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4fd898f1d0a1b05fb75a489c813f40ab413e7054 | wikidoc | Nephrologist | Nephrologist
A nephrologist is a physician who has been trained in the diagnosis and management of kidney disease, by regulating blood pressure, regulating electrolytes, balancing fluids in the body, and administering dialysis. Nephrologists treat many different kidney disorders including acid-base disorders, electrolyte disorders, nephrolithiasis (kidney stones), hypertension (high blood pressure), acute kidney disease and end-stage renal disease. Nephrology is a subspecialty of internal medicine. In the United States, after medical school nephrologists complete a three year residency in internal medicine followed by a two year (or longer) fellowship in nephrology.
Knowledge of internal medicine is required to obtain certification. To become a nephrologist requires many years of school and training. Nephrologists also must be approved by the board. To be approved, the physician must fulfill the requirements for education and training in nephrology in order to qualify to take the board's examination. If a physician passes the examination, then he or she can become a nephrology specialist. Typically, nephrologists also need two to three years of training in an ACGME accredited program in nephrology. Things that a nephrologist learns in this program are fluid and acid base and electrolyte physiology, medical management of acute and chronic renal failure, glomerular and casuclar disorders, tubular/interstitial disorders, mineral metabolism, clinical pharmacology, hypertension, epidemiology, thics, and nutrition. Once training is satisfactorily completed, the physician is eligible to take the ABIM nephrology examination.
Nephrologists may further specialize in pediatric nephrology (treatment of kidney diseases in children) or adult nephrology. Certification in these subspecialties requires satisfactory completion of additional education and training and passing an examination.
# Popular culture
Dr. Gregory House on the fictional TV show House is a nephrologist and infectious disease specialist. | Nephrologist
A nephrologist is a physician who has been trained in the diagnosis and management of kidney disease, by regulating blood pressure, regulating electrolytes, balancing fluids in the body, and administering dialysis. Nephrologists treat many different kidney disorders including acid-base disorders, electrolyte disorders, nephrolithiasis (kidney stones), hypertension (high blood pressure), acute kidney disease and end-stage renal disease. Nephrology is a subspecialty of internal medicine. In the United States, after medical school nephrologists complete a three year residency in internal medicine followed by a two year (or longer) fellowship in nephrology.
Knowledge of internal medicine is required to obtain certification. To become a nephrologist requires many years of school and training. Nephrologists also must be approved by the board. To be approved, the physician must fulfill the requirements for education and training in nephrology in order to qualify to take the board's examination. If a physician passes the examination, then he or she can become a nephrology specialist. Typically, nephrologists also need two to three years of training in an ACGME accredited program in nephrology. Things that a nephrologist learns in this program are fluid and acid base and electrolyte physiology, medical management of acute and chronic renal failure, glomerular and casuclar disorders, tubular/interstitial disorders, mineral metabolism, clinical pharmacology, hypertension, epidemiology, thics, and nutrition. Once training is satisfactorily completed, the physician is eligible to take the ABIM nephrology examination.
Nephrologists may further specialize in pediatric nephrology (treatment of kidney diseases in children) or adult nephrology. Certification in these subspecialties requires satisfactory completion of additional education and training and passing an examination.
# Popular culture
Dr. Gregory House on the fictional TV show House is a nephrologist and infectious disease specialist.
# External links
- http://www.hsc.wvu.edu/som/medicine/nephrology/
- Patient Information on Nephrology & Kidney Disease
Template:WH
Template:WikiDoc Sources
Template:Jb1 | https://www.wikidoc.org/index.php/Nephrologist | |
a9425bf5bf714ff1b0e77c713a9ed511053f5637 | wikidoc | Nerve injury | Nerve injury
There is no single classification system that can describe all the many variations of nerve injury. Most systems attempt to correlate the degree of injury with symptoms, pathology and prognosis. In 1943, Seddon introduced a classification of nerve injuries based on three main types of nerve fiber injury and whether there is continuity of the nerve The three types are : axonotmesis, neurapraxia and neurotmesis.
# Axonotmesis
Axonotmesis is part of Seddon's classification scheme used to classify nerve damage. It is a more severe nerve injury with disruption of the neuronal axon, but with maintenance of the myelin sheath. This type of nerve damage may cause paralysis of the motor, sensory, and autonomic.Mainly seen in crush injury.
If the force creating the nerve damage is removed in a timely fashion, the axon may regenerate, leading to recovery. Electrically, the nerve shows rapid and complete degeneration, with loss of voluntary motor units. Regeneration of the motor end plates will occur, as long as the endoneural tubules are intact.
It involves loss of the relative continuity of the axon and its covering of myelin, but preservation of the connective tissue framework of the nerve ( the encapsulating tissue, the epineurium and perineurium, are preserved ). Because axonal continuity is lost, wallerian degeneration occurs. Electromyography ( EMG ) performed 2 to 3 weeks later shows fibrillations and denervation potentials in musculature distal to the injury site. Loss in both motor and sensory spleens is more complete with axonotmesis than with neurapraxia, and recovery occurs only through regenerations of the axons, a process requiring time. Axonotmesis is usually the result of a more severe crush or contusion than neurapraxia. There is usually an element of retrograde proximal degeneration of the axon, and for regeneration to occur, this loss must first be overcome. The regeneration fibers must cross the injury site and regeneration through the proximal or retrograde area of degeneration may require several weeks. Then the neuritis tip progresses down the distal site, such as the wrist or hand. Proximal lesion may grow distally as fast as 2 to 3 mm per day and distal lesion as slowly as 1.5 mm per day. For regeneration requires a number of weeks.
# Neurapraxia
In this case there is an interruption in conduction of the impulse down the nerve fiber, and recovery takes place without wallerian degeneration. This is the mildest form of nerve injury. This is probably a biochemical lesion caused by a concussion or other shock-like injuries to the fiber. In the case of the role nerve, neurapraxia is brought about by compression or relatively mild, blunt blows, including some low-velocity missile injuries close to the nerve. There is a temporary loss of function which is reversible within hours to months of the injury ( the average is 6-8 weeks ). There is frequently greater involvement of motor than sensory function with autonomic function being retained.
# Neurotmesis
Neurotmesis is the most severe lesion with potential of recovering. It occurs on severe contusion, stretch, laceration, or Local Anesthetic Toxicity. Not only the axon, but the encapsulating connective tissue lose their continuity. The last (extreme) degree of neurotmesis is transsection, but most neurotmetic injuries do not produce gross loss of continuity of the nerve but rather than internal disruption of the architecture of the nerve sufficient to involve perineurium and endoneuruim as well as axons and their covering. Denevertion changes recorded by EMG are the same as those seen with axonotmetic injury. There is a complete loss of motor, sensory and autonomic function. If the nerve loss has been completely divided, axonal regeneration causes a neuroma to form in the proximal stump. For neurotmesis, it is better to use a new more complete classification called Sunderland System. | Nerve injury
There is no single classification system that can describe all the many variations of nerve injury. Most systems attempt to correlate the degree of injury with symptoms, pathology and prognosis. In 1943, Seddon introduced a classification of nerve injuries based on three main types of nerve fiber injury and whether there is continuity of the nerve The three types are : axonotmesis, neurapraxia and neurotmesis.
# Axonotmesis
Axonotmesis is part of Seddon's classification scheme used to classify nerve damage. It is a more severe nerve injury with disruption of the neuronal axon, but with maintenance of the myelin sheath. This type of nerve damage may cause paralysis of the motor, sensory, and autonomic.Mainly seen in crush injury.
If the force creating the nerve damage is removed in a timely fashion, the axon may regenerate, leading to recovery. Electrically, the nerve shows rapid and complete degeneration, with loss of voluntary motor units. Regeneration of the motor end plates will occur, as long as the endoneural tubules are intact.
It involves loss of the relative continuity of the axon and its covering of myelin, but preservation of the connective tissue framework of the nerve ( the encapsulating tissue, the epineurium and perineurium, are preserved ). Because axonal continuity is lost, wallerian degeneration occurs. Electromyography ( EMG ) performed 2 to 3 weeks later shows fibrillations and denervation potentials in musculature distal to the injury site. Loss in both motor and sensory spleens is more complete with axonotmesis than with neurapraxia, and recovery occurs only through regenerations of the axons, a process requiring time. Axonotmesis is usually the result of a more severe crush or contusion than neurapraxia. There is usually an element of retrograde proximal degeneration of the axon, and for regeneration to occur, this loss must first be overcome. The regeneration fibers must cross the injury site and regeneration through the proximal or retrograde area of degeneration may require several weeks. Then the neuritis tip progresses down the distal site, such as the wrist or hand. Proximal lesion may grow distally as fast as 2 to 3 mm per day and distal lesion as slowly as 1.5 mm per day. For regeneration requires a number of weeks.
# Neurapraxia
In this case there is an interruption in conduction of the impulse down the nerve fiber, and recovery takes place without wallerian degeneration. This is the mildest form of nerve injury. This is probably a biochemical lesion caused by a concussion or other shock-like injuries to the fiber. In the case of the role nerve, neurapraxia is brought about by compression or relatively mild, blunt blows, including some low-velocity missile injuries close to the nerve. There is a temporary loss of function which is reversible within hours to months of the injury ( the average is 6-8 weeks ). There is frequently greater involvement of motor than sensory function with autonomic function being retained.
# Neurotmesis
Neurotmesis is the most severe lesion with potential of recovering. It occurs on severe contusion, stretch, laceration, or Local Anesthetic Toxicity. Not only the axon, but the encapsulating connective tissue lose their continuity. The last (extreme) degree of neurotmesis is transsection, but most neurotmetic injuries do not produce gross loss of continuity of the nerve but rather than internal disruption of the architecture of the nerve sufficient to involve perineurium and endoneuruim as well as axons and their covering. Denevertion changes recorded by EMG are the same as those seen with axonotmetic injury. There is a complete loss of motor, sensory and autonomic function. If the nerve loss has been completely divided, axonal regeneration causes a neuroma to form in the proximal stump. For neurotmesis, it is better to use a new more complete classification called Sunderland System. | https://www.wikidoc.org/index.php/Nerve_damage | |
79e92ff241892c47c4169be9740e41f5575d3802 | wikidoc | Neuroscience | Neuroscience
# Overview
Neuroscience is a profound field that is devoted to the scientific study of the nervous system. Such studies span the structure, function, evolutionary history, development, genetics, biochemistry, physiology, pharmacology, informatics, computational neuroscience and pathology of the nervous system. Traditionally it is seen as a branch of biological sciences. However, recently there has been a surge in the convergence of interest from many allied disciplines, including cognitive and neuro-psychology, computer science, statistics, physics, and medicine. The scope of neuroscience has now broadened to include any systematic scientific experimental and theoretical investigation of the central and peripheral nervous system of biological organisms. The empirical methodologies employed by neuroscientists have been enormously expanded, from biochemical and genetic analysis of dynamics of individual nerve cells and their molecular constituents to imaging representations of perceptual and motor tasks in the brain. Many recent theoretical advances in neuroscience have been aided by the use of computational modeling.
The scientific study of the nervous systems underwent a significant increase in the second half of the twentieth century, principally due to revolutions in molecular biology, electrophysiology and computational neuroscience. It has become possible to understand, in much detail, the complex processes occurring within a single neuron. However, understanding of how networks of neurons produce intellectual behavior, cognition, emotion and physiological responses is still poorly understood.
The nervous system is composed of a network of neurons and other supportive cells (such as glial cells). Neurons form functional circuits, each responsible for specific tasks to the behaviors at the organism level. Thus, neuroscience can be studied at many different levels, ranging from molecular level to cellular level to systems level to cognitive level.
At the molecular level, the basic questions addressed in molecular neuroscience include the mechanisms by which neurons express and respond to molecular signals and how axons form complex connectivity patterns. At this level, tools from molecular biology and genetics are used to understand how neurons develop and die, and how genetic changes affect biological functions. The morphology, molecular identity and physiological characteristics of neurons and how they relate to different types of behavior are also of considerable interest. (The ways in which neurons and their connections are modified by experience are addressed at the physiological and cognitive levels.)
At the cellular level, the fundamental questions addressed in cellular neuroscience are the mechanisms of how neurons process signals physiologically and electrochemically. They address how signals are processed by the dendrites, somas and axons, and how neurotransmitters and electrical signals are used to process signals in a neuron.
At the systems level, the questions addressed in systems neuroscience include how the circuits are formed and used anatomically and physiologically to produce the physiological functions, such as reflexes, sensory integration, motor coordination, circadian rhythms, emotional responses, learning and memory, et cetera. In other words, they address how these neural circuits function and the mechanisms through which behaviors are generated. For example, systems level analysis addresses questions concerning specific sensory and motor modalities: how does vision work? How do songbirds learn new songs and bats localize with ultrasound? The related field of neuroethology, in particular, addresses the complex question of how neural substrates underlies specific animal behavior.
At the cognitive level, cognitive neuroscience addresses the questions of how psychological/cognitive functions are produced by the neural circuitry. The emergence of powerful new measurement techniques such as neuroimaging (e.g.,fMRI, PET, SPECT), electrophysiology and human genetic analysis combined with sophisticated experimental techniques from cognitive psychology allows neuroscientists and psychologists to address abstract questions such as how human cognition and emotion are mapped to specific neural circuitries.
Neuroscience is also beginning to become allied with social sciences, and burgeoning interdisciplinary fields of neuroeconomics, decision theory, social neuroscience are starting to address some of the most complex questions involving interactions of brain with environment.
Neuroscience generally includes all scientific studies involving the nervous system. Psychology, as the scientific study of mental processes, may be considered a sub-field of neuroscience, although some mind/body theorists argue that the definition goes the other way — that psychology is a study of mental processes that can be modeled by many other abstract principles and theories, such as behaviorism and traditional cognitive psychology, that are independent of the underlying neural processes. The term neurobiology is sometimes used interchangeably with neuroscience, though the former refers to the biology of nervous system, whereas the latter refers to science of mental functions that form the foundation of the constituent neural circuitries. In Principles of Neural Science, nobel laureate Eric Kandel contends that cognitive psychology is one of the pillar disciplines for understanding the brain in neuroscience.
Neurology and Psychiatry are medical specialties and are generally considered, in academic research, subfields of neuroscience that specifically address the diseases of the nervous system. These terms also refer to clinical disciplines involving diagnosis and treatment of these diseases. Neurology deals with diseases of the central and peripheral nervous systems such as amyotrophic lateral sclerosis (ALS) and stroke, while psychiatry focuses on mental illnesses. The boundaries between the two have been blurring recently and physicians who specialize in either generally receive training in both. Both neurology and psychiatry are heavily involved in and influenced by basic research in neuroscience.
# History of Neuroscience
Evidence of trepanation, the surgical practice of either drilling or scraping a hole into the skull with the aim of curing headaches or mental disorders or relieving cranial pressure, being performed on patients dates back to Neolithic times and has been found in various cultures throughout the world. Manuscripts dating back to 5000BC indicated that the Egyptians had some knowledge about symptoms of brain damage.
Early views on the function of the brain regarded it to be a "cranial stuffing" of sorts. In Egypt, from the late Middle Kingdom onwards, the brain was regularly removed in preparation for mummification. It was believed at the time that the heart was the seat of intelligence. According to Herodotus, during the first step of mummification: 'The most perfect practice is to extract as much of the brain as possible with an iron hook, and what the hook cannot reach is mixed with drugs.'
The view that the heart was the source of consciousness was not challenged until the time of Hippocrates. He believed that the brain was not only involved with sensation, since most specialized organs (e.g., eyes, ears, tongue) are located in the head near the brain, but was also the seat of intelligence. Aristotle, however, believed that the heart was the center of intelligence and that the brain served to cool the blood. This view was generally accepted until the Roman physician Galen, a follower of Hippocrates and physician to Roman gladiators, observed that his patients lost their mental faculties when they had sustained damage to their brains.
In al-Andalus, Abulcasis, the father of modern surgery, developed material and technical designs which are still used in neurosurgery. Averroes suggested the existence of Parkinson's disease and attributed photoreceptor properties to the retina. Avenzoar described meningitis, intracranial thrombophlebitis, mediastinal tumours and made contributions to modern neuropharmacology. Maimonides wrote about neuropsychiatric disorders and described rabies and belladonna intoxication. Elsewhere in medieval Europe, Vesalius (1514-1564) and René Descartes (1596-1650) also made several contributions to neuroscience.
Studies of the brain became more sophisticated after the invention of the microscope and the development of a staining procedure by Camillo Golgi during the late 1890s that used a silver chromate salt to reveal the intricate structures of single neurons. His technique was used by Santiago Ramón y Cajal and led to the formation of the neuron doctrine, the hypothesis that the functional unit of the brain is the neuron. Golgi and Ramón y Cajal shared the Nobel Prize in Physiology or Medicine in 1906 for their extensive observations, descriptions and categorizations of neurons throughout the brain. The hypotheses of the neuron doctrine were supported by experiments following Galvani's pioneering work in the electrical excitability of muscles and neurons. In the late 19th century, DuBois-Reymond, Müller, and von Helmholtz showed neurons were electrically excitable and that their activity predictably affected the electrical state of adjacent neurons.
In parallel with this research, work with brain-damaged patients by Paul Broca suggested that certain regions of the brain were responsible for certain functions. This hypothesis was supported by observations of epileptic patients conducted by John Hughlings Jackson, who correctly deduced the organization of motor cortex by watching the progression of seizures through the body. Wernicke further developed the theory of the specialization of specific brain structures in language comprehension and production. Modern research still uses the Brodmann cytoarchitectonic (referring to study of cell structure) anatomical definitions from this era in continuing to show that distinct areas of the cortex are activated in the execution of specific tasks.
# Major branches
Current neuroscience education and research activities can be very roughly categorized into the following major branches, based on the subject and scale of the system in examination as well as distinct experimental or curricular approaches. Individual neuroscientists, however, often work on questions that span several distinct subfields.
Note: In 1990s, neuroscientist Jaak Panksepp coined the term "affective neuroscience" to emphasize that emotion research should be a branch of neurosciences, distinguishable from the nearby fields like cognitive neuroscience or behavioral neuroscience. More recently, the social aspect of the emotional brain has been integrated in what is called "social-affective neuroscience".
There has also been some research published arguing that some of fair play and the Golden Rule may be stated and rooted in terms of neuroscientific and neuroethical principles.
# Major Themes of Research
Neuroscience research from different areas can also be seen as focusing on a set of specific themes and questions. (Some of these are taken from )
- Behavior/Cognition/Language
- Biological Rhythms
- Brain Imaging or neuroimaging
- Cell Biology
- Cell Imaging & Electrophysiology
- Computational neuroscience
- Development
- Hearing Sciences
- Language
- Learning/Memory
- Mechanisms of Drug Action
- Molecular Neuroscience
- Motor Control
- Neurobiology of Disease
- Neuroethology
- Neuroendocrinology
- Neuroimmunology
- Signal transduction
- Systems Neuroscience
- Universal Grammar
- Vision Sciences
- Neurobiology of the neuron
- Sensation and perception
- Sleep
- Autonomic systems and homeostasis
- Arousal, attention and emotion
- Genetics of the nervous system
- Injury of the nervous systems
# Allied and Overlapping Fields
Neuroscience, by its very interdiciplinary nature, overlaps with and encompasses many different subjects. Below is a list of related subjects and fields.
- Aphasiology
- Biological psychology
- Cognitive Science
- Evolutionary neuroscience
- Generative grammar
- Machine Learning
- Metaplasticity
- Neural Networks
- Neural engineering
- Neuroanatomy
- Neurobiology
- Neurochemistry
- Neuroeconomics
- Neuroergonomics
- Neuroendocrinology
- Neuroesthetics
- Neuroethics
- Neuroethology
- Neurogenetics
- Neurogenomics
- Neuroheuristic
- Neuroimaging
- Neurolinguistics
- Neuromarketing
- Neuropharmacology
- Neurophenomenology
- Neurophilosophy
- Neurophysics
- Neurophysiology
- Neuroproteomics
- Neuroprosthetics
- Neuropsychiatry
- Neuropsychology
- Neuropsychopharmacology
- Neurotheology (also Biotheology)
- Psychiatry
- Psychoneuroimmunology
- Psychopharmacology
- Psychobiology
- Vision
# Future directions | Neuroscience
# Overview
Neuroscience is a profound field that is devoted to the scientific study of the nervous system. Such studies span the structure, function, evolutionary history, development, genetics, biochemistry, physiology, pharmacology, informatics, computational neuroscience and pathology of the nervous system. Traditionally it is seen as a branch of biological sciences. However, recently there has been a surge in the convergence of interest from many allied disciplines, including cognitive and neuro-psychology, computer science, statistics, physics, and medicine. The scope of neuroscience has now broadened to include any systematic scientific experimental and theoretical investigation of the central and peripheral nervous system of biological organisms. The empirical methodologies employed by neuroscientists have been enormously expanded, from biochemical and genetic analysis of dynamics of individual nerve cells and their molecular constituents to imaging representations of perceptual and motor tasks in the brain. Many recent theoretical advances in neuroscience have been aided by the use of computational modeling.
The scientific study of the nervous systems underwent a significant increase in the second half of the twentieth century, principally due to revolutions in molecular biology, electrophysiology and computational neuroscience. It has become possible to understand, in much detail, the complex processes occurring within a single neuron. However, understanding of how networks of neurons produce intellectual behavior, cognition, emotion and physiological responses is still poorly understood.
The nervous system is composed of a network of neurons and other supportive cells (such as glial cells). Neurons form functional circuits, each responsible for specific tasks to the behaviors at the organism level. Thus, neuroscience can be studied at many different levels, ranging from molecular level to cellular level to systems level to cognitive level.
At the molecular level, the basic questions addressed in molecular neuroscience include the mechanisms by which neurons express and respond to molecular signals and how axons form complex connectivity patterns. At this level, tools from molecular biology and genetics are used to understand how neurons develop and die, and how genetic changes affect biological functions. The morphology, molecular identity and physiological characteristics of neurons and how they relate to different types of behavior are also of considerable interest. (The ways in which neurons and their connections are modified by experience are addressed at the physiological and cognitive levels.)
At the cellular level, the fundamental questions addressed in cellular neuroscience are the mechanisms of how neurons process signals physiologically and electrochemically. They address how signals are processed by the dendrites, somas and axons, and how neurotransmitters and electrical signals are used to process signals in a neuron.
At the systems level, the questions addressed in systems neuroscience include how the circuits are formed and used anatomically and physiologically to produce the physiological functions, such as reflexes, sensory integration, motor coordination, circadian rhythms, emotional responses, learning and memory, et cetera. In other words, they address how these neural circuits function and the mechanisms through which behaviors are generated. For example, systems level analysis addresses questions concerning specific sensory and motor modalities: how does vision work? How do songbirds learn new songs and bats localize with ultrasound? The related field of neuroethology, in particular, addresses the complex question of how neural substrates underlies specific animal behavior.
At the cognitive level, cognitive neuroscience addresses the questions of how psychological/cognitive functions are produced by the neural circuitry. The emergence of powerful new measurement techniques such as neuroimaging (e.g.,fMRI, PET, SPECT), electrophysiology and human genetic analysis combined with sophisticated experimental techniques from cognitive psychology allows neuroscientists and psychologists to address abstract questions such as how human cognition and emotion are mapped to specific neural circuitries.
Neuroscience is also beginning to become allied with social sciences, and burgeoning interdisciplinary fields of neuroeconomics, decision theory, social neuroscience are starting to address some of the most complex questions involving interactions of brain with environment.
Neuroscience generally includes all scientific studies involving the nervous system. Psychology, as the scientific study of mental processes, may be considered a sub-field of neuroscience, although some mind/body theorists argue that the definition goes the other way — that psychology is a study of mental processes that can be modeled by many other abstract principles and theories, such as behaviorism and traditional cognitive psychology, that are independent of the underlying neural processes. The term neurobiology is sometimes used interchangeably with neuroscience, though the former refers to the biology of nervous system, whereas the latter refers to science of mental functions that form the foundation of the constituent neural circuitries. In Principles of Neural Science, nobel laureate Eric Kandel contends that cognitive psychology is one of the pillar disciplines for understanding the brain in neuroscience.
Neurology and Psychiatry are medical specialties and are generally considered, in academic research, subfields of neuroscience that specifically address the diseases of the nervous system. These terms also refer to clinical disciplines involving diagnosis and treatment of these diseases. Neurology deals with diseases of the central and peripheral nervous systems such as amyotrophic lateral sclerosis (ALS) and stroke, while psychiatry focuses on mental illnesses. The boundaries between the two have been blurring recently and physicians who specialize in either generally receive training in both. Both neurology and psychiatry are heavily involved in and influenced by basic research in neuroscience.
# History of Neuroscience
Evidence of trepanation, the surgical practice of either drilling or scraping a hole into the skull with the aim of curing headaches or mental disorders or relieving cranial pressure, being performed on patients dates back to Neolithic times and has been found in various cultures throughout the world. Manuscripts dating back to 5000BC[citation needed] indicated that the Egyptians had some knowledge about symptoms of brain damage.
Early views on the function of the brain regarded it to be a "cranial stuffing" of sorts. In Egypt, from the late Middle Kingdom onwards, the brain was regularly removed in preparation for mummification. It was believed at the time that the heart was the seat of intelligence. According to Herodotus, during the first step of mummification: 'The most perfect practice is to extract as much of the brain as possible with an iron hook, and what the hook cannot reach is mixed with drugs.'[citation needed]
The view that the heart was the source of consciousness was not challenged until the time of Hippocrates. He believed that the brain was not only involved with sensation, since most specialized organs (e.g., eyes, ears, tongue) are located in the head near the brain, but was also the seat of intelligence. Aristotle, however, believed that the heart was the center of intelligence and that the brain served to cool the blood. This view was generally accepted until the Roman physician Galen, a follower of Hippocrates and physician to Roman gladiators, observed that his patients lost their mental faculties when they had sustained damage to their brains.
In al-Andalus, Abulcasis, the father of modern surgery, developed material and technical designs which are still used in neurosurgery. Averroes suggested the existence of Parkinson's disease and attributed photoreceptor properties to the retina. Avenzoar described meningitis, intracranial thrombophlebitis, mediastinal tumours and made contributions to modern neuropharmacology. Maimonides wrote about neuropsychiatric disorders and described rabies and belladonna intoxication.[1] Elsewhere in medieval Europe, Vesalius (1514-1564) and René Descartes (1596-1650) also made several contributions to neuroscience.
Studies of the brain became more sophisticated after the invention of the microscope and the development of a staining procedure by Camillo Golgi during the late 1890s that used a silver chromate salt to reveal the intricate structures of single neurons. His technique was used by Santiago Ramón y Cajal and led to the formation of the neuron doctrine, the hypothesis that the functional unit of the brain is the neuron. Golgi and Ramón y Cajal shared the Nobel Prize in Physiology or Medicine in 1906 for their extensive observations, descriptions and categorizations of neurons throughout the brain. The hypotheses of the neuron doctrine were supported by experiments following Galvani's pioneering work in the electrical excitability of muscles and neurons. In the late 19th century, DuBois-Reymond, Müller, and von Helmholtz showed neurons were electrically excitable and that their activity predictably affected the electrical state of adjacent neurons.
In parallel with this research, work with brain-damaged patients by Paul Broca suggested that certain regions of the brain were responsible for certain functions. This hypothesis was supported by observations of epileptic patients conducted by John Hughlings Jackson, who correctly deduced the organization of motor cortex by watching the progression of seizures through the body. Wernicke further developed the theory of the specialization of specific brain structures in language comprehension and production. Modern research still uses the Brodmann cytoarchitectonic (referring to study of cell structure) anatomical definitions from this era in continuing to show that distinct areas of the cortex are activated in the execution of specific tasks.[2]
# Major branches
Current neuroscience education and research activities can be very roughly categorized into the following major branches, based on the subject and scale of the system in examination as well as distinct experimental or curricular approaches. Individual neuroscientists, however, often work on questions that span several distinct subfields.
Note: In 1990s, neuroscientist Jaak Panksepp coined the term "affective neuroscience"[3] to emphasize that emotion research should be a branch of neurosciences, distinguishable from the nearby fields like cognitive neuroscience or behavioral neuroscience. More recently, the social aspect of the emotional brain has been integrated in what is called "social-affective neuroscience".
There has also been some research published arguing that some of fair play and the Golden Rule may be stated and rooted in terms of neuroscientific and neuroethical principles.[4]
# Major Themes of Research
Neuroscience research from different areas can also be seen as focusing on a set of specific themes and questions. (Some of these are taken from http://www.northwestern.edu/nuin/fac/index.htm)
- Behavior/Cognition/Language
- Biological Rhythms
- Brain Imaging or neuroimaging
- Cell Biology
- Cell Imaging & Electrophysiology
- Computational neuroscience
- Development
- Hearing Sciences
- Language
- Learning/Memory
- Mechanisms of Drug Action
- Molecular Neuroscience
- Motor Control
- Neurobiology of Disease
- Neuroethology
- Neuroendocrinology
- Neuroimmunology
- Signal transduction
- Systems Neuroscience
- Universal Grammar
- Vision Sciences
- Neurobiology of the neuron
- Sensation and perception
- Sleep
- Autonomic systems and homeostasis
- Arousal, attention and emotion
- Genetics of the nervous system
- Injury of the nervous systems
# Allied and Overlapping Fields
Neuroscience, by its very interdiciplinary nature, overlaps with and encompasses many different subjects. Below is a list of related subjects and fields.
- Aphasiology
- Biological psychology
- Cognitive Science
- Evolutionary neuroscience
- Generative grammar
- Machine Learning
- Metaplasticity
- Neural Networks
- Neural engineering
- Neuroanatomy
- Neurobiology
- Neurochemistry
- Neuroeconomics
- Neuroergonomics
- Neuroendocrinology
- Neuroesthetics
- Neuroethics
- Neuroethology
- Neurogenetics
- Neurogenomics
- Neuroheuristic
- Neuroimaging
- Neurolinguistics
- Neuromarketing
- Neuropharmacology
- Neurophenomenology
- Neurophilosophy
- Neurophysics
- Neurophysiology
- Neuroproteomics
- Neuroprosthetics
- Neuropsychiatry
- Neuropsychology
- Neuropsychopharmacology
- Neurotheology (also Biotheology)
- Psychiatry
- Psychoneuroimmunology
- Psychopharmacology
- Psychobiology
- Vision
# Future directions | https://www.wikidoc.org/index.php/Neural_science | |
568a64c1d58eb7bccb064a6b37a645fdfd1f8452 | wikidoc | Neuregulin 3 | Neuregulin 3
Neuregulin 3 also known as NRG3 is a neural-enriched member of the neuregulin protein family which in humans is encoded by the NRG3 gene. The NRGs are a group of signaling proteins the superfamily of epidermal growth factor; EGF like polypeptide growth factor. These groups of proteins possess an 'EGF-like domain' that consists of six cysteine residues and three disulfide bridges predicted by the consensus sequence of the cysteine residues.
The neuregulins are a diverse family of proteins formed through alternative splicing from a single gene, they play crucial roles in regulating the growth and differentiation of epithelial, glial and muscle cells. These groups proteins also aid cell-cell associations in the breast, heart and skeletal muscles. Four different kinds of neuregulin genes have been identified, namely; NRG1 NRG2 NRG3 and NRG4. While the NRG1 isoforms have been extensively studied, there is little information available about the other genes of the family. NRGs binds to the ERBB3 and ERBB4 tyrosine kinase receptors, they then form homodimers or heterodimers, often consisting of ERBB2; which is thought to function as a co- receptor as it has not been observed to bind any ligand. NRGs binds to the ERBB receptors to promote phosphorylation of specific tyrosine residues on the C-terminal link of the receptor and the interactions of intracellular signaling proteins.
NRGs also play significant roles in developing maintaining, and repair of the nervous system, this is because NRG1, NRG2 and NRG3 are widely expressed in the central nervous system and also in the olfactory system. Studies have observed that in mice, NRG3 is limited to the developing Central nervous system as well as the adult form, previous studies also highlight the roles of NRG1, ERBB2, and ERBB4 in the development of the heart. Mice deficient in ERBB2, ERBB4, or NRG1 were observed to die at mid-embryogenesis stage from the termination of myocardial trabeculae development in the ventricle. These results confirm that NRG1 expression in the endocardium, is a significant ligand required to activate expression of ERBB2 and ERBB4 in the myocardium
# Function
Neuregulins are ligands of the ERBB-family receptors, while NRG1 and NRG2 are able to bind and activate both ERBB3 and ERBB4, NRG3 binding stimulates tyrosine phosphorylation, and can only bind to the extracellular domain of the ERBB4 receptor tyrosine kinase but not to the other members of the ERBB family receptors; ERBB2 and ERBB3.
NRG1, plays critical roles in the development of the embryonic cerebral cortex when it controls migration and sequencing of the cortical cell. Contrary to NRG1,there is limited information on pre-mRNA splicing of the NRG3 gene, together with its transcriptional profile and function in the brain. The recent discovery of hFBNRG3 (human fetal brain NRG3; DQ857894) which is an alternative cloned isoform of NRG3 from human fetal brain, promotes the survival of oligodendrocyte with the aid of ERBB4/PI3K/AKT1 pathway and also and also partakes in NRG3-ERBB4 signaling in neurodevelopment and brain functionalities.
Even though studies have revealed that NRG1 and NRG3 are paralogues, the EGF domain of NRG3 is only 31% identical to NRG1.The N-terminal domain of NRG3 resembles that of Sensory And Motor Neuron Derived Factor; SMDF because it lacks Ig-like as well as Kringle-like domains that are attributed to many NRG1 isomers. Hydropathy profile studies have shown that NRG3 lacks a hydrophobic N-terminal signal sequence common in secreted proteins, but contains a region of non-polar or uncharged amino acids in position (W66–V91). An amino acid region found in SMDF is similar to this non polar site of NRG3 and has been proposed to act as an internal, uncleaved signal sequence that functions as a translocation agent across the endoplasmic reticulum membrane.
# Clinical significance
Recent human genetic studies reveals neuregulin 3 gene (NRG3) as a potential risk gene responsible for different kinds of neuro-developmental disorders, resulting to schizophrenia, stunted development, attention deficit related disorders and bipolar disorders when structural and genetic variations occur within the gene
Most importantly, variants of the NRG3 gene have been linked to a susceptibility to schizophrenia. An increase in Isoform-specific models of NRG3 involved in schizophrenia have been reported, and observed to have an interaction with rs10748842; a NRG3 risk polymorphism, which indicates that NRG3 transcriptional dysregulation is a molecular risk mechanism.
These isoforms have also been linked to Hirschsprung's disease.
## Schizophrenia
Several genes in the NRG-ERBB signaling pathway have been implicated in genetic predisposition to schizophrenia, Neuregulin 3 (NRG3) encodes a protein similar to its paralog NRG1 and both play important roles in the developing nervous system. As observed with other pathologies like autism and schizophrenia, several members of any given protein family have a high chance of association with the same phenotype, individually or together.
A recent study of the temporal, diagnostic, and tissue-specific modulation of NRG3 isoform expression in human brain development, employed the use of qRT-PCR ; quantitative polymerase chain reaction to quantify 4 classes of NRG3 in human postmortem dorsolateral prefrontal cortex from 286 normal and affected (bipolar or extreme depressive disorder) candidates with age range of 14 weeks to 85 years old. The researches observed that each the 4 isoform class (I-IV) of NRG3 showed unique expression trajectories across human neopallium development and aging.
- NRG3 class I was increased in bipolar and major depressive disorder, in agreement with observations in schizophrenia.
- NRG3 class II was increased in bipolar disorder, and class III was increased in major depression cases.
- NRG3 class I, II and IV were actively involved in the developmental stages,
- The rs10748842 risk genotype predicted elevated class II and III expression, consistent with previous reports in the brain, with tissue-specific analyses suggesting that classes II and III are brain-specific isoforms of NRG3. | Neuregulin 3
Neuregulin 3 also known as NRG3 is a neural-enriched member of the neuregulin protein family which in humans is encoded by the NRG3 gene.[1][2] The NRGs are a group of signaling proteins the superfamily of epidermal growth factor; EGF like polypeptide growth factor. These groups of proteins possess an 'EGF-like domain' that consists of six cysteine residues and three disulfide bridges predicted by the consensus sequence of the cysteine residues.[3]
The neuregulins are a diverse family of proteins formed through alternative splicing from a single gene, they play crucial roles in regulating the growth and differentiation of epithelial, glial and muscle cells. These groups proteins also aid cell-cell associations in the breast, heart and skeletal muscles.[2][4] Four different kinds of neuregulin genes have been identified, namely; NRG1 NRG2 NRG3 and NRG4. While the NRG1 isoforms have been extensively studied, there is little information available about the other genes of the family. NRGs binds to the ERBB3 and ERBB4 tyrosine kinase receptors,[2] they then form homodimers or heterodimers, often consisting of ERBB2; which is thought to function as a co- receptor as it has not been observed to bind any ligand.[5][6] NRGs binds to the ERBB receptors to promote phosphorylation of specific tyrosine residues on the C-terminal link of the receptor and the interactions of intracellular signaling proteins.[7]
NRGs also play significant roles in developing maintaining, and repair of the nervous system, this is because NRG1, NRG2 and NRG3 are widely expressed in the central nervous system and also in the olfactory system.[7] Studies have observed that in mice, NRG3 is limited to the developing Central nervous system as well as the adult form,[2] previous studies also highlight the roles of NRG1, ERBB2, and ERBB4 in the development of the heart. Mice deficient in ERBB2, ERBB4, or NRG1 were observed to die at mid-embryogenesis stage from the termination of myocardial trabeculae development in the ventricle. These results confirm that NRG1 expression in the endocardium, is a significant ligand required to activate expression of ERBB2 and ERBB4 in the myocardium[2]
# Function
Neuregulins are ligands of the ERBB-family receptors, while NRG1 and NRG2 are able to bind and activate both ERBB3 and ERBB4, NRG3 binding stimulates tyrosine phosphorylation, and can only bind to the extracellular domain of the ERBB4 receptor tyrosine kinase but not to the other members of the ERBB family receptors; ERBB2 and ERBB3.[2]
NRG1, plays critical roles in the development of the embryonic cerebral cortex when it controls migration and sequencing of the cortical cell.[8] Contrary to NRG1,there is limited information on pre-mRNA splicing of the NRG3 gene, together with its transcriptional profile and function in the brain.[2] The recent discovery of hFBNRG3 (human fetal brain NRG3; DQ857894) which is an alternative cloned isoform of NRG3 from human fetal brain, promotes the survival of oligodendrocyte with the aid of ERBB4/PI3K/AKT1 pathway and also[9] and also partakes in NRG3-ERBB4 signaling in neurodevelopment and brain functionalities.[10]
Even though studies have revealed that NRG1 and NRG3 are paralogues, the EGF domain of NRG3 is only 31% identical to NRG1.The N-terminal domain of NRG3 resembles that of Sensory And Motor Neuron Derived Factor; SMDF[11] because it lacks Ig-like as well as Kringle-like domains that are attributed to many NRG1 isomers. Hydropathy profile studies have shown that NRG3 lacks a hydrophobic N-terminal signal sequence common in secreted proteins, but contains a region of non-polar or uncharged amino acids in position (W66–V91).[2] An amino acid region found in SMDF is similar to this non polar site of NRG3 and has been proposed to act as an internal, uncleaved signal sequence that functions as a translocation agent across the endoplasmic reticulum membrane.[11]
# Clinical significance
Recent human genetic studies reveals neuregulin 3 gene (NRG3) as a potential risk gene responsible for different kinds of neuro-developmental disorders, resulting to schizophrenia, stunted development, attention deficit related disorders and bipolar disorders when structural and genetic variations occur within the gene[12]
Most importantly, variants of the NRG3 gene have been linked to a susceptibility to schizophrenia.[13] An increase in Isoform-specific models of NRG3 involved in schizophrenia have been reported, and observed to have an interaction with rs10748842; a NRG3 risk polymorphism, which indicates that NRG3 transcriptional dysregulation is a molecular risk mechanism.[14]
These isoforms have also been linked to Hirschsprung's disease.[15]
## Schizophrenia
Several genes in the NRG-ERBB signaling pathway have been implicated in genetic predisposition to schizophrenia, Neuregulin 3 (NRG3) encodes a protein similar to its paralog NRG1 and both play important roles in the developing nervous system. As observed with other pathologies like autism and schizophrenia, several members of any given protein family have a high chance of association with the same phenotype, individually or together.[16][17]
A recent study of the temporal, diagnostic, and tissue-specific modulation of NRG3 isoform expression in human brain development, employed the use of qRT-PCR ; quantitative polymerase chain reaction to quantify 4 classes of NRG3 in human postmortem dorsolateral prefrontal cortex from 286 normal and affected (bipolar or extreme depressive disorder) candidates with age range of 14 weeks to 85 years old.[14] The researches observed that each the 4 isoform class (I-IV) of NRG3 showed unique expression trajectories across human neopallium development and aging.
- NRG3 class I was increased in bipolar and major depressive disorder, in agreement with observations in schizophrenia.
- NRG3 class II was increased in bipolar disorder, and class III was increased in major depression cases.
- NRG3 class I, II and IV were actively involved in the developmental stages,
- The rs10748842 risk genotype predicted elevated class II and III expression, consistent with previous reports in the brain, with tissue-specific analyses suggesting that classes II and III are brain-specific isoforms of NRG3.[14] | https://www.wikidoc.org/index.php/Neuregulin_3 | |
a18dd3ae274beaae7c885982e3d6699674bcc7b9 | wikidoc | Neuregulin 4 | Neuregulin 4
Neuregulin 4 also known as NRG4 is a member of the neuregulin protein family which in humans is encoded by the NRG4 gene.
# Function
The neuregulins, including NRG4, activate erb-b2 receptor tyrosine kinase 4 (ERBB4) to initiating cell signaling through cytosolic tyrosine phosphorylation.
# Clinical significance
Loss of expression of NRG4 is frequently seen in advanced bladder cancer while increased NRG4 expression correlates to better survival. | Neuregulin 4
Neuregulin 4 also known as NRG4 is a member of the neuregulin protein family which in humans is encoded by the NRG4 gene.[1][2][3]
# Function
The neuregulins, including NRG4, activate erb-b2 receptor tyrosine kinase 4 (ERBB4) to initiating cell signaling through cytosolic tyrosine phosphorylation.[3]
# Clinical significance
Loss of expression of NRG4 is frequently seen in advanced bladder cancer while increased NRG4 expression correlates to better survival.[4] | https://www.wikidoc.org/index.php/Neuregulin_4 | |
65012525b597ad24b3a527f87305b813382b0450 | wikidoc | Neurobiology | Neurobiology
Neurobiology is the study of cells of the nervous system and the organization of these cells into functional circuits that process information and mediate behavior. It is a subdiscipline of both biology and neuroscience. Neurobiology differs from neuroscience, a much broader field that is concerned with any scientific study of the nervous system. Neurobiology should also not be confused with other subdisciplines of neuroscience such as computational neuroscience, cognitive neuroscience, behavioral neuroscience, biological psychiatry, neurology, and neuropsychology despite the overlap with these subdisciplines. (There is also a use of the term "neurobiology"--common among scientists in the field and lay people alike--in which it is synonymous with "neuroscience".) Scientists that study neurobiology are called neurobiologists.
# Neurons and glial cells
Main articles: neuron, glial cell
Neurons are cells that are specialized to receive, propagate, and transmit electrochemical impulses. In the human brain alone, there are over a hundred billion neurons. Neurons are diverse with respect to morphology and function. Thus, not all neurons correspond to the stereotypical motor neuron with dendrites and myelinated axons that conduct action potentials. Some neurons such as photoreceptors, for example, do not have myelinated axons that conduct action potentials. Other unipolar neurons found in invertebrates do not even have distinguishing processes such as dendrites. Moreover, the distinctions based on function between neurons and other cells such as cardiac and muscle cells are not helpful. Thus, the fundamental difference between a neuron and a nonneuronal cell is a matter of degree.
Another major class of cells found in the nervous system are glial cells. Despite the abundance of glial cells relative to neurons in the nervous system (there are ten glial cells for every single neuron), glial cells are only recently beginning to receive attention from neurobiologists for being involved not just in nourishment and support of neurons, but also in modulating synapses. For example, Schwann cells, which are a type of glial cell found in the peripheral nervous system, modulate synaptic connections between presynaptic terminals of motor neuron endplates and muscle fibers at neuromuscular junctions.
# Neuronal function
One prominent characteristic of many neurons is excitability. Neurons generate electrical impulses or changes in voltage of two types: graded potentials and action potentials. Graded potentials occur when the membrane potential depolarizes and hyperpolarizes in a graded fashion relative to the amount of stimulus that is applied to the neuron. An action potential on the other hand is an all-or-none electrical impulse. Despite being slower than graded potentials, action potentials have the advantage of traveling long distances in axons with little or no decrement. Much of the current knowledge of action potentials comes from squid axon experiments by Sir Alan Lloyd Hodgkin and Sir Andrew Huxley.
## Action potential
The Hodgkin-Huxley Model of an action potential in the squid giant axon has been the basis for much of the current understanding of the ionic bases of action potentials. Briefly, the model states that the generation of an action potential is determined by two ions: Na+ and K+. An action potential can be divided into several sequential phases: threshold, rising phase, falling phase, undershoot phase, and recovery. Following several local graded depolarizations of the membrane potential, the threshold of excitation is reached, voltage-gated sodium channels are activated, which leads to an influx of Na+ ions. As Na+ ions enter the cell, the membrane potential is further depolarized, and more voltage-gated sodium channels are activated. Such a process is also known as a positive-feedback loop. As the rising phase reaches its peak, voltage-gated Na+ channels are inactivated whereas voltage-gated K+ channels are activated, resulting in a net outward movement of K+ ions, which repolarizes the membrane potential towards the resting membrane potential. Repolarization of the membrane potential continues, resulting in an undershoot phase or absolute refractory period. The undershoot phase occurs because unlike voltage-gated sodium channels, voltage-gated potassium channels inactivate much more slowly. Nevertheless, as more voltage-gated K+ channels become inactivated, the membrane potential recovers to its normal resting steady state.
## Structure and formation of synapses
Neurons communicate with one another via synapses. Synapses are specialized junctions between two cells in close apposition to one another. In a synapse, the neuron that sends the signal is the presynaptic neuron and the target cell receives that signal is the postsynaptic neuron or cell. Synapses can be either electrical or chemical. Electrical synapses are characterized by the formation of gap junctions that allow ions and other organic compound to instantaneously pass from one cell to another. Chemical synapses are characterized by the presynaptic release of neurotransmitters that diffuse across a synaptic cleft to bind with postsynaptic receptors. A neurotransmitter is a chemical messenger that is synthesized within neurons themselves and released by these same neurons to communicate with their postsynaptic target cells. A receptor is a transmembrane protein molecule that a neurotransmitter or drug binds. Chemical synapses are slower than electrical synapses.
## Neurotransmitter transporters, receptors, and signaling mechanisms
After neurotransmitters are synthesized, they are packaged and stored in vesicles. These vesicles are pooled together in terminal boutons of the presynaptic neuron. When there is a change in voltage in the terminal bouton, voltage-gated calcium channels embedded in the membranes of these boutons become activated. These allow Ca2+ ions to diffuse through these channels and bind with synaptic vesicles within the terminal buttons. Once bounded with Ca2+, the vesicles dock and fuse with the presynaptic membrane, and release neurotransmitters into the synaptic cleft by a process known as exocytosis. The neurotransmitters then diffuse across the synaptic cleft and binds to postsynaptic receptors embedded on the postsynaptic membrane of another neuron. There are two families of receptors: ionotropic and metabotropic receptors. Ionotropic receptors are a combination of a receptor and an ion channel. When ionotropic receptors are activated, certain ion species such as Na+ to enter the postsynaptic neuron, which depolarizes the postsynaptic membrane. If more of the same type of postsynaptic receptors are activated, then more Na+ will enter the postsynaptic membrane and depolarize cell. Metabotropic receptors on the other hand activate second messenger cascade systems that result in the opening of ion channel located some place else on the same postsynaptic membrane. Although slower than ionotropic receptors that function as on-and-off switches, metabotropic receptors have the advantage of changing the cell's responsiveness to ions and other metabolites, examples being Gamma Amino-Butyric Acid (inhibitory transmitter), Glutamic Acid (excitatory transmitter), Dopamine, Norepinephrine, Epinephrine, Melanin, Serotonin, Melatonin, and Substance P.
Postsynaptic depolarizations can be either excitatory or inhibitory. Those that are excitatory are referred to as excitatory postsynaptic potential (EPSP). Alternatively, some postsynaptic receptors allow Cl- ions to enter the cell or K+ ions to leave the cell, which results in an inhibitory postsynaptic potential (IPSP). If the EPSP is dominant, the threshold of excitation in the postynaptic neuron may be reached, resulting in the generation and propagation of an action potential in the postynaptic neuron.
# Synaptic plasticity
Synaptic plasticity is the process whereby strengths of synaptic connections are altered. For example, long-term changes in synaptic connection may result in more postsynaptic receptors being embedded in the postsynaptic membrane, resulting in the strengthening of the synapse. Synaptic plasticity is also found to be the neural mechanism that underlies learning and memory.
# Sensory systems
The auditory system is a sensory system for the sense of hearing. It consists of the outer ear, the middle ear, and the inner ear.
The olfactory system is the sensory system used for olfaction. The accessory olfactory system senses pheromones. The olfactory system is often spoken of along with the gustatory system as the chemosensory senses because both transduce chemical signals into perception. Linda B. Buck and Richard Axel won the 2004 Nobel Prize in Physiology or Medicine for their work on the olfactory system.
The visual system is the part of the nervous system which allows organisms to see. It interprets the information from visible light to build a representation of the world surrounding the body. The visual system has the complex task of (re)constructing a three dimensional world from a two dimensional projection of that world. Note that different species are able to see different parts of the light spectrum; for example, some can see into the ultraviolet, while others can see into the infrared.
# Neural development
Neural development is the process whereby the nervous system grows and develops. In humans, aside from the primitive gut, the nervous system is the first organ system to develop and the last system to reach maturity. Development of the nervous system begins when the ectoderm thickens to form a neural plate. The neural plate in turns thickens to form the neural tube, which then twists, turns and kinks to form the three primary brain vesicles and five secondary brain vesicles. Within this neural tube totipotent cells migrate and differentiate into neurons and glial cells. | Neurobiology
Template:Portalpar
Template:Portalpar
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Neurobiology is the study of cells of the nervous system and the organization of these cells into functional circuits that process information and mediate behavior.[1] It is a subdiscipline of both biology and neuroscience. Neurobiology differs from neuroscience, a much broader field that is concerned with any scientific study of the nervous system. Neurobiology should also not be confused with other subdisciplines of neuroscience such as computational neuroscience, cognitive neuroscience, behavioral neuroscience, biological psychiatry, neurology, and neuropsychology despite the overlap with these subdisciplines. (There is also a use of the term "neurobiology"--common among scientists in the field and lay people alike--in which it is synonymous with "neuroscience".) Scientists that study neurobiology are called neurobiologists.
# Neurons and glial cells
Main articles: neuron, glial cell
Neurons are cells that are specialized to receive, propagate, and transmit electrochemical impulses. In the human brain alone, there are over a hundred billion neurons. Neurons are diverse with respect to morphology and function. Thus, not all neurons correspond to the stereotypical motor neuron with dendrites and myelinated axons that conduct action potentials. Some neurons such as photoreceptors, for example, do not have myelinated axons that conduct action potentials. Other unipolar neurons found in invertebrates do not even have distinguishing processes such as dendrites. Moreover, the distinctions based on function between neurons and other cells such as cardiac and muscle cells are not helpful. Thus, the fundamental difference between a neuron and a nonneuronal cell is a matter of degree.
Another major class of cells found in the nervous system are glial cells. Despite the abundance of glial cells relative to neurons in the nervous system (there are ten glial cells for every single neuron), glial cells are only recently beginning to receive attention from neurobiologists for being involved not just in nourishment and support of neurons, but also in modulating synapses. For example, Schwann cells, which are a type of glial cell found in the peripheral nervous system, modulate synaptic connections between presynaptic terminals of motor neuron endplates and muscle fibers at neuromuscular junctions.
# Neuronal function
One prominent characteristic of many neurons is excitability. Neurons generate electrical impulses or changes in voltage of two types: graded potentials and action potentials. Graded potentials occur when the membrane potential depolarizes and hyperpolarizes in a graded fashion relative to the amount of stimulus that is applied to the neuron. An action potential on the other hand is an all-or-none electrical impulse. Despite being slower than graded potentials, action potentials have the advantage of traveling long distances in axons with little or no decrement. Much of the current knowledge of action potentials comes from squid axon experiments by Sir Alan Lloyd Hodgkin and Sir Andrew Huxley.
## Action potential
The Hodgkin-Huxley Model of an action potential in the squid giant axon has been the basis for much of the current understanding of the ionic bases of action potentials. Briefly, the model states that the generation of an action potential is determined by two ions: Na+ and K+. An action potential can be divided into several sequential phases: threshold, rising phase, falling phase, undershoot phase, and recovery. Following several local graded depolarizations of the membrane potential, the threshold of excitation is reached, voltage-gated sodium channels are activated, which leads to an influx of Na+ ions. As Na+ ions enter the cell, the membrane potential is further depolarized, and more voltage-gated sodium channels are activated. Such a process is also known as a positive-feedback loop. As the rising phase reaches its peak, voltage-gated Na+ channels are inactivated whereas voltage-gated K+ channels are activated, resulting in a net outward movement of K+ ions, which repolarizes the membrane potential towards the resting membrane potential. Repolarization of the membrane potential continues, resulting in an undershoot phase or absolute refractory period. The undershoot phase occurs because unlike voltage-gated sodium channels, voltage-gated potassium channels inactivate much more slowly. Nevertheless, as more voltage-gated K+ channels become inactivated, the membrane potential recovers to its normal resting steady state.
## Structure and formation of synapses
Neurons communicate with one another via synapses. Synapses are specialized junctions between two cells in close apposition to one another. In a synapse, the neuron that sends the signal is the presynaptic neuron and the target cell receives that signal is the postsynaptic neuron or cell. Synapses can be either electrical or chemical. Electrical synapses are characterized by the formation of gap junctions that allow ions and other organic compound to instantaneously pass from one cell to another.[2] Chemical synapses are characterized by the presynaptic release of neurotransmitters that diffuse across a synaptic cleft to bind with postsynaptic receptors. A neurotransmitter is a chemical messenger that is synthesized within neurons themselves and released by these same neurons to communicate with their postsynaptic target cells. A receptor is a transmembrane protein molecule that a neurotransmitter or drug binds. Chemical synapses are slower than electrical synapses.
## Neurotransmitter transporters, receptors, and signaling mechanisms
After neurotransmitters are synthesized, they are packaged and stored in vesicles. These vesicles are pooled together in terminal boutons of the presynaptic neuron. When there is a change in voltage in the terminal bouton, voltage-gated calcium channels embedded in the membranes of these boutons become activated. These allow Ca2+ ions to diffuse through these channels and bind with synaptic vesicles within the terminal buttons. Once bounded with Ca2+, the vesicles dock and fuse with the presynaptic membrane, and release neurotransmitters into the synaptic cleft by a process known as exocytosis. The neurotransmitters then diffuse across the synaptic cleft and binds to postsynaptic receptors embedded on the postsynaptic membrane of another neuron. There are two families of receptors: ionotropic and metabotropic receptors. Ionotropic receptors are a combination of a receptor and an ion channel. When ionotropic receptors are activated, certain ion species such as Na+ to enter the postsynaptic neuron, which depolarizes the postsynaptic membrane. If more of the same type of postsynaptic receptors are activated, then more Na+ will enter the postsynaptic membrane and depolarize cell. Metabotropic receptors on the other hand activate second messenger cascade systems that result in the opening of ion channel located some place else on the same postsynaptic membrane. Although slower than ionotropic receptors that function as on-and-off switches, metabotropic receptors have the advantage of changing the cell's responsiveness to ions and other metabolites, examples being Gamma Amino-Butyric Acid (inhibitory transmitter), Glutamic Acid (excitatory transmitter), Dopamine, Norepinephrine, Epinephrine, Melanin, Serotonin, Melatonin, and Substance P.
Postsynaptic depolarizations can be either excitatory or inhibitory. Those that are excitatory are referred to as excitatory postsynaptic potential (EPSP). Alternatively, some postsynaptic receptors allow Cl- ions to enter the cell or K+ ions to leave the cell, which results in an inhibitory postsynaptic potential (IPSP). If the EPSP is dominant, the threshold of excitation in the postynaptic neuron may be reached, resulting in the generation and propagation of an action potential in the postynaptic neuron.
# Synaptic plasticity
Synaptic plasticity is the process whereby strengths of synaptic connections are altered. For example, long-term changes in synaptic connection may result in more postsynaptic receptors being embedded in the postsynaptic membrane, resulting in the strengthening of the synapse. Synaptic plasticity is also found to be the neural mechanism that underlies learning and memory.
# Sensory systems
The auditory system is a sensory system for the sense of hearing. It consists of the outer ear, the middle ear, and the inner ear.
The olfactory system is the sensory system used for olfaction. The accessory olfactory system senses pheromones. The olfactory system is often spoken of along with the gustatory system as the chemosensory senses because both transduce chemical signals into perception. Linda B. Buck and Richard Axel won the 2004 Nobel Prize in Physiology or Medicine for their work on the olfactory system.
The visual system is the part of the nervous system which allows organisms to see. It interprets the information from visible light to build a representation of the world surrounding the body. The visual system has the complex task of (re)constructing a three dimensional world from a two dimensional projection of that world. Note that different species are able to see different parts of the light spectrum; for example, some can see into the ultraviolet, while others can see into the infrared.
# Neural development
Neural development is the process whereby the nervous system grows and develops. In humans, aside from the primitive gut, the nervous system is the first organ system to develop and the last system to reach maturity. Development of the nervous system begins when the ectoderm thickens to form a neural plate. The neural plate in turns thickens to form the neural tube, which then twists, turns and kinks to form the three primary brain vesicles and five secondary brain vesicles. Within this neural tube totipotent cells migrate and differentiate into neurons and glial cells. | https://www.wikidoc.org/index.php/Neurobiology | |
dc5d9765e9159a6b5edc880a4c663f52ce61139f | wikidoc | Phakomatoses | Phakomatoses
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
Phakomatoses (or "neurocutaneous syndromes") are disorders of central nervous system that additionally result in lesions on the skin and the retina. These tissues have a common ectodermal origin. The term, which means "spot", was introduced by Jan van der Hoeve in the 1920s, before the distinct genetic basis of each of these diseases was understood.
# Examples of phakomatoses
- Neurofibromatosis
- Tuberous sclerosis
- Ataxia telangiectasia
- Sturge-Weber syndrome
- von Hippel-Lindau disease
- Incontinentia pigmenti | Phakomatoses
Template:DiseaseDisorder infobox
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [1] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
Phakomatoses (or "neurocutaneous syndromes") are disorders of central nervous system that additionally result in lesions on the skin and the retina. These tissues have a common ectodermal origin. The term, which means "spot", was introduced by Jan van der Hoeve in the 1920s, before the distinct genetic basis of each of these diseases was understood.
# Examples of phakomatoses
- Neurofibromatosis
- Tuberous sclerosis
- Ataxia telangiectasia
- Sturge-Weber syndrome
- von Hippel-Lindau disease
- Incontinentia pigmenti | https://www.wikidoc.org/index.php/Neurocutaneous_syndrome | |
6c747f5e9161b72988b30af9386c2f0e8ca9a453 | wikidoc | Neurogenin-3 | Neurogenin-3
Neurogenin-3 is a protein that in humans is encoded by the NEUROG3 gene.
Neurogenin-3 is expressed in endocrine progenitor cells and is required for endocrine cell development in the pancreas and intestine. It belongs to a family of basic helix-loop-helix (bHLH) transcription factors involved in the determination of neural precursor cells in the neuroectoderm.
Neurogenin 3 (NGN3) is expressed by 2-10% of acinar and duct cells in the histologically normal adult human pancreas. NGN3+ cells isolated from cultured exocrine tissue by coexpressed cell surface glycoprotein CD133 have a transcriptome consistent with exocrine dedifferentiation, a phenotype that resembles endocrine progenitor cells during development, and a capacity for endocrine differentiation in vitro. Human and rodent exocrine cells have been reprogrammed into cells with an islet cell-like phenotype following direct expression of NGN3 or manipulation that leads to its expression.
# Detail
Much more at Neurogenins#Neurogenin-3 | Neurogenin-3
Neurogenin-3 is a protein that in humans is encoded by the NEUROG3 gene.[1]
Neurogenin-3 is expressed in endocrine progenitor cells and is required for endocrine cell development in the pancreas and intestine.[2] It belongs to a family of basic helix-loop-helix (bHLH) transcription factors involved in the determination of neural precursor cells in the neuroectoderm.[3]
Neurogenin 3 (NGN3) is expressed by 2-10% of acinar and duct cells in the histologically normal adult human pancreas. NGN3+ cells isolated from cultured exocrine tissue by coexpressed cell surface glycoprotein CD133 have a transcriptome consistent with exocrine dedifferentiation, a phenotype that resembles endocrine progenitor cells during development, and a capacity for endocrine differentiation in vitro.[4] Human[5] and rodent[6][7][8][9][10][11][12][13][14] exocrine cells have been reprogrammed into cells with an islet cell-like phenotype following direct expression of NGN3 or manipulation that leads to its expression.
# Detail
Much more at Neurogenins#Neurogenin-3 | https://www.wikidoc.org/index.php/Neurogenin-3 | |
7651ba45663f3811a700f253f5cc5af52788f931 | wikidoc | Neurokinin A | Neurokinin A
Neurokinin A, formerly known as Substance K, is a neurologically active peptide translated from the pre-protachykinin gene. Neurokinin A has many excitatory effects on mammalian nervous systems and is also influential on the mammalian inflammatory and pain responses.
# Introduction
Neurokinin A (formally known as substance K) is a member of the tachykinin family of neuropeptide neurotransmitters. Tachykinins are important contributors to nociceptive processing, satiety, and smooth muscle contraction. Tachykinins are known to be highly excitatory neurotransmitters in major central neural systems. Neurokinin A is ubiquitous in both the central and peripheral mammalian nervous systems, and seems to be involved in reactions to pain and the inflammatory responses. It is produced from the same preprotachykinin A gene as the neuropeptide substance P. Both substance P and neurokinin A are encoded by the same mRNA, which when alternatively spliced can be translated into either compound. It has various roles in the body of humans and other animals, specifically stimulation of extravascular smooth muscle, vasodilation, hypertensive action, immune system activation, and pain management. The deduced amino acid sequence of neurokinin A is as follows:
- His Lys Asp Ser Phe Val Gly Leu Met (HKTDSFVGLM)
with amidation at the C-terminus.
# Mechanism of action
Modified from: Sun J, Ramnath RD, Tamizhselvi R, Bhatia M."Neurokinin A engages neurokinin-1 receptor to induce NF-kappaB-dependent gene expression in murine macrophages: implications of ERK1/2 and PI 3-kinase/Akt pathways." Am J Physiol Cell Physiol. 2008 Sep;295(3):C679-91
Like Substance P , Neurokinin A is present in excitatory neurons and secretory cells of the hypothalamic–pituitary–adrenal axis. Additionally both SP neurokinin A is found in the neurosensory system and modulates a wide range of inflammatory and tissue repairing processes . In various tissues, such as the skin, the release of bioactive tachykinins by sensory nerve fibers C, that extend from the dorsal root ganglia into the epidermis, directly influence the activity of keratinocytes. Inflammation, tissue healing and cell proliferation have been linked to both SP and neurokinin A release into surrounding tissues.
## Nervous system
The overstimulation of the hypothalamic–pituitary–adrenal axis system and elevated secretion of corticotropin-releasing hormone from the hypothalamus, have been studied in many clinical manifestations of pathological depression. Studies have shown that stress-induced activation of the noradrenergic prefrontal lobe system may be under the control of both endogenously released corticotrophin-releasing hormone and SP and neurokinin A. This study directly links the secretion of neurokinin A and SP to certain forms of depression characterized by the corticoid receptor hypothesis of depression.
Inflammatory responses within the central nervous system (CNS) are often the result of traumatic injury or exposure to infectious agents. Inflammation provides a protective immune response to such stresses may also result in progressive damage to the CNS. There is significant evidence to indicate that tachykinins are a major component of the neural inflammatory response at peripheral tissues as well as the CNS. The ability to regulate tachykinin secreation represents an important mechanism for designing potentially useful drugs to treat inflammation. Neurokinin A has been associated with the chemokines interleukin-1 and interleukin-6, both of which are heavily involved in the inflammatory process during infections.
Neuronal tissue can be severely damaged either through physical trauma or intracellular stresses, either chronic or acute. Either of these scenarios can result in calcium overload, protein degradation, the unfolded protein response or an accumulation of DNA damage. Endogenous cellular responses are activated within neurve tissue in response to damage in order to protect cellular, protein, and nucleic acid integrity. A large variety of neuroprotective signaling mechanisms exist, which can be manipulated by drugs to reduce damage from cellular damage in neurons. Tachykinins thus have a number of neuroprotective physiological roles in medical conditions
## Immune system
The immune system is a highly integrated system which receives input from many sources, such as sites of injury, nocireceptors and white blood cells. Chemical signals therefore are an important component of paracrine, autocrine and endocrine signaling.
Neurokinin A was shown to be a potent chemo attractor for T-cells increasing the migration into infected tissues. This migration is necessary for the pathogen seeking activity of T-cells. Some chemokines trigger the intravascular adhesion of T-cells whereas others direct the migration of leukocytes into and within the extravascular space. Since lymphocytes must be positioned correctly to interact with other cells, the pattern of chemokine receptors and the type and distribution of chemokines in tissues critically influence immune responses. The molecular mechanism behind neurokinin's role as a chemoattractor is currently unclear.
Neurokinin A has an inhibitory effect on the formation of myeloid cells, and appear to be involved in one specific receptor since the effect can be completely abolished by a NK-2 receptor-selective antagonist. The inhibitory effect of neuronkinin A is countered by the excitatory effect of a structurally similar compound: substance P. The opposite effects on myelogenesis by substance P and neurokinin A may represent an important feedback mechanism for maintenance of homeostasis.
## Respiratory system
The binding of neurokinin A to the NKR-2 results in bronchoconstriction, mucus production in the lungs and process neurogenic inflammation. This release is propagated through the stimulation of e-NANC nerves in the bronchial epithelium via an axon-reflex mechanism.
## Cardiovascular system
Neurokinin has been shown to contribute to both bradycardia and myocardial infarctions through the activation of NK2 receptors.
The dual sensory-motor function of neurokinin A containing afferent neurons is a component of the intracardiac nervous system. Varicose processes of tachykinin-containing nerves are abundant in coronary arteries and in the cardiac ganglia. The diverse responses that are triggered by locally released tachykinins produce beneficial effects such as modulation of ganglion transmission. However, it is also possible that excessive stimulation of cardiac afferents and release of tachykinins, during pathological conditions such as myocardial infarction, could contribute to certain human pathologies.
# Receptor
Tachykinins selectively bind and activate the G-protein coupled receptors NK1R, NK2R, and NK3R. Neurokinin A binds to the G-protein coupled receptor ultimately increasing the release of inositol-phosphate and calcium second messengers. Each receptor demonstrates a specific affinity for either neurokinin A or substance P peptides. Both peptides, however, can act as full agonists on either receptor, although their potency is decreased when not bound to their specific receptor.
## NK-2 receptor
NK-2 receptors are expressed predominantly in the CNS. Networks involved in emotional processing, such as the prefrontal cortex, cingulate cortex, and amygdala, show the highest concentration of NK-2 receptors. NK-2 receptor antagonists have been theorized to have antidepressant benefits and are presently in clinical trials. As a consequence of its ability to stimulate intestinal smooth muscle, NKA is considered to be specifically active in regulating intestinal motility by its action on NK2 receptors.
### Antagonists
MEN 11420 has been demonstrated to be a potent, selective and competitive antagonist of tachykinin NK2 receptors, both in animal and human models. In vivo animal models, MEN 11420 produces an effective and long-lasting blockade of the NK2 receptors expressed in the smooth muscle of the intestinal, genito-urinary and respiratory tract.
# History
Neurokinin A was isolated from porcine spinal cord in 1983 by von Euler and Gaddum.
# Structure
Tachykinis are a structurally related group of neuropeptides sharing the C-terminal sequence Phe-X-Gly-Leu-Met-NH2. The amino acid sequence of substance P and neurokinin A are well conserved across mammals species. Structure of mammalian neurokinin A was obtained using CD spectropolarimetry and 2D proton NMR. Analysis showed that in water, the peptide adopts an extended conformation while in the presence of micelles (a model cell membrane system), an alpha helical conformation is induced in the central core (Asp4-Met10).
## Genetic overview
The pre-protachykinin-1 and pre-protachykinin-2 genes in mice encode four very distinct peptides with varying physiological function. Alternative splicing of the pre-protachykinin-1 gene gives rise to four different peptide precursors(alphatac1, betatac1, deltatac1 und gammatac1), which are further processed into several related peptides including neurokinin A and substance P. The alpha tac1 and beta tac1 precursors encode synthesis of both Substance P and neurokinin A.
Modified from:Nakanishi, Shigetada. "Molecular Mechanisms Of Intercellular Communication In The Hormonal And Neural Systems." IUBMB Life 58.5/6 (2006): 349-357
### Mouse models
pre-protachykinin-1 -/- mice show normal fertility and behavioral patterns (litter-mate socialization and pup rearing), but have a reduced sense of anxiety when threatened, compared to both wild-type mice and other mouse models of depression.
# Applications
## Cancer
Circulating concentrations of neurokinin A is an independent indicator of poor prognosis in certain cancers such as carcinoids. Patients presenting with neurokinin A plasma concentrations of >50 pmol/l showed a poorer 3 year survival rate than patients presenting with neurokinin A concentrations of less than 50 pmol/l. These types of studies show that measuring tachykinin levels in human patients may have clinical relevance.
Patients with Midgut Carcinoid disease (MGC) commonly receive neurokinin A test to determine the progression of their disease. Midgut Carcinoid disease is an uncommon disease with occurrence rates of approximately 1.4 per 100,000 of the population per year. MGC has an unpredictable disease progression depending on the patient, symptoms and progression range from rapid and aggressive to chronic. Treatment is difficult because of the varying degrees of severity, so assessing the extent of the disease is extremely important in effective treatment.
## Asthma
The blocking of neuropeptide signaling has come become a novel therapeutic target for suppression of bronchial constriction in asthma patients.
Bronchoconstriction is among the most prominent and extensively studied effects caused by tachykinins. Tachykinins have numerous effects in the respiratory systems especially in asthma patients who are more responsive to tachykinin administration. Through studies with human airways researchers have examined the role tachykinins play in bronchoconstriction, most notably through the receptor NK2, though regulation of NK2 receptors seems to be mediated by the activity of NK1 receptors eluting to complicated inhibition mechanism.
Administration of DNK333 (a dual tachykinin receptor NK1/NK2 antagonist) have shown protective activity against neurokinin A induced bronchoconstriction.
## Psychiatric disorders
Neurokinin A is involved in many stress induced neurological disorders, such as depression, schizophrenia and epilepsy.
### Affective disorders
Affective disorders are characterized by a frequent, fluctuating alteration in mood, affecting the patient’s thoughts, emotions, and behaviors. Affective disorders include depression, anxiety, and bipolar disorder. A number of approaches have been utilized to study the role that neurokinin A plays in the manifestation and continuation of human affective disorders. The measurement of serum peptide levels in depressed patients as well as anxious patients displayed higher plasma levels of tachykinins than their low-anxiety counterparts. In addition to studies of plasma levels of TKs, cerebrospinal fluid (CSF) levels of neurokinin A have also been directly correlated with depression. Under states of depression, neurokinin immunoreactivity is increased in the frontal cortex, and decreased in the striatum. These peptide levels were not found to be normalized by lithium treatment in mice. Elevated levels of tachykinins in CSF have been found in patients with fibromyalgia syndrome, a disorder that is strongly correlated with depression in human patients. Tachykinin ligands have been extensively studied and determined to be functionally linked to the control of affective phenotypes in a complex physiological manner.
### Epilepsy
Epilepsy is a broad category of disorders with varying types of severity and presented symptoms. Neurokinins have been experimentally determined as possible predictor in the generation of certain forms of epilepsy. Experimentally when substance P is injected into the rat hippocampus, it significantly lowers the initiation threshold for seizures induced in a dose-dependent manner. Experimental data thus has indicated a pro-convulsant role for the Pre-protachykinin-1 gene and thus substance P and neurokinin A.
# Further reading
- NCBI
- AJPLUNG
- Science Direct
- Journal of Immunology | Neurokinin A
Neurokinin A, formerly known as Substance K, is a neurologically active peptide translated from the pre-protachykinin gene.[2] Neurokinin A has many excitatory effects on mammalian nervous systems and is also influential on the mammalian inflammatory and pain responses.[3]
# Introduction
Neurokinin A (formally known as substance K) is a member of the tachykinin family of neuropeptide neurotransmitters. Tachykinins are important contributors to nociceptive processing, satiety, and smooth muscle contraction. Tachykinins are known to be highly excitatory neurotransmitters in major central neural systems.[3] Neurokinin A is ubiquitous in both the central and peripheral mammalian nervous systems, and seems to be involved in reactions to pain and the inflammatory responses. It is produced from the same preprotachykinin A gene as the neuropeptide substance P. Both substance P and neurokinin A are encoded by the same mRNA, which when alternatively spliced can be translated into either compound.[2] It has various roles in the body of humans and other animals, specifically stimulation of extravascular smooth muscle, vasodilation, hypertensive action, immune system activation, and pain management. The deduced amino acid sequence of neurokinin A is as follows:[4]
- His Lys Asp Ser Phe Val Gly Leu Met (HKTDSFVGLM)
with amidation at the C-terminus.
# Mechanism of action
Modified from: Sun J, Ramnath RD, Tamizhselvi R, Bhatia M."Neurokinin A engages neurokinin-1 receptor to induce NF-kappaB-dependent gene expression in murine macrophages: implications of ERK1/2 and PI 3-kinase/Akt pathways." Am J Physiol Cell Physiol. 2008 Sep;295(3):C679-91
Like Substance P [SP], Neurokinin A is present in excitatory neurons and secretory cells of the hypothalamic–pituitary–adrenal axis.[5] Additionally both SP neurokinin A is found in the neurosensory system and modulates a wide range of inflammatory and tissue repairing processes [1]. In various tissues, such as the skin, the release of bioactive tachykinins by sensory nerve fibers C, that extend from the dorsal root ganglia into the epidermis, directly influence the activity of keratinocytes.[6] Inflammation, tissue healing and cell proliferation have been linked to both SP and neurokinin A release into surrounding tissues.
## Nervous system
The overstimulation of the hypothalamic–pituitary–adrenal axis system and elevated secretion of corticotropin-releasing hormone from the hypothalamus, have been studied in many clinical manifestations of pathological depression.[5] Studies have shown that stress-induced activation of the noradrenergic prefrontal lobe system may be under the control of both endogenously released corticotrophin-releasing hormone and SP and neurokinin A. This study directly links the secretion of neurokinin A and SP to certain forms of depression characterized by the corticoid receptor hypothesis of depression.[7]
Inflammatory responses within the central nervous system (CNS) are often the result of traumatic injury or exposure to infectious agents.[8] Inflammation provides a protective immune response to such stresses may also result in progressive damage to the CNS. There is significant evidence to indicate that tachykinins are a major component of the neural inflammatory response at peripheral tissues as well as the CNS.[8] The ability to regulate tachykinin secreation represents an important mechanism for designing potentially useful drugs to treat inflammation. Neurokinin A has been associated with the chemokines interleukin-1 and interleukin-6, both of which are heavily involved in the inflammatory process during infections.[8]
Neuronal tissue can be severely damaged either through physical trauma or intracellular stresses, either chronic or acute. Either of these scenarios can result in calcium overload, protein degradation, the unfolded protein response or an accumulation of DNA damage.[8] Endogenous cellular responses are activated within neurve tissue in response to damage in order to protect cellular, protein, and nucleic acid integrity. A large variety of neuroprotective signaling mechanisms exist, which can be manipulated by drugs to reduce damage from cellular damage in neurons. Tachykinins thus have a number of neuroprotective physiological roles in medical conditions [8]
## Immune system
The immune system is a highly integrated system which receives input from many sources, such as sites of injury, nocireceptors and white blood cells. Chemical signals therefore are an important component of paracrine, autocrine and endocrine signaling.
Neurokinin A was shown to be a potent chemo attractor for T-cells increasing the migration into infected tissues.[9] This migration is necessary for the pathogen seeking activity of T-cells. Some chemokines trigger the intravascular adhesion of T-cells whereas others direct the migration of leukocytes into and within the extravascular space. Since lymphocytes must be positioned correctly to interact with other cells, the pattern of chemokine receptors and the type and distribution of chemokines in tissues critically influence immune responses.[10] The molecular mechanism behind neurokinin's role as a chemoattractor is currently unclear.
Neurokinin A has an inhibitory effect on the formation of myeloid cells, and appear to be involved in one specific receptor since the effect can be completely abolished by a NK-2 receptor-selective antagonist.[9] The inhibitory effect of neuronkinin A is countered by the excitatory effect of a structurally similar compound: substance P.[9] The opposite effects on myelogenesis by substance P and neurokinin A may represent an important feedback mechanism for maintenance of homeostasis.
## Respiratory system
The binding of neurokinin A to the NKR-2 results in bronchoconstriction, mucus production in the lungs and process neurogenic inflammation.[11] This release is propagated through the stimulation of e-NANC nerves in the bronchial epithelium via an axon-reflex mechanism.
## Cardiovascular system
Neurokinin has been shown to contribute to both bradycardia and myocardial infarctions through the activation of NK2 receptors.[12]
The dual sensory-motor function of neurokinin A containing afferent neurons is a component of the intracardiac nervous system.[13] Varicose processes of tachykinin-containing nerves are abundant in coronary arteries and in the cardiac ganglia. The diverse responses that are triggered by locally released tachykinins produce beneficial effects such as modulation of ganglion transmission.[13] However, it is also possible that excessive stimulation of cardiac afferents and release of tachykinins, during pathological conditions such as myocardial infarction, could contribute to certain human pathologies.[13]
# Receptor
Tachykinins selectively bind and activate the G-protein coupled receptors NK1R, NK2R, and NK3R.[5] Neurokinin A binds to the G-protein coupled receptor ultimately increasing the release of inositol-phosphate and calcium second messengers.[14] Each receptor demonstrates a specific affinity for either neurokinin A or substance P peptides. Both peptides, however, can act as full agonists on either receptor, although their potency is decreased when not bound to their specific receptor.[8]
## NK-2 receptor
NK-2 receptors are expressed predominantly in the CNS. Networks involved in emotional processing, such as the prefrontal cortex, cingulate cortex, and amygdala, show the highest concentration of NK-2 receptors.[15][16] NK-2 receptor antagonists have been theorized to have antidepressant benefits and are presently in clinical trials.[15] As a consequence of its ability to stimulate intestinal smooth muscle, NKA is considered to be specifically active in regulating intestinal motility by its action on NK2 receptors.[17]
### Antagonists
MEN 11420 has been demonstrated to be a potent, selective and competitive antagonist of tachykinin NK2 receptors, both in animal and human models. In vivo animal models, MEN 11420 produces an effective and long-lasting blockade of the NK2 receptors expressed in the smooth muscle of the intestinal, genito-urinary and respiratory tract.[17]
# History
Neurokinin A was isolated from porcine spinal cord in 1983 by von Euler and Gaddum.[18]
# Structure
Tachykinis are a structurally related group of neuropeptides sharing the C-terminal sequence Phe-X-Gly-Leu-Met-NH2.[5] The amino acid sequence of substance P and neurokinin A are well conserved across mammals species.[8] Structure of mammalian neurokinin A was obtained using CD spectropolarimetry and 2D proton NMR.[1] Analysis showed that in water, the peptide adopts an extended conformation while in the presence of micelles (a model cell membrane system), an alpha helical conformation is induced in the central core (Asp4-Met10).[1]
## Genetic overview
The pre-protachykinin-1 and pre-protachykinin-2 genes in mice encode four very distinct peptides with varying physiological function.[5] Alternative splicing of the pre-protachykinin-1 gene gives rise to four different peptide precursors(alphatac1, betatac1, deltatac1 und gammatac1), which are further processed into several related peptides including neurokinin A and substance P.[5] The alpha tac1 and beta tac1 precursors encode synthesis of both Substance P and neurokinin A.[5]
Modified from:Nakanishi, Shigetada. "Molecular Mechanisms Of Intercellular Communication In The Hormonal And Neural Systems." IUBMB Life 58.5/6 (2006): 349-357
### Mouse models
pre-protachykinin-1 -/- mice show normal fertility and behavioral patterns (litter-mate socialization and pup rearing), but have a reduced sense of anxiety when threatened, compared to both wild-type mice and other mouse models of depression.[5]
# Applications
## Cancer
Circulating concentrations of neurokinin A is an independent indicator of poor prognosis in certain cancers such as carcinoids.[19] Patients presenting with neurokinin A plasma concentrations of >50 pmol/l showed a poorer 3 year survival rate than patients presenting with neurokinin A concentrations of less than 50 pmol/l.[19] These types of studies show that measuring tachykinin levels in human patients may have clinical relevance.
Patients with Midgut Carcinoid disease (MGC) commonly receive neurokinin A test to determine the progression of their disease. Midgut Carcinoid disease is an uncommon disease with occurrence rates of approximately 1.4 per 100,000 of the population per year.[19] MGC has an unpredictable disease progression depending on the patient, symptoms and progression range from rapid and aggressive to chronic.[19] Treatment is difficult because of the varying degrees of severity, so assessing the extent of the disease is extremely important in effective treatment.
## Asthma
The blocking of neuropeptide signaling has come become a novel therapeutic target for suppression of bronchial constriction in asthma patients.[11]
Bronchoconstriction is among the most prominent and extensively studied effects caused by tachykinins. Tachykinins have numerous effects in the respiratory systems especially in asthma patients who are more responsive to tachykinin administration.[20] Through studies with human airways researchers have examined the role tachykinins play in bronchoconstriction, most notably through the receptor NK2, though regulation of NK2 receptors seems to be mediated by the activity of NK1 receptors eluting to complicated inhibition mechanism.[20]
Administration of DNK333 (a dual tachykinin receptor NK1/NK2 antagonist) have shown protective activity against neurokinin A induced bronchoconstriction.[20]
## Psychiatric disorders
Neurokinin A is involved in many stress induced neurological disorders, such as depression, schizophrenia and epilepsy.[15]
### Affective disorders
Affective disorders are characterized by a frequent, fluctuating alteration in mood, affecting the patient’s thoughts, emotions, and behaviors. Affective disorders include depression, anxiety, and bipolar disorder.[8] A number of approaches have been utilized to study the role that neurokinin A plays in the manifestation and continuation of human affective disorders.[8] The measurement of serum peptide levels in depressed patients as well as anxious patients displayed higher plasma levels of tachykinins than their low-anxiety counterparts.[8] In addition to studies of plasma levels of TKs, cerebrospinal fluid (CSF) levels of neurokinin A have also been directly correlated with depression.[8] Under states of depression, neurokinin immunoreactivity is increased in the frontal cortex, and decreased in the striatum. These peptide levels were not found to be normalized by lithium treatment in mice.[15] Elevated levels of tachykinins in CSF have been found in patients with fibromyalgia syndrome, a disorder that is strongly correlated with depression in human patients. Tachykinin ligands have been extensively studied and determined to be functionally linked to the control of affective phenotypes in a complex physiological manner.
### Epilepsy
Epilepsy is a broad category of disorders with varying types of severity and presented symptoms. Neurokinins have been experimentally determined as possible predictor in the generation of certain forms of epilepsy.[8] Experimentally when substance P is injected into the rat hippocampus, it significantly lowers the initiation threshold for seizures induced in a dose-dependent manner.[8] Experimental data thus has indicated a pro-convulsant role for the Pre-protachykinin-1 gene and thus substance P and neurokinin A.
# Further reading
- NCBI
- AJPLUNG
- Science Direct
- Journal of Immunology | https://www.wikidoc.org/index.php/Neurokinin_A | |
6f29652d1a0e5bcc0565fe92c98fac64b58e79f3 | wikidoc | Neuromedin B | Neuromedin B
Neuromedin B (NMB) is a bombesin-related peptide in mammals. It was originally purified from pig spinal cord, and later shown to be present in human central nervous system and gastrointestinal tract.
# Sequence
The sequence of the C-terminal decapeptide is highly conserved across mammalian species: GNLWATGHFM-(NH2); this decapeptide is sometimes noted as neuromedin B, but it is more accurately described as neuromedin B 23-32. The sequence of neuromedin B (in rat) is : TPFSWDLPEPRSRASKIRVHPRGNLWATGHFM-(NH2).
# Function
Neuromedin regulates the following functions:
- exocrine and endocrine secretions
- cell growth
- body temperature
- blood pressure and glucose level
# Neuromedin signaling pathway
NMB acts by binding to its high affinity cell surface receptor, neuromedin B receptor (NMBR). This receptor is a G protein-coupled receptor with seven transmembrane spanning regions, hence the receptor is also denoted as a 7-transmembrane receptor (7-TMR). Upon binding several intracellular signaling pathways are triggered (see Figure 2).
When NMB binds to its 7-TMR, the heterotrimeric G protein that is attached to the receptor is activated. The G-protein is called heterotrimeric because it consists of 3 polypeptides: α subunit, β subunit, and γ subunit. In the activated NMBR/G-protein complex, there occurs an exchange of GTP for GDP bound to G-α subunit. The G-α subunit, in turn, dissociated form the G-βγ subunits. The free G-α inactivates adenylate cyclase (AC), which, in turn, catalyzes the conversion of ATP to cAMP, the latter of which functioning as a second messenger. cAMP activates of the enzyme Protein Kinase A (PKA). PKA enters the nucleus and activates the cAMP response element-binding protein. The activated CREB binds along with CREB binding protein, co-activator to the CRE region of the DNA in the nucleus. CREB and CBP are held together by leucine zippers. CRE is the control that activates number of growth factors, and thus cell proliferation and some anti-apoptotic genes. In the brain, CREB plays a role in long-term memory and learning. | Neuromedin B
Neuromedin B (NMB) is a bombesin-related peptide in mammals.[1][2] It was originally purified from pig spinal cord, and later shown to be present in human central nervous system and gastrointestinal tract.[3]
# Sequence
The sequence of the C-terminal decapeptide is highly conserved across mammalian species: GNLWATGHFM-(NH2); this decapeptide is sometimes noted as neuromedin B, but it is more accurately described as neuromedin B 23-32. The sequence of neuromedin B (in rat) is : TPFSWDLPEPRSRASKIRVHPRGNLWATGHFM-(NH2).[4]
# Function
Neuromedin regulates the following functions:
- exocrine and endocrine secretions
- cell growth
- body temperature
- blood pressure and glucose level
# Neuromedin signaling pathway
NMB acts by binding to its high affinity cell surface receptor, neuromedin B receptor (NMBR). This receptor is a G protein-coupled receptor with seven transmembrane spanning regions, hence the receptor is also denoted as a 7-transmembrane receptor (7-TMR). Upon binding several intracellular signaling pathways are triggered (see Figure 2).
When NMB binds to its 7-TMR, the heterotrimeric G protein that is attached to the receptor is activated. The G-protein is called heterotrimeric because it consists of 3 polypeptides: α subunit, β subunit, and γ subunit. In the activated NMBR/G-protein complex, there occurs an exchange of GTP for GDP bound to G-α subunit. The G-α subunit, in turn, dissociated form the G-βγ subunits. The free G-α inactivates adenylate cyclase (AC), which, in turn, catalyzes the conversion of ATP to cAMP, the latter of which functioning as a second messenger. cAMP activates of the enzyme Protein Kinase A (PKA). PKA enters the nucleus and activates the cAMP response element-binding protein. The activated CREB binds along with CREB binding protein, co-activator to the CRE region of the DNA in the nucleus. CREB and CBP are held together by leucine zippers. CRE is the control that activates number of growth factors, and thus cell proliferation and some anti-apoptotic genes. In the brain, CREB plays a role in long-term memory and learning. | https://www.wikidoc.org/index.php/Neuromedin_B | |
a133af79543589e8c2c59da10f1334d76e7e61ba | wikidoc | Neuromedin U | Neuromedin U
Neuromedin U (or NmU) is a neuropeptide found in the brain of humans and other mammals, which has a number of diverse functions including contraction of smooth muscle, regulation of blood pressure, pain perception, appetite, bone growth, and hormone release. It was first isolated from the spinal cord in 1985, and named after its ability to cause smooth muscle contraction in the uterus.
# Structure
Neuromedin U is a highly conserved neuropeptide present in many species, existing as multiple isoforms. For example, in humans it is a 25 amino acid peptide (U-25) in rats it is 23-aas long (U-23) and it has been found to be as low as 8-aas long in some mammals. NMU-8 is identical to the C terminus of NMU-25, thus is the most highly conserved region of the entire peptide. The relative contribution of the different isoforms to the biological function of neuromedin U is generally not well understood. Neuromedin U, like many neuroactive peptides, is amidated at the C-terminus, and all isoforms have identical C-terminal heptapeptides.
The sequence of neuromedin U-23 in rats is: YKVNEYQGPVAPSGGFFLFRPRN-(NH2).
# Function
The activation of NmU receptors leads to intracellular signal transduction via calcium mobilization, phosphoinositide (or PI) signaling, and the inhibition of cAMP production
NmU will contract smooth muscle only in a tissue- and species-specific manner. Intracerebroventricular (or i.c.v) administration of the neuropeptide mediates stress response and increases both the arterial pressure and heart rate. i.c.v administration of NmU elevates the plasma adrenaline levels, though has no effect on the amount of plasma noradrenaline. It has been suggested that large doses () of NmU inhibits the activity of the paraventricular nucleus of hypothalamus and/or the sympathetic preganglionic neurons, thus controlling the activity.
# Regulation
Neuromedin U is mediated by two receptors, peripheral NmUR1 and central nervous system NmUR2. Both receptors are examples of Class A G-protein coupled receptors (or GPCRs) with a distinct distributional pattern. NmUR1 is expressed predominantly in the peripheral nervous system, with highest levels in the gastrointestinal tract, whereas NmUR2 is mostly found in the central nervous system, with greatest expression in the hypothalamus, medulla, and spinal cord.
The discovery of set distribution patterns has begun to allow assignation of specific roles of the two receptor subtypes within the body. What is known for certain is that recombinant NmU receptors will increase the internal calcium concentration, signaling via the MAPK/ERK pathway
# Role in disease
## Cancer
Its role in cancer is not yet fully understood, though NmU and its receptor NMUR2 have been shown to be over-expressed in human pancreatic cancers compared to normal cells. Studies also showed NmU serum levels decreased after the tumors were removed, as NmU and its receptor are localized predominantly in cancer cells. Although NmU exerts no effect on cancer cell proliferation, it induces c-Met, a proto-oncogene that encodes the mesenchymal-epithelial transition factor (MET) protein. Increased invasiveness as well as an increased hepatocyte growth factor (HGF)-mediated scattering suggest NmU is also involved in the HGF-c-Met paracrine loop regulating cell migration.
## Pain perception and stress response
The effect of NmU on stress and pain perception pathways has been demonstrated using mice. In contrast to NmU peptide-deficient mice, NmUR2 knockout (KO) mice appeared normal with regard to stress, anxiety, body weight regulation, and food consumption. However, the NmUR2 KO mice exhibit reduced pain sensitivity in both hot plate test and the chronic phase of the formalin test. Furthermore, facilitated excitatory synaptic transmission in spinal dorsal horn neurons, a mechanism by which NmU stimulates pain, did not occur in NmUR2 KO mice. Both NmUR2 expression and NmU-23 binding sites are highly localized to the outer layers of the spinal dorsal horn, and administration of NmU via intracerebroventricular (ICV) injections usually increases pain sensitivity in rats and mice.
The expression of NmUR2 in the paraventricular nucleus of hypothalamus (PVN), a major site for the release of Corticotropin-releasing hormone (CRH), suggests an alternative role in mediating stress response. NmU and its receptors are also abundantly expressed in nociceptive sensory pathways, including the dorsal root ganglia (DRG), spinal cord, and brainstem. In particular, NmU induces hyperalgesia, allodynia, and increased persistent pain after formalin injection. ICV injections of NmU in rats and mice induce behavior responses associated with activation of the nociceptive pathways, for example it will increase plasma levels of corticosterone, and stimulates the release of CRH from hypothalamic explants in vitro. Central administration of NmU also induces expression of key genes in hypothalamic areas associated with stress, as well as stress-related behaviours that can be blocked by CRH antagonist (this is absent from CRH knockout mice).
Certain stress responses are abolished in NmU knockout mice. These results suggest that NmU significantly modulates nociceptive sensory transmission. | Neuromedin U
Neuromedin U (or NmU) is a neuropeptide found in the brain of humans and other mammals, which has a number of diverse functions including contraction of smooth muscle, regulation of blood pressure, pain perception, appetite, bone growth, and hormone release. It was first isolated from the spinal cord in 1985, and named after its ability to cause smooth muscle contraction in the uterus.[1][2][3][4][5][6][7][8]
# Structure
Neuromedin U is a highly conserved neuropeptide present in many species, existing as multiple isoforms. For example, in humans it is a 25 amino acid peptide (U-25) in rats it is 23-aas long (U-23) and it has been found to be as low as 8-aas long in some mammals. NMU-8 is identical to the C terminus of NMU-25, thus is the most highly conserved region of the entire peptide.[9] The relative contribution of the different isoforms to the biological function of neuromedin U is generally not well understood. Neuromedin U, like many neuroactive peptides, is amidated at the C-terminus, and all isoforms have identical C-terminal heptapeptides.
The sequence of neuromedin U-23 in rats is: YKVNEYQGPVAPSGGFFLFRPRN-(NH2).[1]
# Function
The activation of NmU receptors leads to intracellular signal transduction via calcium mobilization, phosphoinositide (or PI) signaling, and the inhibition of cAMP production[10]
NmU will contract smooth muscle only in a tissue- and species-specific manner. Intracerebroventricular (or i.c.v) administration of the neuropeptide mediates stress response and increases both the arterial pressure and heart rate.[11] i.c.v administration of NmU elevates the plasma adrenaline levels, though has no effect on the amount of plasma noradrenaline. It has been suggested that large doses () of NmU inhibits the activity of the paraventricular nucleus of hypothalamus and/or the sympathetic preganglionic neurons, thus controlling the activity.
# Regulation
Neuromedin U is mediated by two receptors, peripheral NmUR1 and central nervous system NmUR2. Both receptors are examples of Class A G-protein coupled receptors (or GPCRs) with a distinct distributional pattern. NmUR1 is expressed predominantly in the peripheral nervous system, with highest levels in the gastrointestinal tract, whereas NmUR2 is mostly found in the central nervous system, with greatest expression in the hypothalamus, medulla, and spinal cord.
The discovery of set distribution patterns has begun to allow assignation of specific roles of the two receptor subtypes within the body. What is known for certain is that recombinant NmU receptors will increase the internal calcium concentration, signaling via the MAPK/ERK pathway[11]
# Role in disease
## Cancer
Its role in cancer is not yet fully understood, though NmU and its receptor NMUR2 have been shown to be over-expressed in human pancreatic cancers compared to normal cells. Studies also showed NmU serum levels decreased after the tumors were removed, as NmU and its receptor are localized predominantly in cancer cells. Although NmU exerts no effect on cancer cell proliferation, it induces c-Met, a proto-oncogene that encodes the mesenchymal-epithelial transition factor (MET) protein. Increased invasiveness as well as an increased hepatocyte growth factor (HGF)-mediated scattering suggest NmU is also involved in the HGF-c-Met paracrine loop regulating cell migration.[10]
## Pain perception and stress response
The effect of NmU on stress and pain perception pathways has been demonstrated using mice. In contrast to NmU peptide-deficient mice, NmUR2 knockout (KO) mice appeared normal with regard to stress, anxiety, body weight regulation, and food consumption. However, the NmUR2 KO mice exhibit reduced pain sensitivity in both hot plate test and the chronic phase of the formalin test. Furthermore, facilitated excitatory synaptic transmission in spinal dorsal horn neurons, a mechanism by which NmU stimulates pain, did not occur in NmUR2 KO mice. Both NmUR2 expression and NmU-23 binding sites are highly localized to the outer layers of the spinal dorsal horn, and administration of NmU via intracerebroventricular (ICV) injections usually increases pain sensitivity in rats and mice.
The expression of NmUR2 in the paraventricular nucleus of hypothalamus (PVN), a major site for the release of Corticotropin-releasing hormone (CRH), suggests an alternative role in mediating stress response. NmU and its receptors are also abundantly expressed in nociceptive sensory pathways, including the dorsal root ganglia (DRG), spinal cord, and brainstem. In particular, NmU induces hyperalgesia, allodynia, and increased persistent pain after formalin injection. ICV injections of NmU in rats and mice induce behavior responses associated with activation of the nociceptive pathways, for example it will increase plasma levels of corticosterone, and stimulates the release of CRH from hypothalamic explants in vitro. Central administration of NmU also induces expression of key genes in hypothalamic areas associated with stress, as well as stress-related behaviours that can be blocked by CRH antagonist (this is absent from CRH knockout mice).
Certain stress responses are abolished in NmU knockout mice. These results suggest that NmU significantly modulates nociceptive sensory transmission.[9] | https://www.wikidoc.org/index.php/Neuromedin_U | |
981debd15772eb287af954192a0ef70775829e70 | wikidoc | Neuropeptide | Neuropeptide
A neuropeptide is any of the variety of peptides found in neural tissue; e.g. endorphins, enkephalins. Now, about 100 different peptides are known to be released by different populations of neurons in the mammalian brain.
Neurons use many different chemical signals to communicate information, including neurotransmitters, peptides, cannabinoids, and even some gases, like nitric oxide.
Many populations of neurons have distinctive biochemical phenotypes. For example, in one subpopulation of about 3000 neurons in the arcuate nucleus of the hypothalamus, three anorectic peptides are co-expressed: α-melanocyte-stimulating hormone (α-MSH), galanin-like peptide, and cocaine-and-amphetamine-regulated transcript (CART), and in another subpopulation two orexigenic peptides are co-expressed, neuropeptide Y and agouti-related peptide (AGRP). These are not the only peptides in the arcuate nucleus; β-endorphin, dynorphin, enkephalin, galanin, ghrelin, growth-hormone releasing hormone, neurotensin, neuromedin U, and somatostatin are also expressed in subpopulations of arcuate neurons. These peptides are all released centrally and act on other neurons at specific receptors. The neuropeptide Y neurons also make the classical inhibitory neurotransmitter GABA.
Peptide signals play a role in information processing that is different to that of conventional neurotransmitters, and many appear to be particularly associated with specific behaviors. For example, oxytocin and vasopressin have striking and specific effects on social behaviors, including maternal behavior and pair bonding.
Generally, peptides act at metabotropic or G-protein-coupled receptors expressed by selective populations of neurons - so peptides act as specific signals between one population of neurons and another. Neurotransmitters generally affect the excitability of other neurons, by depolarising them or by hyperpolarising them. Peptides have much more diverse effects; amongst other things, they can affect gene expression, local blood flow, synaptogenesis, and glial cell morphology. Peptides tend to have prolonged actions, and some have striking effects on behavior.
Neurons very often make both a conventional neurotransmitter (such as glutamate, GABA or dopamine) and one or more neuropeptides. Peptides are generally packaged in large dense-core vesicles, and the co-existing neurotransmitters in small synaptic vesicles. The large dense-core vesicles are often found in all parts of a neuron, including the soma, dendrites, axonal swellings and nerve endings, whereas the small synaptic vesicles are mainly found in clusters at presynaptic locations. Release of the large vesicles and the small vesicles is regulated differentially.
# Examples of neuroactive peptides coexisting with other neurotransmitters
Transmitter names are shown in bold.
Norepinephrine (noradrenaline).
In neurons of the A2 cell group in the nucleus of the solitary tract), norepinephrine co-exists with:
- Galanin
- Enkephalin
- Neuropeptide Y
GABA
- Somatostatin(in the hippocampus)
- Cholecystokinin
- Neuropeptide Y (in the arcuate nucleus)
Acetylcholine
- VIP
- Substance P
Dopamine
- Cholecystokinin
- Neurotensin
Epinephrine (adrenaline)
- Neuropeptide Y
- Neurotensin
Serotonin(5-HT)
- Substance P
- TRH
- Enkephalin
Some neurons make several different peptides. For instance,
Vasopressin co-exists with dynorphin and galanin in magnocellular neurons of the supraoptic nucleus and paraventricular nucleus, and with CRF (in parvocellular neurons of the paraventricular nucleus)
Oxytocin in the supraoptic nucleus co-exists with enkephalin, dynorphin, cocaine-and amphetamine regulated transcript (CART) and cholecystokinin.
# Diabetes Link
A new discovery might have important implications for treatment of diabetes. Researchers at the Toronto Hospital for Sick Children injected capsaicin into NOD mice (Non-obese diabetic mice, a strain that is genetically predisposed to develop the equivalent of type 1 diabetes) to kill the pancreatic sensory nerves. This treatment reduced the development of diabetes in these mice by 80%, suggesting a link between neuropeptides and the development of diabetes. When the researchers injected the pancreas of the diabetic mice with sensory neuropeptide (sP), they were cured of the diabetes for as long as 4 months. Also, insulin resistance (characteristic of type 2 diabetes) was reduced. These research results are in the process of being confirmed, and their applicability in humans will have to be established in the future. Any treatment that could result from this research is probably years away. | Neuropeptide
A neuropeptide is any of the variety of peptides found in neural tissue; e.g. endorphins, enkephalins. Now, about 100 different peptides are known to be released by different populations of neurons in the mammalian brain.
Neurons use many different chemical signals to communicate information, including neurotransmitters, peptides, cannabinoids, and even some gases, like nitric oxide.
Many populations of neurons have distinctive biochemical phenotypes. For example, in one subpopulation of about 3000 neurons in the arcuate nucleus of the hypothalamus, three anorectic peptides are co-expressed: α-melanocyte-stimulating hormone (α-MSH), galanin-like peptide, and cocaine-and-amphetamine-regulated transcript (CART), and in another subpopulation two orexigenic peptides are co-expressed, neuropeptide Y and agouti-related peptide (AGRP). These are not the only peptides in the arcuate nucleus; β-endorphin, dynorphin, enkephalin, galanin, ghrelin, growth-hormone releasing hormone, neurotensin, neuromedin U, and somatostatin are also expressed in subpopulations of arcuate neurons. These peptides are all released centrally and act on other neurons at specific receptors. The neuropeptide Y neurons also make the classical inhibitory neurotransmitter GABA.
Peptide signals play a role in information processing that is different to that of conventional neurotransmitters, and many appear to be particularly associated with specific behaviors. For example, oxytocin and vasopressin have striking and specific effects on social behaviors, including maternal behavior and pair bonding.
Generally, peptides act at metabotropic or G-protein-coupled receptors expressed by selective populations of neurons - so peptides act as specific signals between one population of neurons and another. Neurotransmitters generally affect the excitability of other neurons, by depolarising them or by hyperpolarising them. Peptides have much more diverse effects; amongst other things, they can affect gene expression, local blood flow, synaptogenesis, and glial cell morphology. Peptides tend to have prolonged actions, and some have striking effects on behavior.
Neurons very often make both a conventional neurotransmitter (such as glutamate, GABA or dopamine) and one or more neuropeptides. Peptides are generally packaged in large dense-core vesicles, and the co-existing neurotransmitters in small synaptic vesicles. The large dense-core vesicles are often found in all parts of a neuron, including the soma, dendrites, axonal swellings and nerve endings, whereas the small synaptic vesicles are mainly found in clusters at presynaptic locations. Release of the large vesicles and the small vesicles is regulated differentially.
# Examples of neuroactive peptides coexisting with other neurotransmitters
Transmitter names are shown in bold.
Norepinephrine (noradrenaline).
In neurons of the A2 cell group in the nucleus of the solitary tract), norepinephrine co-exists with:
- Galanin
- Enkephalin
- Neuropeptide Y
GABA
- Somatostatin(in the hippocampus)
- Cholecystokinin
- Neuropeptide Y (in the arcuate nucleus)
Acetylcholine
- VIP
- Substance P
Dopamine
- Cholecystokinin
- Neurotensin
Epinephrine (adrenaline)
- Neuropeptide Y
- Neurotensin
Serotonin(5-HT)
- Substance P
- TRH
- Enkephalin
Some neurons make several different peptides. For instance,
Vasopressin co-exists with dynorphin and galanin in magnocellular neurons of the supraoptic nucleus and paraventricular nucleus, and with CRF (in parvocellular neurons of the paraventricular nucleus)
Oxytocin in the supraoptic nucleus co-exists with enkephalin, dynorphin, cocaine-and amphetamine regulated transcript (CART) and cholecystokinin.
# Diabetes Link
A new discovery might have important implications for treatment of diabetes. Researchers at the Toronto Hospital for Sick Children injected capsaicin into NOD mice (Non-obese diabetic mice, a strain that is genetically predisposed to develop the equivalent of type 1 diabetes) to kill the pancreatic sensory nerves. This treatment reduced the development of diabetes in these mice by 80%, suggesting a link between neuropeptides and the development of diabetes. When the researchers injected the pancreas of the diabetic mice with sensory neuropeptide (sP), they were cured of the diabetes for as long as 4 months. Also, insulin resistance (characteristic of type 2 diabetes) was reduced. These research results are in the process of being confirmed, and their applicability in humans will have to be established in the future. Any treatment that could result from this research is probably years away. | https://www.wikidoc.org/index.php/Neuropeptide | |
da678016b2d81aedba8e9e190100418ebd541dff | wikidoc | Neuropilin 1 | Neuropilin 1
Neuropilin-1 is a protein that in humans is encoded by the NRP1 gene. In humans, the neuropilin 1 gene is located at 10p11.22. This is one of two human neuropilins.
# Function
NRP1 is a membrane-bound coreceptor to a tyrosine kinase receptor for both vascular endothelial growth factor (VEGF; MIM 192240) and semaphorin (see SEMA3A; MIM 603961) family members. NRP1 plays versatile roles in angiogenesis, axon guidance, cell survival, migration, and invasion.
# Interactions
Neuropilin 1 has been shown to interact with Vascular endothelial growth factor A.
# Implication in cancer
Neuropilin 1 has been implicated in the vascularization and progression of cancers. NRP1 expression has been shown to be elevated in a number of human patient tumor samples, including brain, prostate, breast, colon, and lung cancers and NRP1 levels are positively correlated with metastasis.
In prostate cancer NRP1 has been demonstrated to be an androgen-suppressed gene, upregulated during the adaptive response of prostate tumors to androgen-targeted therapies and a prognostic biomarker of clinical metastasis and lethal PCa. In vitro and in vivo mouse studies have shown membrane bound NRP1 to be proangiogenic and that NRP1 promotes the vascularization of prostate tumors.
Elevated NRP1 expression is also correlated with the invasiveness of non-small cell lung cancer both in vitro and in vivo.
## Target for cancer therapies
As a co-receptor for VEGF, NRP1 is a potential target for cancer therapies. A synthetic peptide, EG3287, was generated in 2005 and has been shown to block NRP1 activity. EG3287 has been shown to induce apoptosis in tumor cells with elevated NRP1 expression. A patent for EG3287 was filed in 2002 and approved in 2003. As of 2015 there were no clinical trials ongoing or completed for EG3287 as a human cancer therapy.
Soluble NRP1 has the opposite effect of membrane bound NRP1 and has anti-VEGF activity. In vivo mouse studies have shown that injections of sNRP-1 inhibits progression of acute myeloid leukemia in mice. | Neuropilin 1
Neuropilin-1 is a protein that in humans is encoded by the NRP1 gene.[1][2][3] In humans, the neuropilin 1 gene is located at 10p11.22. This is one of two human neuropilins.
# Function
NRP1 is a membrane-bound coreceptor to a tyrosine kinase receptor for both vascular endothelial growth factor (VEGF; MIM 192240) and semaphorin (see SEMA3A; MIM 603961) family members. NRP1 plays versatile roles in angiogenesis, axon guidance, cell survival, migration, and invasion.[supplied by OMIM][3]
# Interactions
Neuropilin 1 has been shown to interact with Vascular endothelial growth factor A.[1][4]
# Implication in cancer
Neuropilin 1 has been implicated in the vascularization and progression of cancers. NRP1 expression has been shown to be elevated in a number of human patient tumor samples, including brain, prostate, breast, colon, and lung cancers and NRP1 levels are positively correlated with metastasis.[5][6][7][8][9][10]
In prostate cancer NRP1 has been demonstrated to be an androgen-suppressed gene, upregulated during the adaptive response of prostate tumors to androgen-targeted therapies and a prognostic biomarker of clinical metastasis and lethal PCa.[5] In vitro and in vivo mouse studies have shown membrane bound NRP1 to be proangiogenic and that NRP1 promotes the vascularization of prostate tumors.[11]
Elevated NRP1 expression is also correlated with the invasiveness of non-small cell lung cancer both in vitro and in vivo.[10]
## Target for cancer therapies
As a co-receptor for VEGF, NRP1 is a potential target for cancer therapies. A synthetic peptide, EG3287, was generated in 2005 and has been shown to block NRP1 activity.[12] EG3287 has been shown to induce apoptosis in tumor cells with elevated NRP1 expression.[12] A patent for EG3287 was filed in 2002 and approved in 2003.[13] As of 2015 there were no clinical trials ongoing or completed for EG3287 as a human cancer therapy.
Soluble NRP1 has the opposite effect of membrane bound NRP1 and has anti-VEGF activity. In vivo mouse studies have shown that injections of sNRP-1 inhibits progression of acute myeloid leukemia in mice.[14] | https://www.wikidoc.org/index.php/Neuropilin_1 | |
66e2ab2393982d2ab2fbb51deed7bb1a5c6e0872 | wikidoc | Neurotrophin | Neurotrophin
Assistant Editor-in-Chief: Nelofar Adnan, M.D.
# Overview
Neurotrophins, also called "neurotrophic factors", are a family of protein which induce the survival of neurons. They belong to a family of growth factors, secreted proteins usually found in the blood stream which are capable of signaling particular cells to survive, differentiate, or grow. Neurotrophic factors are secreted by target tissue and act by preventing the associated neuron from initiating programmed cell death - thus allowing the neurons to survive. Neurotrophins also induce differentiation of progenitor cells, to form neurons.
The neurotrophin family includes nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-1 (NT-1), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4).
# Receptors
There are two classes of receptors, p75 and the "Trk" family of Tyrosine kinases receptors.
- p75 is a low affinity neurotrophin receptor, to which all neurotrophins bind.
- The Trk family include TrkA, TrkB, and TrkC, and will only bind with specific neurotrophins, but with a much higher affinity. The Trks mediate the functional signals of the neurotrophins.
# Nerve growth factor
Nerve growth factor (NGF), the prototypical growth factor, is a protein secreted by a neuron's target. NGF is critical for the survival and maintenance of sympathetic and sensory neurons. NGF is released from the target cells, binds to and activates its high affinity receptor TrkA, and is internalized into the responsive neuron. The NGF/TrkA complex is subsequently trafficked back to the cell body. This movement of NGF from axon tip to soma is thought to be involved in the long-distance signaling of neurons.
# Brain-derived neurotrophic factor
Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor found originally in the brain, but also found in the periphery. More specifically, it is a protein which has activity on certain neurons of the central nervous system and the peripheral nervous system; it helps to support the survival of existing neurons, and encourage the growth and differentiation of new neurons and synapses through axonal and dendritic sprouting. In the brain, it is active in the hippocampus, cortex, cerebellum, and basal forebrain—areas vital to learning, memory, and higher thinking. BDNF was the second neurotrophic factor to be characterized, after NGF and before neurotrophin-3.
Although the vast majority of neurons in the mammalian brain are formed prenatally, parts of the adult brain retain the ability to grow new neurons from neural stem cells; a process known as neurogenesis. Neurotrophins are chemicals that help to stimulate and control neurogenesis, BDNF being one of the most active. Mice born without the ability to make BDNF suffer developmental defects in the brain and sensory nervous system, and usually die soon after birth, suggesting that BDNF plays an important role in normal neural development.
Despite its name, BDNF is actually found in a range of tissue and cell types, not just the brain. Expression can be seen in the retina, the CNS, motor neurons, the kidneys, and the prostate.Neurotrophin self-production by an individual is described in "Keep Your Brain Alive" Workman Publishing 1999
# Neurotrophin-1
Neurotrophin-1 (NT-1) is also known as "B cell-stimulating factor-3" (BSF-3) or "cardiotrophin-like cytokine factor 1" (CLCF1), and is a cytokine belonging to the interleukin-6 family. It is a secreted protein, found predominantly in lymph nodes and spleen, which contains 225 amino acids with a molecular mass of 22 kDa in its mature form. It is closely related to other proteins called cardiotrophin-1 and ciliary neurotrophic factor.
NNT-1/BSF-3 induces tyrosine phosphorylation of the IL-6 receptor common subunit glycoprotein 130 (gp130), leukemia inhibitory factor receptor beta, and the transcription factor STAT3. It has been implicated in the induction of IL-1 (via induction of corticosterone and IL-6) and serum amyloid A, and in B cell hyperplasia. This cytokine is capable of B cell activation via gp130 receptor stimulation.
# Neurotrophin-3
Neurotrophin-3, or NT-3, is a neurotrophic factor, in the NGF-family of neurotrophins. It is a protein growth factor which has activity on certain neurons of the peripheral and central nervous system; it helps to support the survival and differentiation of existing neurons, and encourages the growth and differentiation of new neurons and synapses. NT-3 was the third neurotrophic factor to be characterized, after NGF and BDNF.
Although the vast majority of neurons in the mammalian brain are formed prenatally, parts of the adult brain retain the ability to grow new neurons from neural stem cells; a process known as neurogenesis. Neurotrophins are chemicals that help to stimulate and control neurogenesis. NT-3 is unique in the number of neurons it can potentially stimulate, given its ability to activate two of the receptor tyrosine kinase neurotrophin receptors (TrkC and TrkB - see below). Mice born without the ability to make NT-3 have loss of proprioceptive and subsets of mechanoreceptive sensory neurons.
Interestingly, anti-depressant drugs produce behavioural changes mainly through gradual effect on BDNF and desensitisement of autoreceptors.
# Neurotrophin-4
Neurotrophin-4 (NT-4) like BDNF, is a neurotrophic factor that signals predominantly through the TrkB receptor tyrosine kinase. It is also known as NT4, NT5, NTF4, and NT-4/5. | Neurotrophin
Assistant Editor-in-Chief: Nelofar Adnan, M.D. [1]
# Overview
Neurotrophins, also called "neurotrophic factors", are a family of protein which induce the survival of neurons. They belong to a family of growth factors, secreted proteins usually found in the blood stream which are capable of signaling particular cells to survive, differentiate, or grow. Neurotrophic factors are secreted by target tissue and act by preventing the associated neuron from initiating programmed cell death - thus allowing the neurons to survive. Neurotrophins also induce differentiation of progenitor cells, to form neurons.
The neurotrophin family includes nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-1 (NT-1), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4).
# Receptors
There are two classes of receptors, p75 and the "Trk" family of Tyrosine kinases receptors.
- p75 is a low affinity neurotrophin receptor, to which all neurotrophins bind.
- The Trk family include TrkA, TrkB, and TrkC, and will only bind with specific neurotrophins, but with a much higher affinity. The Trks mediate the functional signals of the neurotrophins.
# Nerve growth factor
Nerve growth factor (NGF), the prototypical growth factor, is a protein secreted by a neuron's target. NGF is critical for the survival and maintenance of sympathetic and sensory neurons. NGF is released from the target cells, binds to and activates its high affinity receptor TrkA, and is internalized into the responsive neuron. The NGF/TrkA complex is subsequently trafficked back to the cell body. This movement of NGF from axon tip to soma is thought to be involved in the long-distance signaling of neurons.
# Brain-derived neurotrophic factor
Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor found originally in the brain, but also found in the periphery. More specifically, it is a protein which has activity on certain neurons of the central nervous system and the peripheral nervous system; it helps to support the survival of existing neurons, and encourage the growth and differentiation of new neurons and synapses through axonal and dendritic sprouting. In the brain, it is active in the hippocampus, cortex, cerebellum, and basal forebrain—areas vital to learning, memory, and higher thinking. BDNF was the second neurotrophic factor to be characterized, after NGF and before neurotrophin-3.
Although the vast majority of neurons in the mammalian brain are formed prenatally, parts of the adult brain retain the ability to grow new neurons from neural stem cells; a process known as neurogenesis. Neurotrophins are chemicals that help to stimulate and control neurogenesis, BDNF being one of the most active. Mice born without the ability to make BDNF suffer developmental defects in the brain and sensory nervous system, and usually die soon after birth, suggesting that BDNF plays an important role in normal neural development.
Despite its name, BDNF is actually found in a range of tissue and cell types, not just the brain. Expression can be seen in the retina, the CNS, motor neurons, the kidneys, and the prostate.Neurotrophin self-production by an individual is described in "Keep Your Brain Alive" Workman Publishing 1999
# Neurotrophin-1
Neurotrophin-1 (NT-1) is also known as "B cell-stimulating factor-3" (BSF-3) or "cardiotrophin-like cytokine factor 1" (CLCF1), and is a cytokine belonging to the interleukin-6 family. It is a secreted protein, found predominantly in lymph nodes and spleen, which contains 225 amino acids with a molecular mass of 22 kDa in its mature form. It is closely related to other proteins called cardiotrophin-1 and ciliary neurotrophic factor.
NNT-1/BSF-3 induces tyrosine phosphorylation of the IL-6 receptor common subunit glycoprotein 130 (gp130), leukemia inhibitory factor receptor beta, and the transcription factor STAT3. It has been implicated in the induction of IL-1 (via induction of corticosterone and IL-6) and serum amyloid A, and in B cell hyperplasia. This cytokine is capable of B cell activation via gp130 receptor stimulation.[1]
# Neurotrophin-3
Neurotrophin-3, or NT-3, is a neurotrophic factor, in the NGF-family of neurotrophins. It is a protein growth factor which has activity on certain neurons of the peripheral and central nervous system; it helps to support the survival and differentiation of existing neurons, and encourages the growth and differentiation of new neurons and synapses. NT-3 was the third neurotrophic factor to be characterized, after NGF and BDNF.
Although the vast majority of neurons in the mammalian brain are formed prenatally, parts of the adult brain retain the ability to grow new neurons from neural stem cells; a process known as neurogenesis. Neurotrophins are chemicals that help to stimulate and control neurogenesis. NT-3 is unique in the number of neurons it can potentially stimulate, given its ability to activate two of the receptor tyrosine kinase neurotrophin receptors (TrkC and TrkB - see below). Mice born without the ability to make NT-3 have loss of proprioceptive and subsets of mechanoreceptive sensory neurons.
Interestingly, anti-depressant drugs produce behavioural changes mainly through gradual effect on BDNF and desensitisement of autoreceptors.
# Neurotrophin-4
Neurotrophin-4 (NT-4) like BDNF, is a neurotrophic factor that signals predominantly through the TrkB receptor tyrosine kinase. It is also known as NT4, NT5, NTF4, and NT-4/5.[2] | https://www.wikidoc.org/index.php/Neurotrophic_factor | |
41b3a7b571a32f0b9f362b486181c4b72e84926f | wikidoc | Neutrophilia | Neutrophilia
# Overview
Neutrophilia (also called neutrophil leukocytosis or occasionally neutrocytosis) is leukocytosis of neutrophils, that is, a high number of neutrophil granulocytes in the blood.
A "left shift" refers to the presence of increased proportions of younger, less well differentiated neutrophils and neutrophil-precursor cells in the blood. This generally reflects early or premature release of myeloid cells from the bone marrow, the site where neutrophils are generated. A severe neutrophilia with left shift is referred to as a leukemoid reaction. The leukocyte alkaline phosphatase (LAP) score, which refers to the amount of alkaline phosphatase per neutrophil, will increase. In a severe infection, toxic granulation changes happen to the neutrophils.
This can resemble Pelger-Huet anomaly.
# Historical Perspective
# Classification
# Pathophysiology
# Causes
Neutrophil are the primary white blood cells that respond to a bacterial infection, so the most common cause of neutrophilia is a bacterial infection, especially pyogenic infections.
Neutrophils are also increased in any acute inflammation, so will be raised after a heart attack, other infarct or burns.
Some drugs, such as prednisone, have the same effect as cortisol and adrenaline (epinephrine), causing marginated neutrophils to enter the blood stream. Nervousness will very slightly raise the neutrophil count because of this effect.
A neutrophilia might also be the result of a malignancy. Chronic myelogenous leukemia (CML or chronic myeloid leukaemia) is a disease where the blood cells proliferate out of control. These cells may be neutrophils. Neutrophilia can also be caused by appendicitis and splenectomy.
Primary neutrophilia can additionally be a result of Leukocyte adhesion deficiency.
# Differentiating Neutrophilia from Other Diseases
# Epidemiology and Demographics
# Risk Factors
# Screening
# Natural History, Complications, and Prognosis
## Natural History
## Complications
## Prognosis
# Diagnosis
## Diagnostic Criteria
## History and Symptoms
## Physical Examination
## Laboratory Findings
## Imaging Findings
## Other Diagnostic Studies
# Treatment
## Medical Therapy
## Surgery
## Prevention | Neutrophilia
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Neutrophilia (also called neutrophil leukocytosis or occasionally neutrocytosis) is leukocytosis of neutrophils, that is, a high number of neutrophil granulocytes in the blood.[1]
A "left shift" refers to the presence of increased proportions of younger, less well differentiated neutrophils and neutrophil-precursor cells in the blood. This generally reflects early or premature release of myeloid cells from the bone marrow, the site where neutrophils are generated. A severe neutrophilia with left shift is referred to as a leukemoid reaction. The leukocyte alkaline phosphatase (LAP) score, which refers to the amount of alkaline phosphatase per neutrophil, will increase. In a severe infection, toxic granulation changes happen to the neutrophils.
This can resemble Pelger-Huet anomaly.[2][3]
# Historical Perspective
# Classification
# Pathophysiology
# Causes
Neutrophil are the primary white blood cells that respond to a bacterial infection, so the most common cause of neutrophilia is a bacterial infection, especially pyogenic infections.[4]
Neutrophils are also increased in any acute inflammation, so will be raised after a heart attack,[4] other infarct or burns.[4]
Some drugs, such as prednisone, have the same effect as cortisol and adrenaline (epinephrine), causing marginated neutrophils to enter the blood stream. Nervousness will very slightly raise the neutrophil count because of this effect.
A neutrophilia might also be the result of a malignancy. Chronic myelogenous leukemia (CML or chronic myeloid leukaemia) is a disease where the blood cells proliferate out of control. These cells may be neutrophils. Neutrophilia can also be caused by appendicitis and splenectomy.[5]
Primary neutrophilia can additionally be a result of Leukocyte adhesion deficiency.[6]
# Differentiating Neutrophilia from Other Diseases
# Epidemiology and Demographics
# Risk Factors
# Screening
# Natural History, Complications, and Prognosis
## Natural History
## Complications
## Prognosis
# Diagnosis
## Diagnostic Criteria
## History and Symptoms
## Physical Examination
## Laboratory Findings
## Imaging Findings
## Other Diagnostic Studies
# Treatment
## Medical Therapy
## Surgery
## Prevention | https://www.wikidoc.org/index.php/Neutrophilia | |
207df7ecc1a57a0f9e3d09d42ea7fe75943626e7 | wikidoc | Nevus of Ota | Nevus of Ota
# Overview
Nevus of Ota (also known as "congenital melanosis bulbi", "nevus fuscoceruleus ophthalmomaxillaris", "oculodermal melanocytosis",:700 and "Oculomucodermal melanocytosis") is a blue hyperpigmentation that occurs on the face. It was first reported by Dr. M. T. Ota of Japan in 1939.
Nevus of Ota is caused by the entrapment of melanocytes in the upper third of the dermis. It is found on the face unilaterally and involves the first two branches of the trigeminal nerve. The sclera is involved in two-thirds of cases (causing an increased risk of glaucoma). It should not be confused with Mongolian spot, which is a birthmark caused by entrapment of melanocytes in the dermis but is located in the lumbosacral region. Women are nearly five times more likely to be affected than men, and it is rare among caucasian people. Nevus of Ota may not be congenital, and may appear during puberty.
# Diagnosis
## Physcial Examination
### Eye
- Naevus of ota. With permission from Dermatology Atlas.
- Naevus of ota- bilateral type. With permission from Dermatology Atlas.
# Treatment
A Q-switched laser has been successfully used to treat the condition.
Hydroquinone preparations are also helpful in partially treating this condition. | Nevus of Ota
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [3]
# Overview
Nevus of Ota (also known as "congenital melanosis bulbi",[1] "nevus fuscoceruleus ophthalmomaxillaris", "oculodermal melanocytosis",[2]:700 and "Oculomucodermal melanocytosis"[1]) is a blue hyperpigmentation[3] that occurs on the face. It was first reported by Dr. M. T. Ota of Japan in 1939.[4]
Nevus of Ota is caused by the entrapment of melanocytes in the upper third of the dermis. It is found on the face unilaterally and involves the first two branches of the trigeminal nerve. The sclera is involved in two-thirds of cases (causing an increased risk of glaucoma). It should not be confused with Mongolian spot, which is a birthmark caused by entrapment of melanocytes in the dermis but is located in the lumbosacral region. Women are nearly five times more likely to be affected than men, and it is rare among caucasian people.[5][full citation needed] Nevus of Ota may not be congenital, and may appear during puberty.
# Diagnosis
## Physcial Examination
### Eye
- Naevus of ota. With permission from Dermatology Atlas.[6]
- Naevus of ota- bilateral type. With permission from Dermatology Atlas.[6]
# Treatment
A Q-switched laser has been successfully used to treat the condition.[7][8]
Hydroquinone preparations are also helpful in partially treating this condition. | https://www.wikidoc.org/index.php/Nevus_of_Ota | |
ccfc5a16c9644e5b8274549d836c4245488370ec | wikidoc | Nicotinamide | Nicotinamide
# Overview
Nicotinamide, also known as niacinamide, is the amide of niacin (vitamin B(3)) which has the chemical formula C6H6N2O. Niacinamide is a derivative of vitamin B-3 can be used for the treatment of arthritis by aiding the body in its production of cartilage.This product is often used for energy drinks.
Nicotinamide is a water-soluble component of the vitamin B complex group. In vivo, Nicotinamide is incorporated into nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). NAD and NADP function as coenzymes in a wide variety of enzymatic oxidation-reduction reactions essential for tissue respiration, lipid metabolism, and glycogenolysis.
Nicotinamide has demonstrated anti-inflammatory actions which may be of benefit in patients with inflammatory acne vulgaris, including but not limited to, suppression of antigen induced-lymphocytic transformation and inhibition of 3'-5' cyclic AMP phosphodiesterase. Nicotinamide has demonstrated the ability to block the inflammatory actions of iodides known to precipitate or exacerbate inflammatory acne.
Nicotinamide lacks the vasodilator, gastrointestinal, hepatic, and hypolipemic actions of nicotinic acid or niacin. As such nicotinamide has not been shown to produce the flushing, itching and burning sensations of the skin as is commonly seen when large doses of nicotinic acid or niacin are administered orally. | Nicotinamide
Template:Chembox new
# Overview
Nicotinamide, also known as niacinamide, is the amide of niacin (vitamin B(3)) which has the chemical formula C6H6N2O. Niacinamide is a derivative of vitamin B-3 can be used for the treatment of arthritis by aiding the body in its production of cartilage.This product is often used for energy drinks.
Nicotinamide is a water-soluble component of the vitamin B complex group. In vivo, Nicotinamide is incorporated into nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). NAD and NADP function as coenzymes in a wide variety of enzymatic oxidation-reduction reactions essential for tissue respiration, lipid metabolism, and glycogenolysis.
Nicotinamide has demonstrated anti-inflammatory actions which may be of benefit in patients with inflammatory acne vulgaris, including but not limited to, suppression of antigen induced-lymphocytic transformation and inhibition of 3'-5' cyclic AMP phosphodiesterase. Nicotinamide has demonstrated the ability to block the inflammatory actions of iodides known to precipitate or exacerbate inflammatory acne.
Nicotinamide lacks the vasodilator, gastrointestinal, hepatic, and hypolipemic actions of nicotinic acid or niacin. As such nicotinamide has not been shown to produce the flushing, itching and burning sensations of the skin as is commonly seen when large doses of nicotinic acid or niacin are administered orally. | https://www.wikidoc.org/index.php/Niacinamide | |
b48afdc751d0cdf6f96b99f79559c5f0725b4fec | wikidoc | Nicomorphine | Nicomorphine
# Overview
Nicomorphine (Vilan, Subellan, Gevilan, MorZet) is the 3,6-dinicotinate ester of morphine. It is a strong opioid agonist analgesic two to three times as potent as morphine with a side effect profile similar to that of dihydromorphine, morphine, and diamorphine. Nicomorphine was patented as Vilan by Lannacher Heilmittel Ges. m.b.H. of Austria in 1957 and was first synthesized in 1904 either there or at another firm in what was then Austria-Hungary. The hydrochloride salt is available as ampoules of 10 mg/ml solution for injection, 5 mg tablets, and 10 mg suppositories. It is possible that other manufacturers distribute 10 mg tablets and other concentrations of injectable nicomorphine in ampoules and multidose vials. It is used, particularly in the German-speaking countries and elsewhere in Central Europe and some other countries in Europe and the former USSR in particular, for post-operative, cancer, chronic non-malignant and other neuropathic pain. It is commonly used in patient-controlled analgesia (PCA) units. The usual starting dose is 5–10 mg given every 3–5 hours.
The 3,6-diesters of morphine are drugs with more rapid and complete central nervous system penetration due to increased lipid solubility and other structural considerations. The prototype for this subgroup of semi-synthetic opiates is heroin and the group also includes dipropanoylmorphine, diacetyldihydromorphine, disalicylmorphine and others. Whilst this produces an enhanced "bang" when the drug is administered intravenously, it cannot be distinguished from morphine via other routes, although the different side effect profile, including lower incidence of nausea, is very apparent.
# Side effects
Nicomorphine's side effects are similar to those of other opioids and include itching, nausea and respiratory depression. It is considered by doctors to be one of the better analgesics for the comprehensive mitigation of suffering, as opposed to purely clouding the noxious pain stimulus, in the alleviation of chronic pain conditions.
# Legality
Nicomorphine is regulated in much the same fashion as morphine worldwide but is a Schedule I controlled substance in the United States and was never introduced there.
Nicomorphine may appear on rare occasions on the European black market and other channels for unsupervised opioid users. It can be produced as part of a mixture of salts and derivatives of morphine by end users by means of treating morphine with nicotinic anhydride or related chemicals in an analogue of the heroin homebake process.
CAS number of hydrochloride: 35055-78-8
US DEA ACSCN: 9312
Free base conversion ratios of salts:
Nicomorphine Hydrochloride: 0.93 | Nicomorphine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Nicomorphine (Vilan, Subellan, Gevilan, MorZet) is the 3,6-dinicotinate ester of morphine. It is a strong opioid agonist analgesic two to three times as potent as morphine with a side effect profile similar to that of dihydromorphine, morphine, and diamorphine. Nicomorphine was patented as Vilan by Lannacher Heilmittel Ges. m.b.H. of Austria in 1957 and was first synthesized in 1904 either there or at another firm in what was then Austria-Hungary. The hydrochloride salt is available as ampoules of 10 mg/ml solution for injection, 5 mg tablets, and 10 mg suppositories. It is possible that other manufacturers distribute 10 mg tablets and other concentrations of injectable nicomorphine in ampoules and multidose vials. It is used, particularly in the German-speaking countries and elsewhere in Central Europe and some other countries in Europe and the former USSR in particular, for post-operative, cancer, chronic non-malignant and other neuropathic pain. It is commonly used in patient-controlled analgesia (PCA) units. The usual starting dose is 5–10 mg given every 3–5 hours.
The 3,6-diesters of morphine are drugs with more rapid and complete central nervous system penetration due to increased lipid solubility and other structural considerations. The prototype for this subgroup of semi-synthetic opiates is heroin and the group also includes dipropanoylmorphine, diacetyldihydromorphine, disalicylmorphine and others. Whilst this produces an enhanced "bang" when the drug is administered intravenously, it cannot be distinguished from morphine via other routes, although the different side effect profile, including lower incidence of nausea, is very apparent.
# Side effects
Nicomorphine's side effects are similar to those of other opioids and include itching, nausea and respiratory depression. It is considered by doctors to be one of the better analgesics for the comprehensive mitigation of suffering, as opposed to purely clouding the noxious pain stimulus, in the alleviation of chronic pain conditions.[1]
# Legality
Nicomorphine is regulated in much the same fashion as morphine worldwide but is a Schedule I controlled substance in the United States and was never introduced there.
Nicomorphine may appear on rare occasions on the European black market and other channels for unsupervised opioid users. It can be produced as part of a mixture of salts and derivatives of morphine by end users by means of treating morphine with nicotinic anhydride or related chemicals in an analogue of the heroin homebake process.
CAS number of hydrochloride: 35055-78-8
US DEA ACSCN: 9312
Free base conversion ratios of salts:
Nicomorphine Hydrochloride: 0.93 | https://www.wikidoc.org/index.php/Nicomorphine | |
e9367a98cfbb2b7cd808d0ce7fb0a9e2f3f0f2f0 | wikidoc | Nicotine gum | Nicotine gum
Nicotine gum is a type of chewing gum that delivers nicotine to the body. It is used as an aid in smoking cessation and in quitting smokeless tobacco. The nicotine is delivered to the bloodstream via absorption by the tissues of the mouth.
It is currently available over-the-counter in the US. The pieces are usually available in individual foil packages and come in various flavors including orange, and mint. Each piece typically contains 2 or 4 mg of nicotine (roughly the nicotine content of 1 or 2 cigarettes) with the appropriate dosage depending on the smoking habits of the user. Popular brands include Nicorette and Nicotinell in the UK.
Alternative nicotine replacement products include the nicotine patch, nicotine pastilles/lozenges and the nicotine inhaler.
# Usage
The gum is first chewed until it is soft and a tingly sensation and/or peppery taste is noticed, after which it is pressed between the cheek and gums. When the tingly sensation stops, the gum is chewed again, and then pinched between the cheek and gums in a different place in the mouth. This is continued until the gum is depleted of nicotine (about 30 minutes).
# Availability
Various regimes exist worldwide as to the accessibility of these medications. Originally (in the early 1990s) they were sold only in the USA by prescription.
In the USA, they are currently available at drugstores over-the-counter subject to the same restrictions on underage purchases as tobacco. Usually the purchaser is directed to the pharmacist but in other cases the display of the nicotine therapy products is adjacent to the cigarette display. In some locations, nicotine gum can be simply purchased off the shelf. At locations such as large retailers, where self-checkout lines exist, the product can be purchased without human contact, thus granting the possibility of abuse by children or recreational users.
In Hong Kong, the large chain "chemist" (drugstore) shops usually, but not always, require the purchaser of the stronger therapy (4 mg dose) to sign a register with passport number or Hong Kong ID.
In Paris, the widest and least expensive variety of these aids seems to be available and while underage sales are strictly prohibited and this prohibition is enforced, sales to adults are least restricted and the largest range of alternative therapies appears to be available.
The per-dose cost in the USA is about 40 (US) cents. The per-dose cost in Hong Kong is 40 cents. This means that the price of nicotine gum often exceeds that of the cigarettes it is designed to replace, depending on the price of cigarettes in that particular locale. In counties where the price of cigarettes has been significantly augmented by progressively higher taxes, nicotine gum may in fact be a cheaper alternative. Additionally, several generic brands have appeared in recent years in much reduced cost than the nominal name brands.Nicotine is an addictive element in cigarettes. Behavioral, social, and self-image components of cigarette use also add to their addictive power. For instance, one useful technique for stopping smoking emphasises learning to concentrate on breathing differently whenever the craving for a cigarette arises. A potential for addiction to nicotine gum exists.
The drug companies' studies indicate that changing to nicotine gum leads people to quit both the gum and smoking. For many, the use of the nicotine replacement gum becomes chronic as well. Although much safer healthwise than smoking (significant evidence exists for a powerful neuroprotective effect from nicotine -alone-: e.g., a lower chance of acquiring Alzheimer's or Parkinsonian diseases), years of nicotine gum use will nevertheless still cost the addicted user many thousands of dollars.
Nicotine gum may also drive the user to "dip" tobacco because it replaces the activity of "lighting up" with a reinforced oral self-dosage, and when the nicotine gum user runs out of the gum (or cannot afford its prices, which are very high in the USA) he may turn to hazardous forms of "dip" or chewing tobacco. This is less likely to be a problem for residents of the United Kingdom where nicotine gum is also available on prescription from general practitioners, free of charge for users on low incomes and at the subsidised National Health Service prescription charge for other users.
# Risks
## Side effects
Two unpleasant symptoms noticed by new users and by existing users who make excessive use of the gum in times of stress are hiccups and a perceived constriction of the throat muscles. Gum chewing is also considered uncultured in many countries; this problem can be addressed by using pastille, although the pastille is not always as available. | Nicotine gum
Template:Pov
Nicotine gum is a type of chewing gum that delivers nicotine to the body. It is used as an aid in smoking cessation and in quitting smokeless tobacco. The nicotine is delivered to the bloodstream via absorption by the tissues of the mouth.
It is currently available over-the-counter in the US. The pieces are usually available in individual foil packages and come in various flavors including orange, and mint. Each piece typically contains 2 or 4 mg of nicotine (roughly the nicotine content of 1 or 2 cigarettes) with the appropriate dosage depending on the smoking habits of the user. Popular brands include Nicorette and Nicotinell in the UK.
Alternative nicotine replacement products include the nicotine patch, nicotine pastilles/lozenges and the nicotine inhaler.
# Usage
The gum is first chewed until it is soft and a tingly sensation and/or peppery taste is noticed, after which it is pressed between the cheek and gums. When the tingly sensation stops, the gum is chewed again, and then pinched between the cheek and gums in a different place in the mouth. This is continued until the gum is depleted of nicotine (about 30 minutes).
# Availability
Various regimes exist worldwide as to the accessibility of these medications. Originally (in the early 1990s) they were sold only in the USA by prescription.
In the USA, they are currently available at drugstores over-the-counter subject to the same restrictions on underage purchases as tobacco. Usually the purchaser is directed to the pharmacist but in other cases the display of the nicotine therapy products is adjacent to the cigarette display. In some locations, nicotine gum can be simply purchased off the shelf. At locations such as large retailers, where self-checkout lines exist, the product can be purchased without human contact, thus granting the possibility of abuse by children or recreational users.
In Hong Kong, the large chain "chemist" (drugstore) shops usually, but not always, require the purchaser of the stronger therapy (4 mg dose) to sign a register with passport number or Hong Kong ID.
In Paris, the widest and least expensive variety of these aids seems to be available and while underage sales are strictly prohibited and this prohibition is enforced, sales to adults are least restricted and the largest range of alternative therapies appears to be available.
The per-dose cost in the USA is about 40 (US) cents. The per-dose cost in Hong Kong is 40 cents. This means that the price of nicotine gum often exceeds that of the cigarettes it is designed to replace, depending on the price of cigarettes in that particular locale. In counties where the price of cigarettes has been significantly augmented by progressively higher taxes, nicotine gum may in fact be a cheaper alternative. Additionally, several generic brands have appeared in recent years in much reduced cost than the nominal name brands.Nicotine is an addictive element in cigarettes. Behavioral, social, and self-image components of cigarette use also add to their addictive power. For instance, one useful technique for stopping smoking emphasises learning to concentrate on breathing differently whenever the craving for a cigarette arises. A potential for addiction to nicotine gum exists.
The drug companies' studies indicate that changing to nicotine gum leads people to quit both the gum and smoking. For many, the use of the nicotine replacement gum becomes chronic as well. Although much safer healthwise than smoking (significant evidence exists for a powerful neuroprotective effect from nicotine -alone-: e.g., a lower chance of acquiring Alzheimer's or Parkinsonian diseases), years of nicotine gum use will nevertheless still cost the addicted user many thousands of dollars.
Nicotine gum may also drive the user to "dip" tobacco because it replaces the activity of "lighting up" with a reinforced oral self-dosage, and when the nicotine gum user runs out of the gum (or cannot afford its prices, which are very high in the USA) he may turn to hazardous forms of "dip" or chewing tobacco. This is less likely to be a problem for residents of the United Kingdom where nicotine gum is also available on prescription from general practitioners, free of charge for users on low incomes and at the subsidised National Health Service prescription charge for other users.
# Risks
## Side effects
Two unpleasant symptoms noticed by new users and by existing users who make excessive use of the gum in times of stress[citation needed] are hiccups[1] and a perceived constriction of the throat muscles. Gum chewing is also considered uncultured in many countries; this problem can be addressed by using pastille, although the pastille is not always as available.
# External links
- Medline Plus entry
- YourFirstStop.org | https://www.wikidoc.org/index.php/Nicotine_gum | |
74cd2b973ac05219997c0e479355dec7518846bf | wikidoc | Night terror | Night terror
# Overview
A night terror, also known as pavor nocturnus, is a parasomnia sleep disorder characterized by extreme terror and a temporary inability to regain full consciousness. The subject wakes abruptly from slow-wave sleep, with waking usually accompanied by gasping, moaning, or screaming. It is often impossible to fully awaken the person, and after the episode the subject normally settles back to sleep without waking. A night terror can rarely be recalled by the subject. They typically occur during non-rapid eye movement sleep.
# Night terrors versus nightmares
Night terrors are distinct from nightmares in several key ways. First, the subject is not fully awake when roused, and even when efforts are made to awaken the sleeper, he/she may continue to experience the night terror for ten to twenty minutes. Unlike nightmares, which occur during REM sleep, night terrors occur during slow-wave sleep, the deepest level of NREM sleep. Even if awakened, the subject often cannot remember the episode except for a sense of panic, while nightmares usually can be easily recalled.
Unlike nightmares, which are frequently dreams of a frightening nature, night terrors are not dreams. Usually there is no situation or event (scary or otherwise) that is dreamt, but rather the emotion of fear itself is felt. Often, this is coupled with tension and apprehension without any distinct sounds or visual imagery, although sometimes a vague object of fear is identified by the sufferer. These emotions, generally without a focusing event or scenario, increase emotions in a cumulative effect. The lack of a dream itself leaves those awakened from a night terror in a state of disorientation much more severe than that caused by a normal nightmare. This can include a short period of amnesia during which the subjects may be unable to recall their names, locations, ages, or any other identifying features of themselves.
# In children
Children from age two to six are most prone to night terrors, and they affect about fifteen percent of all children, (although people of any age may experience them). Episodes may reoccur for a couple of weeks then suddenly disappear. The symptoms also tend to be different, like the child being able to recall the experience, and while nearly arisen, hallucinate. Strong evidence has shown that a predisposition to night terrors and other parasomniac disorders can be passed genetically. Though there are a multitude of triggers; emotional stress during the previous day and a high fever are thought to precipitate most episodes. Also, Nyquil and Dayquil may increase risk of night terrors. Ensuring that the right amount of sleep is gained is an important factor.
Special consideration must be used when the subject suffers from narcolepsy. They may be linked.
# In adults
Though the symptoms of night terrors in adolescents and adults are similar, the etiology, prognosis and treatment are qualitatively different. Adult night terrors are much less common, occasionally trauma-based rather than genetic, chronic, and often respond to treatment in the form of psychotherapy and antidepressant medication. There is some evidence of a link between adult night terrors and hypoglycemia.
In addition to night terrors, some adult night terror sufferers have many of the characteristics of abused and depressed individuals including inhibition of aggression, self-directed anger, passivity, anxiety, impaired memory,, and the ability to ignore pain.. | Night terror
For patient information click here
Template:DiseaseDisorder infobox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
A night terror, also known as pavor nocturnus, is a parasomnia sleep disorder characterized by extreme terror and a temporary inability to regain full consciousness. The subject wakes abruptly from slow-wave sleep, with waking usually accompanied by gasping, moaning, or screaming. It is often impossible to fully awaken the person, and after the episode the subject normally settles back to sleep without waking. A night terror can rarely be recalled by the subject. They typically occur during non-rapid eye movement sleep.
# Night terrors versus nightmares
Night terrors are distinct from nightmares in several key ways. First, the subject is not fully awake when roused, and even when efforts are made to awaken the sleeper, he/she may continue to experience the night terror for ten to twenty minutes. Unlike nightmares, which occur during REM sleep, night terrors occur during slow-wave sleep, the deepest level of NREM sleep. Even if awakened, the subject often cannot remember the episode except for a sense of panic, while nightmares usually can be easily recalled.
Unlike nightmares, which are frequently dreams of a frightening nature, night terrors are not dreams. Usually there is no situation or event (scary or otherwise) that is dreamt, but rather the emotion of fear itself is felt. Often, this is coupled with tension and apprehension without any distinct sounds or visual imagery, although sometimes a vague object of fear is identified by the sufferer. These emotions, generally without a focusing event or scenario, increase emotions in a cumulative effect. The lack of a dream itself leaves those awakened from a night terror in a state of disorientation much more severe than that caused by a normal nightmare. This can include a short period of amnesia during which the subjects may be unable to recall their names, locations, ages, or any other identifying features of themselves.
# In children
Children from age two to six are most prone to night terrors, and they affect about fifteen percent of all children,[1] (although people of any age may experience them). Episodes may reoccur for a couple of weeks then suddenly disappear. The symptoms also tend to be different, like the child being able to recall the experience, and while nearly arisen, hallucinate. Strong evidence has shown that a predisposition to night terrors and other parasomniac disorders can be passed genetically. Though there are a multitude of triggers; emotional stress during the previous day and a high fever are thought to precipitate most episodes. Also, Nyquil and Dayquil may increase risk of night terrors. Ensuring that the right amount of sleep is gained is an important factor.
Special consideration must be used when the subject suffers from narcolepsy. They may be linked.
# In adults
Though the symptoms of night terrors in adolescents and adults are similar, the etiology, prognosis and treatment are qualitatively different. Adult night terrors are much less common, occasionally trauma-based rather than genetic, chronic, and often respond to treatment in the form of psychotherapy and antidepressant medication. There is some evidence of a link between adult night terrors and hypoglycemia.
In addition to night terrors, some adult night terror sufferers have many of the characteristics of abused and depressed individuals including inhibition of aggression,[2] self-directed anger,[2] passivity,[3] anxiety, impaired memory,[4], and the ability to ignore pain.[5]. | https://www.wikidoc.org/index.php/Night_terror | |
3f37933b61052e211d37062d052982731041ca9a | wikidoc | Nitazoxanide | Nitazoxanide
# Disclaimer
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# Overview
Nitazoxanide is an anti-infective agent that is FDA approved for the treatment of diarrhea caused by Giardia lamblia or Cryptosporidium parvum. Common adverse reactions include abdominal pain, diarrhea, nausea, vomiting,headache.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
# Indications
Diarrhea caused by Giardia lamblia or Cryptosporidium parvum:
- Alinia for Oral Suspension (patients 1 year of age and older) and Alinia Tablets (patients 12 years and older) are indicated for the treatment of diarrhea caused by Giardia lamblia or Cryptosporidium parvum.
- Alinia for Oral Suspension and Alinia Tablets have not been shown to be superior to placebo for the treatment of diarrhea caused by Cryptosporidium parvum in HIV-infected or immunodeficient patients
# Dosage
DIRECTIONS FOR MIXING ALINIA FOR ORAL SUSPENSION
- Prepare a suspension at time of dispensing as follows: The amount of water required for preparation of the suspension is 48 mL. Tap bottle until all powder flows freely. Add approximately one-half of the total amount of water required for reconstitution and shake vigorously to suspend powder. Add remainder of water and again shake vigorously.
- The container should be kept tightly closed, and the suspension should be shaken well before each administration. The suspension may be stored for 7 days, after which any unused portion must be discarded.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Nitazoxanide in adult patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Nitazoxanide in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
# Indications
Diarrhea caused by Giardia lamblia or Cryptosporidium parvum:
- Alinia for Oral Suspension (patients 1 year of age and older) and Alinia Tablets (patients 12 years and older) are indicated for the treatment of diarrhea caused by Giardia lamblia or Cryptosporidium parvum.
- Alinia for Oral Suspension and Alinia Tablets have not been shown to be superior to placebo for the treatment of diarrhea caused by Cryptosporidium parvum in HIV-infected or immunodeficient patients
# Dosage
DIRECTIONS FOR MIXING ALINIA FOR ORAL SUSPENSION
- Prepare a suspension at time of dispensing as follows: The amount of water required for preparation of the suspension is 48 mL. Tap bottle until all powder flows freely. Add approximately one-half of the total amount of water required for reconstitution and shake vigorously to suspend powder. Add remainder of water and again shake vigorously.
- The container should be kept tightly closed, and the suspension should be shaken well before each administration. The suspension may be stored for 7 days, after which any unused portion must be discarded.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Nitazoxanide in pediatric patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Nitazoxanide in pediatric patients.
# Contraindications
- Alinia Tablets and Alinia for Oral Suspension are contraindicated in patients with a prior hypersensitivity to nitazoxanide or any other ingredient in the formulations.
# Warnings
- There is limited information regarding Warning of Nitazoxanide in pediatric patients.
# Adverse Reactions
## Clinical Trials Experience
- Alinia Tablets: In controlled and uncontrolled clinical studies of 1,657 HIV-uninfected patients age 12 years and older who received various dosage regimens of Alinia Tablets, the most common adverse events reported regardless of causality assessment were: abdominal pain (6.6%), diarrhea (4.2%), headache (3.1%) and nausea (3.0%). In placebo-controlled clinical trials using the recommended dose, the rates of occurrence of these events did not differ significantly from those of the placebo. In placebo-controlled trials of HIV-uninfected patients age 12 years and older who received Alinia Tablets for the treatment of diarrhea caused by Giardia lamblia or Cryptosporidium parvum, less than 1% of patients discontinued therapy because of an adverse event.
- Adverse events occurring in less than 1% of the patients age 12 years and older participating in clinical trials of Alinia Tablets are listed below:
- Body as a Whole: asthenia, fever, pain, allergic reaction, pelvic pain, back pain, chills, chills and fever, flu syndrome.
- Nervous System: dizziness, somnolence, insomnia, tremor, hypesthesia.
- Digestive System: vomiting, dyspepsia, anorexia, flatulence, constipation, dry mouth, thirst.
- Urogenital System: discolored urine, dysuria, amenorrhea, metrorrhagia, kidney pain, edema labia.
- Metabolic & Nutrition: increased SGPT.
- Hemic & Lymphatic Systems: anemia, leukocytosis.
- Skin: rash, pruritus.
- Special Senses: eye discoloration, ear ache.
- Respiratory System: epistaxis, lung disease, pharyngitis.
- Cardiovascular System: tachycardia, syncope, hypertension.
- Muscular System: myalgia, leg cramps, spontaneous bone fracture.
Alinia for Oral Suspension:
- In controlled and uncontrolled clinical studies of 613 HIV-uninfected pediatric patients who received Alinia for Oral Suspension, the most frequent adverse events reported regardless of causality assessment were: abdominal pain (7.8%), diarrhea (2.1%), vomiting (1.1%) and headache (1.1%). These were typically mild and transient in nature. In placebo-controlled clinical trials, the rates of occurrence of these events did not differ significantly from those of the placebo. None of the 613 pediatric patients discontinued therapy because of adverse events.
- Adverse events occurring in less than 1% of the pediatric patients participating in clinical trials of Alinia for Oral Suspension are listed below:
- Digestive System: nausea, anorexia, flatulence, appetite increase, enlarged salivary glands.
- Body as a Whole: fever, infection, malaise.
- Metabolic & Nutrition: increased creatinine, increased SGPT.
- Skin: pruritus, sweat.
- Special Senses: eye discoloration (pale yellow).
- Respiratory System: rhinitis.
- Nervous System: dizziness.
- Urogenital System: discolored urine.
- The adverse events seen in adult patients treated with Alinia for Oral Suspension were similar to those observed in adult patients treated with Alinia Tablets.
## Postmarketing Experience
- There is limited information regarding Postmarketing Experience of Nitazoxanide in the drug label.
# Drug Interactions
- Tizoxanide is highly bound to plasma protein (>99.9%). Therefore, caution should be used when administering nitazoxanide concurrently with other highly plasma protein-bound drugs with narrow therapeutic indices, as competition for binding sites may occur (e.g., warfarin). In vitro metabolism studies have demonstrated that tizoxanide has no significant inhibitory effect on cytochrome P450 enzymes. Although no drug-drug interaction studies have been conducted in vivo, it is expected that no significant interaction would occur when nitazoxanide is co-administered with drugs that either are metabolized by or inhibit cytochrome P450 enzymes.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category B: Reproduction studies have been performed at doses up to 3,200 mg/kg/day in rats (approximately 26 times the clinical adult dose adjusted for body surface area) and 100 mg/kg/day in rabbits (approximately 2 times the clinical adult dose adjusted for surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to nitazoxanide. There are, however, no adequate and well-controlled studies in pregnant women.
Pregnancy Category (AUS):
- There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Nitazoxanide in women who are pregnant.
### Labor and Delivery
- There is no FDA guidance on use of Nitazoxanide during labor and delivery.
### Nursing Mothers
- It is not known whether nitazoxanide is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when nitazoxanide is administered to a nursing woman.
### Pediatric Use
- A single Alinia Tablet contains a greater amount of nitazoxanide than is recommended for pediatric dosing and should therefore not be used in pediatric patients 11 years or younger. Alinia for Oral Suspension should be used for dosing nitazoxanide in pediatric patients.
- Safety and effectiveness of Alinia for Oral Suspension in pediatric patients less than 1 year of age have not been studied.
### Geriatic Use
- Clinical studies of Alinia Tablets and Alinia for Oral Suspension did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in elderly patients should be considered when prescribing Alinia Tablets and Alinia for Oral Suspension. As stated in the precautions section, this therapy must be administered with caution to patients with renal and or hepatic impairment.
### Gender
- There is no FDA guidance on the use of Nitazoxanide with respect to specific gender populations.
### Race
- There is no FDA guidance on the use of Nitazoxanide with respect to specific racial populations.
### Renal Impairment
- There is no FDA guidance on the use of Nitazoxanide in patients with renal impairment.
### Hepatic Impairment
- There is no FDA guidance on the use of Nitazoxanide in patients with hepatic impairment.
### Females of Reproductive Potential and Males
- There is no FDA guidance on the use of Nitazoxanide in women of reproductive potentials and males.
### Immunocompromised Patients
- There is no FDA guidance one the use of Nitazoxanide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- There is limited information regarding Monitoring of Nitazoxanide in the drug label.
# IV Compatibility
- There is limited information regarding IV Compatibility of Nitazoxanide in the drug label.
# Overdosage
- Information on nitazoxanide overdosage is not available. In acute studies in rodents and dogs, the oral LD50 was higher than 10,000 mg/kg. Single oral doses of up to 4,000 mg nitazoxanide have been administered to healthy adult volunteers without significant adverse effects. In the event of overdose, gastric lavage may be appropriate soon after oral administration. Patients should be carefully observed and given symptomatic and supportive treatment.
# Pharmacology
## Mechanism of Action
- The antiprotozoal activity of nitazoxanide is believed to be due to interference with the pyruvate:ferredoxin oxidoreductase (PFOR) enzyme-dependent electron transfer reaction which is essential to anaerobic energy metabolism. Studies have shown that the PFOR enzyme from Giardia lamblia directly reduces nitazoxanide by transfer of electrons in the absence of ferredoxin. The DNA-derived PFOR protein sequence of Cryptosporidium parvum appears to be similar to that of Giardia lamblia. Interference with the PFOR enzyme-dependent electron transfer reaction may not be the only pathway by which nitazoxanide exhibits antiprotozoal activity.
## Structure
- Alinia Tablets and Alinia for Oral Suspension contain the active ingredient, nitazoxanide, a synthetic antiprotozoal agent for oral administration. Nitazoxanide is a light yellow crystalline powder. It is poorly soluble in ethanol and practically insoluble in water. Chemically, nitazoxanide is 2-acetyloxy-N-(5-nitro-2-thiazolyl)benzamide. The molecular formula is C12H9N3O5S and the molecular weight is 307.3. The structural formula is:
- Alinia Tablets contain 500 mg of nitazoxanide and the following inactive ingredients: maize starch, pregelatinized corn starch, hydroxypropyl methylcellulose, sucrose, sodium starch glycollate, talc, magnesium stearate, soy lecithin, polyvinyl alcohol, xanthan gum, titanium dioxide, FD&C Yellow No. 10 Aluminum Lake, FD&C Yellow No. 6 Aluminum Lake, and FD&C Blue No. 2 Aluminum Lake.
- Alinia for Oral Suspension, when reconstituted with 48 mL of water, produces 60 mL of a homogeneous suspension with a pink color that contains 100 mg nitazoxanide per 5 mL and the following inactive ingredients: sodium benzoate, sucrose, xanthan gum, microcrystalline cellulose and carboxymethylcellulose sodium, anhydrous citric acid, sodium citrate dihydrate, maltodextrin, modified food starch, triacetin, FD&C Red #40 and artificial strawberry flavoring.
## Pharmacodynamics
- There is limited information regarding Pharmacodynamics of Nitazoxanide in the drug label.
## Pharmacokinetics
- There is limited information regarding Pharmacokinetics of Nitazoxanide in the drug label.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
- Long-term carcinogenicity studies have not been conducted.
- Nitazoxanide was not genotoxic in the Chinese hamster ovary (CHO) cell chromosomal aberration assay or the mouse micronucleus assay. Nitazoxanide was genotoxic in 1 tester strain (TA 100) in the Ames bacterial mutation assay.
- Nitazoxanide did not adversely affect male or female fertility in the rat at 2,400 mg/kg/day (approximately 20 times the clinical adult dose adjusted for body surface area).
# Clinical Studies
Diarrhea caused by Giardia lamblia in adults and adolescents 12 years of age or older:
- In a double-blind, controlled study (Study 1) conducted in Peru and Egypt in adults and adolescents with diarrhea caused by Giardia lamblia, a three-day course of treatment with Alinia Tablets administered 500 mg BID was compared with a placebo tablet for 3 days. A third group of patients received open-label Alinia for Oral Suspension administered 500mg/25mL of suspension BID for 3 days. A second double-blind, controlled study (Study 2) conducted in Egypt in adults and adolescents with diarrhea caused by Giardia lamblia compared Alinia Tablets administered 500 mg BID for 3 days to a placebo tablet. For both of these studies, clinical response was evaluated 4 to 7 days following the end of treatment. A clinical response of 'well' was defined as 'no symptoms, no watery stools and no more than 2 soft stools with no hematochezia within the past 24 hours' or 'no symptoms and no unformed stools within the past 48 hours.' The following clinical response rates were obtained:
Adult and Adolescent Patients with Diarrhea Caused by Giardia lamblia
- Some patients with 'well' clinical responses had Giardia lamblia cysts in their stool samples 4 to 7 days following the end of treatment. The relevance of stool examination results in these patients is unknown. Patients should be managed based upon clinical response to treatment.
Diarrhea caused by Giardia lamblia in pediatric patients 1 through 11 years of age:
- In a randomized, controlled study conducted in Peru in 110 pediatric patients with diarrhea caused by Giardia lamblia, a three-day course of treatment with nitazoxanide (100 mg BID in pediatric patients ages 24-47 months, 200 mg BID in pediatric patients ages 4 through 11 years) was compared to a five-day course of treatment with metronidazole (125 mg BID in pediatric patients ages 2 through 5 years, 250 mg BID in pediatric patients ages 6 through 11 years). Clinical response was evaluated 7 to 10 days following initiation of treatment with a 'well' response defined as 'no symptoms, no watery stools and no more than 2 soft stools with no hematochezia within the past 24 hours' or 'no symptoms and no unformed stools within the past 48 hours.' The following clinical cure rates were obtained:
Pediatric Patients with Diarrhea Caused by Giardia lamblia
- Some patients with 'well' clinical responses had Giardia lamblia cysts in their stool samples 4 to 7 days following the end of treatment. The relevance of stool examination results in these patients is unknown. Patients should be managed based upon clinical response to treatment.
Diarrhea caused by Cryptosporidium parvum in adults and adolescents 12 years of age or older:
- In a double-blind, controlled study conducted in Egypt in adults and adolescents with diarrhea caused by Cryptosporidium parvum, a three-day course of treatment with Alinia Tablets administered 500 mg BID was compared with a placebo tablet for 3 days. A third group of patients received open-label Alinia for Oral Suspension administered 500mg/25mL of suspension BID for 3 days. Clinical response was evaluated 4 to 7 days following the end of treatment. A clinical response of 'well' was defined as 'no symptoms, no watery stools and no more than 2 soft stools within the past 24 hours' or 'no symptoms and no unformed stools within the past 48 hours.' The following clinical response rates were obtained:
Adult and Adolescent Patients with Diarrhea Caused by Cryptosporidium parvum
- In a second double-blind, placebo-controlled study of nitazoxanide tablets conducted in Egypt in adults and adolescents with diarrhea caused by Cryptosporidium parvum as the sole pathogen, clinical and parasitological response rates showed a similar trend to the first study. Clinical response rates, evaluated 2 to 6 days following the end of treatment, were 71% (15/21) in the nitazoxanide group and 42.9% (9/21) in the placebo group.
- Some patients with 'well' clinical responses had Cryptosporidium parvum oocysts in their stool samples 4 to 7 days following the end of treatment. The relevance of stool examination results in these patients is unknown. Patients should be managed based upon clinical response to treatment.
Diarrhea caused by Cryptosporidium parvum in pediatric patients 1 through 11 years of age:
- In two double-blind, controlled studies in pediatric patients with diarrhea caused by Cryptosporidium parvum, a three-day course of treatment with nitazoxanide (100 mg BID in pediatric patients ages 12-47 months, 200 mg BID in pediatric patients ages 4 through 11 years) was compared with a placebo. One study was conducted in Egypt in outpatients ages 1 through 11 years with diarrhea caused by Cryptosporidium parvum. Another study was conducted in Zambia in malnourished pediatric patients admitted to the hospital with diarrhea caused by Cryptosporidium parvum. Clinical response was evaluated 3 to 7 days post-therapy with a 'well' response defined as 'no symptoms, no watery stools and no more than 2 soft stools within the past 24 hours' or 'no symptoms and no unformed stools within the past 48 hours.' The following clinical response rates were obtained:
Pediatric Patients with Diarrhea Caused by Cryptosporidium parvum
- Some patients with 'well' clinical responses had Cryptosporidium oocysts in their stool samples 3 to 7 days following the end of treatment. The relevance of stool examination results in these patients is unknown. Patients should be managed based upon clinical response to treatment.
Diarrhea caused by Cryptosporidium parvum in AIDS patients:
- A double-blind, placebo-controlled study did not produce clinical cure rates that were significantly different from the placebo control when conducted in hospitalized, severely malnourished pediatric patients with acquired immune deficiency syndrome (AIDS) in Zambia. In this study, the pediatric patients received a three day course of nitazoxanide suspension (100 mg BID in pediatric patients ages 12-47 months, 200 mg BID in pediatric patients ages 4 through 11 years) and were evaluated for response four days after the end of treatment.
# How Supplied
- Alinia Tablets are round, yellow, film-coated tablets debossed with ALINIA on one side and 500 on the other side. Each tablet contains 500 mg of nitazoxanide. The tablets are packaged in HDPE bottles of 30 tablets.
Bottles of 30 NDC 67546-111-12
- Alinia for Oral Suspension is a pink-colored powder formulation that, when reconstituted as directed, contains 100 mg nitazoxanide/5 mL. The reconstituted suspension has a pink color and strawberry flavor. Alinia for Oral Suspension is available as:
Bottles of 60 mL NDC 67546-212-21
## Storage
- Storage and Stability: Store the tablets, unsuspended powder, and the reconstituted oral suspension at 25°C (77°F); excursions permitted to 15-30°C (59-86°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Information for Patients
- Alinia Tablets and Alinia for Oral Suspension should be taken with food.
- Diabetic patients and caregivers should be aware that the oral suspension contains 1.48 grams of sucrose per 5 mL.
# Precautions with Alcohol
- Alcohol-Nitazoxanide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- ALINIA ®
# Look-Alike Drug Names
- A® — B®
# Drug Shortage Status
# Price | Nitazoxanide
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2]
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# Overview
Nitazoxanide is an anti-infective agent that is FDA approved for the treatment of diarrhea caused by Giardia lamblia or Cryptosporidium parvum. Common adverse reactions include abdominal pain, diarrhea, nausea, vomiting,headache.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
# Indications
Diarrhea caused by Giardia lamblia or Cryptosporidium parvum:
- Alinia for Oral Suspension (patients 1 year of age and older) and Alinia Tablets (patients 12 years and older) are indicated for the treatment of diarrhea caused by Giardia lamblia or Cryptosporidium parvum.
- Alinia for Oral Suspension and Alinia Tablets have not been shown to be superior to placebo for the treatment of diarrhea caused by Cryptosporidium parvum in HIV-infected or immunodeficient patients
# Dosage
DIRECTIONS FOR MIXING ALINIA FOR ORAL SUSPENSION
- Prepare a suspension at time of dispensing as follows: The amount of water required for preparation of the suspension is 48 mL. Tap bottle until all powder flows freely. Add approximately one-half of the total amount of water required for reconstitution and shake vigorously to suspend powder. Add remainder of water and again shake vigorously.
- The container should be kept tightly closed, and the suspension should be shaken well before each administration. The suspension may be stored for 7 days, after which any unused portion must be discarded.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Nitazoxanide in adult patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Nitazoxanide in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
# Indications
Diarrhea caused by Giardia lamblia or Cryptosporidium parvum:
- Alinia for Oral Suspension (patients 1 year of age and older) and Alinia Tablets (patients 12 years and older) are indicated for the treatment of diarrhea caused by Giardia lamblia or Cryptosporidium parvum.
- Alinia for Oral Suspension and Alinia Tablets have not been shown to be superior to placebo for the treatment of diarrhea caused by Cryptosporidium parvum in HIV-infected or immunodeficient patients
# Dosage
DIRECTIONS FOR MIXING ALINIA FOR ORAL SUSPENSION
- Prepare a suspension at time of dispensing as follows: The amount of water required for preparation of the suspension is 48 mL. Tap bottle until all powder flows freely. Add approximately one-half of the total amount of water required for reconstitution and shake vigorously to suspend powder. Add remainder of water and again shake vigorously.
- The container should be kept tightly closed, and the suspension should be shaken well before each administration. The suspension may be stored for 7 days, after which any unused portion must be discarded.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Nitazoxanide in pediatric patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Nitazoxanide in pediatric patients.
# Contraindications
- Alinia Tablets and Alinia for Oral Suspension are contraindicated in patients with a prior hypersensitivity to nitazoxanide or any other ingredient in the formulations.
# Warnings
- There is limited information regarding Warning of Nitazoxanide in pediatric patients.
# Adverse Reactions
## Clinical Trials Experience
- Alinia Tablets: In controlled and uncontrolled clinical studies of 1,657 HIV-uninfected patients age 12 years and older who received various dosage regimens of Alinia Tablets, the most common adverse events reported regardless of causality assessment were: abdominal pain (6.6%), diarrhea (4.2%), headache (3.1%) and nausea (3.0%). In placebo-controlled clinical trials using the recommended dose, the rates of occurrence of these events did not differ significantly from those of the placebo. In placebo-controlled trials of HIV-uninfected patients age 12 years and older who received Alinia Tablets for the treatment of diarrhea caused by Giardia lamblia or Cryptosporidium parvum, less than 1% of patients discontinued therapy because of an adverse event.
- Adverse events occurring in less than 1% of the patients age 12 years and older participating in clinical trials of Alinia Tablets are listed below:
- Body as a Whole: asthenia, fever, pain, allergic reaction, pelvic pain, back pain, chills, chills and fever, flu syndrome.
- Nervous System: dizziness, somnolence, insomnia, tremor, hypesthesia.
- Digestive System: vomiting, dyspepsia, anorexia, flatulence, constipation, dry mouth, thirst.
- Urogenital System: discolored urine, dysuria, amenorrhea, metrorrhagia, kidney pain, edema labia.
- Metabolic & Nutrition: increased SGPT.
- Hemic & Lymphatic Systems: anemia, leukocytosis.
- Skin: rash, pruritus.
- Special Senses: eye discoloration, ear ache.
- Respiratory System: epistaxis, lung disease, pharyngitis.
- Cardiovascular System: tachycardia, syncope, hypertension.
- Muscular System: myalgia, leg cramps, spontaneous bone fracture.
Alinia for Oral Suspension:
- In controlled and uncontrolled clinical studies of 613 HIV-uninfected pediatric patients who received Alinia for Oral Suspension, the most frequent adverse events reported regardless of causality assessment were: abdominal pain (7.8%), diarrhea (2.1%), vomiting (1.1%) and headache (1.1%). These were typically mild and transient in nature. In placebo-controlled clinical trials, the rates of occurrence of these events did not differ significantly from those of the placebo. None of the 613 pediatric patients discontinued therapy because of adverse events.
- Adverse events occurring in less than 1% of the pediatric patients participating in clinical trials of Alinia for Oral Suspension are listed below:
- Digestive System: nausea, anorexia, flatulence, appetite increase, enlarged salivary glands.
- Body as a Whole: fever, infection, malaise.
- Metabolic & Nutrition: increased creatinine, increased SGPT.
- Skin: pruritus, sweat.
- Special Senses: eye discoloration (pale yellow).
- Respiratory System: rhinitis.
- Nervous System: dizziness.
- Urogenital System: discolored urine.
- The adverse events seen in adult patients treated with Alinia for Oral Suspension were similar to those observed in adult patients treated with Alinia Tablets.
## Postmarketing Experience
- There is limited information regarding Postmarketing Experience of Nitazoxanide in the drug label.
# Drug Interactions
- Tizoxanide is highly bound to plasma protein (>99.9%). Therefore, caution should be used when administering nitazoxanide concurrently with other highly plasma protein-bound drugs with narrow therapeutic indices, as competition for binding sites may occur (e.g., warfarin). In vitro metabolism studies have demonstrated that tizoxanide has no significant inhibitory effect on cytochrome P450 enzymes. Although no drug-drug interaction studies have been conducted in vivo, it is expected that no significant interaction would occur when nitazoxanide is co-administered with drugs that either are metabolized by or inhibit cytochrome P450 enzymes.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category B: Reproduction studies have been performed at doses up to 3,200 mg/kg/day in rats (approximately 26 times the clinical adult dose adjusted for body surface area) and 100 mg/kg/day in rabbits (approximately 2 times the clinical adult dose adjusted for surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to nitazoxanide. There are, however, no adequate and well-controlled studies in pregnant women.
Pregnancy Category (AUS):
- There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Nitazoxanide in women who are pregnant.
### Labor and Delivery
- There is no FDA guidance on use of Nitazoxanide during labor and delivery.
### Nursing Mothers
- It is not known whether nitazoxanide is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when nitazoxanide is administered to a nursing woman.
### Pediatric Use
- A single Alinia Tablet contains a greater amount of nitazoxanide than is recommended for pediatric dosing and should therefore not be used in pediatric patients 11 years or younger. Alinia for Oral Suspension should be used for dosing nitazoxanide in pediatric patients.
- Safety and effectiveness of Alinia for Oral Suspension in pediatric patients less than 1 year of age have not been studied.
### Geriatic Use
- Clinical studies of Alinia Tablets and Alinia for Oral Suspension did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in elderly patients should be considered when prescribing Alinia Tablets and Alinia for Oral Suspension. As stated in the precautions section, this therapy must be administered with caution to patients with renal and or hepatic impairment.
### Gender
- There is no FDA guidance on the use of Nitazoxanide with respect to specific gender populations.
### Race
- There is no FDA guidance on the use of Nitazoxanide with respect to specific racial populations.
### Renal Impairment
- There is no FDA guidance on the use of Nitazoxanide in patients with renal impairment.
### Hepatic Impairment
- There is no FDA guidance on the use of Nitazoxanide in patients with hepatic impairment.
### Females of Reproductive Potential and Males
- There is no FDA guidance on the use of Nitazoxanide in women of reproductive potentials and males.
### Immunocompromised Patients
- There is no FDA guidance one the use of Nitazoxanide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- There is limited information regarding Monitoring of Nitazoxanide in the drug label.
# IV Compatibility
- There is limited information regarding IV Compatibility of Nitazoxanide in the drug label.
# Overdosage
- Information on nitazoxanide overdosage is not available. In acute studies in rodents and dogs, the oral LD50 was higher than 10,000 mg/kg. Single oral doses of up to 4,000 mg nitazoxanide have been administered to healthy adult volunteers without significant adverse effects. In the event of overdose, gastric lavage may be appropriate soon after oral administration. Patients should be carefully observed and given symptomatic and supportive treatment.
# Pharmacology
## Mechanism of Action
- The antiprotozoal activity of nitazoxanide is believed to be due to interference with the pyruvate:ferredoxin oxidoreductase (PFOR) enzyme-dependent electron transfer reaction which is essential to anaerobic energy metabolism. Studies have shown that the PFOR enzyme from Giardia lamblia directly reduces nitazoxanide by transfer of electrons in the absence of ferredoxin. The DNA-derived PFOR protein sequence of Cryptosporidium parvum appears to be similar to that of Giardia lamblia. Interference with the PFOR enzyme-dependent electron transfer reaction may not be the only pathway by which nitazoxanide exhibits antiprotozoal activity.
## Structure
- Alinia Tablets and Alinia for Oral Suspension contain the active ingredient, nitazoxanide, a synthetic antiprotozoal agent for oral administration. Nitazoxanide is a light yellow crystalline powder. It is poorly soluble in ethanol and practically insoluble in water. Chemically, nitazoxanide is 2-acetyloxy-N-(5-nitro-2-thiazolyl)benzamide. The molecular formula is C12H9N3O5S and the molecular weight is 307.3. The structural formula is:
- Alinia Tablets contain 500 mg of nitazoxanide and the following inactive ingredients: maize starch, pregelatinized corn starch, hydroxypropyl methylcellulose, sucrose, sodium starch glycollate, talc, magnesium stearate, soy lecithin, polyvinyl alcohol, xanthan gum, titanium dioxide, FD&C Yellow No. 10 Aluminum Lake, FD&C Yellow No. 6 Aluminum Lake, and FD&C Blue No. 2 Aluminum Lake.
- Alinia for Oral Suspension, when reconstituted with 48 mL of water, produces 60 mL of a homogeneous suspension with a pink color that contains 100 mg nitazoxanide per 5 mL and the following inactive ingredients: sodium benzoate, sucrose, xanthan gum, microcrystalline cellulose and carboxymethylcellulose sodium, anhydrous citric acid, sodium citrate dihydrate, maltodextrin, modified food starch, triacetin, FD&C Red #40 and artificial strawberry flavoring.
## Pharmacodynamics
- There is limited information regarding Pharmacodynamics of Nitazoxanide in the drug label.
## Pharmacokinetics
- There is limited information regarding Pharmacokinetics of Nitazoxanide in the drug label.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
- Long-term carcinogenicity studies have not been conducted.
- Nitazoxanide was not genotoxic in the Chinese hamster ovary (CHO) cell chromosomal aberration assay or the mouse micronucleus assay. Nitazoxanide was genotoxic in 1 tester strain (TA 100) in the Ames bacterial mutation assay.
- Nitazoxanide did not adversely affect male or female fertility in the rat at 2,400 mg/kg/day (approximately 20 times the clinical adult dose adjusted for body surface area).
# Clinical Studies
Diarrhea caused by Giardia lamblia in adults and adolescents 12 years of age or older:
- In a double-blind, controlled study (Study 1) conducted in Peru and Egypt in adults and adolescents with diarrhea caused by Giardia lamblia, a three-day course of treatment with Alinia Tablets administered 500 mg BID was compared with a placebo tablet for 3 days. A third group of patients received open-label Alinia for Oral Suspension administered 500mg/25mL of suspension BID for 3 days. A second double-blind, controlled study (Study 2) conducted in Egypt in adults and adolescents with diarrhea caused by Giardia lamblia compared Alinia Tablets administered 500 mg BID for 3 days to a placebo tablet. For both of these studies, clinical response was evaluated 4 to 7 days following the end of treatment. A clinical response of 'well' was defined as 'no symptoms, no watery stools and no more than 2 soft stools with no hematochezia within the past 24 hours' or 'no symptoms and no unformed stools within the past 48 hours.' The following clinical response rates were obtained:
Adult and Adolescent Patients with Diarrhea Caused by Giardia lamblia
- Some patients with 'well' clinical responses had Giardia lamblia cysts in their stool samples 4 to 7 days following the end of treatment. The relevance of stool examination results in these patients is unknown. Patients should be managed based upon clinical response to treatment.
Diarrhea caused by Giardia lamblia in pediatric patients 1 through 11 years of age:
- In a randomized, controlled study conducted in Peru in 110 pediatric patients with diarrhea caused by Giardia lamblia, a three-day course of treatment with nitazoxanide (100 mg BID in pediatric patients ages 24-47 months, 200 mg BID in pediatric patients ages 4 through 11 years) was compared to a five-day course of treatment with metronidazole (125 mg BID in pediatric patients ages 2 through 5 years, 250 mg BID in pediatric patients ages 6 through 11 years). Clinical response was evaluated 7 to 10 days following initiation of treatment with a 'well' response defined as 'no symptoms, no watery stools and no more than 2 soft stools with no hematochezia within the past 24 hours' or 'no symptoms and no unformed stools within the past 48 hours.' The following clinical cure rates were obtained:
Pediatric Patients with Diarrhea Caused by Giardia lamblia
- Some patients with 'well' clinical responses had Giardia lamblia cysts in their stool samples 4 to 7 days following the end of treatment. The relevance of stool examination results in these patients is unknown. Patients should be managed based upon clinical response to treatment.
Diarrhea caused by Cryptosporidium parvum in adults and adolescents 12 years of age or older:
- In a double-blind, controlled study conducted in Egypt in adults and adolescents with diarrhea caused by Cryptosporidium parvum, a three-day course of treatment with Alinia Tablets administered 500 mg BID was compared with a placebo tablet for 3 days. A third group of patients received open-label Alinia for Oral Suspension administered 500mg/25mL of suspension BID for 3 days. Clinical response was evaluated 4 to 7 days following the end of treatment. A clinical response of 'well' was defined as 'no symptoms, no watery stools and no more than 2 soft stools within the past 24 hours' or 'no symptoms and no unformed stools within the past 48 hours.' The following clinical response rates were obtained:
Adult and Adolescent Patients with Diarrhea Caused by Cryptosporidium parvum
- In a second double-blind, placebo-controlled study of nitazoxanide tablets conducted in Egypt in adults and adolescents with diarrhea caused by Cryptosporidium parvum as the sole pathogen, clinical and parasitological response rates showed a similar trend to the first study. Clinical response rates, evaluated 2 to 6 days following the end of treatment, were 71% (15/21) in the nitazoxanide group and 42.9% (9/21) in the placebo group.
- Some patients with 'well' clinical responses had Cryptosporidium parvum oocysts in their stool samples 4 to 7 days following the end of treatment. The relevance of stool examination results in these patients is unknown. Patients should be managed based upon clinical response to treatment.
Diarrhea caused by Cryptosporidium parvum in pediatric patients 1 through 11 years of age:
- In two double-blind, controlled studies in pediatric patients with diarrhea caused by Cryptosporidium parvum, a three-day course of treatment with nitazoxanide (100 mg BID in pediatric patients ages 12-47 months, 200 mg BID in pediatric patients ages 4 through 11 years) was compared with a placebo. One study was conducted in Egypt in outpatients ages 1 through 11 years with diarrhea caused by Cryptosporidium parvum. Another study was conducted in Zambia in malnourished pediatric patients admitted to the hospital with diarrhea caused by Cryptosporidium parvum. Clinical response was evaluated 3 to 7 days post-therapy with a 'well' response defined as 'no symptoms, no watery stools and no more than 2 soft stools within the past 24 hours' or 'no symptoms and no unformed stools within the past 48 hours.' The following clinical response rates were obtained:
Pediatric Patients with Diarrhea Caused by Cryptosporidium parvum
- Some patients with 'well' clinical responses had Cryptosporidium oocysts in their stool samples 3 to 7 days following the end of treatment. The relevance of stool examination results in these patients is unknown. Patients should be managed based upon clinical response to treatment.
Diarrhea caused by Cryptosporidium parvum in AIDS patients:
- A double-blind, placebo-controlled study did not produce clinical cure rates that were significantly different from the placebo control when conducted in hospitalized, severely malnourished pediatric patients with acquired immune deficiency syndrome (AIDS) in Zambia. In this study, the pediatric patients received a three day course of nitazoxanide suspension (100 mg BID in pediatric patients ages 12-47 months, 200 mg BID in pediatric patients ages 4 through 11 years) and were evaluated for response four days after the end of treatment.
# How Supplied
- Alinia Tablets are round, yellow, film-coated tablets debossed with ALINIA on one side and 500 on the other side. Each tablet contains 500 mg of nitazoxanide. The tablets are packaged in HDPE bottles of 30 tablets.
Bottles of 30 NDC 67546-111-12
- Alinia for Oral Suspension is a pink-colored powder formulation that, when reconstituted as directed, contains 100 mg nitazoxanide/5 mL. The reconstituted suspension has a pink color and strawberry flavor. Alinia for Oral Suspension is available as:
Bottles of 60 mL NDC 67546-212-21
## Storage
- Storage and Stability: Store the tablets, unsuspended powder, and the reconstituted oral suspension at 25°C (77°F); excursions permitted to 15-30°C (59-86°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Information for Patients
- Alinia Tablets and Alinia for Oral Suspension should be taken with food.
- Diabetic patients and caregivers should be aware that the oral suspension contains 1.48 grams of sucrose per 5 mL.
# Precautions with Alcohol
- Alcohol-Nitazoxanide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- ALINIA ®[1]
# Look-Alike Drug Names
- A® — B®[2]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Nitazoxanide | |
3c920dc420b411628a22d42104f069c05219a904 | wikidoc | Nitrendipine | Nitrendipine
# Overview
Nitrendipine is a dihydropyridine calcium channel blocker. It is used in the treatment of primary (essential) hypertension to decrease blood pressure.
# Molecular Problem
Hypertension is the chronic condition where the blood pressure is elevated beyond normal levels that vary among individuals. The
elevated levels in blood pressure increases the systemic vascular pressure, which increases the workload of the heart. The mechanical stress on the heart initiates a protein cascade involving G-proteins, cyclic-AMP and PKA that result in activation of genes that produce more cardiac muscle cells. The increased stress on the heart causes the heart to enlarge to accommodate the workload. However, the enlarged heart also needs structural support, which is why it produces scarring. The enlargement of the heart can make it hard for some cells to get nutrients because they are too distant from the blood vessels. Also, scarring can interfere with the electrical signals that cause the heart to contract and it also limits the ability of the heart to contract and relax. In both cases there is an increase risk of heart failure.
# Nature of the Treatment
Nitrendipine is given to hypertensive individuals in 20 mg oral tablets every day. This amount is effective in reducing blood pressure by 15-20% within 1–2 hours of administration . With long-term treatments, the dosage may rise to as much as 40 mg/day; in elderly individuals, a lower dosage of up to 5 mg/day may be equally effective (this reduction in drug amount is attributed to decreased liver function or “first pass” metabolism) . Once digested, Nitrendipine is absorbed into the blood and binds to plasma proteins. The majority (98%) is bound to plasma proteins and 70-80% of its inactive polar metabolites are also bound to plasma proteins . Following hepatic metabolism, 80% of the 20 mg dose can be recovered in the first 96 hours as inactive polar metabolites. The specific volume of distribution of the drug is 2-6 L/kg. In terms of drug half-life, Nitrendipine has a half-life of 12–24 hours . The reported side effects include: headache, flushing, edema and palpitations. These side effects can all be attributed to the
vasodilation effect of this drug .
# Mechanism of Action
Once Nitrendipine is ingested, it is absorbed by the gut and metabolized by the liver before it goes into the systemic circulation and reaches the cells of the smooth muscles and cardiac muscle cells. It binds more effectively with L-type calcium channels in smooth muscle cells because of its lower resting membrane potential. The Nitrendipine diffuses into the membrane and binds to its high affinity binding site on the inactivated L-type calcium channel that’s located in between each of the 4 intermembrane components of the α1 subunit . The exact mechanism of action of Nitrendipine is unknown, but it is believed to have important tyrosine and threonine residues in its binding pocket and its binding interferes with the voltage sensor and gating mechanism of the channel . Thought to have a domain-interface model of binding. In hypertension, the binding of Nitrendipine causes a decrease in the probability of open L-type calcium channels and reduces the influx of calcium. The reduced levels of calcium prevent smooth muscle contraction within these muscle cells. Prevention of muscle contraction enables smooth muscle dilation. Dilation of the vasculature reduces total peripheral resistance, which decreases the workload on the heart and prevents scarring of the heart or heart failure. | Nitrendipine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Sheng Shi, M.D. [2]
# Overview
Nitrendipine is a dihydropyridine calcium channel blocker. It is used in the treatment of primary (essential) hypertension to decrease blood pressure.
# Molecular Problem
Hypertension is the chronic condition where the blood pressure is elevated beyond normal levels that vary among individuals. The
elevated levels in blood pressure increases the systemic vascular pressure, which increases the workload of the heart. The mechanical stress on the heart initiates a protein cascade involving G-proteins, cyclic-AMP and PKA that result in activation of genes that produce more cardiac muscle cells.[1] The increased stress on the heart causes the heart to enlarge to accommodate the workload. However, the enlarged heart also needs structural support, which is why it produces scarring.[2] The enlargement of the heart can make it hard for some cells to get nutrients because they are too distant from the blood vessels. Also, scarring can interfere with the electrical signals that cause the heart to contract and it also limits the ability of the heart to contract and relax. In both cases there is an increase risk of heart failure.
# Nature of the Treatment
Nitrendipine is given to hypertensive individuals in 20 mg oral tablets every day.[3] This amount is effective in reducing blood pressure by 15-20% within 1–2 hours of administration [3]. With long-term treatments, the dosage may rise to as much as 40 mg/day; in elderly individuals, a lower dosage of up to 5 mg/day may be equally effective (this reduction in drug amount is attributed to decreased liver function or “first pass” metabolism) [3]. Once digested, Nitrendipine is absorbed into the blood and binds to plasma proteins. The majority (98%) is bound to plasma proteins and 70-80% of its inactive polar metabolites are also bound to plasma proteins [3]. Following hepatic metabolism, 80% of the 20 mg dose can be recovered in the first 96 hours as inactive polar metabolites. The specific volume of distribution of the drug is 2-6 L/kg. In terms of drug half-life, Nitrendipine has a half-life of 12–24 hours [3]. The reported side effects include: headache, flushing, edema and palpitations. These side effects can all be attributed to the
vasodilation effect of this drug [3].
# Mechanism of Action
Once Nitrendipine is ingested, it is absorbed by the gut and metabolized by the liver before it goes into the systemic circulation and reaches the cells of the smooth muscles and cardiac muscle cells. It binds more effectively with L-type calcium channels in smooth muscle cells because of its lower resting membrane potential.[4] The Nitrendipine diffuses into the membrane and binds to its high affinity binding site on the inactivated L-type calcium channel that’s located in between each of the 4 intermembrane components of the α1 subunit [4]. The exact mechanism of action of Nitrendipine is unknown, but it is believed to have important tyrosine and threonine residues in its binding pocket and its binding interferes with the voltage sensor and gating mechanism of the channel [4]. Thought to have a domain-interface model of binding. In hypertension, the binding of Nitrendipine causes a decrease in the probability of open L-type calcium channels and reduces the influx of calcium. The reduced levels of calcium prevent smooth muscle contraction within these muscle cells. Prevention of muscle contraction enables smooth muscle dilation. Dilation of the vasculature reduces total peripheral resistance, which decreases the workload on the heart and prevents scarring of the heart or heart failure. | https://www.wikidoc.org/index.php/Nitrendipine | |
7e037cef288d9ddec867bd427211448f7452bb78 | wikidoc | Nitrobenzene | Nitrobenzene
# Overview
Nitrobenzene, also known as nitrobenzol or oil of mirbane, is a poisonous organic compound with an almond odor and chemical formula C6H5NO2. It may be found as either bright yellow crystals or an oily water-insoluble liquid.
It is used as a solvent and as a mild oxidizing agent. It is most frequently used specifically in the manufacture of aniline, but also used in the manufacture of insulating compounds and polishes.
# Uses
While nitrobenzene is primarily used in the production of aniline and aniline derivatives, such as methylene diphenyl diisocyanate (MDI), it also finds use in the manufacture of rubber chemicals, pesticides, dyes, and pharmaceuticals. Nitrobenzene is also used in shoe and floor polishes, leather dressings, paint solvents, and other materials to mask unpleasant odors. Substitution reactions with nitrobenzene are used to form m-derivatives (Mannsville 1991; Sittig 1991). Redistilled, as oil of mirbane, nitrobenzene has been used as an inexpensive perfume for soaps. A significant merchant market for nitrobenzene is its use in the production of the analgesic paracetamol (also known as acetaminophen) (Mannsville 1991). Nitrobenzene is also used in Kerr cells, as it has an unusually large Kerr constant.
# Production
There were four producers of nitrobenzene in the United States in 1991: First Chemicals Corporation, Mobay, DuPont Chemicals, and Rubicon Inc. In 1991, the estimated total production capacity of nitrobenzene in the U.S. was 617000 tonnes (Mannsville 1991).
The classic method for forming nitrobenzene is to react benzene with a mixture of concentrated sulfuric acid and nitric acid. This mixture of acids forms an electrophile which reacts with the benzene in an electrophilic aromatic substitution reaction. This reaction is often known as a nitration reaction.
The nitric acid is protonated by the sulphuric acid to form H2NO3+ which then loses water to form NO2+. The concentrated sulphuric acid has a high affinity for the water, this helps the reaction go. | Nitrobenzene
Template:Chembox new
# Overview
Nitrobenzene, also known as nitrobenzol or oil of mirbane, is a poisonous organic compound with an almond odor and chemical formula C6H5NO2. It may be found as either bright yellow crystals or an oily water-insoluble liquid.
It is used as a solvent and as a mild oxidizing agent. It is most frequently used specifically in the manufacture of aniline, but also used in the manufacture of insulating compounds and polishes.
# Uses
While nitrobenzene is primarily used in the production of aniline and aniline derivatives, such as methylene diphenyl diisocyanate (MDI), it also finds use in the manufacture of rubber chemicals, pesticides, dyes, and pharmaceuticals. Nitrobenzene is also used in shoe and floor polishes, leather dressings, paint solvents, and other materials to mask unpleasant odors. Substitution reactions with nitrobenzene are used to form m-derivatives (Mannsville 1991; Sittig 1991)[citation needed]. Redistilled, as oil of mirbane, nitrobenzene has been used as an inexpensive perfume for soaps. A significant merchant market for nitrobenzene is its use in the production of the analgesic paracetamol (also known as acetaminophen) (Mannsville 1991). Nitrobenzene is also used in Kerr cells, as it has an unusually large Kerr constant.
# Production
There were four producers of nitrobenzene in the United States in 1991: First Chemicals Corporation, Mobay, DuPont Chemicals, and Rubicon Inc. In 1991, the estimated total production capacity of nitrobenzene in the U.S. was 617000 tonnes (Mannsville 1991)[citation needed].
The classic method for forming nitrobenzene is to react benzene with a mixture of concentrated sulfuric acid and nitric acid. This mixture of acids forms an electrophile which reacts with the benzene in an electrophilic aromatic substitution reaction. This reaction is often known as a nitration reaction.
The nitric acid is protonated by the sulphuric acid to form H2NO3+ which then loses water to form NO2+. The concentrated sulphuric acid has a high affinity for the water, this helps the reaction go. | https://www.wikidoc.org/index.php/Nitrobenzene | |
b11b0535342fd4706c672f9ee05f0f5e6dd69e26 | wikidoc | Nocardiaceae | Nocardiaceae
The Nocardiaceae are a family of aerobic, non-fastidious, high G+C, Gram-positive actinomycetes that are commonly found in soil and water. Some bacteria from this family are even indigenous to the Antarctic. Nocardiaceae present coccobacilli, filamentous or, rarely, fragmented and palisading forms, and filamentous species grow in a branching morphological pattern similar to fungal hyphae.
# Pathogenic capacity
Some species colonize animals, and members of the Nocardia and Rhodococcus genera can cause infection in humans and livestock. Many members of this family integrate mycolic acids into their cell wall, and as a result, Nocardia spp. may be mistaken for mycobacteria when viewed under a microscope following an acid-fast stain.
# Environmental effects
## Wastewater foaming
Nocardia species are often responsible for the accumulation of foam that occurs in activate sludge during wastewater treatment. Biological foaming can be problematic for the water treatment process, and foam accumulation is reduced by adding surfactants to the wastewater.
## Bioremediation of hydrocarbons
Soil Nocardiaceae can degrade hydrocarbons (e.g. petroleum distillates) and have been proposed as bioremediation agents for environmental spills.
# Nomenclature changes
In the 1980's, all Micropolyspora spp. were transferred to the genera Nocardia, Nonomuraea in family Streptosporangiaceae, or Saccharopolyspora in family Pseudonocardiaceae. This effectively ended the official status of this genus, but the name persists in older research articles. | Nocardiaceae
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
The Nocardiaceae are a family of aerobic, non-fastidious, high G+C, Gram-positive actinomycetes that are commonly found in soil and water.[1] Some bacteria from this family are even indigenous to the Antarctic.[2] Nocardiaceae present coccobacilli, filamentous or, rarely, fragmented and palisading forms,[3] and filamentous species grow in a branching morphological pattern similar to fungal hyphae.[4]
# Pathogenic capacity
Some species colonize animals, and members of the Nocardia and Rhodococcus genera can cause infection in humans and livestock.[5] Many members of this family integrate mycolic acids into their cell wall, and as a result, Nocardia spp. may be mistaken for mycobacteria when viewed under a microscope following an acid-fast stain.[6]
# Environmental effects
## Wastewater foaming
Nocardia species are often responsible for the accumulation of foam that occurs in activate sludge during wastewater treatment.[4][7][8][9] Biological foaming can be problematic for the water treatment process, and foam accumulation is reduced by adding surfactants to the wastewater.[10][11]
## Bioremediation of hydrocarbons
Soil Nocardiaceae can degrade hydrocarbons (e.g. petroleum distillates) and have been proposed as bioremediation agents for environmental spills.[12]
# Nomenclature changes
In the 1980's, all Micropolyspora spp. were transferred to the genera Nocardia, Nonomuraea in family Streptosporangiaceae, or Saccharopolyspora in family Pseudonocardiaceae.[13] This effectively ended the official status of this genus, but the name persists in older research articles. | https://www.wikidoc.org/index.php/Nocardiaceae | |
73ffd1ff00a8e1f49cedd671679e977814c5e5dd | wikidoc | Nocturnality | Nocturnality
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As an animal behavior, nocturnality describes sleeping during the daytime and being active at night - the opposite of the diurnal human lifestyle, and that of those animals with which we are most familiar. The intermediate crepuscular schedule (twilight activity) is also common. Some species are active both during the day and night. Living at night can be seen as a form of niche differentiation, where a species' niche is partitioned not by resources but by time itself, i.e. temporal division of the ecological niche. It can also be viewed as a form of crypsis, in other words an adaptation to avoid or enhance predation. There are other reasons for nocturnality as well, such as keeping out of the heat of the day. This is especially true in deserts, where many animals' nocturnal behavior prevents them from losing precious water during the hot, dry daytime. This is an adaptation that enhances osmoregulation.
Many species which are otherwise diurnal exhibit some nocturnal behaviour; for example, many seabirds and sea turtles attend breeding sites or colonies nocturnally to reduce the risk of predation (to themselves or their offspring) but are otherwise diurnal. Some animals are not really nocturnal and are instead crepuscular, being mostly active in twilight.
Nocturnal animals generally have highly developed senses of hearing and smell, and specially adapted eyesight. In zoos, nocturnal animals are usually kept in special night-illumination enclosures to reverse their normal sleep-wake cycle and to keep them active during the hours when visitors will be attempting to see them.
Some animals, such as cats, have eyes that can adapt to both night and day levels of illumination. Others, e.g. bushbabies and bats, can only function at night.
A person who exhibits nocturnal habits is referred to as a night owl; he or she is of the "eveningness" chronotype. | Nocturnality
Lua error in Module:Redirect at line 65: could not parse redirect on page "Nocturnal".
As an animal behavior, nocturnality describes sleeping during the daytime and being active at night - the opposite of the diurnal human lifestyle, and that of those animals with which we are most familiar. The intermediate crepuscular schedule (twilight activity) is also common. Some species are active both during the day and night. Living at night can be seen as a form of niche differentiation, where a species' niche is partitioned not by resources but by time itself, i.e. temporal division of the ecological niche. It can also be viewed as a form of crypsis, in other words an adaptation to avoid or enhance predation. There are other reasons for nocturnality as well, such as keeping out of the heat of the day. This is especially true in deserts, where many animals' nocturnal behavior prevents them from losing precious water during the hot, dry daytime. This is an adaptation that enhances osmoregulation.[1]
Many species which are otherwise diurnal exhibit some nocturnal behaviour; for example, many seabirds and sea turtles attend breeding sites or colonies nocturnally to reduce the risk of predation (to themselves or their offspring) but are otherwise diurnal. Some animals are not really nocturnal and are instead crepuscular, being mostly active in twilight.
Nocturnal animals generally have highly developed senses of hearing and smell, and specially adapted eyesight. In zoos, nocturnal animals are usually kept in special night-illumination enclosures to reverse their normal sleep-wake cycle and to keep them active during the hours when visitors will be attempting to see them.
Some animals, such as cats, have eyes that can adapt to both night and day levels of illumination. Others, e.g. bushbabies and bats, can only function at night.
A person who exhibits nocturnal habits is referred to as a night owl; he or she is of the "eveningness" chronotype. | https://www.wikidoc.org/index.php/Nocturnal | |
dd768af137a79d54828a0fdc4b6972d7f68ad5ee | wikidoc | Norpethidine | Norpethidine
Norpethidine (Normeperidine, Pethidine Intermediate B) is a 4-phenylpiperidine derivative that is both a metabolite of and a precursor to pethidine (meperidine).
Norpethidine is a controlled drug because of its potential uses in manufacturing both pethidine itself and a range of N-substituted derivatives, but it has little opioid activity in its own right. Instead, norpethidine acts as a stimulant and causes convulsions.
Build up of norpethidine is a major complication when pethidine is used in medicine as an analgesic, as when pethidine is used in high doses or administered by intravenous infusion, norpethidine can accumulate in the body at a faster rate than it is being excreted, particularly in elderly patients or those with compromised liver or kidney function, resulting in a range of toxic effects, mainly convulsions, but also myoclonus and hyponatremia. These complications can be serious and have sometimes resulted in death.
Metabolism of pethidine to norpethidine is carried out mainly by CYP enzymes in the liver, and since the activity of these enzymes can vary between individuals, the rate and extent of norpethidine production can be difficult to predict. | Norpethidine
Norpethidine (Normeperidine, Pethidine Intermediate B) is a 4-phenylpiperidine derivative that is both a metabolite of and a precursor to pethidine (meperidine).
Norpethidine is a controlled drug because of its potential uses in manufacturing both pethidine itself and a range of N-substituted derivatives, but it has little opioid activity in its own right. Instead, norpethidine acts as a stimulant and causes convulsions.[1][2]
Build up of norpethidine is a major complication when pethidine is used in medicine as an analgesic, as when pethidine is used in high doses[3] or administered by intravenous infusion,[4] norpethidine can accumulate in the body at a faster rate than it is being excreted, particularly in elderly patients[5] or those with compromised liver or kidney function,[6] resulting in a range of toxic effects, mainly convulsions, but also myoclonus[7] and hyponatremia.[8] These complications can be serious and have sometimes resulted in death.[9]
Metabolism of pethidine to norpethidine is carried out mainly by CYP enzymes in the liver, and since the activity of these enzymes can vary between individuals, the rate and extent of norpethidine production can be difficult to predict.[10][11]
Template:Pharm-stub | https://www.wikidoc.org/index.php/Norpethidine | |
3c1c32be3d601986d88adab06fcb28c837aef4f5 | wikidoc | Nose-picking | Nose-picking
Nose-picking, or rhinotillexis (Greek, rhino "nose" + tillexis "habit of picking"), is the act of extracting mucus and/or foreign bodies from the nose with a finger or other object. This is an extremely common habit, with some surveys indicating that it is almost universal, with people picking their nose an average of about four times a day.
The mucus membranes constantly produce wet mucus that is exposed to dry inhaled air. Once dried, the mucus typically causes a sensation of irritation that leads to the compulsion to dislodge the itch via rhinotillexis. However, extreme nose picking resulting in severe nasal trauma is termed rhinotillexomania (etymology: Greek, rhino "nose" + tillexis "habit of picking" + mania), it may be caused by Obsessive Compulsive Disorder or Body Dysmorphic Disorder.
Although a very common habit, it is a mildly taboo subject in most cultures. While nose picking appears to be an almost universal practice amongst humans, the observation of the activity in another commonly provokes the basic emotion of disgust. The earliest record of nose picking comes from ancient Egypt, ca. 1330 BC, where a papyrus scroll found by the eminent archaeologist Dr. Wilbur Leakey details the financial payment of three heads of cattle, and food and lodging, to Tutankhamen's personal nose picker. A 1995 study into nose picking requesting information from 1000 randomly selected adults gathered 254 respondants. It defined nose picking as "the insertion of a finger (or other object) into the nose with the intention of removing dried nasal secretion." Of those whom responded, 91% were current nose pickers (but only 75% of these believed everyone did it) and 2 people spent between 15 to 30 minutes and 1 to >2 hours a day picking their nose.
Nose-picking may carry a number of medical risks, thus most doctors recommend against it and encourage the use of a tissue instead. Risks include nasal infections, occasional nosebleeds (in 25% of those who pick their nose) and in rare cases perforation of the nasal septum (self-induced ethmoidectomy). Nose picking, however, should not affect the sense of smell, as the nasal cavity where the olfactory nerves are located are too high up to reach. Also, due to the special nature of the blood supply to the nose and surrounding area, it is possible for retrograde infections from the nasal area to spread to the brain, although this scenario is unlikely to arise from normal rhinotillexisis. For this reason, the area from the corners of the mouth to the bridge of the nose, including the nose and maxilla, is known to doctors as the "danger triangle of the face." A minority of doctors claim that nose-picking, combined with nasal mucus eating, may benefit the immune system.
Children's literature often makes reference to it, to amuse readers (for example Jacques Charpentreau's poem "De l'Education!" and Gordon Korman's Nose Pickers series). John Allen Paulos's imaginary novel, Rucker: a life fractal has a section where "proboscis probing is discussed at length."
A popular saying holds that "You can pick your friends and you can pick your nose, but you can't pick your friends' noses." This phrase became the title of a talk show parody on Saturday Night Live on March 15, 1986; in that sketch, some members of a television panel attempted to have a discussion while their colleagues made efforts to pick each others' noses, thus earning a rebuke from the host for violating the rules of the show. | Nose-picking
Nose-picking, or rhinotillexis (Greek, rhino "nose" + tillexis "habit of picking"), is the act of extracting mucus and/or foreign bodies from the nose with a finger or other object. This is an extremely common habit, with some surveys indicating that it is almost universal, with people picking their nose an average of about four times a day.[1]
The mucus membranes constantly produce wet mucus that is exposed to dry inhaled air. Once dried, the mucus typically causes a sensation of irritation that leads to the compulsion to dislodge the itch via rhinotillexis. However, extreme nose picking resulting in severe nasal trauma is termed rhinotillexomania (etymology: Greek, rhino "nose" + tillexis "habit of picking" + mania), it may be caused by Obsessive Compulsive Disorder or Body Dysmorphic Disorder.[2]
Although a very common habit, it is a mildly taboo subject in most cultures. While nose picking appears to be an almost universal practice amongst humans, the observation of the activity in another commonly provokes the basic emotion of disgust. The earliest record of nose picking comes from ancient Egypt, ca. 1330 BC, where a papyrus scroll found by the eminent archaeologist Dr. Wilbur Leakey details the financial payment of three heads of cattle, and food and lodging, to Tutankhamen's personal nose picker.[3] A 1995 study into nose picking requesting information from 1000 randomly selected adults gathered 254 respondants. It defined nose picking as "the insertion of a finger (or other object) into the nose with the intention of removing dried nasal secretion." Of those whom responded, 91% were current nose pickers (but only 75% of these believed everyone did it) and 2 people spent between 15 to 30 minutes and 1 to >2 hours a day picking their nose.[4]
Nose-picking may carry a number of medical risks, thus most doctors recommend against it and encourage the use of a tissue instead. Risks include nasal infections, occasional nosebleeds (in 25% of those who pick their nose)[1] and in rare cases perforation of the nasal septum (self-induced ethmoidectomy).[5] Nose picking, however, should not affect the sense of smell, as the nasal cavity where the olfactory nerves are located are too high up to reach. Also, due to the special nature of the blood supply to the nose and surrounding area, it is possible for retrograde infections from the nasal area to spread to the brain, although this scenario is unlikely to arise from normal rhinotillexisis. For this reason, the area from the corners of the mouth to the bridge of the nose, including the nose and maxilla, is known to doctors as the "danger triangle of the face." A minority of doctors claim that nose-picking, combined with nasal mucus eating, may benefit the immune system.[6]
Children's literature often makes reference to it, to amuse readers (for example Jacques Charpentreau's poem "De l'Education!" and Gordon Korman's Nose Pickers series). John Allen Paulos's imaginary novel, Rucker: a life fractal has a section where "proboscis probing is discussed at length."[7]
A popular saying holds that "You can pick your friends and you can pick your nose, but you can't pick your friends' noses." This phrase became the title of a talk show parody on Saturday Night Live on March 15, 1986; in that sketch, some members of a television panel attempted to have a discussion while their colleagues made efforts to pick each others' noses, thus earning a rebuke from the host for violating the rules of the show. | https://www.wikidoc.org/index.php/Nose-picking | |
7473d348d1401db0d357562a0b5be2a950cb6e8a | wikidoc | Nuclear fuel | Nuclear fuel
Nuclear fuel is any material that can be consumed to derive nuclear energy, by analogy to chemical fuel that is burned to derive energy. By far the most common type of nuclear fuel is heavy fissile elements that can be made to undergo nuclear fission chain reactions in a nuclear fission reactor; nuclear fuel can refer to the material or to physical objects (for example fuel bundles composed of fuel rods) composed of the fuel material, perhaps mixed with structural, neutron moderating, or neutron reflecting materials. The most common fissile nuclear fuels are 235U and 239Pu, and the actions of mining, refining, purifying, using, and ultimately disposing of these elements together make up the nuclear fuel cycle, which is important for its relevance to nuclear power generation and nuclear weapons.
Not all nuclear fuels are used in fission chain reactions. For example, 238Pu and some other elements are used to produce small amounts of nuclear power by radioactive decay in radiothermal generators, and other atomic batteries. Light isotopes such as 3H (tritium) are used as fuel for nuclear fusion. If one looks at binding energy of specific isotopes, there can be an energy gain from fusing most elements with a lower atomic number than iron, and fissioning isotopes with a higher atomic number than iron.
# Oxide fuel
The thermal conductivity of uranium dioxide is low; it is affected by porosity and burn-up. The burn-up results in fission products being dissolved in the lattice (such as lanthanides), the precipitation of fission products such as palladium, the formation of fission gas bubbles due to fission products such as xenon and krypton and radiation damage of the lattice. The low thermal conductivity can lead to overheating of the center part of the pellets during use. The porosity results in a decrease in both the thermal conductivity of the fuel and the swelling which occurs during use.
According to the International Nuclear Safety Center the thermal conductivity of uranium dioxide can be predicted under different conditions by a series of equations.
The bulk density of the fuel can be related to the thermal conductivity
Where ρ is the bulk density of the fuel and ρtd is the theoretical density of the uranium dioxide.
Then the thermal conductivity of the porous phase (Kf)is related to the conductivity of the perfect phase (Ko, no porosity) by the following equation. Note that s is a term for the shape factor of the holes.
Rather than measuring the thermal conductivity using the traditional methods in physics such as lees's disk, the Forbes' method or Searle's bar it is common to use a laser flash method where a small disc of fuel is placed in a furnace. After being heated to the required temperature one side of the disc is illuminated with a laser pulse, the time required for the heat wave to flow through the disc, the density of the disc, and the thickness of the disk can then be used to calculated to give the thermal conductivity.
- λ thermal conductivity
- ρ density
- Cp heat capacity
- α thermal diffusivity
If t1/2 is defined as the time required for the non illuminated surface to experience half its final temperature rise then.
L is the thickness of the disc
For details see
## UOX
Uranium dioxide is a black semiconductor solid. It can be made by reacting uranyl nitrate with a base (ammonia) to form a solid (ammonium uranate). It is heated (calcined) to form U3O8 that can than be converted by heating in an argon / hydrogen mixture (700 oC) to form UO2. The UO2 is then mixed with an organic binder and pressed into pellets, these pellets are then fired at a much higher temperature (in H2/Ar) to sinter the solid. The aim is to form a dense solid which has few pores.
The thermal conductivity of uranium dioxide is very low compared with that of zirconium metal, and it goes down as the temperature goes up.
It is important to note that the corrosion of uranium dioxide in an aqueous environment is controlled by similar electrochemical processes to the galvanic corrosion of a metal surface.
## MOX
Mixed oxide, or MOX fuel, is a blend of plutonium and natural or depleted uranium which behaves similarly (though not identically) to the enriched uranium feed for which most nuclear reactors were designed. MOX fuel is an alternative to low enriched uranium (LEU) fuel used in the light water reactors which predominate nuclear power generation.
Some concern has been expressed that used MOX cores will introduce new disposal challenges, though MOX is itself a means to dispose of surplus plutonium by transmutation.
Currently (March, 2005) reprocessing of commercial nuclear fuel to make MOX is done in England and France, and to a lesser extent in Russia, India and Japan. China plans to develop fast breeder reactors and reprocessing.
The Global Nuclear Energy Partnership, is a U.S. plan to form an international partnership to see spent nuclear fuel reprocessed in a way that renders the plutonium in it usable for nuclear fuel but not for nuclear weapons. Reprocessing of spent commercial-reactor nuclear fuel has not been permitted in the United States due to nonproliferation considerations. All of the other reprocessing nations have long had nuclear weapons from military-focused "research"-reactor fuels except for Japan.
# Metal fuel
Metal fuels have the advantage of a much higher heat conductivity than oxide fuels but cannot survive equally high temperatures.
## TRIGA fuel
TRIGA fuel is used in TRIGA (Training, Research, Isotopes, General Atomics) reactors.
The TRIGA reactor uses uranium-zirconium-hydride (UZrH) fuel, which has a prompt negative temperature coefficient, meaning that as the temperature of the core increases, the reactivity decreases - so it is physically impossible for a meltdown to occur. Most cores that use this fuel are "high leakage" cores where the excess leaked neutrons can be utilized for research. TRIGA fuel was originally designed to use highly enriched uranium, however in 1978 the U.S. Department of Energy launched its Reduced Enrichment for Research Test Reactors program, which promoted reactor conversion to low-enriched uranium fuel. A total of 35 TRIGA reactors have been installed at locations across the USA. A further 35 reactors have been installed in other countries.
## Actinide Fuel
In a fast neutron reactor the minor actinides produced by neutron capture of uranium and plutonium can be used as fuel. Metal actinide fuel is typically an alloy of zirconium , uranium, plutonium and the minor actinides. It can be made inherently safe as thermal expansion of the metal alloy will increase neutron leakage.
# Less common chemical forms
### Ceramic fuels
Ceramic fuels other than oxides have the advantage of a high heat conductivities and melting points, but they are more prone to swelling than oxide fuels and are much less well understood.
This is often the fuel of choice for reactor designs that NASA produces, one advantage is that UN has a better thermal conductivity than UO2. Uranium nitride has a very high melting point. This fuel has the disadvantage that unless 15N was used (in place of the more common 14N) that a large amount of 14C would be generated from the nitrogen by the pn reaction. As the nitrogen required for such a fuel would be so expensive it is likely that the fuel would have to be reprocessed by a pyro method to enable to the 15N to be recovered. It is likely that if the fuel was processed and dissolved in nitric acid that the nitrogen enriched with 15N would be diluted with the common 14N.
Much of what is known about uranium carbide is in the form of pin-type fuel elements for liquid metal fast breeder reactors during their intense study during the 60's and 70's. However, recently there has been a revived interest in uranium carbide in the form of plate fuel and most notably, micro fuel particles (such as TRISO particles).
The high thermal conductivity and high melting point make uranium carbide an attractive fuel. In addition, because of the absence of oxygen in this fuel (during the course of radiation, excess gas pressure can build from the formation O2 or other gases) as well as the ability to compliment a ceramic coating (a ceramic-ceramic interface has structural and chemical advantages), uranium carbide could be the ideal fuel candidate for certain Generation IV reactors such as the gas-cooled fast reactor.
### Liquid fuels
These include fuels where the fuel is dissolved in the coolant. They were used in the molten salt reactor experiment and numerous other liquid core reactor experiments, such as the Liquid fluoride reactor. The liquid fuel for the molten salt reactor was LiF-BeF2-ThF4-UF4 (72-16-12-0.4 mol%), it had a peak operating temperature of 705 °C in the experiment but could have gone to much higher temperatures since the boiling point of the molten salt was in excess of 1400 °C.
The Aqueous Homogeneous Reactors uses a solution of uranyl sulfate or other uranium salt in water. This homogenous reactor type has not been used for any large power reactors. One of its disadvantages is that the fuel is in a form which is easy to disperse in the event of an accident.
# Common physical forms of nuclear fuel
For use as nuclear fuel, enriched UF6 is converted into uranium dioxide (UO2) powder that is then processed into pellet form. The pellets are then fired in a high-temperature, sintering furnace to create hard, ceramic pellets of enriched uranium. The cylindrical pellets then undergo a grinding process to achieve a uniform pellet size. The pellets are stacked, according to each nuclear core's design specifications, into tubes of corrosion-resistant metal alloy. The tubes are sealed to contain the fuel pellets: these tubes are called fuel rods. The finished fuel rods are grouped in special fuel assemblies that are then used to build up the nuclear fuel core of a power reactor.
The metal used for the tubes depends on the design of the reactor - stainless steel was used in the past, but most reactors now use a zirconium alloy. For the most common types of reactors (BWRs and PWRs) the tubes are assembled into bundles with the tubes spaced precise distances apart. These bundles are then given a unique identification number, which enables them to be tracked from manufacture through use and into disposal
## PWR fuel
Pressurized water reactor (PWR) fuel consists of cylindrical rods put into bundles. A uranium oxide ceramic is formed into pellets and inserted into Zircaloy tubes that are bundled together. The Zircaloy tubes are about 1 cm in diameter, and the fuel cladding gap is filled with helium gas to improve the conduction of heat from the fuel to the cladding. There are about 179-264 fuel rods per fuel bundle and about 121 to 193 fuel bundles are loaded into a reactor core. Generally, the fuel bundles consist of fuel rods bundled 14x14 to 17x17. PWR fuel bundles are about 4 meters in length. In PWR fuel bundles, control rods are inserted through the top directly into the fuel bundle. The fuel bundles usually are enriched several percent in 235U. The uranium oxide is dried before inserting into the tubes to try to eliminate moisture in the ceramic fuel that can lead to corrosion and hydrogen embrittlement. The Zircaloy tubes are pressurized with helium to try to minimize pellet cladding interaction (PCI) which can lead to fuel rod failure over long periods.
## BWR fuel
In boiling water reactors (BWR), the fuel is similar to PWR fuel except that the bundles are "canned"; that is, there is a thin tube surrounding each bundle. This is primarily done to prevent local density variations from effecting neutronics and thermal hydraulics of the nuclear core on a global scale. In modern BWR fuel bundles, there are either 91, 92, or 96 fuel rods per assembly depending on the manufacturer. A range between 368 assemblies for the smallest and 800 assemblies for the largest U.S. BWR forms the reactor core. Each BWR fuel rod is back filled with helium to a pressure of about three atmospheres (300 kPa).
## CANDU fuel
CANDU fuel bundles are about a half meter in length and 10 cm in diameter. They consist of sintered (UO2) pellets in Zirconium alloy tubes, welded to Zirconium alloy end plates. Each bundle is roughly 20 kg, and a typical core loading is on the order of 4500-6500 bundles, depending on the design. Modern types typically have 37 identical fuel pins radially arranged about the long axis of the bundle, but in the past several different configurations and numbers of pins have been used. The CANFLEX bundle has 43 fuel elements, with two element sizes. It is also about 10 cm (four inches) in diameter, 0.5 m (20 inches long) and weighs about 20 kg (44 lbs) and replaces 37-pin standard bundle. It has been designed specifically to increase fuel performance by utilizing two different pin diameters. Current CANDU designs do not need enriched uranium to achieve criticality (due to their more efficient heavy water moderator), however, some newer concepts call for low enrichment to help reduce the size of the reactors.
# Less common fuel forms
Various other nuclear fuel forms find use in specific applications, but lack the widespread use of those found in BWRs, PWRs, and CANDU power plants. Many of these fuel forms are only found in research reactors, or have military applications.
### TRISO fuel
Tristructural-isotropic (TRISO) fuel is a type of micro fuel particle. It consists of a fuel kernel composed of UOX (sometimes UC or UCO) in the center, coated with four layers of three isotropic materials. The four layers are a porous buffer layer made of carbon, followed by a dense inner layer of pyrolytic carbon (PyC), followed by a ceramic layer of SiC to retain fission products at elevated temperatures and to give the TRISO particle more structural integrity, followed by a dense outer layer of PyC. TRISO fuel particles are designed not to crack due to the stresses from processes (such as differential thermal expansion or fission gas pressure) at temperatures beyond 1600°C, and therefore can contain the fuel in the worst of accident scenarios in a properly designed reactor. Two such reactor designs are the pebble bed reactor (PBR), in which thousands of TRISO fuel particles are dispersed into graphite pebbles, and the prismatic-block gas-cooled reactor (such as the GT-MHR), in which the TRISO fuel particles are fabricated into compacts and placed in a graphite block matrix. Both of these reactor designs are very high temperature reactors (VHTR) , one of the six classes of reactor designs in the Generation IV initiative.
TRISO fuel particles were originally developed in Germany for high-temperature gas-cooled reactors. The first nuclear reactor to use TRISO fuels was the AVR and the first powerplant was the THTR-300. Currently, TRISO fuel compacts are being used in the experimental reactors, the HTR-10 in China, and the HTTR in Japan.
### RBMK fuel
RBMK reactor fuel was used in Soviet designed and built RBMK type reactors. This is a low enriched uranium oxide fuel. The fuel elements in an RBMK are 3m long each, and two of these sit back-to-back on each fuel channel, pressure tube. The nucler fuel that is used to make fuel for an RBMK is used (spent) fuel from possible a PWR, or VVER if of Russian design.
### CerMet fuel
CerMet fuel consists of ceramic fuel particles (usually uranium oxide) embedded in a metal matrix. It is hypothesized that this type of fuel is what is used in US Navy reactors. This fuel has high heat transport characteristics and can withstand a large amount of expansion.
### Plate type fuel
Plate type fuel has grown out of favor over the years. It is currently used in the Advanced Test Reactor (ATR) at Idaho National Laboratory.
# Spent nuclear fuel
Used nuclear fuel is a complex mixture of the fission products, uranium, plutonium and the transplutonium metals. In fuel which has been used at high temperature in power reactors it is common for the fuel not to be homogenous; often the fuel will contain nanoparticles of platinum group metals such as palladium. Also the fuel may well have cracked, swelled and been used close to its melting point. Despite the fact that the used fuel can be cracked it is very insoluble in water, and is able to retain the vast majority of the actinides and fission products within the uranium dioxide crystal lattice.
## Oxide fuel under accident conditions
Two main modes of release exist, the fission products can be vapourised or small particles of the fuel can be dispersed.
# Fuel behavior and post irradiation examination (PIE)
Materials in a high radiation environment (such as a reactor) can undergo unique behaviors such as swelling and non-thermal creep. If there are nuclear reactions within the material (such as what happens in the fuel), the stoichiometry will also change slowly over time. These behaviors can lead to new material properties, cracking, and fission gas release:
- Fission gas release
As the fuel is degraded or heated the more volatile fission products which are trapped within the uranium dioxide may become free. For example see J.Y. Colle, J.P. Hiernaut, D. Papaioannou, C. Ronchi, A. Sasahara, Journal of Nuclear Materials, 2006, 348, 229.
- As the fuel is degraded or heated the more volatile fission products which are trapped within the uranium dioxide may become free. For example see J.Y. Colle, J.P. Hiernaut, D. Papaioannou, C. Ronchi, A. Sasahara, Journal of Nuclear Materials, 2006, 348, 229.
- Fuel cracking
As the fuel expands on heating, the core of the pellet expands more than the rim which may lead to cracking. Because of the thermal stress thus formed the fuel cracks, the cracks tend to go from the centre to the edge in a star shaped pattern.
- As the fuel expands on heating, the core of the pellet expands more than the rim which may lead to cracking. Because of the thermal stress thus formed the fuel cracks, the cracks tend to go from the centre to the edge in a star shaped pattern.
In order to better understand and control these changes in materials, these behaviors are studied. A common experiment to do this is post irradiation examination, in which fuel will be examined after it is put through reactor-like conditions . Due to the intensely radioactive nature of the used fuel this is done in a hot cell. A combination of nondestructive and destructive methods of PIE are common.
The PIE is used to check that the fuel is both safe and effective. After major accidents the core (or what is left of it) is normally subject to PIE in order to find out what happened. One site where PIE is done is the ITU which is the EU centre for the study of highly radioactive materials.
In addition to the effects of radiation and the fission products on materials, scientists also need to consider the temperature of materials in a reactor, and in particular, the fuel. Too high of fuel temperatures can compromise the fuel, and therefore it is important to control the temperature in order to control the fission chain reaction.
The temperature of the fuel varies as a function of the distance from the centre to the rim. At distance x from the centre the temperature (Tx) is described by the equation where ρ is the power density (W m-3) and Kf is the thermal conductivity.
To explain this for a series of fuel pellets being used with a rim temperature of 200 oC (typical for a BWR) with different diameters and power densities of 250 MW m-3 have been modeled using the above equation. Note that these fuel pellets are rather large; it is normal to use oxide pellets which are about 10 mm in diameter.
Reference Radiochemistry and Nuclear Chemistry, G. Choppin, J-O Liljenzin and J. Rydberg, 3rd Ed, 2002, Butterworth-Heinemann, ISBN 0-7506-7463-6
# Radioisotope decay fuels
## Radioisotope battery
The terms atomic battery, nuclear battery and radioisotope battery are used interchangely to describe a device which uses the radioactive decay to generate electricity. These systems use radioisotopes that produce low energy beta particles or sometimes alpha particles of varying energies. Low energy beta particles are needed to prevent the production of high energy penetrating Bremsstrahlung radiation that would require heavy shielding. Radioisotopes such as tritium, nickel-63, promethium-147, and technetium-99 have been tested. Plutonium-238, curium-242, curium-244 and strontium-90 have been used.
There are two main categories of atomic batteries: thermal and non-thermal. The non-thermal atomic batteries, which have many different designs, exploit charged alpha and beta particles. These designs include the direct charging generators, Betavoltaics, the optoelectric nuclear battery, and the radioisotope piezoelectric generator. The thermal atomic batteries on the other hand, convert the heat from the radioactive decay to electricity. These designs include thermionic converter, thermophotovoltaic cells, alkali-metal thermal to electric converter, and the most common design, the radioisotope thermoelectric generator.
## Radioisotope thermoelectric generators
A radioisotope thermoelectric generator (RTG) is a simple electrical generator which converts heat into electricity from a radioisotope using an array of thermocouples.
238Pu has become the most widely used fuel for RTGs. In the form of plutonium dioxide it has a half-life of 87.7 years, reasonable energy density and exceptionally low gamma and neutron radiation levels. Some Russian terrestrial RTGs have used 90Sr; this isotope has a shorter half-life and a much lower energy density, but is cheaper. Early RTGs, first built in 1958 by the U.S. Atomic Energy Commission, have used 210Po. This fuel provides phenomenally huge energy density, (a single gram of polonium-210 generates 140 watts thermal) but has limited use because of its very short half-life and gamma production and has been phased out of use in this application.
## Radioisotope heater units (RHU)
Radioisotope heater units normally provide about 1 watt of heat each, derived from the decay of a few grams of Plutonium-238. This heat is given off continuously for several decades.
Their function is to provide highly localised heating of sensitive equipment (such as electronics) in deep space. The Cassini-Huygens orbiter to Saturn contains 82 of these units (in addition to its 3 main RTG's for power generation). The Huygens probe to Titan contains 35 devices.
# Fusion fuels
Most fusion fuels fit in here. They include tritium (3H) and deuterium (2H) as well as helium three (3He). Many other elements can be fused together if they can be forced close enough to each other at high enough temperatures. In general, fusion fuels are expected to have at least three generations based on the ease of fusing light atomic nuclei together.
## First generation fusion fuel
Deuterium and tritium are both considered first-generation fusion fuels; with many permutations in which they can be fused together. The three most commonly cited are;
## Second generation fusion fuel
Second generation fuels require either higher confinement temperatures or longer confinement time than those required of first generation fusion fuels. This group consists of deuterium and helium three. The products of these reactants are all charged particles, but there may be non-beneficial side reactions leading to radioactive activation of fusion reactor components.
## Third generation fusion fuel
There are several potential third generation fusion fuels. Third generation fusion fuels produce only charged particles in the primary reactions and any side reactions are relatively unimportant. Therefore, there would be little radioactive activation of the fusion reactor. This is often seen as the end goal of fusion research. 3He has the highest Maxwellian reactivity of any 3rd generation fusion fuel, but there are no significant natural sources of this substance on Earth.
Another potential aneutronic fusion reaction is the proton-boron reaction:
Under reasonable assumptions, side reactions will result in about 0.1% of the fusion power being carried by neutrons. With 123 keV, the optimum temperature for this reaction is nearly ten times higher than that for the pure hydrogen reactions, the energy confinement must be 500 times better than that required for the D-T reaction, and the power density will be 2500 times lower than for D-T. | Nuclear fuel
Nuclear fuel is any material that can be consumed to derive nuclear energy, by analogy to chemical fuel that is burned to derive energy. By far the most common type of nuclear fuel is heavy fissile elements that can be made to undergo nuclear fission chain reactions in a nuclear fission reactor; nuclear fuel can refer to the material or to physical objects (for example fuel bundles composed of fuel rods) composed of the fuel material, perhaps mixed with structural, neutron moderating, or neutron reflecting materials. The most common fissile nuclear fuels are 235U and 239Pu, and the actions of mining, refining, purifying, using, and ultimately disposing of these elements together make up the nuclear fuel cycle, which is important for its relevance to nuclear power generation and nuclear weapons.
Not all nuclear fuels are used in fission chain reactions. For example, 238Pu and some other elements are used to produce small amounts of nuclear power by radioactive decay in radiothermal generators, and other atomic batteries. Light isotopes such as 3H (tritium) are used as fuel for nuclear fusion. If one looks at binding energy of specific isotopes, there can be an energy gain from fusing most elements with a lower atomic number than iron, and fissioning isotopes with a higher atomic number than iron.
# Oxide fuel
The thermal conductivity of uranium dioxide is low; it is affected by porosity and burn-up. The burn-up results in fission products being dissolved in the lattice (such as lanthanides), the precipitation of fission products such as palladium, the formation of fission gas bubbles due to fission products such as xenon and krypton and radiation damage of the lattice. The low thermal conductivity can lead to overheating of the center part of the pellets during use. The porosity results in a decrease in both the thermal conductivity of the fuel and the swelling which occurs during use.
According to the International Nuclear Safety Center [1] the thermal conductivity of uranium dioxide can be predicted under different conditions by a series of equations.
The bulk density of the fuel can be related to the thermal conductivity
Where ρ is the bulk density of the fuel and ρtd is the theoretical density of the uranium dioxide.
Then the thermal conductivity of the porous phase (Kf)is related to the conductivity of the perfect phase (Ko, no porosity) by the following equation. Note that s is a term for the shape factor of the holes.
Rather than measuring the thermal conductivity using the traditional methods in physics such as lees's disk, the Forbes' method or Searle's bar it is common to use a laser flash method where a small disc of fuel is placed in a furnace. After being heated to the required temperature one side of the disc is illuminated with a laser pulse, the time required for the heat wave to flow through the disc, the density of the disc, and the thickness of the disk can then be used to calculated to give the thermal conductivity.
- λ thermal conductivity
- ρ density
- Cp heat capacity
- α thermal diffusivity
If t1/2 is defined as the time required for the non illuminated surface to experience half its final temperature rise then.
L is the thickness of the disc
For details see [2]
## UOX
Uranium dioxide is a black semiconductor solid. It can be made by reacting uranyl nitrate with a base (ammonia) to form a solid (ammonium uranate). It is heated (calcined) to form U3O8 that can than be converted by heating in an argon / hydrogen mixture (700 oC) to form UO2. The UO2 is then mixed with an organic binder and pressed into pellets, these pellets are then fired at a much higher temperature (in H2/Ar) to sinter the solid. The aim is to form a dense solid which has few pores.
The thermal conductivity of uranium dioxide is very low compared with that of zirconium metal, and it goes down as the temperature goes up.
It is important to note that the corrosion of uranium dioxide in an aqueous environment is controlled by similar electrochemical processes to the galvanic corrosion of a metal surface.
## MOX
Mixed oxide, or MOX fuel, is a blend of plutonium and natural or depleted uranium which behaves similarly (though not identically) to the enriched uranium feed for which most nuclear reactors were designed. MOX fuel is an alternative to low enriched uranium (LEU) fuel used in the light water reactors which predominate nuclear power generation.
Some concern has been expressed that used MOX cores will introduce new disposal challenges, though MOX is itself a means to dispose of surplus plutonium by transmutation.
Currently (March, 2005) reprocessing of commercial nuclear fuel to make MOX is done in England and France, and to a lesser extent in Russia, India and Japan. China plans to develop fast breeder reactors and reprocessing.
The Global Nuclear Energy Partnership, is a U.S. plan to form an international partnership to see spent nuclear fuel reprocessed in a way that renders the plutonium in it usable for nuclear fuel but not for nuclear weapons. Reprocessing of spent commercial-reactor nuclear fuel has not been permitted in the United States due to nonproliferation considerations. All of the other reprocessing nations have long had nuclear weapons from military-focused "research"-reactor fuels except for Japan.
# Metal fuel
Metal fuels have the advantage of a much higher heat conductivity than oxide fuels but cannot survive equally high temperatures.
## TRIGA fuel
TRIGA fuel is used in TRIGA (Training, Research, Isotopes, General Atomics) reactors.
The TRIGA reactor uses uranium-zirconium-hydride (UZrH) fuel, which has a prompt negative temperature coefficient, meaning that as the temperature of the core increases, the reactivity decreases - so it is physically impossible for a meltdown to occur. Most cores that use this fuel are "high leakage" cores where the excess leaked neutrons can be utilized for research. TRIGA fuel was originally designed to use highly enriched uranium, however in 1978 the U.S. Department of Energy launched its Reduced Enrichment for Research Test Reactors program, which promoted reactor conversion to low-enriched uranium fuel. A total of 35 TRIGA reactors have been installed at locations across the USA. A further 35 reactors have been installed in other countries.
## Actinide Fuel
In a fast neutron reactor the minor actinides produced by neutron capture of uranium and plutonium can be used as fuel. Metal actinide fuel is typically an alloy of zirconium , uranium, plutonium and the minor actinides. It can be made inherently safe as thermal expansion of the metal alloy will increase neutron leakage.
# Less common chemical forms
### Ceramic fuels
Ceramic fuels other than oxides have the advantage of a high heat conductivities and melting points, but they are more prone to swelling than oxide fuels and are much less well understood.
This is often the fuel of choice for reactor designs that NASA produces, one advantage is that UN has a better thermal conductivity than UO2. Uranium nitride has a very high melting point. This fuel has the disadvantage that unless 15N was used (in place of the more common 14N) that a large amount of 14C would be generated from the nitrogen by the pn reaction. As the nitrogen required for such a fuel would be so expensive it is likely that the fuel would have to be reprocessed by a pyro method to enable to the 15N to be recovered. It is likely that if the fuel was processed and dissolved in nitric acid that the nitrogen enriched with 15N would be diluted with the common 14N.
Much of what is known about uranium carbide is in the form of pin-type fuel elements for liquid metal fast breeder reactors during their intense study during the 60's and 70's. However, recently there has been a revived interest in uranium carbide in the form of plate fuel and most notably, micro fuel particles (such as TRISO particles).
The high thermal conductivity and high melting point make uranium carbide an attractive fuel. In addition, because of the absence of oxygen in this fuel (during the course of radiation, excess gas pressure can build from the formation O2 or other gases) as well as the ability to compliment a ceramic coating (a ceramic-ceramic interface has structural and chemical advantages), uranium carbide could be the ideal fuel candidate for certain Generation IV reactors such as the gas-cooled fast reactor.
### Liquid fuels
These include fuels where the fuel is dissolved in the coolant. They were used in the molten salt reactor experiment and numerous other liquid core reactor experiments, such as the Liquid fluoride reactor. The liquid fuel for the molten salt reactor was LiF-BeF2-ThF4-UF4 (72-16-12-0.4 mol%), it had a peak operating temperature of 705 °C in the experiment but could have gone to much higher temperatures since the boiling point of the molten salt was in excess of 1400 °C.
The Aqueous Homogeneous Reactors uses a solution of uranyl sulfate or other uranium salt in water. This homogenous reactor type has not been used for any large power reactors. One of its disadvantages is that the fuel is in a form which is easy to disperse in the event of an accident.
# Common physical forms of nuclear fuel
For use as nuclear fuel, enriched UF6 is converted into uranium dioxide (UO2) powder that is then processed into pellet form. The pellets are then fired in a high-temperature, sintering furnace to create hard, ceramic pellets of enriched uranium. The cylindrical pellets then undergo a grinding process to achieve a uniform pellet size. The pellets are stacked, according to each nuclear core's design specifications, into tubes of corrosion-resistant metal alloy. The tubes are sealed to contain the fuel pellets: these tubes are called fuel rods. The finished fuel rods are grouped in special fuel assemblies that are then used to build up the nuclear fuel core of a power reactor.
The metal used for the tubes depends on the design of the reactor - stainless steel was used in the past, but most reactors now use a zirconium alloy. For the most common types of reactors (BWRs and PWRs) the tubes are assembled into bundles with the tubes spaced precise distances apart. These bundles are then given a unique identification number, which enables them to be tracked from manufacture through use and into disposal
## PWR fuel
Pressurized water reactor (PWR) fuel consists of cylindrical rods put into bundles. A uranium oxide ceramic is formed into pellets and inserted into Zircaloy tubes that are bundled together. The Zircaloy tubes are about 1 cm in diameter, and the fuel cladding gap is filled with helium gas to improve the conduction of heat from the fuel to the cladding. There are about 179-264 fuel rods per fuel bundle and about 121 to 193 fuel bundles are loaded into a reactor core. Generally, the fuel bundles consist of fuel rods bundled 14x14 to 17x17. PWR fuel bundles are about 4 meters in length. In PWR fuel bundles, control rods are inserted through the top directly into the fuel bundle. The fuel bundles usually are enriched several percent in 235U. The uranium oxide is dried before inserting into the tubes to try to eliminate moisture in the ceramic fuel that can lead to corrosion and hydrogen embrittlement. The Zircaloy tubes are pressurized with helium to try to minimize pellet cladding interaction (PCI) which can lead to fuel rod failure over long periods.
## BWR fuel
In boiling water reactors (BWR), the fuel is similar to PWR fuel except that the bundles are "canned"; that is, there is a thin tube surrounding each bundle. This is primarily done to prevent local density variations from effecting neutronics and thermal hydraulics of the nuclear core on a global scale. In modern BWR fuel bundles, there are either 91, 92, or 96 fuel rods per assembly depending on the manufacturer. A range between 368 assemblies for the smallest and 800 assemblies for the largest U.S. BWR forms the reactor core. Each BWR fuel rod is back filled with helium to a pressure of about three atmospheres (300 kPa).
## CANDU fuel
CANDU fuel bundles are about a half meter in length and 10 cm in diameter. They consist of sintered (UO2) pellets in Zirconium alloy tubes, welded to Zirconium alloy end plates. Each bundle is roughly 20 kg, and a typical core loading is on the order of 4500-6500 bundles, depending on the design. Modern types typically have 37 identical fuel pins radially arranged about the long axis of the bundle, but in the past several different configurations and numbers of pins have been used. The CANFLEX bundle has 43 fuel elements, with two element sizes. It is also about 10 cm (four inches) in diameter, 0.5 m (20 inches long) and weighs about 20 kg (44 lbs) and replaces 37-pin standard bundle. It has been designed specifically to increase fuel performance by utilizing two different pin diameters. Current CANDU designs do not need enriched uranium to achieve criticality (due to their more efficient heavy water moderator), however, some newer concepts call for low enrichment to help reduce the size of the reactors.
# Less common fuel forms
Various other nuclear fuel forms find use in specific applications, but lack the widespread use of those found in BWRs, PWRs, and CANDU power plants. Many of these fuel forms are only found in research reactors, or have military applications.
### TRISO fuel
Tristructural-isotropic (TRISO) fuel is a type of micro fuel particle. It consists of a fuel kernel composed of UOX (sometimes UC or UCO) in the center, coated with four layers of three isotropic materials. The four layers are a porous buffer layer made of carbon, followed by a dense inner layer of pyrolytic carbon (PyC), followed by a ceramic layer of SiC to retain fission products at elevated temperatures and to give the TRISO particle more structural integrity, followed by a dense outer layer of PyC. TRISO fuel particles are designed not to crack due to the stresses from processes (such as differential thermal expansion or fission gas pressure) at temperatures beyond 1600°C, and therefore can contain the fuel in the worst of accident scenarios in a properly designed reactor. Two such reactor designs are the pebble bed reactor (PBR), in which thousands of TRISO fuel particles are dispersed into graphite pebbles, and the prismatic-block gas-cooled reactor (such as the GT-MHR), in which the TRISO fuel particles are fabricated into compacts and placed in a graphite block matrix. Both of these reactor designs are very high temperature reactors (VHTR) [formally known as the high-temperature gas-cooled reactors (HTGR)], one of the six classes of reactor designs in the Generation IV initiative.
TRISO fuel particles were originally developed in Germany for high-temperature gas-cooled reactors. The first nuclear reactor to use TRISO fuels was the AVR and the first powerplant was the THTR-300. Currently, TRISO fuel compacts are being used in the experimental reactors, the HTR-10 in China, and the HTTR in Japan.
### RBMK fuel
RBMK reactor fuel was used in Soviet designed and built RBMK type reactors. This is a low enriched uranium oxide fuel. The fuel elements in an RBMK are 3m long each, and two of these sit back-to-back on each fuel channel, pressure tube. The nucler fuel that is used to make fuel for an RBMK is used (spent) fuel from possible a PWR, or VVER if of Russian design.
### CerMet fuel
CerMet fuel consists of ceramic fuel particles (usually uranium oxide) embedded in a metal matrix. It is hypothesized that this type of fuel is what is used in US Navy reactors. This fuel has high heat transport characteristics and can withstand a large amount of expansion.
### Plate type fuel
Plate type fuel has grown out of favor over the years. It is currently used in the Advanced Test Reactor (ATR) at Idaho National Laboratory.
# Spent nuclear fuel
Used nuclear fuel is a complex mixture of the fission products, uranium, plutonium and the transplutonium metals. In fuel which has been used at high temperature in power reactors it is common for the fuel not to be homogenous; often the fuel will contain nanoparticles of platinum group metals such as palladium. Also the fuel may well have cracked, swelled and been used close to its melting point. Despite the fact that the used fuel can be cracked it is very insoluble in water, and is able to retain the vast majority of the actinides and fission products within the uranium dioxide crystal lattice.
## Oxide fuel under accident conditions
Two main modes of release exist, the fission products can be vapourised or small particles of the fuel can be dispersed.
# Fuel behavior and post irradiation examination (PIE)
Materials in a high radiation environment (such as a reactor) can undergo unique behaviors such as swelling[3] and non-thermal creep. If there are nuclear reactions within the material (such as what happens in the fuel), the stoichiometry will also change slowly over time. These behaviors can lead to new material properties, cracking, and fission gas release:
- Fission gas release
As the fuel is degraded or heated the more volatile fission products which are trapped within the uranium dioxide may become free. For example see J.Y. Colle, J.P. Hiernaut, D. Papaioannou, C. Ronchi, A. Sasahara, Journal of Nuclear Materials, 2006, 348, 229.
- As the fuel is degraded or heated the more volatile fission products which are trapped within the uranium dioxide may become free. For example see J.Y. Colle, J.P. Hiernaut, D. Papaioannou, C. Ronchi, A. Sasahara, Journal of Nuclear Materials, 2006, 348, 229.
- Fuel cracking
As the fuel expands on heating, the core of the pellet expands more than the rim which may lead to cracking. Because of the thermal stress thus formed the fuel cracks, the cracks tend to go from the centre to the edge in a star shaped pattern.
- As the fuel expands on heating, the core of the pellet expands more than the rim which may lead to cracking. Because of the thermal stress thus formed the fuel cracks, the cracks tend to go from the centre to the edge in a star shaped pattern.
In order to better understand and control these changes in materials, these behaviors are studied. A common experiment to do this is post irradiation examination, in which fuel will be examined after it is put through reactor-like conditions [4][5] [6] [7]. Due to the intensely radioactive nature of the used fuel this is done in a hot cell. A combination of nondestructive and destructive methods of PIE are common.
The PIE is used to check that the fuel is both safe and effective. After major accidents the core (or what is left of it) is normally subject to PIE in order to find out what happened. One site where PIE is done is the ITU which is the EU centre for the study of highly radioactive materials.
In addition to the effects of radiation and the fission products on materials, scientists also need to consider the temperature of materials in a reactor, and in particular, the fuel. Too high of fuel temperatures can compromise the fuel, and therefore it is important to control the temperature in order to control the fission chain reaction.
The temperature of the fuel varies as a function of the distance from the centre to the rim. At distance x from the centre the temperature (Tx) is described by the equation where ρ is the power density (W m-3) and Kf is the thermal conductivity.
To explain this for a series of fuel pellets being used with a rim temperature of 200 oC (typical for a BWR) with different diameters and power densities of 250 MW m-3 have been modeled using the above equation. Note that these fuel pellets are rather large; it is normal to use oxide pellets which are about 10 mm in diameter.
Reference Radiochemistry and Nuclear Chemistry, G. Choppin, J-O Liljenzin and J. Rydberg, 3rd Ed, 2002, Butterworth-Heinemann, ISBN 0-7506-7463-6
# Radioisotope decay fuels
## Radioisotope battery
The terms atomic battery, nuclear battery and radioisotope battery are used interchangely to describe a device which uses the radioactive decay to generate electricity. These systems use radioisotopes that produce low energy beta particles or sometimes alpha particles of varying energies. Low energy beta particles are needed to prevent the production of high energy penetrating Bremsstrahlung radiation that would require heavy shielding. Radioisotopes such as tritium, nickel-63, promethium-147, and technetium-99 have been tested. Plutonium-238, curium-242, curium-244 and strontium-90 have been used.
There are two main categories of atomic batteries: thermal and non-thermal. The non-thermal atomic batteries, which have many different designs, exploit charged alpha and beta particles. These designs include the direct charging generators, Betavoltaics, the optoelectric nuclear battery, and the radioisotope piezoelectric generator. The thermal atomic batteries on the other hand, convert the heat from the radioactive decay to electricity. These designs include thermionic converter, thermophotovoltaic cells, alkali-metal thermal to electric converter, and the most common design, the radioisotope thermoelectric generator.
## Radioisotope thermoelectric generators
A radioisotope thermoelectric generator (RTG) is a simple electrical generator which converts heat into electricity from a radioisotope using an array of thermocouples.
238Pu has become the most widely used fuel for RTGs. In the form of plutonium dioxide it has a half-life of 87.7 years, reasonable energy density and exceptionally low gamma and neutron radiation levels. Some Russian terrestrial RTGs have used 90Sr; this isotope has a shorter half-life and a much lower energy density, but is cheaper. Early RTGs, first built in 1958 by the U.S. Atomic Energy Commission, have used 210Po. This fuel provides phenomenally huge energy density, (a single gram of polonium-210 generates 140 watts thermal) but has limited use because of its very short half-life and gamma production and has been phased out of use in this application.
## Radioisotope heater units (RHU)
Radioisotope heater units normally provide about 1 watt of heat each, derived from the decay of a few grams of Plutonium-238. This heat is given off continuously for several decades.
Their function is to provide highly localised heating of sensitive equipment (such as electronics) in deep space. The Cassini-Huygens orbiter to Saturn contains 82 of these units (in addition to its 3 main RTG's for power generation). The Huygens probe to Titan contains 35 devices.
# Fusion fuels
Most fusion fuels fit in here. They include tritium (3H) and deuterium (2H) as well as helium three (3He). Many other elements can be fused together if they can be forced close enough to each other at high enough temperatures. In general, fusion fuels are expected to have at least three generations based on the ease of fusing light atomic nuclei together.
## First generation fusion fuel
Deuterium and tritium are both considered first-generation fusion fuels; with many permutations in which they can be fused together. The three most commonly cited are;
## Second generation fusion fuel
Second generation fuels require either higher confinement temperatures or longer confinement time than those required of first generation fusion fuels. This group consists of deuterium and helium three. The products of these reactants are all charged particles, but there may be non-beneficial side reactions leading to radioactive activation of fusion reactor components.
## Third generation fusion fuel
There are several potential third generation fusion fuels. Third generation fusion fuels produce only charged particles in the primary reactions and any side reactions are relatively unimportant. Therefore, there would be little radioactive activation of the fusion reactor. This is often seen as the end goal of fusion research. 3He has the highest Maxwellian reactivity of any 3rd generation fusion fuel, but there are no significant natural sources of this substance on Earth.
Another potential aneutronic fusion reaction is the proton-boron reaction:
Under reasonable assumptions, side reactions will result in about 0.1% of the fusion power being carried by neutrons. With 123 keV, the optimum temperature for this reaction is nearly ten times higher than that for the pure hydrogen reactions, the energy confinement must be 500 times better than that required for the D-T reaction, and the power density will be 2500 times lower than for D-T. | https://www.wikidoc.org/index.php/Nuclear_fuel | |
6bd2d2d9a3fa10a154af26e1a2e8ff164949fc2f | wikidoc | Nuclear pore | Nuclear pore
Nuclear pores are large protein complexes that cross the nuclear envelope, which is the double membrane surrounding the eukaryotic cell nucleus. There are about on average 2000 nuclear pore complexes in the nuclear envelope of a vertebrate cell, but it varies depending on the number of transcriptions of the cell. The proteins that make up the nuclear pore complex are known as nucleoporins. About half of the nucleoporins typically contain either an alpha solenoid or a beta-propeller fold, or in some cases both as separate structural domains. The other half exhibit structural characteristics typical of "natively unfolded" proteins, i.e. they are highly flexible proteins that lack ordered secondary structure. These disordered proteins are the FG nucleoporins, so called because their amino-acid sequence contains many repeats of the peptide phenylalanine—glycine.
Nuclear pores allow the transport of water-soluble molecules across the nuclear envelope. This transport includes RNA and ribosomes moving from nucleus to the cytoplasm and proteins (such as DNA polymerase and lamins), carbohydrates, signal molecules and lipids moving into the nucleus. It is notable that the nuclear pore complex (NPC) can actively conduct 1000 translocations per complex per second. Although smaller molecules simply diffuse through the pores, larger molecules may be recognized by specific signal sequences and then be diffused with the help of nucleoporins into or out of the nucleus. This is known as the RAN cycle. Each of the eight protein subunits surrounding the actual pore (the outer ring) projects a spoke-shaped protein into the pore channel. The center of the pore often appears to contains a plug-like structure. It is yet unknown whether this corresponds to an actual plug or is merely cargo caught in transit.
# Size and complexity
The entire pore complex has a diameter of about 120 nm, the diameter of the opening is about 50 nm wide and its "depth" is about 200 nm. The molecular mass of the NPC is about 125 million dalton and contains approximately 50 different proteins components.
# Transport through the nuclear pore complex
Small particles (< 50 kDa) are able to pass through the nuclear pore complex by passive diffusion. Larger particles are also able to pass through the large diameter of the pore but at almost negligible rates. Efficient passage through the complex requires several protein factors. Karyopherins, which may act as importins or exportins are part of the Importin-β super-family which all share a similar three-dimensional structure.
Three models have been suggested to explain the translocation mechanism:
- Affinity gradients along the central plug
- Brownian affinity gating
- Selective phase
## Import of proteins
Any cargo with a nuclear localization signal (NLS) exposed will be destined for quick and efficient transport through the pore. Several NLS sequences are known, generally containing a conserved polypeptide sequence with basic residues such as PKKKRKV. Any material with an NLS will be taken up by importins to the nucleus.
The classical scheme of NLS-protein importation begins with Importin-α first binding to the NLS sequence, and acts as a bridge for Importin-β to attach. The importinβ—importinα—cargo complex is then directed towards the nuclear pore and diffuses through it. Once the complex is in the nucleus, RanGTP binds to Importin-β and displaces it from the complex. Then the cellular apoptosis susceptibility protein (CAS), an exportin which in the nucleus is bound to RanGTP, displaces Importin-α from the cargo. The NLS-protein is thus free in the nucleoplasm. The Importinβ-RanGTP and Importinα-CAS-RanGTP complex diffuses back to the cytoplasm where GTPs are hydrolyzed to GDP leading to the release of Importinβ and Importinα which become available for a new NLS-protein import round.
Although cargo passes through the pore with the assistance of chaperone proteins, the translocation through the pore itself is not energy dependent. However, the whole import cycle needs the hydrolysis of 2 GTPs and is thus energy dependent and has to be considered as active transport. The import cycle is powered by the nucleo-cytoplasmic RanGTP gradient. This gradient arises from the exclusive nuclear localization of RanGEFs, proteins that exchange GDP to GTP on Ran molecules. Thus there is an elevated RanGTP concentration in the nucleus compared to the cytoplasm.
## Export of proteins
Some nuclear proteins need to be exported from the nucleus to the cytoplasm, as do ribosome subunits and messenger RNAs. Thus there is an export mechanism similar to the import mechanism.
In the classical export scheme, proteins with an nuclear export sequence (NES) can bind in the nucleus to form a heterotrimeric complex with an exportin and RanGTP (for example the exportin CRM1). The complex can then diffuse to the cytoplasm where GTP is hydrolysed and the NES-protein is released. CRM1-RanGDP diffuses back to the nucleus where GDP is exchanged to GTP by RanGEFs. This process is also energy dependent as it consumes one GTP. Export with the exportin CRM1 can be inhibited by Leptomycin B.
## Export of RNA
Different export pathways from NPC for each RNA class exist. RNA export is also signal mediated (NES), the NES is in RNA-binding proteins (except for tRNA which has no adapter). It is notable that all viral RNAs and cellular RNAs (tRNA, rRNA, U snRNA, microRNA) except mRNA are dependent on RanGTP. Conseved mRNA export factors are necessary for mRNA nuclear export. Export factors are Mex67/Tap (large subunit) and Mtr2/p15 (small subunit). An adapter binds to the large export factor subunit mediating the export process.
# Additional images
- The Ran-GTP cycle | Nuclear pore
Nuclear pores are large protein complexes that cross the nuclear envelope, which is the double membrane surrounding the eukaryotic cell nucleus. There are about on average 2000 nuclear pore complexes in the nuclear envelope of a vertebrate cell, but it varies depending on the number of transcriptions of the cell. The proteins that make up the nuclear pore complex are known as nucleoporins. About half of the nucleoporins typically contain either an alpha solenoid or a beta-propeller fold, or in some cases both as separate structural domains. The other half exhibit structural characteristics typical of "natively unfolded" proteins, i.e. they are highly flexible proteins that lack ordered secondary structure.[1] These disordered proteins are the FG nucleoporins, so called because their amino-acid sequence contains many repeats of the peptide phenylalanine—glycine.[2]
Nuclear pores allow the transport of water-soluble molecules across the nuclear envelope. This transport includes RNA and ribosomes moving from nucleus to the cytoplasm and proteins (such as DNA polymerase and lamins), carbohydrates, signal molecules and lipids moving into the nucleus. It is notable that the nuclear pore complex (NPC) can actively conduct 1000 translocations per complex per second. Although smaller molecules simply diffuse through the pores, larger molecules may be recognized by specific signal sequences and then be diffused with the help of nucleoporins into or out of the nucleus. This is known as the RAN cycle. Each of the eight protein subunits surrounding the actual pore (the outer ring) projects a spoke-shaped protein into the pore channel. The center of the pore often appears to contains a plug-like structure. It is yet unknown whether this corresponds to an actual plug or is merely cargo caught in transit.
# Size and complexity
The entire pore complex has a diameter of about 120 nm, the diameter of the opening is about 50 nm wide and its "depth" is about 200 nm.[citation needed] The molecular mass of the NPC is about 125 million dalton and contains approximately 50 different proteins components.
# Transport through the nuclear pore complex
Small particles (< 50 kDa) are able to pass through the nuclear pore complex by passive diffusion. Larger particles are also able to pass through the large diameter of the pore but at almost negligible rates.[3] Efficient passage through the complex requires several protein factors.[4] Karyopherins, which may act as importins or exportins are part of the Importin-β super-family which all share a similar three-dimensional structure.
Three models have been suggested to explain the translocation mechanism:
- Affinity gradients along the central plug
- Brownian affinity gating
- Selective phase
## Import of proteins
Any cargo with a nuclear localization signal (NLS) exposed will be destined for quick and efficient transport through the pore. Several NLS sequences are known, generally containing a conserved polypeptide sequence with basic residues such as PKKKRKV. Any material with an NLS will be taken up by importins to the nucleus.
The classical scheme of NLS-protein importation begins with Importin-α first binding to the NLS sequence, and acts as a bridge for Importin-β to attach. The importinβ—importinα—cargo complex is then directed towards the nuclear pore and diffuses through it. Once the complex is in the nucleus, RanGTP binds to Importin-β and displaces it from the complex. Then the cellular apoptosis susceptibility protein (CAS), an exportin which in the nucleus is bound to RanGTP, displaces Importin-α from the cargo. The NLS-protein is thus free in the nucleoplasm. The Importinβ-RanGTP and Importinα-CAS-RanGTP complex diffuses back to the cytoplasm where GTPs are hydrolyzed to GDP leading to the release of Importinβ and Importinα which become available for a new NLS-protein import round.
Although cargo passes through the pore with the assistance of chaperone proteins, the translocation through the pore itself is not energy dependent. However, the whole import cycle needs the hydrolysis of 2 GTPs and is thus energy dependent and has to be considered as active transport. The import cycle is powered by the nucleo-cytoplasmic RanGTP gradient. This gradient arises from the exclusive nuclear localization of RanGEFs, proteins that exchange GDP to GTP on Ran molecules. Thus there is an elevated RanGTP concentration in the nucleus compared to the cytoplasm.
## Export of proteins
Some nuclear proteins need to be exported from the nucleus to the cytoplasm, as do ribosome subunits and messenger RNAs. Thus there is an export mechanism similar to the import mechanism.
In the classical export scheme, proteins with an nuclear export sequence (NES) can bind in the nucleus to form a heterotrimeric complex with an exportin and RanGTP (for example the exportin CRM1). The complex can then diffuse to the cytoplasm where GTP is hydrolysed and the NES-protein is released. CRM1-RanGDP diffuses back to the nucleus where GDP is exchanged to GTP by RanGEFs. This process is also energy dependent as it consumes one GTP. Export with the exportin CRM1 can be inhibited by Leptomycin B.
## Export of RNA
Different export pathways from NPC for each RNA class exist. RNA export is also signal mediated (NES), the NES is in RNA-binding proteins (except for tRNA which has no adapter). It is notable that all viral RNAs and cellular RNAs (tRNA, rRNA, U snRNA, microRNA) except mRNA are dependent on RanGTP. Conseved mRNA export factors are necessary for mRNA nuclear export. Export factors are Mex67/Tap (large subunit) and Mtr2/p15 (small subunit). An adapter binds to the large export factor subunit mediating the export process.
# Additional images
- The Ran-GTP cycle | https://www.wikidoc.org/index.php/Nuclear_pore | |
8380cfbc3326c811539b3a0bbe69b1be921eba01 | wikidoc | Nucleic acid | Nucleic acid
# Overview
A nucleic acid is a macromolecule composed of nucleotide chains. In biochemistry these molecules carry genetic information or form structures within cells. The most common nucleic acids are deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). Nucleic acids are universal in living things, as they are found in all cells. They are also found in viruses.
Artificial nucleic acids include peptide nucleic acid (PNA), Morpholino and locked nucleic acid (LNA), as well as glycol nucleic acid (GNA) and threose nucleic acid (TNA). Each of these is distinguished from naturally-occurring DNA or RNA by changes to the backbone of the molecule.
# Chemical structure
The term "nucleic acid" is the generic name for a family of biopolymers, named for their role in the cell nucleus. The monomers from which nucleic acids are constructed are called nucleotides.
Each nucleotide consists of three components: a nitrogenous heterocyclic base, which is either a purine or a pyrimidine; a pentose sugar; and a phosphate group. Nucleic acid types differ in the structure of the sugar in their nucleotides - DNA contains 2-deoxyriboses while RNA contains ribose. Also, the nitrogenous bases found in the two nucleic acid types are different: adenine, cytosine, and guanine are found in both RNA and DNA, while thymine only occurs in DNA and uracil only occurs in RNA. Other rare nucleic acid bases can occur, for example inosine in strands of mature transfer RNA.
Nucleic acids are usually either single-stranded or double-stranded, though structures with three or more strands can form. A double-stranded nucleic acid consists of two single-stranded nucleic acids held together by hydrogen bonds, such as in the DNA double helix. In contrast, RNA is usually single-stranded, but any given strand may fold back upon itself to form secondary structure as in tRNA and rRNA. Within cells, DNA is usually double-stranded, though some viruses have single-stranded DNA as their genome. Retroviruses have single-stranded RNA as their genome.
The sugars and phosphates in nucleic acids are connected to each other in an alternating chain, linked by shared oxygens, forming a phosphodiester functional group. In conventional nomenclature, the carbons to which the phosphate groups attach are the 3' end and the 5' end carbons of the sugar. This gives nucleic acids polarity. The bases extend from a glycosidic linkage to the 1"carbon of the pentose sugar ring.
Bases are joined through N-1 of pyrimidines and N-9 of purins to 1' carbon of ribose through N-β glycosyl bond.
# Types of nucleic acids
## Ribonucleic acid
Ribonucleic acid, or RNA, is a nucleic acid polymer consisting of nucleotide monomers, which plays several important roles in the processes of translating genetic information from deoxyribonucleic acid (DNA) into proteins. RNA acts as a messenger between DNA and the protein synthesis complexes known as ribosomes, forms vital portions of ribosomes, and serves as an essential carrier molecule for amino acids to be used in protein synthesis.
## Deoxyribonucleic acid
Deoxyribonucleic acid (DNA) is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms. The main role of DNA molecules is the long-term storage of information and DNA is often compared to a set of blueprints, since it contains the instructions needed to construct other components of cells, such as proteins and RNA molecules. The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in regulating the use of this genetic information.
# Nucleic acid components
## Nucleobases
Nucleobases are heterocyclic aromatic organic compounds containing nitrogen atoms. Nucleobases are the parts of RNA and DNA involved in base pairing. Cytosine, guanine, adenine, thymine are found predominantly in DNA, while in RNA uracil replaces thymine. These are abbreviated as C, G, A, T, U, respectively.
Nucleobases are complementary, and when forming base pairs, must always join accordingly: cytosine-guanine, adenine-thymine (adenine-uracil when RNA). The strength of the interaction between cytosine and guanine is stronger than between adenine and thymine because the former pair has three hydrogen bonds joining them while the latter pair have only two. Thus, the higher the GC content of double-stranded DNA, the more stable the molecule and the higher the melting temperature.
Two main nucleobase classes exist, named for the molecule which forms their skeleton. These are the double-ringed purines and single-ringed pyrimidines. Adenine and guanine are purines (abbreviated as R), while cytosine, thymine, and uracil are all pyrimidines (abbreviated as Y).
Hypoxanthine and xanthine are mutant forms of adenine and guanine, respectively, created through mutagen presence, through deamination (replacement of the amine-group with a hydroxyl-group). These are abbreviated HX and X.
## Nucleosides
Nucleosides are glycosylamines made by attaching a nucleobase (often referred to simply as bases) to a ribose or deoxyribose (sugar) ring. In short, a nucleoside is a base linked to sugar. The names derive from the nucleobase names. The nucleosides commonly occurring in DNA and RNA include cytidine, uridine, adenosine, guanosine and thymidine. When a phosphate is added to a nucleoside (by phosphorylated by a specific kinase enzyme), a nucleotide is produced.
Nucleoside analogues, such as acyclovir, are used as antiviral agents.
## Nucleotides and deoxynucleotides
A nucleotide consists of a nucleoside and one or more phosphate groups. Nucleotides are the monomers of RNA and DNA, as well as forming the structural units of several important cofactors - CoA, flavin adenine dinucleotide, flavin mononucleotide, adenosine triphosphate and nicotinamide adenine dinucleotide phosphate. In the cell nucleotides play important roles in metabolism, and signaling.
Nucleotides are named after the nucleoside on which they are based, in conjunction with the number of phosphates they contain, for example:
- Adenine bonded to ribose forms the nucleoside adenosine.
- Adenosine bonded to a phosphate forms adenosine monophosphate.
- As phosphates are added, adenosine diphosphate and adenosine triphosphate are formed, in sequence. | Nucleic acid
Template:Wiktionarypar
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
A nucleic acid is a macromolecule composed of nucleotide chains. In biochemistry these molecules carry genetic information or form structures within cells. The most common nucleic acids are deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). Nucleic acids are universal in living things, as they are found in all cells. They are also found in viruses.
Artificial nucleic acids include peptide nucleic acid (PNA), Morpholino and locked nucleic acid (LNA), as well as glycol nucleic acid (GNA) and threose nucleic acid (TNA). Each of these is distinguished from naturally-occurring DNA or RNA by changes to the backbone of the molecule.
# Chemical structure
The term "nucleic acid" is the generic name for a family of biopolymers, named for their role in the cell nucleus. The monomers from which nucleic acids are constructed are called nucleotides.
Each nucleotide consists of three components: a nitrogenous heterocyclic base, which is either a purine or a pyrimidine; a pentose sugar; and a phosphate group. Nucleic acid types differ in the structure of the sugar in their nucleotides - DNA contains 2-deoxyriboses while RNA contains ribose. Also, the nitrogenous bases found in the two nucleic acid types are different: adenine, cytosine, and guanine are found in both RNA and DNA, while thymine only occurs in DNA and uracil only occurs in RNA. Other rare nucleic acid bases can occur, for example inosine in strands of mature transfer RNA.
Nucleic acids are usually either single-stranded or double-stranded, though structures with three or more strands can form. A double-stranded nucleic acid consists of two single-stranded nucleic acids held together by hydrogen bonds, such as in the DNA double helix. In contrast, RNA is usually single-stranded, but any given strand may fold back upon itself to form secondary structure as in tRNA and rRNA. Within cells, DNA is usually double-stranded, though some viruses have single-stranded DNA as their genome. Retroviruses have single-stranded RNA as their genome.
The sugars and phosphates in nucleic acids are connected to each other in an alternating chain, linked by shared oxygens, forming a phosphodiester functional group. In conventional nomenclature, the carbons to which the phosphate groups attach are the 3' end and the 5' end carbons of the sugar. This gives nucleic acids polarity. The bases extend from a glycosidic linkage to the 1"carbon of the pentose sugar ring.
Bases are joined through N-1 of pyrimidines and N-9 of purins to 1' carbon of ribose through N-β glycosyl bond.
# Types of nucleic acids
## Ribonucleic acid
Ribonucleic acid, or RNA, is a nucleic acid polymer consisting of nucleotide monomers, which plays several important roles in the processes of translating genetic information from deoxyribonucleic acid (DNA) into proteins. RNA acts as a messenger between DNA and the protein synthesis complexes known as ribosomes, forms vital portions of ribosomes, and serves as an essential carrier molecule for amino acids to be used in protein synthesis.
## Deoxyribonucleic acid
Deoxyribonucleic acid (DNA) is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms. The main role of DNA molecules is the long-term storage of information and DNA is often compared to a set of blueprints, since it contains the instructions needed to construct other components of cells, such as proteins and RNA molecules. The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in regulating the use of this genetic information.
# Nucleic acid components
## Nucleobases
Nucleobases are heterocyclic aromatic organic compounds containing nitrogen atoms. Nucleobases are the parts of RNA and DNA involved in base pairing. Cytosine, guanine, adenine, thymine are found predominantly in DNA, while in RNA uracil replaces thymine. These are abbreviated as C, G, A, T, U, respectively.
Nucleobases are complementary, and when forming base pairs, must always join accordingly: cytosine-guanine, adenine-thymine (adenine-uracil when RNA). The strength of the interaction between cytosine and guanine is stronger than between adenine and thymine because the former pair has three hydrogen bonds joining them while the latter pair have only two. Thus, the higher the GC content of double-stranded DNA, the more stable the molecule and the higher the melting temperature.
Two main nucleobase classes exist, named for the molecule which forms their skeleton. These are the double-ringed purines and single-ringed pyrimidines. Adenine and guanine are purines (abbreviated as R), while cytosine, thymine, and uracil are all pyrimidines (abbreviated as Y).
Hypoxanthine and xanthine are mutant forms of adenine and guanine, respectively, created through mutagen presence, through deamination (replacement of the amine-group with a hydroxyl-group). These are abbreviated HX and X.
## Nucleosides
Nucleosides are glycosylamines made by attaching a nucleobase (often referred to simply as bases) to a ribose or deoxyribose (sugar) ring. In short, a nucleoside is a base linked to sugar. The names derive from the nucleobase names. The nucleosides commonly occurring in DNA and RNA include cytidine, uridine, adenosine, guanosine and thymidine. When a phosphate is added to a nucleoside (by phosphorylated by a specific kinase enzyme), a nucleotide is produced.
Nucleoside analogues, such as acyclovir, are used as antiviral agents.
## Nucleotides and deoxynucleotides
A nucleotide consists of a nucleoside and one or more phosphate groups. Nucleotides are the monomers of RNA and DNA, as well as forming the structural units of several important cofactors - CoA, flavin adenine dinucleotide, flavin mononucleotide, adenosine triphosphate and nicotinamide adenine dinucleotide phosphate. In the cell nucleotides play important roles in metabolism, and signaling.
Nucleotides are named after the nucleoside on which they are based, in conjunction with the number of phosphates they contain, for example:
- Adenine bonded to ribose forms the nucleoside adenosine.
- Adenosine bonded to a phosphate forms adenosine monophosphate.
- As phosphates are added, adenosine diphosphate and adenosine triphosphate are formed, in sequence.
# External links
- Prediction of hairpin forming potential in nucleotide sequences
- Interview with Aaron Klug, Nobel Laureate for structural elucidation of biologically important nucleic-acid protein complexes provided by the Vega Science Trust.
Template:Nucleic acids
bg:Нуклеинова киселина
bs:Nukleinske kiseline
ca:Àcid nucleic
cs:Nukleová kyselina
da:Nukleinsyre
de:Nukleinsäure
el:Νουκλεϊκά οξέα
eo:Nuklea acido
eu:Azido nukleiko
fa:اسید نوکلئیک
fi:Nukleiinihappo
gl:Ácido nucleico
he:חומצת גרעין
hr:Nukleinske kiseline
id:Asam nukleat
it:Acido nucleico
ko:핵산
lb:Nukleinsaier
lt:Nukleino rūgštis
lv:Nukleīnskābes
mk:Нуклеинска киселина
ms:Asid nukleik
nl:Nucleïnezuur
oc:Acid nucleïc
sh:Nukleinska kiselina
simple:Nucleic acid
sk:Nukleová kyselina
sr:Нуклеинске киселине
su:Asam nukléat
sv:Nukleinsyra
th:กรดนิวคลีอิก
uk:Нуклеїнові кислоти
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Nucleic_Acid | |
71c3073656e8045bda6b79af7e0704d19ef4b57b | wikidoc | Nuphar lutea | Nuphar lutea
Nuphar lutea, the spatterdock, yellow water-lily, cow lily, or yellow pond-lily, is an aquatic plant of the family Nymphaeaceae, native to Eurasia. It grows in eutrophic freshwater beds, with its roots fixed into the ground and its leaves floating on the water's surface.
The plant's inflorescence is a solitary, terminal hermaphrodite flower, pollinated by insects, which blooms from June to September in the Northern Hemisphere. The flower is followed by achenes which are distributed by the water current.
Spatterdock was long used in traditional medicine, with the root applied to the skin and/or both the root and seeds eaten for a variety of conditions. The seeds are edible, and can be ground into flour. The root is edible too, but can prove to be incredibly bitter in some plants.
Possible botanical synonyms include Nuphar luteum (L.) Sibthorp & Sm. and Nuphar advena (Ait) Ait f. | Nuphar lutea
Nuphar lutea, the spatterdock, yellow water-lily, cow lily, or yellow pond-lily, is an aquatic plant of the family Nymphaeaceae, native to Eurasia. It grows in eutrophic freshwater beds, with its roots fixed into the ground and its leaves floating on the water's surface.
The plant's inflorescence is a solitary, terminal hermaphrodite flower, pollinated by insects, which blooms from June to September in the Northern Hemisphere. The flower is followed by achenes which are distributed by the water current.
Spatterdock was long used in traditional medicine, with the root applied to the skin and/or both the root and seeds eaten for a variety of conditions. The seeds are edible, and can be ground into flour. The root is edible too, but can prove to be incredibly bitter in some plants.
Possible botanical synonyms include Nuphar luteum (L.) Sibthorp & Sm. and Nuphar advena (Ait) Ait f. | https://www.wikidoc.org/index.php/Nuphar_lutea | |
4d97162adbc059344404ba99c924f69c316e496f | wikidoc | Nursing home | Nursing home
# Overview
A nursing home or skilled nursing facility (SNF), also known as a rest home, is a type of care of residents: it is a place of residence for people who require constant nursing care and have significant deficiencies with activities of daily living. Residents include the elderly and younger adults with physical disabilities. Adults 18 or older can stay in a skilled nursing facility to receive physical, occupational, and other rehabilitative therapies following an accident or illness.
# United States
In the US, nursing homes are required to have a licensed nurse on duty 24 hours a day, and during at least one shift each day, one of those nurses must be a Registered Nurse. In April, 2005 there were a total of 16,094 nursing homes in the United States, down from 16,516 in December, 2002. Some states have nursing homes that are called nursing facilities (NF), which do not have beds certified for Medicare patients, but can only treat patients whose payments source is Private Payment, Private Insurance or Medicaid.
## Services
Services provided in nursing homes include services of nurses, nursing aides and assistants; physical, occupational and speech therapists; social workers and recreational assistants; and room and board. Most care in nursing facilities is provided by certified nursing assistants, not by skilled personnel. In 2004, there were, on average, 40 certified nursing assistants per 100 resident beds. The number of registered nurses and licensed practical nurses were significantly lower at 7 per 100 resident beds and 13 per 100 resident beds, respectively.(38)
Nursing facilities that participate in the Medicare and Medicaid programs are subject to federal requirements regarding staffing and quality of care for residents (42 CFR Part 483). In 2004, 98.5% of the 16,100 nursing facilities nationwide were certified to participate in Medicare, Medicaid, or both.
Medicare covers nursing home services for beneficiaries who require skilled nursing care and/or rehabilitation services following a hospitalization of at least three consecutive days. The program does not cover nursing care if only custodial care is needed -- for example, when a person needs assistance with bathing, walking, or transferring from a bed to a chair. To be eligible for Medicare-covered skilled nursing facility (SNF) care, a physician must certify that the beneficiary needs daily skilled nursing care or other skilled rehabilitation services that are related to the hospitalization,(1) and that these services, as a practical matter, can be provided only on an inpatient basis. For example, a beneficiary released from the hospital after a stroke and in need of physical therapy, or a beneficiary in need of skilled nursing care for wound treatment following a surgical procedure, might be eligible for Medicare-covered SNF care.
SNF services may be offered in a free-standing or hospital-based facility. A freestanding facility is generally part of a nursing home that covers Medicare SNF services as well as long-term care(2) services for people who pay out-of-pocket, through Medicaid, and/or through a long-term care insurance policy. Generally, Medicare SNF patients make up just a small portion of the total resident population of a free-standing nursing home.
Medicaid also covers nursing home care for certain persons who require custodial care, meet a state's means-tested income and asset tests, and require the level-of-care offered in a nursing home. Nursing home residents have physical or cognitive impairments and require 24-hour care.
Many patients who live in nursing homes often begin paying out-of-pocket. Some deplete their resources on the often high cost of care. If eligible, Medicaid will cover continued stays in nursing home for these individuals.
## Government regulations and oversight
All nursing homes in the United States that receive Medicare and/or Medicaid funding are subject to federal regulations. People who inspect nursing homes are called surveyors or, most commonly, state surveyors.
The Minimum Data Set (MDS) is part of the U.S. federally mandated process for clinical assessment of all residents in Medicare or Medicaid certified nursing homes. This process provides a comprehensive assessment of each resident's functional capabilities and helps nursing home staff identify health problems.
For United States homes, the Centers for Medicare and Medicaid Services has a website which allows users to see how well facilities perform in certain metrics (see Nursing Home Compare in the link below).
Care homes for adults in England are regulated by the Commission for Social Care Inspection.
Nursing homes are subject to federal regulations and also strict state regulations. The nursing home industry is considered one of the two most heavily regulated industries in the United States (the other being the nuclear power industry).
## Consumer choices
Current trends are to provide people with significant needs for long term supports and services with a variety of living arrangements. Indeed, research in the U.S as a result of the Real Choice Systems Change Grants, shows that many people are able to return to their own homes in the community. Private nursing agencies may be able to provide live-in nurses to stay and work with patients in their own homes.
When considering living arrangements for those who are unable to live by themselves, it is important to carefully look at many nursing homes and assisted living facilities as well as retirement homes, keeping in mind the person's abilities to take care of themselves independently. While certainly not a residential option, many families choose to have their elderly loved one spend several hours per day at an adult daycare center.
Beginning in 2002, Medicare began hosting an online resource known as Nursing Home Compare (see the "External Links" section at the bottom of the page). The program is intended to foster quality improving competition between nursing homes. Informed consumer choice has long been missing from decisions regarding the placement of the elderly in need.
### Trends
Nursing homes are beginning to change the way they are managed and organized to create a more resident-centered environment, so they are more "home-like" and less "hospital-like." In these homes, nursing home units are replaced with a small set of rooms surrounding a common kitchen and living room. The staff giving care is assigned to one of these "households." Residents have far more choices about when they awake, when they eat and what they want to do during the day. They also have access to more companionship such as pets. Some organizations working toward these goals are the Pioneer Network, the Eden Alternative, and the Green House Project. Many of the facilities utilizing these models refer to such changes as the "Culture Shift" or "Culture Change" occurring in the LTC industry.
## Quality of life
### Resident-oriented care
Resident oriented care is where nurses are assigned to particular patients and have the ability to develop relationships with individual patients. Patients are treated more as family, as opposed to random patients. Using resident-oriented care, nurses are able to become familiar with each patient and cater more to their specific needs, whether they be emotional or medical.
According to various findings residents who receive resident-oriented care experience a higher quality of life, in respect to attention and time spent with patients and the number of fault reports after the introduction of Primary Nursing. Although resident-oriented nursing does not lengthen life, nursing home residents are able to connect with someone, which allows them to dispel many feelings of loneliness and discontent.
"Resident assignment" refers to the extent to which residents are allocated to the same nurse. With this particular system one person is responsible for the entire admission period of the resident. However, this system can cause difficulties for the nurse or care-giver should one of the residents they are assigned to pass away or move to a different facility, as the nurse/caregiver may become attached to the resident(s) they are caring for.
In coming to this conclusion three guidelines must be assessed: structure, process and outcome. Structure is the assessment of the instrumentalities of care and their organization; Process being the quality of the way in which care is given; Outcome being usually specified in terms of health, well being, patient satisfaction, etc. Using these three criteria find that are strengthened when residents experience resident oriented care.
Communication is also heightened when residents feel comfortable discussing various issues with someone who is experienced with their particular case. In this particular situation nurses are also better able to do longitudinal follow up, which insures the implementation of more lasting results.
Various findings suggest that task-oriented care produces less satisfied residents. In many cases, residents are disoriented and unsure of who to disclose information to and as a result decide not to share information at all.
Patients usually complain of loneliness and feelings of displacement.
"Resident assignment" is allocated to numerous nurses as opposed to one person carrying the responsibility of one resident. Because the load on one nurse can become so great, various nurses are unable to identify with gradual emotional and physical changes experienced by one particular resident. Resident information has the ability to get misplaced or undocumented because of the numerous amounts of nurses that deal with one resident.
### Task-oriented care
Task oriented care is where nurses are assigned specific tasks to perform for numerous residents on a specific ward. Residents in this particular situation are exposed to multiple nurses at any given time. Because of the random disbursement of tasks, nurses are declined the ability to develop more in depth relations with any particular resident. | Nursing home
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Template:Globalize/USA
# Overview
A nursing home or skilled nursing facility (SNF), also known as a rest home, is a type of care of residents: it is a place of residence for people who require constant nursing care and have significant deficiencies with activities of daily living. Residents include the elderly and younger adults with physical disabilities. Adults 18 or older can stay in a skilled nursing facility to receive physical, occupational, and other rehabilitative therapies following an accident or illness.
# United States
In the US, nursing homes are required to have a licensed nurse on duty 24 hours a day, and during at least one shift each day, one of those nurses must be a Registered Nurse. In April, 2005 there were a total of 16,094 nursing homes in the United States, down from 16,516 in December, 2002. Some states have nursing homes that are called nursing facilities (NF), which do not have beds certified for Medicare patients, but can only treat patients whose payments source is Private Payment, Private Insurance or Medicaid.
## Services
Services provided in nursing homes include services of nurses, nursing aides and assistants; physical, occupational and speech therapists; social workers and recreational assistants; and room and board. Most care in nursing facilities is provided by certified nursing assistants, not by skilled personnel. In 2004, there were, on average, 40 certified nursing assistants per 100 resident beds. The number of registered nurses and licensed practical nurses were significantly lower at 7 per 100 resident beds and 13 per 100 resident beds, respectively.(38)
Nursing facilities that participate in the Medicare and Medicaid programs are subject to federal requirements regarding staffing and quality of care for residents (42 CFR Part 483). In 2004, 98.5% of the 16,100 nursing facilities nationwide were certified to participate in Medicare, Medicaid, or both.
Medicare covers nursing home services for beneficiaries who require skilled nursing care and/or rehabilitation services following a hospitalization of at least three consecutive days. The program does not cover nursing care if only custodial care is needed -- for example, when a person needs assistance with bathing, walking, or transferring from a bed to a chair. To be eligible for Medicare-covered skilled nursing facility (SNF) care, a physician must certify that the beneficiary needs daily skilled nursing care or other skilled rehabilitation services that are related to the hospitalization,(1) and that these services, as a practical matter, can be provided only on an inpatient basis. For example, a beneficiary released from the hospital after a stroke and in need of physical therapy, or a beneficiary in need of skilled nursing care for wound treatment following a surgical procedure, might be eligible for Medicare-covered SNF care.
SNF services may be offered in a free-standing or hospital-based facility. A freestanding facility is generally part of a nursing home that covers Medicare SNF services as well as long-term care(2) services for people who pay out-of-pocket, through Medicaid, and/or through a long-term care insurance policy. Generally, Medicare SNF patients make up just a small portion of the total resident population of a free-standing nursing home.
Medicaid also covers nursing home care for certain persons who require custodial care, meet a state's means-tested income and asset tests, and require the level-of-care offered in a nursing home. Nursing home residents have physical or cognitive impairments and require 24-hour care.
Many patients who live in nursing homes often begin paying out-of-pocket. Some deplete their resources on the often high cost of care. If eligible, Medicaid will cover continued stays in nursing home for these individuals.
## Government regulations and oversight
All nursing homes in the United States that receive Medicare and/or Medicaid funding are subject to federal regulations. People who inspect nursing homes are called surveyors or, most commonly, state surveyors.
The Minimum Data Set (MDS) is part of the U.S. federally mandated process for clinical assessment of all residents in Medicare or Medicaid certified nursing homes. This process provides a comprehensive assessment of each resident's functional capabilities and helps nursing home staff identify health problems.
For United States homes, the Centers for Medicare and Medicaid Services has a website which allows users to see how well facilities perform in certain metrics (see Nursing Home Compare in the link below).
Care homes for adults in England are regulated by the Commission for Social Care Inspection.
Nursing homes are subject to federal regulations and also strict state regulations. The nursing home industry is considered one of the two most heavily regulated industries in the United States (the other being the nuclear power industry).[citation needed]
## Consumer choices
Current trends are to provide people with significant needs for long term supports and services with a variety of living arrangements. Indeed, research in the U.S as a result of the Real Choice Systems Change Grants, shows that many people are able to return to their own homes in the community. Private nursing agencies may be able to provide live-in nurses to stay and work with patients in their own homes.
When considering living arrangements for those who are unable to live by themselves, it is important to carefully look at many nursing homes and assisted living facilities as well as retirement homes, keeping in mind the person's abilities to take care of themselves independently. While certainly not a residential option, many families choose to have their elderly loved one spend several hours per day at an adult daycare center.
Beginning in 2002, Medicare began hosting an online resource known as Nursing Home Compare (see the "External Links" section at the bottom of the page). The program is intended to foster quality improving competition between nursing homes. Informed consumer choice has long been missing from decisions regarding the placement of the elderly in need.
### Trends
Nursing homes are beginning to change the way they are managed and organized to create a more resident-centered environment, so they are more "home-like" and less "hospital-like." In these homes, nursing home units are replaced with a small set of rooms surrounding a common kitchen and living room. The staff giving care is assigned to one of these "households." Residents have far more choices about when they awake, when they eat and what they want to do during the day. They also have access to more companionship such as pets. Some organizations working toward these goals are the Pioneer Network, the Eden Alternative, and the Green House Project. Many of the facilities utilizing these models refer to such changes as the "Culture Shift" or "Culture Change" occurring in the LTC industry.
## Quality of life
### Resident-oriented care
Resident oriented care is where nurses are assigned to particular patients and have the ability to develop relationships with individual patients. Patients are treated more as family, as opposed to random patients. Using resident-oriented care, nurses are able to become familiar with each patient and cater more to their specific needs, whether they be emotional or medical.
According to various findings residents who receive resident-oriented care experience a higher quality of life, in respect to attention and time spent with patients and the number of fault reports after the introduction of Primary Nursing. Although resident-oriented nursing does not lengthen life, nursing home residents are able to connect with someone, which allows them to dispel many feelings of loneliness and discontent.
"Resident assignment" refers to the extent to which residents are allocated to the same nurse. With this particular system one person is responsible for the entire admission period of the resident. However, this system can cause difficulties for the nurse or care-giver should one of the residents they are assigned to pass away or move to a different facility, as the nurse/caregiver may become attached to the resident(s) they are caring for.
In coming to this conclusion three guidelines must be assessed: structure, process and outcome. Structure is the assessment of the instrumentalities of care and their organization; Process being the quality of the way in which care is given; Outcome being usually specified in terms of health, well being, patient satisfaction, etc. Using these three criteria find that are strengthened when residents experience resident oriented care.
Communication is also heightened when residents feel comfortable discussing various issues with someone who is experienced with their particular case. In this particular situation nurses are also better able to do longitudinal follow up, which insures the implementation of more lasting results.
Various findings suggest that task-oriented care produces less satisfied residents. In many cases, residents are disoriented and unsure of who to disclose information to and as a result decide not to share information at all.
Patients usually complain of loneliness and feelings of displacement.
"Resident assignment" is allocated to numerous nurses as opposed to one person carrying the responsibility of one resident. Because the load on one nurse can become so great, various nurses are unable to identify with gradual emotional and physical changes experienced by one particular resident. Resident information has the ability to get misplaced or undocumented because of the numerous amounts of nurses that deal with one resident.[citation needed]
### Task-oriented care
Task oriented care is where nurses are assigned specific tasks to perform for numerous residents on a specific ward. Residents in this particular situation are exposed to multiple nurses at any given time. Because of the random disbursement of tasks, nurses are declined the ability to develop more in depth relations with any particular resident. | https://www.wikidoc.org/index.php/Nursing_home | |
b83d35d9d890a565ee26c42105581f14c6c9e834 | wikidoc | O.H. Frazier | O.H. Frazier
Dr. O. Howard Frazier (also known as Bud Frazier) is a distinguished heart surgeon. He is the Director of the Cardiovascular Surgical Research program and the Chief of Cardiopulmonary Transplantation at the Texas Heart Institute (THI). He is also the Chief of Transplant Services at St. Luke's Episcopal Hospital and the Co-Director of the Cullen Cardiovascular Research Laboratories at THI.
In February 2006, the Houston Chronicle announced that Dr. Frazier and his team of transplant surgeons had completed their 1,000th heart transplant, perhaps more than any other surgeon in the world.
Dr. Frazier obtained his B.A. from the University of Texas at Austin in 1963 and his medical degree from Baylor College of Medicine at Houston in 1967.
He is certified by the American Board of Surgery and the American Board of Thoracic Surgery. To date, he has authored or co-authored more than 490 scientific articles.
# External link
- Houston Chronicle Article
- The Mysterious Human Heart
- Surgical Associates of Texas | O.H. Frazier
Template:Infobox Person
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Dr. O. Howard Frazier (also known as Bud Frazier) is a distinguished heart surgeon. He is the Director of the Cardiovascular Surgical Research program and the Chief of Cardiopulmonary Transplantation at the Texas Heart Institute (THI). He is also the Chief of Transplant Services at St. Luke's Episcopal Hospital and the Co-Director of the Cullen Cardiovascular Research Laboratories at THI.
In February 2006, the Houston Chronicle announced that Dr. Frazier and his team of transplant surgeons had completed their 1,000th heart transplant, perhaps more than any other surgeon in the world.
Dr. Frazier obtained his B.A. from the University of Texas at Austin in 1963 and his medical degree from Baylor College of Medicine at Houston in 1967.
He is certified by the American Board of Surgery and the American Board of Thoracic Surgery. To date, he has authored or co-authored more than 490 scientific articles.
# External link
- Houston Chronicle Article
- The Mysterious Human Heart
- Surgical Associates of Texas
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/O.H._Frazier | |
0383e51111021638dbe6def6aa21b1af195c34ec | wikidoc | Oncostatin M | Oncostatin M
Oncostatin M, also known as OSM, is a protein that in humans is encoded by the OSM gene.
OSM is a pleiotropic cytokine that belongs to the interleukin 6 group of cytokines. Of these cytokines it most closely resembles leukemia inhibitory factor (LIF) in both structure and function. However, it is as yet poorly defined and is proving important in liver development, haematopoeisis, inflammation and possibly CNS development. It is also associated with bone formation and destruction.
OSM signals through cell surface receptors that contain the protein gp130. The type I receptor is composed of gp130 and LIFR, the type II receptor is composed of gp130 and OSMR.
# Discovery, isolation and cloning
The human form of OSM was originally isolated in 1986 from the growth media of PMA treated U-937 histiocytic lymphoma cells by its ability to inhibit the growth of cell lines established from melanomas and other solid tumours. A robust protein, OSM is stable between pH2 and 11 and resistant to heating for one hour at 56 °C. A partial amino acid sequence allowed the isolation of human OSM cDNA and subsequently genomic clones. The full cDNA clone of hOSM encodes a 252 amino acid precursor, the first 25 amino acids of which functions as a secretory signal peptide, which on removal yields the soluble 227 amino acid pro-OSM. Cleavage of the C-terminal most 31 residues at a trypsin like cleavage site yields the fully active 196 residue form. Two potential N-glycosylation sites are present in hOSM both of which are retained in the mature form.
The 196 residue OSM is the predominant form isolated form a variety of cell lines and corresponds to a glycoprotein of 28 KDa, although the larger 227 residue pro-OSM can be isolated from over transfected cells. Pro-OSM although an order of magnitude less efficacious in growth inhibition assays, displays similar binding affinity toward cells in radio ligand binding assays. Thus post translational processing may play a significant role in the in vivo function of OSM. Like many cytokines OSM is produced from cells by de novo synthesis followed by release through the classical secretion pathway. However, OSM can be released from preformed stores within polymorphonuclear leukocytes on degranulation. It still remains unclear how OSM is targeted to these intracellular compartments.
# Structure
Primary sequence analysis of OSM allocates it to the gp130 group of cytokines. OSM most resembles LIF, bearing 22% sequence identity and 30% similarity. Incidentally the genes for OSM and LIF occur in tandem on human chromosome 22. Both LIF and OSM genes have very similar gene structures sharing similar promoter elements and intron-exon structure. These data suggest that OSM and LIF arose relatively recently in evolutionary terms by gene duplication. Of the five cysteine residues within the human OSM sequence four participate in disulfide bridges, one of these disulfide bonds namely between helices A and B is necessary for OSM activity. The free cysteine residue does not appear to mediate dimerisation of OSM.
The three-dimensional structure of human OSM has been solved to atomic resolution, confirming the predicted long chain four helix bundle topology. Comparing this structure with the known structures of other known LC cytokines shows it to be most closely related to LIF (RMSD of 2.1 Å across 145 equivalent Cα). A distinctive kink in the A helix arises from departure of the classical alpha helical H-bonding pattern, a feature shared with all known structures of LIFR using cytokines. This “kink” in effect results in a different special positioning of one extreme of the bundle to the other, significantly affecting the relative positioning of site III with sites I and II (see:Receptor recruitment sites)
# Receptors
Receptors for OSM can be found on a variety of cells from a variety of tissues. In general cells derived from endothelial and tumour origins express high levels of OSM receptors, whereas cells of Haematopoietic origin tend to express lower numbers.
Scatchard analysis of radio ligand binding data from 125I-OSM binding to a variety of OSM responsive cell lines produced curvilinear graphs which the authors interpreted as the presence of two receptor species, a high affinity form with an approximate dissociation constant Kd of 1-10 pM, and a low affinity form of 0.4-1 nM. Subsequently it was shown that the presence of gp130 alone was sufficient to reproduce the low affinity form of the receptor, and co-transfection of COS-7 cells with LIFR and gp130 produced a high affinity receptor. However further experiments demonstrated that not all actions of OSM could be replicated by LIF, that is certain cells that are irresponsive to LIF would respond to OSM. This data hinted to the existence of an additional ligand specific receptor chain which led to the cloning of OSMR. These two receptor complexes, namely gp130/LIFR and gp130/OSMR, were termed the type I and type II Oncostatin-M receptors.
The ability of OSM to signal via two receptor complexes conveniently offers a molecular explanation to the shared and unique effects of OSM with respect to LIF. Thus common biological activities of LIF and OSM are mediated through the type I receptor and OSM specific activities are mediated through the type II receptor.
The murine homologue of OSM was not discovered until 1996, whereas the murine OSMR homologue was not cloned until 1998. Until recently, it was thought that mOSM only signals through the murine type II receptor, namely through mOSMR/mgp130 complexes, because of a low affinity for the type I receptor counterpart. However, it is now known that, in bone at least, mOSM is able to signal through both mOSMR/mgp130 and mLIFR/mgp130.
# Receptor recruitment sites
Oncostatin M triggers the formation of receptor complexes by binding to receptors via two binding sites named site II and site III. The nomenclature of these sites is taken by direct analogy to Growth Hormone, probably the best studied of four helix bundle cytokines.
Site II consists of exposed residues within the A and C helices, and confers binding to gp130.
The crucial residues of site III are located at the N-terminal extremity of the D-helix. This site is the most conserved amongst IL-6 like cytokines. OSM contains a conserved Phenylalanine and Lysine residues (F160 and K163). Cytokines that recruit LIFR via site 3 i.e. LIF, OSM, CNTF and CT-1 possess these conserved phenylalanine and lysine residues and is known as the FK motif.
# Signal transduction through OSM receptors
Signalling by type I and type II OSM receptors have now been shown to be qualitatively distinct. These differences in signaling character, in addition to the tissue distribution profiles of OSMRb and LIFRb, offer another variable in the distinction between the common and specific cellular effects of OSM with respect to LIF. All IL-6 cytokines whether they homo- or heterodimerise gp130 seem to activate JAK1, JAK2 and to a lesser degree Tyk2. It should be noted however that JAK1, JAK2, and tyk2 are not interchangeable in the gp130 system, this has been demonstrated with the use of JAK1, Jak2 or Tyk2 deficient cell lines obtained from mutant mice. Cells from JAK1 deficient mice show reduced STAT activation and generation of biological responses in response to IL-6 and LIF. In contrast, fibroblasts derived from JAK2 null mice can respond to IL-6, with demonstratable tyrosine phosphorylation of gp130, JAK1 and TYK2. Thus it seems JAK1 is the critical JAK required for gp130 signalling. Activation of the same Jaks by all three receptor combinations (gp130/gp130, gp130/LIFR, gp130/OSMR) raises the question of how IL6, LIF and OSM can activate distinct intracellular signaling pathways. Selection of particular substrates, i.e. STAT isoform, depended not on which Jak is activated, but instead are determined by specific motifs, especially tyrosine-based motifs, within each receptor intracellular domain.
Aligning the intracellular domains of gp130, LIFR and hOSMR results in some interesting observations. Sequence identity is generally quite low across the group averaging at 4.6%. However, as with many Class I Haematopoeitin receptors, two short membrane proximal motifs, termed box 1 and box 2 are present. In addition these receptors also contain a serine rich region and a third more poorly conserved motif termed box 3. Box 1 is present in all signalling cytokine receptors. It is characteristically rich in proline residues and is essential for the association and activation of JAKs. Box 2 is also important for association with JAKs. Gp130 contains box1 and box2 sequences within the membrane-proximal part of the cytoplasmic region, lying within the minimum 61 amino acids required for receptor activation. Mutations within the box1 region reduce the ability of gp130 to associate with Jaks and abolish ligand-induced activation of Jak1 and Jak2. Box 2 also contributes to activation and binding of JAKs. Studies with various gp130 truncation mutants show a reduction of Jak2 binding and abrogation of certain biological effects upon deletion of box2. However, Jaks are able to associate with gp130 devoid of box2 when overexpressed.
LIFR and OSMR also contain the membrane-proximal box1/box2-like regions. The first 65 amino acid residues in the cytoplasmic domain of LIFR, in combination with full length gp130, can generate signalling on treatment with LIF. Coprecipitation of Jak1, Jak2 and Tyk2 with receptors containing cytoplasmic parts of the LIFR or OSMR. All beta receptor subunits of the gp130 system also possess a box 3 region. This region corresponds to the C-terminal amino acids of the OSMR and LIFR receptors respectively. Box 3 is necessary for the action of OSMR; however Box3 is dispensable for the action of LIFR. In the case of gp130 box 3 is dispensable for activity, however the presence of an intact box 3 sequence is required for certain aspects of gp130 signalling, i.e. stimulation of transcription through the STAT-3 response element. In addition to the poor sequence conservation amongst the intracellular domains of gp130 receptors, the number and position of conserved tyrosine residues are also poorly conserved. For example, LIFR and OSMR share three homologous tyrosines. In contrast none of the tyrosine residues present in the intracellular domain of gp130 share equivalents with LIFR or OSMR, even though the intracellular regions of LIFR and gp130 share more sequence identity than LIFR and OSMR.
Of the proteins recruited to type I cytokine receptors STAT proteins remain the best studied. Homodimerisation of gp130 has been shown to phosphorylate and activate both STAT1 and STAT3. gp130 preferentially activates STAT3 which it can do through four STAT3 activation consensus sequences YXXQ: (YRHQ), (YFKQ), Y905 (YLPQ), Y915 (YMPQ). The lower propensity for STAT1 activation may be a reflection of the lower number of STAT1 activation sequences, YZPQ (where X is any residue and Z is any uncharged residue), namely Y905 and Y915. Cytokines that signal via homodimeric complexes of LIFR or OSMR (i.e. devoid of gp130) are currently unknown in nature. However, various investigators have attempted artificial homodimerisation of LIFR and OSMR intracellular domains, with conflicting results, by constructing receptor chimeras that fuse the extracellular domain of one cytokine receptor with the intracellular domain of LIFR or OSMR.
Signalling by LIFR intracellular domain homodimerisation has been demonstrated in hepatoma and neuroblastoma cells, embryonic stem cells and COS-1 cells by using chimeric receptors that homodimerise upon stimulation with their cognate cytokines (i.e. GCSF, neurotrophin-3, EGF). However a GCSFR/LIFR chimera was not capable of signaling in M1 or Baf cells.
# Anti- or pro-inflammatory?
The role of OSM as an inflammatory mediator was clear as early as 1986. Its precise effect on the immune system, as with any cytokine, is far from clear. However, two schools of thought are emerging: The first proposes that OSM is pro-inflammatory; whilst the other holds the opposite view, claiming OSM is anti-inflammatory. It is important to note that before 1997 differences in human and murine OSM receptor usage were unknown. As a result, several investigators used human OSM in mouse assays and thus any conclusion drawn from the results of these experiments will be representative of LIF, i.e. signalling through gp130/LIFR complexes.
OSM is synthesized by stimulated T-cells and monocytes. The effects of OSM on endothelial cells suggest a pro-inflammatory role for OSM. Endothelial cells possess a large number of OSM receptors. Stimulation of a primary endothelial culture (HUVEC) with hOSM results in delayed but prolonged upregulation of P-selectin, which facilitates leukocyte adhesion and rolling, necessary for their extravasation. OSM also promotes the production of IL-6 from these cells.
As mentioned above the action of OSM as a quencher of the inflammatory response is by no means established yet. For example, conflicting results exist as to the action of OSM on various models of arthritis. For example, OSM reduces the degree of joint destruction in an antibody induced model of rheumatoid arthritis.
OSM is a major growth factor for Kaposi’s sarcoma “spindle cells”, which are of endothelial origin. These cells do not express LIFR but do express OSMR at high levels.
For example, OSM can modulate the expression of IL-6, an important regulator of the host defence system. OSM can regulate the expression of acute phase proteins. OSM regulates the expression of various protease and protease inhibitors, for example Gelatinase and a1-chymotrypsin inhibitor. | Oncostatin M
Oncostatin M, also known as OSM, is a protein that in humans is encoded by the OSM gene.[1]
OSM is a pleiotropic cytokine that belongs to the interleukin 6 group of cytokines.[2] Of these cytokines it most closely resembles leukemia inhibitory factor (LIF) in both structure and function.[2] However, it is as yet poorly defined and is proving important in liver development, haematopoeisis, inflammation and possibly CNS development. It is also associated with bone formation and destruction.[3]
OSM signals through cell surface receptors that contain the protein gp130. The type I receptor is composed of gp130 and LIFR, the type II receptor is composed of gp130 and OSMR.[4]
# Discovery, isolation and cloning
The human form of OSM was originally isolated in 1986 from the growth media of PMA treated U-937 histiocytic lymphoma cells by its ability to inhibit the growth of cell lines established from melanomas and other solid tumours.[5] A robust protein, OSM is stable between pH2 and 11 and resistant to heating for one hour at 56 °C. A partial amino acid sequence allowed the isolation of human OSM cDNA and subsequently genomic clones.[6] The full cDNA clone of hOSM encodes a 252 amino acid precursor, the first 25 amino acids of which functions as a secretory signal peptide, which on removal yields the soluble 227 amino acid pro-OSM. Cleavage of the C-terminal most 31 residues at a trypsin like cleavage site yields the fully active 196 residue form. Two potential N-glycosylation sites are present in hOSM both of which are retained in the mature form.[7][8]
The 196 residue OSM is the predominant form isolated form a variety of cell lines and corresponds to a glycoprotein of 28 KDa, although the larger 227 residue pro-OSM can be isolated from over transfected cells. Pro-OSM although an order of magnitude less efficacious in growth inhibition assays, displays similar binding affinity toward cells in radio ligand binding assays.[8] Thus post translational processing may play a significant role in the in vivo function of OSM. Like many cytokines OSM is produced from cells by de novo synthesis followed by release through the classical secretion pathway. However, OSM can be released from preformed stores within polymorphonuclear leukocytes on degranulation.[9] It still remains unclear how OSM is targeted to these intracellular compartments.
# Structure
Primary sequence analysis of OSM allocates it to the gp130 group of cytokines. OSM most resembles LIF, bearing 22% sequence identity and 30% similarity. Incidentally the genes for OSM and LIF occur in tandem on human chromosome 22. Both LIF and OSM genes have very similar gene structures sharing similar promoter elements and intron-exon structure.[11] These data suggest that OSM and LIF arose relatively recently in evolutionary terms by gene duplication.[1] Of the five cysteine residues within the human OSM sequence four participate in disulfide bridges, one of these disulfide bonds namely between helices A and B is necessary for OSM activity. The free cysteine residue does not appear to mediate dimerisation of OSM.
The three-dimensional structure of human OSM has been solved to atomic resolution, confirming the predicted long chain four helix bundle topology.[10] Comparing this structure with the known structures of other known LC cytokines shows it to be most closely related to LIF (RMSD of 2.1 Å across 145 equivalent Cα). A distinctive kink in the A helix arises from departure of the classical alpha helical H-bonding pattern, a feature shared with all known structures of LIFR using cytokines. This “kink” in effect results in a different special positioning of one extreme of the bundle to the other, significantly affecting the relative positioning of site III with sites I and II (see:Receptor recruitment sites)
# Receptors
Receptors for OSM can be found on a variety of cells from a variety of tissues. In general cells derived from endothelial and tumour origins express high levels of OSM receptors, whereas cells of Haematopoietic origin tend to express lower numbers.
Scatchard analysis of radio ligand binding data from 125I-OSM binding to a variety of OSM responsive cell lines produced curvilinear graphs which the authors interpreted as the presence of two receptor species, a high affinity form with an approximate dissociation constant Kd of 1-10 pM, and a low affinity form of 0.4-1 nM.[12] Subsequently it was shown that the presence of gp130 alone was sufficient to reproduce the low affinity form of the receptor, and co-transfection of COS-7 cells with LIFR and gp130 produced a high affinity receptor.[13] However further experiments demonstrated that not all actions of OSM could be replicated by LIF, that is certain cells that are irresponsive to LIF would respond to OSM.[14] This data hinted to the existence of an additional ligand specific receptor chain which led to the cloning of OSMR.[15] These two receptor complexes, namely gp130/LIFR and gp130/OSMR, were termed the type I and type II Oncostatin-M receptors.
The ability of OSM to signal via two receptor complexes conveniently offers a molecular explanation to the shared and unique effects of OSM with respect to LIF. Thus common biological activities of LIF and OSM are mediated through the type I receptor and OSM specific activities are mediated through the type II receptor.
The murine homologue of OSM was not discovered until 1996,[16] whereas the murine OSMR homologue was not cloned until 1998.[17] Until recently, it was thought that mOSM only signals through the murine type II receptor, namely through mOSMR/mgp130 complexes, because of a low affinity for the type I receptor counterpart.[18] However, it is now known that, in bone at least, mOSM is able to signal through both mOSMR/mgp130 and mLIFR/mgp130.[3]
# Receptor recruitment sites
Oncostatin M triggers the formation of receptor complexes by binding to receptors via two binding sites named site II and site III. The nomenclature of these sites is taken by direct analogy to Growth Hormone, probably the best studied of four helix bundle cytokines.
Site II consists of exposed residues within the A and C helices, and confers binding to gp130.
The crucial residues of site III are located at the N-terminal extremity of the D-helix. This site is the most conserved amongst IL-6 like cytokines. OSM contains a conserved Phenylalanine and Lysine residues (F160 and K163). Cytokines that recruit LIFR via site 3 i.e. LIF, OSM, CNTF and CT-1 possess these conserved phenylalanine and lysine residues and is known as the FK motif.
# Signal transduction through OSM receptors
Signalling by type I and type II OSM receptors have now been shown to be qualitatively distinct. These differences in signaling character, in addition to the tissue distribution profiles of OSMRb and LIFRb, offer another variable in the distinction between the common and specific cellular effects of OSM with respect to LIF. All IL-6 cytokines whether they homo- or heterodimerise gp130 seem to activate JAK1, JAK2 and to a lesser degree Tyk2.[4][19] It should be noted however that JAK1, JAK2, and tyk2 are not interchangeable in the gp130 system, this has been demonstrated with the use of JAK1, Jak2 or Tyk2 deficient cell lines obtained from mutant mice. Cells from JAK1 deficient mice show reduced STAT activation and generation of biological responses in response to IL-6 and LIF.[20] In contrast, fibroblasts derived from JAK2 null mice can respond to IL-6, with demonstratable tyrosine phosphorylation of gp130, JAK1 and TYK2.[21] Thus it seems JAK1 is the critical JAK required for gp130 signalling. Activation of the same Jaks by all three receptor combinations (gp130/gp130, gp130/LIFR, gp130/OSMR) raises the question of how IL6, LIF and OSM can activate distinct intracellular signaling pathways. Selection of particular substrates, i.e. STAT isoform, depended not on which Jak is activated, but instead are determined by specific motifs, especially tyrosine-based motifs, within each receptor intracellular domain.
Aligning the intracellular domains of gp130, LIFR and hOSMR results in some interesting observations. Sequence identity is generally quite low across the group averaging at 4.6%. However, as with many Class I Haematopoeitin receptors, two short membrane proximal motifs, termed box 1 and box 2 are present. In addition these receptors also contain a serine rich region and a third more poorly conserved motif termed box 3. Box 1 is present in all signalling cytokine receptors. It is characteristically rich in proline residues and is essential for the association and activation of JAKs.[22] Box 2 is also important for association with JAKs. Gp130 contains box1 and box2 sequences within the membrane-proximal part of the cytoplasmic region, lying within the minimum 61 amino acids required for receptor activation.[23] Mutations within the box1 region reduce the ability of gp130 to associate with Jaks[24] and abolish ligand-induced activation of Jak1 and Jak2.[23][25] Box 2 also contributes to activation and binding of JAKs. Studies with various gp130 truncation mutants show a reduction of Jak2 binding and abrogation of certain biological effects upon deletion of box2.[23][26] However, Jaks are able to associate with gp130 devoid of box2 when overexpressed.[24]
LIFR and OSMR also contain the membrane-proximal box1/box2-like regions. The first 65 amino acid residues in the cytoplasmic domain of LIFR, in combination with full length gp130, can generate signalling on treatment with LIF.[27] Coprecipitation of Jak1, Jak2 and Tyk2 with receptors containing cytoplasmic parts of the LIFR[28] or OSMR.[4] All beta receptor subunits of the gp130 system also possess a box 3 region. This region corresponds to the C-terminal amino acids of the OSMR and LIFR receptors respectively. Box 3 is necessary for the action of OSMR; however Box3 is dispensable for the action of LIFR.[29] In the case of gp130 box 3 is dispensable for activity, however the presence of an intact box 3 sequence is required for certain aspects of gp130 signalling, i.e. stimulation of transcription through the STAT-3 response element. In addition to the poor sequence conservation amongst the intracellular domains of gp130 receptors, the number and position of conserved tyrosine residues are also poorly conserved. For example, LIFR and OSMR share three homologous tyrosines. In contrast none of the tyrosine residues present in the intracellular domain of gp130 share equivalents with LIFR or OSMR, even though the intracellular regions of LIFR and gp130 share more sequence identity than LIFR and OSMR.
Of the proteins recruited to type I cytokine receptors STAT proteins remain the best studied. Homodimerisation of gp130 has been shown to phosphorylate and activate both STAT1 and STAT3. gp130 preferentially activates STAT3 which it can do through four STAT3 activation consensus sequences YXXQ: (YRHQ), (YFKQ), Y905 (YLPQ), Y915 (YMPQ). The lower propensity for STAT1 activation may be a reflection of the lower number of STAT1 activation sequences, YZPQ (where X is any residue and Z is any uncharged residue), namely Y905 and Y915.[30] Cytokines that signal via homodimeric complexes of LIFR or OSMR (i.e. devoid of gp130) are currently unknown in nature. However, various investigators have attempted artificial homodimerisation of LIFR and OSMR intracellular domains, with conflicting results, by constructing receptor chimeras that fuse the extracellular domain of one cytokine receptor with the intracellular domain of LIFR or OSMR.
Signalling by LIFR intracellular domain homodimerisation has been demonstrated in hepatoma and neuroblastoma cells,[27] embryonic stem cells[31][32] and COS-1 cells[33] by using chimeric receptors that homodimerise upon stimulation with their cognate cytokines (i.e. GCSF, neurotrophin-3, EGF). However a GCSFR/LIFR chimera was not capable of signaling in M1 or Baf cells.[32]
# Anti- or pro-inflammatory?
The role of OSM as an inflammatory mediator was clear as early as 1986.[5] Its precise effect on the immune system, as with any cytokine, is far from clear. However, two schools of thought are emerging: The first proposes that OSM is pro-inflammatory; whilst the other holds the opposite view, claiming OSM is anti-inflammatory. It is important to note that before 1997[34] differences in human and murine OSM receptor usage were unknown. As a result, several investigators used human OSM in mouse assays and thus any conclusion drawn from the results of these experiments will be representative of LIF, i.e. signalling through gp130/LIFR complexes.
OSM is synthesized by stimulated T-cells and monocytes.[6] The effects of OSM on endothelial cells suggest a pro-inflammatory role for OSM. Endothelial cells possess a large number of OSM receptors.[35] Stimulation of a primary endothelial culture (HUVEC) with hOSM results in delayed but prolonged upregulation of P-selectin,[36] which facilitates leukocyte adhesion and rolling, necessary for their extravasation. OSM also promotes the production of IL-6 from these cells.[35]
As mentioned above the action of OSM as a quencher of the inflammatory response is by no means established yet. For example, conflicting results exist as to the action of OSM on various models of arthritis. For example, OSM reduces the degree of joint destruction in an antibody induced model of rheumatoid arthritis.[37]
OSM is a major growth factor for Kaposi’s sarcoma “spindle cells”, which are of endothelial origin.[38] These cells do not express LIFR but do express OSMR at high levels.[39]
For example, OSM can modulate the expression of IL-6, an important regulator of the host defence system.[35] OSM can regulate the expression of acute phase proteins.[40] OSM regulates the expression of various protease and protease inhibitors, for example Gelatinase and a1-chymotrypsin inhibitor. | https://www.wikidoc.org/index.php/OSM | |
d8f19b6e72d44dd30a1aa6166e77f652ffa51690 | wikidoc | Obie Baizley | Obie Baizley
William Obadiah Baizley (May 25, 1917 – May 3, 2000) was a politician in Manitoba, Canada. He was a Progressive Conservative Party of Manitoba member of the Legislative Assembly of Manitoba from 1959 to 1969, and served as a cabinet minister in the governments of Dufferin Roblin and Walter Weir.
Born in Montreal, Quebec, Baizley was educated at Glenlawn Collegiatein St. Vital, Manitoba and the Lincoln Chiropractic College in Indiana. He returned to Manitoba in 1937 and worked as a chiropractor, also serving as president of the Manitoba Chiropractors' Association before entering political life. During World War II, he was a member of the Royal Canadian Air Force.
He was first elected to the Manitoba legislature in the Manitoba general election, 1959, unexpectedly defeating Manitoba Cooperative Commonwealth Federation leader Lloyd Stinson by 326 votes in the south-central Winnipeg riding of Osborne (Manitoba riding). He served as a backbench supporter of Roblin's government for the next four years.
Re-elected without difficulty in the Manitoba general election, 1962, Baizley was appointed to cabinet on February 27, 1963 as Minister of Labour (Manitoba). He held this position until September 24, 1968, when he was named Minister of Municipal Affairs (Manitoba). He endorsed Walter Weir to succeed Roblin as Progressive Conservative leader in 1967.
Baizley was re-elected easily in the Manitoba general election, 1966, but lost to Ian Turnbull (politician) of the Manitoba New Democratic Party by 623 votes in Manitoba general election, 1969. He did not seek a return to office after this time.
During the 1970s, Baizley was chair of the Manitoba Labour Board. He also served as president of Riverview United Church of Canada.
de:Obie Baizley | Obie Baizley
William Obadiah Baizley (May 25, 1917 – May 3, 2000) was a politician in Manitoba, Canada. He was a Progressive Conservative Party of Manitoba member of the Legislative Assembly of Manitoba from 1959 to 1969, and served as a cabinet minister in the governments of Dufferin Roblin and Walter Weir.
Born in Montreal, Quebec, Baizley was educated at Glenlawn Collegiatein St. Vital, Manitoba and the Lincoln Chiropractic College in Indiana. He returned to Manitoba in 1937 and worked as a chiropractor, also serving as president of the Manitoba Chiropractors' Association before entering political life. During World War II, he was a member of the Royal Canadian Air Force.
He was first elected to the Manitoba legislature in the Manitoba general election, 1959, unexpectedly defeating Manitoba Cooperative Commonwealth Federation leader Lloyd Stinson by 326 votes in the south-central Winnipeg riding of Osborne (Manitoba riding). He served as a backbench supporter of Roblin's government for the next four years.
Re-elected without difficulty in the Manitoba general election, 1962, Baizley was appointed to cabinet on February 27, 1963 as Minister of Labour (Manitoba). He held this position until September 24, 1968, when he was named Minister of Municipal Affairs (Manitoba). He endorsed Walter Weir to succeed Roblin as Progressive Conservative leader in 1967.
Baizley was re-elected easily in the Manitoba general election, 1966, but lost to Ian Turnbull (politician) of the Manitoba New Democratic Party by 623 votes in Manitoba general election, 1969. He did not seek a return to office after this time.
During the 1970s, Baizley was chair of the Manitoba Labour Board. He also served as president of Riverview United Church of Canada.
Template:Chiropractic
Template:ATTRIB
de:Obie Baizley | https://www.wikidoc.org/index.php/Obie_Baizley | |
0e9caebec85792b5a9c6fa41c68fff241eb6dfc9 | wikidoc | Obinutuzumab | Obinutuzumab
# Disclaimer
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# Black Box Warning
# Overview
Obinutuzumab is an antineoplastic agent that is FDA approved for the treatment of chronic lymphoid leukemia,previously untreated. There is a Black Box Warning for this drug as shown here. Common adverse reactions include anemia, neutropenia,thrombocytopenia, musculoskeletal system disorder,cough, fever.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
# Indications
- Obinutuzumab , in combination with chlorambucil, is indicated for the treatment of patients with previously untreated chronic lymphocytic leukemia(CLL).
# Dosage
Recommended Dosage Regimen
- Premedicate before each infusion.
- Administer only as an intravenous infusion through a dedicated line.
- Do not administer as an intravenous push or bolus.
- Monitor blood counts at regular intervals.
- Obinutuzumab should only be administered by a healthcare professional with appropriate medical support to manage severe infusion reactions that can be fatal if they occur.
Recommended Dose:
- Each dose of Obinutuzumab is 1000 mg, administered intravenously, with the exception of the first infusions in Cycle 1, which are administered on day 1 (100 mg) and day 2 (900 mg).
- If a planned dose of Obinutuzumab is missed, administer the missed dose as soon as possible and adjust dosing schedule accordingly. If appropriate, patients who do not complete the Day 1 Cycle 1 dose may proceed to the day 2 Cycle 1 dose.
- If a patient experiences an infusion reaction of any grade during infusion, adjust the infusion as follows:
- Grade 4 (life-threatening): Stop infusion immediately and permanently discontinue Obinutuzumab therapy.
- Grade 3 (severe): Interrupt infusion and manage symptoms. Upon resolution of symptoms, consider restarting Obinutuzumab infusion at no more than half the previous rate (the rate being used at the time that the infusion reaction occurred) and, if patient does not experience any further infusion reaction symptoms, infusion rate escalation may resume at the increments and intervals as appropriate for the treatment cycle dose. Day 1 infusion rate may be increased back up to 25 mg/hr after 1 hour but not increased further. Permanently discontinue treatment if patients experience a Grade 3 infusion-related symptom at rechallenge.
- Grade 1–2 (mild to moderate): Reduce infusion rate or interrupt infusion and treat symptoms. Upon resolution of symptoms, continue or resume infusion and, if patient does not experience any further infusion reaction symptoms, infusion rate escalation may resume at the increments and intervals as appropriate for the treatment cycle dose. Day 1 infusion rate may be increased back up to 25 mg/hr after 1 hour but not increased further.
Recommended Premedication
- Premedication is recommended to reduce the risk of infusion reactions as outlined in TABLE 2.
- Hypotension may occur during Obinutuzumab intravenous infusions. Consider withholding antihypertensive treatments for 12 hours prior to and throughout each Obinutuzumab infusion and for the first hour after administration.
- For patients with high tumor burden and/or high circulating absolute lymphocyte counts (greater than 25 × 109/L), premedicate with anti-hyperuricemics (e.g., allopurinol) beginning 12–24 hours prior to start of therapy and ensure adequate hydration for prophylaxis of tumor lysis syndrome.
Premedication for Antimicrobial Prophylaxis
- Patients with neutropenia are strongly recommended to receive antimicrobial prophylaxis throughout the treatment period. Antiviral and antifungal prophylaxis should be considered.
Treatment Interruption for Toxicity
Consider treatment interruption if patients experience an infection, Grade 3 or 4 cytopenia, or a ≥ Grade 2 non-hematologic toxicity.
# DOSAGE FORMS AND STRENGTHS
- 1000 mg/40 mL (25 mg/mL) single-use vial.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Obinutuzumab in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Obinutuzumab in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Obinutuzumab in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Obinutuzumab in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Obinutuzumab in pediatric patients.
# Contraindications
- None
# Warnings
Hepatitis B Virus Reactivation
- Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with anti-CD20 antibodies such as Obinutuzumab. HBV reactivation has been reported in patients who are hepatitis B surface antigen (HBsAg) positive and also in patients who are HBsAg negative but are hepatitis B core antibody (anti-HBc) positive. Reactivation has also occurred in patients who appear to have resolved hepatitis B infection (i.e., HBsAg negative, anti-HBc positive, and hepatitis B surface antibody positive).
- HBV reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level or detection of HBsAg in a person who was previously HBsAg negative and anti-HBc positive. Reactivation of HBV replication is often followed by hepatitis, i.e., increase in transaminase levels and, in severe cases, increase in bilirubin levels, liver failure, and death.
- Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with Obinutuzumab. For patients who show evidence of hepatitis B infection (HBsAg positive or HBsAg negative but anti-HBc positive), consult physicians with expertise in managing hepatitis B regarding monitoring and consideration for HBV antiviral therapy.
- Monitor patients with evidence of current or prior HBV infection for clinical and laboratory signs of hepatitis or HBV reactivation during and for several months following treatment with Obinutuzumab. HBV reactivation has been reported for other CD20-directed cytolytic antibodies following completion of therapy.
- In patients who develop reactivation of HBV while receiving Obinutuzumab, immediately discontinue Obinutuzumab and any concomitant chemotherapy and institute appropriate treatment. Resumption of Obinutuzumab in patients whose HBV reactivation resolves should be discussed with physicians with expertise in managing hepatitis B. Insufficient data exist regarding the safety of resuming Obinutuzumab in patients who develop HBV reactivation.
Progressive Multifocal Leukoencephalopathy
- JC virus infection resulting in progressive multifocal leukoencephalopathy (PML), which can be fatal, was observed in patients treated with Obinutuzumab. Consider the diagnosis of PML in any patient presenting with new onset or changes to preexisting neurologic manifestations. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture. Discontinue Obinutuzumab therapy and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML.
Infusion Reactions
- Obinutuzumab can cause severe and life-threatening infusion reactions. Two thirds of patients experienced a reaction to the first 1000 mg infused of Obinutuzumab. Infusion reactions can also occur with subsequent infusions. Symptoms may include hypotension, tachycardia, dyspnea, and respiratory symptoms (e.g., bronchospasm, larynx and throat irritation, wheezing, laryngeal edema). Other common symptoms include nausea, vomiting, diarrhea, hypertension, flushing, headache, pyrexia, and chills.
- Premedicate patients with acetaminophen, antihistamine, and a glucocorticoid. Institute medical management (e.g., glucocorticoids, epinephrine, bronchodilators, and/or oxygen) for infusion reactions as needed. Closely monitor patients during the entire infusion. Infusion reactions within 24 hours of receiving Obinutuzumab have occurred .
- For patients with any Grade 4 infusion reactions, including but not limited to anaphylaxis, acute life-threatening respiratory symptoms, or other life-threatening infusion reaction: Stop the Obinutuzumab infusion. Permanently discontinue Obinutuzumab therapy.
- For patients with Grade 1, 2, or 3 infusion reactions: Interrupt Obinutuzumab for Grade 3 reactions until resolution of symptoms. Interrupt or reduce the rate of the infusion for Grade 1 or 2 reactions and manage symptoms.
- For patients with preexisting cardiac or pulmonary conditions, monitor more frequently throughout the infusion and the post-infusion period since they may be at greater risk of experiencing more severe reactions. Hypotension may occur as part of the Obinutuzumab infusion reaction. Consider withholding antihypertensive treatments for 12 hours prior to, during each Obinutuzumab infusion, and for the first hour after administration until blood pressure is stable. For patients at increased risk of hypertensive crisis, consider the benefits versus the risks of withholding their antihypertensive medication as is suggested here.
Tumor Lysis Syndrome
- Acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, and/or hyperphosphatemia from Tumor Lysis Syndrome (TLS) can occur within 12–24 hours after the first infusion. Patients with high tumor burden and/or high circulating lymphocyte count (> 25 × 109/L) are at greater risk for TLS and should receive appropriate tumor lysis prophylaxis with anti-hyperuricemics (e.g., allopurinol) and hydration beginning 12–24 hours prior to the infusion of Obinutuzumab. For treatment of TLS, correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, including dialysis as indicated.
Infections
- Serious bacterial, fungal, and new or reactivated viral infections can occur during and following Obinutuzumab therapy. Fatal infections have been reported with Obinutuzumab. Do not administer Obinutuzumab to patients with an active infection. Patients with a history of recurring or chronic infections may be at increased risk of infection.
Neutropenia
- Obinutuzumab in combination with chlorambucil caused Grade 3 or 4 neutropenia in 33% of patients in the trial. Patients with Grade 3 to 4 neutropenia should be monitored frequently with regular laboratory tests until resolution. Anticipate, evaluate, and treat any symptoms or signs of developing infection.
- Neutropenia can also be of late onset (occurring more than 28 days after completion of treatment) and/or prolonged (lasting longer than 28 days).
- Patients with neutropenia are strongly recommended to receive antimicrobial prophylaxis throughout the treatment period. Antiviral and antifungal prophylaxis should be considered.
Thrombocytopenia
- Obinutuzumab in combination with chlorambucil caused Grade 3 or 4 thrombocytopenia in 10% of patients in the trial. In 4% of patients, Obinutuzumab caused acute thrombocytopenia occurring within 24 hours after the Obinutuzumab infusion. Fatal hemorrhagic events during Cycle 1 have also been reported in patients treated with Obinutuzumab.
- Monitor all patients frequently for thrombocytopenia and hemorrhagic events, especially during the first cycle. In patients with Grade 3 or 4 thrombocytopenia, monitor platelet counts more frequently until resolution and consider subsequent dose delays of Obinutuzumab and chlorambucil or dose reductions of chlorambucil. Transfusion of blood products (i.e., platelet transfusion) may be necessary. Consider withholding concomitant medications which may increase bleeding risk (platelet inhibitors, anticoagulants), especially during the first cycle.
Immunization
- The safety and efficacy of immunization with live or attenuated viral vaccines during or following Obinutuzumab therapy has not been studied. Immunization with live virus vaccines is not recommended during treatment and until B-cell recovery.
# Adverse Reactions
## Clinical Trials Experience
- The following adverse reactions are discussed in greater detail in other sections of the label:
- Hepatitis B reactivation
- Progressive multifocal leukoencephalopathy
- Infusion reactions
- Tumor lysis syndrome
- Infections
- Neutropenia
- Thrombocytopenia
- The most common adverse reactions (incidence ≥ 10%) were infusion reactions, neutropenia, thrombocytopenia, anemia, pyrexia, cough, nausea, and diarrhea.
Clinical Trial 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 data described in Tables 3–6 below are based on a safety population of 773 previously untreated patients with CLL. Patients were treated with chlorambucil alone, Obinutuzumab in combination with chlorambucil, or rituximab in combination with chlorambucil. The Stage 1 analysis compared Obinutuzumab in combination with chlorambucil vs. chlorambucil alone, and Stage 2 compared Obinutuzumab in combination with chlorambucil vs. rituximab in combination with chlorambucil. Patients received three 1000 mg doses of Obinutuzumab on the first cycle and a single dose of 1000 mg once every 28 days for 5 additional cycles in combination with chlorambucil (6 cycles of 28 days each in total). In the last 140 patients enrolled, the first dose of Obinutuzumab was split between day 1 (100 mg) and day 2 (900 mg).In total, 81% of patients received all 6 cycles (of 28 days each) of Obinutuzumab-based therapy.
- Infusion Reactions: The incidence of infusion reactions was 65% with the first infusion of Obinutuzumab. The incidence of Grade 3 or 4 infusion reactions was 20% with 7% of patients discontinuing therapy. The incidence of reactions with subsequent infusions was 3% with the second 1000 mg and < 1% thereafter. No Grade 3 or 4 infusion reactions were reported beyond the first 1000 mg infused.
Of the first 53 patients receiving Obinutuzumab on the trial, 47 (89%) experienced an infusion reaction. After this experience, study protocol modifications were made to require pre-medication with a corticosteroid, antihistamine, and acetaminophen. The first dose was also divided into two infusions (100 mg on day 1 and 900 mg on day 2). For the 140 patients for whom these mitigation measures were implemented, 74 patients (53%) experienced a reaction with the first 1000 mg (64 patients on day 1, 3 patients on day 2, and 7 patients on both days) and < 3% thereafter.
- Neutropenia: The incidence of neutropenia reported as an adverse reaction was 38% in the Obinutuzumab treated arm and 32% in the rituximab treated arm, with the incidence of serious adverse events being 1% and < 1%, respectively (TABLE 4). Cases of late-onset neutropenia (occurring 28 days after completion of treatment or later) were 16% in the Obinutuzumab treated arm and 12% in the rituximab treated arm.
- Infection: The incidence of infections was similar between Obinutuzumab and rituximab treated arms. Thirty-eight percent of patients in the Obinutuzumab treated arm and 37% in the rituximab treated arm experienced an infection, with Grade 3–4 rates being 11% and 13%, respectively. Fatal events were reported in 1% of patients in both arms.
- Thrombocytopenia: The overall incidence of thrombocytopenia reported as an adverse reaction was higher in the Obinutuzumab treated arm (14%) compared to the rituximab treated arm (7%), with the incidence of Grade 3–4 events being 10% and 3%, respectively (TABLE 4). The difference in incidences between the treatment arms is driven by events occurring during the first cycle. The incidence of thrombocytopenia (all grades) in the first cycle were 11% in the Obinutuzumab and 3% in the rituximab treated arms, with Grade 3–4 rates being 8% and 2%, respectively. Four percent of patients in the Obinutuzumab treated arm experienced acute thrombocytopenia (occurring within 24 hours after the Obinutuzumab infusion).
The overall incidence of hemorrhagic events and the number of fatal hemorrhagic events were similar between the treatment arms, with 3 in the rituximab and 4 in the Obinutuzumab treated arms. However, all fatal hemorrhagic events in patients treated with Obinutuzumab occurred in Cycle 1.
- Tumor Lysis Syndrome: The incidence of Grade 3 or 4 tumor lysis syndrome was 2% in the Obinutuzumab treated arm versus 0% in the rituximab treated arm.
- Musculoskeletal Disorders: Adverse events related to musculoskeletal disorders (all events from the System Organ Class), including pain, have been reported in the Obinutuzumab treated arm with higher incidence than in the rituximab treated arm (18% vs. 15%).
- Liver Enzyme Elevations: Hepatic enzyme elevations have occurred in patients who received Obinutuzumab in clinical trials and had normal baseline hepatic enzyme levels (AST, ALT, and ALP). The events occurred most frequently within 24-48 hours of the first infusion. In some patients, elevations in liver enzymes were observed concurrently with infusion reactions or tumor lysis syndrome. In the pivotal study, there was no clinically meaningful difference in overall hepatotoxicity adverse events between all arms (4% of patients in the Obinutuzumab treated arm). Medications commonly used to prevent infusion reactions (e.g., acetaminophen) may also be implicated in these events. Monitor liver function tests during treatment, especially during the first cycle. Consider treatment interruption or discontinuation for hepatotoxicity.
Immunogenicity
- Serum samples from patients with previously untreated CLL were tested during and after treatment for antibodies to Obinutuzumab. Of the Obinutuzumab treated patients, 7% (18/271) tested positive for anti-Obinutuzumab antibodies at one or more time points. Neutralizing activity of anti-Obinutuzumab antibodies has not been assessed.
- Immunogenicity data are highly dependent on the sensitivity and specificity of the test methods used. Additionally, the observed incidence of a positive result in a test method may be influenced by several factors, including sample handling, timing of sample collection, drug interference, concomitant medication, and the underlying disease. Therefore, comparison of the incidence of antibodies to Obinutuzumab with the incidence of antibodies to other products may be misleading. Clinical significance of anti-Obinutuzumab antibodies is not known.
Additional Clinical Trial Experience
- Worsening of Pre-existing Cardiac Conditions: Fatal cardiac events have been reported in patients treated with Obinutuzumab.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Obinutuzumab in the drug label.
# Drug Interactions
- No formal drug interaction studies have been conducted with Obinutuzumab.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Pregnancy Category C
Risk Summary
- There are no adequate and well-controlled studies of Obinutuzumab in pregnant women. Women of childbearing potential should use effective contraception while receiving Obinutuzumab and for 12 months following treatment. Obinutuzumab should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Mothers who have been exposed to Obinutuzumab during pregnancy should discuss the safety and timing of live virus vaccinations for their infants with their child's healthcare providers.
Animal Data
- In a pre- and post-natal development study, pregnant cynomolgus monkeys received weekly intravenous doses of 25 or 50 mg/kg obinutuzumab from day 20 of pregnancy until parturition. There were no teratogenic effects in animals. The high dose results in an exposure (AUC) that is 2.4 times the exposure in patients with CLL at the recommended label dose. When first measured on day 28 postpartum, obinutuzumab was detected in offspring, and B cells were completely depleted. The B-cell counts returned to normal levels, and immunologic function was restored within 6 months after birth.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Obinutuzumab in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Obinutuzumab during labor and delivery.
### Nursing Mothers
- It is not known whether obinutuzumab is excreted in human milk. However, obinutuzumab is excreted in the milk of lactating cynomolgus monkeys, and human IgG is known to be 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 obinutuzumab, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- The safety and effectiveness of Obinutuzumab in pediatric patients has not been established.
### Geriatic Use
- Of 336 previously untreated CLL patients who received Obinutuzumab in combination with chlorambucil, 273 patients (81%) were ≥ 65 years of age and 156 patients (46%) were ≥ 75 years of age. The median age was 74 years. Of the 156 patients ≥ 75 years of age, 72 (46%) experienced serious adverse events and 11 (7%) experienced adverse events leading to death. For 180 patients < 75 years of age, 59 (33%) experienced a serious adverse event and 4 (2%) an adverse event leading to death. No significant differences in efficacy were observed between patients ≥ 75 years of age and those < 75 years of age
### Gender
There is no FDA guidance on the use of Obinutuzumab with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Obinutuzumab with respect to specific racial populations.
### Renal Impairment
- Based on population pharmacokinetic analysis, a baseline creatinine clearance (CrCl) ≥ 30 mL/min does not affect the pharmacokinetics of Obinutuzumab. Obinutuzumab has not been studied in patients with a baseline CrCl < 30 mL/min
### Hepatic Impairment
- Obinutuzumab has not been studied in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Obinutuzumab in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Obinutuzumab in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
Preparation and Administration
Preparation
Prepare the solution for infusion, using aseptic technique, as follows:
- Inspect visually for any particulate matter and discoloration prior to administration.
- Dilute into a 0.9% sodium chloride PVC or non-PVC polyolefin infusion bag. Do not use other diluents such as dextrose (5%).
- Preparation of solution for infusion on day 1 (100 mg) and day 2 (900 mg) of Cycle 1:
- Withdraw 40 mL of Obinutuzumab solution from the vial.
- Dilute 4 mL (100 mg) of Obinutuzumab into a 100 mL 0.9% sodium chloride infusion bag for immediate administration.
- Dilute the remaining 36 mL (900 mg) into a 250 mL 0.9% sodium chloride infusion bag at the same time for use on day 2 and store at 2°C to 8°C (36°F to 46°F) for up to 24 hours. After allowing the diluted bag to come to room temperature, use immediately.
- Clearly label each infusion bag.
- Preparation of solution for infusion on day 8 and 15 of Cycle 1 and day 1 Cycles 2–6:
- Withdraw 40 mL of Obinutuzumab solution from the vial.
- Dilute 40 mL (1000 mg) into a 250 mL 0.9% sodium chloride infusion bag.
- Mix diluted solution by gentle inversion. Do not shake or freeze.
- For microbiological stability, the diluted Obinutuzumab infusion solution should be used immediately. Dilute under appropriate aseptic conditions. If not used immediately, the solution may be stored in a refrigerator at 2°C to 8°C (36°F to 46°F) for up to 24 hours prior to use.
The product can be administered at a final concentration of 0.4 mg/mL to 4 mg/mL.
Administration
- Administer as an intravenous infusion only.
- Do not administer as an intravenous push or bolus.
- Do not mix Obinutuzumab with other drugs.
- No incompatibilities between Obinutuzumab and polyvinylchloride (PVC) or non-PVC polyolefin bags and administration sets have been observed.
### Monitoring
There is limited information regarding Monitoring of Obinutuzumab in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Obinutuzumab in the drug label.
# Overdosage
- There has been no experience with overdose in human clinical trials. Doses ranging from 50 mg up to and including 2000 mg per infusion have been administered in clinical trials. For patients who experience overdose, treatment should consist of immediate interruption or reduction of Obinutuzumab and supportive therapy.
# Pharmacology
## Mechanism of Action
- Obinutuzumab is a monoclonal antibody that targets the CD20 antigen expressed on the surface of pre B- and mature B-lymphocytes. Upon binding to CD20, obinutuzumab mediates B-cell lysis through (1) engagement of immune effector cells, (2) by directly activating intracellular death signaling pathways (direct cell death), and/or (3) activation of the complement cascade. The immune effector cell mechanisms include antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis.
- As an antibody with reduced fucose content, obinutuzumab induces greater ADCC activity than rituximab in vitro using human cancer cell lines. Obinutuzumab also demonstrated an increased ability to induce direct cell death when compared to rituximab. Obinutuzumab binds to FcγRIII using purified proteins with a higher affinity than rituximab. Obinutuzumab and rituximab bind with similar affinity to overlapping epitopes on CD20.
## Structure
- Obinutuzumab is a humanized anti-CD20 monoclonal antibody of the IgG1 subclass. It recognizes a specific epitope of the CD20 molecule found on B cells. The molecular mass of the antibody is approximately 150 kDa.
- Obinutuzumab is produced by mammalian cell (CHO) suspension culture. Obinutuzumab was engineered for reduced fucose content as compared to a typical IgG1 produced in CHO cells. Obinutuzumab is a sterile, clear, colorless to slightly brown, preservative-free liquid concentrate for intravenous administration. Obinutuzumab is supplied at a concentration of 25 mg/mL in 1000 mg single-use vials. The product is formulated in 20 mM L-histidine/L-histidine hydrochloride, 240 mM trehalose, 0.02% poloxamer 188. The pH is 6.0.
## Pharmacodynamics
- In clinical trials in patients with CLL, Obinutuzumab caused CD19 B-cell depletion (defined as CD19 B-cell counts < 0.07 × 109/L). Initial CD19 B-cell recovery was observed in some patients approximately 9 months after the last Obinutuzumab dose. At 18 months of follow-up, some patients remain B-cell depleted.
- Although the depletion of B cells in the peripheral blood is a measurable pharmacodynamic effect, it is not directly correlated with the depletion of B cells in solid organs or in malignant deposits. B-cell depletion has not been shown to be directly correlated to clinical response.
Cardiac Electrophysiology
- The potential effects of Obinutuzumab on the QTc interval have not been studied.
## Pharmacokinetics
- Based on a population pharmacokinetic (pop-PK) analysis, the geometric mean (CV%) volume of distribution of obinutuzumab at steady state is approximately 3.9 (21) L.
- The elimination of obinutuzumab is comprised of a linear clearance pathway and a time-dependent non-linear clearance pathway. As Obinutuzumab treatment progresses, the impact of the time-dependent pathway diminishes in a manner suggesting target-mediated drug disposition (TMDD). Based on a pop-PK analysis, the geometric mean (CV%) terminal obinutuzumab clearance and half-life are approximately 0.09 (37%) L/day and 29.7 (35%) days, respectively.
Specific Populations:
- Age: Age did not affect the pharmacokinetics of Obinutuzumab.
- Body Weight: Volume of distribution and steady-state clearance both increased with body weight; however, the expected change in exposure does not warrant a dose modification.
- Renal Impairment: Based on the population pharmacokinetic analysis, a baseline creatinine clearance (CrCl) > 30 mL/min does not affect the pharmacokinetics of Obinutuzumab. Obinutuzumab has not been studied in patients with a baseline CrCl < 30 mL/min.
- Hepatic Impairment: Obinutuzumab has not been studied in patients with hepatic impairment.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
- No carcinogenicity or genotoxicity studies have been conducted with obinutuzumab.
- No specific studies have been conducted to evaluate potential effects on fertility; however, no adverse effects on male or female reproductive organs were observed in the 26-week repeat-dose toxicity study in cynomolgus monkeys.
# Clinical Studies
Chronic Lymphocytic Leukemia
- Obinutuzumab was evaluated in a three-arm, open-label, active-controlled, randomized, multicenter trial (Study 1) in 781 patients with previously untreated CD20+ chronic lymphocytic leukemia requiring treatment who had coexisting medical conditions or reduced renal function as measured by creatinine clearance (CrCl) < 70 mL/min. Patients with CrCl < 30 mL/min, active infections, positive hepatitis B (HBsAg or anti-HBc positive; patients positive for anti-HBc could be included if hepatitis B viral DNA was not detectable) and hepatitis C serology, or immunization with live virus vaccine within 28 days prior to randomization were excluded from the trial. Patients were treated with chlorambucil control (Arm 1), Obinutuzumab in combination with chlorambucil (Arm 2), or rituximab in combination with chlorambucil (Arm 3). The safety and efficacy of Obinutuzumab was evaluated in a Stage 1 comparison of Arm 1 vs. Arm 2 in 356 patients and a Stage 2 comparison of Arm 2 vs. Arm 3 in 663 patients.
- The majority of patients received 1000 mg of Obinutuzumab on days 1, 8, and 15 of the first cycle, followed by treatment on the first day of 5 subsequent cycles (total of 6 cycles, 28 days each). The first dose of Obinutuzumab was divided between day 1 (100 mg) and day 2 (900 mg), which was implemented in 140 patients. Chlorambucil was given orally at 0.5 mg/kg on day 1 and day 15 of all treatment cycles (1 to 6).
- In Study 1, the median age was 73 years, 62% were male, and 95% were Caucasian. Sixty-five percent had a CrCl < 70 mL/min and 76% had multiple coexisting medical conditions. Twenty-two percent of patients were Binet stage A, 42% were stage B, and 36% were stage C. The median estimated CrCl was 62 mL/min. Eighty-one percent of patients treated with Obinutuzumab in combination with chlorambucil received all 6 cycles compared to 89% of patients in the rituximab treated arm and 67% in the chlorambucil alone arm.
- In the Stage 1 analysis of Study 1, the median progression-free survival (PFS) in the Obinutuzumab in combination with chlorambucil arm was 27.2 months and 11.2 months in the chlorambucil alone arm (median observation time 22.8 months) as assessed by independent review and is consistent with investigator-assessed PFS. The median overall survival (OS) was not yet reached with a total of 46 deaths: 22 (9%) in the Obinutuzumab in combination with chlorambucil arm and 24 (20%) in the chlorambucil arm. The hazard ratio for OS was 0.41 (95% CI: 0.23-0.74).
- In the Stage 2 analysis of Study 1, the median PFS was 26.7 months in the Obinutuzumab arm and 14.9 months in the rituximab arm with a median observation time of 18.7 months (HR: 0.42, 95% CI: 0.33-0.54, p-value <0.0001). These results were assessed by independent review and are consistent with investigator-assessed PFS. Minimal Residual Disease (MRD) was evaluated using allele-specific oligonucleotide polymerase chain reaction (ASO-PCR). The cutoff for a negative status was one CLL cell per 104 leukocytes in the sample (i.e., an MRD value of <10-4 was considered negative). Among patients who achieved complete response (CR) and complete response with incomplete marrow recovery (CRi) (94 patients in the Obinutuzumab arm and 34 patients in the rituximab arm), 18 patients (19%) had negative MRD in the bone marrow in the Obinutuzumab arm compared to 2 patients (6%) in the rituximab arm. Out of the patients who achieved CR and CRi, 39 patients (41%) in the Obinutuzumab arm and 4 patients (12%) in the rituximab arm were MRD negative in peripheral blood samples collected at least 3 months after the end of treatment.
- Efficacy results are shown in TABLE 7, and the Kaplan-Meier curves for Stage 1a Overall Survival and Stage 2 PFS are shown in FIGURES 1 and 2, respectively.
# How Supplied
- Obinutuzumab 1000 mg/40 mL (25 mg/mL) single-use vials containing preservative-free solution (NDC 50242-070-01) are stable at 2°C to 8°C (36°F to 46°F). Do not use beyond expiration date stamped on carton. Obinutuzumab vials should be protected from light. DO NOT FREEZE. DO NOT SHAKE.
- For the diluted product, chemical and physical stability have been demonstrated in 0.9% NaCl at concentrations of 0.4 mg/mL to 20 mg/mL for 24 hours at 2°C to 8°C (36°F to 46°F) followed by 48 hours (including infusion time) at room temperature (≤ 30°C/86°F). Obinutuzumab does not contain antimicrobial preservatives. Therefore, care must be taken to ensure that the solution for infusion is not microbiologically compromised during preparation. The solution for infusion should be used immediately. If not used immediately, the prepared solution may be stored up to 24 hours at 2 to 8°C. No incompatibilities between Obinutuzumab and polyvinyl chloride or polyolefin infusion materials have been observed in concentration ranges from 0.4 mg/mL to 20.0 mg/mL after dilution of Obinutuzumab with 0.9% sodium chloride.
## Storage
There is limited information regarding Obinutuzumab Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Advise patients to seek immediate medical attention for any of the following:
- Signs and symptoms of infusion reactions including dizziness, nausea, chills, fever, vomiting, diarrhea, breathing problems, or chest pain.
- Symptoms of tumor lysis syndrome such as nausea, vomiting, diarrhea, and lethargy.
- Signs of infections including fever and cough.
- Symptoms of hepatitis including worsening fatigue or yellow discoloration of skin or eyes.
- New or changes in neurological symptoms such as confusion, dizziness or loss of balance, difficulty talking or walking, or vision problems.
Advise patients of the need for:
- Periodic monitoring of blood counts.
- Avoid vaccinations with live viral vaccines.
- Patients with a history of hepatitis B infection (based on the blood test) should be monitored and sometimes treated for their hepatitis.
# Precautions with Alcohol
- Alcohol-Obinutuzumab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- GAZYVA- ®
# Look-Alike Drug Names
- A® — B®
# Drug Shortage Status
# Price | Obinutuzumab
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2]
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# Black Box Warning
# Overview
Obinutuzumab is an antineoplastic agent that is FDA approved for the treatment of chronic lymphoid leukemia,previously untreated. There is a Black Box Warning for this drug as shown here. Common adverse reactions include anemia, neutropenia,thrombocytopenia, musculoskeletal system disorder,cough, fever.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
# Indications
- Obinutuzumab , in combination with chlorambucil, is indicated for the treatment of patients with previously untreated chronic lymphocytic leukemia(CLL).
# Dosage
Recommended Dosage Regimen
- Premedicate before each infusion.
- Administer only as an intravenous infusion through a dedicated line.
- Do not administer as an intravenous push or bolus.
- Monitor blood counts at regular intervals.
- Obinutuzumab should only be administered by a healthcare professional with appropriate medical support to manage severe infusion reactions that can be fatal if they occur.
Recommended Dose:
- Each dose of Obinutuzumab is 1000 mg, administered intravenously, with the exception of the first infusions in Cycle 1, which are administered on day 1 (100 mg) and day 2 (900 mg).
- If a planned dose of Obinutuzumab is missed, administer the missed dose as soon as possible and adjust dosing schedule accordingly. If appropriate, patients who do not complete the Day 1 Cycle 1 dose may proceed to the day 2 Cycle 1 dose.
- If a patient experiences an infusion reaction of any grade during infusion, adjust the infusion as follows:
- Grade 4 (life-threatening): Stop infusion immediately and permanently discontinue Obinutuzumab therapy.
- Grade 3 (severe): Interrupt infusion and manage symptoms. Upon resolution of symptoms, consider restarting Obinutuzumab infusion at no more than half the previous rate (the rate being used at the time that the infusion reaction occurred) and, if patient does not experience any further infusion reaction symptoms, infusion rate escalation may resume at the increments and intervals as appropriate for the treatment cycle dose. Day 1 infusion rate may be increased back up to 25 mg/hr after 1 hour but not increased further. Permanently discontinue treatment if patients experience a Grade 3 infusion-related symptom at rechallenge.
- Grade 1–2 (mild to moderate): Reduce infusion rate or interrupt infusion and treat symptoms. Upon resolution of symptoms, continue or resume infusion and, if patient does not experience any further infusion reaction symptoms, infusion rate escalation may resume at the increments and intervals as appropriate for the treatment cycle dose. Day 1 infusion rate may be increased back up to 25 mg/hr after 1 hour but not increased further.
Recommended Premedication
- Premedication is recommended to reduce the risk of infusion reactions as outlined in TABLE 2.
- Hypotension may occur during Obinutuzumab intravenous infusions. Consider withholding antihypertensive treatments for 12 hours prior to and throughout each Obinutuzumab infusion and for the first hour after administration.
- For patients with high tumor burden and/or high circulating absolute lymphocyte counts (greater than 25 × 109/L), premedicate with anti-hyperuricemics (e.g., allopurinol) beginning 12–24 hours prior to start of therapy and ensure adequate hydration for prophylaxis of tumor lysis syndrome.
Premedication for Antimicrobial Prophylaxis
- Patients with neutropenia are strongly recommended to receive antimicrobial prophylaxis throughout the treatment period. Antiviral and antifungal prophylaxis should be considered.
Treatment Interruption for Toxicity
Consider treatment interruption if patients experience an infection, Grade 3 or 4 cytopenia, or a ≥ Grade 2 non-hematologic toxicity.
# DOSAGE FORMS AND STRENGTHS
- 1000 mg/40 mL (25 mg/mL) single-use vial.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Obinutuzumab in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Obinutuzumab in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Obinutuzumab in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Obinutuzumab in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Obinutuzumab in pediatric patients.
# Contraindications
- None
# Warnings
Hepatitis B Virus Reactivation
- Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with anti-CD20 antibodies such as Obinutuzumab. HBV reactivation has been reported in patients who are hepatitis B surface antigen (HBsAg) positive and also in patients who are HBsAg negative but are hepatitis B core antibody (anti-HBc) positive. Reactivation has also occurred in patients who appear to have resolved hepatitis B infection (i.e., HBsAg negative, anti-HBc positive, and hepatitis B surface antibody [anti-HBs] positive).
- HBV reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level or detection of HBsAg in a person who was previously HBsAg negative and anti-HBc positive. Reactivation of HBV replication is often followed by hepatitis, i.e., increase in transaminase levels and, in severe cases, increase in bilirubin levels, liver failure, and death.
- Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with Obinutuzumab. For patients who show evidence of hepatitis B infection (HBsAg positive [regardless of antibody status] or HBsAg negative but anti-HBc positive), consult physicians with expertise in managing hepatitis B regarding monitoring and consideration for HBV antiviral therapy.
- Monitor patients with evidence of current or prior HBV infection for clinical and laboratory signs of hepatitis or HBV reactivation during and for several months following treatment with Obinutuzumab. HBV reactivation has been reported for other CD20-directed cytolytic antibodies following completion of therapy.
- In patients who develop reactivation of HBV while receiving Obinutuzumab, immediately discontinue Obinutuzumab and any concomitant chemotherapy and institute appropriate treatment. Resumption of Obinutuzumab in patients whose HBV reactivation resolves should be discussed with physicians with expertise in managing hepatitis B. Insufficient data exist regarding the safety of resuming Obinutuzumab in patients who develop HBV reactivation.
Progressive Multifocal Leukoencephalopathy
- JC virus infection resulting in progressive multifocal leukoencephalopathy (PML), which can be fatal, was observed in patients treated with Obinutuzumab. Consider the diagnosis of PML in any patient presenting with new onset or changes to preexisting neurologic manifestations. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture. Discontinue Obinutuzumab therapy and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML.
Infusion Reactions
- Obinutuzumab can cause severe and life-threatening infusion reactions. Two thirds of patients experienced a reaction to the first 1000 mg infused of Obinutuzumab. Infusion reactions can also occur with subsequent infusions. Symptoms may include hypotension, tachycardia, dyspnea, and respiratory symptoms (e.g., bronchospasm, larynx and throat irritation, wheezing, laryngeal edema). Other common symptoms include nausea, vomiting, diarrhea, hypertension, flushing, headache, pyrexia, and chills.
- Premedicate patients with acetaminophen, antihistamine, and a glucocorticoid. Institute medical management (e.g., glucocorticoids, epinephrine, bronchodilators, and/or oxygen) for infusion reactions as needed. Closely monitor patients during the entire infusion. Infusion reactions within 24 hours of receiving Obinutuzumab have occurred .
- For patients with any Grade 4 infusion reactions, including but not limited to anaphylaxis, acute life-threatening respiratory symptoms, or other life-threatening infusion reaction: Stop the Obinutuzumab infusion. Permanently discontinue Obinutuzumab therapy.
- For patients with Grade 1, 2, or 3 infusion reactions: Interrupt Obinutuzumab for Grade 3 reactions until resolution of symptoms. Interrupt or reduce the rate of the infusion for Grade 1 or 2 reactions and manage symptoms.
- For patients with preexisting cardiac or pulmonary conditions, monitor more frequently throughout the infusion and the post-infusion period since they may be at greater risk of experiencing more severe reactions. Hypotension may occur as part of the Obinutuzumab infusion reaction. Consider withholding antihypertensive treatments for 12 hours prior to, during each Obinutuzumab infusion, and for the first hour after administration until blood pressure is stable. For patients at increased risk of hypertensive crisis, consider the benefits versus the risks of withholding their antihypertensive medication as is suggested here.
Tumor Lysis Syndrome
- Acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, and/or hyperphosphatemia from Tumor Lysis Syndrome (TLS) can occur within 12–24 hours after the first infusion. Patients with high tumor burden and/or high circulating lymphocyte count (> 25 × 109/L) are at greater risk for TLS and should receive appropriate tumor lysis prophylaxis with anti-hyperuricemics (e.g., allopurinol) and hydration beginning 12–24 hours prior to the infusion of Obinutuzumab. For treatment of TLS, correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, including dialysis as indicated.
Infections
- Serious bacterial, fungal, and new or reactivated viral infections can occur during and following Obinutuzumab therapy. Fatal infections have been reported with Obinutuzumab. Do not administer Obinutuzumab to patients with an active infection. Patients with a history of recurring or chronic infections may be at increased risk of infection.
Neutropenia
- Obinutuzumab in combination with chlorambucil caused Grade 3 or 4 neutropenia in 33% of patients in the trial. Patients with Grade 3 to 4 neutropenia should be monitored frequently with regular laboratory tests until resolution. Anticipate, evaluate, and treat any symptoms or signs of developing infection.
- Neutropenia can also be of late onset (occurring more than 28 days after completion of treatment) and/or prolonged (lasting longer than 28 days).
- Patients with neutropenia are strongly recommended to receive antimicrobial prophylaxis throughout the treatment period. Antiviral and antifungal prophylaxis should be considered.
Thrombocytopenia
- Obinutuzumab in combination with chlorambucil caused Grade 3 or 4 thrombocytopenia in 10% of patients in the trial. In 4% of patients, Obinutuzumab caused acute thrombocytopenia occurring within 24 hours after the Obinutuzumab infusion. Fatal hemorrhagic events during Cycle 1 have also been reported in patients treated with Obinutuzumab.
- Monitor all patients frequently for thrombocytopenia and hemorrhagic events, especially during the first cycle. In patients with Grade 3 or 4 thrombocytopenia, monitor platelet counts more frequently until resolution and consider subsequent dose delays of Obinutuzumab and chlorambucil or dose reductions of chlorambucil. Transfusion of blood products (i.e., platelet transfusion) may be necessary. Consider withholding concomitant medications which may increase bleeding risk (platelet inhibitors, anticoagulants), especially during the first cycle.
Immunization
- The safety and efficacy of immunization with live or attenuated viral vaccines during or following Obinutuzumab therapy has not been studied. Immunization with live virus vaccines is not recommended during treatment and until B-cell recovery.
# Adverse Reactions
## Clinical Trials Experience
- The following adverse reactions are discussed in greater detail in other sections of the label:
- Hepatitis B reactivation
- Progressive multifocal leukoencephalopathy
- Infusion reactions
- Tumor lysis syndrome
- Infections
- Neutropenia
- Thrombocytopenia
- The most common adverse reactions (incidence ≥ 10%) were infusion reactions, neutropenia, thrombocytopenia, anemia, pyrexia, cough, nausea, and diarrhea.
Clinical Trial 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 data described in Tables 3–6 below are based on a safety population of 773 previously untreated patients with CLL. Patients were treated with chlorambucil alone, Obinutuzumab in combination with chlorambucil, or rituximab in combination with chlorambucil. The Stage 1 analysis compared Obinutuzumab in combination with chlorambucil vs. chlorambucil alone, and Stage 2 compared Obinutuzumab in combination with chlorambucil vs. rituximab in combination with chlorambucil. Patients received three 1000 mg doses of Obinutuzumab on the first cycle and a single dose of 1000 mg once every 28 days for 5 additional cycles in combination with chlorambucil (6 cycles of 28 days each in total). In the last 140 patients enrolled, the first dose of Obinutuzumab was split between day 1 (100 mg) and day 2 (900 mg).In total, 81% of patients received all 6 cycles (of 28 days each) of Obinutuzumab-based therapy.
- Infusion Reactions: The incidence of infusion reactions was 65% with the first infusion of Obinutuzumab. The incidence of Grade 3 or 4 infusion reactions was 20% with 7% of patients discontinuing therapy. The incidence of reactions with subsequent infusions was 3% with the second 1000 mg and < 1% thereafter. No Grade 3 or 4 infusion reactions were reported beyond the first 1000 mg infused.
Of the first 53 patients receiving Obinutuzumab on the trial, 47 (89%) experienced an infusion reaction. After this experience, study protocol modifications were made to require pre-medication with a corticosteroid, antihistamine, and acetaminophen. The first dose was also divided into two infusions (100 mg on day 1 and 900 mg on day 2). For the 140 patients for whom these mitigation measures were implemented, 74 patients (53%) experienced a reaction with the first 1000 mg (64 patients on day 1, 3 patients on day 2, and 7 patients on both days) and < 3% thereafter.
- Neutropenia: The incidence of neutropenia reported as an adverse reaction was 38% in the Obinutuzumab treated arm and 32% in the rituximab treated arm, with the incidence of serious adverse events being 1% and < 1%, respectively (TABLE 4). Cases of late-onset neutropenia (occurring 28 days after completion of treatment or later) were 16% in the Obinutuzumab treated arm and 12% in the rituximab treated arm.
- Infection: The incidence of infections was similar between Obinutuzumab and rituximab treated arms. Thirty-eight percent of patients in the Obinutuzumab treated arm and 37% in the rituximab treated arm experienced an infection, with Grade 3–4 rates being 11% and 13%, respectively. Fatal events were reported in 1% of patients in both arms.
- Thrombocytopenia: The overall incidence of thrombocytopenia reported as an adverse reaction was higher in the Obinutuzumab treated arm (14%) compared to the rituximab treated arm (7%), with the incidence of Grade 3–4 events being 10% and 3%, respectively (TABLE 4). The difference in incidences between the treatment arms is driven by events occurring during the first cycle. The incidence of thrombocytopenia (all grades) in the first cycle were 11% in the Obinutuzumab and 3% in the rituximab treated arms, with Grade 3–4 rates being 8% and 2%, respectively. Four percent of patients in the Obinutuzumab treated arm experienced acute thrombocytopenia (occurring within 24 hours after the Obinutuzumab infusion).
The overall incidence of hemorrhagic events and the number of fatal hemorrhagic events were similar between the treatment arms, with 3 in the rituximab and 4 in the Obinutuzumab treated arms. However, all fatal hemorrhagic events in patients treated with Obinutuzumab occurred in Cycle 1.
- Tumor Lysis Syndrome: The incidence of Grade 3 or 4 tumor lysis syndrome was 2% in the Obinutuzumab treated arm versus 0% in the rituximab treated arm.
- Musculoskeletal Disorders: Adverse events related to musculoskeletal disorders (all events from the System Organ Class), including pain, have been reported in the Obinutuzumab treated arm with higher incidence than in the rituximab treated arm (18% vs. 15%).
- Liver Enzyme Elevations: Hepatic enzyme elevations have occurred in patients who received Obinutuzumab in clinical trials and had normal baseline hepatic enzyme levels (AST, ALT, and ALP). The events occurred most frequently within 24-48 hours of the first infusion. In some patients, elevations in liver enzymes were observed concurrently with infusion reactions or tumor lysis syndrome. In the pivotal study, there was no clinically meaningful difference in overall hepatotoxicity adverse events between all arms (4% of patients in the Obinutuzumab treated arm). Medications commonly used to prevent infusion reactions (e.g., acetaminophen) may also be implicated in these events. Monitor liver function tests during treatment, especially during the first cycle. Consider treatment interruption or discontinuation for hepatotoxicity.
Immunogenicity
- Serum samples from patients with previously untreated CLL were tested during and after treatment for antibodies to Obinutuzumab. Of the Obinutuzumab treated patients, 7% (18/271) tested positive for anti-Obinutuzumab antibodies at one or more time points. Neutralizing activity of anti-Obinutuzumab antibodies has not been assessed.
- Immunogenicity data are highly dependent on the sensitivity and specificity of the test methods used. Additionally, the observed incidence of a positive result in a test method may be influenced by several factors, including sample handling, timing of sample collection, drug interference, concomitant medication, and the underlying disease. Therefore, comparison of the incidence of antibodies to Obinutuzumab with the incidence of antibodies to other products may be misleading. Clinical significance of anti-Obinutuzumab antibodies is not known.
Additional Clinical Trial Experience
- Worsening of Pre-existing Cardiac Conditions: Fatal cardiac events have been reported in patients treated with Obinutuzumab.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Obinutuzumab in the drug label.
# Drug Interactions
- No formal drug interaction studies have been conducted with Obinutuzumab.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Pregnancy Category C
Risk Summary
- There are no adequate and well-controlled studies of Obinutuzumab in pregnant women. Women of childbearing potential should use effective contraception while receiving Obinutuzumab and for 12 months following treatment. Obinutuzumab should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Mothers who have been exposed to Obinutuzumab during pregnancy should discuss the safety and timing of live virus vaccinations for their infants with their child's healthcare providers.
Animal Data
- In a pre- and post-natal development study, pregnant cynomolgus monkeys received weekly intravenous doses of 25 or 50 mg/kg obinutuzumab from day 20 of pregnancy until parturition. There were no teratogenic effects in animals. The high dose results in an exposure (AUC) that is 2.4 times the exposure in patients with CLL at the recommended label dose. When first measured on day 28 postpartum, obinutuzumab was detected in offspring, and B cells were completely depleted. The B-cell counts returned to normal levels, and immunologic function was restored within 6 months after birth.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Obinutuzumab in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Obinutuzumab during labor and delivery.
### Nursing Mothers
- It is not known whether obinutuzumab is excreted in human milk. However, obinutuzumab is excreted in the milk of lactating cynomolgus monkeys, and human IgG is known to be 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 obinutuzumab, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- The safety and effectiveness of Obinutuzumab in pediatric patients has not been established.
### Geriatic Use
- Of 336 previously untreated CLL patients who received Obinutuzumab in combination with chlorambucil, 273 patients (81%) were ≥ 65 years of age and 156 patients (46%) were ≥ 75 years of age. The median age was 74 years. Of the 156 patients ≥ 75 years of age, 72 (46%) experienced serious adverse events and 11 (7%) experienced adverse events leading to death. For 180 patients < 75 years of age, 59 (33%) experienced a serious adverse event and 4 (2%) an adverse event leading to death. No significant differences in efficacy were observed between patients ≥ 75 years of age and those < 75 years of age
### Gender
There is no FDA guidance on the use of Obinutuzumab with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Obinutuzumab with respect to specific racial populations.
### Renal Impairment
- Based on population pharmacokinetic analysis, a baseline creatinine clearance (CrCl) ≥ 30 mL/min does not affect the pharmacokinetics of Obinutuzumab. Obinutuzumab has not been studied in patients with a baseline CrCl < 30 mL/min
### Hepatic Impairment
- Obinutuzumab has not been studied in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Obinutuzumab in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Obinutuzumab in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
Preparation and Administration
Preparation
Prepare the solution for infusion, using aseptic technique, as follows:
- Inspect visually for any particulate matter and discoloration prior to administration.
- Dilute into a 0.9% sodium chloride PVC or non-PVC polyolefin infusion bag. Do not use other diluents such as dextrose (5%).
- Preparation of solution for infusion on day 1 (100 mg) and day 2 (900 mg) of Cycle 1:
- Withdraw 40 mL of Obinutuzumab solution from the vial.
- Dilute 4 mL (100 mg) of Obinutuzumab into a 100 mL 0.9% sodium chloride infusion bag for immediate administration.
- Dilute the remaining 36 mL (900 mg) into a 250 mL 0.9% sodium chloride infusion bag at the same time for use on day 2 and store at 2°C to 8°C (36°F to 46°F) for up to 24 hours. After allowing the diluted bag to come to room temperature, use immediately.
- Clearly label each infusion bag.
- Preparation of solution for infusion on day 8 and 15 of Cycle 1 and day 1 Cycles 2–6:
- Withdraw 40 mL of Obinutuzumab solution from the vial.
- Dilute 40 mL (1000 mg) into a 250 mL 0.9% sodium chloride infusion bag.
- Mix diluted solution by gentle inversion. Do not shake or freeze.
- For microbiological stability, the diluted Obinutuzumab infusion solution should be used immediately. Dilute under appropriate aseptic conditions. If not used immediately, the solution may be stored in a refrigerator at 2°C to 8°C (36°F to 46°F) for up to 24 hours prior to use.
The product can be administered at a final concentration of 0.4 mg/mL to 4 mg/mL.
Administration
- Administer as an intravenous infusion only.
- Do not administer as an intravenous push or bolus.
- Do not mix Obinutuzumab with other drugs.
- No incompatibilities between Obinutuzumab and polyvinylchloride (PVC) or non-PVC polyolefin bags and administration sets have been observed.
### Monitoring
There is limited information regarding Monitoring of Obinutuzumab in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Obinutuzumab in the drug label.
# Overdosage
- There has been no experience with overdose in human clinical trials. Doses ranging from 50 mg up to and including 2000 mg per infusion have been administered in clinical trials. For patients who experience overdose, treatment should consist of immediate interruption or reduction of Obinutuzumab and supportive therapy.
# Pharmacology
## Mechanism of Action
- Obinutuzumab is a monoclonal antibody that targets the CD20 antigen expressed on the surface of pre B- and mature B-lymphocytes. Upon binding to CD20, obinutuzumab mediates B-cell lysis through (1) engagement of immune effector cells, (2) by directly activating intracellular death signaling pathways (direct cell death), and/or (3) activation of the complement cascade. The immune effector cell mechanisms include antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis.
- As an antibody with reduced fucose content, obinutuzumab induces greater ADCC activity than rituximab in vitro using human cancer cell lines. Obinutuzumab also demonstrated an increased ability to induce direct cell death when compared to rituximab. Obinutuzumab binds to FcγRIII using purified proteins with a higher affinity than rituximab. Obinutuzumab and rituximab bind with similar affinity to overlapping epitopes on CD20.
## Structure
- Obinutuzumab is a humanized anti-CD20 monoclonal antibody of the IgG1 subclass. It recognizes a specific epitope of the CD20 molecule found on B cells. The molecular mass of the antibody is approximately 150 kDa.
- Obinutuzumab is produced by mammalian cell (CHO) suspension culture. Obinutuzumab was engineered for reduced fucose content as compared to a typical IgG1 produced in CHO cells. Obinutuzumab is a sterile, clear, colorless to slightly brown, preservative-free liquid concentrate for intravenous administration. Obinutuzumab is supplied at a concentration of 25 mg/mL in 1000 mg single-use vials. The product is formulated in 20 mM L-histidine/L-histidine hydrochloride, 240 mM trehalose, 0.02% poloxamer 188. The pH is 6.0.
## Pharmacodynamics
- In clinical trials in patients with CLL, Obinutuzumab caused CD19 B-cell depletion (defined as CD19 B-cell counts < 0.07 × 109/L). Initial CD19 B-cell recovery was observed in some patients approximately 9 months after the last Obinutuzumab dose. At 18 months of follow-up, some patients remain B-cell depleted.
- Although the depletion of B cells in the peripheral blood is a measurable pharmacodynamic effect, it is not directly correlated with the depletion of B cells in solid organs or in malignant deposits. B-cell depletion has not been shown to be directly correlated to clinical response.
Cardiac Electrophysiology
- The potential effects of Obinutuzumab on the QTc interval have not been studied.
## Pharmacokinetics
- Based on a population pharmacokinetic (pop-PK) analysis, the geometric mean (CV%) volume of distribution of obinutuzumab at steady state is approximately 3.9 (21) L.
- The elimination of obinutuzumab is comprised of a linear clearance pathway and a time-dependent non-linear clearance pathway. As Obinutuzumab treatment progresses, the impact of the time-dependent pathway diminishes in a manner suggesting target-mediated drug disposition (TMDD). Based on a pop-PK analysis, the geometric mean (CV%) terminal obinutuzumab clearance and half-life are approximately 0.09 (37%) L/day and 29.7 (35%) days, respectively.
Specific Populations:
- Age: Age did not affect the pharmacokinetics of Obinutuzumab.
- Body Weight: Volume of distribution and steady-state clearance both increased with body weight; however, the expected change in exposure does not warrant a dose modification.
- Renal Impairment: Based on the population pharmacokinetic analysis, a baseline creatinine clearance (CrCl) > 30 mL/min does not affect the pharmacokinetics of Obinutuzumab. Obinutuzumab has not been studied in patients with a baseline CrCl < 30 mL/min.
- Hepatic Impairment: Obinutuzumab has not been studied in patients with hepatic impairment.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
- No carcinogenicity or genotoxicity studies have been conducted with obinutuzumab.
- No specific studies have been conducted to evaluate potential effects on fertility; however, no adverse effects on male or female reproductive organs were observed in the 26-week repeat-dose toxicity study in cynomolgus monkeys.
# Clinical Studies
Chronic Lymphocytic Leukemia
- Obinutuzumab was evaluated in a three-arm, open-label, active-controlled, randomized, multicenter trial (Study 1) in 781 patients with previously untreated CD20+ chronic lymphocytic leukemia requiring treatment who had coexisting medical conditions or reduced renal function as measured by creatinine clearance (CrCl) < 70 mL/min. Patients with CrCl < 30 mL/min, active infections, positive hepatitis B (HBsAg or anti-HBc positive; patients positive for anti-HBc could be included if hepatitis B viral DNA was not detectable) and hepatitis C serology, or immunization with live virus vaccine within 28 days prior to randomization were excluded from the trial. Patients were treated with chlorambucil control (Arm 1), Obinutuzumab in combination with chlorambucil (Arm 2), or rituximab in combination with chlorambucil (Arm 3). The safety and efficacy of Obinutuzumab was evaluated in a Stage 1 comparison of Arm 1 vs. Arm 2 in 356 patients and a Stage 2 comparison of Arm 2 vs. Arm 3 in 663 patients.
- The majority of patients received 1000 mg of Obinutuzumab on days 1, 8, and 15 of the first cycle, followed by treatment on the first day of 5 subsequent cycles (total of 6 cycles, 28 days each). The first dose of Obinutuzumab was divided between day 1 (100 mg) and day 2 (900 mg), which was implemented in 140 patients. Chlorambucil was given orally at 0.5 mg/kg on day 1 and day 15 of all treatment cycles (1 to 6).
- In Study 1, the median age was 73 years, 62% were male, and 95% were Caucasian. Sixty-five percent had a CrCl < 70 mL/min and 76% had multiple coexisting medical conditions. Twenty-two percent of patients were Binet stage A, 42% were stage B, and 36% were stage C. The median estimated CrCl was 62 mL/min. Eighty-one percent of patients treated with Obinutuzumab in combination with chlorambucil received all 6 cycles compared to 89% of patients in the rituximab treated arm and 67% in the chlorambucil alone arm.
- In the Stage 1 analysis of Study 1, the median progression-free survival (PFS) in the Obinutuzumab in combination with chlorambucil arm was 27.2 months and 11.2 months in the chlorambucil alone arm (median observation time 22.8 months) as assessed by independent review and is consistent with investigator-assessed PFS. The median overall survival (OS) was not yet reached with a total of 46 deaths: 22 (9%) in the Obinutuzumab in combination with chlorambucil arm and 24 (20%) in the chlorambucil arm. The hazard ratio for OS was 0.41 (95% CI: 0.23-0.74).
- In the Stage 2 analysis of Study 1, the median PFS was 26.7 months in the Obinutuzumab arm and 14.9 months in the rituximab arm with a median observation time of 18.7 months (HR: 0.42, 95% CI: 0.33-0.54, p-value <0.0001). These results were assessed by independent review and are consistent with investigator-assessed PFS. Minimal Residual Disease (MRD) was evaluated using allele-specific oligonucleotide polymerase chain reaction (ASO-PCR). The cutoff for a negative status was one CLL cell per 104 leukocytes in the sample (i.e., an MRD value of <10-4 was considered negative). Among patients who achieved complete response (CR) and complete response with incomplete marrow recovery (CRi) (94 patients in the Obinutuzumab arm and 34 patients in the rituximab arm), 18 patients (19%) had negative MRD in the bone marrow in the Obinutuzumab arm compared to 2 patients (6%) in the rituximab arm. Out of the patients who achieved CR and CRi, 39 patients (41%) in the Obinutuzumab arm and 4 patients (12%) in the rituximab arm were MRD negative in peripheral blood samples collected at least 3 months after the end of treatment.
- Efficacy results are shown in TABLE 7, and the Kaplan-Meier curves for Stage 1a Overall Survival and Stage 2 PFS are shown in FIGURES 1 and 2, respectively.
# How Supplied
- Obinutuzumab 1000 mg/40 mL (25 mg/mL) single-use vials containing preservative-free solution (NDC 50242-070-01) are stable at 2°C to 8°C (36°F to 46°F). Do not use beyond expiration date stamped on carton. Obinutuzumab vials should be protected from light. DO NOT FREEZE. DO NOT SHAKE.
- For the diluted product, chemical and physical stability have been demonstrated in 0.9% NaCl at concentrations of 0.4 mg/mL to 20 mg/mL for 24 hours at 2°C to 8°C (36°F to 46°F) followed by 48 hours (including infusion time) at room temperature (≤ 30°C/86°F). Obinutuzumab does not contain antimicrobial preservatives. Therefore, care must be taken to ensure that the solution for infusion is not microbiologically compromised during preparation. The solution for infusion should be used immediately. If not used immediately, the prepared solution may be stored up to 24 hours at 2 to 8°C. No incompatibilities between Obinutuzumab and polyvinyl chloride or polyolefin infusion materials have been observed in concentration ranges from 0.4 mg/mL to 20.0 mg/mL after dilution of Obinutuzumab with 0.9% sodium chloride.
## Storage
There is limited information regarding Obinutuzumab Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Advise patients to seek immediate medical attention for any of the following:
- Signs and symptoms of infusion reactions including dizziness, nausea, chills, fever, vomiting, diarrhea, breathing problems, or chest pain.
- Symptoms of tumor lysis syndrome such as nausea, vomiting, diarrhea, and lethargy.
- Signs of infections including fever and cough.
- Symptoms of hepatitis including worsening fatigue or yellow discoloration of skin or eyes.
- New or changes in neurological symptoms such as confusion, dizziness or loss of balance, difficulty talking or walking, or vision problems.
Advise patients of the need for:
- Periodic monitoring of blood counts.
- Avoid vaccinations with live viral vaccines.
- Patients with a history of hepatitis B infection (based on the blood test) should be monitored and sometimes treated for their hepatitis.
# Precautions with Alcohol
- Alcohol-Obinutuzumab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- GAZYVA* ®[1]
# Look-Alike Drug Names
- A® — B®[2]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Obinutuzumab | |
fcfc27c4fc704a40667eb359efab11e2e3b925f7 | wikidoc | Ochratoxin A | Ochratoxin A
# Overview
Ochratoxin A, a toxin produced by Aspergillus ochraceus and Penicillium verrucosum, is one of the most abundant food-contaminating mycotoxins in the world. Human exposure occurs mainly through consumption of improperly stored food products, particularly contaminated grain and pork products, as well as coffee, wine grapes and dried grapes. The toxin has been found in the tissues and organs of animals, including human blood and breast milk. Ochratoxin A toxicity has large species- and sex-specific differences.
Synonyms:
- (R)-N--L-phenylalanine
- (-)-N--3-phenylalanine
# Impact on human and animal health
## Carcinogenicity
Ochratoxin A is potentially carcinogenic to humans (Group 2B). Ochratoxin A has been shown to be weakly mutagenic, possibly by induction of oxidative DNA damage.
There is sufficient evidence in experimental animals for the carcinogenicity of ochratoxin A. Ochratoxin A was tested for carcinogenicity by oral administration in mice and rats. It increased the incidence of hepato-cellular tumours in mice of each sex and produced renal-cell adenomas and carcinomas in male mice and in rats of each sex.
# Immuno suppression and immunotoxicity
Ochratoxin A can cause immunosuppression and immunotoxicity in animals. The toxin's immunosuppressant activity in animals may include depressed antibody responses, reduced size of immune organs (such as the thymus, spleen, and lymph nodes), changes in immune cell number and function, and altered cytokine production. Immunotoxicity probably results from cell death following apoptosis and necrosis, in combination with slow replacement of affected immune cells due to inhibition of protein synthesis.
## Potential link to Balkan endemic nephropathy
A number of descriptive studies have suggested a correlation between exposure to ochratoxin A and Balkan endemic nephropathy, and have found a correlation between the geographical distribution of Balkan endemic nephropathy and a high incidence of, and mortality from, urothelial urinary tract tumours. However, there is currently insufficient information to conclusively link ochratoxin A to Balkan endemic nephropathy. The toxin may require synergistic interactions with predisposing genotypes or other environmental toxicants to induce Balkan endemic nephropathy.
## Food animal industry impact
Ochratoxin-contaminated feed has its major economic impact on the poultry industry. Chickens, turkeys and ducklings are susceptible to this toxin. Clinical signs of avian ochratoxicosis are similar to other toxins and generally involve reduction in weight gains, poor feed conversion, reduced egg production, poor egg shell quality and kidney poisoning.
Acute toxicity does not seem to constitute a problem in cattle. | Ochratoxin A
Template:Chembox new
# Overview
Ochratoxin A, a toxin produced by Aspergillus ochraceus and Penicillium verrucosum, is one of the most abundant food-contaminating mycotoxins in the world.[1] Human exposure occurs mainly through consumption of improperly stored food products,[2] particularly contaminated grain and pork products, as well as coffee[3], wine grapes [4] and dried grapes. The toxin has been found in the tissues and organs of animals, including human blood and breast milk.[5] Ochratoxin A toxicity has large species- and sex-specific differences.[3]
Synonyms:
- (R)-N-[(5-Chloro-3,4-dihydro-8-hydroxy-3-methyl-1-oxo-1H-2-benzopyran-7-yl)-carbonyl]-L-phenylalanine
- (-)-N-[(5-Chloro-8-hydroxy-3-methyl-1-oxo-7-isochromanyl)carbonyl]-3-phenylalanine
# Impact on human and animal health
## Carcinogenicity
Ochratoxin A is potentially carcinogenic to humans (Group 2B). Ochratoxin A has been shown to be weakly mutagenic, possibly by induction of oxidative DNA damage.[6]
There is sufficient evidence in experimental animals for the carcinogenicity of ochratoxin A. Ochratoxin A was tested for carcinogenicity by oral administration in mice and rats. It increased the incidence of hepato-cellular tumours in mice of each sex and produced renal-cell adenomas and carcinomas in male mice and in rats of each sex.
# Immuno suppression and immunotoxicity
Ochratoxin A can cause immunosuppression and immunotoxicity in animals.[1] The toxin's immunosuppressant activity in animals may include depressed antibody responses, reduced size of immune organs (such as the thymus, spleen, and lymph nodes), changes in immune cell number and function, and altered cytokine production.[1] Immunotoxicity probably results from cell death following apoptosis and necrosis, in combination with slow replacement of affected immune cells due to inhibition of protein synthesis.[1]
## Potential link to Balkan endemic nephropathy
A number of descriptive studies have suggested a correlation between exposure to ochratoxin A and Balkan endemic nephropathy, and have found a correlation between the geographical distribution of Balkan endemic nephropathy and a high incidence of, and mortality from, urothelial urinary tract tumours.[7] However, there is currently insufficient information to conclusively link ochratoxin A to Balkan endemic nephropathy.[8] The toxin may require synergistic interactions with predisposing genotypes or other environmental toxicants to induce Balkan endemic nephropathy.[9]
## Food animal industry impact
Ochratoxin-contaminated feed has its major economic impact on the poultry industry. Chickens, turkeys and ducklings are susceptible to this toxin. Clinical signs of avian ochratoxicosis are similar to other toxins and generally involve reduction in weight gains, poor feed conversion, reduced egg production, poor egg shell quality and kidney poisoning.[citation needed]
Acute toxicity does not seem to constitute a problem in cattle.[citation needed] | https://www.wikidoc.org/index.php/Ochratoxin_A | |
60c048b3500589ba002a3f179e93e7b286e2b3f0 | wikidoc | Ohmefentanyl | Ohmefentanyl
Ohmefentanyl (β-hydroxy-3-methylfentanyl) is an extremely potent analgesic drug which selectively binds to the µ-opioid receptor.
Ohmefentanyl is one of the most potent μ-receptor agonists known, comparable to super-potent opioids such as carfentanil and etorphine which are used for tranquilizing large animals such as elephants in veterinary medicine. In mouse studies, the most active isomer 3R,4S,βS-ohmefentanyl was 28 times more powerful as a painkiller than fentanyl, the chemical from which it is derived, and 6300 times more effective than morphine.. Ohmefentanyl has three stereogenic centers and so has eight stereoisomers, which are named F9201-F9208. Researchers are studying the different pharmaceutical properties of these isomers..
The 4"-fluoro analogue of the 3R,4S,βS isomer of ohmefentanyl is the most powerful opioid yet discovered, possessing an analgesic potency approximately 18,000-fold greater than morphine. | Ohmefentanyl
Ohmefentanyl (β-hydroxy-3-methylfentanyl) is an extremely potent analgesic drug which selectively binds to the µ-opioid receptor.
Ohmefentanyl is one of the most potent μ-receptor agonists known, comparable to super-potent opioids such as carfentanil and etorphine which are used for tranquilizing large animals such as elephants in veterinary medicine. In mouse studies, the most active isomer 3R,4S,βS-ohmefentanyl was 28 times more powerful as a painkiller than fentanyl, the chemical from which it is derived, and 6300 times more effective than morphine.[1]. Ohmefentanyl has three stereogenic centers and so has eight stereoisomers, which are named F9201-F9208. Researchers are studying the different pharmaceutical properties of these isomers.[2].
The 4"-fluoro analogue of the 3R,4S,βS isomer of ohmefentanyl is the most powerful opioid yet discovered, possessing an analgesic potency approximately 18,000-fold greater than morphine.[3] | https://www.wikidoc.org/index.php/Ohmefentanyl | |
609c943ff33efc9ce071991db2ac8f01fd7647fc | wikidoc | Pegaspargase | Pegaspargase
# 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
Pegaspargase is an asparginase that is FDA approved for the treatment of acute lymphoblastic leukemia (ALL) and acute lymphoblastic leukemia and hypersensitivity to asparaginase. Common adverse reactions include allergic reactions (including anaphylaxis), central nervous system thrombosis, coagulopathy, elevated transaminases, hyperbilirubinemia, hyperglycemia, and pancreatitis.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Recommended Dose
- The recommended dose of Pegaspargase is 2,500 International Units/m2 intramuscularly or intravenously. Pegaspargase should be administered no more frequently than every 14 days.
### Instructions for Administration
- When Pegaspargase is administered intramuscularly, the volume at a single injection site should be limited to 2 mL. If the volume to be administered is greater than 2 mL, multiple injection sites should be used. Pegaspargase does not contain a preservative. Use only one dose per vial; discard unused product.
- When administered intravenously, Pegaspargase should be given over a period of 1 to 2 hours in 100 mL of sodium chloride or dextrose injection 5%, through an infusion that is already running. After the solution is diluted for intravenous use, the solution should be used immediately. If immediate use is not possible, the diluted solution should be stored refrigerated at 2°C to 8°C (36°F to 46°F). Storage after dilution should not exceed 48 hours from the time of preparation to completion of administration. Protect infusion bags from direct sunlight.
### Preparation and Handling Precautions
Do not administer Pegaspargase if drug has been:
- frozen
- stored at room temperature 15° to 25°C (59° to 77°F) for more than 48 hours
- shaken or vigorously agitated
Parenteral drug products should be inspected visually for particulate matter, cloudiness, or discoloration prior to administration, whenever solution and container permit. If any of these are present, discard the vial.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pegaspargase in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Pegaspargase in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Pegaspargase 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 Pegaspargase in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Pegaspargase in pediatric patients.
# Contraindications
- History of serious allergic reactions to Pegaspargase.
- History of serious thrombosis with prior L-asparaginase therapy.
- History of pancreatitis with prior L-asparaginase therapy.
- History of serious hemorrhagic events with prior L-asparaginase therapy.
# Warnings
### Anaphylaxis and Serious Allergic Reactions
- Anaphylaxis and serious allergic reactions can occur in patients receiving Pegaspargase. The risk of serious allergic reactions is higher in patients with known hypersensitivity to other forms of L-asparaginase. Observe patients for 1 hour after administration of Pegaspargase in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (for example, epinephrine, oxygen, intravenous steroids, antihistamines). Discontinue Pegaspargase in patients with serious allergic reactions.
### Thrombosis
- Serious thrombotic events, including sagittal sinus thrombosis can occur in patients receiving Pegaspargase. Discontinue Pegaspargase in patients with serious thrombotic events.
### Pancreatitis
- Pancreatitis can occur in patients receiving Pegaspargase. Evaluate patients with abdominal pain for evidence of pancreatitis. Discontinue Pegaspargase in patients with pancreatitis.
### Glucose Intolerance
- Glucose intolerance can occur in patients receiving Pegaspargase. In some cases, glucose intolerance is irreversible. Monitor serum glucose.
### Coagulopathy
- Increased prothrombin time, increased partial thromboplastin time, and hypofibrinogenemia can occur in patients receiving Pegaspargase Monitor coagulation parameters at baseline and periodically during and after treatment. Initiate treatment with fresh-frozen plasma to replace coagulation factors in patients with severe or symptomatic coagulopathy.
### Hepatotoxicity and Abnormal Liver Function
- Hepatotoxicity and abnormal liver function, including elevations of AST (SGOT), ALT (SGPT), alkaline phosphatase, bilirubin (direct and indirect), and depression of serum albumin, and plasma fibrinogen can occur. Perform appropriate monitoring.
# Adverse Reactions
## Clinical Trials Experience
The following serious adverse reactions are described in greater detail in other sections of the label:
- Anaphylaxis and serious allergic reactions.
- Serious thrombosis.
- Pancreatitis.
- Glucose intolerance.
- Coagulopathy.
- Hepatotoxicity and abnormal liver function.
The most common adverse reactions with Pegaspargase are allergic reactions (including anaphylaxis), hyperglycemia, pancreatitis, central nervous system (CNS) thrombosis, coagulopathy, hyperbilirubinemia, and elevated transaminases. Hyperlipidemia (hypercholesterolemia and hypertriglyceridemia) has been reported in patients exposed to Pegaspargase.
### Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice.
- The data presented below are derived from 2 studies in patients with standard-risk ALL who received Pegaspargase as a component of first-line multi-agent chemotherapy. Study 1 was a randomized (1:1), active-controlled study that enrolled 118 patients, with a median age of 4.7 years (1.1-9.9 years), of whom 54% were males and 65% White, 14% Hispanic, 8% Black, 8% Asian, and 6% other. Of the 59 patients in Study 1 who were randomized to Pegaspargase 48 patients (81%) received all 3 planned doses of Pegaspargase 6 (10%) received 2 doses, 4 (7%) received 1 dose, and 1 patient (2%) did not receive the assigned treatment. Study 2 is an ongoing, multi-factorial design study in which all patients received Pegaspargase as a component of various multi-agent chemotherapy regimens; interim safety data are available for 2,770 patients. Study participants had a median age of 4 years (1-10 years), and were 55% male, 68% White, 18% Hispanic, 4% Black, 3% Asian, and 7% other. Per protocol, the schedule of Pegaspargase varied by treatment arm, with intermittent doses of Pegaspargase for up to 10 months.
- In Study 1, detailed safety information was collected for pre-specified adverse reactions identified as asparaginase-induced adverse reactions and for grade 3 and 4 non-hematologic adverse reactions according to the Children’s Cancer Group (CCG) Toxicity and Complication Criteria. The per-patient incidence, by treatment arm, for these selected adverse reactions occurring at a severity of grade 3 or 4 are presented in TABLE 1 below:
- Safety data were collected in Study 2 only for National Cancer Institute Common Toxicity Criteria (NCI CTC) version 2.0, grade 3 and 4 non-hematologic toxicities. In this study, the per-patient incidence for the following adverse reactions occurring during treatment courses in which patients received Pegaspargase were: elevated transaminases, 11%; coagulopathy, 7%; hyperglycemia, 5%; CNS thrombosis/hemorrhage, 2%; pancreatitis, 2%; clinical allergic reaction, 1%; and hyperbilirubinemia, 1%. There were 3 deaths due to pancreatitis.
- Adverse reaction information was obtained from 5 clinical trials that enrolled a total of 174 patients with relapsed ALL who received Pegaspargase as a single agent or in combination with multi-agent chemotherapy. The toxicity profile of Pegaspargase in patients with previously treated relapsed ALL is similar to that reported above with the exception of clinical allergic reactions (see TABLE 2). The most common adverse reactions of Pegaspargase were clinical allergic reactions, elevated transaminases, hyperbilirubinemia, and coagulopathies. The most common serious adverse events due to Pegaspargase treatment were thrombosis (4%), hyperglycemia requiring insulin therapy (3%), and pancreatitis (1%).
### Allergic Reactions
Allergic reactions include the following: bronchospasm, hypotension, laryngeal edema, local erythema or swelling, systemic rash, and urticaria.
- Among 58 Pegaspargase-treated patients enrolled in Study 1, clinical allergic reactions were reported in 2 patients (3%). One patient experienced a grade 1 allergic reaction and the other grade 3 hives; both occurred during the first delayed intensification phase of the study (see TABLE 2).
- Among 62 patients with relapsed ALL and prior hypersensitivity reactions to asparaginase, 35 patients (56%) had a history of clinical allergic reactions to native Escherichia (E.) coli L-asparaginase, and 27 patients (44%) had history of clinical allergic reactions to both native E. coli and native Erwinia L-asparaginase. Twenty (32%) of these 62 patients experienced clinical allergic reactions to Pegaspargase (see TABLE 2).
- Among 112 patients with relapsed ALL with no prior hypersensitivity reactions to asparaginase, 11 patients (10%) experienced clinical allergic reactions to Pegaspargase (see TABLE 2).
### Immunogenicity
- As with all therapeutic proteins, there is a potential for immunogenicity, defined as development of binding and/or neutralizing antibodies to the product.
- In Study 1, Pegaspargase-treated patients were assessed for evidence of binding antibodies using an enzyme-linked immunosorbent assay (ELISA) method. The incidence of protocol-specified “high-titer” antibody formation was 2% in Induction (n=48), 10% in Delayed Intensification 1 (n=50), and 11% in Delayed Intensification 2 (n=44). There is insufficient information to determine whether the development of antibodies is associated with an increased risk of clinical allergic reactions, altered pharmacokinetics, or loss of anti-leukemic efficacy.
- The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay, and the observed incidence of antibody positivity in an assay may be influenced by several factors including sample handling, concomitant medications, and underlying disease. Therefore, comparison of the incidence of antibodies to Pegaspargase with the incidence of antibodies to other products may be misleading.
## Postmarketing Experience
There is limited information regarding Pegaspargase Postmarketing Experience in the drug label.
# Drug Interactions
- No formal drug interaction studies, between Pegaspargase and other drugs, have been performed.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Animal reproduction studies have not been conducted with Pegaspargase It is also not known whether Pegaspargase can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Pegaspargase should be given to a pregnant woman only if clearly needed.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Pegaspargase in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Pegaspargase during labor and delivery.
### Nursing Mothers
- It is not known whether Pegaspargase 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 Pegaspargase, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
There is no FDA guidance on the use of Pegaspargase in pediatric settings.
### Geriatic Use
- Clinical studies of Pegaspargase did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently than younger subjects.
### Gender
There is no FDA guidance on the use of Pegaspargase with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Pegaspargase with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Pegaspargase in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Pegaspargase in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Pegaspargase in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Pegaspargase in patients who are immunocompromised.
### Others
# Administration and Monitoring
### Administration
There is limited information regarding Pegaspargase Administration in the drug label.
### Monitoring
There is limited information regarding Pegaspargase Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Pegaspargase and IV administrations.
# Overdosage
- Three patients received 10,000 International Units/m2 of Pegaspargase as an intravenous infusion. One patient experienced a slight increase in liver enzymes. A second patient developed a rash 10 minutes after the start of the infusion, which was controlled with the administration of an antihistamine and by slowing down the infusion rate. A third patient did not experience any adverse reactions.
# Pharmacology
## Mechanism of Action
- The mechanism of action of Pegaspargase is thought to be based on selective killing of leukemic cells due to depletion of plasma asparagine. Some leukemic cells are unable to synthesize asparagine due to a lack of asparagine synthetase and are dependent on an exogenous source of asparagine for survival. Depletion of asparagine, which results from treatment with the enzyme L-asparaginase, kills the leukemic cells. Normal cells, however, are less affected by the depletion due to their ability to synthesize asparagine.
## Structure
- Pegaspargase (pegaspargase) is L-asparaginase (L-asparagine amidohydrolase) that is covalently conjugated to monomethoxypolyethylene glycol (mPEG). L-asparaginase is a tetrameric enzyme that is produced endogenously by E. coli and consists of identical 34.5 kDa subunits. Approximately 69 to 82 molecules of mPEG are linked to L-asparaginase; the molecular weight of each mPEG molecule is about 5 kDa. Pegaspargase activity is expressed in International Units. One International Unit of L-asparaginase is defined as the amount of enzyme required to generate 1 micromole of ammonia per minute at pH 7.3 and 37°C.
## Pharmacodynamics
- In Study 1, pharmacodynamics were assessed in 57 newly diagnosed pediatric patients with standard-risk ALL who received three intramuscular doses of Pegaspargase (2,500 International Units/m2), one each during induction and two delayed intensification treatment phases. Pharmacodynamic activity was assessed through serial measurements of asparagine in sera (n=57) and cerebrospinal fluid (CSF) (n=50). The data for asparagine depletion are presented in clinical studies.
## Pharmacokinetics
- Pharmacokinetic assessments were based on an enzymatic assay measuring asparaginase activity. Serum pharmacokinetics were assessed in 34 newly diagnosed pediatric patients with standard-risk ALL in Study 1 following intramuscular administration of 2,500 International Units/m2. The elimination half-life of Pegaspargase was approximately 5.8 days during the induction phase. Similar elimination half-lives were observed during Delayed Intensification 1 and Delayed Intensification 2. Concentrations greater than 0.1 International Units/mL were observed in over 90% of the samples from patients treated with Pegaspargase during induction, Delayed Intensification 1, and Delayed Intensification 2 for approximately 20 days.
- In 3 pharmacokinetic studies, 37 patients with relapsed ALL received Pegaspargase at 2,500 International Units/m2 intramuscularly every 2 weeks. The plasma half-life of Pegaspargase was 3.2 ± 1.8 days in 9 patients who were previously hypersensitive to native E. coli L-asparaginase and 5.7 ± 3.2 days in 28 non-hypersensitive patients. The area under the plasma concentration-time curve (AUC) was 9.5 ± 4.0 International Units/mL/day in the previously hypersensitive patients and 9.8 ± 6.0 International Units/mL/day in the non-hypersensitive patients.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
- No long-term carcinogenicity studies in animals have been performed with Pegaspargase.
- No relevant studies addressing mutagenic potential have been conducted. Pegaspargase did not exhibit a mutagenic effect when tested against Salmonella typhimurium strains in the Ames assay.
- No studies have been performed on impairment of fertility.
# Clinical Studies
There is limited information regarding Pegaspargase Clinical Studies in the drug label.
# How Supplied
- Pegaspargase (pegaspargase) is supplied as a sterile solution in Type I single-use vials containing 3,750 International Units of L-asparaginase per 5 mL solution (NDC 54482-301-01).
## Storage
- Store Pegaspargase under refrigeration at 2°C to 8ºC (36°F to 46°F). Do not shake or freeze product. Protect from light. Do not use Pegaspargase after the expiration date on the vial.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Pegaspargase Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Pegaspargase interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Oncaspar
# Look-Alike Drug Names
There is limited information regarding Pegaspargase Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Pegaspargase
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alberto Plate [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
Pegaspargase is an asparginase that is FDA approved for the treatment of acute lymphoblastic leukemia (ALL) and acute lymphoblastic leukemia and hypersensitivity to asparaginase. Common adverse reactions include allergic reactions (including anaphylaxis), central nervous system thrombosis, coagulopathy, elevated transaminases, hyperbilirubinemia, hyperglycemia, and pancreatitis.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Recommended Dose
- The recommended dose of Pegaspargase is 2,500 International Units/m2 intramuscularly or intravenously. Pegaspargase should be administered no more frequently than every 14 days.
### Instructions for Administration
- When Pegaspargase is administered intramuscularly, the volume at a single injection site should be limited to 2 mL. If the volume to be administered is greater than 2 mL, multiple injection sites should be used. Pegaspargase does not contain a preservative. Use only one dose per vial; discard unused product.
- When administered intravenously, Pegaspargase should be given over a period of 1 to 2 hours in 100 mL of sodium chloride or dextrose injection 5%, through an infusion that is already running. After the solution is diluted for intravenous use, the solution should be used immediately. If immediate use is not possible, the diluted solution should be stored refrigerated at 2°C to 8°C (36°F to 46°F). Storage after dilution should not exceed 48 hours from the time of preparation to completion of administration. Protect infusion bags from direct sunlight.
### Preparation and Handling Precautions
Do not administer Pegaspargase if drug has been:
- frozen
- stored at room temperature 15° to 25°C (59° to 77°F) for more than 48 hours
- shaken or vigorously agitated
Parenteral drug products should be inspected visually for particulate matter, cloudiness, or discoloration prior to administration, whenever solution and container permit. If any of these are present, discard the vial.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pegaspargase in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Pegaspargase in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Pegaspargase 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 Pegaspargase in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Pegaspargase in pediatric patients.
# Contraindications
- History of serious allergic reactions to Pegaspargase.
- History of serious thrombosis with prior L-asparaginase therapy.
- History of pancreatitis with prior L-asparaginase therapy.
- History of serious hemorrhagic events with prior L-asparaginase therapy.
# Warnings
### Anaphylaxis and Serious Allergic Reactions
- Anaphylaxis and serious allergic reactions can occur in patients receiving Pegaspargase. The risk of serious allergic reactions is higher in patients with known hypersensitivity to other forms of L-asparaginase. Observe patients for 1 hour after administration of Pegaspargase in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (for example, epinephrine, oxygen, intravenous steroids, antihistamines). Discontinue Pegaspargase in patients with serious allergic reactions.
### Thrombosis
- Serious thrombotic events, including sagittal sinus thrombosis can occur in patients receiving Pegaspargase. Discontinue Pegaspargase in patients with serious thrombotic events.
### Pancreatitis
- Pancreatitis can occur in patients receiving Pegaspargase. Evaluate patients with abdominal pain for evidence of pancreatitis. Discontinue Pegaspargase in patients with pancreatitis.
### Glucose Intolerance
- Glucose intolerance can occur in patients receiving Pegaspargase. In some cases, glucose intolerance is irreversible. Monitor serum glucose.
### Coagulopathy
- Increased prothrombin time, increased partial thromboplastin time, and hypofibrinogenemia can occur in patients receiving Pegaspargase Monitor coagulation parameters at baseline and periodically during and after treatment. Initiate treatment with fresh-frozen plasma to replace coagulation factors in patients with severe or symptomatic coagulopathy.
### Hepatotoxicity and Abnormal Liver Function
- Hepatotoxicity and abnormal liver function, including elevations of AST (SGOT), ALT (SGPT), alkaline phosphatase, bilirubin (direct and indirect), and depression of serum albumin, and plasma fibrinogen can occur. Perform appropriate monitoring.
# Adverse Reactions
## Clinical Trials Experience
The following serious adverse reactions are described in greater detail in other sections of the label:
- Anaphylaxis and serious allergic reactions.
- Serious thrombosis.
- Pancreatitis.
- Glucose intolerance.
- Coagulopathy.
- Hepatotoxicity and abnormal liver function.
The most common adverse reactions with Pegaspargase are allergic reactions (including anaphylaxis), hyperglycemia, pancreatitis, central nervous system (CNS) thrombosis, coagulopathy, hyperbilirubinemia, and elevated transaminases. Hyperlipidemia (hypercholesterolemia and hypertriglyceridemia) has been reported in patients exposed to Pegaspargase.
### Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice.
- The data presented below are derived from 2 studies in patients with standard-risk ALL who received Pegaspargase as a component of first-line multi-agent chemotherapy. Study 1 was a randomized (1:1), active-controlled study that enrolled 118 patients, with a median age of 4.7 years (1.1-9.9 years), of whom 54% were males and 65% White, 14% Hispanic, 8% Black, 8% Asian, and 6% other. Of the 59 patients in Study 1 who were randomized to Pegaspargase 48 patients (81%) received all 3 planned doses of Pegaspargase 6 (10%) received 2 doses, 4 (7%) received 1 dose, and 1 patient (2%) did not receive the assigned treatment. Study 2 is an ongoing, multi-factorial design study in which all patients received Pegaspargase as a component of various multi-agent chemotherapy regimens; interim safety data are available for 2,770 patients. Study participants had a median age of 4 years (1-10 years), and were 55% male, 68% White, 18% Hispanic, 4% Black, 3% Asian, and 7% other. Per protocol, the schedule of Pegaspargase varied by treatment arm, with intermittent doses of Pegaspargase for up to 10 months.
- In Study 1, detailed safety information was collected for pre-specified adverse reactions identified as asparaginase-induced adverse reactions and for grade 3 and 4 non-hematologic adverse reactions according to the Children’s Cancer Group (CCG) Toxicity and Complication Criteria. The per-patient incidence, by treatment arm, for these selected adverse reactions occurring at a severity of grade 3 or 4 are presented in TABLE 1 below:
- Safety data were collected in Study 2 only for National Cancer Institute Common Toxicity Criteria (NCI CTC) version 2.0, grade 3 and 4 non-hematologic toxicities. In this study, the per-patient incidence for the following adverse reactions occurring during treatment courses in which patients received Pegaspargase were: elevated transaminases, 11%; coagulopathy, 7%; hyperglycemia, 5%; CNS thrombosis/hemorrhage, 2%; pancreatitis, 2%; clinical allergic reaction, 1%; and hyperbilirubinemia, 1%. There were 3 deaths due to pancreatitis.
- Adverse reaction information was obtained from 5 clinical trials that enrolled a total of 174 patients with relapsed ALL who received Pegaspargase as a single agent or in combination with multi-agent chemotherapy. The toxicity profile of Pegaspargase in patients with previously treated relapsed ALL is similar to that reported above with the exception of clinical allergic reactions (see TABLE 2). The most common adverse reactions of Pegaspargase were clinical allergic reactions, elevated transaminases, hyperbilirubinemia, and coagulopathies. The most common serious adverse events due to Pegaspargase treatment were thrombosis (4%), hyperglycemia requiring insulin therapy (3%), and pancreatitis (1%).
### Allergic Reactions
Allergic reactions include the following: bronchospasm, hypotension, laryngeal edema, local erythema or swelling, systemic rash, and urticaria.
- Among 58 Pegaspargase-treated patients enrolled in Study 1, clinical allergic reactions were reported in 2 patients (3%). One patient experienced a grade 1 allergic reaction and the other grade 3 hives; both occurred during the first delayed intensification phase of the study (see TABLE 2).
- Among 62 patients with relapsed ALL and prior hypersensitivity reactions to asparaginase, 35 patients (56%) had a history of clinical allergic reactions to native Escherichia (E.) coli L-asparaginase, and 27 patients (44%) had history of clinical allergic reactions to both native E. coli and native Erwinia L-asparaginase. Twenty (32%) of these 62 patients experienced clinical allergic reactions to Pegaspargase (see TABLE 2).
- Among 112 patients with relapsed ALL with no prior hypersensitivity reactions to asparaginase, 11 patients (10%) experienced clinical allergic reactions to Pegaspargase (see TABLE 2).
### Immunogenicity
- As with all therapeutic proteins, there is a potential for immunogenicity, defined as development of binding and/or neutralizing antibodies to the product.
- In Study 1, Pegaspargase-treated patients were assessed for evidence of binding antibodies using an enzyme-linked immunosorbent assay (ELISA) method. The incidence of protocol-specified “high-titer” antibody formation was 2% in Induction (n=48), 10% in Delayed Intensification 1 (n=50), and 11% in Delayed Intensification 2 (n=44). There is insufficient information to determine whether the development of antibodies is associated with an increased risk of clinical allergic reactions, altered pharmacokinetics, or loss of anti-leukemic efficacy.
- The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay, and the observed incidence of antibody positivity in an assay may be influenced by several factors including sample handling, concomitant medications, and underlying disease. Therefore, comparison of the incidence of antibodies to Pegaspargase with the incidence of antibodies to other products may be misleading.
## Postmarketing Experience
There is limited information regarding Pegaspargase Postmarketing Experience in the drug label.
# Drug Interactions
- No formal drug interaction studies, between Pegaspargase and other drugs, have been performed.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Animal reproduction studies have not been conducted with Pegaspargase It is also not known whether Pegaspargase can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Pegaspargase should be given to a pregnant woman only if clearly needed.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Pegaspargase in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Pegaspargase during labor and delivery.
### Nursing Mothers
- It is not known whether Pegaspargase 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 Pegaspargase, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
There is no FDA guidance on the use of Pegaspargase in pediatric settings.
### Geriatic Use
- Clinical studies of Pegaspargase did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently than younger subjects.
### Gender
There is no FDA guidance on the use of Pegaspargase with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Pegaspargase with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Pegaspargase in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Pegaspargase in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Pegaspargase in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Pegaspargase in patients who are immunocompromised.
### Others
# Administration and Monitoring
### Administration
There is limited information regarding Pegaspargase Administration in the drug label.
### Monitoring
There is limited information regarding Pegaspargase Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Pegaspargase and IV administrations.
# Overdosage
- Three patients received 10,000 International Units/m2 of Pegaspargase as an intravenous infusion. One patient experienced a slight increase in liver enzymes. A second patient developed a rash 10 minutes after the start of the infusion, which was controlled with the administration of an antihistamine and by slowing down the infusion rate. A third patient did not experience any adverse reactions.
# Pharmacology
## Mechanism of Action
- The mechanism of action of Pegaspargase is thought to be based on selective killing of leukemic cells due to depletion of plasma asparagine. Some leukemic cells are unable to synthesize asparagine due to a lack of asparagine synthetase and are dependent on an exogenous source of asparagine for survival. Depletion of asparagine, which results from treatment with the enzyme L-asparaginase, kills the leukemic cells. Normal cells, however, are less affected by the depletion due to their ability to synthesize asparagine.
## Structure
- Pegaspargase (pegaspargase) is L-asparaginase (L-asparagine amidohydrolase) that is covalently conjugated to monomethoxypolyethylene glycol (mPEG). L-asparaginase is a tetrameric enzyme that is produced endogenously by E. coli and consists of identical 34.5 kDa subunits. Approximately 69 to 82 molecules of mPEG are linked to L-asparaginase; the molecular weight of each mPEG molecule is about 5 kDa. Pegaspargase activity is expressed in International Units. One International Unit of L-asparaginase is defined as the amount of enzyme required to generate 1 micromole of ammonia per minute at pH 7.3 and 37°C.
## Pharmacodynamics
- In Study 1, pharmacodynamics were assessed in 57 newly diagnosed pediatric patients with standard-risk ALL who received three intramuscular doses of Pegaspargase (2,500 International Units/m2), one each during induction and two delayed intensification treatment phases. Pharmacodynamic activity was assessed through serial measurements of asparagine in sera (n=57) and cerebrospinal fluid (CSF) (n=50). The data for asparagine depletion are presented in clinical studies.
## Pharmacokinetics
- Pharmacokinetic assessments were based on an enzymatic assay measuring asparaginase activity. Serum pharmacokinetics were assessed in 34 newly diagnosed pediatric patients with standard-risk ALL in Study 1 following intramuscular administration of 2,500 International Units/m2. The elimination half-life of Pegaspargase was approximately 5.8 days during the induction phase. Similar elimination half-lives were observed during Delayed Intensification 1 and Delayed Intensification 2. Concentrations greater than 0.1 International Units/mL were observed in over 90% of the samples from patients treated with Pegaspargase during induction, Delayed Intensification 1, and Delayed Intensification 2 for approximately 20 days.
- In 3 pharmacokinetic studies, 37 patients with relapsed ALL received Pegaspargase at 2,500 International Units/m2 intramuscularly every 2 weeks. The plasma half-life of Pegaspargase was 3.2 ± 1.8 days in 9 patients who were previously hypersensitive to native E. coli L-asparaginase and 5.7 ± 3.2 days in 28 non-hypersensitive patients. The area under the plasma concentration-time curve (AUC) was 9.5 ± 4.0 International Units/mL/day in the previously hypersensitive patients and 9.8 ± 6.0 International Units/mL/day in the non-hypersensitive patients.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
- No long-term carcinogenicity studies in animals have been performed with Pegaspargase.
- No relevant studies addressing mutagenic potential have been conducted. Pegaspargase did not exhibit a mutagenic effect when tested against Salmonella typhimurium strains in the Ames assay.
- No studies have been performed on impairment of fertility.
# Clinical Studies
There is limited information regarding Pegaspargase Clinical Studies in the drug label.
# How Supplied
- Pegaspargase (pegaspargase) is supplied as a sterile solution in Type I single-use vials containing 3,750 International Units of L-asparaginase per 5 mL solution (NDC 54482-301-01).
## Storage
- Store Pegaspargase under refrigeration at 2°C to 8ºC (36°F to 46°F). Do not shake or freeze product. Protect from light. Do not use Pegaspargase after the expiration date on the vial.
# Images
## Drug Images
## Package and Label Display Panel
-
-
# Patient Counseling Information
There is limited information regarding Pegaspargase Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Pegaspargase interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Oncaspar
# Look-Alike Drug Names
There is limited information regarding Pegaspargase Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Oncaspar | |
770f17bd515790da4291f632b78e91fae5ec721b | wikidoc | Oophorectomy | Oophorectomy
Oophorectomy (or ovariectomy) is the surgical removal of an ovary or ovaries. In the case of animals, it is also called spaying and is a form of sterilization. Removal of the ovaries in women is the biological equivalent of castration in males, and the term is occasionally used in the medical literature instead of oophorectomy.
In the case of humans, oophorectomies are most often performed due to diseases such as ovarian cysts or cancer; prophylactially to reduce the chances of developing ovarian cancer or breast cancer; or in conjunction with removal of the uterus.
The removal of an ovary together with a Fallopian tube is called salpingo-oophorectomy or bilateral salpingo-oophorectomy if both ovaries and tubes are removed. Oophorectomy and salpingo-oophorectomy are not common forms of birth control in humans; more usual is tubal ligation, in which the Fallopian tubes are blocked but the ovaries remain intact. In many cases, surgical removal of the ovaries is performed concurrent with a hysterectomy. The surgery is then called "ovariohysterectomy" casually or "total abdominal hysterectomy with bilateral salpingo-oophorectomy" (sometimes abbreviated TAH-BSO), the more correct medical term. However, the term "hysterectomy" is often used colloquially yet incorrectly to refer to removal of any parts of the female reproductive system, including just the ovaries.
# Hormone replacement
In general, hormone replacement therapy is somewhat controversial due to the known carcinogenic and coagulative properties of estrogen; however, many physicians and patients feel the benefits outweigh the risks in women who may face serious health and quality of life issues as a consequence of early surgical menopause. The ovarian hormones of estrogen, progesterone, and testosterone are involved in the regulation of hundreds of bodily functions; it is believed by some doctors that hormone therapy programs mitigate surgical menopause side effects such as increased risk of cardiovascular disease , and female sexual dysfunction . There are many options for hormone replacement currently available and a considerable controversy exists in regards to synthetic versus natural or bio-identical regimens.
# Benefits
## Reduced breast cancer risk
Women with a risk of breast cancer, especially those women with mutated BRCA1 and/or BRCA2 genes, have been shown to have a significantly reduced risk of developing breast cancer after prophylactic oophorectomy. In addition, removal of the uterus in conjunction with prophylactic oophorectomy allows estrogen-based HRT to be prescribed to aid the woman through her transition into surgical menopause, instead of mixed hormone HRT, which has a significant contribution to breast cancer as well.
## Reduced ovarian cancer risk
Women with a risk of ovarian cancer, especially those women with mutated BRCA1 and/or BRCA2 genes, have been shown to have a significantly reduced risk of developing ovarian cancer after prophylactic oophorectomy. Risk is not reduced to zero, however, because the possibility of developing primary peritoneal cancer, which is basically ovarian cancer that begins outside the ovaries, does persist.
## Reduced problems of endometriosis
In rare cases, oophorectomy can be used to treat endometriosis. This is done to remove a source of hormones that fuel uterine lining growth, thus reducing the overgrowth responsible for endometriosis. Oophorectomy for endometriosis is usually a last-resort surgery, since hormonal agonists such as Lupron are usually prescribed first to alter the hormonal cycle. Oophorectomy for endometriosis is often done in conjunction with a hysterectomy as a final shot at removing all traces of endometriosis in cases where non-surgical treatments such as hormonal agonists have failed to stop the uterine overgrowth.
Ovarian cyst removal not involving total oophorectomy is often used to treat milder cases of endometriosis when non-surgical hormonal treatments fail to stop cyst formation. Removal of ovarian cysts through partial oophorectomy is also used to treat extreme pelvic pain from chronic hormonal-related pelvic issues.
# Risks
## Longevity Risk
Removal of ovaries causes hormonal changes and symptoms similar to, but generally more severe than, menopause. Women who have had an oophorectomy are usually encouraged to take hormone replacement drugs to prevent other conditions often associated with menopause. Women younger than 45 who have had their ovaries removed face a mortality risk 1.7 times greater than women who have retained their ovaries. . Retaining the ovaries when a hysterectomy is performed is associated with greater longevity. However, hormone therapy is commonly believed by many doctors to mitigate the mortality risks of oophorectomy .
Women who have had bilateral oophorectomy surgeries lose most of their ability to produce the hormones estrogen and progesterone, and lose about half of their ability to produce testosterone, and subsequently enter what is known as "surgical menopause" (as opposed to normal menopause, which occurs naturally in women as part of the aging process). "Surgical menopause" differs from naturally occurring menopause in several respects: Surgical menopause is an iatrogenic procedure, while menopause is a natural event. A menopausal woman has intact functional female organs, a woman with surgical menopause does not. In natural menopause the ovaries generally continue to produce low levels of hormones, while in surgical menopause the ovaries and their hormones are absent, which can explain why surgical menopause is generally accompanied by a more sudden and severe onset of symptoms than natural menopause, symptoms which may continue until natural age of menopause arrives . These symptoms are commonly addressed through hormone therapy, utilizing various forms of estrogen, testosterone, progesterone or a combination of them.
## Cardiovascular Risk
When the ovaries are removed a woman is at a seven times greater risk of cardiovascular disease, but the mechanisms are not precisely known. The hormones produced by the ovaries cannot be truly replaced. The ovaries produce hormones a woman needs throughout her entire life, in the quantity they are needed, at the time they are needed, and released directly into the blood stream in a continuous fashion, in response to and as part of the complex endocrine system.
## Bone Density Risk
In women under the age of 50 who have undergone oophorectomy, hormone supplements (usually estrogen) are often prescribed as part of hormone replacement therapy (HRT) to offset the negative effects of sudden hormonal loss (most notably an increased risk for early-onset osteoporosis) as well as menopausal problems like hot flashes that are usually more severe than those experienced by women undergoing natural menopause.
Some studies have found that increased bone loss or fracture risk is associated with oophorectomy.
Reduced levels of testosterone in women is predictive of height loss, which may occur as a result of reduced bone density,
## Sexuality Risk
Oophorectomy generally greatly impacts sexuality in women, reducing or eliminating the ability to have an orgasm, and lowering sexual desire. This reduction is greater than that seen in women undergoing natural menopause . Some of these problems can be addressed by taking hormone replacement.
Increased testosterone levels in women are associated with a greater sense of sexual desire, and oophorectomy greatly reduces testosterone levels. Reduction in sexual wellbeing was reported in women who had been given a hysterectomy with both ovaries removed.
# Statistics
According to the Center for Disease Control, 454,000 women in the United States underwent this type of operation in 2004.
# Technique
When performed alone (without hysterectomy), an oophorectomy is generally performed by abdominal laparotomy.
# Managing side effects of prophylactic oophorectomy
### Non-hormonal treatments
The side effects of oophorectomy may be alleviated by medicines other than hormonal replacement. Non-hormonal biphosphonates (such as Fosamax and Actonel) increase bone strength and are available as once-a-week pills. Low-dose Selective Serotonin Reuptake Inhibitors (e.g. Paxil, Prozac) alleviate vasomotor menopausal symptoms, i.e. "hot flashes".
### Hormonal treatments
Short-term hormone replacement with estrogen, in high-risk BRCA mutation carriers, was not shown to increase the risk of breast cancer in women who are post-oophorectomy. The results were published in JCO in 2004, and the conclusions based on a computerized simulation using models of risk and benefit, a lower level of data than a randomized trial per se. This result can probably be generalized to other women at high risk, in whom short term (i.e., one or two year) treatment with estrogen for hot flashes, may be acceptable. | Oophorectomy
Template:Interventions infobox
Oophorectomy (or ovariectomy) is the surgical removal of an ovary or ovaries. In the case of animals, it is also called spaying and is a form of sterilization. Removal of the ovaries in women is the biological equivalent of castration in males, and the term is occasionally used in the medical literature instead of oophorectomy.
In the case of humans, oophorectomies are most often performed due to diseases such as ovarian cysts or cancer; prophylactially to reduce the chances of developing ovarian cancer or breast cancer; or in conjunction with removal of the uterus.
The removal of an ovary together with a Fallopian tube is called salpingo-oophorectomy or bilateral salpingo-oophorectomy if both ovaries and tubes are removed. Oophorectomy and salpingo-oophorectomy are not common forms of birth control in humans; more usual is tubal ligation, in which the Fallopian tubes are blocked but the ovaries remain intact. In many cases, surgical removal of the ovaries is performed concurrent with a hysterectomy. The surgery is then called "ovariohysterectomy" casually or "total abdominal hysterectomy with bilateral salpingo-oophorectomy" (sometimes abbreviated TAH-BSO), the more correct medical term. However, the term "hysterectomy" is often used colloquially yet incorrectly to refer to removal of any parts of the female reproductive system, including just the ovaries.
# Hormone replacement
In general, hormone replacement therapy is somewhat controversial due to the known carcinogenic and coagulative properties of estrogen; however, many physicians and patients feel the benefits outweigh the risks in women who may face serious health and quality of life issues as a consequence of early surgical menopause. The ovarian hormones of estrogen, progesterone, and testosterone are involved in the regulation of hundreds of bodily functions; it is believed by some doctors that hormone therapy programs mitigate surgical menopause side effects such as increased risk of cardiovascular disease [1], and female sexual dysfunction [2]. There are many options for hormone replacement currently available and a considerable controversy exists in regards to synthetic versus natural or bio-identical regimens.
# Benefits
## Reduced breast cancer risk
Women with a risk of breast cancer, especially those women with mutated BRCA1 and/or BRCA2 genes, have been shown to have a significantly reduced risk of developing breast cancer after prophylactic oophorectomy[3]. In addition, removal of the uterus in conjunction with prophylactic oophorectomy allows estrogen-based HRT to be prescribed to aid the woman through her transition into surgical menopause, instead of mixed hormone HRT, which has a significant contribution to breast cancer as well[4].
## Reduced ovarian cancer risk
Women with a risk of ovarian cancer, especially those women with mutated BRCA1 and/or BRCA2 genes, have been shown to have a significantly reduced risk of developing ovarian cancer after prophylactic oophorectomy. Risk is not reduced to zero, however, because the possibility of developing primary peritoneal cancer, which is basically ovarian cancer that begins outside the ovaries, does persist.
## Reduced problems of endometriosis
In rare cases, oophorectomy can be used to treat endometriosis. This is done to remove a source of hormones that fuel uterine lining growth, thus reducing the overgrowth responsible for endometriosis. Oophorectomy for endometriosis is usually a last-resort surgery, since hormonal agonists such as Lupron are usually prescribed first to alter the hormonal cycle. Oophorectomy for endometriosis is often done in conjunction with a hysterectomy as a final shot at removing all traces of endometriosis in cases where non-surgical treatments such as hormonal agonists have failed to stop the uterine overgrowth.
Ovarian cyst removal not involving total oophorectomy is often used to treat milder cases of endometriosis when non-surgical hormonal treatments fail to stop cyst formation. Removal of ovarian cysts through partial oophorectomy is also used to treat extreme pelvic pain from chronic hormonal-related pelvic issues.
# Risks
## Longevity Risk
Removal of ovaries causes hormonal changes and symptoms similar to, but generally more severe than, menopause. Women who have had an oophorectomy are usually encouraged to take hormone replacement drugs to prevent other conditions often associated with menopause. Women younger than 45 who have had their ovaries removed face a mortality risk 1.7 times greater than women who have retained their ovaries. [5]. Retaining the ovaries when a hysterectomy is performed is associated with greater longevity.[6] However, hormone therapy is commonly believed by many doctors to mitigate the mortality risks of oophorectomy [7].
Women who have had bilateral oophorectomy surgeries lose most of their ability to produce the hormones estrogen and progesterone, and lose about half of their ability to produce testosterone, and subsequently enter what is known as "surgical menopause" (as opposed to normal menopause, which occurs naturally in women as part of the aging process). "Surgical menopause" differs from naturally occurring menopause in several respects: Surgical menopause is an iatrogenic procedure, while menopause is a natural event. A menopausal woman has intact functional female organs, a woman with surgical menopause does not. In natural menopause the ovaries generally continue to produce low levels of hormones, while in surgical menopause the ovaries and their hormones are absent, which can explain why surgical menopause is generally accompanied by a more sudden and severe onset of symptoms than natural menopause, symptoms which may continue until natural age of menopause arrives [8]. These symptoms are commonly addressed through hormone therapy, utilizing various forms of estrogen, testosterone, progesterone or a combination of them.
## Cardiovascular Risk
When the ovaries are removed a woman is at a seven times greater risk of cardiovascular disease, [9][10][11] [12] but the mechanisms are not precisely known. The hormones produced by the ovaries cannot be truly replaced. The ovaries produce hormones a woman needs throughout her entire life, in the quantity they are needed, at the time they are needed, and released directly into the blood stream in a continuous fashion, in response to and as part of the complex endocrine system.
## Bone Density Risk
In women under the age of 50 who have undergone oophorectomy, hormone supplements (usually estrogen) are often prescribed as part of hormone replacement therapy (HRT) to offset the negative effects of sudden hormonal loss (most notably an increased risk for early-onset osteoporosis) as well as menopausal problems like hot flashes that are usually more severe than those experienced by women undergoing natural menopause.
Some studies have found that increased bone loss or fracture risk is associated with oophorectomy.
[13]
[14]
[15]
[16]
[17]
Reduced levels of testosterone in women is predictive of height loss, which may occur as a result of reduced bone density,[18]
## Sexuality Risk
Oophorectomy generally greatly impacts sexuality in women, reducing or eliminating the ability to have an orgasm, and lowering sexual desire. This reduction is greater than that seen in women undergoing natural menopause [19]. Some of these problems can be addressed by taking hormone replacement.
Increased testosterone levels in women are associated with a greater sense of sexual desire, and oophorectomy greatly reduces testosterone levels. [20] Reduction in sexual wellbeing was reported in women who had been given a hysterectomy with both ovaries removed.[21]
# Statistics
According to the Center for Disease Control, 454,000 women in the United States underwent this type of operation in 2004.
# Technique
When performed alone (without hysterectomy), an oophorectomy is generally performed by abdominal laparotomy.
# Managing side effects of prophylactic oophorectomy
### Non-hormonal treatments
The side effects of oophorectomy may be alleviated by medicines other than hormonal replacement. Non-hormonal biphosphonates (such as Fosamax and Actonel) increase bone strength and are available as once-a-week pills. Low-dose Selective Serotonin Reuptake Inhibitors (e.g. Paxil, Prozac) alleviate vasomotor menopausal symptoms, i.e. "hot flashes".[22]
### Hormonal treatments
Short-term hormone replacement with estrogen, in high-risk BRCA mutation carriers, was not shown to increase the risk of breast cancer in women who are post-oophorectomy. The results were published in JCO in 2004, and the conclusions based on a computerized simulation using models of risk and benefit, a lower level of data than a randomized trial per se.[23] This result can probably be generalized to other women at high risk, in whom short term (i.e., one or two year) treatment with estrogen for hot flashes, may be acceptable. | https://www.wikidoc.org/index.php/Oophorectomy | |
d32c4e10b6b656684d650a51e180bb651a05bf21 | wikidoc | Ophioglossum | Ophioglossum
Ophioglossum (adder's-tongue) is a genus of about 25-30 species of Ophioglossales in the family Ophioglossaceae, with a cosmopolitan but primarily tropical and subtropical distribution. The name Ophioglossum comes from the Greek, and means "snake-tongue".
Adders-tongues are so-called because the spore-bearing stalk is thought to resemble a snake's tongue. Each plant typically sends up a small, undivided leaf blade with netted venation, and the spore stalk forks from the leaf stalk, terminating in sporangia which are partially concealed within a structure with slitted sides. The plant grows from a central, budding, fleshy structure with fleshy, radiating roots. When the leaf blade is present, there is not always a spore stalk present, and the plants do not always send up a leaf, sometimes going for a year to a period of years living only under the soil, nourished by association with soil fungi.
Ophioglossum has the highest chromosome count of any known living organism, with up to 1,400 chromosomes.
However, most species only have chromosomes in the 240-300+ range. | Ophioglossum
Ophioglossum (adder's-tongue) is a genus of about 25-30 species of Ophioglossales in the family Ophioglossaceae, with a cosmopolitan but primarily tropical and subtropical distribution. The name Ophioglossum comes from the Greek, and means "snake-tongue".
Adders-tongues are so-called because the spore-bearing stalk is thought to resemble a snake's tongue. Each plant typically sends up a small, undivided leaf blade with netted venation, and the spore stalk forks from the leaf stalk, terminating in sporangia which are partially concealed within a structure with slitted sides. The plant grows from a central, budding, fleshy structure with fleshy, radiating roots. When the leaf blade is present, there is not always a spore stalk present, and the plants do not always send up a leaf, sometimes going for a year to a period of years living only under the soil, nourished by association with soil fungi.
Ophioglossum has the highest chromosome count of any known living organism, with up to 1,400 chromosomes.[1]
However, most species only have chromosomes in the 240-300+ range. | https://www.wikidoc.org/index.php/Ophioglossum | |
69ba8078b28b986770e30653a498ce3602b37210 | wikidoc | Opisthotonus | Opisthotonus
# Overview
Opisthotonus or opisthotonos, from Greek roots, opistho meaning "behind" and tonos meaning "tension", is a state of a severe hyperextension and spasticity in which an individual's head, neck and spinal column enter into a complete "bridging" or "arching" position. This abnormal posturing is an extrapyramidal effect and is caused by spasm of the axial muscles along the spinal column. It is seen in some cases of severe cerebral palsy and traumatic brain injury or as a result of the severe muscular spasms associated with tetanus.
# Pathophysiology
Opisthotonus can be produced experimentally in animals by transection of the midbrain (between superior and inferior colliculus) which results in severing all the corticoreticular fibers. Hyperextension occurs because facilitation of anterior reticulospinal tract due to removal of inhibitory corticoreticular fibers to the pons reticular formation.
Opisthotonus is more pronounced in infants. Opisthotonus in the neonate may be a symptom of meningitis or tetanus. This marked extensor tone can cause infants to "rear backwards" and stiffen out as the mother or nurse attempts to hold or feed them. Opisthotonus can be induced by any attempt at movement such as smiling, feeding, vocalization, or by seizure activity. Individuals with opisthotonus are quite challenging to position, especially in wheelchairs and car seats.
It can some times be a side effect of anti-psychotic medication or mood stabilizer, i.e. lithium intoxication.
# Differential Diagnosis of Causes of Opisthotonus
In alphabetical order.
- Airway obstruction
- Meningitis
- Encephalitis
- Cerebral malaria
- Athetosis
- Cerebral hemorrhage
- Brain tumor
- Neck injury
- Drugs
- Tetanus
- Rabies
- Tay-Sachs disease
- Cerebral palsy
- Severe head injury
- Seizures
- Glutaric aciduria type 1
- Kernicterus
- Meningoencephalitis
- Strychnine
- Arnold-Chiari malformation type 3
- Hereditary methemoglobinemia, recessive, type II
- Perinatal hypophosphatasia
- Phenothiazine, Perphenazine
- Antenatal infection
- Schinzel-Giedion syndrome
# Physical examination findings
Image courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology
- Opisthotonus: Meningitis, One Year Old Child: Pus in Subarachnoid Space causes Neck Muscle Spasms
- Opisthotonus: Perinatal Hypoxia; Note Spastic Quadriparesis, | Opisthotonus
For patient information, click here
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief: Cafer Zorkun, M.D., Ph.D. [2]
# Overview
Opisthotonus or opisthotonos, from Greek roots, opistho meaning "behind" and tonos meaning "tension", is a state of a severe hyperextension and spasticity in which an individual's head, neck and spinal column enter into a complete "bridging" or "arching" position. This abnormal posturing is an extrapyramidal effect and is caused by spasm of the axial muscles along the spinal column. It is seen in some cases of severe cerebral palsy and traumatic brain injury or as a result of the severe muscular spasms associated with tetanus.
# Pathophysiology
Opisthotonus can be produced experimentally in animals by transection of the midbrain (between superior and inferior colliculus) which results in severing all the corticoreticular fibers. Hyperextension occurs because facilitation of anterior reticulospinal tract due to removal of inhibitory corticoreticular fibers to the pons reticular formation.
Opisthotonus is more pronounced in infants. Opisthotonus in the neonate may be a symptom of meningitis or tetanus. This marked extensor tone can cause infants to "rear backwards" and stiffen out as the mother or nurse attempts to hold or feed them. Opisthotonus can be induced by any attempt at movement such as smiling, feeding, vocalization, or by seizure activity. Individuals with opisthotonus are quite challenging to position, especially in wheelchairs and car seats.
It can some times be a side effect of anti-psychotic medication or mood stabilizer, i.e. lithium intoxication.
# Differential Diagnosis of Causes of Opisthotonus
In alphabetical order. [1] [2]
- Airway obstruction
- Meningitis
- Encephalitis
- Cerebral malaria
- Athetosis
- Cerebral hemorrhage
- Brain tumor
- Neck injury
- Drugs
- Tetanus
- Rabies
- Tay-Sachs disease
- Cerebral palsy
- Severe head injury
- Seizures
- Glutaric aciduria type 1
- Kernicterus
- Meningoencephalitis
- Strychnine
- Arnold-Chiari malformation type 3
- Hereditary methemoglobinemia, recessive, type II
- Perinatal hypophosphatasia
- Phenothiazine, Perphenazine
- Antenatal infection
- Schinzel-Giedion syndrome
# Physical examination findings
Image courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology
- Opisthotonus: Meningitis, One Year Old Child: Pus in Subarachnoid Space causes Neck Muscle Spasms
- Opisthotonus: Perinatal Hypoxia; Note Spastic Quadriparesis,
# External links
- Template:GPnotebook
Template:WikiDoc Sources
- ↑ Sailer, Christian, Wasner, Susanne. Differential Diagnosis Pocket. Hermosa Beach, CA: Borm Bruckmeir Publishing LLC, 2002:77 ISBN 1591032016
- ↑ Kahan, Scott, Smith, Ellen G. In A Page: Signs and Symptoms. Malden, Massachusetts: Blackwell Publishing, 2004:68 ISBN 140510368X | https://www.wikidoc.org/index.php/Opisthotonos | |
2ed103b33e557db6d5b67f7a933ac0c5a3c452d9 | wikidoc | Optic chiasm | Optic chiasm
# Overview
The optic chiasm (Greek χίασμα, "crossing", from the Greek χλαζειν 'to mark with an X', after the Greek letter 'Χ', chi) is the part of the brain where the optic nerves partially cross.
# Pathways
Specifically, in the optic chiasm, the nerves connected to the right eye that attend to the right temporal visual field (located in the nasal portion of the right retina) cross to the left half of the brain, while the nerves from the left eye that attend to the left temporal visual field (located in the nasal portion of the left retina) cross to the right half of the brain.
This allows for parts of both eyes that attend to the right visual field to be processed in the left visual system in the brain, and vice versa.
# Optic chiasm in cats
In Siamese cats with certain genotypes of the albino gene, this wiring is disrupted, with less of the nerve-crossing than is normal, as a number of scholars have reported. To compensate for lack of crossing in their brains, they cross their eyes (strabismus).
This is also seen in albino tigers, as Guillery & Kaas report.
# Additional images
- Mesal aspect of a brain sectioned in the median sagittal plane.
- Median sagittal section of brain.
- Scheme showing central connections of the optic nerves and optic tracts.
- Base of brain.
- Coronal section of brain through anterior commissure.
- The fornix and corpus callosum from below.
- Diagram showing the positions of the three principal subarachnoid cisternæ.
- The left optic nerve and the optic tracts.
- The hypophysis cerebri in position. Shown in sagittal section.
- Median sagittal through the hypophysis of an adult monkey. Semidiagrammatic.
- 3D schematic representation of optic tracts | Optic chiasm
Template:Infobox Brain
# Overview
The optic chiasm (Greek χίασμα, "crossing", from the Greek χλαζειν 'to mark with an X', after the Greek letter 'Χ', chi) is the part of the brain where the optic nerves partially cross.
# Pathways
Specifically, in the optic chiasm, the nerves connected to the right eye that attend to the right temporal visual field (located in the nasal portion of the right retina) cross to the left half of the brain, while the nerves from the left eye that attend to the left temporal visual field (located in the nasal portion of the left retina) cross to the right half of the brain.
This allows for parts of both eyes that attend to the right visual field to be processed in the left visual system in the brain, and vice versa.
# Optic chiasm in cats
In Siamese cats with certain genotypes of the albino gene, this wiring is disrupted, with less of the nerve-crossing than is normal, as a number of scholars have reported. [1] To compensate for lack of crossing in their brains, they cross their eyes (strabismus). [2]
This is also seen in albino tigers, as Guillery & Kaas report.[3]
# Additional images
- Mesal aspect of a brain sectioned in the median sagittal plane.
- Median sagittal section of brain.
- Scheme showing central connections of the optic nerves and optic tracts.
- Base of brain.
- Coronal section of brain through anterior commissure.
- The fornix and corpus callosum from below.
- Diagram showing the positions of the three principal subarachnoid cisternæ.
- The left optic nerve and the optic tracts.
- The hypophysis cerebri in position. Shown in sagittal section.
- Median sagittal through the hypophysis of an adult monkey. Semidiagrammatic.
- 3D schematic representation of optic tracts | https://www.wikidoc.org/index.php/Optic_chiasm | |
2f5e04317429d47b8fd2dc3a91875e936da70ed5 | wikidoc | Oral Surgery | Oral Surgery
# Overview
Oral Surgery is a recognised international specalist training course in Dentistry.
In many areas of the world it is separate from Oral and Maxillofacial surgery (OMS, OMFS, or "Maxfacs"), which is a unique specialty usually requiring both medical and dental qualifications.
In the United States however, Oral and Maxillofacial surgery is one of the 9 dental specialties recognized by the American Dental Association and requires at least 4-6 years of training.
Oral surgery is a specialty is defined within Europe under the dental Directive 2001/19/EC (Official Journal of the European Communities L 206, 31.07.2001). It requires 3 years of further University training after a formal qualification in Dentistry.
The Directive 2001/19/EC also distinguishes Oral Surgery from other evidence of formal qualifications in specialised Medicine, such as Oral and Maxillofacial Surgery, which requires both medical and dental training in the European Union.
In 2007 the United Kingdom's General Dental Council transferred dentists on the specialist list in Surgical Dentistry to a reconfigured Oral Surgery list.
- ↑ GDC | Oral Surgery
# Overview
Oral Surgery is a recognised international specalist training course in Dentistry.
In many areas of the world it is separate from Oral and Maxillofacial surgery (OMS, OMFS, or "Maxfacs"), which is a unique specialty usually requiring both medical and dental qualifications.
In the United States however, Oral and Maxillofacial surgery is one of the 9 dental specialties recognized by the American Dental Association and requires at least 4-6 years of training.
Oral surgery is a specialty is defined within Europe under the dental Directive 2001/19/EC (Official Journal of the European Communities L 206, 31.07.2001). It requires 3 years of further University training after a formal qualification in Dentistry.
The Directive 2001/19/EC also distinguishes Oral Surgery from other evidence of formal qualifications in specialised Medicine, such as Oral and Maxillofacial Surgery, which requires both medical and dental training in the European Union.
In 2007 the United Kingdom's General Dental Council transferred dentists on the specialist list in Surgical Dentistry to a reconfigured Oral Surgery list. [1]
Template:WH
Template:WikiDoc Sources
- ↑ GDC | https://www.wikidoc.org/index.php/Oral_Surgery | |
bab3a8a26378bae01e0fd13a28e1bd66edd47ffb | wikidoc | Orange juice | Orange juice
Orange juice is a fruit juice obtained by squeezing, pressing or otherwise crushing the interior of an orange. The largest exporter of orange juice is Brazil, followed by the United States.
A single orange will typically produce about 90 grams of juice. Freshly squeezed orange juice has a typically acidic citrus taste, but is generally considerably sweeter than the juice of lemons or limes. Besides water and sugar, it is an excellent source of vitamin C (ascorbic acid) and potassium. It is also an important natural source of folic acid (Vitamin B9), which is recommended for women who are pregnant or may become pregnant. Citrus juices contain flavonoids that are believed to have beneficial health effects. However, if drunk on an empty stomach, orange juice can exacerbate present gastro-intestinal conditions and/or cause mild and temporary stomach upset. Due to the citric acid, orange juice typically has a pH of 3.5. Drinking, or sipping, orange juice over a long period of time can therefore potentially erode tooth enamel.
# Commercial orange juice and concentrate
Refrigerated juice shipped in liquid form is traded between producers as direct juice. In the USA all commercial orange juice is pasteurized. Some refrigerated fresh juice is sold to consumers. In the U.S., Canada and the U.K. it is labeled "not from concentrate".
Some producers add citric acid or ascorbic acid to juice beyond what is naturally found in the orange. Some also include other nutrients such as calcium and Vitamin D, not found naturally in oranges. Reduced-acid varieties of orange juice are also marketed.
## Frozen orange juice concentrate
Freshly squeezed juice and filtered orange juice is pasteurized and is evaporated under vacuum and heat to remove most of the water before it is frozen. This process strips out certain essences and oils. The concentrated juice, about 65° brix, is then stored at about +10°F. At this point essences and oils (recovered during the vacuum concentration process) are added back to restore the flavor. To make cans of frozen concentrate for sale, filtered water is added back to bring the brix level down to 42° (about 3 times more concentrated than fresh juice).
When water is added to freshly-unfrozen concentrated orange juice, it is reconstituted. Most of orange juice sold today throughout the world is reconstituted juice. There is a huge difference in the volume of frozen concentrated orange juice and unprocessed juice and this makes a difference in the price the consumer is charged.
Orange juice containing pulp seems to be more nutritious than no-pulp varieties because of the flavonoids contained in the pulp.
The major commodity exchanges, including the New York Board of Trade and the Brazilian Mercantile and Futures Exchange, sell futures on frozen orange juice concentrate. FCOJ had a major role in 1983 movie Trading Places.
## Canned orange juice
A small fraction of fresh orange juice is canned. Canned orange juice does retain Vitamin C better than bottled juice. However, the canned product loses flavor when stored at room temperature for over 12 weeks.
## Additives
Some producers add citric acid or ascorbic acid to juice beyond what is naturally found in the orange. Some also include other nutrients such as calcium and Vitamin D, not found naturally in oranges. Reduced-acid varieties of orange juice are also marketed. also the blood red orange juice is a more healthy type of orange juice as it contains less acid | Orange juice
Template:Pp-semi-protected
Orange juice is a fruit juice obtained by squeezing, pressing or otherwise crushing the interior of an orange. The largest exporter of orange juice is Brazil, followed by the United States.
A single orange will typically produce about 90 grams of juice. Freshly squeezed orange juice has a typically acidic citrus taste, but is generally considerably sweeter than the juice of lemons or limes.[citation needed] Besides water and sugar, it is an excellent source of vitamin C (ascorbic acid) and potassium. It is also an important natural source of folic acid (Vitamin B9), which is recommended for women who are pregnant or may become pregnant.[1] Citrus juices contain flavonoids that are believed to have beneficial health effects. However, if drunk on an empty stomach, orange juice can exacerbate present gastro-intestinal conditions and/or cause mild and temporary stomach upset. Due to the citric acid, orange juice typically has a pH of 3.5.[2] Drinking, or sipping, orange juice over a long period of time can therefore potentially erode tooth enamel.
# Commercial orange juice and concentrate
Refrigerated juice shipped in liquid form is traded between producers as direct juice. In the USA all commercial orange juice is pasteurized. Some refrigerated fresh juice is sold to consumers. In the U.S., Canada and the U.K. it is labeled "not from concentrate".
Some producers add citric acid or ascorbic acid to juice beyond what is naturally found in the orange. Some also include other nutrients such as calcium and Vitamin D, not found naturally in oranges. Reduced-acid varieties of orange juice are also marketed.
## Frozen orange juice concentrate
Freshly squeezed juice and filtered orange juice is pasteurized and is evaporated under vacuum and heat to remove most of the water before it is frozen. This process strips out certain essences and oils. The concentrated juice, about 65° brix, is then stored at about +10°F. At this point essences and oils (recovered during the vacuum concentration process) are added back to restore the flavor. To make cans of frozen concentrate for sale, filtered water is added back to bring the brix level down to 42° (about 3 times more concentrated than fresh juice).
When water is added to freshly-unfrozen concentrated orange juice, it is reconstituted. Most of orange juice sold today throughout the world is reconstituted juice. There is a huge difference in the volume of frozen concentrated orange juice and unprocessed juice and this makes a difference in the price the consumer is charged.
Orange juice containing pulp seems to be more nutritious than no-pulp varieties because of the flavonoids contained in the pulp.[3]
The major commodity exchanges, including the New York Board of Trade and the Brazilian Mercantile and Futures Exchange, sell futures on frozen orange juice concentrate. FCOJ had a major role in 1983 movie Trading Places.
## Canned orange juice
A small fraction of fresh orange juice is canned. Canned orange juice does retain Vitamin C better than bottled juice. However, the canned product loses flavor when stored at room temperature for over 12 weeks.[4]
## Additives
Some producers add citric acid or ascorbic acid to juice beyond what is naturally found in the orange. Some also include other nutrients such as calcium and Vitamin D, not found naturally in oranges. Reduced-acid varieties of orange juice are also marketed. also the blood red orange juice is a more healthy type of orange juice as it contains less acid | https://www.wikidoc.org/index.php/Orange_juice | |
af928e8676ec18d8399c0d0c28e86b57e84c55fc | wikidoc | Oregon-grape | Oregon-grape
Oregon-grape (Mahonia aquifolium, Berberidaceae) is an evergreen shrub related to the barberry. Some authors place Mahonia in the barberry genus, Berberis. The Oregon-grape is not closely related to grapes, but gets its name from the purple clusters of berries whose color and slightly dusted appearance is reminiscent of grapes. It is sometimes called Tall Oregon-grape to distinguish it from Creeping Oregon-grape (M. repens) and "Cascade" or Dwarf Oregon-grape (M. nervosa). The name is often left un-hyphenated as Oregon grape, though doing so invites confusion with the true grapes. It also occasionally appears in print as Oregongrape.
Oregon-grape grows to 1-5 m tall. Its leathery leaves resemble holly and the stems and twigs have a thickened, corky appearance. The flowers, borne in late spring, are an attractive yellow.
Oregon-grape is used in landscaping similarly to barberry, as a plant suited for low-maintenance plantings and loose hedges. Oregon-grape is resistant to summer drought, tolerates poor soils, and does not create excessive leaf litter. Its berries attract birds.
The small purplish-black fruits, which are quite tart and contain large seeds, are sometimes used locally mixed with Salal to make jelly. The fruit is bitter, and generally not eaten without being sweetened first. As the leaves of Oregon-grape are holly-like and resist wilting, the foliage is sometimes used by florists for greenery and a small gathering industry has been established in the Pacific Northwest. The inner bark of the larger stems and roots of Oregon-grape yield a yellow dye.
Oregon-grape is a native plant on the North American west coast from British Columbia to northern California, occurring in the understory of Douglas-fir forests and in brushlands. It is the state flower of Oregon.
In some areas outside its native range, Oregon-grape has been classified as an invasive exotic species that may displace native vegetation.
# Medicinal Use
The plant is used medicinally by herbalists. Recent studies indicate that M. aquifolium contains a specific multidrug resistance pump inhibitor (MDR Inhibitor) named 5'methoxyhydnocarpin (5'MHC) which works to decrease bacterial resistance to antibiotics and antibacterial agents.
Oregon grape root is commonly used medicinally as an effective alternative to the threatened goldenseal. Both plants similarly contain the alkaloid berberine, known as an anti-inflammatory and anti-bacterial used in the treatment of infection. Berberine and other alkaloids present in Oregon grape root have been shown to kill a wide range of microbes and have been effective in speeding recovery from giardia, candida, viral diarrhea, and cholera. Mahonia aquifolium is also known to be capable of treatment on inflammatory skin diseases such as Eczema and Psoriasis. Oregon grape root also has anticancer properties that are receiving more attention by researchers. Other actions may include alterative, diuretic, laxative and tonic.
Health Warning: Because of a potential toxicity or adverse effects of berberine, consult a reputable herbalist regarding dosages and treatments. Use of berberine is not recommended during pregnancy or breastfeeding. | Oregon-grape
Oregon-grape (Mahonia aquifolium, Berberidaceae) is an evergreen shrub related to the barberry. Some authors place Mahonia in the barberry genus, Berberis. The Oregon-grape is not closely related to grapes, but gets its name from the purple clusters of berries whose color and slightly dusted appearance is reminiscent of grapes. It is sometimes called Tall Oregon-grape to distinguish it from Creeping Oregon-grape (M. repens) and "Cascade" or Dwarf Oregon-grape (M. nervosa). The name is often left un-hyphenated as Oregon grape, though doing so invites confusion with the true grapes. It also occasionally appears in print as Oregongrape.
Oregon-grape grows to 1-5 m tall. Its leathery leaves resemble holly and the stems and twigs have a thickened, corky appearance. The flowers, borne in late spring, are an attractive yellow.
Oregon-grape is used in landscaping similarly to barberry, as a plant suited for low-maintenance plantings and loose hedges. Oregon-grape is resistant to summer drought, tolerates poor soils, and does not create excessive leaf litter. Its berries attract birds.
The small purplish-black fruits, which are quite tart and contain large seeds, are sometimes used locally mixed with Salal to make jelly. The fruit is bitter, and generally not eaten without being sweetened first. As the leaves of Oregon-grape are holly-like and resist wilting, the foliage is sometimes used by florists for greenery and a small gathering industry has been established in the Pacific Northwest. The inner bark of the larger stems and roots of Oregon-grape yield a yellow dye.
Oregon-grape is a native plant on the North American west coast from British Columbia to northern California, occurring in the understory of Douglas-fir forests and in brushlands. It is the state flower of Oregon.
In some areas outside its native range, Oregon-grape has been classified as an invasive exotic species that may displace native vegetation.[1][2][3][4]
# Medicinal Use
The plant is used medicinally by herbalists. Recent studies indicate that M. aquifolium contains a specific multidrug resistance pump inhibitor (MDR Inhibitor) named 5'methoxyhydnocarpin (5'MHC) which works to decrease bacterial resistance to antibiotics and antibacterial agents.[5]
Oregon grape root is commonly used medicinally as an effective alternative to the threatened goldenseal. Both plants similarly contain the alkaloid berberine, known as an anti-inflammatory and anti-bacterial used in the treatment of infection.[6] Berberine and other alkaloids present in Oregon grape root have been shown to kill a wide range of microbes and have been effective in speeding recovery from giardia, candida, viral diarrhea, and cholera.[citation needed] Mahonia aquifolium is also known to be capable of treatment on inflammatory skin diseases such as Eczema and Psoriasis.[7][8][9] Oregon grape root also has anticancer properties that are receiving more attention by researchers.[citation needed] Other actions may include alterative, diuretic, laxative and tonic.[10]
Health Warning: Because of a potential toxicity or adverse effects of berberine, consult a reputable herbalist regarding dosages and treatments. Use of berberine is not recommended during pregnancy or breastfeeding.[11] | https://www.wikidoc.org/index.php/Oregon-grape | |
76b27bfdb7bb1cd416c65c1cc74132c434d4e645 | wikidoc | Organic food | Organic food
Organic foods are produced according to certain production standards, meaning they are grown without the use of conventional pesticides, artificial fertilizers, human waste, or sewage sludge, and that they were processed without ionizing radiation or food additives. Livestock are reared without the routine use of antibiotics and without the use of growth hormones. In most countries, organic produce must not be genetically modified.
Organic food production is legally regulated. Currently, the United States, the European Union, Japan and many other countries require producers to obtain organic certification in order to market food as organic.
Historically, organic farms have been relatively small family-run farms — which is why organic food was once only available in small stores or farmers' markets. However, since the early 1990s organic food has had growth rates of around 20% a year, far ahead of the rest of the food industry, in both developed and developing nations. As of April 2008, organic food accounts for 1-2% of food sales worldwide. Future growth is expected to range from 10-50% annually depending on the country.
# Identifying organic food
Processed organic food usually contains only organic ingredients, or where there are a number of ingredients, at least a minimum percentage of the plant and animal ingredients must be organic (95% in the United States and Australia). Any non-organically produced ingredients must still meet requirements. Foods claiming to be organic must be free of artificial food additives, and are often processed with fewer artificial methods, materials and conditions (no chemical ripening, no food irradiation, and no genetically modified ingredients, etc.).
They may also be required to be produced using energy-saving technologies and packaged using recyclable or biodegradable materials when possible.
Early consumers interested in organic food would look for non-chemically treated, fresh or minimally processed food. They mostly had to buy directly from growers: "Know your farmer, know your food" was the motto. Personal definitions of what constituted "organic" were developed through firsthand experience: by talking to farmers, seeing farm conditions, and farming activities. Small farms grew vegetables (and raised livestock) using organic farming practices, with or without certification, and the individual consumer monitored. As demand for organic foods continues to increase, high volume sales through mass outlets such as supermarkets are rapidly replacing the direct farmer connection. However, for supermarket consumers, food production is not easily observable, and product labelling, like "certified organic", is relied on. Government regulations and third-party inspectors are looked to for assurance. A "certified organic" label is usually the only way for consumers to know that a processed product is "organic".
## Legal definition
To be certified organic, products must be grown and manufactured in a manner that adheres to standards set by the country they are sold in:
- Australia: NASAA Organic Standard
- Britain: Organic Farmers and Growers Organic Standards and the Soil Association
- Canada: Canada Gazette, Government of Canada
- European Union: EU-Eco-regulation
Sweden: KRAV
- Sweden: KRAV
- India: NPOP, (National Program for Organic Production)
- Japan: JAS Standards.
- United States: National Organic Program (NOP) Standards
# Environmental impact
Several surveys and studies have attempted to examine and compare conventional and organic systems of farming. The general consensus across these surveys is that, in the short term, organic farming is less damaging for the following reasons:
- Organic farms do not consume or release synthetic pesticides into the environment — some of which have the potential to harm soil, water and local terrestrial and aquatic wildlife.
- Organic farms are better than conventional farms at sustaining diverse ecosystems, i.e., populations of plants and insects, as well as animals.
- When calculated either per unit area or per unit of yield, organic farms use less energy and produce less waste, e.g., waste such as packaging materials for chemicals.
However, many critics of organic farming methods believe that the increased land needed to farm organic food could potentially destroy the rainforests and wipe out many ecosystems.
## Yield
One study found a 20% smaller yield from organic farms using 50% less fertilizer and 97% less pesticide. Studies comparing yields have had mixed results. Supporters claim that organically managed soil has a higher quality and higher water retention. This may help increase yields for organic farms in drought years. One study of two organic farming systems and one conventional found that, in one year's severe crop season drought, organic soybean yields were 52% and 96% higher than the conventional system and organic maize yields were 37% higher in one system, but 62% lower in the other.
One study from the Danish Environmental Protection Agency found that, area-for-area, organic farms of potatoes, sugar beet and seed grass produce as little as half the output of conventional farming. Findings like these, and the dependence of organic food on manure from low-yield cattle, has prompted criticism from many scientists that organic farming is environmentally unsound and incapable of feeding the world population. Among these critics are Norman Borlaug, father of the "green revolution," and winner of the Nobel Peace Prize, who asserts that organic farming practices can at most feed 4 billion people, after expanding cropland dramatically and destroying ecosystems in the process.
However a recent study compiling research from 293 different comparisons into a single study to assess the overall efficiency of the two agricultural systems has concluded that
-rganic methods could produce enough food on a global per capita basis to sustain the current human population, and potentially an even larger population, without increasing the agricultural land base (from the abstract)
The researchers also found that while in developed countries, organic systems on average produce 92% of the yield produced by conventional agriculture, organic systems produce 80% more than conventional farms in developing countries, because the materials needed for organic farming are more accessible than synthetic farming materials to farmers in poor countries.
## Energy Efficiency
Some studies are also consistent in showing that organic farms are more energy efficient. However, alternative views hold that this may be deceptive, based on fossil fuel usage but ignoring energy costs of plowing and other laborious practices used on organic farms to maintain yields.
## Pesticides and farmers
There have been many studies on the health effects of pesticide exposure to those who work on farms. Even when pesticides are used correctly, they still end up in the air and bodies of farm workers. Through these studies, organophosphate pesticides have become associated with acute health problems such as abdominal pain, dizziness, headaches, nausea, vomiting, as well as skin and eye problems. In addition, there have been many other studies that have found pesticide exposure is associated with more severe health problems such as respiratory problems, memory disorders, dermatologic conditions, cancer, depression, neurologic deficits, miscarriages, and birth defects. Summaries of peer-reviewed research have examined the link between pesticide exposure and neurological outcomes and cancer in organophosphate-exposed workers.
Imported fruits and vegetables from South America are more likely to contain high level of pesticides, even pesticides banned for use in the United States. Migratory birds, such as Swainson’s hawks, have wintering grounds in Argentina where thousands of them were found dead from monocrotophos insecticide poisoning.
## Pesticide residue
A study published in 2002 showed that "Organically grown foods consistently had about one-third as many residues as conventionally grown foods."
Monitoring of pesticide residues in the United States is carried out by the Pesticide Data Program (part of USDA, which was created in 1990. It has since tested over 60 different types of food for over 400 different types of pesticides - with samples collected close to the point of consumption. Their most recent results found in 2005 that:
Several studies corroborate this finding by having found that while 77 percent of conventional food carries synthetic pesticide residues, only about 25 percent of organic food does.
A study published by the National Research Council in 1993 determined that for infants and children, the major source of exposure to pesticides is through diet. A recent study in 2006 measured the levels of organophosphorus pesticide exposure in 23 schoolchildren before and after replacing their diet with organic food. In this study it was found that levels of organophosphorus pesticide exposure dropped dramatically and immediately when the children switched to an organic diet. Food residue limits established by law are set specifically with children in mind and consider a child's lifetime ingestion of each pesticide.
There are controversial data on the health implications of certain pesticides. For example, the herbicide Atrazine has been shown in some experiments to be a teratogen, causing demasculinization in male frogs exposed to small concentrations. Under the effects of Atrazine, male frogs were found to have greatly increased occurrencesof either malformed gonads, or testicular gonads which contain non-degenerate eggs. Effects were however significantly reduced in high concentrations, as is consistent with other teratogens affecting the endocrine system, such as estradiol.
Organic farming standards do not allow the use of synthetic pesticides, but they do allow the use of specific pesticides derived from plants. The most common organic pesticides, accepted for restricted use by most organic standards, include Bt, pyrethrum, and rotenone. Some organic pesticides, such as rotenone, have high toxicity to fish and aquatic creatures with some toxicity to mammals. It causes Parkinson's disease if injected into rats.
The United States Environmental Protection Agency and state agencies periodically review the licensing of suspect pesticides, but the process of de-listing is slow. One example of this slow process is exemplified by the pesticide Dichlorvos, or DDVP, which as recently as the year 2006 the EPA proposed its continued sale. The EPA has almost banned this pesticide on several occasions since the 1970s, but it never did so despite considerable evidence that suggests DDVP is not only carcinogenic but dangerous to the human nervous system — especially in children.
# Taste and nutritional value
The biggest study ever of organic food was completed in 2007 (which has neither been peer-reviewed nor published yet ) and found that organic fruit and vegetables contain up to 40% more antioxidants than conventional equivalents, and that the figure was 90% for organic milk. The 4-year study was funded by the European Union and was the largest of its kind ever undertaken.
A 2001 study by researchers at Washington State University concluded, under judgement by a panel of tasters, that organic apples were sweeter. Along with taste and sweetness, the texture as well as firmness of the apples were also rated higher than those grown conventionally. These differences are attributed to the greater soil quality resulting from organic farming techniques compared to those of conventional farming.
Some studies have shown higher nutrient levels in organic fruit and vegetables compared with conventionally grown products. However, due to the difficulty with designing such experiments, the evidence was not considered conclusive() until the release of the University of Sheffield study in 2007 (see above).
A 2002 meta-analysis (a review of all past studies on the subject) found no proof that organic food offers greater nutritional values, more consumer safety or any distinguishable difference in taste.
A new report published in March 2008 by The Organic Center, which promotes organic food, claims that organic food is on average 25% more nutritious than conventional food.
# Cost
Organic products typically cost 10 to 40% more than similar conventionally produced products. Processed organic foods vary in price when compared to their conventional counterparts. An Australian study by Choice magazine in 2004 found processed organic foods in supermarkets to be 65% more expensive, but noted this was not consistent.
Prices may be higher because organic produce is produced on a smaller scale, and may need to be milled or processed separately. Furthermore, there is an increase in shipping costs from more centralized production in otherwise regional markets. In the case of dairy and eggs, the animal's requirements such as the number of animals that can be raised per acre, or the breed of animal and its feed conversion ratio affects the cost.
# Related movements
Various alternative organic standards are emerging. They generally bypass formal certification, which can be expensive and cumbersome, and provide their own definition of organic food. One such, the Authentic Food standard, proposed by leading US organic farmer Eliot Coleman, includes criteria that are incompatible with current agribusiness:
- Fresh fruits and vegetables, milk, eggs and meat products are produced within a 50-mile radius of their place of their final sale.
- The seed and storage crops (grains, beans, nuts, potatoes, etc.) are produced within a 300-mile radius of their final sale.
- Only traditional processed foods such as cheese, wine, bread and lactofermented products may claim, "Made with Authentic ingredients."
Some are also implementing new approaches to defining and buying food. Community-supported agriculture (CSA) is one such approach, that cuts out all the middlemen by having consumers partner with local farmers. CSA members prepurchase "shares" in a season's harvest, and pick up their weekly portions from distribution sites. Thus, consumers provide direct financing for farms, participate in the risks and rewards of annual growing conditions, and participate with farmers in distribution networks.
CSA is one example of "buying locally," which is often valued by both the organic food consumer and producer. Generally speaking, locally-grown seasonal food can be brought to market more quickly than food that has to be transported long distances, and therefore can be better tasting and to some degree more nutritious by virtue of its freshness. Additionally, the act of buying foods that are locally-grown benefits local farmers and other employers. This local food approach is seen as a direct investment in one's own community and a way to reduce economic dependence.
Organic food is also often linked with the fair trade movement, based on the principle that social and environmental sustainability are inextricably interdependent.
The "buy local" movement is also related to the organic movement. Michael Pollan, author of “The Omnivore's Dilemma”, notes that in the whole chain of food production and distribution, only one-fifth of the energy is used on the farm, the rest in distribution. Yet a report published by DEFRA, Britain's environment and farming ministry, concluded that shifts toward a local food production and distribution system, as advocated by many organic food proponents, would actually increase the amount of energy being invested in food due to the a higher level of small-scale transport systems, which suffer from inefficiencies compared to standard large-scale supermarket systems.
As highlighted by a recent New York Times article, food supply is a global issue that will become increasingly prominent in the near future. "Everywhere, the cost of food is rising sharply. Whether the world is in for a long period of continued increases has become one of the most urgent issues in economics. ... Farmers the world over are producing flat-out. American agricultural exports are expected to increase 23 percent this year to $101 billion, a record. The world’s grain stockpiles have fallen to the lowest levels in decades.
'Everyone wants to eat like an American on this globe,' said Daniel W. Basse of the AgResource Company, a Chicago consultancy. 'But if they do, we’re going to need another two or three globes to grow it all.'" Given the debate around Organic's ability to match the yields of conventional methods and the rising global demand for food, this debate is likely to see increased scrutiny in the future.
# Facts and statistics
While organic food accounts for 1–2% of total food sales worldwide, the organic food market is growing rapidly, far ahead of the rest of the food industry, in both developed and developing nations.
- World organic food sales jumped from US $23 billion in 2002 to $40 billion in 2006.
- The world organic market has been growing by 20% a year since the early 1990s, with future growth estimates ranging from 10-50% annually depending on the country.
## North America
- Organic food sales have grown by 17 to 20 percent a year for the past few years while sales of conventional food have grown at only about 2 to 3 percent a year.
- In 2003 organic products were available in nearly 20,000 natural food stores and 73% of conventional grocery stores.
- Organic products account for 2.6% of total food sales in the year 2005.
- Two thirds of organic milk and cream and half of organic cheese and yogurt are sold through conventional supermarkets.
- Organic food sales surpassed $1 billion in 2006, accounting for 0.9% of food sales in Canada.
- Organic food sales by grocery stores were 28% higher in 2006 than in 2005.
- British Columbians account for 13% of the Canadian population, but purchased 26% of the organic food sold in Canada in 2006.
## Europe
In the European Union (EU25) 3.9% of the total utilized agricultural area is used for organic production. The countries with the highest proportion of organic land are Austria (11%) and Italy (8.4), followed by Czech Republic and Greece (both 7.2%). The lowest figures are shown for Malta (0.1%), Poland (0.6%) and Ireland (0.8%)
- 11.6% of all farmers produced organically in 2007. The government has created incentives to increase the figure to 20% by 2010.
- 4.9% of all food products sold in Austrian supermarkets (including discount stores) in 2006 were organic. 8000 different organic products were available in the same year.
- Since 2005 all school lunches must be organic by law.
- In 2005 168,000 ha of land were under organic management. 7 percent of Polish consumers buy food that was produced according to the EU-Eco-regulation. The value of the organic market is estimated at 50 million Euros (2006).
- Organic food sales increased from just over £100 million in 1993/94 to £1.21 billion in 2004 (an 11% increase on 2003).
## Caribbean
- After the collapse of the Soviet Union in 1990, agricultural inputs that had previously been purchased from Eastern bloc countries were no longer available in Cuba, and many Cuban farms converted to organic methods out of necessity. Consequently, organic agriculture is a mainstream practice in Cuba, while it remains an alternative practice in most other countries. Although some products called organic in Cuba would not satisfy certification requirements in other countries (crops may be genetically modified, for example), Cuba exports organic citrus and citrus juices to EU markets that meet EU organic standards. Cuba's forced conversion to organic methods may position the country to be a global supplier of organic products. | Organic food
Organic foods are produced according to certain production standards, meaning they are grown without the use of conventional pesticides, artificial fertilizers, human waste, or sewage sludge, and that they were processed without ionizing radiation or food additives.[1] Livestock are reared without the routine use of antibiotics and without the use of growth hormones. In most countries, organic produce must not be genetically modified.
Organic food production is legally regulated. Currently, the United States, the European Union, Japan and many other countries require producers to obtain organic certification in order to market food as organic.
Historically, organic farms have been relatively small family-run farms[2] — which is why organic food was once only available in small stores or farmers' markets. However, since the early 1990s organic food has had growth rates of around 20% a year, far ahead of the rest of the food industry, in both developed and developing nations. As of April 2008, organic food accounts for 1-2% of food sales worldwide. Future growth is expected to range from 10-50% annually depending on the country.
# Identifying organic food
Processed organic food usually contains only organic ingredients, or where there are a number of ingredients, at least a minimum percentage of the plant and animal ingredients must be organic (95% in the United States[3] and Australia). Any non-organically produced ingredients must still meet requirements. Foods claiming to be organic must be free of artificial food additives, and are often processed with fewer artificial methods, materials and conditions (no chemical ripening, no food irradiation, and no genetically modified ingredients, etc.).
They may also be required to be produced using energy-saving technologies and packaged using recyclable or biodegradable materials when possible.[citation needed]
Early consumers interested in organic food would look for non-chemically treated, fresh or minimally processed food. They mostly had to buy directly from growers: "Know your farmer, know your food" was the motto. Personal definitions of what constituted "organic" were developed through firsthand experience: by talking to farmers, seeing farm conditions, and farming activities. Small farms grew vegetables (and raised livestock) using organic farming practices, with or without certification, and the individual consumer monitored. As demand for organic foods continues to increase, high volume sales through mass outlets such as supermarkets are rapidly replacing the direct farmer connection. However, for supermarket consumers, food production is not easily observable, and product labelling, like "certified organic", is relied on. Government regulations and third-party inspectors are looked to for assurance. A "certified organic" label is usually the only way for consumers to know that a processed product is "organic".
## Legal definition
Template:Seealso
To be certified organic, products must be grown and manufactured in a manner that adheres to standards set by the country they are sold in:
- Australia: NASAA Organic Standard
- Britain: Organic Farmers and Growers Organic Standards and the Soil Association
- Canada: Canada Gazette, Government of Canada
- European Union: EU-Eco-regulation
Sweden: KRAV
- Sweden: KRAV
- India: NPOP, (National Program for Organic Production)
- Japan: JAS Standards.
- United States: National Organic Program (NOP) Standards
# Environmental impact
Several surveys and studies have attempted to examine and compare conventional and organic systems of farming. The general consensus across these surveys[4][5] is that, in the short term, organic farming is less damaging for the following reasons:
- Organic farms do not consume or release synthetic pesticides into the environment — some of which have the potential to harm soil, water and local terrestrial and aquatic wildlife.
- Organic farms are better than conventional farms at sustaining diverse ecosystems, i.e., populations of plants and insects, as well as animals.
- When calculated either per unit area or per unit of yield, organic farms use less energy and produce less waste, e.g., waste such as packaging materials for chemicals.
However, many critics of organic farming methods believe that the increased land needed to farm organic food could potentially destroy the rainforests and wipe out many ecosystems.[6] [7]
## Yield
One study found a 20% smaller yield from organic farms using 50% less fertilizer and 97% less pesticide.[8] Studies comparing yields have had mixed results.[9] Supporters claim that organically managed soil has a higher quality[10] and higher water retention. This may help increase yields for organic farms in drought years. One study of two organic farming systems and one conventional found that, in one year's severe crop season drought, organic soybean yields were 52% and 96% higher than the conventional system and organic maize yields were 37% higher in one system, but 62% lower in the other.[11]
One study from the Danish Environmental Protection Agency found that, area-for-area, organic farms of potatoes, sugar beet and seed grass produce as little as half the output of conventional farming.[12] Findings like these, and the dependence of organic food on manure from low-yield cattle, has prompted criticism from many scientists that organic farming is environmentally unsound and incapable of feeding the world population.[13] Among these critics are Norman Borlaug, father of the "green revolution," and winner of the Nobel Peace Prize, who asserts that organic farming practices can at most feed 4 billion people, after expanding cropland dramatically and destroying ecosystems in the process.[14]
However a recent study [15] compiling research from 293 different comparisons into a single study to assess the overall efficiency of the two agricultural systems has concluded that
organic methods could produce enough food on a global per capita basis to sustain the current human population, and potentially an even larger population, without increasing the agricultural land base (from the abstract)
The researchers also found that while in developed countries, organic systems on average produce 92% of the yield produced by conventional agriculture, organic systems produce 80% more than conventional farms in developing countries, because the materials needed for organic farming are more accessible than synthetic farming materials to farmers in poor countries.
## Energy Efficiency
Some studies are also consistent in showing that organic farms are more energy efficient.[16] However, alternative views hold that this may be deceptive, based on fossil fuel usage but ignoring energy costs of plowing and other laborious practices used on organic farms to maintain yields[citation needed].
## Pesticides and farmers
There have been many studies on the health effects of pesticide exposure to those who work on farms.[17] Even when pesticides are used correctly, they still end up in the air and bodies of farm workers. Through these studies, organophosphate pesticides have become associated with acute health problems such as abdominal pain, dizziness, headaches, nausea, vomiting, as well as skin and eye problems.[18] In addition, there have been many other studies that have found pesticide exposure is associated with more severe health problems such as respiratory problems, memory disorders, dermatologic conditions,[19][20] cancer,[21] depression, neurologic deficits,[22][23] miscarriages, and birth defects.[24] Summaries of peer-reviewed research have examined the link between pesticide exposure and neurological outcomes and cancer in organophosphate-exposed workers.[25][26]
Imported fruits and vegetables from South America are more likely to contain high level of pesticides,[27] even pesticides banned for use in the United States.[28] Migratory birds, such as Swainson’s hawks, have wintering grounds in Argentina where thousands of them were found dead from monocrotophos insecticide poisoning.
## Pesticide residue
A study published in 2002 showed that "Organically grown foods consistently had about one-third as many residues as conventionally grown foods."[29][30]
Monitoring of pesticide residues in the United States is carried out by the Pesticide Data Program (part of USDA, which was created in 1990. It has since tested over 60 different types of food for over 400 different types of pesticides - with samples collected close to the point of consumption. Their most recent results found in 2005 that:
Several studies corroborate this finding by having found that while 77 percent of conventional food carries synthetic pesticide residues, only about 25 percent of organic food does.[32][33][34][35][36][37][38][39][40][41]
A study published by the National Research Council in 1993 determined that for infants and children, the major source of exposure to pesticides is through diet.[42] A recent study in 2006 measured the levels of organophosphorus pesticide exposure in 23 schoolchildren before and after replacing their diet with organic food. In this study it was found that levels of organophosphorus pesticide exposure dropped dramatically and immediately when the children switched to an organic diet.[43] Food residue limits established by law are set specifically with children in mind and consider a child's lifetime ingestion of each pesticide.[44]
There are controversial data on the health implications of certain pesticides. For example, the herbicide Atrazine has been shown in some experiments to be a teratogen, causing demasculinization in male frogs exposed to small concentrations. Under the effects of Atrazine, male frogs were found to have greatly increased occurrencesof either malformed gonads, or testicular gonads which contain non-degenerate eggs.[45] Effects were however significantly reduced in high concentrations, as is consistent with other teratogens affecting the endocrine system, such as estradiol.
Organic farming standards do not allow the use of synthetic pesticides, but they do allow the use of specific pesticides derived from plants. The most common organic pesticides, accepted for restricted use by most organic standards, include Bt, pyrethrum, and rotenone. Some organic pesticides, such as rotenone, have high toxicity to fish and aquatic creatures with some toxicity to mammals. It causes Parkinson's disease if injected into rats.[46]
The United States Environmental Protection Agency and state agencies periodically review the licensing of suspect pesticides, but the process of de-listing is slow. One example of this slow process is exemplified by the pesticide Dichlorvos, or DDVP, which as recently as the year 2006 the EPA proposed its continued sale. The EPA has almost banned this pesticide on several occasions since the 1970s, but it never did so despite considerable evidence that suggests DDVP is not only carcinogenic but dangerous to the human nervous system — especially in children.[47]
# Taste and nutritional value
The biggest study ever of organic food was completed in 2007 (which has neither been peer-reviewed nor published yet [48]) and found that organic fruit and vegetables contain up to 40% more antioxidants than conventional equivalents, and that the figure was 90% for organic milk. The 4-year study was funded by the European Union and was the largest of its kind ever undertaken.[49]
A 2001 study by researchers at Washington State University concluded, under judgement by a panel of tasters, that organic apples were sweeter. Along with taste and sweetness, the texture as well as firmness of the apples were also rated higher than those grown conventionally. These differences are attributed to the greater soil quality resulting from organic farming techniques compared to those of conventional farming.[50]
Some studies have shown higher nutrient levels in organic fruit and vegetables compared with conventionally grown products. However, due to the difficulty with designing such experiments, the evidence was not considered conclusive([51]) until the release of the University of Sheffield study in 2007 (see above).
A 2002 meta-analysis (a review of all past studies on the subject) found no proof that organic food offers greater nutritional values, more consumer safety or any distinguishable difference in taste.[52][53][54][55]
A new report published in March 2008 by The Organic Center, which promotes organic food, claims that organic food is on average 25% more nutritious than conventional food.[56]
# Cost
Organic products typically cost 10 to 40% more than similar conventionally produced products.[57] Processed organic foods vary in price when compared to their conventional counterparts. An Australian study by Choice magazine in 2004 found processed organic foods in supermarkets to be 65% more expensive, but noted this was not consistent.
Prices may be higher because organic produce is produced on a smaller scale, and may need to be milled or processed separately. Furthermore, there is an increase in shipping costs from more centralized production in otherwise regional markets. In the case of dairy and eggs, the animal's requirements such as the number of animals that can be raised per acre, or the breed of animal and its feed conversion ratio affects the cost.
# Related movements
Various alternative organic standards are emerging. They generally bypass formal certification, which can be expensive and cumbersome, and provide their own definition of organic food. One such, the Authentic Food standard, proposed by leading US organic farmer Eliot Coleman, includes criteria that are incompatible with current agribusiness:
=
- Fresh fruits and vegetables, milk, eggs and meat products are produced within a 50-mile radius of their place of their final sale.
- The seed and storage crops (grains, beans, nuts, potatoes, etc.) are produced within a 300-mile radius of their final sale.
- Only traditional processed foods such as cheese, wine, bread and lactofermented products may claim, "Made with Authentic ingredients."[58]
Some are also implementing new approaches to defining and buying food. Community-supported agriculture (CSA) is one such approach, that cuts out all the middlemen by having consumers partner with local farmers. CSA members prepurchase "shares" in a season's harvest, and pick up their weekly portions from distribution sites. Thus, consumers provide direct financing for farms, participate in the risks and rewards of annual growing conditions, and participate with farmers in distribution networks.
CSA is one example of "buying locally," which is often valued by both the organic food consumer and producer. Generally speaking, locally-grown seasonal food can be brought to market more quickly than food that has to be transported long distances, and therefore can be better tasting and to some degree more nutritious by virtue of its freshness. Additionally, the act of buying foods that are locally-grown benefits local farmers and other employers. This local food approach is seen as a direct investment in one's own community and a way to reduce economic dependence.
Organic food is also often linked with the fair trade movement, based on the principle that social and environmental sustainability are inextricably interdependent.
The "buy local" movement is also related to the organic movement. Michael Pollan, author of “The Omnivore's Dilemma”, notes that in the whole chain of food production and distribution, only one-fifth of the energy is used on the farm, the rest in distribution. Yet a report published by DEFRA, Britain's environment and farming ministry, concluded that shifts toward a local food production and distribution system, as advocated by many organic food proponents, would actually increase the amount of energy being invested in food due to the a higher level of small-scale transport systems, which suffer from inefficiencies compared to standard large-scale supermarket systems.[59]
As highlighted by a recent New York Times article, food supply is a global issue that will become increasingly prominent in the near future. "Everywhere, the cost of food is rising sharply. Whether the world is in for a long period of continued increases has become one of the most urgent issues in economics. ... Farmers the world over are producing flat-out. American agricultural exports are expected to increase 23 percent this year to $101 billion, a record. The world’s grain stockpiles have fallen to the lowest levels in decades.
'Everyone wants to eat like an American on this globe,' said Daniel W. Basse of the AgResource Company, a Chicago consultancy. 'But if they do, we’re going to need another two or three globes to grow it all.'"[60] Given the debate around Organic's ability to match the yields of conventional methods and the rising global demand for food, this debate is likely to see increased scrutiny in the future.
# Facts and statistics
While organic food accounts for 1–2% of total food sales worldwide, the organic food market is growing rapidly, far ahead of the rest of the food industry, in both developed and developing nations.
- World organic food sales jumped from US $23 billion in 2002[61] to $40 billion in 2006.[62]
- The world organic market has been growing by 20% a year since the early 1990s, with future growth estimates ranging from 10-50% annually depending on the country.
## North America
- Organic food sales have grown by 17 to 20 percent a year for the past few years[63] while sales of conventional food have grown at only about 2 to 3 percent a year.[64]
- In 2003 organic products were available in nearly 20,000 natural food stores and 73% of conventional grocery stores.[65]
- Organic products account for 2.6% of total food sales in the year 2005.[66]
- Two thirds of organic milk and cream and half of organic cheese and yogurt are sold through conventional supermarkets.[67]
- Organic food sales surpassed $1 billion in 2006, accounting for 0.9% of food sales in Canada.[68]
- Organic food sales by grocery stores were 28% higher in 2006 than in 2005. [69]
- British Columbians account for 13% of the Canadian population, but purchased 26% of the organic food sold in Canada in 2006. [70]
## Europe
In the European Union (EU25) 3.9% of the total utilized agricultural area is used for organic production. The countries with the highest proportion of organic land are Austria (11%) and Italy (8.4), followed by Czech Republic and Greece (both 7.2%). The lowest figures are shown for Malta (0.1%), Poland (0.6%) and Ireland (0.8%)[71]
- 11.6% of all farmers produced organically in 2007.[72] The government has created incentives to increase the figure to 20% by 2010.[73]
- 4.9% of all food products sold in Austrian supermarkets (including discount stores) in 2006 were organic.[74] 8000 different organic products were available in the same year.[75]
- Since 2005 all school lunches must be organic by law.[76]
- In 2005 168,000 ha of land were under organic management. 7 percent of Polish consumers buy food that was produced according to the EU-Eco-regulation. The value of the organic market is estimated at 50 million Euros (2006).[77]
- Organic food sales increased from just over £100 million in 1993/94 to £1.21 billion in 2004 (an 11% increase on 2003).[78]
## Caribbean
- After the collapse of the Soviet Union in 1990, agricultural inputs that had previously been purchased from Eastern bloc countries were no longer available in Cuba, and many Cuban farms converted to organic methods out of necessity.[79] Consequently, organic agriculture is a mainstream practice in Cuba, while it remains an alternative practice in most other countries. Although some products called organic in Cuba would not satisfy certification requirements in other countries (crops may be genetically modified, for example[80][81]), Cuba exports organic citrus and citrus juices to EU markets that meet EU organic standards. Cuba's forced conversion to organic methods may position the country to be a global supplier of organic products.[82] | https://www.wikidoc.org/index.php/Organic_food | |
013ff3ee13175b85657afad38de102c55b2f94b6 | wikidoc | Organonickel | Organonickel
Organonickel chemistry is a branch of organometallic chemistry that deals with organic compounds containing a nickel to carbon bond and their reactions . They are used as a catalyst, as a building block in organic chemistry and in chemical vapor deposition. Organonickel compounds are also short-lived intermediates in organic reactions. The first organonickel compound ever discovered was nickel tetracarbonyl Ni(CO)4 in 1890 and quickly put to use in the Mond process for nickel purification.
# Overview
Organonickel compounds can have oxidation state 0 or +2 and in many ways resemble organopalladium compounds in the same Group 10 element column of the periodic table. Both metals are reducing agents: Raney nickel for nickel and a host of palladium catalysts such as palladium on carbon. Many reactions of nickel compounds are based on reductive elimination / oxidative addition sequences.
## Ni alkene complexes
Many complexes exist of nickel coordinated to an alkene. In these comounds nickel is formally zerovalent Ni0 and the bonding is based on the Dewar-Chatt-Duncanson model. One widely available representative is bis(1,5-cyclooctadiene)nickel(0) or Ni(COD)2 containing two cyclooctadiene units. It is a 18VE compound with 10 electrons provided by nickel itself and 4x2 electrons more by the double bonds. This solid melts at 60°C and is used as a catalyst.
## Ni allyl complexes
Allyl halides react with Ni(CO)4 to form nickel pi-allyl complexes. These compounds in turn are sources of allyl nucleophiles in reaction with alkyl halides. In allyl(cyclopentadienyl)nickel(II) nickel has oxidation number +2. The electron count is 18 (8 from nickel, 6 from the Cp unit and 4 more from the allyl anion).
## Nickelocenes
The nickel metallocene pendant is nickelocene NiCp2 with +2 Ni oxidation state and with 20 valence electrons. It is easily reduced to a 19 VE nickelicinium ion. In contrast, the corresponding palladocene based on palladium is an unknown compound.
## Nickel carbene complexes
With electron-rich alkenes nickel forms nickel transition metal carbene complexes containing C=Ni double bonds.
## Nickel 12 VE compounds
Nickel compounds of the type NiR2 also exist with just 12 valence electrons. In solution however solvent molecules always interact with the metal atom increasing the electron count. One true 12 VE compound is di(mesityl)nickel prepared from allyl nickel bromide and the corresponding Grignard reagent.
# Organonickel Reactions
## Alkene/alkyne oligomerizations
Nickel compound catalyze the oligomerization of alkenes and alkynes. This property came to light as part as the development of Ziegler-Natta catalyst in the 1950s. It was found that nickel impurities originating from an autoclave killed the propagation reaction (Aufbau) in favor of termination reaction to a terminal alkene: the polymerization of ethylene simply stopped at 1-butene. This so-called nickel effect prompted the search for other catalyst capable of this reaction during which other catalysts that actually gave high mlar mass polymers (the actual Ziegler-Natta catalysts).
One practical implementation of alkyne oligomerization is the Reppe synthesis for example in the synthesis of cyclooctatetraene:
The oligomerization of butadiene with ethylene to trans-1,4-hexadiene at one time was an industrial process.
The formation of organonickel compounds in this type of reaction is not always obvious but in a carefully designed experiment two such intermediates were formed quantitatively :
## Coupling reactions
Nickel compounds cause the coupling reaction between allyl and aryl halides. Other coupling reactions involving nickel in catalytic amounts are the Kumada coupling and the Negishi coupling.
## Ni carbonylation
Ni catalyzes the addition of carbon monoxide to alkenes and alkynes. The industrial production of acrylic acid at one time consisted of combining acetylene, carbon monoxide and water at 40-55 atm and 160-200°C with nickel(II) bromide and a copper halide. | Organonickel
Organonickel chemistry is a branch of organometallic chemistry that deals with organic compounds containing a nickel to carbon bond and their reactions [1] [2]. They are used as a catalyst, as a building block in organic chemistry and in chemical vapor deposition. Organonickel compounds are also short-lived intermediates in organic reactions. The first organonickel compound ever discovered was nickel tetracarbonyl Ni(CO)4 in 1890 and quickly put to use in the Mond process for nickel purification.
# Overview
Organonickel compounds can have oxidation state 0 or +2 and in many ways resemble organopalladium compounds in the same Group 10 element column of the periodic table. Both metals are reducing agents: Raney nickel for nickel and a host of palladium catalysts such as palladium on carbon. Many reactions of nickel compounds are based on reductive elimination / oxidative addition sequences.
## Ni alkene complexes
Many complexes exist of nickel coordinated to an alkene. In these comounds nickel is formally zerovalent Ni0 and the bonding is based on the Dewar-Chatt-Duncanson model. One widely available representative is bis(1,5-cyclooctadiene)nickel(0) or Ni(COD)2 containing two cyclooctadiene units. It is a 18VE compound with 10 electrons provided by nickel itself and 4x2 electrons more by the double bonds. This solid melts at 60°C [3] and is used as a catalyst.
## Ni allyl complexes
Allyl halides react with Ni(CO)4 to form nickel pi-allyl complexes. These compounds in turn are sources of allyl nucleophiles in reaction with alkyl halides. In allyl(cyclopentadienyl)nickel(II) [4] nickel has oxidation number +2. The electron count is 18 (8 from nickel, 6 from the Cp unit and 4 more from the allyl anion).
## Nickelocenes
The nickel metallocene pendant is nickelocene NiCp2 with +2 Ni oxidation state and with 20 valence electrons. It is easily reduced to a 19 VE nickelicinium ion. In contrast, the corresponding palladocene based on palladium is an unknown compound.
## Nickel carbene complexes
With electron-rich alkenes nickel forms nickel transition metal carbene complexes containing C=Ni double bonds.
## Nickel 12 VE compounds
Nickel compounds of the type NiR2 also exist with just 12 valence electrons. In solution however solvent molecules always interact with the metal atom increasing the electron count. One true 12 VE compound is di(mesityl)nickel prepared from allyl nickel bromide and the corresponding Grignard reagent.
# Organonickel Reactions
## Alkene/alkyne oligomerizations
Nickel compound catalyze the oligomerization of alkenes and alkynes. This property came to light as part as the development of Ziegler-Natta catalyst in the 1950s. It was found that nickel impurities originating from an autoclave killed the propagation reaction (Aufbau) in favor of termination reaction to a terminal alkene: the polymerization of ethylene simply stopped at 1-butene. This so-called nickel effect prompted the search for other catalyst capable of this reaction during which other catalysts that actually gave high mlar mass polymers (the actual Ziegler-Natta catalysts).
One practical implementation of alkyne oligomerization is the Reppe synthesis for example in the synthesis of cyclooctatetraene:
The oligomerization of butadiene with ethylene to trans-1,4-hexadiene at one time was an industrial process.
The formation of organonickel compounds in this type of reaction is not always obvious but in a carefully designed experiment two such intermediates were formed quantitatively [5] [6]:
## Coupling reactions
Nickel compounds cause the coupling reaction between allyl and aryl halides. Other coupling reactions involving nickel in catalytic amounts are the Kumada coupling and the Negishi coupling.
## Ni carbonylation
Ni catalyzes the addition of carbon monoxide to alkenes and alkynes. The industrial production of acrylic acid at one time consisted of combining acetylene, carbon monoxide and water at 40-55 atm and 160-200°C with nickel(II) bromide and a copper halide. | https://www.wikidoc.org/index.php/Organonickel | |
2bc1d9586773b5c0d0f490c2bda82bd7723a0a88 | wikidoc | Ormeloxifene | Ormeloxifene
# Overview
Ormeloxifene (also known as centchroman) is one of the selective estrogen receptor modulators, or SERMs, a class of medication which acts on the estrogen receptor. It is best known as a non-hormonal, non-steroidal oral contraceptive which is taken once per week. In India, ormeloxifene has been available as birth control since the early 1990s, and it is currently marketed there under the trade name Saheli. Ormeloxifene has also been licensed under the trade names Novex-DS, Centron and Sevista.
# Medical uses
Ormeloxifene is primarily used as a contraceptive but may also be effective for dysfunctional uterine bleeding and advanced breast cancer.
## Birth control
Ormeloxifene may be used as a weekly oral contraceptive. The weekly schedule is an advantage for women who prefer an oral contraceptive, but find it difficult or impractical to adhere to a daily schedule required by other oral contraceptives.
For the first twelve weeks of use, it is advised to take the ormeloxifene pill twice per week. From the thirteenth week on, it is taken once per week.
The consensus is that backup protection in the first month is a cautious but sensible choice. A standard dose is 30 mg weekly, but 60 mg loading doses can reduce pregnancy rates by 38%.
It has a failure rate of about 1-2% with ideal use which is slightly less effective than found for combined oral contraceptive pills.
## Other indications
- Ormeloxifene has also been tested in experimental setting as a treatment for menorrhagia.
- use in treatment of mastalgia and fibroadenoma has also been described.
# Adverse effects
There are concerns that ormeloxifene may cause delayed mensturation.
# Method of action
Ormeloxifene is a SERM, or selective estrogen receptor modulator. In some parts of the body, its action is estrogenic (e.g., bones), in other parts of the body, its action is anti-estrogenic (e.g., uterus, breasts.) It causes an asynchrony in the menstrual cycle between ovulation and the development of the uterine lining, although its exact mode of action is not well defined. In clinical trials, it caused ovulation to occur later than it normally would in some women, but did not affect ovulation in the majority of women, while causing the lining of the uterus to build more slowly. It speeds the transport of any fertilized egg through the fallopian tubes more quickly than is normal. Presumably, this combination of effects creates an environment such that if fertilization occurs, implantation will not be possible.
# Marketing
Ormeloxifene is only legally available in India as of 2009.
Ormeloxifene has been tested and licensed as a form of birth control, as well as a treatment for dysfunctional uterine bleeding. It was first manufactured by Torrent Pharmaceuticals, and marketed as birth control under the trade name Centron. Centron was discontinued. A new license for ormeloxifene was issued to Hindustan Latex Ltd., which now manufactures ormeloxifene as birth control under the trade name Saheli, Novex and Novex-DS. Torrent Pharmaceuticals has resumed manufacture of ormeloxifene under the trade name Sevista, as a treatment for dysfunctional uterine bleeding.
# Synthesis | Ormeloxifene
Template:Infobox Birth control
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Ormeloxifene (also known as centchroman) is one of the selective estrogen receptor modulators,[1] or SERMs, a class of medication which acts on the estrogen receptor. It is best known as a non-hormonal, non-steroidal oral contraceptive which is taken once per week. In India, ormeloxifene has been available as birth control since the early 1990s, and it is currently marketed there under the trade name Saheli.[2] Ormeloxifene has also been licensed under the trade names Novex-DS, Centron and Sevista.
# Medical uses
Ormeloxifene is primarily used as a contraceptive but may also be effective for dysfunctional uterine bleeding and advanced breast cancer.[3]
## Birth control
Ormeloxifene may be used as a weekly oral contraceptive.[3] The weekly schedule is an advantage for women who prefer an oral contraceptive, but find it difficult or impractical to adhere to a daily schedule required by other oral contraceptives.
For the first twelve weeks of use, it is advised to take the ormeloxifene pill twice per week.[3] From the thirteenth week on, it is taken once per week.[3][4]
The consensus is that backup protection in the first month is a cautious but sensible choice. A standard dose is 30 mg weekly, but 60 mg loading doses can reduce pregnancy rates by 38%.[5]
It has a failure rate of about 1-2% with ideal use which is slightly less effective than found for combined oral contraceptive pills.[6]
## Other indications
- Ormeloxifene has also been tested in experimental setting as a treatment for menorrhagia.[7]
- use in treatment of mastalgia and fibroadenoma has also been described.[8]
# Adverse effects
There are concerns that ormeloxifene may cause delayed mensturation.[9]
# Method of action
Ormeloxifene is a SERM, or selective estrogen receptor modulator. In some parts of the body, its action is estrogenic (e.g., bones), in other parts of the body, its action is anti-estrogenic (e.g., uterus, breasts.[10][11]) It causes an asynchrony in the menstrual cycle between ovulation and the development of the uterine lining, although its exact mode of action is not well defined. In clinical trials, it caused ovulation to occur later than it normally would in some women,[6] but did not affect ovulation in the majority of women, while causing the lining of the uterus to build more slowly. It speeds the transport of any fertilized egg through the fallopian tubes more quickly than is normal.[6] Presumably, this combination of effects creates an environment such that if fertilization occurs, implantation will not be possible.[6]
# Marketing
Ormeloxifene is only legally available in India as of 2009.[12]
Ormeloxifene has been tested and licensed as a form of birth control, as well as a treatment for dysfunctional uterine bleeding. It was first manufactured by Torrent Pharmaceuticals, and marketed as birth control under the trade name Centron. Centron was discontinued. A new license for ormeloxifene was issued to Hindustan Latex Ltd., which now manufactures ormeloxifene as birth control under the trade name Saheli, Novex and Novex-DS. Torrent Pharmaceuticals has resumed manufacture of ormeloxifene under the trade name Sevista, as a treatment for dysfunctional uterine bleeding.
# Synthesis | https://www.wikidoc.org/index.php/Ormeloxifene | |
e3535a4b894fc2b7ce0590594e1ba9df9f0ed20c | wikidoc | Rare disease | Rare disease
# Overview
A rare disease (sometimes known as an orphan disease) has such a low prevalence in a population that a doctor in a busy general practice would not expect to see more than one case a year. Rare diseases, including those of genetic origin, are life-threatening or chronically debilitating diseases which are of such low prevalence that special combined efforts are needed to address them.
# Prevalence
As a guide, low prevalence is taken as prevalence of less than 5 per 10,000 in the community .
The NIH's Office of Rare Diseases states that, "an orphan or rare disease is generally considered to have a prevalence of fewer than 200,000 affected individuals in the United States" .
Rare diseases can vary in prevalence between populations, so a disease that is rare in some populations may be common in others. This is especially true of genetic diseases and infectious diseases. An example is cystic fibrosis, a genetic disease: it is rare in most parts of Asia but relatively common in Europe and in populations of European descent. Many infectious diseases are prevalent in a given geographic area but rare everywhere else. Other diseases, such as many rare forms of cancer, have no apparent pattern of distribution but are simply rare.
Eurordis (European Organisation for rare Diseases) estimates that there exist between 5,000 and 8,000 distinct rare diseases, affecting between 6% and 8% of the population.
# Characteristics
Rare diseases are usually chronic and life-threatening. This is so because, given its rarity, less severe illness are just not identified as such. Eurordis estimates that at least 80% of them have identified genetic origins. Other rare diseases are the result of infections and allergies or due to degenerative and proliferative causes. Symptoms of some rare diseases may appear at birth or in childhood, whereas others only appear once adulthood is reached. | Rare disease
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
A rare disease (sometimes known as an orphan disease) has such a low prevalence in a population that a doctor in a busy general practice would not expect to see more than one case a year. Rare diseases, including those of genetic origin, are life-threatening or chronically debilitating diseases which are of such low prevalence that special combined efforts are needed to address them.
# Prevalence
As a guide, low prevalence is taken as prevalence of less than 5 per 10,000 in the community [2].
The NIH's Office of Rare Diseases states that, "an orphan or rare disease is generally considered to have a prevalence of fewer than 200,000 affected individuals in the United States" [3].
Rare diseases can vary in prevalence between populations, so a disease that is rare in some populations may be common in others. This is especially true of genetic diseases and infectious diseases. An example is cystic fibrosis, a genetic disease: it is rare in most parts of Asia but relatively common in Europe and in populations of European descent. Many infectious diseases are prevalent in a given geographic area but rare everywhere else. Other diseases, such as many rare forms of cancer, have no apparent pattern of distribution but are simply rare.
Eurordis (European Organisation for rare Diseases) estimates that there exist between 5,000 and 8,000 distinct rare diseases, affecting between 6% and 8% of the population.
# Characteristics
Rare diseases are usually chronic and life-threatening. This is so because, given its rarity, less severe illness are just not identified as such. Eurordis estimates that at least 80% of them have identified genetic origins. Other rare diseases are the result of infections and allergies or due to degenerative and proliferative causes. Symptoms of some rare diseases may appear at birth or in childhood, whereas others only appear once adulthood is reached. | https://www.wikidoc.org/index.php/Orphan_disease | |
42a4cef4787089cdb7aaccd046496255fad3259d | wikidoc | Orthodontics | Orthodontics
# Overview
Orthodontics is a specialty of dentistry that is concerned with the study and treatment of malocclusions (improper bites), which may be a result of tooth irregularity, disproportionate jaw relationships, or both. The word comes from the Greek words ortho meaning straight and odons meaning tooth.
Orthodontic treatment can focus on dental displacement only, or can deal with the control and modification of facial growth. In the latter case it is better defined as "dentofacial orthopedics".
Orthodontic treatment can be carried out for purely aesthetic reasons—improving the general appearance of patients' teeth and face for cosmetic reasons—but treatment is often prescribed for practical reasons, providing the patient with a functionally improved bite (occlusion).
The father of orthodontics is Dr. E. H. Angle.
# Methods
If the main goal of the treatment is the dental displacement, most commonly a fixed multibracket therapy is used. In this case orthodontic wires are inserted into dental braces, which can be made from stainless steel or a more esthetic ceramic material.
Also removable appliances, or "plates", headgear, expansion appliances, and many other devices can be used to move teeth. Functional and orthopaedics appliances are used in growing patients (age 5 to 13) with the aim to modify the jaw dimensions and relationship if these are altered. (See Prognathism.) This therapy is frequently followed by a fixed multibracket therapy to align the teeth and refine the occlusion.
After a course of active orthodontic treatment, patients will often wear retainers, which will maintain the teeth in their improved position while the surrounding bone reforms around them. The retainers are generally worn full-time for a short period, perhaps 6 months to a year, and then worn periodically (typically nightly during sleep) for as long as the orthodontist recommends. It is possible for the teeth to stay aligned without regular retainer wear. However, there are many reasons teeth will crowd as a person ages; thus there is no guarantee that teeth, orthodontically treated or otherwise, will stay aligned without retention. For this reason, many orthodontists recommend periodic retainer wear for many years (or indefinitely) after orthodontic treatment.
Appropriately trained doctors align the teeth with respect to the surrounding soft tissues, with or without movement of the underlying bones, which can be moved either through growth modification in children or jaw surgery (orthognathic surgery) in adults.
Several appliances are utilized for growth modification; including functional appliances, Headgear and Facemasks.
These "orthopedic appliances" may influence the development of an adolescent's profile and give an improved aesthetic and functional result.
# Conditions
The most common condition that the methods of orthodontics are used for is correcting anteroposterior discrepancies. Another common situation leading to orthodontic treatment is crowding of the teeth.
## Anteroposterior discrepancies
Anteroposterior discrepancies are deviations between the teeth of the upper and lower jaw in the anteroposterior direction. For instance, the top teeth can be too far forward relative to the lower teeth ("increased overjet".) The headgear is attached to the braces via metal hooks or a facebow and is anchored from the back of the head or neck with straps or a head-cap. Elastic bands are typically then used to apply pressure to the bow or hooks. Its purpose is to slow-down or stop the upper jaw from growing, hence preventing or correcting an overjet. For more details and photographs, see Headgear - Orthodontic.
## Crowding of teeth
Another common situation leading to orthodontic treatment is crowding of the teeth. In this situation, there is insufficient room for the normal complement of adult teeth, which can sometimes motivate tooth extraction|teeth being extracted in order to make enough room for the remaining teeth.
# Diagnosis and treatment planning
In diagnosis and treatment planning, the orthodontist must
- recognize the various characteristics of malocclusion and dentofacial deformity;
- define the nature of the problem, including the etiology if possible; and
- design a treatment strategy based on the specific needs and desires of the individual.
- present the treatment strategy to the patient in such a way that the patient fully understands the ramifications of his/her decision.
# Image Gallery
- Hawley retainers are the most common type of retainers. This picture shows retainers for the top and bottom of the mouth.
- Dental braces, with a powerchain, removed after completion of treatment.
- Headgear & J-hooks for connection into the patients mouth.
- Unilateral Posterior Crossbite
- Crossbite
- Crossbite
- Crossbite (Image courtesy of Berna Zorkun DMD and copylefted)
- Crossbite (Image courtesy of Berna Zorkun DMD and copylefted)
- Crossbite (Image courtesy of Berna Zorkun DMD and copylefted)
- Crossbite (Image courtesy of Berna Zorkun DMD and copylefted)
- Crossbite (Image courtesy of Berna Zorkun DMD and copylefted)
- Unilateral cross bite where the maxillary molar is lingual (towards the tongue) than the occluding mandibular molar.
- A cantilever is used to obtain the buccal displacement of tooth 1.4 which is in cross bite.
- Cantilever attached to a power arm . The power arm is applied on the lateral incisor bracket, whereby the force, delivered by the cantilever, generates a M/F ratio at the bracket equal to the length of the power arm (if this is perpendicular to the line of action of the force).
- TwoComposite Cantilevers. Two cantilevers made out of beta titanium 0.018" are welded to a beta titanium transpalatal arch.
- Palatal expander
- Rapid palatal expander
- Rapid palatal expander
- Rapid palatal expander
- 10-year-old boy with false maxillary prognathism
- Alveolar prognathism, caused by thumb sucking and tongue thrusting in a 7 yr old girl.
- Facemask or reverse-pull headgear with straps hooks for connection of elastic bands into the patients mouth, typically worn 12 to 22 hours a day depending on treatment plan.
- Essix retainer in the foreground (used on upper); illustration of an early Hawley retainer in the background.
- The bottom (as worn) of an upper Hawley retainer resting on top of a retainer case.
# Training
Various countries have their own systems for training and registering specialist orthodontists; generally a period of full-time post-graduate study is required for a dentist to qualify as an orthodontist. The orthodontic specialty is the earliest dental specialty.
## Europe
In the United Kingdom, this training period lasts three years, after completion of a membership from a Royal College. A further two years is then completed to train to consultant level, after which a fellowship examination from the Royal College is sat. In other parts of Europe, a similar pattern is followed. It is always worth contacting the professional body responsible for registering orthodontists to ensure that the orthodontist you wish to consult is a recognized specialist.
## United States
A number of medical and dental schools in the United States offer advanced education in the specialty of Orthodontics to dentists seeking postgraduate education. The courses range from two to three years of full-time classes and clinical work in the clinical and theoretical aspects of orthodontics. Generally, admission is based on an application process followed by an extensive interviewing process by the institution, in order to select the best candidate. Candidates usually have to contact the individual school directly for the application process. A list of orthodontic schools can be obtained from the American Association of Orthodontists. | Orthodontics
Editor in Chief: Berna Zorkun DMD [1]
# Overview
Orthodontics is a specialty of dentistry that is concerned with the study and treatment of malocclusions (improper bites), which may be a result of tooth irregularity, disproportionate jaw relationships, or both. The word comes from the Greek words ortho meaning straight and odons meaning tooth.
Orthodontic treatment can focus on dental displacement only, or can deal with the control and modification of facial growth. In the latter case it is better defined as "dentofacial orthopedics".
Orthodontic treatment can be carried out for purely aesthetic reasons—improving the general appearance of patients' teeth and face for cosmetic reasons—but treatment is often prescribed for practical reasons, providing the patient with a functionally improved bite (occlusion).
The father of orthodontics is Dr. E. H. Angle.
# Methods
If the main goal of the treatment is the dental displacement, most commonly a fixed multibracket therapy is used. In this case orthodontic wires are inserted into dental braces, which can be made from stainless steel or a more esthetic ceramic material.
Also removable appliances, or "plates", headgear, expansion appliances, and many other devices can be used to move teeth. Functional and orthopaedics appliances are used in growing patients (age 5 to 13) with the aim to modify the jaw dimensions and relationship if these are altered. (See Prognathism.) This therapy is frequently followed by a fixed multibracket therapy to align the teeth and refine the occlusion.
After a course of active orthodontic treatment, patients will often wear retainers, which will maintain the teeth in their improved position while the surrounding bone reforms around them. The retainers are generally worn full-time for a short period, perhaps 6 months to a year, and then worn periodically (typically nightly during sleep) for as long as the orthodontist recommends. It is possible for the teeth to stay aligned without regular retainer wear. However, there are many reasons teeth will crowd as a person ages; thus there is no guarantee that teeth, orthodontically treated or otherwise, will stay aligned without retention. For this reason, many orthodontists recommend periodic retainer wear for many years (or indefinitely) after orthodontic treatment.
Appropriately trained doctors align the teeth with respect to the surrounding soft tissues, with or without movement of the underlying bones, which can be moved either through growth modification in children or jaw surgery (orthognathic surgery) in adults.
Several appliances are utilized for growth modification; including functional appliances, Headgear and Facemasks.
These "orthopedic appliances" may influence the development of an adolescent's profile and give an improved aesthetic and functional result.
# Conditions
The most common condition that the methods of orthodontics are used for is correcting anteroposterior discrepancies. Another common situation leading to orthodontic treatment is crowding of the teeth.
## Anteroposterior discrepancies
Anteroposterior discrepancies are deviations between the teeth of the upper and lower jaw in the anteroposterior direction. For instance, the top teeth can be too far forward relative to the lower teeth ("increased overjet".) The headgear is attached to the braces via metal hooks or a facebow and is anchored from the back of the head or neck with straps or a head-cap. Elastic bands are typically then used to apply pressure to the bow or hooks. Its purpose is to slow-down or stop the upper jaw from growing, hence preventing or correcting an overjet. For more details and photographs, see Headgear - Orthodontic.
## Crowding of teeth
Another common situation leading to orthodontic treatment is crowding of the teeth. In this situation, there is insufficient room for the normal complement of adult teeth, which can sometimes motivate tooth extraction|teeth being extracted in order to make enough room for the remaining teeth.
# Diagnosis and treatment planning
In diagnosis and treatment planning, the orthodontist must
- recognize the various characteristics of malocclusion and dentofacial deformity;
- define the nature of the problem, including the etiology if possible; and
- design a treatment strategy based on the specific needs and desires of the individual.
- present the treatment strategy to the patient in such a way that the patient fully understands the ramifications of his/her decision. [1]
# Image Gallery
- Hawley retainers are the most common type of retainers. This picture shows retainers for the top and bottom of the mouth.
- Dental braces, with a powerchain, removed after completion of treatment.
- Headgear & J-hooks for connection into the patients mouth.
- Unilateral Posterior Crossbite
- Crossbite
- Crossbite
- Crossbite (Image courtesy of Berna Zorkun DMD and copylefted)
- Crossbite (Image courtesy of Berna Zorkun DMD and copylefted)
- Crossbite (Image courtesy of Berna Zorkun DMD and copylefted)
- Crossbite (Image courtesy of Berna Zorkun DMD and copylefted)
- Crossbite (Image courtesy of Berna Zorkun DMD and copylefted)
- Unilateral cross bite where the maxillary molar is lingual (towards the tongue) than the occluding mandibular molar.
- A cantilever is used to obtain the buccal displacement of tooth 1.4 which is in cross bite.
- Cantilever attached to a power arm . The power arm is applied on the lateral incisor bracket, whereby the force, delivered by the cantilever, generates a M/F ratio at the bracket equal to the length of the power arm (if this is perpendicular to the line of action of the force).
- TwoComposite Cantilevers. Two cantilevers made out of beta titanium 0.018" are welded to a beta titanium transpalatal arch.
- Palatal expander
- Rapid palatal expander
- Rapid palatal expander
- Rapid palatal expander
- 10-year-old boy with false maxillary prognathism
- Alveolar prognathism, caused by thumb sucking and tongue thrusting in a 7 yr old girl.
- Facemask or reverse-pull headgear with straps hooks for connection of elastic bands into the patients mouth, typically worn 12 to 22 hours a day depending on treatment plan.
- Essix retainer in the foreground (used on upper); illustration of an early Hawley retainer in the background.
- The bottom (as worn) of an upper Hawley retainer resting on top of a retainer case.
# Training
Various countries have their own systems for training and registering specialist orthodontists; generally a period of full-time post-graduate study is required for a dentist to qualify as an orthodontist. The orthodontic specialty is the earliest dental specialty.
## Europe
In the United Kingdom, this training period lasts three years, after completion of a membership from a Royal College. A further two years is then completed to train to consultant level, after which a fellowship examination from the Royal College is sat. In other parts of Europe, a similar pattern is followed. It is always worth contacting the professional body responsible for registering orthodontists to ensure that the orthodontist you wish to consult is a recognized specialist.
## United States
A number of medical and dental schools in the United States offer advanced education in the specialty of Orthodontics to dentists seeking postgraduate education. The courses range from two to three years of full-time classes and clinical work in the clinical and theoretical aspects of orthodontics. Generally, admission is based on an application process followed by an extensive interviewing process by the institution, in order to select the best candidate. Candidates usually have to contact the individual school directly for the application process. A list of orthodontic schools can be obtained from the American Association of Orthodontists[2]. | https://www.wikidoc.org/index.php/Orthodontic | |
5dd1a8039653364e94c38f16b6c8b172005bfc5e | wikidoc | Oswaldo Cruz | Oswaldo Cruz
Oswaldo Gonçalves Cruz, better know as Oswaldo Cruz (pron. Template:IPA2), (b. August 5, 1872, São Luíz de Paraitinga, São Paulo state, Brazil; d. February 11, 1917, Petrópolis, Rio de Janeiro state) was a Brazilian physician, bacteriologist, epidemiologist and public health officer and the founder of the Oswaldo Cruz Institute.
# Early Years
Oswaldo Gonçalves Cruz was born on August 5, 1872 in São Luis de Paraitinga, a small city in São Paulo State, to the physician Bento Gonçalvez Cruz and Amália Bulhões Cruz. Still a child, he moved to Rio de Janeiro with his family. At the age of 15 he started to study at the Faculty of Medicine of Rio de Janeiro and in 1892 he graduated as medical doctor with a thesis on water as vehicle for the propagation of microbes. Inspired by the great work of Louis Pasteur, who had developed the germ theory of disease, four years later he went to Paris to specialize in Bacteriology at the Pasteur Institute, which gathered the great names of this branch of science of that time. He was financed by his father-in-law, a wealthy Portuguese merchant.
# Work in Brazil
Cruz found the seaport of Santos ravaged by a violent epidemic of bubonic plague that threatened to reach Rio de Janeiro and engaged himself immediately in the combat of this disease. The mayor of Rio de Janeiro authorized the construction of a plant for manufacturing the serum against the disease which had been developed at the Pasteur Institute by Alexandre Yersin and coworkers, and asked the institution for a scientist who could bring to Brazil this know-how. The Pasteur Institute responded that such a person was already available in Brazil and he was Dr. Oswaldo Cruz.
Thus, on May 25, 1900, the Federal Serotherapy Institute destined to the production of sera and vaccines against the bubonic plague was created with the Baron Pedro Afonso as Director General and the young bacteriologist Oswaldo Cruz as Technical Director. The new Institute was established in the old farm of Manguinhos at the western shores of Guanabara Bay. In 1902, Cruz accepted the office of Director General of the new institute and soon amplified its scope of activities, now no longer restricted to the production of sera but also dedicated to basic and applied research and to the building of human resources. In the following year, Oswaldo Cruz was appointed Director General of Public Health, a position corresponding to that of a today's Minister of Health. Using the Federal Serotherapy Institute as technical-scientific base, he started a quick succession of memorable sanitation campaigns. His first adversary: a series of yellow fever endemics, which had earned Rio de Janeiro the sinister reputation of Foreigners' Grave. Between 1897 and 1906, 4,000 European immigrants had died there from this disease.
Cruz was initially successful in the sanitary campaign against the bubonic plague, to which end he used obligatory notification of cases, isolation of sick people, treatment with the sera produced at Manguinhos and extermination of the rats populating the city.
# Smallpox Vaccination Controversy
In 1904, a smallpox epidemic was threatening the capital. In the course of the first five months of that year, more than 1,800 persons had already been hospitalized. A law imposing smallpox vaccination of children had existed since 1837 but had never had been put into practice. Therefore, on June 9, 1904, following a proposal by Oswaldo Cruz, the government presented a bill to the Congress requesting the reestablishment of obligatory smallpox vaccination. The extremely rigid and severe provisions of this instrument terrified the people. Popular opposition against Oswaldo Cruz increased sharply and opposition newspapers started a violent campaign against this measure and the federal government in general. Members of the parliament and labor unions protested. An Anti-vaccination League was organized.
On November 10th, the Vaccine Revolt exploded in Rio. Violent confrontations with the police ensued, with strikes, barricades, and shootings in the streets, as the population rose in protest against the government. On November 14, the Military Academy adhered to the revolt but the cadets where dispersed after an intense shooting. The government declared a state of siege. On November 16, the uprising was controlled and the obligatory vaccination was suspended. But in 1908, a violent smallpox epidemic made the people rush en masse to the vaccination units and Cruz was vindicated, and his merit recognized.
# Later Work
Among the international scientific community, his prestige was already uncontested. In 1907, on occasion of the 14th International Congress on Hygiene and Demography in Berlin, he was awarded with the gold medal in recognition of the sanitation of Rio de Janeiro. In 1909, Oswaldo Cruz retired from the position as Director General for Public Health, dedicating himself exclusively to the Manguinhos Institute, which has been named after him. From the Institute he organized important scientific expeditions, which allowed a better knowledge about the health and life conditions in the interior of the country and contributed to the colonization of different regions. He eradicated the urban yellow fever in the State of Pará. His sanitation campaign in the state of Amazonas allowed concluding the construction of the Madeira-Mamoré railroad, which was interrupted due to the great number of deaths of malaria and yellow fever among the workers.
In 1913, he was elected a member of the Brazilian Academy of Arts and Letters. In 1915, due to health problems, he resigned from the directorship of the Oswaldo Cruz Institute and moved to Petrópolis, a small city in the mountains near Rio. On August 18, 1916, he was elected mayor of that city and outlined an extensive urbanization project he would not see implemented. In the morning of February 11, 1917, at only 44 years of age, he died of kidney failure.
As a consequence of the short but fruitful life of Dr. Oswaldo Cruz, an extremely important scientific and health institution was born, which marked the beginning of experimental medicine in Brazil in many areas. To this day it exerts a strong influence on Brazilian science, technology and public health. | Oswaldo Cruz
Template:Infobox Scientist
Oswaldo Gonçalves Cruz, better know as Oswaldo Cruz (pron. Template:IPA2), (b. August 5, 1872, São Luíz de Paraitinga, São Paulo state, Brazil; d. February 11, 1917, Petrópolis, Rio de Janeiro state) was a Brazilian physician, bacteriologist, epidemiologist and public health officer and the founder of the Oswaldo Cruz Institute.
# Early Years
Oswaldo Gonçalves Cruz was born on August 5, 1872 in São Luis de Paraitinga, a small city in São Paulo State, to the physician Bento Gonçalvez Cruz and Amália Bulhões Cruz. Still a child, he moved to Rio de Janeiro with his family. At the age of 15 he started to study at the Faculty of Medicine of Rio de Janeiro and in 1892 he graduated as medical doctor with a thesis on water as vehicle for the propagation of microbes. Inspired by the great work of Louis Pasteur, who had developed the germ theory of disease, four years later he went to Paris to specialize in Bacteriology at the Pasteur Institute, which gathered the great names of this branch of science of that time. He was financed by his father-in-law, a wealthy Portuguese merchant.
# Work in Brazil
Cruz found the seaport of Santos ravaged by a violent epidemic of bubonic plague that threatened to reach Rio de Janeiro and engaged himself immediately in the combat of this disease. The mayor of Rio de Janeiro authorized the construction of a plant for manufacturing the serum against the disease which had been developed at the Pasteur Institute by Alexandre Yersin and coworkers, and asked the institution for a scientist who could bring to Brazil this know-how. The Pasteur Institute responded that such a person was already available in Brazil and he was Dr. Oswaldo Cruz.
Thus, on May 25, 1900, the Federal Serotherapy Institute destined to the production of sera and vaccines against the bubonic plague was created with the Baron Pedro Afonso as Director General and the young bacteriologist Oswaldo Cruz as Technical Director. The new Institute was established in the old farm of Manguinhos at the western shores of Guanabara Bay. In 1902, Cruz accepted the office of Director General of the new institute and soon amplified its scope of activities, now no longer restricted to the production of sera but also dedicated to basic and applied research and to the building of human resources. In the following year, Oswaldo Cruz was appointed Director General of Public Health, a position corresponding to that of a today's Minister of Health. Using the Federal Serotherapy Institute as technical-scientific base, he started a quick succession of memorable sanitation campaigns. His first adversary: a series of yellow fever endemics, which had earned Rio de Janeiro the sinister reputation of Foreigners' Grave. Between 1897 and 1906, 4,000 European immigrants had died there from this disease.
Cruz was initially successful in the sanitary campaign against the bubonic plague, to which end he used obligatory notification of cases, isolation of sick people, treatment with the sera produced at Manguinhos and extermination of the rats populating the city.
# Smallpox Vaccination Controversy
In 1904, a smallpox epidemic was threatening the capital. In the course of the first five months of that year, more than 1,800 persons had already been hospitalized. A law imposing smallpox vaccination of children had existed since 1837 but had never had been put into practice. Therefore, on June 9, 1904, following a proposal by Oswaldo Cruz, the government presented a bill to the Congress requesting the reestablishment of obligatory smallpox vaccination. The extremely rigid and severe provisions of this instrument terrified the people. Popular opposition against Oswaldo Cruz increased sharply and opposition newspapers started a violent campaign against this measure and the federal government in general. Members of the parliament and labor unions protested. An Anti-vaccination League was organized.
On November 10th, the Vaccine Revolt exploded in Rio. Violent confrontations with the police ensued, with strikes, barricades, and shootings in the streets, as the population rose in protest against the government. On November 14, the Military Academy adhered to the revolt but the cadets where dispersed after an intense shooting. The government declared a state of siege. On November 16, the uprising was controlled and the obligatory vaccination was suspended. But in 1908, a violent smallpox epidemic made the people rush en masse to the vaccination units and Cruz was vindicated, and his merit recognized.
# Later Work
Among the international scientific community, his prestige was already uncontested. In 1907, on occasion of the 14th International Congress on Hygiene and Demography in Berlin, he was awarded with the gold medal in recognition of the sanitation of Rio de Janeiro. In 1909, Oswaldo Cruz retired from the position as Director General for Public Health, dedicating himself exclusively to the Manguinhos Institute, which has been named after him. From the Institute he organized important scientific expeditions, which allowed a better knowledge about the health and life conditions in the interior of the country and contributed to the colonization of different regions. He eradicated the urban yellow fever in the State of Pará. His sanitation campaign in the state of Amazonas allowed concluding the construction of the Madeira-Mamoré railroad, which was interrupted due to the great number of deaths of malaria and yellow fever among the workers.
In 1913, he was elected a member of the Brazilian Academy of Arts and Letters. In 1915, due to health problems, he resigned from the directorship of the Oswaldo Cruz Institute and moved to Petrópolis, a small city in the mountains near Rio. On August 18, 1916, he was elected mayor of that city and outlined an extensive urbanization project he would not see implemented. In the morning of February 11, 1917, at only 44 years of age, he died of kidney failure.
As a consequence of the short but fruitful life of Dr. Oswaldo Cruz, an extremely important scientific and health institution was born, which marked the beginning of experimental medicine in Brazil in many areas. To this day it exerts a strong influence on Brazilian science, technology and public health. | https://www.wikidoc.org/index.php/Oswaldo_Cruz | |
6eb96ef5061d8b95f652321d6c511e608e5bd1b8 | wikidoc | Otosclerosis | Otosclerosis
Synonyms and keywords:
# Overview
Otosclerosis is a word derived from the Greek word "sklērós" meaning hardening and oto meaning ear. Otosclerosis is an osseous dyscrasia of the otic capsule, which should be an endochondral dense bony part in the labyrinth, replaced by irregularly laid spongy bone leading to the fixation of stapes. It is one of the most common causes of conductive deafness with normal tympanic membranes. Thereby affecting sound transmission to the inner ear at the level of the oval window Though majority of cases are observed at the oval window, otosclerosis can also affect the round window, cochlear apex, posterior to the oval window, posterior and anterior wall of the internal auditory canal (IAC), cochlear aqueduct, semicircular canals, and within the stapes footplate. It can be asymptomatic or in advanced cases extend into the bony labyrinth and affect cochlea which causes mixed conductive and sensorineural hearing loss depending on the position of foci. Otosclerosis is common in Caucasians and predominantly women. Hormonal fluctuations in women like during pregnancy and menopause may aggravate the disease. Many genetic factors contribute to the development of otosclerosis. And it is an autosomal dominant inheritance with incomplete penetrance. Measles was found to be one of the reasons for otosclerosis. Other factors include inflammatory cytokine and cytotoxic mediators secondary to inflammation. (CT) scanning of the temporal bone can often demonstrate foci of demineralization in the otic capsule in cases of cochlear otosclerosis. The treatment for hearing loss is essentially stapes surgery with successful improvement of 90%-95% in the first 5 years; decreases to 63% after 30years and rarely need revision surgery. Additionally, hearing aid and cochlear implants could be used along with surgery.
# Historical Perspective
- 1704:Antonio Maria Valsalva identified fixation of stapes as a cause of hearing loss..
- 1841:Toyn bee stated, "osseous ankylosis of the stapes to the fenestra ovalis as one of the causes of deafness".
- 1876:Johannes Kessel described stapes surgery as the treatment.
- 1930-1950: Used Julius Lempert’s single-stage fenestration of stapes as treatment.
- 1956:John Shea modernized stapedectomy.
# Classification
- Grade 1: Fenestral Otosclerosis
- Grade 2: Cochlear Otosclerosis
Grade 2A:Basal cochlear turn Otosclerosis
Grade 2B:Middle/Apical turn Otosclerosis
Grade 2C:Both Basal and Middle/apical Otosclerosis
- Grade 2A:Basal cochlear turn Otosclerosis
- Grade 2B:Middle/Apical turn Otosclerosis
- Grade 2C:Both Basal and Middle/apical Otosclerosis
- Grade 3:Diffuse confluent cochlear involvement (with or without fenestral involvement)
# Pathophysiology
## Embryology
Table explains the embryological process for the development of bony labyrinth
- In certain cases, completion of the third stage of bone formation doesn't occur leading to cartilages between bony structures.
- During labyrinth bone formation, the anterior to the oval window is usually the last area to develop. This area is the most common site for otosclerosis.
## Pathogenesis
- Accumulation of bone deposits because of increased bone remodeling which is bone resorption followed by bone deposition in the otic capsule result in otosclerosis.
- Audiological findings are directly proportionate to the extent of bone remodeling.
- Bone remodeling happens in 3 phases:
- The lesions occur mostly in the anterior to the oval window by calcifying of annular ligament or by involving stapes footplate (80%).
- While 30% of cases have the lesion at the round window,21% have it at peri cochlear region, and 19% at the anterior segment of the internal auditory canal.
## Associated Conditions
Conditions associated with otosclerosis include:
- Pregnancy
- Measles
- Trauma and Major surgeries also cause otosclerosis.
- Autoimmune
# Causes
Common causes of otosclerosis include:
- During the maturation of the otic capsule of the labyrinth, certain places skip the complete conversion to endochondral, leading to irregularly laid spongy bone. This most commonly is seen at fissula ante fenestram.
- Studies have been conducted and found Type 1 collagen gene(COL1A1), a component essential for bone metabolism plays a role in otosclerosis.
- TGF-beta 1(BMP 2 and BMP 4 gene and Angiotensin II (AGT M235T and ACE I/D genes) are also found associated with otosclerosis.
- Other genetic causes for otosclerosis include sex hormones, autoimmune reaction, human leucocyte antigen, inflammatory and regulatory cytokines, parathyroid hormone, and expression of parathyroid hormone-related peptides receptors, and oxidative stress
# Differentiating otosclerosis from other diseases
# Epidemiology and Demographics
- Though a variable pattern of inheritance is observed, 60% of patients report a family with a history of otosclerosis. Thus researchers conclude this condition as an autosomal dominant with incomplete penetrance.
- Greater preponderance in women compared to men in a ratio of 2:1.
- Even though the disease begins in the second and third decade of life, it doesn't result in hearing loss until the fourth decade.
- Clinical prevalence of otosclerosis is found to be higher in Caucasians by 0.04%-1% while the histological incidence of otosclerosis increases to 10% in the same..The incidence of histological otosclerosis is 1% and 5% in African and Asian population respectively.
# Risk Factors
Common risk factors in the development of otosclerosis include.
- Genetic factor
- Hormonal conditions
- Measles
# Screening
Even though otosclerosis appears to be genetic deafness, early prevention can help in combating the disorder and its prevention.
- Systematic Impedance-audiometry screening: The purpose of this screening is to detect a possible diphasic impedance change (on-off effect) by eliciting stapedius reflex. It is done in school going-children and helps in the early detection of stapedial fixation.
- Systematic Bone-conducted audiometry screening: It is done in young children with a family history of otosclerosis.
# Natural History, Complications, and Prognosis
## Complications
Post-op complications of otosclerosis include:
- Perilymph fistula: Progressive hearing loss, Tinnitus, or vertigo.
- Taste disturbance
- Facial nerve injury
- Sensorineural hearing loss
- Post stapedectomy granulomas
- Vertigo
## Prognosis
- Most of the patients find improvement in their hearing ability after the surgery.
- Only a few don't have any change post-surgery and rarely hearing loss worsens.
- There have been cases where the prosthesis was found displaced from its original position, causing conductive hearing loss again in some patients.
- The second surgery was observed to be less successful than the first.
# Diagnosis
## Diagnostic Study of Choice
There are no established criteria for the diagnosis of otosclerosis.
## History and Symptoms
Patients present with the following:
- Most cases are asymptomatic and diagnosed as an incidental finding in temporal autopsies.
- Bilateral(80%) or unilateral involvement earlier in the disease.
- Progressive hearing loss, which might worsen with lower tone and frequencies like male voices and vowels.
- vertigo(10%)
- tinnitus (50%)
- Schwartz sign or flamingos pink sign(not necessary for diagnosis): redness along the promontory of tympanic membrane on otoscopic examination
## Physical Examination
### Tuning fork
- Pros of using a tuning fork for diagnosis:
Negative Rinne test
Weber test lateralizes to the ear with severe conductive loss.
- Negative Rinne test
- Weber test lateralizes to the ear with severe conductive loss.
- Cons of using tuning fork for diagnosis
Rinne test cannot differentiate between sensorineural hearing loss and normal hearing loss.
Weber test's inability to differentiate a bilateral hearing loss.
- Rinne test cannot differentiate between sensorineural hearing loss and normal hearing loss.
- Weber test's inability to differentiate a bilateral hearing loss.
## Audiometry and tympanometry
- Carhart's notch: Bone conduction depression in threshold at 2000 Hz.
- After stapedectomy carhart's notch disappears.
- Tympanometry normal at early disease.
- In severe cases, flattening and stiffening of curve representing low compliance of ossicular chain and tympanic membrane.
- Good test to differentiate between otosclerosis and pathologies with low resonance.
## Laboratory Findings
There are no diagnostic laboratory findings associated with otosclerosis.
## Electrocardiogram
There are no ECG findings associated with otosclerosis.
## X-ray
There are no x-ray findings associated with otosclerosis.
## Echocardiography or Ultrasound
There are no echocardiography/ultrasound findings associated with otosclerosis.
## CT scan
- High resolution computed tomography (CT) of the temporal bones is the imaging technique of choice in the diagnosis of otosclerosis.
- However, preoperative CT has little to add in establishing otosclerosis diagnosis and may not even be necessary to confirm diagnosis.
- CT is recommended to be reserved for those patients with presumed additional abnormalities, for specific preoperative planning, or for legal necessity.
- Common CT findings diagnostic of otosclerosis include increased bony radiolucency in the otic capsule around the anterior footplate, thickening of the stapes, and widening of the oval window.
- Early sign on CT: halo sign; demineralized area outlining the cochlea.
## MRI
There are no MRI findings associated with otosclerosis.
## Other Imaging Findings
There are no other imaging findings associated with otosclerosis.
## Other Diagnostic Studies
There are no other diagnostic studies associated with otosclerosis.
# Treatment
Surgery is the mainstay of treatment for otosclerosis.
## Medical Therapy
- Sodium fluoride: Though controversial, it is used to slow the progression of otosclerosis.
- Bisphosphonates: By inducing osteoclastic apoptosis, bisphosphonates cause antiresorptive action, with promising results.
## Surgery
- Stapedotomy or Stapedectomy along with placement of a prosthesis, has shown a good prognosis with improved hearing ability.
- Only rare cases have shown no benefit.
- Revision surgery is controversial but proposed for patients with no improvement of hearing loss, facial nerve damage, or persistent vertigo.
- Most common cause of stapedectomy failure is prosthesis displacement with or without incus erosion.
- Revision surgery is also recommended post surgery for patients with footplate fixation, perilymph fistula, otosclerotic regrowth.
- Post surgery, some are still encouraged to use a hearing aid.
## Primary Prevention
Otosclerosis cannot be prevented but early detection of the disease can help in combating the disease better.
## Secondary Prevention
There are no established measures for the secondary prevention of otosclerosis. | Otosclerosis
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: CSN, M.D.
Synonyms and keywords:
# Overview
Otosclerosis is a word derived from the Greek word "sklērós" meaning hardening and oto meaning ear. Otosclerosis is an osseous dyscrasia of the otic capsule, which should be an endochondral dense bony part in the labyrinth, replaced by irregularly laid spongy bone leading to the fixation of stapes. It is one of the most common causes of conductive deafness with normal tympanic membranes. Thereby affecting sound transmission to the inner ear at the level of the oval window Though majority of cases are observed at the oval window, otosclerosis can also affect the round window, cochlear apex, posterior to the oval window, posterior and anterior wall of the internal auditory canal (IAC), cochlear aqueduct, semicircular canals, and within the stapes footplate. It can be asymptomatic or in advanced cases extend into the bony labyrinth and affect cochlea which causes mixed conductive and sensorineural hearing loss depending on the position of foci. Otosclerosis is common in Caucasians and predominantly women. Hormonal fluctuations in women like during pregnancy and menopause may aggravate the disease. Many genetic factors contribute to the development of otosclerosis. And it is an autosomal dominant inheritance with incomplete penetrance. Measles was found to be one of the reasons for otosclerosis. Other factors include inflammatory cytokine and cytotoxic mediators secondary to inflammation. (CT) scanning of the temporal bone can often demonstrate foci of demineralization in the otic capsule in cases of cochlear otosclerosis. The treatment for hearing loss is essentially stapes surgery with successful improvement of 90%-95% in the first 5 years; decreases to 63% after 30years and rarely need revision surgery. Additionally, hearing aid and cochlear implants could be used along with surgery.
# Historical Perspective
- 1704:Antonio Maria Valsalva identified fixation of stapes as a cause of hearing loss.[1][2][3].
- 1841:Toyn bee stated, "osseous ankylosis of the stapes to the fenestra ovalis as one of the causes of deafness".
- 1876:Johannes Kessel described stapes surgery as the treatment.
- 1930-1950: Used Julius Lempert’s single-stage fenestration of stapes as treatment.
- 1956:John Shea modernized stapedectomy.
# Classification
- Grade 1: Fenestral Otosclerosis
- Grade 2: Cochlear Otosclerosis
Grade 2A:Basal cochlear turn Otosclerosis
Grade 2B:Middle/Apical turn Otosclerosis
Grade 2C:Both Basal and Middle/apical Otosclerosis
- Grade 2A:Basal cochlear turn Otosclerosis
- Grade 2B:Middle/Apical turn Otosclerosis
- Grade 2C:Both Basal and Middle/apical Otosclerosis
- Grade 3:Diffuse confluent cochlear involvement (with or without fenestral involvement)
# Pathophysiology
## Embryology
Table explains the embryological process for the development of bony labyrinth
- In certain cases, completion of the third stage of bone formation doesn't occur leading to cartilages between bony structures.[5][6]
- During labyrinth bone formation, the anterior to the oval window is usually the last area to develop. This area is the most common site for otosclerosis.
## Pathogenesis
- Accumulation of bone deposits because of increased bone remodeling which is bone resorption followed by bone deposition in the otic capsule result in otosclerosis.[7]
- Audiological findings are directly proportionate to the extent of bone remodeling.[8][9]
- Bone remodeling happens in 3 phases:
- The lesions occur mostly in the anterior to the oval window by calcifying of annular ligament or by involving stapes footplate (80%).
- While 30% of cases have the lesion at the round window,21% have it at peri cochlear region, and 19% at the anterior segment of the internal auditory canal.
## Associated Conditions
Conditions associated with otosclerosis include:[10]
- Pregnancy
- Measles
- Trauma and Major surgeries also cause otosclerosis.
- Autoimmune
# Causes
Common causes of otosclerosis include:
- During the maturation of the otic capsule of the labyrinth, certain places skip the complete conversion to endochondral, leading to irregularly laid spongy bone. This most commonly is seen at fissula ante fenestram.[13]
- Studies have been conducted and found Type 1 collagen gene(COL1A1), a component essential for bone metabolism plays a role in otosclerosis.[14]
- TGF-beta 1(BMP 2 and BMP 4 gene and Angiotensin II (AGT M235T and ACE I/D genes) are also found associated with otosclerosis.[15][16]
- Other genetic causes for otosclerosis include sex hormones, autoimmune reaction, human leucocyte antigen, inflammatory and regulatory cytokines, parathyroid hormone, and expression of parathyroid hormone-related peptides receptors, and oxidative stress
# Differentiating otosclerosis from other diseases
# Epidemiology and Demographics
- Though a variable pattern of inheritance is observed, 60% of patients report a family with a history of otosclerosis. Thus researchers conclude this condition as an autosomal dominant with incomplete penetrance.
- Greater preponderance in women compared to men in a ratio of 2:1.
- Even though the disease begins in the second and third decade of life, it doesn't result in hearing loss until the fourth decade.
- Clinical prevalence of otosclerosis is found to be higher in Caucasians by 0.04%-1% while the histological incidence of otosclerosis increases to 10% in the same..The incidence of histological otosclerosis is 1% and 5% in African and Asian population respectively.
# Risk Factors
Common risk factors in the development of otosclerosis include[17].
- Genetic factor
- Hormonal conditions
- Measles
# Screening
Even though otosclerosis appears to be genetic deafness, early prevention can help in combating the disorder and its prevention.[20]
- Systematic Impedance-audiometry screening: The purpose of this screening is to detect a possible diphasic impedance change (on-off effect) by eliciting stapedius reflex. It is done in school going-children and helps in the early detection of stapedial fixation.
- Systematic Bone-conducted audiometry screening: It is done in young children with a family history of otosclerosis.
# Natural History, Complications, and Prognosis
## Complications
Post-op complications of otosclerosis include:[21]
- Perilymph fistula: Progressive hearing loss, Tinnitus, or vertigo.
- Taste disturbance
- Facial nerve injury
- Sensorineural hearing loss
- Post stapedectomy granulomas
- Vertigo
## Prognosis
- Most of the patients find improvement in their hearing ability after the surgery.[22][23]
- Only a few don't have any change post-surgery and rarely hearing loss worsens.
- There have been cases where the prosthesis was found displaced from its original position, causing conductive hearing loss again in some patients.
- The second surgery was observed to be less successful than the first.
# Diagnosis
## Diagnostic Study of Choice
There are no established criteria for the diagnosis of otosclerosis.
## History and Symptoms
Patients present with the following:[24][25]
- Most cases are asymptomatic and diagnosed as an incidental finding in temporal autopsies.
- Bilateral(80%) or unilateral involvement earlier in the disease.
- Progressive hearing loss, which might worsen with lower tone and frequencies like male voices and vowels.
- vertigo(10%)
- tinnitus (50%)
- Schwartz sign or flamingos pink sign(not necessary for diagnosis): redness along the promontory of tympanic membrane on otoscopic examination
## Physical Examination
### Tuning fork
- Pros of using a tuning fork for diagnosis:[26][27]
Negative Rinne test
Weber test lateralizes to the ear with severe conductive loss.
- Negative Rinne test
- Weber test lateralizes to the ear with severe conductive loss.
- Cons of using tuning fork for diagnosis
Rinne test cannot differentiate between sensorineural hearing loss and normal hearing loss.
Weber test's inability to differentiate a bilateral hearing loss.
- Rinne test cannot differentiate between sensorineural hearing loss and normal hearing loss.
- Weber test's inability to differentiate a bilateral hearing loss.
## Audiometry and tympanometry
- Carhart's notch: Bone conduction depression in threshold at 2000 Hz.
- After stapedectomy carhart's notch disappears.[28]
- Tympanometry normal at early disease.
- In severe cases, flattening and stiffening of curve representing low compliance of ossicular chain and tympanic membrane.
- Good test to differentiate between otosclerosis and pathologies with low resonance.
## Laboratory Findings
There are no diagnostic laboratory findings associated with otosclerosis.
## Electrocardiogram
There are no ECG findings associated with otosclerosis.
## X-ray
There are no x-ray findings associated with otosclerosis.
## Echocardiography or Ultrasound
There are no echocardiography/ultrasound findings associated with otosclerosis.
## CT scan
- High resolution computed tomography (CT) of the temporal bones is the imaging technique of choice in the diagnosis of otosclerosis.[29][30]
- However, preoperative CT has little to add in establishing otosclerosis diagnosis and may not even be necessary to confirm diagnosis.
- CT is recommended to be reserved for those patients with presumed additional abnormalities, for specific preoperative planning, or for legal necessity.
- Common CT findings diagnostic of otosclerosis include increased bony radiolucency in the otic capsule around the anterior footplate, thickening of the stapes, and widening of the oval window.
- Early sign on CT: halo sign; demineralized area outlining the cochlea.
## MRI
There are no MRI findings associated with otosclerosis.
## Other Imaging Findings
There are no other imaging findings associated with otosclerosis.
## Other Diagnostic Studies
There are no other diagnostic studies associated with otosclerosis.
# Treatment
Surgery is the mainstay of treatment for otosclerosis.[31][32][33][34][35]
## Medical Therapy
- Sodium fluoride: Though controversial, it is used to slow the progression of otosclerosis.[36]
- Bisphosphonates: By inducing osteoclastic apoptosis, bisphosphonates cause antiresorptive action, with promising results.
## Surgery
- Stapedotomy or Stapedectomy along with placement of a prosthesis, has shown a good prognosis with improved hearing ability.[37][38][39]
- Only rare cases have shown no benefit.
- Revision surgery is controversial but proposed for patients with no improvement of hearing loss, facial nerve damage, or persistent vertigo.
- Most common cause of stapedectomy failure is prosthesis displacement with or without incus erosion.
- Revision surgery is also recommended post surgery for patients with footplate fixation, perilymph fistula, otosclerotic regrowth.
- Post surgery, some are still encouraged to use a hearing aid.
## Primary Prevention
Otosclerosis cannot be prevented but early detection of the disease can help in combating the disease better.
## Secondary Prevention
There are no established measures for the secondary prevention of otosclerosis. | https://www.wikidoc.org/index.php/Otosclerosis | |
90c970f26b678e0570c176d537578941736f5753 | wikidoc | Ovarian cyst | Ovarian cyst
# Overview
An ovarian cyst is any collection of fluid, surrounded by a very thin wall, within an ovary. Any ovarian follicle that is larger than about two centimeters is termed an ovarian cyst. An ovarian cyst can be as small as a pea, or as large as a grapefruit.
Most ovarian cysts are functional in nature, and harmless (benign). In the US ovarian cysts are found in nearly all premenopausal women, and in up to 14.8% of postmenopausal women. The incidence of ovarian carcinoma is approximately 15 cases per 100,000 women per year.
Ovarian cysts affect women of all ages. They occur most often, however, during a woman's childbearing years.
Some ovarian cysts cause problems, such as bleeding and pain. Surgery may be required to remove those cysts.
# Types
## Functional cysts
Some, called functional cysts, or simple cysts, are part of the normal process of menstruation. They have nothing to do with disease, and can be treated.
### Graafian follicle cyst
One type of simple cyst, which is the most common type of ovarian cyst, is the graafian follicle cyst, follicular cyst, or dentigerous cyst. This type can form when ovulation doesn't occur, and a follicle doesn't rupture or release its egg but instead grows until it becomes a cyst, or when a mature follicle involutes (collapses on itself). It usually forms during ovulation, and can grow to about 2.3 inches in diameter. It is thin-walled, lined by one or more layers of granulosa cell, and filled with clear fluid. Its rupture can create sharp, severe pain on the side of the ovary on which the cyst appears. This sharp pain (sometimes called mittelschmerz) occurs in the middle of the menstrual cycle, during ovulation. About a fourth of women with this type of cyst experience pain. Usually, these cysts produce no symptoms and disappear by themselves within a few months. Ultrasound is the primary tool used to document the follicular cyst. A pelvic exam will also aid in the diagnosis if the cyst is large enough to be seen. A doctor monitors these to make sure they disappear, and looks at treatment options if they do not.
### Corpus luteum cyst
Another is a corpus luteum cyst (which may rupture about the time of menstruation, and take up to three months to disappear entirely). This type of functional cyst occurs after an egg has been released from a follicle. The follicle then becomes a new, temporarily little secretory gland that is known as a corpus luteum. The ruptured follicle begins producing large quantities of estrogen and progesterone in preparation for conception. If a pregnancy doesn't occur, the corpus luteum usually breaks down and disappears. It may, however, fill with fluid or blood, causing the corpus luteum to expand into a cyst, and stay on the ovary. Usually, this cyst is on only one side, and does not produce any symptoms. It can however grow to almost 4 inches in diameter and has the potential to bleed into itself or twist the ovary, causing pelvic or abdominal pain. If it fills with blood, the cyst may rupture, causing internal bleeding and sudden, sharp pain. The fertility drug clomiphene citrate (Clomid, Serophene), used to induce ovulation, increases the risk of a corpus luteum cyst developing after ovulation. These cysts don't prevent or threaten a resulting pregnancy. Women on birth control pills usually do not form these cysts; in fact, preventing these cysts is one way the pill works.
### Hemorrhagic cyst
A third type of functional cyst, which is common, is a Hemorrhagic cyst, which is also called a blood cyst, hematocele, and hematocyst. It occurs when a very small blood vessel in the wall of the cyst breaks, and the blood enters the cyst. Abdominal pain on one side of the body, often the right side, may be present. The bleeding may occur quickly, and rapidly stretch the covering of the ovary, causing pain. As the blood collects within the ovary, clots form which can be seen on a sonogram. Occasionally hemorrhagic cysts can rupture, with blood entering the abdominal cavity. No blood is seen out of the vagina. If a cyst ruptures, it is usually very painful. Hemorrhagic cysts that rupture are less common. Most hemorrhagic cysts are self-limiting; some need surgical intervention. Even if a hemorrhagic cyst ruptures, in many cases it resolves without surgery. Patients who don't require surgery will experience pain for 4 - 10 days after, and may require several days rest. Studies have found that women on tetracycline antibiotics recover 25% earlier than the majority of patients, a surprising correlation found in 2004. Sometimes surgery is necessary, such as a laparoscopy ("belly-button surgery" that uses small tools inserted through one or more tiny slits in the abdomen).
## Dermoid cyst
A dermoid cyst, also called a dermoid or mature cystic teratoma, is an abnormal relatively rare cyst that usually affects women during their childbearing years (15-40; the average age is 30), is usually benign, and can range in size from half an inch to 17 inches in diameter. It is similar to those present on skin tissue, and can contain fat and occasionally hair, bone, nails, teeth, eyes, cartilage, and thyroid tissue. Up to 10-15% of women with them have them in both ovaries. It develops from a totipotential germ cell (a primary oocyte) that is retained within the ovary. A CT scan and MRI can show the presence of fat and dense calcifications. Though it often does not cause any symptoms, it can on the other hand become inflamed, and can also twist around (a condition known as ovarian torsion), causing severe abdominal pain and imperiling its blood supply, which is an emergency and calls for urgent surgery. These cysts can generally be removed easily, which is usually the treatment of choice, with either conventional surgery (laparotomy; open surgery) or laparoscopy. Removal does not generally affect fertility. The larger it is, the greater the risk of rupture with spillage of the contents, which can create problems with adhesions and pain. Although the large majority (about 98%) are benign, the remaining fraction (about 2%) becomes cancerous (malignant) -- those are usually in women over 40.
## Endometrioid cyst
An endometrioma, endometrioid cyst, endometrial cyst, or chocolate cyst is caused by endometriosis, and formed when a tiny patch of endometrial tissue (the mucous membrane that makes up the inner layer of the uterine wall) bleeds, sloughs off, becomes transplanted, and grows and enlarges inside the ovaries. As the blood builds up over months and years, it turns brown. When it ruptures, the material spills over into the pelvis and onto the surface of the uterus, bladder, bowel, and the corresponding spaces between. Treatment for endometriosis can be medical or surgical. Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently used first in patients with pelvic pain, particularly if the diagnosis of endometriosis has not been definitively established. The goal of directed medical treatment is to achieve an anovulatory state. Typically, this is achieved initially using hormonal contraception. This can also be accomplished with progestational agents (i.e., medroxyprogesterone), danazol, gestrinone, or gonadotropin-releasing hormone agonists (GnRH), as well as other less well-known agents. These agents are generally used if oral contraceptives and NSAIDs are ineffective. GnRH can be combined with estrogen and progestogen (add-back therapy) without loss of efficacy but with fewer hypoestrogenic symptoms. Laparoscopic surgical approaches include ablation of implants, lysis of adhesions, removal of endometriomas, uterosacral nerve ablation, and presacral neurectomy. They frequently require surgical removal. Conservative surgery can be performed to preserve fertility in young patients. Laparoscopic surgery provides pain relief and improved fertility over diagnostic laparoscopy without surgery. Definitive surgery is a hysterectomy and bilateral oophorectomy.
## Pathological cysts
Other cysts are pathological, such as those found in polycystic ovary syndrome, or those associated with tumors.
A polycystic-appearing ovary is diagnosed based on its enlarged size — usually twice normal —with small cysts present around the outside of the ovary. It can be found in "normal" women, and in women with endocrine disorders. An ultrasound is used to view the ovary in diagnosing the condition. Polycystic-appearing ovary is different from the polycystic ovarian syndrome, which includes other symptoms in addition to the presence of ovarian cysts, and involves metabolic and cardiovascular risks linked to insulin resistance. These risks include increased glucose tolerance, type 2 diabetes, and high blood pressure. Polycystic ovarian syndrome is associated with infertility, abnormal bleeding, increased incidences of pregnancy loss, and pregnancy-related complications. Polycystic ovarian syndrome is extremely common, is thought to occur in 4-7% of women of reproductive age, and is associated with an increased risk for endometrial cancer. More tests than an ultrasound alone are required to diagnose polycystic ovarian syndrome.
# Ovarian cyst differential diagnosis
# Symptoms
Some or all of the following symptoms may be present, though it is possible not to experience any symptoms:
- Dull aching, or severe, sudden, and sharp pain or discomfort in the lower abdomen (one or both sides), pelvis, vagina, lower back, or thighs; pain may be constant or intermittent -- this is the most common symptom
- Fullness, heaviness, pressure, swelling, or bloating in the abdomen
- Breast tenderness
- Pain during or shortly after beginning or end of menstrual period
- Irregular periods, or abnormal uterine bleeding or spotting
- Change in frequency or ease of urination (such as inability to fully empty the bladder), or difficulty with bowel movements due to pressure on adjacent pelvic anatomy
- Weight gain
- Nausea or vomiting
- Fatigue
- Infertility
- Increased level of hair growth
- Increased facial hair or body hair
# Imaging studies
CT and US images demonstrate a right ovarian cyst
## Imaging Findings for Hemorrhagic ovarian cyst
- Hemorrhagic cysts have a variety of appearances depending on the stage of evolution of the clot.
- Most typically appearance: lacelike reticular echoes or an intracystic solid clot are most typical.
- Complex cysts with such appearances should lead to follow-up US or further assessment with MR imaging.
- The most helpful feature in distinguishing hemorrhagic cysts from ovarian neoplasms is the presence of papillary projections and nodular septa in the latter.
Patient #1
Patient #2: Lacelike internal echos are noted in this hemorrhage ovarian cyst
# Treatment
About 95% of ovarian cysts are benign, meaning they are not cancerous.
Treatment for cysts depends on the size of the cyst and symptoms. For small, asymptomatic cysts, the wait and see approach with regular check-ups will most likely be recommended.
Pain caused by ovarian cysts may be treated with:
- pain relievers, including nonsteroidal anti-inflammatory drugs such as ibuprofen (Motrin, Advil), acetaminophen (Tylenol), or narcotic pain medicine (by prescription) may help reduce pelvic pain. NSAIDs usually work best when taken at the first signs of the pain.
- a warm bath, or heating pad, or hot water bottle applied to the lower abdomen near the ovaries can relax tense muscles and relieve cramping, lessen discomfort, and stimulate circulation and healing in the ovaries. Bags of ice covered with towels can be used alternately as cold treatments to increase local circulation.
- chamomile herbal tea (Matricaria recutita) can reduce ovarian cyst pain and soothe tense muscles.
- urinating as soon as the urge presents itself.
- avoiding constipation, which does not cause ovarian cysts but may further increase pelvic discomfort.
- in diet, eliminating caffeine and alcohol, reducing sugars, increasing foods rich in vitamin A and carotenoids (e.g., carrots, tomatoes, and salad greens) and B vitamins (e.g., whole grains).
- combined methods of hormonal contraception such as the combined oral contraceptive pill -- the hormones in the pills may regulate the menstrual cycle, prevent the formation of follicles that can turn into cysts, and possibly shrink an existing cyst. (American College of Obstetricians and Gynecologists, 1999c; Mayo Clinic, 2002e)
Also, limiting strenuous activity may reduce the risk of cyst rupture or torsion.
Cysts that persist beyond two or three menstrual cycles, or occur in post-menopausal women, may indicate more serious disease and should be investigated through ultrasonography and laparoscopy, especially in cases where family members have had ovarian cancer. Such cysts may require surgical biopsy. Additionally, a blood test may be taken before surgery to check for elevated CA-125, a tumor marker, which is often found in increased levels in ovarian cancer, although it can also be elevated by other conditions resulting in a large number of false positives.
For more serious cases where cysts are large and persisting, doctors may suggest surgery. Some surgeries can be performed to successfully remove the cyst(s) without hurting the ovaries, while others may require removal of one or both ovaries.
### Contraindicated medications
Ovarian cyst is considered an absolute contraindication to the use of the following medications:
- Clomifene
- Choriogonadotropin alfa
- Follitropin beta
- Urofollitropin
it:Cisti ovarica
- ↑ Morin L, Cargill YM, Glanc P (2016). "Ultrasound Evaluation of First Trimester Complications of Pregnancy". J Obstet Gynaecol Can. 38 (10): 982–988. doi:10.1016/j.jogc.2016.06.001. PMID 27720100..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}
- ↑ Balthazar EJ, Birnbaum BA, Yee J, Megibow AJ, Roshkow J, Gray C (1994). "Acute appendicitis: CT and US correlation in 100 patients". Radiology. 190 (1): 31–5. doi:10.1148/radiology.190.1.8259423. PMID 8259423.
- ↑ Bottomley C, Bourne T (2009). "Diagnosis and management of ovarian cyst accidents". Best Pract Res Clin Obstet Gynaecol. 23 (5): 711–24. doi:10.1016/j.bpobgyn.2009.02.001. PMID 19299205.
- ↑ Jump up to: 4.0 4.1 4.2 Bhavsar AK, Gelner EJ, Shorma T (2016). "Common Questions About the Evaluation of Acute Pelvic Pain". Am Fam Physician. 93 (1): 41–8. PMID 26760839.
- ↑ {{Cite journal
| author = W. E. Stamm
| title = Etiology and management of the acute urethral syndrome
| journal = Sexually transmitted diseases
| volume = 8
| issue = 3
| pages = 235–238
| year = 1981
| month = July-September
| pmid = 7292216
- ↑ {{Cite journal
| author = W. E. Stamm, K. F. Wagner, R. Amsel, E. R. Alexander, M. Turck, G. W. Counts & K. K. Holmes
| title = Causes of the acute urethral syndrome in women
| journal = The New England journal of medicine
| volume = 303
| issue = 8
| pages = 409–415
| year = 1980
| month = August
| doi = 10.1056/NEJM198008213030801
| pmid = 6993946 | Ovarian cyst
For patient information, click here
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
An ovarian cyst is any collection of fluid, surrounded by a very thin wall, within an ovary. Any ovarian follicle that is larger than about two centimeters is termed an ovarian cyst. An ovarian cyst can be as small as a pea, or as large as a grapefruit.
Most ovarian cysts are functional in nature, and harmless (benign).[2] In the US ovarian cysts are found in nearly all premenopausal women, and in up to 14.8% of postmenopausal women. The incidence of ovarian carcinoma is approximately 15 cases per 100,000 women per year.[3]
Ovarian cysts affect women of all ages. They occur most often, however, during a woman's childbearing years.
Some ovarian cysts cause problems, such as bleeding and pain. Surgery may be required to remove those cysts.
# Types
## Functional cysts
Some, called functional cysts, or simple cysts, are part of the normal process of menstruation. They have nothing to do with disease, and can be treated.
### Graafian follicle cyst
One type of simple cyst, which is the most common type of ovarian cyst, is the graafian follicle cyst, follicular cyst, or dentigerous cyst. This type can form when ovulation doesn't occur, and a follicle doesn't rupture or release its egg but instead grows until it becomes a cyst, or when a mature follicle involutes (collapses on itself). It usually forms during ovulation, and can grow to about 2.3 inches in diameter. It is thin-walled, lined by one or more layers of granulosa cell, and filled with clear fluid. Its rupture can create sharp, severe pain on the side of the ovary on which the cyst appears. This sharp pain (sometimes called mittelschmerz) occurs in the middle of the menstrual cycle, during ovulation. About a fourth of women with this type of cyst experience pain. Usually, these cysts produce no symptoms and disappear by themselves within a few months. Ultrasound is the primary tool used to document the follicular cyst. A pelvic exam will also aid in the diagnosis if the cyst is large enough to be seen. A doctor monitors these to make sure they disappear, and looks at treatment options if they do not.[4][5][6][7][8][9][10]
### Corpus luteum cyst
Another is a corpus luteum cyst (which may rupture about the time of menstruation, and take up to three months to disappear entirely). This type of functional cyst occurs after an egg has been released from a follicle. The follicle then becomes a new, temporarily little secretory gland that is known as a corpus luteum. The ruptured follicle begins producing large quantities of estrogen and progesterone in preparation for conception. If a pregnancy doesn't occur, the corpus luteum usually breaks down and disappears. It may, however, fill with fluid or blood, causing the corpus luteum to expand into a cyst, and stay on the ovary. Usually, this cyst is on only one side, and does not produce any symptoms.[11][12][13] It can however grow to almost 4 inches in diameter and has the potential to bleed into itself or twist the ovary, causing pelvic or abdominal pain. If it fills with blood, the cyst may rupture, causing internal bleeding and sudden, sharp pain. The fertility drug clomiphene citrate (Clomid, Serophene), used to induce ovulation, increases the risk of a corpus luteum cyst developing after ovulation. These cysts don't prevent or threaten a resulting pregnancy.[14][15] Women on birth control pills usually do not form these cysts; in fact, preventing these cysts is one way the pill works.[16]
### Hemorrhagic cyst
A third type of functional cyst, which is common, is a Hemorrhagic cyst, which is also called a blood cyst, hematocele, and hematocyst.[17] It occurs when a very small blood vessel in the wall of the cyst breaks, and the blood enters the cyst. Abdominal pain on one side of the body, often the right side, may be present. The bleeding may occur quickly, and rapidly stretch the covering of the ovary, causing pain. As the blood collects within the ovary, clots form which can be seen on a sonogram.[18] Occasionally hemorrhagic cysts can rupture, with blood entering the abdominal cavity. No blood is seen out of the vagina. If a cyst ruptures, it is usually very painful. Hemorrhagic cysts that rupture are less common. Most hemorrhagic cysts are self-limiting; some need surgical intervention. Even if a hemorrhagic cyst ruptures, in many cases it resolves without surgery. Patients who don't require surgery will experience pain for 4 - 10 days after, and may require several days rest. Studies have found that women on tetracycline antibiotics recover 25% earlier than the majority of patients, a surprising correlation found in 2004. Sometimes surgery is necessary,[19][20] such as a laparoscopy ("belly-button surgery" that uses small tools inserted through one or more tiny slits in the abdomen).[21]
## Dermoid cyst
A dermoid cyst, also called a dermoid or mature cystic teratoma, is an abnormal relatively rare cyst that usually affects women during their childbearing years (15-40; the average age is 30), is usually benign, and can range in size from half an inch to 17 inches in diameter. It is similar to those present on skin tissue, and can contain fat and occasionally hair, bone, nails, teeth, eyes, cartilage, and thyroid tissue. Up to 10-15% of women with them have them in both ovaries. It develops from a totipotential germ cell (a primary oocyte) that is retained within the ovary. A CT scan and MRI can show the presence of fat and dense calcifications. Though it often does not cause any symptoms, it can on the other hand become inflamed, and can also twist around (a condition known as ovarian torsion), causing severe abdominal pain and imperiling its blood supply, which is an emergency and calls for urgent surgery. These cysts can generally be removed easily, which is usually the treatment of choice, with either conventional surgery (laparotomy; open surgery) or laparoscopy. Removal does not generally affect fertility. The larger it is, the greater the risk of rupture with spillage of the contents, which can create problems with adhesions and pain. Although the large majority (about 98%) are benign, the remaining fraction (about 2%) becomes cancerous (malignant) -- those are usually in women over 40. [22][23][24][25]
## Endometrioid cyst
An endometrioma, endometrioid cyst, endometrial cyst, or chocolate cyst is caused by endometriosis, and formed when a tiny patch of endometrial tissue (the mucous membrane that makes up the inner layer of the uterine wall) bleeds, sloughs off, becomes transplanted, and grows and enlarges inside the ovaries. As the blood builds up over months and years, it turns brown. When it ruptures, the material spills over into the pelvis and onto the surface of the uterus, bladder, bowel, and the corresponding spaces between. Treatment for endometriosis can be medical or surgical. Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently used first in patients with pelvic pain, particularly if the diagnosis of endometriosis has not been definitively established. The goal of directed medical treatment is to achieve an anovulatory state. Typically, this is achieved initially using hormonal contraception. This can also be accomplished with progestational agents (i.e., medroxyprogesterone), danazol, gestrinone, or gonadotropin-releasing hormone agonists (GnRH), as well as other less well-known agents. These agents are generally used if oral contraceptives and NSAIDs are ineffective. GnRH can be combined with estrogen and progestogen (add-back therapy) without loss of efficacy but with fewer hypoestrogenic symptoms. Laparoscopic surgical approaches include ablation of implants, lysis of adhesions, removal of endometriomas, uterosacral nerve ablation, and presacral neurectomy. They frequently require surgical removal. Conservative surgery can be performed to preserve fertility in young patients. Laparoscopic surgery provides pain relief and improved fertility over diagnostic laparoscopy without surgery. Definitive surgery is a hysterectomy and bilateral oophorectomy.
[26][27][28][29][30]
## Pathological cysts
Other cysts are pathological, such as those found in polycystic ovary syndrome, or those associated with tumors.
A polycystic-appearing ovary is diagnosed based on its enlarged size — usually twice normal —with small cysts present around the outside of the ovary. It can be found in "normal" women, and in women with endocrine disorders. An ultrasound is used to view the ovary in diagnosing the condition. Polycystic-appearing ovary is different from the polycystic ovarian syndrome, which includes other symptoms in addition to the presence of ovarian cysts, and involves metabolic and cardiovascular risks linked to insulin resistance. These risks include increased glucose tolerance, type 2 diabetes, and high blood pressure. Polycystic ovarian syndrome is associated with infertility, abnormal bleeding, increased incidences of pregnancy loss, and pregnancy-related complications. Polycystic ovarian syndrome is extremely common, is thought to occur in 4-7% of women of reproductive age, and is associated with an increased risk for endometrial cancer. More tests than an ultrasound alone are required to diagnose polycystic ovarian syndrome.
# Ovarian cyst differential diagnosis
# Symptoms
Some or all of the following symptoms may be present, though it is possible not to experience any symptoms:
- Dull aching, or severe, sudden, and sharp pain or discomfort in the lower abdomen (one or both sides), pelvis, vagina, lower back, or thighs; pain may be constant or intermittent -- this is the most common symptom
- Fullness, heaviness, pressure, swelling, or bloating in the abdomen
- Breast tenderness
- Pain during or shortly after beginning or end of menstrual period
- Irregular periods, or abnormal uterine bleeding or spotting
- Change in frequency or ease of urination (such as inability to fully empty the bladder), or difficulty with bowel movements due to pressure on adjacent pelvic anatomy
- Weight gain
- Nausea or vomiting
- Fatigue
- Infertility
- Increased level of hair growth
- Increased facial hair or body hair
# Imaging studies
CT and US images demonstrate a right ovarian cyst
-
-
-
-
-
## Imaging Findings for Hemorrhagic ovarian cyst
- Hemorrhagic cysts have a variety of appearances depending on the stage of evolution of the clot.
- Most typically appearance: lacelike reticular echoes or an intracystic solid clot are most typical.
- Complex cysts with such appearances should lead to follow-up US or further assessment with MR imaging.
- The most helpful feature in distinguishing hemorrhagic cysts from ovarian neoplasms is the presence of papillary projections and nodular septa in the latter.
Patient #1
-
-
-
Patient #2: Lacelike internal echos are noted in this hemorrhage ovarian cyst
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-
-
# Treatment
About 95% of ovarian cysts are benign, meaning they are not cancerous.
Treatment for cysts depends on the size of the cyst and symptoms. For small, asymptomatic cysts, the wait and see approach with regular check-ups will most likely be recommended.
Pain caused by ovarian cysts may be treated with:
- pain relievers, including nonsteroidal anti-inflammatory drugs such as ibuprofen (Motrin, Advil), acetaminophen (Tylenol), or narcotic pain medicine (by prescription) may help reduce pelvic pain.[31] NSAIDs usually work best when taken at the first signs of the pain.
- a warm bath, or heating pad, or hot water bottle applied to the lower abdomen near the ovaries can relax tense muscles and relieve cramping, lessen discomfort, and stimulate circulation and healing in the ovaries.[32] Bags of ice covered with towels can be used alternately as cold treatments to increase local circulation.[33]
- chamomile herbal tea (Matricaria recutita) can reduce ovarian cyst pain and soothe tense muscles.[34][35]
- urinating as soon as the urge presents itself.[36]
- avoiding constipation, which does not cause ovarian cysts but may further increase pelvic discomfort.[37]
- in diet, eliminating caffeine and alcohol, reducing sugars, increasing foods rich in vitamin A and carotenoids (e.g., carrots, tomatoes, and salad greens) and B vitamins (e.g., whole grains).[38]
- combined methods of hormonal contraception such as the combined oral contraceptive pill -- the hormones in the pills may regulate the menstrual cycle, prevent the formation of follicles that can turn into cysts, and possibly shrink an existing cyst. (American College of Obstetricians and Gynecologists, 1999c; Mayo Clinic, 2002e)[39]
Also, limiting strenuous activity may reduce the risk of cyst rupture or torsion.
Cysts that persist beyond two or three menstrual cycles, or occur in post-menopausal women, may indicate more serious disease and should be investigated through ultrasonography and laparoscopy, especially in cases where family members have had ovarian cancer. Such cysts may require surgical biopsy. Additionally, a blood test may be taken before surgery to check for elevated CA-125, a tumor marker, which is often found in increased levels in ovarian cancer, although it can also be elevated by other conditions resulting in a large number of false positives.
For more serious cases where cysts are large and persisting, doctors may suggest surgery. Some surgeries can be performed to successfully remove the cyst(s) without hurting the ovaries, while others may require removal of one or both ovaries.[40]
### Contraindicated medications
Ovarian cyst is considered an absolute contraindication to the use of the following medications:
- Clomifene
- Choriogonadotropin alfa
- Follitropin beta
- Urofollitropin
Template:Diseases of the pelvis, genitals and breasts
it:Cisti ovarica
Template:WikiDoc Sources
- ↑ Morin L, Cargill YM, Glanc P (2016). "Ultrasound Evaluation of First Trimester Complications of Pregnancy". J Obstet Gynaecol Can. 38 (10): 982–988. doi:10.1016/j.jogc.2016.06.001. PMID 27720100..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}
- ↑ Balthazar EJ, Birnbaum BA, Yee J, Megibow AJ, Roshkow J, Gray C (1994). "Acute appendicitis: CT and US correlation in 100 patients". Radiology. 190 (1): 31–5. doi:10.1148/radiology.190.1.8259423. PMID 8259423.
- ↑ Bottomley C, Bourne T (2009). "Diagnosis and management of ovarian cyst accidents". Best Pract Res Clin Obstet Gynaecol. 23 (5): 711–24. doi:10.1016/j.bpobgyn.2009.02.001. PMID 19299205.
- ↑ Jump up to: 4.0 4.1 4.2 Bhavsar AK, Gelner EJ, Shorma T (2016). "Common Questions About the Evaluation of Acute Pelvic Pain". Am Fam Physician. 93 (1): 41–8. PMID 26760839.
- ↑ {{Cite journal
| author = W. E. Stamm
| title = Etiology and management of the acute urethral syndrome
| journal = Sexually transmitted diseases
| volume = 8
| issue = 3
| pages = 235–238
| year = 1981
| month = July-September
| pmid = 7292216
- ↑ {{Cite journal
| author = W. E. Stamm, K. F. Wagner, R. Amsel, E. R. Alexander, M. Turck, G. W. Counts & K. K. Holmes
| title = Causes of the acute urethral syndrome in women
| journal = The New England journal of medicine
| volume = 303
| issue = 8
| pages = 409–415
| year = 1980
| month = August
| doi = 10.1056/NEJM198008213030801
| pmid = 6993946 | https://www.wikidoc.org/index.php/Ovarian_Cyst | |
8f9267707a2e901169da70c9a67ab8fce987246a | wikidoc | Oyster plant | Oyster plant
# Overview
Oyster plant is a common name used for various flowering plants, including:
- Acanthus mollis, (also called bear's breeches), native to the Mediterranean
- Mertensia maritima (also called oysterleaf), native to Europe and North America with leaves said to taste like oysters
- Scorzonera hispanica (also called black salsify), cultivated for its dark-skinned edible root
- Tragopogon porrifolius (also called purple salsify), cultivated for its light-skinned edible root
- Tradescantia spathacea (synonyms Tradescantia discolor, Rhoeo spathacea, Rhoeo discolor); (also called Oyster Herb, Daun Kepah, Nanas Kerang, Boatlily (Cây Lẻ Bạn, Lảo Bạn, Sò Huyết), Moses in a basket, Cradle Lily, Moses in His Cradle, Moses on a Raft, Moses in the Bulrushes, Men in a Boat, Moses-in-Cradle, (Chinese) 蚌花) | Oyster plant
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Oyster plant is a common name used for various flowering plants, including:
- Acanthus mollis, (also called bear's breeches), native to the Mediterranean
- Mertensia maritima (also called oysterleaf), native to Europe and North America with leaves said to taste like oysters
- Scorzonera hispanica (also called black salsify), cultivated for its dark-skinned edible root
- Tragopogon porrifolius (also called purple salsify), cultivated for its light-skinned edible root
- Tradescantia spathacea (synonyms Tradescantia discolor, Rhoeo spathacea, Rhoeo discolor); (also called Oyster Herb, Daun Kepah, Nanas Kerang, Boatlily (Cây Lẻ Bạn, Lảo Bạn, Sò Huyết), Moses in a basket, Cradle Lily, Moses in His Cradle, Moses on a Raft, Moses in the Bulrushes, Men in a Boat, Moses-in-Cradle, (Chinese) 蚌花) | https://www.wikidoc.org/index.php/Oyster_plant | |
23093ea3fb60ef7c98192d09b87fdfcfec07e516 | wikidoc | P2X Receptor | P2X Receptor
P2X receptors are a family of cation-permeable ligand gated ion channels that open in response to the binding of extracellular adenosine 5'-triphosphate (ATP). They belong to a larger family of receptors known as the purinergic receptors. P2X receptors are present in a diverse array of organisms including humans, mouse, rat, rabbit, chicken, zebrafish, bullfrog, fluke, and amoeba.
# Basic Structure and Nomenclature
Each functional P2X receptor is a trimer, with the three protein subunits arranged around an ion-permeable channel pore. To date, seven separate genes coding for P2X subunits have been identified, and referred to as P2X1 through P2X7.
The subunits all share a common topology, possessing two plasma membrane spanning domains, a large extracellular loop and intracellular carboxyl and amino termini. With the exception of P2X6, each subunit can readily form a functional homomeric receptor. A P2X receptor made up of only P2X1 subunits is termed a P2X1 receptor. The general consensus is that P2X6 cannot form a functional homomeric receptor when expressed alone, but nevertheless can co-assemble with other subunits to form functional heteromeric receptors. Current data suggests that, all of the P2X subunits are capable of forming heteromeric P2X receptors with at least one other subunit type. A P2X receptor made up of P2X2 and P2X3 subunits is known as a P2X2/3 receptor.
The relationship between the structure and function of P2X receptors has been the subject of considerable research, and key protein domains responsible for regulating ATP binding, ion permeation, pore dilation and desensitization have been identified.
# Pharmacology
The pharmacology of a given P2X receptor is largely determined by its subunit makeup. Different subunits exhibit different sensitivities to purinergic agonists such as ATP, α,β-meATP and BzATP; and antagonists such as pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS) and suramin. Of continuing interest is the fact that some P2X receptors (P2X2, P2X4, human P2X5, and P2X7) exhibit multiple open states in response to ATP, characterized by a time-dependent increase in the permeabilities of large organic ions such as N-methyl-D-glucamine (NMDG+) and nucleotide binding dyes such as propidium iodide (YO-PRO-1). Whether this change in permeability is due to a widening of the P2X receptor channel pore itself or the opening of a separate ion-permeable pore is the subject of continued investigation.
# Tissue Distribution
P2X receptors are expressed in cells from a wide variety of animal tissues. On presynaptic and postsynaptic nerve terminals throughout the central, peripheral and autonomic nervous systems, P2X receptors have been shown to modulate synaptic transmission. Furthermore, P2X receptors are able to initiate contraction in cells of the heart muscle, skeletal muscle, and various smooth muscle tissues, including that of the vasculature, vas deferens and urinary bladder. P2X receptors are also expressed on leukocytes, including lymphocytes and macrophages, and are present on blood platelets. There is some degree of subtype specificity as to which P2X receptor subtypes are expressed on specific cell types, with P2X1 receptors being particularly prominent in smooth muscle cells, and P2X2 being widespread throughout the autonomic nervous system. However, such trends are very general and there is considerable overlap in subunit distribution, with most cell types expressing more than one subunits. For example, P2X2 and P2X3 subunits are commonly found co-expressed in sensory neurons, where they often co-assemble into functional P2X2/3 receptors.
# Physiological Roles
In keeping with their wide distribution throughout the body, P2X receptors are involved in a variety of physiological processes, including:
- Modulation of cardiac rhythm and contractility
- Modulation of vascular tone
- Mediation of nociception - e.g. hypersensitivity to innocuous stimuli following upregulation of P2X4 in the spinal cord
- Contraction of the vas deferens during ejaculation
# Activation and Channel Opening
ATP binds to the extracellular loop of the P2X receptor, whereupon it evokes a conformational change in the structure of the ion channel that results in the opening of the ion-permeable pore. This allows cations such as Na+ and Ca2+ to enter the cell, leading to depolarization of the cell membrane and the activation of various Ca2+-sensitive intracellular processes. The channel opening time is dependent upon the subunit makeup of the receptor. For example, P2X1 and P2X3 receptors desensitize rapidly (a few hundred milliseconds) in the continued presence of ATP, whereas the P2X2 receptor channel remains open for as long as ATP is bound to it. Three ATP molecules are thought to be required to activate a P2X receptor, suggesting that ATP needs to bind to each of the three subunits in order to open the channel pore, though recent evidence suggests that ATP binds at the three subunit interfaces. The precise mechanism by which the binding of ATP leads to the opening of the P2X receptor channel pore is not well understood, but is currently under investigation.
# Allosteric Modulation
The sensitivity of P2X receptors to ATP is strongly modulated by changes in extracellular pH and by the presence of heavy metals (e.g. zinc and cadmium). For example, the ATP sensitivity of P2X1, P2X3 and P2X4 receptors is attenuated when the extracellular pH<7, whereas the ATP sensitivity of P2X2 is significantly increased. On the other hand, zinc potentiates ATP-gated currents through P2X2, P2X3 and P2X4, and inhibits currents through P2X1. The allosteric modulation of P2X receptors by pH and metals appears to be conferred by the presence of histidine side chains in the extracellular domain. In contrast to the other members of the P2X receptor family, P2X4 receptors are also very sensitive to modulation by the macrocyclic lactone, ivermectin. Ivermectin potentiates ATP-gated currents through P2X4 receptors by increasing the open probability of the channel in the presence of ATP, which it appears to do by interacting with the transmembrane domains from within the lipid bilayer. | P2X Receptor
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
P2X receptors are a family of cation-permeable ligand gated ion channels that open in response to the binding of extracellular adenosine 5'-triphosphate (ATP). They belong to a larger family of receptors known as the purinergic receptors. P2X receptors are present in a diverse array of organisms including humans, mouse, rat, rabbit, chicken, zebrafish, bullfrog, fluke, and amoeba.[1]
# Basic Structure and Nomenclature
Each functional P2X receptor is a trimer, with the three protein subunits arranged around an ion-permeable channel pore.[2] To date, seven separate genes coding for P2X subunits have been identified, and referred to as P2X1 through P2X7.[1][3]
The subunits all share a common topology, possessing two plasma membrane spanning domains, a large extracellular loop and intracellular carboxyl and amino termini. With the exception of P2X6, each subunit can readily form a functional homomeric receptor. A P2X receptor made up of only P2X1 subunits is termed a P2X1 receptor. The general consensus is that P2X6 cannot form a functional homomeric receptor when expressed alone, but nevertheless can co-assemble with other subunits to form functional heteromeric receptors. Current data suggests that, all of the P2X subunits are capable of forming heteromeric P2X receptors with at least one other subunit type. A P2X receptor made up of P2X2 and P2X3 subunits is known as a P2X2/3 receptor.
The relationship between the structure and function of P2X receptors has been the subject of considerable research, and key protein domains responsible for regulating ATP binding, ion permeation, pore dilation and desensitization have been identified.[4][5]
# Pharmacology
The pharmacology of a given P2X receptor is largely determined by its subunit makeup.[3] Different subunits exhibit different sensitivities to purinergic agonists such as ATP, α,β-meATP and BzATP; and antagonists such as pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS) and suramin.[1] Of continuing interest is the fact that some P2X receptors (P2X2, P2X4, human P2X5, and P2X7) exhibit multiple open states in response to ATP, characterized by a time-dependent increase in the permeabilities of large organic ions such as N-methyl-D-glucamine (NMDG+) and nucleotide binding dyes such as propidium iodide (YO-PRO-1). Whether this change in permeability is due to a widening of the P2X receptor channel pore itself or the opening of a separate ion-permeable pore is the subject of continued investigation.
# Tissue Distribution
P2X receptors are expressed in cells from a wide variety of animal tissues. On presynaptic and postsynaptic nerve terminals throughout the central, peripheral and autonomic nervous systems, P2X receptors have been shown to modulate synaptic transmission.[1][6] Furthermore, P2X receptors are able to initiate contraction in cells of the heart muscle, skeletal muscle, and various smooth muscle tissues, including that of the vasculature, vas deferens and urinary bladder. P2X receptors are also expressed on leukocytes, including lymphocytes and macrophages, and are present on blood platelets. There is some degree of subtype specificity as to which P2X receptor subtypes are expressed on specific cell types, with P2X1 receptors being particularly prominent in smooth muscle cells, and P2X2 being widespread throughout the autonomic nervous system. However, such trends are very general and there is considerable overlap in subunit distribution, with most cell types expressing more than one subunits. For example, P2X2 and P2X3 subunits are commonly found co-expressed in sensory neurons, where they often co-assemble into functional P2X2/3 receptors.
# Physiological Roles
In keeping with their wide distribution throughout the body, P2X receptors are involved in a variety of physiological processes,[1][7] including:
- Modulation of cardiac rhythm and contractility[8]
- Modulation of vascular tone[1]
- Mediation of nociception[9] - e.g. hypersensitivity to innocuous stimuli following upregulation of P2X4 in the spinal cord
- Contraction of the vas deferens during ejaculation[1]
# Activation and Channel Opening
ATP binds to the extracellular loop of the P2X receptor, whereupon it evokes a conformational change in the structure of the ion channel that results in the opening of the ion-permeable pore. This allows cations such as Na+ and Ca2+ to enter the cell, leading to depolarization of the cell membrane and the activation of various Ca2+-sensitive intracellular processes. The channel opening time is dependent upon the subunit makeup of the receptor. For example, P2X1 and P2X3 receptors desensitize rapidly (a few hundred milliseconds) in the continued presence of ATP, whereas the P2X2 receptor channel remains open for as long as ATP is bound to it. Three ATP molecules are thought to be required to activate a P2X receptor, suggesting that ATP needs to bind to each of the three subunits in order to open the channel pore, though recent evidence suggests that ATP binds at the three subunit interfaces.[10] The precise mechanism by which the binding of ATP leads to the opening of the P2X receptor channel pore is not well understood, but is currently under investigation.[4]
# Allosteric Modulation
The sensitivity of P2X receptors to ATP is strongly modulated by changes in extracellular pH and by the presence of heavy metals (e.g. zinc and cadmium). For example, the ATP sensitivity of P2X1, P2X3 and P2X4 receptors is attenuated when the extracellular pH<7, whereas the ATP sensitivity of P2X2 is significantly increased. On the other hand, zinc potentiates ATP-gated currents through P2X2, P2X3 and P2X4, and inhibits currents through P2X1. The allosteric modulation of P2X receptors by pH and metals appears to be conferred by the presence of histidine side chains in the extracellular domain.[1] In contrast to the other members of the P2X receptor family, P2X4 receptors are also very sensitive to modulation by the macrocyclic lactone, ivermectin.[11] Ivermectin potentiates ATP-gated currents through P2X4 receptors by increasing the open probability of the channel in the presence of ATP, which it appears to do by interacting with the transmembrane domains from within the lipid bilayer.[12] | https://www.wikidoc.org/index.php/P2X_Receptor | |
2b240169831061d0fd6608290d0d2e26522bb8bc | wikidoc | P2X receptor | P2X receptor
# Overview
P2X receptors are a family of cation-permeable ligand gated ion channels that open in response to extracellular adenosine 5'-triphosphate (ATP). They belong to a larger family of receptors known as the purinergic receptors. P2X receptors are present in a diverse array of organisms including amoeba (1), fluke, zebrafish, bullfrog, chicken, mouse, rat, rabbit, and humans .
# Basic Structure and Nomenclature
Each functional P2X receptor is made up of three protein subunits. To date, seven separate genes coding for P2X subunits have been identified, and referred to as P2X1 through P2X7. The three subunits making up the assembled P2X receptor channel are arranged to form a gated, ion-permeable pore. The subunits all share a common topology, possessing two plasma membrane spanning domains, a large extracellular loop and intracellular carboxyl and amino termini. With the exception of P2X6, each subunit can readily form a functional homomeric receptor. A P2X receptor made up of only P2X1 subunits is simply termed a P2X1 receptor. The general consensus is that P2X6 cannot form a functional homomeric receptor when expressed alone, but nevertheless can co-assemble with other subunits to form functional heteromeric receptors. Current data suggests that, with the exception of P2X7, all of the P2X subunits are capable of forming heteromeric P2X receptors with at least one other subunit type. A P2X receptor made up of P2X2 and P2X3 subunits is known as the P2X2/3 receptor.
# Activation and Channel Opening
ATP binds to the extracellular loop of the P2X receptor, whereupon it evokes a conformational change in the structure of the ion channel that results in the opening of the ion-permeable pore. This allows cations such as Na+ and Ca2+ to enter the cell, leading to depolarization of the cell membrane and the activation of various Ca2+-sensitive intracellular processes. At least three ATP molecules are required to activate a P2X receptor, suggesting that ATP needs to bind to each of the three subunits in order to open the channel pore. The precise mechanism by which the binding of ATP leads to the opening of the P2X receptor channel pore is not well understood, but is currently under investigation.
# Pharmacology
The pharmacology of a given P2X receptor is largely determined by its subunit makeup. For example, P2X1 and P2X3 receptors desensitize rapidly in the continued presence of ATP, whereas the P2X7 receptor channel mostly remains open for as long as ATP is bound to it. The different subunits also exhibit different sensitivities to purinergic agonists such as ATP, α,β-meATP and BzATP; and antagonists such as pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS) and suramin (2,3). Of continuing interest is the fact that some P2X receptors (P2X2, P2X4, human P2X5, and P2X7) exhibit multiple open states in response to ATP, characterized by a time-dependent increase in the permeabilities of large organic ions such as N-methyl-D-glucamine (NMDG+) and nucleotide binding dyes such as propidium iodide (YO-PRO-1). Interestingly, the time-dependent increase in permeability of P2X7 receptors to YO-PRO-1 is unaffected by selective deletion of 18 amino acids in the carboxyl terminal tail, even though this abolishes NMDG+ permeability. This suggests that separate pathways may underlie “pore-dilation” (i.e. the gradual increase in permeability to NMDG+) and “dye-uptake” (i.e., the gradual increase in permeability to nucleic acid stains) for this receptor. This hypothesis is supported by recent studies (4,5), in which RNA interference directed against pannexin-1 hemichannels significantly reduced dye-uptake without effecting cation flux through the pore. Thus, it may be the case that the P2X7 channel uses two different methods to move large ions across the cell surface membrane. The first is a gradual dilation of the integral P2X7 channel pore that ultimately results in an increase in permeability to larger monovalent cations. The second is an indirect activation of ethidium-permeable pannexin-1 channels that may result from a protein-protein interaction with the P2X7 receptor. Whether the dye-uptake initiated by other P2X family members also involves activation of pannexin-1 hemichannels is unknown.
# Tissue Distribution
P2X receptors are expressed in cells from a wide variety of animal tissues. On presynaptic and postsynaptic nerve terminals throughout the central, peripheral and autonomic nervous systems, P2X receptors have been shown to modulate synaptic transmission. Furthermore, P2X receptors are able to initiate contraction in cells of the heart muscle, skeletal muscle, and various smooth muscle tissues, including that of the vasculature, vas deferens and urinary bladder. P2X receptors are also expressed on leukocytes, including lymphocytes and macrophages, and are present on blood platelets. There is some degree of subtype specificity as to which P2X receptor subtypes are expressed on specific cell types, with P2X1 receptors being particularly prominent in smooth muscle cells, and P2X2 being widespread throughout the autonomic nervous system. However, such trends are very general and there is considerable overlap in subunit distribution, with most cell types expressing more than one subunits. For example, P2X2 and P2X3 subunits are commonly found co-expressed in sensory neurons, where they often co-assemble into functional P2X2/3 receptors.
# Physiological Roles
In keeping with their wide distribution throughout the body, P2X receptors are involved in a variety of phsyiological processes, including:
- Modulation of cardiac rhythm and contractility - Sodium entry speeds depolarisation and calcium entry increases force of contraction
- Modulation of vascular tone
- Mediation of nociception - e.g. hypersensitivity to innocuous stimuli following upregulation of P2X4 in the spinal cord
- Contraction of the vas deferens during ejaculation - mediated by noradrenaline release onto α1 receptors | P2X receptor
# Overview
P2X receptors are a family of cation-permeable ligand gated ion channels that open in response to extracellular adenosine 5'-triphosphate (ATP). They belong to a larger family of receptors known as the purinergic receptors. P2X receptors are present in a diverse array of organisms including amoeba (1), fluke, zebrafish, bullfrog, chicken, mouse, rat, rabbit, and humans .
# Basic Structure and Nomenclature
Each functional P2X receptor is made up of three protein subunits. To date, seven separate genes coding for P2X subunits have been identified, and referred to as P2X1 through P2X7. The three subunits making up the assembled P2X receptor channel are arranged to form a gated, ion-permeable pore. The subunits all share a common topology, possessing two plasma membrane spanning domains, a large extracellular loop and intracellular carboxyl and amino termini. With the exception of P2X6, each subunit can readily form a functional homomeric receptor. A P2X receptor made up of only P2X1 subunits is simply termed a P2X1 receptor. The general consensus is that P2X6 cannot form a functional homomeric receptor when expressed alone, but nevertheless can co-assemble with other subunits to form functional heteromeric receptors. Current data suggests that, with the exception of P2X7, all of the P2X subunits are capable of forming heteromeric P2X receptors with at least one other subunit type. A P2X receptor made up of P2X2 and P2X3 subunits is known as the P2X2/3 receptor.
# Activation and Channel Opening
ATP binds to the extracellular loop of the P2X receptor, whereupon it evokes a conformational change in the structure of the ion channel that results in the opening of the ion-permeable pore. This allows cations such as Na+ and Ca2+ to enter the cell, leading to depolarization of the cell membrane and the activation of various Ca2+-sensitive intracellular processes. At least three ATP molecules are required to activate a P2X receptor, suggesting that ATP needs to bind to each of the three subunits in order to open the channel pore. The precise mechanism by which the binding of ATP leads to the opening of the P2X receptor channel pore is not well understood, but is currently under investigation.
# Pharmacology
The pharmacology of a given P2X receptor is largely determined by its subunit makeup. For example, P2X1 and P2X3 receptors desensitize rapidly in the continued presence of ATP, whereas the P2X7 receptor channel mostly remains open for as long as ATP is bound to it. The different subunits also exhibit different sensitivities to purinergic agonists such as ATP, α,β-meATP and BzATP; and antagonists such as pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS) and suramin (2,3). Of continuing interest is the fact that some P2X receptors (P2X2, P2X4, human P2X5, and P2X7) exhibit multiple open states in response to ATP, characterized by a time-dependent increase in the permeabilities of large organic ions such as N-methyl-D-glucamine (NMDG+) and nucleotide binding dyes such as propidium iodide (YO-PRO-1). Interestingly, the time-dependent increase in permeability of P2X7 receptors to YO-PRO-1 is unaffected by selective deletion of 18 amino acids in the carboxyl terminal tail, even though this abolishes NMDG+ permeability. This suggests that separate pathways may underlie “pore-dilation” (i.e. the gradual increase in permeability to NMDG+) and “dye-uptake” (i.e., the gradual increase in permeability to nucleic acid stains) for this receptor. This hypothesis is supported by recent studies (4,5), in which RNA interference directed against pannexin-1 hemichannels significantly reduced dye-uptake without effecting cation flux through the pore. Thus, it may be the case that the P2X7 channel uses two different methods to move large ions across the cell surface membrane. The first is a gradual dilation of the integral P2X7 channel pore that ultimately results in an increase in permeability to larger monovalent cations. The second is an indirect activation of ethidium-permeable pannexin-1 channels that may result from a protein-protein interaction with the P2X7 receptor. Whether the dye-uptake initiated by other P2X family members also involves activation of pannexin-1 hemichannels is unknown.
# Tissue Distribution
P2X receptors are expressed in cells from a wide variety of animal tissues. On presynaptic and postsynaptic nerve terminals throughout the central, peripheral and autonomic nervous systems, P2X receptors have been shown to modulate synaptic transmission. Furthermore, P2X receptors are able to initiate contraction in cells of the heart muscle, skeletal muscle, and various smooth muscle tissues, including that of the vasculature, vas deferens and urinary bladder. P2X receptors are also expressed on leukocytes, including lymphocytes and macrophages, and are present on blood platelets. There is some degree of subtype specificity as to which P2X receptor subtypes are expressed on specific cell types, with P2X1 receptors being particularly prominent in smooth muscle cells, and P2X2 being widespread throughout the autonomic nervous system. However, such trends are very general and there is considerable overlap in subunit distribution, with most cell types expressing more than one subunits. For example, P2X2 and P2X3 subunits are commonly found co-expressed in sensory neurons, where they often co-assemble into functional P2X2/3 receptors.
# Physiological Roles
In keeping with their wide distribution throughout the body, P2X receptors are involved in a variety of phsyiological processes, including:
- Modulation of cardiac rhythm and contractility - Sodium entry speeds depolarisation and calcium entry increases force of contraction
- Modulation of vascular tone
- Mediation of nociception - e.g. hypersensitivity to innocuous stimuli following upregulation of P2X4 in the spinal cord
- Contraction of the vas deferens during ejaculation - mediated by noradrenaline release onto α1 receptors | https://www.wikidoc.org/index.php/P2X_Receptors | |
1f88038a52e62b0d3181c7d2e471b8c92bcd22a3 | wikidoc | P90x workout | P90x workout
Are you in search for the precise assistance for your health exercise? Are you interested with bodybuilding?
This article will help you together with all the instruction to achieve a toned yet healthy body. Some people tend to be paranoid when it comes to their weight. They are inclined to do different things such as starvation, diet cut, gym, aerobics, weights and many more in order to effectively handle their weight particularly the women. Most ladies desire to have a good, well-shaped body for different reasons.
The reason could be emotional and commercial. Do not just perform anything to shape your body. You must only believe the advice of the experts. If you will do all of these things on your own you may simply wind up facing terrible outcomes. You can shape your body only if you are adequately patient. Besides, it would be impossible to change somebody else's weight overtime. Choosing the shortcuts could be harmful as well. You would be able to notice the side effects sooner or later.
For individuals who deem bodybuilding to be very costly or merely created for the wealthier class of individuals, who could pay for the regular visit in a costly fitness center, you have to think through. With the use of p90x workout program
, bodybuilding can now be possible at the home. p90x workout is considered the most modern and most accurate workout program for people who are more apt to weight loss tactics and bodybuilding.
This program is so simple. It summarizes strict workout routines that are expected to give result within 90 days of habitual or everyday workouts. It makes a person to be more precise with the work out schedule. In short such program is completely nothing but a discipline manager of your exercises. This unique workout come with CDs or DVDs for easy home viewing and self-exercises trainings. If you wish to have that toned or well-shaped body in just 90 days, therefore you should start employing the p90x workout programs.
However, perhaps you know that nothing comes so simple in life. Thus, this means that you need to exert too much hard work in order to attain a well-shaped body in only 90 days. Obviously, the supplements of p90x can also help you. But many resolutions will be required on an individual level. Initially, you would need to make sure about your choice in using the p90x workout. You should be sure of your decision before using program.
The program may employ a lot of resources so you need to critically take it. However, the great thing about this is that it would be you investment permanently. You don't need to spend regular money periodically so as to achieve the help of a trainer. Through p90x workout programs you need to buy the DVDs and other devices or requirements for definite workout practices. | P90x workout
Are you in search for the precise assistance for your health exercise? Are you interested with bodybuilding?
This article will help you together with all the instruction to achieve a toned yet healthy body. Some people tend to be paranoid when it comes to their weight. They are inclined to do different things such as starvation, diet cut, gym, aerobics, weights and many more in order to effectively handle their weight particularly the women. Most ladies desire to have a good, well-shaped body for different reasons.
The reason could be emotional and commercial. Do not just perform anything to shape your body. You must only believe the advice of the experts. If you will do all of these things on your own you may simply wind up facing terrible outcomes. You can shape your body only if you are adequately patient. Besides, it would be impossible to change somebody else's weight overtime. Choosing the shortcuts could be harmful as well. You would be able to notice the side effects sooner or later.
For individuals who deem bodybuilding to be very costly or merely created for the wealthier class of individuals, who could pay for the regular visit in a costly fitness center, you have to think through. With the use of p90x workout program
, bodybuilding can now be possible at the home. p90x workout is considered the most modern and most accurate workout program for people who are more apt to weight loss tactics and bodybuilding.
This program is so simple. It summarizes strict workout routines that are expected to give result within 90 days of habitual or everyday workouts. It makes a person to be more precise with the work out schedule. In short such program is completely nothing but a discipline manager of your exercises. This unique workout come with CDs or DVDs for easy home viewing and self-exercises trainings. If you wish to have that toned or well-shaped body in just 90 days, therefore you should start employing the p90x workout programs.
However, perhaps you know that nothing comes so simple in life. Thus, this means that you need to exert too much hard work in order to attain a well-shaped body in only 90 days. Obviously, the supplements of p90x can also help you. But many resolutions will be required on an individual level. Initially, you would need to make sure about your choice in using the p90x workout. You should be sure of your decision before using program.
The program may employ a lot of resources so you need to critically take it. However, the great thing about this is that it would be you investment permanently. You don't need to spend regular money periodically so as to achieve the help of a trainer. Through p90x workout programs you need to buy the DVDs and other devices or requirements for definite workout practices. | https://www.wikidoc.org/index.php/P90x_workout | |
b584cbf903d1f2f45efffcb973ea84e522e62757 | wikidoc | PALLAS trial | PALLAS trial
The following information is drawn from a Sanofi Aventis press release.
On July 7th 2011, Sanofi Aventis discontinued the PALLAS Phase IIIb trial in patients with permanent [[Atrial
Fibrillation]] (AF), a population different from the population with non-permanent (paroxysmal) AF for which
Multaq® (dronedarone) is currently approved. The decision followed recommendations from the
study’s Operations Committee and the Data Monitoring Committee (DMC) which observed a
significant increase in cardiovascular events in the dronedarone arm. The decision to terminate the
study was not related to any hepatic adverse event.
Sanofi has informed regulatory authorities of this decision. The company also has asked all
PALLAS clinical investigators to inform their patients included in the trial to stop taking the study
medication and consult their clinical trial center. This direction applies to the PALLAS study patients
-nly.
The benefit-risk of Multaq remains unchanged in its approved indication in non-permanent AF.
Patients currently taking Multaq should not stop their therapy and should consult their treating
physician should they have any questions.
In the PALLAS population, 70% of the 3,149 patients enrolled had
permanent AF for over 2 years; approximately 70% had NYHA heart failure Class I to III at baseline.
In contrast, in the study supporting the current indication (ATHENA), no patients enrolled had
permanent AF and less than 30% of patients had NYHA heart failure Class I to III. PALLAS
patients were also older than ATHENA patients.
Multaq is currently approved in the EU in adult clinically stable patients with a history of, or current
non-permanent atrial fibrillation (AF) to prevent recurrence of AF or to lower ventricular rate. In the
U.S., Multaq is indicated to reduce the risk of cardiovascular hospitalization in patients with
paroxysmal or persistent atrial fibrillation (AF) or atrial flutter (AFL), with a recent episode of AF/AFL
and associated cardiovascular risk factors (i.e., age >70, hypertension, diabetes, prior
cerebrovascular accident, left atrial diameter ≥50 mm or left ventricular ejection fraction
<40%), who are in sinus rhythm or who will be cardioverted.
About PALLAS
PALLAS (Permanent Atrial fibriLLAtion outcome Study using Dronedarone on top of standard
therapy) was a multinational, randomized, double-blind, parallel-group, placebo-controlled,
multicenter Phase IIIb trial comparing the efficacy of dronedarone 400mg twice-daily to placebo in
permanent AF patients. Patients were required to have an age above 65 years with co-morbid
conditions, such as systemic arterial embolism, myocardial infarction, documented coronary artery
disease, prior stroke, symptomatic heart failure, or the combination of age above 75 years,
hypertension and diabetes mellitus. Exclusion criteria included New York Heart Association (NYHA)
Class IV heart failure or unstable NYHA Class III heart failure.
The trial had two composite co-primary endpoints: 1. Major cardiovascular events (stroke, systemic
arterial embolism, myocardial infarction or cardiovascular death). 2. Cardiovascular hospitalization
-r death from any cause.
About Permanent Atrial Fibrillation
According to ACC/AHA/ESC guidelines, permanent AF is the designation given when sinus rhythm
cannot be sustained after cardioversion of AF (medical intervention designed to restore sinus
rhythm) or when the patient and physician have decided to allow AF to continue without further
efforts to restore sinus rhythm. In the Euro Heart Survey one year follow-up, one year mortality in
patients suffering from AF was high and the risk continuously present. Mortality (5.3%) was
comparable with results of previous studies, which is also the case for the observed higher mortality
in permanent AF than in other AF types. | PALLAS trial
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
The following information is drawn from a Sanofi Aventis press release.
On July 7th 2011, Sanofi Aventis discontinued the PALLAS Phase IIIb trial in patients with permanent [[Atrial
Fibrillation]] (AF), a population different from the population with non-permanent (paroxysmal) AF for which
Multaq® (dronedarone) is currently approved. The decision followed recommendations from the
study’s Operations Committee and the Data Monitoring Committee (DMC) which observed a
significant increase in cardiovascular events in the dronedarone arm. The decision to terminate the
study was not related to any hepatic adverse event.
Sanofi has informed regulatory authorities of this decision. The company also has asked all
PALLAS clinical investigators to inform their patients included in the trial to stop taking the study
medication and consult their clinical trial center. This direction applies to the PALLAS study patients
only.
The benefit-risk of Multaq remains unchanged in its approved indication in non-permanent AF.
Patients currently taking Multaq should not stop their therapy and should consult their treating
physician should they have any questions.
In the PALLAS population, 70% of the 3,149 patients enrolled had
permanent AF for over 2 years; approximately 70% had NYHA heart failure Class I to III at baseline.
2/3
In contrast, in the study supporting the current indication (ATHENA), no patients enrolled had
permanent AF and less than 30% of patients had NYHA heart failure Class I to III. PALLAS
patients were also older than ATHENA patients.
Multaq is currently approved in the EU in adult clinically stable patients with a history of, or current
non-permanent atrial fibrillation (AF) to prevent recurrence of AF or to lower ventricular rate. In the
U.S., Multaq is indicated to reduce the risk of cardiovascular hospitalization in patients with
paroxysmal or persistent atrial fibrillation (AF) or atrial flutter (AFL), with a recent episode of AF/AFL
and associated cardiovascular risk factors (i.e., age >70, hypertension, diabetes, prior
cerebrovascular accident, left atrial diameter ≥50 mm or left ventricular ejection fraction [LVEF]
<40%), who are in sinus rhythm or who will be cardioverted.
About PALLAS
PALLAS (Permanent Atrial fibriLLAtion outcome Study using Dronedarone on top of standard
therapy) was a multinational, randomized, double-blind, parallel-group, placebo-controlled,
multicenter Phase IIIb trial comparing the efficacy of dronedarone 400mg twice-daily to placebo in
permanent AF patients. Patients were required to have an age above 65 years with co-morbid
conditions, such as systemic arterial embolism, myocardial infarction, documented coronary artery
disease, prior stroke, symptomatic heart failure, or the combination of age above 75 years,
hypertension and diabetes mellitus. Exclusion criteria included New York Heart Association (NYHA)
Class IV heart failure or unstable NYHA Class III heart failure.
The trial had two composite co-primary endpoints: 1. Major cardiovascular events (stroke, systemic
arterial embolism, myocardial infarction or cardiovascular death). 2. Cardiovascular hospitalization
or death from any cause.
About Permanent Atrial Fibrillation
According to ACC/AHA/ESC guidelines, permanent AF is the designation given when sinus rhythm
cannot be sustained after cardioversion of AF (medical intervention designed to restore sinus
rhythm) or when the patient and physician have decided to allow AF to continue without further
efforts to restore sinus rhythm. In the Euro Heart Survey one year follow-up, one year mortality in
patients suffering from AF was high and the risk continuously present. Mortality (5.3%) was
comparable with results of previous studies, which is also the case for the observed higher mortality
in permanent AF than in other AF types. | https://www.wikidoc.org/index.php/PALLAS_trial | |
da6e918634e46076f9a9e20593bdc5fd1e4b9810 | wikidoc | Polyhexanide | Polyhexanide
# Overview
Polyhexanide (polyhexamethylene biguanide, PHMB) is a polymer used as a disinfectant and antiseptic. In dermatological use it is spelled polihexanide (INN) and sold under names such as Lavasept, Serasept, and Omnicide. PHMB has been shown to be effective against Pseudomonas aeruginosa, Staphylococcus aureus (also the methicillin-resistant type, MRSA), Escherichia coli, Candida albicans (yeast), Aspergillus brasiliensis (mold), vancomycin-resistant enterococci, and Klebsiella pneumoniae (carbapenem-resistant enterobacteriaceae).
Some products containing PHMB are used for inter-operative irrigation, pre- and post-surgery skin and mucous membrane disinfection, post-operative dressings, surgical and non-surgical wound dressings, surgical bath/hydrotherapy, chronic wounds like diabetic foot ulcer and burn wound management, routine antisepsis during minor incisions, catheterization, scopy, first aid, surface disinfection, and linen disinfection.
Branded as Baquacil, it also has an application as a swimming-pool and spa water sanitizer in place of chlorine- or bromine-based products.
PHMB is also used as an ingredient in some contact lens cleaning products, cosmetics, personal deodorants and some veterinary products.
The PHMB hydrochloride salt (solution) is used in the majority of formulations. | Polyhexanide
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Polyhexanide (polyhexamethylene biguanide, PHMB) is a polymer used as a disinfectant and antiseptic. In dermatological use[1] it is spelled polihexanide (INN) and sold under names such as Lavasept, Serasept, and Omnicide.[2] PHMB has been shown to be effective against Pseudomonas aeruginosa, Staphylococcus aureus (also the methicillin-resistant type, MRSA), Escherichia coli, Candida albicans (yeast), Aspergillus brasiliensis (mold), vancomycin-resistant enterococci, and Klebsiella pneumoniae (carbapenem-resistant enterobacteriaceae).[3]
Some products containing PHMB are used for inter-operative irrigation, pre- and post-surgery skin and mucous membrane disinfection, post-operative dressings, surgical and non-surgical wound dressings, surgical bath/hydrotherapy, chronic wounds like diabetic foot ulcer and burn wound management, routine antisepsis during minor incisions, catheterization, scopy, first aid, surface disinfection, and linen disinfection.[4]
Branded as Baquacil, it also has an application as a swimming-pool and spa water sanitizer in place of chlorine- or bromine-based products.
PHMB is also used as an ingredient in some contact lens cleaning products, cosmetics, personal deodorants and some veterinary products.
The PHMB hydrochloride salt (solution) is used in the majority of formulations. | https://www.wikidoc.org/index.php/PHMB | |
c2f67b5631822ed8e498d86cf5c197165a2d7f65 | wikidoc | Pyrazinamide | Pyrazinamide
# 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
Pyrazinamide is an antitubercular, anti- infective agent that is FDA approved for the treatment of the initial treatment of active tuberculosis in adults and children when combined with other antituberculous agents. Common adverse reactions include hyperuricemia, nausea, vomiting, arthralgia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- HIV infection - Tuberculosis: (40 to 55 kg) 1000 mg ORALLY once daily OR 1500 mg ORALLY 3 times a week OR 2000 mg ORALLY 2 times a week in combination with other antitubercular agents; twice-weekly dosing not recommended in HIV-patients with CD4 lymphocyte counts less than 100 cells/millimeter(3)
- HIV infection - Tuberculosis: (56 to 75 kg) 1500 mg ORALLY once daily OR 2500 mg ORALLY 3 times a week OR 3000 mg ORALLY 2 times a week in combination with other antitubercular agents; twice-weekly dosing not recommended in HIV-patients with CD4 lymphocyte counts less than 100 cells/millimeter(3)
- HIV infection - Tuberculosis: (76 to 90 kg) 2000 mg ORALLY once daily OR 3000 mg ORALLY 3 times a week OR 4000 mg ORALLY 2 times a week in combination with other antitubercular agents; twice-weekly dosing not recommended in HIV-patients with CD4 lymphocyte counts less than 100 cells/millimeter(3)
- Dosing Information
- Tuberculosis: (40 to 55 kg) 1000 mg ORALLY once daily OR 1500 mg ORALLY 3 times a week OR 2000 mg ORALLY 2 times a week in combination with other antitubercular agents
- Tuberculosis: (56 to 75 kg) 1500 mg ORALLY once daily OR 2500 mg ORALLY 3 times a week OR 3000 mg ORALLY 2 times a week in combination with other antitubercular agents
- Tuberculosis: (76 to 90 kg) 2000 mg ORALLY once daily OR 3000 mg ORALLY 3 times a week OR 4000 mg ORALLY 2 times a week in combination with other antitubercular agents
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Pyrazinamide in adult patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Pyrazinamide in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- HIV infection - Tuberculosis: 15 to 30 mg/kg ORALLY once daily (MAX, 2000 mg/day) OR 50 mg/kg ORALLY 2 times a week (MAX, 4000 mg/day) in combination with other antitubercular agents
- Dosing Information
- Tuberculosis: 15 to 30 mg/kg ORALLY once daily (MAX, 2000 mg/day) OR 50 mg/kg ORALLY 2 times a week (MAX, 4000 mg/day) in combination with other antitubercular agents
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Pyrazinamide in pediatric patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Pyrazinamide in pediatric patients.
# Contraindications
- Pyrazinamide is contraindicated in persons:
- with severe hepatic damage.
- who have shown hypersensitivity to it.
- with acute gout.
# Warnings
- Patients started on pyrazinamide should have baseline serum uric acid and liver function determinations. Those patients with preexisting liver disease or those at increased risk for drug related hepatitis (e.g., alcohol abusers) should be followed closely.
- Pyrazinamide should be discontinued and not be resumed if signs of hepatocellular damage or hyperuricemia accompanied by an acute gouty arthritis appear.
### PRECAUTIONS
- Pyrazinamide inhibits renal excretion of urates, frequently resulting in hyperuricemia which is usually asymptomatic. If hyperuricemia is accompanied by acute gouty arthritis, pyrazinamide should be discontinued.
- Pyrazinamide should be used with caution in patients with a history of diabetes mellitus, as management may be more difficult.
- Primary resistance of M. tuberculosis to pyrazinamide is uncommon. In cases with known or suspected drug resistance, in vitro susceptibility tests with recent cultures of M. tuberculosis against pyrazinamide and the usual primary drugs should be performed. There are few reliable in vitro tests for pyrazinamide resistance. A reference laboratory capable of performing these studies must be employed.
- Patients should be instructed to notify their physicians promptly if they experience any of the following: fever, loss of appetite, malaise, nausea and vomiting, darkened urine, yellowish discoloration of the skin and eyes, pain or swelling of the joints.
- Compliance with the full course of therapy must be emphasized, and the importance of not missing any doses must be stressed.
- Baseline liver function studies and uric acid levels should be determined prior to therapy. Appropriate laboratory testing should be performed at periodic intervals and if any clinical signs or symptoms occur during therapy.
- Pyrazinamide has been reported to interfere with ACETEST® and KETOSTIX® urine tests to produce a pink-brown color.
- In lifetime bioassays in rats and mice, pyrazinamide was administered in the diet at concentrations of up to 10,000 ppm. This resulted in estimated daily doses for the mouse of 2 g/kg, or 40 times the maximum human dose, and for the rat of 0.5 g/kg, or 10 times the maximum human dose. Pyrazinamide was not carcinogenic in rats or male mice and no conclusion was possible for female mice due to insufficient numbers of surviving control mice.
- Pyrazinamide was not mutagenic in the Ames bacterial test, but induced chromosomal aberrations in human lymphocyte cell cultures.
- Animal reproduction studies have not been conducted with pyrazinamide. It is also not known whether pyrazinamide can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Pyrazinamide should be given to a pregnant woman only if clearly needed.
- Pyrazinamide has been found in small amounts in breast milk. Therefore, it is advised the pyrazinamide be used with caution in nursing mothers taking into account the risk-benefit of this therapy.
- Pyrazinamide regimens employed in adults are probably equally effective in children. Pyrazinamide appears to be well tolerated in children.
- Clinical studies of pyrazinamide did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. 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 or renal function, and of concomitant disease or other drug therapy.
- It does not appear that patients with impaired renal function require a reduction in dose. It may be prudent to select doses at the low end of the dosing range, however.
# Adverse Reactions
## Clinical Trials Experience
General
- Fever, porphyria and dysuria have rarely been reported. Gout (see PRECAUTIONS).
Gastrointestinal
- The principal adverse effect is a hepatic reaction (see WARNINGS). Hepatotoxicity appears to be dose related, and may appear at any time during therapy. GI disturbances including nausea, vomiting and anorexia have also been reported.
Hematologic and Lymphatic
- Thrombocytopenia and sideroblastic anemia with erythroid hyperplasia, vacuolation of erythrocytes and increased serum iron concentration have occurred rarely with this drug. Adverse effects on blood clotting mechanisms have also been rarely reported.
Other
- Mild arthralgia and myalgia have been reported frequently. Hypersensitivity reactions including rashes, urticaria, and pruritus have been reported. Fever, acne, photosensitivity, porphyria, dysuria and interstitial nephritis have been reported rarely.
## Postmarketing Experience
There is limited information regarding Pyrazinamide Postmarketing Experience in the drug label.
# Drug Interactions
There is limited information regarding Pyrazinamide Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Pyrazinamide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Pyrazinamide during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Pyrazinamide with respect to nursing mothers.
### Pediatric Use
There is no FDA guidance on the use of Pyrazinamide with respect to pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of Pyrazinamide with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Pyrazinamide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Pyrazinamide with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Pyrazinamide in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Pyrazinamide in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Pyrazinamide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Pyrazinamide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Pyrazinamide should always be administered with other effective antituberculous drugs. It is administered for the initial 2 months of a 6-month or longer treatment regimen for drug-susceptible patients. Patients who are known or suspected to have drug-resistant disease should be treated with regimens individualized to their situation. Pyrazinamide frequently will be an important component of such therapy.
- Patients with concomitant HIV infection may require longer courses of therapy. Physicians treating such patients should be alert to any revised recommendations from CDC for this group of patients.
- Usual dose: Pyrazinamide is administered orally, 15 to 30 mg/kg once daily. Older regimens employed 3 to 4 divided doses daily, but most current recommendations are for once a day. Three grams per day should not be exceeded. The CDC recommendations do not exceed 2 g per day when given as a daily regimen (see table).
- Alternatively, a twice weekly dosing regimen (50 to 70 mg/kg twice weekly based on lean body weight) has been developed to promote patient compliance with a regimen on an outpatient basis. In studies evaluating the twice weekly regimen, doses of pyrazinamide in excess of 3 g twice weekly have been administered. This exceeds the recommended maximum 3 g/daily dose. However, an increased incidence of adverse reactions has not been reported.
- The table is taken from the CDC-American Thoracic Society joint recommendations
### Monitoring
- There is limited information regarding Monitoring of Pyrazinamide in the drug label.
# IV Compatibility
- There is limited information regarding IV Compatibility of Pyrazinamide in the drug label.
# Overdosage
- Overdosage experience is limited. In one case report of overdose, abnormal liver function tests developed. These spontaneously reverted to normal when the drug was stopped. Clinical monitoring and supportive therapy should be employed. Pyrazinamide is dialyzable.
# Pharmacology
## Mechanism of Action
## Structure
- Pyrazinamide, the pyrazine analogue of nicotinamide, is an antituberculous agent. It is a white crystalline powder, stable at room temperature, and sparingly soluble in water. Pyrazinamide has the following structural formula:
- C5H5N3O- M.W. 123.11
- Each Pyrazinamide tablet for oral administration contains 500 mg of pyrazinamide and the following inactive ingredients: Corn Starch, Magnesium Stearate, Pregelatinized Starch and Stearic Acid.
## Pharmacodynamics
- There is limited information regarding Pharmacodynamics of Pyrazinamide in the drug label.
## Pharmacokinetics
- Pyrazinamide is well absorbed from the GI tract and attains peak plasma concentrations within 2 hours. Plasma concentrations generally range from 30 to 50 mcg/mL with doses of 20 to 25 mg/kg. It is widely distributed in body tissues and fluids including the liver, lungs and cerebrospinal fluid (CSF). The CSF concentration is approximately equal to concurrent steady-state plasma concentrations in patients with inflamed meninges.1 Pyrazinamide is approximately 10% bound to plasma proteins.2
- The half-life (t1/2) of pyrazinamide is 9 to 10 hours in patients with normal renal and hepatic function. The plasma half-life may be prolonged in patients with impaired renal or hepatic function. Pyrazinamide is hydrolyzed in the liver to its major active metabolite, pyrazinoic acid. Pyrazinoic acid is hydroxylated to the main excretory product, 5-hydroxypyrazinoic acid. 3
- Approximately 70% of an oral dose is excreted in urine, mainly by glomerular filtration within 24 hours. 3
- Pyrazinamide may be bacteriostatic or bactericidal against Mycobacterium tuberculosis depending on the concentration of the drug attained at the site of infection. The mechanism of action is unknown. In vitro and in vivo the drug is active only at a slightly acidic pH.
## Nonclinical Toxicology
- There is limited information regarding Nonclinical Toxicology of Pyrazinamide in the drug label.
# Clinical Studies
- There is limited information regarding Clinical Studies of Pyrazinamide in the drug label.
# How Supplied
## Storage
There is limited information regarding Pyrazinamide 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 Pyrazinamide in the drug label.
# Precautions with Alcohol
- Alcohol-Pyrazinamide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
# Look-Alike Drug Names
- A® — B®
# Drug Shortage Status
# Price | Pyrazinamide
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Deepika Beereddy, MBBS [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
Pyrazinamide is an antitubercular, anti- infective agent that is FDA approved for the treatment of the initial treatment of active tuberculosis in adults and children when combined with other antituberculous agents. Common adverse reactions include hyperuricemia, nausea, vomiting, arthralgia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- HIV infection - Tuberculosis: (40 to 55 kg) 1000 mg ORALLY once daily OR 1500 mg ORALLY 3 times a week OR 2000 mg ORALLY 2 times a week in combination with other antitubercular agents; twice-weekly dosing not recommended in HIV-patients with CD4 lymphocyte counts less than 100 cells/millimeter(3)
- HIV infection - Tuberculosis: (56 to 75 kg) 1500 mg ORALLY once daily OR 2500 mg ORALLY 3 times a week OR 3000 mg ORALLY 2 times a week in combination with other antitubercular agents; twice-weekly dosing not recommended in HIV-patients with CD4 lymphocyte counts less than 100 cells/millimeter(3)
- HIV infection - Tuberculosis: (76 to 90 kg) 2000 mg ORALLY once daily OR 3000 mg ORALLY 3 times a week OR 4000 mg ORALLY 2 times a week in combination with other antitubercular agents; twice-weekly dosing not recommended in HIV-patients with CD4 lymphocyte counts less than 100 cells/millimeter(3)
- Dosing Information
- Tuberculosis: (40 to 55 kg) 1000 mg ORALLY once daily OR 1500 mg ORALLY 3 times a week OR 2000 mg ORALLY 2 times a week in combination with other antitubercular agents
- Tuberculosis: (56 to 75 kg) 1500 mg ORALLY once daily OR 2500 mg ORALLY 3 times a week OR 3000 mg ORALLY 2 times a week in combination with other antitubercular agents
- Tuberculosis: (76 to 90 kg) 2000 mg ORALLY once daily OR 3000 mg ORALLY 3 times a week OR 4000 mg ORALLY 2 times a week in combination with other antitubercular agents
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Pyrazinamide in adult patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Pyrazinamide in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- HIV infection - Tuberculosis: 15 to 30 mg/kg ORALLY once daily (MAX, 2000 mg/day) OR 50 mg/kg ORALLY 2 times a week (MAX, 4000 mg/day) in combination with other antitubercular agents
- Dosing Information
- Tuberculosis: 15 to 30 mg/kg ORALLY once daily (MAX, 2000 mg/day) OR 50 mg/kg ORALLY 2 times a week (MAX, 4000 mg/day) in combination with other antitubercular agents
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Pyrazinamide in pediatric patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Pyrazinamide in pediatric patients.
# Contraindications
- Pyrazinamide is contraindicated in persons:
- with severe hepatic damage.
- who have shown hypersensitivity to it.
- with acute gout.
# Warnings
- Patients started on pyrazinamide should have baseline serum uric acid and liver function determinations. Those patients with preexisting liver disease or those at increased risk for drug related hepatitis (e.g., alcohol abusers) should be followed closely.
- Pyrazinamide should be discontinued and not be resumed if signs of hepatocellular damage or hyperuricemia accompanied by an acute gouty arthritis appear.
### PRECAUTIONS
- Pyrazinamide inhibits renal excretion of urates, frequently resulting in hyperuricemia which is usually asymptomatic. If hyperuricemia is accompanied by acute gouty arthritis, pyrazinamide should be discontinued.
- Pyrazinamide should be used with caution in patients with a history of diabetes mellitus, as management may be more difficult.
- Primary resistance of M. tuberculosis to pyrazinamide is uncommon. In cases with known or suspected drug resistance, in vitro susceptibility tests with recent cultures of M. tuberculosis against pyrazinamide and the usual primary drugs should be performed. There are few reliable in vitro tests for pyrazinamide resistance. A reference laboratory capable of performing these studies must be employed.
- Patients should be instructed to notify their physicians promptly if they experience any of the following: fever, loss of appetite, malaise, nausea and vomiting, darkened urine, yellowish discoloration of the skin and eyes, pain or swelling of the joints.
- Compliance with the full course of therapy must be emphasized, and the importance of not missing any doses must be stressed.
- Baseline liver function studies [especially ALT (SGPT), AST (SGOT) determinations] and uric acid levels should be determined prior to therapy. Appropriate laboratory testing should be performed at periodic intervals and if any clinical signs or symptoms occur during therapy.
- Pyrazinamide has been reported to interfere with ACETEST® and KETOSTIX® urine tests to produce a pink-brown color.
- In lifetime bioassays in rats and mice, pyrazinamide was administered in the diet at concentrations of up to 10,000 ppm. This resulted in estimated daily doses for the mouse of 2 g/kg, or 40 times the maximum human dose, and for the rat of 0.5 g/kg, or 10 times the maximum human dose. Pyrazinamide was not carcinogenic in rats or male mice and no conclusion was possible for female mice due to insufficient numbers of surviving control mice.
- Pyrazinamide was not mutagenic in the Ames bacterial test, but induced chromosomal aberrations in human lymphocyte cell cultures.
- Animal reproduction studies have not been conducted with pyrazinamide. It is also not known whether pyrazinamide can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Pyrazinamide should be given to a pregnant woman only if clearly needed.
- Pyrazinamide has been found in small amounts in breast milk. Therefore, it is advised the pyrazinamide be used with caution in nursing mothers taking into account the risk-benefit of this therapy.
- Pyrazinamide regimens employed in adults are probably equally effective in children. Pyrazinamide appears to be well tolerated in children.
- Clinical studies of pyrazinamide did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. 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 or renal function, and of concomitant disease or other drug therapy.
- It does not appear that patients with impaired renal function require a reduction in dose. It may be prudent to select doses at the low end of the dosing range, however.
# Adverse Reactions
## Clinical Trials Experience
General
- Fever, porphyria and dysuria have rarely been reported. Gout (see PRECAUTIONS).
Gastrointestinal
- The principal adverse effect is a hepatic reaction (see WARNINGS). Hepatotoxicity appears to be dose related, and may appear at any time during therapy. GI disturbances including nausea, vomiting and anorexia have also been reported.
Hematologic and Lymphatic
- Thrombocytopenia and sideroblastic anemia with erythroid hyperplasia, vacuolation of erythrocytes and increased serum iron concentration have occurred rarely with this drug. Adverse effects on blood clotting mechanisms have also been rarely reported.
Other
- Mild arthralgia and myalgia have been reported frequently. Hypersensitivity reactions including rashes, urticaria, and pruritus have been reported. Fever, acne, photosensitivity, porphyria, dysuria and interstitial nephritis have been reported rarely.
## Postmarketing Experience
There is limited information regarding Pyrazinamide Postmarketing Experience in the drug label.
# Drug Interactions
There is limited information regarding Pyrazinamide Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Pyrazinamide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Pyrazinamide during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Pyrazinamide with respect to nursing mothers.
### Pediatric Use
There is no FDA guidance on the use of Pyrazinamide with respect to pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of Pyrazinamide with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Pyrazinamide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Pyrazinamide with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Pyrazinamide in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Pyrazinamide in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Pyrazinamide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Pyrazinamide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Pyrazinamide should always be administered with other effective antituberculous drugs. It is administered for the initial 2 months of a 6-month or longer treatment regimen for drug-susceptible patients. Patients who are known or suspected to have drug-resistant disease should be treated with regimens individualized to their situation. Pyrazinamide frequently will be an important component of such therapy.
- Patients with concomitant HIV infection may require longer courses of therapy. Physicians treating such patients should be alert to any revised recommendations from CDC for this group of patients.
- Usual dose: Pyrazinamide is administered orally, 15 to 30 mg/kg once daily. Older regimens employed 3 to 4 divided doses daily, but most current recommendations are for once a day. Three grams per day should not be exceeded. The CDC recommendations do not exceed 2 g per day when given as a daily regimen (see table).
- Alternatively, a twice weekly dosing regimen (50 to 70 mg/kg twice weekly based on lean body weight) has been developed to promote patient compliance with a regimen on an outpatient basis. In studies evaluating the twice weekly regimen, doses of pyrazinamide in excess of 3 g twice weekly have been administered. This exceeds the recommended maximum 3 g/daily dose. However, an increased incidence of adverse reactions has not been reported.
- The table is taken from the CDC-American Thoracic Society joint recommendations
### Monitoring
- There is limited information regarding Monitoring of Pyrazinamide in the drug label.
# IV Compatibility
- There is limited information regarding IV Compatibility of Pyrazinamide in the drug label.
# Overdosage
- Overdosage experience is limited. In one case report of overdose, abnormal liver function tests developed. These spontaneously reverted to normal when the drug was stopped. Clinical monitoring and supportive therapy should be employed. Pyrazinamide is dialyzable.
# Pharmacology
## Mechanism of Action
-
## Structure
- Pyrazinamide, the pyrazine analogue of nicotinamide, is an antituberculous agent. It is a white crystalline powder, stable at room temperature, and sparingly soluble in water. Pyrazinamide has the following structural formula:
- C5H5N3O- M.W. 123.11
- Each Pyrazinamide tablet for oral administration contains 500 mg of pyrazinamide and the following inactive ingredients: Corn Starch, Magnesium Stearate, Pregelatinized Starch and Stearic Acid.
## Pharmacodynamics
- There is limited information regarding Pharmacodynamics of Pyrazinamide in the drug label.
## Pharmacokinetics
- Pyrazinamide is well absorbed from the GI tract and attains peak plasma concentrations within 2 hours. Plasma concentrations generally range from 30 to 50 mcg/mL with doses of 20 to 25 mg/kg. It is widely distributed in body tissues and fluids including the liver, lungs and cerebrospinal fluid (CSF). The CSF concentration is approximately equal to concurrent steady-state plasma concentrations in patients with inflamed meninges.1 Pyrazinamide is approximately 10% bound to plasma proteins.2
- The half-life (t1/2) of pyrazinamide is 9 to 10 hours in patients with normal renal and hepatic function. The plasma half-life may be prolonged in patients with impaired renal or hepatic function. Pyrazinamide is hydrolyzed in the liver to its major active metabolite, pyrazinoic acid. Pyrazinoic acid is hydroxylated to the main excretory product, 5-hydroxypyrazinoic acid. 3
- Approximately 70% of an oral dose is excreted in urine, mainly by glomerular filtration within 24 hours. 3
- Pyrazinamide may be bacteriostatic or bactericidal against Mycobacterium tuberculosis depending on the concentration of the drug attained at the site of infection. The mechanism of action is unknown. In vitro and in vivo the drug is active only at a slightly acidic pH.
## Nonclinical Toxicology
- There is limited information regarding Nonclinical Toxicology of Pyrazinamide in the drug label.
# Clinical Studies
- There is limited information regarding Clinical Studies of Pyrazinamide in the drug label.
# How Supplied
-
## Storage
There is limited information regarding Pyrazinamide 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 Pyrazinamide in the drug label.
# Precautions with Alcohol
- Alcohol-Pyrazinamide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- ®[1]
# Look-Alike Drug Names
- A® — B®[2]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/PZA | |
0c33ee58cf515105b1e1d7c116fd0f14911e970d | wikidoc | Page history | Page history
# Overview
All editable pages on WikiDoc have an associated page history, which lists all changes made to the page in reverse-chronological order. This may also be referred to as the revision history or edit history.
# Quick Tutorial
- To view a specific version, click a date .
- To compare an old version with the current version, click cur.
- To compare a version with its predecessor, click last.
- To compare to specific versions, tick the right-column radio button of the newer version and the left-column radio button of the older version, and then click the "Compare selected versions" button.
- Minor edits are denoted as m.
# Detailed tutorial
The page history consists HUJ of the old versions of the wikitext, as well as a record of the date and time (in UTC) of every edit, the username or IP address of the user who wrote it, and their Help:Edit summary/edit summary. Access the page history by clicking the "history" tab at the top of the page.
## Using page history
Below is an example of a page history using the default skin:
Edits are shown from newest to oldest. Each edit takes up one line which shows; time & date, the contributor's name or IP and the edit summary, as well as other diagnostic information.
Let's look at some of the functions of this page:
- The page name stays the same, but the "history" tab is highlighted.
- These links take you to the users most recent edits (Latest), oldest edits (Earliest) or the next or previous page of edits (Next n / Previous n). Note that the black text in brackets will become links, when applicable.
- The blue numbers list the number of edits displayed on a page - 20, 50, 100, 250 or 500. A higher number increases the length of a page but reduces the number of pages. The number you select replaces n in the links to the previous or next pages e.g. (Next 100 / Previous 100).
- (cur) takes you to a diff page, showing the difference between that edit and the current version. The current revision appears below the changes, so you can see how the page is now rendered.
- (last) takes you to a diff page showing the changes between that edit and the previous version. The most recent version (the one on the same line as the "last" you clicked on) appears below the changes, so you can see how the page was rendered.
- The two columns of radio buttons can be used to select any two versions on the page. Lets say you want to compare the versions corresponding to numbers 10 & 11 on the image. First, click the left radio button next to number 11. The right column of buttons will then fill as far as number 11. Then click the right button next to number 10. Finally click Compare selected versions. This takes you to a diff page showing the changes between the two versions. The most recent version (in this case number 10) appears below the changes, so you can see how the page was rendered.
- This gives the time and date of the edit, expressed in local time according to the preference setting
- The username or IP of the contributor appears here.
- This is the edit summary. It is the text the user wrote in the edit summary box (below the edit box).
- This edit summary begins with an arrow link and grey text. This means the user has only edited a section of the page (named in the grey text). This text is automatically added when you edit a section. A standard edit summary can be added by the user. This appears in black text.
- m stands for minor edit (small corrections to a page). These help you understand the type of changes that have been made.
If the "move page" feature has been used in the past to change a page's name, the entire edit history of the article, before and after the move, is shown. The old title becomes a redirect and loses its edit history. After merging two pages, typically one becomes a redirect. In this case the revision history of the redirect is kept.
Edits made to deleted pages are not kept in contributor's User Contributions pages. However, the revision history is kept and can be retrieved by an administrator, who can also undelete the page (see w:Wikipedia:Viewing and restoring deleted pages by sysops).
## Reverting a page
If your new pages edits aren't to your liking, don't panic; you can 'revert' the page to any previous version.
## Composite pages (transclusion)
A section of a page may be an included separate page (via a method known as transclusion), see composite pages. A separate edit history is provided for the section, and this transcluded page must be watched separately. See m:Help:A simple composite example.
## Image history
An "image" (in the broad sense of an uploaded file) can be edited, or, more generally, be replaced by a different image, by uploading a new image file with the same name. Again all versions are kept. The image history listing forms part of the image description page, which appears when clicking on the image. The image history consists of this and the old versions themselves.
Not kept are images which have been deleted (not to be confused with images that are no longer used in articles), the only record available is the upload log, deletion log and possibly the "votes for deletion" archive. Neither the latest nor older versions are kept by the system, hence it is not possible to undelete an image.
## Linking to a specific version of a page
It is occasionally useful to link to a specific version of an article (a snapshot of it). For example, one might have done a review of a Wikipedia article and want to indicate which particular version was reviewed.
If the version is not the current version, one can use the page history to view the old version of the page. The URL of this old version is suitable for use to permanently reference this version, and can usually be obtained from the browser's location bar.
See also URLs of old versions of pages.
The history of the wikitext should not be confused with the history of the rendered page:
- If a page contains a time-based variable, its rendered content varies with time; for example, {{CURRENTTIME}} gives the time of viewing the page; if at some stage the tag {{subst:CURRENTTIME}} has been placed, it has been replaced in the wikitext by the time of saving that revision; there is no variable for the time of saving the particular revision.
In particular, templates and images will vary if they are referred to with an expression containing a variable depending on time
- In particular, templates and images will vary if they are referred to with an expression containing a variable depending on time
- The current versions of templates and images are used - it is not possible to specify a particular revision, unless old versions are given different names. Note that also templates used within these templates may have been revised.
For a true permalink, upload the rendered page as HTML file (if enabled by the system) and link to the URL, e.g. (see also the image page w:en:Image:Wikitest.html; by the way, this page was not uploaded because of templates or images, but because of added functionality using JavaScript, not allowed in wikitext).
The HTML contains the contents of the templates, so the page is not affected by a change or deletion of a template. It further contains URL-references to images; it is not affected by an image revision, but it is by a deletion.
To produce a wikitext version not depending on templates use "subst:", if necessary recursively.
See also Help:Downloading pages.
## Special:Export
Special:Export produces an XML-file, without the MediaWiki user interface, with the wikitext of the current and optionally all old versions of one or more specified pages, with date, time, user name, and edit summary. How it is displayed, e.g. with or without XML tags, and with or without applying new lines, depends on the browser. Some browsers show "+" and "-" links to view or hide selected parts. Alternatively the XML-source can be viewed using the "view source" feature of the browser, or after saving the XML file locally, with a program of choice.
The feature also allows searching for a text in all versions of one or more specified pages. See also XML export.
## Archiving
Archiving texts in separate pages is superior to using the page history as archive: texts in archive pages can be found by search engines. Page histories can only be searched after applying Special:Export. Also, archive pages can be organized and titled afterwards in a suitable way, while e.g. edit summaries can not be supplied afterwards. However, an index of old versions of a page, with links to them, could be prepared.
# Watched pages
If one views the history of a watched page directly, without first viewing the page, the edit at the top (the most recent one) may be marked with update marker "updated (since my last visit)" (or the content of MediaWiki:Updatedmarker); this applies if the edit was made by someone else and you have not viewed the page (while logged in) since it was made. The positioning of the message, suggesting that it is a property of an edit rather than a property of the page, is somewhat misleading, because not all edits which have not been viewed yet are marked.
# Web feed | Page history
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
All editable pages on WikiDoc have an associated page history, which lists all changes made to the page in reverse-chronological order. This may also be referred to as the revision history or edit history.
# Quick Tutorial
- To view a specific version, click a date .
- To compare an old version with the current version, click cur.
- To compare a version with its predecessor, click last.
- To compare to specific versions, tick the right-column radio button of the newer version and the left-column radio button of the older version, and then click the "Compare selected versions" button.
- Minor edits are denoted as m.
# Detailed tutorial
The page history consists HUJ of the old versions of the wikitext, as well as a record of the date and time (in UTC) of every edit, the username or IP address of the user who wrote it, and their Help:Edit summary/edit summary. Access the page history by clicking the "history" tab at the top of the page.
## Using page history
Below is an example of a page history using the default skin:
Edits are shown from newest to oldest. Each edit takes up one line which shows; time & date, the contributor's name or IP and the edit summary, as well as other diagnostic information.
Let's look at some of the functions of this page:
- The page name stays the same, but the "history" tab is highlighted.
- These links take you to the users most recent edits (Latest), oldest edits (Earliest) or the next or previous page of edits (Next n / Previous n). Note that the black text in brackets will become links, when applicable.
- The blue numbers list the number of edits displayed on a page - 20, 50, 100, 250 or 500. A higher number increases the length of a page but reduces the number of pages. The number you select replaces n in the links to the previous or next pages e.g. (Next 100 / Previous 100).
- (cur) takes you to a diff page, showing the difference between that edit and the current version. The current revision appears below the changes, so you can see how the page is now rendered.
- (last) takes you to a diff page showing the changes between that edit and the previous version. The most recent version (the one on the same line as the "last" you clicked on) appears below the changes, so you can see how the page was rendered.
- The two columns of radio buttons can be used to select any two versions on the page. Lets say you want to compare the versions corresponding to numbers 10 & 11 on the image. First, click the left radio button next to number 11. The right column of buttons will then fill as far as number 11. Then click the right button next to number 10. Finally click Compare selected versions. This takes you to a diff page showing the changes between the two versions. The most recent version (in this case number 10) appears below the changes, so you can see how the page was rendered.
- This gives the time and date of the edit, expressed in local time according to the preference setting
- The username or IP of the contributor appears here.
- This is the edit summary. It is the text the user wrote in the edit summary box (below the edit box).
- This edit summary begins with an arrow link and grey text. This means the user has only edited a section of the page (named in the grey text). This text is automatically added when you edit a section. A standard edit summary can be added by the user. This appears in black text.
- m stands for minor edit (small corrections to a page). These help you understand the type of changes that have been made.
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9e65e43c001636ff09ed8f20e3d673464a199271 | wikidoc | Paleontology | Paleontology
Paleontology is a study of fossils, plant and animal remains found on the Earth.
Paleontology is a large subject because it includes aspects of geology and biology. Depending on the particular branch of paleontology studied, it may also require knowledge of chemistry, climatology, physics, and astronomy among others. It may also involve creating new techniques both in application and in theory. Paleontologists may work in outdoors, in an office or laboratory, or in a library; they may use a huge range of tools from bull dozers to computers.
The study of paleontology covers the entire history of life on Earth, which is about 4 billion years.
Paleontology is the branch of science dealing with study of past life. Paleontologists are the scientists that carry out this study.
The study of past life is done through the study of fossils which are evidence of that past life. Fossils may be the remains of organisms (plants, animals, etc.) or the remains of their activities (footprints, burrows, etc.). The later are called trace fossils.
Paleontology covers the entire span of life on Earth, from the first organisms around 4 billion years ago, up to the present day. However, scientists which study recent human activity, the last 12,000 years or so, are generally called archaeologists, and their study is called archaeology. There is a blurry line where archaeology begins and paleontology leaves off.
Paleontology is generally considered a part of geology, though because it involves life, it can also be considered a part of biology. Paleontologists must know something of both geology and biology. In particular in geology they must understand sedimentary geology - the study of sediments. In biology paleontologists need to know something about comparative anatomy, and in particular the anatomy of the organisms they study.
There are many sub-groups within paleontology, depending on what specifically is being studied. Among these is Vertebrate Paleontology (the study of fossil animals with backbones), Invertebrate Paleontology (the study of animals without backbones), Paleobotany (the study of fossil plants), and Paleoecology (the study of ancient environments). Almost everything within paleontology has it's own specialist name.
# Theoretical paleontology
Def. the "tudy of the forms of life existing in prehistoric or geologic times" is called paleontology.
Clades from the paleontological rock record sometimes display a clade asymmetry. "(Our two cases of Metazoa and mammals represent the first filling of life's ecological "barrel" for multicellular animals, and the radiation of mammals into roles formerly occupied by dinosaurs.)"
# Fossils
Def. "he mineralized remains of an animal or plant" or "ny preserved evidence of ancient life, including shells, imprints, burrows, coprolites, and organically-produced chemicals" is called a fossil.
Derived terms include ichnofossil, index fossil, living fossil, mesofossil, microfossil, and trace fossil.
# Colors
"On December 9, 1833, the English fossil collector Elizabeth Philpot sent a letter to naturalist William Buckland. In addition to requesting back some vertebrae of a marine reptile Buckland had borrowed, Philpot also included notes on a recent trip with a young upstart fossil hound—the pioneering paleontologist Mary Anning. But what made the note special was an illustration Philpot had included with the letter. It depicted the toothy smile of an Ichthyosaurus skull, drawn after one of the many such fossils that Philpot, her sisters and Anning were finding in the ancient rocks of England’s southern coast. And it wasn’t drawn in any ordinary ink. The sepia tones were made from the preserved ink of a squid-like creature found in the same deposits as the ichthyosaur, revitalized after 200 million years."
"On the surface, Philpot’s drawing might only seem to be a neat fossiliferous trick. In 2009, another drawing made from ancient ink kicked up renewed attention for the surprising fact that traces of prehistoric color could persist to the 21st century. But the fact that such primordial shades can be recovered at all opens up a realm of scientific possibility. With the right specimens, experts can start to color in the fossil record."
"Researchers have known about fossil insect color patterns and mollusk color patterns all the way back to the Victorian era."
"The biological key to solving the coloration puzzle comes down to miniscule structures called melanosomes. These are tiny, blobby organelles that contain pigment, or melanin, and are present in soft tissues such as skin, scales, and feathers. And while these details were often cast aside as fossil bacteria in decades past, renewed efforts in the 21st century have been able to find the relationship between these tiny structures and colors."
"The discovery of preserved melanosomes opens up the possibility of interpreting the colour of extinct birds and other dinosaurs."
"Pulling color from the past requires a combination of lucky finds with advanced imaging techniques."
"First, paleontologists need a fossil which is likely to have preserved melanin—a fossil not just with bones, but feathers, skin or hair. These fossils often contain both melanosomes as well as chemically-degraded melanin pigment, and when paleontologists find such a fossil, then they can use modern technology to take a closer look."
"You start by looking for the microbodies using instruments like scanning electron microscopes."
"Once those characteristic shapes turn up, chemical analysis can confirm the presence of melanin pigment."
"This was particularly critical early on in fossil melanin studies because there was still some doubt that the microbodies were in fact melanosomes and not other similar structures, like bacteria. From there, comparisons of the physical and chemical signatures of the melanosomes and melanin can be compared to those of living animals, for which color is known, to reconstruct the look of creatures long dead."
"When paleontologists announced the discovery of the feathered dinosaur Anchiornis in 2009, the preserved plumage surrounding the skeleton was a dark, carbon-colored shade. But analysis of another Anchiornis fossil the following year revealed a striking color pattern that had previously been invisible. The distribution and details of the preserved melanosomes indicated that Anchiornis was covered in feathers of black and white—not dissimilar from a magpie—with a splash of red feathers on the top of its head. For the first time, a dinosaur had been fully restored in living color."
"The week before the Anchiornis paper came out, the small, fuzzy dinosaur Sinosauropteryx was shown to have a vibrant, red-and-white banded tail. In 2012, the stacked arrangement of melanosomes found in the feathers of four-winged dinosaur Microraptor was shown to create an iridescent sheen similar to that of a modern raven. (Avian dinosaurs joined the list, too, with giant fossil penguins bearing color patterns of black, red and gray.) And while early studies focused on feathers, paleontologists soon found that melanosomes can reveal the hues of scaly dinosaurs, too. The beaky, horned dinosaur Psittacosaurus was countershaded dark above and light below to help with camouflage, and the immense armored dinosaur Borealopelta sported reddish-brown tones."
"Comparison of melanosome proportions and body contour feather morphology in extinct penguins Inkayacu paracasensis (A and B) and representative extant penguins (C and D)."
"In the case Borealopelta, for example—with a pattern of rusty red on top, light on bottom—the shading might have been a way for the low-slung dinosaur to hide from the ravenous tyrannosaurs of the time. Other dinosaurs were flashier. The candy-cane tail of Sinosauropteryx was likely a social signal, used by these dinosaurs to communicate with each other when they met."
"The dinosaur is portrayed in the predicted open habitat in which it lived around the Jehol lakes, preying on the lizard Dalinghosaurus."
# Micropaleontology
Micropaleontology is a study of fossil micro-organisms, including foraminifera, which have applications in stratigraphic correlation and age dating along with paleoecology and paleoclimatology.
The image at the right shows microspheric and megalospheric Nummulitid specimens.
# Paleobotany
Paleobotany is the study of plant or plant-like fossils.
The image at the right shows fronds impressed onto shale in a specimen on display at the Paläontologische Museum München. The fossil is from Scalby Ness, Scarborough, England.
# Palynology
Although regarded as a separate field of its own, in a real sense palynology is the micropaleontological equivalent of paleobotany that involves the study of fossil pollen and spores.
The image at right contains a spore tetrad (in green) of genus Scylaspora and trilete spores (blue, ~30-35μm diameter) from a late Silurian sporangium (Burgsvik beds, Sweden).
# Invertebrate paleontology
Invertebrate paleontology is a study of fossil invertebrate animals, those which lack a backbone. Included are magafaunas whose study doesn't require a microscope, found in various phyla. Applications include stratigraphic dating and correlation, and paleo-ecology.
At the right is an example of invertebrate paleontology, specifically bryozoan fossils in an Ordovician oil shale from Estonia.
# Vertebrate paleontology
Vertebrate paleontology is any study of prehistoric animals with backbones, e.g. fish of various kinds, marine and terrestrial reptiles, dinosaurs, birds, and mammals.
As a representative of vertebrate paleontology, the image at the right shows a skeleton of Mosasaurus hoffmannii on display at the Natural History Museum of Masstricht.
# Paleoecology
In the image on the right, a group of Brancasaurus brancai are portrayed in an artists impression of their natural habitat together with some pycnodontiformes, Caturus and Hybodus in the far background.
# Paleoclimatology
Paleoclimatology is the study of ancient climates. This helps paleontologists understand the environments that existed over the history of the Earth.
Paleoclimatology is also particularly important in understanding how climate might change in the future.
# Geologic time
At right is a geologic clock representation. It shows some of the major units of geological time and definitive events of Earth history. The Hadean eon represents the time before fossil record of life on Earth; its upper boundary is now regarded as 4.0 Ga (billion years ago). Other subdivisions reflect the evolution of life; the Archean and Proterozoic are both eons, the Palaeozoic, Mesozoic and Cenozoic are eras of the Phanerozoic eon. The two million year Quaternary period, the time of recognizable humans, is too small to be visible at this scale.
The following four timelines show the geologic time scale. The first shows the entire time from the formation of the Earth to the present, but this compresses the most recent eon. Therefore the second scale shows the most recent eon with an expanded scale. The second scale compresses the most recent era, so the most recent era is expanded in the third scale. Since the Quaternary is a very short period with short epochs, it is further expanded in the fourth scale. The second, third, and fourth timelines are therefore each subsections of their preceding timeline as indicated by asterisks. The Holocene (the latest epoch) is too small to be shown clearly on the third timeline on the right, another reason for expanding the fourth scale. The Pleistocene (P) epoch. Q stands for the Quaternary period.
# Cenozoic Era
After the dinosaurs became extinct, the Cenozoic began.
The Cenozoic Era is comprised of the following:
- Quaternary Period (2.588 mya to present)
Anthropocene Epoch (up to the present)
Holocene Epoch (11,700 yrs to the beginning of the Anthropocene)
Pleistocene Epoch (2.588 mya to 11,700 yrs)
- Anthropocene Epoch (up to the present)
- Holocene Epoch (11,700 yrs to the beginning of the Anthropocene)
- Pleistocene Epoch (2.588 mya to 11,700 yrs)
- Neogene Period (23.03 to 2.588 mya)
Pliocene Epoch (5.332 to 2.588 mya)
Miocene Epoch (23.03 to 5.332 mya)
- Pliocene Epoch (5.332 to 2.588 mya)
- Miocene Epoch (23.03 to 5.332 mya)
- Paleogene Period (65.5 to 23.03 mya)
Oligocene Epoch (33.9 to 23.03 mya)
Eocene Epoch (55.8 to 33.9 mya)
Paleocene (65.5 to 55.8 mya)
- Oligocene Epoch (33.9 to 23.03 mya)
- Eocene Epoch (55.8 to 33.9 mya)
- Paleocene (65.5 to 55.8 mya)
## Anthropocene Epoch
The Anthropocene Epoch is a newly added geologic time period. It is the "age of humans", when human activity grew to be the dominant force in shaping the Earth. The time of the beginning of this Epoch has not been completely settled upon. Claims run from 12,000 years ago when widespread agriculture began, to 1945 C.E. when the first atomic bomb was exploded.
For purposes of paleontology, the Anthropocene is primarily ignored, and is relegated to the science of archaeology, or the study of history, depending on when it is considered to have begun.
## Holocene Epoch
The Holocene starts at ~11,700 b2k and extends to the beginning of the Anthropocene Epoch.
## Pleistocene Epoch
The Pleistocene dates from 2.588 x 106 to 11,700 b2k.
People appear.
### GIS 3
The stronger GIS 3 interstadial occurred about 27.6 kyr B.P.
"In the Karginian Age (MIS 3) alluvial deposits of the described locality the remains of Elasmotherium sibiricum, Mammuthus ex gr. trogontherii-chosaricus, Mammuthus primigenius, Bison sp. AMS Radiocarbon dating of the Elasmotherium skull gave a young age - 26038 ± 356 BP (UBA-30522)."
### Hasselo stadial
The "Hasselo stadial at approximately 40-38,500 14C years B.P. (Van Huissteden, 1990)."
"The rhinoceros Elasmotherium sibiricum, known as the ‘Siberian unicorn’, was believed to have gone extinct around 200,000 years ago—well before the late Quaternary megafaunal extinction event. However, no absolute dating, genetic analysis or quantitative ecological assessment of this species has been undertaken. accelerator mass spectrometry radiocarbon dating of 23 individuals, including cross-validation by compound-specific analysis, E. sibiricum survived in Eastern Europe and Central Asia until at least 39,000 years ago, corroborating a wave of megafaunal turnover before the Last Glacial Maximum in Eurasia, in addition to the better-known late-glacial event. Stable isotope data indicate a dry steppe niche for E. sibiricum and, together with morphology, a highly specialized diet that probably contributed to its extinction. DNA sequencing data, a very deep phylogenetic split between the subfamilies Elasmotheriinae and Rhinocerotinae that includes all the living rhinoceroses, settling a debate based on fossil evidence and confirming that the two lineages had diverged by the Eocene. As the last surviving member of the Elasmotheriinae, the demise of the ‘Siberian unicorn’ marked the extinction of this subfamily."
## Pliocene Epoch
The Pliocene ranges from 5.332 x 106 to 2.588 x 106 b2k.
## Miocene Epoch
The Miocene dates from 23.03 x 106 to 5.332 x 106 b2k.
"A giant goose that lived on a Mediterranean island between six and nine million years ago had wings tailored for combat."
"Weighing 22 kilograms and standing perhaps 1.5 metres tall, Garganornis ballmanni might be the biggest member of the duck, goose and swan family ever to have lived. Its fossilised bones have been found at Gargano and Scontrone in central Italy – a region that, during the Miocene, consisted of islands populated by unique species."
"Its wing bones are short for its size, suggesting it couldn’t fly. carpometacarpus bone – equivalent to the hand bones in humans – had a rounded lump called the carpal knob, a feature present in modern birds that fight each other over territory. These include some ducks, geese and the extinct Rodrigues solitaire, the closest relative of the dodo."
“It’s covered over with hard skin, so it becomes a really effective weapon. In solitaires, they certainly broke each others’ bones.”
"Battles over territory are the most likely reason for Garganornis‘s fighting adaptation."
"Ducks and geese that live on islands, such as the extinct moanalo of Hawaii, often evolve to be terrestrial and territorial. That’s because fresh water is often in short supply, and so they live in forests as herbivores."
“You’ve got this big bird, with its wings used for fighting, that would have been incredibly aggressive and would have been able to defend its young against most predators.”
Fossils "from the Early Miocene St Bathans Fauna of New Zealand to the former existence of a giant psittaciform, which is described as a new genus and species . The fossils are two incomplete tibiotarsi from a bird with an estimated mass of 7 kg, double that of the heaviest known parrot, the kakapo Strigops habroptila. These psittaciform fossils show that parrots join the growing group of avian taxa prone to giantism in insular species, currently restricted to palaeognaths, anatids, sylviornithids, columbids, aptornithids, ciconiids, tytonids, falconids and accipitrids."
"Insular avifaunas are renowned for the evolution of novelties, usually in the form of extraordinarily large and flightless members of widespread and well-known lineages . Preeminent among these is the columbid Dodo Raphus cucullatus of Mauritius , but the list includes giant Sylviornithidae on New Caledonia (Sylviornis) and Fiji (Megavitiornis) , other giant columbids on Rodrigues (Pezophaps) and on Fiji (Natunaornis) , giant waterfowl on Hawaii and Malta , a giant ciconiid stork on Flores, Indonesia , and giant tytonid owls and other raptors in the Caribbean . Insular rails (Rallidae) tend to be larger than mainland relatives, but the largest, the Takahe (Porphyrio hochstetteri) from New Zealand (NZ), at up to 3.2 kg, is smaller than these insular giants ."
"Since moa were first reported in 1839 , NZ has become recognized as the epitome of the phenomenon of island giantism in birds. In addition to nine moa species (Dinornithiformes), two flightless anserines (Cnemiornis, Anatidae), two gruiforms (Aptornis, Aptornithidae) and a huge eagle (Hieraaetus moorei, Accipitridae) evolved from small ancestors into giant elements of the Holocene avifauna ."
"The fossils, catalogued in the Museum of New Zealand Te Papa Tongarewa collections, are shafts of left and right tibiotarsi probably of one individual . Tibiotarsi of Heracles inexpectatus gen. et sp. nov., left, holotype (a,b,f) NMNZ S.51083 and right, paratype (g), compared to (d,e) left tibiotarsus of Strigops habroptila (Canterbury Museum Av45277), in craniolateral (a) and cranial (b–g) views. (c) Silhouettes of a human and Heracles for scale. Scale bars are 20 mm. Abbreviations: ccl, crista cnemialis lateralis; cl, condylus lateralis; cm, condylus medialis; dtl, distal insertion scar for transverse ligament; fc, fibular crest; lfr, lateral scar for fibular retinaculum; lic, linea intermuscularis cranialis; mfr, mediocranial scar for fibular retinaculum; pons, pons supratendineus; ptl, proximal insertion scar for transverse ligament; se, sulcus extensorius; sf, sulcus m. fibularis; trf, tuberculum retinaculi m. fibularis. Human silhouette from PhyloPic, by T. M. Keesey."
Fossils of Heracles inexpectatus are from a "conglomerate, 9.5–9.58 m above base of Bannockburn Formation, Early Miocene, 19–16 Ma ".
"The holotype of Heracles inexpectatus is the largest fossil bone known among several thousand specimens in the fauna and adds a giant psittaciform to it."
"The St Bathans Fauna has already revealed evidence for an Early Miocene radiation of parrots (Psittaciformes) in NZ, with three small nestorids described in Nelepsittacus, and another the size of Nestor notabilis . Extant nestorids are grouped in Nestor as the sister taxon to Strigops habroptila; the two groups combined form the NZ endemic clade Strigopoidea that is the sister taxon of remaining psittaciforms . Strigops habroptila is the heaviest and only flightless psittaciform , with legbones the largest among parrots . Heracles inexpectatus has similar proportions and morphology to S. habroptila, but is much larger, differing qualitatively in greater medial projection of the proximomedial scar of the transverse ligament and less projection of the lateral fibular retinaculum scar , the last relating to less climbing ability . All known fossil parrots are much smaller than Strigops . Given this similarity and its provenance, the affinity of Heracles inexpectatus may lie with Strigopoidea. The short separation of the mediocranial fibular retinaculum scar from the condyle suggests closer affinity to strigopids than nestorids ."
## Oligocene Epoch
The Oligocene dates from 33.9 ± 0.1 x 106 to 23.03 x 106 b2k.
The Oligocene Epoch covers 34 - 23 Mya.
"As the Earth began to cool, the tropical plants that had previously been found relatively widespread began to recede towards the equator where it was still warm. The general tropical plants began a transition to more forest like areas. The first grasses also appeared in the late Oligocene. The appearance of these grasses led to to evolution of various herbivore animals. With bodies low to the ground, animals would take advantage of the new grasses that appeared."
## Eocene Epoch
The Eocene dates from 55.8 ± 0.2 x 106 to 33.9 ± 0.1 x 106 b2k.
"Death came suddenly for the young fish darting through a lake roughly 50 million years ago."
A "stone slab from the western United States includes the fossils of 257 now-extinct fish (Erismatopterus levatus) bunched together in a dense swarm."
Each "fish’s orientation and position" have been analyzed.
The "ancient fish followed two rules used by their modern counterparts. An individual was repelled by its closest companions — to avoid collisions — and attracted to those farther away, which encouraged clumping. Like a modern-day school, the fossilized grouping had an elongated shape that might have helped to ward off predators."
## Paleocene Epoch
The Paleocene dates from 65.5 ± 0.3 x 106 to 55.8 ± 0.2 x 106 b2k.
# Mesozoic Era
With another mass extinction Mezozoic era started. Now dinosaurs rule.
The Mesozoic Era is divided into the Cretaceous, Jurassic, and Triassic Periods.
"A high diversity of terrestrial vertebrates with dinosaurs as the dominant group is strongly indicated but not much of it is yet recorded."
For much of the dinosaur era, the smallest sauropods are larger than anything else in their habitat, and the largest are an order of magnitude more massive than anything else that has since walked the Earth.
# Cretaceous Period
"The Cretaceous period is the third and final period in the Mesozoic Era. It began 145.5 million years ago after the Jurassic Period and ended 65.5 million years ago, before the Paleogene Period of the Cenozoic Era."
# Late Cretaceous
Rock strata from the Late Cretaceous epoch form the Upper Cretaceous series.
The Late Cretaceous (100.5–66 Ma) is the younger of two epochs, the other being the Early Cretaceous, into which the Cretaceous period is divided in the geologic timescale.
## Maastrichtian
The Maastrichtian is the most recent stage of the upper Cretaceous from 66.0 - 72.1 Ma. The mummified Edmontosaurus annectens in the image on the right is from the Maastrichtian.
The Lameta Formation is a sedimentary rock formation found in Madhya Pradesh, Gujarat, and Maharashtra, India, of Maastrichtian age (Upper Cretaceous), notable for its dinosaur fossils, several genera of dinosaurs from these rocks, including the titanosaur sauropod Isisaurus, the abelisaurs Indosaurus, Indosuchus, Laevisuchus, and Rajasaurus and possible stegosaurs.
Traditionally, pterosaur faunas of the Maastrichtian appeared to be dominated by Azhdarchidae, with other pterosaur groups having become extinct earlier on, but, more recent findings suggest a fairly composite pterosaur diversity: at least six (Nyctosaurus lamegoi, a Mexican humerus, a Jordan humerus and several taxa from Morocco) Nyctosauridae date to this period, as do a few Pteranodontidae, and Navajodactylus, tentatively assigned to Azhdarchidae, lacking any synapomorphies of the group. This seems to underscore a higher diversity of terminal Cretaceous pterosaurs than previously thought.
The specimen second down on the left is Jeletzkytes spedeni from the Maastrichtian (Upper-Cretaceous) Fox Hills Formation, locality - South Dakota, USA. Matrix free specimen is 7.5 cm (3") in diameter, displaying pearly aragonite preservation of the shell.
The type species of Hainosaurus is H. bernardi, named after the Belgian Léopold Bernard, owner of the phosphate chalk exploitation where the fossil was unearthed. In a paper published in 2016, Hainosaurus was considered congeneric with Tylosaurus.
## Campanian
The Campanian was an age when a worldwide marine transgression or sea level rise drowned many coastal areas, preserved as an unconformity beneath a cover of marine sedimentary rocks.
During the Campanian age, an evolutionary radiation among dinosaur species occurred, where in North America, for example, the number of known dinosaur genera rises from 4 at the base of the Campanian to 48 in the upper part, sometimes referred to as the "Campanian Explosion" the generally warm climates and large continental area covered in shallow sea during the Campanian probably favoured the dinosaurs, but in the following Maastrichtian stage, the number of North American dinosaur genera found is 30% less than in the upper Campanian.
The image on the right shows a juvenile Chasmosaurus fossil seen from the side.
"The Ceratopsidae are one of the more immediately recognizable groups of dinosaurs. Characterized by sharp beaks and flamboyant horns and frills, these herbivores almost all lived in what is now Western North America right at the end of the Cretaceous period, 100 to 66 million years ago."
"Chasmosaurus belonged to this group The 75 million-year-old fossilized Chasmosaurus was spotted in 2010 within the Dinosaur Park Formation in Alberta, Canada. In 2013, paleontologists completely unearthed it, and this week, they have described what is undoubtedly a rare specimen."
“For the first time ever, we have a complete skeleton of a baby ceratopsid.”
"Only its forelimbs are completely missing."
"The adult variants are certainly distinctive, with large openings in their head ornaments earning them their appropriate name, which literally means “opening lizard.” Fully grown, they reach a size of up to 4.8 meters (16 feet) and a weight of roughly 2 tonnes (2.2 tons)."
"This juvenile Chasmosaurus is an adorable 1.5 meters (4.9 feet) in length, and would have weighed less than 100 kilograms (220 pounds). It’s so young that its vertebrae had not properly fused, its limbs were not fully articulated (joined up), and it had a particularly short snout. Due to its ornamental opening being fully enclosed by a single bone, scientists have deduced it is likely a species called Chasmosaurus belli."
“We've only had a few isolated bones before to give us an idea of what these animals should look like as youngsters, but we've never had anything to connect all the pieces. All you need is one specimen that ties them all together. Now we have it!”
Tylosaurus proriger is from the Santonian and lower to middle Campanian of North America (Kansas, Alabama, Nebraska, etc.).
## Santonian
The specimen Hungarosaurus tormai designated as the holotype is MTM Gyn/404 (in the collections of the Magyar Természettudományi Múzeum, Budapest, Hungary) and consists of 450 bones, including portions of the skull (premaxilla, left prefrontal, left lacrimal, right postorbital, jugal and quadratojugal, left frontal, pterygoid, vomer, the right quadrate and a fragment of the left quadrate, basioccipital, one hyoid), an incomplete right mandible, three cervical vertebrae, six dorsal vertebrae, ten caudal vertebrae, ossified tendon fragments, three cerival and thirteen dorsal ribs, five chevrons, the left scapulocoracoid, right scapula, portions of the right manus, a partial pelvis, and more than one hundred osteoderms.
The length of Hungarosaurus has been estimated at about 4 to 4.5 meters.
The exposure of the Csehbánya Formation that produced Hungarosaurus tormai has also yielded remains of bony fishes, turtles, lizards, crocodiles, and pterosaurs, along with teeth from a diminutive dromaeosaurid-like theropod and a Rhabdodon-like ornithopod.
The image in the center shows fossil pieces identified as a baby Tylosaurus.
## Coniacian
The holotype of the type species, Futalognkosaurus dukei, was originally estimated at 32-34 m in length. In 2008 this was down-sized to 26 m. Holtz estimated it at 28 m. An estimate by Gregory S. Paul was that Futalognkosaurus had a maximum length of 30 m. Its weight has been estimated between 38.1-50 tonnes. Its long neck contained 14 vertebrae, and was over a meter deep in places, due to its extremely tall neural spines which had a distinctive "shark-fin" shape. The hips were also extremely large and bulky, reaching a width of nearly 3 m.
The genus name is derived from the local indigenous language Mapudungun and is pronounced foo-ta-logn-koh-sohr-us: "futa" means "giant" and "lognko" means "chief".
Futalognkosaurus is a member of the Titanosauridae (or Lithostrotia, depending on the definitions being used), and most closely related to Mendozasaurus, defining a new clade for the group containing both Futalognkosaurus and Mendozasaurus, their common ancestor, and all descendants, which they named the Lognkosauria. Malawisaurus is the sister group of this new clade. Another, much later member of Lognkosauria is the colossal Puertasaurus,
## Turonian
## Cenomanian
During the Cenomanian was the origin of the crown-group Crocodylia, the true-crocodiles
An unnamed Enantiornithes bird is of northern Gondwana
In 1996 in the Neuquén province of Argentina a skeleton of a theropod was discovered in the Sierra del Portezuelo and reported the same year.
In 2002 near the Lago Barreales a second skeleton was uncovered and reported in 2003.
In 2004 it was named and described as a second species: Unenlagia paynemili, where the holotype MUCPv-349, a partial skeleton consisting of a humerus and two pubes and several paratypes were also assigned: MUCPv-343, a claw; MUCPv-409, a partial ilium; MUCPv-415, a phalanx and MUCPv-416, a vertebra.
Neuquenraptor may be a junior subjective synonym of Unenlagia.
The body length of Unenlagia has been disputed, due to the fact that only the leg length is well known and it is uncertain whether this should be extrapolated using the proportions of the low-slung Dromaeosauridae or the long-legged basal birds with estimates varied between a length of 3.5 metres and a weight of 75 kilogrammes on the one hand, and a length of just two metres on the other.
The pelvic region of Unenlagia, especially the form of the ilium, was very similar to that of the early bird Archaeopteryx.
The shoulder girdle of Unenlagia was originally interpreted as if it was adapted for flapping, with a flat scapula positioned on top of the ribcage, making the shoulder joint point more laterally, but this would imply that the shoulder-blade was dorsoventrally flattened instead of laterally as with other theropods and that it thus were more likely the scapula was located on the side of the ribcage.
This conformed to a later hypothesis that non-avian theropods like Unenlagia were unable to lift their forelimbs above their back, as even would still have been the case for the basalmost bird Archaeopteryx.
South-American workers have remained unconvinced though, countering that a laterally positioned scapula would make the coracoid of Unenlagia jut into its ribcage, which seems anatomically implausible.
Unenlagia was a member of the Dromaeosauridae. Unenlagia would have belonged to the extremely bird-like Gondwanan clade of dromaeosaurids called the Unenlagiinae, and be closely related to species such as Buitreraptor and Neuquenraptor (which might be the same species as Unenlagia), with the 'flying raptor' Rahonavis as a member of this group, which would mean that either Unenlagia is secondarily flightless, having evolved from flying, Rahonavis-like ancestors, or that bird-like flight evolved at least twice. Rahonavis was found be the sister taxon of Unenlagia.
But, Unenlagiidae was positioned within Avialae.
The second image down on the right contains a 100-million-year-old chunk of amber found in Myanmar with the head, neck, wing, tail and feet of a hatchling.
"It’s the most complete and detailed view we’ve ever had."
"While it looks as if the actual skin and flesh of the bird are preserved in the amber, it’s basically a very detailed impression of the animal. Studies of similar finds show the flesh has broken down into carbon – and there’s no usable DNA".
"The unfortunate youngster belonged to a group of birds known as the 'opposite birds' that lived alongside the ancestors of modern birds and appear to have been more diverse and successful – until they died out with the dinosaurs 66 million years ago."
"In appearance, opposite birds likely resembled modern birds, but they had a socket-and-ball joint in their shoulders where modern birds have a ball-and-socket joint – hence the name. They also had claws on their wings, and jaws and teeth rather than beaks – but at the time the hatchling lived, the ancestors of modern birds had not yet evolved beaks either."
# Early Cretaceous
## Albian
## Aptian
## Barremian
## Hauterivian
## Valanginian
"The unusual aspect of this is the way the soft tissues, which are so fragile and 133 million years old, have actually been preserved. It’s not the entire brain — it’s just remarkable preservation of soft tissues you wouldn’t expect to have preserved."
"The acid solution would have pickled the parts of the brain that were immersed."
The "highly detailed mineralization of soft tissues associated with a naturally occurring brain endocast of an iguanodontian dinosaur found in c. 133 Ma fluvial sediments of the Wealden at Bexhill, Sussex, UK."
## Berriasian
"This femur is huge! And in an exceptional state of conservation. It's very moving."
# Jurassic Period
"The Jurassic Period takes place after the Triassic Period and before the Cretaceous Period. This period is well known for the reign of the dinosaurs of its time and the global tropical landscape."
"The Jurassic is a geologic period and system that extends from about 199.6±0.6 Ma (million years ago) to 145.5±4 Ma; that is, from the end of the Triassic to the beginning of the Cretaceous. The Jurassic constitutes the middle period of the Mesozoic Era, also known as the Age of Reptiles. The start of the period is marked by the major Triassic–Jurassic extinction event. However, the end of the period did not witness any major extinction event."
The first modern mammals evolved during the Jurassic Period.
## Tithonian
The Tithonian is the latest age of the Late Jurassic epoch or the uppermost stratigraphy stage of the Upper Jurassic series, spanning the time between 152.1 ± 4 Ma and 145.0 ± 4 Ma, preceded by the Kimmeridgian and followed by the Berriasian stage (part of the Cretaceous).
## Kimmeridgian
Lithacosphinctes achilles is from the Kimmeridgian.
The Kimmeridgian is a geology age or stratigraphy stage in the Late or Upper Jurassic geology epoch or stratigraphy series spanning the time between 157.3 ± 1.0 Ma and 152.1 ± 0.9 Ma, following the Oxfordian and preceding the Tithonian.
## Oxfordian
The Oxfordian, in the International Commission on Stratigraphy (ICS) geologic timescale, the earliest age of the Late Jurassic epoch, or the lowest stage of the Upper Jurassic series, spans the time between 163.5 ± 4 Ma and 157.3 ± 4 Maand is preceded by the Callovian and followed by the Kimmeridgian.
## Callovian
On the right is an image of Peltoceras solidum, an ammonite from the Matmor Formation (Jurassic, Callovian), Makhtesh Gadol, Israel.
On the left is an example of Kosmoceras medea.
Another species of Kosmoceras is on the lower right, specifically Kosmoceras proniae.
The Callovian is an age and stage in the Middle Jurassic, lasting between 166.1 ± 4.0 Ma and 163.5 ± 4.0 Ma, the last stage of the Middle Jurassic, following the Bathonian and preceding the Oxfordian.
## Bathonian
The Bathonian is an age and stage of the Middle Jurassic, lasting from approximately 168.3 Ma to around 166.1 Ma which succeeds the Bajocian age and precedes the Callovian age.
## Bajocian
The Bajocian in the Middle Jurassic lasted from approximately 170.3 Ma to around 168.3 Ma and succeeds the Aalenian age and precedes the Bathonian age.
## Aalenian
Leioceras opalinum is an ammonite from the Aalenian.
The Aalenian Age was the earliest part of the Middle Jurassic Period, and lasted from about 174.1 to about 170.3 Ma.
## Toarcian
The Toarcian, in the International Commission on Stratigraphy (ICS) geologic timescale, an age and stage in the Early or Lower Jurassic, spans the time between 182.7 Ma and 174.1 Ma. It follows the Pliensbachian and is followed by the Aalenian.
The base of the Toarcian is defined as the place in the stratigraphic record where the ammonite genus Eodactylites first appears, a GSSP for the base is located at Peniche, Portugal. The top of the stage is at the first appearance of ammonite genus Leioceras.
In the Tethys Ocean domain, the Toarcian contains the following ammonite biozones:
- zone of Pleydellia aalensis
- zone of Dumortieria pseudoradiosa
- zone of Phlyseogrammoceras dispansum
- zone of Grammoceras thouarcense
- zone of Haugia variabilis
- zone of Hildoceras bifrons
- zone of Harpoceras serpentinum
- zone of Dactylioceras tenuicostatum
"The genus Mystriosaurus, established by Kaup in 1834, was one of the first thalattosuchian genera to be named. The holotype, an incomplete skull from the lower Toarcian Posidonienschiefer Formation of Altdorf (Bavaria, southern Germany), is poorly known with a convoluted taxonomic history. For the past 60 years, Mystriosaurus has been considered a subjective junior synonym of Steneosaurus. However, our reassessment of the Mystriosaurus laurillardi holotype demonstrates that it is a distinct and valid taxon. Moreover, we find the holotype of “Steneosaurus” brevior, an almost complete skull from the lower Toarcian Whitby Mudstone Formation of Whitby (Yorkshire, UK), to be a subjective junior synonym of M. laurillardi. Mystriosaurus is diagnosed in having: a heavily and extensively ornamented skull; large and numerous neurovascular foramina on the premaxillae, maxillae and dentaries; anteriorly oriented external nares; and four teeth per premaxilla. Our phylogenetic analyses reveal M. laurillardi to be distantly related to Steneosaurus bollensis, supporting our contention that they are different taxa. Interestingly, our analyses hint that Mystriosaurus may be more closely related to the Chinese teleosauroid (previously known as Peipehsuchus) than any European form."
"A prehistoric crocodile that lived 180 million years ago has finally been identified – nearly 250 years after its fossil was unearthed in Germany."
Second down on the right is a photograph "of teleosauroid thalattosuchian specimen (UH 7), lower Toracian of Holzmaden (southwestern Germany), which was described by Mueller-Töwe (2006) as “Steneosaurus” brevior Blake, 1876, and which we herein refer to tentatively as ?Mystriosaurus sp."
## Pliensbachian
The Pliensbachian, an age of the geologic timescale and stage in the stratigraphic column, is part of the Early or Lower Jurassic epoch or series and spans the time between 190.8 ± 1.5 Ma and 182.7 ± 1.5 Ma. The Pliensbachian is preceded by the Sinemurian and followed by the Toarcian.
The base of the Pliensbachian is at the first appearances of the ammonite species Bifericeras donovani and genera Apoderoceras and Gleviceras, with The Wine Haven profile near Robin Hood's Bay (Yorkshire, England) has been appointed as global reference profile for the base (GSSP).
The Pliensbachian contains five ammonite biozones in the boreal domain:
- zone of Pleuroceras spinatum
- zone of Amaltheus margaritatus
- zone of Prodactylioceras davoei
- zone of Tragophylloceras ibex
- zone of Uptonia jamesoni
In the Tethys Ocean domain, the Pliensbachian contains six biozones:
- zone of Emaciaticeras emaciatum
- zone of Arieticeras algovianum
- zone of Fuciniceras lavinianum
- zone of Prodactylioceras davoei
- zone of Tragophylloceras ibex
- zone of Uptonia jamesoni
## Sinemurian
The Sinemurian is an age in the Early or Lower Jurassic that spans the time between 199.3 ± 2 Ma and 190.8 ± 1.5 Ma (million years ago).
The Sinemurian is preceded by the Hettangian and is followed by the Pliensbachian.
The upper Elliot Formation is a stratigraphic unit dating to roughly between 200 and 190 million years ago and covering the Hettangian to Sinemurian stages.
The "upper Elliot Formation one of the lowermost Jurassic continental successions (Hettangian-Sinemurian, ∼200–195 mya )."
In the second image down on the right are selected preserved elements of Ledumahadi mafube and the geography and stratigraphy of the type locality.
"Preserved bones (A–K) are as follows: (A) middle/posterior cervical vertebra in left lateral view; (B) anterior dorsal vertebra in anterior and right lateral views; (C) middle dorsal vertebra in posterior and right lateral views; (D) first and second “primordial” sacral vertebrae in left lateral view; (E) anterior caudal vertebra in left lateral view; (F) right ulna in proximal and medial views; (G) first metacarpal in proximal and ?dorsal/ventral views; (H) left ?third metacarpal in proximal and ventral views; (I) pedal ungual in ?lateral and proximal views; (J) anterior chevron in posterior view; and (K) distal right femur in distal, lateral, and anterior views."
"(L) Simplified geological map of the Elliot Formation in the Republic of South Africa and Lesotho indicating the location of farm Beginsel 346 and aerial extent of the Elliot Formation outcrop area (map modified after the 1:1,000,000 geological map of Republic of South Africa and Lesotho, 1984)."
"(M) Landscape view of the local geology at the Ledumahadi site. Note that the contact of the lower and upper Elliot Formations (LEF and UEF, respectively) has been identified at 1,685 m above sea level; thus the UEF is ∼60 m thick. The poorly exposed LEF, which is ∼10 m thick here, only contains massive mudstones with very weakly developed pedogenic alteration features, green-gray mottles, and very rare desiccation cracks."
"Abbreviations: ap, anterior process; ns, neural spine; op, olecranon process; poz, postzygapophysis; rf, radial fossa; sr, sacral rib; tfc, tibiofibular crest; vt, ventral tubercle. All scale bars represent 5 cm."
An unnamed ornithischian genus has been reported from the Upper Elliot Formation. Geographically it was located in the Mafeteng district, Lesotho. Ornithischian tracks have been reported from the Upper Elliot Formation. Geographically they were located in Leribe District, Mafeteng district, and Mohales Hoek District, Lesotho. Possible indeterminate ornithischian remains have been reported from the Lower and Upper Elliot Formation of Cape Province, South Africa and the Mohales Hoek District, Lesotho.
## Hettangian
Psiloceras psilonotum, Psiloceras spelae tirolicum and Psiloceras planorbis are from the Hettangian.
The Hettangian Age was the earliest part of the Early Jurassic Period, and lasted from about 199.3 to about 201.3 Ma.
"The dinosaur's remains, which were found in South Africa in 1978 and were being kept in a collection at the University of Witwatersrand in Johannesburg, had been identified as a Massospondylus -- a dinosaur from the Early Jurassic period."
The "dinosaur was in fact not what it seemed by comparing the specimen with other Massospondylus fossils."
"It differed in a large number of ways in terms of the appearance of its skull, and in the shape of its skull bones, and one or two other features -- enough to suggest that it's actually a completely different kind of dinosaur."
"The new dinosaur, which would have measured around 10 feet long and eaten plants and small animals, is thought to have had a chunky body, a long slender neck and a small, boxy head."
"The specimen has now been renamed "Ngwevu intloko," which means "gray skull" in the Xhosa language and was chosen to honor South Africa's heritage."
The "transition between the Triassic and Jurassic periods -- around 200 million years ago -- more complex ecosystems were thriving during the period than previously thought."
On the left is a Micro-CT scan of the Ngwevu intloko skull on the right. Inumerating and comparing skull bones between various specimens of Massospondylus such as the one lowest left allowed sufficient differentiation to indicate that Ngwevu intloko was a distinct species.
# Triassic Period
Although the example of Psiloceras tilmanni is from the Jurassic. Its lowest occurrence is in the New York Canyon section of Nevada USA which may be Triassic.
It was during the Triassic Period that the first dinosaurs evolved.
## Ladinian Age
The Atlasov section of the Ladinian contains the crinoid on the right.
The Ladinian Age was the later stage of the Middle Triassic Period and lasted from about 237 to about 242 Ma.
A phylogenetics analysis in 2013 of the cast of Megachirella wachtleri in the image on the left confirmed that it was a lepidosauromorph closely related to the crown group Lepidosauria.
Geckoes are the earliest crown group squamates, not Iguanomorpha (iguanians).
The specimen was probably transported to a shallow coastal environment due to heavy storms after it died.
## Anisian Age
An example of Ussuriphyllites amurensis (Kiparisova) is on the right. It is from the Lower-most Anisian, Atlasov Cape area.
The Anisian Age was the early part of the Middle Triassic, and lasted from about 242 to about 247.2 Ma.
## Olenekian Age
Olenekoceras meridianum is a "typical Late Olenekian differs in its lithology from the same zone of Russian Island, where the Zhitkov Suite has been rec- ognized (Zakharov, 1997; Zakharov et al., 2004)."
The Olenekian Age was the later part of the Lower Triassic, and lasted from about 247.2 to about 251.2 Ma.
## Induan Age
Hindeodus parvus, a conodont, on the right, is now recognized as the index fossil for the Triassic Induan.
The Induan Age was the earliest part of the Triassic Period, and lasted from about 251.2 to about 251.902 Ma.
# Paleozoic Era
The Paleozoic era spanned 542.0 ± 1.0 to 251.0 ± 0.7 Mb2k.
The mollusks, arthropods, fish, reptiles, and amphibians appeared.
Next 550 mya, after the death of vendobionts, a new era began-the Paleozoic.
After extinction, new spieces named vendobionts appeared.
650 million years ago (mya) a mass extinction happened (mass extinction-is a period when many spieces of animals or plants die).
The Paleozoic Era is divided into eight Periods: the Permian, Carboniferous, Pennsylvanian, Mississippian, Devonian, Silurian, Ordovician, and Cambrian.
# Permian Period
The Permian lasted from 299.0 ± 0.8 to 251.0 ± 0.4 Mb2k.
## Pennsylvanian Period
The Pennsylvanian lasted from 318.1 ± 1.3 to 299.0 ± 0.8 Mb2k.
## Mississippian Period
The Mississippian lasted from 359.2 ± 2.5 to 318.1 ± 1.3 Mb2k.
# Carboniferous Period
The Carboniferous began 359.2 ± 2.5 Mb2k and ended 299.0 ± 0.8 Mb2k.
The first reptiles evolved during this period.
# Devonian Period
The Devonian spanned 416.0 ± 2.8 to 359.2 ± 2.5 Mb2k.
In "the eastern Anti-Atlas Mountains of Morocco several skulls and an almost complete skeleton from two species of Phoebodus, a primitive shark genus that, until now, was known only from its three-cusped teeth ."
The "fossils reveal that Phoebodus had an eel-like body and a long snout, which makes it look a lot like the frilled shark that still roams the deep sea today."
"The fossilized Phoebodus remains were found in a layer estimated to be about 360 to 370 million years old, in what used to be a shallow sea basin. When the sharks died there, the limited water circulation and low oxygen levels created an environment in which their bodies were largely left alone by bacteria, scavengers, and currents, preserving them for posterity."
"The scans revealed some striking similarities to the frilled shark, not just in body shape, but in the teeth as well, which offers some clues to how the more ancient predators might have hunted."
"The frilled shark is a specialized predator, with the ability to suddenly burst forward to catch its prey. The inward-pointing teeth then help to make sure the prey can only go one way: into its throat. Maybe Phoebodus did something similar.”
For "a better understanding of how Phoebodus may have gotten its food, another unrelated species with a surprisingly similar skull, jaw, and teeth, ], a large freshwater fish called the alligator gar. Like Phoebodus, the alligator gar has long jaws and a flat skull, which limit its bite force. Yet there are also benefits to having a head like that."
"They hunt in open water, where they don’t have the luxury of choosing which direction their next meal will come from. And flat heads and long jaws are great for snapping sideways at prey."
"When a certain structure or strategy is effective, there is a tendency for it to show up time and time again—both in living creatures and in the fossil record. While a lot has changed since Phoebodus swam the Devonian oceans, the physics of feeding in water have not.”
# Silurian Period
The Silurian spanned 443.7 ± 1.5 to 416.0 ± 2.8 Mb2k.
# Ordovician Period
The Ordovician spanned 488.3 to 443.7 Ma. It is divided into three Epochs, the Upper Ordovician, Middle Ordovician, and Lower Ordovician. The Upper Ordovician is sometimes referred to as Late.
## Sandbian Stage
"The Lower Sandbian Nemagraptus gracilis Zone comprises one of the most widespread, and easily recognizable graptolite faunas in the Ordovician System. The base of the N. gracilis Zone also marks the base of the Upper Ordovician Series".
The Sandbian was the last stage of the Upper Ordovician
## Middle Ordovician Epoch
On the right is an image of Amplexograptus sp., probably A. perexcavatus (Lapworth, 1876), from the Middle Ordovician near Caney Springs, Tennessee USA.
Paleontologist have no strong agreement of the timespan considered as the Middle Ordovician Epoch, but an approximation is from about 471.8 to about 460.9 Ma.
## Lower Ordovician Epoch
The Lower Ordovician Epoch lasted from about 488.3 to about 471.8 Ma.
### Eurypterids
Although present in the Ordovician around 460 million years ago, about 410 million years ago, the first large marine predators (eurypterids), an order of arthropods, experienced a dramatic decline and are extinct.
# Cambrian Period
The Cambrian lasted from 542.0 ± 1.0 to 488.3 ± 1.7 Mb2k.
## Guzhangian Stage
"The GSSP level contains the lowest occurrence of the cosmopolitan agnostoid trilobite Lejopyge laevigata (base of the L. laevigata Zone)."
The Guzhangian Stage of the Cambrian Period lasted from about 500.5 to about 497 Ma.
## Middle Cambrian
The Burgess Shale is a fossil-bearing deposit exposed in the Canadian Rockies of British Columbia, Canada. It is famous for the exceptional preservation of the soft parts of its fossils. At 508 Ma (Wuliuan, middle Cambrian) old, it is one of the earliest fossil beds containing soft-part imprints.
"Cambroraster was similar in some ways to lampreys, stingrays and horseshoe crabs."
"We really didn't know what to make of it."
The "creature's formal scientific name is now Cambroraster falcatus. (The first part of the name refers to the fact that it lived during a time period called the Cambrian and had rake-like claws)."
"Cambroraster was about the size of a painted turtle or a medium pizza — making it huge by Cambrian standards. At that time, most animals were smaller than your little finger."
"It was an arthropod, a distant relative of crabs, insects and spiders and other animals with jointed legs, although it didn't have any legs itself."
"Like a horseshoe crab (not a true crab but a distant relative of spiders), Cambroraster dug in the muddy bottom for food such as worms, researchers think, although it did so with a set of rake-like claws studded with hooked spines — something horseshoe crabs definitely do not have, but some relatives of real crabs do."
"Cambroraster devoured its prey with a circular, toothy lamprey-like mouth that was the calling card of the extinct group it's part of: the radiodonts (named for their round, toothy mouths), which died out about 350 million years ago."
# Proterozoic Eon
Def. the "eon from 2,500 Ma to 541.0±1.0 Ma, the beginning of the Phanerozoic, marked by the build up of oxygen in the atmosphere and the emergence of primitive multicellular life" is called the Proterozoic.
First era of prehistoric multicellular life.
# Neoproterozoic
Def. "a geologic era within the Proterozoic eon; comprises the Tonian, Cryogenian and Ediacaran periods from about 1000 to 544 million years ago, when algae and sponges flourished" is called the Neoproterozoic.
# Ediacaran
"The fossils were unearthed at Zimnie Gory in the White Sea area of north-west Russia."
"The fossil fat molecules that we've found prove that animals were large and abundant 558 million years ago, millions of years earlier than previously thought."
"Scientists have been fighting for more than 75 years over what Dickinsonia and other bizarre fossils of the Ediacaran Biota were. The fossil fat now confirms Dickinsonia as the oldest known animal fossil, solving a decades-old mystery that has been the Holy Grail of palaeontology."
# Archeon Eon
The Archeon Eon lasted from about 4 billion to about 2500 million years ago. It was during the early Archean that life first appeared on Earth.
# Hadean Eon
The Hadean Eon lasted from the formation of the Earth to about 4 billion years ago. It is the only major division of the geologic time scale without life, and so of little interest to paleontologists.
# Hypotheses
To construct an hypothesis in paleontology requires statements of generalization usually using universals. Establishing that a phenomenon has occurred may require a proof of concept. Demonstrating a change from contemporary knowledge needs a control group for comparison.
- Ammonites are alive today.
# Acknowledgements
The content on this page was first contributed by: Henry A. Hoff.
Initial content for this page in some instances came from Wikiversity. | Paleontology
Editor-In-Chief: Henry A. Hoff
Paleontology is a study of fossils, plant and animal remains found on the Earth.[1]
Paleontology is a large subject because it includes aspects of geology and biology. Depending on the particular branch of paleontology studied, it may also require knowledge of chemistry, climatology, physics, and astronomy among others. It may also involve creating new techniques both in application and in theory. Paleontologists may work in outdoors, in an office or laboratory, or in a library; they may use a huge range of tools from bull dozers to computers.
The study of paleontology covers the entire history of life on Earth, which is about 4 billion years.
Paleontology is the branch of science dealing with study of past life. Paleontologists are the scientists that carry out this study.
The study of past life is done through the study of fossils which are evidence of that past life. Fossils may be the remains of organisms (plants, animals, etc.) or the remains of their activities (footprints, burrows, etc.). The later are called trace fossils.
Paleontology covers the entire span of life on Earth, from the first organisms around 4 billion years ago, up to the present day. However, scientists which study recent human activity, the last 12,000 years or so, are generally called archaeologists, and their study is called archaeology. There is a blurry line where archaeology begins and paleontology leaves off.
Paleontology is generally considered a part of geology, though because it involves life, it can also be considered a part of biology. Paleontologists must know something of both geology and biology. In particular in geology they must understand sedimentary geology - the study of sediments. In biology paleontologists need to know something about comparative anatomy, and in particular the anatomy of the organisms they study.
There are many sub-groups within paleontology, depending on what specifically is being studied. Among these is Vertebrate Paleontology (the study of fossil animals with backbones), Invertebrate Paleontology (the study of animals without backbones), Paleobotany (the study of fossil plants), and Paleoecology (the study of ancient environments). Almost everything within paleontology has it's own specialist name.
# Theoretical paleontology
Def. the "[s]tudy of the forms of life existing in prehistoric or geologic times"[2] is called paleontology.
Clades from the paleontological rock record sometimes display a clade asymmetry. "(Our two cases of Metazoa and mammals represent the first filling of life's ecological "barrel" for multicellular animals, and the radiation of mammals into roles formerly occupied by dinosaurs.)"[3]
# Fossils
Def. "[t]he mineralized remains of an animal or plant" or "[a]ny preserved evidence of ancient life, including shells, imprints, burrows, coprolites, and organically-produced chemicals"[4] is called a fossil.
Derived terms include ichnofossil, index fossil, living fossil, mesofossil, microfossil, and trace fossil.[4]
# Colors
"On December 9, 1833, the English fossil collector Elizabeth Philpot sent a letter to naturalist William Buckland. In addition to requesting back some vertebrae of a marine reptile Buckland had borrowed, Philpot also included notes on a recent trip with a young upstart fossil hound—the pioneering paleontologist Mary Anning. But what made the note special was an illustration Philpot had included with the letter. It depicted the toothy smile of an Ichthyosaurus skull, drawn after one of the many such fossils that Philpot, her sisters and Anning were finding in the ancient rocks of England’s southern coast. And it wasn’t drawn in any ordinary ink. The sepia tones were made from the preserved ink of a squid-like creature found in the same deposits as the ichthyosaur, revitalized after 200 million years."[5]
"On the surface, Philpot’s drawing might only seem to be a neat fossiliferous trick. In 2009, another drawing made from ancient ink kicked up renewed attention for the surprising fact that traces of prehistoric color could persist to the 21st century. But the fact that such primordial shades can be recovered at all opens up a realm of scientific possibility. With the right specimens, experts can start to color in the fossil record."[5]
"Researchers have known about fossil insect color patterns and mollusk color patterns all the way back to the Victorian era."[6]
"The biological key to solving the coloration puzzle comes down to miniscule structures called melanosomes. These are tiny, blobby organelles that contain pigment, or melanin, and are present in soft tissues such as skin, scales, and feathers. And while these details were often cast aside as fossil bacteria in decades past, renewed efforts in the 21st century have been able to find the relationship between these tiny structures and colors."[5]
"The discovery of preserved melanosomes opens up the possibility of interpreting the colour of extinct birds and other dinosaurs."[6]
"Pulling color from the past requires a combination of lucky finds with advanced imaging techniques."[7]
"First, paleontologists need a fossil which is likely to have preserved melanin—a fossil not just with bones, but feathers, skin or hair. These fossils often contain both melanosomes as well as chemically-degraded melanin pigment, and when paleontologists find such a fossil, then they can use modern technology to take a closer look."[5]
"You start by looking for the microbodies using instruments like scanning electron microscopes."[7]
"Once those characteristic shapes turn up, chemical analysis can confirm the presence of melanin pigment."[5]
"This was particularly critical early on in fossil melanin studies because there was still some doubt that the microbodies were in fact melanosomes and not other similar structures, like bacteria. From there, comparisons of the physical and chemical signatures of the melanosomes and melanin can be compared to those of living animals, for which color is known, to reconstruct the look of creatures long dead."[7]
"When paleontologists announced the discovery of the feathered dinosaur Anchiornis in 2009, the preserved plumage surrounding the skeleton was a dark, carbon-colored shade. But analysis of another Anchiornis fossil [...] the following year revealed a striking color pattern that had previously been invisible. The distribution and details of the preserved melanosomes indicated that Anchiornis was covered in feathers of black and white—not dissimilar from a magpie—with a splash of red feathers on the top of its head. For the first time, a dinosaur had been fully restored in living color."[5]
"The week before the Anchiornis paper came out, the small, fuzzy dinosaur Sinosauropteryx was shown to have a vibrant, red-and-white banded tail. In 2012, the stacked arrangement of melanosomes found in the feathers of four-winged dinosaur Microraptor was shown to create an iridescent sheen similar to that of a modern raven. (Avian dinosaurs joined the list, too, with giant fossil penguins bearing color patterns of black, red and gray.) And while early studies focused on feathers, paleontologists soon found that melanosomes can reveal the hues of scaly dinosaurs, too. The beaky, horned dinosaur Psittacosaurus was countershaded dark above and light below to help with camouflage, and the immense armored dinosaur Borealopelta sported reddish-brown tones."[5]
"Comparison [is] of melanosome proportions and body contour feather morphology in extinct penguins Inkayacu paracasensis (A and B) and representative extant penguins (C and D)."[5]
"In the case Borealopelta, for example—with a pattern of rusty red on top, light on bottom—the shading might have been a way for the low-slung dinosaur to hide from the ravenous tyrannosaurs of the time. Other dinosaurs were flashier. The candy-cane tail of Sinosauropteryx was likely a social signal, used by these dinosaurs to communicate with each other when they met."[5]
"The dinosaur [Sinosauropteryx] is portrayed in the predicted open habitat in which it lived around the Jehol lakes, preying on the lizard Dalinghosaurus."[5]
# Micropaleontology
Micropaleontology is a study of fossil micro-organisms, including foraminifera, which have applications in stratigraphic correlation and age dating along with paleoecology and paleoclimatology.
The image at the right shows microspheric and megalospheric Nummulitid specimens.
# Paleobotany
Paleobotany is the study of plant or plant-like fossils.
The image at the right shows fronds impressed onto shale in a specimen on display at the Paläontologische Museum München. The fossil is from Scalby Ness, Scarborough, England.
# Palynology
Although regarded as a separate field of its own, in a real sense palynology is the micropaleontological equivalent of paleobotany that involves the study of fossil pollen and spores.
The image at right contains a spore tetrad (in green) of genus Scylaspora and trilete spores (blue, ~30-35μm diameter) from a late Silurian sporangium (Burgsvik beds, Sweden).
# Invertebrate paleontology
Invertebrate paleontology is a study of fossil invertebrate animals, those which lack a backbone. Included are magafaunas whose study doesn't require a microscope, found in various phyla. Applications include stratigraphic dating and correlation, and paleo-ecology.
At the right is an example of invertebrate paleontology, specifically bryozoan fossils in an Ordovician oil shale from Estonia.
# Vertebrate paleontology
Vertebrate paleontology is any study of prehistoric animals with backbones, e.g. fish of various kinds, marine and terrestrial reptiles, dinosaurs, birds, and mammals.
As a representative of vertebrate paleontology, the image at the right shows a skeleton of Mosasaurus hoffmannii on display at the Natural History Museum of Masstricht.
# Paleoecology
In the image on the right, a group of Brancasaurus brancai are portrayed in an artists impression of their natural habitat together with some pycnodontiformes, Caturus and Hybodus in the far background.
# Paleoclimatology
Paleoclimatology is the study of ancient climates. This helps paleontologists understand the environments that existed over the history of the Earth.
Paleoclimatology is also particularly important in understanding how climate might change in the future.
# Geologic time
At right is a geologic clock representation. It shows some of the major units of geological time and definitive events of Earth history. The Hadean eon represents the time before fossil record of life on Earth; its upper boundary is now regarded as 4.0 Ga (billion years ago).[8] Other subdivisions reflect the evolution of life; the Archean and Proterozoic are both eons, the Palaeozoic, Mesozoic and Cenozoic are eras of the Phanerozoic eon. The two million year Quaternary period, the time of recognizable humans, is too small to be visible at this scale.
The following four timelines show the geologic time scale. The first shows the entire time from the formation of the Earth to the present, but this compresses the most recent eon. Therefore the second scale shows the most recent eon with an expanded scale. The second scale compresses the most recent era, so the most recent era is expanded in the third scale. Since the Quaternary is a very short period with short epochs, it is further expanded in the fourth scale. The second, third, and fourth timelines are therefore each subsections of their preceding timeline as indicated by asterisks. The Holocene (the latest epoch) is too small to be shown clearly on the third timeline on the right, another reason for expanding the fourth scale. The Pleistocene (P) epoch. Q stands for the Quaternary period.
# Cenozoic Era
After the dinosaurs became extinct, the Cenozoic began.
The Cenozoic Era is comprised of the following:
- Quaternary Period (2.588 mya to present)
Anthropocene Epoch (up to the present)
Holocene Epoch (11,700 yrs to the beginning of the Anthropocene)
Pleistocene Epoch (2.588 mya to 11,700 yrs)
- Anthropocene Epoch (up to the present)
- Holocene Epoch (11,700 yrs to the beginning of the Anthropocene)
- Pleistocene Epoch (2.588 mya to 11,700 yrs)
- Neogene Period (23.03 to 2.588 mya)
Pliocene Epoch (5.332 to 2.588 mya)
Miocene Epoch (23.03 to 5.332 mya)
- Pliocene Epoch (5.332 to 2.588 mya)
- Miocene Epoch (23.03 to 5.332 mya)
- Paleogene Period (65.5 to 23.03 mya)
Oligocene Epoch (33.9 to 23.03 mya)
Eocene Epoch (55.8 to 33.9 mya)
Paleocene (65.5 to 55.8 mya)
- Oligocene Epoch (33.9 to 23.03 mya)
- Eocene Epoch (55.8 to 33.9 mya)
- Paleocene (65.5 to 55.8 mya)
## Anthropocene Epoch
The Anthropocene Epoch is a newly added geologic time period. It is the "age of humans", when human activity grew to be the dominant force in shaping the Earth. The time of the beginning of this Epoch has not been completely settled upon. Claims run from 12,000 years ago when widespread agriculture began, to 1945 C.E. when the first atomic bomb was exploded.
For purposes of paleontology, the Anthropocene is primarily ignored, and is relegated to the science of archaeology, or the study of history, depending on when it is considered to have begun.
## Holocene Epoch
The Holocene starts at ~11,700 b2k and extends to the beginning of the Anthropocene Epoch.
## Pleistocene Epoch
The Pleistocene dates from 2.588 x 106 to 11,700 b2k.
People appear.
### GIS 3
The stronger GIS 3 interstadial occurred about 27.6 kyr B.P.[9]
"In the Karginian Age (MIS 3) alluvial deposits of the described locality [occur] the remains of Elasmotherium sibiricum, Mammuthus ex gr. trogontherii-chosaricus, Mammuthus primigenius, Bison sp. AMS Radiocarbon dating of the Elasmotherium skull gave a young age - 26038 ± 356 BP (UBA-30522)."[10]
### Hasselo stadial
The "Hasselo stadial [is] at approximately 40-38,500 14C years B.P. (Van Huissteden, 1990)."[11]
"The rhinoceros Elasmotherium sibiricum, known as the ‘Siberian unicorn’, was believed to have gone extinct around 200,000 years ago—well before the late Quaternary megafaunal extinction event. However, no absolute dating, genetic analysis or quantitative ecological assessment of this species has been undertaken. [By] accelerator mass spectrometry radiocarbon dating of 23 individuals, including cross-validation by compound-specific analysis, [...] E. sibiricum survived in Eastern Europe and Central Asia until at least 39,000 years ago, corroborating a wave of megafaunal turnover before the Last Glacial Maximum in Eurasia, in addition to the better-known late-glacial event. Stable isotope data indicate a dry steppe niche for E. sibiricum and, together with morphology, a highly specialized diet that probably contributed to its extinction. [With] DNA sequencing data, a very deep phylogenetic split between the subfamilies Elasmotheriinae and Rhinocerotinae [occurred] that includes all the living rhinoceroses, settling a debate based on fossil evidence and confirming that the two lineages had diverged by the Eocene. As the last surviving member of the Elasmotheriinae, the demise of the ‘Siberian unicorn’ marked the extinction of this subfamily."[12]
## Pliocene Epoch
The Pliocene ranges from 5.332 x 106 to 2.588 x 106 b2k.
## Miocene Epoch
The Miocene dates from 23.03 x 106 to 5.332 x 106 b2k.
"A giant goose that lived on a Mediterranean island between six and nine million years ago had wings tailored for combat."[13]
"Weighing 22 kilograms and standing perhaps 1.5 metres tall, Garganornis ballmanni might be the biggest member of the duck, goose and swan family ever to have lived. Its fossilised bones have been found at Gargano and Scontrone in central Italy – a region that, during the Miocene, consisted of islands populated by unique species."[13]
"Its wing bones are short for its size, suggesting it couldn’t fly. [The] carpometacarpus bone – equivalent to the hand bones in humans – had a rounded lump called the carpal knob, a feature present in modern birds that fight each other over territory. These include some ducks, geese and the extinct Rodrigues solitaire, the closest relative of the dodo."[13]
“It’s covered over with hard skin, so it becomes a really effective weapon. In solitaires, they certainly broke each others’ bones.”[14]
"Battles over territory are the most likely reason for Garganornis‘s fighting adaptation."[14]
"Ducks and geese that live on islands, such as the extinct moanalo of Hawaii, often evolve to be terrestrial and territorial. That’s because fresh water is often in short supply, and so they live in forests as herbivores."[13]
“You’ve got this big bird, with its wings used for fighting, that would have been incredibly aggressive and would have been able to defend its young against most predators.”[14]
Fossils "from the Early Miocene St Bathans Fauna of New Zealand [attest] to the former existence of a giant psittaciform, which is described as a new genus and species [image on the left]. The fossils are two incomplete tibiotarsi from a bird with an estimated mass of 7 kg, double that of the heaviest known parrot, the kakapo Strigops habroptila. These psittaciform fossils show that parrots join the growing group of avian taxa prone to giantism in insular species, currently restricted to palaeognaths, anatids, sylviornithids, columbids, aptornithids, ciconiids, tytonids, falconids and accipitrids."[15]
"Insular avifaunas are renowned for the evolution of novelties, usually in the form of extraordinarily large and flightless members of widespread and well-known lineages [1–4]. Preeminent among these is the columbid Dodo Raphus cucullatus of Mauritius [5], but the list includes giant Sylviornithidae on New Caledonia (Sylviornis) and Fiji (Megavitiornis) [6–8], other giant columbids on Rodrigues (Pezophaps) and on Fiji (Natunaornis) [5,9], giant waterfowl on Hawaii [10] and Malta [11], a giant ciconiid stork on Flores, Indonesia [12], and giant tytonid owls and other raptors in the Caribbean [13–16]. Insular rails (Rallidae) tend to be larger than mainland relatives, but the largest, the Takahe (Porphyrio hochstetteri) from New Zealand (NZ), at up to 3.2 kg, is smaller than these insular giants [17,18]."[15]
"Since moa were first reported in 1839 [22], NZ has become recognized as the epitome of the phenomenon of island giantism in birds. In addition to nine moa species (Dinornithiformes), two flightless anserines (Cnemiornis, Anatidae), two gruiforms (Aptornis, Aptornithidae) and a huge eagle (Hieraaetus moorei, Accipitridae) evolved from small ancestors into giant elements of the Holocene avifauna [23–28]."[15]
"The fossils, catalogued in the Museum of New Zealand Te Papa Tongarewa collections, are shafts of left and right tibiotarsi probably of one individual [image on the left]. [...] Tibiotarsi of Heracles inexpectatus gen. et sp. nov., left, holotype (a,b,f) NMNZ S.51083 and right, paratype (g), compared to (d,e) left tibiotarsus of Strigops habroptila (Canterbury Museum Av45277), in craniolateral (a) and cranial (b–g) views. (c) Silhouettes of a human and Heracles for scale. Scale bars are 20 mm. Abbreviations: ccl, crista cnemialis lateralis; cl, condylus lateralis; cm, condylus medialis; dtl, distal insertion scar for transverse ligament; fc, fibular crest; lfr, lateral scar for fibular retinaculum; lic, linea intermuscularis cranialis; mfr, mediocranial scar for fibular retinaculum; pons, pons supratendineus; ptl, proximal insertion scar for transverse ligament; se, sulcus extensorius; sf, sulcus m. fibularis; trf, tuberculum retinaculi m. fibularis. Human silhouette from PhyloPic, by T. M. Keesey."[15]
Fossils of Heracles inexpectatus are from a "conglomerate, 9.5–9.58 m above base of Bannockburn Formation, Early Miocene, 19–16 Ma [32]".[15]
"The holotype of Heracles inexpectatus is the largest fossil bone known among several thousand specimens in the fauna and adds a giant psittaciform to it."[15]
"The St Bathans Fauna has already revealed evidence for an Early Miocene radiation of parrots (Psittaciformes) in NZ, with three small nestorids described in Nelepsittacus, and another the size of Nestor notabilis [34]. Extant nestorids are grouped in Nestor as the sister taxon to Strigops habroptila; the two groups combined form the NZ endemic clade Strigopoidea that is the sister taxon of remaining psittaciforms [39]. Strigops habroptila is the heaviest and only flightless psittaciform [38,40], with legbones the largest among parrots [35]. Heracles inexpectatus has similar proportions and morphology to S. habroptila, but is much larger, differing qualitatively in greater medial projection of the proximomedial scar of the transverse ligament and less projection of the lateral fibular retinaculum scar [image on the left], the last relating to less climbing ability [34]. All known fossil parrots are much smaller than Strigops [34]. Given this similarity and its provenance, the affinity of Heracles inexpectatus may lie with Strigopoidea. The short separation of the mediocranial fibular retinaculum scar from the condyle suggests closer affinity to strigopids than nestorids [34]."[15]
## Oligocene Epoch
The Oligocene dates from 33.9 ± 0.1 x 106 to 23.03 x 106 b2k.
The Oligocene Epoch covers 34 - 23 Mya.[16]
"As the Earth began to cool, the tropical plants that had previously been found relatively widespread began to recede towards the equator where it was still warm. The general tropical plants began a transition to more forest like areas. The first grasses also appeared in the late Oligocene. The appearance of these grasses led to to evolution of various herbivore animals. With bodies low to the ground, animals would take advantage of the new grasses that appeared."[16]
## Eocene Epoch
The Eocene dates from 55.8 ± 0.2 x 106 to 33.9 ± 0.1 x 106 b2k.
"Death came suddenly for the young fish darting through a lake roughly 50 million years ago."[17]
A "stone slab [in the image on the left] from the western United States [...] includes the fossils of 257 now-extinct fish (Erismatopterus levatus) bunched together in a dense swarm."[17]
Each "fish’s orientation and position" have been analyzed.[17]
The "ancient fish followed two rules used by their modern counterparts. An individual was repelled by its closest companions — to avoid collisions — and attracted to those farther away, which encouraged clumping. Like a modern-day school, the fossilized grouping had an elongated shape that might have helped to ward off predators."[17]
## Paleocene Epoch
The Paleocene dates from 65.5 ± 0.3 x 106 to 55.8 ± 0.2 x 106 b2k.
# Mesozoic Era
With another mass extinction Mezozoic era started. Now dinosaurs rule.
The Mesozoic Era is divided into the Cretaceous, Jurassic, and Triassic Periods.
"A high diversity of terrestrial vertebrates with dinosaurs as the dominant group is strongly indicated but not much of it is yet recorded."[18]
For much of the dinosaur era, the smallest sauropods are larger than anything else in their habitat, and the largest are an order of magnitude more massive than anything else that has since walked the Earth.
# Cretaceous Period
"The Cretaceous period is the third and final period in the Mesozoic Era. It began 145.5 million years ago after the Jurassic Period and ended 65.5 million years ago, before the Paleogene Period of the Cenozoic Era."[19]
# Late Cretaceous
Rock strata from the Late Cretaceous epoch form the Upper Cretaceous series.
The Late Cretaceous (100.5–66 Ma) is the younger of two epochs, the other being the Early Cretaceous, into which the Cretaceous period is divided in the geologic timescale.
## Maastrichtian
The Maastrichtian is the most recent stage of the upper Cretaceous from 66.0 - 72.1 Ma. The mummified Edmontosaurus annectens in the image on the right is from the Maastrichtian.
The Lameta Formation is a sedimentary rock formation found in Madhya Pradesh, Gujarat, and Maharashtra, India, of Maastrichtian age (Upper Cretaceous), notable for its dinosaur fossils, several genera of dinosaurs from these rocks, including the titanosaur sauropod Isisaurus, the abelisaurs Indosaurus, Indosuchus, Laevisuchus, and Rajasaurus and possible stegosaurs.[20][21]
Traditionally, pterosaur faunas of the Maastrichtian appeared to be dominated by Azhdarchidae, with other pterosaur groups having become extinct earlier on, but, more recent findings suggest a fairly composite pterosaur diversity: at least six (Nyctosaurus lamegoi, a Mexican humerus, a Jordan humerus and several taxa from Morocco) Nyctosauridae date to this period, as do a few Pteranodontidae, and Navajodactylus, tentatively assigned to Azhdarchidae, lacking any synapomorphies of the group.[22][23] This seems to underscore a higher diversity of terminal Cretaceous pterosaurs than previously thought.[24][25][26]
The specimen second down on the left is Jeletzkytes spedeni from the Maastrichtian (Upper-Cretaceous) Fox Hills Formation, locality - South Dakota, USA. Matrix free specimen is 7.5 cm (3") in diameter, displaying pearly aragonite preservation of the shell.
The type species of Hainosaurus is H. bernardi, named after the Belgian Léopold Bernard, owner of the phosphate chalk exploitation where the fossil was unearthed.[27] In a paper published in 2016, Hainosaurus was considered congeneric with Tylosaurus.[28]
## Campanian
The Campanian was an age when a worldwide marine transgression or sea level rise drowned many coastal areas, preserved as an unconformity beneath a cover of marine sedimentary rocks.[29][30]
During the Campanian age, an evolutionary radiation among dinosaur species occurred, where in North America, for example, the number of known dinosaur genera rises from 4 at the base of the Campanian to 48 in the upper part, sometimes referred to as the "Campanian Explosion" the generally warm climates and large continental area covered in shallow sea during the Campanian probably favoured the dinosaurs, but in the following Maastrichtian stage, the number of North American dinosaur genera found is 30% less than in the upper Campanian.[31]
The image on the right shows a juvenile Chasmosaurus fossil seen from the side.
"The Ceratopsidae are one of the more immediately recognizable groups of dinosaurs. Characterized by sharp beaks and flamboyant horns and frills, these herbivores almost all lived in what is now Western North America right at the end of the Cretaceous period, 100 to 66 million years ago."[32]
"Chasmosaurus belonged to this group [...] The 75 million-year-old fossilized Chasmosaurus was spotted in 2010 within the Dinosaur Park Formation in Alberta, Canada. In 2013, paleontologists completely unearthed it, and this week, they have described what is undoubtedly a rare specimen."[32]
“For the first time ever, we have a complete skeleton of a baby ceratopsid.”[33]
"Only its forelimbs are completely missing."[32]
"The adult variants are certainly distinctive, with large openings in their head ornaments earning them their appropriate name, which literally means “opening lizard.” Fully grown, they reach a size of up to 4.8 meters (16 feet) and a weight of roughly 2 tonnes (2.2 tons)."[32]
"This juvenile Chasmosaurus is an adorable 1.5 meters (4.9 feet) in length, and would have weighed less than 100 kilograms (220 pounds). It’s so young that its vertebrae had not properly fused, its limbs were not fully articulated (joined up), and it had a particularly short snout. Due to its ornamental opening being fully enclosed by a single bone, scientists have deduced it is likely a species called Chasmosaurus belli."[32]
“We've only had a few isolated bones before to give us an idea of what these animals should look like as youngsters, but we've never had anything to connect all the pieces. All you need is one specimen that ties them all together. Now we have it!”[33]
Tylosaurus proriger is from the Santonian and lower to middle Campanian of North America (Kansas, Alabama, Nebraska, etc.).[34]
## Santonian
The specimen Hungarosaurus tormai designated as the holotype is MTM Gyn/404 (in the collections of the Magyar Természettudományi Múzeum, Budapest, Hungary) and consists of 450 bones, including portions of the skull (premaxilla, left prefrontal, left lacrimal, right postorbital, jugal and quadratojugal, left frontal, pterygoid, vomer, the right quadrate and a fragment of the left quadrate, basioccipital, one hyoid), an incomplete right mandible, three cervical vertebrae, six dorsal vertebrae, ten caudal vertebrae, ossified tendon fragments, three cerival and thirteen dorsal ribs, five chevrons, the left scapulocoracoid, right scapula, portions of the right manus, a partial pelvis, and more than one hundred osteoderms.[35]
The length of Hungarosaurus has been estimated at about 4 to 4.5 meters.[36]
The exposure of the Csehbánya Formation that produced Hungarosaurus tormai has also yielded remains of bony fishes, turtles, lizards, crocodiles, and pterosaurs, along with teeth from a diminutive dromaeosaurid-like theropod and a Rhabdodon-like ornithopod.[35]
The image in the center shows fossil pieces identified as a baby Tylosaurus.
## Coniacian
The holotype of the type species, Futalognkosaurus dukei, was originally estimated at 32-34 m in length.[37] In 2008 this was down-sized to 26 m.[38] Holtz estimated it at 28 m.[39] An estimate by Gregory S. Paul was that Futalognkosaurus had a maximum length of 30 m.[40] Its weight has been estimated between 38.1-50 tonnes.[41][42][40] Its long neck contained 14 vertebrae, and was over a meter deep in places, due to its extremely tall neural spines which had a distinctive "shark-fin" shape. The hips were also extremely large and bulky, reaching a width of nearly 3 m.[43]
The genus name is derived from the local indigenous language Mapudungun and is pronounced foo-ta-logn-koh-sohr-us: "futa" means "giant" and "lognko" means "chief".[37]
Futalognkosaurus is a member of the Titanosauridae (or Lithostrotia, depending on the definitions being used), and most closely related to Mendozasaurus, defining a new clade for the group containing both Futalognkosaurus and Mendozasaurus, their common ancestor, and all descendants, which they named the Lognkosauria.[37] Malawisaurus is the sister group of this new clade. Another, much later member of Lognkosauria is the colossal Puertasaurus,[44]
## Turonian
## Cenomanian
During the Cenomanian was the origin of the crown-group Crocodylia, the true-crocodiles[45]
An unnamed Enantiornithes bird is of northern Gondwana[46]
In 1996 in the Neuquén province of Argentina a skeleton of a theropod was discovered in the Sierra del Portezuelo and reported the same year.[47]
In 2002 near the Lago Barreales a second skeleton was uncovered and reported in 2003.[48]
In 2004 it was named and described as a second species: Unenlagia paynemili, where the holotype MUCPv-349, a partial skeleton consisting of a humerus and two pubes and several paratypes were also assigned: MUCPv-343, a claw; MUCPv-409, a partial ilium; MUCPv-415, a phalanx and MUCPv-416, a vertebra.[49]
Neuquenraptor may be a junior subjective synonym of Unenlagia.[50]
The body length of Unenlagia has been disputed, due to the fact that only the leg length is well known and it is uncertain whether this should be extrapolated using the proportions of the low-slung Dromaeosauridae or the long-legged basal birds with estimates varied between a length of 3.5 metres and a weight of 75 kilogrammes on the one hand,[51] and a length of just two metres on the other.[52]
The pelvic region of Unenlagia, especially the form of the ilium, was very similar to that of the early bird Archaeopteryx.[53]
The shoulder girdle of Unenlagia was originally interpreted as if it was adapted for flapping, with a flat scapula positioned on top of the ribcage, making the shoulder joint point more laterally, but this would imply that the shoulder-blade was dorsoventrally flattened instead of laterally as with other theropods and that it thus were more likely the scapula was located on the side of the ribcage.[54]
This conformed to a later hypothesis that non-avian theropods like Unenlagia were unable to lift their forelimbs above their back, as even would still have been the case for the basalmost bird Archaeopteryx.[55]
South-American workers have remained unconvinced though, countering that a laterally positioned scapula would make the coracoid of Unenlagia jut into its ribcage, which seems anatomically implausible.[52]
Unenlagia was a member of the Dromaeosauridae.[56][57] Unenlagia would have belonged to the extremely bird-like Gondwanan clade of dromaeosaurids called the Unenlagiinae, and be closely related to species such as Buitreraptor and Neuquenraptor (which might be the same species as Unenlagia), with the 'flying raptor' Rahonavis as a member of this group, which would mean that either Unenlagia is secondarily flightless, having evolved from flying, Rahonavis-like ancestors, or that bird-like flight evolved at least twice.[58] Rahonavis was found be the sister taxon of Unenlagia.[59]
But, Unenlagiidae was positioned within Avialae.[60]
The second image down on the right contains a 100-million-year-old chunk of amber found in Myanmar with the head, neck, wing, tail and feet of a hatchling.
"It’s the most complete and detailed view we’ve ever had."[61]
"While it looks as if the actual skin and flesh of the bird are preserved in the amber, it’s basically a very detailed impression of the animal. Studies of similar finds show the flesh has broken down into carbon – and there’s no usable DNA".[61]
"The unfortunate youngster belonged to a group of birds known as the 'opposite birds' that lived alongside the ancestors of modern birds and appear to have been more diverse and successful – until they died out with the dinosaurs 66 million years ago."[62]
"In appearance, opposite birds likely resembled modern birds, but they had a socket-and-ball joint in their shoulders where modern birds have a ball-and-socket joint – hence the name. They also had claws on their wings, and jaws and teeth rather than beaks – but at the time the hatchling lived, the ancestors of modern birds had not yet evolved beaks either."[62]
# Early Cretaceous
## Albian
## Aptian
## Barremian
## Hauterivian
## Valanginian
"The unusual aspect of this [fossilized dinosaur brain, second image down on the right] is the way the soft tissues, which are so fragile and 133 million years old, have actually been preserved. It’s not the entire brain — it’s just remarkable preservation of soft tissues you wouldn’t expect to have preserved."[63]
"The acid solution would have pickled the parts of the brain that were immersed."[63]
The "highly detailed mineralization of soft tissues associated with a naturally occurring brain endocast of an iguanodontian dinosaur [was] found in c. 133 Ma fluvial sediments of the Wealden at Bexhill, Sussex, UK."[64]
## Berriasian
"This femur [in the centered image] is huge! And in an exceptional state of conservation. It's very moving."[65]
# Jurassic Period
"The Jurassic Period takes place after the Triassic Period and before the Cretaceous Period. This period is well known for the reign of the dinosaurs of its time and the global tropical landscape."[66]
"The Jurassic is a geologic period and system that extends from about 199.6±0.6 Ma (million years ago) to 145.5±4 Ma; that is, from the end of the Triassic to the beginning of the Cretaceous. The Jurassic constitutes the middle period of the Mesozoic Era, also known as the Age of Reptiles. The start of the period is marked by the major Triassic–Jurassic extinction event. However, the end of the period did not witness any major extinction event."[67]
The first modern mammals evolved during the Jurassic Period.
## Tithonian
The Tithonian is the latest age of the Late Jurassic epoch or the uppermost stratigraphy stage of the Upper Jurassic series, spanning the time between 152.1 ± 4 Ma and 145.0 ± 4 Ma, preceded by the Kimmeridgian and followed by the Berriasian stage (part of the Cretaceous).[68]
## Kimmeridgian
Lithacosphinctes achilles is from the Kimmeridgian.
The Kimmeridgian is a geology age or stratigraphy stage in the Late or Upper Jurassic geology epoch or stratigraphy series spanning the time between 157.3 ± 1.0 Ma and 152.1 ± 0.9 Ma, following the Oxfordian and preceding the Tithonian.[69]
## Oxfordian
The Oxfordian, in the International Commission on Stratigraphy (ICS) geologic timescale, the earliest age of the Late Jurassic epoch, or the lowest stage of the Upper Jurassic series, spans the time between 163.5 ± 4 Ma and 157.3 ± 4 Maand is preceded by the Callovian and followed by the Kimmeridgian.[70]
## Callovian
On the right is an image of Peltoceras solidum, an ammonite from the Matmor Formation (Jurassic, Callovian), Makhtesh Gadol, Israel.
On the left is an example of Kosmoceras medea.
Another species of Kosmoceras is on the lower right, specifically Kosmoceras proniae.
The Callovian is an age and stage in the Middle Jurassic, lasting between 166.1 ± 4.0 Ma and 163.5 ± 4.0 Ma, the last stage of the Middle Jurassic, following the Bathonian and preceding the Oxfordian.[71]
## Bathonian
The Bathonian is an age and stage of the Middle Jurassic, lasting from approximately 168.3 Ma to around 166.1 Ma which succeeds the Bajocian age and precedes the Callovian age.[72]
## Bajocian
The Bajocian in the Middle Jurassic lasted from approximately 170.3 Ma to around 168.3 Ma and succeeds the Aalenian age and precedes the Bathonian age.[73]
## Aalenian
Leioceras opalinum is an ammonite from the Aalenian.
The Aalenian Age was the earliest part of the Middle Jurassic Period, and lasted from about 174.1 to about 170.3 Ma.
## Toarcian
The Toarcian, in the International Commission on Stratigraphy (ICS) geologic timescale, an age and stage in the Early or Lower Jurassic, spans the time between 182.7 Ma and 174.1 Ma.[74] It follows the Pliensbachian and is followed by the Aalenian.[75]
The base of the Toarcian is defined as the place in the stratigraphic record where the ammonite genus Eodactylites first appears, a GSSP for the base is located at Peniche, Portugal. The top of the stage is at the first appearance of ammonite genus Leioceras.
In the Tethys Ocean domain, the Toarcian contains the following ammonite biozones:
- zone of Pleydellia aalensis
- zone of Dumortieria pseudoradiosa
- zone of Phlyseogrammoceras dispansum
- zone of Grammoceras thouarcense
- zone of Haugia variabilis
- zone of Hildoceras bifrons
- zone of Harpoceras serpentinum
- zone of Dactylioceras tenuicostatum
"The genus Mystriosaurus, established by Kaup in 1834, was one of the first thalattosuchian genera to be named. The holotype, an incomplete skull from the lower Toarcian Posidonienschiefer Formation of Altdorf (Bavaria, southern Germany), is poorly known with a convoluted taxonomic history. For the past 60 years, Mystriosaurus has been considered a subjective junior synonym of Steneosaurus. However, our reassessment of the Mystriosaurus laurillardi holotype demonstrates that it is a distinct and valid taxon. Moreover, we find the holotype of “Steneosaurus” brevior, an almost complete skull from the lower Toarcian Whitby Mudstone Formation of Whitby (Yorkshire, UK), to be a subjective junior synonym of M. laurillardi. Mystriosaurus is diagnosed in having: a heavily and extensively ornamented skull; large and numerous neurovascular foramina on the premaxillae, maxillae and dentaries; anteriorly oriented external nares; and four teeth per premaxilla. Our phylogenetic analyses reveal M. laurillardi to be distantly related to Steneosaurus bollensis, supporting our contention that they are different taxa. Interestingly, our analyses hint that Mystriosaurus may be more closely related to the Chinese teleosauroid (previously known as Peipehsuchus) than any European form."[76]
"A prehistoric crocodile [Mystriosaurus laurillardi] that lived 180 million years ago has finally been identified – nearly 250 years after its fossil was unearthed in Germany."[77]
Second down on the right is a photograph "of teleosauroid thalattosuchian specimen (UH 7), lower Toracian of Holzmaden (southwestern Germany), which was described by Mueller-Töwe (2006) as “Steneosaurus” brevior Blake, 1876, and which we herein refer to tentatively as ?Mystriosaurus sp."[76]
## Pliensbachian
The Pliensbachian, an age of the geologic timescale and stage in the stratigraphic column, is part of the Early or Lower Jurassic epoch or series and spans the time between 190.8 ± 1.5 Ma and 182.7 ± 1.5 Ma.[74] The Pliensbachian is preceded by the Sinemurian and followed by the Toarcian.[78]
The base of the Pliensbachian is at the first appearances of the ammonite species Bifericeras donovani and genera Apoderoceras and Gleviceras, with The Wine Haven profile near Robin Hood's Bay (Yorkshire, England) has been appointed as global reference profile for the base (GSSP).[79]
The Pliensbachian contains five ammonite biozones in the boreal domain:
- zone of Pleuroceras spinatum
- zone of Amaltheus margaritatus
- zone of Prodactylioceras davoei
- zone of Tragophylloceras ibex
- zone of Uptonia jamesoni
In the Tethys Ocean domain, the Pliensbachian contains six biozones:
- zone of Emaciaticeras emaciatum
- zone of Arieticeras algovianum
- zone of Fuciniceras lavinianum
- zone of Prodactylioceras davoei
- zone of Tragophylloceras ibex
- zone of Uptonia jamesoni
## Sinemurian
The Sinemurian is an age in the Early or Lower Jurassic that spans the time between 199.3 ± 2 Ma and 190.8 ± 1.5 Ma (million years ago).[74]
The Sinemurian is preceded by the Hettangian and is followed by the Pliensbachian.[80]
The upper Elliot Formation is a stratigraphic unit dating to roughly between 200 and 190 million years ago and covering the Hettangian to Sinemurian stages.[81]
The "upper Elliot Formation [is] one of the lowermost Jurassic continental successions (Hettangian-Sinemurian, ∼200–195 mya [...])."[82]
In the second image down on the right are selected preserved elements of Ledumahadi mafube and the geography and stratigraphy of the type locality.
"Preserved bones (A–K) are as follows: (A) middle/posterior cervical vertebra in left lateral view; (B) anterior dorsal vertebra in anterior and right lateral views; (C) middle dorsal vertebra in posterior and right lateral views; (D) first and second “primordial” sacral vertebrae in left lateral view; (E) anterior caudal vertebra in left lateral view; (F) right ulna in proximal and medial views; (G) first metacarpal in proximal and ?dorsal/ventral views; (H) left ?third metacarpal in proximal and ventral views; (I) pedal ungual in ?lateral and proximal views; (J) anterior chevron in posterior view; and (K) distal right femur in distal, lateral, and anterior views."[82]
"(L) Simplified geological map of the Elliot Formation in the Republic of South Africa and Lesotho indicating the location of farm Beginsel 346 and aerial extent of the Elliot Formation outcrop area (map modified after the 1:1,000,000 geological map of Republic of South Africa and Lesotho, 1984)."[82]
"(M) Landscape view of the local geology at the Ledumahadi site. Note that the contact of the lower and upper Elliot Formations (LEF and UEF, respectively) has been identified at 1,685 m above sea level; thus the UEF is ∼60 m thick. The poorly exposed LEF, which is ∼10 m thick here, only contains massive mudstones with very weakly developed pedogenic alteration features, green-gray mottles, and very rare desiccation cracks."[82]
"Abbreviations: ap, anterior process; ns, neural spine; op, olecranon process; poz, postzygapophysis; rf, radial fossa; sr, sacral rib; tfc, tibiofibular crest; vt, ventral tubercle. All scale bars represent 5 cm."[82]
An unnamed ornithischian genus has been reported from the Upper Elliot Formation.[83] Geographically it was located in the Mafeteng district, Lesotho.[83] Ornithischian tracks have been reported from the Upper Elliot Formation.[83] Geographically they were located in Leribe District,[84] Mafeteng district, and Mohales Hoek District, Lesotho.[83] Possible indeterminate ornithischian remains have been reported from the Lower and Upper Elliot Formation of Cape Province, South Africa[84] and the Mohales Hoek District, Lesotho.[83]
## Hettangian
Psiloceras psilonotum, Psiloceras spelae tirolicum and Psiloceras planorbis are from the Hettangian.
The Hettangian Age was the earliest part of the Early Jurassic Period, and lasted from about 199.3 to about 201.3 Ma.
"The dinosaur's remains, which were found in South Africa in 1978 and were being kept in a collection at the University of Witwatersrand in Johannesburg, had been identified as a Massospondylus -- a dinosaur from the Early Jurassic period."[85]
The "dinosaur was in fact not what it seemed by comparing the specimen with other Massospondylus fossils."[85]
"It differed in a large number of ways in terms of the appearance of its skull, and in the shape of its skull bones, and one or two other features -- enough to suggest that it's actually a completely different kind of dinosaur."[86]
"The new dinosaur, which would have measured around 10 feet long and eaten plants and small animals, is thought to have had a chunky body, a long slender neck and a small, boxy head."[85]
"The specimen has now been renamed "Ngwevu intloko," which means "gray skull" in the Xhosa language and was chosen to honor South Africa's heritage."[85]
The "transition between the Triassic and Jurassic periods -- around 200 million years ago -- [suggests] more complex ecosystems were thriving during the period than previously thought."[85]
On the left is a Micro-CT scan of the Ngwevu intloko skull on the right. Inumerating and comparing skull bones between various specimens of Massospondylus such as the one lowest left allowed sufficient differentiation to indicate that Ngwevu intloko was a distinct species.
# Triassic Period
Although the example of Psiloceras tilmanni is from the Jurassic. Its lowest occurrence is in the New York Canyon section of Nevada USA which may be Triassic.
It was during the Triassic Period that the first dinosaurs evolved.
## Ladinian Age
The Atlasov section of the Ladinian contains the crinoid on the right.
The Ladinian Age was the later stage of the Middle Triassic Period and lasted from about 237 to about 242 Ma.
A phylogenetics analysis in 2013 of the cast of Megachirella wachtleri in the image on the left confirmed that it was a lepidosauromorph closely related to the crown group Lepidosauria.[87]
Geckoes are the earliest crown group squamates, not Iguanomorpha (iguanians).[88][89]
The specimen was probably transported to a shallow coastal environment due to heavy storms after it died.[90]
## Anisian Age
An example of Ussuriphyllites amurensis (Kiparisova) is on the right. It is from the Lower-most Anisian, Atlasov Cape area.[91]
The Anisian Age was the early part of the Middle Triassic, and lasted from about 242 to about 247.2 Ma.
## Olenekian Age
Olenekoceras meridianum is a "typical Late Olenekian [fossil which] differs in its lithology from the same zone of Russian Island, where the Zhitkov Suite has been rec- ognized (Zakharov, 1997; Zakharov et al., 2004)."[91]
The Olenekian Age was the later part of the Lower Triassic, and lasted from about 247.2 to about 251.2 Ma.
## Induan Age
Hindeodus parvus, a conodont, on the right, is now recognized as the index fossil for the Triassic Induan.
The Induan Age was the earliest part of the Triassic Period, and lasted from about 251.2 to about 251.902 Ma.
# Paleozoic Era
The Paleozoic era spanned 542.0 ± 1.0 to 251.0 ± 0.7 Mb2k.
The mollusks, arthropods, fish, reptiles, and amphibians appeared.
Next 550 mya, after the death of vendobionts, a new era began-the Paleozoic.
After extinction, new spieces named vendobionts appeared.
650 million years ago (mya) a mass extinction happened (mass extinction-is a period when many spieces of animals or plants die).
The Paleozoic Era is divided into eight Periods: the Permian, Carboniferous, Pennsylvanian, Mississippian, Devonian, Silurian, Ordovician, and Cambrian.
# Permian Period
The Permian lasted from 299.0 ± 0.8 to 251.0 ± 0.4 Mb2k.
## Pennsylvanian Period
The Pennsylvanian lasted from 318.1 ± 1.3 to 299.0 ± 0.8 Mb2k.
## Mississippian Period
The Mississippian lasted from 359.2 ± 2.5 to 318.1 ± 1.3 Mb2k.
# Carboniferous Period
The Carboniferous began 359.2 ± 2.5 Mb2k and ended 299.0 ± 0.8 Mb2k.
The first reptiles evolved during this period.
# Devonian Period
The Devonian spanned 416.0 ± 2.8 to 359.2 ± 2.5 Mb2k.
In "the eastern Anti-Atlas Mountains of Morocco [...] several skulls and an almost complete skeleton from two species of Phoebodus, a primitive shark genus that, until now, was known only from its three-cusped teeth [have been found]."[92]
The "fossils reveal that Phoebodus had an eel-like body and a long snout, which makes it look a lot like the frilled shark that still roams the deep sea today."[92]
"The fossilized Phoebodus remains were found in a layer estimated to be about 360 to 370 million years old, in what used to be a shallow sea basin. When the sharks died there, the limited water circulation and low oxygen levels created an environment in which their bodies were largely left alone by bacteria, scavengers, and currents, preserving them for posterity."[92]
"The [CT] scans revealed some striking similarities to the frilled shark, not just in body shape, but in the teeth as well, which offers some clues to how the more ancient predators might have hunted."[92]
"The frilled shark is a specialized predator, with the ability to suddenly burst forward to catch its prey. The inward-pointing teeth then help to make sure the prey can only go one way: into its throat. Maybe Phoebodus did something similar.”[93]
For "a better understanding of how Phoebodus may have gotten its food, [...] another unrelated species with a surprisingly similar skull, jaw, and teeth, [was looked at]], a large freshwater fish called the alligator gar. Like Phoebodus, the alligator gar has long jaws and a flat skull, which limit its bite force. Yet there are also benefits to having a head like that."[94]
"They hunt in open water, where they don’t have the luxury of choosing which direction their next meal will come from. And flat heads and long jaws are great for snapping sideways at prey."[94]
"When a certain structure or strategy is effective, there is a tendency for it to show up time and time again—both in living creatures and in the fossil record. While a lot has changed since Phoebodus swam the Devonian oceans, the physics of feeding in water have not.”[94]
# Silurian Period
The Silurian spanned 443.7 ± 1.5 to 416.0 ± 2.8 Mb2k.
# Ordovician Period
The Ordovician spanned 488.3 to 443.7 Ma. It is divided into three Epochs, the Upper Ordovician, Middle Ordovician, and Lower Ordovician. The Upper Ordovician is sometimes referred to as Late.
## Sandbian Stage
"The Lower Sandbian Nemagraptus gracilis Zone comprises one of the most widespread, and easily recognizable graptolite faunas in the Ordovician System. The base of the N. gracilis Zone also marks the base of the Upper Ordovician Series".[95]
The Sandbian was the last stage of the Upper Ordovician
## Middle Ordovician Epoch
On the right is an image of Amplexograptus sp., probably A. perexcavatus (Lapworth, 1876), from the Middle Ordovician near Caney Springs, Tennessee USA.
Paleontologist have no strong agreement of the timespan considered as the Middle Ordovician Epoch, but an approximation is from about 471.8 to about 460.9 Ma.
## Lower Ordovician Epoch
The Lower Ordovician Epoch lasted from about 488.3 to about 471.8 Ma.
### Eurypterids
Although present in the Ordovician around 460 million years ago, about 410 million years ago, the first large marine predators (eurypterids), an order of arthropods, experienced a dramatic decline and are extinct.[96]
# Cambrian Period
The Cambrian lasted from 542.0 ± 1.0 to 488.3 ± 1.7 Mb2k.
## Guzhangian Stage
"The GSSP level [for the Guzhangian] contains the lowest occurrence of the cosmopolitan agnostoid trilobite Lejopyge laevigata [in the image on the left] (base of the L. laevigata Zone)."[97]
The Guzhangian Stage of the Cambrian Period lasted from about 500.5 to about 497 Ma.
## Middle Cambrian
The Burgess Shale is a fossil-bearing deposit exposed in the Canadian Rockies of British Columbia, Canada.[98] It is famous for the exceptional preservation of the soft parts of its fossils. At 508 Ma (Wuliuan, middle Cambrian) old,[99] it is one of the earliest fossil beds containing soft-part imprints.
"Cambroraster was similar in some ways to lampreys, stingrays and horseshoe crabs."[100]
"We really didn't know what to make of it."[101]
The "creature's formal scientific name is now Cambroraster falcatus. (The first part of the name refers to the fact that it lived during a time period called the Cambrian and had rake-like claws)."[100]
"Cambroraster was about the size of a painted turtle or a medium pizza — making it huge by Cambrian standards. At that time, most animals were smaller than your little finger."[101]
"It was an arthropod, a distant relative of crabs, insects and spiders and other animals with jointed legs, although it didn't have any legs itself."[100]
"Like a horseshoe crab (not a true crab but a distant relative of spiders), Cambroraster dug in the muddy bottom for food such as worms, researchers think, although it did so with a set of rake-like claws studded with hooked spines — something horseshoe crabs definitely do not have, but some relatives of real crabs do."[100]
"Cambroraster devoured its prey with a circular, toothy lamprey-like mouth that was the calling card of the extinct group it's part of: the radiodonts (named for their round, toothy mouths), which died out about 350 million years ago."[100]
# Proterozoic Eon
Def. the "eon from 2,500 Ma to 541.0±1.0 Ma, the beginning of the Phanerozoic, marked by the build up of oxygen in the atmosphere and the emergence of primitive multicellular life"[102] is called the Proterozoic.
First era of prehistoric multicellular life.
# Neoproterozoic
Def. "a geologic era within the Proterozoic eon; comprises the Tonian, Cryogenian and Ediacaran periods from about 1000 to 544 million years ago, when algae and sponges flourished"[103] is called the Neoproterozoic.
# Ediacaran
"The fossils [of Dickinsonia] were unearthed at Zimnie Gory in the White Sea area of north-west Russia."[104]
"The fossil fat molecules that we've found prove that animals were large and abundant 558 million years ago, millions of years earlier than previously thought."[105]
"Scientists have been fighting for more than 75 years over what Dickinsonia and other bizarre fossils of the Ediacaran Biota were. The fossil fat now confirms Dickinsonia as the oldest known animal fossil, solving a decades-old mystery that has been the Holy Grail of palaeontology."[105]
# Archeon Eon
The Archeon Eon lasted from about 4 billion to about 2500 million years ago. It was during the early Archean that life first appeared on Earth.
# Hadean Eon
The Hadean Eon lasted from the formation of the Earth to about 4 billion years ago. It is the only major division of the geologic time scale without life, and so of little interest to paleontologists.
# Hypotheses
To construct an hypothesis in paleontology requires statements of generalization usually using universals. Establishing that a phenomenon has occurred may require a proof of concept. Demonstrating a change from contemporary knowledge needs a control group for comparison.
- Ammonites are alive today.
# Acknowledgements
The content on this page was first contributed by: Henry A. Hoff.
Initial content for this page in some instances came from Wikiversity. | https://www.wikidoc.org/index.php/Paleontology | |
e1dec7ee56ac29f25fd011f39be76109079911a6 | wikidoc | Pancrelipase | Pancrelipase
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# Overview
Pancrelipase is a gastrointestinal agent that is FDA approved for the treatment of exocrine pancreatic insufficiency due to cystic fibrosis, chronic pancreatitis, pancreatectomy, or other conditions. Common adverse reactions include vomiting, dizziness, cough, hyperglycemia, hypoglycemia, abdominal pain, abnormal feces, flatulence, frequent bowel movements, and nasopharyngitis.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- CREON® (pancrelipase) is indicated for the treatment of exocrine pancreatic insufficiency due to cystic fibrosis, chronic pancreatitis, pancreatectomy, or other conditions.
- Dosing Information
- CREON is not interchangeable with other pancrelipase products.
- CREON is orally administered. Therapy should be initiated at the lowest recommended dose and gradually increased. The dosage of CREON should be individualized based on clinical symptoms, the degree of steatorrhea present, and the fat content of the diet.
- Adults with Exocrine Pancreatic Insufficiency Due to Chronic Pancreatitis or Pancreatectomy:
- The initial starting dose and increases in the dose per meal should be individualized based on clinical symptoms, the degree of steatorrhea present, and the fat content of the diet.
- In one clinical trial, patients received CREON at a dose of 72,000 lipase units per meal while consuming at least 100 g of fat per day. Lower starting doses recommended in the literature are consistent with the 500 lipase units/kg of body weight per meal lowest starting dose recommended for adults in the Cystic Fibrosis Foundation Consensus Conferences Guidelines.1, 2, 3, 4 Usually, half of the prescribed CREON dose for an individualized full meal should be given with each snack.
- DOSAGE FORMS AND STRENGTHS
- The active ingredient in CREON evaluated in clinical trials is lipase. CREON is dosed by lipase units.
- Other active ingredients include protease and amylase. Each CREON delayed-release capsule strength contains the specified amounts of lipase, protease, and amylase as follows:
- 3,000 USP units of lipase; 9,500 USP units of protease; 15,000 USP units of amylase delayed-release capsules have a white opaque cap with imprint “CREON 1203” and a white opaque body.
- 6,000 USP units of lipase; 19,000 USP units of protease; 30,000 USP units of amylase delayed-release capsules have an orange opaque cap with imprint “CREON 1206” and a blue opaque body.
- 12,000 USP units of lipase; 38,000 USP units of protease; 60,000 USP units of amylase delayed-release capsules have a brown opaque cap with imprint “CREON 1212” and a colorless transparent body.
- 24,000 USP units of lipase; 76,000 USP units of protease; 120,000 USP units of amylase delayed-release capsules have an orange opaque cap with imprint “CREON 1224” and a colorless transparent body.
- 36,000 USP units of lipase; 114,000 USP units of protease; 180,000 USP units of amylase delayed-release capsules have a blue opaque cap with imprint “CREON 1236” and a colorless transparent body.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pancrelipase (patient information) in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Pancrelipase (patient information) in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- Dosage recommendations for pancreatic enzyme replacement therapy were published following the Cystic Fibrosis Foundation Consensus Conferences.1, 2, 3 CREON should be administered in a manner consistent with the recommendations of the Cystic Fibrosis Foundation Consensus Conferences (also known as Conferences) provided in the following paragraphs, except for infants. Although the Conferences recommend doses of 2,000 to 4,000 lipase units in infants up to 12 months, CREON is available in a 3,000 lipase unit capsule. Therefore, the recommended dose of CREON in infants up to 12 months is 3,000 lipase units per 120 mL of formula or per breast-feeding. Patients may be dosed on a fat ingestion-based or actual body weight-based dosing scheme.
- Additional recommendations for pancreatic enzyme therapy in patients with exocrine pancreatic insufficiency due to chronic pancreatitis or pancreatectomy are based on a clinical trial conducted in these populations.
- Infants (up to 12 months):
- CREON is available in the strength of 3,000 USP units of lipase thus infants may be given 3,000 lipase units (one capsule) per 120 mL of formula or per breast-feeding. Do not mix CREON capsule contents directly into formula or breast milk prior to administration.
- Children Older than 12 Months and Younger than 4 Years:
- Enzyme dosing should begin with 1,000 lipase units/kg of body weight per meal for children less than age 4 years to a maximum of 2,500 lipase units/kg of body weight per meal (or less than or equal to 10,000 lipase units/kg of body weight per day), or less than 4,000 lipase units/g fat ingested per day.
- Children 4 Years and Older and Adults:
- Enzyme dosing should begin with 500 lipase units/kg of body weight per meal for those older than age 4 years to a maximum of 2,500 lipase units/kg of body weight per meal (or less than or equal to 10,000 lipase units/kg of body weight per day), or less than 4,000 lipase units/g fat ingested per day.
- Usually, half of the prescribed CREON dose for an individualized full meal should be given with each snack. The total daily dose should reflect approximately three meals plus two or three snacks per day.
- Enzyme doses expressed as lipase units/kg of body weight per meal should be decreased in older patients because they weigh more but tend to ingest less fat per kilogram of body weight.
- Limitations on Dosing:
- Dosing should not exceed the recommended maximum dosage set forth by the Cystic Fibrosis Foundation Consensus Conferences Guidelines.1, 2, 3 If symptoms and signs of steatorrhea persist, the dosage may be increased by the healthcare professional. Patients should be instructed not to increase the dosage on their own. There is great inter-individual variation in response to enzymes; thus, a range of doses is recommended. Changes in dosage may require an adjustment period of several days. If doses are to exceed 2,500 lipase units/kg of body weight per meal, further investigation is warranted. Doses greater than 2,500 lipase units/kg of body weight per meal (or greater than 10,000 lipase units/kg of body weight per day) should be used with caution and only if they are documented to be effective by 3-day fecal fat measures that indicate a significantly improved coefficient of fat absorption. Doses greater than 6,000 lipase units/kg of body weight per meal have been associated with colonic stricture, indicative of fibrosing colonopathy, in children less than 12 years of age. Patients currently receiving higher doses than 6,000 lipase units/kg of body weight per meal should be examined and the dosage either immediately decreased or titrated downward to a lower range.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pancrelipase (patient information) in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Pancrelipase (patient information) in pediatric patients.
# Contraindications
None.
# Warnings
Fibrosing Colonopathy
- Fibrosing colonopathy has been reported following treatment with different pancreatic enzyme products. 5, 6 Fibrosing colonopathy is a rare, serious adverse reaction initially described in association with high-dose pancreatic enzyme use, usually over a prolonged period of time and most commonly reported in pediatric patients with cystic fibrosis. The underlying mechanism of fibrosing colonopathy remains unknown. Doses of pancreatic enzyme products exceeding 6,000 lipase units/kg of body weight per meal have been associated with colonic stricture in children less than 12 years of age.1 Patients with fibrosing colonopathy should be closely monitored because some patients may be at risk of progressing to stricture formation. It is uncertain whether regression of fibrosing colonopathy occurs.1 It is generally recommended, unless clinically indicated, that enzyme doses should be less than 2,500 lipase units/kg of body weight per meal (or less than 10,000 lipase units/kg of body weight per day) or less than 4,000 lipase units/g fat ingested per day.
- Doses greater than 2,500 lipase units/kg of body weight per meal (or greater than 10,000 lipase units/kg of body weight per day) should be used with caution and only if they are documented to be effective by 3-day fecal fat measures that indicate a significantly improved coefficient of fat absorption. Patients receiving higher doses than 6,000 lipase units/kg of body weight per meal should be examined and the dosage either immediately decreased or titrated downward to a lower range.
Potential for Irritation to Oral Mucosa
- Care should be taken to ensure that no drug is retained in the mouth. CREON should not be crushed or chewed or mixed in foods having a pH greater than 4.5. These actions can disrupt the protective enteric coating resulting in early release of enzymes, irritation of oral mucosa, and/or loss of enzyme activity. For patients who are unable to swallow intact capsules, the capsules may be carefully opened and the contents added to a small amount of acidic soft food with a pH of 4.5 or less, such as applesauce, at room temperature. The CREON-soft food mixture should be swallowed immediately and followed with water or juice to ensure complete ingestion.
Potential for Risk of Hyperuricemia
- Caution should be exercised when prescribing CREON to patients with gout, renal impairment, or hyperuricemia. Porcine-derived pancreatic enzyme products contain purines that may increase blood uric acid levels.
Potential Viral Exposure from the Product Source
- CREON is sourced from pancreatic tissue from swine used for food consumption. Although the risk that CREON will transmit an infectious agent to humans has been reduced by testing for certain viruses during manufacturing and by inactivating certain viruses during manufacturing, there is a theoretical risk for transmission of viral disease, including diseases caused by novel or unidentified viruses. Thus, the presence of porcine viruses that might infect humans cannot be definitely excluded. However, no cases of transmission of an infectious illness associated with the use of porcine pancreatic extracts have been reported.
Allergic Reactions
- Caution should be exercised when administering pancrelipase to a patient with a known allergy to proteins of porcine origin. Rarely, severe allergic reactions including anaphylaxis, asthma, hives, and pruritus, have been reported with other pancreatic enzyme products with different formulations of the same active ingredient (pancrelipase). The risks and benefits of continued CREON treatment in patients with severe allergy should be taken into consideration with the overall clinical needs of the patient.
# Adverse Reactions
## Clinical Trials Experience
- The most serious adverse reactions reported with different pancreatic enzyme products of the same active ingredient (pancrelipase) that are described elsewhere in the label include fibrosing colonopathy, hyperuricemia and allergic reactions.
- 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 the rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- The short-term safety of CREON was assessed in clinical trials conducted in 121 patients with exocrine pancreatic insufficiency (EPI): 67 patients with EPI due to cystic fibrosis (CF) and 25 patients with EPI due to chronic pancreatitis or pancreatectomy were treated with CREON.
Cystic Fibrosis:
- Studies 1 and 2 were randomized, double-blind, placebo-controlled, crossover studies of 49 patients, ages 7 to 43 years, with EPI due to CF. Study 1 included 32 patients ages 12 to 43 years and Study 2 included 17 patients ages 7 to 11 years. In these studies, patients were randomized to receive CREON at a dose of 4,000 lipase units/g fat ingested per day or matching placebo for 5 to 6 days of treatment, followed by crossover to the alternate treatment for an additional 5 to 6 days. The mean exposure to CREON during these studies was 5 days.
- In Study 1, one patient experienced duodenitis and gastritis of moderate severity 16 days after completing treatment with CREON. Transient neutropenia without clinical sequelae was observed as an abnormal laboratory finding in one patient receiving CREON and a macrolide antibiotic.
- In Study 2, adverse reactions that occurred in at least 2 patients (greater than or equal to 12%) treated with CREON were vomiting and headache. Vomiting occurred in 2 patients treated with CREON and did not occur in patients treated with placebo; headache occurred in 2 patients treated with CREON and did not occur in patients treated with placebo.
- The most common adverse reactions (greater than or equal to 4%) in Studies 1 and 2 were vomiting, dizziness, and cough. Table 1 enumerates adverse reactions that occurred in at least 2 patients (greater than or equal to 4%) treated with CREON at a higher rate than with placebo in Studies 1 and 2.
- An additional open-label, single-arm study assessed the short-term safety and tolerability of CREON in 18 infants and children, ages 4 months to 6 years, with EPI due to cystic fibrosis. Patients received their usual pancreatic enzyme replacement therapy (mean dose of 7,000 lipase units/kg/day for a mean duration of 18.2 days) followed by CREON (mean dose of 7,500 lipase units/kg/day for a mean duration of 12.6 days). There were no serious adverse reactions. Adverse reactions that occurred in patients during treatment with CREON were vomiting, irritability, and decreased appetite, each occurring in 6% of patients.
Chronic Pancreatitis or Pancreatectomy:
- A randomized, double-blind, placebo-controlled, parallel group study was conducted in 54 adult patients, ages 32 to 75 years, with EPI due to chronic pancreatitis or pancreatectomy. Patients received single-blind placebo treatment during a 5-day run-in period followed by an intervening period of up to 16 days of investigator-directed treatment with no restrictions on pancreatic enzyme replacement therapy. Patients were then randomized to receive CREON or matching placebo for 7 days. The CREON dose was 72,000 lipase units per main meal (3 main meals) and 36,000 lipase units per snack (2 snacks). The mean exposure to CREON during this study was 6.8 days in the 25 patients that received CREON.
- The most common adverse reactions reported during the study were related to glycemic control and were reported more commonly during CREON treatment than during placebo treatment.
- Table 2 enumerates adverse reactions that occurred in at least 1 patient (greater than or equal to 4%) treated with CREON at a higher rate than with placebo.
## Postmarketing Experience
- Postmarketing data from this formulation of CREON have been available since 2009. The following adverse reactions have been identified during post approval use of this formulation of CREON. 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.
- Gastrointestinal disorders (including abdominal pain, diarrhea, flatulence, constipation and nausea), skin disorders (including pruritus, urticaria and rash), blurred vision, myalgia], muscle spasm, and asymptomatic elevations of liver enzymes have been reported with this formulation of CREON.
- Delayed- and immediate-release pancreatic enzyme products with different formulations of the same active ingredient (pancrelipase) have been used for the treatment of patients with exocrine pancreatic insufficiency due to cystic fibrosis and other conditions, such as chronic pancreatitis. The long-term safety profile of these products has been described in the medical literature. The most serious adverse reactions included fibrosing colonopathy, distal intestinal obstruction syndrome (DIOS), recurrence of pre-existing carcinoma, and severe allergic reactions including anaphylaxis, asthma, hives, and pruritus.
# Drug Interactions
- No drug interactions have been identified. No formal interaction studies have been conducted.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
Teratogenic effects
- Pregnancy Category C: Animal reproduction studies have not been conducted with pancrelipase. It is also not known whether pancrelipase can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. CREON should be given to a pregnant woman only if clearly needed. The risk and benefit of pancrelipase should be considered in the context of the need to provide adequate nutritional support to a pregnant woman with exocrine pancreatic insufficiency. Adequate caloric intake during pregnancy is important for normal maternal weight gain and fetal growth. Reduced maternal weight gain and malnutrition can be associated with adverse pregnancy outcomes.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Pancrelipase in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Pancrelipase 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 CREON is administered to a nursing woman. The risk and benefit of pancrelipase should be considered in the context of the need to provide adequate nutritional support to a nursing mother with exocrine pancreatic insufficiency.
### Pediatric Use
- The short-term safety and effectiveness of CREON were assessed in two randomized, double-blind, placebo-controlled, crossover studies of 49 patients with EPI due to cystic fibrosis, 25 of whom were pediatric patients. Study 1 included 8 adolescents between 12 and 17 years of age. Study 2 included 17 children between 7 and 11 years of age. The safety and efficacy in pediatric patients in these studies were similar to adult patients.
- An open-label, single-arm, short-term study of CREON was conducted in 18 infants and children, ages 4 months to six years of age, with EPI due to cystic fibrosis. Patients received their usual pancreatic enzyme replacement therapy (mean dose of 7,000 lipase units/kg/day for a mean duration of 18.2 days) followed by CREON (mean dose of 7,500 lipase units/kg/day for a mean duration of 12.6 days). The mean daily fat intake was 48 grams during treatment with usual pancreatic enzyme replacement therapy and 47 grams during treatment with CREON. When patients were switched from their usual pancreatic enzyme replacement therapy to CREON, they demonstrated similar spot fecal fat testing results; the clinical relevance of spot fecal fat testing has not been demonstrated. Adverse reactions that occurred in patients during treatment with CREON were vomiting, irritability, and decreased appetite.
- The safety and efficacy of pancreatic enzyme products with different formulations of pancrelipase consisting of the same active ingredient (lipases, proteases, and amylases) for treatment of children with exocrine pancreatic insufficiency due to cystic fibrosis have been described in the medical literature and through clinical experience.
- Dosing of pediatric patients should be in accordance with recommended guidance from the Cystic Fibrosis Foundation Consensus Conferences. Doses of other pancreatic enzyme products exceeding 6,000 lipase units/kg of body weight per meal have been associated with fibrosing colonopathy and colonic strictures in children less than 12 years of age.
### Geriatic Use
- Clinical studies of CREON 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.
### Gender
There is no FDA guidance on the use of Pancrelipase with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Pancrelipase with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Pancrelipase in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Pancrelipase in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Pancrelipase in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Pancrelipase in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Infants (up to 12 months)
- CREON should be administered to infants immediately prior to each feeding, using a dosage of 3,000 lipase units per 120 mL of formula or prior to breast-feeding. Contents of the capsule may be administered directly to the mouth or with a small amount of applesauce. *Administration should be followed by breast milk or formula. Contents of the capsule should not be mixed directly into formula or breast milk as this may diminish efficacy. Care should be taken to ensure that CREON is not crushed or chewed or retained in the mouth, to avoid irritation of the oral mucosa.
Children and Adults
- CREON should be taken during meals or snacks, with sufficient fluid. CREON capsules and capsule contents should not be crushed or chewed. Capsules should be swallowed whole.
- For patients who are unable to swallow intact capsules, the capsules may be carefully opened and the contents added to a small amount of acidic soft food with a pH of 4.5 or less, such as applesauce, at room temperature. The CREON-soft food mixture should be swallowed immediately without crushing or chewing, and followed with water or juice to ensure complete ingestion. Care should be taken to ensure that no drug is retained in the mouth.
### Monitoring
- Patients with fibrosing colonopathy should be closely monitored because some patients may be at risk of progressing to stricture formation.
# IV Compatibility
There is limited information regarding the compatibility of Pancrelipase and IV administrations.
# Overdosage
- There have been no reports of overdose in clinical trials or postmarketing surveillance with this formulation of CREON. Chronic high doses of pancreatic enzyme products have been associated with fibrosing colonopathy and colonic strictures. High doses of pancreatic enzyme products have been associated with hyperuricosuria and hyperuricemia, and should be used with caution in patients with a history of hyperuricemia, gout, or renal impairment.
# Pharmacology
## Mechanism of Action
- The pancreatic enzymes in CREON catalyze the hydrolysis of fats to monoglyceride, glycerol and free fatty acids, proteins into peptides and amino acids, and starches into dextrins and short chain sugars such as maltose and maltriose in the duodenum and proximal small intestine, thereby acting like digestive enzymes physiologically secreted by the pancreas.
## Structure
- CREON is a pancreatic enzyme preparation consisting of pancrelipase, an extract derived from porcine pancreatic glands. Pancrelipase contains multiple enzyme classes, including porcine-derived lipases, proteases, and amylases.
- Pancrelipase is a beige-white amorphous powder. It is miscible in water and practically insoluble or insoluble in alcohol and ether.
- Each delayed-release capsule for oral administration contains enteric-coated spheres (0.71–1.60 mm in diameter).
- The active ingredient evaluated in clinical trials is lipase. CREON is dosed by lipase units.
- Other active ingredients include protease and amylase.
- CREON contains the following inactive ingredients: cetyl alcohol, dimethicone, hypromellose phthalate, polyethylene glycol, and triethyl citrate.
- 3,000 USP units of lipase; 9,500 USP units of protease; 15,000 USP units of amylase delayed-release capsules have a white opaque cap with imprint “CREON 1203” and a white opaque body. The shells contain titanium dioxide and hypromellose.
- 6,000 USP units of lipase; 19,000 USP units of protease; 30,000 USP units of amylase delayed-release capsules have a Swedish-orange opaque cap with imprint “CREON 1206” and a blue opaque body. The shells contain FD&C Blue No. 2, gelatin, red iron oxide, sodium lauryl sulfate, titanium dioxide, and yellow iron oxide.
- 12,000 USP units of lipase; 38,000 USP units of protease; 60,000 USP units of amylase delayed-release capsules have a brown opaque cap with imprint “CREON 1212” and a colorless transparent body. The shells contain black iron oxide, gelatin, red iron oxide, sodium lauryl sulfate, titanium dioxide, and yellow iron oxide.
- 24,000 USP units of lipase; 76,000 USP units of protease; 120,000 USP units of amylase delayed-release capsules have a Swedish-orange opaque cap with imprint “CREON 1224” and a colorless transparent body. The shells contain gelatin, red iron oxide, sodium lauryl sulfate, titanium dioxide, and yellow iron oxide.
- 36,000 USP units of lipase; 114,000 USP units of protease; 180,000 USP units of amylase delayed-release capsules have a blue opaque cap with imprint “CREON 1236” and a colorless transparent body. The shells contain gelatin, titanium dioxide, FD&C Blue No. 2 and sodium lauryl sulfate.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Pancrelipase in the drug label.
## Pharmacokinetics
- The pancreatic enzymes in CREON are enteric-coated to minimize destruction or inactivation in gastric acid. CREON is designed to release most of the enzymes in vivo at an approximate pH of 5.5 or greater. Pancreatic enzymes are not absorbed from the gastrointestinal tract in appreciable amounts.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
- Carcinogenicity, genetic toxicology, and animal fertility studies have not been performed with pancrelipase.
# Clinical Studies
- The short-term efficacy of CREON was evaluated in three studies conducted in 103 patients with exocrine pancreatic insufficiency (EPI). Two studies were conducted in 49 patients with EPI due to cystic fibrosis (CF); one study was conducted in 54 patients with EPI due to chronic pancreatitis or pancreatectomy.
Cystic Fibrosis
- Studies 1 and 2 were randomized, double-blind, placebo-controlled, crossover studies in 49 patients, ages 7 to 43 years, with exocrine pancreatic insufficiency due to cystic fibrosis. Study 1 included patients aged 12 to 43 years (n = 32). The final analysis population was limited to 29 patients; 3 patients were excluded due to protocol deviations. Study 2 included patients aged 7 to 11 years (n = 17). The final analysis population was limited to 16 patients; 1 patient withdrew consent prior to stool collection during treatment with CREON. In each study, patients were randomized to receive CREON at a dose of 4,000 lipase units/g fat ingested per day or matching placebo for 5 to 6 days of treatment, followed by crossover to the alternate treatment for an additional 5 to 6 days. All patients consumed a high-fat diet (greater than or equal to 90 grams of fat per day, 40% of daily calories derived from fat) during the treatment periods.
- The coefficient of fat absorption (CFA) was determined by a 72-hour stool collection during both treatments, when both fat excretion and fat ingestion were measured. Each patient's CFA during placebo treatment was used as their no-treatment CFA value.
- In Study 1, mean CFA was 89% with CREON treatment compared to 49% with placebo treatment. The mean difference in CFA was 41 percentage points in favor of CREON treatment with 95% CI: (34, 47) and p<0.001.
- In Study 2, mean CFA was 83% with CREON treatment compared to 47% with placebo treatment. The mean difference in CFA was 35 percentage points in favor of CREON treatment with 95% CI: (27, 44) and p<0.001.
- Subgroup analyses of the CFA results in Studies 1 and 2 showed that mean change in CFA with CREON treatment was greater in patients with lower no-treatment (placebo) CFA values than in patients with higher no-treatment (placebo) CFA values. There were no differences in response to CREON by age or gender, with similar responses to CREON observed in male and female patients, and in younger (under 18 years of age) and older patients.
- The coefficient of nitrogen absorption (CNA) was determined by a 72-hour stool collection during both treatments, when nitrogen excretion was measured and nitrogen ingestion from a controlled diet was estimated (based on the assumption that proteins contain 16% nitrogen). Each patient's CNA during placebo treatment was used as their no-treatment CNA value.
- In Study 1, mean CNA was 86% with CREON treatment compared to 49% with placebo treatment. The mean difference in CNA was 37 percentage points in favor of CREON treatment with 95% CI: (31, 42) and p<0.001.
- In Study 2, mean CNA was 80% with CREON treatment compared to 45% with placebo treatment. The mean difference in CNA was 35 percentage points in favor of CREON treatment with 95% CI: (26, 45) and p<0.001.
Chronic Pancreatitis or Pancreatectomy
- A randomized, double-blind, placebo-controlled, parallel group study was conducted in 54 adult patients, ages 32 to 75 years, with EPI due to chronic pancreatitis or pancreatectomy. The final analysis population was limited to 52 patients; 2 patients were excluded due to protocol violations. Ten patients had a history of pancreatectomy (7 were treated with CREON). In this study, patients received placebo for 5 days (run-in period), followed by pancreatic enzyme replacement therapy as directed by the investigator for 16 days; this was followed by randomization to CREON or matching placebo for 7 days of treatment (double-blind period). Only patients with CFA less than 80% in the run-in period were randomized to the double-blind period. The dose of CREON during the double-blind period was 72,000 lipase units per main meal (3 main meals) and 36,000 lipase units per snack (2 snacks). All patients consumed a high-fat diet (greater than or equal to 100 grams of fat per day) during the treatment period.
- The CFA was determined by a 72-hour stool collection during the run-in and double-blind treatment periods, when both fat excretion and fat ingestion were measured. The mean change in CFA from the run-in period to the end of the double-blind period in the CREON and Placebo groups is shown in Table 3.
- Subgroup analyses of the CFA results showed that mean change in CFA was greater in patients with lower run-in period CFA values than in patients with higher run-in period CFA values. Only 1 of the patients with a history of total pancreatectomy was treated with CREON in the study. That patient had a CFA of 26% during the run-in period and a CFA of 73% at the end of the double-blind period. The remaining 6 patients with a history of partial pancreatectomy treated with CREON on the study had a mean CFA of 42% during the run-in period and a mean CFA of 84% at the end of the double-blind period.
# How Supplied
CREON (pancrelipase) Delayed-Release Capsules
- 3,000 USP units of lipase; 9,500 USP units of protease; 15,000 USP units of amylase
- Each CREON capsule is available as a two piece hypromellose capsule with a white opaque cap with imprint “CREON 1203” and a white opaque body that contains tan colored, delayed-release pancrelipase supplied in bottles of:
CREON (pancrelipase) Delayed-Release Capsules
- 6,000 USP units of lipase; 19,000 USP units of protease; 30,000 USP units of amylase
- Each CREON capsule is available as a two-piece gelatin capsule with orange opaque cap with imprint “CREON 1206” and a blue opaque body that contains tan-colored, delayed-release pancrelipase supplied in bottles of:
- 100 capsules (NDC 0032-1206-01)
- 250 capsules (NDC 0032-1206-07)
CREON (pancrelipase) Delayed-Release Capsules
- 12,000 USP units of lipase; 38,000 USP units of protease; 60,000 USP units of amylase
- Each CREON capsule is available as a two-piece gelatin capsule with a brown opaque cap with imprint “CREON 1212” and a colorless transparent body that contains tan-colored, delayed-release pancrelipase supplied in bottles of:
- 100 capsules (NDC 0032-1212-01)
- 250 capsules (NDC 0032-1212-07)
CREON (pancrelipase) Delayed-Release Capsules
- 24,000 USP units of lipase; 76,000 USP units of protease; 120,000 USP units of amylase
- Each CREON capsule is available as a two-piece gelatin capsule with orange opaque cap with imprint “CREON 1224” and a colorless transparent body that contains tan-colored, delayed-release pancrelipase supplied in bottles of:
- 100 capsules (NDC 0032-1224-01)
- 250 capsules (NDC 0032-1224-07)
CREON (pancrelipase) Delayed-Release Capsules
- 36,000 USP units of lipase; 114,000 USP units of protease; 180,000 USP units of amylase
- Each CREON capsule is available as a two-piece gelatin capsule with blue opaque cap with imprint “CREON 1236” and a colorless transparent body that contains tan-colored, delayed-release pancrelipase supplied in bottles of:
- 100 capsules (NDC 0032-3016-13)
- 250 capsules (NDC 0032-3016-28)
## Storage
Storage and Handling
- CREON must be stored at room temperature up to 25°C (77°F) and protected from moisture. Temperature excursions are permitted between 25°C to 40°C (77°F and 104°F) for up to 30 days. Product should be discarded if exposed to higher temperature and moisture conditions higher than 70%. After opening, keep bottle tightly closed between uses to protect from moisture.
- Bottles of CREON 3,000 USP units of lipase must be stored and dispensed in the original container.
- Do not crush CREON delayed-release capsules or the capsule contents.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise patients and caregivers to follow dosing instructions carefully, as doses of pancreatic enzyme products exceeding 6,000 lipase units/kg of body weight per meal have been associated with colonic strictures in children below the age of 12 years.
Allergic Reactions
- Advise patients and caregivers to contact their healthcare professional immediately if allergic reactions to CREON develop.
Pregnancy and Breast Feeding
- Instruct patients to notify their healthcare professional if they are pregnant or are thinking of becoming pregnant during treatment with CREON.
- Instruct patients to notify their healthcare professional if they are breast feeding or are thinking of breast feeding during treatment with CREON.
# Precautions with Alcohol
- Alcohol-Pancrelipase interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
Creon
Pancreaze
Zenpep,
Pangestyme EC,
Ultracaps,
Pancrelipase,
Palcaps,
Panocaps.
# Look-Alike Drug Names
There is limited information regarding Pancrelipase Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Pancrelipase
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Deepika Beereddy, MBBS [2]
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# Overview
Pancrelipase is a gastrointestinal agent that is FDA approved for the treatment of exocrine pancreatic insufficiency due to cystic fibrosis, chronic pancreatitis, pancreatectomy, or other conditions. Common adverse reactions include vomiting, dizziness, cough, hyperglycemia, hypoglycemia, abdominal pain, abnormal feces, flatulence, frequent bowel movements, and nasopharyngitis.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- CREON® (pancrelipase) is indicated for the treatment of exocrine pancreatic insufficiency due to cystic fibrosis, chronic pancreatitis, pancreatectomy, or other conditions.
- Dosing Information
- CREON is not interchangeable with other pancrelipase products.
- CREON is orally administered. Therapy should be initiated at the lowest recommended dose and gradually increased. The dosage of CREON should be individualized based on clinical symptoms, the degree of steatorrhea present, and the fat content of the diet.
- Adults with Exocrine Pancreatic Insufficiency Due to Chronic Pancreatitis or Pancreatectomy:
- The initial starting dose and increases in the dose per meal should be individualized based on clinical symptoms, the degree of steatorrhea present, and the fat content of the diet.
- In one clinical trial, patients received CREON at a dose of 72,000 lipase units per meal while consuming at least 100 g of fat per day. Lower starting doses recommended in the literature are consistent with the 500 lipase units/kg of body weight per meal lowest starting dose recommended for adults in the Cystic Fibrosis Foundation Consensus Conferences Guidelines.1, 2, 3, 4 Usually, half of the prescribed CREON dose for an individualized full meal should be given with each snack.
- DOSAGE FORMS AND STRENGTHS
- The active ingredient in CREON evaluated in clinical trials is lipase. CREON is dosed by lipase units.
- Other active ingredients include protease and amylase. Each CREON delayed-release capsule strength contains the specified amounts of lipase, protease, and amylase as follows:
- 3,000 USP units of lipase; 9,500 USP units of protease; 15,000 USP units of amylase delayed-release capsules have a white opaque cap with imprint “CREON 1203” and a white opaque body.
- 6,000 USP units of lipase; 19,000 USP units of protease; 30,000 USP units of amylase delayed-release capsules have an orange opaque cap with imprint “CREON 1206” and a blue opaque body.
- 12,000 USP units of lipase; 38,000 USP units of protease; 60,000 USP units of amylase delayed-release capsules have a brown opaque cap with imprint “CREON 1212” and a colorless transparent body.
- 24,000 USP units of lipase; 76,000 USP units of protease; 120,000 USP units of amylase delayed-release capsules have an orange opaque cap with imprint “CREON 1224” and a colorless transparent body.
- 36,000 USP units of lipase; 114,000 USP units of protease; 180,000 USP units of amylase delayed-release capsules have a blue opaque cap with imprint “CREON 1236” and a colorless transparent body.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pancrelipase (patient information) in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Pancrelipase (patient information) in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- Dosage recommendations for pancreatic enzyme replacement therapy were published following the Cystic Fibrosis Foundation Consensus Conferences.1, 2, 3 CREON should be administered in a manner consistent with the recommendations of the Cystic Fibrosis Foundation Consensus Conferences (also known as Conferences) provided in the following paragraphs, except for infants. Although the Conferences recommend doses of 2,000 to 4,000 lipase units in infants up to 12 months, CREON is available in a 3,000 lipase unit capsule. Therefore, the recommended dose of CREON in infants up to 12 months is 3,000 lipase units per 120 mL of formula or per breast-feeding. Patients may be dosed on a fat ingestion-based or actual body weight-based dosing scheme.
- Additional recommendations for pancreatic enzyme therapy in patients with exocrine pancreatic insufficiency due to chronic pancreatitis or pancreatectomy are based on a clinical trial conducted in these populations.
- Infants (up to 12 months):
- CREON is available in the strength of 3,000 USP units of lipase thus infants may be given 3,000 lipase units (one capsule) per 120 mL of formula or per breast-feeding. Do not mix CREON capsule contents directly into formula or breast milk prior to administration.
- Children Older than 12 Months and Younger than 4 Years:
- Enzyme dosing should begin with 1,000 lipase units/kg of body weight per meal for children less than age 4 years to a maximum of 2,500 lipase units/kg of body weight per meal (or less than or equal to 10,000 lipase units/kg of body weight per day), or less than 4,000 lipase units/g fat ingested per day.
- Children 4 Years and Older and Adults:
- Enzyme dosing should begin with 500 lipase units/kg of body weight per meal for those older than age 4 years to a maximum of 2,500 lipase units/kg of body weight per meal (or less than or equal to 10,000 lipase units/kg of body weight per day), or less than 4,000 lipase units/g fat ingested per day.
- Usually, half of the prescribed CREON dose for an individualized full meal should be given with each snack. The total daily dose should reflect approximately three meals plus two or three snacks per day.
- Enzyme doses expressed as lipase units/kg of body weight per meal should be decreased in older patients because they weigh more but tend to ingest less fat per kilogram of body weight.
- Limitations on Dosing:
- Dosing should not exceed the recommended maximum dosage set forth by the Cystic Fibrosis Foundation Consensus Conferences Guidelines.1, 2, 3 If symptoms and signs of steatorrhea persist, the dosage may be increased by the healthcare professional. Patients should be instructed not to increase the dosage on their own. There is great inter-individual variation in response to enzymes; thus, a range of doses is recommended. Changes in dosage may require an adjustment period of several days. If doses are to exceed 2,500 lipase units/kg of body weight per meal, further investigation is warranted. Doses greater than 2,500 lipase units/kg of body weight per meal (or greater than 10,000 lipase units/kg of body weight per day) should be used with caution and only if they are documented to be effective by 3-day fecal fat measures that indicate a significantly improved coefficient of fat absorption. Doses greater than 6,000 lipase units/kg of body weight per meal have been associated with colonic stricture, indicative of fibrosing colonopathy, in children less than 12 years of age. Patients currently receiving higher doses than 6,000 lipase units/kg of body weight per meal should be examined and the dosage either immediately decreased or titrated downward to a lower range.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pancrelipase (patient information) in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Pancrelipase (patient information) in pediatric patients.
# Contraindications
None.
# Warnings
Fibrosing Colonopathy
- Fibrosing colonopathy has been reported following treatment with different pancreatic enzyme products. 5, 6 Fibrosing colonopathy is a rare, serious adverse reaction initially described in association with high-dose pancreatic enzyme use, usually over a prolonged period of time and most commonly reported in pediatric patients with cystic fibrosis. The underlying mechanism of fibrosing colonopathy remains unknown. Doses of pancreatic enzyme products exceeding 6,000 lipase units/kg of body weight per meal have been associated with colonic stricture in children less than 12 years of age.1 Patients with fibrosing colonopathy should be closely monitored because some patients may be at risk of progressing to stricture formation. It is uncertain whether regression of fibrosing colonopathy occurs.1 It is generally recommended, unless clinically indicated, that enzyme doses should be less than 2,500 lipase units/kg of body weight per meal (or less than 10,000 lipase units/kg of body weight per day) or less than 4,000 lipase units/g fat ingested per day.
- Doses greater than 2,500 lipase units/kg of body weight per meal (or greater than 10,000 lipase units/kg of body weight per day) should be used with caution and only if they are documented to be effective by 3-day fecal fat measures that indicate a significantly improved coefficient of fat absorption. Patients receiving higher doses than 6,000 lipase units/kg of body weight per meal should be examined and the dosage either immediately decreased or titrated downward to a lower range.
Potential for Irritation to Oral Mucosa
- Care should be taken to ensure that no drug is retained in the mouth. CREON should not be crushed or chewed or mixed in foods having a pH greater than 4.5. These actions can disrupt the protective enteric coating resulting in early release of enzymes, irritation of oral mucosa, and/or loss of enzyme activity. For patients who are unable to swallow intact capsules, the capsules may be carefully opened and the contents added to a small amount of acidic soft food with a pH of 4.5 or less, such as applesauce, at room temperature. The CREON-soft food mixture should be swallowed immediately and followed with water or juice to ensure complete ingestion.
Potential for Risk of Hyperuricemia
- Caution should be exercised when prescribing CREON to patients with gout, renal impairment, or hyperuricemia. Porcine-derived pancreatic enzyme products contain purines that may increase blood uric acid levels.
Potential Viral Exposure from the Product Source
- CREON is sourced from pancreatic tissue from swine used for food consumption. Although the risk that CREON will transmit an infectious agent to humans has been reduced by testing for certain viruses during manufacturing and by inactivating certain viruses during manufacturing, there is a theoretical risk for transmission of viral disease, including diseases caused by novel or unidentified viruses. Thus, the presence of porcine viruses that might infect humans cannot be definitely excluded. However, no cases of transmission of an infectious illness associated with the use of porcine pancreatic extracts have been reported.
Allergic Reactions
- Caution should be exercised when administering pancrelipase to a patient with a known allergy to proteins of porcine origin. Rarely, severe allergic reactions including anaphylaxis, asthma, hives, and pruritus, have been reported with other pancreatic enzyme products with different formulations of the same active ingredient (pancrelipase). The risks and benefits of continued CREON treatment in patients with severe allergy should be taken into consideration with the overall clinical needs of the patient.
# Adverse Reactions
## Clinical Trials Experience
- The most serious adverse reactions reported with different pancreatic enzyme products of the same active ingredient (pancrelipase) that are described elsewhere in the label include fibrosing colonopathy, hyperuricemia and allergic reactions.
- 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 the rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- The short-term safety of CREON was assessed in clinical trials conducted in 121 patients with exocrine pancreatic insufficiency (EPI): 67 patients with EPI due to cystic fibrosis (CF) and 25 patients with EPI due to chronic pancreatitis or pancreatectomy were treated with CREON.
Cystic Fibrosis:
- Studies 1 and 2 were randomized, double-blind, placebo-controlled, crossover studies of 49 patients, ages 7 to 43 years, with EPI due to CF. Study 1 included 32 patients ages 12 to 43 years and Study 2 included 17 patients ages 7 to 11 years. In these studies, patients were randomized to receive CREON at a dose of 4,000 lipase units/g fat ingested per day or matching placebo for 5 to 6 days of treatment, followed by crossover to the alternate treatment for an additional 5 to 6 days. The mean exposure to CREON during these studies was 5 days.
- In Study 1, one patient experienced duodenitis and gastritis of moderate severity 16 days after completing treatment with CREON. Transient neutropenia without clinical sequelae was observed as an abnormal laboratory finding in one patient receiving CREON and a macrolide antibiotic.
- In Study 2, adverse reactions that occurred in at least 2 patients (greater than or equal to 12%) treated with CREON were vomiting and headache. Vomiting occurred in 2 patients treated with CREON and did not occur in patients treated with placebo; headache occurred in 2 patients treated with CREON and did not occur in patients treated with placebo.
- The most common adverse reactions (greater than or equal to 4%) in Studies 1 and 2 were vomiting, dizziness, and cough. Table 1 enumerates adverse reactions that occurred in at least 2 patients (greater than or equal to 4%) treated with CREON at a higher rate than with placebo in Studies 1 and 2.
- An additional open-label, single-arm study assessed the short-term safety and tolerability of CREON in 18 infants and children, ages 4 months to 6 years, with EPI due to cystic fibrosis. Patients received their usual pancreatic enzyme replacement therapy (mean dose of 7,000 lipase units/kg/day for a mean duration of 18.2 days) followed by CREON (mean dose of 7,500 lipase units/kg/day for a mean duration of 12.6 days). There were no serious adverse reactions. Adverse reactions that occurred in patients during treatment with CREON were vomiting, irritability, and decreased appetite, each occurring in 6% of patients.
Chronic Pancreatitis or Pancreatectomy:
- A randomized, double-blind, placebo-controlled, parallel group study was conducted in 54 adult patients, ages 32 to 75 years, with EPI due to chronic pancreatitis or pancreatectomy. Patients received single-blind placebo treatment during a 5-day run-in period followed by an intervening period of up to 16 days of investigator-directed treatment with no restrictions on pancreatic enzyme replacement therapy. Patients were then randomized to receive CREON or matching placebo for 7 days. The CREON dose was 72,000 lipase units per main meal (3 main meals) and 36,000 lipase units per snack (2 snacks). The mean exposure to CREON during this study was 6.8 days in the 25 patients that received CREON.
- The most common adverse reactions reported during the study were related to glycemic control and were reported more commonly during CREON treatment than during placebo treatment.
- Table 2 enumerates adverse reactions that occurred in at least 1 patient (greater than or equal to 4%) treated with CREON at a higher rate than with placebo.
## Postmarketing Experience
- Postmarketing data from this formulation of CREON have been available since 2009. The following adverse reactions have been identified during post approval use of this formulation of CREON. 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.
- Gastrointestinal disorders (including abdominal pain, diarrhea, flatulence, constipation and nausea), skin disorders (including pruritus, urticaria and rash), blurred vision, myalgia], muscle spasm, and asymptomatic elevations of liver enzymes have been reported with this formulation of CREON.
- Delayed- and immediate-release pancreatic enzyme products with different formulations of the same active ingredient (pancrelipase) have been used for the treatment of patients with exocrine pancreatic insufficiency due to cystic fibrosis and other conditions, such as chronic pancreatitis. The long-term safety profile of these products has been described in the medical literature. The most serious adverse reactions included fibrosing colonopathy, distal intestinal obstruction syndrome (DIOS), recurrence of pre-existing carcinoma, and severe allergic reactions including anaphylaxis, asthma, hives, and pruritus.
# Drug Interactions
- No drug interactions have been identified. No formal interaction studies have been conducted.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
Teratogenic effects
- Pregnancy Category C: Animal reproduction studies have not been conducted with pancrelipase. It is also not known whether pancrelipase can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. CREON should be given to a pregnant woman only if clearly needed. The risk and benefit of pancrelipase should be considered in the context of the need to provide adequate nutritional support to a pregnant woman with exocrine pancreatic insufficiency. Adequate caloric intake during pregnancy is important for normal maternal weight gain and fetal growth. Reduced maternal weight gain and malnutrition can be associated with adverse pregnancy outcomes.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Pancrelipase in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Pancrelipase 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 CREON is administered to a nursing woman. The risk and benefit of pancrelipase should be considered in the context of the need to provide adequate nutritional support to a nursing mother with exocrine pancreatic insufficiency.
### Pediatric Use
- The short-term safety and effectiveness of CREON were assessed in two randomized, double-blind, placebo-controlled, crossover studies of 49 patients with EPI due to cystic fibrosis, 25 of whom were pediatric patients. Study 1 included 8 adolescents between 12 and 17 years of age. Study 2 included 17 children between 7 and 11 years of age. The safety and efficacy in pediatric patients in these studies were similar to adult patients.
- An open-label, single-arm, short-term study of CREON was conducted in 18 infants and children, ages 4 months to six years of age, with EPI due to cystic fibrosis. Patients received their usual pancreatic enzyme replacement therapy (mean dose of 7,000 lipase units/kg/day for a mean duration of 18.2 days) followed by CREON (mean dose of 7,500 lipase units/kg/day for a mean duration of 12.6 days). The mean daily fat intake was 48 grams during treatment with usual pancreatic enzyme replacement therapy and 47 grams during treatment with CREON. When patients were switched from their usual pancreatic enzyme replacement therapy to CREON, they demonstrated similar spot fecal fat testing results; the clinical relevance of spot fecal fat testing has not been demonstrated. Adverse reactions that occurred in patients during treatment with CREON were vomiting, irritability, and decreased appetite.
- The safety and efficacy of pancreatic enzyme products with different formulations of pancrelipase consisting of the same active ingredient (lipases, proteases, and amylases) for treatment of children with exocrine pancreatic insufficiency due to cystic fibrosis have been described in the medical literature and through clinical experience.
- Dosing of pediatric patients should be in accordance with recommended guidance from the Cystic Fibrosis Foundation Consensus Conferences. Doses of other pancreatic enzyme products exceeding 6,000 lipase units/kg of body weight per meal have been associated with fibrosing colonopathy and colonic strictures in children less than 12 years of age.
### Geriatic Use
- Clinical studies of CREON 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.
### Gender
There is no FDA guidance on the use of Pancrelipase with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Pancrelipase with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Pancrelipase in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Pancrelipase in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Pancrelipase in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Pancrelipase in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Infants (up to 12 months)
- CREON should be administered to infants immediately prior to each feeding, using a dosage of 3,000 lipase units per 120 mL of formula or prior to breast-feeding. Contents of the capsule may be administered directly to the mouth or with a small amount of applesauce. *Administration should be followed by breast milk or formula. Contents of the capsule should not be mixed directly into formula or breast milk as this may diminish efficacy. Care should be taken to ensure that CREON is not crushed or chewed or retained in the mouth, to avoid irritation of the oral mucosa.
Children and Adults
- CREON should be taken during meals or snacks, with sufficient fluid. CREON capsules and capsule contents should not be crushed or chewed. Capsules should be swallowed whole.
- For patients who are unable to swallow intact capsules, the capsules may be carefully opened and the contents added to a small amount of acidic soft food with a pH of 4.5 or less, such as applesauce, at room temperature. The CREON-soft food mixture should be swallowed immediately without crushing or chewing, and followed with water or juice to ensure complete ingestion. Care should be taken to ensure that no drug is retained in the mouth.
### Monitoring
- Patients with fibrosing colonopathy should be closely monitored because some patients may be at risk of progressing to stricture formation.
# IV Compatibility
There is limited information regarding the compatibility of Pancrelipase and IV administrations.
# Overdosage
- There have been no reports of overdose in clinical trials or postmarketing surveillance with this formulation of CREON. Chronic high doses of pancreatic enzyme products have been associated with fibrosing colonopathy and colonic strictures. High doses of pancreatic enzyme products have been associated with hyperuricosuria and hyperuricemia, and should be used with caution in patients with a history of hyperuricemia, gout, or renal impairment.
# Pharmacology
## Mechanism of Action
- The pancreatic enzymes in CREON catalyze the hydrolysis of fats to monoglyceride, glycerol and free fatty acids, proteins into peptides and amino acids, and starches into dextrins and short chain sugars such as maltose and maltriose in the duodenum and proximal small intestine, thereby acting like digestive enzymes physiologically secreted by the pancreas.
## Structure
- CREON is a pancreatic enzyme preparation consisting of pancrelipase, an extract derived from porcine pancreatic glands. Pancrelipase contains multiple enzyme classes, including porcine-derived lipases, proteases, and amylases.
- Pancrelipase is a beige-white amorphous powder. It is miscible in water and practically insoluble or insoluble in alcohol and ether.
- Each delayed-release capsule for oral administration contains enteric-coated spheres (0.71–1.60 mm in diameter).
- The active ingredient evaluated in clinical trials is lipase. CREON is dosed by lipase units.
- Other active ingredients include protease and amylase.
- CREON contains the following inactive ingredients: cetyl alcohol, dimethicone, hypromellose phthalate, polyethylene glycol, and triethyl citrate.
- 3,000 USP units of lipase; 9,500 USP units of protease; 15,000 USP units of amylase delayed-release capsules have a white opaque cap with imprint “CREON 1203” and a white opaque body. The shells contain titanium dioxide and hypromellose.
- 6,000 USP units of lipase; 19,000 USP units of protease; 30,000 USP units of amylase delayed-release capsules have a Swedish-orange opaque cap with imprint “CREON 1206” and a blue opaque body. The shells contain FD&C Blue No. 2, gelatin, red iron oxide, sodium lauryl sulfate, titanium dioxide, and yellow iron oxide.
- 12,000 USP units of lipase; 38,000 USP units of protease; 60,000 USP units of amylase delayed-release capsules have a brown opaque cap with imprint “CREON 1212” and a colorless transparent body. The shells contain black iron oxide, gelatin, red iron oxide, sodium lauryl sulfate, titanium dioxide, and yellow iron oxide.
- 24,000 USP units of lipase; 76,000 USP units of protease; 120,000 USP units of amylase delayed-release capsules have a Swedish-orange opaque cap with imprint “CREON 1224” and a colorless transparent body. The shells contain gelatin, red iron oxide, sodium lauryl sulfate, titanium dioxide, and yellow iron oxide.
- 36,000 USP units of lipase; 114,000 USP units of protease; 180,000 USP units of amylase delayed-release capsules have a blue opaque cap with imprint “CREON 1236” and a colorless transparent body. The shells contain gelatin, titanium dioxide, FD&C Blue No. 2 and sodium lauryl sulfate.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Pancrelipase in the drug label.
## Pharmacokinetics
- The pancreatic enzymes in CREON are enteric-coated to minimize destruction or inactivation in gastric acid. CREON is designed to release most of the enzymes in vivo at an approximate pH of 5.5 or greater. Pancreatic enzymes are not absorbed from the gastrointestinal tract in appreciable amounts.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
- Carcinogenicity, genetic toxicology, and animal fertility studies have not been performed with pancrelipase.
# Clinical Studies
- The short-term efficacy of CREON was evaluated in three studies conducted in 103 patients with exocrine pancreatic insufficiency (EPI). Two studies were conducted in 49 patients with EPI due to cystic fibrosis (CF); one study was conducted in 54 patients with EPI due to chronic pancreatitis or pancreatectomy.
Cystic Fibrosis
- Studies 1 and 2 were randomized, double-blind, placebo-controlled, crossover studies in 49 patients, ages 7 to 43 years, with exocrine pancreatic insufficiency due to cystic fibrosis. Study 1 included patients aged 12 to 43 years (n = 32). The final analysis population was limited to 29 patients; 3 patients were excluded due to protocol deviations. Study 2 included patients aged 7 to 11 years (n = 17). The final analysis population was limited to 16 patients; 1 patient withdrew consent prior to stool collection during treatment with CREON. In each study, patients were randomized to receive CREON at a dose of 4,000 lipase units/g fat ingested per day or matching placebo for 5 to 6 days of treatment, followed by crossover to the alternate treatment for an additional 5 to 6 days. All patients consumed a high-fat diet (greater than or equal to 90 grams of fat per day, 40% of daily calories derived from fat) during the treatment periods.
- The coefficient of fat absorption (CFA) was determined by a 72-hour stool collection during both treatments, when both fat excretion and fat ingestion were measured. Each patient's CFA during placebo treatment was used as their no-treatment CFA value.
- In Study 1, mean CFA was 89% with CREON treatment compared to 49% with placebo treatment. The mean difference in CFA was 41 percentage points in favor of CREON treatment with 95% CI: (34, 47) and p<0.001.
- In Study 2, mean CFA was 83% with CREON treatment compared to 47% with placebo treatment. The mean difference in CFA was 35 percentage points in favor of CREON treatment with 95% CI: (27, 44) and p<0.001.
- Subgroup analyses of the CFA results in Studies 1 and 2 showed that mean change in CFA with CREON treatment was greater in patients with lower no-treatment (placebo) CFA values than in patients with higher no-treatment (placebo) CFA values. There were no differences in response to CREON by age or gender, with similar responses to CREON observed in male and female patients, and in younger (under 18 years of age) and older patients.
- The coefficient of nitrogen absorption (CNA) was determined by a 72-hour stool collection during both treatments, when nitrogen excretion was measured and nitrogen ingestion from a controlled diet was estimated (based on the assumption that proteins contain 16% nitrogen). Each patient's CNA during placebo treatment was used as their no-treatment CNA value.
- In Study 1, mean CNA was 86% with CREON treatment compared to 49% with placebo treatment. The mean difference in CNA was 37 percentage points in favor of CREON treatment with 95% CI: (31, 42) and p<0.001.
- In Study 2, mean CNA was 80% with CREON treatment compared to 45% with placebo treatment. The mean difference in CNA was 35 percentage points in favor of CREON treatment with 95% CI: (26, 45) and p<0.001.
Chronic Pancreatitis or Pancreatectomy
- A randomized, double-blind, placebo-controlled, parallel group study was conducted in 54 adult patients, ages 32 to 75 years, with EPI due to chronic pancreatitis or pancreatectomy. The final analysis population was limited to 52 patients; 2 patients were excluded due to protocol violations. Ten patients had a history of pancreatectomy (7 were treated with CREON). In this study, patients received placebo for 5 days (run-in period), followed by pancreatic enzyme replacement therapy as directed by the investigator for 16 days; this was followed by randomization to CREON or matching placebo for 7 days of treatment (double-blind period). Only patients with CFA less than 80% in the run-in period were randomized to the double-blind period. The dose of CREON during the double-blind period was 72,000 lipase units per main meal (3 main meals) and 36,000 lipase units per snack (2 snacks). All patients consumed a high-fat diet (greater than or equal to 100 grams of fat per day) during the treatment period.
- The CFA was determined by a 72-hour stool collection during the run-in and double-blind treatment periods, when both fat excretion and fat ingestion were measured. The mean change in CFA from the run-in period to the end of the double-blind period in the CREON and Placebo groups is shown in Table 3.
- Subgroup analyses of the CFA results showed that mean change in CFA was greater in patients with lower run-in period CFA values than in patients with higher run-in period CFA values. Only 1 of the patients with a history of total pancreatectomy was treated with CREON in the study. That patient had a CFA of 26% during the run-in period and a CFA of 73% at the end of the double-blind period. The remaining 6 patients with a history of partial pancreatectomy treated with CREON on the study had a mean CFA of 42% during the run-in period and a mean CFA of 84% at the end of the double-blind period.
# How Supplied
CREON (pancrelipase) Delayed-Release Capsules
- 3,000 USP units of lipase; 9,500 USP units of protease; 15,000 USP units of amylase
- Each CREON capsule is available as a two piece hypromellose capsule with a white opaque cap with imprint “CREON 1203” and a white opaque body that contains tan colored, delayed-release pancrelipase supplied in bottles of:
CREON (pancrelipase) Delayed-Release Capsules
- 6,000 USP units of lipase; 19,000 USP units of protease; 30,000 USP units of amylase
- Each CREON capsule is available as a two-piece gelatin capsule with orange opaque cap with imprint “CREON 1206” and a blue opaque body that contains tan-colored, delayed-release pancrelipase supplied in bottles of:
- 100 capsules (NDC 0032-1206-01)
- 250 capsules (NDC 0032-1206-07)
CREON (pancrelipase) Delayed-Release Capsules
- 12,000 USP units of lipase; 38,000 USP units of protease; 60,000 USP units of amylase
- Each CREON capsule is available as a two-piece gelatin capsule with a brown opaque cap with imprint “CREON 1212” and a colorless transparent body that contains tan-colored, delayed-release pancrelipase supplied in bottles of:
- 100 capsules (NDC 0032-1212-01)
- 250 capsules (NDC 0032-1212-07)
CREON (pancrelipase) Delayed-Release Capsules
- 24,000 USP units of lipase; 76,000 USP units of protease; 120,000 USP units of amylase
- Each CREON capsule is available as a two-piece gelatin capsule with orange opaque cap with imprint “CREON 1224” and a colorless transparent body that contains tan-colored, delayed-release pancrelipase supplied in bottles of:
- 100 capsules (NDC 0032-1224-01)
- 250 capsules (NDC 0032-1224-07)
CREON (pancrelipase) Delayed-Release Capsules
- 36,000 USP units of lipase; 114,000 USP units of protease; 180,000 USP units of amylase
- Each CREON capsule is available as a two-piece gelatin capsule with blue opaque cap with imprint “CREON 1236” and a colorless transparent body that contains tan-colored, delayed-release pancrelipase supplied in bottles of:
- 100 capsules (NDC 0032-3016-13)
- 250 capsules (NDC 0032-3016-28)
## Storage
Storage and Handling
- CREON must be stored at room temperature up to 25°C (77°F) and protected from moisture. Temperature excursions are permitted between 25°C to 40°C (77°F and 104°F) for up to 30 days. Product should be discarded if exposed to higher temperature and moisture conditions higher than 70%. After opening, keep bottle tightly closed between uses to protect from moisture.
- Bottles of CREON 3,000 USP units of lipase must be stored and dispensed in the original container.
- Do not crush CREON delayed-release capsules or the capsule contents.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise patients and caregivers to follow dosing instructions carefully, as doses of pancreatic enzyme products exceeding 6,000 lipase units/kg of body weight per meal have been associated with colonic strictures in children below the age of 12 years.
Allergic Reactions
- Advise patients and caregivers to contact their healthcare professional immediately if allergic reactions to CREON develop.
Pregnancy and Breast Feeding
- Instruct patients to notify their healthcare professional if they are pregnant or are thinking of becoming pregnant during treatment with CREON.
- Instruct patients to notify their healthcare professional if they are breast feeding or are thinking of breast feeding during treatment with CREON.
# Precautions with Alcohol
- Alcohol-Pancrelipase interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
Creon
Pancreaze
Zenpep,
Pangestyme EC,
Ultracaps,
Pancrelipase,
Palcaps,
Panocaps.
# Look-Alike Drug Names
There is limited information regarding Pancrelipase Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Pancrelipase | |
2b719a43d93e06fd1825aca0554284cd071d9ec0 | wikidoc | Panniculitis | Panniculitis
Panniculitis is a group of diseases whose hallmark is inflammation of subcutaneous fatty and muscle tissue. Symptoms include tender skin nodules, and systemic signs such as weight loss and fatigue.
# Classification
## Histological
It can occur in any fatty tissue (cutaneous or visceral) and is often diagnosed on the basis of a deep skin biopsy, and can be further classified by histological characteristics based on the location of the inflammatory cells (within fatty lobules or in the septa which separate them) and on the presence or absence of vasculitis.
There are thus four main histological subtypes:
- lobular panniculitis without vasculitis (acute panniculitis, previously termed Weber-Christian disease , systemic nodular panniculitis)
- lobular panniculitis with vasculitis
- septal panniculitis without vasculitis
- septal panniculitis with vasculitis
## Symptomatic
Panniculitis can also be classified based on the presence or absence of systemic symptoms:
- Panniculitis without systemic disease can be a result of trauma or cold ;
- Panniculitis with systemic disease can be caused...
by connective tissue disorders such as lupus erythematosus or scleroderma;
by lymphoproliferative disease such as lymphoma or histiocytosis;
by pancreatitis or pancreatic cancer;
and by many other causes.
- by connective tissue disorders such as lupus erythematosus or scleroderma;
- by lymphoproliferative disease such as lymphoma or histiocytosis;
- by pancreatitis or pancreatic cancer;
- and by many other causes.
# Associated conditions
Lipoatrophy (the loss of subcutaneous tissue) can occur in any of these conditions. | Panniculitis
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Panniculitis is a group of diseases whose hallmark is inflammation of subcutaneous fatty and muscle tissue. Symptoms include tender skin nodules, and systemic signs such as weight loss and fatigue.
# Classification
## Histological
It can occur in any fatty tissue (cutaneous or visceral) and is often diagnosed on the basis of a deep skin biopsy, and can be further classified by histological characteristics based on the location of the inflammatory cells (within fatty lobules or in the septa which separate them) and on the presence or absence of vasculitis.
There are thus four main histological subtypes:
- lobular panniculitis without vasculitis (acute panniculitis, previously termed Weber-Christian disease [2], systemic nodular panniculitis)
- lobular panniculitis with vasculitis
- septal panniculitis without vasculitis
- septal panniculitis with vasculitis
## Symptomatic
Panniculitis can also be classified based on the presence or absence of systemic symptoms:
- Panniculitis without systemic disease can be a result of trauma or cold [3];
- Panniculitis with systemic disease can be caused...
by connective tissue disorders such as lupus erythematosus or scleroderma;
by lymphoproliferative disease such as lymphoma or histiocytosis;
by pancreatitis or pancreatic cancer;
and by many other causes.
- by connective tissue disorders such as lupus erythematosus or scleroderma;
- by lymphoproliferative disease such as lymphoma or histiocytosis;
- by pancreatitis or pancreatic cancer;
- and by many other causes.
# Associated conditions
Lipoatrophy (the loss of subcutaneous tissue) can occur in any of these conditions. | https://www.wikidoc.org/index.php/Panniculitis | |
a013e4e8c547e4b4d8cfa1c1e53b925d37696fb2 | wikidoc | Panobinostat | Panobinostat
# Disclaimer
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# Black Box Warning
# Overview
Panobinostat is a histone deacetylase inhibitor that is FDA approved for the treatment of patients with multiple myeloma (in combination with bortezomib and dexamethasone) who have received at least 2 prior regimens, including bortezomib and an immunomodulatory agent. There is a Black Box Warning for this drug as shown here. Common adverse reactions include diarrhea, fatigue, nausea, peripheral edema, decreased appetite, pyrexia, and vomiting (≥20%).
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Panobinostat, a histone deacetylase inhibitor, in combination with bortezomib and dexamethasone, is indicated for the treatment of patients with multiple myeloma who have received at least 2 prior regimens, including bortezomib and an immunomodulatory agent. This indication is approved under accelerated approval based on progression free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
- Recommended Dosing
- The recommended starting dose of Panobinostat is 20 mg, taken orally once every other day for 3 doses per week in Weeks 1 and 2 of each 21-day cycle for up to 8 cycles. Consider continuing treatment for an additional 8 cycles for patients with clinical benefit who do not experience unresolved severe or medically significant toxicity. The total duration of treatment may be up to 16 cycles (48 weeks). Panobinostat is administered in combination with bortezomib and dexamethasone as shown in Table 1 and Table 2.
- The recommended dose of bortezomib is 1.3 mg/m2 given as an injection. The recommended dose of dexamethasone is 20 mg taken orally per scheduled day, on a full stomach.
- Table 1: Recommended Dosing Schedule of Panobinostat in Combination with Bortezomib and Dexamethasone During Cycles 1 to 8
FARYDAK: Panobinostat's Brand name
- Table 2: Recommended Dosing Schedule of Panobinostat in Combination with Bortezomib and Dexamethasone During Cycles 9 to 16
FARYDAK: Panobinostat's Brand name
- Dose Adjustments and Modifications for Toxicity
- Dose and/or schedule modification of Panobinostat may be required based on toxicity. Management of adverse drug reactions may require treatment interruption and/or dose reductions. If dose reduction is required, the dose of Panobinostat should be reduced in increments of 5 mg (i.e., from 20 mg to 15 mg, or from 15 mg to 10 mg). If the dosing of Panobinostat is reduced below 10 mg given 3 times per week, discontinue Panobinostat. Keep the same treatment schedule (3-week treatment cycle) when reducing dose. The table also lists Bortezomib (BTZ) dose modification procedures from the clinical trials.
- Table 3: Dose Modifications for Most Common Toxicities
FARYDAK: Panobinostat's Brand name
- Myelosuppression
- Interrupt or reduce the dose of Panobinostat in patients who have thrombocytopenia, neutropenia or anemia according to instructions in Table 3. For patients with severe thrombocytopenia, consider platelet transfusions. Discontinue Panobinostat treatment if thrombocytopenia does not improve despite the recommended treatment modifications or if repeated platelet transfusions are required.
- In the event of Grade 3 or 4 neutropenia, consider dose reduction and/or the use of growth factors (e.g., G-CSF). Discontinue Panobinostat if neutropenia does not improve despite dose modifications, colony-stimulating factors, or in case of severe infection.
- Gastrointestinal Toxicity
- Gastrointestinal toxicity is common in patients treated with Panobinostat. Patients who experience diarrhea, nausea, or vomiting may require treatment interruption or dose reduction (Table 3). At the first sign of abdominal cramping, loose stools, or onset of diarrhea, patients should be treated with anti-diarrheal medication (e.g., loperamide). Consider and administer prophylactic anti-emetics as clinically indicated.
- Other Adverse Drug Reactions
- For patients experiencing Grade 3/4 adverse drug reactions other than thrombocytopenia, neutropenia, or gastrointestinal toxicity, the recommendation is the following:
- CTC Grade 2 toxicity recurrence and CTC Grade 3 and 4 - omit the dose until recovery to CTC Grade 1 or less and restart treatment at a reduced dose
- CTC Grade 3 or 4 toxicity recurrence, a further dose reduction may be considered once the adverse events have resolved to CTC Grade 1 or less.
- Dose Modifications for Use in Hepatic Impairment
- Reduce the starting dose of Panobinostat to 15 mg in patients with mild hepatic impairment and 10 mg in patients with moderate hepatic impairment. Avoid use in patients with severe hepatic impairment. Monitor patients frequently for adverse events and adjust dose as needed for toxicity.
- Dose Modifications for Use with Strong CYP3A Inhibitors
- Reduce the starting dose of Panobinostat to 10 mg when coadministered with strong CYP3A inhibitors (e.g., boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir).
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Panobinostat in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Panobinostat in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
The safety and efficacy of Panobinostat in children has not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Panobinostat in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Panobinostat in pediatric patients.
# Contraindications
None
# Warnings
Severe diarrhea occurred in 25% of patients treated with Panobinostat. Diarrhea of any grade occurred in 68% of patients treated with Panobinostat compared to 42% of patients in the control arm. Diarrhea can occur at any time. Monitor patient hydration status and electrolyte blood levels, including potassium, magnesium and phosphate, at baseline and weekly (or more frequently as clinically indicated) during therapy and correct to prevent dehydration and electrolyte disturbances. Initiate anti-diarrheal medication at the onset of diarrhea. Interrupt Panobinostat at the onset of moderate diarrhea (4 to 6 stools per day). Ensure that patients initiating therapy with Panobinostat have anti-diarrheal medications on hand.
Severe and fatal cardiac ischemic events, as well as severe arrhythmias, and electrocardiogram (ECG) changes occurred in patients receiving Panobinostat. Arrhythmias occurred in 12% of patients receiving Panobinostat, compared to 5% of patients in the control arm. Cardiac ischemic events occurred in 4% of patients treated with Panobinostat compared with 1% of patients in the control arm. Do not initiate Panobinostat treatment in patients with history of recent myocardial infarction or unstable angina.
Electrocardiographic abnormalities such as ST-segment depression and T-wave abnormalities also occurred more frequently in patients receiving Panobinostat compared to the control arm: 22% versus 4% and 40% versus 18%, respectively. Panobinostat may prolong cardiac ventricular repolarization (QT interval). Do not initiate treatment with Panobinostat in patients with a QTcF >450 msec or clinically significant baseline ST-segment or T-wave abnormalities. Arrhythmias may be exacerbated by electrolyte abnormalities. If during treatment with Panobinostat, the QTcF increases to ≥480 msec, interrupt treatment. Correct any electrolyte abnormalities. If QT prolongation does not resolve, permanently discontinue treatment with Panobinostat.
Obtain ECG at baseline and periodically during treatment as clinically indicated. Monitor electrolytes during treatment with Panobinostat and correct abnormalities as clinically indicated.
Fatal and serious hemorrhage occurred during treatment with Panobinostat. In the clinical trial in patients with relapsed multiple myeloma, 5 patients receiving Panobinostat compared to 1 patient in the control arm died due to a hemorrhagic event. All 5 patients had grade ≥3 thrombocytopenia at the time of the event. Grade 3/4 hemorrhage was reported in 4% of patients treated with the Panobinostat arm and 2% of patients in the control arm.
Panobinostat causes myelosuppression, including severe thrombocytopenia, neutropenia and anemia. In the clinical trial in patients with relapsed multiple myeloma, 67% of patients treated with Panobinostat developed Grade 3 to 4 thrombocytopenia compared with 31% in the control arm. Thrombocytopenia led to treatment interruption and or dose modification in 31% of patients receiving Panobinostat compared to 11% of patients in the control arm. For patients receiving Panobinostat, 33% required platelet transfusion compared to 10% of patients in the control arm.
Severe neutropenia occurred in 34% of patients treated with Panobinostat, compared to 11% of patients in the control arm. Neutropenia led to treatment interruption and or dose modification in 10% of patients receiving Panobinostat. The use of granulocyte-colony stimulating factor (G-CSF) was higher in patients treated with Panobinostat compared to the control arm, 13% compared to 4%, respectively.
Obtain a baseline CBC and monitor the CBC weekly during treatment (or more frequently if clinically indicated). Dose modifications are recommended for Myelosuppression. Monitor CBCs more frequently in patients over 65 years of age due to the increased frequency of myelosuppression in these patients.
Localized and systemic infections, including pneumonia, bacterial infections, invasive fungal infections, and viral infections have been reported in patients taking Panobinostat. Severe infections occurred in 31% of patients (including 10 deaths) treated with Panobinostat compared with 24% of patients (including 6 deaths) in the control arm. Infections of all grades occurred at a similar rate between arms. Panobinostat treatment should not be initiated in patients with active infections. Monitor patients for signs and symptoms of infections during treatment; if a diagnosis of infection is made, institute appropriate anti-infective treatment promptly and consider interruption or discontinuation of Panobinostat.
Hepatic dysfunction, primarily elevations in aminotransferases and total bilirubin, occurred in patients treated with Panobinostat. Liver function should be monitored prior to treatment and regularly during treatment. If abnormal liver function tests are observed dose adjustments may be considered and the patient should be followed until values return to normal or pretreatment levels.
Panobinostat can cause fetal harm when administered to a pregnant woman. Panobinostat was teratogenic in rats and rabbits. If Panobinostat is used during pregnancy, or if the patient becomes pregnant while taking Panobinostat, the patient should be apprised of the potential hazard to the fetus.
Advise females of reproductive potential to avoid becoming pregnant while taking Panobinostat. Advise sexually-active females of reproductive potential to use effective contraception while taking Panobinostat and for at least 3 months after the last dose of Panobinostat.
Advise sexually active men to use condoms while on treatment and for 6 months after their last dose of Panobinostat.
# Adverse Reactions
## Clinical Trials Experience
The following adverse reactions are described in detail in other sections of the label:
- Diarrhea
- Cardiac Toxicities
- Hemorrhage
- Myelosuppression
- Infections
- Hepatotoxicity
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 data reflect subject exposure to Panobinostat from a clinical trial, in which 758 subjects with relapsed multiple myeloma received Panobinostat in combination with bortezomib and dexamethasone or placebo in combination with bortezomib and dexamethasone (referred to as the control arm). The median duration of exposure to Panobinostat was 5 months with 16% of patients exposed to study treatment for ≥48 weeks.
Serious adverse events (SAEs) occurred in 60% of patients in the Panobinostat, bortezomib, and dexamethasone compared to 42% of patients in the control arm. The most frequent (≥5%) treatment-emergent SAEs reported for patients treated with Panobinostat were pneumonia (18%), diarrhea, (11%), thrombocytopenia (7%), fatigue (6%), and sepsis (6%).
Adverse reactions that led to discontinuation of Panobinostat occurred in 36% of patients. The most common adverse reactions leading to treatment discontinuations were diarrhea, fatigue, and pneumonia.
Deaths occurred in 8% of patients in the Panobinostat arm versus 5% on the control arm. The most frequent causes of death were infection and hemorrhage.
Table 4 summarizes the adverse reactions occurring in at least 10% of patients with ≥ 5% greater incidence in the Panobinostat arm, and Table 5 summarizes the treatment-emergent laboratory abnormalities.
- Table 4: Adverse Reactions (≥10% Incidence and ≥5% Greater Incidence in Panobinostat-Arm) in Patients with Multiple Myeloma
FARYDAK: Panobinostat's Brand name
Other Adverse Reactions
Other notable adverse drug reactions of Panobinostat not described above, which were either clinically significant, or occurred with a frequency less than 10% but had a frequency in the Panobinostat arm greater than 2% over the control arm in the multiple myeloma clinical trial are listed below:
- Infections and infestations: hepatitis B.
- Endocrine disorders: hypothyroidism.
- Metabolism and nutrition disorders: hyperglycemia, dehydration, fluid retention, hyperuricemia, hypomagnesemia.
- Nervous system disorders: dizziness, headache, syncope, tremor, dysgeusia.
- Cardiac disorders: palpitations.
- Vascular disorders: hypotension, hypertension, orthostatic hypotension.
- Respiratory, thoracic and mediastinal disorders: cough, dyspnea, respiratory failure, rales, wheezing.
- Gastrointestinal disorders: abdominal pain, dyspepsia, gastritis, cheilitis,abdominal distension,dry mouth, flatulence, colitis, gastrointestinal pain.
- Skin and subcutaneous disorders: skin lesions, rash, erythema.
- Musculoskeletal and connective tissue disorders: joint swelling.
- Renal and urinary disorders: renal failure, urinary incontinence.
- General disorders and administration site conditions: chills.
- Investigations: blood urea increased, glomerular filtration rate decreased, blood alkaline phosphatase increased.
- Psychiatric disorders: insomnia.
- Table 5: Treatment-emergent Laboratory Abnormalities (≥10% Incidence and ≥5% Greater Incidence in Panobinostat-arm) in Patients with Multiple Myeloma
FARYDAK: Panobinostat's Brand name
Fatigue and Asthenia
Grade 1 to Grade 4 asthenic conditions (fatigue, malaise, asthenia, and lethargy) were reported in 60% of the patients in the Panobinostat arm compared to 42% of patients in the control arm. Grade ≥3 asthenic conditions were reported in 25% of the patients in the Panobinostat arm compared to 12% of patients in the control arm. Asthenic conditions led to treatment discontinuation in 6% of patients in the Panobinostat arm versus 3% of patients in the control arm.
The prespecified sub-group upon which the efficacy and safety of Panobinostat was based had a similar adverse reaction profile to the entire safety population of patients treated with Panobinostat, bortezomib, and dexamethasone.
## Postmarketing Experience
There is limited information regarding Panobinostat Postmarketing Experience in the drug label.
# Drug Interactions
Panobinostat is a CYP3A substrate and inhibits CYP2D6. Panobinostat is a P-glycoprotein (P-gp) transporter system substrate.
- CYP3A Inhibitors: Coadministration of Panobinostat with a strong CYP3A inhibitor increased the Cmax and AUC of panobinostat by 62% and 73% respectively, compared to when Panobinostat was given alone.
- Reduce dose to 10 mg when coadministered with strong CYP3A inhibitors (e.g., boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole). Instruct patients to avoid star fruit, pomegranate or pomegranate juice, and grapefruit or grapefruit juice because these foods are known to inhibit CYP3A enzymes.
- CYP3A Inducers: Coadministration of Panobinostat with strong CYP3A inducers was not evaluated in vitro or in a clinical trial however, a reduction in panobinostat exposure is likely. An approximately 70% decrease in the systemic exposure of panobinostat in the presence of strong inducers of CYP3A was observed in simulations using mechanistic models. Therefore, the concomitant use of strong CYP3A inducers should be avoided.
- CYP2D6 Substrates: Panobinostat increased the median Cmax and AUC of a sensitive substrate of CYP2D6 by approximately 80% and 60%, respectively; however this was highly variable. Avoid coadministrating Panobinostat with sensitive CYP2D6 substrates (i.e., atomoxetine, desipramine, dextromethorphan,metoprolol, nebivolol, perphenazine, tolterodine, and venlafaxine) or CYP2D6 substrates that have a narrow therapeutic index (i.e., thioridazine, pimozide). If concomitant use of CYP2D6 substrates is unavoidable, monitor patients frequently for adverse reactions.
- Concomitant use of anti-arrhythmic medicines (including, but not limited to amiodarone, disopyramide, procainamide, quinidine and sotalol) and other drugs that are known to prolong the QT interval (including, but not limited to chloroquine, halofantrine, clarithromycin, methadone, moxifloxacin, bepridil and pimozide) is not recommended. Anti-emetic drugs with known QT prolonging risk, such as dolasetron, ondansetron, and tropisetron can be used with frequent ECG monitoring.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): N
- Risk Summary
- Panobinostat can cause fetal harm when administered to a pregnant woman. Panobinostat was teratogenic in rats and rabbits. If Panobinostat is used during pregnancy or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus.
- Data
- Animal Data
- In embryofetal development studies, panobinostat was administered orally 3 times per week during the period of organogenesis to pregnant rats (30, 100, and 300 mg/kg) and rabbits (10, 40, and 80 mg/kg). In rats, maternal toxicity including death was observed at doses greater than or equal to 100 mg/kg/day. Embryofetal toxicities occurred at 30 mg/kg (the only dose with live fetuses) and consisted of fetal malformations and anomalies, such as cleft palate, short tail, extra presacral vertebrae, and extra ribs. The dose of 30 mg/kg resulted in exposures (AUCs) approximately 3-fold the human exposure at the human dose of 20 mg. In rabbits, maternal toxicity including death was observed at doses greater than or equal to 80 mg/kg. Increased pre- and/or post-implantation loss occurred at all doses tested. Embryofetal toxicities included decreased fetal weights at doses greater than or equal to 40 mg/kg and malformations (absent digits, cardiac interventricular septal defects, aortic arch interruption, missing gallbladder, and irregular ossification of skull) at 80 mg/kg. The dose of 40 mg/kg in rabbits results in systemic exposure approximately 4-fold the human exposure and the dose of 80 mg/kg results in exposure 7-fold the human exposure, at the human dose of 20 mg.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Panobinostat in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Panobinostat during labor and delivery.
### Nursing Mothers
It is not known whether Panobinostat is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse drug reactions in nursing infants, decide 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 efficacy of Panobinostat in children has not been established.
### Geriatic Use
In clinical trials of Panobinostat in patients with multiple myeloma, 42% of patients were 65 years of age or older.
Patients over 65 years of age had a higher frequency of selected adverse events and of discontinuation of treatment due to adverse events. In patients over 65 years of age, the incidence of deaths not related to disease progression was 9% in patients ≥65 years of age compared to 5 % in patients <65.
In the randomized clinical trial in patients with relapsed multiple myeloma, no major differences in effectiveness were observed in older patients compared to younger patients. Adverse reactions leading to permanent discontinuation occurred in 45% of patients ≥65 years of age in the Panobinostat treatment arm compared to 30% of patients <65 years age in the Panobinostat treatment arm. Monitor for toxicity more frequently in patients over 65 years of age, especially for gastrointestinal toxicity, myelosuppression, and cardiac toxicity.
### Gender
There is no FDA guidance on the use of Panobinostat with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Panobinostat with respect to specific racial populations.
### Renal Impairment
Mild (creatinine clearance (CrCl) ≥50 to <80 mL/min) to severe renal impairment (CrCl <30 mL/min) did not impact the plasma exposure of panobinostat. Panobinostat has not been studied in patients with end stage renal disease (ESRD) or patients on dialysis. The dialyzability of panobinostat is unknown.
### Hepatic Impairment
The safety and efficacy of Panobinostat in patients with hepatic impairment has not been evaluated.
In a pharmacokinetic trial, patients with mild (bilirubin ≤1xULN and AST >1xULN, or bilirubin >1.0 to 1.5x ULN and any AST) or moderate (bilirubin >1.5x to 3.0x ULN, any AST) hepatic impairment (NCI-ODWG criteria) had increased AUC of panobinostat by 43% and 105%, respectively. Reduce the starting dose of Panobinostat in patients with mild or moderate hepatic impairment. Avoid use in patients with severe hepatic impairment. Monitor patients with hepatic impairment frequently for adverse events.
### Females of Reproductive Potential and Males
Embryofetal toxicity including malformations occurred in embryofetal development studies in rats.
Pregnancy Testing
Perform pregnancy testing in women of childbearing potential prior to starting treatment with Panobinostat and intermittently during treatment with Panobinostat.
Contraception
- Females
- Panobinostat can cause fetal harm. Advise females of reproductive potential to avoid becoming pregnant while taking Panobinostat. Advise sexually-active females of reproductive potential to use effective contraception while taking Panobinostat and for at least 3 months after the last dose of Panobinostat. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking Panobinostat.
- Males
- Advise sexually active men to use condoms while on treatment and for at least 6 months after their last dose of Panobinostat.
### Immunocompromised Patients
There is no FDA guidance one the use of Panobinostat in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Panobinostat should be taken orally once on each scheduled day at about the same time, either with or without food
- Panobinostat capsules should be swallowed whole with a cup of water. Do not open, crush, or chew the capsules
- If a dose is missed it can be taken up to 12 hours after the specified dose time. If vomiting occurs the patient should not repeat the dose, but should take the next usual scheduled dose.
- Counsel patients on the correct dosing schedule, technique of administration of Panobinostat, and when to take Panobinostat if dosing adjustments are made.
### Monitoring
Prior to the start of Panobinostat treatment and during treatment, monitoring should include:
- Complete Blood Count (CBC): Obtain a CBC before initiating treatment. Verify that the baseline platelet count is at least 100 x 109/L and the baseline absolute neutrophil count (ANC) is at least 1.5 x 109/L. Monitor the CBC weekly (or more often as clinically indicated) during treatment.
- ECG: Perform an ECG prior to the start of therapy and repeat periodically during treatment as clinically indicated. Verify that the QTcF is less than 450 msec prior to initiation of treatment with Panobinostat. If during treatment with Panobinostat, the QTcF increases to ≥480 msec, interrupt treatment. Correct any electrolyte abnormalities. If QT prolongation does not resolve, permanently discontinue treatment with Panobinostat. During the clinical trial, ECGs were performed at baseline and prior to initiation of each cycle for the first 8 cycles.
- Serum Electrolytes: Obtain electrolytes, including potassium and magnesium, at baseline and monitor during therapy. Correct abnormal electrolyte values before treatment. During the trial, monitoring was conducted prior to the start of each cycle, at Day 11 of cycles 1 to 8, and at the start of each cycle for cycles 9 to 16.
For additional information please refer to the bortezomib and dexamethasone prescribing information.
# IV Compatibility
There is limited information regarding the compatibility of Panobinostat and IV administrations.
# Overdosage
There is limited experience with overdosage. Expect exaggeration of adverse reactions observed during the clinical trial, including hematologic and gastrointestinal reactions such as thrombocytopenia, pancytopenia, diarrhea, nausea, vomiting and anorexia. Monitor cardiac status including ECGs, and assess and correct electrolytes. Consider platelet transfusions for thrombocytopenic bleeding. It is not known if Panobinostat is dialyzable.
# Pharmacology
## Mechanism of Action
Panobinostat is a histone deacetylase (HDAC) inhibitor that inhibits the enzymatic activity of HDACs at nanomolar concentrations. HDACs catalyze the removal of acetyl groups from the lysine residues of histones and some non-histone proteins. Inhibition of HDAC activity results in increased acetylation of histone proteins, an epigenetic alteration that results in a relaxing of chromatin, leading to transcriptional activation. In vitro, panobinostat caused the accumulation of acetylated histones and other proteins, inducing cell cycle arrest and/or apoptosis of some transformed cells. Increased levels of acetylated histones were observed in xenografts from mice that were treated with panobinostat. Panobinostat shows more cytotoxicity towards tumor cells compared to normal cells.
## Structure
Panobinostat lactate is a histone deacetylase inhibitor.
The chemical name of panobinostat lactate is 2-Hydroxypropanoic acid, compd. with 2-(E)-N-hydroxy-3-amino)methyl]phenyl]-2-propenamide (1:1).
The structural formula is:
Panobinostat lactate anhydrous is a white to slightly yellowish or brownish powder. The molecular formula is C21H23N3O2C3H6O3 (lactate); its molecular weight is 439.51 (as a lactate), equivalent to 349.43 (free base). Panobinostat lactate anhydrous is light sensitive. Panobinostat lactate anhydrous is both chemically and thermodynamically a stable crystalline form with no polymorphic behavior. Panobinostat free base is not chiral and shows no specific optical rotation. Panobinostat lactate anhydrous is slightly soluble in water. Solubility of panobinostat lactate anhydrous is pH-dependent, with the highest solubility in buffer pH 3.0 (citrate).
Panobinostat capsules contain 10 mg, 15 mg, or 20 mg panobinostat free base (equivalent to 12.58 mg, 18.86 mg, and 25.15 mg respectively of panobinostat lactate). The inactive ingredients are magnesium stearate, mannitol, microcrystalline cellulose and pregelatinized starch. The capsules contain gelatin, FD&C Blue 1 (10 mg capsules), yellow iron oxide (10 mg and 15 mg capsules), red iron oxide (15 mg and 20 mg capsules) and titanium dioxide.
## Pharmacodynamics
Cardiac Electrophysiology
Panobinostat may prolong cardiac ventricular repolarization (QT interval). In the randomized multiple myeloma trial, QTc prolongation with values between 451 msec to 480 msec occurred in 10.8% of Panobinostat treated patients. Events with values of 481 msec to 500 msec occurred in 1.3% of Panobinostat treated patients. A maximum QTcF increase from baseline of between 31 msec and 60 msec was reported in 14.5% of Panobinostat treated patients. A maximum QTcF increase from baseline of >60 msec was reported in 0.8% of Panobinostat treated patients. No episodes of QTcF prolongation >500 msec have been reported with the dose of 20 mg Panobinostat in the randomized multiple myeloma trial conducted in combination with bortezomib and dexamethasone. Pooled clinical data from over 500 patients treated with single agent Panobinostat in multiple indications and at different dose levels has shown that the incidence of CTC Grade 3 QTc prolongation (QTcF >500 msec) was approximately 1% overall and 5% or more at a dose of 60 mg or higher.
## Pharmacokinetics
Absorption
The absolute oral bioavailability of Panobinostat is approximately 21%. Peak concentrations of panobinostat are observed within 2 hours (Tmax) of oral administration in patients with advanced cancer. Panobinostat exhibits an approximate dose proportional increase in both Cmax and AUC over the dosing range.
Plasma panobinostat Cmax and AUC(0–48) were approximately 44% and 16% lower compared to fasting conditions, respectively, following ingestion of an oral Panobinostat dose 30 minutes after a high-fat meal by 36 patients with advanced cancer. The median Tmax was also delayed by 2.5 hours in these patients.
The aqueous solubility of panobinostat is pH dependent, with higher pH resulting in lower solubility. Coadministration of Panobinostat with drugs that elevate the gastric pH was not evaluated in vitro or in a clinical trial; however, altered panobinostat absorption was not observed in simulations using physiologically-based pharmacokinetic (PBPK) models.
Distribution
Panobinostat is approximately 90% bound to human plasma proteins in vitro and is independent of concentration. Panobinostat is a P-gp substrate.
Metabolism
Panobinostat is extensively metabolized. Pertinent metabolic pathways involved in the biotransformation of panobinostat are reduction, hydrolysis, oxidation, and glucuronidation processes. The fraction metabolized through CYP3A accounts for approximately 40% of the total hepatic panobinostat elimination. In vitro, additional contributions from the CYP2D6 and CYP2C19 pathways are minor. In vitro, UGT1A1, UGT1A3, UGT1A7, UGT1A8, UGT1A9, and UGT2B4 contribute to the glucuronidation of panobinostat.
Elimination
Twenty-nine percent to 51% of administered radioactivity is excreted in urine and 44% to 77% in the feces after a single oral dose of panobinostat in 4 patients with advanced cancer. Unchanged panobinostat accounted for <2.5% of the dose in urine and <3.5% of the dose in feces with the remainder consisting of metabolites.
An oral clearance (CL/F) and terminal elimination half-life (t1/2) of approximately 160 L/hr and 37 hours, respectively, was estimated using a population based pharmacokinetic (pop-PK) model in patients with advanced cancer. An inter-subject variability 65% on the clearance estimate was also reported. Up to 2-fold accumulation was observed with chronic oral dosing in patients with advanced cancer.
Specific Populations
- Population pharmacokinetic (PK) analyses of Panobinostat indicated that body surface area, gender, age, and race do not have a clinically meaningful influence on clearance.
- Hepatic Impairment: The effect of hepatic impairment on the pharmacokinetics of panobinostat was evaluated in a phase 1 study in 24 patients with advanced cancer with varying degrees of hepatic impairment. In patients with NCI-CTEP class mild (i.e., Group B) and moderate (i.e., Group C) hepatic impairment, AUC(0-inf) increased 43% and 105% compared to the group with normal hepatic function, respectively. The relative change in Cmax followed a similar pattern. The effect of severe hepatic impairment was indeterminate in this study due to the small sample size (n=1). A dose modification is recommended for patients with mild and moderate hepatic impairment.
- Renal Impairment: The effect of renal impairment on the pharmacokinetics of panobinostat was assessed in a phase 1 trial of 37 patients with advanced cancer and varying degrees of renal impairment. Panobinostat AUC(0–inf) in the mild, moderate and severe renal impairment groups were 64%, 99% and 59%, of the normal group, respectively. The relative change in Cmax followed a similar pattern.
Drug Interactions:
- Strong CYP3A Inhibitors: Coadministration of a single 20 mg Panobinostat dose with ketoconazole (200 mg twice daily for 14 days) increased the Cmax and AUC(0–48) of panobinostat by 62% and 73% respectively, compared to when Panobinostat was given alone in 14 patients with advanced cancer. Tmax was unchanged. A modified starting dose is recommended.
- Strong CYP3A Inducers: The human oxidative metabolism of panobinostat via the cytochrome P450 system primarily involves CYP3A isozymes. Simulations using PBPK models, predicted an approximately 70% decrease in the systemic exposure of panobinostat in the presence of strong inducers of CYP3A. Avoid coadministration of Panobinostat with strong CYP3A inducers.
- CYP2D6 Substrates: Coadministration of a single 60 mg dextromethorphan (DM) dose with Panobinostat (20 mg once per day, on Days 3, 5, and 8) increased the Cmax and AUC(0–∞) of DM by 20% to 200% and 20% to 130% (interquartile ranges), respectively, compared to when DM was given alone in 14 patients with advanced cancer. These DM exposures were extremely variable (CV% >150%). Avoid coadministration of Panobinostat with sensitive CYP2D6 substrates or CYP2D6 substrates that have a narrow therapeutic index.
- CYP3A Substrates: Simulations using PBPK models predict that an exposure increase of less than 10% for the sensitive CYP3A substrate midazolam is likely following coadministration with panobinostat. The clinical implications of this finding are not known.
- In vitro studies with CYP or UDPglucuronosyltransferase (UGT) substrates: Panobinostat inhibits CYP2D6, CYP2C19 and CYP3A4 (time-dependent), but does not inhibit CYP1A2, CYP2C8, CYP2C9, and CYP2E. Panobinostat does not induce CYP1A1/2, CYP2B6, CYP2C8/9/19, CYP3A and UGT1A1.
- In vitro studies with drug transporter system substrates: Panobinostat inhibits OAT3, OCT1, OCT2, OATP1B1 and OATP1B3, but does not inhibit P-gp and breast cancer resistant protein (BCRP), or OAT1. Panobinostat does not induce P-gp and multidrug resistance protein 2 (MRP2) transporters.
## Nonclinical Toxicology
Carcinogenicity studies have not been conducted with panobinostat.
Panobinostat was mutagenic in the Ames assay, and caused endo-reduplication (increased number of chromosomes) in human peripheral blood lymphocytes in vitro and DNA damage in an in vitro COMET assay in mouse lymphoma L5178Y cells.
Panobinostat may impair male and female fertility. In an oral fertility study conducted in rats, 10, 30, or 100 mg/kg doses of panobinostat were administered to females 3 times weekly (Days 1, 3, and 5) for 2 weeks prior to mating, then during the mating period, and on gestation Days 0, 3, and 6. An increase in early resorption and/or post-implantation loss in female rats were observed at doses ≥10 mg/kg. Number of pregnancies was reduced at doses ≥30 mg/kg. Prostate atrophy accompanied by reduced secretory granules, and testicular degeneration, oligospermia and increased epididymal debris were observed in repeated dose oral toxicity studies in dogs, e.g., in the 4-week study at the dose of 1.5 mg/kg. These effects were not completely reversed following a 4-week nondosing period.
Adverse findings observed in animals and not reported (or reported with low incidence) in patients treated with panobinostat include thyroid, bone marrow, and skin findings. Thyroid hormone changes in oral studies in rats and dogs included decreases in triodothyronine (T3), tetraiodothyronine (T4) and thyroid stimulating hormone (TSH). Histopathology changes of the thyroid included decreases in follicular colloid and epithelial vacuolation, and increases in thyroid follicular hypertrophy. A benign thyroid follicular cell adenoma was also seen in 1 rat in the 26-week study. Bone marrow findings in one or both species included hyperostosis, plasmacytosis, increased number of granulocytic cells, and presence of abnormal cytoplasmic granulation. Osseous metaplasia of the lung and skin hyperplasia and papilloma were observed in dogs in the 39-week study.
# Clinical Studies
The efficacy and safety of Panobinostat in combination with bortezomib and dexamethasone was evaluated in a randomized, double-blind, placebo-controlled, multicenter study in patients with relapsed multiple myeloma who had received 1 to 3 prior lines of therapy.
Patients received bortezomib (1.3 mg/m2 injected intravenously) with dexamethasone (20 mg) in addition to Panobinostat 20 mg (or placebo), taken orally every other day, for 3 doses per week in Weeks 1 and 2 of each 21-day cycle. Treatment was administered for a maximum of 16 cycles (48 weeks).
A total of 768 patients were randomized in a 1:1 ratio to receive either the combination of Panobinostat, bortezomib, dexamethasone (n=387) or placebo, bortezomib, dexamethasone (n=381), stratified by prior use of bortezomib and the number of prior lines of anti-myeloma therapy. Demographics and baseline disease characteristics were balanced between arms. The median age was 63 years (range 28 to 84); 42% of patients were older than 65 years; 53% of patients were male; Caucasians comprised 65% of the study population, Asians 30%, and blacks 3%. The ECOG performance status was 0 to 1 in 93% of patients. The median number of prior therapies was 1; 48% of patients received 2 or 3 prior lines of therapy. More than half (57%) of the patients had prior stem cell transplantation. The most common prior antineoplastic therapies were corticosteroids (90%), melphalan (80%), thalidomide (53%), cyclophosphamide (47%), bortezomib (44%), and lenalidomide (19%). The median duration of follow-up was 29 months in both arms.
The primary endpoint was progression-free survival (PFS), using modified European Bone Marrow Transplant Group (EBMT) criteria, as assessed by the investigators. In the overall trial population, the median PFS (95% CI) was 12 months (10.3, 12.9) in the Panobinostat, bortezomib, dexamethasone arm and 8.1 months (7.6, 9.2) in the placebo, bortezomib, dexamethasone arm, . At the time of interim analysis, overall survival was not statistically different between arms. The approval of Panobinostat was based upon the efficacy and safety in a prespecified subgroup analysis of 193 patients who had received prior treatment with both bortezomib and an immunomodulatory agent and a median of 2 prior therapies as the benefit:risk appeared to be greater in this more heavily pretreated population than in the overall trial population. Of these 193 patients, 76% of them had received ≥2 prior lines of therapy. The median PFS (95% CI) was 10.6 months (7.6, 13.8) in the Panobinostat, bortezomib, and dexamethasone arm and 5.8 months (4.4, 7.1) in the placebo, bortezomib, and dexamethasone arm . Efficacy results are summarized in Table 6 and the Kaplan- Meier curves for PFS are provided in Figure 1.
- Table 6: Efficacy Results from the Multiple Myeloma Trial in Patients who Received Prior Treatment with Bortezomib and an Immunomodulating Agent
FARYDAK: Panobinostat's Brand name
- Figure 1: Kaplan-Meier Plot of Progression-Free Survival in Patients with Multiple Myeloma who Received Prior Treatment with Both Bortezomib and an Immunomodulatory Agent
FARYDAK: Panobinostat's Brand name
In the subgroup of patients who had received prior treatment with both bortezomib and an immunomodulatory agent (n=193), the overall response rate using modified EBMT criteria was 59% in the Panobinostat, bortezomib, and dexamethasone arm and 41% in the placebo, bortezomib, and dexamethasone arm. Response rates are summarized in Table 7.
- Table 7: Response Rates
FARYDAK: Panobinostat's Brand name
# How Supplied
- Panobinostat 10 mg (equivalent to 12.58 mg of panobinostat lactate): Size # 3 light green opaque capsule, radial markings on cap with black ink “LBH 10 mg” and two radial bands with black ink on body, containing white to almost white powder.
- Panobinostat 15 mg (equivalent to 18.86 mg of panobinostat lactate): Size #1 orange opaque capsule, radial markings on cap with black ink “LBH 15 mg” and two radial bands with black ink on body, containing white to off-white powder.
- Panobinostat 20 mg (equivalent to 25.15 mg of panobinostat lactate): Size #1 red opaque capsule, radial markings on cap with black ink “LBH 20 mg” and two radial bands with black ink on body, containing white to off-white powder.
Panobinostat capsules are packaged in PVC/PCTFE blister packs.
10 mg: Blister packs containing 6 capsules ………………………….…….NDC 0078-0650-06
15 mg: Blister packs containing 6 capsules ………………………….…….NDC 0078-0651-06
20 mg: Blister packs containing 6 capsules ………………………….…….NDC 0078-0652-06
## Storage
Store at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C and 30°C (59°F and 86°F). Store blister pack in original carton to protect from light. Panobinostat capsules should not be opened, crushed, or chewed. Direct contact of the powder in Panobinostat capsules with the skin or mucous membranes should be avoided. If such contact occurs wash thoroughly. Personnel should avoid exposure to crushed and/or broken capsules.
Panobinostat is a cytotoxic drug. Follow special handling and disposal procedures.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
- Dosing and Administration
- Instruct patients to take Panobinostat exactly as prescribed and not to change their dose or to stop taking Panobinostat unless they are told to do so by their healthcare provider. If a patient misses a dose, advise them to take their dose as soon possible and up to 12 hours after the specified dose time. If vomiting occurs advise the patient not to repeat the dose, but to take the next usual prescribed dose on schedule.
- Cardiac Toxicity/Electrocardiographic Changes
- Inform patients to report chest pain or discomfort, changes in heart beat (fast or slow), palpitations, lightheadedness, fainting, dizziness, blue discoloration of lips, shortness of breath, and swelling of lower limbs or skin as these may be warning signs of a heart problem.
- Bleeding Risk
- Inform patients that Panobinostat is associated with thrombocytopenia. Advise patients to contact their healthcare provider right away if they experience any signs of bleeding and inform patients that it might take longer than usual for them to stop bleeding. Advise patients of the need to monitor blood chemistry and hematology prior to the start of Panobinostat therapy and periodically thereafter.
- Infections
- Inform patients of the risk of neutropenia and severe and life-threatening infections. Instruct patients to contact their physician immediately if they develop a fever and/or any exhibit any signs of infection.
- Gastrointestinal Toxicities
- Inform patients that Panobinostat can cause severe nausea, vomiting and diarrhea which may require medication for treatment. Advise patients to contact their physician at the start of diarrhea, for persistent vomiting, or signs of dehydration. Inform patients to consult with their physicians prior to using medications with laxative properties.
- Pregnancy
- Inform patients that Panobinostat can cause fetal harm. Advise women of reproductive potential to avoid pregnancy while taking Panobinostat. Advise women of reproductive potential to use effective contraception while taking Panobinostat and for at least 3 months after the last dose of the drug.
- Advise sexually active men to use condoms while receiving Panobinostat and for at least 6 months following the last dose of the drug.
- Lactation
- Advise women not to breastfeed while taking Panobinostat.
# Precautions with Alcohol
Alcohol-Panobinostat interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
FARYDAK®
# Look-Alike Drug Names
There is limited information regarding Panobinostat Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Panobinostat
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Martin Nino [2]
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# Black Box Warning
# Overview
Panobinostat is a histone deacetylase inhibitor that is FDA approved for the treatment of patients with multiple myeloma (in combination with bortezomib and dexamethasone) who have received at least 2 prior regimens, including bortezomib and an immunomodulatory agent. There is a Black Box Warning for this drug as shown here. Common adverse reactions include diarrhea, fatigue, nausea, peripheral edema, decreased appetite, pyrexia, and vomiting (≥20%).
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Panobinostat, a histone deacetylase inhibitor, in combination with bortezomib and dexamethasone, is indicated for the treatment of patients with multiple myeloma who have received at least 2 prior regimens, including bortezomib and an immunomodulatory agent. This indication is approved under accelerated approval based on progression free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
- Recommended Dosing
- The recommended starting dose of Panobinostat is 20 mg, taken orally once every other day for 3 doses per week in Weeks 1 and 2 of each 21-day cycle for up to 8 cycles. Consider continuing treatment for an additional 8 cycles for patients with clinical benefit who do not experience unresolved severe or medically significant toxicity. The total duration of treatment may be up to 16 cycles (48 weeks). Panobinostat is administered in combination with bortezomib and dexamethasone as shown in Table 1 and Table 2.
- The recommended dose of bortezomib is 1.3 mg/m2 given as an injection. The recommended dose of dexamethasone is 20 mg taken orally per scheduled day, on a full stomach.
- Table 1: Recommended Dosing Schedule of Panobinostat in Combination with Bortezomib and Dexamethasone During Cycles 1 to 8
FARYDAK: Panobinostat's Brand name
- Table 2: Recommended Dosing Schedule of Panobinostat in Combination with Bortezomib and Dexamethasone During Cycles 9 to 16
FARYDAK: Panobinostat's Brand name
- Dose Adjustments and Modifications for Toxicity
- Dose and/or schedule modification of Panobinostat may be required based on toxicity. Management of adverse drug reactions may require treatment interruption and/or dose reductions. If dose reduction is required, the dose of Panobinostat should be reduced in increments of 5 mg (i.e., from 20 mg to 15 mg, or from 15 mg to 10 mg). If the dosing of Panobinostat is reduced below 10 mg given 3 times per week, discontinue Panobinostat. Keep the same treatment schedule (3-week treatment cycle) when reducing dose. The table also lists Bortezomib (BTZ) dose modification procedures from the clinical trials.
- Table 3: Dose Modifications for Most Common Toxicities
FARYDAK: Panobinostat's Brand name
- Myelosuppression
- Interrupt or reduce the dose of Panobinostat in patients who have thrombocytopenia, neutropenia or anemia according to instructions in Table 3. For patients with severe thrombocytopenia, consider platelet transfusions. Discontinue Panobinostat treatment if thrombocytopenia does not improve despite the recommended treatment modifications or if repeated platelet transfusions are required.
- In the event of Grade 3 or 4 neutropenia, consider dose reduction and/or the use of growth factors (e.g., G-CSF). Discontinue Panobinostat if neutropenia does not improve despite dose modifications, colony-stimulating factors, or in case of severe infection.
- Gastrointestinal Toxicity
- Gastrointestinal toxicity is common in patients treated with Panobinostat. Patients who experience diarrhea, nausea, or vomiting may require treatment interruption or dose reduction (Table 3). At the first sign of abdominal cramping, loose stools, or onset of diarrhea, patients should be treated with anti-diarrheal medication (e.g., loperamide). Consider and administer prophylactic anti-emetics as clinically indicated.
- Other Adverse Drug Reactions
- For patients experiencing Grade 3/4 adverse drug reactions other than thrombocytopenia, neutropenia, or gastrointestinal toxicity, the recommendation is the following:
- CTC Grade 2 toxicity recurrence and CTC Grade 3 and 4 - omit the dose until recovery to CTC Grade 1 or less and restart treatment at a reduced dose
- CTC Grade 3 or 4 toxicity recurrence, a further dose reduction may be considered once the adverse events have resolved to CTC Grade 1 or less.
- Dose Modifications for Use in Hepatic Impairment
- Reduce the starting dose of Panobinostat to 15 mg in patients with mild hepatic impairment and 10 mg in patients with moderate hepatic impairment. Avoid use in patients with severe hepatic impairment. Monitor patients frequently for adverse events and adjust dose as needed for toxicity.
- Dose Modifications for Use with Strong CYP3A Inhibitors
- Reduce the starting dose of Panobinostat to 10 mg when coadministered with strong CYP3A inhibitors (e.g., boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir).
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Panobinostat in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Panobinostat in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
The safety and efficacy of Panobinostat in children has not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Panobinostat in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Panobinostat in pediatric patients.
# Contraindications
None
# Warnings
Severe diarrhea occurred in 25% of patients treated with Panobinostat. Diarrhea of any grade occurred in 68% of patients treated with Panobinostat compared to 42% of patients in the control arm. Diarrhea can occur at any time. Monitor patient hydration status and electrolyte blood levels, including potassium, magnesium and phosphate, at baseline and weekly (or more frequently as clinically indicated) during therapy and correct to prevent dehydration and electrolyte disturbances. Initiate anti-diarrheal medication at the onset of diarrhea. Interrupt Panobinostat at the onset of moderate diarrhea (4 to 6 stools per day). Ensure that patients initiating therapy with Panobinostat have anti-diarrheal medications on hand.
Severe and fatal cardiac ischemic events, as well as severe arrhythmias, and electrocardiogram (ECG) changes occurred in patients receiving Panobinostat. Arrhythmias occurred in 12% of patients receiving Panobinostat, compared to 5% of patients in the control arm. Cardiac ischemic events occurred in 4% of patients treated with Panobinostat compared with 1% of patients in the control arm. Do not initiate Panobinostat treatment in patients with history of recent myocardial infarction or unstable angina.
Electrocardiographic abnormalities such as ST-segment depression and T-wave abnormalities also occurred more frequently in patients receiving Panobinostat compared to the control arm: 22% versus 4% and 40% versus 18%, respectively. Panobinostat may prolong cardiac ventricular repolarization (QT interval). Do not initiate treatment with Panobinostat in patients with a QTcF >450 msec or clinically significant baseline ST-segment or T-wave abnormalities. Arrhythmias may be exacerbated by electrolyte abnormalities. If during treatment with Panobinostat, the QTcF increases to ≥480 msec, interrupt treatment. Correct any electrolyte abnormalities. If QT prolongation does not resolve, permanently discontinue treatment with Panobinostat.
Obtain ECG at baseline and periodically during treatment as clinically indicated. Monitor electrolytes during treatment with Panobinostat and correct abnormalities as clinically indicated.
Fatal and serious hemorrhage occurred during treatment with Panobinostat. In the clinical trial in patients with relapsed multiple myeloma, 5 patients receiving Panobinostat compared to 1 patient in the control arm died due to a hemorrhagic event. All 5 patients had grade ≥3 thrombocytopenia at the time of the event. Grade 3/4 hemorrhage was reported in 4% of patients treated with the Panobinostat arm and 2% of patients in the control arm.
Panobinostat causes myelosuppression, including severe thrombocytopenia, neutropenia and anemia. In the clinical trial in patients with relapsed multiple myeloma, 67% of patients treated with Panobinostat developed Grade 3 to 4 thrombocytopenia compared with 31% in the control arm. Thrombocytopenia led to treatment interruption and or dose modification in 31% of patients receiving Panobinostat compared to 11% of patients in the control arm. For patients receiving Panobinostat, 33% required platelet transfusion compared to 10% of patients in the control arm.
Severe neutropenia occurred in 34% of patients treated with Panobinostat, compared to 11% of patients in the control arm. Neutropenia led to treatment interruption and or dose modification in 10% of patients receiving Panobinostat. The use of granulocyte-colony stimulating factor (G-CSF) was higher in patients treated with Panobinostat compared to the control arm, 13% compared to 4%, respectively.
Obtain a baseline CBC and monitor the CBC weekly during treatment (or more frequently if clinically indicated). Dose modifications are recommended for Myelosuppression. Monitor CBCs more frequently in patients over 65 years of age due to the increased frequency of myelosuppression in these patients.
Localized and systemic infections, including pneumonia, bacterial infections, invasive fungal infections, and viral infections have been reported in patients taking Panobinostat. Severe infections occurred in 31% of patients (including 10 deaths) treated with Panobinostat compared with 24% of patients (including 6 deaths) in the control arm. Infections of all grades occurred at a similar rate between arms. Panobinostat treatment should not be initiated in patients with active infections. Monitor patients for signs and symptoms of infections during treatment; if a diagnosis of infection is made, institute appropriate anti-infective treatment promptly and consider interruption or discontinuation of Panobinostat.
Hepatic dysfunction, primarily elevations in aminotransferases and total bilirubin, occurred in patients treated with Panobinostat. Liver function should be monitored prior to treatment and regularly during treatment. If abnormal liver function tests are observed dose adjustments may be considered and the patient should be followed until values return to normal or pretreatment levels.
Panobinostat can cause fetal harm when administered to a pregnant woman. Panobinostat was teratogenic in rats and rabbits. If Panobinostat is used during pregnancy, or if the patient becomes pregnant while taking Panobinostat, the patient should be apprised of the potential hazard to the fetus.
Advise females of reproductive potential to avoid becoming pregnant while taking Panobinostat. Advise sexually-active females of reproductive potential to use effective contraception while taking Panobinostat and for at least 3 months after the last dose of Panobinostat.
Advise sexually active men to use condoms while on treatment and for 6 months after their last dose of Panobinostat.
# Adverse Reactions
## Clinical Trials Experience
The following adverse reactions are described in detail in other sections of the label:
- Diarrhea
- Cardiac Toxicities
- Hemorrhage
- Myelosuppression
- Infections
- Hepatotoxicity
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 data reflect subject exposure to Panobinostat from a clinical trial, in which 758 subjects with relapsed multiple myeloma received Panobinostat in combination with bortezomib and dexamethasone or placebo in combination with bortezomib and dexamethasone (referred to as the control arm). The median duration of exposure to Panobinostat was 5 months with 16% of patients exposed to study treatment for ≥48 weeks.
Serious adverse events (SAEs) occurred in 60% of patients in the Panobinostat, bortezomib, and dexamethasone compared to 42% of patients in the control arm. The most frequent (≥5%) treatment-emergent SAEs reported for patients treated with Panobinostat were pneumonia (18%), diarrhea, (11%), thrombocytopenia (7%), fatigue (6%), and sepsis (6%).
Adverse reactions that led to discontinuation of Panobinostat occurred in 36% of patients. The most common adverse reactions leading to treatment discontinuations were diarrhea, fatigue, and pneumonia.
Deaths occurred in 8% of patients in the Panobinostat arm versus 5% on the control arm. The most frequent causes of death were infection and hemorrhage.
Table 4 summarizes the adverse reactions occurring in at least 10% of patients with ≥ 5% greater incidence in the Panobinostat arm, and Table 5 summarizes the treatment-emergent laboratory abnormalities.
- Table 4: Adverse Reactions (≥10% Incidence and ≥5% Greater Incidence in Panobinostat-Arm) in Patients with Multiple Myeloma
FARYDAK: Panobinostat's Brand name
Other Adverse Reactions
Other notable adverse drug reactions of Panobinostat not described above, which were either clinically significant, or occurred with a frequency less than 10% but had a frequency in the Panobinostat arm greater than 2% over the control arm in the multiple myeloma clinical trial are listed below:
- Infections and infestations: hepatitis B.
- Endocrine disorders: hypothyroidism.
- Metabolism and nutrition disorders: hyperglycemia, dehydration, fluid retention, hyperuricemia, hypomagnesemia.
- Nervous system disorders: dizziness, headache, syncope, tremor, dysgeusia.
- Cardiac disorders: palpitations.
- Vascular disorders: hypotension, hypertension, orthostatic hypotension.
- Respiratory, thoracic and mediastinal disorders: cough, dyspnea, respiratory failure, rales, wheezing.
- Gastrointestinal disorders: abdominal pain, dyspepsia, gastritis, cheilitis,abdominal distension,dry mouth, flatulence, colitis, gastrointestinal pain.
- Skin and subcutaneous disorders: skin lesions, rash, erythema.
- Musculoskeletal and connective tissue disorders: joint swelling.
- Renal and urinary disorders: renal failure, urinary incontinence.
- General disorders and administration site conditions: chills.
- Investigations: blood urea increased, glomerular filtration rate decreased, blood alkaline phosphatase increased.
- Psychiatric disorders: insomnia.
- Table 5: Treatment-emergent Laboratory Abnormalities (≥10% Incidence and ≥5% Greater Incidence in Panobinostat-arm) in Patients with Multiple Myeloma
FARYDAK: Panobinostat's Brand name
Fatigue and Asthenia
Grade 1 to Grade 4 asthenic conditions (fatigue, malaise, asthenia, and lethargy) were reported in 60% of the patients in the Panobinostat arm compared to 42% of patients in the control arm. Grade ≥3 asthenic conditions were reported in 25% of the patients in the Panobinostat arm compared to 12% of patients in the control arm. Asthenic conditions led to treatment discontinuation in 6% of patients in the Panobinostat arm versus 3% of patients in the control arm.
The prespecified sub-group upon which the efficacy and safety of Panobinostat was based had a similar adverse reaction profile to the entire safety population of patients treated with Panobinostat, bortezomib, and dexamethasone.
## Postmarketing Experience
There is limited information regarding Panobinostat Postmarketing Experience in the drug label.
# Drug Interactions
Panobinostat is a CYP3A substrate and inhibits CYP2D6. Panobinostat is a P-glycoprotein (P-gp) transporter system substrate.
- CYP3A Inhibitors: Coadministration of Panobinostat with a strong CYP3A inhibitor increased the Cmax and AUC of panobinostat by 62% and 73% respectively, compared to when Panobinostat was given alone.
- Reduce dose to 10 mg when coadministered with strong CYP3A inhibitors (e.g., boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole). Instruct patients to avoid star fruit, pomegranate or pomegranate juice, and grapefruit or grapefruit juice because these foods are known to inhibit CYP3A enzymes.
- CYP3A Inducers: Coadministration of Panobinostat with strong CYP3A inducers was not evaluated in vitro or in a clinical trial however, a reduction in panobinostat exposure is likely. An approximately 70% decrease in the systemic exposure of panobinostat in the presence of strong inducers of CYP3A was observed in simulations using mechanistic models. Therefore, the concomitant use of strong CYP3A inducers should be avoided.
- CYP2D6 Substrates: Panobinostat increased the median Cmax and AUC of a sensitive substrate of CYP2D6 by approximately 80% and 60%, respectively; however this was highly variable. Avoid coadministrating Panobinostat with sensitive CYP2D6 substrates (i.e., atomoxetine, desipramine, dextromethorphan,metoprolol, nebivolol, perphenazine, tolterodine, and venlafaxine) or CYP2D6 substrates that have a narrow therapeutic index (i.e., thioridazine, pimozide). If concomitant use of CYP2D6 substrates is unavoidable, monitor patients frequently for adverse reactions.
- Concomitant use of anti-arrhythmic medicines (including, but not limited to amiodarone, disopyramide, procainamide, quinidine and sotalol) and other drugs that are known to prolong the QT interval (including, but not limited to chloroquine, halofantrine, clarithromycin, methadone, moxifloxacin, bepridil and pimozide) is not recommended. Anti-emetic drugs with known QT prolonging risk, such as dolasetron, ondansetron, and tropisetron can be used with frequent ECG monitoring.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): N
- Risk Summary
- Panobinostat can cause fetal harm when administered to a pregnant woman. Panobinostat was teratogenic in rats and rabbits. If Panobinostat is used during pregnancy or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus.
- Data
- Animal Data
- In embryofetal development studies, panobinostat was administered orally 3 times per week during the period of organogenesis to pregnant rats (30, 100, and 300 mg/kg) and rabbits (10, 40, and 80 mg/kg). In rats, maternal toxicity including death was observed at doses greater than or equal to 100 mg/kg/day. Embryofetal toxicities occurred at 30 mg/kg (the only dose with live fetuses) and consisted of fetal malformations and anomalies, such as cleft palate, short tail, extra presacral vertebrae, and extra ribs. The dose of 30 mg/kg resulted in exposures (AUCs) approximately 3-fold the human exposure at the human dose of 20 mg. In rabbits, maternal toxicity including death was observed at doses greater than or equal to 80 mg/kg. Increased pre- and/or post-implantation loss occurred at all doses tested. Embryofetal toxicities included decreased fetal weights at doses greater than or equal to 40 mg/kg and malformations (absent digits, cardiac interventricular septal defects, aortic arch interruption, missing gallbladder, and irregular ossification of skull) at 80 mg/kg. The dose of 40 mg/kg in rabbits results in systemic exposure approximately 4-fold the human exposure and the dose of 80 mg/kg results in exposure 7-fold the human exposure, at the human dose of 20 mg.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Panobinostat in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Panobinostat during labor and delivery.
### Nursing Mothers
It is not known whether Panobinostat is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse drug reactions in nursing infants, decide 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 efficacy of Panobinostat in children has not been established.
### Geriatic Use
In clinical trials of Panobinostat in patients with multiple myeloma, 42% of patients were 65 years of age or older.
Patients over 65 years of age had a higher frequency of selected adverse events and of discontinuation of treatment due to adverse events. In patients over 65 years of age, the incidence of deaths not related to disease progression was 9% in patients ≥65 years of age compared to 5 % in patients <65.
In the randomized clinical trial in patients with relapsed multiple myeloma, no major differences in effectiveness were observed in older patients compared to younger patients. Adverse reactions leading to permanent discontinuation occurred in 45% of patients ≥65 years of age in the Panobinostat treatment arm compared to 30% of patients <65 years age in the Panobinostat treatment arm. Monitor for toxicity more frequently in patients over 65 years of age, especially for gastrointestinal toxicity, myelosuppression, and cardiac toxicity.
### Gender
There is no FDA guidance on the use of Panobinostat with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Panobinostat with respect to specific racial populations.
### Renal Impairment
Mild (creatinine clearance (CrCl) ≥50 to <80 mL/min) to severe renal impairment (CrCl <30 mL/min) did not impact the plasma exposure of panobinostat. Panobinostat has not been studied in patients with end stage renal disease (ESRD) or patients on dialysis. The dialyzability of panobinostat is unknown.
### Hepatic Impairment
The safety and efficacy of Panobinostat in patients with hepatic impairment has not been evaluated.
In a pharmacokinetic trial, patients with mild (bilirubin ≤1xULN and AST >1xULN, or bilirubin >1.0 to 1.5x ULN and any AST) or moderate (bilirubin >1.5x to 3.0x ULN, any AST) hepatic impairment (NCI-ODWG criteria) had increased AUC of panobinostat by 43% and 105%, respectively. Reduce the starting dose of Panobinostat in patients with mild or moderate hepatic impairment. Avoid use in patients with severe hepatic impairment. Monitor patients with hepatic impairment frequently for adverse events.
### Females of Reproductive Potential and Males
Embryofetal toxicity including malformations occurred in embryofetal development studies in rats.
Pregnancy Testing
Perform pregnancy testing in women of childbearing potential prior to starting treatment with Panobinostat and intermittently during treatment with Panobinostat.
Contraception
- Females
- Panobinostat can cause fetal harm. Advise females of reproductive potential to avoid becoming pregnant while taking Panobinostat. Advise sexually-active females of reproductive potential to use effective contraception while taking Panobinostat and for at least 3 months after the last dose of Panobinostat. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking Panobinostat.
- Males
- Advise sexually active men to use condoms while on treatment and for at least 6 months after their last dose of Panobinostat.
### Immunocompromised Patients
There is no FDA guidance one the use of Panobinostat in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Panobinostat should be taken orally once on each scheduled day at about the same time, either with or without food
- Panobinostat capsules should be swallowed whole with a cup of water. Do not open, crush, or chew the capsules
- If a dose is missed it can be taken up to 12 hours after the specified dose time. If vomiting occurs the patient should not repeat the dose, but should take the next usual scheduled dose.
- Counsel patients on the correct dosing schedule, technique of administration of Panobinostat, and when to take Panobinostat if dosing adjustments are made.
### Monitoring
Prior to the start of Panobinostat treatment and during treatment, monitoring should include:
- Complete Blood Count (CBC): Obtain a CBC before initiating treatment. Verify that the baseline platelet count is at least 100 x 109/L and the baseline absolute neutrophil count (ANC) is at least 1.5 x 109/L. Monitor the CBC weekly (or more often as clinically indicated) during treatment.
- ECG: Perform an ECG prior to the start of therapy and repeat periodically during treatment as clinically indicated. Verify that the QTcF is less than 450 msec prior to initiation of treatment with Panobinostat. If during treatment with Panobinostat, the QTcF increases to ≥480 msec, interrupt treatment. Correct any electrolyte abnormalities. If QT prolongation does not resolve, permanently discontinue treatment with Panobinostat. During the clinical trial, ECGs were performed at baseline and prior to initiation of each cycle for the first 8 cycles.
- Serum Electrolytes: Obtain electrolytes, including potassium and magnesium, at baseline and monitor during therapy. Correct abnormal electrolyte values before treatment. During the trial, monitoring was conducted prior to the start of each cycle, at Day 11 of cycles 1 to 8, and at the start of each cycle for cycles 9 to 16.
For additional information please refer to the bortezomib and dexamethasone prescribing information.
# IV Compatibility
There is limited information regarding the compatibility of Panobinostat and IV administrations.
# Overdosage
There is limited experience with overdosage. Expect exaggeration of adverse reactions observed during the clinical trial, including hematologic and gastrointestinal reactions such as thrombocytopenia, pancytopenia, diarrhea, nausea, vomiting and anorexia. Monitor cardiac status including ECGs, and assess and correct electrolytes. Consider platelet transfusions for thrombocytopenic bleeding. It is not known if Panobinostat is dialyzable.
# Pharmacology
## Mechanism of Action
Panobinostat is a histone deacetylase (HDAC) inhibitor that inhibits the enzymatic activity of HDACs at nanomolar concentrations. HDACs catalyze the removal of acetyl groups from the lysine residues of histones and some non-histone proteins. Inhibition of HDAC activity results in increased acetylation of histone proteins, an epigenetic alteration that results in a relaxing of chromatin, leading to transcriptional activation. In vitro, panobinostat caused the accumulation of acetylated histones and other proteins, inducing cell cycle arrest and/or apoptosis of some transformed cells. Increased levels of acetylated histones were observed in xenografts from mice that were treated with panobinostat. Panobinostat shows more cytotoxicity towards tumor cells compared to normal cells.
## Structure
Panobinostat lactate is a histone deacetylase inhibitor.
The chemical name of panobinostat lactate is 2-Hydroxypropanoic acid, compd. with 2-(E)-N-hydroxy-3-[4-[([2-(2-methyl-1H-indol-3-yl)ethyl]amino)methyl]phenyl]-2-propenamide (1:1).
The structural formula is:
Panobinostat lactate anhydrous is a white to slightly yellowish or brownish powder. The molecular formula is C21H23N3O2•C3H6O3 (lactate); its molecular weight is 439.51 (as a lactate), equivalent to 349.43 (free base). Panobinostat lactate anhydrous is light sensitive. Panobinostat lactate anhydrous is both chemically and thermodynamically a stable crystalline form with no polymorphic behavior. Panobinostat free base is not chiral and shows no specific optical rotation. Panobinostat lactate anhydrous is slightly soluble in water. Solubility of panobinostat lactate anhydrous is pH-dependent, with the highest solubility in buffer pH 3.0 (citrate).
Panobinostat capsules contain 10 mg, 15 mg, or 20 mg panobinostat free base (equivalent to 12.58 mg, 18.86 mg, and 25.15 mg respectively of panobinostat lactate). The inactive ingredients are magnesium stearate, mannitol, microcrystalline cellulose and pregelatinized starch. The capsules contain gelatin, FD&C Blue 1 (10 mg capsules), yellow iron oxide (10 mg and 15 mg capsules), red iron oxide (15 mg and 20 mg capsules) and titanium dioxide.
## Pharmacodynamics
Cardiac Electrophysiology
Panobinostat may prolong cardiac ventricular repolarization (QT interval). In the randomized multiple myeloma trial, QTc prolongation with values between 451 msec to 480 msec occurred in 10.8% of Panobinostat treated patients. Events with values of 481 msec to 500 msec occurred in 1.3% of Panobinostat treated patients. A maximum QTcF increase from baseline of between 31 msec and 60 msec was reported in 14.5% of Panobinostat treated patients. A maximum QTcF increase from baseline of >60 msec was reported in 0.8% of Panobinostat treated patients. No episodes of QTcF prolongation >500 msec have been reported with the dose of 20 mg Panobinostat in the randomized multiple myeloma trial conducted in combination with bortezomib and dexamethasone. Pooled clinical data from over 500 patients treated with single agent Panobinostat in multiple indications and at different dose levels has shown that the incidence of CTC Grade 3 QTc prolongation (QTcF >500 msec) was approximately 1% overall and 5% or more at a dose of 60 mg or higher.
## Pharmacokinetics
Absorption
The absolute oral bioavailability of Panobinostat is approximately 21%. Peak concentrations of panobinostat are observed within 2 hours (Tmax) of oral administration in patients with advanced cancer. Panobinostat exhibits an approximate dose proportional increase in both Cmax and AUC over the dosing range.
Plasma panobinostat Cmax and AUC(0–48) were approximately 44% and 16% lower compared to fasting conditions, respectively, following ingestion of an oral Panobinostat dose 30 minutes after a high-fat meal by 36 patients with advanced cancer. The median Tmax was also delayed by 2.5 hours in these patients.
The aqueous solubility of panobinostat is pH dependent, with higher pH resulting in lower solubility. Coadministration of Panobinostat with drugs that elevate the gastric pH was not evaluated in vitro or in a clinical trial; however, altered panobinostat absorption was not observed in simulations using physiologically-based pharmacokinetic (PBPK) models.
Distribution
Panobinostat is approximately 90% bound to human plasma proteins in vitro and is independent of concentration. Panobinostat is a P-gp substrate.
Metabolism
Panobinostat is extensively metabolized. Pertinent metabolic pathways involved in the biotransformation of panobinostat are reduction, hydrolysis, oxidation, and glucuronidation processes. The fraction metabolized through CYP3A accounts for approximately 40% of the total hepatic panobinostat elimination. In vitro, additional contributions from the CYP2D6 and CYP2C19 pathways are minor. In vitro, UGT1A1, UGT1A3, UGT1A7, UGT1A8, UGT1A9, and UGT2B4 contribute to the glucuronidation of panobinostat.
Elimination
Twenty-nine percent to 51% of administered radioactivity is excreted in urine and 44% to 77% in the feces after a single oral dose of [14C] panobinostat in 4 patients with advanced cancer. Unchanged panobinostat accounted for <2.5% of the dose in urine and <3.5% of the dose in feces with the remainder consisting of metabolites.
An oral clearance (CL/F) and terminal elimination half-life (t1/2) of approximately 160 L/hr and 37 hours, respectively, was estimated using a population based pharmacokinetic (pop-PK) model in patients with advanced cancer. An inter-subject variability 65% on the clearance estimate was also reported. Up to 2-fold accumulation was observed with chronic oral dosing in patients with advanced cancer.
Specific Populations
- Population pharmacokinetic (PK) analyses of Panobinostat indicated that body surface area, gender, age, and race do not have a clinically meaningful influence on clearance.
- Hepatic Impairment: The effect of hepatic impairment on the pharmacokinetics of panobinostat was evaluated in a phase 1 study in 24 patients with advanced cancer with varying degrees of hepatic impairment. In patients with NCI-CTEP class mild (i.e., Group B) and moderate (i.e., Group C) hepatic impairment, AUC(0-inf) increased 43% and 105% compared to the group with normal hepatic function, respectively. The relative change in Cmax followed a similar pattern. The effect of severe hepatic impairment was indeterminate in this study due to the small sample size (n=1). A dose modification is recommended for patients with mild and moderate hepatic impairment.
- Renal Impairment: The effect of renal impairment on the pharmacokinetics of panobinostat was assessed in a phase 1 trial of 37 patients with advanced cancer and varying degrees of renal impairment. Panobinostat AUC(0–inf) in the mild, moderate and severe renal impairment groups were 64%, 99% and 59%, of the normal group, respectively. The relative change in Cmax followed a similar pattern.
Drug Interactions:
- Strong CYP3A Inhibitors: Coadministration of a single 20 mg Panobinostat dose with ketoconazole (200 mg twice daily for 14 days) increased the Cmax and AUC(0–48) of panobinostat by 62% and 73% respectively, compared to when Panobinostat was given alone in 14 patients with advanced cancer. Tmax was unchanged. A modified starting dose is recommended.
- Strong CYP3A Inducers: The human oxidative metabolism of panobinostat via the cytochrome P450 system primarily involves CYP3A isozymes. Simulations using PBPK models, predicted an approximately 70% decrease in the systemic exposure of panobinostat in the presence of strong inducers of CYP3A. Avoid coadministration of Panobinostat with strong CYP3A inducers.
- CYP2D6 Substrates: Coadministration of a single 60 mg dextromethorphan (DM) dose with Panobinostat (20 mg once per day, on Days 3, 5, and 8) increased the Cmax and AUC(0–∞) of DM by 20% to 200% and 20% to 130% (interquartile ranges), respectively, compared to when DM was given alone in 14 patients with advanced cancer. These DM exposures were extremely variable (CV% >150%). Avoid coadministration of Panobinostat with sensitive CYP2D6 substrates or CYP2D6 substrates that have a narrow therapeutic index.
- CYP3A Substrates: Simulations using PBPK models predict that an exposure increase of less than 10% for the sensitive CYP3A substrate midazolam is likely following coadministration with panobinostat. The clinical implications of this finding are not known.
- In vitro studies with CYP or UDPglucuronosyltransferase (UGT) substrates: Panobinostat inhibits CYP2D6, CYP2C19 and CYP3A4 (time-dependent), but does not inhibit CYP1A2, CYP2C8, CYP2C9, and CYP2E. Panobinostat does not induce CYP1A1/2, CYP2B6, CYP2C8/9/19, CYP3A and UGT1A1.
- In vitro studies with drug transporter system substrates: Panobinostat inhibits OAT3, OCT1, OCT2, OATP1B1 and OATP1B3, but does not inhibit P-gp and breast cancer resistant protein (BCRP), or OAT1. Panobinostat does not induce P-gp and multidrug resistance protein 2 (MRP2) transporters.
## Nonclinical Toxicology
Carcinogenicity studies have not been conducted with panobinostat.
Panobinostat was mutagenic in the Ames assay, and caused endo-reduplication (increased number of chromosomes) in human peripheral blood lymphocytes in vitro and DNA damage in an in vitro COMET assay in mouse lymphoma L5178Y cells.
Panobinostat may impair male and female fertility. In an oral fertility study conducted in rats, 10, 30, or 100 mg/kg doses of panobinostat were administered to females 3 times weekly (Days 1, 3, and 5) for 2 weeks prior to mating, then during the mating period, and on gestation Days 0, 3, and 6. An increase in early resorption and/or post-implantation loss in female rats were observed at doses ≥10 mg/kg. Number of pregnancies was reduced at doses ≥30 mg/kg. Prostate atrophy accompanied by reduced secretory granules, and testicular degeneration, oligospermia and increased epididymal debris were observed in repeated dose oral toxicity studies in dogs, e.g., in the 4-week study at the dose of 1.5 mg/kg. These effects were not completely reversed following a 4-week nondosing period.
Adverse findings observed in animals and not reported (or reported with low incidence) in patients treated with panobinostat include thyroid, bone marrow, and skin findings. Thyroid hormone changes in oral studies in rats and dogs included decreases in triodothyronine (T3), tetraiodothyronine (T4) and thyroid stimulating hormone (TSH). Histopathology changes of the thyroid included decreases in follicular colloid and epithelial vacuolation, and increases in thyroid follicular hypertrophy. A benign thyroid follicular cell adenoma was also seen in 1 rat in the 26-week study. Bone marrow findings in one or both species included hyperostosis, plasmacytosis, increased number of granulocytic cells, and presence of abnormal cytoplasmic granulation. Osseous metaplasia of the lung and skin hyperplasia and papilloma were observed in dogs in the 39-week study.
# Clinical Studies
The efficacy and safety of Panobinostat in combination with bortezomib and dexamethasone was evaluated in a randomized, double-blind, placebo-controlled, multicenter study in patients with relapsed multiple myeloma who had received 1 to 3 prior lines of therapy.
Patients received bortezomib (1.3 mg/m2 injected intravenously) with dexamethasone (20 mg) in addition to Panobinostat 20 mg (or placebo), taken orally every other day, for 3 doses per week in Weeks 1 and 2 of each 21-day cycle. Treatment was administered for a maximum of 16 cycles (48 weeks).
A total of 768 patients were randomized in a 1:1 ratio to receive either the combination of Panobinostat, bortezomib, dexamethasone (n=387) or placebo, bortezomib, dexamethasone (n=381), stratified by prior use of bortezomib and the number of prior lines of anti-myeloma therapy. Demographics and baseline disease characteristics were balanced between arms. The median age was 63 years (range 28 to 84); 42% of patients were older than 65 years; 53% of patients were male; Caucasians comprised 65% of the study population, Asians 30%, and blacks 3%. The ECOG performance status was 0 to 1 in 93% of patients. The median number of prior therapies was 1; 48% of patients received 2 or 3 prior lines of therapy. More than half (57%) of the patients had prior stem cell transplantation. The most common prior antineoplastic therapies were corticosteroids (90%), melphalan (80%), thalidomide (53%), cyclophosphamide (47%), bortezomib (44%), and lenalidomide (19%). The median duration of follow-up was 29 months in both arms.
The primary endpoint was progression-free survival (PFS), using modified European Bone Marrow Transplant Group (EBMT) criteria, as assessed by the investigators. In the overall trial population, the median PFS (95% CI) was 12 months (10.3, 12.9) in the Panobinostat, bortezomib, dexamethasone arm and 8.1 months (7.6, 9.2) in the placebo, bortezomib, dexamethasone arm, [HR: 0.63 (95% CI: 0.52, 0.76)]. At the time of interim analysis, overall survival was not statistically different between arms. The approval of Panobinostat was based upon the efficacy and safety in a prespecified subgroup analysis of 193 patients who had received prior treatment with both bortezomib and an immunomodulatory agent and a median of 2 prior therapies as the benefit:risk appeared to be greater in this more heavily pretreated population than in the overall trial population. Of these 193 patients, 76% of them had received ≥2 prior lines of therapy. The median PFS (95% CI) was 10.6 months (7.6, 13.8) in the Panobinostat, bortezomib, and dexamethasone arm and 5.8 months (4.4, 7.1) in the placebo, bortezomib, and dexamethasone arm [HR: 0.52 (0.36, 0.76)]. Efficacy results are summarized in Table 6 and the Kaplan- Meier curves for PFS are provided in Figure 1.
- Table 6: Efficacy Results from the Multiple Myeloma Trial in Patients who Received Prior Treatment with Bortezomib and an Immunomodulating Agent
FARYDAK: Panobinostat's Brand name
- Figure 1: Kaplan-Meier Plot of Progression-Free Survival in Patients with Multiple Myeloma who Received Prior Treatment with Both Bortezomib and an Immunomodulatory Agent
FARYDAK: Panobinostat's Brand name
In the subgroup of patients who had received prior treatment with both bortezomib and an immunomodulatory agent (n=193), the overall response rate using modified EBMT criteria was 59% in the Panobinostat, bortezomib, and dexamethasone arm and 41% in the placebo, bortezomib, and dexamethasone arm. Response rates are summarized in Table 7.
- Table 7: Response Rates
FARYDAK: Panobinostat's Brand name
# How Supplied
- Panobinostat 10 mg (equivalent to 12.58 mg of panobinostat lactate): Size # 3 light green opaque capsule, radial markings on cap with black ink “LBH 10 mg” and two radial bands with black ink on body, containing white to almost white powder.
- Panobinostat 15 mg (equivalent to 18.86 mg of panobinostat lactate): Size #1 orange opaque capsule, radial markings on cap with black ink “LBH 15 mg” and two radial bands with black ink on body, containing white to off-white powder.
- Panobinostat 20 mg (equivalent to 25.15 mg of panobinostat lactate): Size #1 red opaque capsule, radial markings on cap with black ink “LBH 20 mg” and two radial bands with black ink on body, containing white to off-white powder.
Panobinostat capsules are packaged in PVC/PCTFE blister packs.
10 mg: Blister packs containing 6 capsules ………………………….…….NDC 0078-0650-06
15 mg: Blister packs containing 6 capsules ………………………….…….NDC 0078-0651-06
20 mg: Blister packs containing 6 capsules ………………………….…….NDC 0078-0652-06
## Storage
Store at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C and 30°C (59°F and 86°F). Store blister pack in original carton to protect from light. Panobinostat capsules should not be opened, crushed, or chewed. Direct contact of the powder in Panobinostat capsules with the skin or mucous membranes should be avoided. If such contact occurs wash thoroughly. Personnel should avoid exposure to crushed and/or broken capsules.
Panobinostat is a cytotoxic drug. Follow special handling and disposal procedures.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
- Dosing and Administration
- Instruct patients to take Panobinostat exactly as prescribed and not to change their dose or to stop taking Panobinostat unless they are told to do so by their healthcare provider. If a patient misses a dose, advise them to take their dose as soon possible and up to 12 hours after the specified dose time. If vomiting occurs advise the patient not to repeat the dose, but to take the next usual prescribed dose on schedule.
- Cardiac Toxicity/Electrocardiographic Changes
- Inform patients to report chest pain or discomfort, changes in heart beat (fast or slow), palpitations, lightheadedness, fainting, dizziness, blue discoloration of lips, shortness of breath, and swelling of lower limbs or skin as these may be warning signs of a heart problem.
- Bleeding Risk
- Inform patients that Panobinostat is associated with thrombocytopenia. Advise patients to contact their healthcare provider right away if they experience any signs of bleeding and inform patients that it might take longer than usual for them to stop bleeding. Advise patients of the need to monitor blood chemistry and hematology prior to the start of Panobinostat therapy and periodically thereafter.
- Infections
- Inform patients of the risk of neutropenia and severe and life-threatening infections. Instruct patients to contact their physician immediately if they develop a fever and/or any exhibit any signs of infection.
- Gastrointestinal Toxicities
- Inform patients that Panobinostat can cause severe nausea, vomiting and diarrhea which may require medication for treatment. Advise patients to contact their physician at the start of diarrhea, for persistent vomiting, or signs of dehydration. Inform patients to consult with their physicians prior to using medications with laxative properties.
- Pregnancy
- Inform patients that Panobinostat can cause fetal harm. Advise women of reproductive potential to avoid pregnancy while taking Panobinostat. Advise women of reproductive potential to use effective contraception while taking Panobinostat and for at least 3 months after the last dose of the drug.
- Advise sexually active men to use condoms while receiving Panobinostat and for at least 6 months following the last dose of the drug.
- Lactation
- Advise women not to breastfeed while taking Panobinostat.
# Precautions with Alcohol
Alcohol-Panobinostat interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
FARYDAK®
# Look-Alike Drug Names
There is limited information regarding Panobinostat Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Panobinostat | |
4fd68eba13b32f5440be142d25d7366bd25d4f04 | wikidoc | Parechovirus | Parechovirus
# Overview
Parechovirus is a viral genus in the family Picornaviridae. The genus is composed of two species: Human parechovirus and Ljungan virus.
Six types of human parechovirus have been identified: human parechovirus 1 (formerly echovirus 22), human parechovirus 2 (formerly echovirus 23), and human parechoviruses 3, 4, 5 and 6, respectively. Human parechoviruses cause mild, gastrointestinal or respiratory illness, but have been implicated in cases of myocarditis and encephalitis. Human parechoviruses are commonly spread and more than 95% of humans are infected by human parechoviruses early in life, within two to five years of age.
The Ljungan virus was first isolated from bank voles (Myodes glareolus, formerly Clethrionomys glareolus). Ljungan virus has been proposed as a zoonotic virus, associated with diabetes and intrauterine fetal death in human. However, the data regarding these features is currently limited and needs to be confirmed. | Parechovirus
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Parechovirus is a viral genus in the family Picornaviridae. The genus is composed of two species: Human parechovirus and Ljungan virus.[1]
Six types of human parechovirus have been identified: human parechovirus 1 (formerly echovirus 22), human parechovirus 2 (formerly echovirus 23), and human parechoviruses 3, 4, 5 and 6, respectively.[2][3][4] Human parechoviruses cause mild, gastrointestinal or respiratory illness, but have been implicated in cases of myocarditis and encephalitis. Human parechoviruses are commonly spread and more than 95% of humans are infected by human parechoviruses early in life, within two to five years of age.[5][6]
The Ljungan virus was first isolated from bank voles (Myodes glareolus, formerly Clethrionomys glareolus).[7] Ljungan virus has been proposed as a zoonotic virus, associated with diabetes and intrauterine fetal death in human.[8][9] However, the data regarding these features is currently limited and needs to be confirmed. | https://www.wikidoc.org/index.php/Parechovirus | |
3dd7bb3dbc668d47fa72fd760afb0bda61dce8e5 | wikidoc | Parietal eye | Parietal eye
A parietal eye, also known as a parietal organ or third-eye is a part of the epithalamus present in some animal species. The eye may be photoreceptive and is usually associated with the pineal gland, regulating circadian rhythmicity and hormone production for thermoregulation.
# Function
The lizard-like reptile tuatara has a "well-developed parietal eye, with small lens and retina". Parietal eyes are also found in lizards, frogs and lampreys, as well as some species of fish, such as tuna and pelagic sharks, where it is visible as a light-sensitive spot on top of their head. A poorly developed version, often called the parapineal gland, occurs in salamanders. In birds and mammals the parietal organ (but not the pineal gland) is absent.
# Physiology
The parietal eye is a part of the epithalamus, which can be divided into two major parts; the epiphysis (the pineal organ, or pineal gland if mostly endocrine) and the parietal organ, often called the parietal eye, or third eye, if photoreceptive. It arises as an anterior evagination of the pineal organ or as a separate outgrowth of the roof of the diencephalon. In some species, it protrudes through the skull. The parietal eye uses a different biochemical method of detecting light than rod cells or cone cells in a normal eye. | Parietal eye
A parietal eye, also known as a parietal organ or third-eye is a part of the epithalamus present in some animal species. The eye may be photoreceptive and is usually associated with the pineal gland, regulating circadian rhythmicity and hormone production for thermoregulation.[1]
# Function
The lizard-like reptile tuatara has a "well-developed parietal eye, with small lens and retina".[2] Parietal eyes are also found in lizards, frogs and lampreys, as well as some species of fish, such as tuna and pelagic sharks, where it is visible as a light-sensitive spot on top of their head. A poorly developed version, often called the parapineal gland, occurs in salamanders. In birds and mammals the parietal organ (but not the pineal gland) is absent.
# Physiology
The parietal eye is a part of the epithalamus, which can be divided into two major parts; the epiphysis (the pineal organ, or pineal gland if mostly endocrine) and the parietal organ, often called the parietal eye, or third eye, if photoreceptive. It arises as an anterior evagination of the pineal organ or as a separate outgrowth of the roof of the diencephalon. In some species, it protrudes through the skull.[3] The parietal eye uses a different biochemical method of detecting light than rod cells or cone cells in a normal eye.[4] | https://www.wikidoc.org/index.php/Parietal_eye | |
f855deb3e6ef35126c298aeaf056d76bdffe04ec | wikidoc | Pathogenesis | Pathogenesis
Pathogenesis is the mechanism by which a certain etiological factor causes disease (pathos = disease, genesis = development).
The term can also be used to describe the development of the disease, whether it is acute, chronic, recurrent etc.
Some forms of pathogenesis are:
- Inflammation
- Malignancy
- Tissue breakdown
In most diseases, there are multiple pathogenetical processes at work. For example, certain cancers arise from dysfunction of the immune system (skin tumors and lymphoma after a renal transplant - which requires immunosuppression).
Often, a potential etiology is identified by epidemiological observations before a pathological link can be drawn between the cause and the disease. | Pathogenesis
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Pathogenesis is the mechanism by which a certain etiological factor causes disease (pathos = disease, genesis = development).
The term can also be used to describe the development of the disease, whether it is acute, chronic, recurrent etc.
Some forms of pathogenesis are:
- Inflammation
- Malignancy
- Tissue breakdown
In most diseases, there are multiple pathogenetical processes at work. For example, certain cancers arise from dysfunction of the immune system (skin tumors and lymphoma after a renal transplant - which requires immunosuppression).
Often, a potential etiology is identified by epidemiological observations before a pathological link can be drawn between the cause and the disease. | https://www.wikidoc.org/index.php/Pathogenesis | |
56ecb6f72ca770f9d80a103796d6d157cb5cef24 | wikidoc | Peginesatide | Peginesatide
# Overview
Peginesatide(INN/USAN, trade name Omontys, formerly Hematide), developed by Affymax and Takeda, is an erythropoietic agent, a functional analog of erythropoietin.
It was approved by the U.S. Food and Drug Administration for treatment of anemia associated with chronic kidney disease (CKD) in adult patients on dialysis. On February 23, 2013, Affymax and Takeda issued a press release indicating that they were recalling all batches of peginesatide from the market.
Two randomized controlled trials published in 2013 found that the effectiveness of peginesatide was not inferior to epoetin for patients receiving dialysis (the EMERALD study), or to darbepoetin for patients with chronic kidney disease who were not receiving dialysis (the PEARL study). However, the safety endpoint of cardiovascular events and death was worse for peginesatide than for darbepoetin in the PEARL study.
# Medical uses
The FDA approved the use of peginesatide for the treatment of anemia due to chronic kidney disease in adult patients on dialysis.
# Chemistry and mechanism of action
Peginesatide is a synthetic peptide, attached to polyethylene glycol ("PEGylated"). It mimics the structure of erythropoietin, the human glycoprotein which promotes red blood cell development.
# Related drugs
The erythropoietin analogs currently used to treat anemia in the United States are epoetin alfa (sold under the names Procrit and Epogen) and darbepoetin alfa (which is a more glycosylated form of epoetin, sold under the name Aranesp). There are similar biologic agents, such as Mircera(a monoPEGylated erythropoietin-beta), sold by Roche in Europe, however United States patent law currently forbids their sale. | Peginesatide
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Peginesatide(INN/USAN, trade name Omontys, formerly Hematide), developed by Affymax and Takeda, is an erythropoietic agent, a functional analog of erythropoietin.
It was approved by the U.S. Food and Drug Administration for treatment of anemia associated with chronic kidney disease (CKD) in adult patients on dialysis. On February 23, 2013, Affymax and Takeda issued a press release indicating that they were recalling all batches of peginesatide from the market.
Two randomized controlled trials published in 2013 found that the effectiveness of peginesatide was not inferior to epoetin for patients receiving dialysis (the EMERALD study), or to darbepoetin for patients with chronic kidney disease who were not receiving dialysis (the PEARL study). However, the safety endpoint of cardiovascular events and death was worse for peginesatide than for darbepoetin in the PEARL study.
# Medical uses
The FDA approved the use of peginesatide for the treatment of anemia due to chronic kidney disease in adult patients on dialysis.
# Chemistry and mechanism of action
Peginesatide is a synthetic peptide, attached to polyethylene glycol ("PEGylated"). It mimics the structure of erythropoietin, the human glycoprotein which promotes red blood cell development.
# Related drugs
The erythropoietin analogs currently used to treat anemia in the United States are epoetin alfa (sold under the names Procrit and Epogen) and darbepoetin alfa (which is a more glycosylated form of epoetin, sold under the name Aranesp). There are similar biologic agents, such as Mircera(a monoPEGylated erythropoietin-beta), sold by Roche in Europe, however United States patent law currently forbids their sale. | https://www.wikidoc.org/index.php/Peginesatide | |
b637df47e160ad60b131a087b63df02d51c17ae9 | wikidoc | Penning trap | Penning trap
Penning traps are devices for the storage of charged particles using a constant static magnetic field and a spatially inhomogeneous static electric field. This kind of trap is particularly well suited to precision measurements of properties of ions and stable subatomic particles which have electric charge. Recently this trap has been used in the physical realization of quantum computation and quantum information processing as well. Currently Penning traps are used in many laboratories worldwide, for example at CERN it is used to store antiprotons. The Penning Trap was named after F. M. Penning(1894-1953) by Hans Georg Dehmelt who built the first trap. Dehmelt got inspiration from the vacuum gauge built by F. M. Penning where a current through a discharge tube in a magnetic field is proportional to the pressure. Citation from H. Dehmelts autobiography: "I began to focus on the magnetron/Penning discharge geometry, which, in the Penning ion gauge, had caught my interest already at Göttingen and at Duke. In their 1955 cyclotron resonance work on photoelectrons in vacuum Franken and Liebes had reported undesirable frequency shifts caused by accidental electron trapping. Their analysis made me realize that in a pure electric quadrupole field the shift would not depend on the location of the electron in the trap. This is an important advantage over many other traps that I decided to exploit. A magnetron trap of this type had been briefly discussed in J.R. Pierce's 1949 book, and I developed a simple description of the axial, magnetron, and cyclotron motions of an electron in it. With the help of the expert glassblower of the Department, Jake Jonson, I built my first high vacuum magnetron trap in 1959 and was soon able to trap electrons for about 10 sec and to detect axial, magnetron and cyclotron resonances. "
H. Dehmelt shared the Nobel Prize in Physics in 1989 for the development of the ion trap technique.
# How it works
Penning traps use a strong homogeneous axial magnetic field to confine particles radially and a quadrupole electric field to confine the particles axially. The static electric potential can be generated using a set of three electrodes: a ring and two endcaps. In an ideal Penning trap the ring and endcaps are hyperboloids of revolution. For trapping of positive (negative) ions, the endcap electrodes are kept at a positive (negative) potential relative to the ring. This potential produces a saddle point in the centre of the trap, which traps ions along the axial direction. The electric field causes ions to oscillate (harmonically in the case of an ideal Penning trap) along the trap axis. The magnetic field in combination with the electric field causes charged particles to move in the radial plane with a motion which traces out an epitrochoid.
The orbital motion of ions in the radial plane is composed of two modes at frequencies which are called the magnetron \omega_{-}and the modified cyclotron \omega_{+} frequencies. These motions are similar to the deferent and epicycle, respectively, of the Ptolemaic model of the solar system.
The sum of these two frequencies is the cyclotron frequency, which depends only on the ratio of electric charge to mass and on the strength of the magnetic field. This frequency can be measured very accurately and can be used to measure the masses of charged particles. Many of the highest-precision mass measurements (masses of the electron, proton, 2H, 20Ne and 28Si) come from Penning traps.
Buffer gas cooling, resistive cooling, and laser cooling are techniques to remove energy from ions in a Penning trap.
Buffer gas cooling relies on collisions between the ions and neutral gas molecules that bring the ion energy closer the energy of the gas molecules.
In resistive cooling, moving image charges in the electrodes are made to do work through an external resistor, effectively removing energy from the ions.
Laser cooling can be used to remove energy from some kinds of ions in Penning traps. This technique requires ions with an appropriate electronic structure.
Radiative cooling is the process by which the ions lose energy by creating electromagnetic waves by virtue of their acceleration in the magnetic field. This process dominates the cooling of electrons in Penning traps, but is very small and usually negligible for heavier particles.
Using the Penning trap can have advantages over the radio frequency
trap (Paul trap). Firstly, in the Penning trap only static fields are applied and
therefore there is no micro-motion and resultant heating of the ion due to the
dynamic fields. Also, the Penning trap can be made larger whilst maintaining strong
trapping. The trapped ion can then be held further away from the electrode
surfaces. Interaction with patch potentials on the electrode surfaces can be responsible
for heating and decoherence effects and these effects scale as a high power
-f the inverse distance between the ion and the electrode.
# Fourier transform mass spectrometry
Fourier transform ion cyclotron resonance mass spectrometry (also known as Fourier transform mass spectrometry), is a type of mass spectrometry used for determining the mass-to-charge ratio (m/z) of ions based on the cyclotron frequency of the ions in a fixed magnetic field. The ions are trapped in a Penning trap where they are excited to a larger cyclotron radius by an oscillating electric field perpendicular to the magnetic field. The excitation also results in the ions moving in phase (in a packet). The signal is detected as an image current on a pair of plates which the packet of ions passes close to as they cyclotron. The resulting signal is called a free induction decay (fid), transient or interferogram that consists of a superposition of sine waves. The useful signal is extracted from this data by performing a Fourier transform to give a mass spectrum. | Penning trap
Template:Antimatter
Penning traps are devices for the storage of charged particles using a constant static magnetic field and a spatially inhomogeneous static electric field. This kind of trap is particularly well suited to precision measurements of properties of ions and stable subatomic particles which have electric charge. Recently this trap has been used in the physical realization of quantum computation and quantum information processing as well. Currently Penning traps are used in many laboratories worldwide, for example at CERN it is used to store antiprotons. The Penning Trap was named after F. M. Penning(1894-1953) by Hans Georg Dehmelt who built the first trap. Dehmelt got inspiration from the vacuum gauge built by F. M. Penning where a current through a discharge tube in a magnetic field is proportional to the pressure. Citation from H. Dehmelts autobiography: "I began to focus on the magnetron/Penning discharge geometry, which, in the Penning ion gauge, had caught my interest already at Göttingen and at Duke. In their 1955 cyclotron resonance work on photoelectrons in vacuum Franken and Liebes had reported undesirable frequency shifts caused by accidental electron trapping. Their analysis made me realize that in a pure electric quadrupole field the shift would not depend on the location of the electron in the trap. This is an important advantage over many other traps that I decided to exploit. A magnetron trap of this type had been briefly discussed in J.R. Pierce's 1949 book, and I developed a simple description of the axial, magnetron, and cyclotron motions of an electron in it. With the help of the expert glassblower of the Department, Jake Jonson, I built my first high vacuum magnetron trap in 1959 and was soon able to trap electrons for about 10 sec and to detect axial, magnetron and cyclotron resonances. "
H. Dehmelt shared the Nobel Prize in Physics in 1989 for the development of the ion trap technique.
# How it works
Penning traps use a strong homogeneous axial magnetic field to confine particles radially and a quadrupole electric field to confine the particles axially. The static electric potential can be generated using a set of three electrodes: a ring and two endcaps. In an ideal Penning trap the ring and endcaps are hyperboloids of revolution. For trapping of positive (negative) ions, the endcap electrodes are kept at a positive (negative) potential relative to the ring. This potential produces a saddle point in the centre of the trap, which traps ions along the axial direction. The electric field causes ions to oscillate (harmonically in the case of an ideal Penning trap) along the trap axis. The magnetic field in combination with the electric field causes charged particles to move in the radial plane with a motion which traces out an epitrochoid.
The orbital motion of ions in the radial plane is composed of two modes at frequencies which are called the magnetron <math>\omega_{-}</math>and the modified cyclotron <math>\omega_{+}</math> frequencies. These motions are similar to the deferent and epicycle, respectively, of the Ptolemaic model of the solar system.
The sum of these two frequencies is the cyclotron frequency, which depends only on the ratio of electric charge to mass and on the strength of the magnetic field. This frequency can be measured very accurately and can be used to measure the masses of charged particles. Many of the highest-precision mass measurements (masses of the electron, proton, 2H, 20Ne and 28Si) come from Penning traps.
Buffer gas cooling, resistive cooling, and laser cooling are techniques to remove energy from ions in a Penning trap.
Buffer gas cooling relies on collisions between the ions and neutral gas molecules that bring the ion energy closer the energy of the gas molecules.
In resistive cooling, moving image charges in the electrodes are made to do work through an external resistor, effectively removing energy from the ions.
Laser cooling can be used to remove energy from some kinds of ions in Penning traps. This technique requires ions with an appropriate electronic structure.
Radiative cooling is the process by which the ions lose energy by creating electromagnetic waves by virtue of their acceleration in the magnetic field. This process dominates the cooling of electrons in Penning traps, but is very small and usually negligible for heavier particles.
Using the Penning trap can have advantages over the radio frequency
trap (Paul trap). Firstly, in the Penning trap only static fields are applied and
therefore there is no micro-motion and resultant heating of the ion due to the
dynamic fields. Also, the Penning trap can be made larger whilst maintaining strong
trapping. The trapped ion can then be held further away from the electrode
surfaces. Interaction with patch potentials on the electrode surfaces can be responsible
for heating and decoherence effects and these effects scale as a high power
of the inverse distance between the ion and the electrode.
# Fourier transform mass spectrometry
Fourier transform ion cyclotron resonance mass spectrometry (also known as Fourier transform mass spectrometry), is a type of mass spectrometry used for determining the mass-to-charge ratio (m/z) of ions based on the cyclotron frequency of the ions in a fixed magnetic field.[1] The ions are trapped in a Penning trap where they are excited to a larger cyclotron radius by an oscillating electric field perpendicular to the magnetic field. The excitation also results in the ions moving in phase (in a packet). The signal is detected as an image current on a pair of plates which the packet of ions passes close to as they cyclotron. The resulting signal is called a free induction decay (fid), transient or interferogram that consists of a superposition of sine waves. The useful signal is extracted from this data by performing a Fourier transform to give a mass spectrum. | https://www.wikidoc.org/index.php/Penning_trap | |
80d6cb81415d9e8b08bd1f91c3a56622f588cf26 | wikidoc | Pentagastrin | Pentagastrin
# 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
Pentagastrin is a diagnostic aid that is FDA approved for the diagnosis of Anacidity, Hypersecretory conditions. Common adverse reactions include Nausea, abdominal cramps.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- Anacidity (diagnosis)—Pentagastrin is indicated as a diagnostic aid for evaluation of gastric acid secretory function. It is effective in testing for anacidity (achlorhydria) in patients with suspected pernicious anemia, atrophic gastritis, or gastric carcinoma. It is also effective in determining the reduction in acid output after operations for peptic ulcer, such as vagotomy or gastric resection.
- Hypersecretory conditions, gastric (diagnosis)—Pentagastrin is indicated as a diagnostic aid in testing for gastric hypersecretion in patients with suspected duodenal ulcer or postoperative stomal ulcer, and for the diagnosis of Zollinger-Ellison tumor
### Dosage
- The intravenous infusion dose has ranged from 0.1 to 12 mcg (0.0001 to 0.012 mg) per kg of body weight per hour administered in a 0.9% sodium chloride injection. It can also be used as a subcutaneous injection for gastric function study with a dose of 6 mcg (0.006 mg) per kg of body weight.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pentagastrin in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Pentagastrin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Pentagastrin in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pentagastrin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Pentagastrin in pediatric patients.
# Contraindications
There is limited information regarding Pentagastrin Contraindications in the drug label.
# Warnings
There is limited information regarding Pentagastrin Warnings' in the drug label.
# Adverse Reactions
## Clinical Trials Experience
- Nausea
- Abdominal cramps
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Pentagastrin in the drug label.
# Drug Interactions
- The following may affect pentagastrin’s action:
- Antacids, anticholinergics, histamine H2-receptor antagosnists, or omeprazole
- Acute, obstructing, penetrating or bleeding peptic ulcers
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Pentagastrin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Pentagastrin during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Pentagastrin with respect to nursing mothers.
### Pediatric Use
There is no FDA guidance on the use of Pentagastrin with respect to pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of Pentagastrin with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Pentagastrin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Pentagastrin with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Pentagastrin in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Pentagastrin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Pentagastrin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Pentagastrin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- intravenous infusion
### Monitoring
There is limited information regarding Monitoring of Pentagastrin in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Pentagastrin in the drug label.
# Overdosage
There is limited information regarding Overdose of Pentagastrin in the drug label.
# Pharmacology
## Mechanism of Action
- The exact mechanism by which Pentagastrin stimulates gastric acid, pepsin, and intrinsic factor secretion is unknown; however, since Pentagastrin is an analogue of natural gastrin, it is believed that it excites the oxyntic cells of the stomach to secrete to their maximum capacity. Pentagastrin stimulates pancreatic secretion, especially when administered in large intramuscular doses. Pentagastrin also increases gastrointestinal motility by a direct effect on the intestinal smooth muscle. However, it delays gastric emptying time probably by stimulation of terminal antral contractions, which enhance retropulsion.
## Structure
- Pentagastrin, a diagnostic aid, is supplied as a sterile solution (1.1 ml/5 ml vial) containing:
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Pentagastrin in the drug label.
## Pharmacokinetics
- The exact mechanism by which Pentagastrin stimulates gastric acid, pepsin, and intrinsic factor secretion is unknown; however, since Pentagastrin is an analogue of natural gastrin, it is believed that it excites the oxyntic cells of the stomach to secrete to their maximum capacity. Pentagastrin stimulates pancreatic secretion, especially when administered in large intramuscular doses. Pentagastrin also increases gastrointestinal motility by a direct effect on the intestinal smooth muscle. However, it delays gastric emptying time probably by stimulation of terminal antral contractions, which enhance retropulsion.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Pentagastrin in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Pentagastrin in the drug label.
# How Supplied
There is limited information regarding Pentagastrin How Supplied in the drug label.
## Storage
- Keep refrigerated between 2◦ and 8◦C. Protect from light
# Images
## Drug Images
## Package and Label Display Panel
### PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
### Ingredients and Appearance
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Pentagastrin in the drug label.
# Precautions with Alcohol
- Alcohol-Pentagastrin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- PENTAGASTRIN ®
# Look-Alike Drug Names
There is limited information regarding Pentagastrin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Pentagastrin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rabin Bista, 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
Pentagastrin is a diagnostic aid that is FDA approved for the diagnosis of Anacidity, Hypersecretory conditions. Common adverse reactions include Nausea, abdominal cramps.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- Anacidity (diagnosis)—Pentagastrin is indicated as a diagnostic aid for evaluation of gastric acid secretory function. It is effective in testing for anacidity (achlorhydria) in patients with suspected pernicious anemia, atrophic gastritis, or gastric carcinoma. It is also effective in determining the reduction in acid output after operations for peptic ulcer, such as vagotomy or gastric resection.
- Hypersecretory conditions, gastric (diagnosis)—Pentagastrin is indicated as a diagnostic aid in testing for gastric hypersecretion in patients with suspected duodenal ulcer or postoperative stomal ulcer, and for the diagnosis of Zollinger-Ellison tumor
### Dosage
- The intravenous infusion dose has ranged from 0.1 to 12 mcg (0.0001 to 0.012 mg) per kg of body weight per hour administered in a 0.9% sodium chloride injection. It can also be used as a subcutaneous injection for gastric function study with a dose of 6 mcg (0.006 mg) per kg of body weight.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pentagastrin in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Pentagastrin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Pentagastrin in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pentagastrin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Pentagastrin in pediatric patients.
# Contraindications
There is limited information regarding Pentagastrin Contraindications in the drug label.
# Warnings
There is limited information regarding Pentagastrin Warnings' in the drug label.
# Adverse Reactions
## Clinical Trials Experience
- Nausea[1]
- Abdominal cramps
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Pentagastrin in the drug label.
# Drug Interactions
- The following may affect pentagastrin’s action:
- Antacids, anticholinergics, histamine H2-receptor antagosnists, or omeprazole
- Acute, obstructing, penetrating or bleeding peptic ulcers
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Pentagastrin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Pentagastrin during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Pentagastrin with respect to nursing mothers.
### Pediatric Use
There is no FDA guidance on the use of Pentagastrin with respect to pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of Pentagastrin with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Pentagastrin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Pentagastrin with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Pentagastrin in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Pentagastrin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Pentagastrin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Pentagastrin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- intravenous infusion
### Monitoring
There is limited information regarding Monitoring of Pentagastrin in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Pentagastrin in the drug label.
# Overdosage
There is limited information regarding Overdose of Pentagastrin in the drug label.
# Pharmacology
## Mechanism of Action
- The exact mechanism by which Pentagastrin stimulates gastric acid, pepsin, and intrinsic factor secretion is unknown; however, since Pentagastrin is an analogue of natural gastrin, it is believed that it excites the oxyntic cells of the stomach to secrete to their maximum capacity. Pentagastrin stimulates pancreatic secretion, especially when administered in large intramuscular doses. Pentagastrin also increases gastrointestinal motility by a direct effect on the intestinal smooth muscle. However, it delays gastric emptying time probably by stimulation of terminal antral contractions, which enhance retropulsion.
## Structure
- Pentagastrin, a diagnostic aid, is supplied as a sterile solution (1.1 ml/5 ml vial) containing:
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Pentagastrin in the drug label.
## Pharmacokinetics
- The exact mechanism by which Pentagastrin stimulates gastric acid, pepsin, and intrinsic factor secretion is unknown; however, since Pentagastrin is an analogue of natural gastrin, it is believed that it excites the oxyntic cells of the stomach to secrete to their maximum capacity. Pentagastrin stimulates pancreatic secretion, especially when administered in large intramuscular doses. Pentagastrin also increases gastrointestinal motility by a direct effect on the intestinal smooth muscle. However, it delays gastric emptying time probably by stimulation of terminal antral contractions, which enhance retropulsion.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Pentagastrin in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Pentagastrin in the drug label.
# How Supplied
There is limited information regarding Pentagastrin How Supplied in the drug label.
## Storage
- Keep refrigerated between 2◦ and 8◦C. Protect from light
# Images
## Drug Images
## Package and Label Display Panel
### PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
### Ingredients and Appearance
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Pentagastrin in the drug label.
# Precautions with Alcohol
- Alcohol-Pentagastrin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- PENTAGASTRIN ®[3]
# Look-Alike Drug Names
There is limited information regarding Pentagastrin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Pentagastrin | |
5b4d26bbf830495d0971b052a6b1db4322bbeede | wikidoc | Pepto-Bismol | Pepto-Bismol
Pepto-Bismol is an over-the-counter medication produced by the Procter and Gamble company used to treat minor digestive system upset. Its active ingredient is bismuth subsalicylate. The primary symptoms aided by Pepto-Bismol are nausea, heartburn, indigestion, upset stomach, diarrhea, and other temporary discomforts of the stomach and gastrointestinal tract.
Pepto-Bismol are made in chewable tablets and swallowable caplets, but is best known for its original formula which is a thick liquid. This original formula is a medium pink color with a strong wintergreen flavor. These traits have become generally associated with the medicine to the degree that something may be described as "Pepto-Bismol pink" or as tasting like "Pepto-Bismol". These are generally considered uncomplimentary traits, because of the unpleasant associations with the medication and the general malaise associated with stomach problems. Also, the drug is commonly referred to as "pink stuff'.
# History
Pepto-Bismol was originally sold as a remedy for infant diarrhea by Norwich Pharmaceutical Company under the name Bismosal: Mixture Cholera Infantum, changing to Pepto-Bismol in 1919, and transferring to Procter and Gamble with their 1982 acquisition of Norwich Eaton Pharmaceuticals. | Pepto-Bismol
Pepto-Bismol is an over-the-counter medication produced by the Procter and Gamble company used to treat minor digestive system upset. Its active ingredient is bismuth subsalicylate. The primary symptoms aided by Pepto-Bismol are nausea, heartburn, indigestion, upset stomach, diarrhea, and other temporary discomforts of the stomach and gastrointestinal tract.
Pepto-Bismol are made in chewable tablets and swallowable caplets, but is best known for its original formula which is a thick liquid. This original formula is a medium pink color with a strong wintergreen flavor. These traits have become generally associated with the medicine to the degree that something may be described as "Pepto-Bismol pink" or as tasting like "Pepto-Bismol". These are generally considered uncomplimentary traits, because of the unpleasant associations with the medication and the general malaise associated with stomach problems. Also, the drug is commonly referred to as "pink stuff'.
# History
Pepto-Bismol was originally sold as a remedy for infant diarrhea by Norwich Pharmaceutical Company under the name Bismosal: Mixture Cholera Infantum, changing to Pepto-Bismol in 1919, and transferring to Procter and Gamble with their 1982 acquisition of Norwich Eaton Pharmaceuticals.
# External links
- Official site
Template:Pharma-stub
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Pepto-Bismol | |
f52b32527dd522676880937cd7503810a924219b | wikidoc | Periodontist | Periodontist
Periodontology, or Periodontics, is the branch of dentistry which studies supporting structures of teeth, and diseases and conditions that affect them.
The supporting tissues are known as the periodontium, which includes the gingiva (gums), alveolar bone, cementum, and the periodontal ligament. The word comes from the Greek words peri meaning around and odons meaning tooth. Literally taken, it means study of that which is "around the tooth".
# Periodontal disease
Periodontal diseases take on many different forms, but are usually a result of a coalescence of bacterial plaque biofilm accumulation of the gingiva and teeth, combined with host immuno-inflammatory mechanisms and other risk factors which lead to destruction of the supporting bone around natural teeth. Untreated, these diseases lead to alveolar bone loss and tooth loss, and to date continue to be the leading cause of tooth loss in adults.
# Periodontists
A Periodontist is a dentist who specializes in the diagnosis and surgical and non-surgical treatment of diseases and conditions of the periodontium. Periodontists are experts in the management of patients with periodontal diseases including gingivitis, periodontitis and gingival recession (gum recession).
## United States
Periodontics is one of the nine American Dental Association recognized specialties of dentistry. Periodontists complete 3 years of additional formal training beyond dental school in an accredited residency training program.
The American Academy of Periodontology is the recognized governing academy for periodontics in the USA.
Periodontists may also earn Board Certification by the American Board of Periodontology' after completion of an American Dental Association accredited residency training program in Periodontics. Board certified periodontists are awarded the title "Diplomate of the American Board of Periodontology".
# India ( Bharath )
Periodontics is offered as specialisation field in dentistry programme in India.This is offered at Master of Dental Surgery ( M.D.S ) course conducted by dental colleges affilated to different universities in India.The minimum qualification required for M.D.S is Bachelor of Dental Surgery ( B.D.S ). Dental council of India is regulating body for dentists in India. | Periodontist
Periodontology, or Periodontics, is the branch of dentistry which studies supporting structures of teeth, and diseases and conditions that affect them.
The supporting tissues are known as the periodontium, which includes the gingiva (gums), alveolar bone, cementum, and the periodontal ligament. The word comes from the Greek words peri meaning around and odons meaning tooth. Literally taken, it means study of that which is "around the tooth".
# Periodontal disease
Periodontal diseases take on many different forms, but are usually a result of a coalescence of bacterial plaque biofilm accumulation of the gingiva and teeth, combined with host immuno-inflammatory mechanisms and other risk factors which lead to destruction of the supporting bone around natural teeth. Untreated, these diseases lead to alveolar bone loss and tooth loss, and to date continue to be the leading cause of tooth loss in adults.
# Periodontists
Template:Global
A Periodontist is a dentist who specializes in the diagnosis and surgical and non-surgical treatment of diseases and conditions of the periodontium. Periodontists are experts in the management of patients with periodontal diseases including gingivitis, periodontitis and gingival recession (gum recession).
## United States
Periodontics is one of the nine American Dental Association recognized specialties of dentistry. Periodontists complete 3 years of additional formal training beyond dental school in an accredited residency training program.
The American Academy of Periodontology is the recognized governing academy for periodontics in the USA.
Periodontists may also earn Board Certification by the American Board of Periodontology' after completion of an American Dental Association accredited residency training program in Periodontics. Board certified periodontists are awarded the title "Diplomate of the American Board of Periodontology".
# India ( Bharath )
Periodontics is offered as specialisation field in dentistry programme in India.This is offered at Master of Dental Surgery ( M.D.S ) course conducted by dental colleges affilated to different universities in India.The minimum qualification required for M.D.S is Bachelor of Dental Surgery ( B.D.S ). Dental council of India is regulating body for dentists in India. | https://www.wikidoc.org/index.php/Periodontist | |
1eebeb092274798f01acec2813fdd671f0ce4a06 | wikidoc | Venous blood | Venous blood
In the circulatory system, venous blood is blood returning to the heart. With one exception (the pulmonary vein) this blood is deoxygenated and high in carbon dioxide, having released oxygen and absorbed CO2 in the tissues. It is also typically warmer than arterial blood, has a lower pH, has lower concentrations of glucose and other nutrients, and has higher concentrations of urea and other waste products.
Venous blood can be obtained by venipuncture (also called phlebotomy), or in small quantities by fingerprick. Most medical laboratory tests are conducted on venous blood, with the exception of arterial blood gases.
Venous blood is often depicted as blue in color in medical diagrams, and veins sometimes look blue when seen through the skin. However, venous blood is actually a dark red color (but looks purple through the opaque skin), while arterial blood is bright red. The appearance of veins as dark blue is a wavelength phenomenon of light, having to do with the reflection of blue light away from the outside of venous tissue if the vein is @ 0.02in deep or more. This is due to the difference in color between deoxyhemoglobin and oxyhemoglobin; the red color ultimately originates from the iron atom in heme. If blood is drawn for a medical test, the dark red color can be seen; however, if it is exposed to oxygen in the air, it will turn bright red like arterial blood. | Venous blood
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
In the circulatory system, venous blood is blood returning to the heart. With one exception (the pulmonary vein) this blood is deoxygenated and high in carbon dioxide, having released oxygen and absorbed CO2 in the tissues. It is also typically warmer than arterial blood, has a lower pH, has lower concentrations of glucose and other nutrients, and has higher concentrations of urea and other waste products.
Venous blood can be obtained by venipuncture (also called phlebotomy), or in small quantities by fingerprick. Most medical laboratory tests are conducted on venous blood, with the exception of arterial blood gases.
Venous blood is often depicted as blue in color in medical diagrams, and veins sometimes look blue when seen through the skin. However, venous blood is actually a dark red color (but looks purple through the opaque skin), while arterial blood is bright red. The appearance of veins as dark blue is a wavelength phenomenon of light, having to do with the reflection of blue light away from the outside of venous tissue if the vein is @ 0.02in deep or more. This is due to the difference in color between deoxyhemoglobin and oxyhemoglobin; the red color ultimately originates from the iron atom in heme. If blood is drawn for a medical test, the dark red color can be seen; however, if it is exposed to oxygen in the air, it will turn bright red like arterial blood.
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Peripheral_blood | |
ca0ac7f38fde6cb7649d1634db33b1d2ba17b84d | wikidoc | Peripherin 2 | Peripherin 2
Peripherin-2 is a protein, that in humans is encoded by the PRPH2 gene. Peripherin-2 is found in the rod and cone cells of the retina of the eye. Defects in this protein result in one form of retinitis pigmentosa, an incurable blindness.
Mutations in the PRPH2 gene are associated with Vitelliform macular dystrophy.
# Function
The protein encoded by this gene is a member of the transmembrane 4 superfamily, also known as the tetraspanin family. Most of these members are cell-surface proteins that are characterized by the presence of four transmembrane helices. Tetraspanins mediate signal transduction events that play a role in the regulation of cell development, activation, growth and motility.
Peripherin 2 (sometimes referred to as peripherin/RDS or simply RDS) is a cell surface glycoprotein found in the outer segment of both rod and cone photoreceptor cells. It is located in the rim regions of the flattened disks that contain rhodopsin, which is the protein that is responsible for initiation of visual phototransduction upon reception of light. Peripherin 2 may function as an adhesion molecule involved in stabilization and compaction of outer segment disks or in the maintenance of the curvature of the rim. This protein is essential for disk morphogenesis.
# Clinical significance
Defects in this gene are associated with both central and peripheral retinal degenerations. Some of the various phenotypically different disorders are autosomal dominant retinitis pigmentosa, progressive macular degeneration, macular dystrophy and retinitis pigmentosa digenic. | Peripherin 2
Peripherin-2 is a protein, that in humans is encoded by the PRPH2 gene.[1][2] Peripherin-2 is found in the rod and cone cells of the retina of the eye. Defects in this protein result in one form of retinitis pigmentosa, an incurable blindness.
Mutations in the PRPH2 gene are associated with Vitelliform macular dystrophy.
# Function
The protein encoded by this gene is a member of the transmembrane 4 superfamily, also known as the tetraspanin family. Most of these members are cell-surface proteins that are characterized by the presence of four transmembrane helices. Tetraspanins mediate signal transduction events that play a role in the regulation of cell development, activation, growth and motility.
Peripherin 2 (sometimes referred to as peripherin/RDS or simply RDS) is a cell surface glycoprotein found in the outer segment of both rod and cone photoreceptor cells. It is located in the rim regions of the flattened disks that contain rhodopsin, which is the protein that is responsible for initiation of visual phototransduction upon reception of light. Peripherin 2 may function as an adhesion molecule involved in stabilization and compaction of outer segment disks or in the maintenance of the curvature of the rim. This protein is essential for disk morphogenesis.[2]
# Clinical significance
Defects in this gene are associated with both central and peripheral retinal degenerations. Some of the various phenotypically different disorders are autosomal dominant retinitis pigmentosa, progressive macular degeneration, macular dystrophy and retinitis pigmentosa digenic.[2] | https://www.wikidoc.org/index.php/Peripherin_2 | |
eb5f877668b793a0a1e27d79e2bde6845201e9e6 | wikidoc | Perphenazine | Perphenazine
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# Black Box Warning
# Overview
Perphenazine is an antipsychotic agent that is FDA approved for the treatment of schizophrenia and for the control of severe nausea and vomiting in adults.. There is a Black Box Warning for this drug as shown here. Common adverse reactions include the extrapyramidal symptoms are more common, and others (e.g., sedative effects, jaundice, and blood dyscrasias) are less frequently seen..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Perphenazine is indicated for use in the treatment of schizophrenia
- Dosage must be individualized and adjusted according to the severity of the condition and the response obtained. As with all potent drugs, the best dose is the lowest dose that will produce the desired clinical effect. Since extrapyramidal symptoms increase in frequency and severity with increased dosage, it is important to employ the lowest effective dose. These symptoms have disappeared upon reduction of dosage, withdrawal of the drug, or administration of an antiparkinsonian agent.
- Prolonged administration of doses exceeding 24 mg daily should be reserved for hospitalized patients or patients under continued observation for early detection and management of adverse reactions. An antiparkinsonian agent, such as trihexyphenidyl hydrochloride or benztropine mesylate, is valuable in controlling drug-induced extrapyramidal symptoms.
- Perphenazine has not been shown effective for the management of behavioral complications in patients with mental retardation.
- 4 to 8 mg t.i.d. initially; reduce as soon as possible to minimum effective dosage.
- 8 to 16 mg b.i.d. to q.i.d.; avoid dosages in excess of 64 mg daily.
- 8 to 16 mg daily in divided doses; 24 mg occasionally may be necessary; early dosage reduction is desirable.
- With increasing age, plasma concentrations of perphenazine per daily ingested dose increase. Geriatric dosages of perphenazine preparations have not been established, but initiation of lower dosages is recommended. Optimal clinical effect or benefit may require lower doses for a longer duration. Dosing of perphenazine may occur before bedtime, if required.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Perphenazine in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Perphenazine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Perphenazine products are not recommended for pediatric patients under 12 years of age.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Perphenazine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Perphenazine in pediatric patients.
# Contraindications
- Perphenazine products are contraindicated in comatose or greatly obtunded patients and in patients receiving large doses of central nervous system depressants (barbiturates, alcohol, narcotics, analgesics, or antihistamines); in the presence of existing blood dyscrasias, bone marrow depression, or liver damage; and in patients who have shown hypersensitivity to perphenazine products, their components, or related compounds.
- Perphenazine products are also contraindicated in patients with suspected or established subcortical brain damage, with or without hypothalamic damage, since a hyperthermic reaction with temperatures in excess of 104°F may occur in such patients, sometimes not until 14 to 16 hours after drug administration. *Total body ice-packing is recommended for such a reaction; antipyretics may also be useful.
# Warnings
- Increased Mortality in Elderly Patients with Dementia-Related Psychosis
- Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Perphenazine is not approved for the treatment of patients with dementia-related psychosis.
- Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with antipsychotic drugs. Older patients are at increased risk for development of tardive dyskinesia. *Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.
- Both the risk of developing the syndrome and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. *However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses.
- There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome, and thereby may possibly mask the underlying disease process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.
- Given these considerations, especially in the elderly, antipsychotics should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that 1) is known to respond to antipsychotic drugs, and 2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.
- If signs and symptoms of tardive dyskinesia appear in a patient on antipsychotics, drug discontinuation should be considered. However, some patients may require treatment despite the presence of the syndrome.
- A potentially fatal symptom complex, sometimes referred to as Neuroleptic Malignant Syndrome (NMS), has been reported in association with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias).
- The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology.
- The management of NMS should include 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and medical monitoring, and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS.
- If a patient requires antipsychotic drug treatment after recovery from NMS, the reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported.
- In clinical trial and postmarketing experience, events of leukopenia/neutropenia and agranulocytosis have been reported temporally related to antipsychotic agents.
- Possible risk factors for leukopenia/neutropenia include preexisting low white blood cell count (WBC) and history of drug induced leukopenia/neutropenia. Patients with a preexisting low WBC or a history of drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and should discontinue perphenazine tablets USP at the first sign of a decline in WBC in the absence of other causative factors.
- Patients with neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue perphenazine tablets USP and have their WBC followed until recovery.
- If hypotension develops, epinephrine should not be administered since its action is blocked and partially reversed by perphenazine. If a vasopressor is needed, norepinephrine may be used. Severe, acute hypotension has occurred with the use of phenothiazines and is particularly likely to occur in patients with mitral insufficiency or pheochromocytoma. Rebound hypertension may occur in pheochromocytoma patients.
- Perphenazine products can lower the convulsive threshold in susceptible individuals; they should be used with caution in alcohol withdrawal and in patients with convulsive disorders. If the patient is being treated with an anticonvulsant agent, increased dosage of that agent may be required when perphenazine products are used concomitantly.
- Perphenazine products should be used with caution in patients with psychic depression.
- Perphenazine may impair the mental and/or physical abilities required for the performance of hazardous tasks such as driving a car or operating machinery; therefore, the patient should be warned accordingly.
- The possibility of suicide in depressed patients remains during treatment and until significant remission occurs. This type of patient should not have access to large quantities of this drug.
- As with all phenothiazine compounds, perphenazine should not be used indiscriminately. Caution should be observed in giving it to patients who have previously exhibited severe adverse reactions to other phenothiazines. Some of the untoward actions of perphenazine tend to appear more frequently when high doses are used. However, as with other phenothiazine compounds, patients receiving perphenazine products in any dosage should be kept under close supervision.
- Antipsychotic drugs elevate prolactin levels; the elevation persists during chronic administration. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with a previously detected breast cancer. Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported, the clinical significance of elevated serum prolactin levels is unknown for most patients. An increase in mammary neoplasms has been found in rodents after chronic administration of antipsychotic drugs. Neither clinical studies nor epidemiologic studies conducted to date, however, have shown an association between chronic administration of these drugs and mammary tumorigenesis; the available evidence is considered too limited to be conclusive at this time.
- The antiemetic effect of perphenazine may obscure signs of toxicity due to overdosage of other drugs, or render more difficult the diagnosis of disorders such as brain tumors or intestinal obstruction.
- A significant, not otherwise explained, rise in body temperature may suggest individual intolerance to perphenazine, in which case it should be discontinued.
- Patients on large doses of a phenothiazine drug who are undergoing surgery should be watched carefully for possible hypotensive phenomena. Moreover, reduced amounts of anesthetics or central nervous system depressants may be necessary.
- Since phenothiazines and central nervous system depressants (opiates, analgesics, antihistamines, barbiturates) can potentiate each other, less than the usual dosage of the added drug is recommended and caution is advised when they are administered concomitantly.
- Use with caution in patients who are receiving atropine or related drugs because of additive anticholinergic effects and also in patients who will be exposed to extreme heat or phosphorus insecticides.
- Use with caution in patients suffering from respiratory impairment due to acute pulmonary infections, or in chronic respiratory disorders such as severe asthma or emphysema.
- In general, phenothiazines, including perphenazine, do not produce psychic dependence. Gastritis, nausea and vomiting, dizziness, and tremulousness have been reported following abrupt cessation of high-dose therapy. Reports suggest that these symptoms can be reduced by continuing concomitant antiparkinson agents for several weeks after the phenothiazine is withdrawn.
- The possibility of liver damage, corneal and lenticular deposits, and irreversible dyskinesias should be kept in mind when patients are on long-term therapy.
- Because photosensitivity has been reported, undue exposure to the sun should be avoided during phenothiazine treatment.
# Adverse Reactions
## Clinical Trials Experience
- Not all of the following adverse reactions have been reported with this specific drug; however, pharmacological similarities among various phenothiazine derivatives require that each be considered. With the piperazine group (of which perphenazine is an example), the extrapyramidal symptoms are more common, and others (e.g., sedative effects, jaundice, and blood dyscrasias) are less frequently seen.
- Extrapyramidal Reactions
- opisthotonus, trismus, torticollis, retrocollis, aching and numbness of the limbs, motor restlessness, oculogyric crisis, hyperreflexia, dystonia, including protrusion, discoloration, aching and rounding of the tongue, tonic spasm of the masticatory muscles, tight feeling in the throat, slurred speech, dysphagia, akathisia, dyskinesia, parkinsonism, and ataxia. Their incidence and severity usually increase with an increase in dosage, but there is considerable individual variation in the tendency to develop such symptoms. Extrapyramidal symptoms can usually be controlled by the concomitant use of effective antiparkinsonian drugs, such as benztropine mesylate, and/or by reduction in dosage. In some instances, however, these extrapyramidal reactions may persist after discontinuation of treatment with perphenazine.
- Dystonia
- Class effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment.Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. :*While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.
- Persistent Tardive Dyskinesia
- As with all antipsychotic agents, tardive dyskinesia may appear in some patients on long-term therapy or may appear after drug therapy has been discontinued. Although the risk appears to be greater in elderly patients on high-dose therapy, especially females, it may occur in either sex and in children. The symptoms are persistent and in some patients appear to be irreversible. The syndrome is characterized by rhythmical, involuntary movements of the tongue, face, mouth or jaw (e.g., protrusion of tongue, puffing of cheeks, puckering of mouth, chewing movements). :*Sometimes these may be accompanied by involuntary movements of the extremities. There is no known effective treatment for tardive dyskinesia; antiparkinsonism agents usually do not alleviate the symptoms of this syndrome. It is suggested that all antipsychotic agents be discontinued if these symptoms appear. :*Should it be necessary to reinstitute treatment, or increase the dosage of the agent, or switch to a different antipsychotic agent, the syndrome may be masked. It has been reported that fine, vermicular movements of the tongue may be an early sign of the syndrome, and if the medication is stopped at that time the syndrome may not develop.
- Other CNS Effects include cerebral edema; abnormality of cerebrospinal fluid proteins; convulsive seizures, particularly in patients with EEG abnormalities or a history of such disorders; and headaches.
- Neuroleptic malignant syndrome has been reported in patients treated with antipsychotic drugs.
- Drowsiness may occur, particularly during the first or second week, after which it generally disappears. If troublesome, lower the dosage. Hypnotic effects appear to be minimal, especially in patients who are permitted to remain active.
- Adverse behavioral effects include paradoxical exacerbation of psychotic symptoms, catatonic-like states, paranoid reactions, lethargy, paradoxical excitement, restlessness, hyperactivity, nocturnal confusion, bizarre dreams, and insomnia.
- Hyperreflexia has been reported in the newborn when a phenothiazine was used during pregnancy.
- Dry mouth or salivation, nausea, vomiting, diarrhea, anorexia, constipation, obstipation, fecal impaction, urinary retention, frequency or incontinence, bladder paralysis, polyuria, nasal congestion, pallor, myosis, mydriasis, blurred vision, glaucoma, perspiration, hypertension, hypotension, and change in pulse rate occasionally may occur. Significant autonomic effects have been infrequent in patients receiving less than 24 mg perphenazine daily.
- Occasionally occurs with phenothiazine therapy, and if severe, can result in complications and death. It is of particular concern in psychiatric patients, who may fail to seek treatment of the condition.
- Urticaria, erythema, eczema, exfoliative dermatitis, pruritus, photosensitivity, asthma, fever, anaphylactoid reactions, laryngeal edema, and angioneurotic edema; contact dermatitis in nursing personnel administering the drug; and in extremely rare instances, individual idiosyncrasy or hypersensitivity to phenothiazines has resulted in cerebral edema, circulatory collapse, and death.
- Lactation, galactorrhea, moderate breast enlargement in females and gynecomastia in males on large doses, disturbances in the menstrual cycle, amenorrhea, changes in libido, inhibition of ejaculation, syndrome of inappropriate ADH (antidiuretic hormone) secretion, false positive pregnancy tests, hyperglycemia, hypoglycemia, glycosuria.
- Postural hypotension, tachycardia (especially with sudden marked increase in dosage), bradycardia, cardiac arrest, faintness, and dizziness. Occasionally the hypotensive effect may produce a shock-like condition. ECG changes, nonspecific (quinidine-like effect) usually reversible, have been observed in some patients receiving phenothiazine antipsychotics.
- Sudden death has occasionally been reported in patients who have received phenothiazines. In some cases, the death was apparently due to cardiac arrest; in others, the cause appeared to be asphyxia due to failure of the cough reflex. In some patients, the cause could not be determined nor could it be established that the death was due to the phenothiazine.
- Agranulocytosis, eosinophilia, leukopenia, hemolytic anemia, thrombocytopenic purpura, and pancytopenia. Most cases of agranulocytosis have occurred between the fourth and tenth weeks of therapy. Patients should be watched closely, especially during that period, for the sudden appearance of sore throat or signs of infection. If white blood cell and differential cell counts show significant cellular depression, discontinue the drug and start appropriate therapy. However, a slightly lowered white count is not in itself an indication to discontinue the drug.
- Special considerations in long-term therapy include pigmentation of the skin, occurring chiefly in the exposed areas; ocular changes consisting of deposition of fine particulate matter in the cornea and lens, progressing in more severe cases to star-shaped lenticular opacities; epithelial keratopathies; and pigmentary retinopathy. Also noted: peripheral edema, reversed epinephrine effect, increase in PBI not attributable to an increase in thyroxine, parotid swelling (rare), hyperpyrexia, systemic lupus erythematosus-like syndrome, increases in appetite and weight, polyphagia, photophobia, and muscle weakness.
- Liver damage (biliary stasis) may occur. Jaundice may occur, usually between the second and fourth weeks of treatment, and is regarded as a hypersensitivity reaction. Incidence is low. The clinical picture resembles infectious hepatitis but with laboratory features of obstructive jaundice. It is usually reversible; however, chronic jaundice has been reported.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Perphenazine in the drug label.
# Drug Interactions
- Metabolism of a number of medications, including antipsychotics, antidepressants, ß-blockers, and antiarrhythmics, occurs through the cytochrome P450 2D6 isoenzyme (debrisoquine hydroxylase). Approximately 10% of the Caucasian population has reduced activity of this enzyme, so-called “poor” metabolizers. Among other populations the prevalence is not known. Poor metabolizers demonstrate higher plasma concentrations of antipsychotic drugs at usual doses, which may correlate with emergence of side effects.
- In one study of 45 elderly patients suffering from dementia treated with perphenazine, the 5 patients who were prospectively identified as poor P450 2D6 metabolizers had reported significantly greater side effects during the first 10 days of treatment than the 40 extensive metabolizers, following which the groups tended to converge. Prospective phenotyping of elderly patients prior to antipsychotic treatment may identify those at risk for adverse events.
- The concomitant administration of other drugs that inhibit the activity of P450 2D6 may acutely increase plasma concentrations of antipsychotics. Among these are tricyclic antidepressants and selective serotonin reuptake inhibitors, e.g., fluoxetine, sertraline and paroxetine. When prescribing these drugs to patients already receiving antipsychotic therapy, close monitoring is essential and dose reduction may become necessary to avoid toxicity. Lower doses than usually prescribed for either the antipsychotic or the other drug may be required.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Neonates exposed to antipsychotic drugs, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization.
- Perphenazine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Safe use of perphenazine during pregnancy and lactation has not been established; therefore, in administering the drug to pregnant patients or women who may become pregnant, the possible benefits must be weighed against the possible hazards to mother and child.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of perphenazine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of perphenazine during labor and delivery.
### Nursing Mothers
- Safe use of perphenazine during lactation has not been established; therefore, in administering the drug to nursing mothers the possible benefits must be weighed against the possible hazards to mother and child.
### Pediatric Use
- Perphenazine products are not recommended for pediatric patients under 12 years of age
### Geriatic Use
- Clinical studies of perphenazine products did not include sufficient numbers of subjects aged 65 and over to determine whether elderly subjects 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 function, concomitant disease or other drug therapy.
- Geriatric patients are particularly sensitive to the side effects of antipsychotics, including perphenazine. These side effects include extrapyramidal symptoms (tardive dyskinesia, antipsychotic-induced parkinsonism, akathisia), anticholinergic effects, sedation and orthostatic hypotension .
- Elderly patients taking psychotropic drugs may be at increased risk for falling and consequent hip fractures. Elderly patients should be started on lower doses and observed closely.
### Gender
There is no FDA guidance on the use of perphenazine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of perphenazine with respect to specific racial populations.
### Renal Impairment
- The use of phenothiazine derivatives in patients with diminished renal function should be undertaken with caution.
### Hepatic Impairment
There is no FDA guidance on the use of perphenazine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of perphenazine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of perphenazine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Blood counts and hepatic and renal functions should be checked periodically. The appearance of signs of blood dyscrasias requires the discontinuance of the drug and institution of appropriate therapy. If abnormalities in hepatic tests occur, phenothiazine treatment should be discontinued. *Renal function in patients on long-term therapy should be monitored; if blood urea nitrogen (BUN) becomes abnormal, treatment with the drug should be discontinued.
- Patients with a preexisting low WBC or a history of drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and should discontinue perphenazine tablets USP at the first sign of a decline in WBC in the absence of other causative factors.
- When prescribing these drugs to patients already receiving antipsychotic therapy, close monitoring is essential and dose reduction may become necessary to avoid toxicity. Lower doses than usually prescribed for either the antipsychotic or the other drug may be required.
- An electrocardiogram should be taken and close monitoring of cardiac function instituted if there is any sign of abnormality.Close monitoring of cardiac function is advisable for not less than five days.
# IV Compatibility
There is limited information regarding IV Compatibility of perphenazine in the drug label.
# Overdosage
- In the event of overdosage, emergency treatment should be started immediately. Consultation with a poison center should be considered. All patients suspected of having taken an overdose should be hospitalized as soon as possible.
- The toxic effects of perphenazine are typically mild to moderate with death occurring in cases involving a large overdose. *Overdosage of perphenazine primarily involves the extrapyramidal mechanism and produces the side effects. It is usually evidenced by stupor or coma; children may have convulsive seizures. Signs of arousal may not occur for 48 hours. The primary effects of medical concern are cardiac in origin including tachycardia, prolongation of the QRS or QTc intervals, atrioventricular block, torsade de pointes, ventricular dysrhythmia, hypotension or cardiac arrest, which indicate serious poisoning. Deaths by deliberate or accidental overdosage have occurred with this class of drugs.
- Treatment is symptomatic and supportive. Induction of emesis is not recommended because of the possibility of a seizure, CNS depression, or dystonic reaction of the head or neck and subsequent aspiration. Gastric lavage (after intubation, if the patient is unconscious) and administration of activated charcoal together with a laxative should be considered. There is no specific antidote.
- Standard measures (oxygen, intravenous fluids, corticosteroids) should be used to manage circulatory shock or metabolic acidosis. An open airway and adequate fluid intake should be maintained. Body temperature should be regulated. Hypothermia is expected, but severe hyperthermia may occur and must be treated vigorously.
- An electrocardiogram should be taken and close monitoring of cardiac function instituted if there is any sign of abnormality.Close monitoring of cardiac function is advisable for not less than five days. Vasopressors such as norepinephrine may be used to treat hypotension, but epinephrine should NOT be used.
- Hemodialysis and peritoneal dialysis is of no value because of low plasma concentrations of the drug.
- Since overdosage is often deliberate, patients may attempt suicide by other means during the recovery phase.
# Pharmacology
## Mechanism of Action
- Perphenazine has actions at all levels of the central nervous system, particularly the hypothalamus. However, the site and mechanism of action of therapeutic effect are not known.
## Structure
- Perphenazine (4--1-piperazineethanol), a piperazinyl phenothiazine, having the chemical formula, C21H26CIN3OS. It is available as oral tablets containing 2 mg, 4 mg, 8 mg, and 16 mg of perphenazine.
- Inactive ingredients: lactose (monohydrate), hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, starch (corn), titanium dioxide, and polysorbate 80. Its structural formula is:
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Perphenazine in the drug label.
## Pharmacokinetics
- Following oral administration of perphenazine tablets, mean peak plasma perphenazine concentrations were observed between 1 to 3 hours. The plasma elimination half-life of perphenazine was independent of dose and ranged between 9 and 12 hours. In a study in which normal volunteers (n=12) received perphenazine 4 mg q8h for 5 days, steady-state concentrations of perphenazine were reached within 72 hours. Mean (%CV) Cmax and Cmin values for perphenazine and 7-hydroxyperphenazine at steady-state are listed below:
- Peak 7-hydroxyperphenazine concentrations were observed between 2 to 4 hours with a terminal phase half-life ranging between 9.9 to 18.8 hours. Perphenazine is extensively metabolized in the liver to a number of metabolites by sulfoxidation, hydroxylation, dealkylation, and glucuronidation. The pharmacokinetics of perphenazine covary with the hydroxylation of debrisoquine which is mediated by cytochrome P450 2D6 (CYP 2D6) and thus is subject to genetic polymorphism – i.e., 7% to 10% of Caucasians and a low percentage of Asians have little or no activity and are called “poor metabolizers.” Poor metabolizers of CYP 2D6 will metabolize perphenazine more slowly and will experience higher concentrations compared with normal or “extensive” metabolizers.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Perphenazine in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Perphenazine in the drug label.
# How Supplied
- Perphenazine tablets, USP are round, unscored, film-coated white tablets available as:
- 2 mg: debossed GG 18 on one side and plain on the reverse side, supplied as:
- NDC 0781-1046-01 bottles of 100 tablets
- NDC 0781-1046-10 bottles of 1000 tablets
- NDC 0781-1046-13 unit dose packages of 100 tablets
- 4 mg: debossed GG 107 on one side and plain on the reverse side, supplied as:
- NDC 0781-1047-01 bottles of 100 tablets
- NDC 0781-1047-05 bottles of 500 tablets
- NDC 0781-1047-10 bottles of 1000 tablets
- NDC 0781-1047-13 unit dose packages of 100 tablets
- 8 mg: debossed GG 108 on one side and plain on the reverse side, supplied as:
- NDC 0781-1048-01 bottles of 100 tablets
- NDC 0781-1048-05 bottles of 500 tablets
- NDC 0781-1048-10 bottles of 1000 tablets
- NDC 0781-1048-13 unit dose packages of 100 tablets
- 16 mg: debossed GG 109 on one side and plain on the reverse side, supplied as:
- NDC 0781-1049-01 bottles of 100 tablets
- NDC 0781-1049-10 bottles of 1000 tablets
- NDC 0781-1049-13 unit dose packages of 100 tablets
## Storage
- Store at 20°-25°C (68°-77°F) (see USP Controlled Room Temperature). Dispense in a tight, light-resistant container.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- This information is intended to aid in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects.
- Given the likelihood that a substantial proportion of patients exposed chronically to antipsychotics will develop tardive dyskinesia, it is advised that all patients in whom chronic use is contemplated be given, if possible, full information about this risk. The decision to inform patients and/or their guardians must obviously take into account the clinical circumstances and the competency of the patient to understand the information provided.
# Precautions with Alcohol
- The use of alcohol should be avoided, since additive effects and hypotension may occur. Patients should be cautioned that their response to alcohol may be increased while they are being treated with perphenazine products. The risk of suicide and the danger of overdose may be increased in patients who use alcohol excessively due to its potentiation of the drug’s effect..
# Brand Names
# Look-Alike Drug Names
- A® — B®
# Drug Shortage Status
# Price | Perphenazine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aparna Vuppala, M.B.B.S. [2]
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# Black Box Warning
# Overview
Perphenazine is an antipsychotic agent that is FDA approved for the treatment of schizophrenia and for the control of severe nausea and vomiting in adults.. There is a Black Box Warning for this drug as shown here. Common adverse reactions include the extrapyramidal symptoms are more common, and others (e.g., sedative effects, jaundice, and blood dyscrasias) are less frequently seen..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Perphenazine is indicated for use in the treatment of schizophrenia
- Dosage must be individualized and adjusted according to the severity of the condition and the response obtained. As with all potent drugs, the best dose is the lowest dose that will produce the desired clinical effect. Since extrapyramidal symptoms increase in frequency and severity with increased dosage, it is important to employ the lowest effective dose. These symptoms have disappeared upon reduction of dosage, withdrawal of the drug, or administration of an antiparkinsonian agent.
- Prolonged administration of doses exceeding 24 mg daily should be reserved for hospitalized patients or patients under continued observation for early detection and management of adverse reactions. An antiparkinsonian agent, such as trihexyphenidyl hydrochloride or benztropine mesylate, is valuable in controlling drug-induced extrapyramidal symptoms.
- Perphenazine has not been shown effective for the management of behavioral complications in patients with mental retardation.
- 4 to 8 mg t.i.d. initially; reduce as soon as possible to minimum effective dosage.
- 8 to 16 mg b.i.d. to q.i.d.; avoid dosages in excess of 64 mg daily.
- 8 to 16 mg daily in divided doses; 24 mg occasionally may be necessary; early dosage reduction is desirable.
- With increasing age, plasma concentrations of perphenazine per daily ingested dose increase. Geriatric dosages of perphenazine preparations have not been established, but initiation of lower dosages is recommended. Optimal clinical effect or benefit may require lower doses for a longer duration. Dosing of perphenazine may occur before bedtime, if required.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Perphenazine in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Perphenazine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Perphenazine products are not recommended for pediatric patients under 12 years of age.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Perphenazine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Perphenazine in pediatric patients.
# Contraindications
- Perphenazine products are contraindicated in comatose or greatly obtunded patients and in patients receiving large doses of central nervous system depressants (barbiturates, alcohol, narcotics, analgesics, or antihistamines); in the presence of existing blood dyscrasias, bone marrow depression, or liver damage; and in patients who have shown hypersensitivity to perphenazine products, their components, or related compounds.
- Perphenazine products are also contraindicated in patients with suspected or established subcortical brain damage, with or without hypothalamic damage, since a hyperthermic reaction with temperatures in excess of 104°F may occur in such patients, sometimes not until 14 to 16 hours after drug administration. *Total body ice-packing is recommended for such a reaction; antipyretics may also be useful.
# Warnings
- Increased Mortality in Elderly Patients with Dementia-Related Psychosis
- Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Perphenazine is not approved for the treatment of patients with dementia-related psychosis.
- Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with antipsychotic drugs. Older patients are at increased risk for development of tardive dyskinesia. *Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.
- Both the risk of developing the syndrome and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. *However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses.
- There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome, and thereby may possibly mask the underlying disease process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.
- Given these considerations, especially in the elderly, antipsychotics should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that 1) is known to respond to antipsychotic drugs, and 2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.
- If signs and symptoms of tardive dyskinesia appear in a patient on antipsychotics, drug discontinuation should be considered. However, some patients may require treatment despite the presence of the syndrome.
- A potentially fatal symptom complex, sometimes referred to as Neuroleptic Malignant Syndrome (NMS), has been reported in association with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias).
- The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology.
- The management of NMS should include 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and medical monitoring, and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS.
- If a patient requires antipsychotic drug treatment after recovery from NMS, the reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported.
- In clinical trial and postmarketing experience, events of leukopenia/neutropenia and agranulocytosis have been reported temporally related to antipsychotic agents.
- Possible risk factors for leukopenia/neutropenia include preexisting low white blood cell count (WBC) and history of drug induced leukopenia/neutropenia. Patients with a preexisting low WBC or a history of drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and should discontinue perphenazine tablets USP at the first sign of a decline in WBC in the absence of other causative factors.
- Patients with neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue perphenazine tablets USP and have their WBC followed until recovery.
- If hypotension develops, epinephrine should not be administered since its action is blocked and partially reversed by perphenazine. If a vasopressor is needed, norepinephrine may be used. Severe, acute hypotension has occurred with the use of phenothiazines and is particularly likely to occur in patients with mitral insufficiency or pheochromocytoma. Rebound hypertension may occur in pheochromocytoma patients.
- Perphenazine products can lower the convulsive threshold in susceptible individuals; they should be used with caution in alcohol withdrawal and in patients with convulsive disorders. If the patient is being treated with an anticonvulsant agent, increased dosage of that agent may be required when perphenazine products are used concomitantly.
- Perphenazine products should be used with caution in patients with psychic depression.
- Perphenazine may impair the mental and/or physical abilities required for the performance of hazardous tasks such as driving a car or operating machinery; therefore, the patient should be warned accordingly.
- The possibility of suicide in depressed patients remains during treatment and until significant remission occurs. This type of patient should not have access to large quantities of this drug.
- As with all phenothiazine compounds, perphenazine should not be used indiscriminately. Caution should be observed in giving it to patients who have previously exhibited severe adverse reactions to other phenothiazines. Some of the untoward actions of perphenazine tend to appear more frequently when high doses are used. However, as with other phenothiazine compounds, patients receiving perphenazine products in any dosage should be kept under close supervision.
- Antipsychotic drugs elevate prolactin levels; the elevation persists during chronic administration. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with a previously detected breast cancer. Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported, the clinical significance of elevated serum prolactin levels is unknown for most patients. An increase in mammary neoplasms has been found in rodents after chronic administration of antipsychotic drugs. Neither clinical studies nor epidemiologic studies conducted to date, however, have shown an association between chronic administration of these drugs and mammary tumorigenesis; the available evidence is considered too limited to be conclusive at this time.
- The antiemetic effect of perphenazine may obscure signs of toxicity due to overdosage of other drugs, or render more difficult the diagnosis of disorders such as brain tumors or intestinal obstruction.
- A significant, not otherwise explained, rise in body temperature may suggest individual intolerance to perphenazine, in which case it should be discontinued.
- Patients on large doses of a phenothiazine drug who are undergoing surgery should be watched carefully for possible hypotensive phenomena. Moreover, reduced amounts of anesthetics or central nervous system depressants may be necessary.
- Since phenothiazines and central nervous system depressants (opiates, analgesics, antihistamines, barbiturates) can potentiate each other, less than the usual dosage of the added drug is recommended and caution is advised when they are administered concomitantly.
- Use with caution in patients who are receiving atropine or related drugs because of additive anticholinergic effects and also in patients who will be exposed to extreme heat or phosphorus insecticides.
- Use with caution in patients suffering from respiratory impairment due to acute pulmonary infections, or in chronic respiratory disorders such as severe asthma or emphysema.
- In general, phenothiazines, including perphenazine, do not produce psychic dependence. Gastritis, nausea and vomiting, dizziness, and tremulousness have been reported following abrupt cessation of high-dose therapy. Reports suggest that these symptoms can be reduced by continuing concomitant antiparkinson agents for several weeks after the phenothiazine is withdrawn.
- The possibility of liver damage, corneal and lenticular deposits, and irreversible dyskinesias should be kept in mind when patients are on long-term therapy.
- Because photosensitivity has been reported, undue exposure to the sun should be avoided during phenothiazine treatment.
# Adverse Reactions
## Clinical Trials Experience
- Not all of the following adverse reactions have been reported with this specific drug; however, pharmacological similarities among various phenothiazine derivatives require that each be considered. With the piperazine group (of which perphenazine is an example), the extrapyramidal symptoms are more common, and others (e.g., sedative effects, jaundice, and blood dyscrasias) are less frequently seen.
- Extrapyramidal Reactions
- opisthotonus, trismus, torticollis, retrocollis, aching and numbness of the limbs, motor restlessness, oculogyric crisis, hyperreflexia, dystonia, including protrusion, discoloration, aching and rounding of the tongue, tonic spasm of the masticatory muscles, tight feeling in the throat, slurred speech, dysphagia, akathisia, dyskinesia, parkinsonism, and ataxia. Their incidence and severity usually increase with an increase in dosage, but there is considerable individual variation in the tendency to develop such symptoms. Extrapyramidal symptoms can usually be controlled by the concomitant use of effective antiparkinsonian drugs, such as benztropine mesylate, and/or by reduction in dosage. In some instances, however, these extrapyramidal reactions may persist after discontinuation of treatment with perphenazine.
- Dystonia
- Class effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment.Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. :*While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.
- Persistent Tardive Dyskinesia
- As with all antipsychotic agents, tardive dyskinesia may appear in some patients on long-term therapy or may appear after drug therapy has been discontinued. Although the risk appears to be greater in elderly patients on high-dose therapy, especially females, it may occur in either sex and in children. The symptoms are persistent and in some patients appear to be irreversible. The syndrome is characterized by rhythmical, involuntary movements of the tongue, face, mouth or jaw (e.g., protrusion of tongue, puffing of cheeks, puckering of mouth, chewing movements). :*Sometimes these may be accompanied by involuntary movements of the extremities. There is no known effective treatment for tardive dyskinesia; antiparkinsonism agents usually do not alleviate the symptoms of this syndrome. It is suggested that all antipsychotic agents be discontinued if these symptoms appear. :*Should it be necessary to reinstitute treatment, or increase the dosage of the agent, or switch to a different antipsychotic agent, the syndrome may be masked. It has been reported that fine, vermicular movements of the tongue may be an early sign of the syndrome, and if the medication is stopped at that time the syndrome may not develop.
- Other CNS Effects include cerebral edema; abnormality of cerebrospinal fluid proteins; convulsive seizures, particularly in patients with EEG abnormalities or a history of such disorders; and headaches.
- Neuroleptic malignant syndrome has been reported in patients treated with antipsychotic drugs.
- Drowsiness may occur, particularly during the first or second week, after which it generally disappears. If troublesome, lower the dosage. Hypnotic effects appear to be minimal, especially in patients who are permitted to remain active.
- Adverse behavioral effects include paradoxical exacerbation of psychotic symptoms, catatonic-like states, paranoid reactions, lethargy, paradoxical excitement, restlessness, hyperactivity, nocturnal confusion, bizarre dreams, and insomnia.
- Hyperreflexia has been reported in the newborn when a phenothiazine was used during pregnancy.
- Dry mouth or salivation, nausea, vomiting, diarrhea, anorexia, constipation, obstipation, fecal impaction, urinary retention, frequency or incontinence, bladder paralysis, polyuria, nasal congestion, pallor, myosis, mydriasis, blurred vision, glaucoma, perspiration, hypertension, hypotension, and change in pulse rate occasionally may occur. Significant autonomic effects have been infrequent in patients receiving less than 24 mg perphenazine daily.
- Occasionally occurs with phenothiazine therapy, and if severe, can result in complications and death. It is of particular concern in psychiatric patients, who may fail to seek treatment of the condition.
- Urticaria, erythema, eczema, exfoliative dermatitis, pruritus, photosensitivity, asthma, fever, anaphylactoid reactions, laryngeal edema, and angioneurotic edema; contact dermatitis in nursing personnel administering the drug; and in extremely rare instances, individual idiosyncrasy or hypersensitivity to phenothiazines has resulted in cerebral edema, circulatory collapse, and death.
- Lactation, galactorrhea, moderate breast enlargement in females and gynecomastia in males on large doses, disturbances in the menstrual cycle, amenorrhea, changes in libido, inhibition of ejaculation, syndrome of inappropriate ADH (antidiuretic hormone) secretion, false positive pregnancy tests, hyperglycemia, hypoglycemia, glycosuria.
- Postural hypotension, tachycardia (especially with sudden marked increase in dosage), bradycardia, cardiac arrest, faintness, and dizziness. Occasionally the hypotensive effect may produce a shock-like condition. ECG changes, nonspecific (quinidine-like effect) usually reversible, have been observed in some patients receiving phenothiazine antipsychotics.
- Sudden death has occasionally been reported in patients who have received phenothiazines. In some cases, the death was apparently due to cardiac arrest; in others, the cause appeared to be asphyxia due to failure of the cough reflex. In some patients, the cause could not be determined nor could it be established that the death was due to the phenothiazine.
- Agranulocytosis, eosinophilia, leukopenia, hemolytic anemia, thrombocytopenic purpura, and pancytopenia. Most cases of agranulocytosis have occurred between the fourth and tenth weeks of therapy. Patients should be watched closely, especially during that period, for the sudden appearance of sore throat or signs of infection. If white blood cell and differential cell counts show significant cellular depression, discontinue the drug and start appropriate therapy. However, a slightly lowered white count is not in itself an indication to discontinue the drug.
- Special considerations in long-term therapy include pigmentation of the skin, occurring chiefly in the exposed areas; ocular changes consisting of deposition of fine particulate matter in the cornea and lens, progressing in more severe cases to star-shaped lenticular opacities; epithelial keratopathies; and pigmentary retinopathy. Also noted: peripheral edema, reversed epinephrine effect, increase in PBI not attributable to an increase in thyroxine, parotid swelling (rare), hyperpyrexia, systemic lupus erythematosus-like syndrome, increases in appetite and weight, polyphagia, photophobia, and muscle weakness.
- Liver damage (biliary stasis) may occur. Jaundice may occur, usually between the second and fourth weeks of treatment, and is regarded as a hypersensitivity reaction. Incidence is low. The clinical picture resembles infectious hepatitis but with laboratory features of obstructive jaundice. It is usually reversible; however, chronic jaundice has been reported.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Perphenazine in the drug label.
# Drug Interactions
- Metabolism of a number of medications, including antipsychotics, antidepressants, ß-blockers, and antiarrhythmics, occurs through the cytochrome P450 2D6 isoenzyme (debrisoquine hydroxylase). Approximately 10% of the Caucasian population has reduced activity of this enzyme, so-called “poor” metabolizers. Among other populations the prevalence is not known. Poor metabolizers demonstrate higher plasma concentrations of antipsychotic drugs at usual doses, which may correlate with emergence of side effects.
- In one study of 45 elderly patients suffering from dementia treated with perphenazine, the 5 patients who were prospectively identified as poor P450 2D6 metabolizers had reported significantly greater side effects during the first 10 days of treatment than the 40 extensive metabolizers, following which the groups tended to converge. Prospective phenotyping of elderly patients prior to antipsychotic treatment may identify those at risk for adverse events.
- The concomitant administration of other drugs that inhibit the activity of P450 2D6 may acutely increase plasma concentrations of antipsychotics. Among these are tricyclic antidepressants and selective serotonin reuptake inhibitors, e.g., fluoxetine, sertraline and paroxetine. When prescribing these drugs to patients already receiving antipsychotic therapy, close monitoring is essential and dose reduction may become necessary to avoid toxicity. Lower doses than usually prescribed for either the antipsychotic or the other drug may be required.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Neonates exposed to antipsychotic drugs, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization.
- Perphenazine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Safe use of perphenazine during pregnancy and lactation has not been established; therefore, in administering the drug to pregnant patients or women who may become pregnant, the possible benefits must be weighed against the possible hazards to mother and child.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of perphenazine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of perphenazine during labor and delivery.
### Nursing Mothers
- Safe use of perphenazine during lactation has not been established; therefore, in administering the drug to nursing mothers the possible benefits must be weighed against the possible hazards to mother and child.
### Pediatric Use
- Perphenazine products are not recommended for pediatric patients under 12 years of age
### Geriatic Use
- Clinical studies of perphenazine products did not include sufficient numbers of subjects aged 65 and over to determine whether elderly subjects 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 function, concomitant disease or other drug therapy.
- Geriatric patients are particularly sensitive to the side effects of antipsychotics, including perphenazine. These side effects include extrapyramidal symptoms (tardive dyskinesia, antipsychotic-induced parkinsonism, akathisia), anticholinergic effects, sedation and orthostatic hypotension .
- Elderly patients taking psychotropic drugs may be at increased risk for falling and consequent hip fractures. Elderly patients should be started on lower doses and observed closely.
### Gender
There is no FDA guidance on the use of perphenazine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of perphenazine with respect to specific racial populations.
### Renal Impairment
- The use of phenothiazine derivatives in patients with diminished renal function should be undertaken with caution.
### Hepatic Impairment
There is no FDA guidance on the use of perphenazine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of perphenazine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of perphenazine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Blood counts and hepatic and renal functions should be checked periodically. The appearance of signs of blood dyscrasias requires the discontinuance of the drug and institution of appropriate therapy. If abnormalities in hepatic tests occur, phenothiazine treatment should be discontinued. *Renal function in patients on long-term therapy should be monitored; if blood urea nitrogen (BUN) becomes abnormal, treatment with the drug should be discontinued.
- Patients with a preexisting low WBC or a history of drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and should discontinue perphenazine tablets USP at the first sign of a decline in WBC in the absence of other causative factors.
- When prescribing these drugs to patients already receiving antipsychotic therapy, close monitoring is essential and dose reduction may become necessary to avoid toxicity. Lower doses than usually prescribed for either the antipsychotic or the other drug may be required.
- An electrocardiogram should be taken and close monitoring of cardiac function instituted if there is any sign of abnormality.Close monitoring of cardiac function is advisable for not less than five days.
# IV Compatibility
There is limited information regarding IV Compatibility of perphenazine in the drug label.
# Overdosage
- In the event of overdosage, emergency treatment should be started immediately. Consultation with a poison center should be considered. All patients suspected of having taken an overdose should be hospitalized as soon as possible.
- The toxic effects of perphenazine are typically mild to moderate with death occurring in cases involving a large overdose. *Overdosage of perphenazine primarily involves the extrapyramidal mechanism and produces the side effects. It is usually evidenced by stupor or coma; children may have convulsive seizures. Signs of arousal may not occur for 48 hours. The primary effects of medical concern are cardiac in origin including tachycardia, prolongation of the QRS or QTc intervals, atrioventricular block, torsade de pointes, ventricular dysrhythmia, hypotension or cardiac arrest, which indicate serious poisoning. Deaths by deliberate or accidental overdosage have occurred with this class of drugs.
- Treatment is symptomatic and supportive. Induction of emesis is not recommended because of the possibility of a seizure, CNS depression, or dystonic reaction of the head or neck and subsequent aspiration. Gastric lavage (after intubation, if the patient is unconscious) and administration of activated charcoal together with a laxative should be considered. There is no specific antidote.
- Standard measures (oxygen, intravenous fluids, corticosteroids) should be used to manage circulatory shock or metabolic acidosis. An open airway and adequate fluid intake should be maintained. Body temperature should be regulated. Hypothermia is expected, but severe hyperthermia may occur and must be treated vigorously.
- An electrocardiogram should be taken and close monitoring of cardiac function instituted if there is any sign of abnormality.Close monitoring of cardiac function is advisable for not less than five days. Vasopressors such as norepinephrine may be used to treat hypotension, but epinephrine should NOT be used.
- Hemodialysis and peritoneal dialysis is of no value because of low plasma concentrations of the drug.
- Since overdosage is often deliberate, patients may attempt suicide by other means during the recovery phase.
# Pharmacology
## Mechanism of Action
- Perphenazine has actions at all levels of the central nervous system, particularly the hypothalamus. However, the site and mechanism of action of therapeutic effect are not known.
## Structure
- Perphenazine (4-[3-(2-chlorophenothiazin-10-yl)propyl]-1-piperazineethanol), a piperazinyl phenothiazine, having the chemical formula, C21H26CIN3OS. It is available as oral tablets containing 2 mg, 4 mg, 8 mg, and 16 mg of perphenazine.
- Inactive ingredients: lactose (monohydrate), hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, starch (corn), titanium dioxide, and polysorbate 80. Its structural formula is:
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Perphenazine in the drug label.
## Pharmacokinetics
- Following oral administration of perphenazine tablets, mean peak plasma perphenazine concentrations were observed between 1 to 3 hours. The plasma elimination half-life of perphenazine was independent of dose and ranged between 9 and 12 hours. In a study in which normal volunteers (n=12) received perphenazine 4 mg q8h for 5 days, steady-state concentrations of perphenazine were reached within 72 hours. Mean (%CV) Cmax and Cmin values for perphenazine and 7-hydroxyperphenazine at steady-state are listed below:
- Peak 7-hydroxyperphenazine concentrations were observed between 2 to 4 hours with a terminal phase half-life ranging between 9.9 to 18.8 hours. Perphenazine is extensively metabolized in the liver to a number of metabolites by sulfoxidation, hydroxylation, dealkylation, and glucuronidation. The pharmacokinetics of perphenazine covary with the hydroxylation of debrisoquine which is mediated by cytochrome P450 2D6 (CYP 2D6) and thus is subject to genetic polymorphism – i.e., 7% to 10% of Caucasians and a low percentage of Asians have little or no activity and are called “poor metabolizers.” Poor metabolizers of CYP 2D6 will metabolize perphenazine more slowly and will experience higher concentrations compared with normal or “extensive” metabolizers.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Perphenazine in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Perphenazine in the drug label.
# How Supplied
- Perphenazine tablets, USP are round, unscored, film-coated white tablets available as:
- 2 mg: debossed GG 18 on one side and plain on the reverse side, supplied as:
- NDC 0781-1046-01 bottles of 100 tablets
- NDC 0781-1046-10 bottles of 1000 tablets
- NDC 0781-1046-13 unit dose packages of 100 tablets
- 4 mg: debossed GG 107 on one side and plain on the reverse side, supplied as:
- NDC 0781-1047-01 bottles of 100 tablets
- NDC 0781-1047-05 bottles of 500 tablets
- NDC 0781-1047-10 bottles of 1000 tablets
- NDC 0781-1047-13 unit dose packages of 100 tablets
- 8 mg: debossed GG 108 on one side and plain on the reverse side, supplied as:
- NDC 0781-1048-01 bottles of 100 tablets
- NDC 0781-1048-05 bottles of 500 tablets
- NDC 0781-1048-10 bottles of 1000 tablets
- NDC 0781-1048-13 unit dose packages of 100 tablets
- 16 mg: debossed GG 109 on one side and plain on the reverse side, supplied as:
- NDC 0781-1049-01 bottles of 100 tablets
- NDC 0781-1049-10 bottles of 1000 tablets
- NDC 0781-1049-13 unit dose packages of 100 tablets
## Storage
- Store at 20°-25°C (68°-77°F) (see USP Controlled Room Temperature). Dispense in a tight, light-resistant container.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- This information is intended to aid in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects.
- Given the likelihood that a substantial proportion of patients exposed chronically to antipsychotics will develop tardive dyskinesia, it is advised that all patients in whom chronic use is contemplated be given, if possible, full information about this risk. The decision to inform patients and/or their guardians must obviously take into account the clinical circumstances and the competency of the patient to understand the information provided.
# Precautions with Alcohol
- The use of alcohol should be avoided, since additive effects and hypotension may occur. Patients should be cautioned that their response to alcohol may be increased while they are being treated with perphenazine products. The risk of suicide and the danger of overdose may be increased in patients who use alcohol excessively due to its potentiation of the drug’s effect..
# Brand Names
- ®[1]
# Look-Alike Drug Names
- A® — B®
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Perphenazine | |
2a64098b5488d751002a5ed8ac9fea53b07c3867 | wikidoc | Peter Griess | Peter Griess
Johann Peter Griess (1829–1888), industrial chemist and an early pioneer of organic chemistry.
# Life
After a finished an agricultural private school he joined the Hessian cavalry, but left the military shortly after. He started his studies at the University of Jena in 1850, but changed to the University of Marburg in 1851. During his student life he was several times sentenced for Karzer and was also banned from the city for one year, in which he listened to lectures of Justus Liebig at the Ludwig Maximilians University of Munich. After most of the family possession were spent he had to start working at the chemical factory of Oehler in Offenbach am Main in 1856. This was only possible after the recommendation of Hermann Kolbe, who was head of the chemistry department in Marburg. The devastating fire of 1857 ended the production of chemicals at the factory and a changed Peter Griess rejoined Hermann Kolbe at the University of Marburg. His new enthusiasm for chemistry yielded the discovery of diazonium salts in 1858. The discovery of a new class of chemicals convinced August Wilhelm von Hofmann to offer Peter Griess to join him at his new position at Royal College of Chemistry. During his time at the Royal College he studied the reactions of nitrogen rich organic molecules. It took him quite long to accustom to his new home in England but the fact that he married in 1869 and founded a family made clear that he would not return to Germany, even though he was offered a position at the BASF.
He left and started a position at the Samuel Allsopp & Sons brewery in 1862 where he worked until his retirement.
His wife died after a long severe illness in 1886, he survived her for two years and died August 30. 1888. He is buried in Burton upon Trent.
# Work
In 1858 he described the Griess diazotization reaction which would form the basis for the Griess test for detection of Nitrite. Most of his work related to brewing remained confidential, but his additional work on organic chemistry was published by him in several articles. | Peter Griess
Template:Infobox Scientist
Johann Peter Griess (1829–1888), industrial chemist [1] and an early pioneer of organic chemistry.
# Life
After a finished an agricultural private school he joined the Hessian cavalry, but left the military shortly after. He started his studies at the University of Jena in 1850, but changed to the University of Marburg in 1851. During his student life he was several times sentenced for Karzer and was also banned from the city for one year, in which he listened to lectures of Justus Liebig at the Ludwig Maximilians University of Munich. After most of the family possession were spent he had to start working at the chemical factory of Oehler in Offenbach am Main in 1856. This was only possible after the recommendation of Hermann Kolbe, who was head of the chemistry department in Marburg. The devastating fire of 1857 ended the production of chemicals at the factory and a changed Peter Griess rejoined Hermann Kolbe at the University of Marburg. His new enthusiasm for chemistry yielded the discovery of diazonium salts in 1858. The discovery of a new class of chemicals convinced August Wilhelm von Hofmann to offer Peter Griess to join him at his new position at Royal College of Chemistry. During his time at the Royal College he studied the reactions of nitrogen rich organic molecules. It took him quite long to accustom to his new home in England but the fact that he married in 1869 and founded a family made clear that he would not return to Germany, even though he was offered a position at the BASF.
He left and started a position at the Samuel Allsopp & Sons brewery in 1862 where he worked until his retirement.
His wife died after a long severe illness in 1886, he survived her for two years and died August 30. 1888. He is buried in Burton upon Trent.
# Work
In 1858 he described the Griess diazotization reaction which would form the basis for the Griess test for detection of Nitrite. Most of his work related to brewing remained confidential, but his additional work on organic chemistry was published by him in several articles. | https://www.wikidoc.org/index.php/Peter_Griess | |
a8475d07c3647bfe5a038eb0fe8fe3032f068865 | wikidoc | Peter Kerley | Peter Kerley
Sir Peter Kerley , born 1900, died 1978 was a radiologist from Dundalk, Ireland and a graduate of University College Dublin (1923). He spent a year training in radiology in Vienna. He obtained his M.D. from the University of Ireland, in 1939. He was Director of Radiology at the Westminster Hospital and was also affiliated with the Royal Chest Hospital, London. He had a ready wit, enjoyed life outdoors and had a flair for diagnosing the unusual. In 1959 he became a member of honour of the Chicago Radiological Society, and in 1962 he was made a Fellow of Honour of the Faculty of Radiologists, Royal College of Surgeons in Ireland, Dublin. The Sir Peter Kerley Lecture of the Royal College of Radiologists is named for him.
He discovered several of the medical signs used in interpreting radiographs. Kerley B lines are a finding of congestive heart failure. These are short parallel lines perpendicular to the lateral lung surface, indicative of increased opacity in the pulmonary septa. Kerley A lines and Kerley C lines are related findings.
He was knighted by Queen Elizabeth II in the 1970s in recognition of his services to Radiology and as Radiologist to the Royal Family. | Peter Kerley
Sir Peter Kerley , born 1900, died 1978 was a radiologist from Dundalk, Ireland and a graduate of University College Dublin (1923). He spent a year training in radiology in Vienna. He obtained his M.D. from the University of Ireland, in 1939. He was Director of Radiology at the Westminster Hospital and was also affiliated with the Royal Chest Hospital, London. He had a ready wit, enjoyed life outdoors and had a flair for diagnosing the unusual. In 1959 he became a member of honour of the Chicago Radiological Society, and in 1962 he was made a Fellow of Honour of the Faculty of Radiologists, Royal College of Surgeons in Ireland, Dublin. The Sir Peter Kerley Lecture of the Royal College of Radiologists is named for him.
He discovered several of the medical signs used in interpreting radiographs. Kerley B lines are a finding of congestive heart failure. These are short parallel lines perpendicular to the lateral lung surface, indicative of increased opacity in the pulmonary septa. Kerley A lines and Kerley C lines are related findings.
He was knighted by Queen Elizabeth II in the 1970s in recognition of his services to Radiology and as Radiologist to the Royal Family. | https://www.wikidoc.org/index.php/Peter_Kerley | |
97103a990dcf84b172b423199f6f662531d552b9 | wikidoc | Phalloplasty | Phalloplasty
Please Join in Editing This Page and Apply to be an Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
# Overview
Phalloplasty refers to the (re-)construction of a penis or, sometimes, artificial modification of the penis by surgery, often for cosmetic purposes. It is also often used to refer to penis enlargement. The first phalloplasty done for the purposes of sexual reassignment was performed on transman Michael Dillon in 1946 by Dr. Harold Gillies, which is documented in Pagan Kennedy's book The First Man-Made Man.
# Complete construction or reconstruction
A complete construction or reconstruction of a penis is done on both cisgendered men who have lost their penis through either illness or accidents, and on transmen, that is, female-to-male transgendered or transsexual people.
The basic procedures have similarities (except in extreme cases of micro/macropenis), although surgery on cisgendered men can be simpler, since the urethra still ends in the front of the genital area, whereas the urethras of transmen end near the vaginal opening and have to be lengthened considerably. The lengthening of the urethra is a difficult part of total phalloplasty, and also the one where complications often occur.
Most people get their penises enlarged due to self confidence issues.
With all types of phalloplasty in transmen, the labia (see vulva) are united to form a scrotum, where prosthetic testicles can be inserted.
An erectile prosthesis can be inserted into the neophallus to replace the erectile tissue and enable sexual penetration. This is usually done in separate surgery for healing reasons. There are several types of erectile prostheses, ranging from malleable rod-like medical devices so the neo-penis can either stand up or hang down, to elaborate pumping systems. Penile implants require a neophallus of appropriate length and volume in order to be a safe option. The long term success rates of implants in a reconstructed penis have been poor. Good sensation of the reconstruction can help reduce the risk for the implant eventually eroding through the skin. It is for this reason that living bone was first used inside the reconstruction. Long-term follow-up studies from Germany and Turkey of more than 10 years now prove that these reconstructions maintain their stiffness without late complications.
There are three different techniques for phalloplasty:
## Graft from the arm, leg, abdomen or musculocutaneous latissimus dorsi
This technique involves using a free graft of tissue that is removed from its original place, rolled up, with a part of it forming the new urethra, and grafted to its new place between the thighs. In the past, the donor site was usually the inner side of the forearm but sometimes the upper arm, leg or abdomen. The arm flap operation is easier to perform but requires an implant and has a cosmetically undesirable scar on the exposed area of the arm. The lower leg operation takes along with the skin a piece of the small bone of the leg. Like the appendix, humans can live fine without it. The scar in the leg is easily covered with a sock and hidden from view. These are the two operations which are used most commonly today in the world. They have normal skin on them and can have good cosmetic results. Skin grafted muscle flaps have fallen from popularity. The grafts have a less natural appearance and are less likely to maintain an implant long term.
Good references for these issues may be found in the Journal of Plastic and Reconstructive Surgery by the authors, Papadapoulos and Biemer, Sengezer, Sadove and McRoberts, and Hage.
Belgrade University School of Medicine admits in the British Journal of Urology, Volume 100, Issue 4, that the four stages of this total phalloplasty method of penile reconstruction over a period of 9–18 months is one of the most demanding tasks in genital reconstructive surgery but the benefits for patients are great.
It satisfies the 12 major aesthetic and functional goals of modern penile reconstruction — a penis that: 1) is large, with substantial volume; 2) enables safe insertion of a prosthesis; 3) is hairless; 4) has satisfactory aesthetic appearance; 5) has normally colored skin; 6) has both penile tactile and erogenous sensation; 7) has a competent neo-urethra with a meatus at the top of the glans; 8) can have sexual intercourse; 9) leaves no conspicuous, disfiguring scars at the donor site; 10) has very low occurrence of disease or other complication; 11) achieves patient satisfaction; and 12) improves quality of life.
Not a major medical goal, but important to many patients, total phalloplasty using the MLD flap enables the person to urinate standing up. This is true of all modern operations.
Suitable candidates for this surgery which creates a penis up to 7 inches (18 cm) long with a circumference up to 5.9 inches (15 cm) include: 1) patients with congenital anomalies such as micropenis, epispadias, and hypospadias; 2) FtM transsexual patients; and 3) victims of minor to serious iatrogenic, accidental or intentional penile trauma injuries (or total emasculation) caused by motor vehicle accidents (but not plane crashes), child abuse, animal bites, gun shots, burns, electrocution or self-mutilation.
For transmen getting a procedure not using the MLD flap, the urethra up to this point is formed by many doctors from the inner labia. Often, this is done in a separate procedure; sometimes a full-scale metoidioplasty is done a few months before the actual phalloplasty to prevent complications or make intervention easier when they occur.
Sensation is retained through the clitoris which is at the base of the neo-phallus; also, often a large nerve in the graft is connected to nerves either from the clitoris or other nearby nerves. In addition, nerves from the graft and the tissue it has been attached to usually connect after a while, thereby allowing additional sensation.
The forearm and leg flaps are the most common surgical techniques for total phalloplasty today. They remain the state of the day for both function and aesthetics. Muscle Flap procedures need long term publications of their function and aesthetics before making extreme claims of their popularity and superiority.
## Abdominal fatty tissue
Another option for transmen is metoidioplasty, where a small penis is created from the clitoris that has been enlarged by hormone replacement therapy. | Phalloplasty
Editors-In-Chief: Martin I. Newman, M.D., FACS, Cleveland Clinic Florida, [1]; Michel C. Samson, M.D., FRCSC, FACS [2]
Please Join in Editing This Page and Apply to be an Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [3] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
# Overview
Phalloplasty refers to the (re-)construction of a penis or, sometimes, artificial modification of the penis by surgery, often for cosmetic purposes. It is also often used to refer to penis enlargement. The first phalloplasty done for the purposes of sexual reassignment was performed on transman Michael Dillon in 1946 by Dr. Harold Gillies, which is documented in Pagan Kennedy's book The First Man-Made Man.
# Complete construction or reconstruction
A complete construction or reconstruction of a penis is done on both cisgendered men who have lost their penis through either illness or accidents, and on transmen, that is, female-to-male transgendered or transsexual people.
The basic procedures have similarities (except in extreme cases of micro/macropenis), although surgery on cisgendered men can be simpler, since the urethra still ends in the front of the genital area, whereas the urethras of transmen end near the vaginal opening and have to be lengthened considerably. The lengthening of the urethra is a difficult part of total phalloplasty, and also the one where complications often occur.
Most people get their penises enlarged due to self confidence issues.
With all types of phalloplasty in transmen, the labia (see vulva) are united to form a scrotum, where prosthetic testicles can be inserted.
An erectile prosthesis can be inserted into the neophallus to replace the erectile tissue and enable sexual penetration. This is usually done in separate surgery for healing reasons. There are several types of erectile prostheses, ranging from malleable rod-like medical devices so the neo-penis can either stand up or hang down, to elaborate pumping systems. Penile implants require a neophallus of appropriate length and volume in order to be a safe option. The long term success rates of implants in a reconstructed penis have been poor. Good sensation of the reconstruction can help reduce the risk for the implant eventually eroding through the skin. It is for this reason that living bone was first used inside the reconstruction. Long-term follow-up studies from Germany and Turkey of more than 10 years now prove that these reconstructions maintain their stiffness without late complications.
There are three different techniques for phalloplasty:
## Graft from the arm, leg, abdomen or musculocutaneous latissimus dorsi
This technique involves using a free graft of tissue that is removed from its original place, rolled up, with a part of it forming the new urethra, and grafted to its new place between the thighs. In the past, the donor site was usually the inner side of the forearm but sometimes the upper arm, leg or abdomen. The arm flap operation is easier to perform but requires an implant and has a cosmetically undesirable scar on the exposed area of the arm. The lower leg operation takes along with the skin a piece of the small bone of the leg. Like the appendix, humans can live fine without it. The scar in the leg is easily covered with a sock and hidden from view. These are the two operations which are used most commonly today in the world. They have normal skin on them and can have good cosmetic results. Skin grafted muscle flaps have fallen from popularity. The grafts have a less natural appearance and are less likely to maintain an implant long term.
Good references for these issues may be found in the Journal of Plastic and Reconstructive Surgery by the authors, Papadapoulos and Biemer, Sengezer, Sadove and McRoberts, and Hage.
Belgrade University School of Medicine admits in the British Journal of Urology, Volume 100, Issue 4, that the four stages of this total phalloplasty method of penile reconstruction over a period of 9–18 months is one of the most demanding tasks in genital reconstructive surgery but the benefits for patients are great.
It satisfies the 12 major aesthetic and functional goals of modern penile reconstruction — a penis that: 1) is large, with substantial volume; 2) enables safe insertion of a prosthesis; 3) is hairless; 4) has satisfactory aesthetic appearance; 5) has normally colored skin; 6) has both penile tactile and erogenous sensation; 7) has a competent neo-urethra with a meatus at the top of the glans; 8) can have sexual intercourse; 9) leaves no conspicuous, disfiguring scars at the donor site; 10) has very low occurrence of disease or other complication; 11) achieves patient satisfaction; and 12) improves quality of life.
Not a major medical goal, but important to many patients, total phalloplasty using the MLD flap enables the person to urinate standing up. This is true of all modern operations.
Suitable candidates for this surgery which creates a penis up to 7 inches (18 cm) long with a circumference up to 5.9 inches (15 cm) include: 1) patients with congenital anomalies such as micropenis, epispadias, and hypospadias; 2) FtM transsexual patients; and 3) victims of minor to serious iatrogenic, accidental or intentional penile trauma injuries (or total emasculation) caused by motor vehicle accidents (but not plane crashes), child abuse, animal bites, gun shots, burns, electrocution or self-mutilation.
For transmen getting a procedure not using the MLD flap, the urethra up to this point is formed by many doctors from the inner labia. Often, this is done in a separate procedure; sometimes a full-scale metoidioplasty is done a few months before the actual phalloplasty to prevent complications or make intervention easier when they occur.
Sensation is retained through the clitoris which is at the base of the neo-phallus; also, often a large nerve in the graft is connected to nerves either from the clitoris or other nearby nerves. In addition, nerves from the graft and the tissue it has been attached to usually connect after a while, thereby allowing additional sensation.
The forearm and leg flaps are the most common surgical techniques for total phalloplasty today. They remain the state of the day for both function and aesthetics. Muscle Flap procedures need long term publications of their function and aesthetics before making extreme claims of their popularity and superiority.
## Abdominal fatty tissue
Another option for transmen is metoidioplasty, where a small penis is created from the clitoris that has been enlarged by hormone replacement therapy. | https://www.wikidoc.org/index.php/Phalloplasty | |
76ce4ba89cf14677220e7539dfbe233918e2e870 | wikidoc | Phantom pain | Phantom pain
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
# Overview
Phantom pain, also called deafferentation pain, anesthesia dolorosa, or denervation pain, is pain that is felt in a part of the body (usually an extremity) that either no longer exists due to amputation or is insensate as a result of nerve severance. It is often described as a burning sensation, though individual accounts vary. This pain does not originate from the limb itself, as such would be impossible in these cases, but is instead the result of the brain receiving messages from the spinal cord which it interprets as pain coming from the affected limb.
# Physiology
Pain usually begins when nerve endings relay information to nerves, which in turn relay it to ganglia just outside the spinal vertebrae, which send it to nociceptive (pain-sensing) neurons inside the spinal cord, which finally send the information to the brain. If the nociceptive neurons cease to receive information to pass on, they will instead send the neurological equivalent of white noise, which the brain then interprets as pain.
In cases in which a traumatic event causes nerve severance and also detaches the nociceptive neurons from the rest of the spinal cord, phantom pain will not develop. Some patients who do not receive adequate relief from nerve blocks, narcotic painkillers, or other methods of pain management may undergo a procedure called dorsal root entry zone (DREZ) lesioning. DREZ lesioning is a form of neurosurgery in which the wayward nociceptive neurons are destroyed. | Phantom pain
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [2] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
# Overview
Phantom pain, also called deafferentation pain, anesthesia dolorosa, or denervation pain, is pain that is felt in a part of the body (usually an extremity) that either no longer exists due to amputation or is insensate as a result of nerve severance. It is often described as a burning sensation, though individual accounts vary. This pain does not originate from the limb itself, as such would be impossible in these cases, but is instead the result of the brain receiving messages from the spinal cord which it interprets as pain coming from the affected limb. [1]
# Physiology
Pain usually begins when nerve endings relay information to nerves, which in turn relay it to ganglia just outside the spinal vertebrae, which send it to nociceptive (pain-sensing) neurons inside the spinal cord, which finally send the information to the brain. If the nociceptive neurons cease to receive information to pass on, they will instead send the neurological equivalent of white noise, which the brain then interprets as pain. [1]
In cases in which a traumatic event causes nerve severance and also detaches the nociceptive neurons from the rest of the spinal cord, phantom pain will not develop. Some patients who do not receive adequate relief from nerve blocks, narcotic painkillers, or other methods of pain management may undergo a procedure called dorsal root entry zone (DREZ) lesioning. DREZ lesioning is a form of neurosurgery in which the wayward nociceptive neurons are destroyed. [1] | https://www.wikidoc.org/index.php/Phantom_anus_pain | |
fa4da3bf6f25c155a5198e323729bd7f37a1f93e | wikidoc | Pharmacology | Pharmacology
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
# Overview
Pharmacology is the study of how drugs interact with living organisms to produce a change in function. If substances have medicinal properties, they are considered pharmaceuticals. The field encompasses drug composition and properties, interactions, toxicology, therapy, and medical applications and antipathogenic capabilities. Pharmacology is not synonymous with pharmacy, though in common usage the two are at times confused. Pharmacology deals with how drugs interact within biological systems to affect function, while pharmacy is a medical science concerned with the safe and effective use of medicines.
The origins of clinical pharmacology date back to the Middle Ages in Avicenna's The Canon of Medicine, Peter of Spain's Commentary on Isaac, and John of St Amand's Commentary on the Antedotary of Nicholas. Pharmacology as a scientific discipline did not further advance until the mid-19th century amid the great biomedical resurgence of that period. Before the second half of the nineteenth century, the remarkable potency and specificity of the actions of drugs such as morphine, quinine and digitalis were explained vaguely and with reference to extraordinary chemical powers and affinities to certain organs or tissues. The first pharmacology department was set up by Buchheim in 1847, in recognition of the need to understand how therapeutic drugs and poisons produced their effects.
The word Pharmacology comes from Greek: pharmakon (φάρμακον) meaning drug, and λόγος, logos, "knowledge". Early pharmacologists focused on natural substances, mainly plant extracts. Pharmacology developed in the 19th century as a new biomedical science that applied the principles of scientific experimentation to therapeutic contexts.
# Divisions
Pharmacology as a chemical science is practiced by pharmacologists. Subdisciplines include
- clinical pharmacology - the medical field of medication effects on humans
- neuro- and psychopharmacology (effects of medication on behavior and nervous system functioning),
- pharmacogenetics (clinical testing of genetic variation that gives rise to differing response to drugs)
- pharmacogenomics (application of genomic technologies to new drug discovery and further characterization of older drugs)
- pharmacoepidemiology (study of effects of drugs in large numbers of people)
- toxicology study of the effects of poisons
- theoretical pharmacology
- posology - how medicines are dosed
- pharmacognosy - deriving medicines from plants
# Scientific background
The study of chemicals requires intimate knowledge of the biological system affected. With the knowledge of cell biology and biochemistry increasing, the field of pharmacology has also changed substantially. It has become possible, through molecular analysis of receptors, to design chemicals that act on specific cellular signaling or metabolic pathways by affecting sites directly on cell-surface receptors (which modulate and mediate cellular signaling pathways controlling cellular function).
A chemical has, from the pharmacological point-of-view, various properties. Pharmacokinetics describes the effect of the body on the chemical (e.g. half-life and volume of distribution), and pharmacodynamics describes the chemical's effect on the body (desired or toxic).
When describing the pharmacokinetic properties of a chemical, pharmacologists are often interested in ADME:
- Absorption - How is the medication absorbed (through the skin, the intestine, the oral mucosa)?
- Distribution - How does it spread through the organism?
- Metabolism - Is the medication converted chemically inside the body, and into which substances. Are these active? Could they be toxic?
- Excretion - How is the medication eliminated (through the bile, urine, breath, skin)?
Medication is said to have a narrow or wide therapeutic index or therapeutic window. This describes the ratio of desired effect to toxic effect. A compound with a narrow therapeutic index (close to one) exerts its desired effect at a dose close to its toxic dose. A compound with a wide therapeutic index (greater than five) exerts its desired effect at a dose substantially below its toxic dose. Those with a narrow margin are more difficult to dose and administer, and may require therapeutic drug monitoring (examples are warfarin, some antiepileptics, aminoglycoside antibiotics). Most anti-cancer drugs have a narrow therapeutic margin: toxic side-effects are almost always encountered at doses used to kill tumors.
# Medicine development and safety testing
Development of medication is a vital concern to medicine, but also has strong economical and political implications. To protect the consumer and prevent abuse, many governments regulate the manufacture, sale, and administration of medication. In the United States, the main body that regulates pharmaceuticals is the Food and Drug Administration and they enforce standards set by the United States Pharmacopoeia. In the European Union, the main body that regulates pharmaceuticals is the EMEA and they enforce standards set by the European Pharmacopoeia.
If the structure of a medicine is altered slightly, this will slightly alter the medicine's properties. This means when a useful activity has been identified, chemists will make many similar compounds called analogues, to attempt and maximise the beneficial effects. This development phase can take up to 3 years and is expensive.
These new analogues need to be developed. It needs to be determined how safe the medicine is for human consumption, its stability in the human body and the best form for dispensing, like tablet or aerosol. After extensive testing, which can take up to 6 years the new medicine is ready for marketing and selling.
As a result of the long time required to develop analogues and test a new medicine and the fact that of every 5000 potential new medicines typically only one will ever reach the open market, this is an expensive way of doing things, costing millions of dollars. To recoup this outlay pharmaceutical companies may do a number of things:
- Carefully research the demand for their potential new product before spending an outlay of company funds.
- Obtain a patent on the new medicine preventing other companies from producing that medicine for a certain allocation of time.
# Drug legislation and safety
In the United States, the Food and Drug Administration (FDA) is responsible for creating guidelines for the approval and use of drugs. The FDA requires that all approved drugs fulfill two requirements:
- The drug must be found to be effective against the disease for which it is seeking approval.
- The drug must meet safety criteria by being subject to extensive animal and controlled human testing.
Gaining FDA approval usually takes several years to attain. Testing done on animals must be extensive and must include several species to help in the evaluation of both the effectiveness and toxicity of the drug. The dosage of any drug approved for use is intended to fall within a range in which the drug produces a therapeutic effect or desired outcome.
The safety and effectiveness of prescription drugs in the U.S. is regulated by the federal Prescription Drug Marketing Act of 1987.
The Medicines and Healthcare products Regulatory Agency (MHRA) has a similar role in the UK.
# Education
The study of pharmacology is offered in many universities worldwide.
Again, pharmacology education programs differ from pharmacy programs. Students of pharmacology are trained as researchers, studying the effects of substances in order to better understand the mechanisms which might lead to new drug discoveries for example. Whereas as pharmacy student will eventually work in a pharmacy dispensing medications or some other position focused on the patient, pharmacologist will typically work within a laboratory setting.
Some higher educational institutions combine pharmacology and toxicology into a single program as does
Michigan State University. Michigan State University offers PhD training in Pharmacology & Toxicology with an optional Environmental Toxicology specialization. They also offer a Professional Science Masters in Integrative Pharmacology. | Pharmacology
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2]
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [3] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
# Overview
Pharmacology is the study of how drugs interact with living organisms to produce a change in function.[1] If substances have medicinal properties, they are considered pharmaceuticals. The field encompasses drug composition and properties, interactions, toxicology, therapy, and medical applications and antipathogenic capabilities. Pharmacology is not synonymous with pharmacy, though in common usage the two are at times confused. Pharmacology deals with how drugs interact within biological systems to affect function, while pharmacy is a medical science concerned with the safe and effective use of medicines.
The origins of clinical pharmacology date back to the Middle Ages in Avicenna's The Canon of Medicine, Peter of Spain's Commentary on Isaac, and John of St Amand's Commentary on the Antedotary of Nicholas.[2] Pharmacology as a scientific discipline did not further advance until the mid-19th century amid the great biomedical resurgence of that period.[3] Before the second half of the nineteenth century, the remarkable potency and specificity of the actions of drugs such as morphine, quinine and digitalis were explained vaguely and with reference to extraordinary chemical powers and affinities to certain organs or tissues.[4] The first pharmacology department was set up by Buchheim in 1847, in recognition of the need to understand how therapeutic drugs and poisons produced their effects.[3]
The word Pharmacology comes from Greek: pharmakon (φάρμακον) meaning drug, and λόγος, logos, "knowledge". Early pharmacologists focused on natural substances, mainly plant extracts. Pharmacology developed in the 19th century as a new biomedical science that applied the principles of scientific experimentation to therapeutic contexts.[5]
# Divisions
Pharmacology as a chemical science is practiced by pharmacologists. Subdisciplines include
- clinical pharmacology - the medical field of medication effects on humans
- neuro- and psychopharmacology (effects of medication on behavior and nervous system functioning),
- pharmacogenetics (clinical testing of genetic variation that gives rise to differing response to drugs)
- pharmacogenomics (application of genomic technologies to new drug discovery and further characterization of older drugs)
- pharmacoepidemiology (study of effects of drugs in large numbers of people)
- toxicology study of the effects of poisons
- theoretical pharmacology
- posology - how medicines are dosed
- pharmacognosy - deriving medicines from plants
# Scientific background
The study of chemicals requires intimate knowledge of the biological system affected. With the knowledge of cell biology and biochemistry increasing, the field of pharmacology has also changed substantially. It has become possible, through molecular analysis of receptors, to design chemicals that act on specific cellular signaling or metabolic pathways by affecting sites directly on cell-surface receptors (which modulate and mediate cellular signaling pathways controlling cellular function).
A chemical has, from the pharmacological point-of-view, various properties. Pharmacokinetics describes the effect of the body on the chemical (e.g. half-life and volume of distribution), and pharmacodynamics describes the chemical's effect on the body (desired or toxic).
When describing the pharmacokinetic properties of a chemical, pharmacologists are often interested in ADME:
- Absorption - How is the medication absorbed (through the skin, the intestine, the oral mucosa)?
- Distribution - How does it spread through the organism?
- Metabolism - Is the medication converted chemically inside the body, and into which substances. Are these active? Could they be toxic?
- Excretion - How is the medication eliminated (through the bile, urine, breath, skin)?
Medication is said to have a narrow or wide therapeutic index or therapeutic window. This describes the ratio of desired effect to toxic effect. A compound with a narrow therapeutic index (close to one) exerts its desired effect at a dose close to its toxic dose. A compound with a wide therapeutic index (greater than five) exerts its desired effect at a dose substantially below its toxic dose. Those with a narrow margin are more difficult to dose and administer, and may require therapeutic drug monitoring (examples are warfarin, some antiepileptics, aminoglycoside antibiotics). Most anti-cancer drugs have a narrow therapeutic margin: toxic side-effects are almost always encountered at doses used to kill tumors.
# Medicine development and safety testing
Development of medication is a vital concern to medicine, but also has strong economical and political implications. To protect the consumer and prevent abuse, many governments regulate the manufacture, sale, and administration of medication. In the United States, the main body that regulates pharmaceuticals is the Food and Drug Administration and they enforce standards set by the United States Pharmacopoeia. In the European Union, the main body that regulates pharmaceuticals is the EMEA and they enforce standards set by the European Pharmacopoeia.
If the structure of a medicine is altered slightly, this will slightly alter the medicine's properties. This means when a useful activity has been identified, chemists will make many similar compounds called analogues, to attempt and maximise the beneficial effects. This development phase can take up to 3 years and is expensive.[6]
These new analogues need to be developed. It needs to be determined how safe the medicine is for human consumption, its stability in the human body and the best form for dispensing, like tablet or aerosol. After extensive testing, which can take up to 6 years the new medicine is ready for marketing and selling.[6]
As a result of the long time required to develop analogues and test a new medicine and the fact that of every 5000 potential new medicines typically only one will ever reach the open market, this is an expensive way of doing things, costing millions of dollars. To recoup this outlay pharmaceutical companies may do a number of things:[6]
- Carefully research the demand for their potential new product before spending an outlay of company funds.[6]
- Obtain a patent on the new medicine preventing other companies from producing that medicine for a certain allocation of time.[6]
# Drug legislation and safety
In the United States, the Food and Drug Administration (FDA) is responsible for creating guidelines for the approval and use of drugs. The FDA requires that all approved drugs fulfill two requirements:
- The drug must be found to be effective against the disease for which it is seeking approval.
- The drug must meet safety criteria by being subject to extensive animal and controlled human testing.
Gaining FDA approval usually takes several years to attain. Testing done on animals must be extensive and must include several species to help in the evaluation of both the effectiveness and toxicity of the drug. The dosage of any drug approved for use is intended to fall within a range in which the drug produces a therapeutic effect or desired outcome.[1]
The safety and effectiveness of prescription drugs in the U.S. is regulated by the federal Prescription Drug Marketing Act of 1987.
The Medicines and Healthcare products Regulatory Agency (MHRA) has a similar role in the UK.
# Education
The study of pharmacology is offered in many universities worldwide.
Again, pharmacology education programs differ from pharmacy programs. Students of pharmacology are trained as researchers, studying the effects of substances in order to better understand the mechanisms which might lead to new drug discoveries for example. Whereas as pharmacy student will eventually work in a pharmacy dispensing medications or some other position focused on the patient, pharmacologist will typically work within a laboratory setting.
Some higher educational institutions combine pharmacology and toxicology into a single program as does
Michigan State University. Michigan State University offers PhD training in Pharmacology & Toxicology with an optional Environmental Toxicology specialization. They also offer a Professional Science Masters in Integrative Pharmacology. | https://www.wikidoc.org/index.php/Pharmacologic | |
c46d321ac82129f8cf4c09b9683f0cb77142a8e7 | wikidoc | Phellandrene | Phellandrene
Phellandrene is the name for a pair of organic compounds that have a similar molecular structure and similar chemical properties. α-Phellandrene and β-phellandrene are cyclic monoterpenes and are double bond isomers. In α-phellandrene both double bonds are endocyclic and in β-phellandrene one of them is exocyclic. Both are insoluble in water, but miscible with ether.
α-Phellandrene is a constituent of the essential oils of Eucalyptus dives and of Eucalyptus phellandra (hence the name). β-Phellandrene has been isolated from the oil of water fennel and Canada balsam oil.
The phellandrenes are used in fragrances because of their pleasing aromas. The odor of β-phellandrene has been described as peppery-minty and slightly citrusy. | Phellandrene
Phellandrene is the name for a pair of organic compounds that have a similar molecular structure and similar chemical properties. α-Phellandrene and β-phellandrene are cyclic monoterpenes and are double bond isomers. In α-phellandrene both double bonds are endocyclic and in β-phellandrene one of them is exocyclic. Both are insoluble in water, but miscible with ether.
α-Phellandrene is a constituent of the essential oils of Eucalyptus dives and of Eucalyptus phellandra (hence the name). β-Phellandrene has been isolated from the oil of water fennel and Canada balsam oil.
The phellandrenes are used in fragrances because of their pleasing aromas. The odor of β-phellandrene has been described as peppery-minty and slightly citrusy.
# External links
de:Phellandren | https://www.wikidoc.org/index.php/Phellandrene | |
f08f195efb9dccc13b5a7f8eed42e60e78fc2bbf | wikidoc | Phentolamine | Phentolamine
# 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
Phentolamine is a vasodilator and alpha-adrenergic blocker that is FDA approved for the {{{indicationType}}} of reversal of the soft-tissue anesthesia. Common adverse reactions include injection site pain, diarrhea, and nasal congestion.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- OraVerse is indicated for reversal of the soft-tissue anesthesia, i.e., anesthesia of the lip and tongue, and the associated functional deficits resulting from an intraoral submucosal injection of a local anesthetic containing a vasoconstrictor. OraVerse is not recommended for use in children less than 6 years of age or weighing less than 15 kg (33 lbs).
- Dosing Information
- The recommended dose of OraVerse is based on the number of cartridges of local anesthetic with vasoconstrictor administered:
- OraVerse should be administered following the dental procedure using the same location(s) and technique(s) (infiltration or block injection) employed for the administration of the local anesthetic.
- Note: Do not administer OraVerse if the product is discolored or contains particulate matter.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Phentolamine in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- Intravenous phentolamine 5 to 20 milligrams is effective for treating hypertensive crises induced by high levels of circulating catecholamines. conditions which phentolamine may by effective for include pheochromocytoma, clonidine withdrawal, and monoamine oxidase inhibitor interactions.
- Phentolamine (1 to 10 milligrams, increasing at 3- to 8-minute intervals up to 25 milligrams) is effective for determining if pain is sympathetically maintained.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- In pediatric patients weighing 15-30 kg, the maximum dose of OraVerse recommended is 1/2 cartridge (0.2 mg).
- Note: Use in pediatric patients under 6 years of age or weighing less than 15 kg (33 lbs) is not recommended. A dose of more than 1 cartridge of OraVerse has not been studied in children less than 12 years of age.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Phentolamine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Phentolamine in pediatric patients.
# Contraindications
- None (phentolamine mesylate solution for submucosal use)
# Warnings
- Cardiovascular Events
- Myocardial infarction, cerebrovascular spasm, and cerebrovascular occlusion have been reported to occur following the parenteral administration of phentolamine. These events usually occurred in association with marked hypotensive episodes producing shock-like states.
- Tachycardia and cardiac arrhythmias may occur with the use of phentolamine or other alpha-adrenergic blocking agents. Although such effects are uncommon after administration of OraVerse, clinicians should be alert to the signs and symptoms of these events, particularly in patients with a prior history of cardiovascular disease.
# Adverse Reactions
## Clinical Trials Experience
- In clinical trials, the most common adverse reaction with OraVerse that was greater than the control group was injection site pain.
- 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.
- Dental patients were administered a dose of either 0.2, 0.4 or 0.8 mg of OraVerse. The majority of adverse reactions were mild and resolved within 48 hours. There were no serious adverse reactions and no discontinuations due to adverse reactions.
- Table 1 lists adverse reactions where the frequency was greater than or equal to 3% in any OraVerse dose group and was equal to or exceeded that of the control group.
- An examination of population subgroups did not reveal a differential adverse reaction incidence on the basis of age, gender, or race.
- Results from the pain assessments in Study 1 and Study 2, involving mandibular and maxillary procedures, respectively, indicated that the majority of dental patients in both OraVerse and control groups experienced no or mild oral pain, with less than 10% of patients in each group reporting moderate oral pain with a similar distribution between the OraVerse and control groups. No patient experienced severe pain in these studies.
- Adverse Reactions in Clinical Trials
- Adverse reactions reported by less than 3% but at least 2 dental patients receiving OraVerse and occurring at a greater incidence than those receiving control, included diarrhea, facial swelling, increased blood pressure/hypertension, injection site reactions, jaw pain, oral pain, paresthesia, pruritus, tenderness, upper abdominal pain and vomiting. The majority of these adverse reactions were mild and resolved within 48 hours. The few reports of paresthesia were mild and transient and resolved during the same time period.
## Postmarketing Experience
- The following adverse reactions have been identified during postapproval parenteral use of phentolamine mesylate. 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.
- Acute and prolonged hypotensive episodes and cardiac arrhythmias have been reported with the use of phentolamine. In addition, weakness, dizziness, flushing, orthostatic hypotension, and nasal stuffiness have occurred.
# Drug Interactions
- Lidocaine and Epinephrine
- When OraVerse was administered as an intraoral submucosal injection 30 minutes after injection of a local anesthetic, 2% lidocaine HCl with 1:100,000 epinephrine, the lidocaine concentration increased immediately after OraVerse intraoral injection. Lidocaine AUC and Cmax values were not affected by administration of OraVerse. OraVerse administration did not affect the PK of epinephrine.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- There are no adequate and well-controlled studies in pregnant women. OraVerse should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Oral administration of phentolamine to pregnant rats and mice at doses at least 24 times the recommended dose (based on a 60 kg human) resulted in slightly decreased growth and slight skeletal immaturity of the fetuses. Immaturity was manifested by increased incidence of incomplete or unossified calcaneal and phalangeal nuclei of the hind limb and of incompletely ossified sternebrae. At oral phentolamine doses at least 60 times the recommended dose (based on a 60 kg human), a slightly lower rate of implantation was found in the rat. Phentolamine did not affect embryonic or fetal development in the rabbit at oral doses at least 20 times the recommended dose (based on a 60 kg human). No teratogenic or embryotoxic effects were observed in the rat, mouse, or rabbit studies.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Phentolamine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Phentolamine during labor and delivery.
### Nursing Mothers
- It is not known whether OraVerse is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when OraVerse is administered to a nursing woman. The unknown risks of limited infant exposure to phentolamine through breast milk following a single maternal dose should be weighed against the known benefits of breastfeeding.
### Pediatric Use
- In clinical studies, pediatric patients between the ages of 3 and 17 years received OraVerse. The safety and effectiveness of OraVerse have been established in the age group 6-17 years. Effectiveness in pediatric patients below the age of 6 years has not been established. Use of OraVerse in patients between the ages of 6 and 17 years old is supported by evidence from adequate and well-controlled studies of OraVerse in adults, with additional adequate and well-controlled studies of OraVerse in pediatric patients ages 12-17 years old and ages 6-11 years old . The safety, but not the efficacy, of OraVerse has been evaluated in pediatric patients under the age of 6 years old. Dosages in pediatric patients may need to be limited based on body weight.
### Geriatic Use
- Of the total number of patients in clinical studies of OraVerse, 55 were 65 and over, while 21 were 75 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
### Gender
There is no FDA guidance on the use of Phentolamine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Phentolamine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Phentolamine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Phentolamine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Phentolamine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Phentolamine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Submucosal use
### Monitoring
There is limited information regarding Monitoring of Phentolamine in the drug label.
- Description
# IV Compatibility
There is limited information regarding IV Compatibility of Phentolamine in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- No deaths due to acute poisoning with phentolamine have been reported.
- Overdosage with parenterally administered phentolamine is characterized chiefly by cardiovascular disturbances, such as arrhythmias, tachycardia, hypotension, and possibly shock. In addition, the following might occur: excitation, headache, sweating, pupillary contraction, visual disturbances, nausea, vomiting, diarrhea, or hypoglycemia.
### Management
- There is no specific antidote; treatment consists of appropriate monitoring and supportive care. Substantial decreases in blood pressure or other evidence of shock-like conditions should be treated vigorously and promptly.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Phentolamine in the drug label.
# Pharmacology
## Mechanism of Action
- The mechanism by which OraVerse accelerates reversal of soft-tissue anesthesia and the associated functional deficits is not fully understood. Phentolamine mesylate, the active ingredient in OraVerse, produces an alpha-adrenergic block of relatively short duration resulting in vasodilatation when applied to vascular smooth muscle. In an animal model, OraVerse increased local blood flow in submucosal tissue of the dog when given after an intraoral injection of lidocaine 2% with 1:100,000 epinephrine.
## Structure
- Phentolamine mesylate USP is a white to off-white, odorless crystalline powder with a molecular weight of 377.46. It is sparingly soluble in water, soluble in alcohol, and slightly soluble in chloroform. The empirical formulation is C 17H19N3OCH4O3S, and the chemical structure is:
- OraVerse (phentolamine mesylate) Injection is a clear, colorless, sterile, non pyrogenic, isotonic, preservative free solution. Each 1.7 mL cartridge contains 0.4 mg phentolamine mesylate, D-mannitol, edetate disodium, and sodium acetate. Either acetic acid or sodium hydroxide is used as necessary to adjust the pH.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Phentolamine in the drug label.
## Pharmacokinetics
- Following OraVerse administration, phentolamine is 100% available from the submucosal injection site and peak concentrations are achieved 10-20 minutes after injection. Phentolamine systemic exposure increased linearly after 0.8 mg compared to 0.4 mg OraVerse intraoral submucosal injection. The terminal elimination half-life of phentolamine in the blood was approximately 2-3 hours.
- Pediatrics
- Following OraVerse administration, the phentolamine Cmax was higher (approximately 3.5-fold) in children who weighed between 15 and 30 kg (33 and 66 lbs) than in children who weighed more than 30 kg. However, phentolamine AUC was similar between the two groups. It is recommended that in children weighing 15-30 kg, the maximum dose of OraVerse should be limited to ½ cartridge (0.2 mg).
- The pharmacokinetics of OraVerse in adults and in children who weighed more than 30 kg (66 lbs) are similar after intraoral submucosal injection.
- OraVerse has not been studied in children under 3 years of age or weighing less than 15 kg (33 lbs). The pharmacokinetics of OraVerse after administration of more than 1 cartridge (0.4mg) has not been studied in children.
## Nonclinical Toxicology
- Carcinogenesis, Mutagenesis, Impairment of Fertility
- Carcinogenicity studies with OraVerse have not been conducted.
- Phentolamine was not mutagenic in the in-vitro bacterial reverse mutation (Ames) assay. In the in-vitro chromosomal aberration study in Chinese hamster ovary cells, numerical aberrations were slightly increased after a 4-hour exposure to phentolamine without metabolic activation and structural aberrations were slightly increased after a 4-hour exposure to phentolamine with metabolic activation only at the highest concentrations tested, but neither numerical nor structural aberrations were increased after a 20-hour exposure without metabolic activation. Phentolamine was not clastogenic in two in-vivo mouse micronucleus assays. At doses up to 150 mg/kg (143 times human therapeutic exposure levels at the Cmax), phentolamine mesylate was shown to have no adverse effects on male fertility in the rat.
# Clinical Studies
- The safety and efficacy of OraVerse when used for reversal of soft-tissue anesthesia (STA), i.e., anesthesia of the lips and tongue following a dental procedure that required local anesthesia containing a vasoconstrictor, were evaluated in the following clinical studies. The efficacy of OraVerse on reversal of local anesthesia of the teeth, mandible and maxilla has not been assessed.
- Two Phase 3, double-blinded, randomized, multi-center, controlled studies were conducted in dental patients who had mandibular (Study 1) or maxillary (Study 2) restorative or periodontal maintenance procedures and who had received a local anesthetic that contained a vasoconstrictor. The primary endpoint was time to normal lip sensation as measured by patient reported responses to lip palpation. The secondary endpoints included patients’ perception of altered function, sensation and appearance, and their actual functional deficits in smiling, speaking, drinking and drooling, as assessed by both the patient and an observer blinded to the treatment. In the mandibular study, the time to recovery of tongue sensation was also a secondary endpoint. Patients were stratified by type and amount of anesthetic administered. OraVerse was administered at a cartridge ratio of 1:1 to local anesthetic. The control was a sham injection.
- OraVerse reduced the median time to recovery of normal sensation in the lower lip by 85 minutes (55%) compared to control. The median time to recovery of normal sensation in the upper lip was reduced by 83 minutes (62%). The differences between these times for both studies are depicted in Kaplan-Meier plots for time to normal lip sensation in Figures 1 and 2. Within 1 hour after administration of OraVerse, 41% of patients reported normal lower lip sensation as compared to 7% in the control group, and 59% of patients in the OraVerse group reported normal upper lip sensation as compared to 12% in the control group.
- In Study 1 (mandibular), OraVerse accelerated: a) the recovery of the perception of normal appearance and function by 60 minutes (40%), b) the recovery of normal function by 60 (50%) minutes, and c) the recovery of normal sensation in the tongue by 65 minutes (52%). In Study 2 (maxillary), the recovery of the perception of normal appearance and function was reduced by 60 minutes (50%) and the recovery of normal function was reduced by 45 minutes (43%).
- Study 3, a pediatric, Phase 2, double-blinded, randomized, multi-center, controlled study was conducted in dental patients who had received 2% lidocaine with 1:100,000 epinephrine. Dental patients (n=152, ages 4-11 years) received 1/2 cartridge of local anesthetic if they weighed ≥15 kg but <30 kg, and one-half or one full cartridge if they weighed ≥30 kg at a cartridge ratio of 1:1 to local anesthetic.
- The median time to normal lip sensation in patients 6 to 11 years of age who were trainable in the lip-palpation procedures, for mandibular and maxillary procedures combined, was reduced by 75 minutes (56%). Within 1 hour after administration of OraVerse, 44 patients (61%) reported normal lip sensation, while only 9 patients (21%) randomized to the control group reported normal lip sensation. In this study, neither the patients’ perception of their appearance or ability to function nor their actual ability to function was evaluated.
# How Supplied
- OraVerse (phentolamine mesylate) Injection 0.4 mg/1.7 mL is supplied in a dental cartridge, in cartons of 10 and 50 cartridges. Each cartridge is individually packaged in a separate compartment of a 10 cartridge blister pack.
- Store at controlled room temperature, 20-25C (68-77F) with brief excursions permitted between 15-30C (59-86F).
- Protect from direct heat and light. Do not permit to freeze.
## Storage
There is limited information regarding Phentolamine 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 Phentolamine in the drug label.
# Precautions with Alcohol
- Alcohol-Phentolamine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Regitine®
- Oraverse®
# Look-Alike Drug Names
- N/A
# Drug Shortage Status
# Price | Phentolamine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gerald Chi
# 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
Phentolamine is a vasodilator and alpha-adrenergic blocker that is FDA approved for the {{{indicationType}}} of reversal of the soft-tissue anesthesia. Common adverse reactions include injection site pain, diarrhea, and nasal congestion.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- OraVerse is indicated for reversal of the soft-tissue anesthesia, i.e., anesthesia of the lip and tongue, and the associated functional deficits resulting from an intraoral submucosal injection of a local anesthetic containing a vasoconstrictor. OraVerse is not recommended for use in children less than 6 years of age or weighing less than 15 kg (33 lbs).
- Dosing Information
- The recommended dose of OraVerse is based on the number of cartridges of local anesthetic with vasoconstrictor administered:
- OraVerse should be administered following the dental procedure using the same location(s) and technique(s) (infiltration or block injection) employed for the administration of the local anesthetic.
- Note: Do not administer OraVerse if the product is discolored or contains particulate matter.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Phentolamine in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- Intravenous phentolamine 5 to 20 milligrams is effective for treating hypertensive crises induced by high levels of circulating catecholamines. conditions which phentolamine may by effective for include pheochromocytoma, clonidine withdrawal, and monoamine oxidase inhibitor interactions.[1]
- Phentolamine (1 to 10 milligrams, increasing at 3- to 8-minute intervals up to 25 milligrams) is effective for determining if pain is sympathetically maintained.[2]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- In pediatric patients weighing 15-30 kg, the maximum dose of OraVerse recommended is 1/2 cartridge (0.2 mg).
- Note: Use in pediatric patients under 6 years of age or weighing less than 15 kg (33 lbs) is not recommended. A dose of more than 1 cartridge [0.4 mg] of OraVerse has not been studied in children less than 12 years of age.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Phentolamine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Phentolamine in pediatric patients.
# Contraindications
- None (phentolamine mesylate solution for submucosal use)
# Warnings
- Cardiovascular Events
- Myocardial infarction, cerebrovascular spasm, and cerebrovascular occlusion have been reported to occur following the parenteral administration of phentolamine. These events usually occurred in association with marked hypotensive episodes producing shock-like states.
- Tachycardia and cardiac arrhythmias may occur with the use of phentolamine or other alpha-adrenergic blocking agents. Although such effects are uncommon after administration of OraVerse, clinicians should be alert to the signs and symptoms of these events, particularly in patients with a prior history of cardiovascular disease.
# Adverse Reactions
## Clinical Trials Experience
- In clinical trials, the most common adverse reaction with OraVerse that was greater than the control group was injection site pain.
- 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.
- Dental patients were administered a dose of either 0.2, 0.4 or 0.8 mg of OraVerse. The majority of adverse reactions were mild and resolved within 48 hours. There were no serious adverse reactions and no discontinuations due to adverse reactions.
- Table 1 lists adverse reactions where the frequency was greater than or equal to 3% in any OraVerse dose group and was equal to or exceeded that of the control group.
- An examination of population subgroups did not reveal a differential adverse reaction incidence on the basis of age, gender, or race.
- Results from the pain assessments in Study 1 and Study 2, involving mandibular and maxillary procedures, respectively, indicated that the majority of dental patients in both OraVerse and control groups experienced no or mild oral pain, with less than 10% of patients in each group reporting moderate oral pain with a similar distribution between the OraVerse and control groups. No patient experienced severe pain in these studies.
- Adverse Reactions in Clinical Trials
- Adverse reactions reported by less than 3% but at least 2 dental patients receiving OraVerse and occurring at a greater incidence than those receiving control, included diarrhea, facial swelling, increased blood pressure/hypertension, injection site reactions, jaw pain, oral pain, paresthesia, pruritus, tenderness, upper abdominal pain and vomiting. The majority of these adverse reactions were mild and resolved within 48 hours. The few reports of paresthesia were mild and transient and resolved during the same time period.
## Postmarketing Experience
- The following adverse reactions have been identified during postapproval parenteral use of phentolamine mesylate. 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.
- Acute and prolonged hypotensive episodes and cardiac arrhythmias have been reported with the use of phentolamine. In addition, weakness, dizziness, flushing, orthostatic hypotension, and nasal stuffiness have occurred.
# Drug Interactions
- Lidocaine and Epinephrine
- When OraVerse was administered as an intraoral submucosal injection 30 minutes after injection of a local anesthetic, 2% lidocaine HCl with 1:100,000 epinephrine, the lidocaine concentration increased immediately after OraVerse intraoral injection. Lidocaine AUC and Cmax values were not affected by administration of OraVerse. OraVerse administration did not affect the PK of epinephrine.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- There are no adequate and well-controlled studies in pregnant women. OraVerse should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Oral administration of phentolamine to pregnant rats and mice at doses at least 24 times the recommended dose (based on a 60 kg human) resulted in slightly decreased growth and slight skeletal immaturity of the fetuses. Immaturity was manifested by increased incidence of incomplete or unossified calcaneal and phalangeal nuclei of the hind limb and of incompletely ossified sternebrae. At oral phentolamine doses at least 60 times the recommended dose (based on a 60 kg human), a slightly lower rate of implantation was found in the rat. Phentolamine did not affect embryonic or fetal development in the rabbit at oral doses at least 20 times the recommended dose (based on a 60 kg human). No teratogenic or embryotoxic effects were observed in the rat, mouse, or rabbit studies.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Phentolamine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Phentolamine during labor and delivery.
### Nursing Mothers
- It is not known whether OraVerse is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when OraVerse is administered to a nursing woman. The unknown risks of limited infant exposure to phentolamine through breast milk following a single maternal dose should be weighed against the known benefits of breastfeeding.
### Pediatric Use
- In clinical studies, pediatric patients between the ages of 3 and 17 years received OraVerse. The safety and effectiveness of OraVerse have been established in the age group 6-17 years. Effectiveness in pediatric patients below the age of 6 years has not been established. Use of OraVerse in patients between the ages of 6 and 17 years old is supported by evidence from adequate and well-controlled studies of OraVerse in adults, with additional adequate and well-controlled studies of OraVerse in pediatric patients ages 12-17 years old [Studies 1 (mandibular procedures) and 2 (maxillary procedures)] and ages 6-11 years old [Study 3 (mandibular and maxillary procedures)]. The safety, but not the efficacy, of OraVerse has been evaluated in pediatric patients under the age of 6 years old. Dosages in pediatric patients may need to be limited based on body weight.
### Geriatic Use
- Of the total number of patients in clinical studies of OraVerse, 55 were 65 and over, while 21 were 75 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
### Gender
There is no FDA guidance on the use of Phentolamine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Phentolamine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Phentolamine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Phentolamine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Phentolamine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Phentolamine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Submucosal use
### Monitoring
There is limited information regarding Monitoring of Phentolamine in the drug label.
- Description
# IV Compatibility
There is limited information regarding IV Compatibility of Phentolamine in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- No deaths due to acute poisoning with phentolamine have been reported.
- Overdosage with parenterally administered phentolamine is characterized chiefly by cardiovascular disturbances, such as arrhythmias, tachycardia, hypotension, and possibly shock. In addition, the following might occur: excitation, headache, sweating, pupillary contraction, visual disturbances, nausea, vomiting, diarrhea, or hypoglycemia.
### Management
- There is no specific antidote; treatment consists of appropriate monitoring and supportive care. Substantial decreases in blood pressure or other evidence of shock-like conditions should be treated vigorously and promptly.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Phentolamine in the drug label.
# Pharmacology
## Mechanism of Action
- The mechanism by which OraVerse accelerates reversal of soft-tissue anesthesia and the associated functional deficits is not fully understood. Phentolamine mesylate, the active ingredient in OraVerse, produces an alpha-adrenergic block of relatively short duration resulting in vasodilatation when applied to vascular smooth muscle. In an animal model, OraVerse increased local blood flow in submucosal tissue of the dog when given after an intraoral injection of lidocaine 2% with 1:100,000 epinephrine.
## Structure
- Phentolamine mesylate USP is a white to off-white, odorless crystalline powder with a molecular weight of 377.46. It is sparingly soluble in water, soluble in alcohol, and slightly soluble in chloroform. The empirical formulation is C 17H19N3O•CH4O3S, and the chemical structure is:
- OraVerse (phentolamine mesylate) Injection is a clear, colorless, sterile, non pyrogenic, isotonic, preservative free solution. Each 1.7 mL cartridge contains 0.4 mg phentolamine mesylate, D-mannitol, edetate disodium, and sodium acetate. Either acetic acid or sodium hydroxide is used as necessary to adjust the pH.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Phentolamine in the drug label.
## Pharmacokinetics
- Following OraVerse administration, phentolamine is 100% available from the submucosal injection site and peak concentrations are achieved 10-20 minutes after injection. Phentolamine systemic exposure increased linearly after 0.8 mg compared to 0.4 mg OraVerse intraoral submucosal injection. The terminal elimination half-life of phentolamine in the blood was approximately 2-3 hours.
- Pediatrics
- Following OraVerse administration, the phentolamine Cmax was higher (approximately 3.5-fold) in children who weighed between 15 and 30 kg (33 and 66 lbs) than in children who weighed more than 30 kg. However, phentolamine AUC was similar between the two groups. It is recommended that in children weighing 15-30 kg, the maximum dose of OraVerse should be limited to ½ cartridge (0.2 mg).
- The pharmacokinetics of OraVerse in adults and in children who weighed more than 30 kg (66 lbs) are similar after intraoral submucosal injection.
- OraVerse has not been studied in children under 3 years of age or weighing less than 15 kg (33 lbs). The pharmacokinetics of OraVerse after administration of more than 1 cartridge (0.4mg) has not been studied in children.
## Nonclinical Toxicology
- Carcinogenesis, Mutagenesis, Impairment of Fertility
- Carcinogenicity studies with OraVerse have not been conducted.
- Phentolamine was not mutagenic in the in-vitro bacterial reverse mutation (Ames) assay. In the in-vitro chromosomal aberration study in Chinese hamster ovary cells, numerical aberrations were slightly increased after a 4-hour exposure to phentolamine without metabolic activation and structural aberrations were slightly increased after a 4-hour exposure to phentolamine with metabolic activation only at the highest concentrations tested, but neither numerical nor structural aberrations were increased after a 20-hour exposure without metabolic activation. Phentolamine was not clastogenic in two in-vivo mouse micronucleus assays. At doses up to 150 mg/kg (143 times human therapeutic exposure levels at the Cmax), phentolamine mesylate was shown to have no adverse effects on male fertility in the rat.
# Clinical Studies
- The safety and efficacy of OraVerse when used for reversal of soft-tissue anesthesia (STA), i.e., anesthesia of the lips and tongue following a dental procedure that required local anesthesia containing a vasoconstrictor, were evaluated in the following clinical studies. The efficacy of OraVerse on reversal of local anesthesia of the teeth, mandible and maxilla has not been assessed.
- Two Phase 3, double-blinded, randomized, multi-center, controlled studies were conducted in dental patients who had mandibular (Study 1) or maxillary (Study 2) restorative or periodontal maintenance procedures and who had received a local anesthetic that contained a vasoconstrictor. The primary endpoint was time to normal lip sensation as measured by patient reported responses to lip palpation. The secondary endpoints included patients’ perception of altered function, sensation and appearance, and their actual functional deficits in smiling, speaking, drinking and drooling, as assessed by both the patient and an observer blinded to the treatment. In the mandibular study, the time to recovery of tongue sensation was also a secondary endpoint. Patients were stratified by type and amount of anesthetic administered. OraVerse was administered at a cartridge ratio of 1:1 to local anesthetic. The control was a sham injection.
- OraVerse reduced the median time to recovery of normal sensation in the lower lip by 85 minutes (55%) compared to control. The median time to recovery of normal sensation in the upper lip was reduced by 83 minutes (62%). The differences between these times for both studies are depicted in Kaplan-Meier plots for time to normal lip sensation in Figures 1 and 2. Within 1 hour after administration of OraVerse, 41% of patients reported normal lower lip sensation as compared to 7% in the control group, and 59% of patients in the OraVerse group reported normal upper lip sensation as compared to 12% in the control group.
- In Study 1 (mandibular), OraVerse accelerated: a) the recovery of the perception of normal appearance and function by 60 minutes (40%), b) the recovery of normal function by 60 (50%) minutes, and c) the recovery of normal sensation in the tongue by 65 minutes (52%). In Study 2 (maxillary), the recovery of the perception of normal appearance and function was reduced by 60 minutes (50%) and the recovery of normal function was reduced by 45 minutes (43%).
- Study 3, a pediatric, Phase 2, double-blinded, randomized, multi-center, controlled study was conducted in dental patients who had received 2% lidocaine with 1:100,000 epinephrine. Dental patients (n=152, ages 4-11 years) received 1/2 cartridge of local anesthetic if they weighed ≥15 kg but <30 kg, and one-half or one full cartridge if they weighed ≥30 kg at a cartridge ratio of 1:1 to local anesthetic.
- The median time to normal lip sensation in patients 6 to 11 years of age who were trainable in the lip-palpation procedures, for mandibular and maxillary procedures combined, was reduced by 75 minutes (56%). Within 1 hour after administration of OraVerse, 44 patients (61%) reported normal lip sensation, while only 9 patients (21%) randomized to the control group reported normal lip sensation. In this study, neither the patients’ perception of their appearance or ability to function nor their actual ability to function was evaluated.
# How Supplied
- OraVerse (phentolamine mesylate) Injection 0.4 mg/1.7 mL is supplied in a dental cartridge, in cartons of 10 and 50 cartridges. Each cartridge is individually packaged in a separate compartment of a 10 cartridge blister pack.
- Store at controlled room temperature, 20-25C (68-77F) with brief excursions permitted between 15-30C (59-86F).
- Protect from direct heat and light. Do not permit to freeze.
## Storage
There is limited information regarding Phentolamine 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 Phentolamine in the drug label.
# Precautions with Alcohol
- Alcohol-Phentolamine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Regitine®
- Oraverse®[3]
# Look-Alike Drug Names
- N/A[4]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Phentolamine | |
26546a8b76bd37123b1576052b88e9c89763d90a | wikidoc | Venipuncture | Venipuncture
In medicine venipuncture or venepuncture (also known as phlebotomy, venesection, blood draw, drawing blood or taking blood) is the process of obtaining a sample of venous blood. Usually a 5 ml to 25 ml sample of blood is adequate depending on what blood tests have been requested. In many circumstances it will be done by a phlebotomist, although nurses, doctors, some EMTs, Paramedics and other medical staff are also trained to take blood.
Blood is most commonly obtained from the median cubital vein, on the anterior forearm (the side within the fold of the elbow). This vein lies close to the surface of the skin, and there is not a large nerve supply.
Minute quantities of blood may be taken by fingersticks sampling and collected from infants by means of a heel stick or from scalp veins with a butterfly needle.
Phlebotomy (incision into a vein) is also the treatment of certain diseases such as hemochromatosis and primary and secondary polycythemia.
# Equipment
There are many ways which blood can be drawn from a vein. The best method varies with the age of the patient, equipment available and tests required.
Most blood collection in the US and UK is done with an evacuated tube system, such as the BD Vacutainer system or similar blood collection equipment consisting of a plastic hub, a hypodermic needle, and a vacuum tube. Under certain circumstances, a syringe may be used, usually with a butterfly needle, which is a plastic catheter attached to a short needle. In the developing world, a needle and syringe are still the most common method of drawing blood.
Blood is usually drawn from a vein in the crook of the elbow, the antecubital region. Tubes have color-coded stoppers to indicate what type of anticoagulant or other substance is in the tube. Tubes may contain no additive, a gel substance which separates cells from serum, or a variety of anticoagulants or preservatives (e.g. sodium heparin, sodium citrate, sodium fluoride and potassium oxalate or potassium EDTA).
## Venipuncture with evacuated or vacuum tubes
Vacuum tubes, or BD Vacutainer tubes are a type of test tube that contain a vacuum that automatically aspirates blood into itself. They are made of glass or plastic. They are commonly used in US and UK hospitals, private doctors' offices and community labs, and are effective in most adult patients and older children. For infants or toddlers, there are smaller size BD Vacutainer tubes available.
Equipment needed includes: a plastic needle holder or "barrel", needles designed specifically for the needle holder, an adjustable tourniquet, appropriate tubes, alcohol swabs, 2x2 gauze pads (cotton balls used to be used, but they have been found to dislodge the clot and the patient bleeds again causing larger hematomas), sticky tape, and a pen for labeling.
Below is a sample of the procedure used when blood is collected with BD Vacutainer tubes.
- First, the patient should be identified -- a test result is useless if it is done on the wrong person. The test subject should be asked their name and date of birth. This should not be a yes or no question, e.g. Are you Stanley Jones?, as many people will just agree, especially if they are elderly and have hearing difficulties or senility.
- The BD Vacutainer tubes needed for the tests required should be determined, and nearby ready to be used. The order that the tubes are used is important, and should be known before puncturing the skin. Other equipment that will or may be needed should also be handy. This includes foil or an amber tube to shield specimins from light, or ice or heat packs for temperature sensitive samples.
- The Tubes for blood collection must be properly labelled and put in order
- A tourniquet should be placed on the arm where blood is to be collected. This should be just tight enough that blood collects in the veins.
- The vein to be used should be palpated; its depth, size and direction should be determined, and the best angle to puncture the skin planned.
- The skin around the area should be wiped with an alcohol swab (or iodine prep if drawing for blood culture) and allowed to air dry. An appropriate needle should be placed into a holder.
- The needle should be inserted into the vein with the bevel facing upwards. It should be pushed quickly and smoothly through the skin to minimize pain and to prevent blood from spouting out through the bevel.
- Once the needle is in the vein, a BD Vacutainer tube should be pushed into the needle holder. Care should be taken to ensure the needle does not move too much. The tube will fill itself up with blood.
- The tube can be removed once full, and the next one pushed into the holder. For tubes that contain additives it is important to be sure that the minimum amount of blood is in the tube or the blood to additive ratio will not be correct. This can impact the suitability of the sample for testing. Some types of tubes such as Sodium Citrate, EDTA, Lithim Heparin, and Sodium Heparin must be mixed after drawing. This is done by inverting the tube seven times, NOT shaking the tube as this can cause hemolysis.
- On the last tube, the tourniquet should be loosened or removed once blood starts to enter the tube. Make sure the tourniquet does not stay on longer than one minute.
- The last tube should be removed from the holder before the needle is pulled from the vein.
- The needle should be pulled out of the skin on the same angle it went in.
- Once the needle is removed, clean gauze should be pressed onto the wound, and the patient instructed to apply pressure to it to minimize bruising or echymosis.
- The needle should then be disposed of into a sharps container in a safe manner to avoid needlestick injury.
- The tubes should be well mixed by inverting them gently a number of times, and labelled straight away. The wound under the gauze should be checked, then the gauze or an adhesive bandage taped to the patient's arm.
- The patient should be instructed not to lift heavy objects or perform strenuous activities for about 12 hours, otherwise bruising is likely to result.
To prevent cross-contamination of samples with additives from other tubes, it is necessary to insert and withdraw BD Vacutainer tubes in a set order, referred to by phlebotomists as the "Order of Draw." When drawing blood for very sensitive testing, it is sometimes advisable to first draw a red top (no additive) tube, which is then discarded, to eliminate from the sample the interstitial fluid that comes from the puncture site rather than from the bloodstream. Subsequent tube order is determined by the need to prevent a tube's contamination by additives used in a previous tube that might affect laboratory analysis.
## Venipuncture with needle and syringe
A syringe is used to manually extract blood from a patient. The very young, very old and anyone with problematic veins are all candidates for this old-fashioned method. Because syringes are manually operated, the amount of suction applied may be easily controlled. The procedure is similar to what is described in the section above. After the needle is inserted into the vein, the phlebotomist receives confirmation of success when a small amount of blood appears in the back of the needle. This is often referred to as 'flash'. The plunger is then pulled backwards and blood fills the syringe. If the syringe plunger is pulled back too quickly red blood cells may be broken (hemolyzed) by turbulence or physical forces as they are forced through the needle. The blood is usually transferred quickly to a BD Vacutainer tube before clotting sets in using a similar defined tube order; normally the opposite of the order of draw when using a BD Vacutainer tube.
# Blood cultures
Most often, blood cultures are drawn using a "butterfly" needle.
When drawing blood cultures, the aerobic culture should be drawn first. Aerobic refers to bacteria that grow in the air and anaerobic refers to bacteria that do not grow in the air. Since there is air in the "butterfly" needle tubing anaerobic specimens cannot be drawn without first removing the air from the tubing. The tops of any containers used when drawing a blood culture should be sterilized with isopropyl alcohol.
# Blood alcohol tests
It is generally not advisable to use isopropyl alcohol to cleanse the venipuncture site when obtaining a specimen for a blood alcohol (BAC) test to test blood alcohol levels. Using soap and hot water is an acceptable alternative to isopropyl alcohol when using venipuncture to collect blood sample for BAC tests. | Venipuncture
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
In medicine venipuncture or venepuncture (also known as phlebotomy, venesection, blood draw, drawing blood or taking blood) is the process of obtaining a sample of venous blood. Usually a 5 ml to 25 ml sample of blood is adequate depending on what blood tests have been requested. In many circumstances it will be done by a phlebotomist, although nurses, doctors, some EMTs, Paramedics and other medical staff are also trained to take blood.
Blood is most commonly obtained from the median cubital vein, on the anterior forearm (the side within the fold of the elbow). This vein lies close to the surface of the skin, and there is not a large nerve supply.
Minute quantities of blood may be taken by fingersticks sampling and collected from infants by means of a heel stick or from scalp veins with a butterfly needle.
Phlebotomy (incision into a vein) is also the treatment of certain diseases such as hemochromatosis and primary and secondary polycythemia.
# Equipment
There are many ways which blood can be drawn from a vein. The best method varies with the age of the patient, equipment available and tests required.
Most blood collection in the US and UK is done with an evacuated tube system, such as the BD Vacutainer system or similar blood collection equipment consisting of a plastic hub, a hypodermic needle, and a vacuum tube. Under certain circumstances, a syringe may be used, usually with a butterfly needle, which is a plastic catheter attached to a short needle. In the developing world, a needle and syringe are still the most common method of drawing blood.
Blood is usually drawn from a vein in the crook of the elbow, the antecubital region. Tubes have color-coded stoppers to indicate what type of anticoagulant or other substance is in the tube. Tubes may contain no additive, a gel substance which separates cells from serum, or a variety of anticoagulants or preservatives (e.g. sodium heparin, sodium citrate, sodium fluoride and potassium oxalate or potassium EDTA).
## Venipuncture with evacuated or vacuum tubes
Vacuum tubes, or BD Vacutainer tubes are a type of test tube that contain a vacuum that automatically aspirates blood into itself. They are made of glass or plastic. They are commonly used in US and UK hospitals, private doctors' offices and community labs, and are effective in most adult patients and older children. For infants or toddlers, there are smaller size BD Vacutainer tubes available.
Equipment needed includes: a plastic needle holder or "barrel", needles designed specifically for the needle holder, an adjustable tourniquet, appropriate tubes, alcohol swabs, 2x2 gauze pads (cotton balls used to be used, but they have been found to dislodge the clot and the patient bleeds again causing larger hematomas), sticky tape, and a pen for labeling.
Below is a sample of the procedure used when blood is collected with BD Vacutainer tubes.
- First, the patient should be identified -- a test result is useless if it is done on the wrong person. The test subject should be asked their name and date of birth. This should not be a yes or no question, e.g. Are you Stanley Jones?, as many people will just agree, especially if they are elderly and have hearing difficulties or senility.
- The BD Vacutainer tubes needed for the tests required should be determined, and nearby ready to be used. The order that the tubes are used is important, and should be known before puncturing the skin. Other equipment that will or may be needed should also be handy. This includes foil or an amber tube to shield specimins from light, or ice or heat packs for temperature sensitive samples.
- The Tubes for blood collection must be properly labelled and put in order
- A tourniquet should be placed on the arm where blood is to be collected. This should be just tight enough that blood collects in the veins.
- The vein to be used should be palpated; its depth, size and direction should be determined, and the best angle to puncture the skin planned.
- The skin around the area should be wiped with an alcohol swab (or iodine prep if drawing for blood culture) and allowed to air dry. An appropriate needle should be placed into a holder.
- The needle should be inserted into the vein with the bevel facing upwards. It should be pushed quickly and smoothly through the skin to minimize pain and to prevent blood from spouting out through the bevel.
- Once the needle is in the vein, a BD Vacutainer tube should be pushed into the needle holder. Care should be taken to ensure the needle does not move too much. The tube will fill itself up with blood.
- The tube can be removed once full, and the next one pushed into the holder. For tubes that contain additives it is important to be sure that the minimum amount of blood is in the tube or the blood to additive ratio will not be correct. This can impact the suitability of the sample for testing. Some types of tubes such as Sodium Citrate, EDTA, Lithim Heparin, and Sodium Heparin must be mixed after drawing. This is done by inverting the tube seven times, NOT shaking the tube as this can cause hemolysis.
- On the last tube, the tourniquet should be loosened or removed once blood starts to enter the tube. Make sure the tourniquet does not stay on longer than one minute.
- The last tube should be removed from the holder before the needle is pulled from the vein.
- The needle should be pulled out of the skin on the same angle it went in.
- Once the needle is removed, clean gauze should be pressed onto the wound, and the patient instructed to apply pressure to it to minimize bruising or echymosis.
- The needle should then be disposed of into a sharps container in a safe manner to avoid needlestick injury.
- The tubes should be well mixed by inverting them gently a number of times, and labelled straight away. The wound under the gauze should be checked, then the gauze or an adhesive bandage taped to the patient's arm.
- The patient should be instructed not to lift heavy objects or perform strenuous activities for about 12 hours, otherwise bruising is likely to result.
To prevent cross-contamination of samples with additives from other tubes, it is necessary to insert and withdraw BD Vacutainer tubes in a set order, referred to by phlebotomists as the "Order of Draw." When drawing blood for very sensitive testing, it is sometimes advisable to first draw a red top (no additive) tube, which is then discarded, to eliminate from the sample the interstitial fluid that comes from the puncture site rather than from the bloodstream. Subsequent tube order is determined by the need to prevent a tube's contamination by additives used in a previous tube that might affect laboratory analysis.
## Venipuncture with needle and syringe
A syringe is used to manually extract blood from a patient. The very young, very old and anyone with problematic veins are all candidates for this old-fashioned method. Because syringes are manually operated, the amount of suction applied may be easily controlled. The procedure is similar to what is described in the section above. After the needle is inserted into the vein, the phlebotomist receives confirmation of success when a small amount of blood appears in the back of the needle. This is often referred to as 'flash'. The plunger is then pulled backwards and blood fills the syringe. If the syringe plunger is pulled back too quickly red blood cells may be broken (hemolyzed) by turbulence or physical forces as they are forced through the needle. The blood is usually transferred quickly to a BD Vacutainer tube before clotting sets in using a similar defined tube order; normally the opposite of the order of draw when using a BD Vacutainer tube.
# Blood cultures
Most often, blood cultures are drawn using a "butterfly" needle.
When drawing blood cultures, the aerobic culture should be drawn first. Aerobic refers to bacteria that grow in the air and anaerobic refers to bacteria that do not grow in the air. Since there is air in the "butterfly" needle tubing anaerobic specimens cannot be drawn without first removing the air from the tubing. The tops of any containers used when drawing a blood culture should be sterilized with isopropyl alcohol.
# Blood alcohol tests
It is generally not advisable to use isopropyl alcohol to cleanse the venipuncture site when obtaining a specimen for a blood alcohol (BAC) test to test blood alcohol levels. Using soap and hot water is an acceptable alternative to isopropyl alcohol when using venipuncture to collect blood sample for BAC tests. | https://www.wikidoc.org/index.php/Phlebotomy_(modern) | |
1baa1c223a734652a38128e25c634f57af85d01f | wikidoc | Phosphamidon | Phosphamidon
# Overview
Phosphamidon is an organophosphate insecticide first reported in 1960. It acts as a cholinesterase inhibitor.
The commercial product typically exists as a mixture of 70% (Z)-isomer and 30% (E)-isomer.
# Toxicity and regulation
Phosphamidon is very highly toxic to mammals and is listed as WHO Hazard Class Ia. A harvester developed symptoms of moderately severe poisoning after working in a field that had been sprayed with the chemical 2 weeks earlier. He collapsed and exhibited significant depression of serum cholinesterase, but recovered completely within 2 days after successful treatment with atropine. International trade of phosphamidon is covered by the Rotterdam Convention. | Phosphamidon
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Phosphamidon is an organophosphate insecticide first reported in 1960. It acts as a cholinesterase inhibitor.
The commercial product typically exists as a mixture of 70% (Z)-isomer and 30% (E)-isomer.
# Toxicity and regulation
Phosphamidon is very highly toxic to mammals and is listed as WHO Hazard Class Ia. A harvester developed symptoms of moderately severe poisoning after working in a field that had been sprayed with the chemical 2 weeks earlier. He collapsed and exhibited significant depression of serum cholinesterase, but recovered completely within 2 days after successful treatment with atropine.[4] International trade of phosphamidon is covered by the Rotterdam Convention. | https://www.wikidoc.org/index.php/Phosphamidon | |
02e3168981e77c5193ea950f2d510a7cf0ce4f90 | wikidoc | Phospho soda | Phospho soda
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
Phospho soda is an over the counter saline laxative. It is often taken to prepare for colonoscopy.
An amount of Phospho soda (normally 1.5 fluid ounce or 45 ml ) is usually mixed with water other clear liquids such as ginger ale. This preparation usually results in a bowel movement anywhere from 30 minutes to 6 hours after it is taken. Phospho soda is also available in flavors to make it more palatable.
When Phospho-Soda is taken for colonoscopy prep the dose is usually 1.5 fluid ounces, twice in one day (3 oz total) usually 6 hours apart & is to be mixed with equal parts water (or other clear liquid) and then followed by 8 oz water. It will create very loose, {liquid} stool within 1/2 hour to 6 hours, usually about one hour.
Phospho-Soda can be used for a general laxative, but is not recommended. The dosage then is best cut in half & used only once instead of twice.
Phospho-Soda works by drawing liquid from the body into the colon, therefore it can cause severe dehydration if not used properly, and sometimes can even then. Use with your doctors knowledge & consent for best results.
Further info can be found on the {Fleet} website. | Phospho soda
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [1] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
Phospho soda is an over the counter saline laxative. It is often taken to prepare for colonoscopy.
An amount of Phospho soda (normally 1.5 fluid ounce or 45 ml [2]) is usually mixed with water other clear liquids such as ginger ale. This preparation usually results in a bowel movement anywhere from 30 minutes to 6 hours after it is taken. Phospho soda is also available in flavors to make it more palatable.
When Phospho-Soda is taken for colonoscopy prep the dose is usually 1.5 fluid ounces, twice in one day (3 oz total) usually 6 hours apart & is to be mixed with equal parts water (or other clear liquid) and then followed by 8 oz water. It will create very loose, {liquid} stool within 1/2 hour to 6 hours, usually about one hour.
Phospho-Soda can be used for a general laxative, but is not recommended. The dosage then is best cut in half & used only once instead of twice.
Phospho-Soda works by drawing liquid from the body into the colon, therefore it can cause severe dehydration if not used properly, and sometimes can even then. Use with your doctors knowledge & consent for best results.
Further info can be found on the {Fleet} website.
# External links
- Fleet's FAQ
Template:SIB
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Phospho_soda | |
3fb8d8fb32ae2f962a9971dffea47c894b781ee6 | wikidoc | Phospholipid | Phospholipid
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
# Overview
Phospholipids are a class of lipids, and a major component of all biological membranes, along with glycolipids, cholesterol and proteins. Understanding of the aggregation properties of these molecules is known as lipid polymorphism and forms part of current academic research.
# Amphipathic character
Due to its polar nature, the head of a phospholipid is hydrophilic (attracted to water); the lipophilic (or often known as hydrophobic) tails are not attracted to water. When placed in water, phospholipids form one of a number of lipid phases. In biological systems this is restricted to bilayers, in which the lipophilic tails line up against one another, forming a membrane with hydrophilic heads on both sides facing the water. This allows it to form liposomes spontaneously, or small lipid vesicles, which can then be used to transport materials into living organisms and study diffusion rates into or out of a cell membrane.
This membrane is partially permeable, capable of elastic movement, and has fluid properties, in which embedded proteins (integral or peripheral proteins) and phospholipid molecules are able to move laterally. Such movement can be described by the Fluid Mosaic Model, that describes the membrane as a mosaic of lipid molecules that act as a solvent for all the substances and proteins within it, so proteins and lipid molecules are then free to diffuse laterally through the lipid matrix and migrate over the membrane. Cholesterol contributes to membrane fluidity by hindering the packing together of phospholipids. However, this model has now been superseded, as through the study of lipid polymorphism it is now known that the behaviour of lipids under physiological (and other) conditions is not simple. | Phospholipid
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [1] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
# Overview
Phospholipids are a class of lipids, and a major component of all biological membranes, along with glycolipids, cholesterol and proteins. Understanding of the aggregation properties of these molecules is known as lipid polymorphism and forms part of current academic research.
# Amphipathic character
Due to its polar nature, the head of a phospholipid is hydrophilic (attracted to water); the lipophilic (or often known as hydrophobic) tails are not attracted to water. When placed in water, phospholipids form one of a number of lipid phases. In biological systems this is restricted to bilayers, in which the lipophilic tails line up against one another, forming a membrane with hydrophilic heads on both sides facing the water. This allows it to form liposomes spontaneously, or small lipid vesicles, which can then be used to transport materials into living organisms and study diffusion rates into or out of a cell membrane.
This membrane is partially permeable, capable of elastic movement, and has fluid properties, in which embedded proteins (integral or peripheral proteins) and phospholipid molecules are able to move laterally. Such movement can be described by the Fluid Mosaic Model, that describes the membrane as a mosaic of lipid molecules that act as a solvent for all the substances and proteins within it, so proteins and lipid molecules are then free to diffuse laterally through the lipid matrix and migrate over the membrane. Cholesterol contributes to membrane fluidity by hindering the packing together of phospholipids. However, this model has now been superseded, as through the study of lipid polymorphism it is now known that the behaviour of lipids under physiological (and other) conditions is not simple. | https://www.wikidoc.org/index.php/Phospholipid | |
98a5454df7ef9c62e82d9154bc977efc0685c0a6 | wikidoc | Phrygian cap | Phrygian cap
# Overview
Phrygian cap is the transverse congenital septum in the fundus of the gallbladder. The original term referred to simple folding of the fundus, suggesting a septum radiographically. A causal relationship to the segmental form ofadenomyomatosis has been suggested but remains doubtful
# Historical Perspective
- Phrygia was an ancient country of Asia Minor, in what is now Turkey.
- The Phrygian cap was adopted by freed slaves in Roman times, and thus this cap became a symbol of liberty.
- This headgear made its last appearance in the 18th century during the French Revolution.
- It can be found atop a sword on the US Seal Of The Department Of The Army.
- Phygian caps are worn by smurfs.
# Diagnosis
On imaging, a transverse septum extends across the fundus of the gallbladder is seen. | Phrygian cap
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Phrygian cap is the transverse congenital septum in the fundus of the gallbladder. The original term referred to simple folding of the fundus, suggesting a septum radiographically. A causal relationship to the segmental form ofadenomyomatosis has been suggested but remains doubtful
# Historical Perspective
- Phrygia was an ancient country of Asia Minor, in what is now Turkey.
- The Phrygian cap was adopted by freed slaves in Roman times, and thus this cap became a symbol of liberty.
- This headgear made its last appearance in the 18th century during the French Revolution.
- It can be found atop a sword on the US Seal Of The Department Of The Army.
- Phygian caps are worn by smurfs.
# Diagnosis
On imaging, a transverse septum extends across the fundus of the gallbladder is seen.
-
- | https://www.wikidoc.org/index.php/Phrygian_cap | |
c40737fb8267a92ae718658f75968fb5c37edeae | wikidoc | Pickled tofu | Pickled tofu
Pickled tofu also called tofu cheese, preserved tofu, or fermented tofu) is a form of processed preservative tofu used in Chinese cuisine.
# Production
In order to produce pickled tofu, cubes of dried tofu are allowed to fully air-dry under hay and slowly ferment from aerial bacteria and fungal spores. Commercially available pickled tofu is made by using dry firm tofu that has been inoculated with the fungal spores of Actinomucor elegans, Mucor racemosus, or Rhizopus spp..
The dry fermented tofu is then soaked in brine, typically enhanced with Chinese rice wine, vinegar, chili peppers or sesame oil, or a paste made of rice and soybeans. In the case of red pickled tofu (Template:Zh-tp), red yeast rice (cultivated with Monascus purpureus) is added for color. Pickled tofu is generally sold in small glass jars.
# Characteristics
Pickled tofu has a special mouthfeel similar to certain dairy products due to the breakdown of its proteins which takes place during the air drying and fermentation. Since it does not have a strong odor by itself, pickled tofu takes on the smells and taste of its soaking liquid. The texture and taste of pickled tofu resembles a firm, smooth paste not unlike creamy blue cheese. (Indeed, this kind of tofu is sometimes called "Chinese cheese" in English). When refrigerated, it can be kept for several years, during which time its flavor is believed to improve.
# Use
Pickled tofu is commonly added in small amounts, together with a little bit of its soaking liquid, to flavor stir-fried or braised vegetable dishes (particularly leafy green vegetables like water spinach). Often, it is eaten directly as a condiment with rice or congee.
# Notes
- ↑ The
Hwang Ryh Shang Company of Taiwan, a major producer of pickled tofu, mislabels this ingredient as "red date" (jujube) on the English-language list of ingredients on its product labels, although the Chinese list of ingredients on the same product lists 紅糟 (red yeast rice). | Pickled tofu
Template:Chinese
Pickled tofu also called tofu cheese, preserved tofu, or fermented tofu) is a form of processed preservative tofu used in Chinese cuisine.
# Production
In order to produce pickled tofu, cubes of dried tofu are allowed to fully air-dry under hay and slowly ferment from aerial bacteria and fungal spores. Commercially available pickled tofu is made by using dry firm tofu that has been inoculated with the fungal spores of Actinomucor elegans, Mucor racemosus, or Rhizopus spp..
The dry fermented tofu is then soaked in brine, typically enhanced with Chinese rice wine, vinegar, chili peppers or sesame oil, or a paste made of rice and soybeans. In the case of red pickled tofu (Template:Zh-tp), red yeast rice (cultivated with Monascus purpureus) is added for color.[1] Pickled tofu is generally sold in small glass jars.
# Characteristics
Pickled tofu has a special mouthfeel similar to certain dairy products due to the breakdown of its proteins which takes place during the air drying and fermentation. Since it does not have a strong odor by itself, pickled tofu takes on the smells and taste of its soaking liquid. The texture and taste of pickled tofu resembles a firm, smooth paste not unlike creamy blue cheese. (Indeed, this kind of tofu is sometimes called "Chinese cheese" in English). When refrigerated, it can be kept for several years, during which time its flavor is believed to improve.
# Use
Pickled tofu is commonly added in small amounts, together with a little bit of its soaking liquid, to flavor stir-fried or braised vegetable dishes (particularly leafy green vegetables like water spinach). Often, it is eaten directly as a condiment with rice or congee.
# Notes
- ↑ The
Hwang Ryh Shang Company of Taiwan, a major producer of pickled tofu, mislabels this ingredient as "red date" (jujube) on the English-language list of ingredients on its product labels[1], although the Chinese list of ingredients on the same product lists 紅糟 (red yeast rice).
# External links
- Guide to making pickled tofu (Chinese) | https://www.wikidoc.org/index.php/Pickled_tofu | |
95b90200291ffddc45128649b400dfba01ee94a0 | wikidoc | Picornavirus | Picornavirus
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
# Overview
A Picornavirus is a virus belonging to the family Picornaviridae. Picornaviruses are non-enveloped, positive-stranded RNA viruses with an icosahedral capsid. The genome RNA is unusual because it has a protein on the 5' end that is used as a primer for transcription by RNA polymerase. The name is derived from pico meaning small, and RNA referring to the ribonucleic acid genome, so "picornavirus" literally means small RNA virus.
Picornaviruses are separated into nine distinct genera and include many important pathogens of humans and animals. The diseases they cause are varied, ranging from acute "common-cold"-like illnesses, to chronic infections in livestock. Two main categories are enteroviruses and rhinoviruses.
# Classification
Picornaviruses are classed under Baltimore's viral classification system as group IV viruses as they contain a single stranded, positive sense RNA genome of between 7.2 and 9.0 kb in length. Like most positive sense RNA genomes, the genetic material alone is infectious; although substantially less virulent than if contained within the viral particle, the RNA can have increased infectivity when transfected into cells. The genome itself is the same sense as mammalian mRNA, being read 5’ to 3’. Unlike mammalian mRNA Picornaviruses do not have a 5’ CAP but a virally encoded protein known as VPg, however like mammalian mRNA the genome does have a poly A tail at the 3’ end. There is an un-translated region (UTR) at both ends of the Picornavirus genome. The 5’ UTR is longer, being around 600-1200 BP in length, compared to that of the 3’ UTR, which is around 50-100bp. It is thought that the 5’ UTR is important in translation and the 3’ in negative strand synthesis; however the 5’ end may also have a role to play in virulence of the virus. The rest of the genome encodes structural proteins at the 5’ end and non-structural proteins at the 3’ end in a single polyprotein.
Experimental data from single step growth curve like experiments have allowed scientists to look at the replication of the picornaviruses in great detail. The whole of replication occurs within the host cell cytoplasm and infection can even happen in cells that do not contain a nucleus (known as enucleated cells) and those treated with actinomycin D (this antibiotic would inhibit viral replication is this occurred in the nucleus.)
# Structure of the Picornaviruses
The capsid is an arrangement of 60 protomers in a tightly packed Icosahedral structure. Each protomer consists of 4 polypeptides known as VP (viral protein)1, 2, 3 and 4. All of these VP polypeptides originate from one protomer known as VP0 that is cleaved to give the different capsid components. The Icosahedral is said to have a triangulation number of 3, this means that in the icosahedral structure each of the 60 triangles that make up the capsid are slip into 3 little triangles with a subunit on the corner.
Depending on the type and degree of dehydration the viral particle is around 27-30nm in diameter. The viral genome is around 2500nm in length so we can therefore conclude that it must be tightly packaged within the capsid along with substances such as sodium ions in order to cancel out the negative charges on the RNA caused by the phosphate groups.
# Picornavirus replication
The viral particle binds to cell surface receptors. This causes a conformational change in the viral capsid proteins, and myristic acids are released. These acids form a pore in the cell membrane through which RNA is injected. Once inside the cell, the RNA un-coats and the genome is translated by host cell machinery in the cytoplasm. This is very rapid with the whole process of replication being completed on average within 8 hours. However as little as 30 minutes after initial infection, cell protein synthesis declines to almost zero output – essentially the macromolecular synthesis of cell proteins is “shut off”. Over the next 1-2 hours there is a loss of margination of chromatin and homogeneity in the nucleus, before the viral proteins start to be synthesized and a vacuole appears in the cytoplasm close to the nucleus that gradually starts to spread as the time after infection reaches around 3 hours. After this time the cell plasma membrane becomes permeable, at 4-6 hours the virus particles assemble, and can sometimes be seen in the cytoplasm. At around 8 hours the cell is effectively dead and lyses to release the viral particles.
# History
In 1897, foot-and-mouth disease virus (FMDV), the first animal virus, was discovered. FMDV is the prototypic member of the Aphthovirus genus in the Picornaviridae family. The plaque assay was developed using poliovirus. Both RNA dependent RNA polymerase and polyprotein synthesis were discovered by studying poliovirus infected cells.
# Types of Picornavirus
Picornaviruses are separated into nine distinct genera. Contained within the picornovirus family are many organisms of importance as vertebrate and human pathogens, shown in the table below.
Enteroviruses infect the enteric tract as it is visible from its name. On the other hand, Rhinoviruses infect primarily the nose and the throat. Enteroviruses replicate at 37°C, whereas Rhinoviruses grow better at 33°C, as this is the lower temperature of the nose. Enteroviruses are stable under acid conditions and thus they are able to survive exposure to gastric acid. In contrast, Rhinoviruses are acid-labile and that is the reason why Rhinoviruses are restricted to the nose and throat. | Picornavirus
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [2] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
# Overview
A Picornavirus is a virus belonging to the family Picornaviridae. Picornaviruses are non-enveloped, positive-stranded RNA viruses with an icosahedral capsid. The genome RNA is unusual because it has a protein on the 5' end that is used as a primer for transcription by RNA polymerase. The name is derived from pico meaning small, and RNA referring to the ribonucleic acid genome, so "picornavirus" literally means small RNA virus.
Picornaviruses are separated into nine distinct genera and include many important pathogens of humans and animals.[1] The diseases they cause are varied, ranging from acute "common-cold"-like illnesses, to chronic infections in livestock. Two main categories are enteroviruses and rhinoviruses.
# Classification
Picornaviruses are classed under Baltimore's viral classification system as group IV viruses as they contain a single stranded, positive sense RNA genome of between 7.2 and 9.0 kb in length. Like most positive sense RNA genomes, the genetic material alone is infectious; although substantially less virulent than if contained within the viral particle, the RNA can have increased infectivity when transfected into cells. The genome itself is the same sense as mammalian mRNA, being read 5’ to 3’. Unlike mammalian mRNA Picornaviruses do not have a 5’ CAP but a virally encoded protein known as VPg, however like mammalian mRNA the genome does have a poly A tail at the 3’ end. There is an un-translated region (UTR) at both ends of the Picornavirus genome. The 5’ UTR is longer, being around 600-1200 BP in length, compared to that of the 3’ UTR, which is around 50-100bp. It is thought that the 5’ UTR is important in translation and the 3’ in negative strand synthesis; however the 5’ end may also have a role to play in virulence of the virus. The rest of the genome encodes structural proteins at the 5’ end and non-structural proteins at the 3’ end in a single polyprotein.
Experimental data from single step growth curve like experiments have allowed scientists to look at the replication of the picornaviruses in great detail. The whole of replication occurs within the host cell cytoplasm and infection can even happen in cells that do not contain a nucleus (known as enucleated cells) and those treated with actinomycin D (this antibiotic would inhibit viral replication is this occurred in the nucleus.)
# Structure of the Picornaviruses
The capsid is an arrangement of 60 protomers in a tightly packed Icosahedral structure. Each protomer consists of 4 polypeptides known as VP (viral protein)1, 2, 3 and 4. All of these VP polypeptides originate from one protomer known as VP0 that is cleaved to give the different capsid components. The Icosahedral is said to have a triangulation number of 3, this means that in the icosahedral structure each of the 60 triangles that make up the capsid are slip into 3 little triangles with a subunit on the corner.
Depending on the type and degree of dehydration the viral particle is around 27-30nm in diameter. The viral genome is around 2500nm in length so we can therefore conclude that it must be tightly packaged within the capsid along with substances such as sodium ions in order to cancel out the negative charges on the RNA caused by the phosphate groups.
# Picornavirus replication
The viral particle binds to cell surface receptors. This causes a conformational change in the viral capsid proteins, and myristic acids are released. These acids form a pore in the cell membrane through which RNA is injected[3]. Once inside the cell, the RNA un-coats and the genome is translated by host cell machinery in the cytoplasm. This is very rapid with the whole process of replication being completed on average within 8 hours. However as little as 30 minutes after initial infection, cell protein synthesis declines to almost zero output – essentially the macromolecular synthesis of cell proteins is “shut off”. Over the next 1-2 hours there is a loss of margination of chromatin and homogeneity in the nucleus, before the viral proteins start to be synthesized and a vacuole appears in the cytoplasm close to the nucleus that gradually starts to spread as the time after infection reaches around 3 hours. After this time the cell plasma membrane becomes permeable, at 4-6 hours the virus particles assemble, and can sometimes be seen in the cytoplasm. At around 8 hours the cell is effectively dead and lyses to release the viral particles.
# History
In 1897, foot-and-mouth disease virus (FMDV), the first animal virus, was discovered. FMDV is the prototypic member of the Aphthovirus genus in the Picornaviridae family. [2]The plaque assay was developed using poliovirus. Both RNA dependent RNA polymerase and polyprotein synthesis were discovered by studying poliovirus infected cells.
# Types of Picornavirus
Picornaviruses are separated into nine distinct genera. Contained within the picornovirus family are many organisms of importance as vertebrate and human pathogens, shown in the table below.
Enteroviruses infect the enteric tract as it is visible from its name. On the other hand, Rhinoviruses infect primarily the nose and the throat. Enteroviruses replicate at 37°C, whereas Rhinoviruses grow better at 33°C, as this is the lower temperature of the nose. Enteroviruses are stable under acid conditions and thus they are able to survive exposure to gastric acid. In contrast, Rhinoviruses are acid-labile and that is the reason why Rhinoviruses are restricted to the nose and throat. | https://www.wikidoc.org/index.php/Picornaviridae | |
d5bdf9d7e67866aa0fb3cd7a4eb7ea7cd59dd43a | wikidoc | Pill testing | Pill testing
Pill Testing is a process used to identify substances contained within a pill, usually illicit substances.
Since illicit drugs like MDMA are bought from drug dealers on the black market, both the source and contents of the substance are unknown. Pills sold by dealers as Ecstasy, may not contain the desired substance, usually being MDMA. Testing the pill can show if substances, such as MDMA, are present.
# Reagent Testing Kits
A test is done by taking a small scraping from a pill and placing it in the reagent testing liquid. The liquid will change colour when reacting with different chemicals to indicate the presence of certain substances.
Testing with a reagent kit does not indicate the pill is safe. While the testing process does show some particular substances are present, it may not show a harmful substance unaccounted for by the testing process.
The EZ Test kits, Mandelin, Marquis, Mecke, Simon's and Robadope's are commercially available reagent testing kits. The EZ Test table is a general guideline of the reactions from each substance and testing kit instructions may indicate different results. Reactions may show different colours if more than one substance is present.
Online testing kits are used by individuals to post reports to the Pill Reports website. At nightclubs and rave events organisations such as Enlighten Harm Reduction in Australia and the Green Party Drugs Group in the UK conduct on-site pill testing.
# GC/MS
EcstasyData.org is an independent laboratory pill testing program co-sponsored by Erowid, TranceSafe, Dancesafe, Multidisciplinary Association for Psychedelic Studies (MAPS), & the Promind Foundation. Testing is done using a Gas chromatography-mass spectrometry (GC/MS) method, which can identify much more substances than a reagent test. Substances identified are listed on their website.
# Controversy
Pill testing is controversial because it can give the user the false impression that a pill is safe. The act of pill testing is illegal in many countries because it requires the tester to come into contact with the illicit substance and who can then be charged with possession of an illicit substance. | Pill testing
Pill Testing is a process used to identify substances contained within a pill, usually illicit substances.
Since illicit drugs like MDMA are bought from drug dealers on the black market, both the source and contents of the substance are unknown. Pills sold by dealers as Ecstasy, may not contain the desired substance, usually being MDMA. Testing the pill can show if substances, such as MDMA, are present.
# Reagent Testing Kits
A test is done by taking a small scraping from a pill and placing it in the reagent testing liquid. The liquid will change colour when reacting with different chemicals to indicate the presence of certain substances.
Testing with a reagent kit does not indicate the pill is safe. While the testing process does show some particular substances are present, it may not show a harmful substance unaccounted for by the testing process.
The EZ Test kits, Mandelin[1], Marquis[2], Mecke[3], Simon's and Robadope's[4] are commercially available reagent testing kits. The EZ Test table is a general guideline of the reactions from each substance and testing kit instructions may indicate different results. Reactions may show different colours if more than one substance is present.
Online testing kits are used by individuals to post reports to the Pill Reports [5] website. At nightclubs and rave events organisations such as Enlighten Harm Reduction in Australia and the Green Party Drugs Group[6] in the UK conduct on-site pill testing.
# GC/MS
EcstasyData.org is an independent laboratory pill testing program co-sponsored by Erowid, TranceSafe, Dancesafe, Multidisciplinary Association for Psychedelic Studies (MAPS), & the Promind Foundation. Testing is done using a Gas chromatography-mass spectrometry (GC/MS) method, which can identify much more substances than a reagent test. Substances identified are listed on their website.
# Controversy
Pill testing is controversial because it can give the user the false impression that a pill is safe. The act of pill testing is illegal in many countries because it requires the tester to come into contact with the illicit substance and who can then be charged with possession of an illicit substance.
# External links
- Substance Testing Kits - Reagents
- Pillreports Online Database | https://www.wikidoc.org/index.php/Pill_testing | |
f0e0d96988af0c5aa1d44831e729d08899272194 | wikidoc | Pimavanserin | Pimavanserin
# 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.
# Black Box Warning
# Overview
Pimavanserin is an atypical antipsychotic that is FDA approved for the treatment of patients with hallucinations and delusions associated with Parkinson's disease psychosis. There is a Black Box Warning for this drug as shown here. Common adverse reactions include peripheral edema and confusional state (≥5% and twice the rate of placebo)..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Pimavanserin is indicated for the treatment of hallucinations and delusions associated with Parkinson's disease psychosis.
- General Dosing Information
The recommended dose of Pimavanserin is 34 mg, taken orally as two 17 mg strength tablets once daily, without titration.
Pimavanserin can be taken with or without food.
- Dosage Modifications for Concomitant Use with CYP3A4 Inhibitors and Inducers
- Coadministration with Strong CYP3A4 Inhibitors
The recommended dose of Pimavanserin when coadministered with strong CYP3A4 inhibitors (e.g., ketoconazole) is 17 mg, taken orally as one tablet once daily.
- Coadministration with Strong CYP3A4 Inducers
Monitor patients for reduced efficacy if Pimavanserin is used concomitantly with strong CYP3A4 inducers; an increase in Pimavanserin dosage may be needed.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pimavanserin in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Pimavanserin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Safety and effectiveness have not been established in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pimavanserin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Pimavanserin in pediatric patients.
# Contraindications
None
# Warnings
Antipsychotic drugs increase the all-cause risk of death in elderly patients with dementia-related psychosis. Analyses of 17 dementia-related psychosis placebo-controlled trials (modal duration of 10 weeks and largely in patients taking atypical antipsychotic drugs) revealed a risk of death in the drug-treated patients of between 1.6- to 1.7-times that in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in placebo-treated patients.
Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Pimavanserin is not approved for the treatment of patients with dementia-related psychosis unrelated to the hallucinations and delusions associated with Parkinson's disease psychosis.
Pimavanserin prolongs the QT interval. The use of Pimavanserin should be avoided in patients with known QT prolongation or in combination with other drugs known to prolong QT interval including Class 1A antiarrhythmics (e.g., quinidine, procainamide) or Class 3 antiarrhythmics (e.g., amiodarone, sotalol), certain antipsychotic medications (e.g., ziprasidone, chlorpromazine, thioridazine), and certain antibiotics (e.g., gatifloxacin, moxifloxacin). Pimavanserin should also be avoided in patients with a history of cardiac arrhythmias, as well as other circumstances that may increase the risk of the occurrence of torsade de pointes and/or sudden death, including symptomatic bradycardia, hypokalemia or hypomagnesemia, and the presence of congenital prolongation of the QT interval.
# Adverse Reactions
## Clinical Trials Experience
The following serious adverse reactions are discussed elsewhere in the labeling:
- Increased Mortality in Elderly Patients with Dementia-Related Psychosis
- QT Interval Prolongation
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 clinical trial database for Pimavanserin consists of over 1200 subjects and patients exposed to one or more doses of Pimavanserin. Of these, 616 were patients with hallucinations and delusions associated with Parkinson's disease psychosis (PDP). In the placebo-controlled setting, the majority of experience in patients comes from studies evaluating once-daily Pimavanserin doses of 34 mg (N=202) compared to placebo (N=231) for up to 6 weeks. In the controlled trial setting, the study population was approximately 64% male and 91% Caucasian, and the mean age was about 71 years at study entry. Additional clinical trial experience in patients with hallucinations and delusions associated with PDP comes from two open-label, safety extension studies (total N=497). The majority of patients receiving long-term treatment received 34 mg once-daily (N=459). Over 300 patients have been treated for more than 6 months; over 270 have been treated for at least 12 months; and over 150 have been treated for at least 24 months.
The following adverse reactions are based on the 6-week, placebo-controlled studies in which Pimavanserin was administered once daily to patients with hallucinations and delusions associated with PDP.
Common Adverse Reactions (incidence ≥5% and at least twice the rate of placebo): peripheral edema (7% Pimavanserin 34 mg vs. 2% placebo) and confusional state (6% Pimavanserin 34 mg vs. 3% placebo).
Adverse Reactions Leading to Discontinuation of Treatment
A total of 8% (16/202) of Pimavanserin 34 mg-treated patients and 4% (10/231) of placebo-treated patients discontinued because of adverse reactions. The adverse reactions that occurred in more than one patient and with an incidence at least twice that of placebo were hallucination (2% Pimavanserin vs. <1% placebo), urinary tract infection (1% Pimavanserin vs. <1% placebo), and fatigue (1% Pimavanserin vs. 0% placebo).
Adverse reactions that occurred in 6-week, placebo-controlled studies and that were reported at an incidence of ≥2% and >placebo are presented in Table 1.
- Table 1 Adverse Reactions in Placebo-Controlled Studies of 6-Week Treatment Duration and Reported in ≥2% and >Placebo
Adverse Reactions in Demographic Subgroups
Examination of population subgroups in the 6-week, placebo-controlled studies did not reveal any differences in safety on the basis of age (≤75 vs. >75 years) or sex. Because the study population was predominantly Caucasian (91%; consistent with reported demographics for PD/PDP), racial or ethnic differences in the safety profile of Pimavanserin could not be assessed. In addition, in the 6-week, placebo-controlled studies, no clinically relevant differences in the incidence of adverse reactions were observed among those with a Mini-Mental State Examination (MMSE) score at entry of <25 versus those with scores ≥25.
## Postmarketing Experience
There is limited information regarding Pimavanserin Postmarketing Experience in the drug label.
# Drug Interactions
- Table 2 Clinically Important Drug Interactions with Pimavanserin
Based on pharmacokinetic studies, no dosage adjustment of carbidopa/levodopa is required when administered concomitantly with Pimavanserin.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Risk Summary
There are no data on Pimavanserin use in pregnant women that would allow assessment of the drug-associated risk of major congenital malformations or miscarriage. In animal reproduction studies, no adverse developmental effects were seen when Pimavanserin was administered orally to rats or rabbits during the period of organogenesis at doses up to 10- or 12-times the maximum recommended human dose (MRHD) of 34 mg/day, respectively. Administration of Pimavanserinto pregnant rats during pregnancy and lactation resulted in maternal toxicity and lower pup survival and body weight at doses which are 2-times the MRHD of 34 mg/day.
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 2-4% and 15-20%, respectively.
- Data
- Animal Data
Pimavanserin was not teratogenic in pregnant rats when administered during the period of organogenesis at oral doses of 0.9, 8.5, and 51 mg/kg/day, which are 0.2- and 10-times the maximum recommended human dose (MRHD) of 34 mg/day based on AUC at mid and high doses, respectively. Maternal toxicity included reduction in body weight and food consumption at the highest dose.
Administration of Pimavanserin to pregnant rats during pregnancy and lactation at oral doses of 8.5, 26, and 51 mg/kg/day, which are 0.14- to 14-times the MRHD of 34 mg/day based on AUC, caused maternal toxicity, including mortality, clinical signs including dehydration, hunched posture, and rales, and decreases in body weight, and/or food consumption at doses ≥26 mg/kg/day (2-times the MRHD based on AUC). At these maternally toxic doses there was a decrease in pup survival, reduced litter size, and reduced pup weights, and food consumption. Pimavanserin had no effect on sexual maturation, neurobehavioral function including learning and memory, or reproductive function in the first generation pups up to 14-times the MRHD of 34 mg/day based on AUC.
Pimavanserin was not teratogenic in pregnant rabbits during the period of organogenesis at oral doses of 4.3, 43, and 85 mg/kg/day, which are 0.2- to 12-times the MRHD of 34 mg/day based on AUC. Maternal toxicity, including mortality, clinical signs of dyspnea and rales, decreases in body weight and/or food consumption, and abortions occurred at doses 12-times the MRHD of 34 mg/day based on AUC.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Pimavanserin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Pimavanserin during labor and delivery.
### Nursing Mothers
There is no information regarding the presence of Pimavanserin in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Pimavanserin and any potential adverse effects on the breastfed infant from Pimavanserin or from the underlying maternal condition.
### Pediatric Use
Safety and effectiveness of Pimavanserin have not been established in pediatric patients.
### Geriatic Use
No dose adjustment is required for elderly patients.
Parkinson's disease is a disorder occurring primarily in individuals over 55 years of age. The mean age of patients enrolled in the 6-week clinical studies with Pimavanserin was 71 years, with 49% 65-75 years old and 31% >75 years old. In the pooled population of patients enrolled in 6-week, placebo-controlled studies (N=614), 27% had MMSE scores from 21 to 24 compared to 73% with scores ≥25. No clinically meaningful differences in safety or effectiveness were noted between these two groups.
### Gender
There is no FDA guidance on the use of Pimavanserin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Pimavanserin with respect to specific racial populations.
### Renal Impairment
No dosage adjustment for Pimavanserin is needed in patients with mild to moderate (CrCL ≥30 mL/min, Cockcroft-Gault) renal impairment.
Use of Pimavanserin is not recommended in patients with severe renal impairment (CrCL <30 mL/min, Cockcroft-Gault). Pimavanserin has not been evaluated in this patient population.
### Hepatic Impairment
Use of Pimavanserin is not recommended in patients with hepatic impairment. Pimavanserin has not been evaluated in this patient population.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Pimavanserin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Pimavanserin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
The recommended dose of Pimavanserin is 34 mg, taken orally as two 17 mg strength tablets once daily, without titration.
Pimavanserin can be taken with or without food.
### Monitoring
There is limited information regarding Pimavanserin Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Pimavanserin and IV administrations.
# Overdosage
Human Experience
The pre-marketing clinical trials involving Pimavanserin in approximately 1200 subjects and patients do not provide information regarding symptoms with overdose. In healthy subject studies, dose-limiting nausea and vomiting were observed.
Management of Overdose
There are no known specific antidotes for Pimavanserin. In managing overdose, cardiovascular monitoring should commence immediately and should include continuous ECG monitoring to detect possible arrhythmias. If antiarrhythmic therapy is administered, disopyramide, procainamide, and quinidine should not be used, as they have the potential for QT-prolonging effects that might be additive to those of Pimavanserin. Consider the long plasma half-life of Pimavanserin (about 57 hours) and the possibility of multiple drug involvement. Consult a Certified Poison Control Center (1-800-222-1222) for up-to-date guidance and advice.
# Pharmacology
## Mechanism of Action
The mechanism of action of Pimavanserin in the treatment of hallucinations and delusions associated with Parkinson's disease psychosis is unknown. However, the effect of Pimavanserin could be mediated through a combination of inverse agonist and antagonist activity at serotonin 5-HT2A receptors and to a lesser extent at serotonin 5-HT2C receptors.
## Structure
There is limited information regarding Pimavanserin Structure in the drug label.
## Pharmacodynamics
In vitro, Pimavanserin acts as an inverse agonist and antagonist at serotonin 5-HT2A receptors with high binding affinity (Ki value 0.087 nM) and at serotonin 5-HT2C receptors with lower binding affinity (Ki value 0.44 nM). Pimavanserin shows low binding to sigma 1 receptors (Ki value 120 nM) and has no appreciable affinity (Ki value >300 nM), to serotonin 5-HT2B, dopaminergic (including D2), muscarinic, histaminergic, or adrenergic receptors, or to calcium channels.
Cardiac Electrophysiology
The effect of Pimavanserin on the QTc interval was evaluated in a randomized placebo- and positive-controlled double-blind, multiple-dose parallel thorough QTc study in 252 healthy subjects. A central tendency analysis of the QTc data at steady-state demonstrated that the maximum mean change from baseline (upper bound of the two-sided 90% CI) was 13.5 (16.6) msec at a dose of twice the therapeutic dose. A pharmacokinetic/ pharmacodynamic analysis with Pimavanserin suggested a concentration-dependent QTc interval prolongation in the therapeutic range.
In the 6-week, placebo-controlled effectiveness studies, mean increases in QTc interval of ~5-8 msec were observed in patients receiving once-daily doses of Pimavanserin 34 mg. These data are consistent with the profile observed in a thorough QT study in healthy subjects. Sporadic QTcF values ≥500 msec and change from baseline values ≥60 msec were observed in subjects treated with Pimavanserin 34 mg; although the incidence was generally similar for Pimavanserin and placebo groups. There were no reports of torsade de pointes or any differences from placebo in the incidence of other adverse reactions associated with delayed ventricular repolarization in studies of Pimavanserin, including those patients with hallucinations and delusions associated with PDP.
## Pharmacokinetics
Pimavanserin demonstrates dose-proportional pharmacokinetics after single oral doses from 17 to 255 mg (0.5- to 7.5-times the recommended dosage). The pharmacokinetics of Pimavanserin are similar in both the study population and healthy subjects. The mean plasma half-lives for Pimavanserin and the active metabolite (N-desmethylated metabolite) are approximately 57 hours and 200 hours, respectively.
Absorption
The median Tmax of Pimavanserin was 6 (range 4-24) hours and was generally unaffected by dose. The bioavailability of Pimavanserin oral tablet and Pimavanserin solution was essentially identical. The formation of the major circulating N-desmethylated metabolite AC-279 (active) from Pimavanserin occurs with a median Tmax of 6 hours.
Ingestion of a high-fat meal had no significant effect on rate (Cmax) and extent (AUC) of Pimavanserin exposure. Cmax decreased by about 9% while AUC increased by about 8% with a high-fat meal.
Distribution
Pimavanserin is highly protein bound (~95%) in human plasma. Protein binding appeared to be dose-independent and did not change significantly over dosing time from Day 1 to Day 14. Following administration of a single dose of Pimavanserin (34 mg), the mean (SD) apparent volume of distribution was 2173 (307) L.
Elimination
- Metabolism
Pimavanserin is predominantly metabolized by CYP3A4 and CYP3A5 and to a lesser extent by CYP2J2, CYP2D6, and various other CYP and FMO enzymes. CYP3A4 is the major enzyme responsible for the formation of its major active metabolite (AC-279). Pimavanserin does not cause clinically significant CYP inhibition or induction of CYP3A4. Based on in vitro data, Pimavanserin is not an irreversible inhibitor of any of the major hepatic and intestinal human CYP enzymes involved in drug metabolism (CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4).
Based on in vitro studies, transporters play no significant role in the disposition of Pimavanserin.
AC-279 is neither a reversible or irreversible (metabolism-dependent) inhibitor of any of the major hepatic and intestinal human CYP enzymes involved in drug metabolism (CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4). AC-279 does not cause clinically significant CYP3A induction and is not predicted to cause induction of any other CYP enzymes involved in drug metabolism.
- Excretion
Approximately 0.55% of the 34 mg oral dose of 14C-Pimavanserin was eliminated as unchanged drug in urine and 1.53% was eliminated in feces after 10 days.
Less than 1% of the administered dose of Pimavanserin and its active metabolite AC-279 were recovered in urine.
Specific Populations
Population PK analysis indicated that exposure of Pimavanserin in patients with mild to moderate renal impairment was similar to exposure in patients with normal renal function. Age, sex, ethnicity, and weight do not have clinically relevant effect on the pharmacokinetics of Pimavanserin.
Pimavanserin has not been studied in patients with severe renal impairment or mild to severe hepatic impairment.
Drug Interaction Studies
CYP3A4 Inhibitor: ketoconazole, a strong inhibitor of CYP3A4, increased Pimavanserin Cmax by 1.5-fold and AUC by 3-fold.
The effect of Pimavanserin on other drugs is shown in Figure 1.
- Figure 1 The Effects of Pimavanserin on the Pharmacokinetics of Other Drugs
NUPLAZID: Pimavanserin's Brand name
## Nonclinical Toxicology
- Carcinogenesis
There was no increase in the incidence of tumors following daily oral administration of Pimavanserin to mice or rats for 2 years. Mice were administered Pimavanserin at oral doses of 2.6, 6, and 13 (males)/8.5, 21, and 43 mg/kg/day (females) which are 0.01- to 1- (males)/0.5- to 7- (females) times the MRHD of 34 mg/day based on AUC. Rats were administered Pimavanserin at oral doses of 2.6, 8.5, and 26 (males)/4.3, 13, and 43 mg/kg/day (females) which are 0.01- to 4- (males)/0.04- to 16- (females) times the MRHD of 34 mg/day based on AUC.
- Mutagenesis
Pimavanserin was not mutagenic in the in vitro Ames reverse mutation test, or in the in vitro mouse lymphoma assay, and was not clastogenic in the in vivo mouse bone marrow micronucleus assay.
- Impairment of Fertility
Pimavanserin was administered orally to male and female rats before mating, through mating, and up to Day 7 of gestation at doses of 8.5, 51, and 77 mg/kg/day, which are approximately 2-, 15-, and 22-times the maximum recommended human dose (MRHD) of 34 mg/day based on mg/m2, respectively. Pimavanserin had no effect on fertility or reproductive performance in male and female rats at doses up to 22-times the MRHD of 34 mg based on mg/m2. Changes in uterine parameters (decreases in the number of corpora lutea, number of implants, viable implants, and increases in pre-implantation loss, early resorptions and post-implantation loss) occurred at the highest dose which was also a maternally toxic dose. Changes in sperm parameters (decreased density and motility) and microscopic findings of cytoplasmic vacuolation in the epididymis occurred at doses approximately 15-times the MRHD of 34 mg/day based on mg/m2.
Phospholipidosis (foamy macrophages and/or cytoplasmic vacuolation) was observed in multiple tissues and organs of mice, rats, and monkeys as early as 14 days following oral daily administration of Pimavanserin. The most severely affected organs were the lungs and kidneys. The occurrence of phospholipidosis was both dose- and duration-dependent. Diffuse phospholipidosis with focal/multifocal chronic inflammation was observed in the lungs of rats treated for ≥3 months at doses ≥10-times the maximum recommended human dose (MRHD) of 34 mg/day based on AUC. As a result of chronic inflammation, inflammatory lung fibrosis was observed in rats treated for 3 and 6 months at doses ≥18-times the MRHD of 34 mg/day based on AUC. The findings in the lungs correlated with increased lung weights (up to 3-times those of controls) and respiratory-related clinical signs including rales, labored breathing, and gasping. Phospholipidosis in lungs of rats caused mortality at doses ≥16-times the MRHD of 34 mg/day based on AUC. The estimated No Observed Effect Level (NOEL) for chronic lung inflammation in rats is 5-fold the MRHD of 34 mg/day based on AUC. Phospholipidosis was associated with increased kidney weights and tubular degeneration in rats at doses ≥10-times the MRHD of 34 mg/day based on AUC. The relevance of these findings to human risk is not known.
# Clinical Studies
The efficacy of Pimavanserin 34 mg as a treatment of hallucinations and delusions associated with Parkinson's disease psychosis was demonstrated in a 6-week, randomized, placebo-controlled, parallel-group study. In this outpatient study, 199 patients were randomized in a 1:1 ratio to Pimavanserin 34 mg or placebo once daily. Study patients (male or female and aged 40 years or older) had a diagnosis of Parkinson's disease (PD) established at least 1 year prior to study entry and had psychotic symptoms (hallucinations and/or delusions) that started after the PD diagnosis and that were severe and frequent enough to warrant treatment with an antipsychotic. At entry, patients were required to have a Mini-Mental State Examination (MMSE) score ≥21 and to be able to self-report symptoms. The majority of patients were on PD medications at entry; these medications were required to be stable for at least 30 days prior to study start and throughout the study period.
The PD-adapted Scale for the Assessment of Positive Symptoms (SAPS-PD) was used to evaluate the efficacy of Pimavanserin 34 mg. SAPS-PD is a 9-item scale adapted for PD from the Hallucinations and Delusions domains of the SAPS. Each item is scored on a scale of 0-5, with 0 being none and 5 representing severe and frequent symptoms. Therefore, the SAPS-PD total score can range from 0 to 45 with higher scores reflecting greater severity of illness. A negative change in score indicates improvement. Primary efficacy was evaluated based on change from baseline to Week 6 in SAPS-PD total score.
As shown in Table 3, Figure 2, and Figure 3, Pimavanserin 34 mg (n=95) was statistically significantly superior to placebo (n=90) in decreasing the frequency and/or severity of hallucinations and delusions in patients with PDP as measured by central, independent, and blinded raters using the SAPS-PD scale. An effect was seen on both the hallucinations and delusions components of the SAPS-PD.
- Table 3 Primary Efficacy Analysis Result Based on SAPS-PD (N=185)
NUPLAZID: Pimavanserin's Brand name
The effect of Pimavanserin on SAPS-PD improved through the six-week trial period, as shown in Figure 2.
- Figure 2 SAPS-PD Change from Baseline through 6 Weeks Total Study Treatment
NUPLAZID: Pimavanserin's Brand name
- Figure 3 Proportion of Patients with SAPS-PD Score Improvement at the End of Week 6 (N=185)
NUPLAZID: Pimavanserin's Brand name
Motor Function in Patients with Hallucinations and Delusions Associated with Parkinson's Disease Psychosis
Pimavanserin 34 mg did not show an effect compared to placebo on motor function, as measured using the Unified Parkinson's Disease Rating Scale Parts II and III (UPDRS Parts II+III) (Figure 4). A negative change in score indicates improvement. The UPDRS Parts II+III was used to assess the patient's Parkinson's disease state during the 6-week double-blind treatment period. The UPDRS score was calculated as the sum of the 40 items from activities of daily living and motor examination, with a range of 0 to 160.
- Figure 4 Motor Function Change from Baseline to Week 6 in UPDRS Parts II+III (LSM - SE)
NUPLAZID: Pimavanserin's Brand name
# How Supplied
Pimavanserin tablets are available as:
17 mg Tablet:
White to off-white, round, immediate-release, film-coated tablet debossed with "P" on one side and "17" on the reverse. . Each tablet contains 20 mg of pimavanserin tartrate, which is equivalent to 17 mg of Pimavanserin free base. Inactive ingredients include pregelatinized starch, magnesium stearate, and microcrystalline cellulose. Additionally, the following inactive ingredients are present as components of the film coat: hypromellose, talc, titanium dioxide, polyethylene glycol, and saccharin sodium.
Bottle of 60: NDC 63090-170-60
## Storage
Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Advise patients to inform their healthcare providers if there are any changes to their current prescription or over-the-counter medications, since there is a potential for drug interactions.
# Precautions with Alcohol
Alcohol-Pimavanserin interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
NUPLAZID™
# Look-Alike Drug Names
There is limited information regarding Pimavanserin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Pimavanserin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Martin Nino, M.D. [2]
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# Black Box Warning
# Overview
Pimavanserin is an atypical antipsychotic that is FDA approved for the treatment of patients with hallucinations and delusions associated with Parkinson's disease psychosis. There is a Black Box Warning for this drug as shown here. Common adverse reactions include peripheral edema and confusional state (≥5% and twice the rate of placebo)..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Pimavanserin is indicated for the treatment of hallucinations and delusions associated with Parkinson's disease psychosis.
- General Dosing Information
The recommended dose of Pimavanserin is 34 mg, taken orally as two 17 mg strength tablets once daily, without titration.
Pimavanserin can be taken with or without food.
- Dosage Modifications for Concomitant Use with CYP3A4 Inhibitors and Inducers
- Coadministration with Strong CYP3A4 Inhibitors
The recommended dose of Pimavanserin when coadministered with strong CYP3A4 inhibitors (e.g., ketoconazole) is 17 mg, taken orally as one tablet once daily.
- Coadministration with Strong CYP3A4 Inducers
Monitor patients for reduced efficacy if Pimavanserin is used concomitantly with strong CYP3A4 inducers; an increase in Pimavanserin dosage may be needed.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pimavanserin in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Pimavanserin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Safety and effectiveness have not been established in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pimavanserin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Pimavanserin in pediatric patients.
# Contraindications
None
# Warnings
Antipsychotic drugs increase the all-cause risk of death in elderly patients with dementia-related psychosis. Analyses of 17 dementia-related psychosis placebo-controlled trials (modal duration of 10 weeks and largely in patients taking atypical antipsychotic drugs) revealed a risk of death in the drug-treated patients of between 1.6- to 1.7-times that in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in placebo-treated patients.
Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Pimavanserin is not approved for the treatment of patients with dementia-related psychosis unrelated to the hallucinations and delusions associated with Parkinson's disease psychosis.
Pimavanserin prolongs the QT interval. The use of Pimavanserin should be avoided in patients with known QT prolongation or in combination with other drugs known to prolong QT interval including Class 1A antiarrhythmics (e.g., quinidine, procainamide) or Class 3 antiarrhythmics (e.g., amiodarone, sotalol), certain antipsychotic medications (e.g., ziprasidone, chlorpromazine, thioridazine), and certain antibiotics (e.g., gatifloxacin, moxifloxacin). Pimavanserin should also be avoided in patients with a history of cardiac arrhythmias, as well as other circumstances that may increase the risk of the occurrence of torsade de pointes and/or sudden death, including symptomatic bradycardia, hypokalemia or hypomagnesemia, and the presence of congenital prolongation of the QT interval.
# Adverse Reactions
## Clinical Trials Experience
The following serious adverse reactions are discussed elsewhere in the labeling:
- Increased Mortality in Elderly Patients with Dementia-Related Psychosis
- QT Interval Prolongation
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 clinical trial database for Pimavanserin consists of over 1200 subjects and patients exposed to one or more doses of Pimavanserin. Of these, 616 were patients with hallucinations and delusions associated with Parkinson's disease psychosis (PDP). In the placebo-controlled setting, the majority of experience in patients comes from studies evaluating once-daily Pimavanserin doses of 34 mg (N=202) compared to placebo (N=231) for up to 6 weeks. In the controlled trial setting, the study population was approximately 64% male and 91% Caucasian, and the mean age was about 71 years at study entry. Additional clinical trial experience in patients with hallucinations and delusions associated with PDP comes from two open-label, safety extension studies (total N=497). The majority of patients receiving long-term treatment received 34 mg once-daily (N=459). Over 300 patients have been treated for more than 6 months; over 270 have been treated for at least 12 months; and over 150 have been treated for at least 24 months.
The following adverse reactions are based on the 6-week, placebo-controlled studies in which Pimavanserin was administered once daily to patients with hallucinations and delusions associated with PDP.
Common Adverse Reactions (incidence ≥5% and at least twice the rate of placebo): peripheral edema (7% Pimavanserin 34 mg vs. 2% placebo) and confusional state (6% Pimavanserin 34 mg vs. 3% placebo).
Adverse Reactions Leading to Discontinuation of Treatment
A total of 8% (16/202) of Pimavanserin 34 mg-treated patients and 4% (10/231) of placebo-treated patients discontinued because of adverse reactions. The adverse reactions that occurred in more than one patient and with an incidence at least twice that of placebo were hallucination (2% Pimavanserin vs. <1% placebo), urinary tract infection (1% Pimavanserin vs. <1% placebo), and fatigue (1% Pimavanserin vs. 0% placebo).
Adverse reactions that occurred in 6-week, placebo-controlled studies and that were reported at an incidence of ≥2% and >placebo are presented in Table 1.
- Table 1 Adverse Reactions in Placebo-Controlled Studies of 6-Week Treatment Duration and Reported in ≥2% and >Placebo
Adverse Reactions in Demographic Subgroups
Examination of population subgroups in the 6-week, placebo-controlled studies did not reveal any differences in safety on the basis of age (≤75 vs. >75 years) or sex. Because the study population was predominantly Caucasian (91%; consistent with reported demographics for PD/PDP), racial or ethnic differences in the safety profile of Pimavanserin could not be assessed. In addition, in the 6-week, placebo-controlled studies, no clinically relevant differences in the incidence of adverse reactions were observed among those with a Mini-Mental State Examination (MMSE) score at entry of <25 versus those with scores ≥25.
## Postmarketing Experience
There is limited information regarding Pimavanserin Postmarketing Experience in the drug label.
# Drug Interactions
- Table 2 Clinically Important Drug Interactions with Pimavanserin
Based on pharmacokinetic studies, no dosage adjustment of carbidopa/levodopa is required when administered concomitantly with Pimavanserin.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Risk Summary
There are no data on Pimavanserin use in pregnant women that would allow assessment of the drug-associated risk of major congenital malformations or miscarriage. In animal reproduction studies, no adverse developmental effects were seen when Pimavanserin was administered orally to rats or rabbits during the period of organogenesis at doses up to 10- or 12-times the maximum recommended human dose (MRHD) of 34 mg/day, respectively. Administration of Pimavanserinto pregnant rats during pregnancy and lactation resulted in maternal toxicity and lower pup survival and body weight at doses which are 2-times the MRHD of 34 mg/day.
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 2-4% and 15-20%, respectively.
- Data
- Animal Data
Pimavanserin was not teratogenic in pregnant rats when administered during the period of organogenesis at oral doses of 0.9, 8.5, and 51 mg/kg/day, which are 0.2- and 10-times the maximum recommended human dose (MRHD) of 34 mg/day based on AUC at mid and high doses, respectively. Maternal toxicity included reduction in body weight and food consumption at the highest dose.
Administration of Pimavanserin to pregnant rats during pregnancy and lactation at oral doses of 8.5, 26, and 51 mg/kg/day, which are 0.14- to 14-times the MRHD of 34 mg/day based on AUC, caused maternal toxicity, including mortality, clinical signs including dehydration, hunched posture, and rales, and decreases in body weight, and/or food consumption at doses ≥26 mg/kg/day (2-times the MRHD based on AUC). At these maternally toxic doses there was a decrease in pup survival, reduced litter size, and reduced pup weights, and food consumption. Pimavanserin had no effect on sexual maturation, neurobehavioral function including learning and memory, or reproductive function in the first generation pups up to 14-times the MRHD of 34 mg/day based on AUC.
Pimavanserin was not teratogenic in pregnant rabbits during the period of organogenesis at oral doses of 4.3, 43, and 85 mg/kg/day, which are 0.2- to 12-times the MRHD of 34 mg/day based on AUC. Maternal toxicity, including mortality, clinical signs of dyspnea and rales, decreases in body weight and/or food consumption, and abortions occurred at doses 12-times the MRHD of 34 mg/day based on AUC.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Pimavanserin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Pimavanserin during labor and delivery.
### Nursing Mothers
There is no information regarding the presence of Pimavanserin in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Pimavanserin and any potential adverse effects on the breastfed infant from Pimavanserin or from the underlying maternal condition.
### Pediatric Use
Safety and effectiveness of Pimavanserin have not been established in pediatric patients.
### Geriatic Use
No dose adjustment is required for elderly patients.
Parkinson's disease is a disorder occurring primarily in individuals over 55 years of age. The mean age of patients enrolled in the 6-week clinical studies with Pimavanserin was 71 years, with 49% 65-75 years old and 31% >75 years old. In the pooled population of patients enrolled in 6-week, placebo-controlled studies (N=614), 27% had MMSE scores from 21 to 24 compared to 73% with scores ≥25. No clinically meaningful differences in safety or effectiveness were noted between these two groups.
### Gender
There is no FDA guidance on the use of Pimavanserin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Pimavanserin with respect to specific racial populations.
### Renal Impairment
No dosage adjustment for Pimavanserin is needed in patients with mild to moderate (CrCL ≥30 mL/min, Cockcroft-Gault) renal impairment.
Use of Pimavanserin is not recommended in patients with severe renal impairment (CrCL <30 mL/min, Cockcroft-Gault). Pimavanserin has not been evaluated in this patient population.
### Hepatic Impairment
Use of Pimavanserin is not recommended in patients with hepatic impairment. Pimavanserin has not been evaluated in this patient population.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Pimavanserin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Pimavanserin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
The recommended dose of Pimavanserin is 34 mg, taken orally as two 17 mg strength tablets once daily, without titration.
Pimavanserin can be taken with or without food.
### Monitoring
There is limited information regarding Pimavanserin Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Pimavanserin and IV administrations.
# Overdosage
Human Experience
The pre-marketing clinical trials involving Pimavanserin in approximately 1200 subjects and patients do not provide information regarding symptoms with overdose. In healthy subject studies, dose-limiting nausea and vomiting were observed.
Management of Overdose
There are no known specific antidotes for Pimavanserin. In managing overdose, cardiovascular monitoring should commence immediately and should include continuous ECG monitoring to detect possible arrhythmias. If antiarrhythmic therapy is administered, disopyramide, procainamide, and quinidine should not be used, as they have the potential for QT-prolonging effects that might be additive to those of Pimavanserin. Consider the long plasma half-life of Pimavanserin (about 57 hours) and the possibility of multiple drug involvement. Consult a Certified Poison Control Center (1-800-222-1222) for up-to-date guidance and advice.
# Pharmacology
## Mechanism of Action
The mechanism of action of Pimavanserin in the treatment of hallucinations and delusions associated with Parkinson's disease psychosis is unknown. However, the effect of Pimavanserin could be mediated through a combination of inverse agonist and antagonist activity at serotonin 5-HT2A receptors and to a lesser extent at serotonin 5-HT2C receptors.
## Structure
There is limited information regarding Pimavanserin Structure in the drug label.
## Pharmacodynamics
In vitro, Pimavanserin acts as an inverse agonist and antagonist at serotonin 5-HT2A receptors with high binding affinity (Ki value 0.087 nM) and at serotonin 5-HT2C receptors with lower binding affinity (Ki value 0.44 nM). Pimavanserin shows low binding to sigma 1 receptors (Ki value 120 nM) and has no appreciable affinity (Ki value >300 nM), to serotonin 5-HT2B, dopaminergic (including D2), muscarinic, histaminergic, or adrenergic receptors, or to calcium channels.
Cardiac Electrophysiology
The effect of Pimavanserin on the QTc interval was evaluated in a randomized placebo- and positive-controlled double-blind, multiple-dose parallel thorough QTc study in 252 healthy subjects. A central tendency analysis of the QTc data at steady-state demonstrated that the maximum mean change from baseline (upper bound of the two-sided 90% CI) was 13.5 (16.6) msec at a dose of twice the therapeutic dose. A pharmacokinetic/ pharmacodynamic analysis with Pimavanserin suggested a concentration-dependent QTc interval prolongation in the therapeutic range.
In the 6-week, placebo-controlled effectiveness studies, mean increases in QTc interval of ~5-8 msec were observed in patients receiving once-daily doses of Pimavanserin 34 mg. These data are consistent with the profile observed in a thorough QT study in healthy subjects. Sporadic QTcF values ≥500 msec and change from baseline values ≥60 msec were observed in subjects treated with Pimavanserin 34 mg; although the incidence was generally similar for Pimavanserin and placebo groups. There were no reports of torsade de pointes or any differences from placebo in the incidence of other adverse reactions associated with delayed ventricular repolarization in studies of Pimavanserin, including those patients with hallucinations and delusions associated with PDP.
## Pharmacokinetics
Pimavanserin demonstrates dose-proportional pharmacokinetics after single oral doses from 17 to 255 mg (0.5- to 7.5-times the recommended dosage). The pharmacokinetics of Pimavanserin are similar in both the study population and healthy subjects. The mean plasma half-lives for Pimavanserin and the active metabolite (N-desmethylated metabolite) are approximately 57 hours and 200 hours, respectively.
Absorption
The median Tmax of Pimavanserin was 6 (range 4-24) hours and was generally unaffected by dose. The bioavailability of Pimavanserin oral tablet and Pimavanserin solution was essentially identical. The formation of the major circulating N-desmethylated metabolite AC-279 (active) from Pimavanserin occurs with a median Tmax of 6 hours.
Ingestion of a high-fat meal had no significant effect on rate (Cmax) and extent (AUC) of Pimavanserin exposure. Cmax decreased by about 9% while AUC increased by about 8% with a high-fat meal.
Distribution
Pimavanserin is highly protein bound (~95%) in human plasma. Protein binding appeared to be dose-independent and did not change significantly over dosing time from Day 1 to Day 14. Following administration of a single dose of Pimavanserin (34 mg), the mean (SD) apparent volume of distribution was 2173 (307) L.
Elimination
- Metabolism
Pimavanserin is predominantly metabolized by CYP3A4 and CYP3A5 and to a lesser extent by CYP2J2, CYP2D6, and various other CYP and FMO enzymes. CYP3A4 is the major enzyme responsible for the formation of its major active metabolite (AC-279). Pimavanserin does not cause clinically significant CYP inhibition or induction of CYP3A4. Based on in vitro data, Pimavanserin is not an irreversible inhibitor of any of the major hepatic and intestinal human CYP enzymes involved in drug metabolism (CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4).
Based on in vitro studies, transporters play no significant role in the disposition of Pimavanserin.
AC-279 is neither a reversible or irreversible (metabolism-dependent) inhibitor of any of the major hepatic and intestinal human CYP enzymes involved in drug metabolism (CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4). AC-279 does not cause clinically significant CYP3A induction and is not predicted to cause induction of any other CYP enzymes involved in drug metabolism.
- Excretion
Approximately 0.55% of the 34 mg oral dose of 14C-Pimavanserin was eliminated as unchanged drug in urine and 1.53% was eliminated in feces after 10 days.
Less than 1% of the administered dose of Pimavanserin and its active metabolite AC-279 were recovered in urine.
Specific Populations
Population PK analysis indicated that exposure of Pimavanserin in patients with mild to moderate renal impairment was similar to exposure in patients with normal renal function. Age, sex, ethnicity, and weight do not have clinically relevant effect on the pharmacokinetics of Pimavanserin.
Pimavanserin has not been studied in patients with severe renal impairment or mild to severe hepatic impairment.
Drug Interaction Studies
CYP3A4 Inhibitor: ketoconazole, a strong inhibitor of CYP3A4, increased Pimavanserin Cmax by 1.5-fold and AUC by 3-fold.
The effect of Pimavanserin on other drugs is shown in Figure 1.
- Figure 1 The Effects of Pimavanserin on the Pharmacokinetics of Other Drugs
NUPLAZID: Pimavanserin's Brand name
## Nonclinical Toxicology
- Carcinogenesis
There was no increase in the incidence of tumors following daily oral administration of Pimavanserin to mice or rats for 2 years. Mice were administered Pimavanserin at oral doses of 2.6, 6, and 13 (males)/8.5, 21, and 43 mg/kg/day (females) which are 0.01- to 1- (males)/0.5- to 7- (females) times the MRHD of 34 mg/day based on AUC. Rats were administered Pimavanserin at oral doses of 2.6, 8.5, and 26 (males)/4.3, 13, and 43 mg/kg/day (females) which are 0.01- to 4- (males)/0.04- to 16- (females) times the MRHD of 34 mg/day based on AUC.
- Mutagenesis
Pimavanserin was not mutagenic in the in vitro Ames reverse mutation test, or in the in vitro mouse lymphoma assay, and was not clastogenic in the in vivo mouse bone marrow micronucleus assay.
- Impairment of Fertility
Pimavanserin was administered orally to male and female rats before mating, through mating, and up to Day 7 of gestation at doses of 8.5, 51, and 77 mg/kg/day, which are approximately 2-, 15-, and 22-times the maximum recommended human dose (MRHD) of 34 mg/day based on mg/m2, respectively. Pimavanserin had no effect on fertility or reproductive performance in male and female rats at doses up to 22-times the MRHD of 34 mg based on mg/m2. Changes in uterine parameters (decreases in the number of corpora lutea, number of implants, viable implants, and increases in pre-implantation loss, early resorptions and post-implantation loss) occurred at the highest dose which was also a maternally toxic dose. Changes in sperm parameters (decreased density and motility) and microscopic findings of cytoplasmic vacuolation in the epididymis occurred at doses approximately 15-times the MRHD of 34 mg/day based on mg/m2.
Phospholipidosis (foamy macrophages and/or cytoplasmic vacuolation) was observed in multiple tissues and organs of mice, rats, and monkeys as early as 14 days following oral daily administration of Pimavanserin. The most severely affected organs were the lungs and kidneys. The occurrence of phospholipidosis was both dose- and duration-dependent. Diffuse phospholipidosis with focal/multifocal chronic inflammation was observed in the lungs of rats treated for ≥3 months at doses ≥10-times the maximum recommended human dose (MRHD) of 34 mg/day based on AUC. As a result of chronic inflammation, inflammatory lung fibrosis was observed in rats treated for 3 and 6 months at doses ≥18-times the MRHD of 34 mg/day based on AUC. The findings in the lungs correlated with increased lung weights (up to 3-times those of controls) and respiratory-related clinical signs including rales, labored breathing, and gasping. Phospholipidosis in lungs of rats caused mortality at doses ≥16-times the MRHD of 34 mg/day based on AUC. The estimated No Observed Effect Level (NOEL) for chronic lung inflammation in rats is 5-fold the MRHD of 34 mg/day based on AUC. Phospholipidosis was associated with increased kidney weights and tubular degeneration in rats at doses ≥10-times the MRHD of 34 mg/day based on AUC. The relevance of these findings to human risk is not known.
# Clinical Studies
The efficacy of Pimavanserin 34 mg as a treatment of hallucinations and delusions associated with Parkinson's disease psychosis was demonstrated in a 6-week, randomized, placebo-controlled, parallel-group study. In this outpatient study, 199 patients were randomized in a 1:1 ratio to Pimavanserin 34 mg or placebo once daily. Study patients (male or female and aged 40 years or older) had a diagnosis of Parkinson's disease (PD) established at least 1 year prior to study entry and had psychotic symptoms (hallucinations and/or delusions) that started after the PD diagnosis and that were severe and frequent enough to warrant treatment with an antipsychotic. At entry, patients were required to have a Mini-Mental State Examination (MMSE) score ≥21 and to be able to self-report symptoms. The majority of patients were on PD medications at entry; these medications were required to be stable for at least 30 days prior to study start and throughout the study period.
The PD-adapted Scale for the Assessment of Positive Symptoms (SAPS-PD) was used to evaluate the efficacy of Pimavanserin 34 mg. SAPS-PD is a 9-item scale adapted for PD from the Hallucinations and Delusions domains of the SAPS. Each item is scored on a scale of 0-5, with 0 being none and 5 representing severe and frequent symptoms. Therefore, the SAPS-PD total score can range from 0 to 45 with higher scores reflecting greater severity of illness. A negative change in score indicates improvement. Primary efficacy was evaluated based on change from baseline to Week 6 in SAPS-PD total score.
As shown in Table 3, Figure 2, and Figure 3, Pimavanserin 34 mg (n=95) was statistically significantly superior to placebo (n=90) in decreasing the frequency and/or severity of hallucinations and delusions in patients with PDP as measured by central, independent, and blinded raters using the SAPS-PD scale. An effect was seen on both the hallucinations and delusions components of the SAPS-PD.
- Table 3 Primary Efficacy Analysis Result Based on SAPS-PD (N=185)
NUPLAZID: Pimavanserin's Brand name
The effect of Pimavanserin on SAPS-PD improved through the six-week trial period, as shown in Figure 2.
- Figure 2 SAPS-PD Change from Baseline through 6 Weeks Total Study Treatment
NUPLAZID: Pimavanserin's Brand name
- Figure 3 Proportion of Patients with SAPS-PD Score Improvement at the End of Week 6 (N=185)
NUPLAZID: Pimavanserin's Brand name
Motor Function in Patients with Hallucinations and Delusions Associated with Parkinson's Disease Psychosis
Pimavanserin 34 mg did not show an effect compared to placebo on motor function, as measured using the Unified Parkinson's Disease Rating Scale Parts II and III (UPDRS Parts II+III) (Figure 4). A negative change in score indicates improvement. The UPDRS Parts II+III was used to assess the patient's Parkinson's disease state during the 6-week double-blind treatment period. The UPDRS score was calculated as the sum of the 40 items from activities of daily living and motor examination, with a range of 0 to 160.
- Figure 4 Motor Function Change from Baseline to Week 6 in UPDRS Parts II+III (LSM - SE)
NUPLAZID: Pimavanserin's Brand name
# How Supplied
Pimavanserin tablets are available as:
17 mg Tablet:
White to off-white, round, immediate-release, film-coated tablet debossed with "P" on one side and "17" on the reverse. . Each tablet contains 20 mg of pimavanserin tartrate, which is equivalent to 17 mg of Pimavanserin free base. Inactive ingredients include pregelatinized starch, magnesium stearate, and microcrystalline cellulose. Additionally, the following inactive ingredients are present as components of the film coat: hypromellose, talc, titanium dioxide, polyethylene glycol, and saccharin sodium.
Bottle of 60: NDC 63090-170-60
## Storage
Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Advise patients to inform their healthcare providers if there are any changes to their current prescription or over-the-counter medications, since there is a potential for drug interactions.
# Precautions with Alcohol
Alcohol-Pimavanserin interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
NUPLAZID™
# Look-Alike Drug Names
There is limited information regarding Pimavanserin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Pimavanserin | |
4dd290d7959bbec53a01fdd6d174bb51777b2a26 | wikidoc | Piperacillin | Piperacillin
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# Overview
Piperacillin is an antibiotic that is FDA approved for the treatment of serious infections caused by susceptible strains ,hepatobiliary and surgical infections caused by E. coli, Pseudomonas aeruginosa, enterococci, Clostridium spp., anaerobic cocci, or Bacteroides spp,urinary tract infections, septicemia, lower respiratorytract infections, skin, infections ,bone and joint infections. Common adverse reactions include thrombophlebitis, erythema multiforme, stevens-johnson syndrome, toxic epidermal necrolysis, agranulocytosis, hemolytic anemia, pancytopenia, anaphylaxis, seizure, renal failure.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Piperacillin is indicated for the treatment of serious infections caused by susceptible strains of the designated microorganisms in the conditions listed below:
- Intra-Abdominal Infections including hepatobiliary and surgical infections caused by E. coli, Pseudomonas aeruginosa, enterococci, Clostridium spp., anaerobic cocci, or Bacteroides spp., including B. fragilis.
- Urinary Tract Infections caused by E. coli, Klebsiella spp., P. aeruginosa, Proteus spp., including P. mirabilis, or enterococci.
- Gynecologic Infections including endometritis, pelvic inflammatory disease, pelvic cellulitis caused by Bacteroides spp., including B. fragilis, anaerobic cocci, Neisseria gonorrhoeae, or enterococci (E. faecalis).
- Septicemia including bacteremia caused by E. coli, Klebsiella spp., Enterobacter spp., Serratia spp., P. mirabilis, S. pneumoniae, enterococci, P. aeruginosa, Bacteroides spp., or anaerobic cocci.
- Lower RespiratoryTract Infections caused by E. coli, Klebsiella spp., Enterobacter spp., P. aeruginosa, Serratia spp., H. influenzae, Bacteroides spp., or anaerobic cocci. - Although improvement has been noted in patients with cystic fibrosis, lasting bacterial eradication may not necessarily be achieved.
- Skin and Skin Structure Infections caused by E. coli, Klebsiella spp., Serratia spp., Acinetobacter spp., Enterobacter spp., P. aeruginosa, Morganella morganii, Providencia rettgeri, Proteus vulgaris, P. mirabilis, Bacteroides spp., including B. fragilis, anaerobic cocci, or enterococci.
- Bone and Joint Infections caused by P. aeruginosa, enterococci, Bacteroides spp., or anaerobic cocci.
- Uncomplicated Gonococcal Urethritis caused by N. gonorrhoeae.
- Piperacillin has also been shown to be clinically effective for the treatment of infections at various sites caused by Streptococcus species including S. pyogenes and S. pneumoniae; however, infections caused by these organisms are ordinarily treated with more narrow spectrum penicillins.
- Because of its broad spectrum of bactericidal activity against gram-positive and gram-negative aerobic and anaerobic bacteria, piperacillin is particularly useful for the treatment of mixed infections and presumptive therapy prior to the identification of the causative organisms.
- Also, piperacillin may be administered as single drug therapy in some situations where normally two antibiotics might be employed.
- Piperacillin has been successfully used with aminoglycosides, especially in patients with impaired host defenses. Both drugs should be used in full therapeutic doses.
- Appropriate cultures should be made for susceptibility testing before initiating therapy and therapy adjusted, if appropriate, once the results are known.
- Piperacillin is indicated for prophylactic use in surgery including intra-abdominal (gastrointestinal and biliary) procedures, vaginal hysterectomy, abdominal hysterectomy, and cesarean section.
- Effective prophylactic use depends on the time of administration; piperacillin should be given one-half to one hour before the operation so that effective levels can be achieved in the site prior to the procedure.
- The prophylactic use of piperacillin should be stopped within 24 hours, since continuing administration of any antibiotic increases the possibility of adverse reactions, but in the majority of surgical procedures, does not reduce the incidence of subsequent infections. If there are signs of infection, specimens for culture and susceptibility testing should be obtained for identification of the causative microorganism so that appropriate therapy can be instituted.
- To reduce the development of drug-resistant bacteria and maintain the effectiveness of piperacillin and other antibacterial drugs, piperacillinshould only be used to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
- Piperacillin may be administered by the intramuscular route or intravenously as a three- to five-minute intravenous injection or as a 20- to 30-minute infusion. The usual dosage of piperacillin for serious infections is 3 to 4 g given every four to six hours as a 20- to 30-minute infusion. For serious infections, the intravenous route should be used.
- Piperacillin should not be mixed with an aminoglycoside in a syringe or infusion bottle since this can result in inactivation of the aminoglycoside.
- The maximum daily dose for adults is usually 24 g/day, although higher doses have been used.
- Intramuscular injections should be limited to 2 g per injection site. This route of administration has been used primarily in the treatment of patients with uncomplicated gonorrhea and urinary tract infections.
- The average duration of piperacillin treatment is from seven to ten days, except in the treatment of gynecologic infections, which is from three to ten days; the duration should be guided by the patient's clinical and bacteriological progress. For most acute infections, treatment should be continued for at least 48 to 72 hours after the patient becomes asymptomatic. - Antibiotic therapy for S. pyogenes infections should be maintained for at least ten days to reduce the risk of rheumatic fever.
- When piperacillin is given concurrently with aminoglycosides, both drugs should be used in full therapeutic doses.
- For patients on hemodialysis, the maximum daily dose is 6 g/day (2 g every 8 hours). In addition, because hemodialysis removes 30% to 50% of piperacillin in 4 hours, a 1-g additional dose should be administered following each dialysis period.
- For patients with renal failure and hepatic insufficiency, measurement of serum levels of piperacillin will provide additional guidance for adjusting dosage.
- When possible, piperacillin should be administered as a 20- to 30-minute infusion just prior to anesthesia. Administration while the patient is awake will facilitate identification of possible adverse reactions during drug infusion.
- Reconstitution Directions for Conventional Vials:
- Reconstitute each gram of piperacillin with at least 5 mL of a suitable diluent (except Lidocaine HCl 0.5%-1% without epinephrine) listed above. Shake well until dissolved. Reconstituted solution may be diluted to the desired volume (eg, 50 or 100 mL) in the above listed intravenous solutions and admixtures.
- Infuse diluted solution over period of about 30 minutes. During infusion, it is desirable to discontinue the primary intravenous solution.
- Reconstituted solution should be injected slowly over a 3-to 5-minute period to help avoid vein irritation.
- Intramuscular Administration (Conventional Vials Only)
- Reconstitution Directions
- Reconstitute each gram of piperacillin with 2 mL of a suitable diluent listed above to achieve a concentration of 1 g per 2.5 mL. Shake well until dissolved.
- When indicated by clinical and bacteriological findings, intramuscular administration of 6 to 8 g daily of piperacillin, in divided doses, may be utilized for initiation of therapy.
- In addition, intramuscular administration of the drug may be considered for maintenance therapy after clinical and bacteriologic improvement has been obtained with intravenous piperacillin sodium treatment. Intramuscular administration should not exceed 2 g per injection at any one site.
- The preferred site is the upper outer quadrant of the buttock (ie, gluteus maximus).
- The deltoid area should be used only if well-developed, and then only with caution to avoid radial nerve injury. Intramuscular injections should not be made into the lower or mid-third of the upper arm.
- Stability of piperacillin Following Reconstitution
- Piperacillin is stable in both glass and plastic containers when reconstituted with recommended diluents and when diluted with the intravenous solutions and intravenous admixtures indicated above.
- Pharmacy vials should be used immediately after reconstitution. Discard any unused portion after 24 hours if stored at room temperature (20° to 25°C ), or after 48 hours if stored at refrigerated temperature (2° to 8°C ). Vials should not be frozen after reconstitution.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Piperacillin in adult patients.
### Non–Guideline-Supported Use
- Febrile neutropenia
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Piperacillin in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Piperacillin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Piperacillin in pediatric patients.
# Contraindications
- Piperacillin is contraindicated in patients with a history of allergic reactions to any of the betalactams, including penicillins and/or cephalosporins.
# Warnings
- SERIOUS AND OCCASIONALLY FATAL HYPERSENSITIVITY (ANAPHYLACTIC/ANAPHYLACTOID) REACTIONS HAVE BEEN REPORTED IN PATIENTS ON PENICILLIN THERAPY. THESE REACTIONS ARE MORE LIKELY TO OCCUR IN INDIVIDUALS WITH A HISTORY OF PENICILLIN HYPERSENSITIVITY AND/OR A HISTORY OF SENSITIVITY TO MULTIPLE ALLERGENS. THERE HAVE BEEN REPORTS OF INDIVIDUALS WITH A HISTORY OF PENICILLIN HYPERSENSITIVITY WHO HAVE EXPERIENCED SEVERE REACTIONS WHEN TREATED WITH CEPHALOSPORINS. BEFORE INITIATING THERAPY WITH piperacillin, CAREFUL INQUIRY SHOULD BE MADE CONCERNING PREVIOUS HYPERSENSITIVITY REACTIONS TO PENICILLINS, CEPHALOSPORINS OR OTHER ALLERGENS. IF AN ALLERGIC REACTION OCCURS, piperacillin SHOULD BE DISCONTINUED AND APPROPRIATE THERAPY INSTITUTED. SERIOUS ANAPHYLACTIC/ANAPHYLACTOID REACTIONS REQUIRE IMMEDIATE EMERGENCY TREATMENT WITH EPINEPHRINE. OXYGEN, INTRAVENOUS STEROIDS AND AIRWAY MANAGEMENT, INCLUDING INTUBATION, SHOULD ALSO BE ADMINISTERED AS INDICATED.
- Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including piperacillin, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.
- C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.
- If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
# Adverse Reactions
## Clinical Trials Experience
There is limited information regarding Clinical Trial Experience of Piperacillin in the drug label.
## Postmarketing Experience
- Piperacillin is generally well tolerated. The most common adverse reactions have been local in nature, following intravenous or intramuscular injection. The following adverse reactions may occur:
- In clinical trials thrombophlebitis was noted in 4% of patients. Pain, erythema, and/or induration at the injection site occurred in 2% of patients. Less frequent reactions including ecchymosis, deep vein thrombosis, and hematomas have also occurred.
- Diarrhea and loose stools were noted in 2% of patients. Other less frequent reactions included vomiting, nausea, increases in liver enzymes (LDH, AST, ALT), hyperbilirubinemia, cholestatic hepatitis, bloody diarrhea, and pseudomembranous colitis. The onset of pseudomembranous colitis symptoms may occur during or after antibiotic treatment.
- Anaphylactic/anaphylactoid reactions (some leading to shock and fatalities) have been reported.
- Rash was noted in 1% of patients. Other less frequent findings included pruritus, vesicular eruptions, and positive Coombs tests.
- Other dermatologic manifestations, such as erythema multiforme, urticaria, toxic epidermal necrolysis and Stevens-Johnson syndrome have been reported.
- Elevations of creatinine or BUN, renal failure and interstitial nephritis have been reported.
- Headache, dizziness, fatigue, and seizures have been reported.
- Hemolytic anemia, agranulocytosis, pancytopenia, prolonged bleeding time, reversible leukopenia, neutropenia, thrombocytopenia, and/or eosinophilia have been reported. As with other β-lactam antibiotics, reversible leukopenia (neutropenia) is more apt to occur in patients receiving prolonged therapy at high dosages or in association with drugs known to cause this reaction.
- Individuals with liver disease or individuals receiving cytotoxic therapy or diuretics were reported to demonstrate a decrease in serum potassium concentrations with high doses of piperacillin.
- Hypokalemia has been reported.
- Prolonged muscle relaxation.
- Fever, superinfection, including candidiasis; hemorrhagic manifestations have been reported.
- Piperacillin therapy has been associated with an increased incidence of fever and rash in cystic fibrosis patients.
# Drug Interactions
- The mixing of piperacillin with an aminoglycoside in vitro can result in substantial inactivation of the aminoglycoside.
- When used in the perioperative period, piperacillin has been implicated in the prolongation of the neuromuscular blockade of vecuronium. Caution is indicated when piperacillin is used perioperatively. In one controlled clinical study, the ureidopenicillins, including piperacillin, were reported to prolong the action of vecuronium. Due to their similar mechanism of action, it is expected that the neuromuscular blockade produced by any of the non-depolarizing muscle relaxants could be prolonged in the presence of piperacillin.
- The oral combination of probenecid before intramuscular injection of piperacillin produces an increase in piperacillin peak serum level of about 30%.
- Coagulation parameters should be tested more frequently and monitored regularly during simultaneous administration of high doses of heparin, oral anticoagulants, or other drugs that may affect the blood coagulation system or the thrombocyte function.
- Piperacillin sodium may reduce the excretion of methotrexate. Therefore, serum levels of methotrexate should be monitored in patients to avoid drug toxicity.
- As with other penicillins, the administration of piperacillin may result in a false-positive reaction for glucose in the urine using a copper-reduction method. It is recommended that glucose tests based on enzymatic glucose oxidase reactions be used.
- There have been reports of positive test results using the Bio-Rad Laboratories Platelia Aspergillus EIA test in patients receiving piperacillin/tazobactam injection who were subsequently found to be free of Aspergillus infection. Cross-reactions with non-Aspergillus polysaccharides and polyfuranoses with the Bio-Rad Laboratories Platelia Aspergillus EIA test have been reported.
- Therefore, positive test results in patients receiving piperacillin should be interpreted cautiously and confirmed by other diagnostic methods.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
- Teratology studies have been performed in mice (I.V.) and rats (I.V., I.P. and SQ) and have revealed no evidence of harm to the fetus due to piperacillin administered up to a dose which is approximately half the maximum recommended human daily dose based on body-surface area (mg/m2). In pharmacokinetic studies in pregnant and nonpregnant rats, in which piperacillin was administered I.V. at a dose which is half the maximum daily dose administered in teratology studies, serum concentrations in rats were approximately 10 times the maximum serum concentration seen in man. In other studies in mice and rats, in which piperacillin (in combination with a beta-lactamase inhibitor, tazobactam) was administered I.V. at approximately half the maximum daily dose administered in teratology studies, plasma concentrations of piperacillin were approximately 2 times (mice) and 5 times (rats) the serum concentrations seen in man.
- There are, however, no adequate and well-controlled studies with piperacillin in pregnant women. Because animal reproduction studies are not always predictive of the 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 Piperacillin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Piperacillin during labor and delivery.
### Nursing Mothers
- Piperacillin is excreted in low concentrations in human milk. Caution should be exercised when piperacillin is administered to nursing mothers.
### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established.
- Data from published pharmacokinetics studies indicate that the elimination half-life of piperacillin in neonates is twofold to fourfold longer than that seen in pediatric patients 1 month of age and above as well as in adults. In infants, children, and adolescents, the elimination half-life of piperacillin is shorter than that observed in adults. As in adults, the elimination of piperacillin is decreased in pediatric patients with renal impairment.
### Geriatic Use
- Clinical studies of piperacillin did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
- 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.
- Piperacillin contains 42.5 mg (1.85 mEq) of sodium per gram. At the usual recommended doses, patients would receive between 255 and 765 mg/day (11.1 and 33.3 mEq) of sodium. The geriatric population may respond with a blunted natriuresis to salt loading. The total sodium content from dietary and non-dietary sources may be clinically important with regard to such diseases as congestive heart failure.
- 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 Piperacillin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Piperacillin with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Piperacillin in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Piperacillin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Piperacillin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Piperacillin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous.
### Monitoring
- Coagulation parameters should be tested more frequently and monitored regularly during simultaneous administration of high doses of heparin, oral anticoagulants, or other drugs that may affect the blood coagulation system or the thrombocyte function.
- Piperacillin sodium may reduce the excretion of methotrexate. Therefore, serum levels of methotrexate should be monitored in patients to avoid drug toxicity.
- 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.
# IV Compatibility
There is limited information regarding IV Compatibility of Piperacillin in the drug label.
# Overdosage
- There is no specific information on overdose with piperacillin. Other penicillin-class drugs in overdosage, however, have the potential to cause neuromuscular hyperirritability or convulsive seizures.
- In case of overdosage, discontinue medication, treat symptomatically, and institute supportive measures as required. Piperacillin can be removed by hemodialysis but not peritoneal dialysis.
# Pharmacology
## Mechanism of Action
There is limited information regarding Piperacillin Mechanism of Action in the drug label.
## Structure
- PIPRACIL, sterile piperacillin sodium, is a semisynthetic broad-spectrum penicillin for parenteral use derived from D(-)-α-aminobenzylpenicillin. The chemical name of piperacillin sodium is sodium (2S,5R,6R)-6--3,-3-dimethyl-7-oxo-4-thia-1-azabicycloheptane-2-carboxylate. The chemical formula is C23H26N5NaO7S, and the molecular weight is 539.54. Its structural formula is:
- Piperacillin sodium powder is a white to off-white solid having the characteristic appearance of products prepared by freeze-drying. It is freely soluble in water and in alcohol. The pH of an aqueous solution containing 400 milligrams per milliliter ranges from 5.5 to 7.5. One g contains 1.85 mEq (42.5 mg) of sodium (Na+).
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Piperacillin in the drug label.
## Pharmacokinetics
- In healthy adult volunteers, mean serum piperacillin concentrations immediately after a two‑to three‑minute intravenous injection of 2, 4, or 6 g were 305, 412, and 775 μg/mL, respectively. Serum concentrations lack dose proportionality.
- A 30-minute infusion of 6 g every 6 h gave, on the fourth day, a mean peak serum concentration of 420 μg/mL.
- Piperacillin is rapidly absorbed after intramuscular injection. In healthy volunteers, the mean peak serum concentration occurs approximately 30 minutes after a single dose of 2 g and is about 36 μg/mL. The oral administration of 1 g probenecid before injection produces an increase in piperacillin peak serum level of about 30%. The area under the curve (AUC) is increased by approximately 60%.
- Piperacillin is not absorbed when given orally. Peak serum concentrations are attained approximately 30 minutes after intramuscular injections and immediately after completion of intravenous injection or infusion. The serum half-life in healthy volunteers ranges from 36 minutes to one hour and 12 minutes. The mean elimination half-life of piperacillin in healthy adult volunteers is 54 minutes following administration of 2 g and 63 minutes following 6 g. As with other penicillins, piperacillin is eliminated primarily by glomerular filtration and tubular secretion; it is excreted rapidly as unchanged drug in high concentrations in the urine.
- Approximately 60% to 80% of the administered dose is excreted in the urine in the first 24 hours. Piperacillin urine concentrations, determined by microbioassay, are as high as 14,100 μg/mL following a 6-g intravenous dose and 8,500 μg/mL following a 4-g intravenous dose. These urine drug concentrations remain well above 1,000 μg/mL throughout the dosing interval.
- Piperacillin binding to human serum proteins is 16%. The drug is widely distributed in human tissues and body fluids, including bone, prostate, and heart, and reaches high concentrations in bile. After a 4-g bolus injection, maximum biliary concentrations average 3,205 μg/mL. It penetrates into the cerebrospinal fluid in the presence of inflamed meninges.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Piperacillin in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Piperacillin in the drug label.
# How Supplied
- PIPRACIL ® (piperacillin for injection) is available in vials containing freeze-dried piperacillin sodium powder equivalent to two, three, and four g of piperacillin. One g of piperacillin (as a monosodium salt) contains 1.85 mEq (42.5 mg) of sodium.
- Product Numbers
- 2 gram/Vial-10 per box-NDC 0206-3879-16
- 3 gram/Vial-10 per box-NDC 0206-3882-55
- 4 gram/Vial-10 per box-NDC 0206-3880-25
## Storage
- Store at controlled room temperature 20°C-25°C
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Piperacillin in the drug label.
# Precautions with Alcohol
- Alcohol-Piperacillin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- PIPRACIL ®
# Look-Alike Drug Names
There is limited information regarding Piperacillin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Piperacillin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]
# Disclaimer
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# Overview
Piperacillin is an antibiotic that is FDA approved for the treatment of serious infections caused by susceptible strains ,hepatobiliary and surgical infections caused by E. coli, Pseudomonas aeruginosa, enterococci, Clostridium spp., anaerobic cocci, or Bacteroides spp,urinary tract infections, septicemia, lower respiratorytract infections, skin, infections ,bone and joint infections. Common adverse reactions include thrombophlebitis, erythema multiforme, stevens-johnson syndrome, toxic epidermal necrolysis, agranulocytosis, hemolytic anemia, pancytopenia, anaphylaxis, seizure, renal failure.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Piperacillin is indicated for the treatment of serious infections caused by susceptible strains of the designated microorganisms in the conditions listed below:
- Intra-Abdominal Infections including hepatobiliary and surgical infections caused by E. coli, Pseudomonas aeruginosa, enterococci, Clostridium spp., anaerobic cocci, or Bacteroides spp., including B. fragilis.
- Urinary Tract Infections caused by E. coli, Klebsiella spp., P. aeruginosa, Proteus spp., including P. mirabilis, or enterococci.
- Gynecologic Infections including endometritis, pelvic inflammatory disease, pelvic cellulitis caused by Bacteroides spp., including B. fragilis, anaerobic cocci, Neisseria gonorrhoeae, or enterococci (E. faecalis).
- Septicemia including bacteremia caused by E. coli, Klebsiella spp., Enterobacter spp., Serratia spp., P. mirabilis, S. pneumoniae, enterococci, P. aeruginosa, Bacteroides spp., or anaerobic cocci.
- Lower RespiratoryTract Infections caused by E. coli, Klebsiella spp., Enterobacter spp., P. aeruginosa, Serratia spp., H. influenzae, Bacteroides spp., or anaerobic cocci. * Although improvement has been noted in patients with cystic fibrosis, lasting bacterial eradication may not necessarily be achieved.
- Skin and Skin Structure Infections caused by E. coli, Klebsiella spp., Serratia spp., Acinetobacter spp., Enterobacter spp., P. aeruginosa, Morganella morganii, Providencia rettgeri, Proteus vulgaris, P. mirabilis, Bacteroides spp., including B. fragilis, anaerobic cocci, or enterococci.
- Bone and Joint Infections caused by P. aeruginosa, enterococci, Bacteroides spp., or anaerobic cocci.
- Uncomplicated Gonococcal Urethritis caused by N. gonorrhoeae.
- Piperacillin has also been shown to be clinically effective for the treatment of infections at various sites caused by Streptococcus species including S. pyogenes and S. pneumoniae; however, infections caused by these organisms are ordinarily treated with more narrow spectrum penicillins.
- Because of its broad spectrum of bactericidal activity against gram-positive and gram-negative aerobic and anaerobic bacteria, piperacillin is particularly useful for the treatment of mixed infections and presumptive therapy prior to the identification of the causative organisms.
- Also, piperacillin may be administered as single drug therapy in some situations where normally two antibiotics might be employed.
- Piperacillin has been successfully used with aminoglycosides, especially in patients with impaired host defenses. Both drugs should be used in full therapeutic doses.
- Appropriate cultures should be made for susceptibility testing before initiating therapy and therapy adjusted, if appropriate, once the results are known.
- Piperacillin is indicated for prophylactic use in surgery including intra-abdominal (gastrointestinal and biliary) procedures, vaginal hysterectomy, abdominal hysterectomy, and cesarean section.
- Effective prophylactic use depends on the time of administration; piperacillin should be given one-half to one hour before the operation so that effective levels can be achieved in the site prior to the procedure.
- The prophylactic use of piperacillin should be stopped within 24 hours, since continuing administration of any antibiotic increases the possibility of adverse reactions, but in the majority of surgical procedures, does not reduce the incidence of subsequent infections. If there are signs of infection, specimens for culture and susceptibility testing should be obtained for identification of the causative microorganism so that appropriate therapy can be instituted.
- To reduce the development of drug-resistant bacteria and maintain the effectiveness of piperacillin and other antibacterial drugs, piperacillinshould only be used to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
- Piperacillin may be administered by the intramuscular route or intravenously as a three- to five-minute intravenous injection or as a 20- to 30-minute infusion. The usual dosage of piperacillin for serious infections is 3 to 4 g given every four to six hours as a 20- to 30-minute infusion. For serious infections, the intravenous route should be used.
- Piperacillin should not be mixed with an aminoglycoside in a syringe or infusion bottle since this can result in inactivation of the aminoglycoside.
- The maximum daily dose for adults is usually 24 g/day, although higher doses have been used.
- Intramuscular injections should be limited to 2 g per injection site. This route of administration has been used primarily in the treatment of patients with uncomplicated gonorrhea and urinary tract infections.
- The average duration of piperacillin treatment is from seven to ten days, except in the treatment of gynecologic infections, which is from three to ten days; the duration should be guided by the patient's clinical and bacteriological progress. For most acute infections, treatment should be continued for at least 48 to 72 hours after the patient becomes asymptomatic. * Antibiotic therapy for S. pyogenes infections should be maintained for at least ten days to reduce the risk of rheumatic fever.
- When piperacillin is given concurrently with aminoglycosides, both drugs should be used in full therapeutic doses.
- For patients on hemodialysis, the maximum daily dose is 6 g/day (2 g every 8 hours). In addition, because hemodialysis removes 30% to 50% of piperacillin in 4 hours, a 1-g additional dose should be administered following each dialysis period.
- For patients with renal failure and hepatic insufficiency, measurement of serum levels of piperacillin will provide additional guidance for adjusting dosage.
- When possible, piperacillin should be administered as a 20- to 30-minute infusion just prior to anesthesia. Administration while the patient is awake will facilitate identification of possible adverse reactions during drug infusion.
- Reconstitution Directions for Conventional Vials:
- Reconstitute each gram of piperacillin with at least 5 mL of a suitable diluent (except Lidocaine HCl 0.5%-1% without epinephrine) listed above. Shake well until dissolved. Reconstituted solution may be diluted to the desired volume (eg, 50 or 100 mL) in the above listed intravenous solutions and admixtures.
- Infuse diluted solution over period of about 30 minutes. During infusion, it is desirable to discontinue the primary intravenous solution.
- Reconstituted solution should be injected slowly over a 3-to 5-minute period to help avoid vein irritation.
- Intramuscular Administration (Conventional Vials Only)
- Reconstitution Directions
- Reconstitute each gram of piperacillin with 2 mL of a suitable diluent listed above to achieve a concentration of 1 g per 2.5 mL. Shake well until dissolved.
- When indicated by clinical and bacteriological findings, intramuscular administration of 6 to 8 g daily of piperacillin, in divided doses, may be utilized for initiation of therapy.
- In addition, intramuscular administration of the drug may be considered for maintenance therapy after clinical and bacteriologic improvement has been obtained with intravenous piperacillin sodium treatment. Intramuscular administration should not exceed 2 g per injection at any one site.
- The preferred site is the upper outer quadrant of the buttock (ie, gluteus maximus).
- The deltoid area should be used only if well-developed, and then only with caution to avoid radial nerve injury. Intramuscular injections should not be made into the lower or mid-third of the upper arm.
- Stability of piperacillin Following Reconstitution
- Piperacillin is stable in both glass and plastic containers when reconstituted with recommended diluents and when diluted with the intravenous solutions and intravenous admixtures indicated above.
- Pharmacy vials should be used immediately after reconstitution. Discard any unused portion after 24 hours if stored at room temperature (20° to 25°C [68° to 77°F]), or after 48 hours if stored at refrigerated temperature (2° to 8°C [36° to 46°F]). Vials should not be frozen after reconstitution.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Piperacillin in adult patients.
### Non–Guideline-Supported Use
- Febrile neutropenia[1]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Piperacillin in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Piperacillin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Piperacillin in pediatric patients.
# Contraindications
- Piperacillin is contraindicated in patients with a history of allergic reactions to any of the betalactams, including penicillins and/or cephalosporins.
# Warnings
- SERIOUS AND OCCASIONALLY FATAL HYPERSENSITIVITY (ANAPHYLACTIC/ANAPHYLACTOID) REACTIONS HAVE BEEN REPORTED IN PATIENTS ON PENICILLIN THERAPY. THESE REACTIONS ARE MORE LIKELY TO OCCUR IN INDIVIDUALS WITH A HISTORY OF PENICILLIN HYPERSENSITIVITY AND/OR A HISTORY OF SENSITIVITY TO MULTIPLE ALLERGENS. THERE HAVE BEEN REPORTS OF INDIVIDUALS WITH A HISTORY OF PENICILLIN HYPERSENSITIVITY WHO HAVE EXPERIENCED SEVERE REACTIONS WHEN TREATED WITH CEPHALOSPORINS. BEFORE INITIATING THERAPY WITH piperacillin, CAREFUL INQUIRY SHOULD BE MADE CONCERNING PREVIOUS HYPERSENSITIVITY REACTIONS TO PENICILLINS, CEPHALOSPORINS OR OTHER ALLERGENS. IF AN ALLERGIC REACTION OCCURS, piperacillin SHOULD BE DISCONTINUED AND APPROPRIATE THERAPY INSTITUTED. SERIOUS ANAPHYLACTIC/ANAPHYLACTOID REACTIONS REQUIRE IMMEDIATE EMERGENCY TREATMENT WITH EPINEPHRINE. OXYGEN, INTRAVENOUS STEROIDS AND AIRWAY MANAGEMENT, INCLUDING INTUBATION, SHOULD ALSO BE ADMINISTERED AS INDICATED.
- Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including piperacillin, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.
- C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.
- If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
# Adverse Reactions
## Clinical Trials Experience
There is limited information regarding Clinical Trial Experience of Piperacillin in the drug label.
## Postmarketing Experience
- Piperacillin is generally well tolerated. The most common adverse reactions have been local in nature, following intravenous or intramuscular injection. The following adverse reactions may occur:
- In clinical trials thrombophlebitis was noted in 4% of patients. Pain, erythema, and/or induration at the injection site occurred in 2% of patients. Less frequent reactions including ecchymosis, deep vein thrombosis, and hematomas have also occurred.
- Diarrhea and loose stools were noted in 2% of patients. Other less frequent reactions included vomiting, nausea, increases in liver enzymes (LDH, AST, ALT), hyperbilirubinemia, cholestatic hepatitis, bloody diarrhea, and pseudomembranous colitis. The onset of pseudomembranous colitis symptoms may occur during or after antibiotic treatment.
- Anaphylactic/anaphylactoid reactions (some leading to shock and fatalities) have been reported.
- Rash was noted in 1% of patients. Other less frequent findings included pruritus, vesicular eruptions, and positive Coombs tests.
- Other dermatologic manifestations, such as erythema multiforme, urticaria, toxic epidermal necrolysis and Stevens-Johnson syndrome have been reported.
- Elevations of creatinine or BUN, renal failure and interstitial nephritis have been reported.
- Headache, dizziness, fatigue, and seizures have been reported.
- Hemolytic anemia, agranulocytosis, pancytopenia, prolonged bleeding time, reversible leukopenia, neutropenia, thrombocytopenia, and/or eosinophilia have been reported. As with other β-lactam antibiotics, reversible leukopenia (neutropenia) is more apt to occur in patients receiving prolonged therapy at high dosages or in association with drugs known to cause this reaction.
- Individuals with liver disease or individuals receiving cytotoxic therapy or diuretics were reported to demonstrate a decrease in serum potassium concentrations with high doses of piperacillin.
- Hypokalemia has been reported.
- Prolonged muscle relaxation.
- Fever, superinfection, including candidiasis; hemorrhagic manifestations have been reported.
- Piperacillin therapy has been associated with an increased incidence of fever and rash in cystic fibrosis patients.
# Drug Interactions
- The mixing of piperacillin with an aminoglycoside in vitro can result in substantial inactivation of the aminoglycoside.
- When used in the perioperative period, piperacillin has been implicated in the prolongation of the neuromuscular blockade of vecuronium. Caution is indicated when piperacillin is used perioperatively. In one controlled clinical study, the ureidopenicillins, including piperacillin, were reported to prolong the action of vecuronium. Due to their similar mechanism of action, it is expected that the neuromuscular blockade produced by any of the non-depolarizing muscle relaxants could be prolonged in the presence of piperacillin.
- The oral combination of probenecid before intramuscular injection of piperacillin produces an increase in piperacillin peak serum level of about 30%.
- Coagulation parameters should be tested more frequently and monitored regularly during simultaneous administration of high doses of heparin, oral anticoagulants, or other drugs that may affect the blood coagulation system or the thrombocyte function.
- Piperacillin sodium may reduce the excretion of methotrexate. Therefore, serum levels of methotrexate should be monitored in patients to avoid drug toxicity.
- As with other penicillins, the administration of piperacillin may result in a false-positive reaction for glucose in the urine using a copper-reduction method. It is recommended that glucose tests based on enzymatic glucose oxidase reactions be used.
- There have been reports of positive test results using the Bio-Rad Laboratories Platelia Aspergillus EIA test in patients receiving piperacillin/tazobactam injection who were subsequently found to be free of Aspergillus infection. Cross-reactions with non-Aspergillus polysaccharides and polyfuranoses with the Bio-Rad Laboratories Platelia Aspergillus EIA test have been reported.
- Therefore, positive test results in patients receiving piperacillin should be interpreted cautiously and confirmed by other diagnostic methods.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
- Teratology studies have been performed in mice (I.V.) and rats (I.V., I.P. and SQ) and have revealed no evidence of harm to the fetus due to piperacillin administered up to a dose which is approximately half the maximum recommended human daily dose based on body-surface area (mg/m2). In pharmacokinetic studies in pregnant and nonpregnant rats, in which piperacillin was administered I.V. at a dose which is half the maximum daily dose administered in teratology studies, serum concentrations in rats were approximately 10 times the maximum serum concentration seen in man. In other studies in mice and rats, in which piperacillin (in combination with a beta-lactamase inhibitor, tazobactam) was administered I.V. at approximately half the maximum daily dose administered in teratology studies, plasma concentrations of piperacillin were approximately 2 times (mice) and 5 times (rats) the serum concentrations seen in man.
- There are, however, no adequate and well-controlled studies with piperacillin in pregnant women. Because animal reproduction studies are not always predictive of the 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 Piperacillin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Piperacillin during labor and delivery.
### Nursing Mothers
- Piperacillin is excreted in low concentrations in human milk. Caution should be exercised when piperacillin is administered to nursing mothers.
### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established.
- Data from published pharmacokinetics studies indicate that the elimination half-life of piperacillin in neonates is twofold to fourfold longer than that seen in pediatric patients 1 month of age and above as well as in adults. In infants, children, and adolescents, the elimination half-life of piperacillin is shorter than that observed in adults. As in adults, the elimination of piperacillin is decreased in pediatric patients with renal impairment.
### Geriatic Use
- Clinical studies of piperacillin did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
- 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.
- Piperacillin contains 42.5 mg (1.85 mEq) of sodium per gram. At the usual recommended doses, patients would receive between 255 and 765 mg/day (11.1 and 33.3 mEq) of sodium. The geriatric population may respond with a blunted natriuresis to salt loading. The total sodium content from dietary and non-dietary sources may be clinically important with regard to such diseases as congestive heart failure.
- 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 Piperacillin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Piperacillin with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Piperacillin in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Piperacillin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Piperacillin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Piperacillin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous.
### Monitoring
- Coagulation parameters should be tested more frequently and monitored regularly during simultaneous administration of high doses of heparin, oral anticoagulants, or other drugs that may affect the blood coagulation system or the thrombocyte function.
- Piperacillin sodium may reduce the excretion of methotrexate. Therefore, serum levels of methotrexate should be monitored in patients to avoid drug toxicity.
- 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.
# IV Compatibility
There is limited information regarding IV Compatibility of Piperacillin in the drug label.
# Overdosage
- There is no specific information on overdose with piperacillin. Other penicillin-class drugs in overdosage, however, have the potential to cause neuromuscular hyperirritability or convulsive seizures.
- In case of overdosage, discontinue medication, treat symptomatically, and institute supportive measures as required. Piperacillin can be removed by hemodialysis but not peritoneal dialysis.
# Pharmacology
## Mechanism of Action
There is limited information regarding Piperacillin Mechanism of Action in the drug label.
## Structure
- PIPRACIL, sterile piperacillin sodium, is a semisynthetic broad-spectrum penicillin for parenteral use derived from D(-)-α-aminobenzylpenicillin. The chemical name of piperacillin sodium is sodium (2S,5R,6R)-6-[(R)-2-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-2-phenylacetamido]-3,-3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate. The chemical formula is C23H26N5NaO7S, and the molecular weight is 539.54. Its structural formula is:
- Piperacillin sodium powder is a white to off-white solid having the characteristic appearance of products prepared by freeze-drying. It is freely soluble in water and in alcohol. The pH of an aqueous solution containing 400 milligrams per milliliter ranges from 5.5 to 7.5. One g contains 1.85 mEq (42.5 mg) of sodium (Na+).
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Piperacillin in the drug label.
## Pharmacokinetics
- In healthy adult volunteers, mean serum piperacillin concentrations immediately after a two‑to three‑minute intravenous injection of 2, 4, or 6 g were 305, 412, and 775 μg/mL, respectively. Serum concentrations lack dose proportionality.
- A 30-minute infusion of 6 g every 6 h gave, on the fourth day, a mean peak serum concentration of 420 μg/mL.
- Piperacillin is rapidly absorbed after intramuscular injection. In healthy volunteers, the mean peak serum concentration occurs approximately 30 minutes after a single dose of 2 g and is about 36 μg/mL. The oral administration of 1 g probenecid before injection produces an increase in piperacillin peak serum level of about 30%. The area under the curve (AUC) is increased by approximately 60%.
- Piperacillin is not absorbed when given orally. Peak serum concentrations are attained approximately 30 minutes after intramuscular injections and immediately after completion of intravenous injection or infusion. The serum half-life in healthy volunteers ranges from 36 minutes to one hour and 12 minutes. The mean elimination half-life of piperacillin in healthy adult volunteers is 54 minutes following administration of 2 g and 63 minutes following 6 g. As with other penicillins, piperacillin is eliminated primarily by glomerular filtration and tubular secretion; it is excreted rapidly as unchanged drug in high concentrations in the urine.
- Approximately 60% to 80% of the administered dose is excreted in the urine in the first 24 hours. Piperacillin urine concentrations, determined by microbioassay, are as high as 14,100 μg/mL following a 6-g intravenous dose and 8,500 μg/mL following a 4-g intravenous dose. These urine drug concentrations remain well above 1,000 μg/mL throughout the dosing interval.
- Piperacillin binding to human serum proteins is 16%. The drug is widely distributed in human tissues and body fluids, including bone, prostate, and heart, and reaches high concentrations in bile. After a 4-g bolus injection, maximum biliary concentrations average 3,205 μg/mL. It penetrates into the cerebrospinal fluid in the presence of inflamed meninges.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Piperacillin in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Piperacillin in the drug label.
# How Supplied
- PIPRACIL ® (piperacillin for injection) is available in vials containing freeze-dried piperacillin sodium powder equivalent to two, three, and four g of piperacillin. One g of piperacillin (as a monosodium salt) contains 1.85 mEq (42.5 mg) of sodium.
- Product Numbers
- 2 gram/Vial-10 per box-NDC 0206-3879-16
- 3 gram/Vial-10 per box-NDC 0206-3882-55
- 4 gram/Vial-10 per box-NDC 0206-3880-25
## Storage
- Store at controlled room temperature 20°C-25°C
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Piperacillin in the drug label.
# Precautions with Alcohol
- Alcohol-Piperacillin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- PIPRACIL ®[2]
# Look-Alike Drug Names
There is limited information regarding Piperacillin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Piperacillin | |
fcc4b91aa1059d5ebb81e8cf27a3d602630e1896 | wikidoc | Pitavastatin | Pitavastatin
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# Overview
Pitavastatin is a HMG-CoA reductase inhibitor that is FDA approved for the treatment of primary hyperlipidemia and mixed dyslipidemia. Common adverse reactions include rhabdomyolysis with myoglobinuria, acute renal failure, myopathy (including myositis) and liver enzyme abnormalities.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Primary Hyperlipidemia and Mixed Dyslipidemia
Indications
- Drug therapy should be one component of multiple-risk-factor intervention in individuals who require modifications of their lipid profile. Lipid-altering agents should be used in addition to a diet restricted in saturated fat and cholesterol only when the response to diet and other nonpharmacological measures has been inadequate.
- Pitavastatin is indicated as an adjunctive therapy to diet to reduce elevated total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), triglycerides (TG), and to increase HDL-C in adult patients with primary hyperlipidemia or mixed dyslipidemia.
General Dosing Information
- Dose range： 1 to 4 mg PO qd at any time of the day with or without food.
- The recommended starting dose: 2 mg and
- Maximum dosage: 4 mg
- . The starting dose and maintenance doses of Pitavastatin should be individualized according to patient characteristics, such as goal of therapy and response.
- After initiation or upon titration of Pitavastatin, lipid levels should be analyzed after 4 weeks and the dosage adjusted accordingly.
Dosage in Patients with Renal Impairment
- Patients with moderate and severe renal impairment (glomerular filtration rate 30 – 59 mL/min/1.73 m2 and 15 – 29 mL/min/1.73 m2 not receiving hemodialysis, respectively) as well as end-stage renal disease receiving hemodialysis should receive
- Starting dose : 1 mg once daily
- Maximum dosage: 2 mg once daily
Use with Erythromycin
- In patients taking erythromycin, a dose of Pitavastatin 1 mg PO qd should not be exceeded
Use with Rifampin
- In patients taking rifampin, a dose of Pitavastatin 2 mg PO qd should not be exceeded
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pitavastatin in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label non-Guideline-Supported Use of Pitavastatin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Safety and effectiveness have not been established
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Pitavastatin in pediatric patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Pitavastatin in pediatric patients.
# Contraindications
- The use of Pitavastatin is contraindicated in the following conditions:
- Patients with a known hypersensitivity to any component of this product. Hypersensitivity reactions including rash, pruritus, and urticaria have been reported with Pitavastatin.
- Patients with active liver disease which may include unexplained persistent elevations of hepatic transaminase levels.
- Women who are pregnant or may become pregnant. Because HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, Pitavastatin may cause fetal harm when administered to pregnant women. Additionally, there is no apparent benefit to therapy during pregnancy, and safety in pregnant women has not been established. If the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus and the lack of known clinical benefit with continued use during pregnancy.
- Nursing mothers. Animal studies have shown that Pitavastatin passes into breast milk. Since HMG-CoA reductase inhibitors have the potential to cause serious adverse reactions in nursing infants, Pitavastatin, like other HMG-CoA reductase inhibitors, is contraindicated in pregnant or nursing mothers.
- Co-administration with cyclosporine
# Warnings
- Cases of myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with HMG-CoA reductase inhibitors, including Pitavastatin. These risks can occur at any dose level, but increase in a dose-dependent manner.
- Pitavastatin should be prescribed with caution in patients with predisposing factors for myopathy. These factors include advanced age (≥65 years), renal impairment, and inadequately treated hypothyroidism. The risk of myopathy may also be increased with concurrent administration of fibrates or lipid-modifying doses of niacin. Pitavastatin should be administered with caution in patients with impaired renal function, in elderly patients, or when used concomitantly with fibrates or lipid-modifying doses of niacin.
- Cases of myopathy, including rhabdomyolysis, have been reported with HMG-CoA reductase inhibitors coadministered with colchicine, and caution should be exercised when prescribing Pitavastatin with colchicine.
- There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents.
- Pitavastatin therapy should be discontinued if markedly elevated creatine kinase (CK) levels occur or myopathy is diagnosed or suspected. Pitavastatin therapy should also be temporarily withheld in any patient with an acute, serious condition suggestive of myopathy or predisposing to the development of renal failure secondary to rhabdomyolysis (e.g., sepsis, hypotension, dehydration, major surgery, trauma, severe metabolic, endocrine, and electrolyte disorders, or uncontrolled seizures). All patients should be advised to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing Pitavastatin.
- Increases in serum transaminases (aspartate aminotransferase /serum glutamic-oxaloacetic transaminase, or alanine aminotransferase /serum glutamic-pyruvic transaminase) have been reported with HMG-CoA reductase inhibitors, including Pitavastatin. In most cases, the elevations were transient and resolved or improved on continued therapy or after a brief interruption in therapy.
- In placebo-controlled Phase 2 studies, ALT >3 times the upper limit of normal was not observed in the placebo, Pitavastatin 1 mg, or Pitavastatin 2 mg groups. One out of 202 patients (0.5%) administered Pitavastatin 4 mg had ALT >3 times the upper limit of normal.
- It is recommended that liver enzyme tests be performed before the initiation of Pitavastatin and if signs or symptoms of liver injury occur.
- There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including pitavastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with Pitavastatin, promptly interrupt therapy. If an alternate etiology is not found do not restart Pitavastatin.
- As with other HMG-CoA reductase inhibitors, Pitavastatin should be used with caution in patients who consume substantial quantities of alcohol. Active liver disease, which may include unexplained persistent transaminase elevations, is a contraindication to the use of Pitavastatin.
- Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including Pitavastatin.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical studies on Pitavastatin are conducted in varying study populations and study designs, the frequency of adverse reactions observed in the clinical studies of Pitavastatin cannot be directly compared with that in the clinical studies of other HMG-CoA reductase inhibitors and may not reflect the frequency of adverse reactions observed in clinical practice.
- Adverse reactions reported in ≥ 2% of patients in controlled clinical studies and at a rate greater than or equal to placebo are shown in Table 1. These studies had treatment duration of up to 12 weeks.
- Other adverse reactions reported from clinical studies were arthralgia, headache, influenza, and nasopharyngitis.
- The following laboratory abnormalities have also been reported: elevated creatine phosphokinase, transaminases, alkaline phosphatase, bilirubin, and glucose.
- In controlled clinical studies and their open-label extensions, 3.9% (1 mg), 3.3% (2 mg), and 3.7% (4 mg) of pitavastatin-treated patients were discontinued due to adverse reactions. The most common adverse reactions that led to treatment discontinuation were: elevated creatine phosphokinase (0.6% on 4 mg) and myalgia (0.5% on 4 mg).
- Hypersensitivity reactions including rash, pruritus, and urticaria have been reported with Pitavastatin.
## Postmarketing Experience
- The following adverse reactions have been identified during postapproval use of Pitavastatin. 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.
- Adverse reactions associated with Pitavastatin therapy reported since market introduction, regardless of causality assessment, include the following: abdominal discomfort, abdominal pain, dyspepsia, nausea, asthenia, fatigue, malaise, hepatitis, jaundice, fatal and non-fatal hepatic failure, dizziness, hypoesthesia, insomnia, depression, interstitial lung disease, erectile dysfunction and muscle spasms.
- There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).
- There have been rare reports of immune-mediated necrotizing myopathy associated with statin use.
# Drug Interactions
- Cyclosporine significantly increased pitavastatin exposure. Co-administration of cyclosporine with Pitavastatin is contraindicated.
- Erythromycin significantly increased pitavastatin exposure. In patients taking erythromycin, a dose of Pitavastatin 1 mg once daily should not be exceeded.
- Rifampin significantly increased pitavastatin exposure. In patients taking rifampin, a dose of Pitavastatin 2 mg once daily should not be exceeded.
- Due to an increased risk of myopathy/rhabdomyolysis when HMG-CoA reductase inhibitors are coadministered with gemfibrozil, concomitant administration of Pitavastatin with gemfibrozil should be avoided.
- Because it is known that the risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with concurrent administration of other fibrates, Pitavastatin should be administered with caution when used concomitantly with other fibrates.
- The risk of skeletal muscle effects may be enhanced when Pitavastatin is used in combination with niacin; a reduction in Pitavastatin dosage should be considered in this setting.
- Cases of myopathy, including rhabdomyolysis, have been reported with HMG-CoA reductase inhibitors coadministered with colchicine, and caution should be exercised when prescribing Pitavastatin with colchicine.
- Pitavastatin had no significant pharmacokinetic interaction with R- and S- warfarin. Pitavastatin had no significant effect on prothrombin time (PT) and international normalized ratio (INR) when administered to patients receiving chronic warfarin treatment. However, patients receiving warfarin should have their PT and INR monitored when pitavastatin is added to their therapy.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): X
- Pitavastatin is contraindicated in women who are or may become pregnant. Serum cholesteroland TG increase during normal pregnancy, and cholesterolproducts are essential for fetal development. Atherosclerosis is a chronic process and discontinuation of lipid-lowering drugs during pregnancy should have little impact on long-term outcomes of primary hyperlipidemia therapy.
- There are no adequate and well-controlled studies of Pitavastatin in pregnant women, although, there have been rare reports of congenital anomalies following intrauterine exposure to HMG-CoA reductase inhibitors. In a review of about 100 prospectively followed pregnancies in women exposed to other HMG-CoA reductase inhibitors, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed the rate expected in the general population. However, this study was only able to exclude a three-to-four-fold increased risk of congenital anomalies over background incidence. In 89% of these cases, drug treatment started before pregnancy and stopped during the first trimester when pregnancy was identified.
- Reproductive toxicity studies have shown that pitavastatin crosses the placenta in rats and is found in fetal tissues at ≤36% of maternal plasma concentrations following a single dose of 1 mg/kg/day during gestation.
- Embryo-fetal developmental studies were conducted in pregnant rats treated with 3, 10, 30 mg/kg/day pitavastatin by oral gavage during organogenesis. No adverse effects were observed at 3 mg/kg/day, systemic exposures 22 times human systemic exposure at 4 mg/day based on AUC.
- Embryo-fetal developmental studies were conducted in pregnant rabbits treated with 0.1, 0.3, 1 mg/kg/day pitavastatin by oral gavage during the period of fetal organogenesis. Maternal toxicity consisting of reduced body weight and abortion was observed at all doses tested (4 times human systemic exposure at 4 mg/day based on AUC).
- In perinatal/postnatal studies in pregnant rats given oral gavage doses of pitavastatin at 0.1, 0.3, 1, 3, 10, 30 mg/kg/day from organogenesis through weaning, maternal toxicity consisting of mortality at ≥0.3 mg/kg/day and impaired lactation at all doses contributed to the decreased survival of neonates in all dose groups (0.1 mg/kg/day represents approximately 1 time human systemic exposure at 4 mg/day dose based on AUC).
- Pitavastatin may cause fetal harm when administered to a pregnant woman. If the patient becomes pregnant while taking Pitavastatin, the patient should be apprised of the potential risks to the fetus and the lack of known clinical benefit with continued use during pregnancy.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Pitavastatin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Pitavastatin during labor and delivery.
### Nursing Mothers
- It is not known whether pitavastatin is excreted in human milk, however, it has been shown that a small amount of another drug in this class passes into human milk. Rat studies have shown that pitavastatin is excreted into breast milk. Because another drug in this class passes into human milk and HMG-CoA reductase inhibitors have a potential to cause serious adverse reactions in nursing infants, women who require Pitavastatin treatment should be advised not to nurse their infants or to discontinue Pitavastatin.
### Pediatric Use
- Safety and effectiveness of Pitavastatin in pediatric patients have not been established.
### Geriatic Use
- Of the 2,800 patients randomized to Pitavastatin 1 mg to 4 mg in controlled clinical studies, 1,209 (43%) were 65 years and older. No significant differences in efficacy or safety were observed between elderly patients and younger patients. However, greater sensitivity of some older individuals cannot be ruled out.
### Gender
There is no FDA guidance on the use of Pitavastatin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Pitavastatin with respect to specific racial populations.
### Renal Impairment
- Patients with moderate and severe renal impairment (glomerular filtration rate 30 – 59 mL/min/1.73 m2 and 15 – 29 mL/min/1.73 m2 not receiving hemodialysis, respectively) as well as end-stage renal disease receiving hemodialysis should receive a starting dose of Pitavastatin 1 mg once daily and a maximum dose of Pitavastatin 2 mg once daily.
### Hepatic Impairment
- Pitavastatin is contraindicated in patients with active liver disease which may include unexplained persistent elevations of hepatic transaminase levels.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Pitavastatin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Pitavastatin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- FDA Package Insert for Pitavastatin contains no information regarding drug monitoring.
# IV Compatibility
- There is limited information about the IV compatibility.
# Overdosage
- There is no known specific treatment in the event of overdose of pitavastatin. In the event of overdose, the patient should be treated symptomatically and supportive measures instituted as required. Hemodialysis is unlikely to be of benefit due to high protein binding ratio of pitavastatin.
# Pharmacology
## Mechanism of Action
- Pitavastatin competitively inhibits HMG-CoA reductase, which is a rate-determining enzyme involved with biosynthesis of cholesterol, in a manner of competition with the substrate so that it inhibits cholesterol synthesis in the liver. As a result, the expression of LDL-receptors followed by the uptake of LDL from blood to liver is accelerated and then the plasma TC decreases. Further, the sustained inhibition of cholesterol synthesis in the liver decreases levels of very low density lipoproteins.
## Structure
- Pitavastatin (pitavastatin) is an inhibitor of HMG-CoA reductase. It is a synthetic lipid-lowering agent for oral administration.
- The chemical name for pitavastatin is (+)monocalcium bis{(3R, 5S, 6E)-7--3,5-dihydroxy-6-heptenoate}. The structural formula is:
- The empirical formula for pitavastatin is C50H46CaF2N2O8 and the molecular weight is 880.98. Pitavastatin is odorless and occurs as white to pale-yellow powder. It is freely soluble in pyridine, chloroform, dilute hydrochloric acid, and tetrahydrofuran, soluble in ethylene glycol, sparingly soluble in octanol, slightly soluble in methanol, very slightly soluble in water or ethanol, and practically insoluble in acetonitrile or diethyl ether. Pitavastatin is hygroscopic and slightly unstable in light.
- Each film-coated tablet of Pitavastatin contains 1.045 mg, 2.09 mg, or 4.18 mg of pitavastatin calcium, which is equivalent to 1 mg, 2 mg, or 4 mg, respectively of free base and the following inactive ingredients: lactose monohydrate, low substituted hydroxypropylcellulose, hypromellose, magnesium aluminometasilicate, magnesium stearate, and film coating containing the following inactive ingredients: hypromellose, titanium dioxide, triethyl citrate, and colloidal anhydrous silica.
## Pharmacodynamics
- In a randomized, double-blind, placebo-controlled, 4-way parallel, active-comparator study with moxifloxacin in 174 healthy participants, Pitavastatin was not associated with clinically meaningful prolongation of the QTc interval or heart rate at daily doses up to 16 mg (4 times the recommended maximum daily dose).
## Pharmacokinetics
Absorption
- Pitavastatin peak plasma concentrations are achieved about 1 hour after oral administration. Both Cmax and AUC0-inf increased in an approximately dose-proportional manner for single Pitavastatin doses from 1 to 24 mg once daily. The absolute bioavailability of pitavastatin oral solution is 51%. Administration of Pitavastatin with a high fat meal (50% fat content) decreases pitavastatin Cmax by 43% but does not significantly reduce pitavastatin AUC. The Cmax and AUC of pitavastatin did not differ following evening or morning drug administration. In healthy volunteers receiving 4 mg pitavastatin, the percent change from baseline for LDL-C following evening dosing was slightly greater than that following morning dosing. Pitavastatin was absorbed in the small intestine but very little in the colon.
Distribution
- Pitavastatin is more than 99% protein bound in human plasma, mainly to albumin and alpha 1-acid glycoprotein, and the mean volume of distribution is approximately 148 L. Association of pitavastatin and/or its metabolites with the blood cells is minimal.
Metabolism
- Pitavastatin is marginally metabolized by CYP2C9 and to a lesser extent by CYP2C8. The major metabolite in human plasma is the lactone which is formed via an ester-type pitavastatin glucuronide conjugate by uridine 5'-diphosphate (UDP) glucuronosyltransferase (UGT1A3 and UGT2B7).
Excretion
- A mean of 15% of radioactivity of orally administered, single 32 mg 14C-labeled pitavastatin dose was excreted in urine, whereas a mean of 79% of the dose was excreted in feces within 7 days. The mean plasma elimination half-life is approximately 12 hours.
Race
- In pharmacokinetic studies pitavastatin Cmax and AUC were 21 and 5% lower, respectively in Black or African American healthy volunteers compared with those of Caucasian healthy volunteers. In pharmacokinetic comparison between Caucasian volunteers and Japanese volunteers, there were no significant differences in Cmax and AUC.
Gender
- In a pharmacokinetic study which compared healthy male and female volunteers, pitavastatin Cmax and AUC were 60 and 54% higher, respectively in females. This had no effect on the efficacy or safety of Pitavastatin in women in clinical studies.
Geriatric
- In a pharmacokinetic study which compared healthy young and elderly (≥65 years) volunteers, pitavastatin Cmax and AUC were 10 and 30% higher, respectively, in the elderly. This had no effect on the efficacy or safety of Pitavastatin in elderly subjects in clinical studies.
Renal Impairment
- In patients with moderate renal impairment (glomerular filtration rate of 30 – 59 mL/min/1.73 m2) and end stage renal disease receiving hemodialysis, pitavastatin AUC0-inf is 102 and 86% higher than those of healthy volunteers, respectively, while pitavastatin Cmax is 60 and 40% higher than those of healthy volunteers, respectively. Patients received hemodialysis immediately before pitavastatin dosing and did not undergo hemodialysis during the pharmacokinetic study. Hemodialysis patients have 33 and 36% increases in the mean unbound fraction of pitavastatin as compared to healthy volunteers and patients with moderate renal impairment, respectively.
- In another pharmacokinetic study, patients with severe renal impairment (glomerular filtration rate 15 – 29 mL/min/1.73 m2) not receiving hemodialysis were administered a single dose of Pitavastatin 4 mg. The AUC0-inf and the Cmax were 36 and 18% higher, respectively, compared with those of healthy volunteers. For both patients with severe renal impairment and healthy volunteers, the mean percentage of protein-unbound pitavastatin was approximately 0.6%.
- The effect of mild renal impairment on pitavastatin exposure has not been studied.
Hepatic Impairment
- The disposition of pitavastatin was compared in healthy volunteers and patients with various degrees of hepatic impairment. The ratio of pitavastatin Cmax between patients with moderate hepatic impairment (Child-Pugh B disease) and healthy volunteers was 2.7. The ratio of pitavastatin AUCinf between patients with moderate hepatic impairment and healthy volunteers was 3.8. The ratio of pitavastatin Cmax between patients with mild hepatic impairment (Child-Pugh A disease) and healthy volunteers was 1.3. The ratio of pitavastatin AUCinf between patients with mild hepatic impairment and healthy volunteers was 1.6. Mean pitavastatin t½ for moderate hepatic impairment, mild hepatic impairment, and healthy were 15, 10, and 8 hours, respectively.
Drug-Drug Interactions
- The principal route of pitavastatin metabolism is glucuronidation via liver UGTs with subsequent formation of pitavastatin lactone. There is only minimal metabolism by the cytochrome P450 system.
Warfarin
- The steady-state pharmacodynamics (international normalized ratio and prothrombin time ) and pharmacokinetics of warfarin in healthy volunteers were unaffected by the co-administration of Pitavastatin 4 mg daily. However, patients receiving warfarin should have their PT time or INR monitored when pitavastatin is added to their therapy.
## Nonclinical Toxicology
## Carcinogenesis, Mutagenesis, Impairment of Fertility
- In a 92-week carcinogenicity study in mice given pitavastatin, at the maximum tolerated dose of 75 mg/kg/day with systemic maximum exposures (AUC) 26 times the clinical maximum exposure at 4 mg/day, there was an absence of drug-related tumors.
- In a 92-week carcinogenicity study in rats given pitavastatin at 1, 5, 25 mg/kg/day by oral gavage there was a significant increase in the incidence of thyroid follicular cell tumors at 25 mg/kg/day, which represents 295 times human systemic exposures based on AUC at the 4 mg/day maximum human dose.
- In a 26-week transgenic mouse (Tg rasH2) carcinogenicity study where animals were given pitavastatin at 30, 75, and 150 mg/kg/day by oral gavage, no clinically significant tumors were observed.
- Pitavastatin was not mutagenic in the Ames test with Salmonella typhimurium and Escherichia coli with and without metabolic activation, the micronucleus test following a single administration in mice and multiple administrations in rats, the unscheduled DNA synthesis test in rats, and a Comet assay in mice. In the chromosomal aberration test, clastogenicity was observed at the highest doses tested which also elicited high levels of cytotoxicity.
- Pitavastatin had no adverse effects on male and female rat fertility at oral doses of 10 and 30 mg/kg/day, respectively, at systemic exposures 56- and 354-times clinical exposure at 4 mg/day based on AUC.
- Pitavastatin treatment in rabbits resulted in mortality in males and females given 1 mg/kg/day (30-times clinical systemic exposure at 4 mg/day based on AUC) and higher during a fertility study. Although the cause of death was not determined, rabbits had gross signs of renal toxicity (kidneys whitened) indicative of possible ischemia. Lower doses (15-times human systemic exposure) did not show significant toxicity in adult males and females. However, decreased implantations, increased resorptions, and decreased viability of fetuses were observed.
## Animal Toxicology and/or Pharmacology
### Central Nervous System Toxicity
- CNS vascular lesions, characterized by perivascular hemorrhages, edema, and mononuclear cell infiltration of perivascular spaces, have been observed in dogs treated with several other members of this drug class. A chemically similar drug in this class produced dose-dependent optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in dogs, at a dose that produced plasma drug levels about 30 times higher than the mean drug level in humans taking the highest recommended dose. Wallerian degeneration has not been observed with pitavastatin. Cataracts and lens opacities were seen in dogs treated for 52 weeks at a dose level of 1 mg/kg/day (9 times clinical exposure at the maximum human dose of 4 mg/day based on AUC comparisons.
# Clinical Studies
## Primary hyperlipidemia or Mixed Dyslipidemia
Dose-ranging study
- A multicenter, randomized, double-blind, placebo-controlled, dose-ranging study was performed to evaluate the efficacy of Pitavastatin compared with placebo in 251 patients with primary hyperlipidemia(Table 4). Pitavastatin given as a single daily dose for 12 weeks significantly reduced plasma LDL-C, TC, TG, and Apo-B compared to placebo and was associated with variable increases in HDL-C across the dose range.
Active-controlled study with atorvastatin (NK-104-301)
- Pitavastatin was compared with the HMG-CoA reductase inhibitor atorvastatin in a randomized, multicenter, double-blind, double-dummy, active-controlled, non-inferiority Phase 3 study of 817 patients with primary hyperlipidemiaor mixed dyslipidemia. Patients entered a 6- to 8-week wash-out/dietary lead-in period and then were randomized to a 12-week treatment with either Pitavastatin or atorvastatin (Table 5). Non-inferiority of pitavastatin to a given dose of atorvastatin was considered to be demonstrated if the lower bound of the 95% CI for the mean treatment difference was greater than 6% for the mean percent change in LDL-C.
- Lipid results are shown in Table 5. For the percent change from baseline to endpoint in LDL-C, Pitavastatin was non-inferior to atorvastatin for the two pairwise comparisons: Pitavastatin 2 mg vs. atorvastatin 10 mg and Pitavastatin 4 mg vs. atorvastatin 20 mg. Mean treatment differences (95% CI) were 0% (-3%, 3%) and 1% (-2%, 4%), respectively.
Active-controlled study with simvastatin (NK-104-302)
- Pitavastatin was compared with the HMG-CoA reductase inhibitor simvastatin in a randomized, multicenter, double-blind, double-dummy, active-controlled, non-inferiority Phase 3 study of 843 patients with primary hyperlipidemiaor mixed dyslipidemia. Patients entered a 6- to 8-week wash-out/dietary lead-in period and then were randomized to a 12 week treatment with either Pitavastatin or simvastatin (Table 6). Non-inferiority of pitavastatin to a given dose of simvastatin was considered to be demonstrated if the lower bound of the 95% CI for the mean treatment difference was greater than 6% for the mean percent change in LDL-C.
- Lipid results are shown in Table 6. For the percent change from baseline to endpoint in LDL-C, Pitavastatin was non-inferior to simvastatin for the two pairwise comparisons: Pitavastatin 2 mg vs. simvastatin 20 mg and Pitavastatin 4 mg vs. simvastatin 40 mg. Mean treatment differences (95% CI) were 4% (1%, 7%) and 1% (-2%, 4%), respectively.
Active-controlled study with pravastatin in elderly (NK-104-306)
- Pitavastatin was compared with the HMG-CoA reductase inhibitor pravastatin in a randomized, multicenter, double-blind, double-dummy, parallel group, active-controlled non-inferiority Phase 3 study of 942 elderly patients (≥65 years) with primary hyperlipidemiaor mixed dyslipidemia. Patients entered a 6- to 8-week wash-out/dietary lead-in period, and then were randomized to a once daily dose of Pitavastatin or pravastatin for 12 weeks (Table 7). Non-inferiority of Pitavastatin to a given dose of pravastatin was assumed if the lower bound of the 95% CI for the treatment difference was greater than -6% for the mean percent change in LDL-C.
- Lipid results are shown in Table 7. Pitavastatin significantly reduced LDL-C compared to pravastatin as demonstrated by the following pairwise dose comparisons: Pitavastatin 1 mg vs. pravastatin 10 mg, Pitavastatin 2 mg vs. pravastatin 20 mg and Pitavastatin 4 mg vs. pravastatin 40 mg. Mean treatment differences (95% CI) were 9% (6%, 12%), 10% (7%, 13%) and 10% (7%, 13% ), respectively.
Active-controlled study with simvastatin in patients with ≥ 2 risk factors for coronary heart disease (NK-104-304)
- Pitavastatin was compared with the HMG-CoA reductase inhibitor simvastatin in a randomized, multicenter, double-blind, double-dummy, active-controlled, non-inferiority Phase 3 study of 351 patients with primary hyperlipidemiaor mixed dyslipidemia with ≥2 risk factors for coronary heart disease. After a 6- to 8-week wash-out/dietary lead-in period, patients were randomized to a 12-week treatment with either Pitavastatin or simvastatin (Table 8). Non-inferiority of Pitavastatin to simvastatin was considered to be demonstrated if the lower bound of the 95% CI for the mean treatment difference was greater than -6% for the mean percent change in LDL-C.
- Lipid results are shown in Table 8. Pitavastatin 4 mg was non-inferior to simvastatin 40 mg for percent change from baseline to endpoint in LDL-C. The mean treatment difference (95% CI) was 0% (-2%, 3%).
Active-controlled study with atorvastatin in patients with type II diabetes mellitus (NK-104-305)
- Pitavastatin was compared with the HMG-CoA reductase inhibitor atorvastatin in a randomized, multicenter, double-blind, double-dummy, parallel group, active-controlled, non-inferiority Phase 3 study of 410 subjects with type II diabetes mellitus and combined dyslipidemia. Patients entered a 6- to 8-week washout/dietary lead-in period and were randomized to a once daily dose of Pitavastatin or atorvastatin for 12 weeks. Non-inferiority of Pitavastatin was considered to be demonstrated if the lower bound of the 95% CI for the mean treatment difference was greater than -6% for the mean percent change in LDL-C.
- Lipid results are shown in Table 9. The treatment difference (95% CI) for LDL-C percent change from baseline was -2% (-6.2%, 1.5%). The two treatment groups were not statistically different on LDL-C. However, the lower limit of the CI was -6.2%, slightly exceeding the -6% non-inferiority limit so that the non-inferiority objective was not achieved.
# How Supplied
- Pitavastatin tablets for oral administration are provided as white, film-coated tablets that contain 1 mg, 2 mg, or 4 mg of pitavastatin. Each tablet has “KC” debossed on one side and a code number specific to the tablet strength on the other.
## Packaging
- Pitavastatin (pitavastatin) Tablets are supplied as:
- NDC 66869-104-90 : 1 mg. Round white film-coated tablet debossed “KC” on one face and “1” on the reverse; HDPE bottles of 90 tablets
- NDC 66869-204-90 : 2 mg. Round white film-coated tablet debossed “KC” on one face and “2” on the reverse; HDPE bottles of 90 tablets
- NDC 66869-404-90 : 4 mg. Round white film-coated tablet debossed “KC” on one face and “4” on the reverse; HDPE bottles of 90 tablets
## Storage
- Store at room temperature between 15°C and 30°C (59° to 86° F). Protect from light.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
# Patient Counseling Information
- The patient should be informed of the following:
## Dosing Time
- Pitavastatin can be taken at any time of the day with or without food.
## Muscle Pain
- Patients should be advised to promptly notify their physician of any unexplained muscle pain, tenderness, or weakness particularly if accompanied by malaise or fever, or if these muscle signs or symptoms persist after discontinuing Pitavastatin. They should discuss all medication, both prescription and over the counter, with their physician.
## Pregnancy
- Women of childbearing age should use an effective method of birth control to prevent pregnancy while using Pitavastatin. Discuss future pregnancy plans with your healthcare professional, and discuss when to stop Pitavastatin if you are trying to conceive. If you are pregnant, stop taking Pitavastatin and call your healthcare professional.
## Breastfeeding
- Women who are breastfeeding should not use Pitavastatin. If you have a lipid disorder and are breastfeeding, stop taking Pitavastatin and consult with your healthcare professional.
## Liver Enzymes
- It is recommended that liver enzyme tests be checked before the initiation of Pitavastatin and if signs or symptoms of liver injury occur. All patients treated with Pitavastatin should be advised to report promptly any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice.
# Precautions with Alcohol
- As with other HMG-CoA reductase inhibitors, Pitavastatin should be used with caution in patients who consume substantial quantities of alcohol.
# Brand Names
Livalo
# Look-Alike Drug Names
- Pitavastatin - pravastatin
# Drug Shortage Status
# Price | Pitavastatin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2]
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# Overview
Pitavastatin is a HMG-CoA reductase inhibitor that is FDA approved for the treatment of primary hyperlipidemia and mixed dyslipidemia. Common adverse reactions include rhabdomyolysis with myoglobinuria, acute renal failure, myopathy (including myositis) and liver enzyme abnormalities.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Primary Hyperlipidemia and Mixed Dyslipidemia
Indications
- Drug therapy should be one component of multiple-risk-factor intervention in individuals who require modifications of their lipid profile. Lipid-altering agents should be used in addition to a diet restricted in saturated fat and cholesterol only when the response to diet and other nonpharmacological measures has been inadequate.
- Pitavastatin is indicated as an adjunctive therapy to diet to reduce elevated total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), triglycerides (TG), and to increase HDL-C in adult patients with primary hyperlipidemia or mixed dyslipidemia.
General Dosing Information
- Dose range： 1 to 4 mg PO qd at any time of the day with or without food.
- The recommended starting dose: 2 mg and
- Maximum dosage: 4 mg
- . The starting dose and maintenance doses of Pitavastatin should be individualized according to patient characteristics, such as goal of therapy and response.
- After initiation or upon titration of Pitavastatin, lipid levels should be analyzed after 4 weeks and the dosage adjusted accordingly.
Dosage in Patients with Renal Impairment
- Patients with moderate and severe renal impairment (glomerular filtration rate 30 – 59 mL/min/1.73 m2 and 15 – 29 mL/min/1.73 m2 not receiving hemodialysis, respectively) as well as end-stage renal disease receiving hemodialysis should receive
- Starting dose : 1 mg once daily
- Maximum dosage: 2 mg once daily
Use with Erythromycin
- In patients taking erythromycin, a dose of Pitavastatin 1 mg PO qd should not be exceeded
Use with Rifampin
- In patients taking rifampin, a dose of Pitavastatin 2 mg PO qd should not be exceeded
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pitavastatin in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label non-Guideline-Supported Use of Pitavastatin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Safety and effectiveness have not been established
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Pitavastatin in pediatric patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Pitavastatin in pediatric patients.
# Contraindications
- The use of Pitavastatin is contraindicated in the following conditions:
- Patients with a known hypersensitivity to any component of this product. Hypersensitivity reactions including rash, pruritus, and urticaria have been reported with Pitavastatin.
- Patients with active liver disease which may include unexplained persistent elevations of hepatic transaminase levels.
- Women who are pregnant or may become pregnant. Because HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, Pitavastatin may cause fetal harm when administered to pregnant women. Additionally, there is no apparent benefit to therapy during pregnancy, and safety in pregnant women has not been established. If the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus and the lack of known clinical benefit with continued use during pregnancy.
- Nursing mothers. Animal studies have shown that Pitavastatin passes into breast milk. Since HMG-CoA reductase inhibitors have the potential to cause serious adverse reactions in nursing infants, Pitavastatin, like other HMG-CoA reductase inhibitors, is contraindicated in pregnant or nursing mothers.
- Co-administration with cyclosporine
# Warnings
- Cases of myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with HMG-CoA reductase inhibitors, including Pitavastatin. These risks can occur at any dose level, but increase in a dose-dependent manner.
- Pitavastatin should be prescribed with caution in patients with predisposing factors for myopathy. These factors include advanced age (≥65 years), renal impairment, and inadequately treated hypothyroidism. The risk of myopathy may also be increased with concurrent administration of fibrates or lipid-modifying doses of niacin. Pitavastatin should be administered with caution in patients with impaired renal function, in elderly patients, or when used concomitantly with fibrates or lipid-modifying doses of niacin.
- Cases of myopathy, including rhabdomyolysis, have been reported with HMG-CoA reductase inhibitors coadministered with colchicine, and caution should be exercised when prescribing Pitavastatin with colchicine.
- There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents.
- Pitavastatin therapy should be discontinued if markedly elevated creatine kinase (CK) levels occur or myopathy is diagnosed or suspected. Pitavastatin therapy should also be temporarily withheld in any patient with an acute, serious condition suggestive of myopathy or predisposing to the development of renal failure secondary to rhabdomyolysis (e.g., sepsis, hypotension, dehydration, major surgery, trauma, severe metabolic, endocrine, and electrolyte disorders, or uncontrolled seizures). All patients should be advised to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing Pitavastatin.
- Increases in serum transaminases (aspartate aminotransferase [AST]/serum glutamic-oxaloacetic transaminase, or alanine aminotransferase [ALT]/serum glutamic-pyruvic transaminase) have been reported with HMG-CoA reductase inhibitors, including Pitavastatin. In most cases, the elevations were transient and resolved or improved on continued therapy or after a brief interruption in therapy.
- In placebo-controlled Phase 2 studies, ALT >3 times the upper limit of normal was not observed in the placebo, Pitavastatin 1 mg, or Pitavastatin 2 mg groups. One out of 202 patients (0.5%) administered Pitavastatin 4 mg had ALT >3 times the upper limit of normal.
- It is recommended that liver enzyme tests be performed before the initiation of Pitavastatin and if signs or symptoms of liver injury occur.
- There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including pitavastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with Pitavastatin, promptly interrupt therapy. If an alternate etiology is not found do not restart Pitavastatin.
- As with other HMG-CoA reductase inhibitors, Pitavastatin should be used with caution in patients who consume substantial quantities of alcohol. Active liver disease, which may include unexplained persistent transaminase elevations, is a contraindication to the use of Pitavastatin.
- Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including Pitavastatin.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical studies on Pitavastatin are conducted in varying study populations and study designs, the frequency of adverse reactions observed in the clinical studies of Pitavastatin cannot be directly compared with that in the clinical studies of other HMG-CoA reductase inhibitors and may not reflect the frequency of adverse reactions observed in clinical practice.
- Adverse reactions reported in ≥ 2% of patients in controlled clinical studies and at a rate greater than or equal to placebo are shown in Table 1. These studies had treatment duration of up to 12 weeks.
- Other adverse reactions reported from clinical studies were arthralgia, headache, influenza, and nasopharyngitis.
- The following laboratory abnormalities have also been reported: elevated creatine phosphokinase, transaminases, alkaline phosphatase, bilirubin, and glucose.
- In controlled clinical studies and their open-label extensions, 3.9% (1 mg), 3.3% (2 mg), and 3.7% (4 mg) of pitavastatin-treated patients were discontinued due to adverse reactions. The most common adverse reactions that led to treatment discontinuation were: elevated creatine phosphokinase (0.6% on 4 mg) and myalgia (0.5% on 4 mg).
- Hypersensitivity reactions including rash, pruritus, and urticaria have been reported with Pitavastatin.
## Postmarketing Experience
- The following adverse reactions have been identified during postapproval use of Pitavastatin. 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.
- Adverse reactions associated with Pitavastatin therapy reported since market introduction, regardless of causality assessment, include the following: abdominal discomfort, abdominal pain, dyspepsia, nausea, asthenia, fatigue, malaise, hepatitis, jaundice, fatal and non-fatal hepatic failure, dizziness, hypoesthesia, insomnia, depression, interstitial lung disease, erectile dysfunction and muscle spasms.
- There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).
- There have been rare reports of immune-mediated necrotizing myopathy associated with statin use.
# Drug Interactions
- Cyclosporine significantly increased pitavastatin exposure. Co-administration of cyclosporine with Pitavastatin is contraindicated.
- Erythromycin significantly increased pitavastatin exposure. In patients taking erythromycin, a dose of Pitavastatin 1 mg once daily should not be exceeded.
- Rifampin significantly increased pitavastatin exposure. In patients taking rifampin, a dose of Pitavastatin 2 mg once daily should not be exceeded.
- Due to an increased risk of myopathy/rhabdomyolysis when HMG-CoA reductase inhibitors are coadministered with gemfibrozil, concomitant administration of Pitavastatin with gemfibrozil should be avoided.
- Because it is known that the risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with concurrent administration of other fibrates, Pitavastatin should be administered with caution when used concomitantly with other fibrates.
- The risk of skeletal muscle effects may be enhanced when Pitavastatin is used in combination with niacin; a reduction in Pitavastatin dosage should be considered in this setting.
- Cases of myopathy, including rhabdomyolysis, have been reported with HMG-CoA reductase inhibitors coadministered with colchicine, and caution should be exercised when prescribing Pitavastatin with colchicine.
- Pitavastatin had no significant pharmacokinetic interaction with R- and S- warfarin. Pitavastatin had no significant effect on prothrombin time (PT) and international normalized ratio (INR) when administered to patients receiving chronic warfarin treatment. However, patients receiving warfarin should have their PT and INR monitored when pitavastatin is added to their therapy.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): X
- Pitavastatin is contraindicated in women who are or may become pregnant. Serum cholesteroland TG increase during normal pregnancy, and cholesterolproducts are essential for fetal development. Atherosclerosis is a chronic process and discontinuation of lipid-lowering drugs during pregnancy should have little impact on long-term outcomes of primary hyperlipidemia therapy.
- There are no adequate and well-controlled studies of Pitavastatin in pregnant women, although, there have been rare reports of congenital anomalies following intrauterine exposure to HMG-CoA reductase inhibitors. In a review of about 100 prospectively followed pregnancies in women exposed to other HMG-CoA reductase inhibitors, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed the rate expected in the general population. However, this study was only able to exclude a three-to-four-fold increased risk of congenital anomalies over background incidence. In 89% of these cases, drug treatment started before pregnancy and stopped during the first trimester when pregnancy was identified.
- Reproductive toxicity studies have shown that pitavastatin crosses the placenta in rats and is found in fetal tissues at ≤36% of maternal plasma concentrations following a single dose of 1 mg/kg/day during gestation.
- Embryo-fetal developmental studies were conducted in pregnant rats treated with 3, 10, 30 mg/kg/day pitavastatin by oral gavage during organogenesis. No adverse effects were observed at 3 mg/kg/day, systemic exposures 22 times human systemic exposure at 4 mg/day based on AUC.
- Embryo-fetal developmental studies were conducted in pregnant rabbits treated with 0.1, 0.3, 1 mg/kg/day pitavastatin by oral gavage during the period of fetal organogenesis. Maternal toxicity consisting of reduced body weight and abortion was observed at all doses tested (4 times human systemic exposure at 4 mg/day based on AUC).
- In perinatal/postnatal studies in pregnant rats given oral gavage doses of pitavastatin at 0.1, 0.3, 1, 3, 10, 30 mg/kg/day from organogenesis through weaning, maternal toxicity consisting of mortality at ≥0.3 mg/kg/day and impaired lactation at all doses contributed to the decreased survival of neonates in all dose groups (0.1 mg/kg/day represents approximately 1 time human systemic exposure at 4 mg/day dose based on AUC).
- Pitavastatin may cause fetal harm when administered to a pregnant woman. If the patient becomes pregnant while taking Pitavastatin, the patient should be apprised of the potential risks to the fetus and the lack of known clinical benefit with continued use during pregnancy.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Pitavastatin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Pitavastatin during labor and delivery.
### Nursing Mothers
- It is not known whether pitavastatin is excreted in human milk, however, it has been shown that a small amount of another drug in this class passes into human milk. Rat studies have shown that pitavastatin is excreted into breast milk. Because another drug in this class passes into human milk and HMG-CoA reductase inhibitors have a potential to cause serious adverse reactions in nursing infants, women who require Pitavastatin treatment should be advised not to nurse their infants or to discontinue Pitavastatin.
### Pediatric Use
- Safety and effectiveness of Pitavastatin in pediatric patients have not been established.
### Geriatic Use
- Of the 2,800 patients randomized to Pitavastatin 1 mg to 4 mg in controlled clinical studies, 1,209 (43%) were 65 years and older. No significant differences in efficacy or safety were observed between elderly patients and younger patients. However, greater sensitivity of some older individuals cannot be ruled out.
### Gender
There is no FDA guidance on the use of Pitavastatin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Pitavastatin with respect to specific racial populations.
### Renal Impairment
- Patients with moderate and severe renal impairment (glomerular filtration rate 30 – 59 mL/min/1.73 m2 and 15 – 29 mL/min/1.73 m2 not receiving hemodialysis, respectively) as well as end-stage renal disease receiving hemodialysis should receive a starting dose of Pitavastatin 1 mg once daily and a maximum dose of Pitavastatin 2 mg once daily.
### Hepatic Impairment
- Pitavastatin is contraindicated in patients with active liver disease which may include unexplained persistent elevations of hepatic transaminase levels.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Pitavastatin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Pitavastatin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- FDA Package Insert for Pitavastatin contains no information regarding drug monitoring.
# IV Compatibility
- There is limited information about the IV compatibility.
# Overdosage
- There is no known specific treatment in the event of overdose of pitavastatin. In the event of overdose, the patient should be treated symptomatically and supportive measures instituted as required. Hemodialysis is unlikely to be of benefit due to high protein binding ratio of pitavastatin.
# Pharmacology
## Mechanism of Action
- Pitavastatin competitively inhibits HMG-CoA reductase, which is a rate-determining enzyme involved with biosynthesis of cholesterol, in a manner of competition with the substrate so that it inhibits cholesterol synthesis in the liver. As a result, the expression of LDL-receptors followed by the uptake of LDL from blood to liver is accelerated and then the plasma TC decreases. Further, the sustained inhibition of cholesterol synthesis in the liver decreases levels of very low density lipoproteins.
## Structure
- Pitavastatin (pitavastatin) is an inhibitor of HMG-CoA reductase. It is a synthetic lipid-lowering agent for oral administration.
- The chemical name for pitavastatin is (+)monocalcium bis{(3R, 5S, 6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3,5-dihydroxy-6-heptenoate}. The structural formula is:
- The empirical formula for pitavastatin is C50H46CaF2N2O8 and the molecular weight is 880.98. Pitavastatin is odorless and occurs as white to pale-yellow powder. It is freely soluble in pyridine, chloroform, dilute hydrochloric acid, and tetrahydrofuran, soluble in ethylene glycol, sparingly soluble in octanol, slightly soluble in methanol, very slightly soluble in water or ethanol, and practically insoluble in acetonitrile or diethyl ether. Pitavastatin is hygroscopic and slightly unstable in light.
- Each film-coated tablet of Pitavastatin contains 1.045 mg, 2.09 mg, or 4.18 mg of pitavastatin calcium, which is equivalent to 1 mg, 2 mg, or 4 mg, respectively of free base and the following inactive ingredients: lactose monohydrate, low substituted hydroxypropylcellulose, hypromellose, magnesium aluminometasilicate, magnesium stearate, and film coating containing the following inactive ingredients: hypromellose, titanium dioxide, triethyl citrate, and colloidal anhydrous silica.
## Pharmacodynamics
- In a randomized, double-blind, placebo-controlled, 4-way parallel, active-comparator study with moxifloxacin in 174 healthy participants, Pitavastatin was not associated with clinically meaningful prolongation of the QTc interval or heart rate at daily doses up to 16 mg (4 times the recommended maximum daily dose).
## Pharmacokinetics
Absorption
- Pitavastatin peak plasma concentrations are achieved about 1 hour after oral administration. Both Cmax and AUC0-inf increased in an approximately dose-proportional manner for single Pitavastatin doses from 1 to 24 mg once daily. The absolute bioavailability of pitavastatin oral solution is 51%. Administration of Pitavastatin with a high fat meal (50% fat content) decreases pitavastatin Cmax by 43% but does not significantly reduce pitavastatin AUC. The Cmax and AUC of pitavastatin did not differ following evening or morning drug administration. In healthy volunteers receiving 4 mg pitavastatin, the percent change from baseline for LDL-C following evening dosing was slightly greater than that following morning dosing. Pitavastatin was absorbed in the small intestine but very little in the colon.
Distribution
- Pitavastatin is more than 99% protein bound in human plasma, mainly to albumin and alpha 1-acid glycoprotein, and the mean volume of distribution is approximately 148 L. Association of pitavastatin and/or its metabolites with the blood cells is minimal.
Metabolism
- Pitavastatin is marginally metabolized by CYP2C9 and to a lesser extent by CYP2C8. The major metabolite in human plasma is the lactone which is formed via an ester-type pitavastatin glucuronide conjugate by uridine 5'-diphosphate (UDP) glucuronosyltransferase (UGT1A3 and UGT2B7).
Excretion
- A mean of 15% of radioactivity of orally administered, single 32 mg 14C-labeled pitavastatin dose was excreted in urine, whereas a mean of 79% of the dose was excreted in feces within 7 days. The mean plasma elimination half-life is approximately 12 hours.
Race
- In pharmacokinetic studies pitavastatin Cmax and AUC were 21 and 5% lower, respectively in Black or African American healthy volunteers compared with those of Caucasian healthy volunteers. In pharmacokinetic comparison between Caucasian volunteers and Japanese volunteers, there were no significant differences in Cmax and AUC.
Gender
- In a pharmacokinetic study which compared healthy male and female volunteers, pitavastatin Cmax and AUC were 60 and 54% higher, respectively in females. This had no effect on the efficacy or safety of Pitavastatin in women in clinical studies.
Geriatric
- In a pharmacokinetic study which compared healthy young and elderly (≥65 years) volunteers, pitavastatin Cmax and AUC were 10 and 30% higher, respectively, in the elderly. This had no effect on the efficacy or safety of Pitavastatin in elderly subjects in clinical studies.
Renal Impairment
- In patients with moderate renal impairment (glomerular filtration rate of 30 – 59 mL/min/1.73 m2) and end stage renal disease receiving hemodialysis, pitavastatin AUC0-inf is 102 and 86% higher than those of healthy volunteers, respectively, while pitavastatin Cmax is 60 and 40% higher than those of healthy volunteers, respectively. Patients received hemodialysis immediately before pitavastatin dosing and did not undergo hemodialysis during the pharmacokinetic study. Hemodialysis patients have 33 and 36% increases in the mean unbound fraction of pitavastatin as compared to healthy volunteers and patients with moderate renal impairment, respectively.
- In another pharmacokinetic study, patients with severe renal impairment (glomerular filtration rate 15 – 29 mL/min/1.73 m2) not receiving hemodialysis were administered a single dose of Pitavastatin 4 mg. The AUC0-inf and the Cmax were 36 and 18% higher, respectively, compared with those of healthy volunteers. For both patients with severe renal impairment and healthy volunteers, the mean percentage of protein-unbound pitavastatin was approximately 0.6%.
- The effect of mild renal impairment on pitavastatin exposure has not been studied.
Hepatic Impairment
- The disposition of pitavastatin was compared in healthy volunteers and patients with various degrees of hepatic impairment. The ratio of pitavastatin Cmax between patients with moderate hepatic impairment (Child-Pugh B disease) and healthy volunteers was 2.7. The ratio of pitavastatin AUCinf between patients with moderate hepatic impairment and healthy volunteers was 3.8. The ratio of pitavastatin Cmax between patients with mild hepatic impairment (Child-Pugh A disease) and healthy volunteers was 1.3. The ratio of pitavastatin AUCinf between patients with mild hepatic impairment and healthy volunteers was 1.6. Mean pitavastatin t½ for moderate hepatic impairment, mild hepatic impairment, and healthy were 15, 10, and 8 hours, respectively.
Drug-Drug Interactions
- The principal route of pitavastatin metabolism is glucuronidation via liver UGTs with subsequent formation of pitavastatin lactone. There is only minimal metabolism by the cytochrome P450 system.
Warfarin
- The steady-state pharmacodynamics (international normalized ratio [INR] and prothrombin time [PT]) and pharmacokinetics of warfarin in healthy volunteers were unaffected by the co-administration of Pitavastatin 4 mg daily. However, patients receiving warfarin should have their PT time or INR monitored when pitavastatin is added to their therapy.
## Nonclinical Toxicology
## Carcinogenesis, Mutagenesis, Impairment of Fertility
- In a 92-week carcinogenicity study in mice given pitavastatin, at the maximum tolerated dose of 75 mg/kg/day with systemic maximum exposures (AUC) 26 times the clinical maximum exposure at 4 mg/day, there was an absence of drug-related tumors.
- In a 92-week carcinogenicity study in rats given pitavastatin at 1, 5, 25 mg/kg/day by oral gavage there was a significant increase in the incidence of thyroid follicular cell tumors at 25 mg/kg/day, which represents 295 times human systemic exposures based on AUC at the 4 mg/day maximum human dose.
- In a 26-week transgenic mouse (Tg rasH2) carcinogenicity study where animals were given pitavastatin at 30, 75, and 150 mg/kg/day by oral gavage, no clinically significant tumors were observed.
- Pitavastatin was not mutagenic in the Ames test with Salmonella typhimurium and Escherichia coli with and without metabolic activation, the micronucleus test following a single administration in mice and multiple administrations in rats, the unscheduled DNA synthesis test in rats, and a Comet assay in mice. In the chromosomal aberration test, clastogenicity was observed at the highest doses tested which also elicited high levels of cytotoxicity.
- Pitavastatin had no adverse effects on male and female rat fertility at oral doses of 10 and 30 mg/kg/day, respectively, at systemic exposures 56- and 354-times clinical exposure at 4 mg/day based on AUC.
- Pitavastatin treatment in rabbits resulted in mortality in males and females given 1 mg/kg/day (30-times clinical systemic exposure at 4 mg/day based on AUC) and higher during a fertility study. Although the cause of death was not determined, rabbits had gross signs of renal toxicity (kidneys whitened) indicative of possible ischemia. Lower doses (15-times human systemic exposure) did not show significant toxicity in adult males and females. However, decreased implantations, increased resorptions, and decreased viability of fetuses were observed.
## Animal Toxicology and/or Pharmacology
### Central Nervous System Toxicity
- CNS vascular lesions, characterized by perivascular hemorrhages, edema, and mononuclear cell infiltration of perivascular spaces, have been observed in dogs treated with several other members of this drug class. A chemically similar drug in this class produced dose-dependent optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in dogs, at a dose that produced plasma drug levels about 30 times higher than the mean drug level in humans taking the highest recommended dose. Wallerian degeneration has not been observed with pitavastatin. Cataracts and lens opacities were seen in dogs treated for 52 weeks at a dose level of 1 mg/kg/day (9 times clinical exposure at the maximum human dose of 4 mg/day based on AUC comparisons.
# Clinical Studies
## Primary hyperlipidemia or Mixed Dyslipidemia
Dose-ranging study
- A multicenter, randomized, double-blind, placebo-controlled, dose-ranging study was performed to evaluate the efficacy of Pitavastatin compared with placebo in 251 patients with primary hyperlipidemia(Table 4). Pitavastatin given as a single daily dose for 12 weeks significantly reduced plasma LDL-C, TC, TG, and Apo-B compared to placebo and was associated with variable increases in HDL-C across the dose range.
Active-controlled study with atorvastatin (NK-104-301)
- Pitavastatin was compared with the HMG-CoA reductase inhibitor atorvastatin in a randomized, multicenter, double-blind, double-dummy, active-controlled, non-inferiority Phase 3 study of 817 patients with primary hyperlipidemiaor mixed dyslipidemia. Patients entered a 6- to 8-week wash-out/dietary lead-in period and then were randomized to a 12-week treatment with either Pitavastatin or atorvastatin (Table 5). Non-inferiority of pitavastatin to a given dose of atorvastatin was considered to be demonstrated if the lower bound of the 95% CI for the mean treatment difference was greater than 6% for the mean percent change in LDL-C.
- Lipid results are shown in Table 5. For the percent change from baseline to endpoint in LDL-C, Pitavastatin was non-inferior to atorvastatin for the two pairwise comparisons: Pitavastatin 2 mg vs. atorvastatin 10 mg and Pitavastatin 4 mg vs. atorvastatin 20 mg. Mean treatment differences (95% CI) were 0% (-3%, 3%) and 1% (-2%, 4%), respectively.
Active-controlled study with simvastatin (NK-104-302)
- Pitavastatin was compared with the HMG-CoA reductase inhibitor simvastatin in a randomized, multicenter, double-blind, double-dummy, active-controlled, non-inferiority Phase 3 study of 843 patients with primary hyperlipidemiaor mixed dyslipidemia. Patients entered a 6- to 8-week wash-out/dietary lead-in period and then were randomized to a 12 week treatment with either Pitavastatin or simvastatin (Table 6). Non-inferiority of pitavastatin to a given dose of simvastatin was considered to be demonstrated if the lower bound of the 95% CI for the mean treatment difference was greater than 6% for the mean percent change in LDL-C.
- Lipid results are shown in Table 6. For the percent change from baseline to endpoint in LDL-C, Pitavastatin was non-inferior to simvastatin for the two pairwise comparisons: Pitavastatin 2 mg vs. simvastatin 20 mg and Pitavastatin 4 mg vs. simvastatin 40 mg. Mean treatment differences (95% CI) were 4% (1%, 7%) and 1% (-2%, 4%), respectively.
Active-controlled study with pravastatin in elderly (NK-104-306)
- Pitavastatin was compared with the HMG-CoA reductase inhibitor pravastatin in a randomized, multicenter, double-blind, double-dummy, parallel group, active-controlled non-inferiority Phase 3 study of 942 elderly patients (≥65 years) with primary hyperlipidemiaor mixed dyslipidemia. Patients entered a 6- to 8-week wash-out/dietary lead-in period, and then were randomized to a once daily dose of Pitavastatin or pravastatin for 12 weeks (Table 7). Non-inferiority of Pitavastatin to a given dose of pravastatin was assumed if the lower bound of the 95% CI for the treatment difference was greater than -6% for the mean percent change in LDL-C.
- Lipid results are shown in Table 7. Pitavastatin significantly reduced LDL-C compared to pravastatin as demonstrated by the following pairwise dose comparisons: Pitavastatin 1 mg vs. pravastatin 10 mg, Pitavastatin 2 mg vs. pravastatin 20 mg and Pitavastatin 4 mg vs. pravastatin 40 mg. Mean treatment differences (95% CI) were 9% (6%, 12%), 10% (7%, 13%) and 10% (7%, 13% ), respectively.
Active-controlled study with simvastatin in patients with ≥ 2 risk factors for coronary heart disease (NK-104-304)
- Pitavastatin was compared with the HMG-CoA reductase inhibitor simvastatin in a randomized, multicenter, double-blind, double-dummy, active-controlled, non-inferiority Phase 3 study of 351 patients with primary hyperlipidemiaor mixed dyslipidemia with ≥2 risk factors for coronary heart disease. After a 6- to 8-week wash-out/dietary lead-in period, patients were randomized to a 12-week treatment with either Pitavastatin or simvastatin (Table 8). Non-inferiority of Pitavastatin to simvastatin was considered to be demonstrated if the lower bound of the 95% CI for the mean treatment difference was greater than -6% for the mean percent change in LDL-C.
- Lipid results are shown in Table 8. Pitavastatin 4 mg was non-inferior to simvastatin 40 mg for percent change from baseline to endpoint in LDL-C. The mean treatment difference (95% CI) was 0% (-2%, 3%).
Active-controlled study with atorvastatin in patients with type II diabetes mellitus (NK-104-305)
- Pitavastatin was compared with the HMG-CoA reductase inhibitor atorvastatin in a randomized, multicenter, double-blind, double-dummy, parallel group, active-controlled, non-inferiority Phase 3 study of 410 subjects with type II diabetes mellitus and combined dyslipidemia. Patients entered a 6- to 8-week washout/dietary lead-in period and were randomized to a once daily dose of Pitavastatin or atorvastatin for 12 weeks. Non-inferiority of Pitavastatin was considered to be demonstrated if the lower bound of the 95% CI for the mean treatment difference was greater than -6% for the mean percent change in LDL-C.
- Lipid results are shown in Table 9. The treatment difference (95% CI) for LDL-C percent change from baseline was -2% (-6.2%, 1.5%). The two treatment groups were not statistically different on LDL-C. However, the lower limit of the CI was -6.2%, slightly exceeding the -6% non-inferiority limit so that the non-inferiority objective was not achieved.
# How Supplied
- Pitavastatin tablets for oral administration are provided as white, film-coated tablets that contain 1 mg, 2 mg, or 4 mg of pitavastatin. Each tablet has “KC” debossed on one side and a code number specific to the tablet strength on the other.
## Packaging
- Pitavastatin (pitavastatin) Tablets are supplied as:
- NDC 66869-104-90 : 1 mg. Round white film-coated tablet debossed “KC” on one face and “1” on the reverse; HDPE bottles of 90 tablets
- NDC 66869-204-90 : 2 mg. Round white film-coated tablet debossed “KC” on one face and “2” on the reverse; HDPE bottles of 90 tablets
- NDC 66869-404-90 : 4 mg. Round white film-coated tablet debossed “KC” on one face and “4” on the reverse; HDPE bottles of 90 tablets
## Storage
- Store at room temperature between 15°C and 30°C (59° to 86° F). Protect from light.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
# Patient Counseling Information
- The patient should be informed of the following:
## Dosing Time
- Pitavastatin can be taken at any time of the day with or without food.
## Muscle Pain
- Patients should be advised to promptly notify their physician of any unexplained muscle pain, tenderness, or weakness particularly if accompanied by malaise or fever, or if these muscle signs or symptoms persist after discontinuing Pitavastatin. They should discuss all medication, both prescription and over the counter, with their physician.
## Pregnancy
- Women of childbearing age should use an effective method of birth control to prevent pregnancy while using Pitavastatin. Discuss future pregnancy plans with your healthcare professional, and discuss when to stop Pitavastatin if you are trying to conceive. If you are pregnant, stop taking Pitavastatin and call your healthcare professional.
## Breastfeeding
- Women who are breastfeeding should not use Pitavastatin. If you have a lipid disorder and are breastfeeding, stop taking Pitavastatin and consult with your healthcare professional.
## Liver Enzymes
- It is recommended that liver enzyme tests be checked before the initiation of Pitavastatin and if signs or symptoms of liver injury occur. All patients treated with Pitavastatin should be advised to report promptly any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice.
# Precautions with Alcohol
- As with other HMG-CoA reductase inhibitors, Pitavastatin should be used with caution in patients who consume substantial quantities of alcohol.
# Brand Names
Livalo
# Look-Alike Drug Names
- Pitavastatin - pravastatin[1]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Pitavastatin | |
744c2a32a321cf21923c775a8e1d71659935ab0f | wikidoc | Planck's law | Planck's law
For a general introduction, see black body.
In physics, Planck's law describes the spectral radiance of electromagnetic radiation at all wavelengths from a black body at temperature T. As a function of frequency \nu, Planck's law is written as:
This function represents the emitted power per unit area of emitting surface, per unit solid angle, and per unit frequency. Sometimes, Planck's law is written as an expression u(\nu,T) = \pi I(\nu,T) for emitted power integrated over all solid angles. In other cases, it is written as u(\nu,T) = 4\pi I(\nu,T)/c for energy per unit volume.
The function I(\nu,T) peaks for h\nu = 2.82kT. It falls off exponentially at higher frequencies and polynomially at lower.
As a function of wavelength λ, Planck's law written (for unit solid angle) as:
This function peaks for hc = 4.97λkT, a factor of 1.76 shorter in wavelength (higher in frequency) than the frequency peak. It is the more commonly used peak in Wien's displacement law.
The radiance emitted over a frequency range or a wavelength range = can be obtained by integrating the respective functions.
The order of the integration limits is reversed because increasing frequencies correspond to decreasing wavelengths.
The following table provides the definition and SI units of measure for each symbol:
# Overview
The wavelength is related to the frequency by:
The law is sometimes written in terms of the spectral energy density
which has units of energy per unit volume per unit frequency (joule per cubic meter per hertz). Integrated over frequency, this expression yields the total energy density. The radiation field of a black body may be thought of as a photon gas, in which case this energy density would be one of the thermodynamic parameters of that gas.
The spectral energy density can also be expressed as a function of wavelength:
as shown in the derivation below.
Max Planck originally produced this law in 1900 (published in 1901) in an attempt to improve upon the Wien approximation, published in 1896 by Wilhelm Wien, which fit the experimental data at short wavelengths (high frequencies) but deviated from it at long wavelengths (low frequencies). The Rayleigh-Jeans law (first published in incomplete form by Rayleigh in 1900) fit well in the complementary domain (long wavelength, low frequency). Planck found that the above function, Planck's function, fitted the data for all wavelengths remarkably well.
In constructing a derivation of this law, he considered the possible ways of distributing electromagnetic energy over the different modes of charged oscillators in matter. Planck's law emerged when he assumed that the energy of these oscillators was limited to a set of discrete, integer multiples of a fundamental unit of energy, E, proportional to the oscillation frequency ν:
Planck made this quantization assumption five years before Albert Einstein hypothesized the existence of photons as a means of explaining the photoelectric effect. At the time, Planck believed that the quantization applied only to the tiny oscillators that were thought to exist in the walls of the cavity (what we now know to be atoms), and made no assumption that light itself propagates in discrete bundles or packets of energy. Moreover, Planck did not attribute any physical significance to this assumption, but rather believed that it was merely a mathematical device that enabled him to derive a single expression for the black body spectrum that matched the empirical data at all wavelengths.
Although Planck's formula predicts that a black body will radiate energy at all frequencies, the formula is only practically applicable when many photons are being measured. For example, a black body at room temperature (300 kelvin) with one square meter of surface area will emit a photon in the visible range once about every thousand years or so, meaning that for most practical purposes, a black body at room temperature does not emit in the visible range. Significance of this fact for the derivation of Planck's law from experimental data, and for the substantiation of the law by the data, is discussed in
Ultimately, Planck's assumption of energy quantization and Einstein's photon hypothesis became the fundamental basis for the development of quantum mechanics.
# Derivation
The following derivation of Planck's law can be found, e.g., in . See also the gas in a box article for a general derivation.
Consider a cube of side L with conducting walls filled with electromagnetic radiation.
At the walls of the cube, the parallel component of the electric field and the orthogonal component of the magnetic field must vanish. Analogous to the wave function of a particle in a box, one finds that the fields are superpositions of periodic functions. The three wavelengths \lambda_{1}, \lambda_{2} and \lambda_{3}, in the three directions orthogonal to the walls can be:
where the n_{i} are integers. For each set of integers n_{i} there are two linear independent solutions (modes). According to quantum theory, the energy levels of a mode are given by:
The quantum number r can be interpreted as the number of photons in the mode. The two modes for each set of n_{i} correspond to the two polarization states of the photon which has a spin of 1. Note that for r=0 the energy of the mode is not zero. This vacuum energy of the electromagnetic field is responsible for the Casimir effect. In the following we will calculate the internal energy of the box at temperature T relative to the vacuum energy.
According to statistical mechanics, the probability distribution over the energy levels of a particular mode is given by:
Here
The denominator Z(\beta), is the partition function of a single mode and makes P_{r} properly normalized:
Here we have implicitly defined
which is the energy of a single photon. As explained here, the average energy in a mode can be expressed in terms of the partition function:
This formula is a special case of the general formula for particles obeying Bose-Einstein statistics. Since there is no restriction on the total number of photons, the chemical potential is zero.
The total energy in the box now follows by summing \left\langle E\right\rangle over all allowed single photon states. This can be done exactly in the thermodynamic limit as L approaches infinity. In this limit, \varepsilon becomes continuous and we can then integrate \left\langle E\right\rangle over this parameter. To calculate the energy in the box in this way, we need to evaluate how many photon states there are in a given energy range. If we write the total number of single photon states with energies between \varepsilon and \varepsilon + d\varepsilon as g(\varepsilon)\,d\varepsilon, where g(\varepsilon) is the density of states which we'll evaluate in a moment, then we can write:
To calculate the density of states we rewrite equation (1) as follows:
where n is the norm of the vector \vec{n}=\left(n_{1},n_{2},n_{3}\right):
For every vector n with integer components larger than or equal to zero there are two photon states. This means that the number of photon states in a certain region of n-space is twice the volume of that region. An energy range of d\varepsilon corresponds to shell of thickness dn= (2L/hc) d\varepsilon in n-space. Because the components of \vec{n} have to be positive, this shell spans an octant of a sphere. The number of photon states g(\varepsilon)\,d\varepsilon in an energy range d\varepsilon is thus given by:
Inserting this in Eq. (2) gives:
From this equation one easily derives the spectral energy density as a function of frequency u(\nu,T) and as a function of wavelength u(\lambda,T):
where:
u(\nu,T) is known as the black body spectrum. It is a spectral energy density function with units of energy per unit frequency per unit volume.
And:
where
This is also a spectral energy density function with units of energy per unit wavelength per unit volume. Integrals of this type for Bose and Fermi gases can be expressed in terms of polylogarithms. In this case, however, it is possible to calculate the integral in closed form using only elementary functions. Substituting
in Eq. (3), makes the integration variable dimensionless giving:
where J is given by:
We prove this result in the Appendix below.
The total electromagnetic energy inside the box is thus given by:
where V=L^3 is the volume of the box. (Note - This is not the Stefan-Boltzmann law, which is the total energy radiated by a black body. See that article for an explanation.) Since the radiation is the same in all directions, and propagates at the speed of light (c), the spectral radiance (energy/time/area/solid angle/frequency) is
which yields
It can be converted to an expression for I'(\lambda,T) in wavelength units by substituting \nu by c/\lambda and evaluating
# Percentiles
The shape of Planck's law is independent of temperature. It is therefore possible to list the percentile points of the total radiation as well as the peaks for wavelength and frequency, in a form which gives the wavelength \lambda when divided by temperature T. The second row of the following table lists those x for which the wavelength \lambda = x/T microns at the radiance percentile point given by the corresponding entry in the first row.
The wavelength and frequency peaks are in bold and occur at 25.0% and 64.6% respectively. The 41.8% point is the wavelength-frequency-neutral peak. These are the points at which the quotients by e^{h\nu/kT}-1 of the respective Planck-law functions 1/\lambda^5, \nu^3, and (\nu/\lambda)^2 attain their maxima.
Which peak to use depends on the application. The conventional choice is the wavelength peak at 25.0% given by Wien's displacement law. For some purposes the median or 50% point dividing the total radiation into two halves may be more suitable. The latter is closer to the frequency peak than to the wavelength peak because the radiance drops exponentially at short wavelengths and only polynomially at long. The neutral peak occurs at a shorter wavelength than the median for the same reason.
For the Sun, T = 5778 K, allowing the percentile points of the Sun's radiation from 10% to 90%, in nanometers, to be tabulated as follows when modeled as a black body radiator, to which the Sun is a fair approximation.
This is the radiation arriving at the top of the atmosphere. Radiation below 400 nm, or ultraviolet, is about 12%, while that above 700 nm, or infrared, starts at about the 49% point and so accounts for 51% of the total. The atmosphere shifts these percentages substantially in favor of visible light as it absorbs most of the ultraviolet and significant amounts of infrared.
# History
Many popular science accounts of quantum theory, as well as some physics textbooks, contain some serious errors in their discussions of the history of Planck's Law. Although these errors were pointed out over forty years ago by historians of physics, they have proved to be difficult to eradicate. An article by Helge Kragh gives a lucid account of what actually happened.
Contrary to popular opinion, Planck did not quantize light; this is evident from his original 1901 paper
and the references therein to his earlier work. He also plainly explains in his book "Theory of Heat Radiation" that his constant refers to Hertzian oscillators. The idea of quantization was developed by others into what we now know as quantum mechanics. The next step along this direction was made by Albert Einstein, who, by studying the photoelectric effect, proposed a model and equation whereby light was not only emitted but also absorbed in packets or photons. Then, in 1924, Satyendra Nath Bose developed the theory of the statistical mechanics of photons, which allowed a theoretical derivation of Planck's law.
Contrary to another myth, Planck did not derive his law in an attempt to resolve the "ultraviolet catastrophe", the name given by Paul Ehrenfest to the paradoxical result that the total energy in the cavity tends to infinity when the equipartition theorem of classical statistical mechanics is applied to black body radiation. Planck did not consider the equipartition theorem to be universally valid, so he never noticed any sort of "catastrophe" — it was only discovered some five years later by Einstein, Lord Rayleigh, and Sir James Jeans.
# Appendix
A simple way to calculate the integral
is to calculate the general case first and then compute the answer at the end. Consider the integral
Since the denominator is always less than one, we can expand it in powers of e^{-x} to get a convergent series
Here we have used the formula for the sum of a geometric series. The fraction on the left is the expression for the series indicated by the summation: 1 + e^{-x} + e^{-2x} + e^{-3x} + \cdots. The common multiplier is e^{-x}.
Then we have
Multiplication by the e^{-x} on the left shifts our summation series one position to the right. That is, 1 + e^{-x} + e^{-2x} + \cdots becomes e^{-x} + e^{-2x} + e^{-3x} + \cdots. Therefore, we bump the index up by one and drop the e^{-x}:
By changing variables such that u = kx, thereby making x^n = \frac{u^n}{k^n} and dx = \frac{du}{k}, we have
-r,
Since each term in the sum represents a convergent integral, we can move the summation out from under the integral sign:
The summation on the left is the Riemann zeta function \zeta(n+1), while the integral on the right is the Gamma function \Gamma(n+1) , and we are finally left with the general result
-r equivalently
For our problem, the numerator contains x^3, leaving us with our specific result
Here we have used the fact that
is the Riemann zeta function evaluated for the argument 4, which is given by \pi^{4}/90. (See "Finding Zeta(4)" at Wallis product for a simple though lengthy derivation of \zeta(4). This fact can also be proven by considering the following contour integral.)
Where C_{R} is a contour of radius R around the origin. In the limit, as R approaches infinity, the integral approaches zero. Using the residue theorem the integral can also be written as a sum of residues at the poles of the integrand. The poles are at zero, the positive and negative integers. The sum of the residues yields precisely twice the desired summation plus the residue at zero. Because the integral approaches zero, the sum of all the residues must be zero. The summation must therefore equal minus one half times the residue at zero. From the series expansion of the cotangent function
\cot(x)=\frac{1}{x} - \frac {x}{3} - \frac {x^3} {45} +\ldots,
we see that the residue at zero is -\pi^{4}/45 which yields the desired result. The evaluation of the Gamma function can be done by recognizing that for integral values of n, \Gamma(n+1) = n!. In the appendix of the article Stefan-Boltzmann law we give a different derivation of this integral. (See also the integral of the Bose-Einstein distribution in the polylogarithm article.) | Planck's law
For a general introduction, see black body.
In physics, Planck's law describes the spectral radiance of electromagnetic radiation at all wavelengths from a black body at temperature <math>T</math>. As a function of frequency <math>\nu</math>, Planck's law is written as:[1]
This function represents the emitted power per unit area of emitting surface, per unit solid angle, and per unit frequency. Sometimes, Planck's law is written as an expression <math>u(\nu,T) = \pi I(\nu,T)</math> for emitted power integrated over all solid angles. In other cases, it is written as <math>u(\nu,T) = 4\pi I(\nu,T)/c</math> for energy per unit volume.
The function <math>I(\nu,T)</math> peaks for h<math>\nu</math> = 2.82kT.[2] It falls off exponentially at higher frequencies and polynomially at lower.
As a function of wavelength λ, Planck's law written (for unit solid angle) as:[3]
This function peaks for hc = 4.97λkT, a factor of 1.76 shorter in wavelength (higher in frequency) than the frequency peak. It is the more commonly used peak in Wien's displacement law.
The radiance emitted over a frequency range <math>[\nu_1,\nu_2]</math> or a wavelength range <math>[\lambda_2,\lambda_1] = [c/\nu_2, c/\nu_1]</math> can be obtained by integrating the respective functions.
The order of the integration limits is reversed because increasing frequencies correspond to decreasing wavelengths.
The following table provides the definition and SI units of measure for each symbol:
# Overview
The wavelength is related to the frequency by:[4]
The law is sometimes written in terms of the spectral energy density[5]
which has units of energy per unit volume per unit frequency (joule per cubic meter per hertz). Integrated over frequency, this expression yields the total energy density. The radiation field of a black body may be thought of as a photon gas, in which case this energy density would be one of the thermodynamic parameters of that gas.
The spectral energy density can also be expressed as a function of wavelength:
as shown in the derivation below.
Max Planck originally produced this law in 1900 (published in 1901[6]) in an attempt to improve upon the Wien approximation, published in 1896 by Wilhelm Wien, which fit the experimental data at short wavelengths (high frequencies) but deviated from it at long wavelengths (low frequencies). The Rayleigh-Jeans law (first published in incomplete form by Rayleigh in 1900) fit well in the complementary domain (long wavelength, low frequency). Planck found that the above function, Planck's function, fitted the data for all wavelengths remarkably well.
In constructing a derivation of this law, he considered the possible ways of distributing electromagnetic energy over the different modes of charged oscillators in matter. Planck's law emerged when he assumed that the energy of these oscillators was limited to a set of discrete, integer multiples of a fundamental unit of energy, E, proportional to the oscillation frequency ν:
Planck made this quantization assumption five years before Albert Einstein hypothesized the existence of photons as a means of explaining the photoelectric effect. At the time, Planck believed that the quantization applied only to the tiny oscillators that were thought to exist in the walls of the cavity (what we now know to be atoms), and made no assumption that light itself propagates in discrete bundles or packets of energy. Moreover, Planck did not attribute any physical significance to this assumption, but rather believed that it was merely a mathematical device that enabled him to derive a single expression for the black body spectrum that matched the empirical data at all wavelengths.
Although Planck's formula predicts that a black body will radiate energy at all frequencies, the formula is only practically applicable when many photons are being measured. For example, a black body at room temperature (300 kelvin) with one square meter of surface area will emit a photon in the visible range once about every thousand years or so, meaning that for most practical purposes, a black body at room temperature does not emit in the visible range. Significance of this fact for the derivation of Planck's law from experimental data, and for the substantiation of the law by the data, is discussed in [7]
Ultimately, Planck's assumption of energy quantization and Einstein's photon hypothesis became the fundamental basis for the development of quantum mechanics.
# Derivation
The following derivation of Planck's law can be found, e.g., in [5]. See also the gas in a box article for a general derivation.
Consider a cube of side <math>L</math> with conducting walls filled with electromagnetic radiation.
At the walls of the cube, the parallel component of the electric field and the orthogonal component of the magnetic field must vanish. Analogous to the wave function of a particle in a box, one finds that the fields are superpositions of periodic functions. The three wavelengths <math>\lambda_{1},</math> <math>\lambda_{2}</math> and <math>\lambda_{3},</math> in the three directions orthogonal to the walls can be:
where the <math>n_{i}</math> are integers. For each set of integers <math>n_{i}</math> there are two linear independent solutions (modes). According to quantum theory, the energy levels of a mode are given by:
The quantum number <math>r</math> can be interpreted as the number of photons in the mode. The two modes for each set of <math>n_{i}</math> correspond to the two polarization states of the photon which has a spin of 1. Note that for <math>r=0</math> the energy of the mode is not zero. This vacuum energy of the electromagnetic field is responsible for the Casimir effect. In the following we will calculate the internal energy of the box at temperature <math>T</math> relative to the vacuum energy.
According to statistical mechanics, the probability distribution over the energy levels of a particular mode is given by:
Here
The denominator <math>Z(\beta)</math>, is the partition function of a single mode and makes <math>P_{r}</math> properly normalized:
Here we have implicitly defined
which is the energy of a single photon. As explained here, the average energy in a mode can be expressed in terms of the partition function:
This formula is a special case of the general formula for particles obeying Bose-Einstein statistics. Since there is no restriction on the total number of photons, the chemical potential is zero.
The total energy in the box now follows by summing <math>\left\langle E\right\rangle</math> over all allowed single photon states. This can be done exactly in the thermodynamic limit as <math>L</math> approaches infinity. In this limit, <math>\varepsilon</math> becomes continuous and we can then integrate <math>\left\langle E\right\rangle</math> over this parameter. To calculate the energy in the box in this way, we need to evaluate how many photon states there are in a given energy range. If we write the total number of single photon states with energies between <math>\varepsilon</math> and <math>\varepsilon + d\varepsilon</math> as <math>g(\varepsilon)\,d\varepsilon</math>, where <math>g(\varepsilon)</math> is the density of states which we'll evaluate in a moment, then we can write:
To calculate the density of states we rewrite equation (1) as follows:
where <math>n</math> is the norm of the vector <math>\vec{n}=\left(n_{1},n_{2},n_{3}\right)</math>:
For every vector <math>n</math> with integer components larger than or equal to zero there are two photon states. This means that the number of photon states in a certain region of n-space is twice the volume of that region. An energy range of <math>d\varepsilon</math> corresponds to shell of thickness <math>dn= (2L/hc) d\varepsilon</math> in n-space. Because the components of <math>\vec{n}</math> have to be positive, this shell spans an octant of a sphere. The number of photon states <math>g(\varepsilon)\,d\varepsilon</math> in an energy range <math>d\varepsilon</math> is thus given by:
Inserting this in Eq. (2) gives:
From this equation one easily derives the spectral energy density as a function of frequency <math>u(\nu,T)</math> and as a function of wavelength <math>u(\lambda,T)</math>:
where:
<math>u(\nu,T)</math> is known as the black body spectrum. It is a spectral energy density function with units of energy per unit frequency per unit volume.
And:
where
This is also a spectral energy density function with units of energy per unit wavelength per unit volume. Integrals of this type for Bose and Fermi gases can be expressed in terms of polylogarithms. In this case, however, it is possible to calculate the integral in closed form using only elementary functions. Substituting
in Eq. (3), makes the integration variable dimensionless giving:
where <math>J</math> is given by:
We prove this result in the Appendix below.
The total electromagnetic energy inside the box is thus given by:
where <math>V=L^3</math> is the volume of the box. (Note - This is not the Stefan-Boltzmann law, which is the total energy radiated by a black body. See that article for an explanation.) Since the radiation is the same in all directions, and propagates at the speed of light (c), the spectral radiance (energy/time/area/solid angle/frequency) is
which yields
It can be converted to an expression for <math>I'(\lambda,T)</math> in wavelength units by substituting <math>\nu</math> by <math>c/\lambda</math> and evaluating
# Percentiles
The shape of Planck's law is independent of temperature. It is therefore possible to list the percentile points of the total radiation as well as the peaks for wavelength and frequency, in a form which gives the wavelength <math>\lambda</math> when divided by temperature T. The second row of the following table lists those x for which the wavelength <math>\lambda</math> = x/T microns at the radiance percentile point given by the corresponding entry in the first row.
The wavelength and frequency peaks are in bold and occur at 25.0% and 64.6% respectively. The 41.8% point is the wavelength-frequency-neutral peak. These are the points at which the quotients by <math>e^{h\nu/kT}-1</math> of the respective Planck-law functions <math>1/\lambda^5</math>, <math>\nu^3</math>, and <math>(\nu/\lambda)^2</math> attain their maxima.
Which peak to use depends on the application. The conventional choice is the wavelength peak at 25.0% given by Wien's displacement law. For some purposes the median or 50% point dividing the total radiation into two halves may be more suitable. The latter is closer to the frequency peak than to the wavelength peak because the radiance drops exponentially at short wavelengths and only polynomially at long. The neutral peak occurs at a shorter wavelength than the median for the same reason.
For the Sun, T = 5778 K, allowing the percentile points of the Sun's radiation from 10% to 90%, in nanometers, to be tabulated as follows when modeled as a black body radiator, to which the Sun is a fair approximation.
This is the radiation arriving at the top of the atmosphere. Radiation below 400 nm, or ultraviolet, is about 12%, while that above 700 nm, or infrared, starts at about the 49% point and so accounts for 51% of the total. The atmosphere shifts these percentages substantially in favor of visible light as it absorbs most of the ultraviolet and significant amounts of infrared.
# History
Many popular science accounts of quantum theory, as well as some physics textbooks, contain some serious errors in their discussions of the history of Planck's Law. Although these errors were pointed out over forty years ago by historians of physics, they have proved to be difficult to eradicate. An article by Helge Kragh gives a lucid account of what actually happened.[8]
Contrary to popular opinion, Planck did not quantize light; this is evident from his original 1901 paper [6]
and the references therein to his earlier work. He also plainly explains in his book "Theory of Heat Radiation" that his constant refers to Hertzian oscillators. The idea of quantization was developed by others into what we now know as quantum mechanics. The next step along this direction was made by Albert Einstein, who, by studying the photoelectric effect, proposed a model and equation whereby light was not only emitted but also absorbed in packets or photons. Then, in 1924, Satyendra Nath Bose developed the theory of the statistical mechanics of photons, which allowed a theoretical derivation of Planck's law.
Contrary to another myth, Planck did not derive his law in an attempt to resolve the "ultraviolet catastrophe", the name given by Paul Ehrenfest to the paradoxical result that the total energy in the cavity tends to infinity when the equipartition theorem of classical statistical mechanics is applied to black body radiation. Planck did not consider the equipartition theorem to be universally valid, so he never noticed any sort of "catastrophe" — it was only discovered some five years later by Einstein, Lord Rayleigh, and Sir James Jeans.
# Appendix
A simple way to calculate the integral
is to calculate the general case first and then compute the answer at the end. Consider the integral
Since the denominator is always less than one, we can expand it in powers of <math>e^{-x}</math> to get a convergent series
Here we have used the formula for the sum of a geometric series. The fraction on the left is the expression for the series indicated by the summation: <math>1 + e^{-x} + e^{-2x} + e^{-3x} + \cdots.</math> The common multiplier is <math>e^{-x}</math>.
Then we have
Multiplication by the <math>e^{-x}</math> on the left shifts our summation series one position to the right. That is, <math>1 + e^{-x} + e^{-2x} + \cdots</math> becomes <math>e^{-x} + e^{-2x} + e^{-3x} + \cdots</math>. Therefore, we bump the index up by one and drop the <math>e^{-x}</math>:
By changing variables such that <math>u = kx</math>, thereby making <math>x^n = \frac{u^n}{k^n}</math> and <math>dx = \frac{du}{k}</math>, we have
or,
Since each term in the sum represents a convergent integral, we can move the summation out from under the integral sign:
The summation on the left is the Riemann zeta function <math>\zeta(n+1)</math>, while the integral on the right is the Gamma function <math> \Gamma(n+1) </math>, and we are finally left with the general result
or equivalently
For our problem, the numerator contains <math>x^3</math>, leaving us with our specific result
Here we have used the fact that
is the Riemann zeta function evaluated for the argument 4, which is given by <math>\pi^{4}/90</math>. (See "Finding Zeta(4)" at Wallis product for a simple though lengthy derivation of <math>\zeta(4)</math>. This fact can also be proven by considering the following contour integral.)
Where <math>C_{R}</math> is a contour of radius <math>R</math> around the origin. In the limit, as <math>R</math> approaches infinity, the integral approaches zero. Using the residue theorem the integral can also be written as a sum of residues at the poles of the integrand. The poles are at zero, the positive and negative integers. The sum of the residues yields precisely twice the desired summation plus the residue at zero. Because the integral approaches zero, the sum of all the residues must be zero. The summation must therefore equal minus one half times the residue at zero. From the series expansion of the cotangent function
\cot(x)=\frac{1}{x} - \frac {x}{3} - \frac {x^3} {45} +\ldots,
</math>
we see that the residue at zero is <math>-\pi^{4}/45</math> which yields the desired result. The evaluation of the Gamma function can be done by recognizing that for integral values of <math>n</math>, <math>\Gamma(n+1) = n!</math>. In the appendix of the article Stefan-Boltzmann law we give a different derivation of this integral. (See also the integral of the Bose-Einstein distribution in the polylogarithm article.) | https://www.wikidoc.org/index.php/Planck%27s_law | |
fc7c5397037d90e7b4f0a52688df899d75372e2b | wikidoc | Plantar arch | Plantar arch
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The plantar arch is formed from:
- dorsalis pedis - aka dorsal artery of the foot
lateral plantar artery
- dorsalis pedis - aka dorsal artery of the foot
- lateral plantar artery
The plantar arch supplies the underside, or sole, of the foot.
The plantar arch runs from the 5th metatarsal and extends medially to the 1st metatarsal (of the big toe).
The arch is formed when the lateral plantar artery turns mediallly to the interval between the bases of the first and second metatarsal bones, where it unites with the deep plantar branch of the dorsalis pedis artery, thus completing the plantar arch (or deep plantar arch). | Plantar arch
Template:Infobox Artery
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [2] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
The plantar arch is formed from:
- dorsalis pedis - aka dorsal artery of the foot
lateral plantar artery
- dorsalis pedis - aka dorsal artery of the foot
- lateral plantar artery
The plantar arch supplies the underside, or sole, of the foot.
The plantar arch runs from the 5th metatarsal and extends medially to the 1st metatarsal (of the big toe).
The arch is formed when the lateral plantar artery turns mediallly to the interval between the bases of the first and second metatarsal bones, where it unites with the deep plantar branch of the dorsalis pedis artery, thus completing the plantar arch (or deep plantar arch).
# External links
- Template:EMedicineDictionary
Template:Arteries of lower limbs
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Plantar_arch | |
7074a14ead08fb4718e1227681eefc29d4717f88 | wikidoc | Pleiotrophin | Pleiotrophin
Pleiotrophin (PTN) also known as heparin-binding brain mitogen (HBBM) or heparin-binding growth factor 8 (HBGF-8) or neurite growth-promoting factor 1 (NEGF1) or heparin affinity regulatory peptide (HARP) or heparin binding growth associated molecule (HB-GAM) is a protein that in humans is encoded by the PTN gene. Pleiotrophin is an 18-kDa growth factor that has a high affinity for heparin. It is structurally related to midkine and retinoic acid induced heparin-binding protein.
# Function
Pleiotrophin was initially recognized as a neurite outgrowth-promoting factor present in rat brain around birth and as a mitogen toward fibroblasts isolated from bovine uterus tissue. Together with midkine these growth-factors constitute a family of (developmentally regulated) secreted heparin-binding proteins now known as the neurite growth-promoting factor (NEGF) family. During embryonic and early postnatal development, pleiotrophin is expressed in the central and peripheral nervous system and also in several non-neural tissues, notably lung, kidney, gut and bone. Pleiotrophin is also expressed by several tumor cells and is thought to be involved in tumor angiogenesis. In the adult central nervous system, pleiotrophin is expressed in an activity-dependent manner in the hippocampus where it can suppress long term potentiation induction. Pleiotrophin expression is low in other areas of the adult brain, but it can be induced by ischemic insults. or targeted neuronal damaged in the entorhinal cortex or in the substantia nigra pars compacta.
# Clinical significance
Pleiotrophin binds to cell-surface nucleolin as a low affinity receptor. This binding can inhibit HIV infection. | Pleiotrophin
Pleiotrophin (PTN) also known as heparin-binding brain mitogen (HBBM) or heparin-binding growth factor 8 (HBGF-8) or neurite growth-promoting factor 1 (NEGF1) or heparin affinity regulatory peptide (HARP) or heparin binding growth associated molecule (HB-GAM) is a protein that in humans is encoded by the PTN gene.[1] Pleiotrophin is an 18-kDa growth factor that has a high affinity for heparin. It is structurally related to midkine and retinoic acid induced heparin-binding protein.
# Function
Pleiotrophin was initially recognized as a neurite outgrowth-promoting factor present in rat brain around birth[2] and as a mitogen toward fibroblasts isolated from bovine uterus tissue.[3] Together with midkine these growth-factors constitute a family of (developmentally regulated) secreted heparin-binding proteins[4] now known as the neurite growth-promoting factor (NEGF) family. During embryonic and early postnatal development, pleiotrophin is expressed in the central and peripheral nervous system and also in several non-neural tissues, notably lung, kidney, gut and bone.[5] Pleiotrophin is also expressed by several tumor cells and is thought to be involved in tumor angiogenesis.[6] In the adult central nervous system, pleiotrophin is expressed in an activity-dependent manner in the hippocampus[7][8] where it can suppress long term potentiation induction.[9] Pleiotrophin expression is low in other areas of the adult brain, but it can be induced by ischemic insults.[10][11] or targeted neuronal damaged in the entorhinal cortex or in the substantia nigra pars compacta.
# Clinical significance
Pleiotrophin binds to cell-surface nucleolin as a low affinity receptor. This binding can inhibit HIV infection.[12] | https://www.wikidoc.org/index.php/Pleiotrophin | |
7d2738bfebcb23f009a981e39fba0109ebb16c1c | wikidoc | Pneumatocele | Pneumatocele
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# Overview
A pneumatocele, or pneumatocyst is a cavity in the lungs filled with air that may result from pulmonary trauma. A pneumatocele results when a lung laceration, a cut or tear in the lung tissue, fills with air. A rupture of a small airway creates the air-filled cavity. Pulmonary lacerations that fill with blood are called pulmonary hematomas. In some cases, both pneumatoceles and hematomas exist in the same injured lung. A pneumatocele can become enlarged, for example when the patient is mechanically ventilated or has acute respiratory distress syndrome, in which case it may not go away for months. Diagnosis can be made using chest X-ray; the lesion shows up as a small, round area filled with air. Computed tomography can give a more detailed understanding of the lesion. Differential diagnoses, other conditions that could cause similar symptoms as pneumatocele, include lung cancer, tuburculosis, and a lung abscess. Treatment includes monitoring and pulmonary toilet (the use of methods such as positioning and suction to keep the airways clear of secretions). | Pneumatocele
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [1] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
# Overview
A pneumatocele, or pneumatocyst is a cavity in the lungs filled with air that may result from pulmonary trauma.[1] A pneumatocele results when a lung laceration, a cut or tear in the lung tissue, fills with air.[2] A rupture of a small airway creates the air-filled cavity.[1] Pulmonary lacerations that fill with blood are called pulmonary hematomas.[2] In some cases, both pneumatoceles and hematomas exist in the same injured lung.[3] A pneumatocele can become enlarged, for example when the patient is mechanically ventilated or has acute respiratory distress syndrome, in which case it may not go away for months.[3] Diagnosis can be made using chest X-ray; the lesion shows up as a small, round area filled with air.[1] Computed tomography can give a more detailed understanding of the lesion.[1] Differential diagnoses, other conditions that could cause similar symptoms as pneumatocele, include lung cancer, tuburculosis, and a lung abscess.[1] Treatment includes monitoring and pulmonary toilet (the use of methods such as positioning and suction to keep the airways clear of secretions).[1] | https://www.wikidoc.org/index.php/Pneumatocele | |
8f0bbe25a8de69428612fbe28e1f6cdeea5b46f9 | wikidoc | Poison sumac | Poison sumac
Poison sumac (Toxicodendron vernix or Rhus vernix) is a woody shrub or small tree growing to 7 m (20 ft) tall. All parts of the plant contain a resin called urushiol that causes skin and mucous membrane irritation to humans. When burned, inhalation of the smoke causes diarrhea and other internal irritations.
# Description
The head of the tree is round and narrow and the branches slender and rather pendulous; often it is simply a shrub. Small branches and young stems pithy. Has acrid, milky, poisonous juice which turns black on exposure.
The compound leaves are pinnate, 25-50 cm long, with 7 - 13 leaflets; the leaflets are 4-10 cm long and sometimes mistaken for individual leaves. The veins from which the leaflets grow are always red.
The fruit is a small white or grey berry, produced in panicles 10-20 cm long; this distinguishes it from other sumacs which have red berries. Differs from other sumacs in having shorter leaves, leaflets fewer, margins are entire. It is found in wet soils, whereas the others like it dry.
- Bark: Smooth, light or dark gray, slightly striate. Branchlets are smooth, reddish brown, covered with small, orange colored, lenticular spots; later they become orange brown and finally light gray.
- Wood: Light yellow with brown lines; light, soft, coarse-grained, brittle. Sp. gr., 0.4382; weight of cu. ft., 27.31 lbs.
- Winter buds: Terminal bud is much larger than the axillary buds, all are acute, dark purple.
- Leaves: Alternate, pinnately compound, seven to fourteen inches long, borne on slender reddish petioles. Leaflets seven to thirteen, obovate, or oblong, three to four inches long, slightly unequal or contracted at the base, entire, acute or rounded at the apex, short petiolate except the terminal one which sometimes has a stalk an inch in length. They come out of the bud orange colored and downy, when full grown are smooth, dark green and shining above, pale beneath; midrib and primary veins prominent. IN autumn they turn scarlet and orange.
- Flowers: June, July. Dioecious; yellow green, borne in long, narrow, axillary panicles crowded near the ends of the branches. Bracts and bractlets are acute, downy, and fall as the flowers open.
- Calyx: Five-lobed, lobes acute, short.
- Corolla: Petals five, acute, yellow green.
- Stamens: Five, with long slender filaments and large orange colored anthers. In the fertile flowers short and rudimentary.
- Pistil: Ovary ovoid-globose, one-celled, surmounted by three thick spreading styles; ovule solitary.
- Fruit: Drupaceous, globular, white, borne in long graceful racemes, often tipped with the dark remnants of the styles. Ripens in September and frequently hangs on the tree the entire winter. Cotyledons flat, leaf-like.
# Distribution
Poison sumac grows exclusively in very wet or flooded soils, usually in swamps and peat bogs, in the eastern United States and Canada.
In the U.S., it can grow as far west as Idaho, where it is found only in the southern part of the state.
# Toxicity
In the U.S., it is listed under the Federal Noxious Weed Act of 1974, as amended (7 U.S.C. 2801 et seq.), as a "noxious weed". Most U.S. states list this plant in similar categories. It is considered one of the "U.S. Invasive Weeds" . In terms of its potential to cause urushiol-induced contact dermatitis, poison sumac is far more virulent than its relatives poison ivy and poison oak. According to some botanists, poison sumac (Toxicodendron vernix) is the most toxic plant species in the United States (Frankel, 1991).
The poison shows itself in painful and long continued swellings and eruptions.
## Avoidance, treatment, and safety
For specific information on prevention and treatment of Toxicodendron rashes, see Urushiol-induced contact dermatitis.
# References and external links
- ↑ Jump up to: 1.0 1.1 1.2 1.3 1.4 Keeler, Harriet L. (1900). Our Native Trees and How to Identify Them. New York: Charles Scriber's Sons. pp. 94–96..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}
- Entry for "TOVE" on PLANTS Database, USDA.
- Wisconsin page for poison sumac.
- Poison ivy / oak / sumac in "The Medicinal Herb FAQ".
- The Poison Sumac Page Photos and facts about poison sumac.
- Poison Oak at Wayne's Word
- Toxicodendron Dermatitis: Identification, Immunologic Mechanisms, Diagnosis, and Treatment
- Frankel, Edward, Ph.D. 1991. Poison Ivy, Poison Oak, Poison Sumac and Their Relatives; Pistachios, Mangoes and Cashews. The Boxwood Press. Pacific Grove, CA. (call #QK 495.A498 F73 1991). 98pages. | Poison sumac
Poison sumac (Toxicodendron vernix or Rhus vernix) is a woody shrub or small tree growing to 7 m (20 ft) tall.[1] All parts of the plant contain a resin called urushiol that causes skin and mucous membrane irritation to humans. When burned, inhalation of the smoke causes diarrhea and other internal irritations.
# Description
The head of the tree is round and narrow and the branches slender and rather pendulous; often it is simply a shrub. Small branches and young stems pithy. Has acrid, milky, poisonous juice which turns black on exposure.[1]
The compound leaves are pinnate, 25-50 cm long, with 7 - 13 leaflets; the leaflets are 4-10 cm long and sometimes mistaken for individual leaves. The veins from which the leaflets grow are always red.
The fruit is a small white or grey berry, produced in panicles 10-20 cm long; this distinguishes it from other sumacs which have red berries. Differs from other sumacs in having shorter leaves, leaflets fewer, margins are entire. It is found in wet soils, whereas the others like it dry.[1]
- Bark: Smooth, light or dark gray, slightly striate. Branchlets are smooth, reddish brown, covered with small, orange colored, lenticular spots; later they become orange brown and finally light gray.
- Wood: Light yellow with brown lines; light, soft, coarse-grained, brittle. Sp. gr., 0.4382; weight of cu. ft., 27.31 lbs.
- Winter buds: Terminal bud is much larger than the axillary buds, all are acute, dark purple.
- Leaves: Alternate, pinnately compound, seven to fourteen inches long, borne on slender reddish petioles. Leaflets seven to thirteen, obovate, or oblong, three to four inches long, slightly unequal or contracted at the base, entire, acute or rounded at the apex, short petiolate except the terminal one which sometimes has a stalk an inch in length. They come out of the bud orange colored and downy, when full grown are smooth, dark green and shining above, pale beneath; midrib and primary veins prominent. IN autumn they turn scarlet and orange.
- Flowers: June, July. Dioecious; yellow green, borne in long, narrow, axillary panicles crowded near the ends of the branches. Bracts and bractlets are acute, downy, and fall as the flowers open.
- Calyx: Five-lobed, lobes acute, short.
- Corolla: Petals five, acute, yellow green.
- Stamens: Five, with long slender filaments and large orange colored anthers. In the fertile flowers short and rudimentary.
- Pistil: Ovary ovoid-globose, one-celled, surmounted by three thick spreading styles; ovule solitary.
- Fruit: Drupaceous, globular, white, borne in long graceful racemes, often tipped with the dark remnants of the styles. Ripens in September and frequently hangs on the tree the entire winter. Cotyledons flat, leaf-like.[1]
# Distribution
Poison sumac grows exclusively in very wet or flooded soils, usually in swamps and peat bogs, in the eastern United States and Canada.
In the U.S., it can grow as far west as Idaho, where it is found only in the southern part of the state.
# Toxicity
In the U.S., it is listed under the Federal Noxious Weed Act of 1974, as amended (7 U.S.C. 2801 et seq.), as a "noxious weed". Most U.S. states list this plant in similar categories. It is considered one of the "U.S. Invasive Weeds" [1]. In terms of its potential to cause urushiol-induced contact dermatitis, poison sumac is far more virulent than its relatives poison ivy and poison oak. According to some botanists, poison sumac (Toxicodendron vernix) is the most toxic plant species in the United States (Frankel, 1991).
The poison shows itself in painful and long continued swellings and eruptions.[1]
## Avoidance, treatment, and safety
For specific information on prevention and treatment of Toxicodendron rashes, see Urushiol-induced contact dermatitis.
# References and external links
- ↑ Jump up to: 1.0 1.1 1.2 1.3 1.4 Keeler, Harriet L. (1900). Our Native Trees and How to Identify Them. New York: Charles Scriber's Sons. pp. 94–96..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}
- Entry for "TOVE" on PLANTS Database, USDA.
- Wisconsin page for poison sumac.
- Poison ivy / oak / sumac in "The Medicinal Herb FAQ".
- The Poison Sumac Page Photos and facts about poison sumac.
- Poison Oak at Wayne's Word
- Toxicodendron Dermatitis: Identification, Immunologic Mechanisms, Diagnosis, and Treatment
- Frankel, Edward, Ph.D. 1991. Poison Ivy, Poison Oak, Poison Sumac and Their Relatives; Pistachios, Mangoes and Cashews. The Boxwood Press. Pacific Grove, CA. (call #QK 495.A498 F73 1991). 98pages. | https://www.wikidoc.org/index.php/Poison_sumac |
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