β‑blocking properties of carvedilol resulting in further slowing of the heart rate or cardiac conduction. Patients should be observed for signs of bradycardia or heart block, particularly when one agent is added to pre-existing treatment with the other.
Conduction disturbance (rarely with hemodynamic compromise) has been observed when carvedilol is coadministered with diltiazem. As with other agents with β‑blocking properties, if carvedilol is to be administered orally with calcium channel blockers of the verapamil or diltiazem type, it is recommended that ECG and blood pressure be monitored.
Agents with β‑blocking properties may enhance the blood‑sugar‑reducing effect of insulin and oral hypoglycemics. Therefore, in patients taking insulin or oral hypoglycemics, regular monitoring of blood glucose is recommended.
There is no clinically meaningful increase in AUC and Cmax with concomitant administration of carvedilol extended‑release capsules with pantoprazole.
If treatment with carvedilol is to be continued perioperatively, particular care should be taken when anesthetic agents which depress myocardial function, such as ether, cyclopropane, and trichloroethylene, are used.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
Studies performed in pregnant rats and rabbits given carvedilol revealed increased post-implantation loss in rats at doses of 300 mg/kg/day (50 times the maximum recommended human dose [MRHD] as mg/m2) and in rabbits at doses of 75 mg/kg/day (25 times the MRHD as mg/m2). In the rats, there was also a decrease in fetal body weight at the maternally toxic dose of 300 mg/kg/day (50 times the MRHD as mg/m2), which was accompanied by an elevation in the frequency of fetuses with delayed skeletal development (missing or stunted 13th rib). In rats the no-observed-effect level for developmental toxicity was 60 mg/kg/day (10 times the MRHD as mg/m2); in rabbits it was 15 mg/kg/day (5 times the MRHD as mg/m2). There are no adequate and well-controlled studies in pregnant women. Carvedilol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Carvedilol in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Carvedilol during labor and delivery.
### Nursing Mothers
It is not known whether this drug is excreted in human milk. Studies in rats have shown that carvedilol and/or its metabolites (as well as other β-blockers) cross the placental barrier and are excreted in breast milk. There was increased mortality at one week post-partum in neonates from rats treated with 60 mg/kg/day (10 times the MRHD as mg/m2) and above during the last trimester through day 22 of lactation. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from β-blockers, especially bradycardia, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. The effects of other α- and β-blocking agents have included perinatal and neonatal distress.
### Pediatric Use
Effectiveness of carvedilol in patients younger than 18 years has not been established.
In a double-blind trial, 161 children (mean age: 6 years, range: 2 months to 17 years; 45% younger than 2 years) with chronic heart failure [NYHA class II-IV, left ventricular ejection fraction <40% for children with a systemic left ventricle (LV), and moderate-severe ventricular dysfunction qualitatively by echo for those with a systemic ventricle that was not an LV] who were receiving standard background treatment were randomized to placebo or to 2 dose levels of carvedilol. These dose levels produced placebo-corrected heart rate reduction of 4 to 6 heart beats per minute, indicative of β-blockade activity. Exposure appeared to be lower in pediatric subjects than adults. After 8 months of follow-up, there was no significant effect of treatment on clinical outcomes. Adverse reactions in this trial that occurred in greater than 10% of subjects treated with carvedilol and at twice the rate of placebo-treated subjects included chest pain (17% versus 6%), dizziness (13% versus 2%), and dyspnea (11% versus 0%).
### Geriatic Use
The initial clinical trials of COREG CR in subjects with hypertension, heart failure, and left ventricular dysfunction following myocardial infarction did not include sufficient numbers of subjects 65 years of age or older to determine whether they respond differently from younger patients.
A randomized trial (n = 405) comparing subjects with mild to severe heart failure switched to carvedilol or maintained on immediate-release carvedilol included 220 subjects who were 65 years of age or older. In this elderly subgroup, the combined incidence of dizziness, hypotension, or syncope was 24% (18/75) in subjects switched from the highest dose of immediate-release carvedilol (25 mg twice daily) to the highest dose of carvedilol (80 mg once daily) compared with 11% (4/36) in subjects maintained on immediate-release carvedilol (25 mg twice daily). When switching from the higher doses of immediate-release carvedilol to carvedilol, a lower starting dose is recommended for elderly patients.
The following information is available for trials with immediate-release carvedilol. Of the 765 subjects with heart failure randomized to carvedilol in US clinical trials, 31% (235) were 65 years of age or older, and 7.3% (56) were 75 years of age or older. Of the 1,156 subjects randomized to carvedilol in a long‑term, placebo‑controlled trial in severe heart failure, 47% (547) were 65 years of age or older, and 15% (174) were 75 years of age or older. Of 3,025 subjects receiving carvedilol in heart failure trials worldwide, 42% were 65 years of age or older. Of the 975 subjects with myocardial infarction randomized to carvedilol in the CAPRICORN trial, 48% (468) were 65 years of age or older, and 11% (111) were 75 years of age or older. Of the 2,065 hypertensive subjects in US clinical trials of efficacy or safety who were treated with carvedilol, 21% (436) were 65 years of age or older. Of 3,722 subjects receiving immediate-release carvedilol in hypertension clinical trials conducted worldwide, 24% were 65 years of age or older.
With the exception of dizziness in hypertensive subjects (incidence 8.8% in the elderly versus 6% in younger subjects), no overall differences in the safety or effectiveness were observed between the older subjects and younger subjects in each of these populations. Similarly, other reported clinical experience has not identified differences in responses between the elderly and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.
### Gender
There is no FDA guidance on the use of Carvedilol with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Carvedilol with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Carvedilol in patients with renal impairment.
### Hepatic Impairment
Carvedilol is contraindicated in patients with severe liver impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Carvedilol in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Carvedilol in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Oral
### Monitoring
DOSAGE MUST BE INDIVIDUALIZED AND CLOSELY MONITORED BY A PHYSICIAN DURING UP‑TITRATION.
# IV Compatibility
There is limited information regarding the compatibility of Carvedilol and IV administrations.
# Overdosage
Overdosage may cause severe hypotension, bradycardia, cardiac insufficiency, cardiogenic shock, and cardiac arrest. Respiratory problems, bronchospasms, vomiting, lapses of consciousness, and generalized seizures may also occur.
The patient should be placed in a supine position and, where necessary, kept under observation and treated under intensive-care conditions. Gastric lavage or pharmacologically induced emesis may be used shortly after ingestion. The following agents may be administered:
- For excessive bradycardia: atropine, 2 mg IV.
- To support cardiovascular function: glucagon, 5 to 10 mg IV rapidly over 30 seconds, followed by a continuous infusion of 5 mg/hour; sympathomimetics (dobutamine, isoprenaline, adrenaline) at doses according to body weight and effect.
If peripheral vasodilation dominates, it may be necessary to administer adrenaline or noradrenaline with continuous monitoring of circulatory conditions. For therapy-resistant bradycardia, pacemaker therapy should be performed. For bronchospasm, β‑sympathomimetics (as aerosol or IV) or aminophylline IV should be given. In the event of seizures, slow IV injection of diazepam or clonazepam is recommended.
NOTE: In the event of severe intoxication where there are symptoms of shock, treatment with antidotes must be continued for a sufficiently long period of time consistent with the 7- to 10-hour half-life of carvedilol.
There is no experience of overdosage with carvedilol. Cases of overdosage with carvedilol alone or in combination with other drugs have been reported. Quantities ingested in some cases exceeded 1,000 milligrams. Symptoms experienced included low blood pressure and heart rate. Standard supportive treatment was provided and individuals recovered.
# Pharmacology
## Mechanism of Action
Carvedilol is a racemic mixture in which nonselective β‑adrenoreceptor blocking activity is present in the S(-) enantiomer and α1‑adrenergic blocking activity is present in both R(+) and S(-) enantiomers at equal potency. Carvedilol has no intrinsic sympathomimetic activity.
## Structure
Carvedilol phosphate is a nonselective β‑adrenergic blocking agent with α1-blocking activity. It is (2RS)-1-(9H-Carbazol-4-yloxy)-3-((2-(2-methoxyphenoxy)ethyl)amino)propan-2-ol phosphate salt (1:1) hemihydrate. It is a racemic mixture with the following structure:
Carvedilol phosphate is a white to almost white solid with a molecular weight of 513.5 (406.5 carvedilol free base) and a molecular formula of C24H26N2O4•H3PO4•1/2 H2O.
COREG CR is available for once-a-day administration as controlled-release oral capsules containing 10, 20, 40, or 80 mg carvedilol phosphate. Carvedilol hard gelatin capsules are filled with carvedilol phosphate immediate-release and controlled-release microparticles that are drug-layered and then coated with methacrylic acid copolymers. Inactive ingredients include crospovidone, hydrogenated castor oil, hydrogenated vegetable oil, magnesium stearate, methacrylic acid copolymers, microcrystalline cellulose, and povidone.
## Pharmacodynamics
The basis for the beneficial effects of carvedilol in patients with heart failure and in patients with left ventricular dysfunction following an acute myocardial infarction is not known. The concentration-response relationship for β1‑blockade following administration of carvedilol is equivalent (±20%) to immediate-release carvedilol tablets.
The mechanism by which β‑blockade produces an antihypertensive effect has not been established.
β‑adrenoreceptor blocking activity has been demonstrated in animal and human studies showing that carvedilol (1) reduces cardiac output in normal subjects; (2) reduces exercise- and/or isoproterenol-induced tachycardia; and (3) reduces reflex orthostatic tachycardia. Significant β‑adrenoreceptor blocking effect is usually seen within 1 hour of drug administration.
α1‑adrenoreceptor blocking activity has been demonstrated in human and animal studies, showing that carvedilol (1) attenuates the pressor effects of phenylephrine; (2) causes vasodilation; and (3) reduces peripheral vascular resistance. These effects contribute to the reduction of blood pressure and usually are seen within 30 minutes of drug administration.
Due to the α1‑receptor blocking activity of carvedilol, blood pressure is lowered more in the standing than in the supine position, and symptoms of orthostatic hypotension (1.8%), including rare instances of syncope, can occur. Following oral administration, when postural hypotension has occurred, it has been transient and is uncommon when immediate-release carvedilol is administered with food at the recommended starting dose and titration increments are closely followed.
In a randomized, double-blind, placebo-controlled trial, the β1‑blocking effect of carvedilol, as measured by heart rate response to submaximal bicycle ergometry, was shown to be equivalent to that observed with immediate-release carvedilol at steady state in adult subjects with essential hypertension.
In hypertensive subjects with normal renal function, therapeutic doses of carvedilol decreased renal vascular resistance with no change in glomerular filtration rate or renal plasma flow. Changes in excretion of sodium, potassium, uric acid, and phosphorus in hypertensive patients with normal renal function were similar after carvedilol and placebo.
Carvedilol has little effect on plasma catecholamines, plasma aldosterone, or electrolyte levels, but it does significantly reduce plasma renin activity when given for at least 4 weeks. It also increases levels of atrial natriuretic peptide.
## Pharmacokinetics
Carvedilol is rapidly and extensively absorbed following oral administration of immediate-release carvedilol tablets, with an absolute bioavailability of approximately 25% to 35% due to a significant degree of first-pass metabolism. Carvedilol extended-release capsules have approximately 85% of the bioavailability of immediate-release carvedilol tablets. For corresponding dosages, the exposure (AUC, Cmax, trough concentration) of carvedilol as carvedilol extended-release capsules is equivalent to those of immediate-release carvedilol tablets when both are administered with food. The absorption of carvedilol from carvedilol is slower and more prolonged compared with the immediate-release carvedilol tablet with peak concentrations achieved approximately 5 hours after administration. Plasma concentrations of carvedilol increase in a dose-proportional manner over the dosage range of carvedilol 10 to 80 mg. Within-subject and between-subject variability for AUC and Cmax is similar for carvedilol and immediate-release carvedilol.
Effect of Food
Administration of carvedilol with a high-fat meal resulted in increases (~20%) in AUC and Cmax compared with carvedilol administered with a standard meal. Decreases in AUC (27%) and Cmax (43%) were observed when carvedilol was administered in the fasted state compared with administration after a standard meal. Carvedilol should be taken with food.
In a trial with adult subjects, sprinkling the contents of the carvedilol capsule on applesauce did not appear to have a significant effect on overall exposure (AUC) compared with administration of the intact capsule following a standard meal but did result in a decrease in Cmax (18%).
Carvedilol is more than 98% bound to plasma proteins, primarily with albumin. The plasma protein binding is independent of concentration over the therapeutic range. Carvedilol is a basic, lipophilic compound with a steady-state volume of distribution of approximately 115 L, indicating substantial distribution into extravascular tissues.
Carvedilol is extensively metabolized. Following oral administration of radiolabelled carvedilol to healthy volunteers, carvedilol accounted for only about 7% of the total radioactivity in plasma as measured by AUC. Less than 2% of the dose was excreted unchanged in the urine. Carvedilol is metabolized primarily by aromatic ring oxidation and glucuronidation. The oxidative metabolites are further metabolized by conjugation via glucuronidation and sulfation. The metabolites of carvedilol are excreted primarily via the bile into the feces. Demethylation and hydroxylation at the phenol ring produce 3 active metabolites with β‑receptor blocking activity. Based on preclinical studies, the 4'-hydroxyphenyl metabolite is approximately 13 times more potent than carvedilol for β‑blockade.
Compared with carvedilol, the 3 active metabolites exhibit weak vasodilating activity. Plasma concentrations of the active metabolites are about one-tenth of those observed for carvedilol and have pharmacokinetics similar to the parent.
Carvedilol undergoes stereoselective first-pass metabolism with plasma levels of R(+)-carvedilol approximately 2 to 3 times higher than S(-)-carvedilol following oral administration of carvedilol in healthy subjects. Apparent clearance is 90 L/h and 213 L/h for R(+)- and S(-)-carvedilol, respectively.
The primary P450 enzymes responsible for the metabolism of both R(+) and S(-)-carvedilol in human liver microsomes were CYP2D6 and CYP2C9 and to a lesser extent CYP3A4, 2C19, 1A2, and 2E1. CYP2D6 is thought to be the major enzyme in the 4’- and 5’-hydroxylation of carvedilol, with a potential contribution from 3A4. CYP2C9 is thought to be of primary importance in the O-methylation pathway of S(-)-carvedilol.
Carvedilol is subject to the effects of genetic polymorphism with poor metabolizers of debrisoquin (a marker for cytochrome P450 2D6) exhibiting 2- to 3-fold higher plasma concentrations of R(+)-carvedilol compared with extensive metabolizers. In contrast, plasma levels of S(-)-carvedilol are increased only about 20% to 25% in poor metabolizers, indicating this enantiomer is metabolized to a lesser extent by cytochrome P450 2D6 than R(+)-carvedilol. The pharmacokinetics of carvedilol do not appear to be different in poor metabolizers of S-mephenytoin (patients deficient in cytochrome P450 2C19).
Heart Failure
Following administration of immediate-release carvedilol tablets, steady‑state plasma concentrations of carvedilol and its enantiomers increased proportionally over the dose range in subjects with heart failure. Compared with healthy subjects, subjects with heart failure had increased mean AUC and Cmax values for carvedilol and its enantiomers, with up to 50% to 100% higher values observed in 6 subjects with NYHA class IV heart failure. The mean apparent terminal elimination half‑life for carvedilol was similar to that observed in healthy subjects.
For corresponding dose levels, the steady-state pharmacokinetics of carvedilol (AUC, Cmax, trough concentrations) observed after administration of carvedilol to subjects with chronic heart failure (mild, moderate, and severe) were similar to those observed after administration of immediate-release carvedilol tablets.
Hypertension
For corresponding dose levels, the pharmacokinetics (AUC, Cmax, and trough concentrations) observed with administration of carvedilol were equivalent (±20%) to those observed with immediate-release carvedilol tablets following repeat dosing in subjects with essential hypertension.
Geriatric
Plasma levels of carvedilol average about 50% higher in the elderly compared with young subjects after administration of immediate-release carvedilol.
Hepatic Impairment
No trials have been performed with carvedilol in subjects with hepatic impairment. Compared with healthy subjects, subjects with severe hepatic impairment (cirrhosis) exhibit a 4- to 7-fold increase in carvedilol levels. Carvedilol is contraindicated in patients with severe liver impairment.
Renal Impairment
No trials have been performed with carvedilol in subjects with renal impairment. Although carvedilol is metabolized primarily by the liver, plasma concentrations of carvedilol have been reported to be increased in patients with renal impairment after dosing with immediate-release carvedilol. Based on mean AUC data, approximately 40% to 50% higher plasma concentrations of carvedilol were observed in hypertensive subjects with moderate to severe renal impairment compared with a control group of hypertensive subjects with normal renal function. However, the ranges of AUC values were similar for both groups. Changes in mean peak plasma levels were less pronounced, approximately 12% to 26% higher in subjects with impaired renal function.
Consistent with its high degree of plasma protein binding, carvedilol does not appear to be cleared significantly by hemodialysis.
## Nonclinical Toxicology
In 2-year studies conducted in rats given carvedilol at doses up to 75 mg/kg/day (12 times the MRHD when compared on a mg/m2 basis) or in mice given up to 200 mg/kg/day (16 times the MRHD on a mg/m2 basis), carvedilol had no carcinogenic effect.
Carvedilol was negative when tested in a battery of genotoxicity assays, including the Ames and the CHO/HGPRT assays for mutagenicity and the in vitro hamster micronucleus and in vivo human lymphocyte cell tests for clastogenicity.
At doses ≥200 mg/kg/day (≥32 times the MRHD as mg/m2) carvedilol was toxic to adult rats (sedation, reduced weight gain) and was associated with a reduced number of successful matings, prolonged mating time, significantly fewer corpora lutea and implants per dam, and complete resorption of 18% of the litters. The no-observed-effect dose level for overt toxicity and impairment of fertility was 60 mg/kg/day (10 times the MRHD as mg/m2).
# Clinical Studies
A total of 6,975 subjects with mild-to-severe heart failure were evaluated in placebo-controlled and active-controlled trials of immediate-release carvedilol.
Mild-to-Moderate Heart Failure
Carvedilol was studied in 5 multicenter, placebo‑controlled trials, and in 1 active-controlled trial (COMET trial) involving subjects with mild-to-moderate heart failure.
Four US multicenter, double‑blind, placebo‑controlled trials enrolled 1,094 subjects (696 randomized to carvedilol) with NYHA class II‑III heart failure and ejection fraction ≤0.35. The vast majority were on digitalis, diuretics, and an ACE inhibitor at trial entry. Subjects were assigned to the trials based upon exercise ability. An Australia‑New Zealand double‑blind, placebo‑controlled trial enrolled 415 subjects (half randomized to immediate‑release carvedilol) with less severe heart failure. All protocols excluded subjects expected to undergo cardiac transplantation during the 7.5 to 15 months of double‑blind follow‑up. All randomized subjects had tolerated a 2‑week course on immediate‑release carvedilol 6.25 mg twice daily.
In each trial, there was a primary end point, either progression of heart failure (1 US trial) or exercise tolerance (2 US trials meeting enrollment goals and the Australia‑New Zealand trial). There were many secondary end points specified in these trials, including NYHA classification, patient and physician global assessments, and cardiovascular hospitalization. Other analyses not prospectively planned included the sum of deaths and total cardiovascular hospitalizations. In situations where the primary end points of a trial do not show a significant benefit of treatment, assignment of significance values to the other results is complex, and such values need to be interpreted cautiously.
The results of the US and Australia‑New Zealand trials were as follows:
- Slowing Progression of Heart Failure: One US multicenter trial (366 subjects) had as its primary end point the sum of cardiovascular mortality, cardiovascular hospitalization, and sustained increase in heart failure medications. Heart failure progression was reduced, during an average follow‑up of 7 months, by 48% (P = 0.008).
In the Australia‑New Zealand trial, death and total hospitalizations were reduced by about 25% over 18 to 24 months. In the 3 largest US trials, death and total hospitalizations were reduced by 19%, 39%, and 49%, nominally statistically significant in the last 2 trials. The Australia‑New Zealand results were statistically borderline.
- Functional Measures: None of the multicenter trials had NYHA classification as a primary end point, but all such trials had it as a secondary end point. There was at least a trend toward improvement in NYHA class in all trials. Exercise tolerance was the primary end point in 3 trials; in none was a statistically significant effect found.
- Subjective Measures: Health-related quality of life, as measured with a standard questionnaire (a primary end point in 1 trial), was unaffected by carvedilol. However, patients’ and investigators’ global assessments showed significant improvement in most trials.
- Mortality: Death was not a pre-specified end point in any trial, but was analyzed in all trials. Overall, in these 4 US trials, mortality was reduced, nominally significantly so in 2 trials.
The COMET Trial
In this double-blind trial, 3,029 subjects with NYHA class II-IV heart failure (left ventricular ejection fraction ≤35%) were randomized to receive either carvedilol (target dose: 25 mg twice daily) or immediate-release metoprolol tartrate (target dose: 50 mg twice daily). The mean age of the subjects was approximately 62 years, 80% were males, and the mean left ventricular ejection fraction at baseline was 26%. Approximately 96% of the subjects had NYHA class II or III heart failure. Concomitant treatment included diuretics (99%), ACE inhibitors (91%), digitalis (59%), aldosterone antagonists (11%), and “statin” lipid-lowering agents (21%). The mean duration of follow-up was 4.8 years. The mean dose of carvedilol was 42 mg per day.
The trial had 2 primary end points: all-cause mortality and the composite of death plus hospitalization for any reason. The results of COMET are presented in Table 5 below. All-cause mortality carried most of the statistical weight and was the primary determinant of the trial size. All-cause mortality was 34% in the subjects treated with carvedilol and was 40% in the immediate-release metoprolol group (P = 0.0017; hazard ratio = 0.83, 95% CI: 0.74 to 0.93). The effect on mortality was primarily due to a reduction in cardiovascular death. The difference between the 2 groups with respect to the composite end point was not significant (P = 0.122). The estimated mean survival was 8.0 years with carvedilol and 6.6 years with immediate-release metoprolol.
It is not known whether this formulation of metoprolol at any dose or this low dose of metoprolol in any formulation has any effect on survival or hospitalization in patients with heart failure. Thus, this trial extends the time over which carvedilol manifests benefits on survival in heart failure, but it is not evidence that carvedilol improves outcome over the formulation of metoprolol with benefits in heart failure.
Severe Heart Failure (COPERNICUS)
In a double-blind trial, 2,289 subjects with heart failure at rest or with minimal exertion and left ventricular ejection fraction <25% (mean 20%), despite digitalis (66%), diuretics (99%), and ACE inhibitors (89%) were randomized to placebo or carvedilol. Carvedilol was titrated from a starting dose of 3.125 mg twice daily to the maximum tolerated dose or up to 25 mg twice daily over a minimum of 6 weeks. Most subjects achieved the target dose of 25 mg. The trial was conducted in Eastern and Western Europe, the United States, Israel, and Canada. Similar numbers of subjects per group (about 100) withdrew during the titration period.
The primary end point of the trial was all‑cause mortality, but cause‑specific mortality and the risk of death or hospitalization (total, cardiovascular [CV], or heart failure [HF]) were also examined. The developing trial data were followed by a data monitoring committee, and mortality analyses were adjusted for these multiple looks. The trial was stopped after a median follow‑up of 10 months because of an observed 35% reduction in mortality (from 19.7% per patient-year on placebo to 12.8% on carvedilol, hazard ratio 0.65, 95% CI: 0.52 to 0.81, P = 0.0014, adjusted). The results of COPERNICUS are shown in the table below.
Cardiovascular = CV; Heart failure = HF.
Figure. Survival Analysis for COPERNICUS (Intent-to-Treat)
The effect on mortality was principally the result of a reduction in the rate of sudden death among subjects without worsening heart failure.
Patients' global assessments, in which carvedilol‑treated subjects were compared with placebo, were based on pre-specified, periodic patient self-assessments regarding whether clinical status post-treatment showed improvement, worsening, or no change compared with baseline. Subjects treated with carvedilol showed significant improvements in global assessments compared with those treated with placebo in COPERNICUS.
The protocol also specified that hospitalizations would be assessed. Fewer subjects on immediate‑release carvedilol than on placebo were hospitalized for any reason (372 versus 432, P= 0.0029), for cardiovascular reasons (246 versus 314, P = 0.0003), or for worsening heart failure (198 versus 268, P = 0.0001).
Immediate‑release carvedilol had a consistent and beneficial effect on all‑cause mortality as well as the combined end points of all‑cause mortality plus hospitalization (total, CV, or for heart failure) in the overall trial population and in all subgroups examined, including men and women, elderly and non‑elderly, blacks and non‑blacks, and diabetics and non-diabetics (see Figure 2).
Figure. Effects on Mortality for Subgroups in COPERNICUS
Although the clinical trials used twice-daily dosing, clinical pharmacologic and pharmacokinetic data provide a reasonable basis for concluding that once-daily dosing with COREG CR should be adequate in the treatment of heart failure.
CAPRICORN was a double‑blind trial comparing carvedilol and placebo in 1,959 subjects with a recent myocardial infarction (within 21 days) and left ventricular ejection fraction of ≤40%, with (47%) or without symptoms of heart failure. Subjects given carvedilol received 6.25 mg twice daily, titrated as tolerated to 25 mg twice daily. Subjects had to have a systolic blood pressure >90 mm Hg, a sitting heart rate >60 beats/minute, and no contraindication to β‑blocker use. Treatment of the index infarction included aspirin (85%), IV or oral β‑blockers (37%), nitrates (73%), heparin (64%), thrombolytics (40%), and acute angioplasty (12%). Background treatment included ACE inhibitors or angiotensin receptor blockers (97%), anticoagulants (20%), lipid‑lowering agents (23%), and diuretics (34%). Baseline population characteristics included an average age of 63 years, 74% male, 95% Caucasian, mean blood pressure 121/74 mm Hg, 22% with diabetes, and 54% with a history of hypertension. Mean dosage achieved of carvedilol was 20 mg twice daily; mean duration of follow‑up was 15 months.
All‑cause mortality was 15% in the placebo group and 12% in the carvedilol group, indicating a 23% risk reduction in subjects treated with carvedilol (95% CI: 2% to 40%,P = 0.03), as shown in Figure 3. The effects on mortality in various subgroups are shown in Figure 4. Nearly all deaths were cardiovascular (which were reduced by 25% by carvedilol), and most of these deaths were sudden or related to pump failure (both types of death were reduced by carvedilol). Another trial end point, total mortality and all-cause hospitalization, did not show a significant improvement.
There was also a significant 40% reduction in fatal or non-fatal myocardial infarction observed in the group treated with carvedilol (95% CI: 11% to 60%, P = 0.01). A similar reduction in the risk of myocardial infarction was also observed in a meta-analysis of placebo-controlled trials of carvedilol in heart failure.
Figure. Survival Analysis for CAPRICORN (Intent-to-Treat)
Figure. Effects on Mortality for Subgroups in CAPRICORN
Although the clinical trials used twice-daily dosing, clinical pharmacologic and pharmacokinetic data provide a reasonable basis for concluding that once-daily dosing with COREG CR should be adequate in the treatment of left ventricular dysfunction following myocardial infarction.
A double-blind, randomized, placebo-controlled, 8-week trial evaluated the blood pressure lowering effects of COREG CR 20 mg, 40 mg, and 80 mg once daily in 338 subjects with essential hypertension (sitting diastolic blood pressure [DBP] ≥90 and ≤109 mm Hg). Of 337 evaluable subjects, a total of 273 subjects (81%) completed the trial. Of the 64 (19%) subjects withdrawn from the trial, 10 (3%) were due to adverse events, 10 (3%) were due to lack of efficacy; the remaining 44 (13%) withdrew for other reasons. The mean age of the subjects was approximately 53 years, 66% were male, and the mean sitting systolic blood pressure (SBP) and DBP at baseline were 150 mm Hg and 99 mm Hg, respectively. Dose titration occurred at 2‑week intervals.
Statistically significant reductions in blood pressure as measured by 24‑hour ambulatory blood pressure monitoring (ABPM) were observed with each dose of COREG CR compared with placebo. Placebo-subtracted mean changes from baseline in mean SBP/DBP were ‑6.1/‑4.0 mm Hg, ‑9.4/‑7.6 mm Hg, and ‑11.8/‑9.2 mm Hg for COREG CR 20 mg, 40 mg, and 80 mg, respectively. Placebo-subtracted mean changes from baseline in mean trough (average of hours 20 to 24) SBP/DBP were ‑3.3/‑2.8 mm Hg, ‑4.9/‑5.2 mm Hg, and ‑8.4/‑7.4 mm Hg for COREG CR 20 mg, 40 mg, and 80 mg, respectively. The placebo-corrected trough to peak (3 to 7 h) ratio was approximately 0.6 for COREG CR 80 mg. In this trial, assessments of 24‑hour ABPM monitoring demonstrated statistically significant blood pressure reductions with COREG CR throughout the dosing period.
Figure. Changes from Baseline in Systolic Blood Pressure and Diastolic Blood Pressure Measured by 24-Hour ABPM
Immediate‑release carvedilol was studied in 2 placebo‑controlled trials that utilized twice‑daily dosing, at total daily doses of 12.5 to 50 mg. In these and other trials, the starting dose did not exceed 12.5 mg. At 50 mg/day, COREG reduced sitting trough (12‑hour) blood pressure by about 9/5.5 mm Hg; at 25 mg/day the effect was about 7.5/3.5 mm Hg. Comparisons of trough‑to‑peak blood pressure showed a trough‑to‑peak ratio for blood pressure response of about 65%. Heart rate fell by about 7.5 beats/minute at 50 mg/day. In general, as is true for other β‑blockers, responses were smaller in black than non‑black subjects. There were no age‑ or gender‑related differences in response. The dose‑related blood pressure response was accompanied by a dose‑related increase in adverse effects.
In a double-blind trial (GEMINI), carvedilol, added to an ACE inhibitor or angiotensin receptor blocker, was evaluated in a population with mild‑to‑moderate hypertension and well-controlled type 2 diabetes mellitus. The mean HbA1c at baseline was 7.2%. COREG was titrated to a mean dose of 17.5 mg twice daily and maintained for 5 months. COREG had no adverse effect on glycemic control, based on HbA1c measurements (mean change from baseline of 0.02%, 95% CI: ‑0.06 to 0.10, P = NS).
# How Supplied
The hard gelatin capsules are available in the following strengths:
- 10 mg – white and green capsule shell printed with “GSK COREG CR” and “10 mg”
- 20 mg – white and yellow capsule shell printed with “GSK COREG CR” and “20 mg”
- 40 mg – yellow and green capsule shell printed with “GSK COREG CR” and “40 mg”
- 80 mg – white capsule shell printed with “GSK COREG CR” and “80 mg”
- 10 mg 30’s: NDC 0007-3370-13
- 20 mg 30’s: NDC 0007-3371-13
- 40 mg 30’s: NDC 0007-3372-13
- 80 mg 30’s: NDC 0007-3373-13
## Storage
Store at 25°C (77°F); excursions 15° to 30°C (59° to 86°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
COREG CR is a prescription medicine that belongs to a group of medicines called “beta-blockers”. COREG CR is used, often with other medicines, for the following conditions:
- to treat patients with certain types of heart failure
- to treat patients who had a heart attack that worsened how well the heart pumps
- to treat patients with high blood pressure (hypertension)
COREG CR is not approved for use in children under 18 years of age.
Do not take carvedilol if you:
- Have severe heart failure and require certain intravenous medicines that help support circulation.
- Have asthma or other breathing problems.
- Have a slow heartbeat or certain conditions that cause your heart to skip a beat (irregular heartbeat).
- Have liver problems.
- Are allergic to any of the ingredients in carvedilol. See “What are the ingredients in carvedilol?”
Tell your doctor about all of your medical conditions, including if you:
- Have asthma or other lung problems (such as bronchitis or emphysema).
- Have problems with blood flow in your feet and legs (peripheral vascular disease). Carvedilol can make some of your symptoms worse.
- Have diabetes.
- Have thyroid problems.
- Have a condition called pheochromocytoma.
- Have had severe allergic reactions.
- Are scheduled for surgery and will be given anesthetic agents.
- Are scheduled for cataract surgery and have taken or are currently taking carvedilol.
- Are pregnant or trying to become pregnant. It is not known if carvedilol is safe for your unborn baby. You and your doctor should talk about the best way to control your high blood pressure during pregnancy.
- Are breastfeeding. It is not known if carvedilol passes into your breast milk. You should not breastfeed while using carvedilol.
Tell your doctor about all of the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. Carvedilol and certain other medicines can affect each other and cause serious side effects. Carvedilol may affect the way other medicines work. Also, other medicines may affect how well carvedilol works.
Know the medicines you take. Keep a list of your medicines and show it to your doctor and pharmacist before you start a new medicine.
- Take carvedilol exactly as prescribed. Take carvedilol one time each day with food. It is important that you take carvedilol only one time each day. To lessen possible side effects, your doctor might begin with a low dose and then slowly increase the dose.
- Swallow carvedilol capsules whole. Do not chew or crush carvedilol capsules.
- If you have trouble swallowing carvedilol whole:
- The capsule may be carefully opened and the beads sprinkled over a spoonful of applesauce which should be eaten right away. The applesauce should not be warm.
- Do not sprinkle beads on foods other than applesauce.
- Do not stop taking carvedilol and do not change the amount of carvedilol you take without talking to your doctor.
- If you miss a dose of carvedilol, take your dose as soon as you remember, unless it is time to take your next dose. Take your next dose at the usual time. Do not take 2 doses at the same time.
- If you take too much carvedilol, call your doctor or poison control center right away.
Carvedilol can cause you to feel dizzy, tired, or faint. Do not drive a car, use machinery, or do anything that needs you to be alert if you have these symptoms.
Serious side effects of carvedilol include:
- Chest pain and heart attack if you suddenly stop taking carvedilol.
- Slow heart beat.
- Low blood pressure (which may cause dizziness or fainting when you stand up). If these happen, sit or lie down, and tell your doctor right away.
- Worsening heart failure. Tell your doctor right away if you have signs and symptoms that your heart failure may be worse, such as weight gain or increased shortness of breath.
- Changes in your blood sugar. If you have diabetes, tell your doctor if you have any changes in your blood sugar levels.
- Masking (hiding) the symptoms of low blood sugar, especially a fast heartbeat.
- New or worsening symptoms of peripheral vascular disease.
- Leg pain that happens when you walk, but goes away when you rest.
- No feeling (numbness) in your legs or feet while you are resting.
- Cold legs or feet.
- Masking the symptoms of hyperthyroidism (overactive thyroid), such as a fast heartbeat.
- Worsening of severe allergic reactions. Medicines to treat a severe allergic reaction may not work as well while you are taking carvedilol.
- Rare but serious allergic reactions (including hives or swelling of the face, lips, tongue, and/or throat that may cause difficulty in breathing or swallowing) have happened in patients who were on carvedilol. These reactions can be life-threatening.
Common side effects of carvedilol include shortness of breath, weight gain, diarrhea, and tiredness. If you wear contact lenses, you may have fewer tears or dry eyes that can become bothersome.
Call your doctor if you have any side effects that bother you or don’t go away.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
- Store carvedilol at less than 86°F (30°C).
- Safely throw away carvedilol that is out of date or no longer needed.
- Keep carvedilol and all medicines out of the reach of children.
Medicines are sometimes prescribed for conditions other than those described in patient information leaflets. Do not use carvedilol for a condition for which it was not prescribed. Do not give carvedilol to other people, even if they have the same symptoms you have. It may harm them.
This leaflet summarizes the most important information about carvedilol. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about carvedilol that is written for healthcare professionals.
Active ingredient: carvedilol phosphate
Inactive ingredients: crospovidone, hydrogenated castor oil, hydrogenated vegetable oil, magnesium stearate, methacrylic acid copolymers, microcrystalline cellulose, and povidone
COREG CR capsules come in the following strengths: 10 mg, 20 mg, 40 mg, 80 mg.
Blood pressure is the force of blood in your blood vessels when your heart beats and when your heart rests. You have high blood pressure when the force is too much. High blood pressure makes the heart work harder to pump blood through the body and causes damage to blood vessels. carvedilol can help your blood vessels relax so your blood pressure is lower. Medicines that lower blood pressure may lower your chance of having a stroke or heart attack.
# Precautions with Alcohol
Alcohol-Carvedilol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
Coreg
# Look-Alike Drug Names
Carvedilol - Captopril
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Carvedilol | |
f96813cf81a94ecdda7e7e42d95600b580193fd1 | wikidoc | Case study | Case study
The case study is one of several ways of doing social science research. Other ways include experiments, surveys, multiple histories, and analysis of archival information (Yin 2003).
Rather than using large samples and following a rigid protocol to examine a limited number of variables, case study methods involve an in-depth, longitudinal examination of a single instance or event: case. They provide a systematic way of looking at events, collecting data, analyzing information, and reporting the results. As a result the researcher may gain a sharpened understanding of why the instance happened as it did, and what might become important to look at more extensively in future research. Case studies lend themselves to both generating and testing hypotheses (Flyvbjerg, 2006).
Yin (2002), on the other hand, suggests that case study should be defined as a research strategy, an empirical inquiry that investigates a phenomenon within its real-life context. Case study research means single and multiple case studies, can include quantitative evidence, relies on multiple sources of evidence and benefits from the prior development of theoretical propositions. He notes that case studies should not be confused with qualitative research and points out that they can be based on any mix of quantitative and qualitative evidence. Single-subject research provides the statistical framework for making inferences from quantitative case-study data. This is also supported and well-formulated in (Lamnek, 2005): "The case study is a research approach, situated between concrete data taking techniques and methodologic paradigms."
# Case selection
When selecting a case for a case study, researchers often use information-oriented sampling, as opposed to random sampling (Flyvbjerg, 2006). This is because the typical or average case is often not the richest in information. Extreme or atypical cases reveal more information because they activate more basic mechanisms and more actors in the situation studied. In addition, from both an understanding-oriented and an action-oriented perspective, it is often more important to clarify the deeper causes behind a given problem and its consequences than to describe the symptoms of the problem and how frequently they occur. Random samples emphasizing representativeness will seldom be able to produce this kind of insight; it is more appropriate to select some few cases chosen for their validity.
Three types of information-oriented cases may be distinguished:
- Extreme or deviant cases
- Critical cases
- Paradigmatic cases.
## Extreme case
The extreme case can be well-suited for getting a point across in an especially dramatic way, which often occurs for well-known case studies such as Freud’s ‘Wolf-Man.’
## Critical case
A critical case can be defined as having strategic importance in relation to the general problem. For example, an occupational medicine clinic wanted to investigate whether people working with organic solvents suffered brain damage. Instead of choosing a representative sample among all those enterprises in the clinic’s area that used organic solvents, the clinic strategically located a single workplace where all safety regulations on cleanliness, air quality, and the like, had been fulfilled. This model enterprise became a critical case: if brain damage related to organic solvents could be found at this particular facility, then it was likely that the same problem would exist at other enterprises which were less careful with safety regulations for organic solvents. Via this type of strategic sampling, one can save both time and money in researching a given problem. Another example of critical case sampling is the strategic selection of lead and feather for the test of whether different objects fall with equal velocity. The selection of materials provided the possibility to formulate a generalization characteristic of critical cases, a generalization of the sort, ‘If it is valid for this case, it is valid for all (or many) cases.’ In its negative form, the generalization would be, ‘If it is not valid for this case, then it is not valid for any (or only few) cases.’
## Paradigmatic case
A Paradigmatic case may be defined as an exemplar or prototype. Thomas Kuhn has shown that the basic skills, or background practices, of natural scientists are organized in terms of ‘exemplars’ or 'paradigms' the role of which in the scientific process can be analyzed. Similarly, scholars like Clifford Geertz and Michel Foucault have often organized their research around specific cultural paradigms: a paradigm for Geertz lay for instance in the ‘deep play’ of the Balinese cockfight, while for Foucault, European prisons and the ‘Panopticon’ are examples. Both instances are examples of paradigmatic cases, that is, cases that highlight more general characteristics of the societies or issues in question. Kuhn has shown that scientific paradigms cannot be expressed as rules or theories. There exists no predictive theory for how predictive theory comes about. A scientific activity is acknowledged or rejected as good science by how close it is to one or more exemplars; that is, practical prototypes of good scientific work. A paradigmatic case of how scientists do science is precisely such a prototype. It operates as a reference point and may function as a focus for the founding of schools of thought.
For more on case selection, see
# Generalizing from case studies
The case study is effective for generalizing using the type of test that Karl Popper called falsification, which forms part of critical reflexivity (Flyvbjerg, 2006). Falsification is one of the most rigorous tests to which a scientific proposition can be subjected: if just one observation does not fit with the proposition it is considered not valid generally and must therefore be either revised or rejected. Popper himself used the now famous example of, "All swans are white," and proposed that just one observation of a single black swan would falsify this proposition and in this way have general significance and stimulate further investigations and theory-building. The case study is well suited for identifying "black swans" because of its in-depth approach: what appears to be "white" often turns out on closer examination to be "black."
For instance, Galileo’s rejection of Aristotle’s law of gravity was based on a case study selected by information-oriented sampling and not random sampling. The rejection consisted primarily of a conceptual experiment and later on of a practical one. These experiments, with the benefit of hindsight, are self-evident. Nevertheless, Aristotle’s incorrect view of gravity dominated scientific inquiry for nearly two thousand years before it was falsified. In his experimental thinking, Galileo reasoned as follows: if two objects with the same weight are released from the same height at the same time, they will hit the ground simultaneously, having fallen at the same speed. If the two objects are then stuck together into one, this object will have double the weight and will according to the Aristotelian view therefore fall faster than the two individual objects. This conclusion seemed contradictory to Galileo. The only way to avoid the contradiction was to eliminate weight as a determinant factor for acceleration in free fall. Galileo’s experimentalism did not involve a large random sample of trials of objects falling from a wide range of randomly selected heights under varying wind conditions, and so on. Rather, it was a matter of a single experiment, that is, a case study.
Galileo’s view continued to be subjected to doubt, however, and the Aristotelian view was not finally rejected until half a century later, with the invention of the air pump. The air pump made it possible to conduct the ultimate experiment, known by every pupil, whereby a coin or a piece of lead inside a vacuum tube falls with the same speed as a feather. After this experiment, Aristotle’s view could be maintained no longer. What is especially worth noting, however, is that the matter was settled by an individual case due to the clever choice of the extremes of metal and feather. One might call it a critical case, for if Galileo’s thesis held for these materials, it could be expected to be valid for all or a large range of materials. Random and large samples were at no time part of the picture.
By selecting cases strategically in this manner one may arrive at case studies that allow generalization.
For more on generalizing from case studies, see
# History of the case study
As a distinct approach to research, use of the case study originated only in the early 20th century. The Oxford English Dictionary traces the phrase case study or case-study back as far as 1934, after the establishment of the concept of a case history in medicine.
The use of case studies for the creation of new theory in social sciences has been further developed by the sociologists Barney Glaser and Anselm Strauss who presented their research method, Grounded theory, in 1967.
The popularity of case studies in testing hypotheses has developed only in recent decades. One of the areas in which case studies have been gaining popularity is education and in particular educational evaluation. Some of the prominent scholars in educational case study are Robert Stake and Jan Nespor (see references).
Case studies have also been used as a teaching method and as part of professional development, especially in business and legal education. The problem-based learning (PBL) movement is such an example. When used in (non-business) education and professional development, case studies are often referred to as critical incidents (see David Tripp in references).
## History of Business Cases
When the Harvard Business School was started, the faculty quickly realized that there were no textbooks suitable to a graduate program in business. Their first solution to this problem was to interview leading practitioners of business and to write detailed accounts of what these managers were doing. Of course the professors could not present these cases as practices to be emulated because there were no criteria available for determining what would succeed and what would not succeed. So the professors instructed their students to read the cases and to come to class prepared to discuss the cases and to offer recommendations for appropriate courses of action. Basically that is the model still being used. See a critique of this approach. | Case study
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
The case study is one of several ways of doing social science research. Other ways include experiments, surveys, multiple histories, and analysis of archival information (Yin 2003).
Rather than using large samples and following a rigid protocol to examine a limited number of variables, case study methods involve an in-depth, longitudinal examination of a single instance or event: case. They provide a systematic way of looking at events, collecting data, analyzing information, and reporting the results. As a result the researcher may gain a sharpened understanding of why the instance happened as it did, and what might become important to look at more extensively in future research. Case studies lend themselves to both generating and testing hypotheses (Flyvbjerg, 2006).
Yin (2002), on the other hand, suggests that case study should be defined as a research strategy, an empirical inquiry that investigates a phenomenon within its real-life context. Case study research means single and multiple case studies, can include quantitative evidence, relies on multiple sources of evidence and benefits from the prior development of theoretical propositions. He notes that case studies should not be confused with qualitative research and points out that they can be based on any mix of quantitative and qualitative evidence. Single-subject research provides the statistical framework for making inferences from quantitative case-study data. This is also supported and well-formulated in (Lamnek, 2005): "The case study is a research approach, situated between concrete data taking techniques and methodologic paradigms."
# Case selection
When selecting a case for a case study, researchers often use information-oriented sampling, as opposed to random sampling (Flyvbjerg, 2006). This is because the typical or average case is often not the richest in information. Extreme or atypical cases reveal more information because they activate more basic mechanisms and more actors in the situation studied. In addition, from both an understanding-oriented and an action-oriented perspective, it is often more important to clarify the deeper causes behind a given problem and its consequences than to describe the symptoms of the problem and how frequently they occur. Random samples emphasizing representativeness will seldom be able to produce this kind of insight; it is more appropriate to select some few cases chosen for their validity.
Three types of information-oriented cases may be distinguished:
- Extreme or deviant cases
- Critical cases
- Paradigmatic cases.
## Extreme case
The extreme case can be well-suited for getting a point across in an especially dramatic way, which often occurs for well-known case studies such as Freud’s ‘Wolf-Man.’
## Critical case
A critical case can be defined as having strategic importance in relation to the general problem. For example, an occupational medicine clinic wanted to investigate whether people working with organic solvents suffered brain damage. Instead of choosing a representative sample among all those enterprises in the clinic’s area that used organic solvents, the clinic strategically located a single workplace where all safety regulations on cleanliness, air quality, and the like, had been fulfilled. This model enterprise became a critical case: if brain damage related to organic solvents could be found at this particular facility, then it was likely that the same problem would exist at other enterprises which were less careful with safety regulations for organic solvents. Via this type of strategic sampling, one can save both time and money in researching a given problem. Another example of critical case sampling is the strategic selection of lead and feather for the test of whether different objects fall with equal velocity. The selection of materials provided the possibility to formulate a generalization characteristic of critical cases, a generalization of the sort, ‘If it is valid for this case, it is valid for all (or many) cases.’ In its negative form, the generalization would be, ‘If it is not valid for this case, then it is not valid for any (or only few) cases.’
## Paradigmatic case
A Paradigmatic case may be defined as an exemplar or prototype. Thomas Kuhn has shown that the basic skills, or background practices, of natural scientists are organized in terms of ‘exemplars’ or 'paradigms' the role of which in the scientific process can be analyzed. Similarly, scholars like Clifford Geertz and Michel Foucault have often organized their research around specific cultural paradigms: a paradigm for Geertz lay for instance in the ‘deep play’ of the Balinese cockfight, while for Foucault, European prisons and the ‘Panopticon’ are examples. Both instances are examples of paradigmatic cases, that is, cases that highlight more general characteristics of the societies or issues in question. Kuhn has shown that scientific paradigms cannot be expressed as rules or theories. There exists no predictive theory for how predictive theory comes about. A scientific activity is acknowledged or rejected as good science by how close it is to one or more exemplars; that is, practical prototypes of good scientific work. A paradigmatic case of how scientists do science is precisely such a prototype. It operates as a reference point and may function as a focus for the founding of schools of thought.
For more on case selection, see [2]
# Generalizing from case studies
The case study is effective for generalizing using the type of test that Karl Popper called falsification, which forms part of critical reflexivity (Flyvbjerg, 2006). Falsification is one of the most rigorous tests to which a scientific proposition can be subjected: if just one observation does not fit with the proposition it is considered not valid generally and must therefore be either revised or rejected. Popper himself used the now famous example of, "All swans are white," and proposed that just one observation of a single black swan would falsify this proposition and in this way have general significance and stimulate further investigations and theory-building. The case study is well suited for identifying "black swans" because of its in-depth approach: what appears to be "white" often turns out on closer examination to be "black."
For instance, Galileo’s rejection of Aristotle’s law of gravity was based on a case study selected by information-oriented sampling and not random sampling. The rejection consisted primarily of a conceptual experiment and later on of a practical one. These experiments, with the benefit of hindsight, are self-evident. Nevertheless, Aristotle’s incorrect view of gravity dominated scientific inquiry for nearly two thousand years before it was falsified. In his experimental thinking, Galileo reasoned as follows: if two objects with the same weight are released from the same height at the same time, they will hit the ground simultaneously, having fallen at the same speed. If the two objects are then stuck together into one, this object will have double the weight and will according to the Aristotelian view therefore fall faster than the two individual objects. This conclusion seemed contradictory to Galileo. The only way to avoid the contradiction was to eliminate weight as a determinant factor for acceleration in free fall. Galileo’s experimentalism did not involve a large random sample of trials of objects falling from a wide range of randomly selected heights under varying wind conditions, and so on. Rather, it was a matter of a single experiment, that is, a case study.
Galileo’s view continued to be subjected to doubt, however, and the Aristotelian view was not finally rejected until half a century later, with the invention of the air pump. The air pump made it possible to conduct the ultimate experiment, known by every pupil, whereby a coin or a piece of lead inside a vacuum tube falls with the same speed as a feather. After this experiment, Aristotle’s view could be maintained no longer. What is especially worth noting, however, is that the matter was settled by an individual case due to the clever choice of the extremes of metal and feather. One might call it a critical case, for if Galileo’s thesis held for these materials, it could be expected to be valid for all or a large range of materials. Random and large samples were at no time part of the picture.
By selecting cases strategically in this manner one may arrive at case studies that allow generalization.
For more on generalizing from case studies, see [3]
# History of the case study
As a distinct approach to research, use of the case study originated only in the early 20th century. The Oxford English Dictionary traces the phrase case study or case-study back as far as 1934, after the establishment of the concept of a case history in medicine.
The use of case studies for the creation of new theory in social sciences has been further developed by the sociologists Barney Glaser and Anselm Strauss who presented their research method, Grounded theory, in 1967.
The popularity of case studies in testing hypotheses has developed only in recent decades. One of the areas in which case studies have been gaining popularity is education and in particular educational evaluation. Some of the prominent scholars in educational case study are Robert Stake and Jan Nespor (see references).
Case studies have also been used as a teaching method and as part of professional development, especially in business and legal education. The problem-based learning (PBL) movement is such an example. When used in (non-business) education and professional development, case studies are often referred to as critical incidents (see David Tripp in references).
## History of Business Cases
When the Harvard Business School was started, the faculty quickly realized that there were no textbooks suitable to a graduate program in business. Their first solution to this problem was to interview leading practitioners of business and to write detailed accounts of what these managers were doing. Of course the professors could not present these cases as practices to be emulated because there were no criteria available for determining what would succeed and what would not succeed. So the professors instructed their students to read the cases and to come to class prepared to discuss the cases and to offer recommendations for appropriate courses of action. Basically that is the model still being used. See a critique of this approach. | https://www.wikidoc.org/index.php/Case_study | |
6eada1e836cee00def8e9cfab98770880c59f79a | wikidoc | Caspase 12 | Caspase 12
Caspase 12 is a protein that belongs to a family of enzymes called caspases which cleave their substrates at C-terminal aspartic acid residues. It is closely related to caspase 1 and other members of the caspase family, known as inflammatory caspases, which process and activate inflammatory cytokines such as interleukin 1 and interleukin 18.
# Gene
It is found on chromosome 11 in humans in a locus with other inflammatory caspases.
CASP12 orthologs have been identified in numerous mammals for which complete genome data are available.
# Clinical significance
The CASP12 gene is subject to polymorphism, which can generate a full length caspase protein (Csp12L) or an inactive truncated form (Csp12S). The functional form appears to be confined to people of African descent and is linked with susceptibility to sepsis; people carrying the functional gene have decreased responses to bacterial molecules such as lipopolysaccharide (LPS).
A study in May 2009 by McGill University Health Centre has suggested that estrogen may serve to block the production of caspase-12, resulting in a stronger inflammatory reaction to bacterial pathogens. The trials were carried out on laboratory mice which had been implanted with the human caspase-12 gene.
The inactive truncated form (Csp12S) of the CASP12 gene was spread and nearly fixed in non-African populations due to positive selection beginning perhaps 60–100 thousand years ago. Its selective advantage is thought to be sepsis resistance in populations that experienced more infectious diseases as population sizes and densities increased. | Caspase 12
Caspase 12 is a protein that belongs to a family of enzymes called caspases which cleave their substrates at C-terminal aspartic acid residues. It is closely related to caspase 1 and other members of the caspase family, known as inflammatory caspases, which process and activate inflammatory cytokines such as interleukin 1 and interleukin 18.
# Gene
It is found on chromosome 11 in humans in a locus with other inflammatory caspases.[1]
CASP12 orthologs[2] have been identified in numerous mammals for which complete genome data are available.
# Clinical significance
The CASP12 gene is subject to polymorphism, which can generate a full length caspase protein (Csp12L) or an inactive truncated form (Csp12S). The functional form appears to be confined to people of African descent and is linked with susceptibility to sepsis; people carrying the functional gene have decreased responses to bacterial molecules such as lipopolysaccharide (LPS).[3][4]
A study in May 2009 by McGill University Health Centre has suggested that estrogen may serve to block the production of caspase-12, resulting in a stronger inflammatory reaction to bacterial pathogens. The trials were carried out on laboratory mice which had been implanted with the human caspase-12 gene.[5][6][7]
The inactive truncated form (Csp12S) of the CASP12 gene was spread and nearly fixed in non-African populations due to positive selection beginning perhaps 60–100 thousand years ago. Its selective advantage is thought to be sepsis resistance in populations that experienced more infectious diseases as population sizes and densities increased.[8][9] | https://www.wikidoc.org/index.php/Caspase_12 | |
7cfcee4ae17967ba383384d28208643bf876d4db | wikidoc | Caspase 14 | Caspase 14
Caspase 14 is an enzyme that in humans is encoded by the CASP14 gene.
The CASP14 gene encodes a member of the cysteine-aspartic acid protease (caspase) family. Sequential activation of caspases plays a central role in the execution-phase of cell apoptosis. Caspases exist as inactive proenzymes which undergo proteolytic processing at conserved aspartic residues to produce two subunits, large and small, that dimerize to form the active enzyme. This caspase has been shown to be processed and activated by caspase 8 and caspase 10 in vitro, and by anti-Fas agonist antibody or TNF-related apoptosis inducing ligand in vivo. The expression and processing of this caspase may be involved in keratinocyte terminal differentiation, which is important for the formation of the skin barrier.
According to the Human Protein Atlas, the CASP14 protein is enriched human skin and mainly expressed in the upper layers of the epidermis.The protein is mainly localised to the cytosol according to the Cell Atlas. | Caspase 14
Caspase 14 is an enzyme that in humans is encoded by the CASP14 gene.[1][2][3]
The CASP14 gene encodes a member of the cysteine-aspartic acid protease (caspase) family. Sequential activation of caspases plays a central role in the execution-phase of cell apoptosis. Caspases exist as inactive proenzymes which undergo proteolytic processing at conserved aspartic residues to produce two subunits, large and small, that dimerize to form the active enzyme. This caspase has been shown to be processed and activated by caspase 8 and caspase 10 in vitro, and by anti-Fas agonist antibody or TNF-related apoptosis inducing ligand in vivo. The expression and processing of this caspase may be involved in keratinocyte terminal differentiation, which is important for the formation of the skin barrier.[3]
According to the Human Protein Atlas[4], the CASP14 protein is enriched human skin and mainly expressed in the upper layers of the epidermis.The protein is mainly localised to the cytosol according to the Cell Atlas[5]. | https://www.wikidoc.org/index.php/Caspase_14 |
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