id
stringlengths 40
40
| source
stringclasses 9
values | title
stringlengths 2
345
| clean_text
stringlengths 35
1.63M
| raw_text
stringlengths 4
1.63M
| url
stringlengths 4
498
| overview
stringlengths 0
10k
|
|---|---|---|---|---|---|---|
8b7fffc314e0a81e4c486c2fb2f244e3d6d27797 | wikidoc | Sandbox:tavr | Sandbox:tavr
# Overview
During the past 50 years, surgical aortic valve replacement (SAVR) was the standard of care for patients with severe AS. Global aging has raised concerns about safety and possibility of surgical procedure in old patients with associated co-morbidities. Transcatheter aortic valve replacement (TAVR) created a new era of safety for this population and enabled physicians to replace the stenotic valve with more certainty.
Preoperation evaluation, selecting the appropriate imaging modality, issues in TAVR procedure and patient follow up are the areas of more focused importance.
We will describe these factors based on the recent expert consensus for TAVR procedure.
# Definition
The most important step is to define the severity of AS and appropriate patient that need TAVR.
Severe sypmtomatic (Stage D) AS is considered as TAVR candidate.
Abbreviations:
ΔP: mean gradient, Vmax: maximum aortic velocity, AVA: aortic valve area. AS: aortic stenosis, AR: aortic regurgitation.
# TAVR Pathway outline
Abbreviations:
CV: Cardiovascular, AVR: aortic valve replacement, AS: aortic stenosis, MR: Mitral regurgitation, AR: Aortic regurgitation, PAP: Pulmonary artery pressure, RV: right ventricle, CTA: CT angiography, PA: Pulmonary artery, TEE: Trans Esophageal Echocardiography, TTE: Trans Thoracic Echocardiography
## Care Providing Team
## Clinical Evaluation
## Cardio-vascular Imaging
# Risk Assessment
Underlying risk for SAVR is basic component to consider patient for TAVR. This risk assessment is based on several components that include:
- The Society of Thoracic Surgeons Predicted Risk of Mortality (STS-PROM) score. To calculate this score please click here.
- Frailty
- Main organ system dysfunction
- Procedure-specific impediments
‡ Examples of major organ system compromise:
- Cardiac: severe LV systolic or diastolic dysfunction or RV dysfunction, fixed pulmonary hypertension
- CKD stage 3 or worse
- Pulmonary dysfunction with FEV1 <50% or DLCO <50% of predicted
- CNS dysfunction (dementia, Alzheimer’s disease, Parkinson’s disease, CVA with persistent physical limitation)
- GI dysfunction: Crohn’s disease, ulcerative colitis, nutritional impairment, or serum albumin <3.0
- Cancer: active malignancy
- Liver: any history of cirrhosis, variceal bleeding, or elevated INR in the absence of VKA therapy.
¶ Examples: tracheostomy present, heavily calcified ascending aorta, chest malformation, arterial coronary graft adherent to posterior chest wall, or radiation damage.
## Integrated Benefit-risk of TAVR and Shared Decision-making
# Heart Valve Team
Patients with severe AS should be evaluated by a multidisciplinary Heart Valve Team when intervention is considered.
Team members include:
- Cardiology Valve Expert
- Cardiovascular Imaging Expert(s)
- Interventional Cardiologist
- Cardio-Thoracic Surgeon
- Cardiovascular Anesthesiologist
- Valve Clinic Care Coordinators
Their specific tasks are:
- Review the patient's medical condition and the severity of the valve abnormality
- Determine which interventions are indicated, technically feasible, and reasonable
- Discuss benefits and risks of these interventions with the patient and family, keeping in mind their values and preferences.
# Initial Assessment
## Functional Assessment
Abbreviations:
BMI: body mass index; CV: cardiovascular; MMSE: mini mental state examination; MNA: mini nutritional assessment.
### Frailty
- Evaluation for frailty, physical function and independence in the activities of daily living (ADL) such as, feeding, bathing, toileting and transferring).
- Evaluation should be start with screening for independence, cognition and slow walking speed (gait speed, 3 timed trials over a 5 meter distance).
- Those with gait speed over 0.83 m/s, preserved cognition and independence are likely not frail.
### Physical functioning
To assess the physical functioning, the 6 minute walk test should be done. It is possible to perform this test in outpatient setting.
### Cognitive Functioning
The Mini Mental Status Examination (MMSE) is utilized to assess the cognitive status and scores less than 24 are considered as abnormal. Also, evaluation for depression must be done by using a validated tool such as, the Center for Epidemiologic Studies Depression Scale.
### Futility
Those patients with <1 year life expectancy and who has a chance of survival with benefit of <25% at 2 years.
Survival with benefit means, survival with improvement by at least 1 New York Heart Association class in heart failure or by at least 1 Canadian Cardiovascular Society class angina symptoms, improvement in quality of life or improvement in life expectancy.
# Imaging for TAVR
## General Principles and Technical Considerations
- Transthoracic Echocardiography (TTE) is the best initial imaging modality for evaluating AS severity. Although, multimodality imaging is needed for preprocedural planning and intraoperative decision making given the complex 3D anatomy of the aortic valve, sinuses, and annulus.
- Multi-Detector CT (MDCT) is a core element of the standard imaging pathway for the preprocedural planning of TAVR.
- In patients being evaluated for TAVR, MDCT systems with at least 64 detectors and a spatial resolution of 0.5 to 0.6 mm are recommended.
- Evaluation of kidney function to avoid contrast induced nephropathy must be taken in to consideration.
Abbreviations:
CV: Cardiovascular, AVR: Aortic valve replacement, AS: Aortic Stenosis, MR: Mitral Regurgitation, AR: Aortic Regurgitation, PAP: Pulmonary Artery Pressure, RV: Right Ventricle, CTA: CT angiography, PA: Pulmonary Artery, TEE: Trans Esophageal Echocardiography, TTE: Trans Thoracic Echocardiography
AVA: Aortic Valve Area; CMR: Cardiovascular Magnetic Resonance Imaging; CT: Computed Tomography; ECG: Electrocardiogram; EF: Ejection Fraction; DSE: Dobutamine Stress Echocardiography; ESRD: End-Stage Renal Disease; GFR: Glomerular Filtration Rate; LFLG: Low-Flow Low-Gradient; LV: Left Ventricular; LVEF: Left Ventricular Ejection Fraction; MAC: Mitral Annular Calcification; MDCT: Multi Detector Computed Tomography; MRA: Magnetic Resonance Angiogram;
MRI: Magnetic Resonance Imaging; MS: Mitral Stenosis; PET: Positron Emission Tomography; TAVR: Trans-catheter Aortic Valve Replacement
## Specific CT measurements for TAVR
# Preprocedural Evaluation
## Aortic Valve Morphology
- Transthoracic Echocardiography (TTE) is performed for initial visualization of aortic valve to identify the number of leaflets; size, location, extent of calcification, leaflet motion, and a preliminary view of annular size and shape.
- If additional imaging is needed, valve anatomy and function can be evaluated by cardiac magnetic resonance imaging (CMR) or ECG-gated MDCT.
## Aortic Valve Function
Doppler echocardiography is superior to other imaging modalities to evaluate Aortic valve function. AS severity should be evaluated according to the ESE/ASE Recommendations for Evaluation of Valvular Stenosis and staged according to the AHA/ACC Guideline for the Management of Patients with Valvular Heart Disease.
## LV Geometry and Other Cardiac Findings
TTE also is recommended for evaluation of LV hypertrophy, chamber size, LV diastolic function, regional wall motion, and ejection fraction as well as newer measures of LV function such as global longitudinal strain. In addition, TTE is useful for assessment of aortic dilation, presence of subvalvular outflow tract obstruction, estimation of pulmonary pressures, and identification of other significant valve abnormalities.
## Annular Sizing
The 3D dataset provided by MDCT are more accurate than TTE findings regarding annular size. Measurement of LV outflow tract diameter on TTE has been well validated for
calculation of aortic valve area and continues to be the standard for determination of AS severity. CMR can also provide comprehensive assessment of the aortic valve, annulus,
and aortic root with good correlation with MDCT. CMR can be a valuable tool in patients who cannot undergo MDCT.
## Aortic Root Measurements
MDCT allows for the careful measurement of the size of the sinuses of Valsalva, the coronary ostia distance from the annulus, the size of the aorta at the sinotubular junction and 40mm above the annulus, and the extent and position of aortic calcifications.
## Presurgical Planning
MDCT also may be of use in identification of coronary artery and coronary bypass graft location and stenosis, evaluation of the RV to chest wall position, and identification of the aorta and LV apex to chest wall position in direct aortic approaches.
## Noncardiac Imaging
Because of high prevalence of dementia and atherosclerosis in this elderly patient population, a preprocedural work-up including carotid ultrasound and cerebrovascular MRI might be considered prior to considering or such patients for TAVR.
## Vascular Access
Because of the relatively large diameter of the delivery sheaths, appropriate vascular access imaging is critical for TAVR. It is important to evaluate the entire thoracoabdominal aorta, major thoracic arterial vasculature, carotids, and iliofemoral vasculature. MDCT is able to provide valuable dataset regarding vascular anatomy.
# Periprocedural Evaluation
## Interventional Planning
MDCT can assist with predicting the optimal delivery angle on fluoroscopy prior to valve deployment.
## Confirmation of annular sizing
Preprocedural MDCT is the best modality to evaluate annular size. At the time of the procedure, Fluoroscopy is the main imaging modality. If questions remain about the correct annular
sizing, balloon inflation with contrast root injection can be performed. Also, 3D TEE is able to evaluate the annular size, at the time of the procedure.
## Valve Placement
Optimal deployment angles are obtained using fluoroscopy and root injections. Deployment is done under fluoroscopy at many institutions, although TEE is an alternative approach.
## Paravalvular Leak
TEE and TTE are required to assess the valve in different aspects. Also, TEE can be used to assess the immediate gradient changes after valve seating. Aortic root angiography also may be used to assess for regurgitation after valve implantation. As the volume of cases performed without general anesthesia increases, there may be an expanding role for periprocedural TTE.
## Procedural Complications
Immediate complications such as annular rupture resulting in pericardial effusion and tamponade can be detected by TEE, TTE, angiography, and direct hemodynamic measurements.
# Long-Term Postprocedural Evaluation
## Evaluate Valve Function
- Echocardiography is recommended to evaluate the valve postprocedurally to search for valvular and paravalvular leak, valve migration, complications such as annular or sinus rupture, valve thrombosis, endocarditis, paravalvular abscess, LV size, function and remodeling, and pulmonary pressures.
- MDCT can be used to evaluate valve anatomy A and to evaluate for valve thrombosis.
- CMR can also be used to quantify AR and can be complementary to TTE for the quantification of paravalvular leak.
## LV Geometry and Other Cardiac Findings
TTE is used to evaluate changes in LV function after TAVR.
# TAVR Procedure
The following table describes the TAVR procedure checklist.
Abbreviations:
AR: aortic regurgitation; AVR: aortic valve replacement; BAV: balloon aortic valvuloplasty; PA: pulmonary artery; TEE: transesophageal echocardiography
## Preprocedural Planning
- The Heart Valve Team must decide and plan for valve selection, access choice and location of procedure.
### Valve Choice
Valve selection is dependent on 2 major factors,
- Which type of valve should be considered (balloon expandable or self expanding) based on anatomical reasons
- Available valve sizes.
There currently are 2 TAVR valves commercially available in the United States:
- The balloon-expandable Sapien family of transcatheter heart valves (Edwards Lifesciences) made of bovine pericardium mounted in a cylindrical, relatively short cobaltchromium stent.
- The self-expanding CoreValve (Medtronic) family of transcatheter heart valves, which are made of porcine pericardium mounted in a taller, nitinol stent with an adaptive shape and supra-annular design.
Randomized clinical trials showed similar 1-year mortality, strokes, and readmissions due to heart failure with either valve.
Important factors that must be considered in valve selection:
- Annulus dimensions and geometry
- Native valve and aortic root/LV outflow tract anatomy
- Coronary height
- Amount and distribution of calcification
Self expanding valves are preferred over balloon expandable in the following circumstances:
- Patients with heavy calcification of the aortic annulus/LV outflow tract with an attendant risk of rupture
- Extremely oval-shaped annulus or for transfemoral access when femoral artery diameter is between 5.0 and 5.5 mm.
Balloon expanding valves are preferred over self expandable in this situations:
- Dilated ascending (>43 mm) aorta
- Severely angulated aorta (aortoventricular angle >70 degrees, particularly for transfemoral access).
- A balloon-expandable valve is the only option in patients needing a transapical approach (e.g., those with a significant aortic calcification and peripheral vascular disease).
Several other valve designs and platforms are currently under investigation, and valve teams of the future will need to have a sound understanding of their relative merits and disadvantages for treating specific subsets of patients with AS.
### Access Choice
The patient’s atherosclerotic load and location, arterial size and tortuosity, and presence of mural thrombus are important factors in access selection.
When possible, transfemoral access is the preferred TAVR delivery route.
### Location of the Procedure
Optimal equipment requirements include a state-of-the-art, large-field-of-view fluoroscopic imaging system with a fixed overhead or floor-mounted system that has positioning capability rather than a portable C-arm system. other equipment that are required in the TAVR center include: 3D echocardiography, MDCT, CMR, full catheterization laboratory hemodynamic capability, cardiopulmonary bypass machines and related ancillary supplies, with an inventory of interventional cardiology equipment for balloon aortic valvuloplasty, coronary balloons, stents, and 0.014-inch wires if coronary occlusion occurs as a complication of device deployment.
The procedure location should also be fully capable of providing anesthesia services, including advanced airway management, general anesthesia, full hemodynamic monitoring, and administration of vasoactive agents into the central circulation.
In addition to the interventional cardiologist, cardiothoracic surgeon, and cardiovascular anesthesiologist, other personnel required during the TAVR procedure include a cardiovascular
imaging specialist, cardiac perfusionists, and other personnel trained in hemodynamic monitoring and able to rapidly deal with procedural complications.
### Anesthetic Considerations
Procedural complications, including hemodynamic collapse are common among patients undergoing TAVR. Preventing prolonged hypotension is a key goal during this procedure. Predictive factors for higher risk patients for intraprocedural instability include:
Depressed EF, elevated pulmonary pressures, significant mitral or tricuspid regurgitation, incomplete revascularization, collateral-dependent coronary and cerebral circulation, chronic lung disease, heart failure, and acute/chronic kidney disease.
TAVR is evolving from a procedure done routinely under general anesthesia with invasive central monitoring, a pulmonary artery catheter and transesophageal echocardiography to one that can safely be performed with conscious sedation and minimal instrumentation. Recent surveys showed better outcomes with conscious sedation than general anesthesia.
Now, it is recommended that TAVR procedures under conscious dsedation should be performed in highly experienced centers, and not as an initial starting strategy for a TAVR program, and only using the transfemoral approach.
Conscious sedation is best avoided in patients requiring TEE guidance during valve deployment and in those with borderline vascular access, cognitive or language barriers, an inability to stay still or lie flat, chronic pain, morbid obesity, or other issues.
### Anticipated complication management
The following table summarizes the common complication for TAVR procedure and their treatment options.
Abbreviations:
AVR: aortic valve replacement; CABG: coronary artery bypass grafting; CPB: cardiopulmonary bypass; CVA: cerebrovascular accident; PCI: percutaneous coronary intervention; PPM: permanent pacemaker; SAVR: surgical aortic valve replacement; TAVR: transcatheter aortic valve replacement
## Procedural Details
### Anesthesia Administration
Typically, a temporary transvenous lead is passed through the femoral or internal jugular veins or, in the case of transapical procedures, can also be sewn directly on the epicardial surface. Arterial pressure monitoring may be done via the radial artery. At least 1 large-volume line is obtained peripherally or centrally. Immediate access to a defibrillator device
is necessary because ventricular fibrillation can occur with manipulation of catheters within the heart or with rapid ventricular pacing. Volume status needs to be supplemented carefully to prevent volume overload and hypovolemia. Inhaled nitric oxide or inhaled epoprostenol should be readily available for the treatment of severe pulmonary hypertension and right ventricular failure.
Routine surgical antibiotic prophylaxis administered prior to surgical incision or vascular access is warranted to decrease the risk of wound infection and endocarditis.
### Vascular Access
Vascular ultrasound may be needed to assess vessel wall calcification prior to puncture.
- For transfemoral access, both percutaneous and cutdown access approaches are used. Percutaneous approaches are preferred when access sites are relatively large and free of significant atherosclerotic disease and calcification, and in patients with wound healing concerns.
- For transapical cases, access is obtained via a left anterior thoracotomy, which is made after localization of the apex by fluoroscopy, TTE, and/or TEE.
- For transaortic cases, access is either through an upper partial sternotomy or a minthoracotomy at the second or third right intercostal space.
### Prevalve Implant
One of the key steps in preimplant is identifying the optimal fluoroscopic and intraprocedural views for device deployment. A pigtail catheter is typically placed in the noncoronary cusp (for self-expanding valves) and right coronary cusp (for balloon-expandable valves) and aortography is performed in a fluoroscopic view perpendicular to the native valve in order to identify the coplanar or coaxial view.
Anticoagulation therapy is usually initiated after insertion of the large sheath into the vasculature, and repeated to maintain an activated clotting time (ACT) of >250–300 seconds.
Following this, the aortic valve is crossed using standard interventional techniques and a stiff wire exchange is performed, with redundancy in the LV cavity to prevent loss of position.
Prior to passage of the valve, predilation of the annulus may be required. Standard techniques of percutaneous balloon aortic valvuloplasty are employed, with rapid pacing during
inflation. Radiographic contrast opacification of the root during maximal inflation may provide useful information when the location of the coronary ostia in relation to the annulus and the
leaflet calcification or any other aortic root pathology requires further delineation.
This is also helpful in situations where valve sizing falls between valve sizes. For example, use a 22-mm or 23-mm Edwards balloon when deciding between a 23-mm and a 26-mm transcatheter valve. If the 22-mm or 23-mm balloon reaches the hinge points and there is no significant leak around the balloon on angiography, then generally the 23-mm transcatheter valve would be selected. If the 22-mm balloon does not reach the hinge points and/or there is clear leak into the ventricle around the balloon, then the 26-mm valve would generally be implanted.
### Valve Delivery and Deployment
The transcatheter valve is positioned across the annulus in the predetermined coaxial annular plane. The optimal landing zone should be identified and will vary depending on the type of
valve.
### Post-deployment Valve Assessments
Immediately following implantation, valve position and location should be checked with echocardiography (TTE or TEE), hemodynamics, and/or aortography. A quick assessment for changes in MV or LV function and new pericardial effusion should also be routinely performed.
Post-TAVR AR must be characterized in terms of its location, severity, and cause and should integrate both central and paravalvular origins to allow for an estimate of overall volumetric impact.
Central regurgitation is generally a result of improper valve deployment or sizing. Paravalvular regurgitation is generally caused by underdeployment of the prosthesis, very low implants (e.g., below the valve skirt of the self-expanding valve), or calcific deposits, which prevent the valve unit from properly seating and sealing within the annulus. Acute leaks may respond to repeat ballooning of the valve to obtain a better seal and greater expansion of the valve.
Following TAVR deployment, the delivery system and sheath are removed. Anticoagulation is typically reversed and access site closure is performed.
# Post-TAVR Clinical Management
The long-term management of patients after TAVR is similar to that of patients after SAVR. The major differences are that patients undergoing TAVR tend to be older and have more comorbid
conditions; an access site replaces the surgical incision; and the long-term durability of transcatheter valves is not yet known.
Basic principles for management of patients after valve replacement include:
- Periodic monitoring of prosthetic valve function
- Management of comorbid conditions
- Monitoring for cardiac conduction defects and heart block
- Promotion of a healthy lifestyle with cardiac risk factor reduction
- Antithrombotic therapy as appropriate
- Optimal dental hygiene and endocarditis prophylaxis
- Patient education and coordination of care
- Cardiac rehabilitation and promotion of physical activity as appropriate.
The following table describes Checklist for Post-TAVR Clinical Management.
Abbreviations:
ACC:American College of Cardiology; ADLs: activities of daily living; AF: atrial fibrillation; AHA:
American Heart Association; AR: aortic regurgitation; ASA: aspirin; ECG: electrocardiogram; GI: gastrointestinal; LV: left ventricular; MD: medical doctor; NOAC: new oral anticoagulant; OT: occupational therapy; PA: pulmonary artery; PT: physical therapy; TAVR: transcatheter aortic valve replacement; VTE: venous thromboembolism.
## Immediate Postprocedure Management
After TAVR procedure, patients should be monitored for recovery from sedation and anesthesia.
### Waking from sedation
When general anesthesia is used, early extubation is encouraged, as for any general anesthesia procedure.
### Postprocedure Monitoring
Monitoring for mental status, telemetry, vital signs, volume status, postprocedure blood testing and access site for adequate hemostasis is required for either conscious sedation or general anesthesia.
### Pain Management
Appropriate pain management, continued mental status monitoring, and early mobilization are especially important post-TAVR as patients often are elderly with a high burden of comorbidities.
### Early Mobilization
Discharge plan should be prepared before the procedure and should include physical and occupational therapy.
### Discharge Planning
Early discharge (within 72 hours) does not increase the risk of 30-day mortality, bleeding, pacer implantation or rehospitalization in selected patients undergoing transfemoral TAVR.
## Long Term Follow up
### Timing
Integration and coordination of medical care is essential post-TAVR to ensure optimal patient outcomes. Outcomes after TAVR depend strongly on overall patient health and clinical conditions other than the aortic valve disease.
Readmission rates are over 40% in the first year after the procedure, most often due to noncardiac causes (60% of readmissions); common readmission diagnoses include respiratory problems, infections and bleeding events. Cardiac readmissions are most often for arrhythmias or heart failure.
Mortality rates after TAVR remain very high, with about 30% of patients dying within 3 years of the procedure. Noncardiac causes of death predominate after the first 6 months. These data emphasize the need for integrated noncardiac and cardiac care in these patients, including end-of-life planning.
The Heart Valve Team is responsible for care for the first 30 days because procedural complications are most likely in this time interval. After 30 days, there should be a formal transfer of care from the Heart Valve Team back to the referring primary cardiologist. In stable patients with no complications and few comorbidities, the primary cardiologist should see the patient at 6 months and then annually, and more frequently as needed for complications or concurrent medical conditions. The primary care provider and cardiologist should communicate frequently to ensure coordination of care, with clear patient instructions on when and how to contact the care team.
### Antithrombotic Therapy
The current standard antithrombotic therapy after TAVR is clopidogrel 75 mg orally daily for 3–6 months with oral aspirin 75–100 mg daily lifelong. Patients with chronic AF or
-ther indications for long-term anticoagulation should receive anticoagulation as per guidelines for AF in patients with prosthetic heart valves. Vitamin-K antagonist therapy may be
considered in the first 3 months after TAVR in patients at risk of AF or valve thrombosis, depending on the specific risk-benefit ratio in that patient. When vitamin-K antagonist therapy is
used, continuation of aspirin is reasonable, but it may be prudent to avoid other antiplatelet therapy in some patients given the increased risk of bleeding with multiple simultaneous antithrombotic agents.
### Concurrent Cardiac Disease
Long-term management focuses on treatment of comorbid cardiac and noncardiac conditions.
noncardiac conditions are best managed by the primary care provider or geriatrician, with the cardiologist providing consultation regarding any changes in cardiac signs or symptoms. Referral back to the Heart Valve Team is appropriate when prosthetic valve dysfunction is a concern or if a second interventional procedure might be needed for another valve or for coronary artery disease. In addition to echocardiography, periodic ECG monitoring is recommended for detection of asymptomatic AF and because heart block or other conduction defects can occur late after TAVR.
### Monitor for Post-TAVR Complications
Echocardiography before discharge provides a new baseline study of transcatheter valve function and should include:
the antegrade TAVR velocity, mean transaortic gradient, valve area, assessment of paravalvular AR, LV size, regional wall motion and ejection fraction, evaluation of MV anatomy and function, estimation of pulmonary pressures and evaluation of the right ventricle.
Repeat echocardiography is recommended at 30 days and then at least annually.
Routine ECG assessment is also recommended owing to a potential need for pacemaker implantation beyond the initial 30-day period, particularly following implantation of the self expanding
TAVR.
The TAVR procedure is associated with a high risk of dislodgement of microdebris from arch atheroma or from the valve itself with subsequent embolic stroke. Clinical cerebrovascular
event rates are around 3%–5% at 30 days.
### Dental Hygiene and Antibiotic Prophylaxis
A TAVR is a risk factor for endocarditis, with reported rates of early prosthetic valve endocarditis ranging from 0.3% to 3.4 % per patient-year.
Standard antibiotic
prophylaxis after TAVR is the same as for all prosthetic valves per ACC Guidelines. In addition, patients should be encouraged to use optimal dental hygiene and see a dentist regularly for routine cleaning and dental care, with antibiotic prophylaxis at each visit. | Sandbox:tavr
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Seyedmahdi Pahlavani, M.D. [2]
# Overview
During the past 50 years, surgical aortic valve replacement (SAVR) was the standard of care for patients with severe AS. Global aging has raised concerns about safety and possibility of surgical procedure in old patients with associated co-morbidities. Transcatheter aortic valve replacement (TAVR) created a new era of safety for this population and enabled physicians to replace the stenotic valve with more certainty.
Preoperation evaluation, selecting the appropriate imaging modality, issues in TAVR procedure and patient follow up are the areas of more focused importance.
We will describe these factors based on the recent expert consensus for TAVR procedure.
# Definition
The most important step is to define the severity of AS and appropriate patient that need TAVR.
Severe sypmtomatic (Stage D) AS is considered as TAVR candidate.
Abbreviations:
ΔP: mean gradient, Vmax: maximum aortic velocity, AVA: aortic valve area. AS: aortic stenosis, AR: aortic regurgitation.
# TAVR Pathway outline
Abbreviations:
CV: Cardiovascular, AVR: aortic valve replacement, AS: aortic stenosis, MR: Mitral regurgitation, AR: Aortic regurgitation, PAP: Pulmonary artery pressure, RV: right ventricle, CTA: CT angiography, PA: Pulmonary artery, TEE: Trans Esophageal Echocardiography, TTE: Trans Thoracic Echocardiography
## Care Providing Team
## Clinical Evaluation
## Cardio-vascular Imaging
# Risk Assessment
Underlying risk for SAVR is basic component to consider patient for TAVR. This risk assessment is based on several components that include:
- The Society of Thoracic Surgeons Predicted Risk of Mortality (STS-PROM) score. To calculate this score please click here.
- Frailty
- Main organ system dysfunction
- Procedure-specific impediments
‡ Examples of major organ system compromise:
- Cardiac: severe LV systolic or diastolic dysfunction or RV dysfunction, fixed pulmonary hypertension
- CKD stage 3 or worse
- Pulmonary dysfunction with FEV1 <50% or DLCO <50% of predicted
- CNS dysfunction (dementia, Alzheimer’s disease, Parkinson’s disease, CVA with persistent physical limitation)
- GI dysfunction: Crohn’s disease, ulcerative colitis, nutritional impairment, or serum albumin <3.0
- Cancer: active malignancy
- Liver: any history of cirrhosis, variceal bleeding, or elevated INR in the absence of VKA therapy.
¶ Examples: tracheostomy present, heavily calcified ascending aorta, chest malformation, arterial coronary graft adherent to posterior chest wall, or radiation damage.
## Integrated Benefit-risk of TAVR and Shared Decision-making
# Heart Valve Team
Patients with severe AS should be evaluated by a multidisciplinary Heart Valve Team when intervention is considered.
Team members include:
- Cardiology Valve Expert
- Cardiovascular Imaging Expert(s)
- Interventional Cardiologist
- Cardio-Thoracic Surgeon
- Cardiovascular Anesthesiologist
- Valve Clinic Care Coordinators
Their specific tasks are:
- Review the patient's medical condition and the severity of the valve abnormality
- Determine which interventions are indicated, technically feasible, and reasonable
- Discuss benefits and risks of these interventions with the patient and family, keeping in mind their values and preferences.
# Initial Assessment
## Functional Assessment
Abbreviations:
BMI: body mass index; CV: cardiovascular; MMSE: mini mental state examination; MNA: mini nutritional assessment.
### Frailty
- Evaluation for frailty, physical function and independence in the activities of daily living (ADL) such as, feeding, bathing, toileting and transferring).[1]
- Evaluation should be start with screening for independence, cognition and slow walking speed (gait speed, 3 timed trials over a 5 meter distance).
- Those with gait speed over 0.83 m/s, preserved cognition and independence are likely not frail.
### Physical functioning
To assess the physical functioning, the 6 minute walk test should be done. It is possible to perform this test in outpatient setting.[2]
### Cognitive Functioning
The Mini Mental Status Examination (MMSE) is utilized to assess the cognitive status and scores less than 24 are considered as abnormal. Also, evaluation for depression must be done by using a validated tool such as, the Center for Epidemiologic Studies Depression Scale.[3]
### Futility
Those patients with <1 year life expectancy and who has a chance of survival with benefit of <25% at 2 years.
Survival with benefit means, survival with improvement by at least 1 New York Heart Association class in heart failure or by at least 1 Canadian Cardiovascular Society class angina symptoms, improvement in quality of life or improvement in life expectancy.[4]
# Imaging for TAVR
## General Principles and Technical Considerations
- Transthoracic Echocardiography (TTE) is the best initial imaging modality for evaluating AS severity.[5] Although, multimodality imaging is needed for preprocedural planning and intraoperative decision making given the complex 3D anatomy of the aortic valve, sinuses, and annulus.[6]
- Multi-Detector CT (MDCT) is a core element of the standard imaging pathway for the preprocedural planning of TAVR.[7]
- In patients being evaluated for TAVR, MDCT systems with at least 64 detectors and a spatial resolution of 0.5 to 0.6 mm are recommended.
- Evaluation of kidney function to avoid contrast induced nephropathy must be taken in to consideration.
Abbreviations:
CV: Cardiovascular, AVR: Aortic valve replacement, AS: Aortic Stenosis, MR: Mitral Regurgitation, AR: Aortic Regurgitation, PAP: Pulmonary Artery Pressure, RV: Right Ventricle, CTA: CT angiography, PA: Pulmonary Artery, TEE: Trans Esophageal Echocardiography, TTE: Trans Thoracic Echocardiography
AVA: Aortic Valve Area; CMR: Cardiovascular Magnetic Resonance Imaging; CT: Computed Tomography; ECG: Electrocardiogram; EF: Ejection Fraction; DSE: Dobutamine Stress Echocardiography; ESRD: End-Stage Renal Disease; GFR: Glomerular Filtration Rate; LFLG: Low-Flow Low-Gradient; LV: Left Ventricular; LVEF: Left Ventricular Ejection Fraction; MAC: Mitral Annular Calcification; MDCT: Multi Detector Computed Tomography; MRA: Magnetic Resonance Angiogram;
MRI: Magnetic Resonance Imaging; MS: Mitral Stenosis; PET: Positron Emission Tomography; TAVR: Trans-catheter Aortic Valve Replacement
## Specific CT measurements for TAVR
# Preprocedural Evaluation
## Aortic Valve Morphology
- Transthoracic Echocardiography (TTE) is performed for initial visualization of aortic valve to identify the number of leaflets; size, location, extent of calcification, leaflet motion, and a preliminary view of annular size and shape.
- If additional imaging is needed, valve anatomy and function can be evaluated by cardiac magnetic resonance imaging (CMR) or ECG-gated MDCT.[8]
## Aortic Valve Function
Doppler echocardiography is superior to other imaging modalities to evaluate Aortic valve function. AS severity should be evaluated according to the ESE/ASE Recommendations for Evaluation of Valvular Stenosis and staged according to the AHA/ACC Guideline for the Management of Patients with Valvular Heart Disease.[9][5]
## LV Geometry and Other Cardiac Findings
TTE also is recommended for evaluation of LV hypertrophy, chamber size, LV diastolic function, regional wall motion, and ejection fraction as well as newer measures of LV function such as global longitudinal strain. In addition, TTE is useful for assessment of aortic dilation, presence of subvalvular outflow tract obstruction, estimation of pulmonary pressures, and identification of other significant valve abnormalities.
## Annular Sizing
The 3D dataset provided by MDCT are more accurate than TTE findings regarding annular size.[10] Measurement of LV outflow tract diameter on TTE has been well validated for
calculation of aortic valve area and continues to be the standard for determination of AS severity. CMR can also provide comprehensive assessment of the aortic valve, annulus,
and aortic root with good correlation with MDCT.[11] CMR can be a valuable tool in patients who cannot undergo MDCT.
## Aortic Root Measurements
MDCT allows for the careful measurement of the size of the sinuses of Valsalva, the coronary ostia distance from the annulus, the size of the aorta at the sinotubular junction and 40mm above the annulus, and the extent and position of aortic calcifications.[12]
## Presurgical Planning
MDCT also may be of use in identification of coronary artery and coronary bypass graft location and stenosis, evaluation of the RV to chest wall position, and identification of the aorta and LV apex to chest wall position in direct aortic approaches.
## Noncardiac Imaging
Because of high prevalence of dementia and atherosclerosis in this elderly patient population, a preprocedural work-up including carotid ultrasound and cerebrovascular MRI might be considered prior to considering or such patients for TAVR.
## Vascular Access
Because of the relatively large diameter of the delivery sheaths, appropriate vascular access imaging is critical for TAVR. It is important to evaluate the entire thoracoabdominal aorta, major thoracic arterial vasculature, carotids, and iliofemoral vasculature. MDCT is able to provide valuable dataset regarding vascular anatomy.
# Periprocedural Evaluation
## Interventional Planning
MDCT can assist with predicting the optimal delivery angle on fluoroscopy prior to valve deployment.
## Confirmation of annular sizing
Preprocedural MDCT is the best modality to evaluate annular size. At the time of the procedure, Fluoroscopy is the main imaging modality. If questions remain about the correct annular
sizing, balloon inflation with contrast root injection can be performed. Also, 3D TEE is able to evaluate the annular size, at the time of the procedure.
## Valve Placement
Optimal deployment angles are obtained using fluoroscopy and root injections. Deployment is done under fluoroscopy at many institutions, although TEE is an alternative approach.
## Paravalvular Leak
TEE and TTE are required to assess the valve in different aspects. Also, TEE can be used to assess the immediate gradient changes after valve seating. Aortic root angiography also may be used to assess for regurgitation after valve implantation. As the volume of cases performed without general anesthesia increases, there may be an expanding role for periprocedural TTE.
## Procedural Complications
Immediate complications such as annular rupture resulting in pericardial effusion and tamponade can be detected by TEE, TTE, angiography, and direct hemodynamic measurements.
# Long-Term Postprocedural Evaluation
## Evaluate Valve Function
- Echocardiography is recommended to evaluate the valve postprocedurally to search for valvular and paravalvular leak, valve migration, complications such as annular or sinus rupture, valve thrombosis, endocarditis, paravalvular abscess, LV size, function and remodeling, and pulmonary pressures.
- MDCT can be used to evaluate valve anatomy A and to evaluate for valve thrombosis.
- CMR can also be used to quantify AR and can be complementary to TTE for the quantification of paravalvular leak.[8]
## LV Geometry and Other Cardiac Findings
TTE is used to evaluate changes in LV function after TAVR.
# TAVR Procedure
The following table describes the TAVR procedure checklist.
Abbreviations:
AR: aortic regurgitation; AVR: aortic valve replacement; BAV: balloon aortic valvuloplasty; PA: pulmonary artery; TEE: transesophageal echocardiography
## Preprocedural Planning
- The Heart Valve Team must decide and plan for valve selection, access choice and location of procedure.
### Valve Choice
Valve selection is dependent on 2 major factors,
- Which type of valve should be considered (balloon expandable or self expanding) based on anatomical reasons
- Available valve sizes.
There currently are 2 TAVR valves commercially available in the United States:
- The balloon-expandable Sapien family of transcatheter heart valves (Edwards Lifesciences) made of bovine pericardium mounted in a cylindrical, relatively short cobaltchromium stent.
- The self-expanding CoreValve (Medtronic) family of transcatheter heart valves, which are made of porcine pericardium mounted in a taller, nitinol stent with an adaptive shape and supra-annular design.
Randomized clinical trials showed similar 1-year mortality, strokes, and readmissions due to heart failure with either valve.[13][14]
Important factors that must be considered in valve selection:
- Annulus dimensions and geometry
- Native valve and aortic root/LV outflow tract anatomy
- Coronary height
- Amount and distribution of calcification
Self expanding valves are preferred over balloon expandable in the following circumstances:
- Patients with heavy calcification of the aortic annulus/LV outflow tract with an attendant risk of rupture
- Extremely oval-shaped annulus or for transfemoral access when femoral artery diameter is between 5.0 and 5.5 mm.
Balloon expanding valves are preferred over self expandable in this situations:
- Dilated ascending (>43 mm) aorta
- Severely angulated aorta (aortoventricular angle >70 degrees, particularly for transfemoral access).
- A balloon-expandable valve is the only option in patients needing a transapical approach (e.g., those with a significant aortic calcification and peripheral vascular disease).
Several other valve designs and platforms are currently under investigation, and valve teams of the future will need to have a sound understanding of their relative merits and disadvantages for treating specific subsets of patients with AS.
### Access Choice
The patient’s atherosclerotic load and location, arterial size and tortuosity, and presence of mural thrombus are important factors in access selection.
When possible, transfemoral access is the preferred TAVR delivery route.
### Location of the Procedure
Optimal equipment requirements include a state-of-the-art, large-field-of-view fluoroscopic imaging system with a fixed overhead or floor-mounted system that has positioning capability rather than a portable C-arm system. other equipment that are required in the TAVR center include: 3D echocardiography, MDCT, CMR, full catheterization laboratory hemodynamic capability, cardiopulmonary bypass machines and related ancillary supplies, with an inventory of interventional cardiology equipment for balloon aortic valvuloplasty, coronary balloons, stents, and 0.014-inch wires if coronary occlusion occurs as a complication of device deployment.
The procedure location should also be fully capable of providing anesthesia services, including advanced airway management, general anesthesia, full hemodynamic monitoring, and administration of vasoactive agents into the central circulation.
In addition to the interventional cardiologist, cardiothoracic surgeon, and cardiovascular anesthesiologist, other personnel required during the TAVR procedure include a cardiovascular
imaging specialist, cardiac perfusionists, and other personnel trained in hemodynamic monitoring and able to rapidly deal with procedural complications.
### Anesthetic Considerations
Procedural complications, including hemodynamic collapse are common among patients undergoing TAVR. Preventing prolonged hypotension is a key goal during this procedure. Predictive factors for higher risk patients for intraprocedural instability include:
Depressed EF, elevated pulmonary pressures, significant mitral or tricuspid regurgitation, incomplete revascularization, collateral-dependent coronary and cerebral circulation, chronic lung disease, heart failure, and acute/chronic kidney disease.
TAVR is evolving from a procedure done routinely under general anesthesia with invasive central monitoring, a pulmonary artery catheter and transesophageal echocardiography to one that can safely be performed with conscious sedation and minimal instrumentation. Recent surveys showed better outcomes with conscious sedation than general anesthesia.[15][16]
Now, it is recommended that TAVR procedures under conscious dsedation should be performed in highly experienced centers, and not as an initial starting strategy for a TAVR program, and only using the transfemoral approach.
Conscious sedation is best avoided in patients requiring TEE guidance during valve deployment and in those with borderline vascular access, cognitive or language barriers, an inability to stay still or lie flat, chronic pain, morbid obesity, or other issues.
### Anticipated complication management
The following table summarizes the common complication for TAVR procedure and their treatment options.
Abbreviations:
AVR: aortic valve replacement; CABG: coronary artery bypass grafting; CPB: cardiopulmonary bypass; CVA: cerebrovascular accident; PCI: percutaneous coronary intervention; PPM: permanent pacemaker; SAVR: surgical aortic valve replacement; TAVR: transcatheter aortic valve replacement
## Procedural Details
### Anesthesia Administration
Typically, a temporary transvenous lead is passed through the femoral or internal jugular veins or, in the case of transapical procedures, can also be sewn directly on the epicardial surface. Arterial pressure monitoring may be done via the radial artery. At least 1 large-volume line is obtained peripherally or centrally. Immediate access to a defibrillator device
is necessary because ventricular fibrillation can occur with manipulation of catheters within the heart or with rapid ventricular pacing. Volume status needs to be supplemented carefully to prevent volume overload and hypovolemia. Inhaled nitric oxide or inhaled epoprostenol should be readily available for the treatment of severe pulmonary hypertension and right ventricular failure.
Routine surgical antibiotic prophylaxis administered prior to surgical incision or vascular access is warranted to decrease the risk of wound infection and endocarditis.
### Vascular Access
Vascular ultrasound may be needed to assess vessel wall calcification prior to puncture.
- For transfemoral access, both percutaneous and cutdown access approaches are used. Percutaneous approaches are preferred when access sites are relatively large and free of significant atherosclerotic disease and calcification, and in patients with wound healing concerns.
- For transapical cases, access is obtained via a left anterior thoracotomy, which is made after localization of the apex by fluoroscopy, TTE, and/or TEE.
- For transaortic cases, access is either through an upper partial sternotomy or a minthoracotomy at the second or third right intercostal space.
### Prevalve Implant
One of the key steps in preimplant is identifying the optimal fluoroscopic and intraprocedural views for device deployment. A pigtail catheter is typically placed in the noncoronary cusp (for self-expanding valves) and right coronary cusp (for balloon-expandable valves) and aortography is performed in a fluoroscopic view perpendicular to the native valve in order to identify the coplanar or coaxial view.
Anticoagulation therapy is usually initiated after insertion of the large sheath into the vasculature, and repeated to maintain an activated clotting time (ACT) of >250–300 seconds.
Following this, the aortic valve is crossed using standard interventional techniques and a stiff wire exchange is performed, with redundancy in the LV cavity to prevent loss of position.
Prior to passage of the valve, predilation of the annulus may be required. Standard techniques of percutaneous balloon aortic valvuloplasty are employed, with rapid pacing during
inflation. Radiographic contrast opacification of the root during maximal inflation may provide useful information when the location of the coronary ostia in relation to the annulus and the
leaflet calcification or any other aortic root pathology requires further delineation.
This is also helpful in situations where valve sizing falls between valve sizes. For example, use a 22-mm or 23-mm Edwards balloon when deciding between a 23-mm and a 26-mm transcatheter valve. If the 22-mm or 23-mm balloon reaches the hinge points and there is no significant leak around the balloon on angiography, then generally the 23-mm transcatheter valve would be selected. If the 22-mm balloon does not reach the hinge points and/or there is clear leak into the ventricle around the balloon, then the 26-mm valve would generally be implanted.
### Valve Delivery and Deployment
The transcatheter valve is positioned across the annulus in the predetermined coaxial annular plane. The optimal landing zone should be identified and will vary depending on the type of
valve.
### Post-deployment Valve Assessments
Immediately following implantation, valve position and location should be checked with echocardiography (TTE or TEE), hemodynamics, and/or aortography. A quick assessment for changes in MV or LV function and new pericardial effusion should also be routinely performed.
Post-TAVR AR must be characterized in terms of its location, severity, and cause and should integrate both central and paravalvular origins to allow for an estimate of overall volumetric impact.[17]
Central regurgitation is generally a result of improper valve deployment or sizing. Paravalvular regurgitation is generally caused by underdeployment of the prosthesis, very low implants (e.g., below the valve skirt of the self-expanding valve), or calcific deposits, which prevent the valve unit from properly seating and sealing within the annulus. Acute leaks may respond to repeat ballooning of the valve to obtain a better seal and greater expansion of the valve.
Following TAVR deployment, the delivery system and sheath are removed. Anticoagulation is typically reversed and access site closure is performed.
# Post-TAVR Clinical Management
The long-term management of patients after TAVR is similar to that of patients after SAVR. The major differences are that patients undergoing TAVR tend to be older and have more comorbid
conditions; an access site replaces the surgical incision; and the long-term durability of transcatheter valves is not yet known.
Basic principles for management of patients after valve replacement include:
- Periodic monitoring of prosthetic valve function
- Management of comorbid conditions
- Monitoring for cardiac conduction defects and heart block
- Promotion of a healthy lifestyle with cardiac risk factor reduction
- Antithrombotic therapy as appropriate
- Optimal dental hygiene and endocarditis prophylaxis
- Patient education and coordination of care
- Cardiac rehabilitation and promotion of physical activity as appropriate.
The following table describes Checklist for Post-TAVR Clinical Management.
Abbreviations:
ACC:American College of Cardiology; ADLs: activities of daily living; AF: atrial fibrillation; AHA:
American Heart Association; AR: aortic regurgitation; ASA: aspirin; ECG: electrocardiogram; GI: gastrointestinal; LV: left ventricular; MD: medical doctor; NOAC: new oral anticoagulant; OT: occupational therapy; PA: pulmonary artery; PT: physical therapy; TAVR: transcatheter aortic valve replacement; VTE: venous thromboembolism.
## Immediate Postprocedure Management
After TAVR procedure, patients should be monitored for recovery from sedation and anesthesia.
### Waking from sedation
When general anesthesia is used, early extubation is encouraged, as for any general anesthesia procedure.
### Postprocedure Monitoring
Monitoring for mental status, telemetry, vital signs, volume status, postprocedure blood testing and access site for adequate hemostasis is required for either conscious sedation or general anesthesia.
### Pain Management
Appropriate pain management, continued mental status monitoring, and early mobilization are especially important post-TAVR as patients often are elderly with a high burden of comorbidities.
### Early Mobilization
Discharge plan should be prepared before the procedure and should include physical and occupational therapy.
### Discharge Planning
Early discharge (within 72 hours) does not increase the risk of 30-day mortality, bleeding, pacer implantation or rehospitalization in selected patients undergoing transfemoral TAVR.[18]
## Long Term Follow up
### Timing
Integration and coordination of medical care is essential post-TAVR to ensure optimal patient outcomes. Outcomes after TAVR depend strongly on overall patient health and clinical conditions other than the aortic valve disease.[19]
Readmission rates are over 40% in the first year after the procedure, most often due to noncardiac causes (60% of readmissions); common readmission diagnoses include respiratory problems, infections and bleeding events. Cardiac readmissions are most often for arrhythmias or heart failure.[20][21]
Mortality rates after TAVR remain very high, with about 30% of patients dying within 3 years of the procedure[22][23]. Noncardiac causes of death predominate after the first 6 months. These data emphasize the need for integrated noncardiac and cardiac care in these patients, including end-of-life planning.
The Heart Valve Team is responsible for care for the first 30 days because procedural complications are most likely in this time interval. After 30 days, there should be a formal transfer of care from the Heart Valve Team back to the referring primary cardiologist. In stable patients with no complications and few comorbidities, the primary cardiologist should see the patient at 6 months and then annually, and more frequently as needed for complications or concurrent medical conditions. The primary care provider and cardiologist should communicate frequently to ensure coordination of care, with clear patient instructions on when and how to contact the care team.
### Antithrombotic Therapy
The current standard antithrombotic therapy after TAVR is clopidogrel 75 mg orally daily for 3–6 months with oral aspirin 75–100 mg daily lifelong. Patients with chronic AF or
other indications for long-term anticoagulation should receive anticoagulation as per guidelines for AF in patients with prosthetic heart valves. Vitamin-K antagonist therapy may be
considered in the first 3 months after TAVR in patients at risk of AF or valve thrombosis, depending on the specific risk-benefit ratio in that patient. When vitamin-K antagonist therapy is
used, continuation of aspirin is reasonable, but it may be prudent to avoid other antiplatelet therapy in some patients given the increased risk of bleeding with multiple simultaneous antithrombotic agents.
### Concurrent Cardiac Disease
Long-term management focuses on treatment of comorbid cardiac and noncardiac conditions.
noncardiac conditions are best managed by the primary care provider or geriatrician, with the cardiologist providing consultation regarding any changes in cardiac signs or symptoms. Referral back to the Heart Valve Team is appropriate when prosthetic valve dysfunction is a concern or if a second interventional procedure might be needed for another valve or for coronary artery disease. In addition to echocardiography, periodic ECG monitoring is recommended for detection of asymptomatic AF and because heart block or other conduction defects can occur late after TAVR.
### Monitor for Post-TAVR Complications
Echocardiography before discharge provides a new baseline study of transcatheter valve function and should include:
the antegrade TAVR velocity, mean transaortic gradient, valve area, assessment of paravalvular AR, LV size, regional wall motion and ejection fraction, evaluation of MV anatomy and function, estimation of pulmonary pressures and evaluation of the right ventricle.
Repeat echocardiography is recommended at 30 days and then at least annually.
Routine ECG assessment is also recommended owing to a potential need for pacemaker implantation beyond the initial 30-day period, particularly following implantation of the self expanding
TAVR.
The TAVR procedure is associated with a high risk of dislodgement of microdebris from arch atheroma or from the valve itself with subsequent embolic stroke. Clinical cerebrovascular
event rates are around 3%–5% at 30 days.[24][25]
### Dental Hygiene and Antibiotic Prophylaxis
A TAVR is a risk factor for endocarditis, with reported rates of early prosthetic valve endocarditis ranging from 0.3% to 3.4 % per patient-year.[26][27]
Standard antibiotic
prophylaxis after TAVR is the same as for all prosthetic valves per ACC Guidelines.[28] In addition, patients should be encouraged to use optimal dental hygiene and see a dentist regularly for routine cleaning and dental care, with antibiotic prophylaxis at each visit. | https://www.wikidoc.org/index.php/Sandbox:tavr | |
ac015458e8ea83444594bfadcdf10535c7bedbb7 | wikidoc | Sandbox 1234 | Sandbox 1234
WARNING: ISCHEMIC HEART DISEASE:
Following abrupt cessation of therapy with certain beta-blocking agents, exacerbations of angina pectoris and, in some cases, myocardial infarction have occurred. When discontinuing chronically administered metoprolol succinate extended-release tablets, particularly in patients with ischemic heart disease, the dosage should be gradually reduced over a period of 1 - 2 weeks and the patient should be carefully monitored. If angina markedly worsens or acute coronary insufficiency develops, metoprolol succinate extended-release tablets administration should be reinstated promptly, at least temporarily, and other measures appropriate for the management of unstable angina should be taken. Warn patients against interruption or discontinuation of therapy without the physician’s advice. Because coronary artery disease is common and may be unrecognized, it may be prudent not to discontinue metoprolol succinate extended-release tablets therapy abruptly even in patients treated only for hypertension (5.1).
# INDICATIONS & USAGE
Metoprolol succinate extended-release tablets are indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents .
Metoprolol succinate extended-release tablets are indicated in the long-term treatment of angina pectoris, to reduce angina attacks and to improve exercise tolerance.
Metoprolol succinate extended-release tablets are indicated for the treatment of stable, symptomatic (NYHA Class II or III) heart failure of ischemic, hypertensive, or cardiomyopathic origin. It was studied in patients already receiving ACE inhibitors, diuretics, and, in the majority of cases, digitalis. In this population, metoprolol succinate extended-release tablets decreased the rate of mortality plus hospitalization, largely through a reduction in cardiovascular mortality and hospitalizations for heart failure.
# DOSAGE & ADMINISTRATION
Metoprolol succinate extended-release is an extended release tablet intended for once daily administration. For treatment of hypertension and angina, when switching from immediate release metoprolol to metoprolol succinate extended-release tablets, use the same total daily dose of metoprolol succinate extended-release tablets. Individualize the dosage of metoprolol succinate extended-release tablets. Titration may be needed in some patients.
Metoprolol succinate extended-release tablets are scored and can be divided; however, do not crush or chew the whole or half tablet.
Adults: The usual initial dosage is 25 to 100 mg daily in a single dose. The dosage may be increased at weekly (or longer) intervals until optimum blood pressure reduction is achieved. In general, the maximum effect of any given dosage level will be apparent after 1 week of therapy. Dosages above 400 mg per day have not been studied.
Pediatric Hypertensive Patients ≥ 6 Years of age: A pediatric clinical hypertension study in patients 6 to 16 years of age did not meet its primary endpoint (dose response for reduction in SBP); however some other endpoints demonstrated effectiveness . If selected for treatment, the recommended starting dose of metoprolol succinate extended-release tablet is 1.0 mg/kg once daily, but the maximum initial dose should not exceed 50 mg once daily. Dosage should be adjusted according to blood pressure response. Doses above 2.0 mg/kg (or in excess of 200 mg) once daily have not been studied in pediatric patients .
Metoprolol succinate extended-release tablet is not recommended in pediatric patients <6 years of age .
Individualize the dosage of metoprolol succinate extended-release tablets. The usual initial dosage is 100 mg daily, given in a single dose. Gradually increase the dosage at weekly intervals until optimum clinical response has been obtained or there is a pronounced slowing of the heart rate. Dosages above 400 mg per day have not been studied. If treatment is to be discontinued, reduce the dosage gradually over a period of 1 - 2 weeks .
Dosage must be individualized and closely monitored during up-titration. Prior to initiation of metoprolol succinate extended-release tablets, stabilize the dose of other heart failure drug therapy. The recommended starting dose of metoprolol succinate extended-release tablet is 25 mg once daily for two weeks in patients with NYHA Class II heart failure and 12.5 mg once daily in patients with more severe heart failure. Double the dose every two weeks to the highest dosage level tolerated by the patient or up to 200 mg of metoprolol succinate extended-release tablets. Initial difficulty with titration should not preclude later attempts to introduce metoprolol succinate extended-release tablets. If patients experience symptomatic bradycardia, reduce the dose of metoprolol succinate extended-release tablets. If transient worsening of heart failure occurs, consider treating with increased doses of diuretics, lowering the dose of metoprolol succinate extended-release tablets or temporarily discontinuing it. The dose of metoprolol succinate extended-release tablets should not be increased until symptoms of worsening heart failure have been stabilized.
# DOSAGE FORMS & STRENGTHS
25 mg tablets: White, oval, biconvex, film-coated scored tablet debossed with “W and 34”
50 mg tablets: White, circular, beveled edge, biconvex, film-coated scored tablet debossed with “W”
100 mg tablets: White, circular, beveled edge, biconvex, film-coated scored tablet debossed with “W”
200 mg tablets: White, oval, beveled edge, biconvex, film-coated scored tablet debossed with “W737”
# CONTRAINDICATIONS
Metoprolol succinate extended-release tablets are contraindicated in severe bradycardia, second or third degree heart block, cardiogenic shock, decompensated cardiac failure, sick sinus syndrome (unless a permanent pacemaker is in place), and in patients who are hypersensitive to any component of this product.
# WARNINGS AND PRECAUTIONS
Following abrupt cessation of therapy with certain beta-blocking agents, exacerbations of angina pectoris and, in some cases, myocardial infarction have occurred. When discontinuing chronically administered metoprolol succinate extended-release tablets, particularly in patients with ischemic heart disease gradually reduce the dosage over a period of 1 - 2 weeks and monitor the patient. If angina markedly worsens or acute coronary ischemia develops, promptly reinstate metoprolol succinate extended-release tablets, and take measures appropriate for the management of unstable angina. Warn patients not to interrupt therapy without their physician's advice. Because coronary artery disease is common and may be unrecognized, avoid abruptly discontinuing metoprolol succinate extended-release tablets in patients treated only for hypertension.
Worsening cardiac failure may occur during up-titration of metoprolol succinate extended-release tablets. If such symptoms occur, increase diuretics and restore clinical stability before advancing the dose of metoprolol succinate extended-release tablets . It may be necessary to lower the dose of metoprolol succinate extended-release tablets or temporarily discontinue it. Such episodes do not preclude subsequent successful titration of metoprolol succinate extended-release tablets.
PATIENTS WITH BRONCHOSPASTIC DISEASES SHOULD, IN GENERAL, NOT RECEIVE BETA-BLOCKERS. Because of its relative beta1 cardio-selectivity, however, metoprolol succinate extended-release tablets may be used in patients with bronchospastic disease who do not respond to, or cannot tolerate, other antihypertensive treatment. Because beta1-selectivity is not absolute, use the lowest possible dose of metoprolol succinate extended-release tablets. Bronchodilators, including beta2-agonists, should be readily available or administered concomitantly .
If metoprolol succinate extended-release tablets are used in the setting of pheochromocytoma, it should be given in combination with an alpha blocker, and only after the alpha blocker has been initiated. Administration of beta-blockers alone in the setting of pheochromocytoma has been associated with a paradoxical increase in blood pressure due to the attenuation of beta-mediated vasodilatation in skeletal muscle.
Avoid initiation of a high-dose regimen of extended release metoprolol in patients undergoing non-cardiac surgery, since such use in patients with cardiovascular risk factors has been associated with bradycardia, hypotension, stroke and death.
Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery, however, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures.
Beta-blockers may mask tachycardia occurring with hypoglycemia, but other manifestations such as dizziness and sweating may not be significantly affected.
Consider initiating metoprolol succinate extended-release tablets therapy at doses lower than those recommended for a given indication; gradually increase dosage to optimize therapy, while monitoring closely for adverse events.
Beta-adrenergic blockade may mask certain clinical signs of hyperthyroidism, such as tachycardia. Abrupt withdrawal of beta-blockade may precipitate a thyroid storm.
While taking beta-blockers, patients with a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated challenge and may be unresponsive to the usual doses of epinephrine used to treat an allergic reaction.
Beta-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease.
Because of significant inotropic and chronotropic effects in patients treated with beta-blockers and calcium channel blockers of the verapamil and diltiazem type, caution should be exercised in patients treated with these agents concomitantly.
# ADVERSE REACTIONS
The following adverse reactions are described elsewhere in labeling:
- Worsening angina or myocardial infarction.
- Worsening heart failure.
- Worsening AV block.
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 adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.
Most adverse reactions have been mild and transient. The most common (>2%) adverse reactions are tiredness, dizziness, depression, diarrhea, shortness of breath, bradycardia, and rash.
Heart Failure: In the MERIT-HF study comparing metoprolol succinate extended-release tablets in daily doses up to 200 mg (mean dose 159 mg once-daily; n=1990) to placebo (n=2001), 10.3% of metoprolol succinate extended-release tablets patients discontinued for adverse reactions vs. 12.2% of placebo patients.
The table below lists adverse reactions in the MERIT-HF study that occurred at an incidence of ≥ 1% in the metoprolol succinate extended-release tablets group and greater than placebo by more than 0.5%, regardless of the assessment of causality.
Adverse Reactions Occurring in the MERIT-HF Study at an Incidence ≥ 1 % in the Metoprolol Succinate Extended-Release Tablets Group and Greater Than Placebo by More Than 0.5 %
Post-operative Adverse Events: In a randomized, double-blind, placebo-controlled trial of 8351 patients with or at risk for atherosclerotic disease undergoing non-vascular surgery and who were not taking beta-blocker therapy, metoprolol succinate extended-release tablets 100 mg was started 2 to 4 hours prior to surgery then continued for 30 days at 200 mg per day. Metoprolol succinate extended-release tablets use was associated with a higher incidence of bradycardia (6.6% vs. 2.4% ; HR 2.74; 95% CI 2.19,3.43), hypotension (15% vs. 9.7%; HR 1.55 95% CI 1.37,1.74), stroke (1.0% vs 0.5%; HR 2.17; 95% CI 1.26,3.74) and death (3.1% vs 2.3%; HR 1.33; 95% CI 1.03, 1.74) compared to placebo.
The following adverse reactions have been identified during post-approval use of metoprolol succinate extended-release tablets or immediate-release metoprolol. 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.
Cardiovascular: Cold extremities, arterial insufficiency (usually of the Raynaud type), palpitations, peripheral edema, syncope, chest pain and hypotension.
Respiratory: Wheezing (bronchospasm), dyspnea.
Central Nervous System: Confusion, short-term memory loss, headache, somnolence, nightmares, insomnia, anxiety/nervousness, hallucinations, paresthesia.
Gastrointestinal: Nausea, dry mouth, constipation, flatulence, heartburn, hepatitis, vomiting.
Hypersensitive Reactions: Pruritus.
Miscellaneous: Musculoskeletal pain, arthralgia, blurred vision, decreased libido, male impotence, tinnitus, reversible alopecia, agranulocytosis, dry eyes, worsening of psoriasis, Peyronie's disease, sweating, photosensitivity, taste disturbance
Potential Adverse Reactions: In addition, there are adverse reactions not listed above that have been reported with other beta-adrenergic blocking agents and should be considered potential adverse reactions to metoprolol succinate extended-release tablets.
Central Nervous System: Reversible mental depression progressing to catatonia; an acute reversible syndrome characterized by disorientation for time and place, short-term memory loss, emotional lability, clouded sensorium, and decreased performance on neuropsychometrics.
Hematologic: Agranulocytosis, nonthrombocytopenic purpura, thrombocytopenic purpura.
Hypersensitive Reactions: Laryngospasm, respiratory distress.
Clinical laboratory findings may include elevated levels of serum transaminase, alkaline phosphatase, and lactate dehydrogenase.
# DRUG INTERACTIONS
Catecholamine-depleting drugs (eg, reserpine, monoamine oxidase (MAO) inhibitors) may have an additive effect when given with beta-blocking agents. Observe patients treated with metoprolol succinate extended-release tablets plus a catecholamine depletor for evidence of hypotension or marked bradycardia, which may produce vertigo, syncope, or postural hypotension.
Drugs that inhibit CYP2D6 such as quinidine, fluoxetine, paroxetine, and propafenone are likely to increase metoprolol concentration. In healthy subjects with CYP2D6 extensive metabolizer phenotype, coadministration of quinidine 100 mg and immediate release metoprolol 200 mg tripled the concentration of S-metoprolol and doubled the metoprolol elimination half-life. In four patients with cardiovascular disease, coadministration of propafenone 150 mg t.i.d. with immediate release metoprolol 50 mg t.i.d. resulted in two- to five-fold increases in the steady-state concentration of metoprolol. These increases in plasma concentration would decrease the cardioselectivity of metoprolol.
Digitalis glycosides, clonidine, diltiazem and verapamil slow atrioventricular conduction and decrease heart rate. Concomitant use with beta blockers can increase the risk of bradycardia.
If clonidine and a beta blocker, such as metoprolol are coadministered, withdraw the beta-blocker several days before the gradual withdrawal of clonidine because beta-blockers may exacerbate the rebound hypertension that can follow the withdrawal of clonidine. If replacing clonidine by beta-blocker therapy, delay the introduction of beta-blockers for several days after clonidine administration has stopped .
# USE IN SPECIFIC POPULATIONS
Pregnancy Category C
Metoprolol tartrate has been shown to increase post-implantation loss and decrease neonatal survival in rats at doses up to 22 times, on a mg/m2 basis, the daily dose of 200 mg in a 60-kg patient. Distribution studies in mice confirm exposure of the fetus when metoprolol tartrate is administered to the pregnant animal. These studies have revealed no evidence of impaired fertility or teratogenicity. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, use this drug during pregnancy only if clearly needed.
Metoprolol is excreted in breast milk in very small quantities. An infant consuming 1 liter of breast milk daily would receive a dose of less than 1 mg of the drug. Consider possible infant exposure when metoprolol succinate extended-release tablet is administered to a nursing woman.
One hundred forty-four hypertensive pediatric patients aged 6 to 16 years were randomized to placebo or to one of three dose levels of metoprolol succinate extended-release tablets (0.2, 1.0 or 2.0 mg/kg once daily) and followed for 4 weeks. The study did not meet its primary endpoint (dose response for reduction in SBP). Some pre-specified secondary endpoints demonstrated effectiveness including:
- Dose-response for reduction in DBP,
- 1.0 mg/kg vs. placebo for change in SBP, and
- 2.0 mg/kg vs. placebo for change in SBP and DBP.
The mean placebo corrected reductions in SBP ranged from 3 to 6 mmHg, and DBP from 1 to 5 mmHg. Mean reduction in heart rate ranged from 5 to 7 bpm but considerably greater reductions were seen in some individuals .
No clinically relevant differences in the adverse event profile were observed for pediatric patients aged 6 to 16 years as compared with adult patients.
Safety and effectiveness of metoprolol succinate extended-release tablets have not been established in patients <6 years of age.
Clinical studies of metoprolol succinate extended-release tablets in hypertension did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience in hypertensive patients has not identified differences in responses between elderly and younger patients.
Of the 1,990 patients with heart failure randomized to metoprolol succinate extended-release tablets in the MERIT-HF trial, 50% (990) were 65 years of age and older and 12% (238) were 75 years of age and older. There were no notable differences in efficacy or the rate of adverse reactions between older and younger patients.
In general, use a low initial starting dose in elderly patients given their greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
No studies have been performed with metoprolol succinate extended-release tablets in patients with hepatic impairment. Because metoprolol succinate extended-release tablet is metabolized by the liver, metoprolol blood levels are likely to increase substantially with poor hepatic function. Therefore, initiate therapy at doses lower than those recommended for a given indication; and increase doses gradually in patients with impaired hepatic function.
The systemic availability and half-life of metoprolol in patients with renal failure do not differ to a clinically significant degree from those in normal subjects. No reduction in dosage is needed in patients with chronic renal failure .
# OVERDOSAGE
Signs and Symptoms - Overdosage of metoprolol succinate extended-release tablets may lead to severe bradycardia, hypotension, and cardiogenic shock. Clinical presentation can also include: atrioventricular block, heart failure, bronchospasm, hypoxia, impairment of consciousness/coma, nausea and vomiting.
Treatment - Consider treating the patient with intensive care. Patients with myocardial infarction or heart failure may be prone to significant hemodynamic instability. Seek consultation with a regional poison control center and a medical toxicologist as needed. Beta-blocker overdose may result in significant resistance to resuscitation with adrenergic agents, including beta-agonists. On the basis of the pharmacologic actions of metoprolol, employ the following measures.
There is very limited experience with the use of hemodialysis to remove metoprolol, however metoprolol is not highly protein bound.
Bradycardia: Administer intravenous atropine; repeat to effect. If the response is inadequate, consider intravenous isoproterenol or other positive chronotropic agents. Evaluate the need for transvenous pacemaker insertion.
Hypotension: Treat underlying bradycardia. Consider intravenous vasopressor infusion, such as dopamine or norepinephrine.
Bronchospasm: Administer a beta2-agonist, including albuterol inhalation, or an oral theophylline derivative.
Cardiac Failure: Administer diuretics or digoxin for congestive heart failure. For cardiogenic shock, consider IV dobutamine, isoproterenol, or glucagon.
# DESCRIPTION
Metoprolol succinate is a beta1-selective (cardioselective) adrenoceptor blocking agent, for oral administration, available as extended release tablets. Metoprolol succinate extended-release tablet has been formulated to provide a controlled and predictable release of metoprolol for once-daily administration. The tablets comprise a multiple unit system containing metoprolol succinate in a multitude of controlled release pellets. Each pellet acts as a separate drug delivery unit and is designed to deliver metoprolol continuously over the dosage interval. The tablets contain 23.75, 47.5, 95 and 190 mg of metoprolol succinate equivalent to 25, 50, 100 and 200 mg of metoprolol tartrate, USP, respectively. Its chemical name is (±)1-(isopropylamino)-3--2-propanol succinate (2:1) (salt). Its structural formula is:
# CLINICAL PHARMACOLOGY
Hypertension: The mechanism of the antihypertensive effects of beta-blocking agents has not been elucidated. However, several possible mechanisms have been proposed: (1) competitive antagonism of catecholamines at peripheral (especially cardiac) adrenergic neuron sites, leading to decreased cardiac output; (2) a central effect leading to reduced sympathetic outflow to the periphery; and (3) suppression of renin activity.
Heart Failure: The precise mechanism for the beneficial effects of beta-blockers in heart failure has not been elucidated.
Clinical pharmacology studies have confirmed the beta-blocking activity of metoprolol in man, as shown by (1) reduction in heart rate and cardiac output at rest and upon exercise, (2) reduction of systolic blood pressure upon exercise, (3) inhibition of isoproterenol-induced tachycardia, and (4) reduction of reflex orthostatic tachycardia.
Metoprolol is a beta1-selective (cardioselective) adrenergic receptor blocking agent. This preferential effect is not absolute, however, and at higher plasma concentrations, metoprolol also inhibits beta2-adrenoreceptors, chiefly located in the bronchial and vascular musculature. Metoprolol has no intrinsic sympathomimetic activity, and membrane-stabilizing activity is detectable only at plasma concentrations much greater than required for beta-blockade. Animal and human experiments indicate that metoprolol slows the sinus rate and decreases AV nodal conduction.
The relative beta1-selectivity of metoprolol has been confirmed by the following: (1) In normal subjects, metoprolol is unable to reverse the beta2-mediated vasodilating effects of epinephrine. This contrasts with the effect of nonselective beta-blockers, which completely reverse the vasodilating effects of epinephrine. (2) In asthmatic patients, metoprolol reduces FEV1 and FVC significantly less than a nonselective beta-blocker, propranolol, at equivalent beta1-receptor blocking doses.
The relationship between plasma metoprolol levels and reduction in exercise heart rate is independent of the pharmaceutical formulation. Using an Emax model, the maximum effect is a 30% reduction in exercise heart rate, which is attributed to beta1-blockade. Beta1-blocking effects in the range of 30-80% of the maximal effect (approximately 8-23% reduction in exercise heart rate) correspond to metoprolol plasma concentrations from 30-540 nmol/L. The relative beta1-selectivity of metoprolol diminishes and blockade or beta2-adrenoceptors increases at plasma concentration above 300 nmol/L.
Although beta-adrenergic receptor blockade is useful in the treatment of angina, hypertension, and heart failure there are situations in which sympathetic stimulation is vital. In patients with severely damaged hearts, adequate ventricular function may depend on sympathetic drive. In the presence of AV block, beta-blockade may prevent the necessary facilitating effect of sympathetic activity on conduction. Beta2-adrenergic blockade results in passive bronchial constriction by interfering with endogenous adrenergic bronchodilator activity in patients subject to bronchospasm and may also interfere with exogenous bronchodilators in such patients.
In other studies, treatment with metoprolol succinate extended-release tablets produced an improvement in left ventricular ejection fraction. Metoprolol succinate extended-release tablet was also shown to delay the increase in left ventricular end-systolic and end-diastolic volumes after 6 months of treatment.
Adults: In man, absorption of metoprolol is rapid and complete. Plasma levels following oral administration of conventional metoprolol tablets, however, approximate 50% of levels following intravenous administration, indicating about 50% first-pass metabolism. Metoprolol crosses the blood-brain barrier and has been reported in the CSF in a concentration 78% of the simultaneous plasma concentration.
Plasma levels achieved are highly variable after oral administration. Only a small fraction of the drug (about 12%) is bound to human serum albumin. Metoprolol is a racemic mixture of R- and S- enantiomers, and is primarily metabolized by CYP2D6. When administered orally, it exhibits stereoselective metabolism that is dependent on oxidation phenotype. Elimination is mainly by biotransformation in the liver, and the plasma half-life ranges from approximately 3 to 7 hours. Less than 5% of an oral dose of metoprolol is recovered unchanged in the urine; the rest is excreted by the kidneys as metabolites that appear to have no beta-blocking activity.
Following intravenous administration of metoprolol, the urinary recovery of unchanged drug is approximately 10%. The systemic availability and half-life of metoprolol in patients with renal failure do not differ to a clinically significant degree from those in normal subjects. Consequently, no reduction in metoprolol succinate dosage is usually needed in patients with chronic renal failure.
Metoprolol is metabolized predominantly by CYP2D6, an enzyme that is absent in about 8% of Caucasians (poor metabolizers) and about 2% of most other populations. CYP2D6 can be inhibited by a number of drugs. Poor metabolizers and extensive metabolizers who concomitantly use CYP2D6 inhibiting drugs will have increased (several-fold) metoprolol blood levels, decreasing metoprolol's cardioselectivity .
In comparison to conventional metoprolol, the plasma metoprolol levels following administration of metoprolol succinate extended-release tablets are characterized by lower peaks, longer time to peak and significantly lower peak to trough variation. The peak plasma levels following once-daily administration of metoprolol succinate extended-release tablet average one-fourth to one-half the peak plasma levels obtained following a corresponding dose of conventional metoprolol, administered once daily or in divided doses. At steady state the average bioavailability of metoprolol following administration of metoprolol succinate extended-release tablets, across the dosage range of 50 to 400 mg once daily, was 77% relative to the corresponding single or divided doses of conventional metoprolol. Nevertheless, over the 24-hour dosing interval, β1-blockade is comparable and dose-related . The bioavailability of metoprolol shows a dose-related, although not directly proportional, increase with dose and is not significantly affected by food following metoprolol succinate extended-release tablets administration.
Pediatrics: The pharmacokinetic profile of metoprolol succinate extended-release tablet was studied in 120 pediatric hypertensive patients (6-17 years of age) receiving doses ranging from 12.5 to 200 mg once daily. The pharmacokinetics of metoprolol were similar to those described previously in adults. Age, gender, race, and ideal body weight had no significant effects on metoprolol pharmacokinetics. Metoprolol apparent oral clearance (CL/F) increased linearly with body weight. Metoprolol pharmacokinetics have not been investigated in patients < 6 years of age.
# NONCLINICAL TOXICOLOGY
Long-term studies in animals have been conducted to evaluate the carcinogenic potential of metoprolol tartrate. In 2-year studies in rats at three oral dosage levels of up to 800 mg/kg/day (41 times, on a mg/m2 basis, the daily dose of 200 mg for a 60-kg patient), there was no increase in the development of spontaneously occurring benign or malignant neoplasms of any type. The only histologic changes that appeared to be drug related were an increased incidence of generally mild focal accumulation of foamy macrophages in pulmonary alveoli and a slight increase in biliary hyperplasia. In a 21-month study in Swiss albino mice at three oral dosage levels of up to 750 mg/kg/day (18 times, on a mg/m2 basis, the daily dose of 200 mg for a 60-kg patient), benign lung tumors (small adenomas) occurred more frequently in female mice receiving the highest dose than in untreated control animals. There was no increase in malignant or total (benign plus malignant) lung tumors, nor in the overall incidence of tumors or malignant tumors. This 21-month study was repeated in CD-1 mice, and no statistically or biologically significant differences were observed between treated and control mice of either sex for any type of tumor.
All genotoxicity tests performed on metoprolol tartrate (a dominant lethal study in mice, chromosome studies in somatic cells, aSalmonella/mammalian-microsome mutagenicity test, and a nucleus anomaly test in somatic interphase nuclei) and metoprolol succinate (aSalmonella/mammalian-microsome mutagenicity test) were negative.
No evidence of impaired fertility due to metoprolol tartrate was observed in a study performed in rats at doses up to 22 times, on a mg/m2basis, the daily dose of 200 mg in a 60-kg patient.
# CLINICAL STUDIES
In five controlled studies in normal healthy subjects, the same daily doses of metoprolol succinate extended-release tablets and immediate release metoprolol were compared in terms of the extent and duration of beta1-blockade produced. Both formulations were given in a dose range equivalent to 100-400 mg of immediate release metoprolol per day. In these studies, metoprolol succinate extended-release tablet was administered once a day and immediate release metoprolol was administered once to four times a day. A sixth controlled study compared the beta1-blocking effects of a 50 mg daily dose of the two formulations. In each study, beta1-blockade was expressed as the percent change from baseline in exercise heart rate following standardized submaximal exercise tolerance tests at steady state. Metoprolol succinate extended-release tablets administered once a day, and immediate release metoprolol administered once to four times a day, provided comparable total beta1-blockade over 24 hours (area under the beta1-blockade versus time curve) in the dose range 100-400 mg. At a dosage of 50 mg once daily, metoprolol succinate extended-release tablets produced significantly higher total beta1-blockade over 24 hours than immediate release metoprolol. For metoprolol succinate extended-release tablets, the percent reduction in exercise heart rate was relatively stable throughout the entire dosage interval and the level of beta1-blockade increased with increasing doses from 50 to 300 mg daily. The effects at peak/trough (ie, at 24-hours post-dosing) were: 14/9, 16/10, 24/14, 27/22 and 27/20% reduction in exercise heart rate for doses of 50, 100, 200, 300 and 400 mg metoprolol succinate extended-release tablets once a day, respectively. In contrast to metoprolol succinate extended-release tablets, immediate release metoprolol given at a dose of 50-100 mg once a day produced a significantly larger peak effect on exercise tachycardia, but the effect was not evident at 24 hours. To match the peak to trough ratio obtained with metoprolol succinate extended-release tablets over the dosing range of 200 to 400 mg, a t.i.d. to q.i.d. divided dosing regimen was required for immediate release metoprolol. A controlled cross-over study in heart failure patients compared the plasma concentrations and beta1-blocking effects of 50 mg immediate release metoprolol administered t.i.d., 100 mg and 200 mg metoprolol succinate extended-release tablets once daily. A 50 mg dose of immediate release metoprolol t.i.d. produced a peak plasma level of metoprolol similar to the peak level observed with 200 mg of metoprolol succinate extended-release tablets. A 200 mg dose of metoprolol succinate extended-release tablets produced a larger effect on suppression of exercise-induced and Holter-monitored heart rate over 24 hours compared to 50 mg t.i.d. of immediate release metoprolol.
In a double-blind study, 1092 patients with mild-to-moderate hypertension were randomized to once daily metoprolol succinate extended-release tablets (25, 100, or 400 mg), PLENDIL® (felodipine extended release tablets), the combination, or placebo. After 9 weeks, metoprolol succinate extended-release tablets alone decreased sitting blood pressure by 6-8/4-7 mmHg (placebo-corrected change from baseline) at 24 hours post-dose. The combination of metoprolol succinate extended-release tablets with PLENDIL has greater effects on blood pressure.
In controlled clinical studies, an immediate release dosage form of metoprolol was an effective antihypertensive agent when used alone or as concomitant therapy with thiazide-type diuretics at dosages of 100-450 mg daily. Metoprolol succinate extended-release tablets, in dosages of 100 to 400 mg once daily, produces similar β1-blockade as conventional metoprolol tablets administered two to four times daily. In addition, metoprolol succinate extended-release tablet administered at a dose of 50 mg once daily lowered blood pressure 24-hours post-dosing in placebo-controlled studies. In controlled, comparative, clinical studies, immediate release metoprolol appeared comparable as an antihypertensive agent to propranolol, methyldopa, and thiazide-type diuretics, and affected both supine and standing blood pressure. Because of variable plasma levels attained with a given dose and lack of a consistent relationship of antihypertensive activity to drug plasma concentration, selection of proper dosage requires individual titration.
By blocking catecholamine-induced increases in heart rate, in velocity and extent of myocardial contraction, and in blood pressure, metoprolol reduces the oxygen requirements of the heart at any given level of effort, thus making it useful in the long-term management of angina pectoris.
In controlled clinical trials, an immediate release formulation of metoprolol has been shown to be an effective antianginal agent, reducing the number of angina attacks and increasing exercise tolerance. The dosage used in these studies ranged from 100 to 400 mg daily. Metoprolol succinate extended-release tablets, in dosages of 100 to 400 mg once daily, has been shown to possess beta-blockade similar to conventional metoprolol tablets administered two to four times daily.
MERIT-HF was a double-blind, placebo-controlled study of metoprolol succinate extended-release tablets conducted in 14 countries including the US. It randomized 3991 patients (1990 to metoprolol succinate extended-release tablets) with ejection fraction ≤0.40 and NYHA Class II-IV heart failure attributable to ischemia, hypertension, or cardiomyopathy. The protocol excluded patients with contraindications to beta-blocker use, those expected to undergo heart surgery, and those within 28 days of myocardial infarction or unstable angina. The primary endpoints of the trial were (1) all-cause mortality plus all-cause hospitalization (time to first event) and (2) all-cause mortality. Patients were stabilized on optimal concomitant therapy for heart failure, including diuretics, ACE inhibitors, cardiac glycosides, and nitrates. At randomization, 41% of patients were NYHA Class II; 55% NYHA Class III; 65% of patients had heart failure attributed to ischemic heart disease; 44% had a history of hypertension; 25% had diabetes mellitus; 48% had a history of myocardial infarction. Among patients in the trial, 90% were on diuretics, 89% were on ACE inhibitors, 64% were on digitalis, 27% were on a lipid-lowering agent, 37% were on an oral anticoagulant, and the mean ejection fraction was 0.28. The mean duration of follow-up was one year. At the end of the study, the mean daily dose of metoprolol succinate extended-release tablets was 159 mg.
The trial was terminated early for a statistically significant reduction in all-cause mortality (34%, nominal p= 0.00009). The risk of all-cause mortality plus all-cause hospitalization was reduced by 19% (p= 0.00012). The trial also showed improvements in heart failure-related mortality and heart failure-related hospitalizations, and NYHA functional class.
The table below shows the principal results for the overall study population. The figure below illustrates principal results for a wide variety of subgroup comparisons, including US vs. non-US populations (the latter of which was not pre-specified). The combined endpoints of all-cause mortality plus all-cause hospitalization and of mortality plus heart failure hospitalization showed consistent effects in the overall study population and the subgroups, including women and the US population. However, in the US subgroup (n=1071) and women (n=898), overall mortality and cardiovascular mortality appeared less affected. Analyses of female and US patients were carried out because they each represented about 25% of the overall population. Nonetheless, subgroup analyses can be difficult to interpret and it is not known whether these represent true differences or chance effects.
# HOW SUPPLIED
Tablets containing metoprolol succinate equivalent to the indicated weight of metoprolol tartrate, USP, are white, biconvex, film-coated, and scored. name="ib13da1b2-ef46-44a7-887b-3227715a2213"
- The 25 mg tablet is scored on both sides.
Store at 20°-25°C (68°-77°F); .
# INFORMATION FOR PATIENTS
Advise patients to take metoprolol succinate extended-release tablets regularly and continuously, as directed, preferably with or immediately following meals. If a dose is missed, the patient should take only the next scheduled dose (without doubling it). Patients should not interrupt or discontinue metoprolol succinate extended-release tablets without consulting the physician.
Advise patients (1) to avoid operating automobiles and machinery or engaging in other tasks requiring alertness until the patient's response to therapy with metoprolol succinate extended-release tablets has been determined; (2) to contact the physician if any difficulty in breathing occurs; (3) to inform the physician or dentist before any type of surgery that he or she is taking metoprolol succinate extended-release tablets.
Heart failure patients should be advised to consult their physician if they experience signs or symptoms of worsening heart failure such as weight gain or increasing shortness of breath.
PLENDIL is trademark of the AstraZeneca group of companies.
Manufactured by:
Wockhardt Limited
Mumbai, India.
Distributed by:
Wockhardt USA LLC.
20 Waterview Blvd.
Parsippany, NJ 07054
USA.
Rev.190312
# PACKAGE LABEL.PRINCIPAL DISPLAY PANEL SECTION
DRUG: METOPROLOL SUCCINATE
GENERIC: METOPROLOL SUCCINATE
DOSAGE: TABLET, FILM COATED, EXTENDED RELEASE
ADMINSTRATION: ORAL
NDC: 52125-230-02
STRENGTH:25 mg
COLOR: white
SHAPE: OVAL
SCORE: Two even pieces
SIZE: 12 mm
IMPRINT: 30
QTY: 30 | Sandbox 1234
WARNING: ISCHEMIC HEART DISEASE:
Following abrupt cessation of therapy with certain beta-blocking agents, exacerbations of angina pectoris and, in some cases, myocardial infarction have occurred. When discontinuing chronically administered metoprolol succinate extended-release tablets, particularly in patients with ischemic heart disease, the dosage should be gradually reduced over a period of 1 - 2 weeks and the patient should be carefully monitored. If angina markedly worsens or acute coronary insufficiency develops, metoprolol succinate extended-release tablets administration should be reinstated promptly, at least temporarily, and other measures appropriate for the management of unstable angina should be taken. Warn patients against interruption or discontinuation of therapy without the physician’s advice. Because coronary artery disease is common and may be unrecognized, it may be prudent not to discontinue metoprolol succinate extended-release tablets therapy abruptly even in patients treated only for hypertension (5.1).
# INDICATIONS & USAGE
[http:/ ]
[http:/ ]
Metoprolol succinate extended-release tablets are indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents [see Dosage and Administration (2)].
[http:/ ]
Metoprolol succinate extended-release tablets are indicated in the long-term treatment of angina pectoris, to reduce angina attacks and to improve exercise tolerance.
[http:/ ]
Metoprolol succinate extended-release tablets are indicated for the treatment of stable, symptomatic (NYHA Class II or III) heart failure of ischemic, hypertensive, or cardiomyopathic origin. It was studied in patients already receiving ACE inhibitors, diuretics, and, in the majority of cases, digitalis. In this population, metoprolol succinate extended-release tablets decreased the rate of mortality plus hospitalization, largely through a reduction in cardiovascular mortality and hospitalizations for heart failure.
# DOSAGE & ADMINISTRATION
[http:/ ]
Metoprolol succinate extended-release is an extended release tablet intended for once daily administration. For treatment of hypertension and angina, when switching from immediate release metoprolol to metoprolol succinate extended-release tablets, use the same total daily dose of metoprolol succinate extended-release tablets. Individualize the dosage of metoprolol succinate extended-release tablets. Titration may be needed in some patients.
Metoprolol succinate extended-release tablets are scored and can be divided; however, do not crush or chew the whole or half tablet.
[http:/ ]
Adults: The usual initial dosage is 25 to 100 mg daily in a single dose. The dosage may be increased at weekly (or longer) intervals until optimum blood pressure reduction is achieved. In general, the maximum effect of any given dosage level will be apparent after 1 week of therapy. Dosages above 400 mg per day have not been studied.
Pediatric Hypertensive Patients ≥ 6 Years of age: A pediatric clinical hypertension study in patients 6 to 16 years of age did not meet its primary endpoint (dose response for reduction in SBP); however some other endpoints demonstrated effectiveness [see Use in Specific Populations (8.4)]. If selected for treatment, the recommended starting dose of metoprolol succinate extended-release tablet is 1.0 mg/kg once daily, but the maximum initial dose should not exceed 50 mg once daily. Dosage should be adjusted according to blood pressure response. Doses above 2.0 mg/kg (or in excess of 200 mg) once daily have not been studied in pediatric patients [see Clinical Pharmacology (12.3)].
Metoprolol succinate extended-release tablet is not recommended in pediatric patients <6 years of age [see Use in Specific Populations (8.4)].
[http:/ ]
Individualize the dosage of metoprolol succinate extended-release tablets. The usual initial dosage is 100 mg daily, given in a single dose. Gradually increase the dosage at weekly intervals until optimum clinical response has been obtained or there is a pronounced slowing of the heart rate. Dosages above 400 mg per day have not been studied. If treatment is to be discontinued, reduce the dosage gradually over a period of 1 - 2 weeks [see Warnings and Precautions (5)].
[http:/ ]
Dosage must be individualized and closely monitored during up-titration. Prior to initiation of metoprolol succinate extended-release tablets, stabilize the dose of other heart failure drug therapy. The recommended starting dose of metoprolol succinate extended-release tablet is 25 mg once daily for two weeks in patients with NYHA Class II heart failure and 12.5 mg once daily in patients with more severe heart failure. Double the dose every two weeks to the highest dosage level tolerated by the patient or up to 200 mg of metoprolol succinate extended-release tablets. Initial difficulty with titration should not preclude later attempts to introduce metoprolol succinate extended-release tablets. If patients experience symptomatic bradycardia, reduce the dose of metoprolol succinate extended-release tablets. If transient worsening of heart failure occurs, consider treating with increased doses of diuretics, lowering the dose of metoprolol succinate extended-release tablets or temporarily discontinuing it. The dose of metoprolol succinate extended-release tablets should not be increased until symptoms of worsening heart failure have been stabilized.
# DOSAGE FORMS & STRENGTHS
[http:/ ]
25 mg tablets: White, oval, biconvex, film-coated scored tablet debossed with “W and 34”
50 mg tablets: White, circular, beveled edge, biconvex, film-coated scored tablet debossed with “W”
100 mg tablets: White, circular, beveled edge, biconvex, film-coated scored tablet debossed with “W”
200 mg tablets: White, oval, beveled edge, biconvex, film-coated scored tablet debossed with “W737”
# CONTRAINDICATIONS
[http:/ ]
Metoprolol succinate extended-release tablets are contraindicated in severe bradycardia, second or third degree heart block, cardiogenic shock, decompensated cardiac failure, sick sinus syndrome (unless a permanent pacemaker is in place), and in patients who are hypersensitive to any component of this product.
# WARNINGS AND PRECAUTIONS
[http:/ ]
[http:/ ]
Following abrupt cessation of therapy with certain beta-blocking agents, exacerbations of angina pectoris and, in some cases, myocardial infarction have occurred. When discontinuing chronically administered metoprolol succinate extended-release tablets, particularly in patients with ischemic heart disease gradually reduce the dosage over a period of 1 - 2 weeks and monitor the patient. If angina markedly worsens or acute coronary ischemia develops, promptly reinstate metoprolol succinate extended-release tablets, and take measures appropriate for the management of unstable angina. Warn patients not to interrupt therapy without their physician's advice. Because coronary artery disease is common and may be unrecognized, avoid abruptly discontinuing metoprolol succinate extended-release tablets in patients treated only for hypertension.
[http:/ ]
Worsening cardiac failure may occur during up-titration of metoprolol succinate extended-release tablets. If such symptoms occur, increase diuretics and restore clinical stability before advancing the dose of metoprolol succinate extended-release tablets [see Dosage and Administration (2)]. It may be necessary to lower the dose of metoprolol succinate extended-release tablets or temporarily discontinue it. Such episodes do not preclude subsequent successful titration of metoprolol succinate extended-release tablets.
[http:/ ]
PATIENTS WITH BRONCHOSPASTIC DISEASES SHOULD, IN GENERAL, NOT RECEIVE BETA-BLOCKERS. Because of its relative beta1 cardio-selectivity, however, metoprolol succinate extended-release tablets may be used in patients with bronchospastic disease who do not respond to, or cannot tolerate, other antihypertensive treatment. Because beta1-selectivity is not absolute, use the lowest possible dose of metoprolol succinate extended-release tablets. Bronchodilators, including beta2-agonists, should be readily available or administered concomitantly [see Dosage and Administration (2)].
[http:/ ]
If metoprolol succinate extended-release tablets are used in the setting of pheochromocytoma, it should be given in combination with an alpha blocker, and only after the alpha blocker has been initiated. Administration of beta-blockers alone in the setting of pheochromocytoma has been associated with a paradoxical increase in blood pressure due to the attenuation of beta-mediated vasodilatation in skeletal muscle.
[http:/ ]
Avoid initiation of a high-dose regimen of extended release metoprolol in patients undergoing non-cardiac surgery, since such use in patients with cardiovascular risk factors has been associated with bradycardia, hypotension, stroke and death.
Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery, however, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures.
[http:/ ]
Beta-blockers may mask tachycardia occurring with hypoglycemia, but other manifestations such as dizziness and sweating may not be significantly affected.
[http:/ ]
Consider initiating metoprolol succinate extended-release tablets therapy at doses lower than those recommended for a given indication; gradually increase dosage to optimize therapy, while monitoring closely for adverse events.
[http:/ ]
Beta-adrenergic blockade may mask certain clinical signs of hyperthyroidism, such as tachycardia. Abrupt withdrawal of beta-blockade may precipitate a thyroid storm.
[http:/ ]
While taking beta-blockers, patients with a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated challenge and may be unresponsive to the usual doses of epinephrine used to treat an allergic reaction.
[http:/ ]
Beta-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease.
[http:/ ]
Because of significant inotropic and chronotropic effects in patients treated with beta-blockers and calcium channel blockers of the verapamil and diltiazem type, caution should be exercised in patients treated with these agents concomitantly.
# ADVERSE REACTIONS
[http:/ ]
The following adverse reactions are described elsewhere in labeling:
- Worsening angina or myocardial infarction. [see Warnings and Precautions (5)]
- Worsening heart failure. [see Warnings and Precautions (5)]
- Worsening AV block. [see Contraindications (4)]
[http:/ ]
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 adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.
Most adverse reactions have been mild and transient. The most common (>2%) adverse reactions are tiredness, dizziness, depression, diarrhea, shortness of breath, bradycardia, and rash.
Heart Failure: In the MERIT-HF study comparing metoprolol succinate extended-release tablets in daily doses up to 200 mg (mean dose 159 mg once-daily; n=1990) to placebo (n=2001), 10.3% of metoprolol succinate extended-release tablets patients discontinued for adverse reactions vs. 12.2% of placebo patients.
The table below lists adverse reactions in the MERIT-HF study that occurred at an incidence of ≥ 1% in the metoprolol succinate extended-release tablets group and greater than placebo by more than 0.5%, regardless of the assessment of causality.
Adverse Reactions Occurring in the MERIT-HF Study at an Incidence ≥ 1 % in the Metoprolol Succinate Extended-Release Tablets Group and Greater Than Placebo by More Than 0.5 %
Post-operative Adverse Events: In a randomized, double-blind, placebo-controlled trial of 8351 patients with or at risk for atherosclerotic disease undergoing non-vascular surgery and who were not taking beta-blocker therapy, metoprolol succinate extended-release tablets 100 mg was started 2 to 4 hours prior to surgery then continued for 30 days at 200 mg per day. Metoprolol succinate extended-release tablets use was associated with a higher incidence of bradycardia (6.6% vs. 2.4% ; HR 2.74; 95% CI 2.19,3.43), hypotension (15% vs. 9.7%; HR 1.55 95% CI 1.37,1.74), stroke (1.0% vs 0.5%; HR 2.17; 95% CI 1.26,3.74) and death (3.1% vs 2.3%; HR 1.33; 95% CI 1.03, 1.74) compared to placebo.
[http:/ ]
The following adverse reactions have been identified during post-approval use of metoprolol succinate extended-release tablets or immediate-release metoprolol. 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.
Cardiovascular: Cold extremities, arterial insufficiency (usually of the Raynaud type), palpitations, peripheral edema, syncope, chest pain and hypotension.
Respiratory: Wheezing (bronchospasm), dyspnea.
Central Nervous System: Confusion, short-term memory loss, headache, somnolence, nightmares, insomnia, anxiety/nervousness, hallucinations, paresthesia.
Gastrointestinal: Nausea, dry mouth, constipation, flatulence, heartburn, hepatitis, vomiting.
Hypersensitive Reactions: Pruritus.
Miscellaneous: Musculoskeletal pain, arthralgia, blurred vision, decreased libido, male impotence, tinnitus, reversible alopecia, agranulocytosis, dry eyes, worsening of psoriasis, Peyronie's disease, sweating, photosensitivity, taste disturbance
Potential Adverse Reactions: In addition, there are adverse reactions not listed above that have been reported with other beta-adrenergic blocking agents and should be considered potential adverse reactions to metoprolol succinate extended-release tablets.
Central Nervous System: Reversible mental depression progressing to catatonia; an acute reversible syndrome characterized by disorientation for time and place, short-term memory loss, emotional lability, clouded sensorium, and decreased performance on neuropsychometrics.
Hematologic: Agranulocytosis, nonthrombocytopenic purpura, thrombocytopenic purpura.
Hypersensitive Reactions: Laryngospasm, respiratory distress.
[http:/ ]
Clinical laboratory findings may include elevated levels of serum transaminase, alkaline phosphatase, and lactate dehydrogenase.
# DRUG INTERACTIONS
[http:/ ]
[http:/ ]
Catecholamine-depleting drugs (eg, reserpine, monoamine oxidase (MAO) inhibitors) may have an additive effect when given with beta-blocking agents. Observe patients treated with metoprolol succinate extended-release tablets plus a catecholamine depletor for evidence of hypotension or marked bradycardia, which may produce vertigo, syncope, or postural hypotension.
[http:/ ]
Drugs that inhibit CYP2D6 such as quinidine, fluoxetine, paroxetine, and propafenone are likely to increase metoprolol concentration. In healthy subjects with CYP2D6 extensive metabolizer phenotype, coadministration of quinidine 100 mg and immediate release metoprolol 200 mg tripled the concentration of S-metoprolol and doubled the metoprolol elimination half-life. In four patients with cardiovascular disease, coadministration of propafenone 150 mg t.i.d. with immediate release metoprolol 50 mg t.i.d. resulted in two- to five-fold increases in the steady-state concentration of metoprolol. These increases in plasma concentration would decrease the cardioselectivity of metoprolol.
[http:/ ]
Digitalis glycosides, clonidine, diltiazem and verapamil slow atrioventricular conduction and decrease heart rate. Concomitant use with beta blockers can increase the risk of bradycardia.
If clonidine and a beta blocker, such as metoprolol are coadministered, withdraw the beta-blocker several days before the gradual withdrawal of clonidine because beta-blockers may exacerbate the rebound hypertension that can follow the withdrawal of clonidine. If replacing clonidine by beta-blocker therapy, delay the introduction of beta-blockers for several days after clonidine administration has stopped [see WARNINGS AND PRECAUTIONS (5.11)].
# USE IN SPECIFIC POPULATIONS
[http:/ ]
[http:/ ]
Pregnancy Category C
Metoprolol tartrate has been shown to increase post-implantation loss and decrease neonatal survival in rats at doses up to 22 times, on a mg/m2 basis, the daily dose of 200 mg in a 60-kg patient. Distribution studies in mice confirm exposure of the fetus when metoprolol tartrate is administered to the pregnant animal. These studies have revealed no evidence of impaired fertility or teratogenicity. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, use this drug during pregnancy only if clearly needed.
[http:/ ]
Metoprolol is excreted in breast milk in very small quantities. An infant consuming 1 liter of breast milk daily would receive a dose of less than 1 mg of the drug. Consider possible infant exposure when metoprolol succinate extended-release tablet is administered to a nursing woman.
[http:/ ]
One hundred forty-four hypertensive pediatric patients aged 6 to 16 years were randomized to placebo or to one of three dose levels of metoprolol succinate extended-release tablets (0.2, 1.0 or 2.0 mg/kg once daily) and followed for 4 weeks. The study did not meet its primary endpoint (dose response for reduction in SBP). Some pre-specified secondary endpoints demonstrated effectiveness including:
- Dose-response for reduction in DBP,
- 1.0 mg/kg vs. placebo for change in SBP, and
- 2.0 mg/kg vs. placebo for change in SBP and DBP.
The mean placebo corrected reductions in SBP ranged from 3 to 6 mmHg, and DBP from 1 to 5 mmHg. Mean reduction in heart rate ranged from 5 to 7 bpm but considerably greater reductions were seen in some individuals [see Dosage and Administration (2.1)].
No clinically relevant differences in the adverse event profile were observed for pediatric patients aged 6 to 16 years as compared with adult patients.
Safety and effectiveness of metoprolol succinate extended-release tablets have not been established in patients <6 years of age.
[http:/ ]
Clinical studies of metoprolol succinate extended-release tablets in hypertension did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience in hypertensive patients has not identified differences in responses between elderly and younger patients.
Of the 1,990 patients with heart failure randomized to metoprolol succinate extended-release tablets in the MERIT-HF trial, 50% (990) were 65 years of age and older and 12% (238) were 75 years of age and older. There were no notable differences in efficacy or the rate of adverse reactions between older and younger patients.
In general, use a low initial starting dose in elderly patients given their greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
[http:/ ]
No studies have been performed with metoprolol succinate extended-release tablets in patients with hepatic impairment. Because metoprolol succinate extended-release tablet is metabolized by the liver, metoprolol blood levels are likely to increase substantially with poor hepatic function. Therefore, initiate therapy at doses lower than those recommended for a given indication; and increase doses gradually in patients with impaired hepatic function.
[http:/ ]
The systemic availability and half-life of metoprolol in patients with renal failure do not differ to a clinically significant degree from those in normal subjects. No reduction in dosage is needed in patients with chronic renal failure [see Clinical Pharmacology (12.3)].
# OVERDOSAGE
[http:/ ]
Signs and Symptoms - Overdosage of metoprolol succinate extended-release tablets may lead to severe bradycardia, hypotension, and cardiogenic shock. Clinical presentation can also include: atrioventricular block, heart failure, bronchospasm, hypoxia, impairment of consciousness/coma, nausea and vomiting.
Treatment - Consider treating the patient with intensive care. Patients with myocardial infarction or heart failure may be prone to significant hemodynamic instability. Seek consultation with a regional poison control center and a medical toxicologist as needed. Beta-blocker overdose may result in significant resistance to resuscitation with adrenergic agents, including beta-agonists. On the basis of the pharmacologic actions of metoprolol, employ the following measures.
There is very limited experience with the use of hemodialysis to remove metoprolol, however metoprolol is not highly protein bound.
Bradycardia: Administer intravenous atropine; repeat to effect. If the response is inadequate, consider intravenous isoproterenol or other positive chronotropic agents. Evaluate the need for transvenous pacemaker insertion.
Hypotension: Treat underlying bradycardia. Consider intravenous vasopressor infusion, such as dopamine or norepinephrine.
Bronchospasm: Administer a beta2-agonist, including albuterol inhalation, or an oral theophylline derivative.
Cardiac Failure: Administer diuretics or digoxin for congestive heart failure. For cardiogenic shock, consider IV dobutamine, isoproterenol, or glucagon.
# DESCRIPTION
[http:/ ]
Metoprolol succinate is a beta1-selective (cardioselective) adrenoceptor blocking agent, for oral administration, available as extended release tablets. Metoprolol succinate extended-release tablet has been formulated to provide a controlled and predictable release of metoprolol for once-daily administration. The tablets comprise a multiple unit system containing metoprolol succinate in a multitude of controlled release pellets. Each pellet acts as a separate drug delivery unit and is designed to deliver metoprolol continuously over the dosage interval. The tablets contain 23.75, 47.5, 95 and 190 mg of metoprolol succinate equivalent to 25, 50, 100 and 200 mg of metoprolol tartrate, USP, respectively. Its chemical name is (±)1-(isopropylamino)-3-[p-(2-methoxyethyl) phenoxy]-2-propanol succinate (2:1) (salt). Its structural formula is:
# CLINICAL PHARMACOLOGY
[http:/ ]
[http:/ ]
Hypertension: The mechanism of the antihypertensive effects of beta-blocking agents has not been elucidated. However, several possible mechanisms have been proposed: (1) competitive antagonism of catecholamines at peripheral (especially cardiac) adrenergic neuron sites, leading to decreased cardiac output; (2) a central effect leading to reduced sympathetic outflow to the periphery; and (3) suppression of renin activity.
Heart Failure: The precise mechanism for the beneficial effects of beta-blockers in heart failure has not been elucidated.
[http:/ ]
Clinical pharmacology studies have confirmed the beta-blocking activity of metoprolol in man, as shown by (1) reduction in heart rate and cardiac output at rest and upon exercise, (2) reduction of systolic blood pressure upon exercise, (3) inhibition of isoproterenol-induced tachycardia, and (4) reduction of reflex orthostatic tachycardia.
Metoprolol is a beta1-selective (cardioselective) adrenergic receptor blocking agent. This preferential effect is not absolute, however, and at higher plasma concentrations, metoprolol also inhibits beta2-adrenoreceptors, chiefly located in the bronchial and vascular musculature. Metoprolol has no intrinsic sympathomimetic activity, and membrane-stabilizing activity is detectable only at plasma concentrations much greater than required for beta-blockade. Animal and human experiments indicate that metoprolol slows the sinus rate and decreases AV nodal conduction.
The relative beta1-selectivity of metoprolol has been confirmed by the following: (1) In normal subjects, metoprolol is unable to reverse the beta2-mediated vasodilating effects of epinephrine. This contrasts with the effect of nonselective beta-blockers, which completely reverse the vasodilating effects of epinephrine. (2) In asthmatic patients, metoprolol reduces FEV1 and FVC significantly less than a nonselective beta-blocker, propranolol, at equivalent beta1-receptor blocking doses.
The relationship between plasma metoprolol levels and reduction in exercise heart rate is independent of the pharmaceutical formulation. Using an Emax model, the maximum effect is a 30% reduction in exercise heart rate, which is attributed to beta1-blockade. Beta1-blocking effects in the range of 30-80% of the maximal effect (approximately 8-23% reduction in exercise heart rate) correspond to metoprolol plasma concentrations from 30-540 nmol/L. The relative beta1-selectivity of metoprolol diminishes and blockade or beta2-adrenoceptors increases at plasma concentration above 300 nmol/L.
Although beta-adrenergic receptor blockade is useful in the treatment of angina, hypertension, and heart failure there are situations in which sympathetic stimulation is vital. In patients with severely damaged hearts, adequate ventricular function may depend on sympathetic drive. In the presence of AV block, beta-blockade may prevent the necessary facilitating effect of sympathetic activity on conduction. Beta2-adrenergic blockade results in passive bronchial constriction by interfering with endogenous adrenergic bronchodilator activity in patients subject to bronchospasm and may also interfere with exogenous bronchodilators in such patients.
In other studies, treatment with metoprolol succinate extended-release tablets produced an improvement in left ventricular ejection fraction. Metoprolol succinate extended-release tablet was also shown to delay the increase in left ventricular end-systolic and end-diastolic volumes after 6 months of treatment.
[http:/ ]
Adults: In man, absorption of metoprolol is rapid and complete. Plasma levels following oral administration of conventional metoprolol tablets, however, approximate 50% of levels following intravenous administration, indicating about 50% first-pass metabolism. Metoprolol crosses the blood-brain barrier and has been reported in the CSF in a concentration 78% of the simultaneous plasma concentration.
Plasma levels achieved are highly variable after oral administration. Only a small fraction of the drug (about 12%) is bound to human serum albumin. Metoprolol is a racemic mixture of R- and S- enantiomers, and is primarily metabolized by CYP2D6. When administered orally, it exhibits stereoselective metabolism that is dependent on oxidation phenotype. Elimination is mainly by biotransformation in the liver, and the plasma half-life ranges from approximately 3 to 7 hours. Less than 5% of an oral dose of metoprolol is recovered unchanged in the urine; the rest is excreted by the kidneys as metabolites that appear to have no beta-blocking activity.
Following intravenous administration of metoprolol, the urinary recovery of unchanged drug is approximately 10%. The systemic availability and half-life of metoprolol in patients with renal failure do not differ to a clinically significant degree from those in normal subjects. Consequently, no reduction in metoprolol succinate dosage is usually needed in patients with chronic renal failure.
Metoprolol is metabolized predominantly by CYP2D6, an enzyme that is absent in about 8% of Caucasians (poor metabolizers) and about 2% of most other populations. CYP2D6 can be inhibited by a number of drugs. Poor metabolizers and extensive metabolizers who concomitantly use CYP2D6 inhibiting drugs will have increased (several-fold) metoprolol blood levels, decreasing metoprolol's cardioselectivity [see Drug Interactions (7.2)].
In comparison to conventional metoprolol, the plasma metoprolol levels following administration of metoprolol succinate extended-release tablets are characterized by lower peaks, longer time to peak and significantly lower peak to trough variation. The peak plasma levels following once-daily administration of metoprolol succinate extended-release tablet average one-fourth to one-half the peak plasma levels obtained following a corresponding dose of conventional metoprolol, administered once daily or in divided doses. At steady state the average bioavailability of metoprolol following administration of metoprolol succinate extended-release tablets, across the dosage range of 50 to 400 mg once daily, was 77% relative to the corresponding single or divided doses of conventional metoprolol. Nevertheless, over the 24-hour dosing interval, β1-blockade is comparable and dose-related [see Clinical Pharmacology (12)]. The bioavailability of metoprolol shows a dose-related, although not directly proportional, increase with dose and is not significantly affected by food following metoprolol succinate extended-release tablets administration.
Pediatrics: The pharmacokinetic profile of metoprolol succinate extended-release tablet was studied in 120 pediatric hypertensive patients (6-17 years of age) receiving doses ranging from 12.5 to 200 mg once daily. The pharmacokinetics of metoprolol were similar to those described previously in adults. Age, gender, race, and ideal body weight had no significant effects on metoprolol pharmacokinetics. Metoprolol apparent oral clearance (CL/F) increased linearly with body weight. Metoprolol pharmacokinetics have not been investigated in patients < 6 years of age.
# NONCLINICAL TOXICOLOGY
[http:/ ]
[http:/ ]
Long-term studies in animals have been conducted to evaluate the carcinogenic potential of metoprolol tartrate. In 2-year studies in rats at three oral dosage levels of up to 800 mg/kg/day (41 times, on a mg/m2 basis, the daily dose of 200 mg for a 60-kg patient), there was no increase in the development of spontaneously occurring benign or malignant neoplasms of any type. The only histologic changes that appeared to be drug related were an increased incidence of generally mild focal accumulation of foamy macrophages in pulmonary alveoli and a slight increase in biliary hyperplasia. In a 21-month study in Swiss albino mice at three oral dosage levels of up to 750 mg/kg/day (18 times, on a mg/m2 basis, the daily dose of 200 mg for a 60-kg patient), benign lung tumors (small adenomas) occurred more frequently in female mice receiving the highest dose than in untreated control animals. There was no increase in malignant or total (benign plus malignant) lung tumors, nor in the overall incidence of tumors or malignant tumors. This 21-month study was repeated in CD-1 mice, and no statistically or biologically significant differences were observed between treated and control mice of either sex for any type of tumor.
All genotoxicity tests performed on metoprolol tartrate (a dominant lethal study in mice, chromosome studies in somatic cells, aSalmonella/mammalian-microsome mutagenicity test, and a nucleus anomaly test in somatic interphase nuclei) and metoprolol succinate (aSalmonella/mammalian-microsome mutagenicity test) were negative.
No evidence of impaired fertility due to metoprolol tartrate was observed in a study performed in rats at doses up to 22 times, on a mg/m2basis, the daily dose of 200 mg in a 60-kg patient.
# CLINICAL STUDIES
[http:/ ]
In five controlled studies in normal healthy subjects, the same daily doses of metoprolol succinate extended-release tablets and immediate release metoprolol were compared in terms of the extent and duration of beta1-blockade produced. Both formulations were given in a dose range equivalent to 100-400 mg of immediate release metoprolol per day. In these studies, metoprolol succinate extended-release tablet was administered once a day and immediate release metoprolol was administered once to four times a day. A sixth controlled study compared the beta1-blocking effects of a 50 mg daily dose of the two formulations. In each study, beta1-blockade was expressed as the percent change from baseline in exercise heart rate following standardized submaximal exercise tolerance tests at steady state. Metoprolol succinate extended-release tablets administered once a day, and immediate release metoprolol administered once to four times a day, provided comparable total beta1-blockade over 24 hours (area under the beta1-blockade versus time curve) in the dose range 100-400 mg. At a dosage of 50 mg once daily, metoprolol succinate extended-release tablets produced significantly higher total beta1-blockade over 24 hours than immediate release metoprolol. For metoprolol succinate extended-release tablets, the percent reduction in exercise heart rate was relatively stable throughout the entire dosage interval and the level of beta1-blockade increased with increasing doses from 50 to 300 mg daily. The effects at peak/trough (ie, at 24-hours post-dosing) were: 14/9, 16/10, 24/14, 27/22 and 27/20% reduction in exercise heart rate for doses of 50, 100, 200, 300 and 400 mg metoprolol succinate extended-release tablets once a day, respectively. In contrast to metoprolol succinate extended-release tablets, immediate release metoprolol given at a dose of 50-100 mg once a day produced a significantly larger peak effect on exercise tachycardia, but the effect was not evident at 24 hours. To match the peak to trough ratio obtained with metoprolol succinate extended-release tablets over the dosing range of 200 to 400 mg, a t.i.d. to q.i.d. divided dosing regimen was required for immediate release metoprolol. A controlled cross-over study in heart failure patients compared the plasma concentrations and beta1-blocking effects of 50 mg immediate release metoprolol administered t.i.d., 100 mg and 200 mg metoprolol succinate extended-release tablets once daily. A 50 mg dose of immediate release metoprolol t.i.d. produced a peak plasma level of metoprolol similar to the peak level observed with 200 mg of metoprolol succinate extended-release tablets. A 200 mg dose of metoprolol succinate extended-release tablets produced a larger effect on suppression of exercise-induced and Holter-monitored heart rate over 24 hours compared to 50 mg t.i.d. of immediate release metoprolol.
In a double-blind study, 1092 patients with mild-to-moderate hypertension were randomized to once daily metoprolol succinate extended-release tablets (25, 100, or 400 mg), PLENDIL® (felodipine extended release tablets), the combination, or placebo. After 9 weeks, metoprolol succinate extended-release tablets alone decreased sitting blood pressure by 6-8/4-7 mmHg (placebo-corrected change from baseline) at 24 hours post-dose. The combination of metoprolol succinate extended-release tablets with PLENDIL has greater effects on blood pressure.
In controlled clinical studies, an immediate release dosage form of metoprolol was an effective antihypertensive agent when used alone or as concomitant therapy with thiazide-type diuretics at dosages of 100-450 mg daily. Metoprolol succinate extended-release tablets, in dosages of 100 to 400 mg once daily, produces similar β1-blockade as conventional metoprolol tablets administered two to four times daily. In addition, metoprolol succinate extended-release tablet administered at a dose of 50 mg once daily lowered blood pressure 24-hours post-dosing in placebo-controlled studies. In controlled, comparative, clinical studies, immediate release metoprolol appeared comparable as an antihypertensive agent to propranolol, methyldopa, and thiazide-type diuretics, and affected both supine and standing blood pressure. Because of variable plasma levels attained with a given dose and lack of a consistent relationship of antihypertensive activity to drug plasma concentration, selection of proper dosage requires individual titration.
[http:/ ]
By blocking catecholamine-induced increases in heart rate, in velocity and extent of myocardial contraction, and in blood pressure, metoprolol reduces the oxygen requirements of the heart at any given level of effort, thus making it useful in the long-term management of angina pectoris.
In controlled clinical trials, an immediate release formulation of metoprolol has been shown to be an effective antianginal agent, reducing the number of angina attacks and increasing exercise tolerance. The dosage used in these studies ranged from 100 to 400 mg daily. Metoprolol succinate extended-release tablets, in dosages of 100 to 400 mg once daily, has been shown to possess beta-blockade similar to conventional metoprolol tablets administered two to four times daily.
[http:/ ]
MERIT-HF was a double-blind, placebo-controlled study of metoprolol succinate extended-release tablets conducted in 14 countries including the US. It randomized 3991 patients (1990 to metoprolol succinate extended-release tablets) with ejection fraction ≤0.40 and NYHA Class II-IV heart failure attributable to ischemia, hypertension, or cardiomyopathy. The protocol excluded patients with contraindications to beta-blocker use, those expected to undergo heart surgery, and those within 28 days of myocardial infarction or unstable angina. The primary endpoints of the trial were (1) all-cause mortality plus all-cause hospitalization (time to first event) and (2) all-cause mortality. Patients were stabilized on optimal concomitant therapy for heart failure, including diuretics, ACE inhibitors, cardiac glycosides, and nitrates. At randomization, 41% of patients were NYHA Class II; 55% NYHA Class III; 65% of patients had heart failure attributed to ischemic heart disease; 44% had a history of hypertension; 25% had diabetes mellitus; 48% had a history of myocardial infarction. Among patients in the trial, 90% were on diuretics, 89% were on ACE inhibitors, 64% were on digitalis, 27% were on a lipid-lowering agent, 37% were on an oral anticoagulant, and the mean ejection fraction was 0.28. The mean duration of follow-up was one year. At the end of the study, the mean daily dose of metoprolol succinate extended-release tablets was 159 mg.
The trial was terminated early for a statistically significant reduction in all-cause mortality (34%, nominal p= 0.00009). The risk of all-cause mortality plus all-cause hospitalization was reduced by 19% (p= 0.00012). The trial also showed improvements in heart failure-related mortality and heart failure-related hospitalizations, and NYHA functional class.
The table below shows the principal results for the overall study population. The figure below illustrates principal results for a wide variety of subgroup comparisons, including US vs. non-US populations (the latter of which was not pre-specified). The combined endpoints of all-cause mortality plus all-cause hospitalization and of mortality plus heart failure hospitalization showed consistent effects in the overall study population and the subgroups, including women and the US population. However, in the US subgroup (n=1071) and women (n=898), overall mortality and cardiovascular mortality appeared less affected. Analyses of female and US patients were carried out because they each represented about 25% of the overall population. Nonetheless, subgroup analyses can be difficult to interpret and it is not known whether these represent true differences or chance effects.
# HOW SUPPLIED
[http:/ ]
Tablets containing metoprolol succinate equivalent to the indicated weight of metoprolol tartrate, USP, are white, biconvex, film-coated, and scored. name="ib13da1b2-ef46-44a7-887b-3227715a2213"
- The 25 mg tablet is scored on both sides.
Store at 20°-25°C (68°-77°F); [see USP Controlled Room Temperature].
# INFORMATION FOR PATIENTS
[http:/ ]
Advise patients to take metoprolol succinate extended-release tablets regularly and continuously, as directed, preferably with or immediately following meals. If a dose is missed, the patient should take only the next scheduled dose (without doubling it). Patients should not interrupt or discontinue metoprolol succinate extended-release tablets without consulting the physician.
Advise patients (1) to avoid operating automobiles and machinery or engaging in other tasks requiring alertness until the patient's response to therapy with metoprolol succinate extended-release tablets has been determined; (2) to contact the physician if any difficulty in breathing occurs; (3) to inform the physician or dentist before any type of surgery that he or she is taking metoprolol succinate extended-release tablets.
Heart failure patients should be advised to consult their physician if they experience signs or symptoms of worsening heart failure such as weight gain or increasing shortness of breath.
PLENDIL is trademark of the AstraZeneca group of companies.
Manufactured by:
Wockhardt Limited
Mumbai, India.
Distributed by:
Wockhardt USA LLC.
20 Waterview Blvd.
Parsippany, NJ 07054
USA.
Rev.190312
# PACKAGE LABEL.PRINCIPAL DISPLAY PANEL SECTION
DRUG: METOPROLOL SUCCINATE
GENERIC: METOPROLOL SUCCINATE
DOSAGE: TABLET, FILM COATED, EXTENDED RELEASE
ADMINSTRATION: ORAL
NDC: 52125-230-02
STRENGTH:25 mg
COLOR: white
SHAPE: OVAL
SCORE: Two even pieces
SIZE: 12 mm
IMPRINT: 30
QTY: 30 | https://www.wikidoc.org/index.php/Sandbox_1234 | |
fe26fb9e53c85badd44f63488b863005a8dceb47 | wikidoc | Sandbox Jose | Sandbox Jose
# Overview
Stroke is the rapidly developing loss of brain functions due to a disturbance in the blood vessels supplying blood to the brain. This can be due to ischemia (lack of blood supply) caused by thrombosis or embolism, or due to a hemorrhage.
Stroke is a medical emergency and can cause permanent neurological damage, complications and death if not promptly diagnosed and treated. It is the third leading cause of death and the leading cause of adult disability in the United States and Europe. It is predicted that stroke will soon become the leading cause of death worldwide. WHO defines stroke as, a neurological deficit of cerebrovascular cause that persists beyond 24 hours or is interrupted by death within 24 hours.
Risk factors for stroke include advanced age, hypertension (high blood pressure), previous stroke or transient ischaemic attack (TIA), diabetes mellitus, high cholesterol, cigarette smoking, atrial fibrillation, migraine with aura, and thrombophilia. In clinical practice, blood pressure is the most important modifiable risk factor of stroke; however many other risk factors, such as cigarette smoking cessation and treatment of atrial fibrillation with anticoagulant drugs, are important. Treatment of ischemic stroke is occasionally with thrombolysis, but usually with supportive care (physiotherapy and occupational therapy) and secondary prevention with antiplatelet drugs (aspirin and often dipyridamole), blood pressure control, statins and anticoagulation (in selected patients). Hemorrhagic stroke is a medical emergency, rapid diagnosis and management is crucial because early deterioration is common in the first few hours after ICH onset.
# Causes
The following table lists causes for stroke.
# Classification
## Transient ischemic attack
- A transient ischemic attack is caused by the temporary disturbance of blood supply to a restricted area of the brain, resulting in brief neurologic dysfunction that usually persists for less than 24 hours.
## Stroke
# Differential diagnosis
Stroke, must be differentiated from other diseases that may cause, altered mental status, motor and or somatosensory deficits. The table below, summarizes the differential diagnosis for stroke:
# Differential diagnosis
Stroke should be differentiated from other causes of muscle weakness and paralysis. The differentials include the following:
# Epidemiology and Demographics
## Stroke in USA
- Stroke is a leading cause of serious long-term disability
- In USA, the incidence and mortality rates of stroke has significantly decreased compared to previous years.
- From year 2003 to 2013, the mortality rates due to stroke declined by 18.5%.
- In 2013, stroke became the fifth leading cause of death.
- The case fatality rate of stroke is estimated to be 41.7 deaths per 100, 000 population
- The incidence of new (610, 000) or recurrent stroke (185, 000) is estimated to be 795000 people annually or 250 cases per 100, 000.
- It is estimated that one incidence of stroke happens every 4 sec with death occurs every 4 min.
- About 87% of all strokes are ischemic strokes
- Stroke costs the United States an estimated $34 billion each year
## Worldwide
- According to WHO, the incidence of stroke is estimated to be 15 million people annually, worldwide..
- Out of these, 5 million die and 5 million are left permanently disabled..
## Age
- Stroke can occur in all age groups. However, the incidence of stroke is less among individuals age less than 40 years of age and the risk increases with increasing age.
- According to WHO, stroke also occurs in about 8% of children with sickle cell disease..
- In 2009, 34% of people hospitalized for stroke were younger than 65 years
- The incidence of stroke in people aged 18 to 50 years is estimated to be approximately 10%.
- The rate of decline in mortality rates of stroke in different age groups is as follows:
- Older then 65 years: from 534.1 to 245.2 per 100,000
45-65 years of age: from 43.5 to 20.2 per 100,000
18 to 44 years of age: from from 3.7 to 2.0 per 100,000
- Older then 65 years: from 534.1 to 245.2 per 100,000
- 45-65 years of age: from 43.5 to 20.2 per 100,000
- 18 to 44 years of age: from from 3.7 to 2.0 per 100,000
## Gender
There is increased incidence of stroke in men as compared to women.
## Race
- The risk of incidence of first stroke is twice in African-American population as compared to Caucasians with increased mortality rates.
## Geographical distribution
- There is increased incidence and mortality rates of stroke in developing countries as compared to developed countries due to low socioeconomic status and heath facilities.
- In the USA, the highest death rates from stroke are in the southeastern United States.
# Diagnosis
Almost 10% of cerebrovascular events that present to the emergency department are not detected during evaluation. This is more common when "presenting neurologic complaints are mild, nonspecific, or transient".
- Diagnosis is based on history of symptoms development, physical examination and imaging findings.
- CT scan and magnetic resonance imaging (MRI) are both reasonable for initial evaluation.
- CT scan without contrast is the initial test performed to diagnose ischemic stroke and rule out hemorrhagic stroke.
- CT is very sensitive for identifying acute hemorrhage and is considered the gold standard.
- Gradient echo and T2 susceptibility-weighted MRI are as sensitive as CT for detection of acute hemorrhage and are more sensitive for identification of prior hemorrhage.
- MR diffusion weighted imaging is the most sensitive and specific test for diagnosing ischemic stroke and may help detect presence of infarction in few minutes of onset of symptoms. It may also help differentiate viable tissue from infarct area if combined with MR perfusion. For diagnosing ischemic stroke in the emergency setting, MRI scan has the sensitivity and specificity of 83% and 98% respectively.
- MRI scan is superior to CT scan for being more sensitive and specific in detection of lacunar and posterior fossa infarcts, differentiation between acute and chronic stroke and detection of microbleeds. Another additional advantage is absence of ionising radiation compared to CT scan. Some of the disadvantages of MRI scan may include lack of availability in acute setting, higher cost, inability to use it in patients with metallic implants. MRI with contrast cannot be used in patients with renal failure. | Sandbox Jose
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [3]; Associate Editor(s)-in-Chief: Seyedmahdi Pahlavani, M.D. [4]Aysha Anwar, M.B.B.S[5],Tarek Nafee, M.D. [6],Sara Mehrsefat, M.D. [7]
# Overview
Stroke is the rapidly developing loss of brain functions due to a disturbance in the blood vessels supplying blood to the brain. This can be due to ischemia (lack of blood supply) caused by thrombosis or embolism, or due to a hemorrhage.[1]
Stroke is a medical emergency and can cause permanent neurological damage, complications and death if not promptly diagnosed and treated. It is the third leading cause of death and the leading cause of adult disability in the United States and Europe. It is predicted that stroke will soon become the leading cause of death worldwide.[2] WHO defines stroke as, a neurological deficit of cerebrovascular cause that persists beyond 24 hours or is interrupted by death within 24 hours.
Risk factors for stroke include advanced age, hypertension (high blood pressure), previous stroke or transient ischaemic attack (TIA), diabetes mellitus, high cholesterol, cigarette smoking, atrial fibrillation, migraine[3] with aura, and thrombophilia. In clinical practice, blood pressure is the most important modifiable risk factor of stroke; however many other risk factors, such as cigarette smoking cessation and treatment of atrial fibrillation with anticoagulant drugs, are important. Treatment of ischemic stroke is occasionally with thrombolysis, but usually with supportive care (physiotherapy and occupational therapy) and secondary prevention with antiplatelet drugs (aspirin and often dipyridamole), blood pressure control, statins and anticoagulation (in selected patients).[4] Hemorrhagic stroke is a medical emergency, rapid diagnosis and management is crucial because early deterioration is common in the first few hours after ICH onset.[5]
# Causes
The following table lists causes for stroke.[6][7][8][9][10][11][12][13][14][15]
# Classification
## Transient ischemic attack
- A transient ischemic attack is caused by the temporary disturbance of blood supply to a restricted area of the brain, resulting in brief neurologic dysfunction that usually persists for less than 24 hours.
## Stroke
# Differential diagnosis
Stroke, must be differentiated from other diseases that may cause, altered mental status, motor and or somatosensory deficits. The table below, summarizes the differential diagnosis for stroke:
# Differential diagnosis
Stroke should be differentiated from other causes of muscle weakness and paralysis. The differentials include the following:[27][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42]
# Epidemiology and Demographics
## Stroke in USA
- Stroke is a leading cause of serious long-term disability
- In USA, the incidence and mortality rates of stroke has significantly decreased compared to previous years.
- From year 2003 to 2013, the mortality rates due to stroke declined by 18.5%.[43]
- In 2013, stroke became the fifth leading cause of death.
- The case fatality rate of stroke is estimated to be 41.7 deaths per 100, 000 population[43]
- The incidence of new (610, 000) or recurrent stroke (185, 000) is estimated to be 795000 people annually or 250 cases per 100, 000.[43]
- It is estimated that one incidence of stroke happens every 4 sec with death occurs every 4 min.[43]
- About 87% of all strokes are ischemic strokes[44]
- Stroke costs the United States an estimated $34 billion each year[44]
## Worldwide
- According to WHO, the incidence of stroke is estimated to be 15 million people annually, worldwide.[45].
- Out of these, 5 million die and 5 million are left permanently disabled.[45].
## Age
- Stroke can occur in all age groups. However, the incidence of stroke is less among individuals age less than 40 years of age and the risk increases with increasing age. [44]
- According to WHO, stroke also occurs in about 8% of children with sickle cell disease.[45].
- In 2009, 34% of people hospitalized for stroke were younger than 65 years[44]
- The incidence of stroke in people aged 18 to 50 years is estimated to be approximately 10%. [43]
- The rate of decline in mortality rates of stroke in different age groups is as follows:[43]
- Older then 65 years: from 534.1 to 245.2 per 100,000
45-65 years of age: from 43.5 to 20.2 per 100,000
18 to 44 years of age: from from 3.7 to 2.0 per 100,000
- Older then 65 years: from 534.1 to 245.2 per 100,000
- 45-65 years of age: from 43.5 to 20.2 per 100,000
- 18 to 44 years of age: from from 3.7 to 2.0 per 100,000
## Gender
There is increased incidence of stroke in men as compared to women.
## Race
- The risk of incidence of first stroke is twice in African-American population as compared to Caucasians with increased mortality rates.[44]
## Geographical distribution
- There is increased incidence and mortality rates of stroke in developing countries as compared to developed countries due to low socioeconomic status and heath facilities.
- In the USA, the highest death rates from stroke are in the southeastern United States.[44]
# Diagnosis
Almost 10% of cerebrovascular events that present to the emergency department are not detected during evaluation.[46] This is more common when "presenting neurologic complaints are mild, nonspecific, or transient".[46]
- Diagnosis is based on history of symptoms development, physical examination and imaging findings.
- CT scan and magnetic resonance imaging (MRI) are both reasonable for initial evaluation.
- CT scan without contrast is the initial test performed to diagnose ischemic stroke and rule out hemorrhagic stroke.
- CT is very sensitive for identifying acute hemorrhage and is considered the gold standard.
- Gradient echo and T2 susceptibility-weighted MRI are as sensitive as CT for detection of acute hemorrhage and are more sensitive for identification of prior hemorrhage.
- MR diffusion weighted imaging is the most sensitive and specific test for diagnosing ischemic stroke and may help detect presence of infarction in few minutes of onset of symptoms. It may also help differentiate viable tissue from infarct area if combined with MR perfusion. For diagnosing ischemic stroke in the emergency setting, MRI scan has the sensitivity and specificity of 83% and 98% respectively.[47]
- MRI scan is superior to CT scan for being more sensitive and specific in detection of lacunar and posterior fossa infarcts, differentiation between acute and chronic stroke and detection of microbleeds. Another additional advantage is absence of ionising radiation compared to CT scan. Some of the disadvantages of MRI scan may include lack of availability in acute setting, higher cost, inability to use it in patients with metallic implants. MRI with contrast cannot be used in patients with renal failure.[48][49] | https://www.wikidoc.org/index.php/Sandbox_Jose | |
c9a68a25adcfe6b70493c9b40c1473821649939b | wikidoc | Sandbox Tree | Sandbox Tree
The Sandbox tree (Hura crepitans; syn. Hura brasiliensis Wild.), also known as Possumwood and Jabillo, is an evergreen tree of the spurge family (Euphorbiaceae), native to tropical regions of North and South America in Amazon Rainforest. It is recognized by the many dark, pointed spines and smooth brown bark. These spines have caused it to be called Monkey no-climb.
Sandbox trees can grow to 100 ft, and the large ovate leaves grow to two feet wide. They are monoecious. The red flowers have no petals. Male flowers grow on long spikes; female flowers are solitary in axils. The fruit is a large capsule with explosive dehiscence. When ripe, pods catapult the seeds as far as 100 meters (328 ft). It has also been known as the Dynamite tree, so named for the explosive sound of the ripe fruit as it splits into segments.
This tree prefers wet soil, and partial shade or partial sun to full sun. It is often cultivated for shade.
Fishermen have been said to use the milky, caustic sap from this tree to poison fish. The wood is used for furniture under the name "hura".
Hura crepitans is an additive to some forms of the hallucinogenic drink Ayahuasca. | Sandbox Tree
The Sandbox tree (Hura crepitans; syn. Hura brasiliensis Wild.), also known as Possumwood and Jabillo, is an evergreen tree of the spurge family (Euphorbiaceae), native to tropical regions of North and South America in Amazon Rainforest. It is recognized by the many dark, pointed spines and smooth brown bark. These spines have caused it to be called Monkey no-climb.
Sandbox trees can grow to 100 ft, and the large ovate leaves grow to two feet wide. They are monoecious. The red flowers have no petals. Male flowers grow on long spikes; female flowers are solitary in axils. The fruit is a large capsule with explosive dehiscence. When ripe, pods catapult the seeds as far as 100 meters (328 ft).[1] It has also been known as the Dynamite tree, so named for the explosive sound of the ripe fruit as it splits into segments.
This tree prefers wet soil, and partial shade or partial sun to full sun. It is often cultivated for shade.
Fishermen have been said to use the milky, caustic sap from this tree to poison fish. The wood is used for furniture under the name "hura".
Hura crepitans is an additive to some forms of the hallucinogenic drink Ayahuasca.[2] | https://www.wikidoc.org/index.php/Sandbox_Tree | |
62a875f227d281fb0428a2dc8722a7bd139fb4c3 | wikidoc | Sandbox ammu | Sandbox ammu
- HIV/AIDS
- 1. Antiretroviral regimen options for treatment-naive patients
- 1.1. Integrase strand transfer inhibitor-based regimens
- Preferred regimen (1): Dolutegravir 50 mg PO qd AND Abacavir 600 mg-Lamivudine 300 mg PO qd in patients who are HLA-B*5701-negative
- Preferred regimen (2): Dolutegravir 50 mg PO qd AND Tenofovir 300 mg-Emtricitabine 200 mg PO qd
- Preferred regimen (3): Elvitegravir 150 mg-Cobicistat 150 mg-Tenofovir 300 mg-Emtricitabine 200 mg PO qd in patients with estimated CrCl ≥ 70 mL/min/1.73
- Preferred regimen (4): Raltegravir 400 mg PO bid AND Tenofovir 300 mg-Emtricitabine 200 mg PO qd
- Alternative regimen (1): Efavirenz 600 mg PO qd OR Tenofovir 300 mg-Emtricitabine 200 mg PO qd
- Alternative regimen (2): Rilpivirine 25 mg PO qd AND (Tenofovir 300 mg PO qd OR Emtricitabine 200 mg PO qd) for patients with CD4 count >200 cells/microL
- Alternative regimen (3): Raltegravir 400 mg PO bid AND (Abacavir 600 mg PO qd OR Lamivudine 300 mg PO qd) in patients who are HLA-B*5701-negative
- 1.2. Protease inhibitor-based regimen
- Preferred regimen: Darunavir 800 mg-Ritonavir 100 mg PO qd AND Tenofovir 300 mg-Emtricitabine 200 mg PO qd
- Alternative regimen (1): Atazanavir 300 mg-Cobicistat 150 mg PO qd AND Tenofovir disoproxil fumarate 300 mg-Emtricitabine 200 mg PO qd only for patients with pre-treatment estimated CrCl ≥70 mL/min
- Alternative regimen (2): Atazanavir 300 mg-Ritonavir 100 mg PO qd AND Tenofovir 300 mg-Emtricitabine 200 mg PO qd
- Alternative regimen (3): (Darunavir 800 mg-Cobicistat 150 mg PO qd OR Darunavir 800 mg-Ritonavir 100 mg PO qd) AND Abacavir 600 mg-Lamivudine 300 mg PO qd only for patients who are HLA-B*5701 negative
- Alternative regimen (4): Darunavir 800 mg-Cobicistat 150 mg PO qd AND Tenofovir disoproxil fumarate 300 mg-Emtricitabine 200 mg PO qd only for patients with pre-treatment estimated CrCl ≥70 mL/min
- Alternative regimen (5): Atazanavir 300 mg-Ritonavir 100 mg PO qd AND Abacavir 600 mg-Lamivudine 300 mg PO qd in patients who are HLA-B*5701-negative and with pre-treatment HIV RNA <100,000 copies/mL
- Alternative regimen (6): Lopinavir 400 mg-Ritonavir 100 mg PO qd or bid AND Abacavir 600 mg-Lamivudine 300 mg PO qd only for patients who are HLA-B*5701 negative
- Alternative regimen (7): Lopinavir 400 mg-Ritonavir 100 mg PO qd or bid AND Tenofovir disoproxil fumarate 300 mg-Emtricitabine 200 mg PO qd
- 1.3. A non-nucleoside reverse transcriptase inhibitor (NNRTI) based regimen
- Alternative regimen (1): Efavirenz 600 mg-Tenofovir 300 mg-Emtricitabine 200 mg PO qd
- Alternative regimen (2): Rilpivirine 25 mg-Tenofovir 300 mg-Emtricitabine 200 mg PO qd
- 1.4. Other regimen options
- 1.4.1. A non-nucleoside reverse transcriptase inhibitor (NNRTI) based regimen
- Preferred regimen (1): Efavirenz 600 mg PO qd AND Abacavir 600 mg-Lamivudine 300 mg PO qd only for patients who are HLA-B*5701 negative and with pre-treatment HIV RNA <100,000 copies/mL.
- 1.4.2. Other regimens when tenofovir or abacavir cannot be used
- Preferred regimen (1): Darunavir 800 mg-Ritonavir 100 mg PO qd AND Raltegravir 400 mg PO qd only for patients with pre-treatment HIV RNA 200 cells/mm3.
- Preferred regimen (2): Lopinavir 400 mg-Ritonavir 100 mg PO bid AND Lamivudine 300 mg PO bid
- 1.5. Pediatric doses
- Abacavir 300 mg PO bid
- Lamivudine 4 mg/kg/dose PO bid; maximum 150 mg PO bid
- Stavudine 1 mg/kg/dose PO bid
- Tenofovir 8 mg/kg/dose PO bid
- Zidovudine 180-240 mg/m2/dose PO bid or 160 mg/m2/dose PO tid (range 90 mg/m2/dose-180 mg/m2/dose)
- Lopinavir 400 mg PO bid
- Nelfinavir 50 mg/kg/dose PO bid
- Raltegravir 300 mg PO bid
- Didanosine
- 20 to < 25 kg: 200 mg PO qd
- 25 to < 60 kg: 250 mg PO qd
- ≥60 kg: 400 mg PO qd
- Efavirenz
- 10 to < 15 kg: 200 mg PO qd
- 15 to <20 kg: 250 mg PO qd
- 20 to < 25 kg: 300 mg PO qd
- 25 to < 32.5 kg: 350 mg PO qd
- 32.5 to <40 kg: 400 mg PO qd
- ≥ 40 kg: 600 mg PO qd
- Nevirapine maximum 200 mg per dose
- Between 1 day and 8 years: 200 mg/m2/dose PO qd for 14 days, then 200 mg/m2/dose PO bid
- 8 years and above: 120-150 mg/m2/dose PO qd for 14 days, then 120-150 mg/m2/dose PO bid
- Note (1): Anti retroviral therapy for treatment naive patients is a life long therapy.
- Note (2): Tenofovir disoproxil fumarate should be avoided in patients with a creatinine clearance <50 mL/min.
- Note (3): Rilpivirine should be used in patients with a CD4 cell count >200 copies/mL and should not be used with proton pump inhibitors.
- Note (4): Efavirenz should not be used in pregnant women.
- 2. Pre-exposure prophylaxis (PrEP)
- Preferred regimen: Tenofovir disoproxil fumarate 300 mg-Emtricitabine 200 mg PO qd for ≤90-days
- Note (1): People with high risk behavior such as men who have sex with men, intravenous drug abusers, HIV-positive sexual partner, recent bacterial STI, high number of sex partners, history of inconsistent or no condom use, commercial sex work, people in high-prevalence area or network are advised to take pre-exposure prophylaxis of drugs.
- Note (2): Follow-up visits at least every 3 months to provide the following: HIV test, medication adherence counseling, behavioral risk reduction support, side effect assessment, STI symptom assessment, pregnancy testing.
- Note (3): At 3 months and every 6 months thereafter, assess renal function.
- Note (4): Every 6 months, test for bacterial STIs.
- 3. Post- exposure prophylaxis
- Preferred regimen: Raltegravir 400 mg PO bid AND Tenofovir disoproxil fumarate 300 mg-Emtricitabine 200 mg PO qd
- Preferred basic regimen for low-risk exposures (Eg: mucus membrane):
Zidovudine 100 mg PO qd AND Lamivudine 300 mg PO qd
Zidovudine 100 mg PO qd AND Emtricitabine 200 mg PO qd
Tenofovir 300 mg PO qd AND Lamivudine 300 mg PO qd
Tenofovir 300 mg PO qd AND Emtricitabine 200 mg PO qd
- Zidovudine 100 mg PO qd AND Lamivudine 300 mg PO qd
- Zidovudine 100 mg PO qd AND Emtricitabine 200 mg PO qd
- Tenofovir 300 mg PO qd AND Lamivudine 300 mg PO qd
- Tenofovir 300 mg PO qd AND Emtricitabine 200 mg PO qd
- Preferred expanded regimen for high-risk exposure (Eg: percutaneous needle stick)
Zidovudine 100 mg PO qd AND Lamivudine 300 mg PO qd AND Lopinavir 400 mg-Ritonavir 100 mg PO qd
Zidovudine 100 mg PO qd AND Emtricitabine 200 mg PO qd AND Lopinavir 400 mg-Ritonavir 100 mg PO qd
Tenofovir 300 mg PO qd AND Lamivudine 300 mg PO qd AND Lopinavir 400 mg-Ritonavir 100 mg PO qd
Tenofovir 300 mg PO qd AND Emtricitabine 200 mg PO qdAND Lopinavir 400 mg-Ritonavir 100 mg PO qd
- Zidovudine 100 mg PO qd AND Lamivudine 300 mg PO qd AND Lopinavir 400 mg-Ritonavir 100 mg PO qd
- Zidovudine 100 mg PO qd AND Emtricitabine 200 mg PO qd AND Lopinavir 400 mg-Ritonavir 100 mg PO qd
- Tenofovir 300 mg PO qd AND Lamivudine 300 mg PO qd AND Lopinavir 400 mg-Ritonavir 100 mg PO qd
- Tenofovir 300 mg PO qd AND Emtricitabine 200 mg PO qdAND Lopinavir 400 mg-Ritonavir 100 mg PO qd
- Note: Ideally therapy should be started within hours of exposure and continued for 28 days.
- 4. Perinatal antiretroviral regimen
- 4.1. Antepartum
- 4.1.1. Protease inhibitor-based regimen
- Preferred regimen: (Tenofovir 300 mg-Emtricitabine 200 mg PO qd (fixed dose combination) OR Tenofovir 300 mg-Lamivudine 300 mg PO qd OR Abacavir 600 mg-Lamivudine 300 mg PO qd OR Zidovudine 100 mg-Lamivudine 300 mg PO qd) AND (Atazanavir 300 mg-Ritonavir 100 mg PO qd OR Lopinavir 400 mg-Ritonavir 100 mg PO qd)
- 4.1.2. A non-nucleoside reverse transcriptase inhibitor (NNRTI) based regimen:
- Preferred regimen (1): Efavirenz 600 mg-Tenofovir 300 mg-Emtricitabine 200 mg (fixed dose combination) PO qd
- Preferred regimen (2): Efavirenz 600 mg-Tenofovir 300 mg-Lamivudine 300 mg PO qd
- Alternative regimen: (Abacavir 600 mg-Lamivudine 300 mg PO qd OR Zidovudine 100 mg-Lamivudine 300 mg PO qd) AND Efavirenz 600 mg PO qd
- 4.2. Intrapartum
- Note (1): HIV RNA <1000 copies/mL and good adherance-Continue the regimen during delivery or cessarean section.
- Note (2): HIV RNA >1000 copies/mL near delivery, possible poor adherence, or unknown HIV RNA levels- Intravenous Zidovudine 2 mg/kg IV over 1 hr should be given three hours before cesarean section or delivery and then 1 mg/kg/hr IV continuous infusion until umbilical cord clamping.
- 4.3. Postpartum
- Note: Initiate anti retroviral therapy (ART) and continue after delivery and cessation of breastfeeding.
- 5. Infant antiretroviral prophylaxis for prevention of mother-to-child transmission of HIV
- 5.1 Prophylaxis for HIV-exposed infants of women who received antepartum antiretroviral prophylaxis
- Preferred regimen: Zidovudine (ZDV) 100 mg PO given at birth and continued till six weeks
- Note (1): Dose based on gestational age at birth and weight, initiated as soon after birth as possible and preferably within 6 to 12 hours of delivery.
- Note (2): ≥35 weeks gestation at birth: 4 mg/kg/dose orally (or, if unable to tolerate oral agents, 3 mg/kg/dose IV) every 12 hours.
- Note (3): ≥30 to <35 weeks gestation at birth: 2 mg/kg/dose orally (or 1.5 mg/kg/dose IV) every 12 hours, advanced to 3 mg/kg/dose orally (or 2.3 mg/kg/dose IV) every 12 hours at age 15 days.
- Note (4): <30 weeks gestation at birth: 2 mg/kg/dose orally (or 1.5 mg/kg/dose IV) every 12 hours, advanced to 3 mg/kg/dose orally (or 2.3 mg/kg/dose IV) every 12 hours after age four weeks.
- 5.2. Prophylaxis for HIV-exposed infants of women who received no antepartum antiretroviral prophylaxis
- Dose based on birth weight, initiated as soon after birth as possible.
- Birth weight 1.5 to 2 kg: 8 mg/dose orally.
- Birth weight >2 kg: 12 mg/dose orally.
- Dose based on gestational age at birth and weight, initiated as soon after birth as possible and preferably within 6 to 12 hours of delivery.
- ≥35 weeks gestation at birth: 4 mg/kg/dose orally (or, if unable to tolerate oral agents, 3 mg/kg/dose IV) every 12 hours.
- ≥30 to <35 weeks gestation at birth: 2 mg/kg/dose orally (or 1.5 mg/kg/dose IV) every 12 hours, advanced to 3 mg/kg/dose orally (or 2.3 mg/kg/dose IV) every 12 hours at age 15 days.
- <30 weeks gestation at birth: 2 mg/kg/dose orally (or 1.5 mg/kg/dose IV) every 12 hours, advanced to 3 mg/kg/dose orally (or 2.3 mg/kg/dose IV) every 12 hours after age four weeks.
- Note (1): Three doses in the first week of life.
- Note (2): First dose within 48 hours of birth (birth to 48 hrs).
- Note (3): Second dose 48 hours after first.
- Note (4): Third dose 96 hours after second.
- 6. Treatment and prevention of opportunistic infections
- 6.1. Pneumocystis pneumonia (PCP)
- 6.1.1. Prevention
- Indication
- CD4 count <200 cells/mm3
- Oropharyngeal candidiasis
- CD4 <14%
- History of AIDS-defining illness
- CD4 count >200 but <250 cells/mm3 if monitoring CD4 cell count every 3 months is not possible.
- Preferred regimen: Trimethoprim/sulfamethoxazole 160 mg/800 mg PO qd or 80 mg/400 mg PO qd
- Alternative regimen (1): Trimethoprim/sulfamethoxazole 160 mg/800 mg PO three times weekly
- Alternative regimen (2): Dapsone 100 mg PO qd or 50 mg PO bid
- Alternative regimen (3): Dapsone 50 mg PO qd AND (Pyrimethamine 50 mg-Leucovorin 25 mg) PO weekly
- Alternative regimen (4): Dapsone 200 mg PO qd AND (Pyrimethamine 75 mg-Leucovorin 25 mg) PO weekly
- Alternative regimen (5): Aerosolized Pentamidine 300 mg via Respigard nebulizer every month
- Alternative regimen (6): Atovaquone 1500 mg PO qd
- Alternative regimen (7): Atovaquone 1500 mg AND (Pyrimethamine 25 mg AND Leucovorin 10 mg) PO qd
- 6.1.2. Treatment
- 6.1.2.1. For Moderate-to-Severe PCP'
- Preferred regimen: Trimethoprim 15–20 mg AND Sulfamethoxazole 75–100 mg/kg/day IV given q6h or q8h, may switch to PO after clinical improvement
- Alternative regimen (1): Pentamidine 4 mg/kg IV daily infused over ≥60 minutes
- Note: Reduce dose to 3 mg/kg IV daily if toxic.
- Alternative regimen (2): Primaquine 30 mg (base) PO qd AND (Clindamycin 600 mg q6h IV OR 900 mg IV q8h OR Clindamycin 450 mg PO qid or 600 mg PO tid)
- 6.1.2.2. For Mild-to-Moderate PCP
- Preferred regimen: Trimethoprim 15–20 mg AND Sulfamethoxazole 75–100 mg/kg/day PO in TID OR Trimethoprim/sulfamethoxazole 160 mg/800 mg 2 tablets PO tid
- Alternative regimen (1): Dapsone 100 mg PO qd AND TMP 5 mg/kg PO tid
- Alternative regimen (2): Primaquine 30 mg (base) PO qd AND (Clindamycin 450 mg PO qid or 600 mg PO tid OR Atovaquone 750 mg PO bid with food)
- 6.1.3. Secondary prophylaxis, after completion of PCP treatment
- Preferred regimen (1): Trimethoprim/Sulfamethoxazole 160 mg/800 mg PO qd OR Trimethoprim/Sulfamethoxazole 80 mg/400 mg PO qd
- Alternative regimen (1): Trimethoprim/sulfamethoxazole 160 mg/800 mg PO three times weekly
- Alternative regimen (2): Dapsone 100 mg PO qd
- Alternative regimen (3): Dapsone 50 mg PO qd AND Pyrimethamine 50 mg PO AND Leucovorin 25 mg PO weekly
- Alternative regimen (4): Dapsone 200 mg PO AND Pyrimethamine 75 mg PO AND Leucovorin 25 mg PO weekly
- Alternative regimen (5): Dapsone 100 mg PO qd
- Alternative regimen (6): Dapsone 50 mg PO qd AND Pyrimethamine 50 mg PO AND Leucovorin 25 mg PO weekly
- Alternative regimen (7): Dapsone 200 mg PO AND Pyrimethamine 75 mg PO AND Leucovorin 25 mg PO weekly
- Alternative regimen (8): Aerosolized Pentamidine 300 mg monthly via Respirgard nebulizer
- Alternative regimen (9): Atovaquone 1500 mg PO qd
- Alternative regimen (10): Atovaquone 1500 mg PO AND Pyrimethamine 25 mg PO AND Leucovorin 10 mg PO qd
- 6.1.4. Adjunctive corticosteroids
- Indications- PaO2 35 mmHg.
- Preferred regimen:
- Days 1–5: 40 mg PO bid
- Days 6–10: 40 mg PO qd
- Days 11–21: 20 mg PO qd
- Note (1): Trimethoprim/sulfamethoxazole should be permanently discontinued in patients with possible or definite stevens johnson syndrome or toxic epidermal necrosis.
- Note (2): Whenever possible, patients should be tested for G6PD before use of Dapsone or Primaquine. Alternative regimen should be used in patients found to have G6PD deficiency.
- 6.2. Toxoplasma gondii encephalitis
- 6.2.1. Prevention
- 6.2.1.1. Indication
- Toxoplasma IgG-positive patients with CD4 count <100 cells/µL.
- Seronegative patients receiving PCP prophylaxis not active against toxoplasmosis should have toxoplasma serology retested if CD4 count decline to <100 cellsµL.
- Prophylaxis should be initiated if seroconversion occurred.
- Preferred regimen: Trimethoprim/sulfamethoxazole 160 mg/800 mg PO qd
- Alternative regimen (1): Trimethoprim/sulfamethoxazole 160 mg/800 mg PO three times weekly
- Alternative regimen (2): Trimethoprim/sulfamethoxazole 80 mg/400 mg PO qd
- Alternative regimen (3): Dapsone 50 mg PO qd AND Pyrimethamine 50 mg PO weekly AND Leucovorin 25 mg PO weekly
- Alternative regimen (4): Dapsone 200 mg PO weekly AND Pyrimethamine 75 mg PO weekly AND Leucovorin 25 mg PO weekly
- Alternative regimen (5): Atovaquone 1500 mg PO qd
- Alternative regimen (6): Atovaquone 1500 mg PO qd AND Pyrimethamine 25 mg PO qd AND Leucovorin 10 mg PO qd
- 6.2.2. Treatment
- 6.2.2.1. Treatment of acute infection
- Preferred regimen: Pyrimethamine 200 mg PO single dose, followed by weight-based therapy:
- If <60 kg, Pyrimethamine 50 mg PO qd AND Sulfadiazine 1000 mg PO qid AND Leucovorin 10–25 mg PO qd
- If ≥60 kg, Pyrimethamine 75 mg PO qd AND Sulfadiazine 1500 mg PO qid AND Leucovorin 10–25 mg PO qd
- Note: At least 6 weeks; longer duration if clinical or radiologic disease is extensive or response is incomplete at 6 weeks.
- Alternative regimen (1): Pyrimethamine 50 mg PO qdAND Leucovorin 10–25 mg PO qd AND Clindamycin 600 mg IV or PO q6h
- Alternative regimen (2): Trimethoprim 5 mg/kg-Sulfamethoxazole 25 mg/kg IV or PO bid
- Alternative regimen (3): Atovaquone 1500 mg PO bid with food AND Pyrimethamine 50 mg PO qd AND Leucovorin 10–25 mg PO qd
- Alternative regimen (4): Atovaquone 1500 mg PO bid with food AND Sulfadiazine 1000–1500 mg PO qid (weight-based dosing, as in preferred therapy)
- Alternative regimen (5): Atovaquone 1500 mg PO bid with food
- Alternative regimen (6): Pyrimethamine 50 mg-Leucovorin 10–25 mg PO qd AND Azithromycin 900–1200 mg PO qd
- 6.2.2.2. Chronic maintenance therapy
- Preferred regimen: Pyrimethamine 25–50 mg PO qd AND Sulfadiazine 2000–4000 mg PO qd (in 2–4 divided doses) AND Leucovorin 10–25 mg PO qd
- Alternative regimen (1): Clindamycin 600 mg PO tid AND Pyrimethamine 25–50 mg-Leucovorin 10–25 mg PO qd
- Alternative regimen (2): Trimethoprim/sulfamethoxazole 160 mg/800 mg bid
- Alternative regimen (3): Atovaquone 750–1500 mg PO bid AND Pyrimethamine 25 mg-Leucovorin 10 mg PO qd
- Alternative regimen (4): Atovaquone 750–1500 mg PO bid AND Sulfadiazine 2000–4000 mg PO qd in 2–4 divided doses
- Alternative regimen (5): Atovaquone 750–1500 mg PO bid with food
- 6.3. Mycobacterium tuberculosis infection
- 6.3.1. Prevention
- 6.3.1.1. Indication
- Positive screening test for latent tuberculosis infection, with no evidence of active tuberculosis, and no prior treatment for active tuberculosis or latent tuberculosis infection.
- Close contact with a person with infectious tuberculosis, with no evidence of active tuberculosis, regardless of screening test results.
- Preferred regimen: (Isoniazid 300 mg PO qd AND Pyridoxine 25 mg PO qd for 9 months) OR (Isoniazid 900 mg PO two times a week (by DOT) AND Pyridoxine 25 mg PO qd for 9 months)
- Alternative regimen (1): Rifampin 600 mg PO qd for 4 months
- Alternative regimen (2): Rifabutin (dose adjusted based on concomitant ART) PO qd for 4 months
- 6.3.2. Treatment
- Preferred regimen
- Initiation phase: Isoniazid 300 mg PO qd AND (Rifampin 600 mg PO qd OR Rifabutin 300 mg PO qd) AND Pyrazinamide (upto 2000 mg) PO qd AND Ethambutol (upto 1600 mg) PO qd for initial phase for 2 months.
- Continuation phase: Isoniazid 300 mg PO qd AND (Rifampin 600 mg PO qd OR Rifabutin 300 mg PO qd) (5–7 times/week) or three times a week.
- Duration of therapy:
- Pulmonary tuberculosis: 6 months
- Pulmonary tuberculosis and culture positive after 2 months of tuberculosis treatment: 9 months
- Extra-pulmonary tuberculosis w/CNS infection: 9–12 months
- Extra-pulmonary tuberculosis with bone or joint involvement: 6 to 9 months
- Extra-pulmonary tuberculosis in other sites: 6 months
- Total duration of therapy should be based on number of doses received, not on calendar time
- 6.3.1.3. Treatment for drug-resistant tuberculosis
- Resistant to Isoniazid:
- Preferred regimen (1): (Rifampin 600 mg PO qd OR Rifabutin 300mg PO qd) AND Ethambutol (upto 1600 mg) PO qd AND Pyrazinamide (upto 2000 mg) PO qd AND (Moxifloxacin 400 mg PO or IV qd OR Levofloxacin 500-1000 mg PO or IV qd) for 2 months; followed by Rifampin 600 mg PO qd for 7 months.
- Preferred regimen (2): Rifabutin 300mg PO qd AND Ethambutol (upto 1600 mg) PO qd AND (Moxifloxacin 400 mg PO or IV qdOR Levofloxacin 500-1000 mg PO or IV qd) for 7 months
- 6.4. Disseminated mycobacterium avium complex (MAC) disease
- 6.4.1. Prevention
- 6.4.1.1. Indication-CD4 count <50 cells/µL—after ruling out active disseminated MAC disease based on clinical assessment
- Preferred regimen (1): Azithromycin 1200 mg PO once weekly
- Preferred regimen (2): Clarithromycin 500 mg PO bid
- Preferred regimen (3): Azithromycin 600 mg PO twice weekly.
- 6.4.2. Treatment
- Preferred regimen: Clarithromycin 500 mg PO bid AND Ethambutol 15 mg/kg PO qd OR Azithromycin 500–600 mg PO qd for at least 12 months of therapy
- Note (1): Treatment can be discontinued if no signs and symptoms of MAC disease and sustained (>6 months) CD4 count >100 cells/µL in response to anti retroviral therapy.
- Note (2): Addition of a third or fourth drug should be considered for patients with advanced immunosuppression (CD4 counts 2 log CFU/mL of blood), or in the absence of effective anti retroviral therapy which include Amikacin 10–15 mg/kg IV qd, Streptomycin 1 g IV or IM qd, Moxifloxacin 400 mg PO qd, Levofloxacin 500 mg PO qd.
- 6.5. Streptococcus pneumoniae infection
- 6.5.1. Prevention
- 6.5.1.1. Indication
- 6.5.1.1.1. For individuals who have not received any pneumococcal vaccine, regardless of CD4 count
- Preferred regimen: PCV13 0.5ml IM single dose
- Alternative regimen: PPV23 0.5 mL IM or SQ single dose
- Note (1): If CD4 count ≥200 cells/µL, administer PPV23 0.5 mL IM or SQ at least 8 weeks after the PCV13 vaccine.
- Note (2): If CD4 count <200 cells/µL, PPV23 can be offered at least 8 weeks after receiving PCV13 or can wait until CD4 count increased to ≥200 cells/µL.
- 6.5.1.1.2. For individuals who have previously received PPV23
- Note: One dose of PCV13 should be given atleast 1 year after the last receipt of PPV23
- 6.5.1.1.3. Re-vaccination
- If age 19–64 years and ≥5 years since the first PPV23 dose PPV23 0.5 mL IM or SQ
- If age ≥65 years, and if ≥5 years since the previous PPV23 dose PPV23 0.5 mL IM or SQ
- If age ≥65 years, and if ≥5 years since the previous PPV23 dose PPV23 0.5 mL IM or SQ
- 6.6. Influenza A and B virus infection
- 6.6.1. Prevention
- 6.6.1.1. Indication
- All HIV-infected patients
- Note (1): Inactivated influenza vaccine annually (per recommendation for the season).
- Note (2): Live-attenuated influenza vaccine is contraindicated in HIV-infected patients.
- 6.7. Syphilis
- 6.7.1. Prevention
- 6.7.1.1. Indication
- For individuals exposed to a sex partner with a diagnosis of primary, secondary, or early latent syphilis within past 90 days.
- For individuals exposed to a sex partner >90 days before syphilis diagnosis in the partner, if serologic test results are not available immediately and the opportunity for follow-up is uncertain.
- Preferred regimen: Benzathine penicillin G 2.4 million units IM single dose
- Alternative regimen (1): Doxycycline 100 mg PO bid for 14 days
- Alternative regimen (2): Ceftriaxone 1 g IM or IV q24h for 8– 10 days
- Alternative regimen (3): Azithromycin 2 g PO single dose
- Note: Azithromycin is not recommended for MSM or pregnant women.
- 6.7.2. Treatment
- 6.7.2.1. Early stage (primary, secondary, and early-latent syphilis)
- Preferred regimen: Benzathine penicillin G 2.4 million units IM single dose
- Alternative regimen (1): Doxycycline 100 mg PO bid for 14 days
- Alternative regimen (2): Ceftriaxone 1 g IM or IV q24h for 10–14 days
- Alternative regimen (3): Azithromycin 2 g PO single dose
- 6.7.2.2. Late-stage (tertiary–cardiovascular or gummatous disease)
- Preferred regimen: Benzathine penicillin G 2.4 million units IM weekly for 3 doses
- Alternative regimen: Doxycycline 100 mg PO bid for 28 days
- 6.7.2.3. Neurosyphilis (including otic or ocular disease)
- Preferred regimen: Aqueous crystalline Penicillin G 18– 24 million units per day (administered as 3–4 million units IV q4h or by continuous IV infusion) for 10–14 days with or without Benzathine penicillin G 2.4 million units IM weekly for 3 doses after completion of IV therapy
- Alternative regimen: Procaine penicillin 2.4 million units IM q24h AND Probenecid 500 mg PO qid for 10–14 days with or without Benzathine penicillin G 2.4 million units IM weekly for 3 doses after completion
- Note (1): The Jarisch-Herxheimer reaction is an acute febrile reaction accompanied by headache and myalgia that can occur within the first 24 hours after therapy for syphilis.
- Note (2): This reaction occurs most frequently in patients with early syphilis, high nontreponemal titers and prior penicillin treatment.
- 6.8. Histoplasma capsulatum infection
- 6.8.1. Prevention
- 6.8.1.1. Indication
- CD4 count ≤150 cells/µL and at high risk because of occupational exposure or live in a community with a hyperendemic rate of histoplasmosis (>10 cases/100 patient-years).
- Preferred regimen: Itraconazole 200 mg PO qd
- 6.8.2. Treatment
- 6.8.2.1. Moderately severe to severe disseminated disease
- Induction therapy (for at least 2 weeks or until clinically improved)
- Preferred regimen: Liposomal Amphotericin B 3 mg/kg IV q24h
- Maintenance therapy:
- Preferred regimen: Itraconazole 200 mg PO tid for 3 days, then 200 mg PO bid
- 6.8.2.2. Less severe disseminated disease
- Induction therapy:
- Preferred regimen: Liposomal Amphotericin B 3 mg/kg IV q24h
- Alternative regimen: Amphotericin B lipid complex 3 mg/kg IV q24h OR Amphotericin B cholesteryl sulfate complete 3 mg/kg IV q24h
- Note: Induction therapy should be for at least 2 weeks or until clinically improved.
- Maintenance therapy:
- Preferred regimen: Itraconazole 200 mg PO tid for 3 days and then Itraconazole 200 mg PO bid for 12 months
- Alternative regimen (1): Voriconazole 400 mg PO bid for 1 day, then 200 mg bid
- Alternative regimen (2): Posaconazole 400 mg PO bid
- Alternative regimen (3): Fluconazole 800 mg PO qd
- 6.8.2.3. Meningitis
- Induction therapy:
- Preferred regimen: Liposomal amphotericin B 5 mg/kg/day for 4–6 weeks
- Maintenance therapy:
- Preferred regimen: Itraconazole 200 mg PO bid to tid for ≥1 year
- Note: Treatment continued until resolution of abnormal CSF findings.
- Long-Term Suppression Therapy
- Preferred regimen: Itraconazole 200 mg PO qd
- Alternative regimen: Fluconazole 400 mg PO qd
- Note: Therapeutic drug monitoring and dosage adjustment may be necessary to ensure Triazole antifungal and ARV efficacy and reduce concentration-related toxicities.
- 6.9. Coccidioidomycosis
- 6.9.1. Prevention
- 6.9.1.1. Indication
- A new positive IgM or IgG serologic test in patients who live in a disease-endemic area and with CD4 count <250 cells/µL.
- Preferred regimen: Fluconazole 400 mg PO qd
- 6.9.2. Treatment
- 6.9.2.1. Clinically mild infections (e.g., focal pneumonia)
- Preferred regimen: Fluconazole 400 mg PO qd OR Itraconazole 200 mg PO bid
- Alternative regimen: Posaconazole 200 mg PO bid OR Voriconazole 200 mg PO bid
- 6.9.2.2. Severe, non-meningeal infection (diffuse pulmonary infection or severely ill patients with extrathoracic, disseminated disease)
- Preferred regimen: Amphotericin B deoxycholate 0.7–1.0 mg/kg IV qd OR Lipid formulation Amphotericin B 4–6 mg/kg IV qd
- Alternative regimen: Fluconazole or Itraconazole, with Itraconazole preferred for bone disease 400 mg per day to Amphotericin B therapy and continue triazole once Amphotericin B is stopped.
- 6.9.2.3. Meningeal infections
- Preferred regimen: Fluconazole 400–800 mg IV or PO qd
- Alternative regimen: Itraconazole 200 mg PO tid for 3 days, then 200 mg PO bid OR Posaconazole 200 mg PO bid OR Voriconazole 200–400 mg PO bid
- 6.9.2.4. Chronic suppressive therapy
- Preferred regimen: Fluconazole 400 mg PO qd OR Itraconazole 200 mg PO bid
- Alternative regimen: Posaconazole 200 mg PO bid OR Voriconazole 200 mg PO bid
- Note (1): Therapy should be continued indefinitely in patients with diffuse pulmonary or disseminated diseases because relapse can occur in 25%–33% of HIV-negative patients. It can also occur in HIV-infected patients with CD4 counts >250 cells/µL.
- Note (2): Therapy should be lifelong in patients with meningeal infections because relapse occurs in 80% of HIV-infected patients after discontinuation of triazole therapy.
- 6.10. Herpes simplex virus (HSV) Disease
- 6.10.1. Orolabial lesions (For 5–10 Days)
- Preferred regimen (1): Valacyclovir 1 g PO bid
- Preferred regimen (2): Famciclovir 500 mg PO bid
- Preferred regimen (3): Acyclovir 400 mg PO tid
- 6.10.2. Initial or recurrent genital HSV (For 5–14 Days)
- Preferred regimen (1): Valacyclovir 1 g PO bid
- Preferred regimen (2): Famciclovir 500 mg PO bid
- Preferred regimen (3): Acyclovir 400 mg PO tid
- 6.10.3. Severe mucocutaneous HSV
- Preferred regimen: Initial therapy Acyclovir 5 mg/kg IV q8h.
- Note: After lesions begin to regress, change to PO therapy as above. Continue until lesions are completely healed.
- 6.10.4. Chronic suppressive therapy
- Preferred regimen (1): Valacyclovir 500 mg PO bid
- Preferred regimen (2): Famciclovir 500 mg PO bid
- Preferred regimen (3): Acyclovir 400 mg PO bid
- 6.10.4. For acyclovir-resistant HSV
- Preferred therapy: Foscarnet 80–120 mg/kg/day IV q12h-q8h
- Alternative regimen: Cidofovir IV OR Topical Trifluridine OR Topical Imiquimod for 21-28 days
- Note: Continue indefinitely regardless of CD4 cell count.
- 6.11. Varicella-zoster virus (VZV) infection
- 6.11.1. Varicella-zoster virus (VZV) infection
- 6.11.1.2 Prevention
- 6.11.1.1. Pre-exposure prevention
- Indication: Patients with CD4 counts ≥200 cells/µL who have not been vaccinated, have no history of varicella or herpes zoster, or who are seronegative for VZV.
- Preferred regimen: Primary varicella vaccination, 2 doses (0.5 mL SQ each) administered 3 months apart
- Alternative regimen: VZV-susceptible household contacts of susceptible HIV-infected persons should be vaccinated to prevent potential transmission of VZV to their HIV-infected contacts
- Note (1): Routine VZV serologic testing in HIV-infected adults and adolescents is not recommended.
- Note (2): If vaccination results in disease because of vaccine virus, treatment with Acyclovir is recommended.
- 6.11.1.2. Post-exposure prevention
- Indication: Close contact with a person with chickenpox or herpes zoster; and is susceptible (i.e., no history of vaccination or of either condition, or known to be VZV seronegative).
- Preferred regimen: Varicella-zoster immune globulin (VariZIG™) 125 international units per 10 kg (maximum 625 international units) IM, administered as soon as possible and within 10 days after exposure.
- Alternative regimen (1): Acyclovir 800 mg PO qd for 5– 7 days
- Alternative regimen (2): Valacyclovir 1 g PO tid for 5–7 days
- Note (1): Individuals receiving monthly high-dose IVIG (>400 mg/kg) are likely to be protected if the last dose of IVIG was administered <3 weeks before exposure.
- Note (2): If antiviral therapy is used, varicella vaccines should not be given until at least 72 hours after the last dose of the antiviral drug.
- 6.11.1.2. Treatment
- 6.11.1.2.1 Primary varicella infection (chickenpox)
- 6.11.1.2.1. Uncomplicated cases (For 5–7 Days)
- Preferred regimen (1): Valacyclovir 1 g PO tid
- Preferred regimen (2): Famciclovir 500 mg PO tid
- 6.11.1.2.1. Severe or complicated Cases
- Preferred regimen: Acyclovir 10–15 mg/kg IV q8h for 7–10 days.
- Alternative regimen: Acyclovir 800 mg PO 5 times/day for 5-7 days.
- 6.11.1.2.2. Herpes zoster (Shingles)
- 6.11.1.2.2.1. Acute localized dermatomal
- Preferred regimen (1): Valacyclovir 1 g PO tid for 7–10 days; consider longer duration if lesions are slow to resolve
- Preferred regimen (2): Famciclovir 500 mg tid for 7–10 days; consider longer duration if lesions are slow to resolve
- 6.11.1.2.2.2. Extensive cutaneous lesion or visceral involvement
- Preferred regimen: Acyclovir 10–15 mg/kg IV q8h until clinical improvement is evident.
- Note: Treatment may switch to PO therapy (Valacyclovir, Famciclovir, or Acyclovir) after clinical improvement (i.e., when no new vesicle formation or improvement of signs and symptoms of visceral VZV), to complete a 10–14 day course.
- Alternative regimen: Acyclovir 800 mg PO 5 times/day for 7–10 days; consider longer duration if lesions are slow to resolve.
- 6.11.1.2.2.3. Progressive outer retinal necrosis (PORN)
- Preferred regimen: (Ganciclovir 5 mg/kg with or without Foscarnet 90 mg/kg) IV q12h AND (Ganciclovir 2 mg/0.05mL with or without Foscarnet 1.2 mg/0.05 ml) intravitreal injection biweekly.
- 6.11.1.2.2.4. Acute retinal necrosis (ARN)
- Preferred regimen: Acyclovir 10-15 mg/kg IV q8h AND (Ganciclovir 2 mg/0.05mL intravitreal injection 1-2 doses biweekly for 10-14 days, followed by Valacyclovir 1g PO tid for 6 weeks
- 6.12. Cytomegalovirus (CMV) Disease
- 6.12.1. Treatment
- 6.12.1.1. CMV retinitis
- Induction therapy
- Preferred regimen (1): Ganciclovir 2mg OR Foscarnet 2.4mg intravitreal injections for 1-4 doses over a period of 7-10 days to achieve high intraocular concentration faster
- Preferred regimen (2): Valganciclovir 900 mg PO bid for 14–21 days
- Alternative regimen (1): Ganciclovir 5 mg/kg IV q12h for 14–21 days
- Alternative regimen (2): Foscarnet 90 mg/kg IV q12h or 60 mg/kg q8h for 14–21 days
- Alternative regimen (3): Cidofovir 5 mg/kg/week IV for 2 weeks
- Note: Saline hydration before and after therapy should be given and Probenecid, 2 g PO 3 hours before dose, followed by 1 g PO 2 hours and 8 hours after the dose (total of 4 g) is recommended.
- Chronic maintenance (secondary prophylaxis):
- Preferred regimen: Valganciclovir 900 mg PO qd
- Alternative regimen (1): Ganciclovir 5 mg/kg IV 5–7 times weekly
- Alternative regimen (2): Foscarnet 90–120 mg/kg IV once daily
- Alternative regimen (3): Cidofovir 5 mg/kg/week IV for 2 weeks; saline hydration before and after therapy AND Probenecid, 2 g PO 3 hours before dose, followed by 1 g PO 2 hours and 8 hours after the dose (total of 4 g)
- 6.12.1.2. CMV esophagitis or colitis
- 6.12.1.2.1. Severe condition
- Preferred regimen: Ganciclovir 5 mg/kg IV q12h; may switch to Valganciclovir 900 mg PO bid once the patient can tolerate oral therapy for 21-42 days or till the symptoms are resolved
- Alternative regimen: Foscarnet 90 mg/kg IV q12h or 60 mg/kg q8h for 21-42 days
- Note: For patients with treatment-limiting toxicities to Ganciclovir or with Ganciclovir resistance, above regimen is recommended.
- 6.12.1.2.2. Mild disease and able to tolerate oral therapy
- Preferred regimen: Valganciclovir 900 mg PO bid 21-42 days
- 6.12.1.3. CMV neurological disease
- Preferred regimen: Ganciclovir 5 mg/kg IV q12h AND (Foscarnet 90 mg/kg IV q12h or 60 mg/kg IV q8h) to stabilize disease
- 6.13. HHV-8 Diseases (kaposi sarcoma , primary effusion lymphoma , multicentric castleman’s disease )
- 6.13.1. Treatment
- Mild to moderate KS (ACTG Stage T0)
- Note: Initiate or optimize anti retroviral therapy.
- Advanced KS
- Note: Chemotherapy (per oncology consult) AND anti retroviral therapy.
- Primary effusion lymphoma
- Preferred regimen (1): Valganciclovir 900 mg PO bid for 3 weeks
- Preferred regimen (2): Ganciclovir 5 mg/kg IV q12h for 3 weeks
- Preferred regimen (3): Valganciclovir 900 mg PO bid AND Zidovudine 600 mg PO qid for 7– 21 days
- Alternative regimen: Rituximab (375 mg/m2 given weekly for 4–8 weeks) may be an alternative to or used adjunctively with antiviral therapy
- Note: Valganciclovir PO OR Ganciclovir IV can be used as adjunctive therapy
- 6.14. Human papillomavirus (HPV) infection
- 6.14.1. Prevention
- For females aged 13–26 years
- Preferred regimen (1): HPV quadrivalent vaccine 0.5 mL IM at months 0, 1–2, and 6 OR HPV bivalent vaccine 0.5 mL IM at months 0, 1–2, and 6
- Males aged 13–26 years
- Preferred regimen (1): HPV quadrivalent vaccine 0.5 mL IM at months 0, 1–2, and 6
- 6.14.2. Treatment
- 6.14.2.1. Patient-applied therapy for uncomplicated external warts that can be easily identified by patients
- Preferred regimen (1): Podophyllotoxin (e.g., podofilox 0.5% solution or 0.5% gel)
- Note: Apply to all lesions bid for 3 consecutive days, followed by 4 days of no therapy, repeat weekly for up to 4 cycles, until lesions are no longer visible)
- Preferred regimen (2): Imiquimod 5% cream
- Note: Apply to lesion at bedtime and remove in the morning on 3 nonconsecutive nights weekly for up to 16 weeks, until lesions are no longer visible. Each treatment should be washed with soap and water 6–10 hours after application.
- Preferred regimen (3): Sinecatechins 15% ointment
- Note: Apply to affected areas tid for up to 16 weeks, until warts are completely cleared and not visible
- 6.14.2.2. Provider-applied therapy for complex or multicentric lesions, or lesions inaccessible to patient
- Note (1): Cryotherapy (liquid nitrogen or cryoprobe): Apply until each lesion is thoroughly frozen. Repeat every 1–2 weeks for up to 4 weeks, until lesions are no longer visible. Some providers allow the lesion to thaw, then freeze a second time in each session.
- Note (2): Trichloroacetic acid or bichloroacetic acid cauterization: 80%–90% aqueous solution, apply to wart only, allow to dry until a white frost develops. Repeat weekly for up to 6 weeks, until lesions are no longer visible.
- Note (3): Surgical excision or laser surgery to external or anal warts.
- Note (4): Podophyllin resin 10%–25% in tincture of benzoin: Apply to all lesions (up to 10 cm2 ), then wash off a few hours later, repeat weekly for up to 6 weeks until lesions are no longer visible.
- 6.15. Hepatitis A virus (HAV) infection
- 6.15.1. Prevention
- Indication: HAV-susceptible patients with chronic liver disease, or who are injection-drug users or homosexuals
- Preferred regimen: Hepatitis A vaccine 1 mL IM 2 doses at 0 and 6–12 months.
- Alternative regimen: Combined HAV and HBV vaccine 1 mL IM as a 3-dose (0, 1, and 6 months) or 4-dose series (days 0, 7, 21 to 30, and 12 months).
- Note (1): For patients susceptible to both HAV and hepatitis B virus (HBV) infection, alternative regimen is recommended.
- Note (2): IgG antibody response should be assessed 1 month after vaccination; nonresponders should be revaccinated when CD4 count >200 cells/µL.
- 6.16. Hepatitis B virus (HBV) infection
- 6.16.1. Prevention
- 6.16.1.1. Indication
- Patients without chronic HBV or without immunity to HBV (i.e., anti-HBs <10 international units/mL).
- Patients with isolated anti-HBc and negative HBV DNA.
- Early vaccination is recommended before CD4 count falls below 350 cells/µL.
- However, in patients with low CD4 cell counts, vaccination should not be deferred until CD4 count reaches >350 cells/µL, because some patients with CD4 counts <200 cells/µL do respond to vaccination.
- Preferred regimen (1): HBV vaccine IM (Engerix-B 20 µg/mL or Recombivax HB 10 µg/mL), 0, 1, and 6 months
- Preferred regimen (2): HBV vaccine IM (Engerix-B 40 µg/mL or Recombivax HB 20 µg/mL) 0, 1, 2 and 6 months
- Preferred regimen (3): Combined HAV and HBV vaccine, 1 mL IM as a 3-dose (0, 1, and 6 months) or 4-dose series (days 0, 7, 21 to 30, and 12 months)
- Alternative regimen: Some experts recommend vaccinating with 40-µg doses of either HBV vaccine
- Note: Anti-HBs should be obtained 1 month after completion of the vaccine series. Patients with anti-HBs <10 international units/mL at 1 month are considered nonresponders.
- Vaccine Non-Responders:
- Preferred regimen (1): HBV vaccine IM (Engerix-B 40 µg/mL or Recombivax HB 20 µg/mL), 0, 1, 2 and 6 months.
- Note (1): Vaccination non-responders have anti-HBs <10 international units/mL 1 month after vaccination series.
- Note (2): For patients with low CD4 counts at time of first vaccine series, some experts might delay revaccination until after a sustained increase in CD4 count with anti retroviral therapy.
- 6.16.2. Treatment
- Preferred regimen: Tenofovir 300 mg PO qdAND Emtricitabine 200 mg PO qd OR Lamivudine 300 mg PO qd AND additional drug(s) for HIV
- Note: Anti retroviral therapy regimen should include 2 drugs that are active against both HBV and HIV.
- Alternative regimen: Peginterferon alfa-2a 180 μg SQ once weekly for 48 weeks OR Peginterferon alfa 2b 1.5 μg/kg SQ once weekly for 48 weeks.
- Note: For HBV treatment is indicated for patients with elevated ALT and HBV DNA >2,000 IU/mL significant liver fibrosis, advanced liver disease or cirrhosis, above regimen is indicated.
- 6.17. Penicilliosis marneffei
- 6.17.1. Prevention
- 6.17.1.1. Indication
- Patients with CD4 cell counts <100 cells/µL who live or stay for a long period in rural areas in northern Thailand, Vietnam, or Southern China.
- Preferred regimen: Itraconazole 200 mg PO qd
- Alternative regimen: Fluconazole 400 mg PO once weekly
- 6.17.2. Treatment
- 6.17.2.1. For acute infection in severely ill patients
- Preferred regimen: Liposomal amphotericin B 3–5 mg/kg/day IV for 2 weeks, followed by Itraconazole 200 mg PO bid for 10 weeks, followed by chronic maintenance therapy
- Alternative regimen: Voriconazole 6 mg/kg IV q12h for 1 day, then 4 mg/kg IV q12h for at least 3 days, followed by 200 mg PO bid for a maximum of 12 weeks, followed by maintenance therapy
- 6.17.2.2. For mild disease
- Preferred regimen: Itraconazole 200 mg PO bid for 8 weeks; followed by chronic maintenance therapy
- Alternative regimen: Voriconazole 400 mg PO bid for 1 day, then 200 mg bid for a maximum of 12 weeks, followed by chronic maintenance therapy
- 6.17.2.3. Chronic Maintenance Therapy (Secondary Prophylaxis)
- Preferred regimen: Itraconazole 200 mg PO qd
- Note (1): Anti retroviral therapy should be initiated simultaneously with treatment for penicilliosis to improve treatment outcome.
- Note (2): Itraconazole and Voriconazole may have significant interactions with certain ARV agents. These interactions are complex and can be bi-directional.
- Note (3): Therapeutic drug monitoring and dosage adjustment may be necessary to ensure triazole antifungal and ARV efficacy and reduce concentration-related toxicities.
- 6.18. Isosporiasis
- 6.18.1. Treatment
- For Acute Infection:
- Preferred regimen (1): Trimethoprim/Sulfamethoxazole 160 mg/800 mg PO (or IV) qid for 10 days
- Preferred regimen (2): Trimethoprim/Sulfamethoxazole 160 mg/800 mg PO (or IV) bid for 7–10 days
- Alternative regimen (1): Pyrimethamine 50–75 mg PO daily AND Leucovorin 10–25 mg PO qd
- Alternative regimen (2): Ciprofloxacin 500 mg PO bid for 7 days as a second line alternative
- Chronic Maintenance Therapy (Secondary Prophylaxis):
- Preferred regimen (1): In patients with CD4 count <200/µL, Trimethoprim/sulfamethoxazole 160 mg/800 mg PO three times a week
- Alternative regimen (1): Trimethoprim/sulfamethoxazole 160 mg/800 mg PO qd or (320 mg/1600 mg) three times a week
- Alternative regimen (2): Pyrimethamine 25 mg PO qd AND Leucovorin 5–10 mg PO qd
- Alternative regimen (3): Ciprofloxacin 500 mg three times a week as a second-line alternative
- Note (1): Fluid and electrolyte management in patients with dehydration.
- Note (2): Immune reconstitution with anti retroviral therapy may result in fewer relapses.
- Note (3): IV therapy may be used for patients with potential or documented mal-absorption.
- 6.19. Chagas disease (American trypanosomiasis)
- 6.19.1. Treatment
- For acute, earlychronic, and reactivated Disease:
- Preferred regimen: Benznidazole 5–8 mg/kg/day PO in 2 divided doses for 30–60 days
- Alternative regimen: Nifurtimox 8–10 mg/kg/day PO for 90–120 days.
- 6.20. Leishmaniasis, visceral
- 6.20.1. Leishmaniasis, visceral
- 6.20.1.1. Treatment
- For initial infection:
- Preferred regimen (1): Liposomal amphotericin B 2–4 mg/kg IV qd
- Preferred regimen (2): Liposomal amphotericin B interrupted schedule (e.g., 4 mg/kg on days 1–5, 10, 17, 24, 31, 38)
- Alternative regimen (1): Amphotericin B deoxycholate 0.5–1.0 mg/kg IV q24h for total dose of 1.5–2.0 g
- Alternative regimen (2): Sodium stibogluconate (pentavalent antimony) 20 mg/kg IV or IM q24h for 28 days
- Alternative regimen (3): Miltefosine 100 mg PO qd for 4 weeks
- Chronic maintenance therapy (secondary prophylaxis); Especially in Patients with CD4 Count <200 cells/µL:
- Preferred regimen (1): Liposomal amphotericin B 4 mg/kg every 2–4 weeks
- Preferred regimen (2): Amphotericin B lipid complex 3 mg/kg every 21 days
- Alternative regimen: Sodium stibogluconate 20 mg/kg IV or IM every 4 weeks
- 6.20.2. Leishmaniasis, cutaneous
- Preferred regimen (1): Liposomal amphotericin B 2–4 mg/kg IV daily for 10 days
- Preferred regimen (2): Liposomal amphotericin B interrupted schedule (e.g., 4 mg/kg on days 1–5, 10, 17, 24, 31, 38) to achieve total dose of 20–60 mg/kg
- Preferred regimen (3): Sodium stibogluconate 20 mg/kg IV or IM daily for 3–4 weeks
- 6.21. Aspergillosis, invasive
- 6.21.1. Treatment
- Preferred regimen: Voriconazole 6 mg/kg IV q12h for 1 day, then 4 mg/kg IV q12h, followed by Voriconazole 200 mg PO q12h after clinical improvement until CD4 cell count >200 cells/µL and the infection appears to be resolved.
- Alternative regimen (1): Lipid formulation of Amphotericin B 5 mg/kg IV q24h
- Alternative regimen (2): Amphotericin B deoxycholate 1mg/kg IV q24h
- Alternative regimen (3): Caspofungin 70 mg IV single dose, then 50 mg IV q24h
- Alternative regimen (4): Micafungin 100–150 mg IV q24h
- Alternative regimen (5): Anidulafungin 200 mg IV single dose, then 100 mg IV q24h
- Alternative regimen (6): Posaconazole 200 mg PO qid, then, after condition improved, 400 mg PO bid
- 6.22. Malaria
- 6.22.1. Prevetion
- 6.22.1.1. Prophylaxis in all areas
- Preferred regimen (1): Atovaquone 250 mg and Proguanil hydrochloride 100 mg PO qd
- Pediatric doses: Pediatric tablets contain 62.5 mg atovaquone and 25 mg proguanil hydrochloride
- 5–8 kg: 1/2 pediatric tablet daily
- >8–10 kg: 3/4 pediatric tablet daily
- >10–20 kg: 1 pediatric tablet daily
- >20–30 kg: 2 pediatric tablets daily
- >30–40 kg: 3 pediatric tablets daily
- Note (1): Begin 1–2 days before travel to malarious areas. Take daily at the same time each day while in the malarious area and for 7 days after leaving such areas. Contraindicated in people with severe renal impairment (creatinine clearance <30 mL/min).
- Note (2): Atovaquone-proguanil should be taken with food or a milky drink. Not recommended for prophylaxis for children weighing <5 kg, pregnant women, and women breastfeeding infants weighing <5 kg. Partial tablet doses may need to be prepared by a pharmacist and dispensed in individual capsules.
- Preferred regimen (2): Doxycycline 100 mg PO qd
- Pediatric dose: ≥8 years of age: 2.2 mg/kg up to adult dose of 100 mg/day
- Note: Begin 1–2 days before travel to malarious areas. Take daily at the same time each day while in the malarious area and for 4 weeks after leaving such areas. Contraindicated in children <8 years of age and pregnant women.
- 6.22.1.2. Prophylaxis only in areas with chloroquine-sensitive malaria
- Preferred regimen: Chloroquine phosphate 300 mg base (500 mg salt) PO once a week
- Note: Begin 1–2 weeks before travel to malarious areas. Take weekly on the same day of the week while in the malarious area and for 4 weeks after leaving such areas. May exacerbate psoriasis.
- Alternative regimen: Hydroxychloroquine sulfate 400 mg salt PO once a week
- Note: Begin 1–2 weeks before travel to malarious areas. Take weekly on the same day of the week while in the malarious area and for 4 weeks after leaving such areas.
- Pediatric doses: Chloroquine phosphate 5 mg/kg base (8.3 mg/kg salt) orally, once/week, up to maximum adult dose of 300 mg base; Hydroxychloroquine sulfate 5 mg/kg base (6.5 mg/kg salt) orally, once/week, up to a maximum adult dose of 310 mg base
- 6.22.1.3. Prophylaxis in areas with mefloquine-sensitive malaria
- Preferred regimen: Mefloquine 250 mg PO once a week
- Note (1): Begin ≥2 weeks before travel to malarious areas. Take weekly on the same day of the week while in the malarious area and for 4 weeks after leaving such areas. Contraindicated in people allergic to mefloquine or related compounds (quinine, quinidine) and in people with active depression, a recent history of depression, generalized anxiety disorder, psychosis, schizophrenia, other major psychiatric disorders, or seizures.
- Note (2): Use with caution in persons with psychiatric disturbances or a previous history of depression. Not recommended for persons with cardiac conduction abnormalities.
- Pediatric dose: Mefloquine ≤9 kg: 4.6 mg/kg base (5 mg/kg salt) orally, once/week
- >9–19 kg: 1/4 tablet once/week
- >19–30 kg: 1/2 tablet once/week
- >30–45 kg: 3/4 tablet once/week
- >30–45 kg: 3/4 tablet once/week
- 6.22.1.4. Prophylaxis for short-duration travel to areas with principally Plasmodium vivax
- Preferred regimen: Primaquine 52.6 mg PO qd
- Note: Begin 1–2 days before travel to malarious areas. Take daily at the same time each day while in the malarious area and for 7 days after leaving such areas. Contraindicated in people with G6PD deficiency. Also contraindicated during pregnancy and lactation, unless the infant being breastfed has a documented normal G6PD level.
- Pediatric dose: Primaquine 0.5 mg/kg base (0.8 mg/kg salt) up to adult dose orally, daily
- 6.22.1.5. Terminal prophylaxis to decrease the risk for relapses of Plasmodium vivax and Plasmodium ovale
- Preferred regimen: Primaquine 52.6 mg PO qd for 14 days after departure from the malarious area
- Note: Indicated for people who have had prolonged exposure to P. vivax, P. ovale, or both. Contraindicated in people with G6PD deficiency. Also contraindicated during pregnancy and lactation, unless the infant being breastfed has a documented normal G6PD level.
- Pediatric dose: Primaquine 0.5 mg/kg base (0.8 mg/kg salt) up to adult dose orally, daily for 14 days after departure from the malarious area
- 6.22.2. Treatment
- Note (1): Patients coinfected with HIV should avoid Artesunate AND Sulfadoxine-Pyrimethamine if they are also receiving Co-trimoxazole, and avoid Artesunate AND Amodiaquine if they are also receiving Efavirenz OR Zidovudine.
- Note (2): Because Plasmodium falciparum malaria can progress within hours from mild symptoms or low-grade fever to severe disease or death, all HIV-infected patients with confirmed or suspected P. falciparum infection should be hospitalized for evaluation, initiation of treatment, and observation.
- 6.22.2.1. Plasmodium falciparum
- 6.22.2.1.1. Treatment of uncomplicated Plasmodium falciparum malaria
- 6.22.2.1.1.1. Treat children and adults with uncomplicated Plasmodium falciparum malaria (except pregnant women in their first trimester) with one of the following recommended ACT (artemisinin-based combination therapy)
- Preferred regimen (1): Artemether 5–24 mg/kg/day PO bid AND Lumefantrine 29–144 mg/kg/day PO bid for 3 days
- Note: The first two doses should, ideally, be given 8 hours apart.
- Dosage regimen based on Body weight (kg)
- Body weight (kg)-5 to < 15- Artemether 20 mg PO bid AND Lumefantrine 120 mg PO bid for 3 days
- Body weight (kg)-15 to < 25- Artemether 40 mg PO bid AND Lumefantrine 240 mg PO bid for 3 days
- Body weight (kg)-25 to < 35- Artemether 60 mg PO bid AND Lumefantrine 360 mg PO bid for 3 days
- Body weight (kg) ≥ 35- Artemether 80 mg PO bid AND Lumefantrine 480 mg PO bid for 3 days
- Preferred regimen (2): Artesunate 2–10 mg/kg/day PO qd AND Amodiaquine 7.5–15 mg/kg/day PO qd for 3 days
- Note: A total therapeutic dose range of 6–30 mg/kg/day Artesunate and 22.5–45 mg/kg/day per dose Amodiaquine is recommended.
- Dosage regimen based on body weight (kg)
- Body weight (kg)-4.5 to < 9- Artesunate 25 mg PO qd AND Amodiaquine 67.5 mg PO qd for 3 days
- Body weight (kg)-9 to < 18 - Artesunate 50 mg PO qd AND Amodiaquine 135 mg PO qd for 3 days
- Body weight (kg)-18 to < 36- Artesunate 100 mg PO qd AND Amodiaquine 270 mg PO qd for 3 days
- Body weight (kg) ≥ 36 - Artesunate 200 mg PO qd AND Amodiaquine 540 mg PO qd for 3 days
- Preferred regimen (3): Artesunate 2–10 mg/kg/day PO qd AND Mefloquine 2–10 mg/kg/day PO qd for 3 days
- Dosage regimen based on body weight (kg)
- Body weight (kg)-5 to < 9- Artesunate 25 mg PO qd AND Mefloquine 55 mg PO qd for 3 days
- Body weight (kg)-9to < 18- Artesunate 50 mg PO qd AND Mefloquine 110 mg PO qd for 3 days
- Body weight (kg)-18 to < 36- Artesunate 100 mg PO qd AND Mefloquine 220 mg PO qd for 3 days
- Body weight (kg)- ≥ 36 - Artesunate 200 mg PO qd AND Mefloquine 440 mg PO qd for 3 days
- Preferred regimen (4): Artesunate 2–10 mg/kg/day PO qd for 3 days AND Sulfadoxine-Pyrimethamine 1.25 (25–70 / 1.25–3.5) mg/kg/day PO given as a single dose on day 1
- Dosage regimen based on body weight (kg)
- Body weight (kg)- 5 to < 10- Artesunate 25 mg PO qd for 3 days AND Sulfadoxine-Pyrimethamine 250/12 mg PO given as a single dose on day 1
- Body weight (kg)- 10 to < 25- Artesunate 50 mg PO qd for 3 days AND Sulfadoxine-Pyrimethamine 500/25 mg PO given as a single dose on day 1
- Body weight (kg)- 25 to < 50- Artesunate 100 mg PO qd for 3 days AND Sulfadoxine-Pyrimethamine 1000/50 mg PO given as a single dose on day 1
- Body weight (kg)- ≥50- Artesunate 200 mg PO qd for 3 days AND Sulfadoxine-Pyrimethamine 1500/75 mg PO given as a single dose on day 1
- Preferred regimen (5): Dihydroartemisinin 2–10 mg/kg/day PO qd AND Piperaquine16–27 mg/kg/day PO qd for 3 days
- Dosage regimen based on Body weight (kg)
- Body weight (kg)-5 to < 8: Dihydroartemisinin 20 mg PO qd AND Piperaquine 160 mg PO qd for 3 days
- Body weight (kg)-8 to < 11: Dihydroartemisinin 30 mg PO qd AND Piperaquine 240 mg PO qd for 3 days
- Body weight (kg)-11 to < 17: Dihydroartemisinin 40 mg PO qd AND Piperaquine 320 mg PO qd for 3 days
- Body weight (kg)-17 to < 25: Dihydroartemisinin 60 mg PO qd AND Piperaquine 480 mg PO qd for 3 days
- Body weight (kg)-25 to < 36: Dihydroartemisinin 80 mg PO qd AND Piperaquine 640 mg PO qd for 3 days
- Body weight (kg)-36 to < 60: Dihydroartemisinin 120 mg PO qd AND Piperaquine 960 mg PO qd for 3 days
- Body weight (kg)-60 < 80: Dihydroartemisinin 160 mg PO qd AND Piperaquine 1280 mg PO qd for 3 days
- Body weight (kg)- >80: Dose of Dihydroartemisinin 200 mg PO qd AND Piperaquine 1600 mg PO qd for 3 days
- 6.22.2.1.1.2 Reducing the transmissibility of treated Plasmodium falciparum infections In low-transmission areas in patients with Plasmodium falciparum malaria (except pregnant women, infants aged < 6 months and women breastfeeding infants aged < 6 months)
- Preferred regimen: Primaquine 0.25 mg/kg PO single dose with ACT
- 6.22.2.1.2. Recurrent falciparum malaria
- 6.22.2.1.2.1. Failure within 28 days
- Note: The recommended second-line treatment is an alternative ACT known to be effective in the region. Adherence to 7-day treatment regimens with Artesunate or Quinine both of which should be co-administered with Tetracycline, or Doxycycline or Clindamycin) is likely to be poor if treatment is not directly observed; these regimens are no longer generally recommended.
- 6.22.2.1.2.2. Failure after 28 days
- Note: All presumed treatment failures after 4 weeks of initial treatment should, from an operational standpoint, be considered new infections and be treated with the first-line ACT. However, reuse of Mefloquine within 60 days of first treatment is associated with an increased risk for neuropsychiatric reactions, and an alternative ACT should be used.
- 6.22.2.1.3. Reducing the transmissibility of treated Plasmodium falciparum infections in low-transmission areas in patients with Plasmodium falciparum malaria (except pregnant women, infants aged < 6 months and women breastfeeding infants aged < 6 months)
- Note: Single dose of 0.25 mg/kg biweekly Primaquine with ACT
- 6.22.2.1.4. Treating uncomplicated Plasmodium falciparum malaria in special risk groups
- 6.22.2.1.4.1. Pregnancy
- First trimester of pregnancy : Quinine AND Clindamycin 10 mg/kg/day PO bid for 7 days
- Second and third trimesters : Mefloquine is considered safe for the treatment of malaria during the second and third trimesters; however, it should be given only in combination with an artemisinin derivative.
- Note (1): Quinine is associated with an increased risk for hypoglycaemia in late pregnancy, and it should be used (with clindamycin) only if effective alternatives are not available.
- Note (2): Primaquine and Tetracyclines should not be used in pregnancy.
- 6.22.2.1.4.2. Infants less than 5kg body weight
- Note: They should be treated with an ACT at the same mg/kg bw target dose as for children weighing 5 kg.
- 6.22.2.1.4.4. Large and obese adults
- Note: For obese patients, less drug is often distributed to fat than to other tissues; therefore, they should be dosed on the basis of an estimate of lean body weight, ideal body weight. Patients who are heavy but not obese require the same mg/kg bw doses as lighter patients.
- 6.22.2.1.4.5. Non-immune travellers
- Note: Treat travellers with uncomplicated P. falciparum malaria returning to nonendemic settings with an ACT.
- 6.22.2.1.4.6. Uncomplicated hyperparasitaemia
- Note: People with P. falciparum hyperparasitaemia are at increased risk of treatment failure, severe malaria and death so should be closely monitored, in addition to receiving an ACT.
- 6.22.2.2. Treatment of uncomplicated malaria caused by Plasmodium vivax, Plasmodium ovale, Plasmodium malariae or Plasmodium knowlesi
- 6.22.2.2.1. Blood Stage infection
- 6.22.2.2.1.1. Uncomplicated malaria caused by Plasmodium vivax
- 6.22.2.2.1.1.1. In areas with chloroquine-sensitive Plasmodium vivax
- Preferred regimen: Chloroquine total dose of 25 mg/kg PO. Chloroquine is given at an initial dose of 10 mg/kg, followed by 10 mg/kg on the second day and 5 mg/kg on the third day PO
- 6.22.2.2.1.1.2. In areas with chloroquine-resistant Plasmodium vivax
- Note: ACTs containing Piperaquine, Mefloquine OR Lumefantrine are the recommended treatment, although Artesunate AND Amodiaquine may also be effective in some areas. In the systematic review of ACTs for treating P. vivax malaria, Dihydroartemisinin AND Piperaquine provided a longer prophylactic effect than ACTs with shorter half-lives (Artemether ANDLumefantrine) OR (Artesunate AND Amodiaquine), with significantly fewer recurrent parasitaemias during 9 weeks of follow-up.
- 6.22.2.2.1.2. Uncomplicated malaria caused by Plasmodium ovale, Plasmodium malariae or Plasmodium knowlesi malaria
- Note: Resistance of P. ovale, P. malariae and P. knowlesi to antimalarial drugs is not well characterized, and infections caused by these three species are generally considered to be sensitive to Chloroquine. In only one study, conducted in Indonesia, was resistance to Chloroquine reported in P. malariae. The blood stages of P. ovale, P. malariae and P. knowlesi should therefore be treated with the standard regimen of ACT or Chloroquine, as for vivax malaria.
- 6.22.2.2.1.3. Mixed malaria infections
- Note: ACTs are effective against all malaria species and so are the treatment of choice for mixed infections.
- 6.22.2.2.2. Liver stages (hypnozoites) of Plasmodium vivax and Plasmodium ovale
- Note: To prevent relapse, treat P. vivax or P. ovale malaria in children and adults (except pregnant women, infants aged < 6 months, women breastfeeding infants < 6 months, women breastfeeding older infants unless they are known not to be G6PD deficient and people with G6PD deficiency) with a 14-day course of Primaquine in all transmission settings. Strong recommendation, high-quality evidence In people with G6PD deficiency, consider preventing relapse by giving primaquine base at 0.75 mg base/kg bw once a week for 8 weeks, with close medical supervision for potential primaquine-induced adverse haematological effects.
- 6.22.2.2.2.1. Primaquine for preventive relapse
- Preferred regimen: Primaquine 0.25–0.5 mg/kg/day PO qd for 14 days
- 6.22.2.2.2.2. Primaquine and glucose-6-phosphate dehydrogenase deficiency
- Preferred regimen: Primaquine 0.75 mg base/kg/day PO once a week for 8 weeks
- Note: The decision to give or withhold Primaquine should depend on the possibility of giving the treatment under close medical supervision, with ready access to health facilities with blood transfusion services.
- 6.22.2.2.2.3. Prevention of relapse in pregnant or lacating women and infants
- Note: Primaquine is contraindicated in pregnant women, infants < 6 months of age and in lactating women (unless the infant is known not to be G6PD deficient)
- 6.22.2.3. Treatment of severe malaria
- 6.22.2.3.1. Treatment of severe falciparum infection with Artesunate
- 6.22.2.3.1.1. Adults and children with severe malaria (including infants, pregnant women in all trimesters and lactating women)
- Preferred regimen: Artesunate IV/IM for at least 24 h and until they can tolerate oral medication. Once a patient has received at least 24 h of parenteral therapy and can tolerate oral therapy, complete treatment with 3 days of an ACT (add single dose Primaquine in areas of low transmission).
- 6.22.2.3.1.2. Young children weighing < 20 kg
- Preferred regimen:Artesunate 3 mg/kg per dose IV/IM q24h
- Alternative regimen: use Artemether in preference to quinine for treating children and adults with severe malaria
- 6.22.2.3.2.Treating cases of suspected severe malaria pending transfer to a higher-level facility (pre-referral treatment)
- 6.22.2.3.2.1. Adults and children
- Preferred regimen: Artesunate IM q24h
- Alternative regimen: Artemether IM OR Quinine IM
- 6.22.2.3.2.2. Children < 6 years
- Preferred regimen: Where intramuscular injections of artesunate are not available, treat with a single rectal dose (10 mg/kg) of Artesunate, and refer immediately to an appropriate facility for further care.
- Note: Do not use rectal artesunate in older children and adults.
- 6.22.2.3.3. Pregancy
- Note: Parenteral artesunate is the treatment of choice in all trimesters. Treatment must not be delayed.
- 6.22.2.3.4. Treatment of severe Plasmodium Vivax infection
- Note: Parenteral Artesunate, treatment can be completed with a full treatment course of oral ACT or Chloroquine (in countries where Chloroquine is the treatment of choice). A full course of radical treatment with Primaquine should be given after recovery.
- 6.22.2.3.5. Additional aspects of management in severe malaria
- Fluid therapy: It is not possible to give general recommendations on fluid replacement; each patient must be assessed individually and fluid resuscitation based on the estimated deficit.
- Blood Transfusion: In high-transmission settings, blood transfusion is generally recommended for children with a haemoglobin level of < 5 g/100 mL(haematocrit < 15%). In low-transmission settings, a threshold of 20% (haemoglobin,7 g/100 mL) is recommended.
- Exchange blood transfusion: Exchange blood transfusion requires intensive nursing care and a relatively large volume of blood, and it carries significant risks. There is no consensus on the indications, benefits and dangers involved or on practical details such as the volume of blood that should be exchanged. It is, therefore, not possible to make any recommendation regarding the use of exchange blood transfusion.
- 6.23. Cryptococcosis
- 6.23.1. Treatment
- 6.23.1.1. Cryptococcal meningitis
- 6.23.1.1.1. Induction therapy
- Preferred regimen: Liposomal amphotericin B 3–4 mg/kg IV q24h AND Flucytosine 25 mg/kg PO qid for at least 2 weeks, followed by consolidation therapy
- Alternative regimen (1): Amphotericin B deoxycholate 0.7 mg/kg IV q24h AND Flucytosine 25 mg/kg PO qid
- Alternative regimen (2): Amphotericin B lipid complex 5 mg/kg IV q24h AND Flucytosine 25 mg/kg PO qid
- Alternative regimen (3): Liposomal Amphotericin B 3-4 mg/kg IV q24h AND Fluconazole 800 mg PO or IV q24h
- Alternative regimen (4): Amphotericin B deoxycholate 0.7 mg/kg IV q24h AND Fluconazole 800 mg PO or IV q24h
- Alternative regimen (5): Fluconazole 400–800 mg PO or IV qd AND Flucytosine 25 mg/kg PO qid
- Alternative regimen (6): Fluconazole 1200 mg PO or IV qd
- 6.23.1.1.2. Consolidation therapy
- Preferred regimen: Fluconazole 400 mg PO (or IV) qd for atleast 8 weeks
- Note: Preferred therapy followed by maintenance therapy.
- Maintenance therapy: Fluconazole 200 mg PO qd for at least 12 months
- Alternative regimen: Itraconazole 200 mg PO bid for 8 weeks
- 6.23.1.2. Non-CNS cryptococcosis with mild-to-moderate symptoms and focal pulmonary infiltrates
- Preferred regimen: Fluconazole, 400 mg PO qd for 12 months
- Note: Patients receiving Flucytosine should have either blood levels monitored (peak level 2 hours after dose should be 30–80 mcg/mL) or close monitoring of blood counts for development of cytopenia. Dosage should be adjusted in patients with renal insufficiency.
- 6.24. Mucocutaneous candidiasis
- 6.24.1. Treatment
- 6.24.1.1. For oropharyngeal candidiasis
- Oral Therapy
- Preferred regimen: Fluconazole 100 mg PO qd for 7-14 days.
- Alternative regimen: Itraconazole oral solution 200 mg PO qd for 7-14 days OR Posaconazole oral suspension 400 mg PO bid for 1 day, then 400 mg qd 7-14 days
- Topical therapy
- Preferred regimen: Clotrimazole troches, 10 mg PO 5 times daily OR Miconazole mucoadhesive buccal 50-mg tablet
- Note: Apply to mucosal surface over the canine fossa once daily (do not swallow, chew, or crush).
- Alternative regimen: Nystatin suspension 4–6 mL qid or 1–2 flavored pastilles 4– 5 times daily
- 6.24.1.2. For esophageal candidiasis
- Preferred regimen: Fluconazole 100 mg (up to 400 mg) PO or IV qd for 14-21 days OR Itraconazole oral solution 200 mg PO qd for 14-21 days
- Alternative regimen (1): Voriconazole 200 mg PO or IV bid for 14-21 days
- Alternative regimen (2): Anidulafungin 100 mg IV single dose, then 50 mg IV qd for 14-21 days
- Alternative regimen (3): Caspofungin 50 mg IV qd for 14-21 days
- Alternative regimen (4): Micafungin 150 mg IV qd for 14-21 days
- Alternative regimen (5): Amphotericin B deoxycholate 0.6 mg/kg IV qd for 14-21 days
- Alternative regimen (6): Lipid formulation of amphotericin B 3–4 mg/kg IV qd for 14-21 days
- 6.24.1.3. For uncomplicated vulvo-vaginal candidiasis
- Preferred regimen: Oral Fluconazole 150 mg for 1 dose OR Topical azoles (Clotrimazole, Butoconazole, Miconazole, Tioconazole, or Terconazole) for 3– 7 days
- Alternative regimen: Itraconazole oral solution 200 mg PO qd for 3–7 days
- 6.24.1.4. For severe or recurrent vulvovaginal candidiasis
- Preferred regimen: Fluconazole 100–200 mg PO qd for ≥7 days OR Topical antifungal ≥7 days
- 6.25. Bartonellosis
- 6.25.1. Treatment
- 6.25.1.1. For bacillary angiomatosis, peliosis hepatis, bacteremia, and osteomyelitis
- Preferred regimen (1): Doxycycline 100 mg PO or IV q12h for 3 months
- Preferred regimen (2): Erythromycin 500 mg PO or IV q6h for 3 months
- Alternative regimen (1): Azithromycin 500 mg PO qd
- Alternative regimen (2):} Clarithromycin 500 mg PO bid
- 6.25.1.2. Confirmed bartonella endocarditis
- Preferred regimen: Doxycycline 100 mg IV q12h AND Gentamicin 1 mg/kg IV q8h) for 2 weeks, then continue with Doxycycline 100 mg IV or PO q12h
- Altered regimen: Doxycycline 100 mg IV AND Rifabutin 300 mg PO or IV q12h for 2 weeks, then continue with Doxycycline 100 mg IV or PI q12h
- 6.25.1.3. CNS infections
- Preferred regimen: (Doxycycline 100 mg with or without Rifabutin 300 mg PO or IV q12h
- 6.25.1.4. Other severe infections
- Preferred regimen (1): Doxycycline 100 mg PO or IV with or without Rifabutin 300 mg PO or IV) q12h for 3 months
- Preferred regimen (2): Erythromycin 500 mg PO or IV q6h) with or without Rifabutin) 300 mg PO or IV q12h for 3 months.
- Note: If relapse occurs after initial (>3 month) course of therapy, longterm suppression with Doxycycline or a macrolide is recommended as long as CD4 count <200 cells/µL.
- 6.26. Campylobacteriosis
- 6.26.1. Treatment
- 6.26.1.1. For mild-to-moderate disease (If Susceptible)
- Preferred regimen: Ciprofloxacin 500–750 mg PO or 400 mg IV q12h OR Azithromycin 500 mg PO qd
- Alternative regimen: Levofloxacin 750 mg PO or IV q24h OR Moxifloxacin 400 mg (PO or IV) q24h
- 6.26.1.2. For campylobacter bacteremia
- Preferred regimen: Ciprofloxacin 500–750 mg PO or 400 mg IV q12h AND an aminoglycoside.
- Duration of Therapy:
- Gastroenteritis: 7–10 days (5 days with Azithromycin)
- Bacteremia: ≥14 days
- Recurrent bacteremia: 2–6 weeks.
- 6.27. Shigellosis
- 6.27.1. Treatment
- Preferred regimen: Ciprofloxacin 500–750 mg PO or 400 mg IV q12h
- Duration of Therapy:
- Gastroenteritis: 7–10 days
- Bacteremia: ≥14 days
- Recurrent Infections: 2–6 weeks
- Alternative regimen (1): Levofloxacin 750 mg PO or IV q24h for 5 days
- Alternative regimen (2): Moxifloxacin 400 mg PO or IV q24h for 5 days
- Alternative regimen (3): Trimethoprim/Sulfamethoxazole 160 mg/800 mg PO or IV q12h for 5 days
- Alternative regimen (4): Azithromycin 500 mg PO qd for 5 days
- Note: Antimotility agents should be avoided.
- 6.28. Salmonellosis
- 6.28.1. Treatment
- Preferred regimen: Ciprofloxacin 500–750 mg PO or 400 mg IV q12h
- Alternative regimen (1): Levofloxacin 750 mg PO or IV q24h
- Alternative regimen (2): Moxifloxacin 400 mg PO or IV q24h
- Alternative regimen (3): Trimethoprim/Sulfamethoxazole 160 mg/800 mg PO or IV q12h
- Alternative regimen (4): Cefotaxime 1 g IV q8h
- Alternative regimen (5): Ceftriaxone 1 g IV q24h
- Duration of therapy:
- For gastroenteritis without bacteremia:
- If CD4 count ≥200 cells/µL: 7–14 days.
- If CD4 count <200 cells/µL: 2–6 weeks.
- For gastroenteritis with bacteremia:
- If CD4 count ≥200/µL: 14 days; longer duration if bacteremia persists or if the infection is complicated (e.g., if metastatic foci of infection are present)
- If CD4 count <200 cells/µL: 2–6 weeks
- Note (1): The role of long-term secondary prophylaxis in patients with recurrent Salmonella bacteremia is not well established. Must weigh benefit against risks of long-term antibiotic exposure.
- Note (2): Secondary Prophylaxis Should Be Considered For:
- Patients with recurrent Salmonella gastroenteritis +/- bacteremia.
- Patients with CD4 <200 cells/µL with severe diarrhea.
- 6.29. Bacterial enteric infections
- 6.29.1. Empiric therapy
- Preferred regimen: Ciprofloxacin 500–750 mg PO or 400 mg IV q12h
- Alternative regimen: Ceftriaxone 1 g IV q24h OR Cefotaxime 1 g IV q8h
- Note: Antimotility agents should be avoided if there is concern about inflammatory diarrhea, including Clostridium-difficile-associated diarrhea.
- 6.30.Bacterial respiratory diseases
- 6.30.1. Treatment
- 6.30.1.1. Empiric outpatient therapy
- Preferred regimen: Amoxicillin 500 mg PO AND (Azithromycin 500 mg PO OR Clarithromycin 500 mg PO) qd for 7-10 days
- Alternative regimen: Amoxicillin 500 mg PO AND Doxycycline 100mg PO qd
- Note: Therapy should be adjusted based on the results of diagnostic workup.
- 6.30.1.2. For penicillin-allergic patients
- Preferred regimen: Ceftriaxone 1 g IV q24h AND (Azithromycin 500 mg PO OR Clarithromycin 500 mg PO) qd for 7-10 days
- Alternative regimen: Aztreonam 1 g IV q24h AND Levofloxacin 750 mg IV q24h OR Moxifloxacin 400 mg IV q24h
- 6.30.1.3. Empiric therapy for non-ICU hospitalized patients
- Preferred regimen: Ceftriaxone 1 g IV q24h AND (Azithromycin 500 mg PO OR Clarithromycin 500 mg PO) qd
- 6.30.1.3. Empiric therapy for patients at risk of pseudomonas pneumonia
- Preferred regimen: : Piperacillin-Tazobactam 2 g-0.25 g IV q24h AND (Ciprofloxacin 400 mg IV q8–12h OR Levofloxacin 750 mg IV) q24h
- 6.30.1.4. Empiric therapy for patients at risk for methicillin-resistant staphylococcus aureus pneumonia
- Preferred regimen: Amoxicillin 500 mg PO AND (Azithromycin 500 mg PO OR Clarithromycin 500 mg) PO AND Linezolid 600 mg (IV or PO).
- Note (1): Empiric therapy with a macrolide alone is not routinely recommended, because of increasing pneumococcal resistance.
- Note (2): Chemoprophylaxis can be considered for patients with frequent recurrences of serious bacterial pneumonia.
- 6.31. Cryptosporidiosis
- 6.31.1. Treatment
- Note (1): Initiate or optimize ART for immune restoration to CD4 count >100 cells/µL. Aggressive oral or IV rehydration and replacement of electrolyte loss and symptomatic treatment of diarrhea with anti-motility agents.
- Preferred regimen (1): Nitazoxanide 500–1000 mg PO bid for 14 days
- Preferred regimen (2): Paromomycin 500 mg PO qid for 14–21 days
- Note (2): With optimized anti retroviral therapy, symptomatic treatment and rehydration and electrolyte replacement is recommended. Tincture of opium may be more effective than Loperamide in management of diarrhea.
- 6.32. Microsporidiosis
- 6.32.1. Treatment
- 6.32.1.1. For GI infections caused by enterocytozoon bienuesi
- Note: Initiate or optimize anti retroviral therapy as immune restoration to CD4 count >100 cells/µL AND manage severe dehydration, malnutrition, and wasting by fluid support.
- Preferred therapy (1): Fumagillin 60 mg/day PO bid
- Preferred therapy (2): TNP-470 PO bid
- Preferred therapy (3): Nitazoxanide 1000 mg PO bid
- 6.32.1.2. For intestinal and disseminated (not ocular) infections caused by microsporidia other than E. bienuesi and vittaforma corneae
- Preferred regimen: Albendazole 400 mg PO bid, continue until CD4 count >200 cells/µL for >6 months after initiation of anti retroviral therapy
- Alternative regimen: Itraconazole 400 mg PO qd AND Albendazole 400 mg PO bid
- 6.32.1.3. For ocular infection
- Preferred regimen: Topical fumagillin bicylohexylammonium (Fumidil B) eye drops: 3 mg/mL in saline (fumagillin 70 µg/mL)—2 drops q2h for 4 days, then 2 drops qid AND Albendazole 400 mg PO bid, for management of systemic infection
- Note: Therapy should be continued until resolution of ocular symptoms and CD4 count increase to >200 cells/µL for >6 months in response to anti retroviral therapy.
- 6.33. Progressive Multifocal Leukoencephalopathy (PML)
- Note (1): There is no specific antiviral therapy for JC virus infection. The main treatment approach is to reverse the immunosuppression caused by HIV.
- Note (2): Initiate anti retroviral therapy immediately in anti retroviral therapy naive patients.
- Note (3): Optimize anti retroviral therapy in patients who develop PML in phase of HIV viremia on anti retroviral therapy.
- Note (4): Corticosteroids may be used for PML-IRIS characterized by contrast enhancement, edema or mass effect, and with clinical deterioration.
- West nile virus
- 1.1. Prevention
- No WNV vaccines are licensed for use in humans. In the absence of a vaccine, prevention of WNV disease depends on community-level mosquito control programs to reduce vector densities, personal protective measures to decrease exposure to infected mosquitoes, and screening of blood and organ donors.
- Personal protective measures include use of mosquito repellents, wearing long-sleeved shirts and long pants, and limiting outdoor exposure from dusk to dawn. Using air conditioning, installing window and door screens, and reducing peridomestic mosquito breeding sites, can further decrease the risk for WNV exposure.
- Blood and some organ donations in the United States are screened for WNV infection; health care professionals should remain vigilant for the possible transmission of WNV through blood transfusion or organ transplantation. Any suspected WNV infections temporally associated with blood transfusion or organ transplantation should be reported promptly to the appropriate state health department.
- 1.2. Treatment
- There is no specific treatment for WNV disease; clinical management is supportive. Patients with severe meningeal symptoms often require pain control for headaches and antiemetic therapy and rehydration for associated nausea and vomiting. Patients with encephalitis require close monitoring for the development of elevated intracranial pressure and seizures. Patients with encephalitis or poliomyelitis should be monitored for inability to protect their airway. Acute neuromuscular respiratory failure may develop rapidly and prolonged ventilatory support may be required.
- Measles
- 1.1. Prevention
- 1.1.1. Vaccines
- Note (1): Measles can be prevented with measles-containing vaccine, which is primarily administered as the combination measles-mumps-rubella (MMR) vaccine. The combination measles-mumps-rubella-varicella (MMRV) vaccine can be used for children aged 12 months through 12 years for protection against measles, mumps, rubella and varicella. Single-antigen measles vaccine is not available.
- Note (2): Vaccination recommendations
- Children: CDC recommends routine childhood immunization for MMR vaccine starting with the first dose at 12 through 15 months of age, and the second dose at 4 through 6 years of age or at least 28 days following the first dose.
- Students at post-high school educational institutions: Students at post-high school educational institutions without evidence of measles immunity need two doses of MMR vaccine, with the second dose administered no earlier than 28 days after the first dose.
- Adults: People who are born during or after 1957 who do not have evidence of immunity against measles should get at least one dose of MMR vaccine.
- International travelers: People 6 months of age or older who will be traveling internationally should be protected against measles. Before travelling internationally,
- Infants 6 through 11 months of age should receive one dose of MMR vaccine
- Children 12 months of age or older should have documentation of two doses of MMR vaccine (the first dose of MMR vaccine should be administered at age 12 months or older; the second dose no earlier than 28 days after the first dose)
- Teenagers and adults born during or after 1957 without evidence of immunity against measles should have documentation of two doses of MMR vaccine, with the second dose administered no earlier than 28 days after the first dose
- 1.1.2. Post-exposure Prophylaxis
- 1.1.2.1. Indication
- People exposed to measles who cannot readily show that they have evidence of immunity against measles should be offered post-exposure prophylaxis (PEP) or be excluded from the setting (school, hospital, childcare). MMR vaccine, if administered within 72 hours of initial measles exposure, or immunoglobulin (IG), if administered within six days of exposure, may provide some protection or modify the clinical course of disease.
- Note (1): If MMR vaccine is not administered within 72 hours of exposure as PEP, MMR vaccine should still be offered at any interval following exposure to the disease in order to offer protection from future exposures. People who receive MMR vaccine or IG as PEP should be monitored for signs and symptoms consistent with measles for at least one incubation period.
- Note (2): If many measles cases are occurring among infants younger than 12 months of age, measles vaccination of infants as young as 6 months of age may be used as an outbreak control measure. Note that children vaccinated before their first birthday should be revaccinated when they are 12 through 15 months old and again when they are 4 through 6 years of age.
- Note (3): People who are at risk for severe illness and complications from measles, such as infants younger than 12 months of age, pregnant women without evidence of measles immunity, and people with severely compromised immune systems, should receive IG. Intramuscular IG (IGIM) should be given to all infants younger than 12 months of age who have been exposed to measles.
- Note (4): For infants aged 6 through 11 months, MMR vaccine can be given in place of IG, if administered within 72 hours of exposure. Because pregnant women might be at higher risk for severe measles and complications, intravenous IG (IGIV) should be administered to pregnant women without evidence of measles immunity who have been exposed to measles. People with severely compromised immune systems who are exposed to measles should receive IGIV regardless of immunologic or vaccination status because they might not be protected by MMR vaccine.
- Preferred regimen: The recommended dose of IGIM is 0.5 mL/kg of body weight (maximum dose = 15 mL) and the recommended dose of IGIV is 400 mg/kg.
- Note (5): If a healthcare provider without evidence of immunity is exposed to measles, MMR vaccine should be given within 72 hours, or IG should be given within 6 days when available. Exclude healthcare personnel without evidence of immunity from duty from day 5 after first exposure to day 21 after last exposure, regardless of post-exposure vaccine.
- 1.2. Treatment
- Note (1): There is no specific antiviral therapy for measles. Medical care is supportive and to help relieve symptoms and address complications such as bacterial infections.
- Note (2): Severe measles cases among children, such as those who are hospitalized, should be treated with vitamin A. Vitamin A should be administered immediately on diagnosis and repeated the next day. The recommended age-specific daily doses are
- 50,000 IU for infants younger than 6 months of age
- 100,000 IU for infants 6–11 months of age
- 200,000 IU for children 12 months of age and older
==References==.
- ↑ "AIDSinfoNIH"..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}
- ↑ "Guidelines for the treatment of malaria. Third edition April 2015" (PDF). | Sandbox ammu
- HIV/AIDS
- 1. Antiretroviral regimen options for treatment-naive patients[1]
- 1.1. Integrase strand transfer inhibitor-based regimens
- Preferred regimen (1): Dolutegravir 50 mg PO qd AND Abacavir 600 mg-Lamivudine 300 mg PO qd in patients who are HLA-B*5701-negative
- Preferred regimen (2): Dolutegravir 50 mg PO qd AND Tenofovir 300 mg-Emtricitabine 200 mg PO qd
- Preferred regimen (3): Elvitegravir 150 mg-Cobicistat 150 mg-Tenofovir 300 mg-Emtricitabine 200 mg PO qd in patients with estimated CrCl ≥ 70 mL/min/1.73
- Preferred regimen (4): Raltegravir 400 mg PO bid AND Tenofovir 300 mg-Emtricitabine 200 mg PO qd
- Alternative regimen (1): Efavirenz 600 mg PO qd OR Tenofovir 300 mg-Emtricitabine 200 mg PO qd
- Alternative regimen (2): Rilpivirine 25 mg PO qd AND (Tenofovir 300 mg PO qd OR Emtricitabine 200 mg PO qd) for patients with CD4 count >200 cells/microL
- Alternative regimen (3): Raltegravir 400 mg PO bid AND (Abacavir 600 mg PO qd OR Lamivudine 300 mg PO qd) in patients who are HLA-B*5701-negative
- 1.2. Protease inhibitor-based regimen
- Preferred regimen: Darunavir 800 mg-Ritonavir 100 mg PO qd AND Tenofovir 300 mg-Emtricitabine 200 mg PO qd
- Alternative regimen (1): Atazanavir 300 mg-Cobicistat 150 mg PO qd AND Tenofovir disoproxil fumarate 300 mg-Emtricitabine 200 mg PO qd only for patients with pre-treatment estimated CrCl ≥70 mL/min
- Alternative regimen (2): Atazanavir 300 mg-Ritonavir 100 mg PO qd AND Tenofovir 300 mg-Emtricitabine 200 mg PO qd
- Alternative regimen (3): (Darunavir 800 mg-Cobicistat 150 mg PO qd OR Darunavir 800 mg-Ritonavir 100 mg PO qd) AND Abacavir 600 mg-Lamivudine 300 mg PO qd only for patients who are HLA-B*5701 negative
- Alternative regimen (4): Darunavir 800 mg-Cobicistat 150 mg PO qd AND Tenofovir disoproxil fumarate 300 mg-Emtricitabine 200 mg PO qd only for patients with pre-treatment estimated CrCl ≥70 mL/min
- Alternative regimen (5): Atazanavir 300 mg-Ritonavir 100 mg PO qd AND Abacavir 600 mg-Lamivudine 300 mg PO qd in patients who are HLA-B*5701-negative and with pre-treatment HIV RNA <100,000 copies/mL
- Alternative regimen (6): Lopinavir 400 mg-Ritonavir 100 mg PO qd or bid AND Abacavir 600 mg-Lamivudine 300 mg PO qd only for patients who are HLA-B*5701 negative
- Alternative regimen (7): Lopinavir 400 mg-Ritonavir 100 mg PO qd or bid AND Tenofovir disoproxil fumarate 300 mg-Emtricitabine 200 mg PO qd
- 1.3. A non-nucleoside reverse transcriptase inhibitor (NNRTI) based regimen
- Alternative regimen (1): Efavirenz 600 mg-Tenofovir 300 mg-Emtricitabine 200 mg PO qd
- Alternative regimen (2): Rilpivirine 25 mg-Tenofovir 300 mg-Emtricitabine 200 mg PO qd
- 1.4. Other regimen options
- 1.4.1. A non-nucleoside reverse transcriptase inhibitor (NNRTI) based regimen
- Preferred regimen (1): Efavirenz 600 mg PO qd AND Abacavir 600 mg-Lamivudine 300 mg PO qd only for patients who are HLA-B*5701 negative and with pre-treatment HIV RNA <100,000 copies/mL.
- 1.4.2. Other regimens when tenofovir or abacavir cannot be used
- Preferred regimen (1): Darunavir 800 mg-Ritonavir 100 mg PO qd AND Raltegravir 400 mg PO qd only for patients with pre-treatment HIV RNA <100,000 copies/mL and CD4 cell count >200 cells/mm3.
- Preferred regimen (2): Lopinavir 400 mg-Ritonavir 100 mg PO bid AND Lamivudine 300 mg PO bid
- 1.5. Pediatric doses
- Abacavir 300 mg PO bid
- Lamivudine 4 mg/kg/dose PO bid; maximum 150 mg PO bid
- Stavudine 1 mg/kg/dose PO bid
- Tenofovir 8 mg/kg/dose PO bid
- Zidovudine 180-240 mg/m2/dose PO bid or 160 mg/m2/dose PO tid (range 90 mg/m2/dose-180 mg/m2/dose)
- Lopinavir 400 mg PO bid
- Nelfinavir 50 mg/kg/dose PO bid
- Raltegravir 300 mg PO bid
- Didanosine
- 20 to < 25 kg: 200 mg PO qd
- 25 to < 60 kg: 250 mg PO qd
- ≥60 kg: 400 mg PO qd
- Efavirenz
- 10 to < 15 kg: 200 mg PO qd
- 15 to <20 kg: 250 mg PO qd
- 20 to < 25 kg: 300 mg PO qd
- 25 to < 32.5 kg: 350 mg PO qd
- 32.5 to <40 kg: 400 mg PO qd
- ≥ 40 kg: 600 mg PO qd
- Nevirapine maximum 200 mg per dose
- Between 1 day and 8 years: 200 mg/m2/dose PO qd for 14 days, then 200 mg/m2/dose PO bid
- 8 years and above: 120-150 mg/m2/dose PO qd for 14 days, then 120-150 mg/m2/dose PO bid
- Note (1): Anti retroviral therapy for treatment naive patients is a life long therapy.
- Note (2): Tenofovir disoproxil fumarate should be avoided in patients with a creatinine clearance <50 mL/min.
- Note (3): Rilpivirine should be used in patients with a CD4 cell count >200 copies/mL and should not be used with proton pump inhibitors.
- Note (4): Efavirenz should not be used in pregnant women.
- 2. Pre-exposure prophylaxis (PrEP)
- Preferred regimen: Tenofovir disoproxil fumarate 300 mg-Emtricitabine 200 mg PO qd for ≤90-days
- Note (1): People with high risk behavior such as men who have sex with men, intravenous drug abusers, HIV-positive sexual partner, recent bacterial STI, high number of sex partners, history of inconsistent or no condom use, commercial sex work, people in high-prevalence area or network are advised to take pre-exposure prophylaxis of drugs.
- Note (2): Follow-up visits at least every 3 months to provide the following: HIV test, medication adherence counseling, behavioral risk reduction support, side effect assessment, STI symptom assessment, pregnancy testing.
- Note (3): At 3 months and every 6 months thereafter, assess renal function.
- Note (4): Every 6 months, test for bacterial STIs.
- 3. Post- exposure prophylaxis
- Preferred regimen: Raltegravir 400 mg PO bid AND Tenofovir disoproxil fumarate 300 mg-Emtricitabine 200 mg PO qd
- Preferred basic regimen for low-risk exposures (Eg: mucus membrane):
Zidovudine 100 mg PO qd AND Lamivudine 300 mg PO qd
Zidovudine 100 mg PO qd AND Emtricitabine 200 mg PO qd
Tenofovir 300 mg PO qd AND Lamivudine 300 mg PO qd
Tenofovir 300 mg PO qd AND Emtricitabine 200 mg PO qd
- Zidovudine 100 mg PO qd AND Lamivudine 300 mg PO qd
- Zidovudine 100 mg PO qd AND Emtricitabine 200 mg PO qd
- Tenofovir 300 mg PO qd AND Lamivudine 300 mg PO qd
- Tenofovir 300 mg PO qd AND Emtricitabine 200 mg PO qd
- Preferred expanded regimen for high-risk exposure (Eg: percutaneous needle stick)
Zidovudine 100 mg PO qd AND Lamivudine 300 mg PO qd AND Lopinavir 400 mg-Ritonavir 100 mg PO qd
Zidovudine 100 mg PO qd AND Emtricitabine 200 mg PO qd AND Lopinavir 400 mg-Ritonavir 100 mg PO qd
Tenofovir 300 mg PO qd AND Lamivudine 300 mg PO qd AND Lopinavir 400 mg-Ritonavir 100 mg PO qd
Tenofovir 300 mg PO qd AND Emtricitabine 200 mg PO qdAND Lopinavir 400 mg-Ritonavir 100 mg PO qd
- Zidovudine 100 mg PO qd AND Lamivudine 300 mg PO qd AND Lopinavir 400 mg-Ritonavir 100 mg PO qd
- Zidovudine 100 mg PO qd AND Emtricitabine 200 mg PO qd AND Lopinavir 400 mg-Ritonavir 100 mg PO qd
- Tenofovir 300 mg PO qd AND Lamivudine 300 mg PO qd AND Lopinavir 400 mg-Ritonavir 100 mg PO qd
- Tenofovir 300 mg PO qd AND Emtricitabine 200 mg PO qdAND Lopinavir 400 mg-Ritonavir 100 mg PO qd
- Note: Ideally therapy should be started within hours of exposure and continued for 28 days.
- 4. Perinatal antiretroviral regimen
- 4.1. Antepartum
- 4.1.1. Protease inhibitor-based regimen
- Preferred regimen: (Tenofovir 300 mg-Emtricitabine 200 mg PO qd (fixed dose combination) OR Tenofovir 300 mg-Lamivudine 300 mg PO qd OR Abacavir 600 mg-Lamivudine 300 mg PO qd OR Zidovudine 100 mg-Lamivudine 300 mg PO qd) AND (Atazanavir 300 mg-Ritonavir 100 mg PO qd OR Lopinavir 400 mg-Ritonavir 100 mg PO qd)
- 4.1.2. A non-nucleoside reverse transcriptase inhibitor (NNRTI) based regimen:
- Preferred regimen (1): Efavirenz 600 mg-Tenofovir 300 mg-Emtricitabine 200 mg (fixed dose combination) PO qd
- Preferred regimen (2): Efavirenz 600 mg-Tenofovir 300 mg-Lamivudine 300 mg PO qd
- Alternative regimen: (Abacavir 600 mg-Lamivudine 300 mg PO qd OR Zidovudine 100 mg-Lamivudine 300 mg PO qd) AND Efavirenz 600 mg PO qd
- 4.2. Intrapartum
- Note (1): HIV RNA <1000 copies/mL and good adherance-Continue the regimen during delivery or cessarean section.
- Note (2): HIV RNA >1000 copies/mL near delivery, possible poor adherence, or unknown HIV RNA levels- Intravenous Zidovudine 2 mg/kg IV over 1 hr should be given three hours before cesarean section or delivery and then 1 mg/kg/hr IV continuous infusion until umbilical cord clamping.
- 4.3. Postpartum
- Note: Initiate anti retroviral therapy (ART) and continue after delivery and cessation of breastfeeding.
- 5. Infant antiretroviral prophylaxis for prevention of mother-to-child transmission of HIV
- 5.1 Prophylaxis for HIV-exposed infants of women who received antepartum antiretroviral prophylaxis
- Preferred regimen: Zidovudine (ZDV) 100 mg PO given at birth and continued till six weeks
- Note (1): Dose based on gestational age at birth and weight, initiated as soon after birth as possible and preferably within 6 to 12 hours of delivery.
- Note (2): ≥35 weeks gestation at birth: 4 mg/kg/dose orally (or, if unable to tolerate oral agents, 3 mg/kg/dose IV) every 12 hours.
- Note (3): ≥30 to <35 weeks gestation at birth: 2 mg/kg/dose orally (or 1.5 mg/kg/dose IV) every 12 hours, advanced to 3 mg/kg/dose orally (or 2.3 mg/kg/dose IV) every 12 hours at age 15 days.
- Note (4): <30 weeks gestation at birth: 2 mg/kg/dose orally (or 1.5 mg/kg/dose IV) every 12 hours, advanced to 3 mg/kg/dose orally (or 2.3 mg/kg/dose IV) every 12 hours after age four weeks.
- 5.2. Prophylaxis for HIV-exposed infants of women who received no antepartum antiretroviral prophylaxis
- Dose based on birth weight, initiated as soon after birth as possible.
- Birth weight 1.5 to 2 kg: 8 mg/dose orally.
- Birth weight >2 kg: 12 mg/dose orally.
- Dose based on gestational age at birth and weight, initiated as soon after birth as possible and preferably within 6 to 12 hours of delivery.
- ≥35 weeks gestation at birth: 4 mg/kg/dose orally (or, if unable to tolerate oral agents, 3 mg/kg/dose IV) every 12 hours.
- ≥30 to <35 weeks gestation at birth: 2 mg/kg/dose orally (or 1.5 mg/kg/dose IV) every 12 hours, advanced to 3 mg/kg/dose orally (or 2.3 mg/kg/dose IV) every 12 hours at age 15 days.
- <30 weeks gestation at birth: 2 mg/kg/dose orally (or 1.5 mg/kg/dose IV) every 12 hours, advanced to 3 mg/kg/dose orally (or 2.3 mg/kg/dose IV) every 12 hours after age four weeks.
- Note (1): Three doses in the first week of life.
- Note (2): First dose within 48 hours of birth (birth to 48 hrs).
- Note (3): Second dose 48 hours after first.
- Note (4): Third dose 96 hours after second.
- 6. Treatment and prevention of opportunistic infections
- 6.1. Pneumocystis pneumonia (PCP)
- 6.1.1. Prevention
- Indication
- CD4 count <200 cells/mm3
- Oropharyngeal candidiasis
- CD4 <14%
- History of AIDS-defining illness
- CD4 count >200 but <250 cells/mm3 if monitoring CD4 cell count every 3 months is not possible.
- Preferred regimen: Trimethoprim/sulfamethoxazole 160 mg/800 mg PO qd or 80 mg/400 mg PO qd
- Alternative regimen (1): Trimethoprim/sulfamethoxazole 160 mg/800 mg PO three times weekly
- Alternative regimen (2): Dapsone 100 mg PO qd or 50 mg PO bid
- Alternative regimen (3): Dapsone 50 mg PO qd AND (Pyrimethamine 50 mg-Leucovorin 25 mg) PO weekly
- Alternative regimen (4): Dapsone 200 mg PO qd AND (Pyrimethamine 75 mg-Leucovorin 25 mg) PO weekly
- Alternative regimen (5): Aerosolized Pentamidine 300 mg via Respigard nebulizer every month
- Alternative regimen (6): Atovaquone 1500 mg PO qd
- Alternative regimen (7): Atovaquone 1500 mg AND (Pyrimethamine 25 mg AND Leucovorin 10 mg) PO qd
- 6.1.2. Treatment
- 6.1.2.1. For Moderate-to-Severe PCP'
- Preferred regimen: Trimethoprim 15–20 mg AND Sulfamethoxazole 75–100 mg/kg/day IV given q6h or q8h, may switch to PO after clinical improvement
- Alternative regimen (1): Pentamidine 4 mg/kg IV daily infused over ≥60 minutes
- Note: Reduce dose to 3 mg/kg IV daily if toxic.
- Alternative regimen (2): Primaquine 30 mg (base) PO qd AND (Clindamycin 600 mg q6h IV OR 900 mg IV q8h OR Clindamycin 450 mg PO qid or 600 mg PO tid)
- 6.1.2.2. For Mild-to-Moderate PCP
- Preferred regimen: Trimethoprim 15–20 mg AND Sulfamethoxazole 75–100 mg/kg/day PO in TID OR Trimethoprim/sulfamethoxazole 160 mg/800 mg 2 tablets PO tid
- Alternative regimen (1): Dapsone 100 mg PO qd AND TMP 5 mg/kg PO tid
- Alternative regimen (2): Primaquine 30 mg (base) PO qd AND (Clindamycin 450 mg PO qid or 600 mg PO tid OR Atovaquone 750 mg PO bid with food)
- 6.1.3. Secondary prophylaxis, after completion of PCP treatment
- Preferred regimen (1): Trimethoprim/Sulfamethoxazole 160 mg/800 mg PO qd OR Trimethoprim/Sulfamethoxazole 80 mg/400 mg PO qd
- Alternative regimen (1): Trimethoprim/sulfamethoxazole 160 mg/800 mg PO three times weekly
- Alternative regimen (2): Dapsone 100 mg PO qd
- Alternative regimen (3): Dapsone 50 mg PO qd AND Pyrimethamine 50 mg PO AND Leucovorin 25 mg PO weekly
- Alternative regimen (4): Dapsone 200 mg PO AND Pyrimethamine 75 mg PO AND Leucovorin 25 mg PO weekly
- Alternative regimen (5): Dapsone 100 mg PO qd
- Alternative regimen (6): Dapsone 50 mg PO qd AND Pyrimethamine 50 mg PO AND Leucovorin 25 mg PO weekly
- Alternative regimen (7): Dapsone 200 mg PO AND Pyrimethamine 75 mg PO AND Leucovorin 25 mg PO weekly
- Alternative regimen (8): Aerosolized Pentamidine 300 mg monthly via Respirgard nebulizer
- Alternative regimen (9): Atovaquone 1500 mg PO qd
- Alternative regimen (10): Atovaquone 1500 mg PO AND Pyrimethamine 25 mg PO AND Leucovorin 10 mg PO qd
- 6.1.4. Adjunctive corticosteroids
- Indications- PaO2 <70 mmHg at room air OR Alveolar-arterial O2 gradient >35 mmHg.
- Preferred regimen:
- Days 1–5: 40 mg PO bid
- Days 6–10: 40 mg PO qd
- Days 11–21: 20 mg PO qd
- Note (1): Trimethoprim/sulfamethoxazole should be permanently discontinued in patients with possible or definite stevens johnson syndrome or toxic epidermal necrosis.
- Note (2): Whenever possible, patients should be tested for G6PD before use of Dapsone or Primaquine. Alternative regimen should be used in patients found to have G6PD deficiency.
- 6.2. Toxoplasma gondii encephalitis
- 6.2.1. Prevention
- 6.2.1.1. Indication
- Toxoplasma IgG-positive patients with CD4 count <100 cells/µL.
- Seronegative patients receiving PCP prophylaxis not active against toxoplasmosis should have toxoplasma serology retested if CD4 count decline to <100 cellsµL.
- Prophylaxis should be initiated if seroconversion occurred.
- Preferred regimen: Trimethoprim/sulfamethoxazole 160 mg/800 mg PO qd
- Alternative regimen (1): Trimethoprim/sulfamethoxazole 160 mg/800 mg PO three times weekly
- Alternative regimen (2): Trimethoprim/sulfamethoxazole 80 mg/400 mg PO qd
- Alternative regimen (3): Dapsone 50 mg PO qd AND Pyrimethamine 50 mg PO weekly AND Leucovorin 25 mg PO weekly
- Alternative regimen (4): Dapsone 200 mg PO weekly AND Pyrimethamine 75 mg PO weekly AND Leucovorin 25 mg PO weekly
- Alternative regimen (5): Atovaquone 1500 mg PO qd
- Alternative regimen (6): Atovaquone 1500 mg PO qd AND Pyrimethamine 25 mg PO qd AND Leucovorin 10 mg PO qd
- 6.2.2. Treatment
- 6.2.2.1. Treatment of acute infection
- Preferred regimen: Pyrimethamine 200 mg PO single dose, followed by weight-based therapy:
- If <60 kg, Pyrimethamine 50 mg PO qd AND Sulfadiazine 1000 mg PO qid AND Leucovorin 10–25 mg PO qd
- If ≥60 kg, Pyrimethamine 75 mg PO qd AND Sulfadiazine 1500 mg PO qid AND Leucovorin 10–25 mg PO qd
- Note: At least 6 weeks; longer duration if clinical or radiologic disease is extensive or response is incomplete at 6 weeks.
- Alternative regimen (1): Pyrimethamine 50 mg PO qdAND Leucovorin 10–25 mg PO qd AND Clindamycin 600 mg IV or PO q6h
- Alternative regimen (2): Trimethoprim 5 mg/kg-Sulfamethoxazole 25 mg/kg IV or PO bid
- Alternative regimen (3): Atovaquone 1500 mg PO bid with food AND Pyrimethamine 50 mg PO qd AND Leucovorin 10–25 mg PO qd
- Alternative regimen (4): Atovaquone 1500 mg PO bid with food AND Sulfadiazine 1000–1500 mg PO qid (weight-based dosing, as in preferred therapy)
- Alternative regimen (5): Atovaquone 1500 mg PO bid with food
- Alternative regimen (6): Pyrimethamine 50 mg-Leucovorin 10–25 mg PO qd AND Azithromycin 900–1200 mg PO qd
- 6.2.2.2. Chronic maintenance therapy
- Preferred regimen: Pyrimethamine 25–50 mg PO qd AND Sulfadiazine 2000–4000 mg PO qd (in 2–4 divided doses) AND Leucovorin 10–25 mg PO qd
- Alternative regimen (1): Clindamycin 600 mg PO tid AND Pyrimethamine 25–50 mg-Leucovorin 10–25 mg PO qd
- Alternative regimen (2): Trimethoprim/sulfamethoxazole 160 mg/800 mg bid
- Alternative regimen (3): Atovaquone 750–1500 mg PO bid AND Pyrimethamine 25 mg-Leucovorin 10 mg PO qd
- Alternative regimen (4): Atovaquone 750–1500 mg PO bid AND Sulfadiazine 2000–4000 mg PO qd in 2–4 divided doses
- Alternative regimen (5): Atovaquone 750–1500 mg PO bid with food
- 6.3. Mycobacterium tuberculosis infection
- 6.3.1. Prevention
- 6.3.1.1. Indication
- Positive screening test for latent tuberculosis infection, with no evidence of active tuberculosis, and no prior treatment for active tuberculosis or latent tuberculosis infection.
- Close contact with a person with infectious tuberculosis, with no evidence of active tuberculosis, regardless of screening test results.
- Preferred regimen: (Isoniazid 300 mg PO qd AND Pyridoxine 25 mg PO qd for 9 months) OR (Isoniazid 900 mg PO two times a week (by DOT) AND Pyridoxine 25 mg PO qd for 9 months)
- Alternative regimen (1): Rifampin 600 mg PO qd for 4 months
- Alternative regimen (2): Rifabutin (dose adjusted based on concomitant ART) PO qd for 4 months
- 6.3.2. Treatment
- Preferred regimen
- Initiation phase: Isoniazid 300 mg PO qd AND (Rifampin 600 mg PO qd OR Rifabutin 300 mg PO qd) AND Pyrazinamide (upto 2000 mg) PO qd AND Ethambutol (upto 1600 mg) PO qd for initial phase for 2 months.
- Continuation phase: Isoniazid 300 mg PO qd AND (Rifampin 600 mg PO qd OR Rifabutin 300 mg PO qd) (5–7 times/week) or three times a week.
- Duration of therapy:
- Pulmonary tuberculosis: 6 months
- Pulmonary tuberculosis and culture positive after 2 months of tuberculosis treatment: 9 months
- Extra-pulmonary tuberculosis w/CNS infection: 9–12 months
- Extra-pulmonary tuberculosis with bone or joint involvement: 6 to 9 months
- Extra-pulmonary tuberculosis in other sites: 6 months
- Total duration of therapy should be based on number of doses received, not on calendar time
- 6.3.1.3. Treatment for drug-resistant tuberculosis
- Resistant to Isoniazid:
- Preferred regimen (1): (Rifampin 600 mg PO qd OR Rifabutin 300mg PO qd) AND Ethambutol (upto 1600 mg) PO qd AND Pyrazinamide (upto 2000 mg) PO qd AND (Moxifloxacin 400 mg PO or IV qd OR Levofloxacin 500-1000 mg PO or IV qd) for 2 months; followed by Rifampin 600 mg PO qd for 7 months.
- Preferred regimen (2): Rifabutin 300mg PO qd AND Ethambutol (upto 1600 mg) PO qd AND (Moxifloxacin 400 mg PO or IV qdOR Levofloxacin 500-1000 mg PO or IV qd) for 7 months
- 6.4. Disseminated mycobacterium avium complex (MAC) disease
- 6.4.1. Prevention
- 6.4.1.1. Indication-CD4 count <50 cells/µL—after ruling out active disseminated MAC disease based on clinical assessment
- Preferred regimen (1): Azithromycin 1200 mg PO once weekly
- Preferred regimen (2): Clarithromycin 500 mg PO bid
- Preferred regimen (3): Azithromycin 600 mg PO twice weekly.
- 6.4.2. Treatment
- Preferred regimen: Clarithromycin 500 mg PO bid AND Ethambutol 15 mg/kg PO qd OR Azithromycin 500–600 mg PO qd for at least 12 months of therapy
- Note (1): Treatment can be discontinued if no signs and symptoms of MAC disease and sustained (>6 months) CD4 count >100 cells/µL in response to anti retroviral therapy.
- Note (2): Addition of a third or fourth drug should be considered for patients with advanced immunosuppression (CD4 counts <50 cells/µL), high mycobacterial loads (>2 log CFU/mL of blood), or in the absence of effective anti retroviral therapy which include Amikacin 10–15 mg/kg IV qd, Streptomycin 1 g IV or IM qd, Moxifloxacin 400 mg PO qd, Levofloxacin 500 mg PO qd.
- 6.5. Streptococcus pneumoniae infection
- 6.5.1. Prevention
- 6.5.1.1. Indication
- 6.5.1.1.1. For individuals who have not received any pneumococcal vaccine, regardless of CD4 count
- Preferred regimen: PCV13 0.5ml IM single dose
- Alternative regimen: PPV23 0.5 mL IM or SQ single dose
- Note (1): If CD4 count ≥200 cells/µL, administer PPV23 0.5 mL IM or SQ at least 8 weeks after the PCV13 vaccine.
- Note (2): If CD4 count <200 cells/µL, PPV23 can be offered at least 8 weeks after receiving PCV13 or can wait until CD4 count increased to ≥200 cells/µL.
- 6.5.1.1.2. For individuals who have previously received PPV23
- Note: One dose of PCV13 should be given atleast 1 year after the last receipt of PPV23
- 6.5.1.1.3. Re-vaccination
- If age 19–64 years and ≥5 years since the first PPV23 dose PPV23 0.5 mL IM or SQ
- If age ≥65 years, and if ≥5 years since the previous PPV23 dose PPV23 0.5 mL IM or SQ
- If age ≥65 years, and if ≥5 years since the previous PPV23 dose PPV23 0.5 mL IM or SQ
- 6.6. Influenza A and B virus infection
- 6.6.1. Prevention
- 6.6.1.1. Indication
- All HIV-infected patients
- Note (1): Inactivated influenza vaccine annually (per recommendation for the season).
- Note (2): Live-attenuated influenza vaccine is contraindicated in HIV-infected patients.
- 6.7. Syphilis
- 6.7.1. Prevention
- 6.7.1.1. Indication
- For individuals exposed to a sex partner with a diagnosis of primary, secondary, or early latent syphilis within past 90 days.
- For individuals exposed to a sex partner >90 days before syphilis diagnosis in the partner, if serologic test results are not available immediately and the opportunity for follow-up is uncertain.
- Preferred regimen: Benzathine penicillin G 2.4 million units IM single dose
- Alternative regimen (1): Doxycycline 100 mg PO bid for 14 days
- Alternative regimen (2): Ceftriaxone 1 g IM or IV q24h for 8– 10 days
- Alternative regimen (3): Azithromycin 2 g PO single dose
- Note: Azithromycin is not recommended for MSM or pregnant women.
- 6.7.2. Treatment
- 6.7.2.1. Early stage (primary, secondary, and early-latent syphilis)
- Preferred regimen: Benzathine penicillin G 2.4 million units IM single dose
- Alternative regimen (1): Doxycycline 100 mg PO bid for 14 days
- Alternative regimen (2): Ceftriaxone 1 g IM or IV q24h for 10–14 days
- Alternative regimen (3): Azithromycin 2 g PO single dose
- 6.7.2.2. Late-stage (tertiary–cardiovascular or gummatous disease)
- Preferred regimen: Benzathine penicillin G 2.4 million units IM weekly for 3 doses
- Alternative regimen: Doxycycline 100 mg PO bid for 28 days
- 6.7.2.3. Neurosyphilis (including otic or ocular disease)
- Preferred regimen: Aqueous crystalline Penicillin G 18– 24 million units per day (administered as 3–4 million units IV q4h or by continuous IV infusion) for 10–14 days with or without Benzathine penicillin G 2.4 million units IM weekly for 3 doses after completion of IV therapy
- Alternative regimen: Procaine penicillin 2.4 million units IM q24h AND Probenecid 500 mg PO qid for 10–14 days with or without Benzathine penicillin G 2.4 million units IM weekly for 3 doses after completion
- Note (1): The Jarisch-Herxheimer reaction is an acute febrile reaction accompanied by headache and myalgia that can occur within the first 24 hours after therapy for syphilis.
- Note (2): This reaction occurs most frequently in patients with early syphilis, high nontreponemal titers and prior penicillin treatment.
- 6.8. Histoplasma capsulatum infection
- 6.8.1. Prevention
- 6.8.1.1. Indication
- CD4 count ≤150 cells/µL and at high risk because of occupational exposure or live in a community with a hyperendemic rate of histoplasmosis (>10 cases/100 patient-years).
- Preferred regimen: Itraconazole 200 mg PO qd
- 6.8.2. Treatment
- 6.8.2.1. Moderately severe to severe disseminated disease
- Induction therapy (for at least 2 weeks or until clinically improved)
- Preferred regimen: Liposomal Amphotericin B 3 mg/kg IV q24h
- Maintenance therapy:
- Preferred regimen: Itraconazole 200 mg PO tid for 3 days, then 200 mg PO bid
- 6.8.2.2. Less severe disseminated disease
- Induction therapy:
- Preferred regimen: Liposomal Amphotericin B 3 mg/kg IV q24h
- Alternative regimen: Amphotericin B lipid complex 3 mg/kg IV q24h OR Amphotericin B cholesteryl sulfate complete 3 mg/kg IV q24h
- Note: Induction therapy should be for at least 2 weeks or until clinically improved.
- Maintenance therapy:
- Preferred regimen: Itraconazole 200 mg PO tid for 3 days and then Itraconazole 200 mg PO bid for 12 months
- Alternative regimen (1): Voriconazole 400 mg PO bid for 1 day, then 200 mg bid
- Alternative regimen (2): Posaconazole 400 mg PO bid
- Alternative regimen (3): Fluconazole 800 mg PO qd
- 6.8.2.3. Meningitis
- Induction therapy:
- Preferred regimen: Liposomal amphotericin B 5 mg/kg/day for 4–6 weeks
- Maintenance therapy:
- Preferred regimen: Itraconazole 200 mg PO bid to tid for ≥1 year
- Note: Treatment continued until resolution of abnormal CSF findings.
- Long-Term Suppression Therapy
- Preferred regimen: Itraconazole 200 mg PO qd
- Alternative regimen: Fluconazole 400 mg PO qd
- Note: Therapeutic drug monitoring and dosage adjustment may be necessary to ensure Triazole antifungal and ARV efficacy and reduce concentration-related toxicities.
- 6.9. Coccidioidomycosis
- 6.9.1. Prevention
- 6.9.1.1. Indication
- A new positive IgM or IgG serologic test in patients who live in a disease-endemic area and with CD4 count <250 cells/µL.
- Preferred regimen: Fluconazole 400 mg PO qd
- 6.9.2. Treatment
- 6.9.2.1. Clinically mild infections (e.g., focal pneumonia)
- Preferred regimen: Fluconazole 400 mg PO qd OR Itraconazole 200 mg PO bid
- Alternative regimen: Posaconazole 200 mg PO bid OR Voriconazole 200 mg PO bid
- 6.9.2.2. Severe, non-meningeal infection (diffuse pulmonary infection or severely ill patients with extrathoracic, disseminated disease)
- Preferred regimen: Amphotericin B deoxycholate 0.7–1.0 mg/kg IV qd OR Lipid formulation Amphotericin B 4–6 mg/kg IV qd
- Alternative regimen: Fluconazole or Itraconazole, with Itraconazole preferred for bone disease 400 mg per day to Amphotericin B therapy and continue triazole once Amphotericin B is stopped.
- 6.9.2.3. Meningeal infections
- Preferred regimen: Fluconazole 400–800 mg IV or PO qd
- Alternative regimen: Itraconazole 200 mg PO tid for 3 days, then 200 mg PO bid OR Posaconazole 200 mg PO bid OR Voriconazole 200–400 mg PO bid
- 6.9.2.4. Chronic suppressive therapy
- Preferred regimen: Fluconazole 400 mg PO qd OR Itraconazole 200 mg PO bid
- Alternative regimen: Posaconazole 200 mg PO bid OR Voriconazole 200 mg PO bid
- Note (1): Therapy should be continued indefinitely in patients with diffuse pulmonary or disseminated diseases because relapse can occur in 25%–33% of HIV-negative patients. It can also occur in HIV-infected patients with CD4 counts >250 cells/µL.
- Note (2): Therapy should be lifelong in patients with meningeal infections because relapse occurs in 80% of HIV-infected patients after discontinuation of triazole therapy.
- 6.10. Herpes simplex virus (HSV) Disease
- 6.10.1. Orolabial lesions (For 5–10 Days)
- Preferred regimen (1): Valacyclovir 1 g PO bid
- Preferred regimen (2): Famciclovir 500 mg PO bid
- Preferred regimen (3): Acyclovir 400 mg PO tid
- 6.10.2. Initial or recurrent genital HSV (For 5–14 Days)
- Preferred regimen (1): Valacyclovir 1 g PO bid
- Preferred regimen (2): Famciclovir 500 mg PO bid
- Preferred regimen (3): Acyclovir 400 mg PO tid
- 6.10.3. Severe mucocutaneous HSV
- Preferred regimen: Initial therapy Acyclovir 5 mg/kg IV q8h.
- Note: After lesions begin to regress, change to PO therapy as above. Continue until lesions are completely healed.
- 6.10.4. Chronic suppressive therapy
- Preferred regimen (1): Valacyclovir 500 mg PO bid
- Preferred regimen (2): Famciclovir 500 mg PO bid
- Preferred regimen (3): Acyclovir 400 mg PO bid
- 6.10.4. For acyclovir-resistant HSV
- Preferred therapy: Foscarnet 80–120 mg/kg/day IV q12h-q8h
- Alternative regimen: Cidofovir IV OR Topical Trifluridine OR Topical Imiquimod for 21-28 days
- Note: Continue indefinitely regardless of CD4 cell count.
- 6.11. Varicella-zoster virus (VZV) infection
- 6.11.1. Varicella-zoster virus (VZV) infection
- 6.11.1.2 Prevention
- 6.11.1.1. Pre-exposure prevention
- Indication: Patients with CD4 counts ≥200 cells/µL who have not been vaccinated, have no history of varicella or herpes zoster, or who are seronegative for VZV.
- Preferred regimen: Primary varicella vaccination, 2 doses (0.5 mL SQ each) administered 3 months apart
- Alternative regimen: VZV-susceptible household contacts of susceptible HIV-infected persons should be vaccinated to prevent potential transmission of VZV to their HIV-infected contacts
- Note (1): Routine VZV serologic testing in HIV-infected adults and adolescents is not recommended.
- Note (2): If vaccination results in disease because of vaccine virus, treatment with Acyclovir is recommended.
- 6.11.1.2. Post-exposure prevention
- Indication: Close contact with a person with chickenpox or herpes zoster; and is susceptible (i.e., no history of vaccination or of either condition, or known to be VZV seronegative).
- Preferred regimen: Varicella-zoster immune globulin (VariZIG™) 125 international units per 10 kg (maximum 625 international units) IM, administered as soon as possible and within 10 days after exposure.
- Alternative regimen (1): Acyclovir 800 mg PO qd for 5– 7 days
- Alternative regimen (2): Valacyclovir 1 g PO tid for 5–7 days
- Note (1): Individuals receiving monthly high-dose IVIG (>400 mg/kg) are likely to be protected if the last dose of IVIG was administered <3 weeks before exposure.
- Note (2): If antiviral therapy is used, varicella vaccines should not be given until at least 72 hours after the last dose of the antiviral drug.
- 6.11.1.2. Treatment
- 6.11.1.2.1 Primary varicella infection (chickenpox)
- 6.11.1.2.1. Uncomplicated cases (For 5–7 Days)
- Preferred regimen (1): Valacyclovir 1 g PO tid
- Preferred regimen (2): Famciclovir 500 mg PO tid
- 6.11.1.2.1. Severe or complicated Cases
- Preferred regimen: Acyclovir 10–15 mg/kg IV q8h for 7–10 days.
- Alternative regimen: Acyclovir 800 mg PO 5 times/day for 5-7 days.
- 6.11.1.2.2. Herpes zoster (Shingles)
- 6.11.1.2.2.1. Acute localized dermatomal
- Preferred regimen (1): Valacyclovir 1 g PO tid for 7–10 days; consider longer duration if lesions are slow to resolve
- Preferred regimen (2): Famciclovir 500 mg tid for 7–10 days; consider longer duration if lesions are slow to resolve
- 6.11.1.2.2.2. Extensive cutaneous lesion or visceral involvement
- Preferred regimen: Acyclovir 10–15 mg/kg IV q8h until clinical improvement is evident.
- Note: Treatment may switch to PO therapy (Valacyclovir, Famciclovir, or Acyclovir) after clinical improvement (i.e., when no new vesicle formation or improvement of signs and symptoms of visceral VZV), to complete a 10–14 day course.
- Alternative regimen: Acyclovir 800 mg PO 5 times/day for 7–10 days; consider longer duration if lesions are slow to resolve.
- 6.11.1.2.2.3. Progressive outer retinal necrosis (PORN)
- Preferred regimen: (Ganciclovir 5 mg/kg with or without Foscarnet 90 mg/kg) IV q12h AND (Ganciclovir 2 mg/0.05mL with or without Foscarnet 1.2 mg/0.05 ml) intravitreal injection biweekly.
- 6.11.1.2.2.4. Acute retinal necrosis (ARN)
- Preferred regimen: Acyclovir 10-15 mg/kg IV q8h AND (Ganciclovir 2 mg/0.05mL intravitreal injection 1-2 doses biweekly for 10-14 days, followed by Valacyclovir 1g PO tid for 6 weeks
- 6.12. Cytomegalovirus (CMV) Disease
- 6.12.1. Treatment
- 6.12.1.1. CMV retinitis
- Induction therapy
- Preferred regimen (1): Ganciclovir 2mg OR Foscarnet 2.4mg intravitreal injections for 1-4 doses over a period of 7-10 days to achieve high intraocular concentration faster
- Preferred regimen (2): Valganciclovir 900 mg PO bid for 14–21 days
- Alternative regimen (1): Ganciclovir 5 mg/kg IV q12h for 14–21 days
- Alternative regimen (2): Foscarnet 90 mg/kg IV q12h or 60 mg/kg q8h for 14–21 days
- Alternative regimen (3): Cidofovir 5 mg/kg/week IV for 2 weeks
- Note: Saline hydration before and after therapy should be given and Probenecid, 2 g PO 3 hours before dose, followed by 1 g PO 2 hours and 8 hours after the dose (total of 4 g) is recommended.
- Chronic maintenance (secondary prophylaxis):
- Preferred regimen: Valganciclovir 900 mg PO qd
- Alternative regimen (1): Ganciclovir 5 mg/kg IV 5–7 times weekly
- Alternative regimen (2): Foscarnet 90–120 mg/kg IV once daily
- Alternative regimen (3): Cidofovir 5 mg/kg/week IV for 2 weeks; saline hydration before and after therapy AND Probenecid, 2 g PO 3 hours before dose, followed by 1 g PO 2 hours and 8 hours after the dose (total of 4 g)
- 6.12.1.2. CMV esophagitis or colitis
- 6.12.1.2.1. Severe condition
- Preferred regimen: Ganciclovir 5 mg/kg IV q12h; may switch to Valganciclovir 900 mg PO bid once the patient can tolerate oral therapy for 21-42 days or till the symptoms are resolved
- Alternative regimen: Foscarnet 90 mg/kg IV q12h or 60 mg/kg q8h for 21-42 days
- Note: For patients with treatment-limiting toxicities to Ganciclovir or with Ganciclovir resistance, above regimen is recommended.
- 6.12.1.2.2. Mild disease and able to tolerate oral therapy
- Preferred regimen: Valganciclovir 900 mg PO bid 21-42 days
- 6.12.1.3. CMV neurological disease
- Preferred regimen: Ganciclovir 5 mg/kg IV q12h AND (Foscarnet 90 mg/kg IV q12h or 60 mg/kg IV q8h) to stabilize disease
- 6.13. HHV-8 Diseases (kaposi sarcoma [KS], primary effusion lymphoma [PEL], multicentric castleman’s disease [MCD])
- 6.13.1. Treatment
- Mild to moderate KS (ACTG Stage T0)
- Note: Initiate or optimize anti retroviral therapy.
- Advanced KS [ACTG Stage T1, Including Disseminated Cutaneous (AI) Or Visceral KS]
- Note: Chemotherapy (per oncology consult) AND anti retroviral therapy.
- Primary effusion lymphoma
- Preferred regimen (1): Valganciclovir 900 mg PO bid for 3 weeks
- Preferred regimen (2): Ganciclovir 5 mg/kg IV q12h for 3 weeks
- Preferred regimen (3): Valganciclovir 900 mg PO bid AND Zidovudine 600 mg PO qid for 7– 21 days
- Alternative regimen: Rituximab (375 mg/m2 given weekly for 4–8 weeks) may be an alternative to or used adjunctively with antiviral therapy
- Note: Valganciclovir PO OR Ganciclovir IV can be used as adjunctive therapy
- 6.14. Human papillomavirus (HPV) infection
- 6.14.1. Prevention
- For females aged 13–26 years
- Preferred regimen (1): HPV quadrivalent vaccine 0.5 mL IM at months 0, 1–2, and 6 OR HPV bivalent vaccine 0.5 mL IM at months 0, 1–2, and 6
- Males aged 13–26 years
- Preferred regimen (1): HPV quadrivalent vaccine 0.5 mL IM at months 0, 1–2, and 6
- 6.14.2. Treatment
- 6.14.2.1. Patient-applied therapy for uncomplicated external warts that can be easily identified by patients
- Preferred regimen (1): Podophyllotoxin (e.g., podofilox 0.5% solution or 0.5% gel)
- Note: Apply to all lesions bid for 3 consecutive days, followed by 4 days of no therapy, repeat weekly for up to 4 cycles, until lesions are no longer visible)
- Preferred regimen (2): Imiquimod 5% cream
- Note: Apply to lesion at bedtime and remove in the morning on 3 nonconsecutive nights weekly for up to 16 weeks, until lesions are no longer visible. Each treatment should be washed with soap and water 6–10 hours after application.
- Preferred regimen (3): Sinecatechins 15% ointment
- Note: Apply to affected areas tid for up to 16 weeks, until warts are completely cleared and not visible
- 6.14.2.2. Provider-applied therapy for complex or multicentric lesions, or lesions inaccessible to patient
- Note (1): Cryotherapy (liquid nitrogen or cryoprobe): Apply until each lesion is thoroughly frozen. Repeat every 1–2 weeks for up to 4 weeks, until lesions are no longer visible. Some providers allow the lesion to thaw, then freeze a second time in each session.
- Note (2): Trichloroacetic acid or bichloroacetic acid cauterization: 80%–90% aqueous solution, apply to wart only, allow to dry until a white frost develops. Repeat weekly for up to 6 weeks, until lesions are no longer visible.
- Note (3): Surgical excision or laser surgery to external or anal warts.
- Note (4): Podophyllin resin 10%–25% in tincture of benzoin: Apply to all lesions (up to 10 cm2 ), then wash off a few hours later, repeat weekly for up to 6 weeks until lesions are no longer visible.
- 6.15. Hepatitis A virus (HAV) infection
- 6.15.1. Prevention
- Indication: HAV-susceptible patients with chronic liver disease, or who are injection-drug users or homosexuals
- Preferred regimen: Hepatitis A vaccine 1 mL IM 2 doses at 0 and 6–12 months.
- Alternative regimen: Combined HAV and HBV vaccine 1 mL IM as a 3-dose (0, 1, and 6 months) or 4-dose series (days 0, 7, 21 to 30, and 12 months).
- Note (1): For patients susceptible to both HAV and hepatitis B virus (HBV) infection, alternative regimen is recommended.
- Note (2): IgG antibody response should be assessed 1 month after vaccination; nonresponders should be revaccinated when CD4 count >200 cells/µL.
- 6.16. Hepatitis B virus (HBV) infection
- 6.16.1. Prevention
- 6.16.1.1. Indication
- Patients without chronic HBV or without immunity to HBV (i.e., anti-HBs <10 international units/mL).
- Patients with isolated anti-HBc and negative HBV DNA.
- Early vaccination is recommended before CD4 count falls below 350 cells/µL.
- However, in patients with low CD4 cell counts, vaccination should not be deferred until CD4 count reaches >350 cells/µL, because some patients with CD4 counts <200 cells/µL do respond to vaccination.
- Preferred regimen (1): HBV vaccine IM (Engerix-B 20 µg/mL or Recombivax HB 10 µg/mL), 0, 1, and 6 months
- Preferred regimen (2): HBV vaccine IM (Engerix-B 40 µg/mL or Recombivax HB 20 µg/mL) 0, 1, 2 and 6 months
- Preferred regimen (3): Combined HAV and HBV vaccine, 1 mL IM as a 3-dose (0, 1, and 6 months) or 4-dose series (days 0, 7, 21 to 30, and 12 months)
- Alternative regimen: Some experts recommend vaccinating with 40-µg doses of either HBV vaccine
- Note: Anti-HBs should be obtained 1 month after completion of the vaccine series. Patients with anti-HBs <10 international units/mL at 1 month are considered nonresponders.
- Vaccine Non-Responders:
- Preferred regimen (1): HBV vaccine IM (Engerix-B 40 µg/mL or Recombivax HB 20 µg/mL), 0, 1, 2 and 6 months.
- Note (1): Vaccination non-responders have anti-HBs <10 international units/mL 1 month after vaccination series.
- Note (2): For patients with low CD4 counts at time of first vaccine series, some experts might delay revaccination until after a sustained increase in CD4 count with anti retroviral therapy.
- 6.16.2. Treatment
- Preferred regimen: Tenofovir 300 mg PO qdAND Emtricitabine 200 mg PO qd OR Lamivudine 300 mg PO qd AND additional drug(s) for HIV
- Note: Anti retroviral therapy regimen should include 2 drugs that are active against both HBV and HIV.
- Alternative regimen: Peginterferon alfa-2a 180 μg SQ once weekly for 48 weeks OR Peginterferon alfa 2b 1.5 μg/kg SQ once weekly for 48 weeks.
- Note: For HBV treatment is indicated for patients with elevated ALT and HBV DNA >2,000 IU/mL significant liver fibrosis, advanced liver disease or cirrhosis, above regimen is indicated.
- 6.17. Penicilliosis marneffei
- 6.17.1. Prevention
- 6.17.1.1. Indication
- Patients with CD4 cell counts <100 cells/µL who live or stay for a long period in rural areas in northern Thailand, Vietnam, or Southern China.
- Preferred regimen: Itraconazole 200 mg PO qd
- Alternative regimen: Fluconazole 400 mg PO once weekly
- 6.17.2. Treatment
- 6.17.2.1. For acute infection in severely ill patients
- Preferred regimen: Liposomal amphotericin B 3–5 mg/kg/day IV for 2 weeks, followed by Itraconazole 200 mg PO bid for 10 weeks, followed by chronic maintenance therapy
- Alternative regimen: Voriconazole 6 mg/kg IV q12h for 1 day, then 4 mg/kg IV q12h for at least 3 days, followed by 200 mg PO bid for a maximum of 12 weeks, followed by maintenance therapy
- 6.17.2.2. For mild disease
- Preferred regimen: Itraconazole 200 mg PO bid for 8 weeks; followed by chronic maintenance therapy
- Alternative regimen: Voriconazole 400 mg PO bid for 1 day, then 200 mg bid for a maximum of 12 weeks, followed by chronic maintenance therapy
- 6.17.2.3. Chronic Maintenance Therapy (Secondary Prophylaxis)
- Preferred regimen: Itraconazole 200 mg PO qd
- Note (1): Anti retroviral therapy should be initiated simultaneously with treatment for penicilliosis to improve treatment outcome.
- Note (2): Itraconazole and Voriconazole may have significant interactions with certain ARV agents. These interactions are complex and can be bi-directional.
- Note (3): Therapeutic drug monitoring and dosage adjustment may be necessary to ensure triazole antifungal and ARV efficacy and reduce concentration-related toxicities.
- 6.18. Isosporiasis
- 6.18.1. Treatment
- For Acute Infection:
- Preferred regimen (1): Trimethoprim/Sulfamethoxazole 160 mg/800 mg PO (or IV) qid for 10 days
- Preferred regimen (2): Trimethoprim/Sulfamethoxazole 160 mg/800 mg PO (or IV) bid for 7–10 days
- Alternative regimen (1): Pyrimethamine 50–75 mg PO daily AND Leucovorin 10–25 mg PO qd
- Alternative regimen (2): Ciprofloxacin 500 mg PO bid for 7 days as a second line alternative
- Chronic Maintenance Therapy (Secondary Prophylaxis):
- Preferred regimen (1): In patients with CD4 count <200/µL, Trimethoprim/sulfamethoxazole 160 mg/800 mg PO three times a week
- Alternative regimen (1): Trimethoprim/sulfamethoxazole 160 mg/800 mg PO qd or (320 mg/1600 mg) three times a week
- Alternative regimen (2): Pyrimethamine 25 mg PO qd AND Leucovorin 5–10 mg PO qd
- Alternative regimen (3): Ciprofloxacin 500 mg three times a week as a second-line alternative
- Note (1): Fluid and electrolyte management in patients with dehydration.
- Note (2): Immune reconstitution with anti retroviral therapy may result in fewer relapses.
- Note (3): IV therapy may be used for patients with potential or documented mal-absorption.
- 6.19. Chagas disease (American trypanosomiasis)
- 6.19.1. Treatment
- For acute, earlychronic, and reactivated Disease:
- Preferred regimen: Benznidazole 5–8 mg/kg/day PO in 2 divided doses for 30–60 days
- Alternative regimen: Nifurtimox 8–10 mg/kg/day PO for 90–120 days.
- 6.20. Leishmaniasis, visceral
- 6.20.1. Leishmaniasis, visceral
- 6.20.1.1. Treatment
- For initial infection:
- Preferred regimen (1): Liposomal amphotericin B 2–4 mg/kg IV qd
- Preferred regimen (2): Liposomal amphotericin B interrupted schedule (e.g., 4 mg/kg on days 1–5, 10, 17, 24, 31, 38)
- Alternative regimen (1): Amphotericin B deoxycholate 0.5–1.0 mg/kg IV q24h for total dose of 1.5–2.0 g
- Alternative regimen (2): Sodium stibogluconate (pentavalent antimony) 20 mg/kg IV or IM q24h for 28 days
- Alternative regimen (3): Miltefosine 100 mg PO qd for 4 weeks
- Chronic maintenance therapy (secondary prophylaxis); Especially in Patients with CD4 Count <200 cells/µL:
- Preferred regimen (1): Liposomal amphotericin B 4 mg/kg every 2–4 weeks
- Preferred regimen (2): Amphotericin B lipid complex 3 mg/kg every 21 days
- Alternative regimen: Sodium stibogluconate 20 mg/kg IV or IM every 4 weeks
- 6.20.2. Leishmaniasis, cutaneous
- Preferred regimen (1): Liposomal amphotericin B 2–4 mg/kg IV daily for 10 days
- Preferred regimen (2): Liposomal amphotericin B interrupted schedule (e.g., 4 mg/kg on days 1–5, 10, 17, 24, 31, 38) to achieve total dose of 20–60 mg/kg
- Preferred regimen (3): Sodium stibogluconate 20 mg/kg IV or IM daily for 3–4 weeks
- 6.21. Aspergillosis, invasive
- 6.21.1. Treatment
- Preferred regimen: Voriconazole 6 mg/kg IV q12h for 1 day, then 4 mg/kg IV q12h, followed by Voriconazole 200 mg PO q12h after clinical improvement until CD4 cell count >200 cells/µL and the infection appears to be resolved.
- Alternative regimen (1): Lipid formulation of Amphotericin B 5 mg/kg IV q24h
- Alternative regimen (2): Amphotericin B deoxycholate 1mg/kg IV q24h
- Alternative regimen (3): Caspofungin 70 mg IV single dose, then 50 mg IV q24h
- Alternative regimen (4): Micafungin 100–150 mg IV q24h
- Alternative regimen (5): Anidulafungin 200 mg IV single dose, then 100 mg IV q24h
- Alternative regimen (6): Posaconazole 200 mg PO qid, then, after condition improved, 400 mg PO bid
- 6.22. Malaria
- 6.22.1. Prevetion
- 6.22.1.1. Prophylaxis in all areas
- Preferred regimen (1): Atovaquone 250 mg and Proguanil hydrochloride 100 mg PO qd
- Pediatric doses: Pediatric tablets contain 62.5 mg atovaquone and 25 mg proguanil hydrochloride
- 5–8 kg: 1/2 pediatric tablet daily
- >8–10 kg: 3/4 pediatric tablet daily
- >10–20 kg: 1 pediatric tablet daily
- >20–30 kg: 2 pediatric tablets daily
- >30–40 kg: 3 pediatric tablets daily
- Note (1): Begin 1–2 days before travel to malarious areas. Take daily at the same time each day while in the malarious area and for 7 days after leaving such areas. Contraindicated in people with severe renal impairment (creatinine clearance <30 mL/min).
- Note (2): Atovaquone-proguanil should be taken with food or a milky drink. Not recommended for prophylaxis for children weighing <5 kg, pregnant women, and women breastfeeding infants weighing <5 kg. Partial tablet doses may need to be prepared by a pharmacist and dispensed in individual capsules.
- Preferred regimen (2): Doxycycline 100 mg PO qd
- Pediatric dose: ≥8 years of age: 2.2 mg/kg up to adult dose of 100 mg/day
- Note: Begin 1–2 days before travel to malarious areas. Take daily at the same time each day while in the malarious area and for 4 weeks after leaving such areas. Contraindicated in children <8 years of age and pregnant women.
- 6.22.1.2. Prophylaxis only in areas with chloroquine-sensitive malaria
- Preferred regimen: Chloroquine phosphate 300 mg base (500 mg salt) PO once a week
- Note: Begin 1–2 weeks before travel to malarious areas. Take weekly on the same day of the week while in the malarious area and for 4 weeks after leaving such areas. May exacerbate psoriasis.
- Alternative regimen: Hydroxychloroquine sulfate 400 mg salt PO once a week
- Note: Begin 1–2 weeks before travel to malarious areas. Take weekly on the same day of the week while in the malarious area and for 4 weeks after leaving such areas.
- Pediatric doses: Chloroquine phosphate 5 mg/kg base (8.3 mg/kg salt) orally, once/week, up to maximum adult dose of 300 mg base; Hydroxychloroquine sulfate 5 mg/kg base (6.5 mg/kg salt) orally, once/week, up to a maximum adult dose of 310 mg base
- 6.22.1.3. Prophylaxis in areas with mefloquine-sensitive malaria
- Preferred regimen: Mefloquine 250 mg PO once a week
- Note (1): Begin ≥2 weeks before travel to malarious areas. Take weekly on the same day of the week while in the malarious area and for 4 weeks after leaving such areas. Contraindicated in people allergic to mefloquine or related compounds (quinine, quinidine) and in people with active depression, a recent history of depression, generalized anxiety disorder, psychosis, schizophrenia, other major psychiatric disorders, or seizures.
- Note (2): Use with caution in persons with psychiatric disturbances or a previous history of depression. Not recommended for persons with cardiac conduction abnormalities.
- Pediatric dose: Mefloquine ≤9 kg: 4.6 mg/kg base (5 mg/kg salt) orally, once/week
- >9–19 kg: 1/4 tablet once/week
- >19–30 kg: 1/2 tablet once/week
- >30–45 kg: 3/4 tablet once/week
- >30–45 kg: 3/4 tablet once/week
- 6.22.1.4. Prophylaxis for short-duration travel to areas with principally Plasmodium vivax
- Preferred regimen: Primaquine 52.6 mg PO qd
- Note: Begin 1–2 days before travel to malarious areas. Take daily at the same time each day while in the malarious area and for 7 days after leaving such areas. Contraindicated in people with G6PD deficiency. Also contraindicated during pregnancy and lactation, unless the infant being breastfed has a documented normal G6PD level.
- Pediatric dose: Primaquine 0.5 mg/kg base (0.8 mg/kg salt) up to adult dose orally, daily
- 6.22.1.5. Terminal prophylaxis to decrease the risk for relapses of Plasmodium vivax and Plasmodium ovale
- Preferred regimen: Primaquine 52.6 mg PO qd for 14 days after departure from the malarious area
- Note: Indicated for people who have had prolonged exposure to P. vivax, P. ovale, or both. Contraindicated in people with G6PD deficiency. Also contraindicated during pregnancy and lactation, unless the infant being breastfed has a documented normal G6PD level.
- Pediatric dose: Primaquine 0.5 mg/kg base (0.8 mg/kg salt) up to adult dose orally, daily for 14 days after departure from the malarious area
- 6.22.2. Treatment
- Note (1): Patients coinfected with HIV should avoid Artesunate AND Sulfadoxine-Pyrimethamine if they are also receiving Co-trimoxazole, and avoid Artesunate AND Amodiaquine if they are also receiving Efavirenz OR Zidovudine.
- Note (2): Because Plasmodium falciparum malaria can progress within hours from mild symptoms or low-grade fever to severe disease or death, all HIV-infected patients with confirmed or suspected P. falciparum infection should be hospitalized for evaluation, initiation of treatment, and observation.
- 6.22.2.1. Plasmodium falciparum[2]
- 6.22.2.1.1. Treatment of uncomplicated Plasmodium falciparum malaria
- 6.22.2.1.1.1. Treat children and adults with uncomplicated Plasmodium falciparum malaria (except pregnant women in their first trimester) with one of the following recommended ACT (artemisinin-based combination therapy)
- Preferred regimen (1): Artemether 5–24 mg/kg/day PO bid AND Lumefantrine 29–144 mg/kg/day PO bid for 3 days
- Note: The first two doses should, ideally, be given 8 hours apart.
- Dosage regimen based on Body weight (kg)
- Body weight (kg)-5 to < 15- Artemether 20 mg PO bid AND Lumefantrine 120 mg PO bid for 3 days
- Body weight (kg)-15 to < 25- Artemether 40 mg PO bid AND Lumefantrine 240 mg PO bid for 3 days
- Body weight (kg)-25 to < 35- Artemether 60 mg PO bid AND Lumefantrine 360 mg PO bid for 3 days
- Body weight (kg) ≥ 35- Artemether 80 mg PO bid AND Lumefantrine 480 mg PO bid for 3 days
- Preferred regimen (2): Artesunate 2–10 mg/kg/day PO qd AND Amodiaquine 7.5–15 mg/kg/day PO qd for 3 days
- Note: A total therapeutic dose range of 6–30 mg/kg/day Artesunate and 22.5–45 mg/kg/day per dose Amodiaquine is recommended.
- Dosage regimen based on body weight (kg)
- Body weight (kg)-4.5 to < 9- Artesunate 25 mg PO qd AND Amodiaquine 67.5 mg PO qd for 3 days
- Body weight (kg)-9 to < 18 - Artesunate 50 mg PO qd AND Amodiaquine 135 mg PO qd for 3 days
- Body weight (kg)-18 to < 36- Artesunate 100 mg PO qd AND Amodiaquine 270 mg PO qd for 3 days
- Body weight (kg) ≥ 36 - Artesunate 200 mg PO qd AND Amodiaquine 540 mg PO qd for 3 days
- Preferred regimen (3): Artesunate 2–10 mg/kg/day PO qd AND Mefloquine 2–10 mg/kg/day PO qd for 3 days
- Dosage regimen based on body weight (kg)
- Body weight (kg)-5 to < 9- Artesunate 25 mg PO qd AND Mefloquine 55 mg PO qd for 3 days
- Body weight (kg)-9to < 18- Artesunate 50 mg PO qd AND Mefloquine 110 mg PO qd for 3 days
- Body weight (kg)-18 to < 36- Artesunate 100 mg PO qd AND Mefloquine 220 mg PO qd for 3 days
- Body weight (kg)- ≥ 36 - Artesunate 200 mg PO qd AND Mefloquine 440 mg PO qd for 3 days
- Preferred regimen (4): Artesunate 2–10 mg/kg/day PO qd for 3 days AND Sulfadoxine-Pyrimethamine 1.25 (25–70 / 1.25–3.5) mg/kg/day PO given as a single dose on day 1
- Dosage regimen based on body weight (kg)
- Body weight (kg)- 5 to < 10- Artesunate 25 mg PO qd for 3 days AND Sulfadoxine-Pyrimethamine 250/12 mg PO given as a single dose on day 1
- Body weight (kg)- 10 to < 25- Artesunate 50 mg PO qd for 3 days AND Sulfadoxine-Pyrimethamine 500/25 mg PO given as a single dose on day 1
- Body weight (kg)- 25 to < 50- Artesunate 100 mg PO qd for 3 days AND Sulfadoxine-Pyrimethamine 1000/50 mg PO given as a single dose on day 1
- Body weight (kg)- ≥50- Artesunate 200 mg PO qd for 3 days AND Sulfadoxine-Pyrimethamine 1500/75 mg PO given as a single dose on day 1
- Preferred regimen (5): Dihydroartemisinin 2–10 mg/kg/day PO qd AND Piperaquine16–27 mg/kg/day PO qd for 3 days
- Dosage regimen based on Body weight (kg)
- Body weight (kg)-5 to < 8: Dihydroartemisinin 20 mg PO qd AND Piperaquine 160 mg PO qd for 3 days
- Body weight (kg)-8 to < 11: Dihydroartemisinin 30 mg PO qd AND Piperaquine 240 mg PO qd for 3 days
- Body weight (kg)-11 to < 17: Dihydroartemisinin 40 mg PO qd AND Piperaquine 320 mg PO qd for 3 days
- Body weight (kg)-17 to < 25: Dihydroartemisinin 60 mg PO qd AND Piperaquine 480 mg PO qd for 3 days
- Body weight (kg)-25 to < 36: Dihydroartemisinin 80 mg PO qd AND Piperaquine 640 mg PO qd for 3 days
- Body weight (kg)-36 to < 60: Dihydroartemisinin 120 mg PO qd AND Piperaquine 960 mg PO qd for 3 days
- Body weight (kg)-60 < 80: Dihydroartemisinin 160 mg PO qd AND Piperaquine 1280 mg PO qd for 3 days
- Body weight (kg)- >80: Dose of Dihydroartemisinin 200 mg PO qd AND Piperaquine 1600 mg PO qd for 3 days
- 6.22.2.1.1.2 Reducing the transmissibility of treated Plasmodium falciparum infections In low-transmission areas in patients with Plasmodium falciparum malaria (except pregnant women, infants aged < 6 months and women breastfeeding infants aged < 6 months)
- Preferred regimen: Primaquine 0.25 mg/kg PO single dose with ACT
- 6.22.2.1.2. Recurrent falciparum malaria
- 6.22.2.1.2.1. Failure within 28 days
- Note: The recommended second-line treatment is an alternative ACT known to be effective in the region. Adherence to 7-day treatment regimens with Artesunate or Quinine both of which should be co-administered with Tetracycline, or Doxycycline or Clindamycin) is likely to be poor if treatment is not directly observed; these regimens are no longer generally recommended.
- 6.22.2.1.2.2. Failure after 28 days
- Note: All presumed treatment failures after 4 weeks of initial treatment should, from an operational standpoint, be considered new infections and be treated with the first-line ACT. However, reuse of Mefloquine within 60 days of first treatment is associated with an increased risk for neuropsychiatric reactions, and an alternative ACT should be used.
- 6.22.2.1.3. Reducing the transmissibility of treated Plasmodium falciparum infections in low-transmission areas in patients with Plasmodium falciparum malaria (except pregnant women, infants aged < 6 months and women breastfeeding infants aged < 6 months)
- Note: Single dose of 0.25 mg/kg biweekly Primaquine with ACT
- 6.22.2.1.4. Treating uncomplicated Plasmodium falciparum malaria in special risk groups
- 6.22.2.1.4.1. Pregnancy
- First trimester of pregnancy : Quinine AND Clindamycin 10 mg/kg/day PO bid for 7 days
- Second and third trimesters : Mefloquine is considered safe for the treatment of malaria during the second and third trimesters; however, it should be given only in combination with an artemisinin derivative.
- Note (1): Quinine is associated with an increased risk for hypoglycaemia in late pregnancy, and it should be used (with clindamycin) only if effective alternatives are not available.
- Note (2): Primaquine and Tetracyclines should not be used in pregnancy.
- 6.22.2.1.4.2. Infants less than 5kg body weight
- Note: They should be treated with an ACT at the same mg/kg bw target dose as for children weighing 5 kg.
- 6.22.2.1.4.4. Large and obese adults
- Note: For obese patients, less drug is often distributed to fat than to other tissues; therefore, they should be dosed on the basis of an estimate of lean body weight, ideal body weight. Patients who are heavy but not obese require the same mg/kg bw doses as lighter patients.
- 6.22.2.1.4.5. Non-immune travellers
- Note: Treat travellers with uncomplicated P. falciparum malaria returning to nonendemic settings with an ACT.
- 6.22.2.1.4.6. Uncomplicated hyperparasitaemia
- Note: People with P. falciparum hyperparasitaemia are at increased risk of treatment failure, severe malaria and death so should be closely monitored, in addition to receiving an ACT.
- 6.22.2.2. Treatment of uncomplicated malaria caused by Plasmodium vivax, Plasmodium ovale, Plasmodium malariae or Plasmodium knowlesi
- 6.22.2.2.1. Blood Stage infection
- 6.22.2.2.1.1. Uncomplicated malaria caused by Plasmodium vivax
- 6.22.2.2.1.1.1. In areas with chloroquine-sensitive Plasmodium vivax
- Preferred regimen: Chloroquine total dose of 25 mg/kg PO. Chloroquine is given at an initial dose of 10 mg/kg, followed by 10 mg/kg on the second day and 5 mg/kg on the third day PO
- 6.22.2.2.1.1.2. In areas with chloroquine-resistant Plasmodium vivax
- Note: ACTs containing Piperaquine, Mefloquine OR Lumefantrine are the recommended treatment, although Artesunate AND Amodiaquine may also be effective in some areas. In the systematic review of ACTs for treating P. vivax malaria, Dihydroartemisinin AND Piperaquine provided a longer prophylactic effect than ACTs with shorter half-lives (Artemether ANDLumefantrine) OR (Artesunate AND Amodiaquine), with significantly fewer recurrent parasitaemias during 9 weeks of follow-up.
- 6.22.2.2.1.2. Uncomplicated malaria caused by Plasmodium ovale, Plasmodium malariae or Plasmodium knowlesi malaria
- Note: Resistance of P. ovale, P. malariae and P. knowlesi to antimalarial drugs is not well characterized, and infections caused by these three species are generally considered to be sensitive to Chloroquine. In only one study, conducted in Indonesia, was resistance to Chloroquine reported in P. malariae. The blood stages of P. ovale, P. malariae and P. knowlesi should therefore be treated with the standard regimen of ACT or Chloroquine, as for vivax malaria.
- 6.22.2.2.1.3. Mixed malaria infections
- Note: ACTs are effective against all malaria species and so are the treatment of choice for mixed infections.
- 6.22.2.2.2. Liver stages (hypnozoites) of Plasmodium vivax and Plasmodium ovale
- Note: To prevent relapse, treat P. vivax or P. ovale malaria in children and adults (except pregnant women, infants aged < 6 months, women breastfeeding infants < 6 months, women breastfeeding older infants unless they are known not to be G6PD deficient and people with G6PD deficiency) with a 14-day course of Primaquine in all transmission settings. Strong recommendation, high-quality evidence In people with G6PD deficiency, consider preventing relapse by giving primaquine base at 0.75 mg base/kg bw once a week for 8 weeks, with close medical supervision for potential primaquine-induced adverse haematological effects.
- 6.22.2.2.2.1. Primaquine for preventive relapse
- Preferred regimen: Primaquine 0.25–0.5 mg/kg/day PO qd for 14 days
- 6.22.2.2.2.2. Primaquine and glucose-6-phosphate dehydrogenase deficiency
- Preferred regimen: Primaquine 0.75 mg base/kg/day PO once a week for 8 weeks
- Note: The decision to give or withhold Primaquine should depend on the possibility of giving the treatment under close medical supervision, with ready access to health facilities with blood transfusion services.
- 6.22.2.2.2.3. Prevention of relapse in pregnant or lacating women and infants
- Note: Primaquine is contraindicated in pregnant women, infants < 6 months of age and in lactating women (unless the infant is known not to be G6PD deficient)
- 6.22.2.3. Treatment of severe malaria
- 6.22.2.3.1. Treatment of severe falciparum infection with Artesunate
- 6.22.2.3.1.1. Adults and children with severe malaria (including infants, pregnant women in all trimesters and lactating women)
- Preferred regimen: Artesunate IV/IM for at least 24 h and until they can tolerate oral medication. Once a patient has received at least 24 h of parenteral therapy and can tolerate oral therapy, complete treatment with 3 days of an ACT (add single dose Primaquine in areas of low transmission).
- 6.22.2.3.1.2. Young children weighing < 20 kg
- Preferred regimen:Artesunate 3 mg/kg per dose IV/IM q24h
- Alternative regimen: use Artemether in preference to quinine for treating children and adults with severe malaria
- 6.22.2.3.2.Treating cases of suspected severe malaria pending transfer to a higher-level facility (pre-referral treatment)
- 6.22.2.3.2.1. Adults and children
- Preferred regimen: Artesunate IM q24h
- Alternative regimen: Artemether IM OR Quinine IM
- 6.22.2.3.2.2. Children < 6 years
- Preferred regimen: Where intramuscular injections of artesunate are not available, treat with a single rectal dose (10 mg/kg) of Artesunate, and refer immediately to an appropriate facility for further care.
- Note: Do not use rectal artesunate in older children and adults.
- 6.22.2.3.3. Pregancy
- Note: Parenteral artesunate is the treatment of choice in all trimesters. Treatment must not be delayed.
- 6.22.2.3.4. Treatment of severe Plasmodium Vivax infection
- Note: Parenteral Artesunate, treatment can be completed with a full treatment course of oral ACT or Chloroquine (in countries where Chloroquine is the treatment of choice). A full course of radical treatment with Primaquine should be given after recovery.
- 6.22.2.3.5. Additional aspects of management in severe malaria
- Fluid therapy: It is not possible to give general recommendations on fluid replacement; each patient must be assessed individually and fluid resuscitation based on the estimated deficit.
- Blood Transfusion: In high-transmission settings, blood transfusion is generally recommended for children with a haemoglobin level of < 5 g/100 mL(haematocrit < 15%). In low-transmission settings, a threshold of 20% (haemoglobin,7 g/100 mL) is recommended.
- Exchange blood transfusion: Exchange blood transfusion requires intensive nursing care and a relatively large volume of blood, and it carries significant risks. There is no consensus on the indications, benefits and dangers involved or on practical details such as the volume of blood that should be exchanged. It is, therefore, not possible to make any recommendation regarding the use of exchange blood transfusion.
- 6.23. Cryptococcosis
- 6.23.1. Treatment
- 6.23.1.1. Cryptococcal meningitis
- 6.23.1.1.1. Induction therapy
- Preferred regimen: Liposomal amphotericin B 3–4 mg/kg IV q24h AND Flucytosine 25 mg/kg PO qid for at least 2 weeks, followed by consolidation therapy
- Alternative regimen (1): Amphotericin B deoxycholate 0.7 mg/kg IV q24h AND Flucytosine 25 mg/kg PO qid
- Alternative regimen (2): Amphotericin B lipid complex 5 mg/kg IV q24h AND Flucytosine 25 mg/kg PO qid
- Alternative regimen (3): Liposomal Amphotericin B 3-4 mg/kg IV q24h AND Fluconazole 800 mg PO or IV q24h
- Alternative regimen (4): Amphotericin B deoxycholate 0.7 mg/kg IV q24h AND Fluconazole 800 mg PO or IV q24h
- Alternative regimen (5): Fluconazole 400–800 mg PO or IV qd AND Flucytosine 25 mg/kg PO qid
- Alternative regimen (6): Fluconazole 1200 mg PO or IV qd
- 6.23.1.1.2. Consolidation therapy
- Preferred regimen: Fluconazole 400 mg PO (or IV) qd for atleast 8 weeks
- Note: Preferred therapy followed by maintenance therapy.
- Maintenance therapy: Fluconazole 200 mg PO qd for at least 12 months
- Alternative regimen: Itraconazole 200 mg PO bid for 8 weeks
- 6.23.1.2. Non-CNS cryptococcosis with mild-to-moderate symptoms and focal pulmonary infiltrates
- Preferred regimen: Fluconazole, 400 mg PO qd for 12 months
- Note: Patients receiving Flucytosine should have either blood levels monitored (peak level 2 hours after dose should be 30–80 mcg/mL) or close monitoring of blood counts for development of cytopenia. Dosage should be adjusted in patients with renal insufficiency.
- 6.24. Mucocutaneous candidiasis
- 6.24.1. Treatment
- 6.24.1.1. For oropharyngeal candidiasis
- Oral Therapy
- Preferred regimen: Fluconazole 100 mg PO qd for 7-14 days.
- Alternative regimen: Itraconazole oral solution 200 mg PO qd for 7-14 days OR Posaconazole oral suspension 400 mg PO bid for 1 day, then 400 mg qd 7-14 days
- Topical therapy
- Preferred regimen: Clotrimazole troches, 10 mg PO 5 times daily OR Miconazole mucoadhesive buccal 50-mg tablet
- Note: Apply to mucosal surface over the canine fossa once daily (do not swallow, chew, or crush).
- Alternative regimen: Nystatin suspension 4–6 mL qid or 1–2 flavored pastilles 4– 5 times daily
- 6.24.1.2. For esophageal candidiasis
- Preferred regimen: Fluconazole 100 mg (up to 400 mg) PO or IV qd for 14-21 days OR Itraconazole oral solution 200 mg PO qd for 14-21 days
- Alternative regimen (1): Voriconazole 200 mg PO or IV bid for 14-21 days
- Alternative regimen (2): Anidulafungin 100 mg IV single dose, then 50 mg IV qd for 14-21 days
- Alternative regimen (3): Caspofungin 50 mg IV qd for 14-21 days
- Alternative regimen (4): Micafungin 150 mg IV qd for 14-21 days
- Alternative regimen (5): Amphotericin B deoxycholate 0.6 mg/kg IV qd for 14-21 days
- Alternative regimen (6): Lipid formulation of amphotericin B 3–4 mg/kg IV qd for 14-21 days
- 6.24.1.3. For uncomplicated vulvo-vaginal candidiasis
- Preferred regimen: Oral Fluconazole 150 mg for 1 dose OR Topical azoles (Clotrimazole, Butoconazole, Miconazole, Tioconazole, or Terconazole) for 3– 7 days
- Alternative regimen: Itraconazole oral solution 200 mg PO qd for 3–7 days
- 6.24.1.4. For severe or recurrent vulvovaginal candidiasis
- Preferred regimen: Fluconazole 100–200 mg PO qd for ≥7 days OR Topical antifungal ≥7 days
- 6.25. Bartonellosis
- 6.25.1. Treatment
- 6.25.1.1. For bacillary angiomatosis, peliosis hepatis, bacteremia, and osteomyelitis
- Preferred regimen (1): Doxycycline 100 mg PO or IV q12h for 3 months
- Preferred regimen (2): Erythromycin 500 mg PO or IV q6h for 3 months
- Alternative regimen (1): Azithromycin 500 mg PO qd
- Alternative regimen (2):} Clarithromycin 500 mg PO bid
- 6.25.1.2. Confirmed bartonella endocarditis
- Preferred regimen: Doxycycline 100 mg IV q12h AND Gentamicin 1 mg/kg IV q8h) for 2 weeks, then continue with Doxycycline 100 mg IV or PO q12h
- Altered regimen: Doxycycline 100 mg IV AND Rifabutin 300 mg PO or IV q12h for 2 weeks, then continue with Doxycycline 100 mg IV or PI q12h
- 6.25.1.3. CNS infections
- Preferred regimen: (Doxycycline 100 mg with or without Rifabutin 300 mg PO or IV q12h
- 6.25.1.4. Other severe infections
- Preferred regimen (1): Doxycycline 100 mg PO or IV with or without Rifabutin 300 mg PO or IV) q12h for 3 months
- Preferred regimen (2): Erythromycin 500 mg PO or IV q6h) with or without Rifabutin) 300 mg PO or IV q12h for 3 months.
- Note: If relapse occurs after initial (>3 month) course of therapy, longterm suppression with Doxycycline or a macrolide is recommended as long as CD4 count <200 cells/µL.
- 6.26. Campylobacteriosis
- 6.26.1. Treatment
- 6.26.1.1. For mild-to-moderate disease (If Susceptible)
- Preferred regimen: Ciprofloxacin 500–750 mg PO or 400 mg IV q12h OR Azithromycin 500 mg PO qd
- Alternative regimen: Levofloxacin 750 mg PO or IV q24h OR Moxifloxacin 400 mg (PO or IV) q24h
- 6.26.1.2. For campylobacter bacteremia
- Preferred regimen: Ciprofloxacin 500–750 mg PO or 400 mg IV q12h AND an aminoglycoside.
- Duration of Therapy:
- Gastroenteritis: 7–10 days (5 days with Azithromycin)
- Bacteremia: ≥14 days
- Recurrent bacteremia: 2–6 weeks.
- 6.27. Shigellosis
- 6.27.1. Treatment
- Preferred regimen: Ciprofloxacin 500–750 mg PO or 400 mg IV q12h
- Duration of Therapy:
- Gastroenteritis: 7–10 days
- Bacteremia: ≥14 days
- Recurrent Infections: 2–6 weeks
- Alternative regimen (1): Levofloxacin 750 mg PO or IV q24h for 5 days
- Alternative regimen (2): Moxifloxacin 400 mg PO or IV q24h for 5 days
- Alternative regimen (3): Trimethoprim/Sulfamethoxazole 160 mg/800 mg PO or IV q12h for 5 days
- Alternative regimen (4): Azithromycin 500 mg PO qd for 5 days
- Note: Antimotility agents should be avoided.
- 6.28. Salmonellosis
- 6.28.1. Treatment
- Preferred regimen: Ciprofloxacin 500–750 mg PO or 400 mg IV q12h
- Alternative regimen (1): Levofloxacin 750 mg PO or IV q24h
- Alternative regimen (2): Moxifloxacin 400 mg PO or IV q24h
- Alternative regimen (3): Trimethoprim/Sulfamethoxazole 160 mg/800 mg PO or IV q12h
- Alternative regimen (4): Cefotaxime 1 g IV q8h
- Alternative regimen (5): Ceftriaxone 1 g IV q24h
- Duration of therapy:
- For gastroenteritis without bacteremia:
- If CD4 count ≥200 cells/µL: 7–14 days.
- If CD4 count <200 cells/µL: 2–6 weeks.
- For gastroenteritis with bacteremia:
- If CD4 count ≥200/µL: 14 days; longer duration if bacteremia persists or if the infection is complicated (e.g., if metastatic foci of infection are present)
- If CD4 count <200 cells/µL: 2–6 weeks
- Note (1): The role of long-term secondary prophylaxis in patients with recurrent Salmonella bacteremia is not well established. Must weigh benefit against risks of long-term antibiotic exposure.
- Note (2): Secondary Prophylaxis Should Be Considered For:
- Patients with recurrent Salmonella gastroenteritis +/- bacteremia.
- Patients with CD4 <200 cells/µL with severe diarrhea.
- 6.29. Bacterial enteric infections
- 6.29.1. Empiric therapy
- Preferred regimen: Ciprofloxacin 500–750 mg PO or 400 mg IV q12h
- Alternative regimen: Ceftriaxone 1 g IV q24h OR Cefotaxime 1 g IV q8h
- Note: Antimotility agents should be avoided if there is concern about inflammatory diarrhea, including Clostridium-difficile-associated diarrhea.
- 6.30.Bacterial respiratory diseases
- 6.30.1. Treatment
- 6.30.1.1. Empiric outpatient therapy
- Preferred regimen: Amoxicillin 500 mg PO AND (Azithromycin 500 mg PO OR Clarithromycin 500 mg PO) qd for 7-10 days
- Alternative regimen: Amoxicillin 500 mg PO AND Doxycycline 100mg PO qd
- Note: Therapy should be adjusted based on the results of diagnostic workup.
- 6.30.1.2. For penicillin-allergic patients
- Preferred regimen: Ceftriaxone 1 g IV q24h AND (Azithromycin 500 mg PO OR Clarithromycin 500 mg PO) qd for 7-10 days
- Alternative regimen: Aztreonam 1 g IV q24h AND Levofloxacin 750 mg IV q24h OR Moxifloxacin 400 mg IV q24h
- 6.30.1.3. Empiric therapy for non-ICU hospitalized patients
- Preferred regimen: Ceftriaxone 1 g IV q24h AND (Azithromycin 500 mg PO OR Clarithromycin 500 mg PO) qd
- 6.30.1.3. Empiric therapy for patients at risk of pseudomonas pneumonia
- Preferred regimen: : Piperacillin-Tazobactam 2 g-0.25 g IV q24h AND (Ciprofloxacin 400 mg IV q8–12h OR Levofloxacin 750 mg IV) q24h
- 6.30.1.4. Empiric therapy for patients at risk for methicillin-resistant staphylococcus aureus pneumonia
- Preferred regimen: Amoxicillin 500 mg PO AND (Azithromycin 500 mg PO OR Clarithromycin 500 mg) PO AND Linezolid 600 mg (IV or PO).
- Note (1): Empiric therapy with a macrolide alone is not routinely recommended, because of increasing pneumococcal resistance.
- Note (2): Chemoprophylaxis can be considered for patients with frequent recurrences of serious bacterial pneumonia.
- 6.31. Cryptosporidiosis
- 6.31.1. Treatment
- Note (1): Initiate or optimize ART for immune restoration to CD4 count >100 cells/µL. Aggressive oral or IV rehydration and replacement of electrolyte loss and symptomatic treatment of diarrhea with anti-motility agents.
- Preferred regimen (1): Nitazoxanide 500–1000 mg PO bid for 14 days
- Preferred regimen (2): Paromomycin 500 mg PO qid for 14–21 days
- Note (2): With optimized anti retroviral therapy, symptomatic treatment and rehydration and electrolyte replacement is recommended. Tincture of opium may be more effective than Loperamide in management of diarrhea.
- 6.32. Microsporidiosis
- 6.32.1. Treatment
- 6.32.1.1. For GI infections caused by enterocytozoon bienuesi
- Note: Initiate or optimize anti retroviral therapy as immune restoration to CD4 count >100 cells/µL AND manage severe dehydration, malnutrition, and wasting by fluid support.
- Preferred therapy (1): Fumagillin 60 mg/day PO bid
- Preferred therapy (2): TNP-470 PO bid
- Preferred therapy (3): Nitazoxanide 1000 mg PO bid
- 6.32.1.2. For intestinal and disseminated (not ocular) infections caused by microsporidia other than E. bienuesi and vittaforma corneae
- Preferred regimen: Albendazole 400 mg PO bid, continue until CD4 count >200 cells/µL for >6 months after initiation of anti retroviral therapy
- Alternative regimen: Itraconazole 400 mg PO qd AND Albendazole 400 mg PO bid
- 6.32.1.3. For ocular infection
- Preferred regimen: Topical fumagillin bicylohexylammonium (Fumidil B) eye drops: 3 mg/mL in saline (fumagillin 70 µg/mL)—2 drops q2h for 4 days, then 2 drops qid AND Albendazole 400 mg PO bid, for management of systemic infection
- Note: Therapy should be continued until resolution of ocular symptoms and CD4 count increase to >200 cells/µL for >6 months in response to anti retroviral therapy.
- 6.33. Progressive Multifocal Leukoencephalopathy (PML)
- Note (1): There is no specific antiviral therapy for JC virus infection. The main treatment approach is to reverse the immunosuppression caused by HIV.
- Note (2): Initiate anti retroviral therapy immediately in anti retroviral therapy naive patients.
- Note (3): Optimize anti retroviral therapy in patients who develop PML in phase of HIV viremia on anti retroviral therapy.
- Note (4): Corticosteroids may be used for PML-IRIS characterized by contrast enhancement, edema or mass effect, and with clinical deterioration.
- West nile virus
- 1.1. Prevention
- No WNV vaccines are licensed for use in humans. In the absence of a vaccine, prevention of WNV disease depends on community-level mosquito control programs to reduce vector densities, personal protective measures to decrease exposure to infected mosquitoes, and screening of blood and organ donors.
- Personal protective measures include use of mosquito repellents, wearing long-sleeved shirts and long pants, and limiting outdoor exposure from dusk to dawn. Using air conditioning, installing window and door screens, and reducing peridomestic mosquito breeding sites, can further decrease the risk for WNV exposure.
- Blood and some organ donations in the United States are screened for WNV infection; health care professionals should remain vigilant for the possible transmission of WNV through blood transfusion or organ transplantation. Any suspected WNV infections temporally associated with blood transfusion or organ transplantation should be reported promptly to the appropriate state health department.
- 1.2. Treatment
- There is no specific treatment for WNV disease; clinical management is supportive. Patients with severe meningeal symptoms often require pain control for headaches and antiemetic therapy and rehydration for associated nausea and vomiting. Patients with encephalitis require close monitoring for the development of elevated intracranial pressure and seizures. Patients with encephalitis or poliomyelitis should be monitored for inability to protect their airway. Acute neuromuscular respiratory failure may develop rapidly and prolonged ventilatory support may be required.
- Measles
- 1.1. Prevention
- 1.1.1. Vaccines
- Note (1): Measles can be prevented with measles-containing vaccine, which is primarily administered as the combination measles-mumps-rubella (MMR) vaccine. The combination measles-mumps-rubella-varicella (MMRV) vaccine can be used for children aged 12 months through 12 years for protection against measles, mumps, rubella and varicella. Single-antigen measles vaccine is not available.
- Note (2): Vaccination recommendations
- Children: CDC recommends routine childhood immunization for MMR vaccine starting with the first dose at 12 through 15 months of age, and the second dose at 4 through 6 years of age or at least 28 days following the first dose.
- Students at post-high school educational institutions: Students at post-high school educational institutions without evidence of measles immunity need two doses of MMR vaccine, with the second dose administered no earlier than 28 days after the first dose.
- Adults: People who are born during or after 1957 who do not have evidence of immunity against measles should get at least one dose of MMR vaccine.
- International travelers: People 6 months of age or older who will be traveling internationally should be protected against measles. Before travelling internationally,
- Infants 6 through 11 months of age should receive one dose of MMR vaccine
- Children 12 months of age or older should have documentation of two doses of MMR vaccine (the first dose of MMR vaccine should be administered at age 12 months or older; the second dose no earlier than 28 days after the first dose)
- Teenagers and adults born during or after 1957 without evidence of immunity against measles should have documentation of two doses of MMR vaccine, with the second dose administered no earlier than 28 days after the first dose
- 1.1.2. Post-exposure Prophylaxis
- 1.1.2.1. Indication
- People exposed to measles who cannot readily show that they have evidence of immunity against measles should be offered post-exposure prophylaxis (PEP) or be excluded from the setting (school, hospital, childcare). MMR vaccine, if administered within 72 hours of initial measles exposure, or immunoglobulin (IG), if administered within six days of exposure, may provide some protection or modify the clinical course of disease.
- Note (1): If MMR vaccine is not administered within 72 hours of exposure as PEP, MMR vaccine should still be offered at any interval following exposure to the disease in order to offer protection from future exposures. People who receive MMR vaccine or IG as PEP should be monitored for signs and symptoms consistent with measles for at least one incubation period.
- Note (2): If many measles cases are occurring among infants younger than 12 months of age, measles vaccination of infants as young as 6 months of age may be used as an outbreak control measure. Note that children vaccinated before their first birthday should be revaccinated when they are 12 through 15 months old and again when they are 4 through 6 years of age.
- Note (3): People who are at risk for severe illness and complications from measles, such as infants younger than 12 months of age, pregnant women without evidence of measles immunity, and people with severely compromised immune systems, should receive IG. Intramuscular IG (IGIM) should be given to all infants younger than 12 months of age who have been exposed to measles.
- Note (4): For infants aged 6 through 11 months, MMR vaccine can be given in place of IG, if administered within 72 hours of exposure. Because pregnant women might be at higher risk for severe measles and complications, intravenous IG (IGIV) should be administered to pregnant women without evidence of measles immunity who have been exposed to measles. People with severely compromised immune systems who are exposed to measles should receive IGIV regardless of immunologic or vaccination status because they might not be protected by MMR vaccine.
- Preferred regimen: The recommended dose of IGIM is 0.5 mL/kg of body weight (maximum dose = 15 mL) and the recommended dose of IGIV is 400 mg/kg.
- Note (5): If a healthcare provider without evidence of immunity is exposed to measles, MMR vaccine should be given within 72 hours, or IG should be given within 6 days when available. Exclude healthcare personnel without evidence of immunity from duty from day 5 after first exposure to day 21 after last exposure, regardless of post-exposure vaccine.
- 1.2. Treatment
- Note (1): There is no specific antiviral therapy for measles. Medical care is supportive and to help relieve symptoms and address complications such as bacterial infections.
- Note (2): Severe measles cases among children, such as those who are hospitalized, should be treated with vitamin A. Vitamin A should be administered immediately on diagnosis and repeated the next day. The recommended age-specific daily doses are
- 50,000 IU for infants younger than 6 months of age
- 100,000 IU for infants 6–11 months of age
- 200,000 IU for children 12 months of age and older
==References==.
- ↑ "AIDSinfoNIH"..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}
- ↑ "Guidelines for the treatment of malaria. Third edition April 2015" (PDF). | https://www.wikidoc.org/index.php/Sandbox_ammu | |
c663128fc5c106c5712c1710b27efef83fe72c07 | wikidoc | Sandbox blah | Sandbox blah
# 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
Sandbox blah is a Adrenergic receptor agonist that is FDA approved for the {{{indicationType}}} of a list of indications, separated by commas.. There is a Black Box Warning for this drug as shown here. Common adverse reactions include a list of adverse reactions, separated by commas..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- (Dosage)
- Dosing Information
- (Dosage)
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Developed by: (Organisation)
- Class of Recommendation: (Class) (Link)
- Strength of Evidence: (Category A/B/C) (Link)
- Dosing Information/Recommendation
- (Dosage)
- Developed by: (Organisation)
- Class of Recommendation: (Class) (Link)
- Strength of Evidence: (Category A/B/C) (Link)
- Dosing Information/Recommendation
- (Dosage)
### Non–Guideline-Supported Use
- Dosing Information
- (Dosage)
- Dosing Information
- (Dosage)
- Dosing Information
- (Dosage)
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- (Dosage)
- Dosing Information
- (Dosage)
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- Developed by: (Organisation)
- Class of Recommendation: (Class) (Link)
- Strength of Evidence: (Category A/B/C) (Link)
- Dosing Information/Recommendation
- (Dosage)
- Developed by: (Organisation)
- Class of Recommendation: (Class) (Link)
- Strength of Evidence: (Category A/B/C) (Link)
- Dosing Information/Recommendation
- (Dosage)
### Non–Guideline-Supported Use
- Dosing Information
- (Dosage)
- Dosing Information
- (Dosage)
- Dosing Information
- (Dosage)
# Contraindications
- Condition 1
- Condition 2
- Condition 3
- Condition 4
- Condition 5
# Warnings
(Description)
(Description)
(Description)
# Adverse Reactions
## Clinical Trials Experience
## Postmarketing Experience
(Description)
# Drug Interactions
- Drug 1
- Drug 2
- Drug 3
- Drug 4
- Drug 5
(Description)
(Description)
(Description)
(Description)
(Description)
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
(Description)
Pregnancy Category (AUS):
(Description)
### Labor and Delivery
(Description)
### Nursing Mothers
(Description)
### Pediatric Use
(Description)
### Geriatic Use
(Description)
### Gender
(Description)
### Race
(Description)
### Renal Impairment
(Description)
### Hepatic Impairment
(Description)
### Females of Reproductive Potential and Males
(Description)
### Immunocompromised Patients
(Description)
### Others
(Description)
# Administration and Monitoring
### Administration
(Oral/Intravenous/etc)
### Monitoring
(Description regarding monitoring, from Warnings section)
(Description regarding monitoring, from Warnings section)
(Description regarding monitoring, from Warnings section)
# IV Compatibility
## Solution
### Compatible
- Solution 1
- Solution 2
- Solution 3
### Not Tested
- Solution 1
- Solution 2
- Solution 3
### Variable
- Solution 1
- Solution 2
- Solution 3
### Incompatible
- Solution 1
- Solution 2
- Solution 3
## Y-Site
### Compatible
- Solution 1
- Solution 2
- Solution 3
### Not Tested
- Solution 1
- Solution 2
- Solution 3
### Variable
- Solution 1
- Solution 2
- Solution 3
### Incompatible
- Solution 1
- Solution 2
- Solution 3
## Admixture
### Compatible
- Solution 1
- Solution 2
- Solution 3
### Not Tested
- Solution 1
- Solution 2
- Solution 3
### Variable
- Solution 1
- Solution 2
- Solution 3
### Incompatible
- Solution 1
- Solution 2
- Solution 3
## Syringe
### Compatible
- Solution 1
- Solution 2
- Solution 3
### Not Tested
- Solution 1
- Solution 2
- Solution 3
### Variable
- Solution 1
- Solution 2
- Solution 3
### Incompatible
- Solution 1
- Solution 2
- Solution 3
## TPN/TNA
### Compatible
- Solution 1
- Solution 2
- Solution 3
### Not Tested
- Solution 1
- Solution 2
- Solution 3
### Variable
- Solution 1
- Solution 2
- Solution 3
### Incompatible
- Solution 1
- Solution 2
- Solution 3
# Overdosage
## Acute Overdose
### Signs and Symptoms
(Description)
### Management
(Description)
## Chronic Overdose
### Signs and Symptoms
(Description)
### Management
(Description)
# Pharmacology
## Mechanism of Action
(Description)
## Structure
(Description with picture)
## Pharmacodynamics
(Description)
## Pharmacokinetics
(Description)
## Nonclinical Toxicology
(Description)
# Clinical Studies
(Description)
(Description)
(Description)
# How Supplied
(Description)
## Storage
There is limited information regarding Sandbox blah Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
(Patient Counseling Information)
# Precautions with Alcohol
Alcohol-Sandbox blah interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
There is limited information regarding Sandbox blah Brand Names in the drug label.
# Look-Alike Drug Names
- (Paired Confused Name 1a) — (Paired Confused Name 1b)
- (Paired Confused Name 2a) — (Paired Confused Name 2b)
- (Paired Confused Name 3a) — (Paired Confused Name 3b)
# Drug Shortage Status
Drug Shortage
# Price | Sandbox blah
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Sandbox blah is a Adrenergic receptor agonist that is FDA approved for the {{{indicationType}}} of a list of indications, separated by commas.. There is a Black Box Warning for this drug as shown here. Common adverse reactions include a list of adverse reactions, separated by commas..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- (Dosage)
- Dosing Information
- (Dosage)
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Developed by: (Organisation)
- Class of Recommendation: (Class) (Link)
- Strength of Evidence: (Category A/B/C) (Link)
- Dosing Information/Recommendation
- (Dosage)
- Developed by: (Organisation)
- Class of Recommendation: (Class) (Link)
- Strength of Evidence: (Category A/B/C) (Link)
- Dosing Information/Recommendation
- (Dosage)
### Non–Guideline-Supported Use
- Dosing Information
- (Dosage)
- Dosing Information
- (Dosage)
- Dosing Information
- (Dosage)
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- (Dosage)
- Dosing Information
- (Dosage)
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- Developed by: (Organisation)
- Class of Recommendation: (Class) (Link)
- Strength of Evidence: (Category A/B/C) (Link)
- Dosing Information/Recommendation
- (Dosage)
- Developed by: (Organisation)
- Class of Recommendation: (Class) (Link)
- Strength of Evidence: (Category A/B/C) (Link)
- Dosing Information/Recommendation
- (Dosage)
### Non–Guideline-Supported Use
- Dosing Information
- (Dosage)
- Dosing Information
- (Dosage)
- Dosing Information
- (Dosage)
# Contraindications
- Condition 1
- Condition 2
- Condition 3
- Condition 4
- Condition 5
# Warnings
(Description)
(Description)
(Description)
# Adverse Reactions
## Clinical Trials Experience
## Postmarketing Experience
(Description)
# Drug Interactions
- Drug 1
- Drug 2
- Drug 3
- Drug 4
- Drug 5
(Description)
(Description)
(Description)
(Description)
(Description)
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
(Description)
Pregnancy Category (AUS):
(Description)
### Labor and Delivery
(Description)
### Nursing Mothers
(Description)
### Pediatric Use
(Description)
### Geriatic Use
(Description)
### Gender
(Description)
### Race
(Description)
### Renal Impairment
(Description)
### Hepatic Impairment
(Description)
### Females of Reproductive Potential and Males
(Description)
### Immunocompromised Patients
(Description)
### Others
(Description)
# Administration and Monitoring
### Administration
(Oral/Intravenous/etc)
### Monitoring
(Description regarding monitoring, from Warnings section)
(Description regarding monitoring, from Warnings section)
(Description regarding monitoring, from Warnings section)
# IV Compatibility
## Solution
### Compatible
- Solution 1
- Solution 2
- Solution 3
### Not Tested
- Solution 1
- Solution 2
- Solution 3
### Variable
- Solution 1
- Solution 2
- Solution 3
### Incompatible
- Solution 1
- Solution 2
- Solution 3
## Y-Site
### Compatible
- Solution 1
- Solution 2
- Solution 3
### Not Tested
- Solution 1
- Solution 2
- Solution 3
### Variable
- Solution 1
- Solution 2
- Solution 3
### Incompatible
- Solution 1
- Solution 2
- Solution 3
## Admixture
### Compatible
- Solution 1
- Solution 2
- Solution 3
### Not Tested
- Solution 1
- Solution 2
- Solution 3
### Variable
- Solution 1
- Solution 2
- Solution 3
### Incompatible
- Solution 1
- Solution 2
- Solution 3
## Syringe
### Compatible
- Solution 1
- Solution 2
- Solution 3
### Not Tested
- Solution 1
- Solution 2
- Solution 3
### Variable
- Solution 1
- Solution 2
- Solution 3
### Incompatible
- Solution 1
- Solution 2
- Solution 3
## TPN/TNA
### Compatible
- Solution 1
- Solution 2
- Solution 3
### Not Tested
- Solution 1
- Solution 2
- Solution 3
### Variable
- Solution 1
- Solution 2
- Solution 3
### Incompatible
- Solution 1
- Solution 2
- Solution 3
# Overdosage
## Acute Overdose
### Signs and Symptoms
(Description)
### Management
(Description)
## Chronic Overdose
### Signs and Symptoms
(Description)
### Management
(Description)
# Pharmacology
## Mechanism of Action
(Description)
## Structure
(Description with picture)
## Pharmacodynamics
(Description)
## Pharmacokinetics
(Description)
## Nonclinical Toxicology
(Description)
# Clinical Studies
(Description)
(Description)
(Description)
# How Supplied
(Description)
## Storage
There is limited information regarding Sandbox blah Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
(Patient Counseling Information)
# Precautions with Alcohol
Alcohol-Sandbox blah interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
There is limited information regarding Sandbox blah Brand Names in the drug label.
# Look-Alike Drug Names
- (Paired Confused Name 1a) — (Paired Confused Name 1b)
- (Paired Confused Name 2a) — (Paired Confused Name 2b)
- (Paired Confused Name 3a) — (Paired Confused Name 3b)
# Drug Shortage Status
Drug Shortage
# Price | https://www.wikidoc.org/index.php/Sandbox_blah | |
2fe82e3712cb48f1ce556082a9a47e336b7fd132 | wikidoc | Sandbox drug | Sandbox drug
# 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
Sandbox drug is a Adrenergic receptor agonist that is FDA approved for the {{{indicationType}}} of a list of indications, separated by commas.. There is a Black Box Warning for this drug as shown here. Common adverse reactions include a list of adverse reactions, separated by commas..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- (Dosage)
- Dosing Information
- (Dosage)
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Developed by: (Organisation)
- Class of Recommendation: (Class) (Link)
- Strength of Evidence: (Category A/B/C) (Link)
- Dosing Information/Recommendation
- (Dosage)
- Developed by: (Organisation)
- Class of Recommendation: (Class) (Link)
- Strength of Evidence: (Category A/B/C) (Link)
- Dosing Information/Recommendation
- (Dosage)
### Non–Guideline-Supported Use
- Dosing Information
- (Dosage)
- Dosing Information
- (Dosage)
- Dosing Information
- (Dosage)
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- (Dosage)
- Dosing Information
- (Dosage)
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- Developed by: (Organisation)
- Class of Recommendation: (Class) (Link)
- Strength of Evidence: (Category A/B/C) (Link)
- Dosing Information/Recommendation
- (Dosage)
- Developed by: (Organisation)
- Class of Recommendation: (Class) (Link)
- Strength of Evidence: (Category A/B/C) (Link)
- Dosing Information/Recommendation
- (Dosage)
### Non–Guideline-Supported Use
- Dosing Information
- (Dosage)
- Dosing Information
- (Dosage)
- Dosing Information
- (Dosage)
# Contraindications
- Condition 1
- Condition 2
- Condition 3
- Condition 4
- Condition 5
# Warnings
(Description)
# Adverse Reactions
## Clinical Trials Experience
## Postmarketing Experience
(Description)
# Drug Interactions
- Drug 1
- Drug 2
- Drug 3
- Drug 4
- Drug 5
(Description)
(Description)
(Description)
(Description)
(Description)
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
(Description)
Pregnancy Category (AUS):
(Description)
### Labor and Delivery
(Description)
### Nursing Mothers
(Description)
### Pediatric Use
(Description)
### Geriatic Use
(Description)
### Gender
(Description)
### Race
(Description)
### Renal Impairment
(Description)
### Hepatic Impairment
(Description)
### Females of Reproductive Potential and Males
(Description)
### Immunocompromised Patients
(Description)
### Others
(Description)
# Administration and Monitoring
### Administration
(Oral/Intravenous/etc)
### Monitoring
(Description regarding monitoring, from Warnings section)
(Description regarding monitoring, from Warnings section)
(Description regarding monitoring, from Warnings section)
# IV Compatibility
## Solution
### Compatible
- Solution 1
- Solution 2
- Solution 3
### Not Tested
- Solution 1
- Solution 2
- Solution 3
### Variable
- Solution 1
- Solution 2
- Solution 3
### Incompatible
- Solution 1
- Solution 2
- Solution 3
## Y-Site
### Compatible
- Solution 1
- Solution 2
- Solution 3
### Not Tested
- Solution 1
- Solution 2
- Solution 3
### Variable
- Solution 1
- Solution 2
- Solution 3
### Incompatible
- Solution 1
- Solution 2
- Solution 3
## Admixture
### Compatible
- Solution 1
- Solution 2
- Solution 3
### Not Tested
- Solution 1
- Solution 2
- Solution 3
### Variable
- Solution 1
- Solution 2
- Solution 3
### Incompatible
- Solution 1
- Solution 2
- Solution 3
## Syringe
### Compatible
- Solution 1
- Solution 2
- Solution 3
### Not Tested
- Solution 1
- Solution 2
- Solution 3
### Variable
- Solution 1
- Solution 2
- Solution 3
### Incompatible
- Solution 1
- Solution 2
- Solution 3
## TPN/TNA
### Compatible
- Solution 1
- Solution 2
- Solution 3
### Not Tested
- Solution 1
- Solution 2
- Solution 3
### Variable
- Solution 1
- Solution 2
- Solution 3
### Incompatible
- Solution 1
- Solution 2
- Solution 3
# Overdosage
## Acute Overdose
### Signs and Symptoms
(Description)
### Management
(Description)
## Chronic Overdose
### Signs and Symptoms
(Description)
### Management
(Description)
# Pharmacology
## Mechanism of Action
(Description)
## Structure
(Description with picture)
## Pharmacodynamics
(Description)
## Pharmacokinetics
(Description)
## Nonclinical Toxicology
(Description)
# Clinical Studies
(Description)
(Description)
(Description)
# How Supplied
(Description)
## Storage
There is limited information regarding Sandbox drug Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
(Patient Counseling Information)
# Precautions with Alcohol
Alcohol-Sandbox drug interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
There is limited information regarding Sandbox drug Brand Names in the drug label.
# Look-Alike Drug Names
- (Paired Confused Name 1a) — (Paired Confused Name 1b)
- (Paired Confused Name 2a) — (Paired Confused Name 2b)
- (Paired Confused Name 3a) — (Paired Confused Name 3b)
# Drug Shortage Status
Drug Shortage
# Price | Sandbox drug
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Sandbox drug is a Adrenergic receptor agonist that is FDA approved for the {{{indicationType}}} of a list of indications, separated by commas.. There is a Black Box Warning for this drug as shown here. Common adverse reactions include a list of adverse reactions, separated by commas..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- (Dosage)
- Dosing Information
- (Dosage)
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Developed by: (Organisation)
- Class of Recommendation: (Class) (Link)
- Strength of Evidence: (Category A/B/C) (Link)
- Dosing Information/Recommendation
- (Dosage)
- Developed by: (Organisation)
- Class of Recommendation: (Class) (Link)
- Strength of Evidence: (Category A/B/C) (Link)
- Dosing Information/Recommendation
- (Dosage)
### Non–Guideline-Supported Use
- Dosing Information
- (Dosage)
- Dosing Information
- (Dosage)
- Dosing Information
- (Dosage)
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- (Dosage)
- Dosing Information
- (Dosage)
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- Developed by: (Organisation)
- Class of Recommendation: (Class) (Link)
- Strength of Evidence: (Category A/B/C) (Link)
- Dosing Information/Recommendation
- (Dosage)
- Developed by: (Organisation)
- Class of Recommendation: (Class) (Link)
- Strength of Evidence: (Category A/B/C) (Link)
- Dosing Information/Recommendation
- (Dosage)
### Non–Guideline-Supported Use
- Dosing Information
- (Dosage)
- Dosing Information
- (Dosage)
- Dosing Information
- (Dosage)
# Contraindications
- Condition 1
- Condition 2
- Condition 3
- Condition 4
- Condition 5
# Warnings
(Description)
# Adverse Reactions
## Clinical Trials Experience
## Postmarketing Experience
(Description)
# Drug Interactions
- Drug 1
- Drug 2
- Drug 3
- Drug 4
- Drug 5
(Description)
(Description)
(Description)
(Description)
(Description)
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
(Description)
Pregnancy Category (AUS):
(Description)
### Labor and Delivery
(Description)
### Nursing Mothers
(Description)
### Pediatric Use
(Description)
### Geriatic Use
(Description)
### Gender
(Description)
### Race
(Description)
### Renal Impairment
(Description)
### Hepatic Impairment
(Description)
### Females of Reproductive Potential and Males
(Description)
### Immunocompromised Patients
(Description)
### Others
(Description)
# Administration and Monitoring
### Administration
(Oral/Intravenous/etc)
### Monitoring
(Description regarding monitoring, from Warnings section)
(Description regarding monitoring, from Warnings section)
(Description regarding monitoring, from Warnings section)
# IV Compatibility
## Solution
### Compatible
- Solution 1
- Solution 2
- Solution 3
### Not Tested
- Solution 1
- Solution 2
- Solution 3
### Variable
- Solution 1
- Solution 2
- Solution 3
### Incompatible
- Solution 1
- Solution 2
- Solution 3
## Y-Site
### Compatible
- Solution 1
- Solution 2
- Solution 3
### Not Tested
- Solution 1
- Solution 2
- Solution 3
### Variable
- Solution 1
- Solution 2
- Solution 3
### Incompatible
- Solution 1
- Solution 2
- Solution 3
## Admixture
### Compatible
- Solution 1
- Solution 2
- Solution 3
### Not Tested
- Solution 1
- Solution 2
- Solution 3
### Variable
- Solution 1
- Solution 2
- Solution 3
### Incompatible
- Solution 1
- Solution 2
- Solution 3
## Syringe
### Compatible
- Solution 1
- Solution 2
- Solution 3
### Not Tested
- Solution 1
- Solution 2
- Solution 3
### Variable
- Solution 1
- Solution 2
- Solution 3
### Incompatible
- Solution 1
- Solution 2
- Solution 3
## TPN/TNA
### Compatible
- Solution 1
- Solution 2
- Solution 3
### Not Tested
- Solution 1
- Solution 2
- Solution 3
### Variable
- Solution 1
- Solution 2
- Solution 3
### Incompatible
- Solution 1
- Solution 2
- Solution 3
# Overdosage
## Acute Overdose
### Signs and Symptoms
(Description)
### Management
(Description)
## Chronic Overdose
### Signs and Symptoms
(Description)
### Management
(Description)
# Pharmacology
## Mechanism of Action
(Description)
## Structure
(Description with picture)
## Pharmacodynamics
(Description)
## Pharmacokinetics
(Description)
## Nonclinical Toxicology
(Description)
# Clinical Studies
(Description)
(Description)
(Description)
# How Supplied
(Description)
## Storage
There is limited information regarding Sandbox drug Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
(Patient Counseling Information)
# Precautions with Alcohol
Alcohol-Sandbox drug interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
There is limited information regarding Sandbox drug Brand Names in the drug label.
# Look-Alike Drug Names
- (Paired Confused Name 1a) — (Paired Confused Name 1b)
- (Paired Confused Name 2a) — (Paired Confused Name 2b)
- (Paired Confused Name 3a) — (Paired Confused Name 3b)
# Drug Shortage Status
Drug Shortage
# Price | https://www.wikidoc.org/index.php/Sandbox_drug | |
ea42e0627a94ead7e8044e587d48740a665441c3 | wikidoc | Sandbox id01 | Sandbox id01
# Musculoskeletal
## Osteomyelitis
### Candidal osteomyelitis
- Preferred Regimen
Fluconazole 400 mg (6 mg/kg) IV/po daily OR Lipid-based Amphotericin B 3-5 mg/kg daily for two weeks, followed by Fluconazole
- Fluconazole 400 mg (6 mg/kg) IV/po daily OR Lipid-based Amphotericin B 3-5 mg/kg daily for two weeks, followed by Fluconazole
- Alternative Regimen
Caspofungin 70 mg loading dose, then 50 mg/day IV OR Micafungin 100 mg/day IV or Anidulafungin 200 mg IV loading dose, then 100 mg/day IV
- Caspofungin 70 mg loading dose, then 50 mg/day IV OR Micafungin 100 mg/day IV or Anidulafungin 200 mg IV loading dose, then 100 mg/day IV
### Chronic osteomyelitis
- Preferred Regimen
Systemic antibiotics per culture and susceptibility results AND
Surgical debridement
- Systemic antibiotics per culture and susceptibility results AND
- Surgical debridement
### Contiguous with vascular insufficiency
- Preferred Regimen
Systemic antibiotics per culture and susceptibility results AND
Surgical debridement AND
Revascularization if possible
- Systemic antibiotics per culture and susceptibility results AND
- Surgical debridement AND
- Revascularization if possible
### Contiguous without vascular insufficiency
- Preferred Regimen
Vancomycin 1 gm IV q12h AND
Ceftazidime 2 gm IV q8h OR Cefepime 2 gm IV q12h
- Vancomycin 1 gm IV q12h AND
- Ceftazidime 2 gm IV q8h OR Cefepime 2 gm IV q12h
- Alternative Regimen
Linezolid 600 mg po/IV bid AND
Ceftazidime 2 gm IV q8h OR Cefepime 2 gm IV q12h
- Linezolid 600 mg po/IV bid AND
- Ceftazidime 2 gm IV q8h OR Cefepime 2 gm IV q12h
- Gram-negative bacilli
Ciprofloxacin 750 mg po bid OR Linezolid 600 mg po/IV bid
- Ciprofloxacin 750 mg po bid OR Linezolid 600 mg po/IV bid
- Staphylococcus aureus (MRSA/MSSA)
Ciprofloxacin 750 mg po bid OR Levofloxacin 750 mg po once daily if susceptible AND
Rifampin 300-450 mg po bid OR Rifampin 600 mg po once daily if susceptible
- Ciprofloxacin 750 mg po bid OR Levofloxacin 750 mg po once daily if susceptible AND
- Rifampin 300-450 mg po bid OR Rifampin 600 mg po once daily if susceptible
- MSSA
Nafcillin 2 gm IV q4h OR Oxacillin 2 gm IV q4h OR Cefazolin 2 gm IV q8h
- Nafcillin 2 gm IV q4h OR Oxacillin 2 gm IV q4h OR Cefazolin 2 gm IV q8h
- MRSA
Vancomycin 15-20 mg/kg IV q8-12h targeting trough concentrations of 15-20 mg/L
- Vancomycin 15-20 mg/kg IV q8-12h targeting trough concentrations of 15-20 mg/L
### Diabetic foot
- Chronic infection
Levofloxacin 750 mg IV/PO q24h OR Cefoxitin 1 g IV q4h (or 2 g IV q6–8h) OR Ceftriaxone 1–2 g/day IV/IM q12–24h OR Ampicillin-Sulbactam 1.5–3 g IV/IM q6h OR Moxifloxacin 400 mg IV/PO q24h OR Ertapenem 1 g IV/IM q24h OR Tigecycline 100 mg IV, then 50 mg IV q12h OR Imipenem-Cilastatin 0.5–1 g IV q6–8h
- Levofloxacin 750 mg IV/PO q24h OR Cefoxitin 1 g IV q4h (or 2 g IV q6–8h) OR Ceftriaxone 1–2 g/day IV/IM q12–24h OR Ampicillin-Sulbactam 1.5–3 g IV/IM q6h OR Moxifloxacin 400 mg IV/PO q24h OR Ertapenem 1 g IV/IM q24h OR Tigecycline 100 mg IV, then 50 mg IV q12h OR Imipenem-Cilastatin 0.5–1 g IV q6–8h
- Recent antibiotic use
Levofloxacin 750 mg IV/PO q24h OR Cefoxitin 1 g IV q4h (or 2 g IV q6–8h) OR Ceftriaxone 1–2 g/day IV/IM q12–24h OR Ampicillin-Sulbactam 1.5–3 g IV/IM q6h OR Moxifloxacin 400 mg IV/PO q24h OR Ertapenem 1 g IV/IM q24h OR Tigecycline 100 mg IV, then 50 mg IV q12h OR Imipenem-Cilastatin 0.5–1 g IV q6–8h
- Levofloxacin 750 mg IV/PO q24h OR Cefoxitin 1 g IV q4h (or 2 g IV q6–8h) OR Ceftriaxone 1–2 g/day IV/IM q12–24h OR Ampicillin-Sulbactam 1.5–3 g IV/IM q6h OR Moxifloxacin 400 mg IV/PO q24h OR Ertapenem 1 g IV/IM q24h OR Tigecycline 100 mg IV, then 50 mg IV q12h OR Imipenem-Cilastatin 0.5–1 g IV q6–8h
- High Risk for MRSA
Linezolid 600 mg IV/PO q12h OR Daptomycin 4 mg/kg IV q24h OR Vancomycin 15–20 mg/kg IV q8–12h (trough: 10–20 mg/L)
- Linezolid 600 mg IV/PO q12h OR Daptomycin 4 mg/kg IV q24h OR Vancomycin 15–20 mg/kg IV q8–12h (trough: 10–20 mg/L)
- High Risk for Pseudomonas aeruginosa
Piperacillin–Tazobactam 3.375 g IV q6–8h
- Piperacillin–Tazobactam 3.375 g IV q6–8h
- Polymicrobial Infection
(Vancomycin 15–20 mg/kg IV q8–12h OR Linezolid 600 mg IV/PO q12h OR Daptomycin 4 mg/kg IV q24h) AND
(Piperacillin–Tazobactam 3.375 g IV q6–8h OR Imipenem-Cilastatin 0.5–1 g IV q6–8h OR Ertapenem 1 g IV/IM q24h OR Meropenem 1 g IV/IM q24h) OR (Metronidazole 15 mg/kg IV, then 7.5 mg/kg IV q6h PLUS Ceftazidime 2 g IV q8h OR Cefepime 2 g IV q8h OR Aztreonam 2 g IV q6–8h)
- (Vancomycin 15–20 mg/kg IV q8–12h OR Linezolid 600 mg IV/PO q12h OR Daptomycin 4 mg/kg IV q24h) AND
- (Piperacillin–Tazobactam 3.375 g IV q6–8h OR Imipenem-Cilastatin 0.5–1 g IV q6–8h OR Ertapenem 1 g IV/IM q24h OR Meropenem 1 g IV/IM q24h) OR (Metronidazole 15 mg/kg IV, then 7.5 mg/kg IV q6h PLUS Ceftazidime 2 g IV q8h OR Cefepime 2 g IV q8h OR Aztreonam 2 g IV q6–8h)
### Foot bone
- Preferred Regimen
Ciprofloxacin 750 mg po bid OR Levofloxacin 750 mg po q24h
- Ciprofloxacin 750 mg po bid OR Levofloxacin 750 mg po q24h
- Alternative Regimen
Ceftazidime 2 gm IV q8h OR Cefepime 2 gm IV q8h OR Meropenem 1 gm IV q8h
- Ceftazidime 2 gm IV q8h OR Cefepime 2 gm IV q8h OR Meropenem 1 gm IV q8h
### Foot puncture wound
- Preferred Regimen
Cleanse wound AND
Tetanus booster if due AND
X-ray to exclude presence of radio-opaque foreign body
- Cleanse wound AND
- Tetanus booster if due AND
- X-ray to exclude presence of radio-opaque foreign body
### Hematogenous
- Preferred Regimen
MRSA likely – Vancomycin 15–20 mg/kg IV q8–12h AND (Ceftriaxone 1–2 g/day IV/IM q12–24h OR Ceftazidime 2 gm IV q8h OR Cefepime 2 gm IV q12h)
MRSA unlikely – (Nafcillin OR Oxacillin) AND (Ceftriaxone 1–2 g/day IV/IM q12–24h OR Ceftazidime 2 gm IV q8h OR Cefepime 2 gm IV q12h)
- MRSA likely – Vancomycin 15–20 mg/kg IV q8–12h AND (Ceftriaxone 1–2 g/day IV/IM q12–24h OR Ceftazidime 2 gm IV q8h OR Cefepime 2 gm IV q12h)
- MRSA unlikely – (Nafcillin OR Oxacillin) AND (Ceftriaxone 1–2 g/day IV/IM q12–24h OR Ceftazidime 2 gm IV q8h OR Cefepime 2 gm IV q12h)
- Alternative Regimen
Linezolid 600 mg po/IV bid OR Daptomycin 4 mg/kg IV q24h to replace vancomycin
Ciprofloxacin 750 mg po bid OR Levofloxacin 750 mg IV/PO q24h OR Aztreonam 2 g IV q6–8h to replace a third-generation cephalosporin
- Linezolid 600 mg po/IV bid OR Daptomycin 4 mg/kg IV q24h to replace vancomycin
- Ciprofloxacin 750 mg po bid OR Levofloxacin 750 mg IV/PO q24h OR Aztreonam 2 g IV q6–8h to replace a third-generation cephalosporin
### Hemoglobinopathy
- Preferred Regimen
Ciprofloxacin 400 mg IV q12h OR Ceftriaxone 2 gm IV q24h
- Ciprofloxacin 400 mg IV q12h OR Ceftriaxone 2 gm IV q24h
- Alternative Regimen
Ciprofloxacin 750 mg po bid for 6 weeks OR Levofloxacin 750 mg po q24h for 6 weeks
- Ciprofloxacin 750 mg po bid for 6 weeks OR Levofloxacin 750 mg po q24h for 6 weeks
### Prosthetic joint infection
- MSSA/MSSE
(Nafcillin 2 gm IV q4h OR Oxacillin 2 gm IV q4h IV) PLUS Rifampin 300 mg po bid OR
Cefazolin 2 gm IV q8h PLUS Rifampin 300 mg po bid for 2-6 weeks followed by (Ciprofloxacin 750 mg po bid OR Levofloxacin 750 mg po q24h) PLUS Rifampin 300 mg po bid for 3-6 months
- (Nafcillin 2 gm IV q4h OR Oxacillin 2 gm IV q4h IV) PLUS Rifampin 300 mg po bid OR
- Cefazolin 2 gm IV q8h PLUS Rifampin 300 mg po bid for 2-6 weeks followed by (Ciprofloxacin 750 mg po bid OR Levofloxacin 750 mg po q24h) PLUS Rifampin 300 mg po bid for 3-6 months
- MRSA/MRSE
Vancomycin 15-20 mg/kg IV q8-12h PLUS Rifampin 300 mg po bid for 2-6 weeks followed by (Ciprofloxacin 750 mg po bid OR Levofloxacin 750 mg po q24h) PLUS Rifampin 300 mg po bid for 3-6 months
- Vancomycin 15-20 mg/kg IV q8-12h PLUS Rifampin 300 mg po bid for 2-6 weeks followed by (Ciprofloxacin 750 mg po bid OR Levofloxacin 750 mg po q24h) PLUS Rifampin 300 mg po bid for 3-6 months
- Streptococcus
Penicillin G 20 million units IV continuous infusion q24h or in 6 divided doses OR Ceftriaxone 2 gm IV q24h x 4-6 weeks
- Penicillin G 20 million units IV continuous infusion q24h or in 6 divided doses OR Ceftriaxone 2 gm IV q24h x 4-6 weeks
- Enterococcus
Penicillin-susceptible – Ampicillin 12 gm IV OR Penicillin G 20 million units IV continuous infusion q24h or in 6 divided doses x 4-6 weeks
Penicillin-resistant – Vancomycin 15 mg/kg IV q12h x 4-6 week
- Penicillin-susceptible – Ampicillin 12 gm IV OR Penicillin G 20 million units IV continuous infusion q24h or in 6 divided doses x 4-6 weeks
- Penicillin-resistant – Vancomycin 15 mg/kg IV q12h x 4-6 week
- Propionibacterium acnes
Penicillin G 20 million units IV continuous infusion or in 6 divided doses OR Ceftriaxone 2 gm IV q24h x 4-6 weeks
- Penicillin G 20 million units IV continuous infusion or in 6 divided doses OR Ceftriaxone 2 gm IV q24h x 4-6 weeks
- Gram-negative enteric bacilli
Ertapenem 1 gm q24h IV OR Ceftriaxone 2 gm IV q24h OR Cefepime 2 gm IV q12h for 4-6 weeks
- Ertapenem 1 gm q24h IV OR Ceftriaxone 2 gm IV q24h OR Cefepime 2 gm IV q12h for 4-6 weeks
- Pseudomonas aeruginosa
Cefepime 2 gm IV q12h OR Meropenem 1 gm IV q8h for 4-6 weeks AND
Tobramycin 5.1 mg/kg once daily IV for 4-6 weeks
- Cefepime 2 gm IV q12h OR Meropenem 1 gm IV q8h for 4-6 weeks AND
- Tobramycin 5.1 mg/kg once daily IV for 4-6 weeks
### Spinal implant
- MSSA/MSSE
(Nafcillin 2 gm IV q4h OR Oxacillin 2 gm IV q4h IV) PLUS Rifampin 300 mg po bid OR
Cefazolin 2 gm IV q8h PLUS Rifampin 300 mg po bid for 2-6 weeks followed by (Ciprofloxacin 750 mg po bid OR Levofloxacin 750 mg po q24h) PLUS Rifampin 300 mg po bid for 3-6 months
- (Nafcillin 2 gm IV q4h OR Oxacillin 2 gm IV q4h IV) PLUS Rifampin 300 mg po bid OR
- Cefazolin 2 gm IV q8h PLUS Rifampin 300 mg po bid for 2-6 weeks followed by (Ciprofloxacin 750 mg po bid OR Levofloxacin 750 mg po q24h) PLUS Rifampin 300 mg po bid for 3-6 months
- MRSA/MRSE
Vancomycin 15-20 mg/kg IV q8-12h PLUS Rifampin 300 mg po bid for 2-6 weeks followed by (Ciprofloxacin 750 mg po bid OR Levofloxacin 750 mg po q24h) PLUS Rifampin 300 mg po bid for 3-6 months
- Vancomycin 15-20 mg/kg IV q8-12h PLUS Rifampin 300 mg po bid for 2-6 weeks followed by (Ciprofloxacin 750 mg po bid OR Levofloxacin 750 mg po q24h) PLUS Rifampin 300 mg po bid for 3-6 months
- Streptococcus
Penicillin G 20 million units IV continuous infusion q24h or in 6 divided doses OR Ceftriaxone 2 gm IV q24h x 4-6 weeks
- Penicillin G 20 million units IV continuous infusion q24h or in 6 divided doses OR Ceftriaxone 2 gm IV q24h x 4-6 weeks
- Enterococcus
Penicillin-susceptible – Ampicillin 12 gm IV OR Penicillin G 20 million units IV continuous infusion q24h or in 6 divided doses x 4-6 weeks
Penicillin-resistant – Vancomycin 15 mg/kg IV q12h x 4-6 week
- Penicillin-susceptible – Ampicillin 12 gm IV OR Penicillin G 20 million units IV continuous infusion q24h or in 6 divided doses x 4-6 weeks
- Penicillin-resistant – Vancomycin 15 mg/kg IV q12h x 4-6 week
- Propionibacterium acnes
Penicillin G 20 million units IV continuous infusion or in 6 divided doses OR Ceftriaxone 2 gm IV q24h x 4-6 weeks
- Penicillin G 20 million units IV continuous infusion or in 6 divided doses OR Ceftriaxone 2 gm IV q24h x 4-6 weeks
- Gram-negative enteric bacilli
Ertapenem 1 gm q24h IV OR Ceftriaxone 2 gm IV q24h OR Cefepime 2 gm IV q12h for 4-6 weeks
- Ertapenem 1 gm q24h IV OR Ceftriaxone 2 gm IV q24h OR Cefepime 2 gm IV q12h for 4-6 weeks
- Pseudomonas aeruginosa
Cefepime 2 gm IV q12h OR Meropenem 1 gm IV q8h for 4-6 weeks AND
Tobramycin 5.1 mg/kg once daily IV for 4-6 weeks
- Cefepime 2 gm IV q12h OR Meropenem 1 gm IV q8h for 4-6 weeks AND
- Tobramycin 5.1 mg/kg once daily IV for 4-6 weeks
### Sternal
- Preferred Regimen
Vancomycin 15-30 mg/kg IV q 8-12h targeting trough of 15-20 μg/mL OR Nafcillin 2 gm IV q4h
- Vancomycin 15-30 mg/kg IV q 8-12h targeting trough of 15-20 μg/mL OR Nafcillin 2 gm IV q4h
- Alternative Regimen
Linezolid 600 mg IV/po bid
- Linezolid 600 mg IV/po bid
## Bursitis
- Preferred Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Alternative Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
## Lyme arthritis
- Preferred Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Alternative Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
## Reactive arthritis
- Preferred Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Alternative Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
### Reiter's syndrome
- Preferred Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Alternative Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
### Post-streptococcal arthritis
- Preferred Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Alternative Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
## Septic arthritis
- Preferred Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Alternative Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
### Brucellosis
- Preferred Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Alternative Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
### Candida
- Preferred Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Alternative Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
### Gonococcal, disseminated infection
- Preferred Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Alternative Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
### Gram-negative bacilli
- Preferred Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Alternative Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
### Histoplasmosis
- Preferred Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Alternative Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
### Lyme disease
- Preferred Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Alternative Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
### Mycobacterium tuberculosis
- Preferred Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Alternative Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
### Pneumococcal
- Preferred Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Alternative Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
### Staphylococcal
- Preferred Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Alternative Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
### Streptococcal
- Preferred Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Alternative Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
### Post-intraarticular injection
- Preferred Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Alternative Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
## Gangrene
- Preferred Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Alternative Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
## Myonecrosis
- Preferred Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Alternative Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
## Necrotizing fascitis
- Preferred Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Alternative Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
### Clostridial
- Preferred Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Alternative Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
### Staphylococcal
- Preferred Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Alternative Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
### Streptococcal
- Preferred Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Alternative Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
### Synergistic
- Preferred Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Alternative Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
## Pyomyositis
- Preferred Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Alternative Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration | Sandbox id01
# Musculoskeletal
## Osteomyelitis
### Candidal osteomyelitis
- Preferred Regimen
Fluconazole 400 mg (6 mg/kg) IV/po daily OR Lipid-based Amphotericin B 3-5 mg/kg daily for two weeks, followed by Fluconazole
- Fluconazole 400 mg (6 mg/kg) IV/po daily OR Lipid-based Amphotericin B 3-5 mg/kg daily for two weeks, followed by Fluconazole
- Alternative Regimen
Caspofungin 70 mg loading dose, then 50 mg/day IV OR Micafungin 100 mg/day IV or Anidulafungin 200 mg IV loading dose, then 100 mg/day IV
- Caspofungin 70 mg loading dose, then 50 mg/day IV OR Micafungin 100 mg/day IV or Anidulafungin 200 mg IV loading dose, then 100 mg/day IV
### Chronic osteomyelitis
- Preferred Regimen
Systemic antibiotics per culture and susceptibility results AND
Surgical debridement
- Systemic antibiotics per culture and susceptibility results AND
- Surgical debridement
### Contiguous with vascular insufficiency
- Preferred Regimen
Systemic antibiotics per culture and susceptibility results AND
Surgical debridement AND
Revascularization if possible
- Systemic antibiotics per culture and susceptibility results AND
- Surgical debridement AND
- Revascularization if possible
### Contiguous without vascular insufficiency
- Preferred Regimen
Vancomycin 1 gm IV q12h AND
Ceftazidime 2 gm IV q8h OR Cefepime 2 gm IV q12h
- Vancomycin 1 gm IV q12h AND
- Ceftazidime 2 gm IV q8h OR Cefepime 2 gm IV q12h
- Alternative Regimen
Linezolid 600 mg po/IV bid AND
Ceftazidime 2 gm IV q8h OR Cefepime 2 gm IV q12h
- Linezolid 600 mg po/IV bid AND
- Ceftazidime 2 gm IV q8h OR Cefepime 2 gm IV q12h
- Gram-negative bacilli
Ciprofloxacin 750 mg po bid OR Linezolid 600 mg po/IV bid
- Ciprofloxacin 750 mg po bid OR Linezolid 600 mg po/IV bid
- Staphylococcus aureus (MRSA/MSSA)
Ciprofloxacin 750 mg po bid OR Levofloxacin 750 mg po once daily if susceptible AND
Rifampin 300-450 mg po bid OR Rifampin 600 mg po once daily if susceptible
- Ciprofloxacin 750 mg po bid OR Levofloxacin 750 mg po once daily if susceptible AND
- Rifampin 300-450 mg po bid OR Rifampin 600 mg po once daily if susceptible
- MSSA
Nafcillin 2 gm IV q4h OR Oxacillin 2 gm IV q4h OR Cefazolin 2 gm IV q8h
- Nafcillin 2 gm IV q4h OR Oxacillin 2 gm IV q4h OR Cefazolin 2 gm IV q8h
- MRSA
Vancomycin 15-20 mg/kg IV q8-12h targeting trough concentrations of 15-20 mg/L
- Vancomycin 15-20 mg/kg IV q8-12h targeting trough concentrations of 15-20 mg/L
### Diabetic foot
- Chronic infection
Levofloxacin 750 mg IV/PO q24h OR Cefoxitin 1 g IV q4h (or 2 g IV q6–8h) OR Ceftriaxone 1–2 g/day IV/IM q12–24h OR Ampicillin-Sulbactam 1.5–3 g IV/IM q6h OR Moxifloxacin 400 mg IV/PO q24h OR Ertapenem 1 g IV/IM q24h OR Tigecycline 100 mg IV, then 50 mg IV q12h OR Imipenem-Cilastatin 0.5–1 g IV q6–8h
- Levofloxacin 750 mg IV/PO q24h OR Cefoxitin 1 g IV q4h (or 2 g IV q6–8h) OR Ceftriaxone 1–2 g/day IV/IM q12–24h OR Ampicillin-Sulbactam 1.5–3 g IV/IM q6h OR Moxifloxacin 400 mg IV/PO q24h OR Ertapenem 1 g IV/IM q24h OR Tigecycline 100 mg IV, then 50 mg IV q12h OR Imipenem-Cilastatin 0.5–1 g IV q6–8h
- Recent antibiotic use
Levofloxacin 750 mg IV/PO q24h OR Cefoxitin 1 g IV q4h (or 2 g IV q6–8h) OR Ceftriaxone 1–2 g/day IV/IM q12–24h OR Ampicillin-Sulbactam 1.5–3 g IV/IM q6h OR Moxifloxacin 400 mg IV/PO q24h OR Ertapenem 1 g IV/IM q24h OR Tigecycline 100 mg IV, then 50 mg IV q12h OR Imipenem-Cilastatin 0.5–1 g IV q6–8h
- Levofloxacin 750 mg IV/PO q24h OR Cefoxitin 1 g IV q4h (or 2 g IV q6–8h) OR Ceftriaxone 1–2 g/day IV/IM q12–24h OR Ampicillin-Sulbactam 1.5–3 g IV/IM q6h OR Moxifloxacin 400 mg IV/PO q24h OR Ertapenem 1 g IV/IM q24h OR Tigecycline 100 mg IV, then 50 mg IV q12h OR Imipenem-Cilastatin 0.5–1 g IV q6–8h
- High Risk for MRSA
Linezolid 600 mg IV/PO q12h OR Daptomycin 4 mg/kg IV q24h OR Vancomycin 15–20 mg/kg IV q8–12h (trough: 10–20 mg/L)
- Linezolid 600 mg IV/PO q12h OR Daptomycin 4 mg/kg IV q24h OR Vancomycin 15–20 mg/kg IV q8–12h (trough: 10–20 mg/L)
- High Risk for Pseudomonas aeruginosa
Piperacillin–Tazobactam 3.375 g IV q6–8h
- Piperacillin–Tazobactam 3.375 g IV q6–8h
- Polymicrobial Infection
(Vancomycin 15–20 mg/kg IV q8–12h OR Linezolid 600 mg IV/PO q12h OR Daptomycin 4 mg/kg IV q24h) AND
(Piperacillin–Tazobactam 3.375 g IV q6–8h OR Imipenem-Cilastatin 0.5–1 g IV q6–8h OR Ertapenem 1 g IV/IM q24h OR Meropenem 1 g IV/IM q24h) OR (Metronidazole 15 mg/kg IV, then 7.5 mg/kg IV q6h PLUS Ceftazidime 2 g IV q8h OR Cefepime 2 g IV q8h OR Aztreonam 2 g IV q6–8h)
- (Vancomycin 15–20 mg/kg IV q8–12h OR Linezolid 600 mg IV/PO q12h OR Daptomycin 4 mg/kg IV q24h) AND
- (Piperacillin–Tazobactam 3.375 g IV q6–8h OR Imipenem-Cilastatin 0.5–1 g IV q6–8h OR Ertapenem 1 g IV/IM q24h OR Meropenem 1 g IV/IM q24h) OR (Metronidazole 15 mg/kg IV, then 7.5 mg/kg IV q6h PLUS Ceftazidime 2 g IV q8h OR Cefepime 2 g IV q8h OR Aztreonam 2 g IV q6–8h)
### Foot bone
- Preferred Regimen
Ciprofloxacin 750 mg po bid OR Levofloxacin 750 mg po q24h
- Ciprofloxacin 750 mg po bid OR Levofloxacin 750 mg po q24h
- Alternative Regimen
Ceftazidime 2 gm IV q8h OR Cefepime 2 gm IV q8h OR Meropenem 1 gm IV q8h
- Ceftazidime 2 gm IV q8h OR Cefepime 2 gm IV q8h OR Meropenem 1 gm IV q8h
### Foot puncture wound
- Preferred Regimen
Cleanse wound AND
Tetanus booster if due AND
X-ray to exclude presence of radio-opaque foreign body
- Cleanse wound AND
- Tetanus booster if due AND
- X-ray to exclude presence of radio-opaque foreign body
### Hematogenous
- Preferred Regimen
MRSA likely – Vancomycin 15–20 mg/kg IV q8–12h AND (Ceftriaxone 1–2 g/day IV/IM q12–24h OR Ceftazidime 2 gm IV q8h OR Cefepime 2 gm IV q12h)
MRSA unlikely – (Nafcillin OR Oxacillin) AND (Ceftriaxone 1–2 g/day IV/IM q12–24h OR Ceftazidime 2 gm IV q8h OR Cefepime 2 gm IV q12h)
- MRSA likely – Vancomycin 15–20 mg/kg IV q8–12h AND (Ceftriaxone 1–2 g/day IV/IM q12–24h OR Ceftazidime 2 gm IV q8h OR Cefepime 2 gm IV q12h)
- MRSA unlikely – (Nafcillin OR Oxacillin) AND (Ceftriaxone 1–2 g/day IV/IM q12–24h OR Ceftazidime 2 gm IV q8h OR Cefepime 2 gm IV q12h)
- Alternative Regimen
Linezolid 600 mg po/IV bid OR Daptomycin 4 mg/kg IV q24h to replace vancomycin
Ciprofloxacin 750 mg po bid OR Levofloxacin 750 mg IV/PO q24h OR Aztreonam 2 g IV q6–8h to replace a third-generation cephalosporin
- Linezolid 600 mg po/IV bid OR Daptomycin 4 mg/kg IV q24h to replace vancomycin
- Ciprofloxacin 750 mg po bid OR Levofloxacin 750 mg IV/PO q24h OR Aztreonam 2 g IV q6–8h to replace a third-generation cephalosporin
### Hemoglobinopathy
- Preferred Regimen
Ciprofloxacin 400 mg IV q12h OR Ceftriaxone 2 gm IV q24h
- Ciprofloxacin 400 mg IV q12h OR Ceftriaxone 2 gm IV q24h
- Alternative Regimen
Ciprofloxacin 750 mg po bid for 6 weeks OR Levofloxacin 750 mg po q24h for 6 weeks
- Ciprofloxacin 750 mg po bid for 6 weeks OR Levofloxacin 750 mg po q24h for 6 weeks
### Prosthetic joint infection
- MSSA/MSSE
(Nafcillin 2 gm IV q4h OR Oxacillin 2 gm IV q4h IV) PLUS Rifampin 300 mg po bid OR
Cefazolin 2 gm IV q8h PLUS Rifampin 300 mg po bid for 2-6 weeks followed by (Ciprofloxacin 750 mg po bid OR Levofloxacin 750 mg po q24h) PLUS Rifampin 300 mg po bid for 3-6 months
- (Nafcillin 2 gm IV q4h OR Oxacillin 2 gm IV q4h IV) PLUS Rifampin 300 mg po bid OR
- Cefazolin 2 gm IV q8h PLUS Rifampin 300 mg po bid for 2-6 weeks followed by (Ciprofloxacin 750 mg po bid OR Levofloxacin 750 mg po q24h) PLUS Rifampin 300 mg po bid for 3-6 months
- MRSA/MRSE
Vancomycin 15-20 mg/kg IV q8-12h PLUS Rifampin 300 mg po bid for 2-6 weeks followed by (Ciprofloxacin 750 mg po bid OR Levofloxacin 750 mg po q24h) PLUS Rifampin 300 mg po bid for 3-6 months
- Vancomycin 15-20 mg/kg IV q8-12h PLUS Rifampin 300 mg po bid for 2-6 weeks followed by (Ciprofloxacin 750 mg po bid OR Levofloxacin 750 mg po q24h) PLUS Rifampin 300 mg po bid for 3-6 months
- Streptococcus
Penicillin G 20 million units IV continuous infusion q24h or in 6 divided doses OR Ceftriaxone 2 gm IV q24h x 4-6 weeks
- Penicillin G 20 million units IV continuous infusion q24h or in 6 divided doses OR Ceftriaxone 2 gm IV q24h x 4-6 weeks
- Enterococcus
Penicillin-susceptible – Ampicillin 12 gm IV OR Penicillin G 20 million units IV continuous infusion q24h or in 6 divided doses x 4-6 weeks
Penicillin-resistant – Vancomycin 15 mg/kg IV q12h x 4-6 week
- Penicillin-susceptible – Ampicillin 12 gm IV OR Penicillin G 20 million units IV continuous infusion q24h or in 6 divided doses x 4-6 weeks
- Penicillin-resistant – Vancomycin 15 mg/kg IV q12h x 4-6 week
- Propionibacterium acnes
Penicillin G 20 million units IV continuous infusion or in 6 divided doses OR Ceftriaxone 2 gm IV q24h x 4-6 weeks
- Penicillin G 20 million units IV continuous infusion or in 6 divided doses OR Ceftriaxone 2 gm IV q24h x 4-6 weeks
- Gram-negative enteric bacilli
Ertapenem 1 gm q24h IV OR Ceftriaxone 2 gm IV q24h OR Cefepime 2 gm IV q12h for 4-6 weeks
- Ertapenem 1 gm q24h IV OR Ceftriaxone 2 gm IV q24h OR Cefepime 2 gm IV q12h for 4-6 weeks
- Pseudomonas aeruginosa
Cefepime 2 gm IV q12h OR Meropenem 1 gm IV q8h for 4-6 weeks AND
Tobramycin 5.1 mg/kg once daily IV for 4-6 weeks
- Cefepime 2 gm IV q12h OR Meropenem 1 gm IV q8h for 4-6 weeks AND
- Tobramycin 5.1 mg/kg once daily IV for 4-6 weeks
### Spinal implant
- MSSA/MSSE
(Nafcillin 2 gm IV q4h OR Oxacillin 2 gm IV q4h IV) PLUS Rifampin 300 mg po bid OR
Cefazolin 2 gm IV q8h PLUS Rifampin 300 mg po bid for 2-6 weeks followed by (Ciprofloxacin 750 mg po bid OR Levofloxacin 750 mg po q24h) PLUS Rifampin 300 mg po bid for 3-6 months
- (Nafcillin 2 gm IV q4h OR Oxacillin 2 gm IV q4h IV) PLUS Rifampin 300 mg po bid OR
- Cefazolin 2 gm IV q8h PLUS Rifampin 300 mg po bid for 2-6 weeks followed by (Ciprofloxacin 750 mg po bid OR Levofloxacin 750 mg po q24h) PLUS Rifampin 300 mg po bid for 3-6 months
- MRSA/MRSE
Vancomycin 15-20 mg/kg IV q8-12h PLUS Rifampin 300 mg po bid for 2-6 weeks followed by (Ciprofloxacin 750 mg po bid OR Levofloxacin 750 mg po q24h) PLUS Rifampin 300 mg po bid for 3-6 months
- Vancomycin 15-20 mg/kg IV q8-12h PLUS Rifampin 300 mg po bid for 2-6 weeks followed by (Ciprofloxacin 750 mg po bid OR Levofloxacin 750 mg po q24h) PLUS Rifampin 300 mg po bid for 3-6 months
- Streptococcus
Penicillin G 20 million units IV continuous infusion q24h or in 6 divided doses OR Ceftriaxone 2 gm IV q24h x 4-6 weeks
- Penicillin G 20 million units IV continuous infusion q24h or in 6 divided doses OR Ceftriaxone 2 gm IV q24h x 4-6 weeks
- Enterococcus
Penicillin-susceptible – Ampicillin 12 gm IV OR Penicillin G 20 million units IV continuous infusion q24h or in 6 divided doses x 4-6 weeks
Penicillin-resistant – Vancomycin 15 mg/kg IV q12h x 4-6 week
- Penicillin-susceptible – Ampicillin 12 gm IV OR Penicillin G 20 million units IV continuous infusion q24h or in 6 divided doses x 4-6 weeks
- Penicillin-resistant – Vancomycin 15 mg/kg IV q12h x 4-6 week
- Propionibacterium acnes
Penicillin G 20 million units IV continuous infusion or in 6 divided doses OR Ceftriaxone 2 gm IV q24h x 4-6 weeks
- Penicillin G 20 million units IV continuous infusion or in 6 divided doses OR Ceftriaxone 2 gm IV q24h x 4-6 weeks
- Gram-negative enteric bacilli
Ertapenem 1 gm q24h IV OR Ceftriaxone 2 gm IV q24h OR Cefepime 2 gm IV q12h for 4-6 weeks
- Ertapenem 1 gm q24h IV OR Ceftriaxone 2 gm IV q24h OR Cefepime 2 gm IV q12h for 4-6 weeks
- Pseudomonas aeruginosa
Cefepime 2 gm IV q12h OR Meropenem 1 gm IV q8h for 4-6 weeks AND
Tobramycin 5.1 mg/kg once daily IV for 4-6 weeks
- Cefepime 2 gm IV q12h OR Meropenem 1 gm IV q8h for 4-6 weeks AND
- Tobramycin 5.1 mg/kg once daily IV for 4-6 weeks
### Sternal
- Preferred Regimen
Vancomycin 15-30 mg/kg IV q 8-12h targeting trough of 15-20 μg/mL OR Nafcillin 2 gm IV q4h
- Vancomycin 15-30 mg/kg IV q 8-12h targeting trough of 15-20 μg/mL OR Nafcillin 2 gm IV q4h
- Alternative Regimen
Linezolid 600 mg IV/po bid
- Linezolid 600 mg IV/po bid
## Bursitis
- Preferred Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Alternative Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
## Lyme arthritis
- Preferred Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Alternative Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
## Reactive arthritis
- Preferred Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Alternative Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
### Reiter's syndrome
- Preferred Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Alternative Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
### Post-streptococcal arthritis
- Preferred Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Alternative Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
## Septic arthritis
- Preferred Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Alternative Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
### Brucellosis
- Preferred Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Alternative Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
### Candida
- Preferred Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Alternative Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
### Gonococcal, disseminated infection
- Preferred Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Alternative Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
### Gram-negative bacilli
- Preferred Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Alternative Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
### Histoplasmosis
- Preferred Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Alternative Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
### Lyme disease
- Preferred Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Alternative Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
### Mycobacterium tuberculosis
- Preferred Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Alternative Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
### Pneumococcal
- Preferred Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Alternative Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
### Staphylococcal
- Preferred Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Alternative Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
### Streptococcal
- Preferred Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Alternative Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
### Post-intraarticular injection
- Preferred Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Alternative Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
## Gangrene
- Preferred Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Alternative Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
## Myonecrosis
- Preferred Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Alternative Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
## Necrotizing fascitis
- Preferred Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Alternative Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
### Clostridial
- Preferred Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Alternative Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
### Staphylococcal
- Preferred Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Alternative Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
### Streptococcal
- Preferred Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Alternative Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
### Synergistic
- Preferred Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Alternative Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
## Pyomyositis
- Preferred Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Alternative Regimen
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration AND
- Drug DosageRouteFrequencyDuration OR Drug DosageRouteFrequencyDuration | https://www.wikidoc.org/index.php/Sandbox_id01 | |
5a7ad14973e380d035711c1f1186e6229ff48d2d | wikidoc | Sandbox m ex | Sandbox m ex
# Pap Smear
Cervical dysplasia that is seen on a Pap smear is called squamous intraepithelial lesion (SIL). These changes may be graded as:
- Low-grade (LSIL)
- High-grade (HSIL)
- Possibly cancerous (malignant)
If a Pap smear shows abnormal cells or cervical dysplasia, further testing or monitoring will be recommended:
- Follow-up Pap smears may be recommended for mild cases
- Colposcopy-directed biopsy can confirm the condition
- Cone biopsy may be done after colposcopy
Dysplasia that is seen on a biopsy of the cervix is called cervical intraepithelial neoplasia (CIN). It is grouped into three categories:
- CIN I -- mild dysplasia
- CIN II -- moderate to marked dysplasia
- CIN III -- severe dysplasia to carcinoma in situ
Some strains of human papillomavirus (HPV) are known to cause cervical cancer. An HPV DNA test can identify the high-risk types of HPV linked to such cancer. This may be done:
- As a screening test for women over age 30
- For women of any age who have a slightly abnormal Pap test result
## Hysterectomy
Microinvasive cancer (stage IA) is usually treated by hysterectomy (removal of the whole uterus including part of the vagina). For stage IA2, the lymph nodes are removed as well. An alternative for patients who desire to remain fertile is a local surgical procedure such as a loop electrical excision procedure (LEEP) or cone biopsy.
## Trachelectomy
- If a cone biopsy does not produce clear margins, one more possible treatment option for patients who want to preserve their fertility is a trachelectomy.
- This attempts to surgically remove the cancer while preserving the ovaries and uterus, providing for a more conservative operation than a hysterectomy.
- It is a viable option for those in stage I cervical cancer which has not spread; however, it is not yet considered a standard of care, as few doctors are skilled in this procedure.
- Even the most experienced surgeon cannot promise that a trachelectomy can be performed until after surgical microscopic examination, as the extent of the spread of cancer is unknown.
- If the surgeon is not able to microscopically confirm clear margins of cervical tissue once the patient is under general anesthesia in the operating room, a hysterectomy may still be needed. This can only be done during the same operation if the patient has given prior consent.
- Due to the possible risk of cancer spread to the lymph nodes in stage 1b cancers and some stage 1a cancers, the surgeon may also need to remove some lymph nodes from around the womb for pathologic evaluation.
## Radical Trachelectomy
A radical trachelectomy can be performed abdominally or vaginally and there are conflicting opinions as to which is better. A radical abdominal trachelectomy with lymphadenectomy usually only requires a two to three day hospital stay, and most women recover very quickly (approximately six weeks). Complications are uncommon, although women who are able to conceive after surgery are susceptible to preterm labor and possible late miscarriage. It is generally recommended to wait at least one year before attempting to become pregnant after surgery. Recurrence in the residual cervix is very rare if the cancer has been cleared with the trachelectomy. Yet, it is recommended for patients to practice vigilant prevention and follow up care including pap screenings/colposcopy, with biopsies of the remaining lower uterine segment as needed (every 3-4 months for at least 5 years) to monitor for any recurrence in addition to minimizing any new exposures to HPV through safe sex practices until one is actively trying to conceive.
## Radical Hysterectomy
Early stages (IB1 and IIA less than 4 cm) can be treated with radical hysterectomy with removal of the lymph nodes or radiation therapy. Radiation therapy is given as external beam radiotherapy to the pelvis and brachytherapy (internal radiation). Patients treated with surgery who have high risk features found on pathologic examination are given radiation therapy with or without chemotherapy in order to reduce the risk of relapse.
- Precancerous changes of the cervix and early stage cervical cancer,physical examination findings can be normal. Special tests and tools are needed to spot such conditions:
- A Pap smear is used for screening precancers and cervical cancer, but final diagnosis cannot be made.
- The human papillomavirus (HPV) DNA test may be done along with a pap test. Or it may be used after a woman has had an abnormal Pap test result. It may also be used as a main test.
- If abnormal changes are found, the cervix is usually examined using colposcope.cervical biopsy can be taken form tissue and examined.
## Radiation and Chemotherapy
Larger early stage tumors (IB2 and IIA more than 4 cm) may be treated with radiation therapy and cisplatin-based chemotherapy, hysterectomy (which then usually requires adjuvant radiation therapy), or cisplatin chemotherapy followed by hysterectomy.
Advanced stage tumors (IIB-IVA) are treated with radiation therapy and cisplatin-based chemotherapy.
On June 15, 2006, the US Food and Drug Administration approved the use of a combination of two chemotherapy drugs, hycamtin and cisplatin for women with late-stage (IVB) cervical cancer treatment. Combination treatment has significant risk of neutropenia, anemia, and thrombocytopenia side effects. Hycamtin is manufactured by GlaxoSmithKline.
### Contraindicated medications
Invasive cervical carcinoma is considered a relative contraindication to the use of the following medications:
- Oxytocin
According to the International Federation of Gynecology and Obstetrics, survival improves when radiotherapy is combined with cisplatin-based chemotherapy.
As the cancer metastasizes to other parts of the body, prognosis drops dramatically because treatment of local lesions is generally more effective than whole body treatments such as chemotherapy.
Regular screening has meant that pre cancerous changes and early stage cervical cancers have been detected and treated early. Figures suggest that cervical screening is saving 5,000 lives each year in the UK by preventing cervical cancer.
Interval evaluation of the patient after therapy is imperative. Recurrent cervical cancer detected at its earliest stages might be successfully treated with surgery, radiation, chemotherapy, or a combination of the three. Thirty-five percent of patients with invasive cervical cancer have persistent or recurrent disease after treatment.In screening a general or low-risk population, most Pap results are normal.
In the United States, about 2–3 million abnormal Pap smear results are found each year. Most abnormal results are mildly abnormal (ASC-US (typically 2–5% of Pap results) or low-grade squamous intraepithelial lesion (LSIL) (about 2% of results)), indicating HPV infection. Although most low-grade cervical dysplasias spontaneously regress without ever leading to cervical cancer, dysplasia can serve as an indication that increased vigilance is needed.
In a typical scenario, about 0.5% of Pap results are high-grade SIL (HSIL), and less than 0.5% of results indicate cancer; 0.2 to 0.8% of results indicate Atypical Glandular Cells of Undetermined Significance (AGC-NOS).
As liquid based preparations (LBPs) become a common medium for testing, atypical result rates have increased. The median rate for all preparations with low-grade squamous intraepithelial lesions using LBPs was 2.9% compared with a 2003 median rate of 2.1%. Rates for high-grade squamous intraepithelial lesions (median, 0.5%) and atypical squamous cells have changed little.
It's important for you to take care of yourself by eating well and staying as active as you can during the sometimes rough treatment of cervical cancer. You need the right amount of calories to maintain a good weight. You also need enough protein to keep up your strength. Eating well may help you feel better and have more energy. However, you may not feel like eating during or soon after treatment. You may be uncomfortable or tired. You may find that foods don't taste as good as they used to. In addition, the side effects of treatment (such as poor appetite, nausea, vomiting, or mouth sores) can make it hard to eat well. Your doctor, a registered dietitian, or another health care provider can suggest ways to cope with these problems. Research shows that people with cancer feel better when they stay active. Walking, yoga, swimming, and other activities can keep you strong and increase your energy. Exercise may reduce nausea and pain and make treatment easier to handle. It also can help relieve stress. Whatever physical activity you choose, be sure to talk to your doctor before you start.
You'll need regular checkups after treatment for cervical cancer. Checkups help ensure that any changes in your health are noted and treated if needed. If you have any health problems between checkups, you should contact your doctor. Your doctor will check for the return of cancer. Even when the cancer seems to have been completely removed or destroyed, the disease sometimes returns because undetected cancer cells remained somewhere in the body after treatment. Checkups may include a physical exam, Pap tests, and chest x-rays.
It is often located in the chest area. Most malignant teratomas can spread throughout the body, and have spread by the time of diagnosis.
A number of other cancers are often associated with these tumors, including:
- Acute myelogenous leukemia (AML)
- Embryonal rhabdomyosarcoma
- Malignant histiocytosis
- Myelodysplasia (MDS)
- Small cell undifferentiated carcinoma
# Overview
DiseasesDB = 3604 |
# Pathology classification of individual teratomas
Teratomas commonly are classified using the Gonzalez-Crussi grading system: 0 or mature (benign); 1 or immature, probably benign; 2 or immature, possibly malignant (cancerous); and 3 or frankly malignant. See also cancer staging. Teratomas are also classified by their content: a solid teratoma contains only tissues (perhaps including more complex structures); a cystic teratoma contain only pockets of fluid or semi-fluid such as cerebrospinal fluid, sebum, or fat; a mixed teratoma contains both solid and cystic parts. Cystic teratomas usually are grade 0 and, conversely, grade 0 teratomas usually are cystic.
Grade 0, 1 and 2 pure teratomas have the potential to become malignant (grade 3), and malignant pure teratomas have the potential to metastasize. These rare forms of teratoma with malignant transformation may contain elements of somatic (non germ cell) malignancy such as leukemia, carcinoma or sarcoma.
A teratoma may contain elements of other germ cell tumors, in which case it is not a pure teratoma but rather is a mixed germ cell tumor and is malignant. In infants and young children, these elements usually are endodermal sinus tumor, followed by choriocarcinoma. Finally, a teratoma can be pure and not malignant yet highly aggressive: this is exemplified by growing teratoma syndrome, in which chemotherapy eliminates the malignant elements of a mixed tumor, leaving pure teratoma which paradoxically begins to grow very rapidly.
## "Benign" teratoma may prove to be malignant
A "benign" grade 0 (mature) teratoma nonetheless has a non-zero risk of malignancy. Recurrence with malignant endodermal sinus tumor has been reported in cases of formerly benign mature teratoma, even in fetiform teratoma and fetus in fetu. A grade 1 immature teratoma that appears to be benign (e.g., because AFP is not elevated) has a much higher risk of malignancy, and requires adequate follow-up.
## Teratoma with malignant transformation
A teratoma with malignant transformation or TMT is a very rare form of teratoma that may contain elements of somatic (non germ cell) malignant tumors such as leukemia, carcinoma or sarcoma. Of 641 children with pure teratoma, 9 developed TMT: 5 carcinoma, 2 glioma, and 2 embryonal (here, these last are classified among germ cell tumors).
## Extraspinal ependymoma
Extraspinal ependymoma, usually considered to be a glioma (a type of non-germ cell tumor), may be an unusual form of mature teratoma. | Sandbox m ex
# Pap Smear
Cervical dysplasia that is seen on a Pap smear is called squamous intraepithelial lesion (SIL). These changes may be graded as:
- Low-grade (LSIL)
- High-grade (HSIL)
- Possibly cancerous (malignant)
If a Pap smear shows abnormal cells or cervical dysplasia, further testing or monitoring will be recommended:
- Follow-up Pap smears may be recommended for mild cases
- Colposcopy-directed biopsy can confirm the condition
- Cone biopsy may be done after colposcopy
Dysplasia that is seen on a biopsy of the cervix is called cervical intraepithelial neoplasia (CIN). It is grouped into three categories:
- CIN I -- mild dysplasia
- CIN II -- moderate to marked dysplasia
- CIN III -- severe dysplasia to carcinoma in situ
Some strains of human papillomavirus (HPV) are known to cause cervical cancer. An HPV DNA test can identify the high-risk types of HPV linked to such cancer. This may be done:
- As a screening test for women over age 30
- For women of any age who have a slightly abnormal Pap test result
## Hysterectomy
Microinvasive cancer (stage IA) is usually treated by hysterectomy (removal of the whole uterus including part of the vagina). For stage IA2, the lymph nodes are removed as well. An alternative for patients who desire to remain fertile is a local surgical procedure such as a loop electrical excision procedure (LEEP) or cone biopsy.
## Trachelectomy
- If a cone biopsy does not produce clear margins,[1] one more possible treatment option for patients who want to preserve their fertility is a trachelectomy.[2]
- This attempts to surgically remove the cancer while preserving the ovaries and uterus, providing for a more conservative operation than a hysterectomy.
- It is a viable option for those in stage I cervical cancer which has not spread; however, it is not yet considered a standard of care,[3] as few doctors are skilled in this procedure.
- Even the most experienced surgeon cannot promise that a trachelectomy can be performed until after surgical microscopic examination, as the extent of the spread of cancer is unknown.
- If the surgeon is not able to microscopically confirm clear margins of cervical tissue once the patient is under general anesthesia in the operating room, a hysterectomy may still be needed. This can only be done during the same operation if the patient has given prior consent.
- Due to the possible risk of cancer spread to the lymph nodes in stage 1b cancers and some stage 1a cancers, the surgeon may also need to remove some lymph nodes from around the womb for pathologic evaluation.
## Radical Trachelectomy
A radical trachelectomy can be performed abdominally[4] or vaginally[5] and there are conflicting opinions as to which is better.[6] A radical abdominal trachelectomy with lymphadenectomy usually only requires a two to three day hospital stay, and most women recover very quickly (approximately six weeks). Complications are uncommon, although women who are able to conceive after surgery are susceptible to preterm labor and possible late miscarriage.[7] It is generally recommended to wait at least one year before attempting to become pregnant after surgery.[8] Recurrence in the residual cervix is very rare if the cancer has been cleared with the trachelectomy.[9] Yet, it is recommended for patients to practice vigilant prevention and follow up care including pap screenings/colposcopy, with biopsies of the remaining lower uterine segment as needed (every 3-4 months for at least 5 years) to monitor for any recurrence in addition to minimizing any new exposures to HPV through safe sex practices until one is actively trying to conceive.
## Radical Hysterectomy
Early stages (IB1 and IIA less than 4 cm) can be treated with radical hysterectomy with removal of the lymph nodes or radiation therapy. Radiation therapy is given as external beam radiotherapy to the pelvis and brachytherapy (internal radiation). Patients treated with surgery who have high risk features found on pathologic examination are given radiation therapy with or without chemotherapy in order to reduce the risk of relapse.
- Precancerous changes of the cervix and early stage cervical cancer,physical examination findings can be normal. Special tests and tools are needed to spot such conditions:
- A Pap smear is used for screening precancers and cervical cancer, but final diagnosis cannot be made.
- The human papillomavirus (HPV) DNA test may be done along with a pap test. Or it may be used after a woman has had an abnormal Pap test result. It may also be used as a main test.
- If abnormal changes are found, the cervix is usually examined using colposcope.cervical biopsy can be taken form tissue and examined.
## Radiation and Chemotherapy
Larger early stage tumors (IB2 and IIA more than 4 cm) may be treated with radiation therapy and cisplatin-based chemotherapy, hysterectomy (which then usually requires adjuvant radiation therapy), or cisplatin chemotherapy followed by hysterectomy.
Advanced stage tumors (IIB-IVA) are treated with radiation therapy and cisplatin-based chemotherapy.
On June 15, 2006, the US Food and Drug Administration approved the use of a combination of two chemotherapy drugs, hycamtin and cisplatin for women with late-stage (IVB) cervical cancer treatment.[10] Combination treatment has significant risk of neutropenia, anemia, and thrombocytopenia side effects. Hycamtin is manufactured by GlaxoSmithKline.
### Contraindicated medications
Invasive cervical carcinoma is considered a relative contraindication to the use of the following medications:
- Oxytocin
According to the International Federation of Gynecology and Obstetrics, survival improves when radiotherapy is combined with cisplatin-based chemotherapy.[11]
As the cancer metastasizes to other parts of the body, prognosis drops dramatically because treatment of local lesions is generally more effective than whole body treatments such as chemotherapy.
Regular screening has meant that pre cancerous changes and early stage cervical cancers have been detected and treated early. Figures suggest that cervical screening is saving 5,000 lives each year in the UK by preventing cervical cancer.[12]
Interval evaluation of the patient after therapy is imperative. Recurrent cervical cancer detected at its earliest stages might be successfully treated with surgery, radiation, chemotherapy, or a combination of the three. Thirty-five percent of patients with invasive cervical cancer have persistent or recurrent disease after treatment.[13]In screening a general or low-risk population, most Pap results are normal.
In the United States, about 2–3 million abnormal Pap smear results are found each year.[14] Most abnormal results are mildly abnormal (ASC-US (typically 2–5% of Pap results) or low-grade squamous intraepithelial lesion (LSIL) (about 2% of results)), indicating HPV infection.[citation needed] Although most low-grade cervical dysplasias spontaneously regress without ever leading to cervical cancer, dysplasia can serve as an indication that increased vigilance is needed.
In a typical scenario, about 0.5% of Pap results are high-grade SIL (HSIL), and less than 0.5% of results indicate cancer; 0.2 to 0.8% of results indicate Atypical Glandular Cells of Undetermined Significance (AGC-NOS).
As liquid based preparations (LBPs) become a common medium for testing, atypical result rates have increased. The median rate for all preparations with low-grade squamous intraepithelial lesions using LBPs was 2.9% compared with a 2003 median rate of 2.1%. Rates for high-grade squamous intraepithelial lesions (median, 0.5%) and atypical squamous cells have changed little.[15]
It's important for you to take care of yourself by eating well and staying as active as you can during the sometimes rough treatment of cervical cancer. You need the right amount of calories to maintain a good weight. You also need enough protein to keep up your strength. Eating well may help you feel better and have more energy. However, you may not feel like eating during or soon after treatment. You may be uncomfortable or tired. You may find that foods don't taste as good as they used to. In addition, the side effects of treatment (such as poor appetite, nausea, vomiting, or mouth sores) can make it hard to eat well. Your doctor, a registered dietitian, or another health care provider can suggest ways to cope with these problems. Research shows that people with cancer feel better when they stay active. Walking, yoga, swimming, and other activities can keep you strong and increase your energy. Exercise may reduce nausea and pain and make treatment easier to handle. It also can help relieve stress. Whatever physical activity you choose, be sure to talk to your doctor before you start.
You'll need regular checkups after treatment for cervical cancer. Checkups help ensure that any changes in your health are noted and treated if needed. If you have any health problems between checkups, you should contact your doctor. Your doctor will check for the return of cancer. Even when the cancer seems to have been completely removed or destroyed, the disease sometimes returns because undetected cancer cells remained somewhere in the body after treatment. Checkups may include a physical exam, Pap tests, and chest x-rays.
It is often located in the chest area. Most malignant teratomas can spread throughout the body, and have spread by the time of diagnosis.
A number of other cancers are often associated with these tumors, including:
- Acute myelogenous leukemia (AML)
- Embryonal rhabdomyosarcoma
- Malignant histiocytosis
- Myelodysplasia (MDS)
- Small cell undifferentiated carcinoma
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [11]
# Overview
DiseasesDB = 3604 |
# Pathology classification of individual teratomas
Teratomas commonly are classified using the Gonzalez-Crussi grading system: 0 or mature (benign); 1 or immature, probably benign; 2 or immature, possibly malignant (cancerous); and 3 or frankly malignant. See also cancer staging. Teratomas are also classified by their content: a solid teratoma contains only tissues (perhaps including more complex structures); a cystic teratoma contain only pockets of fluid or semi-fluid such as cerebrospinal fluid, sebum, or fat; a mixed teratoma contains both solid and cystic parts. Cystic teratomas usually are grade 0 and, conversely, grade 0 teratomas usually are cystic.
Grade 0, 1 and 2 pure teratomas have the potential to become malignant (grade 3), and malignant pure teratomas have the potential to metastasize. These rare forms of teratoma with malignant transformation may contain elements of somatic (non germ cell) malignancy such as leukemia, carcinoma or sarcoma.[16]
A teratoma may contain elements of other germ cell tumors, in which case it is not a pure teratoma but rather is a mixed germ cell tumor and is malignant. In infants and young children, these elements usually are endodermal sinus tumor, followed by choriocarcinoma. Finally, a teratoma can be pure and not malignant yet highly aggressive: this is exemplified by growing teratoma syndrome, in which chemotherapy eliminates the malignant elements of a mixed tumor, leaving pure teratoma which paradoxically begins to grow very rapidly.
## "Benign" teratoma may prove to be malignant
A "benign" grade 0 (mature) teratoma nonetheless has a non-zero risk of malignancy. Recurrence with malignant endodermal sinus tumor has been reported in cases of formerly benign mature teratoma,[17] even in fetiform teratoma and fetus in fetu.[18][19] A grade 1 immature teratoma that appears to be benign (e.g., because AFP is not elevated) has a much higher risk of malignancy, and requires adequate follow-up.[20][21][22][23]
## Teratoma with malignant transformation
A teratoma with malignant transformation or TMT is a very rare form of teratoma that may contain elements of somatic (non germ cell) malignant tumors such as leukemia, carcinoma or sarcoma.[16] Of 641 children with pure teratoma, 9 developed TMT[24]: 5 carcinoma, 2 glioma, and 2 embryonal (here, these last are classified among germ cell tumors).
## Extraspinal ependymoma
Extraspinal ependymoma, usually considered to be a glioma (a type of non-germ cell tumor), may be an unusual form of mature teratoma.[25] | https://www.wikidoc.org/index.php/Sandbox_m_ex | |
e04f418278d05339ff5e482fc95bc56b58baa2b1 | wikidoc | Sandbox manp | Sandbox manp
Peptic ulcer diease pathophysiology
# Overview
- The overview section should include the disease name in the first sentence.
- The goal is to summarize the pathophysiology page in several sentences. This section can be the same as the pathophysiology segment on the overview page.
- To see an example of an overview section on a symptoms page, click here.
## Template
- The overview is highly dependent on the individual disease pathophysiology. There is no specific template preference for the first sentence.
Template Sentences:
Examples:
# Pathogenesis
Pathogenesis is the mechanism by which a certain 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, or recurrent. It can also be used to describe whether the disease causes inflammation, malignancy, necrosis etc.
### Template Sentences
- It is found that peptic ulcer disease is the result of self-digestion which occurs due to an excess of auto-peptic power in gastric juice over the defensive power of gastric mucosa and is mediated by two major factors which disrupt mucosal resistance to injury: Helicobacter pylori (formerly Campylobacter pylori) infection in 75% cases and nonsteroidal anti-inflammatory drugs (NSAIDs)
- Helicobacter pylori-gram negative bacteria,spiral-shaped, urease positive and highly motile through flagella .Upon entry ,it display urea- and bicarbonate-mediated chemotactic motility toward the mucus layer . The spiral morphology and flagellar motility then assist in penetration into the viscous mucus layer, where the more pH-neutral conditions allow growth of the gastric Helicobacter species.
It secrete cytotoxins and produce virulence factors like Cag A, VacA, and OipA.Cytotoxin-associated gene pathogenicity encodes protein CagA and vacuolating cytotoxin VacA aids in the colonization of gastric mucosa and it modulates host's immune system.It causes local production of a range of proinflammatory and immunoregulatory cytokines, neutrophil infiltration, specific T- and B- cell responses and the development of gastric lymphoid follicles.Bacterial factors and complement activation leads to neutrophilic activation including reactive oxygen me*It is found that peptic ulcer disease is the result of self-digestion which occurs due to an excess of auto-peptic power in gastric juice over the defensive power of gastric mucosa and is mediated by two major factors which disrupt mucosal resistance to injury: Helicobacter pylori (formerly Campylobacter pylori) infection in 75% cases and nonsteroidal anti-inflammatory drugs (NSAIDs)
- It secrete cytotoxins and produce virulence factors like Cag A, VacA, and OipA.Cytotoxin-associated gene pathogenicity encodes protein CagA and vacuolating cytotoxin VacA aids in the colonization of gastric mucosa and it modulates host's immune system.It causes local production of a range of proinflammatory and immunoregulatory cytokines, neutrophil infiltration, specific T- and B- cell responses and the development of gastric lymphoid follicles.Bacterial factors and complement activation leads to neutrophilic activation including reactive oxygen me*It is found that peptic ulcer disease is the result of self-digestion which occurs due to an excess of auto-peptic power in gastric juice over the defensive power of gastric mucosa and is mediated by two major factors which disrupt mucosal resistance to injury: Helicobacter pylori (formerly Campylobacter pylori) infection in 75% cases and nonsteroidal anti-inflammatory drugs (NSAIDs)
- Helicobacter pylori-gram negative bacteria,spiral-shaped, urease positive and highly motile through flagella .Upon entry ,it display urea- and bicarbonate-mediated chemotactic motabolite.Following injury to astric mucosa it secretes interleukns and chemokines ,which further leads to neutrophilic migration to the site of infection.Cag A and Vac A leads to activation of IL-8 which leads to inflammation of gastric mucosa
It secretes various enzyme :Urease,Phospholipases,Alcohol dehydrogenase and Catalases- causes damage the host gastric muscosa by generating toxic metabolities
- It secretes various enzyme :Urease,Phospholipases,Alcohol dehydrogenase and Catalases- causes damage the host gastric muscosa by generating toxic metabolities
- NSAIDs-
it inhibits systemic prostaglandins production and cause ulcers
more common in the stomach than the duodenum
- it inhibits systemic prostaglandins production and cause ulcers
- more common in the stomach than the duodenum
- Other factors responsible for peptic ulcer disease:
Smoking
It decreases the production of prostaglandins in fundic and antral part of stomach
It causes reflux of bile acids
It causes alteration of blood flow and lead to ischaemia
- Smoking
It decreases the production of prostaglandins in fundic and antral part of stomach
It causes reflux of bile acids
It causes alteration of blood flow and lead to ischaemia
- It decreases the production of prostaglandins in fundic and antral part of stomach
- It causes reflux of bile acids
- It causes alteration of blood flow and lead to ischaemia
- Duodenal ulcer:
Abnormalities of acid secretion:
Increase in basal acid output.
Increase in acid response to GRP
Increased maximal acid response to exogenous gastrin
Increased ratio of basal acid output to maximal gastrin-stimulated output
Increased ratio of maximal GRP-stimulated acid output to maximal gastrin-stimulated output.
Decreased in bicarbonate secretion and low ph leads to gastric metaplasia induced duodenitis which further increases the risk of acid damage and leads to ulcer .
- Abnormalities of acid secretion:
Increase in basal acid output.
Increase in acid response to GRP
Increased maximal acid response to exogenous gastrin
Increased ratio of basal acid output to maximal gastrin-stimulated output
Increased ratio of maximal GRP-stimulated acid output to maximal gastrin-stimulated output.
- Increase in basal acid output.
- Increase in acid response to GRP
- Increased maximal acid response to exogenous gastrin
- Increased ratio of basal acid output to maximal gastrin-stimulated output
- Increased ratio of maximal GRP-stimulated acid output to maximal gastrin-stimulated output.
- Decreased in bicarbonate secretion and low ph leads to gastric metaplasia induced duodenitis which further increases the risk of acid damage and leads to ulcer .
- Gastric ulcer
There is decrease in acid and decrease in parietal cell volume which further predisposes to development to ulcer formation.
# Genetics
- Genes involved in the pathogenesis of peptic ulcer disease is CagA is a gene that codes for an immunodominant antigen, is present only in Helicobacter pylori strains that are associated with peptic ulcer disease
- Duodenal ulcer:HLA-DQA1 genotype related in Helicobacter pylori positive in Duodenal ulcer. Allele frequency DQA1*0301 more common in H. pylori-positive and DQA1*0102 allele are significantly more common in H. pylori-negative
# Associated Conditions
- The most important conditions associated with peptic ulcer disease include:
Gastric cancer-Helicobacter pylori infection in duodenal ulcer leads to gastric metaplasia and gastric atrophy which increases the risk of gastric cancer
Gastric mucosa-associated lymphoid tissue (MALT) lymphoma-helicobacter pylori infection is associated with increased the risk of develeopment of MALT Lymphoma.
Idiopathic thrombocytopenic purpura-The ASH also recommended that eradication therapy for Helicobacter pylori be administered to adults with ITP who were found to have H. pylori based on a test of active infection.the patient who has a peptic ulcer disease is increased the risk of developing idiopathic thrombocytopenic purpura.
- Gastric cancer-Helicobacter pylori infection in duodenal ulcer leads to gastric metaplasia and gastric atrophy which increases the risk of gastric cancer
- Gastric mucosa-associated lymphoid tissue (MALT) lymphoma-helicobacter pylori infection is associated with increased the risk of develeopment of MALT Lymphoma.
- Idiopathic thrombocytopenic purpura-The ASH also recommended that eradication therapy for Helicobacter pylori be administered to adults with ITP who were found to have H. pylori based on a test of active infection.the patient who has a peptic ulcer disease is increased the risk of developing idiopathic thrombocytopenic purpura.
# Gross Pathology
- Gross pathology refers to macroscopic or larger scale manifestations of disease in organs, tissues and body cavities. The term is commonly used by pathologist to refer to diagnostically useful findings made during the gross examination portion of surgical specimen processing or an autopsy.
- Template Sentences 1: On gross pathology, Ulcers, , and are characteristic findings of .
- Template Sentence 2: The most important characteristics of on gross pathology are:
Organ 1: List of characteristics +
Organ 2: List of characteristics + image
Organ 3: List of characteristics + image
- Organ 1: List of characteristics +
- Organ 2: List of characteristics + image
- Organ 3: List of characteristics + image
- This section is a good place to include pictures. Search for copyleft images on The Pathology Wiki and Ask Dr. Wiki .
- For an example of this section, click here
# Microscopic Pathology
- Microscopic pathology is the disease process as it occurs at the microscopic level.
- Template Sentence 1: On microscopic histopathological analysis, , , and are characteristic findings of .
- Template Sentence 2: The most important histopathological characteristics of are summarized in the table below:
- This section is a good place to include pictures. Search for copyleft images on The Pathology Wiki and Ask Dr. Wiki .
- For an example of this section, click here. | Sandbox manp
Peptic ulcer diease pathophysiology
# Overview
- The overview section should include the disease name in the first sentence.
- The goal is to summarize the pathophysiology page in several sentences. This section can be the same as the pathophysiology segment on the overview page.
- To see an example of an overview section on a symptoms page, click here.
## Template
- The overview is highly dependent on the individual disease pathophysiology. There is no specific template preference for the first sentence.
Template Sentences:
Examples:
# Pathogenesis
Pathogenesis is the mechanism by which a certain 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, or recurrent. It can also be used to describe whether the disease causes inflammation, malignancy, necrosis etc.
### Template Sentences
- It is found that peptic ulcer disease is the result of self-digestion which occurs due to an excess of auto-peptic power in gastric juice over the defensive power of gastric mucosa and is mediated by two major factors which disrupt mucosal resistance to injury: Helicobacter pylori (formerly Campylobacter pylori) infection in 75% cases[1] and nonsteroidal anti-inflammatory drugs (NSAIDs)[1][2]
- Helicobacter pylori-gram negative bacteria,spiral-shaped, urease positive and highly motile through flagella .Upon entry ,it display urea- and bicarbonate-mediated chemotactic motility toward the mucus layer . The spiral morphology and flagellar motility then assist in penetration into the viscous mucus layer, where the more pH-neutral conditions allow growth of the gastric Helicobacter species.[3]
It secrete cytotoxins and produce virulence factors like Cag A, VacA, and OipA.Cytotoxin-associated gene pathogenicity encodes protein CagA and vacuolating cytotoxin VacA aids in the colonization of gastric mucosa and it modulates host's immune system.It causes local production of a range of proinflammatory and immunoregulatory cytokines, neutrophil infiltration, specific T- and B- cell responses and the development of gastric lymphoid follicles.Bacterial factors and complement activation leads to neutrophilic activation including reactive oxygen me*It is found that peptic ulcer disease is the result of self-digestion which occurs due to an excess of auto-peptic power in gastric juice over the defensive power of gastric mucosa and is mediated by two major factors which disrupt mucosal resistance to injury: Helicobacter pylori (formerly Campylobacter pylori) infection in 75% cases[1] and nonsteroidal anti-inflammatory drugs (NSAIDs)[1][4]
- It secrete cytotoxins and produce virulence factors like Cag A, VacA, and OipA.Cytotoxin-associated gene pathogenicity encodes protein CagA and vacuolating cytotoxin VacA aids in the colonization of gastric mucosa and it modulates host's immune system.It causes local production of a range of proinflammatory and immunoregulatory cytokines, neutrophil infiltration, specific T- and B- cell responses and the development of gastric lymphoid follicles.Bacterial factors and complement activation leads to neutrophilic activation including reactive oxygen me*It is found that peptic ulcer disease is the result of self-digestion which occurs due to an excess of auto-peptic power in gastric juice over the defensive power of gastric mucosa and is mediated by two major factors which disrupt mucosal resistance to injury: Helicobacter pylori (formerly Campylobacter pylori) infection in 75% cases[1] and nonsteroidal anti-inflammatory drugs (NSAIDs)[1][4]
- Helicobacter pylori-gram negative bacteria,spiral-shaped, urease positive and highly motile through flagella .Upon entry ,it display urea- and bicarbonate-mediated chemotactic motabolite.Following injury to astric mucosa it secretes interleukns and chemokines ,which further leads to neutrophilic migration to the site of infection.Cag A and Vac A leads to activation of IL-8 which leads to inflammation of gastric mucosa [5][6][7]
It secretes various enzyme :Urease,Phospholipases,Alcohol dehydrogenase and Catalases- causes damage the host gastric muscosa by generating toxic metabolities[8][9][10]
- It secretes various enzyme :Urease,Phospholipases,Alcohol dehydrogenase and Catalases- causes damage the host gastric muscosa by generating toxic metabolities[8][9][10]
- NSAIDs-
it inhibits systemic prostaglandins production and cause ulcers[11]
more common in the stomach than the duodenum[12]
- it inhibits systemic prostaglandins production and cause ulcers[11]
- more common in the stomach than the duodenum[12]
- Other factors responsible for peptic ulcer disease:
Smoking
It decreases the production of prostaglandins in fundic and antral part of stomach[13]
It causes reflux of bile acids[14]
It causes alteration of blood flow and lead to ischaemia
- Smoking
It decreases the production of prostaglandins in fundic and antral part of stomach[13]
It causes reflux of bile acids[14]
It causes alteration of blood flow and lead to ischaemia
- It decreases the production of prostaglandins in fundic and antral part of stomach[13]
- It causes reflux of bile acids[14]
- It causes alteration of blood flow and lead to ischaemia
- Duodenal ulcer:
Abnormalities of acid secretion:
Increase in basal acid output.
Increase in acid response to GRP
Increased maximal acid response to exogenous gastrin
Increased ratio of basal acid output to maximal gastrin-stimulated output
Increased ratio of maximal GRP-stimulated acid output to maximal gastrin-stimulated output.[15][16]
Decreased in bicarbonate secretion and low ph leads to gastric metaplasia induced duodenitis which further increases the risk of acid damage and leads to ulcer .[17]
- Abnormalities of acid secretion:
Increase in basal acid output.
Increase in acid response to GRP
Increased maximal acid response to exogenous gastrin
Increased ratio of basal acid output to maximal gastrin-stimulated output
Increased ratio of maximal GRP-stimulated acid output to maximal gastrin-stimulated output.[15][16]
- Increase in basal acid output.
- Increase in acid response to GRP
- Increased maximal acid response to exogenous gastrin
- Increased ratio of basal acid output to maximal gastrin-stimulated output
- Increased ratio of maximal GRP-stimulated acid output to maximal gastrin-stimulated output.[15][16]
- Decreased in bicarbonate secretion and low ph leads to gastric metaplasia induced duodenitis which further increases the risk of acid damage and leads to ulcer .[17]
- Gastric ulcer
There is decrease in acid and decrease in parietal cell volume which further predisposes to development to ulcer formation.[18]
# Genetics
- Genes involved in the pathogenesis of peptic ulcer disease is CagA is a gene that codes for an immunodominant antigen, is present only in Helicobacter pylori strains that are associated with peptic ulcer disease[19]
- Duodenal ulcer:HLA-DQA1 genotype related in Helicobacter pylori positive in Duodenal ulcer. Allele frequency DQA1*0301 more common in H. pylori-positive and DQA1*0102 allele are significantly more common in H. pylori-negative
[20]
# Associated Conditions
- The most important conditions associated with peptic ulcer disease include:
Gastric cancer-Helicobacter pylori infection in duodenal ulcer leads to gastric metaplasia and gastric atrophy which increases the risk of gastric cancer[21]
Gastric mucosa-associated lymphoid tissue (MALT) lymphoma-helicobacter pylori infection is associated with increased the risk of develeopment of MALT Lymphoma.[22]
Idiopathic thrombocytopenic purpura-The ASH also recommended that eradication therapy for Helicobacter pylori be administered to adults with ITP who were found to have H. pylori based on a test of active infection.the patient who has a peptic ulcer disease is increased the risk of developing idiopathic thrombocytopenic purpura.[23][24]
- Gastric cancer-Helicobacter pylori infection in duodenal ulcer leads to gastric metaplasia and gastric atrophy which increases the risk of gastric cancer[21]
- Gastric mucosa-associated lymphoid tissue (MALT) lymphoma-helicobacter pylori infection is associated with increased the risk of develeopment of MALT Lymphoma.[22]
- Idiopathic thrombocytopenic purpura-The ASH also recommended that eradication therapy for Helicobacter pylori be administered to adults with ITP who were found to have H. pylori based on a test of active infection.the patient who has a peptic ulcer disease is increased the risk of developing idiopathic thrombocytopenic purpura.[23][24]
# Gross Pathology
- Gross pathology refers to macroscopic or larger scale manifestations of disease in organs, tissues and body cavities. The term is commonly used by pathologist to refer to diagnostically useful findings made during the gross examination portion of surgical specimen processing or an autopsy.
- Template Sentences 1: On gross pathology, Ulcers, , and [feature3] are characteristic findings of [disease name].
- Template Sentence 2: The most important characteristics of [disease name] on gross pathology are:
Organ 1: List of characteristics +
Organ 2: List of characteristics + image
Organ 3: List of characteristics + image
- Organ 1: List of characteristics +
- Organ 2: List of characteristics + image
- Organ 3: List of characteristics + image
- This section is a good place to include pictures. Search for copyleft images on The Pathology Wiki [1] and Ask Dr. Wiki [2].
- For an example of this section, click here
# Microscopic Pathology
- Microscopic pathology is the disease process as it occurs at the microscopic level.
- Template Sentence 1: On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
- Template Sentence 2: The most important histopathological characteristics of [disease name] are summarized in the table below:
- This section is a good place to include pictures. Search for copyleft images on The Pathology Wiki [3] and Ask Dr. Wiki [4].
- For an example of this section, click here. | https://www.wikidoc.org/index.php/Sandbox_manp | |
9a32956d57d1bd94eb7b5dbdecc687d8f325dda5 | wikidoc | Sandbox mela | Sandbox mela
Melatonin, 5-methoxy-N-acetyltryptamine, is a hormone found in all living creatures from algae to humans, at levels that vary in a diurnal cycle.
Many biological effects of melatonin are produced through activation of melatonin receptors, while others are due to its role as a pervasive and extremely powerful antioxidant with a particular role in the protection of nuclear and mitochondrial DNA.
Melatonin was released into the general health supplement market in the United States in 1993, and met with good consumer acceptance and enthusiasm.
# Production
In higher animals, melatonin is produced by pinealocytes in the pineal gland (located in the brain) and also by the retina, lens and GI tract. It is naturally synthesized from the amino acid tryptophan (via synthesis of serotonin) by the enzyme 5-hydroxyindole-O-methyltransferase.
Production of melatonin by the pineal gland is under the influence of the suprachiasmatic nucleus (SCN) of the hypothalamus which receives information from the retina about the daily pattern of light and darkness.
Melatonin is also synthesized by various plants, such as rice, and ingested melatonin has been shown to be capable of reaching and binding to melatonin binding sites in the brains of mammals.
# Dangerous Side Effects
## Asthma
A study indicates that patients with nocturnal asthma may experience adverse effects from melatonin supplements. According to the study “Immunomodulatory Effects of Melatonin in Asthma”, even small amounts of supplemental melatonin worsen the symptoms of the inflammatory disease asthma by causing the body to release chemicals which provoke inflammation. The inflammatory chemicals include increased production of interleukin-1, interleukin-6, and tumor necrosis factor-alpha .
## Arthritis
An animal study indicates that there may be an association between melatonin and increased severity of arthritis in certain individuals. The scientific article titled "The pineal hormone melatonin exaggerates development of collagen-induced arthritis in mice." showed that mice who were injected with melatonin at day 1-10 developed more severe arthritis while those injected at onset did not differ significantly from corresponding controls. The study's results support the hypothesis that the pineal gland can exaggerate the development of CIA via a high release of melatonin, probably via enhancement of T-cell priming.
## Testis Size
An animal study indicates that there is an association between melatonin and reduced testis size in hamsters. The scientific article is titled "Effects of melatonin and 6-methoxybenzoxazolinone on photoperiodic control of testis size in adult male golden hamsters." In this study, testis widths were determined at 2-3 week intervals, and after 66-73 days testes were removed and weighed. The study found that melatonin significantly influenced testis size in each experiment.
# Distribution
Melatonin produced in the pineal gland acts as an endocrine hormone since it is released into the blood.
By contrast, melatonin produced by the retina and the gastrointestinal (GI) tract acts as a paracrine hormone.
# Roles
## Biological clock
In humans, melatonin is produced by the pineal gland, a gland about the size of a pea, that is located in the center of the brain, on the dorsal surface of diencephalon. The melatonin signal forms part of the system that regulates the circadian cycle, but it is the Central nervous system that controls the daily cycle in most components of the paracrine and endocrine systems rather than the melatonin signal (as was once postulated).
Normally, the production of melatonin by the pineal gland is inhibited by light and permitted by darkness. For this reason melatonin has been called "the hormone of darkness." The secretion of melatonin peaks in the middle of the night, and gradually falls during the second half of the night. Until recent history, humans in temperate climates were exposed to up to eighteen hours of darkness in the winter. In this modern world, artificial lighting typically reduces this to eight hours or less per day all year round. Even low light levels inhibit melatonin production to some extent, but over-illumination can create significant reduction in melatonin production. Reduced melatonin production has been proposed as a likely factor in the significantly higher cancer rates in night workers, and the effect of modern lighting practice on endogenous melatonin has been proposed as a contributory factor to the larger overall incidence of some cancers in the developed world. As inadequate as blood concentrations may be in brightly-lit environments, some scientists now believe that people's overnight output of melatonin can be further jeopardized each time they interrupt their sleep and turn on a bright light (suggesting that the lower brightness level of a nightlight would be safer). Others suggest that such short exposures do no harm.
## Antioxidant
Although the primary site of melatonin's action in humans is the melatonin receptors, it first evolved as an antioxidant. In many lower life forms, it serves only this purpose.
Melatonin is a powerful antioxidant that can easily cross cell membranes and the blood-brain barrier. Unlike other antioxidants, melatonin does not undergo redox cycling, the ability of a molecule to undergo reduction and oxidation repeatedly. Redox cycling may allow other antioxidants (such as vitamin C) to act as pro-oxidants, counterintuitively promoting free radical formation. Melatonin, once oxidized, cannot be reduced to its former state because it forms several stable end-products upon reacting with free radicals. Therefore, it has been referred to as a terminal (or suicidal) antioxidant.
Recent research indicates that the beginning of the melatonin antioxidant pathway may be N(1)-acetyl-N(2)-formyl-5-methoxykynuramine or AFMK rather than the common, excreted 6-hydroxymelatonin sulfate. AFMK alone is detectable in unicellular organisms and metazoans. A single AFMK molecule can neuralize up to 10 ROS/RNS since many of the products of the reaction/derivatives (including melatonin) are themselves antioxidants, and so on. This capacity to absorb free radicals extends at least to the quaternary metabolites of melatonin, a process referred to as "the free radical scavenging cascade". This is not true of other, conventional antioxidants.
In animal models, melatonin has been demonstrated to prevent the damage to DNA by some carcinogens, stopping the mechanism by which they cause cancer.
The antioxidant activity of melatonin may reduce damage caused by some types of Parkinson's disease, may play a role in preventing cardiac arrhythmia and may increase longevity; it has been shown to increase the average life span of mice by 20% in some studies.
## Immune system
While it is clear that melatonin interacts with the immune system, the details of those interactions are unclear. There have been few trials designed to judge the effectiveness of melatonin in disease treatment. Most existing data are based on small, incomplete, clinical trials.
Melatonin is an immunoregulator that can enhance T cell production. When taken in conjunction with calcium, it is an immunostimulator and is used as an adjuvant in some clinical protocols; conversely, the increased immune system activity may aggravate autoimmune disorders.
## Dreaming
Many supplemental melatonin users have reported an increase in the vividness or frequency of dreams. High doses of melatonin (50mg) dramatically increased REM sleep time and dream activity in both narcoleptics and normal people.
Many psychoactive drugs, such as LSD and cocaine, increase melatonin synthesis. It has been suggested that nonpolar (lipid-soluble) indolic hallucinogenic drugs emulate melatonin activity in the awakened state and that both act on the same areas of the brain.
In a 2005 editorial of the British Journal of Psychiatry, Ben Sessa suggested that psychotropic drugs be readmitted in the field of scientific enquiry and therapy. Melatonin, being two endogenous hallucinogenic indoles like N,N-dimethyltryptamine (DMT), is likely to be research priorities in this reemerging field of psychiatry.
# Medical applications
Melatonin appears to have some use against circadian rhythm sleep disorders, such as jet lag and delayed sleep phase syndrome. It has been studied for the treatment of cancer, immune disorders, cardiovascular diseases, depression, seasonal affective disorder (SAD), and sexual dysfunction. A study by Alfred J. Lewy and other researchers at Oregon Health & Science University found that it may ameliorate SAD and circadian misalignment, but as of 2006 it is known to affect the timing of endogenous melatonin production, raising the risk that it can exacerbate both clinical depression and SAD. Basic research indicates that melatonin may play a significant role in modulating the effects of drugs of abuse such as cocaine.
## Preventing ischemic damage
Melatonin has been shown to reduce tissue damage in rats due to ischemia in both the brain and the heart; however, this has not been tested in humans.
## Learning, memory and Alzheimers
Melatonin receptors appear to be important in mechanisms of learning and memory in mice, and melatonin can alter electrophysiological processes associated with memory, such as long-term potentiation (LTP). Melatonin has been shown to prevent the hyperphosphorylation of the tau protein in rats. Hyperphosphorylation of tau protein can result in the formation of neurofibrillary tangles, a pathological feature seen in Alzheimer's disease. Thus, melatonin may be effective for treating Alzheimer's Disease. These same neurofibrillary tangles can be found in the hypothalamus in patients with Alzheimer's, adversely affecting their body's production of melatonin. Those Alzheimer's patients with this specific affliction often show heightened afternoon agitation, called "sundowning," which has been shown in many studies to be effectively treated with melatonin supplements in the evening.
## ADHD
ADHD is most commonly treated with methylphenidate which may cause insomnia in approximately 94% of its users. Research shows that after melatonin is administered to the patients, the time needed to fall asleep is significantly reduced. Before the melatonin was administered, the time needed to fall asleep ranged from 15 minutes to 240 minutes. After the melatonin was administred, the time needed to fall asleep ranged from 15 minutes to 64 minutes. Furthermore, the effects of the melatonin after three months showed no change from its effects after one week of use.
## Fertility
Recent research has concluded that melatonin supplementation in perimenopausal women produces a highly significant improvement in thyroid function and gonadotropin levels, as well as restoring fertility and menstruation and preventing the depression associated with the menopause.
Some resources warn women trying to conceive not to take a melatonin supplement.
## Headaches
Several clinical studies indicate that supplementation with melatonin is an effective preventative treatment for migraines and cluster headaches.
## Depression
Melatonin has been shown to be effective in treating one form of depression, Seasonal Affective Disorder.
## Other
Some studies have shown that melatonin has potential for use in the treatment of various forms of cancer, HIV, and other viral diseases; however, further testing is necessary to confirm this.
Histologically speaking, it is also believed that melatonin has some effects for sexual growth in higher organisms. (*Quoted from Ross Histology and Wheather's Functional Histology.)
# Dietary supplement
The primary motivation for the use of melatonin as a supplement is as a natural aid to better sleep, with other incidental benefits to health and well-being due to its role as an antioxidant and its stimulation of the immune system and several components of the endocrine system.
Victor Herbert, M.D., J.D., of the Mt. Sinai School of Medicine, cites studies from Massachusetts Institute of Technology that say melatonin pills sold as supplements contain three to 10 times the amount needed to produce the desirable physiologic nocturnal blood melatonin level for enhancement of nighttime rest. Dosages are designed to raise melatonin levels for several hours to enhance quality of sleep, but some studies suggest that smaller doses are just as effective at improving sleep quality. High dose melatonin can even be counterproductive: Lewy & al provide support to the "idea that too much melatonin may spill over onto the wrong zone of the melatonin phase-response curve." In their study, 0.5 mg of melatonin was effective while 20 mg wasn't. A practical implication of these results is that effective melatonin supplementation (for sleep problems) thus becomes very accessible: it costs a fraction of what most researchers thought it might cost. Melatonin supplementation for sleep problems is available without prescription in most cases in the United States. Melatonin supplements are available as oral supplements and transdermal melatonin or "melatonin sleep patch".
Melatonin is involved in the regulation of body weight, and may be helpful in treating obesity (especially when combined with calcium).
# Safety
Melatonin is practically nontoxic and exhibits almost no short-term side effects. However, melatonin derived from animal sources may be contaminated with viral material; synthetic melatonin may be taken to avoid this risk. No studies have been conducted yet to determine whether there are any long-term side effects.
Even though it is seen as a relatively safe, benign drug, especially to herbal enthusiasts, it can cause some unwanted side effects, especially at high doses. The bodies of people under age 35 are usually able to produce an adequate supply of melatonin on their own. Ingesting melatonin supplements can cause hormone fluctuations, irritability, reduced blood flow (see below), and increased sleep disturbances, including vivid nightmares.
Melatonin taken in combination with monoamine oxidase inhibitors (MAOIs) can lead to overdose because MAOIs inhibit the breakdown of melatonin by the body. Exogenous melatonin normally does not affect the endogenous melatonin profile in the short or medium-term, merely advancing the phase of endogenous melatonin production in time.
In individuals with auto-immune disorders, there is concern that melatonin supplementation may exacerbate symptoms due to stimulation of the immune system.
Melatonin causes somnolence, and therefore should not be taken within five hours before driving, operating machinery, etc. As melatonin is almost always taken at the end of the waking day, this is generally not an issue.
Individuals who experience orthostatic intolerance, a cardiovascular condition that results in reduced blood pressure and blood flow to the brain when a person stands, may experience a worsening of symptoms when taking melatonin supplements, a study at Penn State College of Medicine's Milton S. Hershey Medical Center suggests. Melatonin can exacerbate the symptoms by reducing nerve activity in those who experience the condition, the study found.
# Role in zoology
Many animals use the variation in duration and quantity of melatonin production in each day as a seasonal clock. In seasonal breeders which do not have long gestation periods, and which mate during longer daylight hours, the melatonin signal controls the seasonal variation in their sexual physiology, and similar physiological effects can be induced by exogenous melatonin in animals including mynah birds and hamsters. Melatonin can suppress libido by inhibiting secretion of luteinizing hormone (LH) and follicle stimulating hormone (FSH) from the anterior pituitary gland, especially in mammals that have a breeding season when daylight hours are long. The reproduction of long-day breeders is repressed by melatonin and the reproduction of short-day breeders is stimulated by melatonin.
Melatonin is also related to the mechanism by which some amphibians and reptiles change the color of their skin.
# In popular culture
- Melatonin is the title of a 1998 song by English rock band Radiohead, released as a b-side, and compiled on the album Airbag/How Am I Driving?.
- Melatonin is mentioned extensively in William Gibson's 2003 novel Pattern Recognition, as the novel deals with jet lag.
- Melatonin is the title of the first track of the Silver Lake-based indie rock band Silversun Pickups' 2006 debut album, Carnavas. | Sandbox mela
Melatonin, 5-methoxy-N-acetyltryptamine, is a hormone found in all living creatures from algae[1] to humans, at levels that vary in a diurnal cycle.
Many biological effects of melatonin are produced through activation of melatonin receptors,[2] while others are due to its role as a pervasive and extremely powerful antioxidant[3] with a particular role in the protection of nuclear and mitochondrial DNA.[4]
Melatonin was released into the general health supplement market in the United States in 1993, and met with good consumer acceptance and enthusiasm.[5]
# Production
In higher animals, melatonin is produced by pinealocytes in the pineal gland (located in the brain) and also by the retina, lens and GI tract. It is naturally synthesized from the amino acid tryptophan (via synthesis of serotonin) by the enzyme 5-hydroxyindole-O-methyltransferase.
Production of melatonin by the pineal gland is under the influence of the suprachiasmatic nucleus (SCN) of the hypothalamus which receives information from the retina about the daily pattern of light and darkness.
Melatonin is also synthesized by various plants, such as rice, and ingested melatonin has been shown to be capable of reaching and binding to melatonin binding sites in the brains of mammals.[6][7]
# Dangerous Side Effects
## Asthma
A study indicates that patients with nocturnal asthma may experience adverse effects from melatonin supplements. According to the study “Immunomodulatory Effects of Melatonin in Asthma”, even small amounts of supplemental melatonin worsen the symptoms of the inflammatory disease asthma by causing the body to release chemicals which provoke inflammation. The inflammatory chemicals include increased production of interleukin-1, interleukin-6, and tumor necrosis factor-alpha [8].
## Arthritis
An animal study indicates that there may be an association between melatonin and increased severity of arthritis in certain individuals. The scientific article titled "The pineal hormone melatonin exaggerates development of collagen-induced arthritis in mice." showed that mice who were injected with melatonin at day 1-10 developed more severe arthritis while those injected at onset did not differ significantly from corresponding controls. The study's results support the hypothesis that the pineal gland can exaggerate the development of CIA via a high release of melatonin, probably via enhancement of T-cell priming.
[9].
## Testis Size
An animal study indicates that there is an association between melatonin and reduced testis size in hamsters. The scientific article is titled "Effects of melatonin and 6-methoxybenzoxazolinone on photoperiodic control of testis size in adult male golden hamsters." In this study, testis widths were determined at 2-3 week intervals, and after 66-73 days testes were removed and weighed. The study found that melatonin significantly influenced testis size in each experiment.[10]
# Distribution
Melatonin produced in the pineal gland acts as an endocrine hormone since it is released into the blood.
By contrast, melatonin produced by the retina and the gastrointestinal (GI) tract acts as a paracrine hormone.
# Roles
## Biological clock
In humans, melatonin is produced by the pineal gland, a gland about the size of a pea, that is located in the center of the brain, on the dorsal surface of diencephalon. The melatonin signal forms part of the system that regulates the circadian cycle, but it is the Central nervous system that controls the daily cycle in most components of the paracrine and endocrine systems[11][12] rather than the melatonin signal (as was once postulated).
Normally, the production of melatonin by the pineal gland is inhibited by light and permitted by darkness. For this reason melatonin has been called "the hormone of darkness." The secretion of melatonin peaks in the middle of the night, and gradually falls during the second half of the night. Until recent history, humans in temperate climates were exposed to up to eighteen hours of darkness in the winter. In this modern world, artificial lighting typically reduces this to eight hours or less per day all year round. Even low light levels inhibit melatonin production to some extent, but over-illumination can create significant reduction in melatonin production. Reduced melatonin production has been proposed as a likely factor in the significantly higher cancer rates in night workers,[13] and the effect of modern lighting practice on endogenous melatonin has been proposed as a contributory factor to the larger overall incidence of some cancers in the developed world.[14] As inadequate as blood concentrations may be in brightly-lit environments, some scientists now believe that people's overnight output of melatonin can be further jeopardized each time they interrupt their sleep and turn on a bright light (suggesting that the lower brightness level of a nightlight would be safer). Others suggest that such short exposures do no harm.[15]
## Antioxidant
Although the primary site of melatonin's action in humans is the melatonin receptors, it first evolved as an antioxidant. In many lower life forms, it serves only this purpose.[16]
Melatonin is a powerful antioxidant that can easily cross cell membranes and the blood-brain barrier.[3] Unlike other antioxidants, melatonin does not undergo redox cycling, the ability of a molecule to undergo reduction and oxidation repeatedly. Redox cycling may allow other antioxidants (such as vitamin C) to act as pro-oxidants, counterintuitively promoting free radical formation. Melatonin, once oxidized, cannot be reduced to its former state because it forms several stable end-products upon reacting with free radicals. Therefore, it has been referred to as a terminal (or suicidal) antioxidant.[17]
Recent research indicates that the beginning of the melatonin antioxidant pathway may be N(1)-acetyl-N(2)-formyl-5-methoxykynuramine or AFMK rather than the common, excreted 6-hydroxymelatonin sulfate. AFMK alone is detectable in unicellular organisms and metazoans. A single AFMK molecule can neuralize up to 10 ROS/RNS since many of the products of the reaction/derivatives (including melatonin) are themselves antioxidants, and so on. This capacity to absorb free radicals extends at least to the quaternary metabolites of melatonin, a process referred to as "the free radical scavenging cascade". This is not true of other, conventional antioxidants.[16]
In animal models, melatonin has been demonstrated to prevent the damage to DNA by some carcinogens, stopping the mechanism by which they cause cancer.[18]
The antioxidant activity of melatonin may reduce damage caused by some types of Parkinson's disease, may play a role in preventing cardiac arrhythmia and may increase longevity; it has been shown to increase the average life span of mice by 20% in some studies.[19][20][21]
## Immune system
Template:POV-check-section
While it is clear that melatonin interacts with the immune system,[22][23] the details of those interactions are unclear. There have been few trials designed to judge the effectiveness of melatonin in disease treatment. Most existing data are based on small, incomplete, clinical trials.
Melatonin is an immunoregulator that can enhance T cell production. When taken in conjunction with calcium, it is an immunostimulator and is used as an adjuvant in some clinical protocols; conversely, the increased immune system activity may aggravate autoimmune disorders.
## Dreaming
Many supplemental melatonin users have reported an increase in the vividness or frequency of dreams. High doses of melatonin (50mg) dramatically increased REM sleep time and dream activity in both narcoleptics and normal people.[24]
Many psychoactive drugs, such as LSD and cocaine, increase melatonin synthesis.[24] It has been suggested that nonpolar (lipid-soluble) indolic hallucinogenic drugs emulate melatonin activity in the awakened state and that both act on the same areas of the brain.[24]
In a 2005 editorial of the British Journal of Psychiatry, Ben Sessa suggested that psychotropic drugs be readmitted in the field of scientific enquiry and therapy.[25] Melatonin, being two endogenous hallucinogenic indoles like N,N-dimethyltryptamine (DMT), is likely to be research priorities in this reemerging field of psychiatry.[26]
# Medical applications
Melatonin appears to have some use against circadian rhythm sleep disorders, such as jet lag and delayed sleep phase syndrome. It has been studied for the treatment of cancer, immune disorders, cardiovascular diseases, depression, seasonal affective disorder (SAD), and sexual dysfunction. A study by Alfred J. Lewy and other researchers at Oregon Health & Science University found that it may ameliorate SAD and circadian misalignment,[27] but as of 2006 it is known to affect the timing of endogenous melatonin production, raising the risk that it can exacerbate both clinical depression and SAD.[28] Basic research indicates that melatonin may play a significant role in modulating the effects of drugs of abuse such as cocaine.[29]
## Preventing ischemic damage
Melatonin has been shown to reduce tissue damage in rats due to ischemia in both the brain[30] and the heart;[31] however, this has not been tested in humans.
## Learning, memory and Alzheimers
Melatonin receptors appear to be important in mechanisms of learning and memory in mice,[32] and melatonin can alter electrophysiological processes associated with memory, such as long-term potentiation (LTP). Melatonin has been shown to prevent the hyperphosphorylation of the tau protein in rats. Hyperphosphorylation of tau protein can result in the formation of neurofibrillary tangles, a pathological feature seen in Alzheimer's disease. Thus, melatonin may be effective for treating Alzheimer's Disease.[33] These same neurofibrillary tangles can be found in the hypothalamus in patients with Alzheimer's, adversely affecting their body's production of melatonin. Those Alzheimer's patients with this specific affliction often show heightened afternoon agitation, called "sundowning," which has been shown in many studies to be effectively treated with melatonin supplements in the evening.[34]
## ADHD
ADHD is most commonly treated with methylphenidate which may cause insomnia in approximately 94% of its users. Research shows that after melatonin is administered to the patients, the time needed to fall asleep is significantly reduced. Before the melatonin was administered, the time needed to fall asleep ranged from 15 minutes to 240 minutes. After the melatonin was administred, the time needed to fall asleep ranged from 15 minutes to 64 minutes. Furthermore, the effects of the melatonin after three months showed no change from its effects after one week of use.[35]
## Fertility
Recent research has concluded that melatonin supplementation in perimenopausal women produces a highly significant improvement in thyroid function and gonadotropin levels, as well as restoring fertility and menstruation and preventing the depression associated with the menopause.[36]
Some resources warn women trying to conceive not to take a melatonin supplement.[37]
## Headaches
Several clinical studies indicate that supplementation with melatonin is an effective preventative treatment for migraines and cluster headaches.[38][39]
## Depression
Melatonin has been shown to be effective in treating one form of depression, Seasonal Affective Disorder. [1]
## Other
Some studies have shown that melatonin has potential for use in the treatment of various forms of cancer, HIV, and other viral diseases; however, further testing is necessary to confirm this.[40]
Histologically speaking, it is also believed that melatonin has some effects for sexual growth in higher organisms. (*Quoted from Ross Histology and Wheather's Functional Histology.)
# Dietary supplement
The primary motivation for the use of melatonin as a supplement is as a natural aid to better sleep, with other incidental benefits to health and well-being due to its role as an antioxidant and its stimulation of the immune system and several components of the endocrine system.
Victor Herbert, M.D., J.D., of the Mt. Sinai School of Medicine, cites studies from Massachusetts Institute of Technology that say melatonin pills sold as supplements contain three to 10 times the amount needed to produce the desirable physiologic nocturnal blood melatonin level for enhancement of nighttime rest. Dosages are designed to raise melatonin levels for several hours to enhance quality of sleep, but some studies suggest that smaller doses are just as effective at improving sleep quality.[41] High dose melatonin can even be counterproductive: Lewy & al[42] provide support to the "idea that too much melatonin may spill over onto the wrong zone of the melatonin phase-response curve." In their study, 0.5 mg of melatonin was effective while 20 mg wasn't. A practical implication of these results is that effective melatonin supplementation (for sleep problems) thus becomes very accessible: it costs a fraction of what most researchers thought it might cost. Melatonin supplementation for sleep problems is available without prescription in most cases in the United States. Melatonin supplements are available as oral supplements and transdermal melatonin or "melatonin sleep patch".
Melatonin is involved in the regulation of body weight, and may be helpful in treating obesity (especially when combined with calcium).[43]
# Safety
Template:POV-check-section
Melatonin is practically nontoxic and exhibits almost no short-term side effects. However, melatonin derived from animal sources may be contaminated with viral material; synthetic melatonin may be taken to avoid this risk.[44] No studies have been conducted yet to determine whether there are any long-term side effects.
Even though it is seen as a relatively safe, benign drug, especially to herbal enthusiasts, it can cause some unwanted side effects, especially at high doses. The bodies of people under age 35 are usually able to produce an adequate supply of melatonin on their own.[citation needed] Ingesting melatonin supplements can cause hormone fluctuations,[2] irritability,[3] reduced blood flow (see below), and increased sleep disturbances, including vivid nightmares.[4]
Melatonin taken in combination with monoamine oxidase inhibitors (MAOIs) can lead to overdose because MAOIs inhibit the breakdown of melatonin by the body. Exogenous melatonin normally does not affect the endogenous melatonin profile in the short or medium-term, merely advancing the phase of endogenous melatonin production in time.
In individuals with auto-immune disorders, there is concern that melatonin supplementation may exacerbate symptoms due to stimulation of the immune system.[45]
Melatonin causes somnolence, and therefore should not be taken within five hours[citation needed] before driving, operating machinery, etc. As melatonin is almost always taken at the end of the waking day, this is generally not an issue.
Individuals who experience orthostatic intolerance, a cardiovascular condition that results in reduced blood pressure and blood flow to the brain when a person stands, may experience a worsening of symptoms when taking melatonin supplements, a study at Penn State College of Medicine's Milton S. Hershey Medical Center suggests. Melatonin can exacerbate the symptoms by reducing nerve activity in those who experience the condition, the study found.[46]
# Role in zoology
Many animals use the variation in duration and quantity of melatonin production in each day as a seasonal clock.[47] In seasonal breeders which do not have long gestation periods, and which mate during longer daylight hours, the melatonin signal controls the seasonal variation in their sexual physiology, and similar physiological effects can be induced by exogenous melatonin in animals including mynah birds[48] and hamsters.[49] Melatonin can suppress libido by inhibiting secretion of luteinizing hormone (LH) and follicle stimulating hormone (FSH) from the anterior pituitary gland, especially in mammals that have a breeding season when daylight hours are long. The reproduction of long-day breeders is repressed by melatonin and the reproduction of short-day breeders is stimulated by melatonin.
Melatonin is also related to the mechanism by which some amphibians and reptiles change the color of their skin.[50][51]
# In popular culture
- Melatonin is the title of a 1998 song by English rock band Radiohead, released as a b-side, and compiled on the album Airbag/How Am I Driving?.
- Melatonin is mentioned extensively in William Gibson's 2003 novel Pattern Recognition, as the novel deals with jet lag.
- Melatonin is the title of the first track of the Silver Lake-based indie rock band Silversun Pickups' 2006 debut album, Carnavas. | https://www.wikidoc.org/index.php/Sandbox_mela | |
69f1c71875c4fe6d514b5e128883850730a755db | wikidoc | Sandbox mona | Sandbox mona
- Soft, tan with with hemorrhage and necrosis
# Causes by Organ System
he main complication of the complete mole is a 2% chance of progression to a cancer called choriocarcinoma.There is also an increased risk of choriocarcinoma, but the risk is lower than with the complete mole.
A salvage regimen is instituted if any of the following occur:
A plateau of the beta-hCG for 3 weeks (defined as a beta-hCG decrease of 10% or less for 3 consecutive weeks).
A rise in beta-hCG of greater than 20% for 2 consecutive weeks.
Appearance of metastases.
In women with complete HM, risk of persistence or neoplastic transformation is approximately doubled in the setting of certain characteristics, which include the following:
- Age older than 35 years or age younger than 20 years
- Pre-evacuation serum beta-hCG greater than 100,000 IU/L
- Large-for-date uterus
- Large uterine molar mass
- Large (>6 cm) ovarian cysts
- Pre-eclampsia
- Hyperthyroidism
- Hyperemesis of pregnancy
- Trophoblastic embolization
- Disseminated intravascular coagulation
An effective form of contraception is important during the follow-up period to avoid the confusion that can occur with a rising beta-hCG as a result of pregnancy.
Chemotherapy is necessary when there is the following:
A rising beta-hCG titer for 2 weeks (3 titers).
A tissue diagnosis of choriocarcinoma.
A plateau of the beta-hCG for 3 weeks.
Persistence of detectable beta-hCG 6 months after mole evacuation.
Metastatic disease.
An elevation in beta-hCG after a normal value.
Postevacuation hemorrhage not caused by retained tissues.
If a diagnosis of GTD is made, routine work-up includes the following:
- Serum beta-hCG.
- Blood work of liver, renal, and marrow function.
- Chest x-ray.
- Pelvic ultrasound.
- Head computed tomography or magnetic resonance imaging (in the case of choriocarcinoma or central nervous system signs).
Treatment of GTD depends on the risk category determined by the Modified WHO Prognostic Scoring System as adapted by the International Federation of Gynecology and Obstetrics (see Table 1). Since the very rare placental-site trophoblastic tumors and the even more rare epithelioid trophoblastic tumors are biologically distinct entities, their management is discussed separately.
Gestational trophoblastic disease (GTD) may be classified as follows:
Hydatidiform mole (HM).
Complete HM.
Partial HM.
Gestational trophoblastic neoplasia.
Invasive mole.
Choriocarcinoma.
Placental-site trophoblastic tumor (PSTT); (very rare).
Epithelioid trophoblastic tumor (ETT); (extremely rare).
Choriocarcinoma, PSTT, and ETT are often grouped under the heading gestational trophoblastic tumors.
Invasive mole Clinical Features The prognosis for cure of patients with GTDs is good even when the disease has spread to distant organs, especially when only the lungs are involved. Therefore, the traditional TNM staging system has limited prognostic value. The probability of cure depends on the following:
- Histologic type (invasive mole or choriocarcinoma)
- Extent of spread of the disease/largest tumor size
- Level of serum beta-hCG
- Duration of disease from the initial pregnancy event to start of treatment
- Number and specific sites of metastases
- Nature of antecedent pregnancy
- Extent of prior treatment
GTDs contain paternal chromosomes and are placental, rather than maternal, in origin. The most common presenting symptoms are vaginal bleeding and a rapidly enlarging uterus, and GTD should be considered whenever a premenopausal woman presents with these findings. Because the vast majority of GTD types are associated with elevated human chorionic gonadotropin (hCG) levels, an hCG blood level and pelvic ultrasound are the initial steps in the diagnostic evaluation. In addition to vaginal bleeding and uterine enlargement, other presenting symptoms or signs may include the following:
Pelvic pain or sensation of pressure.
Anemia.
Hyperemesis gravidarum.
Hyperthyroidism (secondary to the homology between the beta-subunits of hCG and thyroid-stimulating hormone (TSH), which causes hCG to have weak TSH-like activity).
Preeclampsia early in pregnancy.
The most common antecedent pregnancy in GTD is that of an HM.
Choriocarcinoma most commonly follows a molar pregnancy but can follow a normal pregnancy, ectopic pregnancy, or abortion, and it should always be considered when a patient has continued vaginal bleeding in the postdelivery period. Other possible signs include neurologic symptoms (resulting from brain metastases) in a female within the reproductive age group and asymptomatic lesions on routine chest x-ray.
●Choriocarcinoma
●Placental site trophoblastic tumor (PSTT)
●Epithelioid trophoblastic tumor (ETT)
Gestational trophoblastic disease
Hydatidiform mole
- Complete mole
- Partial mole
- Invasive mole
Placental site trophoblastic tumour
Epithelioid trophoblastic tumour
Choriocarcinoma
- Influenza A and B
- Adults
- Preferred regimen:Oseltamivir (Tamiflu)75 mg bid for 5 days OR Zanamivir(Relenza) 10 mg (two 5-mg inhalations)bid for 5 days OR Peramivir(Rapivab) One 600 mg dose, via intravenous infusion for 15-30 minutes for 1 day
- Children
- Preferred regimen:Oseltamivir If younger than 1 yr old: 3 mg/kg/dose bid If 1 yr or older, dose varies by child’s weight: 15 kg or less, the dose is 30 mg bid; >15 to 23 kg, the dose is 45 mg bid ;>23 to 40 kg, the dose is 60 mg bid; >40 kg, the dose is 75 mg bid for 5 days OR
- Zanamivir(Relenza) 10 mg (two 5-mg inhalations)bid
- Note:FDA approved and recommended Peramivir(Rapivab) for use in adults ≥18 yrs
- Dosing in Adult Patients with Renal Impairment
- Oral oseltamivir
- Creatinine clearance 61 to 90 mL/min-75 mg twice a day
- Creatinine clearance 31 to 60 mL/min-30 mg twice a day
- Creatinine clearance 10 to 30 mL/min-30 mg once daily
- ESRD Patients on Hemodialysis
- Creatinine clearance ≤10 mL/min-30 mg after every hemodialysis cycle. Treatment duration not to exceed 5 days
- ESRD Patients on Continuous Ambulatory Peritoneal Dialysis-A single 30 mg dose administered immediately after a dialysis exchange
- Intravenous Peramivir (single dose)
- Creatinine clearance >50 mL/min-600mg
- Creatinine clearance 30 to 49 mL/min-200mg
- Creatinine clearance 10 to 29 mL/min-100mg
- ESRD Patients on Hemodialysis-Dose administered after dialysis at a dose adjusted based on creatinine clearance
avian flu
- 1.Preferred regimen:Oseltamivir 75 mg PO qd for a minimum 10 days
- Note:Patients with severe disease may have diarrhea and may not absorb oseltamivir efficiently
- 2.Patients with Avian Influenza who have diarrhea and malabsorption
- Preferred regimen:Zanamivir10 mg inhaled bid for minimum 5 days OR Peramivir600 mg IV as a single dose for1 day
- Note(1)Preliminary evidence demonstrates that neuraminidase inhibitor can reduce the duration of viral replication and improve survival among patients with avian influenza. In cases of suspected avian influenza, one of the following 3 neuraminidase inhibitors should be administered as soon possible, preferably within 48 hours of symptom onset.
- Note(2)The use of corticosteroids is not recommended.
- Note(3): Physicians may consider increasing either the recommended daily dose and/or the duration of treatment in cases of severe disease.
- Note(4):The use of amantadine is not recommended as most H5N1 and H7N9 avian influenza viruses are resistant to it.
- Note(5):Supportive care is also an important cornerstone of the care of patients with avian influenza. Considering the severity of the illness and the possible complications, patients may require fluid resuscitation, vasopressors, intubation and ventilation, paracentesis, hemodialysis or hemofiltration, and parentral nutrition.
- ↑ Avian Influenza Factsheet. World Health Organization. / Accessed on April 22, 2015
- ↑ WHO guidelines for pharmacological management of pandemic (H1N1) 2009 influenza and other influenza viruses. / Accessed on April 22, 2015
- Chronic granulomatous meningitis.
- Preferred regimen: Pentamidine AND (Clarithromycin OR Azithromycin) AND Fluconazole AND Sulfadiazine AND Flucytosine
- Chronic granulomatous meningitis.
- Preferred regimen: Pentamidine AND (Clarithromycin OR Azithromycin) AND Fluconazole AND Sulfadiazine AND Flucytosine
Babesia microti; babesiosis
- 1.Mild/moderate disease.
- Preferred regimen: Atovaquone 750 mg po bid AND Azithromycin 600 mg po qd for 7-10 days
- 2.Severe babesiosis:
- Preferred regimen: Clindamycin 600 mg po tid AND Quinine 650 mg po tid for 7–10 days OR Clindamycin 1.2 gm IV bid.
- Note(1) For overwhelming infection in asplenic patients and immunocompromised patients, treat for 6 or more weeks
- Note(2)Consider transfusion if 10% parasitemia
IM SbV at 20 mg/kg/day for 14 days for the treatment of
L. major, the national standard for the treatment of CL
- ===1.Cutaneous Leishmaniasis===
- 1.1Systemic Therapy (Parenteral)
- Preferred Regimen: Sodium stibogluconate 20 mg/kg IV/IM once qd for 10-20 days OR Meglumine antimoniate 20 mg/kg IV/IM once qd for 10-20 days
- Alternative Regimen: Liposomal amphotericin B 3 mg/kg/day IV infusion for 6-10 days OR Pentamidine 2-3 mg/kg/day IV/IM for 4-7 days
- Note: Data supporting the use of amphotericin B for treatment of cutaneous (and mucosal) leishmaniasis are anecdotal; standard dosage regimens have not been established. In the United States, pentamidine isethionate is uncommonly used for treatment of cutaneous leishmaniasis. Its limitations include the potential for irreversible toxicity and variable effectiveness.
- 1.2 Systemic Therapy (Oral)
- Preferred Regimen: In adults and adolescents at least 12 years of age who weigh from 33-44 kg:-Miltefosine 50 mg PO q12h for 28 days
- Patients who weigh >45 kg:-Miltefosine 50 mg PO q8h for 28 days
- Alternative Regimen:Ketoconazole 600 mg qd for 28 days OR Fluconazole 200 mg qd for 6 weeks
- Note:The FDA-approved indications are limited to infection caused by three particular species, all three of which are New World species in the Viannia subgenus—namely, Leishmania (V.) braziliensis, L. (V.) panamensis, and L. (V.) guyanensis. The "azoles" showed modest activity against some Leishmania species in some cases, but are not FDA approved
- 1.3Local Therapy
- List of possible local therapies
- Cryotherapy (with liquid nitrogen OR Thermotherapy (use of localized current field radiofrequency heat) OR Intralesional administration of SbV OR Topical application of paromomycin (such as an ointment containing 15% paromomycin/12% methylbenzethonium chloride in soft white paraffin)
- 2.Visceral Leishmaniasis
- 2.1Systemic Therapy (Parenteral)
- Preferred Regimen: Liposomal amphotericin B 3 mg/kg/day IV for 5 days, then once on day 14 and once on day 21 (Total dose: 21 mg/kg) ORSodium stibogluconate 20 mg/kg IV/IM once daily for 28 days OR Meglumine antimoniate 20 mg/kg IV/IM once daily for 28 days'
- Alternative Regimen:Amphotericin B deoxycholate 0.5-1 mg/kg IV once daily (Total dose: 15-20 mg/kg)
- Note: In immunosuppressed patients, dose is 4 mg/kg/day for 5 days, then once on day 10, 17, 24, 31, and 38 (Total dose: 40 mg/kg)
- 2.2 Systemic Therapy (Oral)
- Preferred Regimen:In adults and adolescents at least 12 years of age, who weigh from 33-44 kg:Miltefosine 50 mg PO q12h for 28 days Patients who weigh >45 kg:Miltefosine 50 mg PO q8h for 28 days
## Plasmodium
- 1. Plasmodium falciparum
- 1.1 Treatment of uncomplicated P. falciparum malaria
- 1.1.1 Treat children and adults with uncomplicated P. falciparum malaria (except pregnant women in their first trimester) with one of the following recommended ACT (artemisinin-based combination therapy)
- Preferred regimen (1): Artemether 5–24 mg/kg bw PO AND Lumefantrine 29–144 mg/ kg bw PO, Both are given bid for 3 days (total, six doses). The first two doses should, ideally, be given 8 h apart.
- Dosage regimen based on Body weight (kg)
- Body weight (kg)-5 to < 15- Artemether 20 (mg) AND Lumefantrine 120(mg) given bid for 3 days;
- Body weight (kg)-15 to < 25- Artemether 40 (mg) AND Lumefantrine 240(mg) given bid for 3 days;
- Body weight (kg)-25 to < 35- Artemether 60 (mg) AND Lumefantrine 360(mg) given bid for 3 days;
- Body weight (kg) ≥ 35- Artemether 80 (mg) AND Lumefantrine 480(mg) given bid for 3 days.
- Preferred regimen (2): Artesunate (2–10) mg/kg bw per day AND Amodiaquine(7.5–15) mg/kg bw per day ,both are given once a day for 3 days. A total therapeutic dose range of 6–30 mg/kg bw per day artesunate and 22.5–45 mg/kg bw per dose amodiaquine is recommended
- Dosage regimen based on Body weight (kg)
- Body weight (kg)-4.5 to < 9- Artesunate 25 (mg) AND Amodiaquine 67.5 (mg) given bid for 3 days;
- Body weight (kg)-9 to < 18 - Artesunate 50 (mg) AND Amodiaquine 135 (mg) given bid for 3 days;
- Body weight (kg)-18 to < 36- Artesunate 100 (mg) AND Amodiaquine 270(mg) given bid for 3 days;
- Body weight (kg) ≥ 36 - Artesunate 200 (mg) AND Amodiaquine 540 (mg) given bid for 3 days.
- Preferred regimen (3): Artesunate (2–10) mg/kg bw per dayAND Mefloquine (2–10) mg/kg bw per day both are given once a day for 3 days
- Dosage regimen based on Body weight (kg)
- Body weight (kg)-5 to < 9- Artesunate 25 (mg) AND Mefloquine 55 (mg) given bid for 3 days;
- Body weight (kg)-9to < 18- Artesunate 50 (mg) AND Mefloquine 110 (mg) given bid for 3 days;
- Body weight (kg)-18 to < 36- Artesunate 100 (mg) AND Mefloquine 220 (mg) given bid for 3 days;
- Body weight (kg)- ≥ 36 - Artesunate 200 (mg) AND Mefloquine 440 (mg) given bid for 3 days;
- Preferred regimen (4): Artesunate (2–10) mg/kg bw per day given once a day for 3 days AND Sulfadoxine-Pyrimethamine 1.25 (25–70 / 1.25–3.5) mg/kg bw given as a single dose on day 1
- Dosage regimen based on Body weight (kg)
- Body weight (kg)-5 to < 10- Artesunate 25 (mg) AND Sulfadoxine-Pyrimethamine 250/12(mg) given bid for 3 days;
- Body weight (kg)-10 to < 25- Artesunate 50 (mg) AND Sulfadoxine-Pyrimethamine 500 / 25 (mg) given bid for 3 days;
- Body weight (kg)-25 to < 50- Artesunate 100 (mg) AND Sulfadoxine-Pyrimethamine 1000 / 50 (mg) given bid for 3 days;
- Body weight (kg)- ≥50- Artesunate 200 (mg) AND Sulfadoxine-Pyrimethamine 1500 / 75 (mg) given bid for 3 days;
- Preferred regimen (5): Dihydroartemisinin (2–10) mg/kg bw per day AND Piperaquine(16–27) mg/kg bw per day
- Dosage regimen based on Body weight (kg)
- Body weight (kg)-5 to < 8- Dihydroartemisinin 20(mg) AND Piperaquine 160 (mg) given bid for 3 days;
- Body weight (kg)-8 to < 11- Dihydroartemisinin30 (mg) AND Piperaquine 240 (mg) given bid for 3 days;
- Body weight (kg)-11 to < 17 - Dihydroartemisinin 40 (mg) AND Piperaquine 320 (mg) given bid for 3 days;
- Body weight (kg)-17 to < 25- Dihydroartemisinin 60 (mg) AND Piperaquine 480 (mg) given bid for 3 days;
- Body weight (kg)-25 to < 36- Dihydroartemisinin 80 (mg) AND Piperaquine 640 (mg) given bid for 3 days;
- Body weight (kg)-36 to < 60- Dihydroartemisinin 120 (mg) AND Piperaquine 960 (mg) given bid for 3 days;
- Body weight (kg)-60 < 80 - Dihydroartemisinin 160 (mg) AND Piperaquine 1280 (mg) given bid for 3 days;
- Body weight (kg)- >80- Dose of Dihydroartemisinin 200 (mg) AND Piperaquine 1600 (mg) given bid for 3 days;
- 1.1.2 Reducing the transmissibility of treated P. falciparum infections In low-transmission areas in patients with P. falciparum malaria (except pregnant women, infants aged < 6 months and women breastfeeding infants aged < 6 months)
- Preferred regimen: single dose of 0.25 mg/kg bw Primaquine with ACT
- 1.2 Recurrent Falciparum Malaria
- 1.2.1 Failure within 28 days
- Note:The recommended second-line treatment is an alternative ACT known to be effective in the region. Adherence to 7-day treatment regimens (with artesunate or quinine both of which should be co-administered with + tetracycline, or doxycycline or clindamycin) is likely to be poor if treatment is not directly observed; these regimens are no longer generally recommended.
- 1.2.2 Failure after 28 days
- Note: all presumed treatment failures after 4 weeks of initial treatment should, from an operational standpoint, be considered new infections and be treated with the first-line ACT. However, reuse of mefloquine within 60 days of first treatment is associated with an increased risk for neuropsychiatric reactions, and an alternative ACT should be used
- 1.3 Reducing the transmissibility of treated P. falciparum infections In low-transmission areas in patients with P. falciparum malaria (except pregnant women, infants aged < 6 months and women breastfeeding infants aged < 6 months)
- Note: a single dose of 0.25 mg/kg bw Primaquine with ACT
- 1.4 Treating uncomplicated P. falciparum malaria in special risk groups
- 1.4.1 Pregnancy
- First trimester of pregnancy :Quinine AND Clindamycin PO 10mg/kg bw bid for 7 days
- Second and third trimesters : Mefloquine is considered safe for the treatment of malaria during the second and third trimesters; however, it should be given only in combination with an artemisinin derivative.
- Note: Quinine is associated with an increased risk for hypoglycaemia in late pregnancy, and it should be used (with clindamycin) only if effective alternatives are not available.
- Note: Primaquine and tetracyclines should not be used in pregnancy.
- 1.4.2 Infants less than 5kg body weight : with an ACT at the same mg/kg bw target dose as for children weighing 5 kg.
- 1.4.3 Patients co-infected with HIV: should avoid Artesunate + SP if they are also receiving Co-trimoxazole, and avoid artesunate + amodiaquine if they are also receiving efavirenz or zidovudine.
- 1.4.4 Large and Obese adults: For obese patients, less drug is often distributed to fat than to other tissues; therefore, they should be dosed on the basis of an estimate of lean body weight, ideal body weight. Patients who are heavy but not obese require the same mg/kg bw doses as lighter patients.
- 1.4.5 Patients co-infected with TB: Rifamycins, in particular rifampicin, are potent CYP3A4 inducers with weak antimalarial activity. Concomitant administration of rifampicin during quinine treatment of adults with malaria was associated with a significant decrease in exposure to quinine and a five-fold higher recrudescence rate
- 1.4.6 Non-immune travellers : Treat travellers with uncomplicated P. falciparum malaria returning to nonendemic settings with an ACT.
- 1.4.7 Uncomplicated hyperparasitaemia: People with P. falciparum hyperparasitaemia are at increased risk of treatment failure, severe malaria and death so should be closely monitored, in addition to receiving an ACT
- 2. Treatment of uncomplicated malaria caused by P. vivax, P. ovale, P. malariae or P. knowlesi
- 2.1 Blood Stage infection
- 2.1.1. Uncomplicated malaria caused by P. vivax
- 2.1.1.1 In areas with chloroquine-sensitive P. vivax
- Preferred regimen: Chloroquine PO total dose of 25 mg base/kg bw. Chloroquine is given at an initial dose of 10 mg base/kg bw, followed by 10 mg/kg bw on the second day and 5 mg/kg bw on the third day.
- 2.1.1.2 In areas with chloroquine-resistant P. vivax
- Note: ACTs containing piperaquine, mefloquine or lumefantrine are the recommended treatment, although artesunate + amodiaquine may also be effective in some areas. In the systematic review of ACTs for treating P. vivax malaria, dihydroartemisinin + piperaquine provided a longer prophylactic effect than ACTs with shorter half-lives (artemether + lumefantrine, artesunate + amodiaquine), with significantly fewer recurrent parasitaemias during 9 weeks of follow-up.
- 2.1.2 Uncomplicated malaria caused by P. ovale, P. malariae or P. knowlesi malaria
- Note: Resistance of P. ovale, P. malariae and P. knowlesi to antimalarial drugs is not well characterized, and infections caused by these three species are generally considered to be sensitive to chloroquine. In only one study, conducted in Indonesia, was resistance to chloroquine reported in P. malariae. The blood stages of P. ovale, P. malariae and P. knowlesi should therefore be treated with the standard regimen of ACT or chloroquine, as for vivax malaria.
- 2.1.3 Mixed malaria infections
- Note: ACTs are effective against all malaria species and so are the treatment of choice for mixed infections.
- 2.2 Liver stages (hypnozoites) of P. vivax and P. ovale
- Note: To prevent relapse, treat P. vivax or P. ovale malaria in children and adults (except pregnant women, infants aged < 6 months, women breastfeeding infants < 6 months, women breastfeeding older infants unless they are known not to be G6PD deficient and people with G6PD deficiency) with a 14-day course of primaquine in all transmission settings. Strong recommendation, high-quality evidence In people with G6PD deficiency, consider preventing relapse by giving primaquine base at 0.75 mg base/kg bw once a week for 8 weeks, with close medical supervision for potential primaquine-induced adverse haematological effects.]
- 2.2.1 Primaquine for preventive relapse
- Preferred regimen: Primaquine PO 0.25–0.5 mg/kg bw per day qd for 14 days
- 2.2.2 Primaquine and glucose-6-phosphate dehydrogenase deficiency
- Preferred regimen:Primaquine PO 0.75 mg base/kg bw once a week for 8 weeks.
- Note: The decision to give or withhold Primaquine should depend on the possibility of giving the treatment under close medical supervision, with ready access to health facilities with blood transfusion services.
- 2.2.3 Prevention of relapse in pregnant or lacating women and infants
- Note: Primaquine is contraindicated in pregnant women, infants < 6months of age and in lactating women (unless the infant is known not to be G6PD deficient).
- 3.Treatment of severe malaria
- 3.1 Treatment of severe falciparum infection with Artesunate
- 3.1.1 Adults and children with severe malaria (including infants, pregnant women in all trimesters and lactating women):-
- Preferred regimen: Artesunate IV/IM for at least 24 h and until they can tolerate oral medication. Once a patient has received at least 24 h of parenteral therapy and can tolerate oraltherapy, complete treatment with 3 days of an ACT (add single dose Primaquine in areas of low transmission).
- 3.1.2 Young children weighing < 20 kg
- Preferred regimen:Artesunate (3 mg/kg bw per dose)
- Alternatives regimen: use Artemether in preference to quinine for treating children and adults with severe malaria
- 3.2.Treating cases of suspected severe malaria pending transfer to a higher-level facility (pre-referral treatment)
- 3.2.1 Adults and children
- Preferred regimen: Artesunate IM
- Alternative regimen: Artemether IM OR Quinine IM
- 3.2.2 Children < 6 years
- Preferred regimen: Where intramuscular injections of artesunate are not available , treat with a single rectal dose (10 mg/kg bw) of Artesunate, and refer immediately to an appropriate facility for further care.
- Note: Do not use rectal artesunate in older children and adults.
- 3.3 Pregancy
- Note: Parenteral artesunate is the treatment of choice in all trimesters. Treatment must not be delayed
- 3.4 Treatment of severe P.Vivax infection
- Note: parenteral artesunate, treatment can be completed with a full treatment course of oral ACT or chloroquine (in countries where chloroquine is the treatment of choice). A full course of radical treatment with primaquine should be given after recovery
- 3.5 Additional aspects of management in severe malaria
- Fluid therapy: It is not possible to give general recommendations on fluid replacement; each patient must be assessed individually and fluid resuscitation based on the estimated deficit
- Blood Transfusion :In high-transmission settings, blood transfusion is generally recommended for children with a haemoglobin level of < 5 g/100 mL(haematocrit < 15%). In low-transmission settings, a threshold of 20% (haemoglobin,7 g/100 mL) is recommended
- Exchange blood transfusion: Exchange blood transfusion requires intensive nursing care and a relatively large volume of blood, and it carries significant risks. There is no consensus on the indications, benefits and dangers involved or on practical details such as the volume of blood that should be exchanged. It is, therefore, not possible to make any recommendation regarding the use of exchange blood transfusion
# Toxoplasmosis
- Toxoplasma gondii (treatment)
- 1. Lymphadenopathic toxoplasmosis
- Preferred regimen: Treatment of immunocompetent adults with lymphadenopathic toxoplasmosis is rarely indicated; this form of the disease is usually self-limited.
- 2. Ocular disease
- 2.1 Adults
- Preferred regimen: Pyrimethamine 100 mg for 1 day as a loading dose, then 25 to 50 mg/ day AND Sulfadiazine 1 g m qid AND folinic acid (Leucovorin 5-25 mg with each dose of Pyrimethamine
- 2.2 Pediatric
- Preferred regimen: Pyrimethamine 2 mg/kg first day then 1 mg/kg each day AND Sulfadiazine 50 mg/kg bid AND folinic acid (Leucovorin 7.5 mg per day) for 4 to 6 weeks followed by reevaluation of the patient's condition
- Alternative regimen: The fixed combination of Trimethoprim with Sulfamethoxazole has been used as an alternative.
- Note: If the patient has a hypersensitivity reaction to sulfa drugs, Pyrimethamine AND Clindamycin can be used instead.
- 3. Maternal and fetal infection
- 3.1 First and early second trimesters
- Preferred regimen: Spiramycin is recommended
- 3.2 Late second and third trimesters
- Preferred regimen: Pyrimethamine/Sulfadiazine AND Leucovorin for women with acute T. gondii infection diagnosed at a reference laboratory during gestation.
- 3.3 Infant
- Note: If the infant is likely to be infected, then treatment with drugs such as Pyrimethamine, Atovaquone, Sulfadiazine AND Leucovorin is typical. Congenitally infected newborns are generally treated with pyrimethamine, a sulfonamide, and leucovorin for 1 year.
- 4.Toxoplasma gondii Encephalitis in AIDS
- 4.1 Treatment for acute infection
- Preferred regimen: Pyrimethamine 200 mg PO 1 time, followed by weight-based therapy: If <60 kg, Pyrimethamine 50 mg PO once daily Atovaquone AND Sulfadiazine 1000 mg PO q6h AND Leucovorin 10–25 mg PO once daily, If ≥60 kg, Pyrimethamine 75 mg PO once daily AND Sulfadiazine 1500 mg PO q6h AND Leucovorin 10–25 mg PO once daily. Leucovorin dose can be increased to 50 mg daily or BID. Treatment for at least 6 weeks; longer duration if clinical or radiologic disease is extensive or response is incomplete at 6 weeks.
- Alternative regimen (1) Pyrimethamine Leucovorin AND Clindamycin 600 mg IV/ PO q6h
- Alternative regimen (2)TMP-SMX (TMP 5 mg/kg and SMX 25 mg/kg ) IV/PO BID
- Alternative regimen (3)Atovaquone 1500 mg PO BID )with food ANDPyrimethamine, Leucovorin
- Alternative regimen (4)Atovaquone1500 mg PO BID with food AND sulfadiazine 1000–1500 mg PO q6h (weight-based dosing, as in preferred therapy)
- Alternative regimen (5) Atovaquone 1500 mg PO BID with food
- Alternative regimen (6) Pyrimethamine, Leucovorin AND Azithromycin 900–1200 mg PO daily.
- 4.2 Chronic maintenance therapy
- Preferred regimen: Pyrimethamine 25–50 mg PO daily AND sulfadiazine 2000–4000 mg PO daily (in 2–4 divided doses) AND Leucovorin 10–25 mg PO daily
- Alternative regimen (1): Clindamycin 600 mg PO q8h AND (Pyrimethamine 25–50 mg AND Leucovorin 10–25 mg) PO daily
- Alternative regimen (2): TMP-SMX DS 1 tablet BID
- Alternative regimen (3): Atovaquone 750–1500 mg PO BID AND (Pyrimethamine 25 mg AND Leucovorin 10 mg) PO daily
- Alternative regimen (4): Atovaquone 750–1500 mg PO BID
- Alternative regimen (5): Sulfadiazine 2000–4000 mg PO daily (in 2–4 divided doses ),
- Alternative regimen (6): Atovaquone 750–1500 mg PO BID with food Pyrimethamine and Leucovorin doses are the same as for preferred therapy
- Note: Adjunctive corticosteroids (e.g., Dexamethasone) should only be administered when clinically indicated to treat mass effect associated with focal lesions or associated edema; discontinue as soon as clinically feasible. Anticonvulsants should be administered to patients with a history of seizures and continued through acute treatment, but should not be used as seizure prophylaxis . If Clindamycin is used in place of Sulfadiazine, additional therapy must be added to prevent PCP.
- Toxoplasma gondii (prophylaxis)
- 1. Prophylaxis to prevent first episode of encephalitis in AIDS
- 1.1 Indications
- Toxoplasma IgG-positive patients with CD4 count <100 cells/µL
- Seronegative patients receiving PCP prophylaxis not active against toxoplasmosis should have toxoplasma serology retested if CD4 count decline to <100 cells/µL. Prophylaxis should be initiated if seroconversion occurred.
- 1.2 Prophylactic therapy
- Preferred regimen: TMP-SMX 1 DS PO daily
- Alternative regimen (1): TMP-SMX 1 DS PO three times weekly
- Alternative regimen (2): TMP-SMX 1 SS PO daily
- Alternative regimen (3): Dapsone 50 mg PO daily AND (Pyrimethamine 50 mg AND Leucovorin 25 mg) PO weekly
- Alternative regimen (4): Dapsone 200 mg AND Pyrimethamine 75 mg AND Leucovorin 25 mg PO weekly
- Alternative regimen (5): Atovaquone 1500 mg PO daily
- Alternative regimen (6): Atovaquone 1500 mg AND Pyrimethamine 25 mg AND Leucovorin 10 mg PO daily
# African trypanosomiasis
- Sleeping sickness
- 1. East African trypanosomiasis
- 1.1T. b. rhodesiense, hemolymphatic stage
- Adult
- Preferred regimen: Suramin 1 gm IV on days 1,3,5,14, and 21
- Pediatric
- Preferred regimen: Suramin 20 mg/kg IV on days 1, 3, 5, 14, and 21
- 1.2 T. b. rhodesiense, CNS involvement
- Adult
- Preferred regimen: Melarsoprol 2-3.6 mg/kg/day IV for 3 days.After 7 days, 3.6 mg/kg/day for 3 days. Give a 3rd series of 3.6 mg/kg/d after 7 days.
- Pediatric
- Preferred regimen: Melarsoprol 2-3.6 mg/kg/day IV for 3 days.After 7 days, 3.6 mg/kg/day for 3 days. Give a 3rd series of 3.6 mg/kg/d after 7 days
- 2. West African trypanosomiasis
- 2.1 T. b. gambiense, Hemolymphatic stage
- Adult
- Preferred regimen: Pentamidine 4 mg/kg/day IM or IV for 7-10 days
- Pediatric
- Preferred regimen: Pentamidine 4 mg/kg/day IM or IV for 7-10 days
- Note(1): Pentamidine should be used during pregnancy and lacation only if the potential benefit justifies the potential risk
- Note(2): IM/IV Pentamidine have a similar safety profile in children age 4 months and older as in adults. Pentamidine is listed as a medicine for the treatment of 1st stage African trypanosomiasis infection (Trypanosoma brucei gambiense) on the WHO Model List of Essential Medicines for Children, intended for the use of children up to 12 years of age.
- 2.2 T. b. gambiense, CNS involvement
- Adult
- Preferred regimen: Eflornithine 400 mg/kg/day in 4 doses for 14 days
- Pediatric
- Preferred regimen: Eflornithine 400 mg/kg/day in 4 doses for 14 days
- Note (1): Eflornithine should be used during pregnancy and lactation, only if the potential benefit justifies the potential risk
- Note (2): The safety of Eflornithine in children has not been established. Eflornithine is not approved by the Food and Drug Administration (FDA) for use in pediatric patients. Eflornithine is listed for the treatment of 1st stage African trypanosomiasis inTrypanosoma brucei gambiense infection on the WHO Model List of Essential Medicines for Children, intended for the use of children up to 12 years of age.
# Chagas disease
- Preferred regimen(1):Benznidazole < 12 years5-7.5 mg/kg per day orally in 2 divided doses for 60 days
12 years or older5-7 mg/kg per day orally in 2 divided doses for 60 days
- Preferred regimen(2): Nifurtimox ≤ 10 years15-20 mg/kg per day orally in 3 or 4 divided doses for 90 days
11-16 years12.5-15 mg/kg per day orally in 3 or 4 divided doses for 90 days
17 years or older8-10 mg/kg per day orally in 3 or 4 divided doses for 90 days
- Note: In the United States, nifurtimox and benznidazole are not FDA approved and are available only from CDC under investigational protocols.
# varicella zoster
- 1. varicella zoster
- 1.1 Non Immunocompromised person
- Preferred regimen (1): Acyclovir 500 mg PO five times daily for 7-10 days
- Preferred regimen (2):Famciclovir 500mg PO tid daily for 7 days
- Preferred regimen (3):Valacyclovir 1gm PO tid daily for 7 days
- Preferred regimen (4):Brivudin 125mg PO qd daily for 7 days
- 1.2 Immunocompromised person requiring hospitalization or persons with sever neurologic complications
- Preferred regimen (1): Acyclovir 10 mg/ kg IV q8h for 7-10 days
- Preferred regimen (2):Foscarnet 40 mg/ kg IV q8h until lesions are healed
- Note(1): Brivudin is not available in USA and has not been approved by FDA
- Note(2): Foscarnet is not approve by FDA
- Treatment of VZV complications
- HZ ophthalmicus
- Treatment includes the following
- (1) Famciclovir or Valacyclovir for 7–10 days, preferably started within 72 h of rash onset (with IV Acyclovir given as needed for retinitis), to resolve acute disease and inhibit late inflammatory recurrences
(2) pain medications,
(3) cool to tepid wet compresses (if tolerated);
(4) antibiotic ophthalmic ointment administered bid (e.g.Bacitracin-Polymyxin), to protect the ocular surface;
(6) no topical antivirals, because they are ineffective;
- HZ r
Acute retinal necrosis in immunocompetent patients is a less virulent disease and responds better to antiviral therapy. For such patients, acyclovir is clearly beneficial for preserving useful vision . A suggested antiviral regimen for acute retinal necrosis in the otherwise healthy host is intravenous acyclovir (10–15 mg/kg every 8 h for 10–14 days) followed by oral valacyclovir (1 g 3 times daily for 4–6 weeks), although this treatment approach has not been studied in a controlled fashion
- Preferred regimen: Acyclovir IV 10–15 mg/kg q8h for 10–14 days followed by Valacyclovir PO 1 g tid daily for 4–6 weeks
# Influenza
- Influenza virus Return to Top
- 1. Adults
- Preferred regimen (1): Oseltamivir (Tamiflu®) 75 mg bid
- Preferred regimen (2): Zanamivir (Relenza®) 10 mg (two 5-mg inhalations) bid
- Preferred regimen (3): Peramivir (Rapivab®) 600 mg IV for 15-30 minutes (single dose)
- Note: FDA approved and recommended Peramivir (Rapivab®) for use in adults ≥18 yrs
- 2. Children
- 2.1 < 1 yr
- Preferred regimen: Oseltamivir (Tamiflu®) 3 mg/kg/dose bid
- 2.2 > 1 yr
- 2.2.1 ≤ 15 kg
- Preferred regimen: Oseltamivir (Tamiflu®) 30 mg bid
- 2.2.2 > 15 to 23 kg
- Preferred regimen: Oseltamivir (Tamiflu®) 45 mg bid
- 2.2.3 > 23 to 40 kg
- Preferred regimen: Oseltamivir (Tamiflu®) 60 mg bid
- 2.2.4 > 40 kg
- Preferred regimen: Oseltamivir (Tamiflu®) 75 mg bid
- Note: Zanamivir (Relenza®) 10 mg (two 5-mg inhalations) bid may be considered for children > 7 yrs old
- Adult Patients with Renal Impairment or End Stage Renal Disease (ESRD) on Dialysis
- Oral Oseltamivir
- Creatinine clearance 61 to 90 mL/min-75 mg twice a day
- Creatinine clearance 31 to 60 mL/min-30 mg twice a day
- Creatinine clearance 10 to 30 mL/min-30 mg once daily
- ESRD Patients on Hemodialysis
- Creatinine clearance ≤10 mL/min-30 mg after every hemodialysis cycle. Treatment duration not to exceed 5 days
- ESRD Patients on Continuous Ambulatory Peritoneal Dialysis-A single 30 mg dose administered immediately after a dialysis exchange
- Intravenous Peramivir (single dose)
- Creatinine clearance >50 mL/min-600mg
- Creatinine clearance 30 to 49 mL/min-200mg
- Creatinine clearance 10 to 29 mL/min-100mg
- ESRD Patients on Hemodialysis-Dose administered after dialysis at a dose adjusted based on creatinine clearance
Children-
< 1 yr: 3 mg/kg/dose twice daily
1 yr: dose depends on weight.
≤ 15 kg: 30 mg twice a day
15 to 23 kg: 45 mg twice a day
23 to 40 kg: 60 mg twice a day
40 kg: 75 mg twice a day.
Zanamivir (Relenza®)
Adults
10 mg (two 5-mg inhalations) twice daily
For children > 7 yrs old.
10 mg (two 5-mg inhalations) twice daily
Peramivir (Rapivab®)
Adults
600 mg IV for 15-30 minutes (single dose)
- ↑ Gilbert, David (2015). The Sanford guide to antimicrobial therapy. Sperryville, Va: Antimicrobial Therapy. ISBN 978-1930808843..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}
- ↑ Gilbert, David (2015). The Sanford guide to antimicrobial therapy. Sperryville, Va: Antimicrobial Therapy. ISBN 978-1930808843.
- ↑ Gilbert, David (2015). The Sanford guide to antimicrobial therapy. Sperryville, Va: Antimicrobial Therapy. ISBN 978-1930808843.
- ↑ "Guidelines for the treatment of malaria. Third edition April 2015" (PDF).
- ↑ "Parasites - Toxoplasmosis (Toxoplasma infection)".
- ↑ "Parasites - Toxoplasmosis (Toxoplasma infection)".
- ↑ "Parasites - Toxoplasmosis (Toxoplasma infection)".
- ↑ "Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents" (PDF).
- ↑ "Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents" (PDF).
- ↑ "African Trypanosomiasis". | Sandbox mona
- Soft, tan with with hemorrhage and necrosis
http://www.pathologyoutlines.com/topic/ovarytumorchorio.html
## Causes by Organ System
he main complication of the complete mole is a 2% chance of progression to a cancer called choriocarcinoma.There is also an increased risk of choriocarcinoma, but the risk is lower than with the complete mole.
A salvage regimen is instituted if any of the following occur:
A plateau of the beta-hCG for 3 weeks (defined as a beta-hCG decrease of 10% or less for 3 consecutive weeks).
A rise in beta-hCG of greater than 20% for 2 consecutive weeks.
Appearance of metastases.
In women with complete HM, risk of persistence or neoplastic transformation is approximately doubled in the setting of certain characteristics, which include the following:
- Age older than 35 years or age younger than 20 years
- Pre-evacuation serum beta-hCG greater than 100,000 IU/L
- Large-for-date uterus
- Large uterine molar mass
- Large (>6 cm) ovarian cysts
- Pre-eclampsia
- Hyperthyroidism
- Hyperemesis of pregnancy
- Trophoblastic embolization
- Disseminated intravascular coagulation
An effective form of contraception is important during the follow-up period to avoid the confusion that can occur with a rising beta-hCG as a result of pregnancy.
Chemotherapy is necessary when there is the following:
A rising beta-hCG titer for 2 weeks (3 titers).
A tissue diagnosis of choriocarcinoma.
A plateau of the beta-hCG for 3 weeks.
Persistence of detectable beta-hCG 6 months after mole evacuation.
Metastatic disease.
An elevation in beta-hCG after a normal value.
Postevacuation hemorrhage not caused by retained tissues.
If a diagnosis of GTD is made, routine work-up includes the following:
- Serum beta-hCG.
- Blood work of liver, renal, and marrow function.
- Chest x-ray.
- Pelvic ultrasound.
- Head computed tomography or magnetic resonance imaging (in the case of choriocarcinoma or central nervous system signs).
Treatment of GTD depends on the risk category determined by the Modified WHO Prognostic Scoring System as adapted by the International Federation of Gynecology and Obstetrics (see Table 1). Since the very rare placental-site trophoblastic tumors and the even more rare epithelioid trophoblastic tumors are biologically distinct entities, their management is discussed separately.
Gestational trophoblastic disease (GTD) may be classified as follows:[1]
Hydatidiform mole (HM).
Complete HM.
Partial HM.
Gestational trophoblastic neoplasia.
Invasive mole.
Choriocarcinoma.
Placental-site trophoblastic tumor (PSTT); (very rare).
Epithelioid trophoblastic tumor (ETT); (extremely rare).
Choriocarcinoma, PSTT, and ETT are often grouped under the heading gestational trophoblastic tumors.
Invasive mole Clinical Features The prognosis for cure of patients with GTDs is good even when the disease has spread to distant organs, especially when only the lungs are involved. Therefore, the traditional TNM staging system has limited prognostic value.[4] The probability of cure depends on the following:
- Histologic type (invasive mole or choriocarcinoma)
- Extent of spread of the disease/largest tumor size
- Level of serum beta-hCG
- Duration of disease from the initial pregnancy event to start of treatment
- Number and specific sites of metastases
- Nature of antecedent pregnancy
- Extent of prior treatment
GTDs contain paternal chromosomes and are placental, rather than maternal, in origin. The most common presenting symptoms are vaginal bleeding and a rapidly enlarging uterus, and GTD should be considered whenever a premenopausal woman presents with these findings. Because the vast majority of GTD types are associated with elevated human chorionic gonadotropin (hCG) levels, an hCG blood level and pelvic ultrasound are the initial steps in the diagnostic evaluation. In addition to vaginal bleeding and uterine enlargement, other presenting symptoms or signs may include the following:
Pelvic pain or sensation of pressure.
Anemia.
Hyperemesis gravidarum.
Hyperthyroidism (secondary to the homology between the beta-subunits of hCG and thyroid-stimulating hormone (TSH), which causes hCG to have weak TSH-like activity).
Preeclampsia early in pregnancy.
The most common antecedent pregnancy in GTD is that of an HM.
Choriocarcinoma most commonly follows a molar pregnancy but can follow a normal pregnancy, ectopic pregnancy, or abortion, and it should always be considered when a patient has continued vaginal bleeding in the postdelivery period. Other possible signs include neurologic symptoms (resulting from brain metastases) in a female within the reproductive age group and asymptomatic lesions on routine chest x-ray.
●Choriocarcinoma
●Placental site trophoblastic tumor (PSTT)
●Epithelioid trophoblastic tumor (ETT)
Gestational trophoblastic disease
Hydatidiform mole
• Complete mole
• Partial mole
• Invasive mole
Placental site trophoblastic tumour
Epithelioid trophoblastic tumour
Choriocarcinoma
- Influenza A and B
- Adults
- Preferred regimen:Oseltamivir (Tamiflu)75 mg bid for 5 days OR Zanamivir(Relenza) 10 mg (two 5-mg inhalations)bid for 5 days OR Peramivir(Rapivab) One 600 mg dose, via intravenous infusion for 15-30 minutes for 1 day
- Children
- Preferred regimen:Oseltamivir If younger than 1 yr old: 3 mg/kg/dose bid If 1 yr or older, dose varies by child’s weight: 15 kg or less, the dose is 30 mg bid; >15 to 23 kg, the dose is 45 mg bid ;>23 to 40 kg, the dose is 60 mg bid; >40 kg, the dose is 75 mg bid for 5 days OR
- Zanamivir(Relenza) 10 mg (two 5-mg inhalations)bid
- Note:FDA approved and recommended Peramivir(Rapivab) for use in adults ≥18 yrs
- Dosing in Adult Patients with Renal Impairment
- Oral oseltamivir
- Creatinine clearance 61 to 90 mL/min-75 mg twice a day
- Creatinine clearance 31 to 60 mL/min-30 mg twice a day
- Creatinine clearance 10 to 30 mL/min-30 mg once daily
- ESRD Patients on Hemodialysis
- Creatinine clearance ≤10 mL/min-30 mg after every hemodialysis cycle. Treatment duration not to exceed 5 days
- ESRD Patients on Continuous Ambulatory Peritoneal Dialysis-A single 30 mg dose administered immediately after a dialysis exchange
- Intravenous Peramivir (single dose)
- Creatinine clearance >50 mL/min-600mg
- Creatinine clearance 30 to 49 mL/min-200mg
- Creatinine clearance 10 to 29 mL/min-100mg
- ESRD Patients on Hemodialysis-Dose administered after dialysis at a dose adjusted based on creatinine clearance
avian flu
[2]
- 1.Preferred regimen:Oseltamivir 75 mg PO qd for a minimum 10 days
- Note:Patients with severe disease may have diarrhea and may not absorb oseltamivir efficiently
- 2.Patients with Avian Influenza who have diarrhea and malabsorption
- Preferred regimen:Zanamivir10 mg inhaled bid for minimum 5 days OR Peramivir600 mg IV as a single dose for1 day
- Note(1)Preliminary evidence demonstrates that neuraminidase inhibitor can reduce the duration of viral replication and improve survival among patients with avian influenza. In cases of suspected avian influenza, one of the following 3 neuraminidase inhibitors should be administered as soon possible, preferably within 48 hours of symptom onset.
- Note(2)The use of corticosteroids is not recommended.
- Note(3): Physicians may consider increasing either the recommended daily dose and/or the duration of treatment in cases of severe disease.
- Note(4):The use of amantadine is not recommended as most H5N1 and H7N9 avian influenza viruses are resistant to it.[3]
- Note(5):Supportive care is also an important cornerstone of the care of patients with avian influenza. Considering the severity of the illness and the possible complications, patients may require fluid resuscitation, vasopressors, intubation and ventilation, paracentesis, hemodialysis or hemofiltration, and parentral nutrition.
- ↑ http://picasaweb.google.com/mcmumbi/USMLEIIImages
- ↑ Avian Influenza Factsheet. World Health Organization. http://www.who.int/mediacentre/factsheets/avian_influenza/en/ Accessed on April 22, 2015
- ↑ WHO guidelines for pharmacological management of pandemic (H1N1) 2009 influenza and other influenza viruses. http://www.who.int/csr/resources/publications/swineflu/h1n1_use_antivirals_20090820/en/ Accessed on April 22, 2015
- Chronic granulomatous meningitis.[1]
- Preferred regimen: Pentamidine AND (Clarithromycin OR Azithromycin) AND Fluconazole AND Sulfadiazine AND Flucytosine
- Chronic granulomatous meningitis.[2]
- Preferred regimen: Pentamidine AND (Clarithromycin OR Azithromycin) AND Fluconazole AND Sulfadiazine AND Flucytosine
Babesia microti; babesiosis
- 1.Mild/moderate disease.[3]
- Preferred regimen: Atovaquone 750 mg po bid AND Azithromycin 600 mg po qd for 7-10 days
- 2.Severe babesiosis:
- Preferred regimen: Clindamycin 600 mg po tid AND Quinine 650 mg po tid for 7–10 days OR Clindamycin 1.2 gm IV bid.
- Note(1) For overwhelming infection in asplenic patients and immunocompromised patients, treat for 6 or more weeks
- Note(2)Consider transfusion if 10% parasitemia
IM SbV at 20 mg/kg/day for 14 days for the treatment of
L. major, the national standard for the treatment of CL
- ===1.Cutaneous Leishmaniasis===
- 1.1Systemic Therapy (Parenteral)
- Preferred Regimen: Sodium stibogluconate 20 mg/kg IV/IM once qd for 10-20 days OR Meglumine antimoniate 20 mg/kg IV/IM once qd for 10-20 days
- Alternative Regimen: Liposomal amphotericin B 3 mg/kg/day IV infusion for 6-10 days OR Pentamidine 2-3 mg/kg/day IV/IM for 4-7 days
- Note: Data supporting the use of amphotericin B for treatment of cutaneous (and mucosal) leishmaniasis are anecdotal; standard dosage regimens have not been established. In the United States, pentamidine isethionate is uncommonly used for treatment of cutaneous leishmaniasis. Its limitations include the potential for irreversible toxicity and variable effectiveness.
- 1.2 Systemic Therapy (Oral)
- Preferred Regimen: In adults and adolescents at least 12 years of age who weigh from 33-44 kg:-Miltefosine 50 mg PO q12h for 28 days
- Patients who weigh >45 kg:-Miltefosine 50 mg PO q8h for 28 days
- Alternative Regimen:Ketoconazole 600 mg qd for 28 days OR Fluconazole 200 mg qd for 6 weeks
- Note:The FDA-approved indications are limited to infection caused by three particular species, all three of which are New World species in the Viannia subgenus—namely, Leishmania (V.) braziliensis, L. (V.) panamensis, and L. (V.) guyanensis. The "azoles" showed modest activity against some Leishmania species in some cases, but are not FDA approved
- 1.3Local Therapy
- List of possible local therapies
- Cryotherapy (with liquid nitrogen OR Thermotherapy (use of localized current field radiofrequency heat) OR Intralesional administration of SbV OR Topical application of paromomycin (such as an ointment containing 15% paromomycin/12% methylbenzethonium chloride in soft white paraffin)
- 2.Visceral Leishmaniasis
- 2.1Systemic Therapy (Parenteral)
- Preferred Regimen: Liposomal amphotericin B 3 mg/kg/day IV for 5 days, then once on day 14 and once on day 21 (Total dose: 21 mg/kg) ORSodium stibogluconate 20 mg/kg IV/IM once daily for 28 days OR Meglumine antimoniate 20 mg/kg IV/IM once daily for 28 days'
- Alternative Regimen:Amphotericin B deoxycholate 0.5-1 mg/kg IV once daily (Total dose: 15-20 mg/kg)
- Note: In immunosuppressed patients, dose is 4 mg/kg/day for 5 days, then once on day 10, 17, 24, 31, and 38 (Total dose: 40 mg/kg)
- 2.2 Systemic Therapy (Oral)
- Preferred Regimen:In adults and adolescents at least 12 years of age, who weigh from 33-44 kg:Miltefosine 50 mg PO q12h for 28 days Patients who weigh >45 kg:Miltefosine 50 mg PO q8h for 28 days
### Plasmodium
- 1. Plasmodium falciparum[4]
- 1.1 Treatment of uncomplicated P. falciparum malaria
- 1.1.1 Treat children and adults with uncomplicated P. falciparum malaria (except pregnant women in their first trimester) with one of the following recommended ACT (artemisinin-based combination therapy)
- Preferred regimen (1): Artemether 5–24 mg/kg bw PO AND Lumefantrine 29–144 mg/ kg bw PO, Both are given bid for 3 days (total, six doses). The first two doses should, ideally, be given 8 h apart.
- Dosage regimen based on Body weight (kg)
- Body weight (kg)-5 to < 15- Artemether 20 (mg) AND Lumefantrine 120(mg) given bid for 3 days;
- Body weight (kg)-15 to < 25- Artemether 40 (mg) AND Lumefantrine 240(mg) given bid for 3 days;
- Body weight (kg)-25 to < 35- Artemether 60 (mg) AND Lumefantrine 360(mg) given bid for 3 days;
- Body weight (kg) ≥ 35- Artemether 80 (mg) AND Lumefantrine 480(mg) given bid for 3 days.
- Preferred regimen (2): Artesunate (2–10) mg/kg bw per day AND Amodiaquine(7.5–15) mg/kg bw per day ,both are given once a day for 3 days. A total therapeutic dose range of 6–30 mg/kg bw per day artesunate and 22.5–45 mg/kg bw per dose amodiaquine is recommended
- Dosage regimen based on Body weight (kg)
- Body weight (kg)-4.5 to < 9- Artesunate 25 (mg) AND Amodiaquine 67.5 (mg) given bid for 3 days;
- Body weight (kg)-9 to < 18 - Artesunate 50 (mg) AND Amodiaquine 135 (mg) given bid for 3 days;
- Body weight (kg)-18 to < 36- Artesunate 100 (mg) AND Amodiaquine 270(mg) given bid for 3 days;
- Body weight (kg) ≥ 36 - Artesunate 200 (mg) AND Amodiaquine 540 (mg) given bid for 3 days.
- Preferred regimen (3): Artesunate (2–10) mg/kg bw per dayAND Mefloquine (2–10) mg/kg bw per day both are given once a day for 3 days
- Dosage regimen based on Body weight (kg)
- Body weight (kg)-5 to < 9- Artesunate 25 (mg) AND Mefloquine 55 (mg) given bid for 3 days;
- Body weight (kg)-9to < 18- Artesunate 50 (mg) AND Mefloquine 110 (mg) given bid for 3 days;
- Body weight (kg)-18 to < 36- Artesunate 100 (mg) AND Mefloquine 220 (mg) given bid for 3 days;
- Body weight (kg)- ≥ 36 - Artesunate 200 (mg) AND Mefloquine 440 (mg) given bid for 3 days;
- Preferred regimen (4): Artesunate (2–10) mg/kg bw per day given once a day for 3 days AND Sulfadoxine-Pyrimethamine 1.25 (25–70 / 1.25–3.5) mg/kg bw given as a single dose on day 1
- Dosage regimen based on Body weight (kg)
- Body weight (kg)-5 to < 10- Artesunate 25 (mg) AND Sulfadoxine-Pyrimethamine 250/12(mg) given bid for 3 days;
- Body weight (kg)-10 to < 25- Artesunate 50 (mg) AND Sulfadoxine-Pyrimethamine 500 / 25 (mg) given bid for 3 days;
- Body weight (kg)-25 to < 50- Artesunate 100 (mg) AND Sulfadoxine-Pyrimethamine 1000 / 50 (mg) given bid for 3 days;
- Body weight (kg)- ≥50- Artesunate 200 (mg) AND Sulfadoxine-Pyrimethamine 1500 / 75 (mg) given bid for 3 days;
- Preferred regimen (5): Dihydroartemisinin (2–10) mg/kg bw per day AND Piperaquine(16–27) mg/kg bw per day
- Dosage regimen based on Body weight (kg)
- Body weight (kg)-5 to < 8- Dihydroartemisinin 20(mg) AND Piperaquine 160 (mg) given bid for 3 days;
- Body weight (kg)-8 to < 11- Dihydroartemisinin30 (mg) AND Piperaquine 240 (mg) given bid for 3 days;
- Body weight (kg)-11 to < 17 - Dihydroartemisinin 40 (mg) AND Piperaquine 320 (mg) given bid for 3 days;
- Body weight (kg)-17 to < 25- Dihydroartemisinin 60 (mg) AND Piperaquine 480 (mg) given bid for 3 days;
- Body weight (kg)-25 to < 36- Dihydroartemisinin 80 (mg) AND Piperaquine 640 (mg) given bid for 3 days;
- Body weight (kg)-36 to < 60- Dihydroartemisinin 120 (mg) AND Piperaquine 960 (mg) given bid for 3 days;
- Body weight (kg)-60 < 80 - Dihydroartemisinin 160 (mg) AND Piperaquine 1280 (mg) given bid for 3 days;
- Body weight (kg)- >80- Dose of Dihydroartemisinin 200 (mg) AND Piperaquine 1600 (mg) given bid for 3 days;
- 1.1.2 Reducing the transmissibility of treated P. falciparum infections In low-transmission areas in patients with P. falciparum malaria (except pregnant women, infants aged < 6 months and women breastfeeding infants aged < 6 months)
- Preferred regimen: single dose of 0.25 mg/kg bw Primaquine with ACT
- 1.2 Recurrent Falciparum Malaria
- 1.2.1 Failure within 28 days
- Note:The recommended second-line treatment is an alternative ACT known to be effective in the region. Adherence to 7-day treatment regimens (with artesunate or quinine both of which should be co-administered with + tetracycline, or doxycycline or clindamycin) is likely to be poor if treatment is not directly observed; these regimens are no longer generally recommended.
- 1.2.2 Failure after 28 days
- Note: all presumed treatment failures after 4 weeks of initial treatment should, from an operational standpoint, be considered new infections and be treated with the first-line ACT. However, reuse of mefloquine within 60 days of first treatment is associated with an increased risk for neuropsychiatric reactions, and an alternative ACT should be used
- 1.3 Reducing the transmissibility of treated P. falciparum infections In low-transmission areas in patients with P. falciparum malaria (except pregnant women, infants aged < 6 months and women breastfeeding infants aged < 6 months)
- Note: a single dose of 0.25 mg/kg bw Primaquine with ACT
- 1.4 Treating uncomplicated P. falciparum malaria in special risk groups
- 1.4.1 Pregnancy
- First trimester of pregnancy :Quinine AND Clindamycin PO 10mg/kg bw bid for 7 days
- Second and third trimesters : Mefloquine is considered safe for the treatment of malaria during the second and third trimesters; however, it should be given only in combination with an artemisinin derivative.
- Note: Quinine is associated with an increased risk for hypoglycaemia in late pregnancy, and it should be used (with clindamycin) only if effective alternatives are not available.
- Note: Primaquine and tetracyclines should not be used in pregnancy.
- 1.4.2 Infants less than 5kg body weight : with an ACT at the same mg/kg bw target dose as for children weighing 5 kg.
- 1.4.3 Patients co-infected with HIV: should avoid Artesunate + SP if they are also receiving Co-trimoxazole, and avoid artesunate + amodiaquine if they are also receiving efavirenz or zidovudine.
- 1.4.4 Large and Obese adults: For obese patients, less drug is often distributed to fat than to other tissues; therefore, they should be dosed on the basis of an estimate of lean body weight, ideal body weight. Patients who are heavy but not obese require the same mg/kg bw doses as lighter patients.
- 1.4.5 Patients co-infected with TB: Rifamycins, in particular rifampicin, are potent CYP3A4 inducers with weak antimalarial activity. Concomitant administration of rifampicin during quinine treatment of adults with malaria was associated with a significant decrease in exposure to quinine and a five-fold higher recrudescence rate
- 1.4.6 Non-immune travellers : Treat travellers with uncomplicated P. falciparum malaria returning to nonendemic settings with an ACT.
- 1.4.7 Uncomplicated hyperparasitaemia: People with P. falciparum hyperparasitaemia are at increased risk of treatment failure, severe malaria and death so should be closely monitored, in addition to receiving an ACT
- 2. Treatment of uncomplicated malaria caused by P. vivax, P. ovale, P. malariae or P. knowlesi
- 2.1 Blood Stage infection
- 2.1.1. Uncomplicated malaria caused by P. vivax
- 2.1.1.1 In areas with chloroquine-sensitive P. vivax
- Preferred regimen: Chloroquine PO total dose of 25 mg base/kg bw. Chloroquine is given at an initial dose of 10 mg base/kg bw, followed by 10 mg/kg bw on the second day and 5 mg/kg bw on the third day.
- 2.1.1.2 In areas with chloroquine-resistant P. vivax
- Note: ACTs containing piperaquine, mefloquine or lumefantrine are the recommended treatment, although artesunate + amodiaquine may also be effective in some areas. In the systematic review of ACTs for treating P. vivax malaria, dihydroartemisinin + piperaquine provided a longer prophylactic effect than ACTs with shorter half-lives (artemether + lumefantrine, artesunate + amodiaquine), with significantly fewer recurrent parasitaemias during 9 weeks of follow-up.
- 2.1.2 Uncomplicated malaria caused by P. ovale, P. malariae or P. knowlesi malaria
- Note: Resistance of P. ovale, P. malariae and P. knowlesi to antimalarial drugs is not well characterized, and infections caused by these three species are generally considered to be sensitive to chloroquine. In only one study, conducted in Indonesia, was resistance to chloroquine reported in P. malariae. The blood stages of P. ovale, P. malariae and P. knowlesi should therefore be treated with the standard regimen of ACT or chloroquine, as for vivax malaria.
- 2.1.3 Mixed malaria infections
- Note: ACTs are effective against all malaria species and so are the treatment of choice for mixed infections.
- 2.2 Liver stages (hypnozoites) of P. vivax and P. ovale
- Note: To prevent relapse, treat P. vivax or P. ovale malaria in children and adults (except pregnant women, infants aged < 6 months, women breastfeeding infants < 6 months, women breastfeeding older infants unless they are known not to be G6PD deficient and people with G6PD deficiency) with a 14-day course of primaquine in all transmission settings. Strong recommendation, high-quality evidence In people with G6PD deficiency, consider preventing relapse by giving primaquine base at 0.75 mg base/kg bw once a week for 8 weeks, with close medical supervision for potential primaquine-induced adverse haematological effects.]
- 2.2.1 Primaquine for preventive relapse
- Preferred regimen: Primaquine PO 0.25–0.5 mg/kg bw per day qd for 14 days
- 2.2.2 Primaquine and glucose-6-phosphate dehydrogenase deficiency
- Preferred regimen:Primaquine PO 0.75 mg base/kg bw once a week for 8 weeks.
- Note: The decision to give or withhold Primaquine should depend on the possibility of giving the treatment under close medical supervision, with ready access to health facilities with blood transfusion services.
- 2.2.3 Prevention of relapse in pregnant or lacating women and infants
- Note: Primaquine is contraindicated in pregnant women, infants < 6months of age and in lactating women (unless the infant is known not to be G6PD deficient).
- 3.Treatment of severe malaria
- 3.1 Treatment of severe falciparum infection with Artesunate
- 3.1.1 Adults and children with severe malaria (including infants, pregnant women in all trimesters and lactating women):-
- Preferred regimen: Artesunate IV/IM for at least 24 h and until they can tolerate oral medication. Once a patient has received at least 24 h of parenteral therapy and can tolerate oraltherapy, complete treatment with 3 days of an ACT (add single dose Primaquine in areas of low transmission).
- 3.1.2 Young children weighing < 20 kg
- Preferred regimen:Artesunate (3 mg/kg bw per dose)
- Alternatives regimen: use Artemether in preference to quinine for treating children and adults with severe malaria
- 3.2.Treating cases of suspected severe malaria pending transfer to a higher-level facility (pre-referral treatment)
- 3.2.1 Adults and children
- Preferred regimen: Artesunate IM
- Alternative regimen: Artemether IM OR Quinine IM
- 3.2.2 Children < 6 years
- Preferred regimen: Where intramuscular injections of artesunate are not available , treat with a single rectal dose (10 mg/kg bw) of Artesunate, and refer immediately to an appropriate facility for further care.
- Note: Do not use rectal artesunate in older children and adults.
- 3.3 Pregancy
- Note: Parenteral artesunate is the treatment of choice in all trimesters. Treatment must not be delayed
- 3.4 Treatment of severe P.Vivax infection
- Note: parenteral artesunate, treatment can be completed with a full treatment course of oral ACT or chloroquine (in countries where chloroquine is the treatment of choice). A full course of radical treatment with primaquine should be given after recovery
- 3.5 Additional aspects of management in severe malaria
- Fluid therapy: It is not possible to give general recommendations on fluid replacement; each patient must be assessed individually and fluid resuscitation based on the estimated deficit
- Blood Transfusion :In high-transmission settings, blood transfusion is generally recommended for children with a haemoglobin level of < 5 g/100 mL(haematocrit < 15%). In low-transmission settings, a threshold of 20% (haemoglobin,7 g/100 mL) is recommended
- Exchange blood transfusion: Exchange blood transfusion requires intensive nursing care and a relatively large volume of blood, and it carries significant risks. There is no consensus on the indications, benefits and dangers involved or on practical details such as the volume of blood that should be exchanged. It is, therefore, not possible to make any recommendation regarding the use of exchange blood transfusion
## Toxoplasmosis
- Toxoplasma gondii (treatment)
- 1. Lymphadenopathic toxoplasmosis[5]
- Preferred regimen: Treatment of immunocompetent adults with lymphadenopathic toxoplasmosis is rarely indicated; this form of the disease is usually self-limited.
- 2. Ocular disease[6]
- 2.1 Adults
- Preferred regimen: Pyrimethamine 100 mg for 1 day as a loading dose, then 25 to 50 mg/ day AND Sulfadiazine 1 g m qid AND folinic acid (Leucovorin 5-25 mg with each dose of Pyrimethamine
- 2.2 Pediatric
- Preferred regimen: Pyrimethamine 2 mg/kg first day then 1 mg/kg each day AND Sulfadiazine 50 mg/kg bid AND folinic acid (Leucovorin 7.5 mg per day) for 4 to 6 weeks followed by reevaluation of the patient's condition
- Alternative regimen: The fixed combination of Trimethoprim with Sulfamethoxazole has been used as an alternative.
- Note: If the patient has a hypersensitivity reaction to sulfa drugs, Pyrimethamine AND Clindamycin can be used instead.
- 3. Maternal and fetal infection[7]
- 3.1 First and early second trimesters
- Preferred regimen: Spiramycin is recommended
- 3.2 Late second and third trimesters
- Preferred regimen: Pyrimethamine/Sulfadiazine AND Leucovorin for women with acute T. gondii infection diagnosed at a reference laboratory during gestation.
- 3.3 Infant
- Note: If the infant is likely to be infected, then treatment with drugs such as Pyrimethamine, Atovaquone, Sulfadiazine AND Leucovorin is typical. Congenitally infected newborns are generally treated with pyrimethamine, a sulfonamide, and leucovorin for 1 year.
- 4.Toxoplasma gondii Encephalitis in AIDS[8]
- 4.1 Treatment for acute infection
- Preferred regimen: Pyrimethamine 200 mg PO 1 time, followed by weight-based therapy: If <60 kg, Pyrimethamine 50 mg PO once daily Atovaquone AND Sulfadiazine 1000 mg PO q6h AND Leucovorin 10–25 mg PO once daily, If ≥60 kg, Pyrimethamine 75 mg PO once daily AND Sulfadiazine 1500 mg PO q6h AND Leucovorin 10–25 mg PO once daily. Leucovorin dose can be increased to 50 mg daily or BID. Treatment for at least 6 weeks; longer duration if clinical or radiologic disease is extensive or response is incomplete at 6 weeks.
- Alternative regimen (1) Pyrimethamine Leucovorin AND Clindamycin 600 mg IV/ PO q6h
- Alternative regimen (2)TMP-SMX (TMP 5 mg/kg and SMX 25 mg/kg ) IV/PO BID
- Alternative regimen (3)Atovaquone 1500 mg PO BID )with food ANDPyrimethamine, Leucovorin
- Alternative regimen (4)Atovaquone1500 mg PO BID with food AND sulfadiazine 1000–1500 mg PO q6h (weight-based dosing, as in preferred therapy)
- Alternative regimen (5) Atovaquone 1500 mg PO BID with food
- Alternative regimen (6) Pyrimethamine, Leucovorin AND Azithromycin 900–1200 mg PO daily.
- 4.2 Chronic maintenance therapy
- Preferred regimen: Pyrimethamine 25–50 mg PO daily AND sulfadiazine 2000–4000 mg PO daily (in 2–4 divided doses) AND Leucovorin 10–25 mg PO daily
- Alternative regimen (1): Clindamycin 600 mg PO q8h AND (Pyrimethamine 25–50 mg AND Leucovorin 10–25 mg) PO daily
- Alternative regimen (2): TMP-SMX DS 1 tablet BID
- Alternative regimen (3): Atovaquone 750–1500 mg PO BID AND (Pyrimethamine 25 mg AND Leucovorin 10 mg) PO daily
- Alternative regimen (4): Atovaquone 750–1500 mg PO BID
- Alternative regimen (5): Sulfadiazine 2000–4000 mg PO daily (in 2–4 divided doses ),
- Alternative regimen (6): Atovaquone 750–1500 mg PO BID with food Pyrimethamine and Leucovorin doses are the same as for preferred therapy
- Note: Adjunctive corticosteroids (e.g., Dexamethasone) should only be administered when clinically indicated to treat mass effect associated with focal lesions or associated edema; discontinue as soon as clinically feasible. Anticonvulsants should be administered to patients with a history of seizures and continued through acute treatment, but should not be used as seizure prophylaxis . If Clindamycin is used in place of Sulfadiazine, additional therapy must be added to prevent PCP.
- Toxoplasma gondii (prophylaxis)
- 1. Prophylaxis to prevent first episode of encephalitis in AIDS[9]
- 1.1 Indications
- Toxoplasma IgG-positive patients with CD4 count <100 cells/µL
- Seronegative patients receiving PCP prophylaxis not active against toxoplasmosis should have toxoplasma serology retested if CD4 count decline to <100 cells/µL. Prophylaxis should be initiated if seroconversion occurred.
- 1.2 Prophylactic therapy
- Preferred regimen: TMP-SMX 1 DS PO daily
- Alternative regimen (1): TMP-SMX 1 DS PO three times weekly
- Alternative regimen (2): TMP-SMX 1 SS PO daily
- Alternative regimen (3): Dapsone 50 mg PO daily AND (Pyrimethamine 50 mg AND Leucovorin 25 mg) PO weekly
- Alternative regimen (4): Dapsone 200 mg AND Pyrimethamine 75 mg AND Leucovorin 25 mg PO weekly
- Alternative regimen (5): Atovaquone 1500 mg PO daily
- Alternative regimen (6): Atovaquone 1500 mg AND Pyrimethamine 25 mg AND Leucovorin 10 mg PO daily
## African trypanosomiasis
- Sleeping sickness[10]
- 1. East African trypanosomiasis
- 1.1T. b. rhodesiense, hemolymphatic stage
- Adult
- Preferred regimen: Suramin 1 gm IV on days 1,3,5,14, and 21
- Pediatric
- Preferred regimen: Suramin 20 mg/kg IV on days 1, 3, 5, 14, and 21
- 1.2 T. b. rhodesiense, CNS involvement
- Adult
- Preferred regimen: Melarsoprol 2-3.6 mg/kg/day IV for 3 days.After 7 days, 3.6 mg/kg/day for 3 days. Give a 3rd series of 3.6 mg/kg/d after 7 days.
- Pediatric
- Preferred regimen: Melarsoprol 2-3.6 mg/kg/day IV for 3 days.After 7 days, 3.6 mg/kg/day for 3 days. Give a 3rd series of 3.6 mg/kg/d after 7 days
- 2. West African trypanosomiasis
- 2.1 T. b. gambiense, Hemolymphatic stage
- Adult
- Preferred regimen: Pentamidine 4 mg/kg/day IM or IV for 7-10 days
- Pediatric
- Preferred regimen: Pentamidine 4 mg/kg/day IM or IV for 7-10 days
- Note(1): Pentamidine should be used during pregnancy and lacation only if the potential benefit justifies the potential risk
- Note(2): IM/IV Pentamidine have a similar safety profile in children age 4 months and older as in adults. Pentamidine is listed as a medicine for the treatment of 1st stage African trypanosomiasis infection (Trypanosoma brucei gambiense) on the WHO Model List of Essential Medicines for Children, intended for the use of children up to 12 years of age.
- 2.2 T. b. gambiense, CNS involvement
- Adult
- Preferred regimen: Eflornithine 400 mg/kg/day in 4 doses for 14 days
- Pediatric
- Preferred regimen: Eflornithine 400 mg/kg/day in 4 doses for 14 days
- Note (1): Eflornithine should be used during pregnancy and lactation, only if the potential benefit justifies the potential risk
- Note (2): The safety of Eflornithine in children has not been established. Eflornithine is not approved by the Food and Drug Administration (FDA) for use in pediatric patients. Eflornithine is listed for the treatment of 1st stage African trypanosomiasis inTrypanosoma brucei gambiense infection on the WHO Model List of Essential Medicines for Children, intended for the use of children up to 12 years of age.
## Chagas disease
- Preferred regimen(1):Benznidazole < 12 years5-7.5 mg/kg per day orally in 2 divided doses for 60 days
12 years or older5-7 mg/kg per day orally in 2 divided doses for 60 days
- Preferred regimen(2): Nifurtimox ≤ 10 years15-20 mg/kg per day orally in 3 or 4 divided doses for 90 days
11-16 years12.5-15 mg/kg per day orally in 3 or 4 divided doses for 90 days
17 years or older8-10 mg/kg per day orally in 3 or 4 divided doses for 90 days
- Note: In the United States, nifurtimox and benznidazole are not FDA approved and are available only from CDC under investigational protocols.
## varicella zoster
- 1. varicella zoster
- 1.1 Non Immunocompromised person
- Preferred regimen (1): Acyclovir 500 mg PO five times daily for 7-10 days
- Preferred regimen (2):Famciclovir 500mg PO tid daily for 7 days
- Preferred regimen (3):Valacyclovir 1gm PO tid daily for 7 days
- Preferred regimen (4):Brivudin 125mg PO qd daily for 7 days
- 1.2 Immunocompromised person requiring hospitalization or persons with sever neurologic complications
- Preferred regimen (1): Acyclovir 10 mg/ kg IV q8h for 7-10 days
- Preferred regimen (2):Foscarnet 40 mg/ kg IV q8h until lesions are healed
- Note(1): Brivudin is not available in USA and has not been approved by FDA
- Note(2): Foscarnet is not approve by FDA
- Treatment of VZV complications
- HZ ophthalmicus
- Treatment includes the following
- (1) Famciclovir or Valacyclovir for 7–10 days, preferably started within 72 h of rash onset (with IV Acyclovir given as needed for retinitis), to resolve acute disease and inhibit late inflammatory recurrences
(2) pain medications,
(3) cool to tepid wet compresses (if tolerated);
(4) antibiotic ophthalmic ointment administered bid (e.g.Bacitracin-Polymyxin), to protect the ocular surface;
(6) no topical antivirals, because they are ineffective;
- HZ r
Acute retinal necrosis in immunocompetent patients is a less virulent disease and responds better to antiviral therapy. For such patients, acyclovir is clearly beneficial for preserving useful vision [235]. A suggested antiviral regimen for acute retinal necrosis in the otherwise healthy host is intravenous acyclovir (10–15 mg/kg every 8 h for 10–14 days) followed by oral valacyclovir (1 g 3 times daily for 4–6 weeks), although this treatment approach has not been studied in a controlled fashion
- Preferred regimen: Acyclovir IV 10–15 mg/kg q8h for 10–14 days followed by Valacyclovir PO 1 g tid daily for 4–6 weeks
## Influenza
- Influenza virus Return to Top
- 1. Adults
- Preferred regimen (1): Oseltamivir (Tamiflu®) 75 mg bid
- Preferred regimen (2): Zanamivir (Relenza®) 10 mg (two 5-mg inhalations) bid
- Preferred regimen (3): Peramivir (Rapivab®) 600 mg IV for 15-30 minutes (single dose)
- Note: FDA approved and recommended Peramivir (Rapivab®) for use in adults ≥18 yrs
- 2. Children
- 2.1 < 1 yr
- Preferred regimen: Oseltamivir (Tamiflu®) 3 mg/kg/dose bid
- 2.2 > 1 yr
- 2.2.1 ≤ 15 kg
- Preferred regimen: Oseltamivir (Tamiflu®) 30 mg bid
- 2.2.2 > 15 to 23 kg
- Preferred regimen: Oseltamivir (Tamiflu®) 45 mg bid
- 2.2.3 > 23 to 40 kg
- Preferred regimen: Oseltamivir (Tamiflu®) 60 mg bid
- 2.2.4 > 40 kg
- Preferred regimen: Oseltamivir (Tamiflu®) 75 mg bid
- Note: Zanamivir (Relenza®) 10 mg (two 5-mg inhalations) bid may be considered for children > 7 yrs old
- Adult Patients with Renal Impairment or End Stage Renal Disease (ESRD) on Dialysis
- Oral Oseltamivir
- Creatinine clearance 61 to 90 mL/min-75 mg twice a day
- Creatinine clearance 31 to 60 mL/min-30 mg twice a day
- Creatinine clearance 10 to 30 mL/min-30 mg once daily
- ESRD Patients on Hemodialysis
- Creatinine clearance ≤10 mL/min-30 mg after every hemodialysis cycle. Treatment duration not to exceed 5 days
- ESRD Patients on Continuous Ambulatory Peritoneal Dialysis-A single 30 mg dose administered immediately after a dialysis exchange
- Intravenous Peramivir (single dose)
- Creatinine clearance >50 mL/min-600mg
- Creatinine clearance 30 to 49 mL/min-200mg
- Creatinine clearance 10 to 29 mL/min-100mg
- ESRD Patients on Hemodialysis-Dose administered after dialysis at a dose adjusted based on creatinine clearance
Children-
< 1 yr: 3 mg/kg/dose twice daily
> 1 yr: dose depends on weight.
≤ 15 kg: 30 mg twice a day
> 15 to 23 kg: 45 mg twice a day
> 23 to 40 kg: 60 mg twice a day
> 40 kg: 75 mg twice a day.
Zanamivir (Relenza®)
Adults
10 mg (two 5-mg inhalations) twice daily
For children > 7 yrs old.
10 mg (two 5-mg inhalations) twice daily
Peramivir (Rapivab®)
Adults
600 mg IV for 15-30 minutes (single dose)
- ↑ Gilbert, David (2015). The Sanford guide to antimicrobial therapy. Sperryville, Va: Antimicrobial Therapy. ISBN 978-1930808843..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}
- ↑ Gilbert, David (2015). The Sanford guide to antimicrobial therapy. Sperryville, Va: Antimicrobial Therapy. ISBN 978-1930808843.
- ↑ Gilbert, David (2015). The Sanford guide to antimicrobial therapy. Sperryville, Va: Antimicrobial Therapy. ISBN 978-1930808843.
- ↑ "Guidelines for the treatment of malaria. Third edition April 2015" (PDF).
- ↑ "Parasites - Toxoplasmosis (Toxoplasma infection)".
- ↑ "Parasites - Toxoplasmosis (Toxoplasma infection)".
- ↑ "Parasites - Toxoplasmosis (Toxoplasma infection)".
- ↑ "Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents" (PDF).
- ↑ "Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents" (PDF).
- ↑ "African Trypanosomiasis". | https://www.wikidoc.org/index.php/Sandbox_mona | |
0127b081d6d6fea2033166811f81f02498beb3aa | wikidoc | Sandbox test | Sandbox test
# 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
Sandbox test is a Adrenergic receptor agonist that is FDA approved for the {{{indicationType}}} of a list of indications, separated by commas.. There is a Black Box Warning for this drug as shown here. Common adverse reactions include a list of adverse reactions, separated by commas..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- (Dosage)
- Dosing Information
- (Dosage)
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Developed by: (Organisation)
- Class of Recommendation: (Class) (Link)
- Strength of Evidence: (Category A/B/C) (Link)
- Dosing Information/Recommendation
- (Dosage)
- Developed by: (Organisation)
- Class of Recommendation: (Class) (Link)
- Strength of Evidence: (Category A/B/C) (Link)
- Dosing Information/Recommendation
- (Dosage)
### Non–Guideline-Supported Use
- Dosing Information
- (Dosage)
- Dosing Information
- (Dosage)
- Dosing Information
- (Dosage)
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- (Dosage)
- Dosing Information
- (Dosage)
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- Developed by: (Organisation)
- Class of Recommendation: (Class) (Link)
- Strength of Evidence: (Category A/B/C) (Link)
- Dosing Information/Recommendation
- (Dosage)
- Developed by: (Organisation)
- Class of Recommendation: (Class) (Link)
- Strength of Evidence: (Category A/B/C) (Link)
- Dosing Information/Recommendation
- (Dosage)
### Non–Guideline-Supported Use
- Dosing Information
- (Dosage)
- Dosing Information
- (Dosage)
- Dosing Information
- (Dosage)
# Contraindications
- Condition 1
- Condition 2
- Condition 3
- Condition 4
- Condition 5
# Warnings
(Description)
# Adverse Reactions
## Clinical Trials Experience
## Postmarketing Experience
(Description)
# Drug Interactions
- Drug 1
- Drug 2
- Drug 3
- Drug 4
- Drug 5
(Description)
(Description)
(Description)
(Description)
(Description)
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
(Description)
Pregnancy Category (AUS):
(Description)
### Labor and Delivery
(Description)
### Nursing Mothers
(Description)
### Pediatric Use
(Description)
### Geriatic Use
(Description)
### Gender
(Description)
### Race
(Description)
### Renal Impairment
(Description)
### Hepatic Impairment
(Description)
### Females of Reproductive Potential and Males
(Description)
### Immunocompromised Patients
(Description)
### Others
(Description)
# Administration and Monitoring
### Administration
(Oral/Intravenous/etc)
### Monitoring
(Description regarding monitoring, from Warnings section)
(Description regarding monitoring, from Warnings section)
(Description regarding monitoring, from Warnings section)
# IV Compatibility
## Solution
### Compatible
- Solution 1
- Solution 2
- Solution 3
### Not Tested
- Solution 1
- Solution 2
- Solution 3
### Variable
- Solution 1
- Solution 2
- Solution 3
### Incompatible
- Solution 1
- Solution 2
- Solution 3
## Y-Site
### Compatible
- Solution 1
- Solution 2
- Solution 3
### Not Tested
- Solution 1
- Solution 2
- Solution 3
### Variable
- Solution 1
- Solution 2
- Solution 3
### Incompatible
- Solution 1
- Solution 2
- Solution 3
## Admixture
### Compatible
- Solution 1
- Solution 2
- Solution 3
### Not Tested
- Solution 1
- Solution 2
- Solution 3
### Variable
- Solution 1
- Solution 2
- Solution 3
### Incompatible
- Solution 1
- Solution 2
- Solution 3
## Syringe
### Compatible
- Solution 1
- Solution 2
- Solution 3
### Not Tested
- Solution 1
- Solution 2
- Solution 3
### Variable
- Solution 1
- Solution 2
- Solution 3
### Incompatible
- Solution 1
- Solution 2
- Solution 3
## TPN/TNA
### Compatible
- Solution 1
- Solution 2
- Solution 3
### Not Tested
- Solution 1
- Solution 2
- Solution 3
### Variable
- Solution 1
- Solution 2
- Solution 3
### Incompatible
- Solution 1
- Solution 2
- Solution 3
# Overdosage
## Acute Overdose
### Signs and Symptoms
(Description)
### Management
(Description)
## Chronic Overdose
### Signs and Symptoms
(Description)
### Management
(Description)
# Pharmacology
## Mechanism of Action
(Description)
## Structure
(Description with picture)
## Pharmacodynamics
(Description)
## Pharmacokinetics
(Description)
## Nonclinical Toxicology
(Description)
# Clinical Studies
(Description)
(Description)
(Description)
# How Supplied
(Description)
## Storage
There is limited information regarding Sandbox test Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
(Patient Counseling Information)
# Precautions with Alcohol
Alcohol-Sandbox test interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
There is limited information regarding Sandbox test Brand Names in the drug label.
# Look-Alike Drug Names
- (Paired Confused Name 1a) — (Paired Confused Name 1b)
- (Paired Confused Name 2a) — (Paired Confused Name 2b)
- (Paired Confused Name 3a) — (Paired Confused Name 3b)
# Drug Shortage Status
Drug Shortage
# Price | Sandbox test
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Sandbox test is a Adrenergic receptor agonist that is FDA approved for the {{{indicationType}}} of a list of indications, separated by commas.. There is a Black Box Warning for this drug as shown here. Common adverse reactions include a list of adverse reactions, separated by commas..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- (Dosage)
- Dosing Information
- (Dosage)
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Developed by: (Organisation)
- Class of Recommendation: (Class) (Link)
- Strength of Evidence: (Category A/B/C) (Link)
- Dosing Information/Recommendation
- (Dosage)
- Developed by: (Organisation)
- Class of Recommendation: (Class) (Link)
- Strength of Evidence: (Category A/B/C) (Link)
- Dosing Information/Recommendation
- (Dosage)
### Non–Guideline-Supported Use
- Dosing Information
- (Dosage)
- Dosing Information
- (Dosage)
- Dosing Information
- (Dosage)
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- (Dosage)
- Dosing Information
- (Dosage)
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- Developed by: (Organisation)
- Class of Recommendation: (Class) (Link)
- Strength of Evidence: (Category A/B/C) (Link)
- Dosing Information/Recommendation
- (Dosage)
- Developed by: (Organisation)
- Class of Recommendation: (Class) (Link)
- Strength of Evidence: (Category A/B/C) (Link)
- Dosing Information/Recommendation
- (Dosage)
### Non–Guideline-Supported Use
- Dosing Information
- (Dosage)
- Dosing Information
- (Dosage)
- Dosing Information
- (Dosage)
# Contraindications
- Condition 1
- Condition 2
- Condition 3
- Condition 4
- Condition 5
# Warnings
(Description)
# Adverse Reactions
## Clinical Trials Experience
## Postmarketing Experience
(Description)
# Drug Interactions
- Drug 1
- Drug 2
- Drug 3
- Drug 4
- Drug 5
(Description)
(Description)
(Description)
(Description)
(Description)
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
(Description)
Pregnancy Category (AUS):
(Description)
### Labor and Delivery
(Description)
### Nursing Mothers
(Description)
### Pediatric Use
(Description)
### Geriatic Use
(Description)
### Gender
(Description)
### Race
(Description)
### Renal Impairment
(Description)
### Hepatic Impairment
(Description)
### Females of Reproductive Potential and Males
(Description)
### Immunocompromised Patients
(Description)
### Others
(Description)
# Administration and Monitoring
### Administration
(Oral/Intravenous/etc)
### Monitoring
(Description regarding monitoring, from Warnings section)
(Description regarding monitoring, from Warnings section)
(Description regarding monitoring, from Warnings section)
# IV Compatibility
## Solution
### Compatible
- Solution 1
- Solution 2
- Solution 3
### Not Tested
- Solution 1
- Solution 2
- Solution 3
### Variable
- Solution 1
- Solution 2
- Solution 3
### Incompatible
- Solution 1
- Solution 2
- Solution 3
## Y-Site
### Compatible
- Solution 1
- Solution 2
- Solution 3
### Not Tested
- Solution 1
- Solution 2
- Solution 3
### Variable
- Solution 1
- Solution 2
- Solution 3
### Incompatible
- Solution 1
- Solution 2
- Solution 3
## Admixture
### Compatible
- Solution 1
- Solution 2
- Solution 3
### Not Tested
- Solution 1
- Solution 2
- Solution 3
### Variable
- Solution 1
- Solution 2
- Solution 3
### Incompatible
- Solution 1
- Solution 2
- Solution 3
## Syringe
### Compatible
- Solution 1
- Solution 2
- Solution 3
### Not Tested
- Solution 1
- Solution 2
- Solution 3
### Variable
- Solution 1
- Solution 2
- Solution 3
### Incompatible
- Solution 1
- Solution 2
- Solution 3
## TPN/TNA
### Compatible
- Solution 1
- Solution 2
- Solution 3
### Not Tested
- Solution 1
- Solution 2
- Solution 3
### Variable
- Solution 1
- Solution 2
- Solution 3
### Incompatible
- Solution 1
- Solution 2
- Solution 3
# Overdosage
## Acute Overdose
### Signs and Symptoms
(Description)
### Management
(Description)
## Chronic Overdose
### Signs and Symptoms
(Description)
### Management
(Description)
# Pharmacology
## Mechanism of Action
(Description)
## Structure
(Description with picture)
## Pharmacodynamics
(Description)
## Pharmacokinetics
(Description)
## Nonclinical Toxicology
(Description)
# Clinical Studies
(Description)
(Description)
(Description)
# How Supplied
(Description)
## Storage
There is limited information regarding Sandbox test Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
(Patient Counseling Information)
# Precautions with Alcohol
Alcohol-Sandbox test interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
There is limited information regarding Sandbox test Brand Names in the drug label.
# Look-Alike Drug Names
- (Paired Confused Name 1a) — (Paired Confused Name 1b)
- (Paired Confused Name 2a) — (Paired Confused Name 2b)
- (Paired Confused Name 3a) — (Paired Confused Name 3b)
# Drug Shortage Status
Drug Shortage
# Price | https://www.wikidoc.org/index.php/Sandbox_test | |
4489bd21e34a0bd4cbe2cf0d2751dd55e84cb127 | wikidoc | Sanjay Gupta | Sanjay Gupta
Sanjay Gupta (Hindi: संजय गुप्ता), born 23 October 1969, is a second-generation Indian-American physician and a contributing CNN chief health correspondent based in Atlanta, Georgia. An Assistant Professor of Neurosurgery at Emory University and associate chief of the neurosurgery service at Grady Memorial Hospital in Atlanta, he is also a frequent guest on the news program Anderson Cooper 360°. "Charity Hospital", won a 2006 Emmy Award for Outstanding Feature Story in a Regularly Scheduled Newscast. From 1997 to 1998 he served as one of fifteen White House Fellows, primarily as an advisor to Hillary Clinton. Dr. Gupta currently publishes a column in TIME magazine. He is also host of House Call with Dr Sanjay Gupta. His book Chasing Life was a New York Times and National Best Seller.
# Background
Gupta grew up in Template:City-state, and received both his undergraduate and medical degrees at the University of Michigan in Template:City-state. He completed his residency in neurological surgery within the University of Michigan Health System. His father and mother moved from India to Michigan to work as engineers at the Ford Dearborn Plant in the 1960s.
In 2003, Gupta traveled to Iraq to cover the medical aspects of 2003 invasion of Iraq. While in Iraq, Gupta performed emergency surgery on both U.S. soldiers and Iraqi civilians. Gupta was embedded with a Marine medical unit at the time. A Marine named Jesus Vidana suffered a severe head injury and the Marines asked for Gupta's assistance because of his background in neurosurgery. Vidana survived and was sent back to the United States for rehabilitation.
Gupta was named one of the Sexiest Men of 2003 by People magazine.
In December of 2006, CBS News President Sean McManus negotiated a deal with CNN that will have Gupta file up to 10 reports a year for "The Evening News With Katie Couric" and "60 minutes" while remaining CNN’s chief medical correspondent and associate chief of neurosurgery at Grady Memorial Hospital.
# Medical practice
Dr. Gupta specializes in all facets of neurosurgical care with a strong interest in complicated spine, trauma and 3-D image guided operations. He has recently had articles published in the Journal of Neurosurgery and Neurosurgical Focus on percutaneous pedicle screw placement. He has also published on brain tumors and spinal cord abnormalities.
# Battlefield Controversy
While in Iraq, Dr Gupta was asked to perform brain surgery on five different patients, including Jesus Vidana, a Marine who had been twice pronounced dead on the battlefield. Jesus survived the injuries and now lives in Southern California. Gupta was criticized upon his return and many, including Bob Steele of the Poynter Institute thought Gupta crossed the line when doffing his journalism cap for a surgeon's cap. Gupta was quoted in Newsweek magazine as saying "medically and morally, it was the right thing to do."
# Michael Moore controversy
A July 9, 2007 broadcast of CNN's The Situation Room aired a "fact check" segment by Gupta on Michael Moore's 2007 film Sicko. Immediately following the segment, Moore was interviewed live on CNN by Wolf Blitzer. Moore stated that Gupta's report was inaccurate and biased, and later posted a detailed response on his website. Moore accused CNN and Gupta of being biased in favor of the drug industry because most of the sponsors for their medical coverage, including Dr. Gupta's reports, were drug companies. On July 15, 2007, CNN released a statement in response to Michael Moore's rebuttal. In it, they apologized for an error in their on-air report, having stated that in the film Moore reported Cuba spends $25 per person for health care when the film actually gave that number as $251. CNN blamed this on a transcription error. CNN defended the rest of Dr. Gupta's report and issued a point-by-point response to Moore's response in which CNN contended that Moore's comparison of data from different sources in different years was in effect "cherry picking" results, at the cost of statistical accuracy. CNN also admitted that Gupta had afterwards committed a second error, mistakenly contesting Moore's observation that Gupta's one on-air expert was now associated with a think tank rather than a university (a fact which the chyron on Gupta's original report had stated correctly).
# Merck Gardasil controversy
A July 25, 2007 article on the left-wing counterpunch.org criticized Gupta for publicly backing the drug Gardasil (a cervical cancer vaccine) while at the same time being host of a television show that is sponsored by the manufacturer, Merck. Gupta said "As a doctor, and parent, I would recommend the vaccine for my daughters. I feel the ability to protect them in any way, including from cancer, is my primary obligation." Turner Private Network's television show "AccentHealth" is partially underwritten by Merck. | Sanjay Gupta
Template:Infobox Person
Sanjay Gupta (Hindi: संजय गुप्ता), born 23 October 1969, is a second-generation Indian-American physician and a contributing CNN chief health correspondent based in Atlanta, Georgia. An Assistant Professor of Neurosurgery at Emory University and associate chief of the neurosurgery service at Grady Memorial Hospital in Atlanta, he is also a frequent guest on the news program Anderson Cooper 360°. "Charity Hospital", won a 2006 Emmy Award for Outstanding Feature Story in a Regularly Scheduled Newscast. From 1997 to 1998 he served as one of fifteen White House Fellows, primarily as an advisor to Hillary Clinton. Dr. Gupta currently publishes a column in TIME magazine. He is also host of House Call with Dr Sanjay Gupta. His book Chasing Life was a New York Times and National Best Seller[citation needed].
# Background
Gupta grew up in Template:City-state, and received both his undergraduate and medical degrees at the University of Michigan in Template:City-state. He completed his residency in neurological surgery within the University of Michigan Health System. His father and mother moved from India to Michigan to work as engineers at the Ford Dearborn Plant in the 1960s.
In 2003, Gupta traveled to Iraq to cover the medical aspects of 2003 invasion of Iraq. While in Iraq, Gupta performed emergency surgery on both U.S. soldiers and Iraqi civilians. Gupta was embedded with a Marine medical unit at the time. A Marine named Jesus Vidana suffered a severe head injury and the Marines asked for Gupta's assistance because of his background in neurosurgery. Vidana survived and was sent back to the United States for rehabilitation. [1]
Gupta was named one of the Sexiest Men of 2003 by People magazine.
In December of 2006, CBS News President Sean McManus negotiated a deal with CNN that will have Gupta file up to 10 reports a year for "The Evening News With Katie Couric" and "60 minutes" while remaining CNN’s chief medical correspondent and associate chief of neurosurgery at Grady Memorial Hospital.
# Medical practice
Dr. Gupta specializes in all facets of neurosurgical care with a strong interest in complicated spine, trauma and 3-D image guided operations[citation needed]. He has recently had articles published in the Journal of Neurosurgery and Neurosurgical Focus on percutaneous pedicle screw placement[citation needed]. He has also published on brain tumors and spinal cord abnormalities[citation needed].
# Battlefield Controversy
While in Iraq, Dr Gupta was asked to perform brain surgery on five different patients, including Jesus Vidana, a Marine who had been twice pronounced dead on the battlefield.[2] Jesus survived the injuries and now lives in Southern California. Gupta was criticized upon his return and many, including Bob Steele of the Poynter Institute thought Gupta crossed the line when doffing his journalism cap for a surgeon's cap. Gupta was quoted in Newsweek magazine as saying "medically and morally, it was the right thing to do."
# Michael Moore controversy
A July 9, 2007 broadcast of CNN's The Situation Room aired a "fact check" segment by Gupta on Michael Moore's 2007 film Sicko.[3] Immediately following the segment, Moore was interviewed live on CNN by Wolf Blitzer. Moore stated that Gupta's report was inaccurate and biased, and later posted a detailed response on his website.[4] Moore accused CNN and Gupta of being biased in favor of the drug industry because most of the sponsors for their medical coverage, including Dr. Gupta's reports, were drug companies. On July 15, 2007, CNN released a statement in response to Michael Moore's rebuttal. In it, they apologized for an error in their on-air report, having stated that in the film Moore reported Cuba spends $25 per person for health care when the film actually gave that number as $251. CNN blamed this on a transcription error. CNN defended the rest of Dr. Gupta's report and issued a point-by-point response to Moore's response in which CNN contended that Moore's comparison of data from different sources in different years was in effect "cherry picking" results, at the cost of statistical accuracy.[5] CNN also admitted that Gupta had afterwards committed a second error, mistakenly contesting Moore's observation that Gupta's one on-air expert was now associated with a think tank rather than a university (a fact which the chyron on Gupta's original report had stated correctly).[6][7][8]
# Merck Gardasil controversy
A July 25, 2007 article on the left-wing counterpunch.org criticized Gupta for publicly backing the drug Gardasil (a cervical cancer vaccine) while at the same time being host of a television show that is sponsored by the manufacturer, Merck. Gupta said "As a doctor, and parent, I would recommend the vaccine for my daughters. I feel the ability to protect them in any way, including from cancer, is my primary obligation." Turner Private Network's television show "AccentHealth" is partially underwritten by Merck.[9] | https://www.wikidoc.org/index.php/Sanjay_Gupta | |
16bdf4660abae8562cc9905e5d6f5ef1f84879f1 | wikidoc | Sarsaparilla | Sarsaparilla
Sarsaparilla (pronounced SAS-per-il-luh, IPA /ˌsæspəˈɹɪlə/) (Smilax regelii and other closely related species of Smilax) is a perennial trailing vine with prickly stems native to tropical America and the West Indies. Its name (which is zarzaparrilla in Spanish) comes from the Spanish words zarza for "shrub" and parrilla for "little grape vine."
The name sarsaparilla can also refer to a drink made from the roots of the vine. The name "Sasparilla" is also often used but is a common mis-spelling of Sarsaparilla.
# History
Throughout history, Sarsaparilla has been used to cure syphilis. Native Americans used Saraparilla for its medical benefits also. The root of the plant is what is used in medicine. In the nineteenth century, it was believed it could improve one's vigor.
# Uses
Sarsaparilla contains active principle, Parillin (Smilacin), glucoside, sarsapic acid, sarsapogenin (related to progesterone and used in its synthesis), sarsaponin and starch
Fatty acids:
- palmitic acid
- stearic acid
- behenic acid
- oleic acid
- linolic acid
Oral remedy for psoriasis
# Appearance
The vine has a long prickly stem and shiny leaves, and numerous reddish-brown roots up to 3 meters long. Several species of Smilax are used in agriculture, but the Jamaican S. regelii (syn. S. officinalis) is the species preferred for commercial use. Sarsaparilla is also grown in Mexico, Central America and parts of South America. It is also grown in parts of South India, known in Telugu as Sugandhi-pala, in Kannada as sogade beru and in Tamil as Nannaari. The primary uses of sarsaparilla include the flavoring of beverages, and folk medicine.
Before processing, the roots are bitter, sticky, and have a strong odor. They are dried and boiled in order to produce the extract. In beverages, oil of wintergreen or other flavors may be added in order to mask the natural bitterness of the root. Root beer made from sarsaparilla roots is generally more "birchy" than the sarasparilla extract used in the more popular, commercial brands.
A carbonated beverage, made from and called sarsaparilla, is available in many countries. | Sarsaparilla
Sarsaparilla (pronounced SAS-per-il-luh, IPA /ˌsæspəˈɹɪlə/) (Smilax regelii and other closely related species of Smilax) is a perennial trailing vine with prickly stems native to tropical America and the West Indies. Its name (which is zarzaparrilla in Spanish) comes from the Spanish words zarza for "shrub" and parrilla for "little grape vine."[1]
The name sarsaparilla can also refer to a drink made from the roots of the vine. The name "Sasparilla" is also often used but is a common mis-spelling of Sarsaparilla.
# History
Throughout history, Sarsaparilla has been used to cure syphilis. Native Americans used Saraparilla for its medical benefits also. The root of the plant is what is used in medicine.[2] In the nineteenth century, it was believed it could improve one's vigor.
# Uses
Sarsaparilla contains active principle, Parillin (Smilacin), glucoside, sarsapic acid, sarsapogenin (related to progesterone and used in its synthesis), sarsaponin and starch [3]
Fatty acids:
- palmitic acid
- stearic acid
- behenic acid
- oleic acid
- linolic acid
Oral remedy for psoriasis[4]
# Appearance
The vine has a long prickly stem and shiny leaves, and numerous reddish-brown roots up to 3 meters long. Several species of Smilax are used in agriculture, but the Jamaican S. regelii (syn. S. officinalis) is the species preferred for commercial use. Sarsaparilla is also grown in Mexico, Central America and parts of South America. It is also grown in parts of South India, known in Telugu as Sugandhi-pala, in Kannada as sogade beru and in Tamil as Nannaari. The primary uses of sarsaparilla include the flavoring of beverages, and folk medicine.
Before processing, the roots are bitter, sticky, and have a strong odor. They are dried and boiled in order to produce the extract. In beverages, oil of wintergreen or other flavors may be added in order to mask the natural bitterness of the root. Root beer made from sarsaparilla roots is generally more "birchy" than the sarasparilla extract used in the more popular, commercial brands.
A carbonated beverage, made from and called sarsaparilla, is available in many countries.[5] | https://www.wikidoc.org/index.php/Sarsaparilla | |
7a6289901c509f856d90aaabb1ac7303cef9043e | wikidoc | Scalar field | Scalar field
In mathematics and physics, a scalar field associates a scalar value, which can be either mathematical in definition, or physical, to every point in space. Scalar fields are often used in physics, for instance to indicate the temperature distribution throughout space, or the air pressure. In mathematics, or more specifically, differential geometry, the set of functions defined on a manifold define the commutative ring of functions.
Just as the concept of a scalar in mathematics is identical to the concept of a scalar in physics, so also the scalar field defined in differential geometry is identical to, in the abstract, to the (unquantized) scalar fields of physics.
# Definition
A scalar field is a function from Rn to R. That is, it is a function defined on the n-dimensional Euclidean space with real values. Often it is required to be continuous, or one or more times differentiable, that is, a function of class Ck.
The scalar field can be visualized as a n-dimensional space with a real or complex number attached to each point in the space.
The derivative of a scalar field results in a vector field called the gradient.
# Differential geometry
A scalar field on a Ck-manifold is a Ck function to the real numbers. Taking Rn as manifold gives back the special case of vector calculus.
A scalar field is also a 0-form. The set of all scalar fields on a manifold forms a commutative ring, under the natural operations of multiplication and addition, point by point.
# Uses in physics
In physics, scalar fields can be used to ascribe forces (which are usually vector fields) to a more general scalar field, the gradient of which describes the force.
- Potential fields, such as the Newtonian gravitational potential field for gravitation, or the electric potential in electrostatics, are scalar fields which describes the more familiar forces.
- A temperature, humidity or pressure field, such as those used in meteorology. Note that when modeling weather on a global basis, the surface of the Earth is not flat, and thus the general language of curvature in differential geometry plays a role. Dopplerized weather radar generates a projection of a vector field onto a scalar field.
## Examples in quantum theory and relativity
- In quantum field theory, a scalar field is associated with spin 0 particles, such as mesons or bosons. The scalar field may be real or complex valued (depending on whether it will associate a real or complex number to every point of space-time). Complex scalar fields represent charged particles. These include the Higgs field of the Standard Model, as well as the pion field mediating the strong nuclear interaction.
- In the Standard Model of elementary particles, a scalar field is used to give the leptons their mass, via a combination of the Yukawa interaction and the spontaneous symmetry breaking. This mechanism is known as the Higgs mechanism . This supposes the existence of a (still hypothetical) spin 0 particle called Higgs boson.
- In scalar theories of gravitation scalar fields are used to describe the gravitational field.
- scalar-tensor theories represent the gravitational interaction through both a tensor and a scalar. Such attempts are for example the Jordan theory as a generalization of the Kaluza-Klein theory and the Brans-Dicke theory .
- Scalar fields like the Higgs field can be found within scalar-tensor theories, using as scalar field the Higgs field of the Standard Model , . This field interacts gravitatively and Yukawa-like (short-ranged) with the particles that get mass through it .
- Scalar fields are found within superstring theories as dilaton fields, breaking the conformal symmetry of the string, though balancing the quantum anomalies of this tensor .
- Scalar fields are supposed to cause the accelerated expansion of the universe (inflation ), helping to solve the horizon problem and giving an hypothetical reason for the non-vanishing cosmological constant of cosmology. Massless (i.e. long-ranged) scalar fields in this context are known are inflatons. Massive (i.e. short-ranged) scalar fields are proposed, too, using for example Higgs-like fields (e.g. ).
# Other kinds of fields
- Vector fields, which associate a vector to every point in space. Some examples of vector fields include the electromagnetic field and the Newtonian gravitational field.
- Tensor fields, which associate a tensor to every point in space. For example, in general relativity gravitation is associated with a tensor field (in particular, with the Riemann curvature tensor). In Kaluza-Klein theory, spacetime is extended to five dimensions and its Riemann curvature tensor can be separated out into ordinary four-dimensional gravitation plus an extra set, which is equivalent to Maxwell's equations for the electromagnetic field, plus an extra scalar field known as the "dilaton". | Scalar field
In mathematics and physics, a scalar field associates a scalar value, which can be either mathematical in definition, or physical, to every point in space. Scalar fields are often used in physics, for instance to indicate the temperature distribution throughout space, or the air pressure. In mathematics, or more specifically, differential geometry, the set of functions defined on a manifold define the commutative ring of functions.
Just as the concept of a scalar in mathematics is identical to the concept of a scalar in physics, so also the scalar field defined in differential geometry is identical to, in the abstract, to the (unquantized) scalar fields of physics.
# Definition
A scalar field is a function from Rn to R. That is, it is a function defined on the n-dimensional Euclidean space with real values. Often it is required to be continuous, or one or more times differentiable, that is, a function of class Ck.
The scalar field can be visualized as a n-dimensional space with a real or complex number attached to each point in the space.
The derivative of a scalar field results in a vector field called the gradient.
# Differential geometry
A scalar field on a Ck-manifold is a Ck function to the real numbers. Taking Rn as manifold gives back the special case of vector calculus.
A scalar field is also a 0-form. The set of all scalar fields on a manifold forms a commutative ring, under the natural operations of multiplication and addition, point by point.
# Uses in physics
In physics, scalar fields can be used to ascribe forces (which are usually vector fields) to a more general scalar field, the gradient of which describes the force.
- Potential fields, such as the Newtonian gravitational potential field for gravitation, or the electric potential in electrostatics, are scalar fields which describes the more familiar forces.
- A temperature, humidity or pressure field, such as those used in meteorology. Note that when modeling weather on a global basis, the surface of the Earth is not flat, and thus the general language of curvature in differential geometry plays a role. Dopplerized weather radar generates a projection of a vector field onto a scalar field.
## Examples in quantum theory and relativity
- In quantum field theory, a scalar field is associated with spin 0 particles, such as mesons or bosons. The scalar field may be real or complex valued (depending on whether it will associate a real or complex number to every point of space-time). Complex scalar fields represent charged particles. These include the Higgs field of the Standard Model, as well as the pion field mediating the strong nuclear interaction.
- In the Standard Model of elementary particles, a scalar field is used to give the leptons their mass, via a combination of the Yukawa interaction and the spontaneous symmetry breaking. This mechanism is known as the Higgs mechanism [1]. This supposes the existence of a (still hypothetical) spin 0 particle called Higgs boson.
- In scalar theories of gravitation scalar fields are used to describe the gravitational field.
- scalar-tensor theories represent the gravitational interaction through both a tensor and a scalar. Such attempts are for example the Jordan theory [2] as a generalization of the Kaluza-Klein theory and the Brans-Dicke theory [3].
- Scalar fields like the Higgs field can be found within scalar-tensor theories, using as scalar field the Higgs field of the Standard Model [4], [5]. This field interacts gravitatively and Yukawa-like (short-ranged) with the particles that get mass through it [6].
- Scalar fields are found within superstring theories as dilaton fields, breaking the conformal symmetry of the string, though balancing the quantum anomalies of this tensor [7].
- Scalar fields are supposed to cause the accelerated expansion of the universe (inflation [8]), helping to solve the horizon problem and giving an hypothetical reason for the non-vanishing cosmological constant of cosmology. Massless (i.e. long-ranged) scalar fields in this context are known are inflatons. Massive (i.e. short-ranged) scalar fields are proposed, too, using for example Higgs-like fields (e.g. [9]).
# Other kinds of fields
- Vector fields, which associate a vector to every point in space. Some examples of vector fields include the electromagnetic field and the Newtonian gravitational field.
- Tensor fields, which associate a tensor to every point in space. For example, in general relativity gravitation is associated with a tensor field (in particular, with the Riemann curvature tensor). In Kaluza-Klein theory, spacetime is extended to five dimensions and its Riemann curvature tensor can be separated out into ordinary four-dimensional gravitation plus an extra set, which is equivalent to Maxwell's equations for the electromagnetic field, plus an extra scalar field known as the "dilaton". | https://www.wikidoc.org/index.php/Scalar_field | |
c2e282ef8a059d870b5f8a23cc29b4ec65cb235d | wikidoc | Schizophasia | Schizophasia
In the mental health field, schizophasia, commonly referred to as word salad (see "word salad" for other meanings), is used to describe the symptom of confused, and often repetitious, language that is symptomatic of various mental illnesses. It is usually associated with a manic presentation and other symptoms of serious mental illnesses, such as psychoses, including schizophrenia.
It describes the apparently confused usage of words with no apparent meaning or relationship attached to them. In this context, it is considered to be a symptom of a formal thought disorder. In some cases schizophasia can be a sign of asymptomatic schizophrenia; e.g. the question "Why do people believe in God?" could elicit a response consisting of a series of words commonly associated with religion or prayer but strung together with no regard to language rules.
Schizophasia is in contrast to another symptom of cognitive disruption and cognitive slippage. It may, or may not, be grammatically correct depending on the severity of the disease and the particular mechanisms which have been impacted by it. Thus, "Satan, oscillate my metallic sonatas" as well as "Blue does runs shaky lovely very" can be authentic schizophasias (one grammatically correct, one not) if they were produced as a result of mental disease or defect. In contrast, intentionally producing nonsense, as in the contrived palindrome "Satan, oscillate my metallic sonatas" is not really considered schizophasia, due to the intentional production of that language. Schizophasia refers to a defect in processing and organizing language, as opposed to the ability to create a nonsense word which happens to conform to a very specific set of rules.
The American diagnostic codes, from the DSM-IV, do not specifically code for this disorder although they include it as a symptom under the diagnosis of Schizophrenia. | Schizophasia
In the mental health field, schizophasia, commonly referred to as word salad (see "word salad" for other meanings), is used to describe the symptom of confused, and often repetitious, language that is symptomatic of various mental illnesses. It is usually associated with a manic presentation and other symptoms of serious mental illnesses, such as psychoses, including schizophrenia.
It describes the apparently confused usage of words with no apparent meaning or relationship attached to them. In this context, it is considered to be a symptom of a formal thought disorder. In some cases schizophasia can be a sign of asymptomatic schizophrenia; e.g. the question "Why do people believe in God?" could elicit a response consisting of a series of words commonly associated with religion or prayer but strung together with no regard to language rules.
Schizophasia is in contrast to another symptom of cognitive disruption and cognitive slippage. It may, or may not, be grammatically correct depending on the severity of the disease and the particular mechanisms which have been impacted by it. Thus, "Satan, oscillate my metallic sonatas" as well as "Blue does runs shaky lovely very" can be authentic schizophasias (one grammatically correct, one not) if they were produced as a result of mental disease or defect. In contrast, intentionally producing nonsense, as in the contrived palindrome "Satan, oscillate my metallic sonatas" is not really considered schizophasia, due to the intentional production of that language. Schizophasia refers to a defect in processing and organizing language, as opposed to the ability to create a nonsense word which happens to conform to a very specific set of rules.
The American diagnostic codes, from the DSM-IV, do not specifically code for this disorder although they include it as a symptom under the diagnosis of Schizophrenia.[1] | https://www.wikidoc.org/index.php/Schizophasia | |
767ba80d9cf8c44d88e301f42df41b8a15a824e3 | wikidoc | Science wars | Science wars
The Science wars were a series of intellectual battles in the 1990s between "postmodernists" and "realists" (though neither party would likely use the terms to describe themselves) about the nature of scientific theories. In brief, the postmodernists questioned the objectivity of science and encompass a huge variety of critiques on scientific knowledge and method within cultural studies, cultural anthropology, feminist studies, comparative literature, media studies, and science and technology studies. The realists countered that there is such a thing as objective scientific knowledge and accused the postmodernists of having practically no understanding of the subject they were critiquing.
# Historical background
Until the mid-20th century, the philosophy of science had concentrated on the viability of scientific method and knowledge, proposing justifications for the truth of scientific theories and observations and attempting to discover on a philosophical level why science worked. Already Karl Popper had started a strong attack on this view. He had denied outright that there is something such as a justification for the truth, probability or even only for the belief in scientific theories and so laid fertile foundations for postmodernism to grow on.
During this time there had also been a number of less orthodox philosophers and scientists who believed that logical models of pure science did not apply to actual scientific practice. It was the publication of Thomas Kuhn's The Structure of Scientific Revolutions in 1962, however, which fully opened the study of science to new disciplines by suggesting that the evolution of science was in part sociologically determined and that it did not operate under the simple logical laws put forward by the logical positivist school of philosophy. Kuhn described the development of scientific knowledge not as linear increase in truth and understanding, but as series of periodic revolutions which overturned old scientific order and replaced it with new orders (what he called "paradigms"). Kuhn attributed much of this process to the interactions and strategies of the human participants in science rather than its own innate logical structure. (See sociology of scientific knowledge and Theories and sociology of the history of science).
Some interpreted Kuhn's ideas to mean that scientific theories were, either wholly or in part, social constructs, which many interpreted as diminishing the claim of science to representing objective reality (though many social constructivists do not put forward this claim), and that reality had a lesser or potentially irrelevant role in the formation of scientific theories. In 1971, Jerome Ravetz published Scientific Knowledge and its Social Problems, a book describing the role that the scientific community, as a social construct, plays in accepting or rejecting so-called "objective" scientific knowledge. A number of different philosophical and historical schools, often lumped together as "postmodernism", began reinterpreting scientific achievements of the past through the lens of the practitioners, often assigning political and economic conditions as formative a role in theory development as scientific observations. Rather than being held up as heroes of knowledge, many scientists of the past were scrutinized for their connection to issues of gender, sexual orientation, race, and class. Some more radical philosophers, such as Paul Feyerabend, argued that scientific theories were themselves incoherent and that other forms of knowledge production (such as those used in religion) served the material and spiritual needs of their practitioners with as equal validity as did scientific explanations.
Somewhat of a middle view between the "postmodernist" and "realist" camps is that put forward by thinkers such as Imre Lakatos. For Lakatos, scientific knowledge is progressive, however, it progresses not by a strict linear path where every new element builds upon and incorporates every other, but by an approach where a "core" of a "research program" is established by auxiliary theories which can themselves be falsified or replaced without compromising the core. Social conditions and attitudes affect how strongly one attempts to resist falsification for the core of a program, but the program has an objective status, notwithstanding, based on its relative explanatory power. Resisting falsification only becomes ad-hoc and damaging to knowledge when an alternate program with greater explanatory power is rejected in favor of another with less. But because it is changing a theoretical core, which has broad ramifications for other areas of study, accepting a new program is also revolutionary as well as progressive. Thus, for Lakatos the character of science is that of being both revolutionary and progressive; both socially informed and objectively justified.
# The Science wars
This apparent attack on the validity of science from the humanities and social sciences worried many people in the scientific community, especially as the language of social construction was appropriated by groups which claimed to be proffering alternate scientific paradigms, but which were actually, according to the view of many scientists, attempting to assert political control over the use of science in society (as with creation science, intelligent design and the ongoing creation-evolution controversy). In 1994, scientists Paul R. Gross and Norman Levitt published Higher Superstition: The Academic Left and Its Quarrels With Science, an open attack on the postmodernists. According to supporters, the book brought the shortcomings of relativism into sharp focus, claiming that the postmodernists knew little about the scientific theories they discussed and pursued sloppy scholarship for political reasons. According to scholars in science studies (the postmodernists under attack), the book brought the authors' failure to understand the theoretical approaches they criticize into sharp focus, and relied more on "caricature, misreading, and condescension than argument." The book received a moderate amount of mainstream attention and became a flashpoint for the science wars.
Higher Superstition also served as the inspiration for a conference hosted by the New York Academy of Sciences called "The Flight from Science and Reason" and organized by Gross, Levitt and Gerald Holton. While some participants were critical of the polemical approach of Gross and Levitt, overall the conference was highly critical of the ways non-scientist intellectuals dealt with science.
## Science wars in Social Text
In 1996, Social Text, a journal of critical theory, compiled a special issue entitled "Science Wars", with brief contributions from many of those in the social sciences and humanities labeled as "postmodernists." A number of articles placed the science wars in the context of the changing role of science in culture, as further evidence of the roles social and political factors play in science. In the introduction, Andrew Ross suggested that the backlash against science studies was a conservative reaction to reduced science funding; he characterized the "Flight from Science and Reason" conference as an attempt at "linking together a host of dangerous threats: scientific creationism, New Age alternatives and cults, astrology, UFO-ism, the radical science movement, postmodernism, and critical science studies, alongside the ready-made historical specters of Aryan-Nazi science and the Soviet error of Lysenkoism" that "degenerated into name calling." Historian Dorothy Nelkin characterized the vigorous response of scientists to Gross & Levitt's call to arms—in contrast to the historical tendency of scientists to avoid involvement in perceived political threats to science such as creation science, the animal rights movement, and attempts by anti-abortionists to end fetal research—as a reaction to the failed marriage between science and the state. With the Cold War over, military funding of science continued to decline while funding agencies were demanding increased accountability for grants and research was increasingly directed by private interests; Nelkin claimed that postmodernist critics were "convenient scapegoats" that diverted attention from problems within science.
Physicist Alan Sokal submitted a paper to the issue in which he purported to argue that quantum physics supports postmodernist criticisms of the objectivity of science. It was published in the journal, and later Sokal revealed it to be a hoax and an experiment to see if the journal editors would "publish an article liberally salted with nonsense if (a) it sounded good and (b) it flattered the editors' ideological preconceptions". Its publication, known as the Sokal affair, was simultaneously revealed as a parody in the literary magazine Lingua Franca; this caused an uproar that brought the science wars to the attention of a wide audience of scientists and humanist scholars, and even into the mainstream media.
## Continued conflict
Since the "Science Wars" edition of Social Text, the seriousness and volume of discussion increased significantly, much of it focused on reconciling the "warring" camps of postmodernists and scientists. One significant event was the "Science and Its Critics" conference in early 1997; it brought together scientists and scholars who study science and featured Alan Sokal and Steve Fuller as keynote speakers. The conference generated the final wave of substantial press coverage (in both news media and scientific journals), though by no means resolved the fundamental issues of social construction and objectivity in science.
Other attempts have been made to reconcile the two camps. Mike Nauenberg, a physicist at the University of California at Santa Cruz, organized a small conference in May 1997 that was attended by scientists and sociologists of science alike, among them Alan Sokal, N. David Mermin and Harry Collins. In the same year, Collins organized the Southampton Peace Workshop, which again brought together a broad range of scientists and sociologists. The Peace Workshop gave rise to the idea of a book that intended to map out some of the arguments between the disputing parties. The One Culture, edited by physicist Jay A. Labinger and sociologist Harry Collins, was eventually published in 2001. The book, whose title is an obvious reference to C.P. Snow’s The Two Cultures, contains contributions from authors such as Alan Sokal, Jean Bricmont, Steven Weinberg and Steven Shapin. Also in 2001, Bent Flyvbjerg in his book Making Social Science Matter identified a way out of the Science Wars by arguing that (1) social science is phronesis, whereas natural science is episteme, in the classical Greek meaning of the terms; (2) phronesis is well suited for the reflexive analysis and discussion of values and interests, which any society needs to thrive, whereas episteme is good for the development of predictive theory, and; (3) a well-functioning society needs both phronesis and episteme in balance, and one cannot substitute for the other.
Other important publications related to the science wars include Fashionable Nonsense by Sokal and Jean Bricmont (1998), The Social Construction of What? by Ian Hacking (1999) and Who Rules in Science by James Robert Brown.
For some scholars, the Bogdanov Affair in 2002 served as the bookend to the Sokal controversy: the review, acceptance, and publication of papers, later alleged to be nonsense, in peer-reviewed physics journals. Postmodernists might point out that this occurrence only served to demonstrate what they have always claimed: at the outer reaches of knowledge, where new claims are evaluated and disseminated, no one can be expected to know for certain what is true and what is not.. However, others such as Cornell physics professor Paul Ginsparg have argued that the cases are not at all similar and that the fact some journals and scientific institutions have low or variable standards is "hardly a revelation."
Though the events of the science wars are still occasionally mentioned in mainstream press, they have had little effect on either the scientific community or the community of critical theorists. Both sides continue to maintain that the other does not understand their theories, or misunderstands what are meant to be constructive criticisms or simple scholarly investigations as attacks. As Bruno Latour recently put it, "Scientists always stomp around meetings talking about 'bridging the two-culture gap', but when scores of people from outside the sciences begin to build just that bridge, they recoil in horror and want to impose the strangest of all gags on free speech since Socrates: only scientists should speak about science!".
However, more recently some of the leading critical theorists have recognized that their critiques have at times been counter-productive, and are providing intellectual ammunition for reactionary interests. Writing about these developments in the context of Global warming, Bruno Latour noted that, "... dangerous extremists are using the very same argument of social construction to destroy hard-won evidence that could save our lives. Was I wrong to participate in the invention of this field known as science studies? Is it enough to say that we did not really mean what we meant?". | Science wars
The Science wars were a series of intellectual battles in the 1990s between "postmodernists" and "realists" (though neither party would likely use the terms to describe themselves) about the nature of scientific theories. In brief, the postmodernists questioned the objectivity of science and encompass a huge variety of critiques on scientific knowledge and method within cultural studies, cultural anthropology, feminist studies, comparative literature, media studies, and science and technology studies. The realists countered that there is such a thing as objective scientific knowledge and accused the postmodernists of having practically no understanding of the subject they were critiquing.
# Historical background
Until the mid-20th century, the philosophy of science had concentrated on the viability of scientific method and knowledge, proposing justifications for the truth of scientific theories and observations and attempting to discover on a philosophical level why science worked. Already Karl Popper had started a strong attack on this view. He had denied outright that there is something such as a justification for the truth, probability or even only for the belief in scientific theories and so laid fertile foundations for postmodernism to grow on.[1]
During this time there had also been a number of less orthodox philosophers and scientists who believed that logical models of pure science did not apply to actual scientific practice. It was the publication of Thomas Kuhn's The Structure of Scientific Revolutions in 1962, however, which fully opened the study of science to new disciplines by suggesting that the evolution of science was in part sociologically determined and that it did not operate under the simple logical laws put forward by the logical positivist school of philosophy. Kuhn described the development of scientific knowledge not as linear increase in truth and understanding, but as series of periodic revolutions which overturned old scientific order and replaced it with new orders (what he called "paradigms"). Kuhn attributed much of this process to the interactions and strategies of the human participants in science rather than its own innate logical structure. (See sociology of scientific knowledge and Theories and sociology of the history of science).
Some interpreted Kuhn's ideas to mean that scientific theories were, either wholly or in part, social constructs, which many interpreted as diminishing the claim of science to representing objective reality (though many social constructivists do not put forward this claim), and that reality had a lesser or potentially irrelevant role in the formation of scientific theories. In 1971, Jerome Ravetz published Scientific Knowledge and its Social Problems, a book describing the role that the scientific community, as a social construct, plays in accepting or rejecting so-called "objective" scientific knowledge.[2] A number of different philosophical and historical schools, often lumped together as "postmodernism", began reinterpreting scientific achievements of the past through the lens of the practitioners, often assigning political and economic conditions as formative a role in theory development as scientific observations. Rather than being held up as heroes of knowledge, many scientists of the past were scrutinized for their connection to issues of gender, sexual orientation, race, and class. Some more radical philosophers, such as Paul Feyerabend, argued that scientific theories were themselves incoherent and that other forms of knowledge production (such as those used in religion) served the material and spiritual needs of their practitioners with as equal validity as did scientific explanations.
Somewhat of a middle view between the "postmodernist" and "realist" camps is that put forward by thinkers such as Imre Lakatos. For Lakatos, scientific knowledge is progressive, however, it progresses not by a strict linear path where every new element builds upon and incorporates every other, but by an approach where a "core" of a "research program" is established by auxiliary theories which can themselves be falsified or replaced without compromising the core. Social conditions and attitudes affect how strongly one attempts to resist falsification for the core of a program, but the program has an objective status, notwithstanding, based on its relative explanatory power. Resisting falsification only becomes ad-hoc and damaging to knowledge when an alternate program with greater explanatory power is rejected in favor of another with less. But because it is changing a theoretical core, which has broad ramifications for other areas of study, accepting a new program is also revolutionary as well as progressive. Thus, for Lakatos the character of science is that of being both revolutionary and progressive; both socially informed and objectively justified.
# The Science wars
This apparent attack on the validity of science from the humanities and social sciences worried many people in the scientific community, especially as the language of social construction was appropriated by groups which claimed to be proffering alternate scientific paradigms, but which were actually, according to the view of many scientists, attempting to assert political control over the use of science in society (as with creation science, intelligent design and the ongoing creation-evolution controversy). In 1994, scientists Paul R. Gross and Norman Levitt published Higher Superstition: The Academic Left and Its Quarrels With Science, an open attack on the postmodernists. According to supporters, the book brought the shortcomings of relativism into sharp focus, claiming that the postmodernists knew little about the scientific theories they discussed and pursued sloppy scholarship for political reasons. According to scholars in science studies (the postmodernists under attack), the book brought the authors' failure to understand the theoretical approaches they criticize into sharp focus, and relied more on "caricature, misreading, and condescension than argument."[3] The book received a moderate amount of mainstream attention and became a flashpoint for the science wars.
Higher Superstition also served as the inspiration for a conference hosted by the New York Academy of Sciences called "The Flight from Science and Reason" and organized by Gross, Levitt and Gerald Holton.[4] While some participants were critical of the polemical approach of Gross and Levitt, overall the conference was highly critical of the ways non-scientist intellectuals dealt with science.[5]
## Science wars in Social Text
In 1996, Social Text, a journal of critical theory, compiled a special issue entitled "Science Wars", with brief contributions from many of those in the social sciences and humanities labeled as "postmodernists." A number of articles placed the science wars in the context of the changing role of science in culture, as further evidence of the roles social and political factors play in science. In the introduction, Andrew Ross suggested that the backlash against science studies was a conservative reaction to reduced science funding; he characterized the "Flight from Science and Reason" conference as an attempt at "linking together a host of dangerous threats: scientific creationism, New Age alternatives and cults, astrology, UFO-ism, the radical science movement, postmodernism, and critical science studies, alongside the ready-made historical specters of Aryan-Nazi science and the Soviet error of Lysenkoism" that "degenerated into name calling."[6] Historian Dorothy Nelkin characterized the vigorous response of scientists to Gross & Levitt's call to arms—in contrast to the historical tendency of scientists to avoid involvement in perceived political threats to science such as creation science, the animal rights movement, and attempts by anti-abortionists to end fetal research—as a reaction to the failed marriage between science and the state. With the Cold War over, military funding of science continued to decline while funding agencies were demanding increased accountability for grants and research was increasingly directed by private interests; Nelkin claimed that postmodernist critics were "convenient scapegoats" that diverted attention from problems within science.[7]
Physicist Alan Sokal submitted a paper to the issue in which he purported to argue that quantum physics supports postmodernist criticisms of the objectivity of science. It was published in the journal, and later Sokal revealed it to be a hoax and an experiment to see if the journal editors would "publish an article liberally salted with nonsense if (a) it sounded good and (b) it flattered the editors' ideological preconceptions".[8] Its publication, known as the Sokal affair, was simultaneously revealed as a parody in the literary magazine Lingua Franca; this caused an uproar that brought the science wars to the attention of a wide audience of scientists and humanist scholars, and even into the mainstream media.[9]
## Continued conflict
Since the "Science Wars" edition of Social Text, the seriousness and volume of discussion increased significantly, much of it focused on reconciling the "warring" camps of postmodernists and scientists. One significant event was the "Science and Its Critics" conference in early 1997; it brought together scientists and scholars who study science and featured Alan Sokal and Steve Fuller as keynote speakers. The conference generated the final wave of substantial press coverage (in both news media and scientific journals), though by no means resolved the fundamental issues of social construction and objectivity in science.[10]
Other attempts have been made to reconcile the two camps. Mike Nauenberg, a physicist at the University of California at Santa Cruz, organized a small conference in May 1997 that was attended by scientists and sociologists of science alike, among them Alan Sokal, N. David Mermin and Harry Collins. In the same year, Collins organized the Southampton Peace Workshop, which again brought together a broad range of scientists and sociologists. The Peace Workshop gave rise to the idea of a book that intended to map out some of the arguments between the disputing parties. The One Culture, edited by physicist Jay A. Labinger and sociologist Harry Collins, was eventually published in 2001. The book, whose title is an obvious reference to C.P. Snow’s The Two Cultures, contains contributions from authors such as Alan Sokal, Jean Bricmont, Steven Weinberg and Steven Shapin.[11] Also in 2001, Bent Flyvbjerg in his book Making Social Science Matter identified a way out of the Science Wars by arguing that (1) social science is phronesis, whereas natural science is episteme, in the classical Greek meaning of the terms; (2) phronesis is well suited for the reflexive analysis and discussion of values and interests, which any society needs to thrive, whereas episteme is good for the development of predictive theory, and; (3) a well-functioning society needs both phronesis and episteme in balance, and one cannot substitute for the other.[12]
Other important publications related to the science wars include Fashionable Nonsense by Sokal and Jean Bricmont (1998), The Social Construction of What? by Ian Hacking (1999) and Who Rules in Science by James Robert Brown.
For some scholars, the Bogdanov Affair in 2002 [13] served as the bookend to the Sokal controversy: the review, acceptance, and publication of papers, later alleged to be nonsense, in peer-reviewed physics journals. Postmodernists might point out that this occurrence only served to demonstrate what they have always claimed: at the outer reaches of knowledge, where new claims are evaluated and disseminated, no one can be expected to know for certain what is true and what is not.[citation needed]. However, others such as Cornell physics professor Paul Ginsparg have argued that the cases are not at all similar and that the fact some journals and scientific institutions have low or variable standards is "hardly a revelation."[14]
Though the events of the science wars are still occasionally mentioned in mainstream press, they have had little effect on either the scientific community or the community of critical theorists.[citation needed] Both sides continue to maintain that the other does not understand their theories, or misunderstands what are meant to be constructive criticisms or simple scholarly investigations as attacks. As Bruno Latour recently put it, "Scientists always stomp around meetings talking about 'bridging the two-culture gap', but when scores of people from outside the sciences begin to build just that bridge, they recoil in horror and want to impose the strangest of all gags on free speech since Socrates: only scientists should speak about science!"[15].
However, more recently some of the leading critical theorists have recognized that their critiques have at times been counter-productive, and are providing intellectual ammunition for reactionary interests. Writing about these developments in the context of Global warming, Bruno Latour noted that, "... dangerous extremists are using the very same argument of social construction to destroy hard-won evidence that could save our lives. Was I wrong to participate in the invention of this field known as science studies? Is it enough to say that we did not really mean what we meant?"[16]. | https://www.wikidoc.org/index.php/Science_wars | |
9cb10658ad6747c50dc822faabb0a471d871c355 | wikidoc | Scleractinia | Scleractinia
Scleractinia, also called Stony corals, are exclusively marine animals; they are very similar to sea anemones but generate a hard skeleton. They first appeared in the Middle Triassic and replaced tabulate and rugose corals that went extinct at the end of the Permian. Much of the framework of coral reefs is formed by scleractinians.
There are two groups of Scleractinia:
- colonial corals found in clear, shallow tropical waters; they are the world's primary reef-builders.
- solitary corals are found in all regions of the oceans and do not build reefs. Some live in temperate, polar waters, or below the photic zone down to 6000 meters.
# Anatomy
As mentioned above, Scleractinians may be solitary or compound. The most common forms include conical and horn-shaped scleractinians. In a colonial Scleractinia, the repeated asexual division by the polyps causes the corallites to be interconnected, thus forming the colonies. There are also cases in which the adjacent colonies of the same species form a single colony by fusing.
The modern scleractinian skeleton, which lies external to the polyps that make it, is composed of calcium carbonate in the crystal form aragonite. However, a prehistoric scleractinian (Coelosimilia) had a non-aragonite calcium carbonate skeletal structure.
The skeleton of an individual scleractinian polyp is known as a corallite. Each of its radially-aligned elements, termed septa, lies in the endocoel flanked by the members of a mesenterial pair. The skeleton originates as a thin basal plate from which the septa arise vertically. The structure of both simple and compound scleractinians is light and porous, rather than solid as in the Rugosa.
Septa are secreted by the mesenteries and are therefore added in the same order as the mesenteries. As a result, septa of different ages are adjacent to one another, and the symmetry of the scleractinian skeleton is radial or biradial. This pattern of septal insertion is termed "cyclic" by paleontologists. By contrast, in some fossil corals, adjacent septa lie in order of increasing age, a pattern that is termed serial and that produces a bilateral symmetry. Scleractinians are distinguished from the Rugosa also by their pattern of septal insertion. They secrete an aragonitic exoskeleton in which the septa are inserted between the mesenteries in multiples of six.
In scleractinians, there are two main secondary structures:
- Stereome is an adherent layer of secondary tissue, which covers the septal surface. It consists of transverse bundles of aragonitic needles and protects the scleractinians. However, its function can be nullified by the thickening of the septa itself.
- Coenosteum is a perforated complex tissue that separates individual corallites in a compound scleractinians.
At the beginning of Scleractinia’s development four groups with different microstructure can distinguished. These are:
- Pachytecal: Corals having very thick wall and rudimentary septa. This is the group which probably originated from Rugosa corals.
- Thick Trabecular: Corals with septa built from thick structures, resembling little beams, called trabecules.
- Minitrabecular: Corals with septa built from thin trabecules.
- Fascilcular or non-trabecular: Corals with septa not built from trabecules, but from columns being bunches of aragonite fibres...
# Ecology and life history
Scleractinians fall into one of two main categories:
- zooxanthellate
- non-zooxanthellate.
In zooxanthellate corals, the endodermal cells are replete with symbiotic algae. These symbionts benefit the corals because nearly 95% of the organic carbons produced by zooxanthellae are used as food by the polyps. The oxygen byproduct of photosynthesis and additional energy derived from sugars produced by zooxanthallae enable these corals to grow as much as three times faster than if they had no symbionts present. These corals are restricted to shallow (less than 200 feet - 60 meters), well-lit, warm water with moderate to brisk turbulence and abundant oxygen and prefer firm, non-muddy surfaces on which to settle.
Non-zooxanthellate corals are usually non-reef formers and can be found most abundantly beneath about 500 m of water. They thrive at much colder temperatures and can live in total darkness deriving their energy from the capture of plankton and suspended organic particles. The growth rates of most species of non-zooxanthellate corals are significantly slower than those of their counterparts, and the typical structure for these corals is less calciferous and more susceptible to mechanical damage than that of zooxanthellate corals.
## Life history
There are two main controls on the form of a scleractinian colony. One is the mode of budding and the other is the relative growth rate. There are two types of budding: intratentacular and extratentacular. In an intratentacular budding, polyps are divided by simple fission across the stomodaeum, and each bud retains part of the original stomodaeum and regenerates the rest. Extratentacular budding takes place outside the tentacular ring of the parent. These daughter buds do not share any part in the functions within the parent scleractinians as do the products of intratentacular budding.
# Evolutionary history
There are two main hypotheses about the origin of Scleractinia. The closest scleractinian analog in the Paleozoic is the Rugosa, which suggests direct, possibly polyphyletic, descent, with different scleractinian suborders having originated in different rugosan families. The second hypothesis suggests the similarities of scleractinians to rugosans are due to a common non-skeletalized ancestor in the early Paleozoic. Recently discovered Paleozoic corals with aragonitic skeletons and cyclic septal insertion - two features that characterize Scleractinia - have strengthened the hypothesis for an independent origin of the Scleractinia. | Scleractinia
Scleractinia, also called Stony corals, are exclusively marine animals; they are very similar to sea anemones but generate a hard skeleton. They first appeared in the Middle Triassic and replaced tabulate and rugose corals that went extinct at the end of the Permian. Much of the framework of coral reefs is formed by scleractinians.
There are two groups of Scleractinia:
- colonial corals found in clear, shallow tropical waters; they are the world's primary reef-builders.
- solitary corals are found in all regions of the oceans and do not build reefs. Some live in temperate, polar waters, or below the photic zone down to 6000 meters.
# Anatomy
As mentioned above, Scleractinians may be solitary or compound. The most common forms include conical and horn-shaped scleractinians. In a colonial Scleractinia, the repeated asexual division by the polyps causes the corallites to be interconnected, thus forming the colonies. There are also cases in which the adjacent colonies of the same species form a single colony by fusing.
The modern scleractinian skeleton, which lies external to the polyps that make it, is composed of calcium carbonate in the crystal form aragonite. However, a prehistoric scleractinian (Coelosimilia) had a non-aragonite calcium carbonate skeletal structure.[1]
The skeleton of an individual scleractinian polyp is known as a corallite. Each of its radially-aligned elements, termed septa, lies in the endocoel flanked by the members of a mesenterial pair. The skeleton originates as a thin basal plate from which the septa arise vertically. The structure of both simple and compound scleractinians is light and porous, rather than solid as in the Rugosa.
Septa are secreted by the mesenteries and are therefore added in the same order as the mesenteries. As a result, septa of different ages are adjacent to one another, and the symmetry of the scleractinian skeleton is radial or biradial. This pattern of septal insertion is termed "cyclic" by paleontologists. By contrast, in some fossil corals, adjacent septa lie in order of increasing age, a pattern that is termed serial and that produces a bilateral symmetry. Scleractinians are distinguished from the Rugosa also by their pattern of septal insertion. They secrete an aragonitic exoskeleton in which the septa are inserted between the mesenteries in multiples of six.
In scleractinians, there are two main secondary structures:
- Stereome is an adherent layer of secondary tissue, which covers the septal surface. It consists of transverse bundles of aragonitic needles and protects the scleractinians. However, its function can be nullified by the thickening of the septa itself.
- Coenosteum is a perforated complex tissue that separates individual corallites in a compound scleractinians.
At the beginning of Scleractinia’s development four groups with different microstructure can distinguished. These are:
- Pachytecal: Corals having very thick wall and rudimentary septa. This is the group which probably originated from Rugosa corals.
- Thick Trabecular: Corals with septa built from thick structures, resembling little beams, called trabecules.
- Minitrabecular: Corals with septa built from thin trabecules.
- Fascilcular or non-trabecular: Corals with septa not built from trabecules, but from columns being bunches of aragonite fibres...
# Ecology and life history
Scleractinians fall into one of two main categories:
- zooxanthellate
- non-zooxanthellate.
In zooxanthellate corals, the endodermal cells are replete with symbiotic algae. These symbionts benefit the corals because nearly 95% of the organic carbons produced by zooxanthellae are used as food by the polyps. The oxygen byproduct of photosynthesis and additional energy derived from sugars produced by zooxanthallae enable these corals to grow as much as three times faster than if they had no symbionts present. These corals are restricted to shallow (less than 200 feet - 60 meters), well-lit, warm water with moderate to brisk turbulence and abundant oxygen and prefer firm, non-muddy surfaces on which to settle.
Non-zooxanthellate corals are usually non-reef formers and can be found most abundantly beneath about 500 m of water. They thrive at much colder temperatures and can live in total darkness deriving their energy from the capture of plankton and suspended organic particles. The growth rates of most species of non-zooxanthellate corals are significantly slower than those of their counterparts, and the typical structure for these corals is less calciferous and more susceptible to mechanical damage than that of zooxanthellate corals.
## Life history
There are two main controls on the form of a scleractinian colony. One is the mode of budding and the other is the relative growth rate. There are two types of budding: intratentacular and extratentacular. In an intratentacular budding, polyps are divided by simple fission across the stomodaeum, and each bud retains part of the original stomodaeum and regenerates the rest. Extratentacular budding takes place outside the tentacular ring of the parent. These daughter buds do not share any part in the functions within the parent scleractinians as do the products of intratentacular budding.
# Evolutionary history
There are two main hypotheses about the origin of Scleractinia. The closest scleractinian analog in the Paleozoic is the Rugosa, which suggests direct, possibly polyphyletic, descent, with different scleractinian suborders having originated in different rugosan families. The second hypothesis suggests the similarities of scleractinians to rugosans are due to a common non-skeletalized ancestor in the early Paleozoic. Recently discovered Paleozoic corals with aragonitic skeletons and cyclic septal insertion - two features that characterize Scleractinia - have strengthened the hypothesis for an independent origin of the Scleractinia. | https://www.wikidoc.org/index.php/Scleractinia | |
c56f3618f4783c581b47e12fd93c295856dde30d | wikidoc | Scrotal cyst | Scrotal cyst
Synonyms and keywords:: Idiopathic scrotal calcinosis, idiopathic calcified nodules of the scrotum,
# Overview
Idiopathic scrotal calcinosis (also known as idiopathic calcified nodules of the scrotum) is a cutaneous condition characterized by calcification of the skin resulting from the deposition of calcium and phosphorus occurring on the scrotum.:528 However, the levels of calcium and phosphate in the blood are normal. Idiopathic scrotal calcinosis typically affects young males, with an onset between adolescence and early adulthood. The scrotal calcinosis appears, without any symptoms, as yellowish nodules that range in size from 1 mm to several centimeters.
# Pathogenesis
The cause is not well defined.
# Physical examination
## Gallery
### Skin
- url = >
- url = >
- url = >
- url = >
# Treatment
Treatment may involve surgery, which is currently the only recommended intervention. Surgery should include the removal of even small nodules, to prevent the recurrence of the scrotal calcinosis.
# History
Scrotal calcinosis was first described in 1883 by Lewinski. | Scrotal cyst
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Jesus Rosario Hernandez, M.D. [2].
Synonyms and keywords:: Idiopathic scrotal calcinosis, idiopathic calcified nodules of the scrotum,
# Overview
Idiopathic scrotal calcinosis (also known as idiopathic calcified nodules of the scrotum[1]) is a cutaneous condition characterized by calcification of the skin resulting from the deposition of calcium and phosphorus occurring on the scrotum.[2]:528 However, the levels of calcium and phosphate in the blood are normal.[3] Idiopathic scrotal calcinosis typically affects young males, with an onset between adolescence and early adulthood.[3] The scrotal calcinosis appears, without any symptoms, as yellowish nodules that range in size from 1 mm to several centimeters.[4]
# Pathogenesis
The cause is not well defined.[5][4]
# Physical examination
## Gallery
### Skin
- url = http://www.atlasdermatologico.com.br/disease.jsf?diseaseId=420>
- url = http://www.atlasdermatologico.com.br/disease.jsf?diseaseId=420>
- url = http://www.atlasdermatologico.com.br/disease.jsf?diseaseId=420>
- url = http://www.atlasdermatologico.com.br/disease.jsf?diseaseId=420>
# Treatment
Treatment may involve surgery,[6] which is currently the only recommended intervention.[4] Surgery should include the removal of even small nodules, to prevent the recurrence of the scrotal calcinosis.[4]
# History
Scrotal calcinosis was first described in 1883 by Lewinski.[4] | https://www.wikidoc.org/index.php/Scrotal_cyst | |
bff3bedbc0b4b4ab7e6879ae38af3778710a1654 | wikidoc | Sdasdfadfasf | Sdasdfadfasf
# 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
Sdasdfadfasf is {{{aOrAn}}} {{{drugClass}}} that is FDA approved for the {{{indicationType}}} of {{{indication}}}. Common adverse reactions include {{{adverseReactions}}}.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
There is limited information regarding Sdasdfadfasf FDA-Labeled Indications and Dosage (Adult) in the drug label.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information about Off-Label Guideline-Supported Use of Sdasdfadfasf in adult patients.
### Non–Guideline-Supported Use
There is limited information about Off-Label Non–Guideline-Supported Use of Sdasdfadfasf in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Sdasdfadfasf FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information about Off-Label Guideline-Supported Use of Sdasdfadfasf in pediatric patients.
### Non–Guideline-Supported Use
There is limited information about Off-Label Non–Guideline-Supported Use of Sdasdfadfasf in pediatric patients.
# Contraindications
There is limited information regarding Sdasdfadfasf Contraindications in the drug label.
# Warnings
There is limited information regarding Sdasdfadfasf Warnings' in the drug label.
# Adverse Reactions
## Clinical Trials Experience
Central Nervous System
Cardiovascular
Respiratory
Gastrointestinal
Hypersensitive Reactions
Miscellaneous
## Postmarketing Experience
Central Nervous System
Cardiovascular
Respiratory
Gastrointestinal
Hypersensitive Reactions
Miscellaneous
# Drug Interactions
There is limited information regarding Sdasdfadfasf Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Sdasdfadfasf in women who are pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Sdasdfadfasf in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Sdasdfadfasf during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Sdasdfadfasf in women who are nursing.
### Pediatric Use
There is no FDA guidance on the use of Sdasdfadfasf in pediatric settings.
### Geriatic Use
There is no FDA guidance on the use of Sdasdfadfasf in geriatric settings.
### Gender
There is no FDA guidance on the use of Sdasdfadfasf with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Sdasdfadfasf with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Sdasdfadfasf in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Sdasdfadfasf in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Sdasdfadfasf in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Sdasdfadfasf in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Sdasdfadfasf Administration in the drug label.
### Monitoring
There is limited information regarding Sdasdfadfasf Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Sdasdfadfasf and IV administrations.
# Overdosage
There is limited information regarding Sdasdfadfasf overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
There is limited information regarding Sdasdfadfasf Pharmacology in the drug label.
## Mechanism of Action
There is limited information regarding Sdasdfadfasf Mechanism of Action in the drug label.
## Structure
There is limited information regarding Sdasdfadfasf Structure in the drug label.
## Pharmacodynamics
There is limited information regarding Sdasdfadfasf Pharmacodynamics in the drug label.
## Pharmacokinetics
There is limited information regarding Sdasdfadfasf Pharmacokinetics in the drug label.
## Nonclinical Toxicology
There is limited information regarding Sdasdfadfasf Nonclinical Toxicology in the drug label.
# Clinical Studies
There is limited information regarding Sdasdfadfasf Clinical Studies in the drug label.
# How Supplied
There is limited information regarding Sdasdfadfasf How Supplied in the drug label.
## Storage
There is limited information regarding Sdasdfadfasf Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Sdasdfadfasf Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Sdasdfadfasf interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
There is limited information regarding Sdasdfadfasf Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Sdasdfadfasf Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Sdasdfadfasf
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Sdasdfadfasf is {{{aOrAn}}} {{{drugClass}}} that is FDA approved for the {{{indicationType}}} of {{{indication}}}. Common adverse reactions include {{{adverseReactions}}}.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
There is limited information regarding Sdasdfadfasf FDA-Labeled Indications and Dosage (Adult) in the drug label.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information about Off-Label Guideline-Supported Use of Sdasdfadfasf in adult patients.
### Non–Guideline-Supported Use
There is limited information about Off-Label Non–Guideline-Supported Use of Sdasdfadfasf in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Sdasdfadfasf FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information about Off-Label Guideline-Supported Use of Sdasdfadfasf in pediatric patients.
### Non–Guideline-Supported Use
There is limited information about Off-Label Non–Guideline-Supported Use of Sdasdfadfasf in pediatric patients.
# Contraindications
There is limited information regarding Sdasdfadfasf Contraindications in the drug label.
# Warnings
There is limited information regarding Sdasdfadfasf Warnings' in the drug label.
# Adverse Reactions
## Clinical Trials Experience
Central Nervous System
Cardiovascular
Respiratory
Gastrointestinal
Hypersensitive Reactions
Miscellaneous
## Postmarketing Experience
Central Nervous System
Cardiovascular
Respiratory
Gastrointestinal
Hypersensitive Reactions
Miscellaneous
# Drug Interactions
There is limited information regarding Sdasdfadfasf Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Sdasdfadfasf in women who are pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Sdasdfadfasf in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Sdasdfadfasf during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Sdasdfadfasf in women who are nursing.
### Pediatric Use
There is no FDA guidance on the use of Sdasdfadfasf in pediatric settings.
### Geriatic Use
There is no FDA guidance on the use of Sdasdfadfasf in geriatric settings.
### Gender
There is no FDA guidance on the use of Sdasdfadfasf with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Sdasdfadfasf with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Sdasdfadfasf in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Sdasdfadfasf in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Sdasdfadfasf in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Sdasdfadfasf in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Sdasdfadfasf Administration in the drug label.
### Monitoring
There is limited information regarding Sdasdfadfasf Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Sdasdfadfasf and IV administrations.
# Overdosage
There is limited information regarding Sdasdfadfasf overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
There is limited information regarding Sdasdfadfasf Pharmacology in the drug label.
## Mechanism of Action
There is limited information regarding Sdasdfadfasf Mechanism of Action in the drug label.
## Structure
There is limited information regarding Sdasdfadfasf Structure in the drug label.
## Pharmacodynamics
There is limited information regarding Sdasdfadfasf Pharmacodynamics in the drug label.
## Pharmacokinetics
There is limited information regarding Sdasdfadfasf Pharmacokinetics in the drug label.
## Nonclinical Toxicology
There is limited information regarding Sdasdfadfasf Nonclinical Toxicology in the drug label.
# Clinical Studies
There is limited information regarding Sdasdfadfasf Clinical Studies in the drug label.
# How Supplied
There is limited information regarding Sdasdfadfasf How Supplied in the drug label.
## Storage
There is limited information regarding Sdasdfadfasf Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Sdasdfadfasf Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Sdasdfadfasf interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
There is limited information regarding Sdasdfadfasf Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Sdasdfadfasf Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Sdasdfadfasf | |
49f517d18fc90291ac52bd7e4f0f79a859c69065 | wikidoc | Seabuckthorn | Seabuckthorn
The sea-buckthorns (Hippophae L.) are deciduous shrubs in the genus Hippophae, family Elaeagnaceae. The name sea-buckthorn is hyphenated here to avoid confusion with the buckthorns (Rhamnus, family Rhamnaceae). It is also referred to as "sea buckthorn", seabuckthorn, sandthorn or seaberry.
Since 2005 in the United States, other such developed countries and the global functional food industry, there has been a rapidly growing recognition of sea-buckthorn berries for their consumer product potential, exceptional nutrient content and antioxidant qualities, giving them commercial status as a novel superfruit.
# Description and distribution
There are 6 species and 12 subspecies native over a wide area of Europe and Asia, including China, Mongolia, India, Nepal, Pakistan, Russia, Great Britain, France, Denmark, Netherlands, Germany, Poland, Finland, Sweden and Norway. More than 90 percent or about 1.5 million hectares of the world's sea buckthorn resources can be found in China where the plant is exploited for soil and water conservation purposes. The shrubs reach 0.5–6 m tall, rarely up to 18 m in central Asia, and typically occur in dry, sandy areas. They are tolerant of salt in the air and soil, but demand full sunlight for good growth and do not tolerate shady conditions near larger trees.
The common sea-buckthorn (Hippophae rhamnoides) is by far the most widespread, with a range extending from the Atlantic coasts of Europe right across to northwestern China. In western Europe, it is largely confined to sea coasts where salt spray off the sea prevents other larger plants from out-competing it, but in central Asia it is more widespread in dry semi-desert sites where other plants cannot survive the dry conditions; in central Europe and Asia it also occurs as a subalpine shrub above tree line in mountains, and other sunny areas such as river banks.
Common sea-buckthorn has branches that are dense and stiff, and very thorny. The leaves are a distinct pale silvery-green, lanceolate, 3–8 cm long and less than 7 mm broad. It is dioecious, with separate male and female plants. The male produces brownish flowers which produce wind-distributed pollen.
## Names in different languages
Sea-buckthorn is known in different languages as: Чацаргана (Mongolian), Shaji (Chinese), Astelpaju (Estonian), Duindoorn (Dutch), Tyrni (Finnish), Argousier (French), Sanddorn (German), Olivello Spinoso (Italian), Облепиха (Oblepikha, Russian), Espino de Mar, Falso Espino, Espino Amarillo (Spanish), Havtorn (Swedish and Danish).
## Berries and leaves
The female plants produce orange berries 6–9 mm in diameter, soft and juicy, and rich in vitamin C (on average 600 mg per 100g and sometimes up to 1500 mg per 100g); some varieties are also rich in vitamin A, vitamin E, and oils. The berries are an important winter food resource for some birds, notably Fieldfares.
Leaves are eaten by the larva of the coastal race of the Ash Pug moth and by larvae of other Lepidoptera including Brown-tail, The Dun-bar, Emperor Moth, Mottled Umber and Coleophora elaeagnisella.
Hippophae salicifolia (Willow-leaved Sea-buckthorn) is restricted to the Himalaya, to the south of the common sea-buckthorn, growing at high altitudes in dry valleys; it differs from H. rhamnoides in broader (to 10 mm broad), greener (less silvery) leaves, and yellow berries. A wild variant occurs in the same area, but at even higher altitudes in the alpine zone. It is a low shrub not growing taller than 1 m with small leaves 1-3 cm long.
# Uses
## Harvesting and landscaping
Harvesting is difficult due to the densely thorny nature of the shrubs. A common harvesting technique is to remove an entire branch, though this is destructive to the shrub and reduces future harvests. A branch removed in this way is next frozen, and then the berries can be easily shaken off. The branches are cut, deep frozen to −32°C. They are slightly defrosted on the surface during the removal of the berries from the branches and afterwards cleaned.
The worker then crushes the berries to remove up to 95% of the leaves and other debris. This causes the berries to melt slightly from the surface as the work takes place at ambient temperature (about 20°C). Berries are later stored at -22°C.
The most effective way to harvest the berries and not damage the branches is by using a berry-shaker which was developed in Estonia some time ago. Mechanical harvesting leaves up to 50% in the field and the berries can be harvested only once in two years. They only get about 25% of the yield that could be harvested with this relatively new piece of machinery.
During the Cold War, Russian and East German horticulturists developed new varieties with greater nutritional value, larger berries, different ripening months and a branch form that is easier to harvest. Over the past 20 years, experimental crops have been grown in the United States, one in Nevada and one in Arizona, and in western provinces of Canada.
Sea-buckthorn is also a popular garden and landscaping shrub, particularly making a good vandal-proof barrier hedge with an aggressive basal shoot system exploited in some parts of the world to stabilize riverbanks and steep slopes. They have value in northern climates for their landscape qualities, as their colorful berry clusters are retained through winter. Branches are used by florists for designing ornaments. The plant is the regional flora of the Finnish region of Satakunta.
## Nutrients, potential health effects and cosmetics
Sea-buckthorn berries are multipurposed, edible and nutritious, though very acidic and astringent, unpleasant to eat raw, unless 'bletted' (frosted to reduce the astringency) and/or mixed as a juice with sweeter substances such as apple or grape juice. They can also be used to make pies or jams, lotions and liquors.
When the berries are pressed, the resulting sea-buckthorn juice separates into three layers: on top is a thick, orange cream; in the middle, a layer containing sea-buckthorn's characteristic high content of saturated and polyunsaturated fats; and the bottom layer is sediment and juice. Containing fat sources applicable for cosmetic purposes, the upper two layers can be processed for skin creams and liniments, whereas the bottom layer can be used for edible products.
Nutrient and phytochemical constituents of sea-buckthorn berries have potential value as antioxidants that may affect inflammatory disorders, cancer or other diseases, although no specific health benefits have yet been proved in humans. The seed and pulp oils have nutritional properties that vary under different processing methods
The fruit of the plant has a high vitamin C content—in a range of 114 to 1550 mg per 100 grams with an average content (695 mg per 100 grams) about 12 times greater than the 50 mg of vitamin C per 100 grams found in orange— placing sea-buckthorn fruit among the most enriched plant sources of vitamin C. The fruit also contains dense contents of carotenoids, vitamin E, amino acids, dietary minerals, β-sitosterol and polyphenolic acids.
Sea-buckthorn is used as a source for ingredients in several commercially available cosmetic products and nutritional supplements.
Apart from being nourishing, the juice has a freezing point of −22 degrees Celsius allowing it to remain a liquid even in sub-zero temperatures. For its troops confronting extremely low temperatures (see Siachen), India's Defence Research Development Organization established a factory in Leh to manufacture a multi-vitamin herbal beverage based on sea-buckthorn juice.
## Traditional medicine
Different parts of sea-buckthorn have been used as traditional therapies for diseases (see References). As no applications discussed in this section have been verified by Western science and sufficient clinical trial evidence, such knowledge remains mostly unreferenced outside of Asia and is communicated mainly from person to person.
Grown widely throughout its native China and other mainland regions of Asia, sea-buckthorn is an herbal medicine used over centuries to relieve cough, aid digestion, invigorate blood circulation and alleviate pain. In Mongolia, extracts of sea-buckthorn branches and leaves are used to treat gastrointestinal distress in humans and animals.
Bark and leaves are used for treating diarrhea, gastrointestinal, dermatologic disorders and topical compressions for rheumatoid arthritis. Flowers may be used as a skin softener.
For its hemostatic and anti-inflammatory effects, berry fruits are added to medications for pulmonary, gastrointestinal, cardiac, blood and metabolic disorders in Indian, Chinese and Tibetan medicines. Sea-buckthorn berry components have potential anticarcinogenic activity .
Fresh juice, syrup and berry or seed oils are used for colds, fever, exhaustion, as an analgesic or treatment for stomach ulcers, cancer, and metabolic disorders.
Called 'Chharma' in some native languages, oil from fruits and seeds is used for liver diseases, inflammation, disorders of the gastrointestinal system, including peptic ulcers and gastritis, eczema, canker sores and other ulcerative disorders of mucosal tissues, wounds, inflammation, burns, frostbite, psoriasis, rosacea, lupus erythematosus, and chronic dermatoses. In ophthalmology, berry extracts have been used for keratitis, trachoma, eyelid injuries and conjunctivitis.
# Organizations
An organization called the International Center for Research and Training on Seabuckthorn (ICRTS) was formed jointly in 1988 by the China Research and Training Center on Seabuckthorn, the Seabuckthorn Office of the Yellow River Water Commission, and the Shaanxi Seabuckthorn Development Office. ICRTS published the research journal, Hippophae, from 1995 to 2000; it does not appear to be active currently. In 2005, an international collaboration called "EAN-Seabuck" between European Union states, China, Russia and New Independent States was funded by the European Commission to promote sustainable crop and consumer product development from sea buckthorn. | Seabuckthorn
The sea-buckthorns (Hippophae L.) are deciduous shrubs in the genus Hippophae, family Elaeagnaceae. The name sea-buckthorn is hyphenated here to avoid confusion with the buckthorns (Rhamnus, family Rhamnaceae). It is also referred to as "sea buckthorn", seabuckthorn, sandthorn or seaberry[1].
Since 2005 in the United States, other such developed countries and the global functional food industry, there has been a rapidly growing recognition of sea-buckthorn berries for their consumer product potential, exceptional nutrient content and antioxidant qualities[2], giving them commercial status as a novel superfruit[3].
# Description and distribution
There are 6 species and 12 subspecies native over a wide area of Europe and Asia, including China, Mongolia, India, Nepal, Pakistan, Russia, Great Britain, France, Denmark, Netherlands, Germany, Poland, Finland, Sweden and Norway. More than 90 percent or about 1.5 million hectares of the world's sea buckthorn resources can be found in China where the plant is exploited for soil and water conservation purposes[4]. The shrubs reach 0.5–6 m tall, rarely up to 18 m in central Asia, and typically occur in dry, sandy areas. They are tolerant of salt in the air and soil, but demand full sunlight for good growth and do not tolerate shady conditions near larger trees.
The common sea-buckthorn (Hippophae rhamnoides) is by far the most widespread, with a range extending from the Atlantic coasts of Europe right across to northwestern China. In western Europe, it is largely confined to sea coasts where salt spray off the sea prevents other larger plants from out-competing it, but in central Asia it is more widespread in dry semi-desert sites where other plants cannot survive the dry conditions; in central Europe and Asia it also occurs as a subalpine shrub above tree line in mountains, and other sunny areas such as river banks.
Common sea-buckthorn has branches that are dense and stiff, and very thorny. The leaves are a distinct pale silvery-green, lanceolate, 3–8 cm long and less than 7 mm broad. It is dioecious, with separate male and female plants. The male produces brownish flowers which produce wind-distributed pollen.
## Names in different languages
Sea-buckthorn is known in different languages as: Чацаргана (Mongolian), Shaji (Chinese), Astelpaju (Estonian), Duindoorn (Dutch), Tyrni (Finnish), Argousier (French), Sanddorn (German), Olivello Spinoso (Italian), Облепиха (Oblepikha, Russian), Espino de Mar, Falso Espino, Espino Amarillo (Spanish), Havtorn (Swedish and Danish)[5].
## Berries and leaves
The female plants produce orange berries 6–9 mm in diameter, soft and juicy, and rich in vitamin C (on average 600 mg per 100g and sometimes up to 1500 mg per 100g[6]); some varieties are also rich in vitamin A, vitamin E, and oils. The berries are an important winter food resource for some birds, notably Fieldfares.
Leaves are eaten by the larva of the coastal race of the Ash Pug moth and by larvae of other Lepidoptera including Brown-tail, The Dun-bar, Emperor Moth, Mottled Umber and Coleophora elaeagnisella.
Hippophae salicifolia (Willow-leaved Sea-buckthorn) is restricted to the Himalaya, to the south of the common sea-buckthorn, growing at high altitudes in dry valleys; it differs from H. rhamnoides in broader (to 10 mm broad), greener (less silvery) leaves, and yellow berries. A wild variant occurs in the same area, but at even higher altitudes in the alpine zone[citation needed]. It is a low shrub not growing taller than 1 m with small leaves 1-3 cm long.
# Uses
## Harvesting and landscaping
Harvesting is difficult due to the densely thorny nature of the shrubs. A common harvesting technique is to remove an entire branch, though this is destructive to the shrub and reduces future harvests. A branch removed in this way is next frozen, and then the berries can be easily shaken off. The branches are cut, deep frozen to −32°C. They are slightly defrosted on the surface during the removal of the berries from the branches and afterwards cleaned.
The worker then crushes the berries to remove up to 95% of the leaves and other debris. This causes the berries to melt slightly from the surface as the work takes place at ambient temperature (about 20°C). Berries are later stored at -22°C.
The most effective way to harvest the berries and not damage the branches is by using a berry-shaker which was developed in Estonia some time ago. Mechanical harvesting leaves up to 50% in the field and the berries can be harvested only once in two years. They only get about 25% of the yield that could be harvested with this relatively new piece of machinery.
During the Cold War, Russian and East German horticulturists developed new varieties with greater nutritional value, larger berries, different ripening months and a branch form that is easier to harvest. Over the past 20 years, experimental crops have been grown in the United States, one in Nevada and one in Arizona, and in western provinces of Canada[1].
Sea-buckthorn is also a popular garden and landscaping shrub, particularly making a good vandal-proof barrier hedge with an aggressive basal shoot system exploited in some parts of the world to stabilize riverbanks and steep slopes. They have value in northern climates for their landscape qualities, as their colorful berry clusters are retained through winter.[7] Branches are used by florists for designing ornaments. The plant is the regional flora of the Finnish region of Satakunta.
## Nutrients, potential health effects and cosmetics
Sea-buckthorn berries are multipurposed, edible and nutritious, though very acidic and astringent, unpleasant to eat raw, unless 'bletted' (frosted to reduce the astringency) and/or mixed as a juice with sweeter substances such as apple or grape juice. They can also be used to make pies or jams, lotions and liquors.
When the berries are pressed, the resulting sea-buckthorn juice separates into three layers: on top is a thick, orange cream; in the middle, a layer containing sea-buckthorn's characteristic high content of saturated and polyunsaturated fats; and the bottom layer is sediment and juice[2][3]. Containing fat sources applicable for cosmetic purposes, the upper two layers can be processed for skin creams and liniments, whereas the bottom layer can be used for edible products[4].
Nutrient and phytochemical constituents of sea-buckthorn berries have potential value as antioxidants that may affect inflammatory disorders, cancer[8] or other diseases,[9] although no specific health benefits have yet been proved in humans. The seed and pulp oils have nutritional properties that vary under different processing methods[10]
The fruit of the plant has a high vitamin C content—in a range of 114 to 1550 mg per 100 grams[11] with an average content (695 mg per 100 grams) about 12 times greater than the 50 mg of vitamin C per 100 grams found in orange— placing sea-buckthorn fruit among the most enriched plant sources of vitamin C[5]. The fruit also contains dense contents of carotenoids, vitamin E, amino acids, dietary minerals, β-sitosterol and polyphenolic acids[12][13].
Sea-buckthorn is used as a source for ingredients in several commercially available cosmetic products and nutritional supplements.
Apart from being nourishing, the juice has a freezing point of −22 degrees Celsius allowing it to remain a liquid even in sub-zero temperatures[citation needed]. For its troops confronting extremely low temperatures (see Siachen), India's Defence Research Development Organization established a factory in Leh to manufacture a multi-vitamin herbal beverage based on sea-buckthorn juice[14].
## Traditional medicine
Different parts of sea-buckthorn have been used as traditional therapies for diseases[6] (see References). As no applications discussed in this section have been verified by Western science and sufficient clinical trial evidence, such knowledge remains mostly unreferenced outside of Asia and is communicated mainly from person to person.
Grown widely throughout its native China and other mainland regions of Asia, sea-buckthorn is an herbal medicine used over centuries to relieve cough, aid digestion, invigorate blood circulation and alleviate pain. In Mongolia, extracts of sea-buckthorn branches and leaves are used to treat gastrointestinal distress in humans and animals.
Bark and leaves are used for treating diarrhea, gastrointestinal, dermatologic disorders and topical compressions for rheumatoid arthritis. Flowers may be used as a skin softener.
For its hemostatic and anti-inflammatory effects, berry fruits are added to medications for pulmonary, gastrointestinal, cardiac, blood and metabolic disorders in Indian, Chinese and Tibetan medicines. Sea-buckthorn berry components have potential anticarcinogenic activity [7][8].
Fresh juice, syrup and berry or seed oils are used for colds, fever, exhaustion, as an analgesic or treatment for stomach ulcers, cancer, and metabolic disorders.
Called 'Chharma' in some native languages, oil from fruits and seeds is used for liver diseases, inflammation, disorders of the gastrointestinal system, including peptic ulcers and gastritis, eczema, canker sores and other ulcerative disorders of mucosal tissues, wounds, inflammation, burns, frostbite, psoriasis, rosacea, lupus erythematosus, and chronic dermatoses. In ophthalmology, berry extracts have been used for keratitis, trachoma, eyelid injuries and conjunctivitis.
# Organizations
An organization called the International Center for Research and Training on Seabuckthorn (ICRTS) was formed jointly in 1988 by the China Research and Training Center on Seabuckthorn, the Seabuckthorn Office of the Yellow River Water Commission, and the Shaanxi Seabuckthorn Development Office[15]. ICRTS published the research journal, Hippophae, from 1995 to 2000[16]; it does not appear to be active currently. In 2005, an international collaboration called "EAN-Seabuck" between European Union states, China, Russia and New Independent States was funded by the European Commission to promote sustainable crop and consumer product development from sea buckthorn[17]. | https://www.wikidoc.org/index.php/Seabuckthorn | |
2109432445dd0bb73f84735266cb88e335493b65 | wikidoc | Secobarbital | Secobarbital
- Secobarbital sodium
Secobarbital (marketed by Eli Lilly and Company under the brand names Seconal® and Tuinal) is a barbiturate derivative drug. It possesses anaesthetic, anticonvulsant, sedative and hypnotic properties. In the United Kingdom, it was known as Quinalbarbitone.
# Indications
Secobarbital is indicated for:
- Treatment of epilepsy
- Temporary treatment of insomnia in patients resistant to mainstream hypnotics
- Use as a preoperative medication to produce anaesthesia and anxiolysis in short surgical, diagnostic, or therapeutic procedures which are minimally painful.
# Availability
It is available as either a free acid or a sodium salt. The free acid is a white amorphous powder that is slightly soluble in water and very soluble in ethanol. The salt is a white hygroscopic powder that is soluble in water and ethanol.
### Secobarbital sodium
The sodium salt of secobarbital is classified separately from the free acid, as follows:
- CAS number: 309-43-3
- Chemical formula: C12H18N2NaO3
- Molecular weight: 260.265
# Side effects
Side effects of secobarbital include:
- Somnolence
- Impaired motor functions
Impaired coordination
Impaired balance
Dizziness
- Impaired coordination
- Impaired balance
- Dizziness
- Anxiety
- Confusion
- Agitation, irritability, or excitability
- Headache
- Nausea
- Vomiting
- Nightmares
- Increased sensitivity to pain
- Allergic reactions
Difficulty breathing
Edema
Urticaria
- Difficulty breathing
- Edema
- Urticaria
# Withdrawal
Secobarbital is a fairly addictive drug, and withdrawal symptoms can occur if long-term usage is abruptly ended. Withdrawal symptoms can include:
- Anxiety
- Death
- Insomnia
- Lack of appetite
- Seizures
- Tremors
# Recreational Use
Secobarbital began to be widely abused in the 1960s and 1970s, although with the advent of benzodiazepines, they have become less commonly used.
Secobarbital has acquired many nicknames, the most common being "reds", or "red dillies" (it was originally packaged in red capsules). Another common nickname is "seccies". A less common nickname is "dolls"; this was partly responsible for the title of Jacqueline Susann's novel Valley of the Dolls, whose main characters use secobarbital and other such drugs.
Another popular brand of barbiturate pill Tuinal contained a combination of secobarbital and amobarbital but is now rarely prescribed due to problems with abuse and overdose.
## Cause of Death of Charles Boyer
Two days after his wife died from cancer in 1978, Charles Boyer committed suicide with an overdose of Seconal.
## Cause of Death of Bartley Crum
Bartley Crum was the attorney for some of the so-called "Hollywood Ten" who were subpoenaed to appear before the House Un-American Activities Committee in 1947. The FBI tapped Crum's phones, opened his mail, and shadowed him constantly. Labeled as subversive, he ended up losing most of his clients and, unable to cope with stress from the harassment, committed suicide in 1959 by washing down an entire bottle of Seconal with whisky.
## Cause of Death of Judy Garland
Judy Garland, of "The Wizard of Oz" fame, was found dead in her bathroom by her husband Mickey Deans on June 22, 1969. The stated exact cause of death by coroner Gavin Thursdon was accidental overdose of barbiturates; her blood contained the equivalent of 10 1.5-grain Seconal capsules.
## Role in Death of Jimi Hendrix
Secobarbital played a role in the September 18, 1970 death of legendary rock guitarist Jimi Hendrix, who purportedly took nine Secobarbital tablets after a night of drinking wine and was later found dead in his London apartment. Hendrix' death was caused by asphyxiation, after Hendrix presumably vomited in his sleep as a result of the mixture of the excessive Secobarbital dose and alcohol.
## Role in Death of Anissa Jones
Anissa Jones' fatal overdose was of a combination of cocaine, PCP, Methaqualone, and Seconal. The San Diego County coroner said it was one of the most severe cases of drug overdose ever seen in San Diego County.
## Cause of Death of Carol Landis
On July 5, 1948, Carole Landis committed suicide by taking an overdose of Seconal in her Brentwood Heights, California home.
## Cause of Death of Marilyn Monroe
In March 2007, an LA-based Australian writer and director named Philippe Mora uncovered previously-classified government documents regarding Marilyn Monroe's death. These documents, in turn, cited Seconal as Monroe's barbiturate of choice for her alleged suicide.
## Cause of Death of Alejandra Pizarnik
Alejandra Pizarnik, an Argentine poetess, reportedly died, in 1972 at the age of 36, from a self-induced overdose of seconal.
## Cause of Death of Lupe Velez
Lupe Velez, a Mexican actress who starred in many Hollywood films from 1927 to her death in 1944. On December 13, 1944 she committed suicide with an overdose of Seconal. She was 36 years old.
# Use as a lethal injection
Secobarbital overdose was the most common method of implementing physician-assisted suicide (PAS) in Oregon until Eli Lilly and Company discontinued manufacturing it in May 2001, leading to a shortage of the drug. Since then, pentobarbital has dominated in Oregon PAS. Ranbaxy Laboratories Limited have experienced approval issues in their attempts to produce 100 mg secobarbital capsules, but there is no longer a shortage as of October 2006.
It is a component in the veterinary drug Somulose, used for euthanasia of horses and cattle. | Secobarbital
Redirect to:
- Secobarbital sodium
Secobarbital (marketed by Eli Lilly and Company under the brand names Seconal® and Tuinal) is a barbiturate derivative drug. It possesses anaesthetic, anticonvulsant, sedative and hypnotic properties. In the United Kingdom, it was known as Quinalbarbitone.
# Indications
Secobarbital is indicated for:
- Treatment of epilepsy
- Temporary treatment of insomnia in patients resistant to mainstream hypnotics
- Use as a preoperative medication to produce anaesthesia and anxiolysis in short surgical, diagnostic, or therapeutic procedures which are minimally painful.
# Availability
It is available as either a free acid or a sodium salt. The free acid is a white amorphous powder that is slightly soluble in water and very soluble in ethanol. The salt is a white hygroscopic powder that is soluble in water and ethanol.
### Secobarbital sodium
The sodium salt of secobarbital is classified separately from the free acid, as follows:
- CAS number: 309-43-3
- Chemical formula: C12H18N2NaO3
- Molecular weight: 260.265
# Side effects
Side effects of secobarbital include:
- Somnolence
- Impaired motor functions
Impaired coordination
Impaired balance
Dizziness
- Impaired coordination
- Impaired balance
- Dizziness
- Anxiety
- Confusion
- Agitation, irritability, or excitability
- Headache
- Nausea
- Vomiting
- Nightmares
- Increased sensitivity to pain
- Allergic reactions
Difficulty breathing
Edema
Urticaria
- Difficulty breathing
- Edema
- Urticaria
# Withdrawal
Secobarbital is a fairly addictive drug, and withdrawal symptoms can occur if long-term usage is abruptly ended. Withdrawal symptoms can include:
- Anxiety
- Death
- Insomnia
- Lack of appetite
- Seizures
- Tremors
# Recreational Use
Secobarbital began to be widely abused in the 1960s and 1970s, although with the advent of benzodiazepines, they have become less commonly used.
Secobarbital has acquired many nicknames, the most common being "reds", or "red dillies" (it was originally packaged in red capsules). Another common nickname is "seccies". A less common nickname is "dolls"; this was partly responsible for the title of Jacqueline Susann's novel Valley of the Dolls, whose main characters use secobarbital and other such drugs.
Another popular brand of barbiturate pill Tuinal contained a combination of secobarbital and amobarbital but is now rarely prescribed due to problems with abuse and overdose.
## Cause of Death of Charles Boyer
Two days after his wife died from cancer in 1978, Charles Boyer committed suicide with an overdose of Seconal.
## Cause of Death of Bartley Crum
Bartley Crum was the attorney for some of the so-called "Hollywood Ten" who were subpoenaed to appear before the House Un-American Activities Committee in 1947. The FBI tapped Crum's phones, opened his mail, and shadowed him constantly. Labeled as subversive, he ended up losing most of his clients and, unable to cope with stress from the harassment, committed suicide in 1959 by washing down an entire bottle of Seconal with whisky.
## Cause of Death of Judy Garland
Judy Garland, of "The Wizard of Oz" fame, was found dead in her bathroom by her husband Mickey Deans on June 22, 1969. The stated exact cause of death by coroner Gavin Thursdon was accidental overdose of barbiturates; her blood contained the equivalent of 10 1.5-grain Seconal capsules.[1]
## Role in Death of Jimi Hendrix
Secobarbital played a role in the September 18, 1970 death of legendary rock guitarist Jimi Hendrix, who purportedly took nine Secobarbital tablets after a night of drinking wine and was later found dead in his London apartment. Hendrix' death was caused by asphyxiation, after Hendrix presumably vomited in his sleep as a result of the mixture of the excessive Secobarbital dose and alcohol.
## Role in Death of Anissa Jones
Anissa Jones' fatal overdose was of a combination of cocaine, PCP, Methaqualone, and Seconal. The San Diego County coroner said it was one of the most severe cases of drug overdose ever seen in San Diego County.
## Cause of Death of Carol Landis
On July 5, 1948, Carole Landis committed suicide by taking an overdose of Seconal in her Brentwood Heights, California home.
## Cause of Death of Marilyn Monroe
In March 2007, an LA-based Australian writer and director named Philippe Mora uncovered previously-classified government documents regarding Marilyn Monroe's death. These documents, in turn, cited Seconal as Monroe's barbiturate of choice for her alleged suicide.
## Cause of Death of Alejandra Pizarnik
Alejandra Pizarnik, an Argentine poetess, reportedly died, in 1972 at the age of 36, from a self-induced overdose of seconal.
## Cause of Death of Lupe Velez
Lupe Velez, a Mexican actress who starred in many Hollywood films from 1927 to her death in 1944. On December 13, 1944 she committed suicide with an overdose of Seconal. She was 36 years old.
# Use as a lethal injection
Secobarbital overdose was the most common method of implementing physician-assisted suicide (PAS) in Oregon until Eli Lilly and Company discontinued manufacturing it in May 2001, leading to a shortage of the drug. Since then, pentobarbital has dominated in Oregon PAS. Ranbaxy Laboratories Limited have experienced approval issues in their attempts to produce 100 mg secobarbital capsules, but there is no longer a shortage as of October 2006.
It is a component in the veterinary drug Somulose, used for euthanasia of horses and cattle. | https://www.wikidoc.org/index.php/Seconal_Sodium | |
280f53792e9b80eea6e0271bd8aaf931fbabaca7 | wikidoc | Segmentation | Segmentation
Segmentation in biology refers to the division of some metazoan bodies and plant body plans into a series of semi-repetitive segments, and the question of the benefits and costs of doing so. As such, segmentation is related to the more general concept of modularity.
Examples of segmented animals are the annelids and arthropods. However it does not exist in cnidarians. Vertebrae are also inherited in a segmented way, making it easy for those animals to adapt to have the correct number of these spinal cord segments in the vertebral column. This has been extensively studied in mice. Among plants, the horsetails are a clear example of segmentation.
Segmentation allows for a high degree of specialization of bodily regions. This regional specialization is seen to some degree in annelids, but is an evolutionary development of the body plan of arthropods.
The process of establishing such a segmented body pattern is discussed in morphogenesis.
de:Segmentierung (Biologie)
sv:Segmentering | Segmentation
Segmentation in biology refers to the division of some metazoan bodies and plant body plans into a series of semi-repetitive segments, and the question of the benefits and costs of doing so. As such, segmentation is related to the more general concept of modularity.
Examples of segmented animals are the annelids and arthropods. However it does not exist in cnidarians. Vertebrae are also inherited in a segmented way, making it easy for those animals to adapt to have the correct number of these spinal cord segments in the vertebral column. This has been extensively studied in mice. Among plants, the horsetails are a clear example of segmentation.
Segmentation allows for a high degree of specialization of bodily regions. This regional specialization is seen to some degree in annelids, but is an evolutionary development of the body plan of arthropods.
The process of establishing such a segmented body pattern is discussed in morphogenesis.
Template:Biology-stub
de:Segmentierung (Biologie)
sv:Segmentering
Template:WS | https://www.wikidoc.org/index.php/Segmentation | |
2f8979e72b2a0d7238801d96ce4825221b5db9c5 | wikidoc | Selenic acid | Selenic acid
Selenic acid is the chemical compound with the formula H2SeO4. This oxoacid is more descriptively written (HO)2SeO2, which emphasises that Se is attached to four oxygen atoms. As predicted by VSEPR theory, the selenium center is tetrahedral.
# Preparation and reactions
Selenic acid is prepared by oxidation of selenium dioxide with hydrogen peroxide:
To obtain the anhydrous acid as a crystalline solid, the resulting solution is evaporated at temperatures<140 °C in vacuum.
Like sulfuric acid, selenic acid is a strong acid that is hygroscopic and extremely soluble in water. Concentrated solutions are viscous. Crystalline mono- and di-hydrates are known. Unlike sulfuric acid, H2SeO4 is a sufficiently strong oxidizer to liberate chlorine from chloride ions, being reduced to selenious acid (selenic acid).
Selenic acid reacts with barium salts to precipitate BaSeO4, analogous to the sulfate. Calcium selenate is however more soluble than the sulfate.
Treatment of selenic acid with fluorosulfuric acid gives the dioxydifluoride (b.p. -8.4C):
Hot selenic acid is capable of dissolving gold. | Selenic acid
Template:Chembox new
Selenic acid is the chemical compound with the formula H2SeO4. This oxoacid is more descriptively written (HO)2SeO2, which emphasises that Se is attached to four oxygen atoms. As predicted by VSEPR theory, the selenium center is tetrahedral.
# Preparation and reactions
Selenic acid is prepared by oxidation of selenium dioxide with hydrogen peroxide:
To obtain the anhydrous acid as a crystalline solid, the resulting solution is evaporated at temperatures<140 °C in vacuum.[1]
Like sulfuric acid, selenic acid is a strong acid that is hygroscopic and extremely soluble in water. Concentrated solutions are viscous. Crystalline mono- and di-hydrates are known. Unlike sulfuric acid, H2SeO4 is a sufficiently strong oxidizer to liberate chlorine from chloride ions, being reduced to selenious acid (selenic [IV] acid).
Selenic acid reacts with barium salts to precipitate BaSeO4, analogous to the sulfate. Calcium selenate is however more soluble than the sulfate.
Treatment of selenic acid with fluorosulfuric acid gives the dioxydifluoride (b.p. -8.4C):[1]
Hot selenic acid is capable of dissolving gold. | https://www.wikidoc.org/index.php/Selenic_acid | |
5c5a02fb9693abe0a7799592a049509f3e2f1bb1 | wikidoc | Serotonergic | Serotonergic
Serotonergic or serotoninergic means "related to the neurotransmitter serotonin". A synapse is serotonergic if it uses serotonin as its neurotransmitter. A substance is serotonergic if it produces its effects via interactions with the serotonin system.
A serotonergic, or serotonergic agent, is any chemical which functions to enhance the effects mediated by serotonin in the central nervous system, and they include the following classes of chemicals:
- Serotonin precursors (such as tryptophan and 5-HTP)
- Cofactors required in the body's production of serotonin
- Serotonergic enzymes
- Selective serotonin reuptake inhibitor - A common class of serotonergic antidepressants
- Noradrenergic and specific serotonergic antidepressant - Another class of serotonergic antidepressants
- serotonergic psychedelics - The serotonergic psychedelic drugs | Serotonergic
Serotonergic or serotoninergic means "related to the neurotransmitter serotonin". A synapse is serotonergic if it uses serotonin as its neurotransmitter. A substance is serotonergic if it produces its effects via interactions with the serotonin system.
A serotonergic, or serotonergic agent, is any chemical which functions to enhance the effects mediated by serotonin in the central nervous system, and they include the following classes of chemicals:
- Serotonin precursors (such as tryptophan and 5-HTP)
- Cofactors required in the body's production of serotonin
- Serotonergic enzymes
- Selective serotonin reuptake inhibitor - A common class of serotonergic antidepressants
- Noradrenergic and specific serotonergic antidepressant - Another class of serotonergic antidepressants
- serotonergic psychedelics - The serotonergic psychedelic drugs | https://www.wikidoc.org/index.php/Serotonergic | |
c580bf7a6dde64e45712b8b3d7cac8bb56ab1910 | wikidoc | Serous fluid | Serous fluid
In physiology, the term serous fluid is used for various bodily fluids that are typically pale yellow and transparent, and of a benign nature.
Saliva consists of mucus and serous fluid; the serous fluid contains the enzyme amylase important for the digestion of carbohydrates. Minor salivary glands of von Ebner present on the tongue secrete the amylase. The parotid gland produces purely serous saliva. The other major salivary glands produce mixed (serous and mucus) saliva.
Another type of serous fluid is secreted by the serous membranes (or serosa), two layered membranes which line the body cavities. The serous fluid between the two layers acts as a lubricant and reduces friction from muscle movement.
A common trait of serous fluids is their role in assisting digestion, excretion, and respiration.
Blood serum is the liquid part of blood remaining after clotting, and is therefore lacking in clotting factors. It is therefore distinct from blood plasma. | Serous fluid
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
In physiology, the term serous fluid is used for various bodily fluids that are typically pale yellow and transparent, and of a benign nature.
Saliva consists of mucus and serous fluid; the serous fluid contains the enzyme amylase important for the digestion of carbohydrates. Minor salivary glands of von Ebner present on the tongue secrete the amylase. The parotid gland produces purely serous saliva. The other major salivary glands produce mixed (serous and mucus) saliva.
Another type of serous fluid is secreted by the serous membranes (or serosa), two layered membranes which line the body cavities. The serous fluid between the two layers acts as a lubricant and reduces friction from muscle movement.
A common trait of serous fluids is their role in assisting digestion, excretion, and respiration.
Blood serum is the liquid part of blood remaining after clotting, and is therefore lacking in clotting factors. It is therefore distinct from blood plasma. | https://www.wikidoc.org/index.php/Serous | |
856fbdc9b789aad22fea05ba814dc973532fc0eb | wikidoc | Sertoli cell | Sertoli cell
A Sertoli cell (a kind of sustentacular cell) is a 'nurse' cell of the testes which is part of a seminiferous tubule.
It is activated by follicle-stimulating hormone, and has FSH-receptor on its membranes.
# Functions
Its main function is to nurture the developing sperm cells through the stages of spermatogenesis. Because of this, it has also been called the "mother cell." It provides both secretory and structural support.
## Secretory
Sertoli cells secrete the following substances:
- anti-Müllerian hormone (AMH) - secreted during the early stages of fetal life.
- inhibin and activins - secreted after puberty, and work together to regulate FSH secretion
- androgen binding protein - facilitate spermatogenesis and sperm maturation
- glial cell line-derived neurotrophic factor (GDNF) - has been demonstrated to function in promoting undifferentiating spermatogonia, which ensures stem cell self-renewal during the perinatal period.
- the Ets related molecule (ERM transcription factor) - needed for maintenance of the spermatogonial stem cell in the adult testis.
- transferrin
## Structural
The junctions of Sertoli cells form the blood-testis barrier, a structure that partitions the interstitial blood compartment of the testis from the adluminal compartment of the seminiferous tubules. Sertoli cells control the entry and exit of nutrients, hormones and other chemicals into the tubules of the testis as well as make the adluminal compartment an immune-privileged site.
The cell is also responsible for establishing and maintaining the spermatogonial stem cell niche, which ensures the renewal of stem cells and the differentiation of spermatogonia into mature germ cells that progress stepwise through the long process of spermatogenesis, ending in the release of spermatozoa.
## Other functions
During the Maturation phase of spermiogenesis, the Sertoli cells consume the unneeded portions of the spermatazoa.
# Production of Sertoli cells
Once fully differentiated, the Sertoli cell is unable to proliferate. Therefore, once spermatogenesis has begun, no more Sertoli cells are created.
Recently however, some scientists have found a way to grow these cells outside of the body. This gives rise to the possibility of repairing some defects that cause male infertility.
# Nomenclature
Sertoli cells are called so because of their eponym Enrico Sertoli, an Italian physiologist who discovered them while studying medicine in the University of Pavia, Italy.
He published a description of this cell in 1865. The cell was discovered by Sertoli with a Belthle microscope purchased in 1862, which he used while studying medicine.
In the 1865 publication, his first description used the terms "tree-like cell" or "stringy cell" and most importantly he referred to these "mother cells." It was other scientists who used Enrico's family name, Sertoli, to label these cell in publications, starting in 1888. As of 2006, two textbooks that are devoted specifically to the Sertoli cell have been published.
# Histology
On slides, using standard staining, it can be easy to confuse the Sertoli cells with the other cells of the germinal epithelium. The most distinctive of the Sertoli cells is the dark nucleolus.
# Pathology
Sertoli-Leydig cell tumour are part of the sex cord-stromal tumour group of ovarian neoplasms.
# Additional images
- Transverse section of a tubule of the testis of a rat. X 250. | Sertoli cell
Template:Infobox Anatomy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Template:Editor help
A Sertoli cell (a kind of sustentacular cell) is a 'nurse' cell of the testes which is part of a seminiferous tubule.
It is activated by follicle-stimulating hormone, and has FSH-receptor on its membranes.
# Functions
Its main function is to nurture the developing sperm cells through the stages of spermatogenesis. Because of this, it has also been called the "mother cell." It provides both secretory and structural support.
## Secretory
Sertoli cells secrete the following substances:
- anti-Müllerian hormone (AMH) - secreted during the early stages of fetal life.
- inhibin and activins - secreted after puberty, and work together to regulate FSH secretion
- androgen binding protein - facilitate spermatogenesis and sperm maturation
- glial cell line-derived neurotrophic factor (GDNF) - has been demonstrated to function in promoting undifferentiating spermatogonia, which ensures stem cell self-renewal during the perinatal period.
- the Ets related molecule (ERM transcription factor) - needed for maintenance of the spermatogonial stem cell in the adult testis.
- transferrin[1]
## Structural
The junctions of Sertoli cells form the blood-testis barrier, a structure that partitions the interstitial blood compartment of the testis from the adluminal compartment of the seminiferous tubules. Sertoli cells control the entry and exit of nutrients, hormones and other chemicals into the tubules of the testis as well as make the adluminal compartment an immune-privileged site.
The cell is also responsible for establishing and maintaining the spermatogonial stem cell niche, which ensures the renewal of stem cells and the differentiation of spermatogonia into mature germ cells that progress stepwise through the long process of spermatogenesis, ending in the release of spermatozoa.
## Other functions
During the Maturation phase of spermiogenesis, the Sertoli cells consume the unneeded portions of the spermatazoa.
# Production of Sertoli cells
Once fully differentiated, the Sertoli cell is unable to proliferate. Therefore, once spermatogenesis has begun, no more Sertoli cells are created.
Recently however, some scientists have found a way to grow these cells outside of the body. This gives rise to the possibility of repairing some defects that cause male infertility.
# Nomenclature
Sertoli cells are called so because of their eponym Enrico Sertoli, an Italian physiologist who discovered them while studying medicine in the University of Pavia, Italy. [2]
He published a description of this cell in 1865. The cell was discovered by Sertoli with a Belthle microscope purchased in 1862, which he used while studying medicine.
In the 1865 publication, his first description used the terms "tree-like cell" or "stringy cell" and most importantly he referred to these "mother cells." It was other scientists who used Enrico's family name, Sertoli, to label these cell in publications, starting in 1888. As of 2006, two textbooks that are devoted specifically to the Sertoli cell have been published.
# Histology
On slides, using standard staining, it can be easy to confuse the Sertoli cells with the other cells of the germinal epithelium. The most distinctive of the Sertoli cells is the dark nucleolus.[3]
# Pathology
Sertoli-Leydig cell tumour are part of the sex cord-stromal tumour group of ovarian neoplasms.
# Additional images
- Transverse section of a tubule of the testis of a rat. X 250. | https://www.wikidoc.org/index.php/Sertoli-cell | |
fb237c1383fc8c57c5e0c0e9a029e37e60a02386 | wikidoc | Shear stress | Shear stress
Shear stress is a stress state where the stress is parallel or tangential to a face of the material, as opposed to normal stress when the stress is perpendicular to the face. The variable used to denote shear stress is \tau\, (tau).
Physical quantities of shear stress are measured in force divided by area. In SI, the unit is the pascal (Pa) or newtons per square meter. In United States customary units, shear stress is also commonly measured in pounds-force per square inch or kilopounds-force per square inch. The area is always the area resisting the shear, and not the area that the force is acting upon. These two areas are always at right angles.
There are two forms of shear stress: direct shear and beam shear.
# Direct Shear
The formula for shear stress in a direct shear is:
where
Structural members that are often considered to be in pure shear stress are riveted and bolted joints. For bolts and rivets the two plates must be touching, and locked together for the pure shear case to apply. Welds may also be subjected to pure shear stress depending on the location and loading. Cantilever beams, consoles and column heads are subject to composite loading, consisting of shear, tensile and compressive stress.
# Beam Shear
The formula for shear stress in a beam is:
where
# Semi-monocoque shear
Shear stresses within a semi-monocoque structure may be calculated by idealizing the cross-section of the structure into a set of stringers (carrying only axial loads) and webs (carrying only shear flows). Dividing the shear flow by the thickness of a given portion of the semi-monocoque structure yields the shear stress. Thus, the maximum shear stress will occur either in the web of maximum shear flow or minimum thickness.
Also constructions in soil can fail due to shear; e.g., the weight of an earth-filled dam or dike may cause the subsoil to collapse, like a small landslide.
Shear stress is relevant to the motion of fluids upon surfaces, which result in the generation of shear stress. Particularly, the laminar fluid flow over the surface has a zero velocity and shear stress occurs between the zero-velocity surface and the higher-velocity flow away from the surface.
# Impact Shear
The maximum shear stress created in a solid round bar subject to impact is given.
The equation is
where
and
# Shear Stress in Fluids
A viscous fluid (including air and water) moving along a solid boundary will incur a shear stress on that boundary. The no-slip condition dictates that the speed of the fluid at the boundary (relative to the boundary) is 0, but at some height from the boundary the flow speed must equal that of the fluid. The region between these two points is aptly named the boundary layer. The shear stress is imparted onto the boundary as a result of this loss of velocity and can be expressed as
where
## Diverging Fringe Shear Stress Sensor
This relationship can be exploited to measure the wall shear stress. If a sensor could directly measure the gradient of the velocity profile at the wall, then multiplying by the dynamic viscosity would yield the shear stress. Such a sensor was demonstrated by A. A. Naqwi and W. C. Reynolds. The interference pattern generated by sending a beam of light through two parallel slits forms a network of linearly diverging fringes that seem to originate from the plane of the two slits (see double-slit experiment). As a particle in a fluid passes through the fringes, a receiver detects the reflection of the fringe pattern. The signal can be processed, and knowing the fringe angle, the height and velocity of the particle can be extrapolated. | Shear stress
Shear stress is a stress state where the stress is parallel or tangential to a face of the material, as opposed to normal stress when the stress is perpendicular to the face. The variable used to denote shear stress is <math>\tau\,</math> (tau).
Physical quantities of shear stress are measured in force divided by area. In SI, the unit is the pascal (Pa) or newtons per square meter. In United States customary units, shear stress is also commonly measured in pounds-force per square inch or kilopounds-force per square inch. The area is always the area resisting the shear, and not the area that the force is acting upon. These two areas are always at right angles.
There are two forms of shear stress: direct shear and beam shear.
# Direct Shear
The formula for shear stress in a direct shear is:
where
Structural members that are often considered to be in pure shear stress are riveted and bolted joints. For bolts and rivets the two plates must be touching, and locked together for the pure shear case to apply. Welds may also be subjected to pure shear stress depending on the location and loading. Cantilever beams, consoles and column heads are subject to composite loading, consisting of shear, tensile and compressive stress.
# Beam Shear
The formula for shear stress in a beam is:
where
# Semi-monocoque shear
Shear stresses within a semi-monocoque structure may be calculated by idealizing the cross-section of the structure into a set of stringers (carrying only axial loads) and webs (carrying only shear flows). Dividing the shear flow by the thickness of a given portion of the semi-monocoque structure yields the shear stress. Thus, the maximum shear stress will occur either in the web of maximum shear flow or minimum thickness.
Also constructions in soil can fail due to shear; e.g., the weight of an earth-filled dam or dike may cause the subsoil to collapse, like a small landslide.
Shear stress is relevant to the motion of fluids upon surfaces, which result in the generation of shear stress. Particularly, the laminar fluid flow over the surface has a zero velocity and shear stress occurs between the zero-velocity surface and the higher-velocity flow away from the surface.
# Impact Shear
The maximum shear stress created in a solid round bar subject to impact is given.
The equation is
where
and
# Shear Stress in Fluids
A viscous fluid (including air and water) moving along a solid boundary will incur a shear stress on that boundary. The no-slip condition dictates that the speed of the fluid at the boundary (relative to the boundary) is 0, but at some height from the boundary the flow speed must equal that of the fluid. The region between these two points is aptly named the boundary layer. The shear stress is imparted onto the boundary as a result of this loss of velocity and can be expressed as
where
## Diverging Fringe Shear Stress Sensor
This relationship can be exploited to measure the wall shear stress. If a sensor could directly measure the gradient of the velocity profile at the wall, then multiplying by the dynamic viscosity would yield the shear stress. Such a sensor was demonstrated by A. A. Naqwi and W. C. Reynolds[1]. The interference pattern generated by sending a beam of light through two parallel slits forms a network of linearly diverging fringes that seem to originate from the plane of the two slits (see double-slit experiment). As a particle in a fluid passes through the fringes, a receiver detects the reflection of the fringe pattern. The signal can be processed, and knowing the fringe angle, the height and velocity of the particle can be extrapolated. | https://www.wikidoc.org/index.php/Shear_(fluid) | |
4e3f7b03586f418d9fcc881c7950ca33b44afe22 | wikidoc | Shepard tone | Shepard tone
A Shepard tone, named after Roger Shepard, is a sound consisting of a superposition of sine waves separated by octaves. When played with the base pitch of the tone moving upwards or downwards, it is referred to as the Shepard scale. This creates the auditory illusion of a tone that continually ascends or descends in pitch, yet which ultimately seems to get no higher or lower.
# Construction of a Shepard scale
The illusion can be constructed by creating a series of overlapping ascending or descending scales. Similar to the Penrose stairs optical illusion (as in M.C. Escher's lithograph Ascending and Descending) or a barber's pole, the basic concept is shown in Figure 1.
Each square in the figure indicates a tone, any set of squares in vertical alignment together making one Shepard tone. The color of each square indicates the loudness of the note, with purple being the quietest and green the loudest. Overlapping notes that play at the same time are exactly one octave apart, and each scale fades in and fades out so that hearing the beginning or end of any given scale is impossible. As a conceptual example of an ascending Shepard scale, the first tone could be an almost inaudible C(4) (middle C) and a loud C(5) (an octave higher). The next would be a slightly louder C#(4) and a slightly quieter C#(5); the next would be a still louder D(4) and a still quieter D(5). The two frequencies would be equally loud at the middle of the octave (F#), and the twelfth tone would be a loud B(4) and an almost inaudible B(5) with the addition of an almost inaudible B(3). The thirteenth tone would then be the same as the first, and the cycle could continue indefinitely. (More accurately, each tone consists of ten sine waves with frequencies separated by octaves; the intensity of each is a gaussian function of its separation in semitones from a peak frequency, which in the above example would be B(4).)
The scale as described, with discrete steps between each tone, is known as the discrete Shepard scale. The illusion is more convincing if there is a short time between successive notes (staccato or marcato instead of legato or portamento).
As a more concrete example, consider a brass trio consisting of a trumpet, a horn, and a tuba. They all start to play a repeating C scale (C-D-E-F-G-A-B-C) in their respective ranges, i.e. they all start playing C's, but their notes are all in different octaves. When they reach the G of the scale, the trumpet drops down an octave, but the horn and tuba continue climbing. They're all still playing the same pitch class, but at different octaves. When they reach the B, the horn similarly drops down an octave, but the trumpet and tuba continue to climb, and when they get to what would be the second D of the scale, the tuba drops down to repeat the last seven notes of the scale. So no instrument ever exceeds an octave range, and essentially keeps playing the exact same seven notes over and over again. But because two of the instruments are always "covering" the one that drops down an octave, it seems that the scale never stops rising.
Jean-Claude Risset subsequently created a version of the scale where the steps between each tone are continuous, and it is appropriately called the continuous Risset scale or Shepard-Risset glissando. When done correctly, the tone appears to rise (or descend) continuously in pitch, yet return to its starting note. Risset has also created a similar effect with rhythm in which tempo seems to increase or decrease endlessly.
# Shepard scales in music
Although it is difficult to recreate the illusion with acoustic instruments, James Tenney, who worked with Roger Shepard at Bell Labs in the early 1960s, has created a piece utilizing this effect, For Ann (rising). The piece, in which up to twelve closely but not quite consistently spaced computer-generated sine waves rise steadily from an A pitched below audibility to an A above, fading in, and back out, of audible volume, was then scored for twelve string players. The effect of the electronic work consists both of the Shepard scale, seamless endlessly (rising) glissandos, and of a shimmering caused by the highest perceivable frequency and the inability to focus on the multitude of rising tones. Tenney has also proposed that the piece be revised and realized so that all entrances are timed in such a way that the ratio between successive pitches is the golden mean, which would make each lower first-order combination tone of each successive pair coincide with subsequently spaced, lower, tones.
An independently discovered version of the Shepard tone appears at the beginning and end of the 1976 album A Day At The Races by the band Queen. The piece consists of a number of electric-guitar parts following each other up a scale in harmony, with the notes at the top of the scale fading out as new ones fade in at the bottom. Lose Control by Missy Elliott also seems to feature an ascending Shepard tone as a recurring theme (via the sampled synthesizers from Cybotron's song "Clear".) "Echoes", a 23-minute song by Pink Floyd, concludes with a rising Shepard tone. The Shepard tone is also featured in the fading piano outro to "A Last Straw", off Robert Wyatt's 1974 opus Rock Bottom.
Another independent discovery, in classical music, occurs in the Fantasy and Fugue in G minor for organ, BWV 542, by Bach. Following the first third movement of the Fantasy there is a descending pedal bass line under a chord sequence which traverses the circle of fifths. The gradual addition of stops up to full organ sound creates something akin to a barber-pole pattern with an illusion of ever-deeper descent, even though the bass line actually skips octaves. This effect is only possible on organs with electric consoles and would have been impossible in Bach's time, as it is hard to throw an organ stop in mid-play.
A good example in modern culture is in the video game Super Mario 64; a Shepard scale accompanies the never-ending staircase.
Antonio Carlos Jobim's Waters of March has descending orchestration that is intended to represent the continual flow of water to the ocean; the effect is very much like Shepard tones.
# Example | Shepard tone
A Shepard tone, named after Roger Shepard, is a sound consisting of a superposition of sine waves separated by octaves. When played with the base pitch of the tone moving upwards or downwards, it is referred to as the Shepard scale. This creates the auditory illusion of a tone that continually ascends or descends in pitch, yet which ultimately seems to get no higher or lower.[1]
# Construction of a Shepard scale
The illusion can be constructed by creating a series of overlapping ascending or descending scales. Similar to the Penrose stairs optical illusion (as in M.C. Escher's lithograph Ascending and Descending) or a barber's pole, the basic concept is shown in Figure 1.
Each square in the figure indicates a tone, any set of squares in vertical alignment together making one Shepard tone. The color of each square indicates the loudness of the note, with purple being the quietest and green the loudest. Overlapping notes that play at the same time are exactly one octave apart, and each scale fades in and fades out so that hearing the beginning or end of any given scale is impossible. As a conceptual example of an ascending Shepard scale, the first tone could be an almost inaudible C(4) (middle C) and a loud C(5) (an octave higher). The next would be a slightly louder C#(4) and a slightly quieter C#(5); the next would be a still louder D(4) and a still quieter D(5). The two frequencies would be equally loud at the middle of the octave (F#), and the twelfth tone would be a loud B(4) and an almost inaudible B(5) with the addition of an almost inaudible B(3). The thirteenth tone would then be the same as the first, and the cycle could continue indefinitely. (More accurately, each tone consists of ten sine waves with frequencies separated by octaves; the intensity of each is a gaussian function of its separation in semitones from a peak frequency, which in the above example would be B(4).)
The scale as described, with discrete steps between each tone, is known as the discrete Shepard scale. The illusion is more convincing if there is a short time between successive notes (staccato or marcato instead of legato or portamento).
As a more concrete example, consider a brass trio consisting of a trumpet, a horn, and a tuba. They all start to play a repeating C scale (C-D-E-F-G-A-B-C) in their respective ranges, i.e. they all start playing C's, but their notes are all in different octaves. When they reach the G of the scale, the trumpet drops down an octave, but the horn and tuba continue climbing. They're all still playing the same pitch class, but at different octaves. When they reach the B, the horn similarly drops down an octave, but the trumpet and tuba continue to climb, and when they get to what would be the second D of the scale, the tuba drops down to repeat the last seven notes of the scale. So no instrument ever exceeds an octave range, and essentially keeps playing the exact same seven notes over and over again. But because two of the instruments are always "covering" the one that drops down an octave, it seems that the scale never stops rising.
Jean-Claude Risset subsequently created a version of the scale where the steps between each tone are continuous, and it is appropriately called the continuous Risset scale or Shepard-Risset glissando. When done correctly, the tone appears to rise (or descend) continuously in pitch, yet return to its starting note. Risset has also created a similar effect with rhythm in which tempo seems to increase or decrease endlessly.[2]
# Shepard scales in music
Although it is difficult to recreate the illusion with acoustic instruments, James Tenney, who worked with Roger Shepard at Bell Labs in the early 1960s, has created a piece utilizing this effect, For Ann (rising). The piece, in which up to twelve closely but not quite consistently spaced computer-generated sine waves rise steadily from an A pitched below audibility to an A above, fading in, and back out, of audible volume, was then scored for twelve string players. The effect of the electronic work consists both of the Shepard scale, seamless endlessly (rising) glissandos, and of a shimmering caused by the highest perceivable frequency and the inability to focus on the multitude of rising tones. Tenney has also proposed that the piece be revised and realized so that all entrances are timed in such a way that the ratio between successive pitches is the golden mean, which would make each lower first-order combination tone of each successive pair coincide with subsequently spaced, lower, tones.
An independently discovered version of the Shepard tone appears at the beginning and end of the 1976 album A Day At The Races by the band Queen. The piece consists of a number of electric-guitar parts following each other up a scale in harmony, with the notes at the top of the scale fading out as new ones fade in at the bottom. Lose Control by Missy Elliott also seems to feature an ascending Shepard tone as a recurring theme (via the sampled synthesizers from Cybotron's song "Clear".) "Echoes", a 23-minute song by Pink Floyd, concludes with a rising Shepard tone. The Shepard tone is also featured in the fading piano outro to "A Last Straw", off Robert Wyatt's 1974 opus Rock Bottom.
Another independent discovery, in classical music, occurs in the Fantasy and Fugue in G minor for organ, BWV 542, by Bach. Following the first third movement of the Fantasy there is a descending pedal bass line under a chord sequence which traverses the circle of fifths. The gradual addition of stops up to full organ sound creates something akin to a barber-pole pattern with an illusion of ever-deeper descent, even though the bass line actually skips octaves. This effect is only possible on organs with electric consoles and would have been impossible in Bach's time, as it is hard to throw an organ stop in mid-play[citation needed].
A good example in modern culture is in the video game Super Mario 64; a Shepard scale accompanies the never-ending staircase.
Antonio Carlos Jobim's Waters of March has descending orchestration that is intended to represent the continual flow of water to the ocean; the effect is very much like Shepard tones.
# Example
Template:Multi-listen start
Template:Multi-listen item
Template:Multi-listen end | https://www.wikidoc.org/index.php/Shepard_tone | |
fdd982ae95e403d15cc3d8681e96b317b08a4dd4 | wikidoc | Sialoadhesin | Sialoadhesin
Sialoadhesin is a cell adhesion molecule found on the surface of macrophages. It is found in especially high amounts on macrophages of the spleen, liver, lymph node, bone marrow, colon, and lungs. Also, in patients suffering from rheumatoid arthritis, the protein has been found in great amounts on macrophages of the affected tissues. It is defined as an I-type lectin, since it contains 17 immunoglobulin (Ig) domains (one variable domain and 16 constant domains), and thus also belongs to the immunoglobulin superfamily (IgSF). Sialoadhesin binds to certain molecules called sialic acids. During this binding process a salt bridge (protein) is formed between a highly conserved arginine residue (from the v-set domain to the 3'-sialyllactose) and the carboxylate group of the sialic acid. Since sialoadhesin binds sialic acids with its N-terminal IgV-domain, it is also a member of the SIGLEC family. Alternate names for sialoadhesin include siglec-1 and CD169 (cluster of differentiation 169).
Sialoadhesin predominantly binds neutrophils, but can also bind monocytes, natural killer cells, B cells and a subset of cytotoxic T cells by interacting with sialic acid molecules in the ligands on their surfaces.
Sialaodhesin (CD169) positive macrophages, along with mesenchymal stem cells and beta-adrenergic neurons, form the hematopoietic stem cell niche in the bone marrow. CD169+ macrophages mediate signaling between the various cells and seem to promote hematopoietic stem cell retention to the niche. | Sialoadhesin
Sialoadhesin is a cell adhesion molecule found on the surface of macrophages. It is found in especially high amounts on macrophages of the spleen, liver, lymph node, bone marrow, colon, and lungs. Also, in patients suffering from rheumatoid arthritis, the protein has been found in great amounts on macrophages of the affected tissues.[2] It is defined as an I-type lectin, since it contains 17 immunoglobulin (Ig) domains (one variable domain and 16 constant domains), and thus also belongs to the immunoglobulin superfamily (IgSF). Sialoadhesin binds to certain molecules called sialic acids. During this binding process a salt bridge (protein) is formed between a highly conserved arginine residue (from the v-set domain to the 3'-sialyllactose) and the carboxylate group of the sialic acid.[2] Since sialoadhesin binds sialic acids with its N-terminal IgV-domain, it is also a member of the SIGLEC family. Alternate names for sialoadhesin include siglec-1 and CD169 (cluster of differentiation 169).[3]
Sialoadhesin predominantly binds neutrophils, but can also bind monocytes, natural killer cells, B cells and a subset of cytotoxic T cells by interacting with sialic acid molecules in the ligands on their surfaces.[4]
Sialaodhesin (CD169) positive macrophages, along with mesenchymal stem cells and beta-adrenergic neurons, form the hematopoietic stem cell niche in the bone marrow. CD169+ macrophages mediate signaling between the various cells and seem to promote hematopoietic stem cell retention to the niche. | https://www.wikidoc.org/index.php/Sialoadhesin | |
a715259b44bd98b74cea8fc6e0094778a628110a | wikidoc | Silent birth | Silent birth
Silent birth, sometimes known as quiet birth, is a birthing procedure advised by L. Ron Hubbard and advocated by Scientologists in which "everyone attending the birth should refrain from spoken words as much as possible" and where "... chatty doctors and nurses, shouts to 'PUSH, PUSH' and loud or laughing remarks to 'encourage' are avoided".
Scientology doctrine also bars poking or prodding of the newborn for medical tests; in 2004, Scientologists Ray and Louise Spiering went to federal court to argue that Nebraska's mandatory blood test for infants would violate their right to practice the "Silent Birth Method" of their religion. According to the lawsuit, "... every effort should be made to avoid subjecting the baby to loud sounds, talking, stress or pain during the first seven days of the baby's life ... Because a baby goes through so much pain during the birth process, Scientologists believe that a newborn baby should not be subjected to any further pain or significant sensory experiences."
According to Scientology doctrine, this is because "any words spoken are recorded in the reactive mind and can have an aberrative effect on the mother and the child."
# Scientific opinion
The efficacy of silent birth has been questioned by a number of doctors and other health care professionals. Patricia Devine, MD, a maternal-fetal medicine specialist who directs the Labor and Delivery Unit at Columbia University Medical Center, said, "There's absolutely no scientific evidence that taking away at the time of delivery will have any effect on outcome for the baby or mother."
When asked if there was any medical evidence that indicated that silent birth was beneficial, Damian Alagia, MD, associate clinical professor in the department of obstetrics and gynecology at George Washington University Medical Center, replied, "It may be in the Scientology literature, but it's not in the scientific literature. In my understanding, L. Ron Hubbard never spent any time in medical school, studying pediatrics or studying neonatal development. To think that a baby born in silence is going to do any better than a baby born, say, listening to Hank Williams is just foolhardy."
Other medical experts recommend against silent births as they are believed to hinder the bonding that normally occurs between mother and child in the first week of an infant's life.
# Katie Holmes
The "silent birth" became a source of media interest when it was known that outspoken Scientologist actor Tom Cruise and recently-converted, new wife Katie Holmes were expecting a child; reports that the couple would follow the practice of silent birth were denied, until photos were taken of large placards being delivered to the couple's mansion bearing instructions for the silent birth, such as "Be silent and make all physical movements slow and understandable."
It was often reported in the media during this time that speaking to the infant during the first week of its life was barred by Scientology doctrine as well. A Church spokesperson termed this "a total fabrication." The Church of Scientology International writes, "L. Ron Hubbard never wrote that parents should not speak to their child for seven days following birth". This same website also says, "The idea of silent birth is based on L. Ron Hubbard’s research into the mind and spirit. He found that words spoken during moments of pain and unconsciousness can have adverse effects on an individual later in life". It then says, "Mothers naturally want to give their baby the best possible start in life and thus keep the birth as quiet as possible". | Silent birth
Silent birth, sometimes known as quiet birth, is a birthing procedure advised by L. Ron Hubbard and advocated by Scientologists in which "everyone attending the birth should refrain from spoken words as much as possible" and where "... chatty doctors and nurses, shouts to 'PUSH, PUSH' and loud or laughing remarks to 'encourage' are avoided". [1]
Scientology doctrine also bars poking or prodding of the newborn for medical tests[citation needed]; in 2004, Scientologists Ray and Louise Spiering went to federal court to argue that Nebraska's mandatory blood test for infants would violate their right to practice the "Silent Birth Method" of their religion. According to the lawsuit, "... every effort should be made to avoid subjecting the baby to loud sounds, talking, stress or pain during the first seven days of the baby's life ... Because a baby goes through so much pain during the birth process, Scientologists believe that a newborn baby should not be subjected to any further pain or significant sensory experiences."[2]
According to Scientology doctrine, this is because "any words spoken are recorded in the reactive mind and can have an aberrative effect on the mother and the child."[1]
# Scientific opinion
The efficacy of silent birth has been questioned by a number of doctors and other health care professionals. Patricia Devine, MD, a maternal-fetal medicine specialist who directs the Labor and Delivery Unit at Columbia University Medical Center, said, "There's absolutely no scientific evidence that taking [noise] away at the time of delivery will have any effect on outcome for the baby or mother."[3]
When asked if there was any medical evidence that indicated that silent birth was beneficial, Damian Alagia, MD, associate clinical professor in the department of obstetrics and gynecology at George Washington University Medical Center, replied, "It may be in the Scientology literature, but it's not in the scientific literature. In my understanding, L. Ron Hubbard never spent any time in medical school, studying pediatrics or studying neonatal development. To think that a baby born in silence is going to do any better than a baby born, say, listening to Hank Williams is just foolhardy."[3]
Other medical experts recommend against silent births as they are believed to hinder the bonding that normally occurs between mother and child in the first week of an infant's life.[4]
# Katie Holmes
The "silent birth" became a source of media interest when it was known that outspoken Scientologist actor Tom Cruise and recently-converted, new wife Katie Holmes were expecting a child; reports that the couple would follow the practice of silent birth were denied, until photos were taken of large placards being delivered to the couple's mansion bearing instructions for the silent birth, such as "Be silent and make all physical movements slow and understandable."[5]
It was often reported in the media during this time that speaking to the infant during the first week of its life was barred by Scientology doctrine as well.[6] A Church spokesperson termed this "a total fabrication." The Church of Scientology International writes, "L. Ron Hubbard never wrote that parents should not speak to their child for seven days following birth".[7] This same website also says, "The idea of silent birth is based on L. Ron Hubbard’s research into the mind and spirit. He found that words spoken during moments of pain and unconsciousness can have adverse effects on an individual later in life".[7] It then says, "Mothers naturally want to give their baby the best possible start in life and thus keep the birth as quiet as possible".[7] | https://www.wikidoc.org/index.php/Silent_birth | |
3cdd7b62cdeaf37f41e504896bd9cf491c86eb5d | wikidoc | Silicic acid | Silicic acid
Silicic acid is a general name for a family of chemical compounds of the element silicon, hydrogen, and oxygen, with the general formula n. Some simple silicic acids have been identified in very dilute aqueous solution, such as metasilicic acid (H2SiO3), orthosilicic acid (H4SiO4, pKa1=9.84, pKa2=13.2 at 25° C), disilicic acid (H2Si2O5), and pyrosilicic acid (H6Si2O7); however in the solid state these probably condense to form polymeric silicic acids of complex structure.
Silicic acids may be formed by acidification of silicate salts (such as sodium silicate) in aqueous solution. When heated they lose water to form silica gel, an active form of silicon dioxide.
In the oceans, silicon exists primarily as orthosilicic acid (H4SiO4), and its biogeochemical cycle is regulated by the group of algae known as the diatoms. These algae polymerise the silicic acid to so-called biogenic silica, used to construct their cell walls (called frustules).
Continuing research of the correlation of aluminium and Alzheimer's disease has in the last few years included the use of silicic acid in beverages, due to its abilities to both reduce aluminium uptake in the digestive system as well as cause renal excretion of aluminium.
Orthosilicic acid is the form predominantly absorbed by humans and is found in numerous tissues including bone, tendons, aorta, liver and kidney. Compelling data suggest that silica is essential for health although no RDI has been established. However, deficiency induces deformities in skull and peripheral bones, poorly formed joints, reduced contents of cartilage, collagen, and disruption of mineral balance in the femur and vertebrae.
Choline-stabilized orthosilicic acid is bioavailable nutritional supplement. It has been shown to stimulate collagen type 1 synthesis and osteoblastic differentiation in human osteoblast-like cells in vitro, improve hair tensile strength, have positive effect on skin surface and skin mechanical properties, and on brittleness of hair and nails, abate brittle nail syndrome, partially prevent femoral bone loss in the aged ovariectomized rat model, and increase collagen concentration in calves | Silicic acid
Silicic acid is a general name for a family of chemical compounds of the element silicon, hydrogen, and oxygen, with the general formula [SiOx(OH)4-2x]n. Some simple silicic acids have been identified in very dilute aqueous solution, such as metasilicic acid (H2SiO3), orthosilicic acid (H4SiO4, pKa1=9.84, pKa2=13.2 at 25° C), disilicic acid (H2Si2O5), and pyrosilicic acid (H6Si2O7); however in the solid state these probably condense to form polymeric silicic acids of complex structure.
Silicic acids may be formed by acidification of silicate salts (such as sodium silicate) in aqueous solution. When heated they lose water to form silica gel, an active form of silicon dioxide.
In the oceans, silicon exists primarily as orthosilicic acid (H4SiO4), and its biogeochemical cycle is regulated by the group of algae known as the diatoms. These algae polymerise the silicic acid to so-called biogenic silica, used to construct their cell walls (called frustules).
Continuing research of the correlation of aluminium and Alzheimer's disease has in the last few years included the use of silicic acid in beverages[1][2][3], due to its abilities to both reduce aluminium uptake in the digestive system as well as cause renal excretion of aluminium.
Orthosilicic acid is the form predominantly absorbed by humans and is found in numerous tissues including bone, tendons, aorta, liver and kidney. Compelling data suggest that silica is essential for health although no RDI has been established. However, deficiency induces deformities in skull and peripheral bones, poorly formed joints, reduced contents of cartilage, collagen, and disruption of mineral balance in the femur and vertebrae.
[4]
Choline-stabilized orthosilicic acid is bioavailable nutritional supplement. It has been shown to stimulate collagen type 1 synthesis and osteoblastic differentiation in human osteoblast-like cells in vitro[5], improve hair tensile strength[6], have positive effect on skin surface and skin mechanical properties, and on brittleness of hair and nails[7], abate brittle nail syndrome[8], partially prevent femoral bone loss in the aged ovariectomized rat model[9], and increase collagen concentration in calves
[10]. | https://www.wikidoc.org/index.php/Silicic_acid | |
8d648d37f712c364229366747fd016a47afb1205 | wikidoc | Silver oxide | Silver oxide
Silver oxide is the chemical compound with the formula Ag2O. It is a fine black or dark brown powder that is used to prepare other silver compounds.
# Preparation
Silver oxide is commercially available. It can be easily prepared by combining aqueous solutions of silver nitrate and an alkali hydroxide. Noteworthy is the fact that this reaction does not afford appreciable amounts of silver hydroxide due to the favorable energetics for the following reaction:
# Properties
Like most binary oxides, Ag2O is a three-dimensional polymer with covalent metal-oxygen bonding. It is therefore expected that Ag2O is insoluble in all solvents, except by reaction. It is also slightly soluble in aqueous solution due to the formation of the ion, Ag(OH)2– and possibly related hydrolysis products. It hydrolyzes only slightly in water (1 part in 40,000) and dissolves in ammonium hydroxide solution to give soluble derivatives.
A slurry of Ag2O is readily attacked by acids:
where HX = HF, HCl, HBr, or HI, HO2CCF3. It will also react with solutions of alkali chlorides to precipitate silver chloride, leaving a solution of the corresponding alkali hydroxide.
Like many silver compounds, silver oxide is photosensitive. It also decomposes at temperatures above 280 °C.
# Applications
Silver oxide is used in a silver-oxide battery. Silver oxide reacts easily with ligand precursors such as 1,3-disubstituted imidazolium or benzimidazolium salts to generate the corresponding N-heterocyclic carbene complexes. These silver complexes are useful as carbene-transfer agents, easily displacing labile ligands such as cyclooctadiene or acetonitrile. This is a common way of synthesizing transition metal carbene complexes. | Silver oxide
Template:Chembox new
Silver oxide is the chemical compound with the formula Ag2O. It is a fine black or dark brown powder that is used to prepare other silver compounds.
# Preparation
Silver oxide is commercially available. It can be easily prepared by combining aqueous solutions of silver nitrate and an alkali hydroxide.[1] Noteworthy is the fact that this reaction does not afford appreciable amounts of silver hydroxide due to the favorable energetics for the following reaction:[2]
# Properties
Like most binary oxides, Ag2O is a three-dimensional polymer with covalent metal-oxygen bonding. It is therefore expected that Ag2O is insoluble in all solvents,[3] except by reaction. It is also slightly soluble in aqueous solution due to the formation of the ion, Ag(OH)2– and possibly related hydrolysis products.[4] It hydrolyzes only slightly in water (1 part in 40,000) and dissolves in ammonium hydroxide solution to give soluble derivatives.
A slurry of Ag2O is readily attacked by acids:
where HX = HF, HCl, HBr, or HI, HO2CCF3. It will also react with solutions of alkali chlorides to precipitate silver chloride, leaving a solution of the corresponding alkali hydroxide.[5][4]
Like many silver compounds, silver oxide is photosensitive. It also decomposes at temperatures above 280 °C.[3]
# Applications
Silver oxide is used in a silver-oxide battery. Silver oxide reacts easily with ligand precursors such as 1,3-disubstituted imidazolium or benzimidazolium salts to generate the corresponding N-heterocyclic carbene complexes. These silver complexes are useful as carbene-transfer agents, easily displacing labile ligands such as cyclooctadiene or acetonitrile. This is a common way of synthesizing transition metal carbene complexes.[6] | https://www.wikidoc.org/index.php/Silver_oxide | |
95417e742f5cce3d3561a880e5bc43d1388f435c | wikidoc | Silver stain | Silver stain
# Overview
Silver staining is the use of silver to stain histologic sections. This kind of staining is important especially to show proteins (for example type III collagen) and DNA. It is used to show both substances inside and outside cells. Silver staining is also used in temperature gradient gel electrophoresis and in polyacrylamide gels.
Some cells are argentaffin. These reduce silver solution to metallic silver after formalin fixation. Other cells are argyrophilic. These reduce silver solution to metallic silver after being exposed to the stain that contains a reductant, for example hydroquinone or formalin.
Silver nitrate forms insoluble silver phosphate with phosphate ions. When subjected to a reducing agent, usually hydroquinone, it forms black elementary silver. This is used for study of formation of calcium phosphate particles during bone growth.
Silver staining is used in light microscopy. The metallic silver particles are deposited on sensitised reticulin fibres and are then easily seen in the microscopic preparations.
Silver stain aids in the perception of reticular fibers.
# Use in art
Silver staining is also a technique in traditional stained glass to produce the yellow, brown or amber shading when painting on glass. It is a technique that is often used for realistic hair colors. It was discovered in the 14th Century but was not originally used very frequently. | Silver stain
# Overview
Silver staining is the use of silver to stain histologic sections. This kind of staining is important especially to show proteins (for example type III collagen) and DNA. It is used to show both substances inside and outside cells. Silver staining is also used in temperature gradient gel electrophoresis and in polyacrylamide gels.
Some cells are argentaffin. These reduce silver solution to metallic silver after formalin fixation. Other cells are argyrophilic. These reduce silver solution to metallic silver after being exposed to the stain that contains a reductant, for example hydroquinone or formalin.
Silver nitrate forms insoluble silver phosphate with phosphate ions. When subjected to a reducing agent, usually hydroquinone, it forms black elementary silver. This is used for study of formation of calcium phosphate particles during bone growth.
Silver staining is used in light microscopy. The metallic silver particles are deposited on sensitised reticulin fibres and are then easily seen in the microscopic preparations.
Silver stain aids in the perception of reticular fibers.
# Use in art
Silver staining is also a technique in traditional stained glass to produce the yellow, brown or amber shading when painting on glass. It is a technique that is often used for realistic hair colors. It was discovered in the 14th Century but was not originally used very frequently.
# External links
- Silver Staining of Polyacrylamide Gels
- Template:LoyolaMedEd
de:Silberfärbung
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Silver_stain | |
cf86874481eca965d380f975b73e0e944a16ec17 | wikidoc | Simple stain | Simple stain
The simple stain is a cell staining technique used in microbiology to colorize cells of microbes.
# Background
Cells are normally translucent or transparent, so without colorization of the cells with a staining method, it would be difficult to see the cells if viewed using a common light microscope.
# Technique
In the simple stain technique or method, a small quantity of cells from a microbial culture or cell growth source is dispersed onto a single drop of water on a clean glass slide and allowed to air dry for 5-10 minutes or until all liquid has evaporated.
The slide is then briefly passed over a flame source (cell source facing upward)--this is called heat fixation, and helps the cells to better adhere to the glass. A dye (stain) solution such as crystal violet, safranin, or a similar dye is flooded onto the surface to cover the cells and allowed to bathe the cells for a minute or two before being rinsed or washed off. These dyes work well on bacteria because they have color-bearing ions (chromophores) that are positively charged (cationic). The slide is allowed to dry, and can then be viewed with a light or brightfield optical microscope so that the cells can be observed and studied. | Simple stain
The simple stain is a cell staining technique used in microbiology to colorize cells of microbes.
# Background
Cells are normally translucent or transparent, so without colorization of the cells with a staining method, it would be difficult to see the cells if viewed using a common light microscope.
# Technique
In the simple stain technique or method, a small quantity of cells from a microbial culture or cell growth source is dispersed onto a single drop of water on a clean glass slide and allowed to air dry for 5-10 minutes or until all liquid has evaporated.
The slide is then briefly passed over a flame source (cell source facing upward)--this is called heat fixation, and helps the cells to better adhere to the glass. A dye (stain) solution such as crystal violet, safranin, or a similar dye is flooded onto the surface to cover the cells and allowed to bathe the cells for a minute or two before being rinsed or washed off. These dyes work well on bacteria because they have color-bearing ions (chromophores) that are positively charged (cationic). The slide is allowed to dry, and can then be viewed with a light or brightfield optical microscope so that the cells can be observed and studied.
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Simple_stain | |
ed98adb35649bf70db57a30c1b7167020a8b4e4a | wikidoc | Ski sickness | Ski sickness
Ski sickness is a form of motion sickness suffered by some skiers when weather conditions are bad. Poor visibility in heavy fog can bring on the condition. Symptoms are similar to other sicknesses brought on by motion, namely dizziness, headaches and nausea and in more extreme cases vomiting.
In these whiteout conditions the brain is unable to accurately determine orientation or movement. The condition is caused by the rhythmic turning motion of skiing and other effects such as a reduction in sensory feedback from constrained feet.
Rudolf Häusler of the University of Berne thinks that ski sickness could affect up to 10% of skiers.
Professor Häusler found that over-the-counter prescription medicines for motion sickness relieved the symptoms for most sufferers. | Ski sickness
Ski sickness is a form of motion sickness suffered by some skiers when weather conditions are bad. Poor visibility in heavy fog can bring on the condition. Symptoms are similar to other sicknesses brought on by motion, namely dizziness, headaches and nausea and in more extreme cases vomiting.[1]
In these whiteout conditions the brain is unable to accurately determine orientation or movement. The condition is caused by the rhythmic turning motion of skiing and other effects such as a reduction in sensory feedback from constrained feet.[2]
Rudolf Häusler of the University of Berne thinks that ski sickness could affect up to 10% of skiers.[1]
Professor Häusler found that over-the-counter prescription medicines for motion sickness relieved the symptoms for most sufferers. | https://www.wikidoc.org/index.php/Ski_sickness | |
8452dccea29eedef8e7af20cb551bef5007a2aa1 | wikidoc | Sleepwalking | Sleepwalking
# Overview
Sleepwalking (also called somnambulism or noctambulism), under the larger category of parasomnias or sleep disorders where the sufferer engages in activities that are normally associated with wakefulness while he or she is asleep or in a sleeplike state. Sleepwalking is usually defined by, or involves the person affected apparently shifting from his or her prior sleeping position and moving around and performing normal actions as if awake (cleaning, walking and other activities). Sleepwalkers are not conscious of their actions on a level where memory of the sleepwalking episode can be recalled, and because of this, unless the sleepwalker is woken or aroused by someone else, this sleep disorder can go unnoticed. Sleepwalking is more commonly experienced in people with high levels of stress, anxiety or other psychological factors and in people with genetic factors (family history) or sometimes a combination of both.
A common misconception is that sleepwalking is an individual acting out the physical movements within a dream, but in fact sleepwalking occurs earlier on in the night when rapid eye movement (REM), or the "dream stage" of sleep, has not yet occurred.
# Explanation
A majority of people move their legs while sleeping; however, sleepwalking occurs when both legs move in synchronization, which is much less common.
Sleepwalking can affect people of any age. It generally occurs when an individual awakes suddenly from slow wave sleep (SWS, sometimes referred to as "deep sleep"); causing the sleepwalking episode. In children and young adults, up to 25% of the night is spent in SWS. However this decreases as the person ages until none can be measured in the geriatric individual. For this reason, children and young adults (or anyone else with a high amount of SWS), are more likely to be woken up and, for the same reasons, they are witnessed to have many more episodes than the older individuals.
# Statistics
- 85% of the world's population is prone to sleepwalking.
- Somewhere between 1% and 16.7% of U.S. children sleepwalk, and juveniles are seen to be those more prone to the activity.
- One study showed that the highest prevalence of sleepwalking was 16.7% for children of 11 to 12 years of age.
- Males are seen to be more likely to sleepwalk than females.
Activities such as eating, bathing, urinating, dressing, or even driving cars, whistling, engaging in sexual intercourse, and committing murder have also been recorded as taking place while the subjects are technically asleep. Contrary to popular belief, most cases of sleepwalking do not consist of walking around (without the conscious knowledge of the subject). Most cases of somnambulism occur when the person is awakened (something or someone disturbs their SWS), the person may sit up, look around and immediately go back to sleep. But these kinds of incidences are rarely noticed or reported unless recorded in a sleep clinic.
Sleepwalkers engage in their activities with their eyes open so they can navigate their surroundings, not with their eyes closed and their arms outstretched, as often parodied in cartoons and films. The victims' eyes may have a glazed or empty appearance and if questioned, the subject will be slow to answer and will be unable to respond in an intelligible manner.
# Hazards
Sleepwalkers are more likely to endanger themselves than anyone else. When sleepwalkers are a danger to themselves or others (for example, when climbing up or down steps or trying to use a potentially dangerous tool such as a stove or a knife), steering them away from the danger and back to bed is advisable. It has even been reported that people have fallen out of windows, and died, or were injured as a result. However, sleepwalkers will only engage in behaviors they normally perform when awake. Sleepwalking should not be confused with psychosis.
In some rare cases, sleepwalkers have committed a homicidal act during sleepwalking.
# Causes
## Causes by Organ System
## Causes in Alphabetical Order
# Dealing with sleepwalkers
Often the best way to deal with a sleepwalker safely is to direct him or her back to the bed. However, the person may continue getting up until he or she has accomplished the task that prompted the sleepwalking in the first place. For instance, if a sleepwalker is cleaning - a common sleepwalking activity - assisting in the cleaning may help to end the episode. Telling the person "It looks like you have cleaned it all up" can help him or her to feel as though the "necessary" task has been accomplished. As sleepwalkers do not tend to remember anything said or done while sleepwalking, there is no need to worry about embarrassment to you or the individual afterward.
Sleepwalkers are highly suggestible. Anything they hear or see may trigger another behavior. Often something said by a person or even on a television will cause the sleepwalker to engage in the activity mentioned, provided it is one to which he or she is accustomed to hearing about or doing. If the sleepwalker is also talking, it may be helpful to ask what he or she is trying to accomplish. Ask very simple questions that can be answered in short, simple replies. If asked a question that requires a long answer or explanation, the sleepwalker is unlikely to respond coherently. Talking during sleepwalking varies from person to person and may not always be useful in dealing with a sleepwalker. Because sleepwalkers are unaware of their present surroundings, they may divulge information that they would otherwise keep secret. They may also exhibit behaviors which would be considered embarrassing, such as urinating in inappropriate places, trying to eat invisible foods, cleaning invisible counters, or even trying to bathe or engage in sexual intercourse.
# Trivia
- The 19th Century German chemist and metaphysician Baron Karl Ludwig von Reichenbach made extensive studies of sleepwalkers, and used his discoveries to formulate his theory of the Odic force.
- Sleepwalking is a major theme in the classic silent German Expressionist film Das Kabinett des Dr. Kaligari (English title: The Cabinet of Dr. Caligari) 1920.
- In Shakespeare's famous play Macbeth, Lady Macbeth is mentioned to be a sleepwalker, leading up to her eventual madness and suicide.
- In Dario Argento's Phenomena (1985), the protagonist, Jennifer Corvino (Jennifer Connelly) is a sleepwalker, and witnesses one of the film's murders in her sleepwalking state.
- In the film adaption of Silent Hill, the protagonist's daughter suffers from sleepwalking, and is apparently medicated to prevent the condition. | Sleepwalking
For patient information click here
Template:DiseaseDisorder infobox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Sleepwalking (also called somnambulism or noctambulism[1]), under the larger category of parasomnias or sleep disorders where the sufferer engages in activities that are normally associated with wakefulness while he or she is asleep or in a sleeplike state. Sleepwalking is usually defined by, or involves the person affected apparently shifting from his or her prior sleeping position and moving around and performing normal actions as if awake (cleaning, walking and other activities). Sleepwalkers are not conscious of their actions on a level where memory of the sleepwalking episode can be recalled, and because of this, unless the sleepwalker is woken or aroused by someone else, this sleep disorder can go unnoticed. Sleepwalking is more commonly experienced in people with high levels of stress, anxiety or other psychological factors and in people with genetic factors (family history) or sometimes a combination of both.
A common misconception is that sleepwalking is an individual acting out the physical movements within a dream, but in fact sleepwalking occurs earlier on in the night when rapid eye movement (REM), or the "dream stage" of sleep, has not yet occurred.
# Explanation
A majority of people move their legs while sleeping; however, sleepwalking occurs when both legs move in synchronization, which is much less common.
Sleepwalking can affect people of any age. It generally occurs when an individual awakes suddenly from slow wave sleep (SWS, sometimes referred to as "deep sleep"); causing the sleepwalking episode.[citation needed] In children and young adults, up to 25% of the night is spent in SWS.[citation needed] However this decreases as the person ages until none can be measured in the geriatric individual.[citation needed] For this reason, children and young adults (or anyone else with a high amount of SWS), are more likely to be woken up and, for the same reasons, they are witnessed to have many more episodes than the older individuals.[citation needed]
# Statistics
- 85% of the world's population is prone to sleepwalking.[2][3]
- Somewhere between 1% and 16.7% of U.S. children sleepwalk, and juveniles are seen to be those more prone to the activity.[citation needed]
- One study showed that the highest prevalence of sleepwalking was 16.7% for children of 11 to 12 years of age.[citation needed]
- Males are seen to be more likely to sleepwalk than females.[2]
Activities such as eating, bathing, urinating, dressing, or even driving cars,[4] whistling, engaging in sexual intercourse,[4] and committing murder[5][6][7] have also been recorded as taking place while the subjects are technically asleep. Contrary to popular belief, most cases of sleepwalking do not consist of walking around (without the conscious knowledge of the subject). Most cases of somnambulism occur when the person is awakened (something or someone disturbs their SWS), the person may sit up, look around and immediately go back to sleep. But these kinds of incidences are rarely noticed or reported unless recorded in a sleep clinic.[citation needed]
Sleepwalkers engage in their activities with their eyes open so they can navigate their surroundings, not with their eyes closed and their arms outstretched, as often parodied in cartoons and films. The victims' eyes may have a glazed or empty appearance and if questioned, the subject will be slow to answer and will be unable to respond in an intelligible manner.
# Hazards
Sleepwalkers are more likely to endanger themselves than anyone else. When sleepwalkers are a danger to themselves or others (for example, when climbing up or down steps or trying to use a potentially dangerous tool such as a stove or a knife), steering them away from the danger and back to bed is advisable. It has even been reported that people have fallen out of windows, and died, or were injured as a result[8][citation needed]. However, sleepwalkers will only engage in behaviors they normally perform when awake. Sleepwalking should not be confused with psychosis.
In some rare cases, sleepwalkers have committed a homicidal act during sleepwalking.
# Causes
## Causes by Organ System
## Causes in Alphabetical Order
# Dealing with sleepwalkers
Often the best way to deal with a sleepwalker safely is to direct him or her back to the bed. However, the person may continue getting up until he or she has accomplished the task that prompted the sleepwalking in the first place. For instance, if a sleepwalker is cleaning - a common sleepwalking activity - assisting in the cleaning may help to end the episode. Telling the person "It looks like you have cleaned it all up" can help him or her to feel as though the "necessary" task has been accomplished. As sleepwalkers do not tend to remember anything said or done while sleepwalking, there is no need to worry about embarrassment to you or the individual afterward.
Sleepwalkers are highly suggestible. Anything they hear or see may trigger another behavior. Often something said by a person or even on a television will cause the sleepwalker to engage in the activity mentioned, provided it is one to which he or she is accustomed to hearing about or doing. If the sleepwalker is also talking, it may be helpful to ask what he or she is trying to accomplish. Ask very simple questions that can be answered in short, simple replies. If asked a question that requires a long answer or explanation, the sleepwalker is unlikely to respond coherently. Talking during sleepwalking varies from person to person and may not always be useful in dealing with a sleepwalker. Because sleepwalkers are unaware of their present surroundings, they may divulge information that they would otherwise keep secret. They may also exhibit behaviors which would be considered embarrassing, such as urinating in inappropriate places, trying to eat invisible foods, cleaning invisible counters, or even trying to bathe or engage in sexual intercourse.
# Trivia
Template:Trivia
- The 19th Century German chemist and metaphysician Baron Karl Ludwig von Reichenbach made extensive studies of sleepwalkers, and used his discoveries to formulate his theory of the Odic force.
- Sleepwalking is a major theme in the classic silent German Expressionist film Das Kabinett des Dr. Kaligari (English title: The Cabinet of Dr. Caligari) 1920.
- In Shakespeare's famous play Macbeth, Lady Macbeth is mentioned to be a sleepwalker, leading up to her eventual madness and suicide.
- In Dario Argento's Phenomena (1985), the protagonist, Jennifer Corvino (Jennifer Connelly) is a sleepwalker, and witnesses one of the film's murders in her sleepwalking state.
- In the film adaption of Silent Hill, the protagonist's daughter suffers from sleepwalking, and is apparently medicated to prevent the condition.
- | https://www.wikidoc.org/index.php/Sleepwalking | |
ca012845ced437e708fcac6f722e6996a4b1dd9a | wikidoc | Snake-Stones | Snake-Stones
Snake-Stones or Black-Stones are used to treat snake bites in many parts of the world.
# Black Stone / la Pierre Noire
Black Stone, also known as "the viper's stone, the black stone, der schwarze Stein, la pierre noire, la piedrita negra." or "serpent-stone" is used as a treatment for snake bite in Africa, South America and Asia. Although called a stone, it is made from animal bones.
Black stone is still widely used and promoted.
# Description of use
There are differing accounts of how to use a black stone. Dr. Linnea Smith reports that in Peru, "It is to be applied to the site of a poisonous snakebite and tied firmly in place. It is left there for several days, during which time it supposedly draws the venom from the wound. Once the poison is all removed, the ‘stone’ loosens of its own accord and falls off."
# Making a black stone
The steps suggested in this leaflet are:
- Choose a large dry thigh cow bone
- Cut it into small pieces
- Smooth them with sandpaper
- Wrap the pieces in foil
- Place in a charcoal fire for 15 to 20 minutes
# Views on snakestones expressed in scientific studies
- A Nigerian study recommended "education on the need to avoid the use of popular first aid measures of doubtful benefit." However the same doctors reported a year later that Black Stone may be beneficial.
- A Bolivian medical study stated that "contrary to widespread belief, no efficacy to treat envenomation may be expected of the BS" (Black Stone)
- An Indian study stated that "unscientific methods like ‘black stone’ healing contribute to the delay in seeking appropriate medical care."
- A Nigerian study found that "... black stone appears to have beneficial effects by reducing the average antivenom requirement of patients and more studies are needed ..."
# Medical policy
An International Labour Organization technical workshop stated that "Local medicine, for instance black stone for snake bites, should be provided to those working in the plantations."
In Peru, Dr. Linnea Smith reports that "despite the fact that the state nursing course book admits that no evidence has ever been produced to document the effectiveness of the black stone, each student is required to make ... one ... as a part of the first aid module."
# Snake-Stones
Snake-Stones are usually taken from the head of the snake but have been said to be extracted from the tail as well.
## Arabic
Arab writer Kazwini describes the snake stone as being the size of a small nut. An injury inflected by a venomous creature is to be immersed in warm water or sour milk, the snake stone is then dropped into the liquid which immediately draws out the poison.
# Footnotes
- ↑ Jump up to: 1.0 1.1 Wereld-Missiehulp. "BLACKSTONES" (in Dutch). Retrieved 2007-03-06.CS1 maint: Unrecognized language (link) .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}
- ↑ Jump up to: 2.0 2.1 2.2 JKA Madaki. "Abstract: Pattern of First-Aid Measures Used by Snake-bite Patients and Clinical Outcome at Zamko Comprehensive Health Centre, Langtang, Plateau State". Retrieved 2007-03-07.
- ↑ Tagne, Jean-Bruno. "Pierre noire : Cet aspirateur de venins / Black Stone: This vacuum cleaner of venoms" (in French). Retrieved 2007-03-06.CS1 maint: Unrecognized language (link)
- ↑ Jump up to: 4.0 4.1 B. Adhisivam. "Snakebite Envenomation in India: A Rural Medical Emergency". Retrieved 2007-03-06.
- ↑ CongoForum. "La pierre noire et son usage / The Black Stone and its use" (in French). Retrieved 2007-03-06.CS1 maint: Unrecognized language (link)
- ↑ Shuker, Karl P N (2007). Extraordinary Animals Revisited. CFZ Press.
- ↑ BBC News. "Search for a snakebite cure". Retrieved 2007-03-06.
- ↑ Jump up to: 8.0 8.1 Rural Extension with Africa's Poor. "Black Stone" (PDF). Retrieved 2007-03-07.
- ↑ Jump up to: 9.0 9.1 Dr. Linnea Smith. "Piedra Negra" (PDF). Retrieved 2007-03-07.
- ↑ JKA Madaki. "Abstract: Clinical Presentation And Outcome Of Snake-Bite Patients At Zamko Comprehensive Health Centre, Langtang, Plateau State". Retrieved 2007-03-08.
- ↑ Chippaux JP. "Abstract: Study of the efficacy of the black stone on envenomation by snake bite in the murine model". Retrieved 2007-03-06.
- ↑ International Labour Office. "Technical Workshop on Child Labour on Commercial Agriculture in Africa; Dar es Salaam, United Republic of Tanzania, 27-30 August 1996". Retrieved 2007-03-07. | Snake-Stones
Snake-Stones or Black-Stones are used to treat snake bites in many parts of the world.
# Black Stone / la Pierre Noire
Black Stone, also known as "the viper's stone, the black stone, der schwarze Stein, la pierre noire, la piedrita negra."[1] or "serpent-stone"[2] is used as a treatment for snake bite in Africa, South America and Asia.[3][4] Although called a stone, it is made from animal bones.[5][6]
Black stone is still widely used[7] and promoted.[1][8]
# Description of use
There are differing accounts of how to use a black stone. Dr. Linnea Smith reports that in Peru, "It [black stone] is to be applied to the site of a poisonous snakebite and tied firmly in place. It is left there for several days, during which time it supposedly draws the venom from the wound. Once the poison is all removed, the ‘stone’ loosens of its own accord and falls off."[9]
# Making a black stone
The steps suggested in this leaflet[8] are:
- Choose a large dry thigh cow bone
- Cut it into small pieces
- Smooth them with sandpaper
- Wrap the pieces in foil
- Place in a charcoal fire for 15 to 20 minutes
# Views on snakestones expressed in scientific studies
- A Nigerian study recommended "education on the need to avoid the use of popular first aid measures of doubtful benefit."[10] However the same doctors reported a year later that Black Stone may be beneficial.[2]
- A Bolivian medical study stated that "contrary to widespread belief, no efficacy to treat envenomation may be expected of the BS" (Black Stone)[11]
- An Indian study stated that "unscientific methods like ‘black stone’ healing contribute to the delay in seeking appropriate medical care."[4]
- A Nigerian study found that "... black stone appears to have beneficial effects by reducing the average antivenom requirement of patients and more studies are needed ..."[2]
# Medical policy
An International Labour Organization technical workshop stated that "Local medicine, for instance black stone for snake bites, should be provided to those working in the plantations."[12]
In Peru, Dr. Linnea Smith reports that "despite the fact that the state nursing course book admits that no evidence has ever been produced to document the effectiveness of the black stone, each student is required to make ... one ... as a part of the first aid module."[9]
# Snake-Stones
Snake-Stones are usually taken from the head of the snake but have been said to be extracted from the tail as well.
## Arabic
Arab writer Kazwini describes the snake stone as being the size of a small nut.[citation needed] An injury inflected by a venomous creature is to be immersed in warm water or sour milk, the snake stone is then dropped into the liquid which immediately draws out the poison.
# Footnotes
- ↑ Jump up to: 1.0 1.1 Wereld-Missiehulp. "BLACKSTONES" (in Dutch). Retrieved 2007-03-06.CS1 maint: Unrecognized language (link) .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}
- ↑ Jump up to: 2.0 2.1 2.2 JKA Madaki. "Abstract: Pattern of First-Aid Measures Used by Snake-bite Patients and Clinical Outcome at Zamko Comprehensive Health Centre, Langtang, Plateau State". Retrieved 2007-03-07.
- ↑ Tagne, Jean-Bruno. "Pierre noire : Cet aspirateur de venins / Black Stone: This vacuum cleaner of venoms" (in French). Retrieved 2007-03-06.CS1 maint: Unrecognized language (link)
- ↑ Jump up to: 4.0 4.1 B. Adhisivam. "Snakebite Envenomation in India: A Rural Medical Emergency". Retrieved 2007-03-06.
- ↑ CongoForum. "La pierre noire et son usage / The Black Stone and its use" (in French). Retrieved 2007-03-06.CS1 maint: Unrecognized language (link)
- ↑ Shuker, Karl P N (2007). Extraordinary Animals Revisited. CFZ Press.
- ↑ BBC News. "Search for a snakebite cure". Retrieved 2007-03-06.
- ↑ Jump up to: 8.0 8.1 Rural Extension with Africa's Poor. "Black Stone" (PDF). Retrieved 2007-03-07.
- ↑ Jump up to: 9.0 9.1 Dr. Linnea Smith. "Piedra Negra" (PDF). Retrieved 2007-03-07.
- ↑ JKA Madaki. "Abstract: Clinical Presentation And Outcome Of Snake-Bite Patients At Zamko Comprehensive Health Centre, Langtang, Plateau State". Retrieved 2007-03-08.
- ↑ Chippaux JP. "Abstract: Study of the efficacy of the black stone on envenomation by snake bite in the murine model". Retrieved 2007-03-06.
- ↑ International Labour Office. "Technical Workshop on Child Labour on Commercial Agriculture in Africa; Dar es Salaam, United Republic of Tanzania, 27-30 August 1996". Retrieved 2007-03-07.
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Snake-Stones | |
dee4f3a9bd99ddd53d6157ed35226409964f5738 | wikidoc | Snuff bottle | Snuff bottle
Snuff bottles were used by the Chinese to contain powdered tobacco during the Qing Dynasty. Smoking tobacco was illegal during the Dynasty, but the use of snuff was allowed because the Chinese considered snuff to be a remedy for common illnesses such as colds, headaches and stomach disorders. Therefore, snuff was carried in a small bottle like other medicines. Snuff bottle are comparable to the snuff box used by Europeans.
Tobacco was introduced to the court at Beijing some time during the mid to late 16th century. It was originally smoked in pipes before the establishment of the Qing Dynasty. The use of snuff and snuff bottles spread through the upper class, and by the end of the 17th century it had become a part of social ritual to use snuff. This lasted through most of the 18th century. Eventually, the trend spread into the rest of the country and into every social classe. It was common to offer a pinch of snuff as a way to greet friends and relatives. Snuff bottles soon became an object of beauty and a way to represent status. The highest status went to whomever had the rarest and finest snuff bottle. The peak of snuff bottle manufacture was during the 18th century.
The use of snuff increased and decreased with the rise and fall of the Qing Dynasty and died away soon after the establishment of the Republic of China. However, replica snuff bottles are still being made, and can be purchased in souvenir shops, flea markets and museum gift shops. Original snuff bottles from the Qing period are a desirable target for serious collectors and museums. A good bottle has an extra quality over and above its exquisite beauty and value: that is touch. Snuff bottles were made to be held and so, as a rule, they have a wonderful tactile quality, a ravishing subtlety we are, ironically, unable to experience as the best bottles are carefully locked in museum cases or in connoisseur’s collections. But even some of the more accessible bottles give an indication of this remarkable characteristic.
# Materials and size
The size of a snuff bottle is small enough to fit nicely inside the palm. Snuff bottles were made out of many different materials including porcelain, jade, ivory, wood, tortoiseshell, metal and ceramic, though probably the most commonly used material was glass. The stopper usually had a very small spoon attached for extracting the snuff. Though rare, such bottles were also used by women in Europe in Victorian times, with the bottles typically made of cut glass.
Chinese snuff bottles were typically decorated with paintings or carvings, which distinguished bottles of different quality and value. Decorative bottles were, and remain, time consuming in their production and are thus desirable for today's collectors.
# Symbolism in snuff bottle decoration
Many bottles are completely devoid of decoration, others incredibly ornate. As in all Chinese arts and craft, motifs and symbols play an important part in decorative detail. Symbols are derived from a multitude of sources such as legends, history, religion, philosophy and superstition. The ideas used are almost always directed toward bringing wealth, health, good luck, longevity, even immortality to the owner of an artefact, frequently as a wish expressed in a kind of coded form by the giver of a gift. Probably the most popular decoration is the Shou character, a symbol of happiness and longevity, illustrated at right.
Another popular device is a representation of the 18 Lohan, who were the personal disciples of Buddha, just one group of the many revered immortals in China. Apart from the 18 Lohan there is a constellation of other divines who are portrayed, even their innards. The 8 precious organs of the Buddha are venerated - his heart, gall bladder, spleen, lungs, liver, stomach, kidneys and intestines. These are rarely depicted on snuff bottles. Animals, on the other hand appear with regularity, the most common being the dragon.
A dragon is shown in the example at right on a porcelain bottle in splendid red and blue and clutching the inevitable fiery pearl. One of the traditions of Chinese art is that only the Emperor, his sons and princes of the first and second ranks were permitted to own an artefact illustrated with a dragon having five claws. Four-clawed dragons were restricted to princes of the third and fourth ranks, while the common folk had to be content with a dragon having three claws. However, it is common to find that many older bottles have dragons with five claws.
The horse is another animal frequently used in the decorative work. The horse is one of the Seven Treasures of Buddhism. Its symbolism points to speed, perseverance, rank, power and wealth. The symbolism of wealth and power obviously came about because the horse carried those of importance. In the example at right, the horse seems to be carved in a very amateurish way, but it is quickly discovered that in this school of bottle production, naivete was the style.
The hare is also often found on snuff bottles. Thhe hare represents a wish for long life and even immortality. The example at left shows a hare on a bottle made of wood.
## Other commonly used symbols
The wish for immortality is not totally fatuous since in Chinese tradition it is believed that if one attains a sufficiently high standard of morality and enlightenment, one will be become one of the immortals.
The three legged toad is interesting as it is itself mythical. It was thought to be an animated purse containing an inexhaustible supply of coins, hence it represents wealth and has become a symbol of the unattainable.
Another emblem of wealth and abundance is the fish, for obvious reasons. Being so happy with their element they also represent harmony and connubial bliss. They are used in a variety of decorative ways.
Bamboo, inevitably, is a frequent motif. Because of its durability and its being evergreen it has come, along with many other symbols, to signify longevity. It seems to me that there is something in the universal psyche that hopes for long life and I guess this why there are so many features symbolising this hoped for attribute.
The foregoing is in no way exhaustive. The symbols used are many and their meanings even more varied but this will give an introduction to what can be a fascinating study in itself.
# Inside painted bottles
Without doubt, the class of bottle that arouses most interest in the non-collector is that known as inside painted. No other type of bottle arouses as much curiosity or provokes such amazement. These are glass bottles which have pictures and often written characters painted on the inside surface of the glass.
The quality of the painting and calligraphy to be seen on many of these bottles challenges belief. It has to be remembered that these delightful scenes are, first of all, only an inch or two high and are painted whilst manipulating the brush through the neck of the bottle maybe only a quarter inch across, and also painted in reverse. One can imagine that the degree of training and practice required, not to mention patience, must quite difficult. Ursiula Bourne, in her treatise on snuff, suggests that artisans painted on their backs to make it easier to work through the narrow opening.
It has been said that a skilled artist may complete a simple bottle in a week whilst something special may take a month or more and that the best craftsmen will produce only a few bottles in a year.
The earliest inside painted bottles are thought to have been made in the period between 1820 and 1830. As, by then, the beauty of a snuff bottle was probably more important than utilitarian considerations - and filling this kind of bottle with snuff would surely damage the painting inside - few would have been used for holding snuff. Inside painted bottles are still made today - expensively for collectors and inexpensively as souvenirs.
The modern bottle at right is an interesting example. While it is beautifully painted, the picture does not have the authority of a fine artist - the subject is somewhat commonplace, but the technique is faultless. It was purchased from a Chinese dealer who visits China to buy his stock. So there is no chance of it being bought in a back street shop from someone who did not know its value. It was obviously bought and sold in the normal course of trade, with at least three profit margins - the atelier, the merchant and the dealer. Purchased new at 15 pounds sterling, it beggars belief that such quality is available at that sort of price.
At the far end of the quality scale is this masterpiece. It is signed by a well respected artist called Kuie Hsiang-Ku and is dated 1896. It is painted with consummate skill - just look at the beauty and sensitivity of the image of the grasshopper.
Like other types of snuff bottle, the range of subject matter used on inside painted bottles is without limit. There are scenes, fish, birds, poems, even portraits. They are testament to the skill and inventiveness of Chinese craftsmen.
# Notes
- ↑ Ursula bourne, Snuff, Shire Publcations, 1990, p. 24.
- ↑ Ursula bourne, Snuff, Shire Publcations, 1990, p. 24. | Snuff bottle
Template:Inappropriate tone
Snuff bottles were used by the Chinese to contain powdered tobacco during the Qing Dynasty. Smoking tobacco was illegal during the Dynasty, but the use of snuff was allowed because the Chinese considered snuff to be a remedy for common illnesses such as colds, headaches and stomach disorders. Therefore, snuff was carried in a small bottle like other medicines. Snuff bottle are comparable to the snuff box used by Europeans.
Tobacco was introduced to the court at Beijing some time during the mid to late 16th century. It was originally smoked in pipes before the establishment of the Qing Dynasty. The use of snuff and snuff bottles spread through the upper class, and by the end of the 17th century it had become a part of social ritual to use snuff. This lasted through most of the 18th century. Eventually, the trend spread into the rest of the country and into every social classe. It was common to offer a pinch of snuff as a way to greet friends and relatives. Snuff bottles soon became an object of beauty and a way to represent status. The highest status went to whomever had the rarest and finest snuff bottle. The peak of snuff bottle manufacture was during the 18th century.
The use of snuff increased and decreased with the rise and fall of the Qing Dynasty and died away soon after the establishment of the Republic of China. However, replica snuff bottles are still being made, and can be purchased in souvenir shops, flea markets and museum gift shops. Original snuff bottles from the Qing period are a desirable target for serious collectors and museums. A good bottle has an extra quality over and above its exquisite beauty and value: that is touch. Snuff bottles were made to be held and so, as a rule, they have a wonderful tactile quality, a ravishing subtlety we are, ironically, unable to experience as the best bottles are carefully locked in museum cases or in connoisseur’s collections. But even some of the more accessible bottles give an indication of this remarkable characteristic.
# Materials and size
The size of a snuff bottle is small enough to fit nicely inside the palm. Snuff bottles were made out of many different materials including porcelain, jade, ivory, wood, tortoiseshell, metal and ceramic, though probably the most commonly used material was glass. The stopper usually had a very small spoon attached for extracting the snuff. Though rare, such bottles were also used by women in Europe in Victorian times, with the bottles typically made of cut glass.
[1]
Chinese snuff bottles were typically decorated with paintings or carvings, which distinguished bottles of different quality and value. Decorative bottles were, and remain, time consuming in their production and are thus desirable for today's collectors.
# Symbolism in snuff bottle decoration
Many bottles are completely devoid of decoration, others incredibly ornate. As in all Chinese arts and craft, motifs and symbols play an important part in decorative detail. Symbols are derived from a multitude of sources such as legends, history, religion, philosophy and superstition. The ideas used are almost always directed toward bringing wealth, health, good luck, longevity, even immortality to the owner of an artefact, frequently as a wish expressed in a kind of coded form by the giver of a gift. Probably the most popular decoration is the Shou character, a symbol of happiness and longevity, illustrated at right.
Another popular device is a representation of the 18 Lohan, who were the personal disciples of Buddha, just one group of the many revered immortals in China. Apart from the 18 Lohan there is a constellation of other divines who are portrayed, even their innards. The 8 precious organs of the Buddha are venerated - his heart, gall bladder, spleen, lungs, liver, stomach, kidneys and intestines. These are rarely depicted on snuff bottles. Animals, on the other hand appear with regularity, the most common being the dragon.
A dragon is shown in the example at right on a porcelain bottle in splendid red and blue and clutching the inevitable fiery pearl. One of the traditions of Chinese art is that only the Emperor, his sons and princes of the first and second ranks were permitted to own an artefact illustrated with a dragon having five claws. Four-clawed dragons were restricted to princes of the third and fourth ranks, while the common folk had to be content with a dragon having three claws. However, it is common to find that many older bottles have dragons with five claws.
The horse is another animal frequently used in the decorative work. The horse is one of the Seven Treasures of Buddhism. Its symbolism points to speed, perseverance, rank, power and wealth. The symbolism of wealth and power obviously came about because the horse carried those of importance. In the example at right, the horse seems to be carved in a very amateurish way, but it is quickly discovered that in this school of bottle production, naivete was the style.
The hare is also often found on snuff bottles. Thhe hare represents a wish for long life and even immortality. The example at left shows a hare on a bottle made of wood.
## Other commonly used symbols
The wish for immortality is not totally fatuous since in Chinese tradition it is believed that if one attains a sufficiently high standard of morality and enlightenment, one will be become one of the immortals.
The three legged toad is interesting as it is itself mythical. It was thought to be an animated purse containing an inexhaustible supply of coins, hence it represents wealth and has become a symbol of the unattainable.
Another emblem of wealth and abundance is the fish, for obvious reasons. Being so happy with their element they also represent harmony and connubial bliss. They are used in a variety of decorative ways.
Bamboo, inevitably, is a frequent motif. Because of its durability and its being evergreen it has come, along with many other symbols, to signify longevity. It seems to me that there is something in the universal psyche that hopes for long life and I guess this why there are so many features symbolising this hoped for attribute.
The foregoing is in no way exhaustive. The symbols used are many and their meanings even more varied but this will give an introduction to what can be a fascinating study in itself.
# Inside painted bottles
Without doubt, the class of bottle that arouses most interest in the non-collector is that known as inside painted. No other type of bottle arouses as much curiosity or provokes such amazement. These are glass bottles which have pictures and often written characters painted on the inside surface of the glass.
The quality of the painting and calligraphy to be seen on many of these bottles challenges belief. It has to be remembered that these delightful scenes are, first of all, only an inch or two high and are painted whilst manipulating the brush through the neck of the bottle maybe only a quarter inch across, and also painted in reverse. One can imagine that the degree of training and practice required, not to mention patience, must quite difficult. Ursiula Bourne, in her treatise on snuff, suggests that artisans painted on their backs to make it easier to work through the narrow opening.[2]
It has been said that a skilled artist may complete a simple bottle in a week whilst something special may take a month or more and that the best craftsmen will produce only a few bottles in a year.
The earliest inside painted bottles are thought to have been made in the period between 1820 and 1830. As, by then, the beauty of a snuff bottle was probably more important than utilitarian considerations - and filling this kind of bottle with snuff would surely damage the painting inside - few would have been used for holding snuff. Inside painted bottles are still made today - expensively for collectors and inexpensively as souvenirs.
The modern bottle at right is an interesting example. While it is beautifully painted, the picture does not have the authority of a fine artist - the subject is somewhat commonplace, but the technique is faultless. It was purchased from a Chinese dealer who visits China to buy his stock. So there is no chance of it being bought in a back street shop from someone who did not know its value. It was obviously bought and sold in the normal course of trade, with at least three profit margins - the atelier, the merchant and the dealer. Purchased new at 15 pounds sterling, it beggars belief that such quality is available at that sort of price.
At the far end of the quality scale is this masterpiece. It is signed by a well respected artist called Kuie Hsiang-Ku and is dated 1896. It is painted with consummate skill - just look at the beauty and sensitivity of the image of the grasshopper.
Like other types of snuff bottle, the range of subject matter used on inside painted bottles is without limit. There are scenes, fish, birds, poems, even portraits. They are testament to the skill and inventiveness of Chinese craftsmen.
# Notes
- ↑ Ursula bourne, Snuff, Shire Publcations, 1990, p. 24.
- ↑ Ursula bourne, Snuff, Shire Publcations, 1990, p. 24.
# External links
- Hugh Moss H.K. Ltd - Chinese Snuff Bottle Manifesto - large gallery of designs
- Robert Hall Gallery
- International Chinese Snuff Bottle Society
- A dealer of Asian arts
- Asian arts information
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Snuff_bottle | |
b52abfd7c963a25c48e7b7b3839664829dd32d01 | wikidoc | Social mania | Social mania
Social manias are mass movements which periodically sweep through society, sometimes on a world wide basis. They are characterized by an outpouring of enthusiasm, mass involvement and millennialist goals. Social manias are contagious social epidemics. As social phenomena the must be differentiated from mania in individuals, the general state of frenzy, which is a defined psychiatric disease.
Social manias come in different sizes and strengths. Some social manias fail to 'catch fire', while others persist for hundreds of years (although sometimes in severely attenuated form). Common to all is a vision of salvation, a new way of life, which if realized would radically change everyday life, ushering in a new world of freedom and justice.
# Examples
In recent history, social manias have included Nazism and Communism, including such related phenomena as the Cultural Revolution, McCarthyism; Abolitionism;the Hippies, the Taiping Rebellion; the French Revolution and the current wave of religious fundamentalism, including Islamism, Christian Fundamentalism and Hindu fundamentalism.
The Taiping Rebellion is an excellent illustration, as it was both widespread and destructive and has no modern adherents to whom its use as an example would be a distraction. The Ghost dance which was briefly embraced by Native Americans of the Great Plains in 1890 is another excellent example which may be viewed in some historical perspective, as may The Crusades.
# Assessment
If social manias are to be considered as evil, it is evil that arises from a vision of the good. However, it is a good in competition with other goods, thus implying and resulting in conflict, sometimes very serious conflict resulting in the death of tens of millions of people.
# Further reading
- Jessica Stern, Terror in the Name of God: Why Religious Militants Kill, Harpercollins, August, 2003, hardcover, 400 pages, ISBN 0-06-050532-X | Social mania
Social manias are mass movements which periodically sweep through society, sometimes on a world wide basis. They are characterized by an outpouring of enthusiasm, mass involvement and millennialist goals. Social manias are contagious social epidemics. As social phenomena the must be differentiated from mania in individuals, the general state of frenzy, which is a defined psychiatric disease.
Social manias come in different sizes and strengths. Some social manias fail to 'catch fire', while others persist for hundreds of years (although sometimes in severely attenuated form). Common to all is a vision of salvation, a new way of life, which if realized would radically change everyday life, ushering in a new world of freedom and justice.
# Examples
In recent history, social manias have included Nazism and Communism, including such related phenomena as the Cultural Revolution, McCarthyism; Abolitionism;the Hippies, the Taiping Rebellion; the French Revolution and the current wave of religious fundamentalism, including Islamism, Christian Fundamentalism and Hindu fundamentalism.
The Taiping Rebellion is an excellent illustration, as it was both widespread and destructive and has no modern adherents to whom its use as an example would be a distraction. The Ghost dance which was briefly embraced by Native Americans of the Great Plains in 1890 is another excellent example which may be viewed in some historical perspective, as may The Crusades.
Template:Expand
# Assessment
If social manias are to be considered as evil, it is evil that arises from a vision of the good. However, it is a good in competition with other goods, thus implying and resulting in conflict, sometimes very serious conflict resulting in the death of tens of millions of people.
# Further reading
- Jessica Stern, Terror in the Name of God: Why Religious Militants Kill, Harpercollins, August, 2003, hardcover, 400 pages, ISBN 0-06-050532-X | https://www.wikidoc.org/index.php/Social_mania | |
8673974c5608664ac8f5acbb23124def6328e67b | wikidoc | Sodium oxide | Sodium oxide
Sodium oxide is a chemical compound with the formula Na2O. It is used in ceramics and glasses. Treatment with water affords sodium hydroxide.
The alkali metal oxides M2O (M = Na, K, Rb) crystallise in the antifluorite structure. In this motif the positions of the anions and cations are reversed relative to their positions in CaF2.
# Applications
In the typical application, glass contains around 15% sodium oxide, the other components being silicon dioxide and calcium oxide at around 70% and 9%, respectively. The soda serves as a flux to lower the temperature at which the silica melts. Soda glass has a lower melting temperature vs pure silica, and has improved mechanical properties due to its slight increases in elasticity. These changes arise because the silicon dioxide and soda react to form sodium silicates of the general formula Na2x.
Na2O forms when sodium is treated with oxygen.
Burning sodium in air will produce Na2O and about 20% sodium peroxide Na2O2.
Pure Na2O can be prepared by reaction of liquid sodium with NaNO3. | Sodium oxide
Template:Chembox new
Sodium oxide is a chemical compound with the formula Na2O. It is used in ceramics and glasses. Treatment with water affords sodium hydroxide.
The alkali metal oxides M2O (M = Na, K, Rb) crystallise in the antifluorite structure. In this motif the positions of the anions and cations are reversed relative to their positions in CaF2.[1]
# Applications
In the typical application, glass contains around 15% sodium oxide, the other components being silicon dioxide and calcium oxide at around 70% and 9%, respectively. The soda serves as a flux to lower the temperature at which the silica melts. Soda glass has a lower melting temperature vs pure silica, and has improved mechanical properties due to its slight increases in elasticity. These changes arise because the silicon dioxide and soda react to form sodium silicates of the general formula Na2[SiO2]x[SiO3].
Na2O forms when sodium is treated with oxygen.
Burning sodium in air will produce Na2O and about 20% sodium peroxide Na2O2.
Pure Na2O can be prepared by reaction of liquid sodium with NaNO3. | https://www.wikidoc.org/index.php/Sodium_oxide | |
a4ed4730115f5a0cb082f649bd7feef5b3001dd3 | wikidoc | Solriamfetol | Solriamfetol
# 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
Solriamfetol is a dopamine and norepinephrine reuptake inhibitor (DNRI) that is FDA approved for the treatment of wakefulness in adult patients with excessive daytime sleepiness associated with narcolepsy or obstructive sleep apnea (OSA). Common adverse reactions include headache, nausea, decreased appetite, insomnia, and anxiety..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Solriamfetol is indicated to improve wakefulness in adult patients with excessive daytime sleepiness associated with narcolepsy or obstructive sleep apnea (OSA).
Limitations of Use
- Solriamfetol is not indicated to treat the underlying airway obstruction in OSA. Ensure that the underlying airway obstruction is treated (e.g., with continuous positive airway pressure (CPAP)) for at least one month prior to initiating solriamfetol for excessive daytime sleepiness. Modalities to treat the underlying airway obstruction should be continued during treatment with solriamfetol. Solriamfetol is not a substitute for these modalities.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding solriamfetol Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding solriamfetol Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Safety and effectiveness in pediatric patients have not been established. Clinical studies of solriamfetol in pediatric patients have not been conducted.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding solriamfetol Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding solriamfetol Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
- Solriamfetol is contraindicated in patients receiving concomitant treatment with monoamine oxidase (MAO) inhibitors, or within 14 days following discontinuation of monoamine oxidase inhibitor, because of the risk of hypertensive reaction.
# Warnings
- Solriamfetol increases systolic blood pressure, diastolic blood pressure, and heart rate in a dose-dependent fashion.
- Epidemiological data show that chronic elevations in blood pressure increase the risk of major adverse cardiovascular events (MACE), including stroke, heart attack, and cardiovascular death. The magnitude of the increase in absolute risk is dependent on the increase in blood pressure and the underlying risk of MACE in the population being treated. Many patients with narcolepsy and OSA have multiple risk factors for MACE, including hypertension, diabetes, hyperlipidemia, and high body mass index (BMI).
- Assess blood pressure and control hypertension before initiating treatment with solriamfetol. Monitor blood pressure regularly during treatment and treat new-onset hypertension and exacerbations of pre-existing hypertension. Exercise caution when treating patients at higher risk of MACE, particularly patients with known cardiovascular and cerebrovascular disease, pre-existing hypertension, and patients with advanced age. Use caution with other drugs that increase blood pressure and heart rate.
- Periodically reassess the need for continued treatment with solriamfetol. If a patient experiences increases in blood pressure or heart rate that cannot be managed with dose reduction of solriamfetol or other appropriate medical intervention, consider discontinuation of solriamfetol.
- Patients with moderate or severe renal impairment may be at a higher risk of increases in blood pressure and heart rate because of the prolonged half-life of solriamfetol.
- Psychiatric adverse reactions have been observed in clinical trials with solriamfetol, including anxiety, insomnia, and irritability.
- Solriamfetol has not been evaluated in patients with psychosis or bipolar disorders. Exercise caution when treating patients with solriamfetol who have a history of psychosis or bipolar disorders.
- Patients with moderate or severe renal impairment may be at a higher risk of psychiatric symptoms because of the prolonged half-life of solriamfetol.
- Patients treated with solriamfetol should be observed for the possible emergence or exacerbation of psychiatric symptoms. If psychiatric symptoms develop in association with the administration of solriamfetol, consider dose reduction or discontinuation of solriamfetol.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- The safety of solriamfetol has been evaluated in 930 patients (ages 18 to 75 years) with narcolepsy or OSA. Among these patients, 396 were treated with solriamfetol in the 12-week placebo-controlled trials at doses of 37.5 mg (OSA only), 75 mg, and 150 mg once daily. Information provided below is based on the pooled 12‑week placebo‑controlled studies in patients with narcolepsy or OSA.
Most Common Adverse Reactions
- The most common adverse reactions (incidence ≥ 5% and greater than placebo) reported more frequently with the use of solriamfetol than placebo in either the narcolepsy or OSA populations were headache, nausea, decreased appetite, anxiety, and insomnia.
- Table 1 presents the adverse reactions that occurred at a rate of ≥ 2% and more frequently in solriamfetol-treated patients than in placebo-treated patients in the narcolepsy population.
- Table 2 presents the adverse reactions that occurred at a rate of ≥ 2% and more frequently in solriamfetol-treated patients than in placebo-treated patients in the OSA population.
Other Adverse Reactions Observed During the Premarketing Evaluation of solriamfetol
- Other adverse reactions of < 2% incidence but greater than placebo are shown below. The following list does not include adverse reactions: 1) already listed in previous tables or elsewhere in the labeling, 2) for which a drug cause was remote, 3) which were so general as to be uninformative, or 4) which were not considered to have clinically significant implications.
- Narcolepsy population:
Psychiatric disorders: agitation, bruxism, irritability
Respiratory, thoracic and mediastinal disorders: cough
Skin and subcutaneous tissue disorders: hyperhidrosis
General disorders and administration site conditions: feeling jittery, thirst, chest discomfort, chest pain
Investigations: weight decreased
- Psychiatric disorders: agitation, bruxism, irritability
- Respiratory, thoracic and mediastinal disorders: cough
- Skin and subcutaneous tissue disorders: hyperhidrosis
- General disorders and administration site conditions: feeling jittery, thirst, chest discomfort, chest pain
- Investigations: weight decreased
- OSA population:
Psychiatric disorders: bruxism, restlessness
Nervous system disorders: disturbances in attention, tremor
Respiratory, thoracic and mediastinal disorders: cough, dyspnea
Gastrointestinal disorders: constipation, vomiting
Investigations: weight decreased
- Psychiatric disorders: bruxism, restlessness
- Nervous system disorders: disturbances in attention, tremor
- Respiratory, thoracic and mediastinal disorders: cough, dyspnea
- Gastrointestinal disorders: constipation, vomiting
- Investigations: weight decreased
Dose-Dependent Adverse Reactions
- In the 12-week placebo-controlled clinical trials that compared doses of 37.5 mg, 75 mg, and 150 mg daily of solriamfetol to placebo, the following adverse reactions were dose-related: headache, nausea, decreased appetite, anxiety, diarrhea, and dry mouth (Table 3).
Adverse Reactions Resulting in Discontinuation of Treatment
- In the 12-week placebo-controlled clinical trials, 11 of the 396 patients (3%) who received solriamfetol discontinued because of an adverse reaction compared to 1 of the 226 patients (< 1%) who received placebo. The adverse reactions resulting in discontinuation that occurred in more than one solriamfetol-treated patient and at a higher rate than placebo were: anxiety (2/396; < 1%), palpitations (2/396; < 1%), and restlessness (2/396; < 1%).
Increases in Blood Pressure and Heart Rate
- Solriamfetol’s effects on blood pressure and heart rate are summarized below. Table 4 shows maximum mean changes in blood pressure and heart rate recorded at sessions where the Maintenance of Wakefulness Test (MWT) was administered . Table 5 summarizes 24-hour ambulatory blood pressure monitoring (ABPM) and ambulatory heart rate monitoring performed in the outpatient setting.
## Postmarketing Experience
There is limited information regarding Solriamfetol Postmarketing Experience in the drug label.
# Drug Interactions
- Do not administer solriamfetol concomitantly with MAOIs or within 14 days after discontinuing MAOI treatment. Concomitant use of MAO inhibitors and noradrenergic drugs may increase the risk of a hypertensive reaction. Potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure.
- Concomitant use of solriamfetol with other drugs that increase blood pressure and/or heart rate has not been evaluated, and such combinations should be used with caution.
- Dopaminergic drugs that increase levels of dopamine or that bind directly to dopamine receptors might result in pharmacodynamic interactions with solriamfetol. Interactions with dopaminergic drugs have not been evaluated with solriamfetol. Use caution when concomitantly administering dopaminergic drugs with solriamfetol.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Pregnancy Exposure Registry
- There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to solriamfetol during pregnancy. Healthcare providers are encouraged to register pregnant patients, or pregnant women may enroll themselves in the registry by calling 1-877-283-6220 or contacting the company at WWW.solriamfetolPREGNANCYREGISTRY.COM.
Risk Summary
- Available data from case reports are not sufficient to determine drug-associated risks of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproductive studies, oral administration of solriamfetol during organogenesis caused maternal and fetal toxicities in rats and rabbits at doses ≥ 4 and 5 times and was teratogenic at doses 19 and ≥ 5 times, respectively, the maximum recommended human dose (MRHD) of 150 mg based on mg/m2 body surface area. Oral administration of solriamfetol to pregnant rats during pregnancy and lactation at doses ≥ 7 times the MRHD based on mg/m2 body surface area resulted in maternal toxicity and adverse effects on fertility, growth, and development in offspring.
- The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2% to 4% and 15% to 20%, respectively.
Animal Data
- Solriamfetol was administered orally to pregnant rats during the period of organogenesis at 15, 67, and 295 mg/kg/day, which are approximately 1, 4, and 19 times the MRHD based on mg/m2 body surface area. Solriamfetol at ≥ 4 times the MRHD caused maternal toxicity that included hyperactivity, significant decreases in body weight, weight gain, and food consumption. Fetal toxicity at these maternally toxic doses included increased incidence of early resorption and post-implantation loss, and decreased fetal weight. Solriamfetol was teratogenic at 19 times the MRHD; it increased the incidence of fetal malformations that included severe sternebrae mal-alignment, hindlimb rotation, bent limb bones, and situs inversus. This dose was also maternally toxic. The no-adverse-effect level for malformation is 4 times and for maternal and embryofetal toxicity is approximately 1 times the MRHD based on mg/m2 body surface area.
- Solriamfetol was administered orally to pregnant rabbits during the period of organogenesis at 17, 38, and 76 mg/kg/day, which are approximately 2, 5, and 10 times the MRHD based on mg/m2 body surface area. Solriamfetol at 10 times the MRHD caused maternal toxicity of body weight loss and decreased food consumption. Solriamfetol was teratogenic at ≥ 5 times the MRHD, it caused fetal skeletal malformation (slight-to-moderate sternebrae mal-alignment) and decreased fetal weight. The no-adverse-effect level for malformation and fetal toxicity is approximately 2 times and for maternal toxicity is approximately 5 times the MRHD based on mg/m2 body surface area.
- Solriamfetol was administered orally to pregnant rats during the period of organogenesis from gestation day 7 through lactation day 20 post-partum, at 35, 110, and 350 mg/kg/day, which are approximately 2, 7, and 22 times the MRHD based on mg/m2 body surface area. At ≥ 7 times the MRHD, solriamfetol caused maternal toxicity that included decreased body weight gain, decreased food consumption, and hyperpnea. At these maternally toxic doses, fetal toxicity included increased incidence of stillbirth, postnatal pup mortality, and decreased pup weight. Developmental toxicity in offspring after lactation day 20 included decreased body weight, decreased weight gain, and delayed sexual maturation. Mating and fertility of offspring were decreased at maternal doses 22 times the MRHD without affecting learning and memory. The no-adverse-effect level for maternal and developmental toxicity is approximately 2 times the MRHD based on mg/m2 body surface area.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Solriamfetol in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Solriamfetol during labor and delivery.
### Nursing Mothers
Risk Summary
- There are no data available on the presence of solriamfetol or its metabolites in human milk, the effects on the breastfed infant, or the effect of this drug on milk production.
- Solriamfetol is present in rat milk. When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for solriamfetol and any potential adverse effects on the breastfed child from solriamfetol or from the underlying maternal condition.
Clinical Considerations
- Monitor breastfed infants for adverse reactions, such as agitation, insomnia, anorexia and reduced weight gain.
### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established. Clinical studies of solriamfetol in pediatric patients have not been conducted.
### Geriatic Use
- Of the total number of patients in the narcolepsy and OSA clinical studies treated with solriamfetol, 13% (123/930) were 65 years of age or over.
- No clinically meaningful differences in safety or effectiveness were observed between elderly and younger patients.
- Solriamfetol is predominantly eliminated by the kidney. Because elderly patients are more likely to have decreased renal function, dosing may need to be adjusted based on eGFR in these patients. Consideration should be given to the use of lower doses and close monitoring in this population.
### Gender
There is no FDA guidance on the use of Solriamfetol with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Solriamfetol with respect to specific racial populations.
### Renal Impairment
- Dosage adjustment is not required for patients with mild renal impairment (eGFR 60‑89 mL/min/1.73 m2). Dosage adjustment is recommended for patients with moderate to severe renal impairment (eGFR 15‑59 mL/min/1.73 m2). Solriamfetol is not recommended for patients with end stage renal disease (eGFR <15 mL/min/1.73 m2)
### Hepatic Impairment
There is no FDA guidance on the use of Solriamfetol in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Solriamfetol in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Solriamfetol in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Prior to initiating treatment with solriamfetol, ensure blood pressure is adequately controlled
- Administer solriamfetol orally upon awakening with or without food. Avoid taking solriamfetol within 9 hours of planned bedtime because of the potential to interfere with sleep if taken too late in the day.
- Solriamfetol 75 mg tablets are functionally scored tablets that can be split in half (37.5 mg) at the score line.
- Initiate solriamfetol at 75 mg once daily in adults with narcolepsy. The recommended dose range for solriamfetol is 75 mg to 150 mg once daily. Based on efficacy and tolerability, the dosage of solriamfetol may be doubled at intervals of at least 3 days. The maximum recommended dose is 150 mg once daily. Dosages above 150 mg daily do not confer increased effectiveness sufficient to outweigh dose-related adverse reactions.
- Initiate solriamfetol at 37.5 mg once daily in adults with OSA. The recommended dosage range for solriamfetol is 37.5 mg to 150 mg once daily. Based on efficacy and tolerability, the dosage of solriamfetol may be doubled at intervals of at least 3 days. The maximum recommended dosage is 150 mg once daily. Dosages above 150 mg daily do not confer increased effectiveness sufficient to outweigh dose-related adverse reactions.
- Moderate renal impairment (eGFR 30‑59 mL/min/1.73 m2): Initiate dosing at 37.5 mg once daily. Based on efficacy and tolerability, dose may be increased to a maximum of 75 mg once daily after at least 7 days
- Severe renal impairment (eGFR 15‑29 mL/min/1.73 m2): Administer 37.5 mg once daily. The maximum recommended daily dose is 37.5 mg
- End Stage Renal Disease (eGFR <15 mL/min/1.73 m2): solriamfetol is not recommended for use in patients with ESRD
### Monitoring
There is limited information regarding Solriamfetol Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Solriamfetol and IV administrations.
# Overdosage
- A specific reversal agent for solriamfetol is not available. Hemodialysis removed approximately 21% of a 75 mg dose in end stage renal disease patients. Overdoses should be managed with primarily supportive care, including cardiovascular monitoring.
- Consult with a Certified Poison Control Center at 1-800-222-1222 for latest recommendations.
# Pharmacology
## Mechanism of Action
- The mechanism of action of solriamfetol to improve wakefulness in patients with excessive daytime sleepiness associated with narcolepsy or obstructive sleep apnea is unclear. However, its efficacy could be mediated through its activity as a dopamine and norepinephrine reuptake inhibitor (DNRI).
## Structure
## Pharmacodynamics
- Solriamfetol binds to the dopamine transporter and norepinephrine transporter with low affinity (Ki=14.2 µM and 3.7 µM, respectively), and inhibits the reuptake of dopamine and norepinephrine with low potency (IC50 =2.9 μM and 4.4 μM, respectively). Solriamfetol has no appreciable binding affinity for the serotonin transporter (Ki=81.5 µM) and does not inhibit serotonin reuptake (IC50 > 100 μM). Solriamfetol has no appreciable binding affinity to dopamine, serotonin, norepinephrine, GABA, adenosine, histamine, orexin, benzodiazepine, muscarinic acetylcholine, or nicotinic acetylcholine receptors.
Cardiac Electrophysiology
- The effect of solriamfetol 300 mg and 900 mg (twice and six times the maximum recommended dose, respectively) on the QTc interval was evaluated in a randomized, double-blind, placebo-, and positive-controlled (moxifloxacin 400 mg), 4-period, crossover study in 60 healthy subjects. A large increase in heart rate was observed in both solriamfetol treatment groups (mean change from baseline in HR of 21 and 27 bpm in the 300 and 900 mg groups, respectively, compared with 8 bpm in the placebo group). These heart rate effects impact the interpretability of the QTc effects, particularly in the 900 mg group. In this study, solriamfetol 300 mg did not prolong the QTcF interval to a clinically relevant extent.
## Pharmacokinetics
- Solriamfetol exhibits linear kinetics over the dose range of 42 to 1008 mg (approximately 0.28 to 6.7 times the maximum recommended dosage). Steady state is reached in 3 days, and once‑daily administration is expected to result in minimal accumulation (1.06 times single‑dose exposure).
Absorption
- The oral bioavailability of solriamfetol is approximately 95%. Peak plasma concentration of solriamfetol occurs at a median Tmax of 2 hours (range 1.25 to 3.0 hours) post-dose under fasted conditions.
Effect of Food
- Ingestion of solriamfetol with a high-fat meal resulted in minimal change in Cmax and AUCinf; however, a delay of approximately 1 hour in Tmax was observed.
Distribution
- The apparent volume of distribution of solriamfetol is approximately 199 L. Plasma protein binding ranged from 13.3% to 19.4% over solriamfetol concentration range of 0.059 to 10.1 mcg/mL in human plasma. The mean blood‑to‑plasma concentration ratio ranged from 1.16 to 1.29.
Elimination
- Solriamfetol exhibits first‑order elimination after oral administration. The apparent mean elimination half‑life is about 7.1 hours.
Metabolism
- Solriamfetol is minimally metabolized in humans.
Excretion
- Approximately 95% of the dose was recovered in urine as unchanged solriamfetol, and 1% or less of the dose was recovered as the minor inactive metabolite N‑acetyl solriamfetol in a mass balance study. Renal clearance (18.2 L/h) represented the majority of apparent total clearance (19.5 L/h). Active tubular secretion is likely involved in the renal elimination of the parent drug.
Specific Populations
- Population PK analysis indicated that age, gender, and race do not have clinically relevant effects on the pharmacokinetics of solriamfetol. No dose adjustments were made in clinical studies that enrolled patients ages 65 and above.
Patients with Renal Impairment
- Exposures to solriamfetol in patients with renal impairment compared to subjects with normal renal function (eGFR ≥ 90 mL/min/1.73 m2) are summarized in Figure 1. The half‑life of solriamfetol was increased approximately 1.2‑, 1.9‑, and 3.9‑fold in patients with mild (eGFR 60‑89 mL/min/1.73 m2), moderate (eGFR 30–59 mL/min/1.73 m2), or severe (eGFR <30 mL/min/1.73 m2) renal impairment, respectively. Exposure (AUC) and half-life of solriamfetol was significantly increased in patients with ESRD (eGFR <15 mL/min/1.73 m2). An average of 21% of solriamfetol was removed by hemodialysis. In general, median Tmax values were not affected by renal impairment.
Drug Interaction Studies
In Vitro Studies
- CYP and UGT Enzymes: Solriamfetol was minimally metabolized in vitro. Solriamfetol is not an inhibitor of CYPs 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4. It does not induce CYP1A2, 2B6, 3A4, or UGT1A1 enzymes at clinically relevant concentrations.
- Transporter Systems: Solriamfetol is a low-avidity substrate of OCT2, MATE1, OCTN1, and OCTN2. Solriamfetol is a weak inhibitor of OCT2 (IC50 of 146 μM) and MATE1 (IC50 of 211 μM), and is not an inhibitor of OCT1, MATE2-K, OCTN1, or OCTN2. Solriamfetol does not appear to be a substrate or inhibitor of P-gp, BCRP, OATP1B1, OATP1B3, OAT1, or OAT3.
- Based on in vitro data, clinically significant PK drug interactions with major CYPs and transporters are not expected in patients taking solriamfetol.
## Nonclinical Toxicology
Carcinogenesis
- Solriamfetol did not increase the incidence of tumors in rats or mice treated orally for up to 101 and 104 weeks at 35, 80, and 200 mg/kg/day (rat), and 20, 65, and 200 mg/kg/day (mouse), respectively. These doses are approximately 2, 6, and 18 times (rat), and 0.4, 2.6, and 7 times (mouse) the MRHD based on AUC.
Mutagenesis
- Solriamfetol was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay or clastogenic in the in vitro mammalian chromosomal aberration assay or in the in vivo mouse bone marrow micronucleus assay.
Impairment of Fertility
- Solriamfetol did not affect fertility or sperm parameters when administered orally to male rats for 8 weeks at doses of 35 and 110 mg/kg/day, which are approximately 2 and 7 times the MRHD, based on mg/m2 body surface area. At 350 mg/kg/day, which is approximately 22 times the MRHD based on mg/m2 body surface area, solriamfetol decreased sperm count and sperm concentration without affecting fertility.
- Solriamfetol did not affect fertility when administered orally to female rats for 2 weeks premating, during mating, and through gestation day 7 at 15, 67, and 295 mg/kg/day, which are approximately 1, 4, and 19 times the MRHD, based on mg/m2 body surface area.
# Clinical Studies
- The efficacy of solriamfetol in improving wakefulness and reducing excessive daytime sleepiness was demonstrated in a 12‑week, multi‑center, randomized, double‑blind, placebo‑controlled, parallel-group study (Study 1; NCT02348593) in adult patients with a diagnosis of narcolepsy according to the ICSD‑3 or DSM‑5 criteria.
- Wakefulness and sleepiness were assessed using the Maintenance of Wakefulness Test (MWT) and the Epworth Sleepiness Scale (ESS). The MWT measures an individual’s ability to remain awake during the daytime in a darkened, quiet environment. Patients were instructed to remain awake for as long as possible during 40‑minute test sessions, and sleep latency was determined as the mean number of minutes patients could remain awake in the first four test sessions. The ESS is an 8‑item questionnaire by which patients rate their perceived likelihood of falling asleep during usual daily life activities. Change in overall symptom severity was assessed using the Patient Global Impression of Change (PGIc) scale. The PGIc is a 7‑point patient-reported scale by which patients rate their symptom change since the beginning of the study. Responses range from “very much improved” to “very much worse.” The co-primary efficacy endpoints were change from baseline in MWT and ESS at Week 12. A pre-specified secondary endpoint was percentage of subjects reported as improved (minimally, much, or very much) at Week 12 by PGIc.
- A total of 239 patients with narcolepsy were randomized to receive solriamfetol 75 mg, 150 mg, or 300 mg (two times the maximum recommended daily dose), or placebo once daily. Patients randomized to the 150-mg dose received 75 mg for the first 3 days before increasing to 150 mg.
- Demographic and baseline disease characteristics were similar for the solriamfetol and placebo groups. Median age was 34 years (range 18 to 70 years), 65% were female, 80% were Caucasian, 14% were African American, and 3% were Asian. Approximately 51% of patients had cataplexy.
- Compared to the placebo group, patients randomized to 150 mg solriamfetol showed statistically significant improvements on the MWT (treatment effect difference: 7.7 minutes, Table 6) and on the ESS (treatment effect difference: 3.8 points, Table 7) at Week 12. These effects were apparent at Week 1 and consistent with the results at Week 12. The change on percentage of subjects reported as improved by PGIc was also statistically significant compared with placebo. There were trends toward improvement in the solriamfetol 75-mg treatment group (Tables 6 and 7); however, these changes were not statistically significant. There was no evidence of differential efficacy in patients with cataplexy and patients without cataplexy. Examination of subgroups by age, race, and sex did not suggest differences in response.
- At Week 12, 150 mg of solriamfetol demonstrated improvements in wakefulness compared to placebo as assessed in test sessions 1 (approximately 1 hour post‑dose) through 5 (approximately 9 hours post‑dose) of the MWT (Figure 2). Nighttime sleep as measured with polysomnography was not affected by the use of solriamfetol in Study 1.
- The efficacy of solriamfetol in improving wakefulness and reducing excessive daytime sleepiness in patients with OSA was demonstrated in a 12-week multi‑center, randomized, double-blind, placebo‑controlled study (Study 2; NCT02348606) in adults diagnosed with OSA according to ICSD‑3 criteria. The co-primary efficacy endpoints were change from baseline in MWT and ESS at Week 12; a pre-specified secondary endpoint was percentage of subjects reported as improved (minimally, much, or very much) at Week 12 by PGIc.
- A total of 476 patients with OSA were randomized to receive solriamfetol 37.5 mg, 75 mg, 150 mg, or 300 mg (two times the maximum recommended daily dose), or placebo once daily. Patients randomized to the 150-mg dose received 75 mg for the first 3 days before increasing to 150 mg.
- Demographic and baseline disease characteristics were similar for the solriamfetol and placebo groups. Median age was 55 years (range 20 to 75 years), 37% were female, 76% were Caucasian, 19% were African American, and 4% were Asian.
- Compared to the placebo group, patients randomized to 37.5 mg, 75 mg, and 150 mg solriamfetol showed statistically significant improvements on the MWT (treatment effect difference: 4.5 minutes, 8.9 minutes, and 10.7 minutes respectively; Table 6) and ESS (treatment effect difference: 1.9 points, 1.7 points, and 4.5 points respectively; Table 7) at Week 12. These effects were apparent at Week 1 and consistent with the results at Week 12. The change on percentage of subjects reported as improved by PGIc was also statistically significant compared with placebo. Examination of subgroups by age, race, and sex did not suggest differences in response.
- At Week 12, 37.5 mg, 75 mg, and 150 mg of solriamfetol all demonstrated improvements in wakefulness compared to placebo as assessed in test sessions 1 (approximately 1 hour post‑dose) through 5 (approximately 9 hours post‑dose) of the MWT (Figure 3). Nighttime sleep as measured with polysomnography was not affected by the use of solriamfetol in Study 2. Patients’ compliance with a primary OSA therapy device was similar across the placebo and solriamfetol treatment groups at baseline, and did not change during the 12‑week study period in any treatment group.
- The maintenance of effect of solriamfetol in improving wakefulness and reducing excessive daytime sleepiness in patients with narcolepsy and OSA was assessed in two randomized‑withdrawal, placebo‑controlled studies, Study 3 (NCT02348619) and Study 4 (NCT02348632).
- Study 3 was a 6‑week, multi-center, double-blind, placebo‑controlled, randomized‑withdrawal study in 174 adult patients with a diagnosis of OSA. The co-primary efficacy endpoints were change from the beginning to the end of the randomized withdrawal period in MWT and ESS. During a 2‑week, open-label titration phase, patients were started on solriamfetol 75 mg once daily, and were titrated to the maximum tolerable dose between 75 mg and 300 mg per day (two times the maximum recommended daily dose). Patients were continued on this dose for a 2‑week stable-dose phase. At the end of the stable‑dose phase, 124 patients who reported “much” or “very much” improvement on the PGIc and who showed improvements on the MWT and ESS entered a double-blind withdrawal phase and were randomized 1:1 to either continue solriamfetol at the dose received in the stable‑dose phase or switch to placebo. Compared to patients who remained on solriamfetol, patients randomized to placebo experienced statistically significant worsening of sleepiness as measured by the MWT and ESS (Table 8).
- Study 4 was a 52‑week, open-label study in 638 patients with either narcolepsy or OSA who had completed a prior trial. During a 2‑week, open-label titration phase, patients were started on solriamfetol 75 mg once daily, and were titrated to the maximum tolerable dose between 75 mg and 300 mg per day (two times the maximum recommended daily dose). Patients remained on this dose during a subsequent open‑label treatment period of either 38 (for patients previously enrolled in Study 1 or Study 2) or 50 (all others) weeks. A 2‑week randomized‑withdrawal period was incorporated into the study. After 6 months of stable‑dose treatment, 282 patients (79 with narcolepsy; 203 with OSA) entered the randomized‑withdrawal period. Patients were randomized 1:1 to either continue to receive solriamfetol at the dose received in the maintenance phase or to switch to placebo. The primary efficacy endpoint was change from the beginning to the end of the randomized‑withdrawal period in ESS. Compared to patients who remained on solriamfetol, patients randomized to placebo experienced statistically significant worsening of sleepiness as measured by the ESS (Table 8).
# How Supplied
- Solriamfetol is packaged in 30‑count and 100‑count white, high density polyethylene (HDPE) bottles.
- Solriamfetol tablets, 75 mg ‑ dark yellow oblong tablet with “75” debossed on one side and a functional score line on the opposite side.
## Storage
- Store solriamfetol at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Potential for Abuse and Dependence
- Advise patients that solriamfetol is a federally controlled substance because it has the potential to be abused. Advise patients to keep their medication in a secure place and to dispose of unused solriamfetol as recommended in the Medication Guide.
Primary OSA Therapy Use
- Inform patients that solriamfetol is not indicated to treat the airway obstruction in OSA and they should use a primary OSA therapy, such as CPAP, as prescribed to treat the underlying obstruction. Solriamfetol is not a substitute for primary OSA therapy.
Blood Pressure and Heart Rate Increase
- Instruct patients that solriamfetol can cause elevations of their blood pressure and pulse rate and that they should be monitored for such effects.
Psychiatric Symptoms
- Instruct patients to contact their healthcare provider if they experience, anxiety, insomnia, irritability, agitation, or signs of psychosis or bipolar disorders.
Lactation
- Monitor breastfed infants for adverse reactions such as agitation, insomnia, anorexia, and reduced weight gain.
# Precautions with Alcohol
Alcohol-Solriamfetol interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
Sunosi
# Look-Alike Drug Names
There is limited information regarding Solriamfetol Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Solriamfetol
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Zach Leibowitz [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
Solriamfetol is a dopamine and norepinephrine reuptake inhibitor (DNRI) that is FDA approved for the treatment of wakefulness in adult patients with excessive daytime sleepiness associated with narcolepsy or obstructive sleep apnea (OSA). Common adverse reactions include headache, nausea, decreased appetite, insomnia, and anxiety..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Solriamfetol is indicated to improve wakefulness in adult patients with excessive daytime sleepiness associated with narcolepsy or obstructive sleep apnea (OSA).
Limitations of Use
- Solriamfetol is not indicated to treat the underlying airway obstruction in OSA. Ensure that the underlying airway obstruction is treated (e.g., with continuous positive airway pressure (CPAP)) for at least one month prior to initiating solriamfetol for excessive daytime sleepiness. Modalities to treat the underlying airway obstruction should be continued during treatment with solriamfetol. Solriamfetol is not a substitute for these modalities.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding solriamfetol Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding solriamfetol Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Safety and effectiveness in pediatric patients have not been established. Clinical studies of solriamfetol in pediatric patients have not been conducted.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding solriamfetol Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding solriamfetol Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
- Solriamfetol is contraindicated in patients receiving concomitant treatment with monoamine oxidase (MAO) inhibitors, or within 14 days following discontinuation of monoamine oxidase inhibitor, because of the risk of hypertensive reaction.
# Warnings
- Solriamfetol increases systolic blood pressure, diastolic blood pressure, and heart rate in a dose-dependent fashion.
- Epidemiological data show that chronic elevations in blood pressure increase the risk of major adverse cardiovascular events (MACE), including stroke, heart attack, and cardiovascular death. The magnitude of the increase in absolute risk is dependent on the increase in blood pressure and the underlying risk of MACE in the population being treated. Many patients with narcolepsy and OSA have multiple risk factors for MACE, including hypertension, diabetes, hyperlipidemia, and high body mass index (BMI).
- Assess blood pressure and control hypertension before initiating treatment with solriamfetol. Monitor blood pressure regularly during treatment and treat new-onset hypertension and exacerbations of pre-existing hypertension. Exercise caution when treating patients at higher risk of MACE, particularly patients with known cardiovascular and cerebrovascular disease, pre-existing hypertension, and patients with advanced age. Use caution with other drugs that increase blood pressure and heart rate.
- Periodically reassess the need for continued treatment with solriamfetol. If a patient experiences increases in blood pressure or heart rate that cannot be managed with dose reduction of solriamfetol or other appropriate medical intervention, consider discontinuation of solriamfetol.
- Patients with moderate or severe renal impairment may be at a higher risk of increases in blood pressure and heart rate because of the prolonged half-life of solriamfetol.
- Psychiatric adverse reactions have been observed in clinical trials with solriamfetol, including anxiety, insomnia, and irritability.
- Solriamfetol has not been evaluated in patients with psychosis or bipolar disorders. Exercise caution when treating patients with solriamfetol who have a history of psychosis or bipolar disorders.
- Patients with moderate or severe renal impairment may be at a higher risk of psychiatric symptoms because of the prolonged half-life of solriamfetol.
- Patients treated with solriamfetol should be observed for the possible emergence or exacerbation of psychiatric symptoms. If psychiatric symptoms develop in association with the administration of solriamfetol, consider dose reduction or discontinuation of solriamfetol.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- The safety of solriamfetol has been evaluated in 930 patients (ages 18 to 75 years) with narcolepsy or OSA. Among these patients, 396 were treated with solriamfetol in the 12-week placebo-controlled trials at doses of 37.5 mg (OSA only), 75 mg, and 150 mg once daily. Information provided below is based on the pooled 12‑week placebo‑controlled studies in patients with narcolepsy or OSA.
Most Common Adverse Reactions
- The most common adverse reactions (incidence ≥ 5% and greater than placebo) reported more frequently with the use of solriamfetol than placebo in either the narcolepsy or OSA populations were headache, nausea, decreased appetite, anxiety, and insomnia.
- Table 1 presents the adverse reactions that occurred at a rate of ≥ 2% and more frequently in solriamfetol-treated patients than in placebo-treated patients in the narcolepsy population.
- Table 2 presents the adverse reactions that occurred at a rate of ≥ 2% and more frequently in solriamfetol-treated patients than in placebo-treated patients in the OSA population.
Other Adverse Reactions Observed During the Premarketing Evaluation of solriamfetol
- Other adverse reactions of < 2% incidence but greater than placebo are shown below. The following list does not include adverse reactions: 1) already listed in previous tables or elsewhere in the labeling, 2) for which a drug cause was remote, 3) which were so general as to be uninformative, or 4) which were not considered to have clinically significant implications.
- Narcolepsy population:
Psychiatric disorders: agitation, bruxism, irritability
Respiratory, thoracic and mediastinal disorders: cough
Skin and subcutaneous tissue disorders: hyperhidrosis
General disorders and administration site conditions: feeling jittery, thirst, chest discomfort, chest pain
Investigations: weight decreased
- Psychiatric disorders: agitation, bruxism, irritability
- Respiratory, thoracic and mediastinal disorders: cough
- Skin and subcutaneous tissue disorders: hyperhidrosis
- General disorders and administration site conditions: feeling jittery, thirst, chest discomfort, chest pain
- Investigations: weight decreased
- OSA population:
Psychiatric disorders: bruxism, restlessness
Nervous system disorders: disturbances in attention, tremor
Respiratory, thoracic and mediastinal disorders: cough, dyspnea
Gastrointestinal disorders: constipation, vomiting
Investigations: weight decreased
- Psychiatric disorders: bruxism, restlessness
- Nervous system disorders: disturbances in attention, tremor
- Respiratory, thoracic and mediastinal disorders: cough, dyspnea
- Gastrointestinal disorders: constipation, vomiting
- Investigations: weight decreased
Dose-Dependent Adverse Reactions
- In the 12-week placebo-controlled clinical trials that compared doses of 37.5 mg, 75 mg, and 150 mg daily of solriamfetol to placebo, the following adverse reactions were dose-related: headache, nausea, decreased appetite, anxiety, diarrhea, and dry mouth (Table 3).
Adverse Reactions Resulting in Discontinuation of Treatment
- In the 12-week placebo-controlled clinical trials, 11 of the 396 patients (3%) who received solriamfetol discontinued because of an adverse reaction compared to 1 of the 226 patients (< 1%) who received placebo. The adverse reactions resulting in discontinuation that occurred in more than one solriamfetol-treated patient and at a higher rate than placebo were: anxiety (2/396; < 1%), palpitations (2/396; < 1%), and restlessness (2/396; < 1%).
Increases in Blood Pressure and Heart Rate
- Solriamfetol’s effects on blood pressure and heart rate are summarized below. Table 4 shows maximum mean changes in blood pressure and heart rate recorded at sessions where the Maintenance of Wakefulness Test (MWT) was administered [see Clinical Studies (14)]. Table 5 summarizes 24-hour ambulatory blood pressure monitoring (ABPM) and ambulatory heart rate monitoring performed in the outpatient setting.
## Postmarketing Experience
There is limited information regarding Solriamfetol Postmarketing Experience in the drug label.
# Drug Interactions
- Do not administer solriamfetol concomitantly with MAOIs or within 14 days after discontinuing MAOI treatment. Concomitant use of MAO inhibitors and noradrenergic drugs may increase the risk of a hypertensive reaction. Potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure.
- Concomitant use of solriamfetol with other drugs that increase blood pressure and/or heart rate has not been evaluated, and such combinations should be used with caution.
- Dopaminergic drugs that increase levels of dopamine or that bind directly to dopamine receptors might result in pharmacodynamic interactions with solriamfetol. Interactions with dopaminergic drugs have not been evaluated with solriamfetol. Use caution when concomitantly administering dopaminergic drugs with solriamfetol.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Pregnancy Exposure Registry
- There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to solriamfetol during pregnancy. Healthcare providers are encouraged to register pregnant patients, or pregnant women may enroll themselves in the registry by calling 1-877-283-6220 or contacting the company at WWW.solriamfetolPREGNANCYREGISTRY.COM.
Risk Summary
- Available data from case reports are not sufficient to determine drug-associated risks of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproductive studies, oral administration of solriamfetol during organogenesis caused maternal and fetal toxicities in rats and rabbits at doses ≥ 4 and 5 times and was teratogenic at doses 19 and ≥ 5 times, respectively, the maximum recommended human dose (MRHD) of 150 mg based on mg/m2 body surface area. Oral administration of solriamfetol to pregnant rats during pregnancy and lactation at doses ≥ 7 times the MRHD based on mg/m2 body surface area resulted in maternal toxicity and adverse effects on fertility, growth, and development in offspring.
- The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2% to 4% and 15% to 20%, respectively.
Animal Data
- Solriamfetol was administered orally to pregnant rats during the period of organogenesis at 15, 67, and 295 mg/kg/day, which are approximately 1, 4, and 19 times the MRHD based on mg/m2 body surface area. Solriamfetol at ≥ 4 times the MRHD caused maternal toxicity that included hyperactivity, significant decreases in body weight, weight gain, and food consumption. Fetal toxicity at these maternally toxic doses included increased incidence of early resorption and post-implantation loss, and decreased fetal weight. Solriamfetol was teratogenic at 19 times the MRHD; it increased the incidence of fetal malformations that included severe sternebrae mal-alignment, hindlimb rotation, bent limb bones, and situs inversus. This dose was also maternally toxic. The no-adverse-effect level for malformation is 4 times and for maternal and embryofetal toxicity is approximately 1 times the MRHD based on mg/m2 body surface area.
- Solriamfetol was administered orally to pregnant rabbits during the period of organogenesis at 17, 38, and 76 mg/kg/day, which are approximately 2, 5, and 10 times the MRHD based on mg/m2 body surface area. Solriamfetol at 10 times the MRHD caused maternal toxicity of body weight loss and decreased food consumption. Solriamfetol was teratogenic at ≥ 5 times the MRHD, it caused fetal skeletal malformation (slight-to-moderate sternebrae mal-alignment) and decreased fetal weight. The no-adverse-effect level for malformation and fetal toxicity is approximately 2 times and for maternal toxicity is approximately 5 times the MRHD based on mg/m2 body surface area.
- Solriamfetol was administered orally to pregnant rats during the period of organogenesis from gestation day 7 through lactation day 20 post-partum, at 35, 110, and 350 mg/kg/day, which are approximately 2, 7, and 22 times the MRHD based on mg/m2 body surface area. At ≥ 7 times the MRHD, solriamfetol caused maternal toxicity that included decreased body weight gain, decreased food consumption, and hyperpnea. At these maternally toxic doses, fetal toxicity included increased incidence of stillbirth, postnatal pup mortality, and decreased pup weight. Developmental toxicity in offspring after lactation day 20 included decreased body weight, decreased weight gain, and delayed sexual maturation. Mating and fertility of offspring were decreased at maternal doses 22 times the MRHD without affecting learning and memory. The no-adverse-effect level for maternal and developmental toxicity is approximately 2 times the MRHD based on mg/m2 body surface area.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Solriamfetol in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Solriamfetol during labor and delivery.
### Nursing Mothers
Risk Summary
- There are no data available on the presence of solriamfetol or its metabolites in human milk, the effects on the breastfed infant, or the effect of this drug on milk production.
- Solriamfetol is present in rat milk. When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for solriamfetol and any potential adverse effects on the breastfed child from solriamfetol or from the underlying maternal condition.
Clinical Considerations
- Monitor breastfed infants for adverse reactions, such as agitation, insomnia, anorexia and reduced weight gain.
### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established. Clinical studies of solriamfetol in pediatric patients have not been conducted.
### Geriatic Use
- Of the total number of patients in the narcolepsy and OSA clinical studies treated with solriamfetol, 13% (123/930) were 65 years of age or over.
- No clinically meaningful differences in safety or effectiveness were observed between elderly and younger patients.
- Solriamfetol is predominantly eliminated by the kidney. Because elderly patients are more likely to have decreased renal function, dosing may need to be adjusted based on eGFR in these patients. Consideration should be given to the use of lower doses and close monitoring in this population.
### Gender
There is no FDA guidance on the use of Solriamfetol with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Solriamfetol with respect to specific racial populations.
### Renal Impairment
- Dosage adjustment is not required for patients with mild renal impairment (eGFR 60‑89 mL/min/1.73 m2). Dosage adjustment is recommended for patients with moderate to severe renal impairment (eGFR 15‑59 mL/min/1.73 m2). Solriamfetol is not recommended for patients with end stage renal disease (eGFR <15 mL/min/1.73 m2)
### Hepatic Impairment
There is no FDA guidance on the use of Solriamfetol in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Solriamfetol in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Solriamfetol in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Prior to initiating treatment with solriamfetol, ensure blood pressure is adequately controlled
- Administer solriamfetol orally upon awakening with or without food. Avoid taking solriamfetol within 9 hours of planned bedtime because of the potential to interfere with sleep if taken too late in the day.
- Solriamfetol 75 mg tablets are functionally scored tablets that can be split in half (37.5 mg) at the score line.
- Initiate solriamfetol at 75 mg once daily in adults with narcolepsy. The recommended dose range for solriamfetol is 75 mg to 150 mg once daily. Based on efficacy and tolerability, the dosage of solriamfetol may be doubled at intervals of at least 3 days. The maximum recommended dose is 150 mg once daily. Dosages above 150 mg daily do not confer increased effectiveness sufficient to outweigh dose-related adverse reactions.
- Initiate solriamfetol at 37.5 mg once daily in adults with OSA. The recommended dosage range for solriamfetol is 37.5 mg to 150 mg once daily. Based on efficacy and tolerability, the dosage of solriamfetol may be doubled at intervals of at least 3 days. The maximum recommended dosage is 150 mg once daily. Dosages above 150 mg daily do not confer increased effectiveness sufficient to outweigh dose-related adverse reactions.
- Moderate renal impairment (eGFR 30‑59 mL/min/1.73 m2): Initiate dosing at 37.5 mg once daily. Based on efficacy and tolerability, dose may be increased to a maximum of 75 mg once daily after at least 7 days
- Severe renal impairment (eGFR 15‑29 mL/min/1.73 m2): Administer 37.5 mg once daily. The maximum recommended daily dose is 37.5 mg
- End Stage Renal Disease (eGFR <15 mL/min/1.73 m2): solriamfetol is not recommended for use in patients with ESRD
### Monitoring
There is limited information regarding Solriamfetol Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Solriamfetol and IV administrations.
# Overdosage
- A specific reversal agent for solriamfetol is not available. Hemodialysis removed approximately 21% of a 75 mg dose in end stage renal disease patients. Overdoses should be managed with primarily supportive care, including cardiovascular monitoring.
- Consult with a Certified Poison Control Center at 1-800-222-1222 for latest recommendations.
# Pharmacology
## Mechanism of Action
- The mechanism of action of solriamfetol to improve wakefulness in patients with excessive daytime sleepiness associated with narcolepsy or obstructive sleep apnea is unclear. However, its efficacy could be mediated through its activity as a dopamine and norepinephrine reuptake inhibitor (DNRI).
## Structure
## Pharmacodynamics
- Solriamfetol binds to the dopamine transporter and norepinephrine transporter with low affinity (Ki=14.2 µM and 3.7 µM, respectively), and inhibits the reuptake of dopamine and norepinephrine with low potency (IC50 =2.9 μM and 4.4 μM, respectively). Solriamfetol has no appreciable binding affinity for the serotonin transporter (Ki=81.5 µM) and does not inhibit serotonin reuptake (IC50 > 100 μM). Solriamfetol has no appreciable binding affinity to dopamine, serotonin, norepinephrine, GABA, adenosine, histamine, orexin, benzodiazepine, muscarinic acetylcholine, or nicotinic acetylcholine receptors.
Cardiac Electrophysiology
- The effect of solriamfetol 300 mg and 900 mg (twice and six times the maximum recommended dose, respectively) on the QTc interval was evaluated in a randomized, double-blind, placebo-, and positive-controlled (moxifloxacin 400 mg), 4-period, crossover study in 60 healthy subjects. A large increase in heart rate was observed in both solriamfetol treatment groups (mean change from baseline in HR of 21 and 27 bpm in the 300 and 900 mg groups, respectively, compared with 8 bpm in the placebo group). These heart rate effects impact the interpretability of the QTc effects, particularly in the 900 mg group. In this study, solriamfetol 300 mg did not prolong the QTcF interval to a clinically relevant extent.
## Pharmacokinetics
- Solriamfetol exhibits linear kinetics over the dose range of 42 to 1008 mg (approximately 0.28 to 6.7 times the maximum recommended dosage). Steady state is reached in 3 days, and once‑daily administration is expected to result in minimal accumulation (1.06 times single‑dose exposure).
Absorption
- The oral bioavailability of solriamfetol is approximately 95%. Peak plasma concentration of solriamfetol occurs at a median Tmax of 2 hours (range 1.25 to 3.0 hours) post-dose under fasted conditions.
Effect of Food
- Ingestion of solriamfetol with a high-fat meal resulted in minimal change in Cmax and AUCinf; however, a delay of approximately 1 hour in Tmax was observed.
Distribution
- The apparent volume of distribution of solriamfetol is approximately 199 L. Plasma protein binding ranged from 13.3% to 19.4% over solriamfetol concentration range of 0.059 to 10.1 mcg/mL in human plasma. The mean blood‑to‑plasma concentration ratio ranged from 1.16 to 1.29.
Elimination
- Solriamfetol exhibits first‑order elimination after oral administration. The apparent mean elimination half‑life is about 7.1 hours.
Metabolism
- Solriamfetol is minimally metabolized in humans.
Excretion
- Approximately 95% of the dose was recovered in urine as unchanged solriamfetol, and 1% or less of the dose was recovered as the minor inactive metabolite N‑acetyl solriamfetol in a mass balance study. Renal clearance (18.2 L/h) represented the majority of apparent total clearance (19.5 L/h). Active tubular secretion is likely involved in the renal elimination of the parent drug.
Specific Populations
- Population PK analysis indicated that age, gender, and race do not have clinically relevant effects on the pharmacokinetics of solriamfetol. No dose adjustments were made in clinical studies that enrolled patients ages 65 and above.
Patients with Renal Impairment
- Exposures to solriamfetol in patients with renal impairment compared to subjects with normal renal function (eGFR ≥ 90 mL/min/1.73 m2) are summarized in Figure 1. The half‑life of solriamfetol was increased approximately 1.2‑, 1.9‑, and 3.9‑fold in patients with mild (eGFR 60‑89 mL/min/1.73 m2), moderate (eGFR 30–59 mL/min/1.73 m2), or severe (eGFR <30 mL/min/1.73 m2) renal impairment, respectively. Exposure (AUC) and half-life of solriamfetol was significantly increased in patients with ESRD (eGFR <15 mL/min/1.73 m2). An average of 21% of solriamfetol was removed by hemodialysis. In general, median Tmax values were not affected by renal impairment.
Drug Interaction Studies
In Vitro Studies
- CYP and UGT Enzymes: Solriamfetol was minimally metabolized in vitro. Solriamfetol is not an inhibitor of CYPs 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4. It does not induce CYP1A2, 2B6, 3A4, or UGT1A1 enzymes at clinically relevant concentrations.
- Transporter Systems: Solriamfetol is a low-avidity substrate of OCT2, MATE1, OCTN1, and OCTN2. Solriamfetol is a weak inhibitor of OCT2 (IC50 of 146 μM) and MATE1 (IC50 of 211 μM), and is not an inhibitor of OCT1, MATE2-K, OCTN1, or OCTN2. Solriamfetol does not appear to be a substrate or inhibitor of P-gp, BCRP, OATP1B1, OATP1B3, OAT1, or OAT3.
- Based on in vitro data, clinically significant PK drug interactions with major CYPs and transporters are not expected in patients taking solriamfetol.
## Nonclinical Toxicology
Carcinogenesis
- Solriamfetol did not increase the incidence of tumors in rats or mice treated orally for up to 101 and 104 weeks at 35, 80, and 200 mg/kg/day (rat), and 20, 65, and 200 mg/kg/day (mouse), respectively. These doses are approximately 2, 6, and 18 times (rat), and 0.4, 2.6, and 7 times (mouse) the MRHD based on AUC.
Mutagenesis
- Solriamfetol was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay or clastogenic in the in vitro mammalian chromosomal aberration assay or in the in vivo mouse bone marrow micronucleus assay.
Impairment of Fertility
- Solriamfetol did not affect fertility or sperm parameters when administered orally to male rats for 8 weeks at doses of 35 and 110 mg/kg/day, which are approximately 2 and 7 times the MRHD, based on mg/m2 body surface area. At 350 mg/kg/day, which is approximately 22 times the MRHD based on mg/m2 body surface area, solriamfetol decreased sperm count and sperm concentration without affecting fertility.
- Solriamfetol did not affect fertility when administered orally to female rats for 2 weeks premating, during mating, and through gestation day 7 at 15, 67, and 295 mg/kg/day, which are approximately 1, 4, and 19 times the MRHD, based on mg/m2 body surface area.
# Clinical Studies
- The efficacy of solriamfetol in improving wakefulness and reducing excessive daytime sleepiness was demonstrated in a 12‑week, multi‑center, randomized, double‑blind, placebo‑controlled, parallel-group study (Study 1; NCT02348593) in adult patients with a diagnosis of narcolepsy according to the ICSD‑3 or DSM‑5 criteria.
- Wakefulness and sleepiness were assessed using the Maintenance of Wakefulness Test (MWT) and the Epworth Sleepiness Scale (ESS). The MWT measures an individual’s ability to remain awake during the daytime in a darkened, quiet environment. Patients were instructed to remain awake for as long as possible during 40‑minute test sessions, and sleep latency was determined as the mean number of minutes patients could remain awake in the first four test sessions. The ESS is an 8‑item questionnaire by which patients rate their perceived likelihood of falling asleep during usual daily life activities. Change in overall symptom severity was assessed using the Patient Global Impression of Change (PGIc) scale. The PGIc is a 7‑point patient-reported scale by which patients rate their symptom change since the beginning of the study. Responses range from “very much improved” to “very much worse.” The co-primary efficacy endpoints were change from baseline in MWT and ESS at Week 12. A pre-specified secondary endpoint was percentage of subjects reported as improved (minimally, much, or very much) at Week 12 by PGIc.
- A total of 239 patients with narcolepsy were randomized to receive solriamfetol 75 mg, 150 mg, or 300 mg (two times the maximum recommended daily dose), or placebo once daily. Patients randomized to the 150-mg dose received 75 mg for the first 3 days before increasing to 150 mg.
- Demographic and baseline disease characteristics were similar for the solriamfetol and placebo groups. Median age was 34 years (range 18 to 70 years), 65% were female, 80% were Caucasian, 14% were African American, and 3% were Asian. Approximately 51% of patients had cataplexy.
- Compared to the placebo group, patients randomized to 150 mg solriamfetol showed statistically significant improvements on the MWT (treatment effect difference: 7.7 minutes, Table 6) and on the ESS (treatment effect difference: 3.8 points, Table 7) at Week 12. These effects were apparent at Week 1 and consistent with the results at Week 12. The change on percentage of subjects reported as improved by PGIc was also statistically significant compared with placebo. There were trends toward improvement in the solriamfetol 75-mg treatment group (Tables 6 and 7); however, these changes were not statistically significant. There was no evidence of differential efficacy in patients with cataplexy and patients without cataplexy. Examination of subgroups by age, race, and sex did not suggest differences in response.
- At Week 12, 150 mg of solriamfetol demonstrated improvements in wakefulness compared to placebo as assessed in test sessions 1 (approximately 1 hour post‑dose) through 5 (approximately 9 hours post‑dose) of the MWT (Figure 2). Nighttime sleep as measured with polysomnography was not affected by the use of solriamfetol in Study 1.
- The efficacy of solriamfetol in improving wakefulness and reducing excessive daytime sleepiness in patients with OSA was demonstrated in a 12-week multi‑center, randomized, double-blind, placebo‑controlled study (Study 2; NCT02348606) in adults diagnosed with OSA according to ICSD‑3 criteria. The co-primary efficacy endpoints were change from baseline in MWT and ESS at Week 12; a pre-specified secondary endpoint was percentage of subjects reported as improved (minimally, much, or very much) at Week 12 by PGIc.
- A total of 476 patients with OSA were randomized to receive solriamfetol 37.5 mg, 75 mg, 150 mg, or 300 mg (two times the maximum recommended daily dose), or placebo once daily. Patients randomized to the 150-mg dose received 75 mg for the first 3 days before increasing to 150 mg.
- Demographic and baseline disease characteristics were similar for the solriamfetol and placebo groups. Median age was 55 years (range 20 to 75 years), 37% were female, 76% were Caucasian, 19% were African American, and 4% were Asian.
- Compared to the placebo group, patients randomized to 37.5 mg, 75 mg, and 150 mg solriamfetol showed statistically significant improvements on the MWT (treatment effect difference: 4.5 minutes, 8.9 minutes, and 10.7 minutes respectively; Table 6) and ESS (treatment effect difference: 1.9 points, 1.7 points, and 4.5 points respectively; Table 7) at Week 12. These effects were apparent at Week 1 and consistent with the results at Week 12. The change on percentage of subjects reported as improved by PGIc was also statistically significant compared with placebo. Examination of subgroups by age, race, and sex did not suggest differences in response.
- At Week 12, 37.5 mg, 75 mg, and 150 mg of solriamfetol all demonstrated improvements in wakefulness compared to placebo as assessed in test sessions 1 (approximately 1 hour post‑dose) through 5 (approximately 9 hours post‑dose) of the MWT (Figure 3). Nighttime sleep as measured with polysomnography was not affected by the use of solriamfetol in Study 2. Patients’ compliance with a primary OSA therapy device was similar across the placebo and solriamfetol treatment groups at baseline, and did not change during the 12‑week study period in any treatment group.
- The maintenance of effect of solriamfetol in improving wakefulness and reducing excessive daytime sleepiness in patients with narcolepsy and OSA was assessed in two randomized‑withdrawal, placebo‑controlled studies, Study 3 (NCT02348619) and Study 4 (NCT02348632).
- Study 3 was a 6‑week, multi-center, double-blind, placebo‑controlled, randomized‑withdrawal study in 174 adult patients with a diagnosis of OSA. The co-primary efficacy endpoints were change from the beginning to the end of the randomized withdrawal period in MWT and ESS. During a 2‑week, open-label titration phase, patients were started on solriamfetol 75 mg once daily, and were titrated to the maximum tolerable dose between 75 mg and 300 mg per day (two times the maximum recommended daily dose). Patients were continued on this dose for a 2‑week stable-dose phase. At the end of the stable‑dose phase, 124 patients who reported “much” or “very much” improvement on the PGIc and who showed improvements on the MWT and ESS entered a double-blind withdrawal phase and were randomized 1:1 to either continue solriamfetol at the dose received in the stable‑dose phase or switch to placebo. Compared to patients who remained on solriamfetol, patients randomized to placebo experienced statistically significant worsening of sleepiness as measured by the MWT and ESS (Table 8).
- Study 4 was a 52‑week, open-label study in 638 patients with either narcolepsy or OSA who had completed a prior trial. During a 2‑week, open-label titration phase, patients were started on solriamfetol 75 mg once daily, and were titrated to the maximum tolerable dose between 75 mg and 300 mg per day (two times the maximum recommended daily dose). Patients remained on this dose during a subsequent open‑label treatment period of either 38 (for patients previously enrolled in Study 1 or Study 2) or 50 (all others) weeks. A 2‑week randomized‑withdrawal period was incorporated into the study. After 6 months of stable‑dose treatment, 282 patients (79 with narcolepsy; 203 with OSA) entered the randomized‑withdrawal period. Patients were randomized 1:1 to either continue to receive solriamfetol at the dose received in the maintenance phase or to switch to placebo. The primary efficacy endpoint was change from the beginning to the end of the randomized‑withdrawal period in ESS. Compared to patients who remained on solriamfetol, patients randomized to placebo experienced statistically significant worsening of sleepiness as measured by the ESS (Table 8).
# How Supplied
- Solriamfetol is packaged in 30‑count and 100‑count white, high density polyethylene (HDPE) bottles.
- Solriamfetol tablets, 75 mg ‑ dark yellow oblong tablet with “75” debossed on one side and a functional score line on the opposite side.
## Storage
- Store solriamfetol at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Potential for Abuse and Dependence
- Advise patients that solriamfetol is a federally controlled substance because it has the potential to be abused. Advise patients to keep their medication in a secure place and to dispose of unused solriamfetol as recommended in the Medication Guide.
Primary OSA Therapy Use
- Inform patients that solriamfetol is not indicated to treat the airway obstruction in OSA and they should use a primary OSA therapy, such as CPAP, as prescribed to treat the underlying obstruction. Solriamfetol is not a substitute for primary OSA therapy.
Blood Pressure and Heart Rate Increase
- Instruct patients that solriamfetol can cause elevations of their blood pressure and pulse rate and that they should be monitored for such effects.
Psychiatric Symptoms
- Instruct patients to contact their healthcare provider if they experience, anxiety, insomnia, irritability, agitation, or signs of psychosis or bipolar disorders.
Lactation
- Monitor breastfed infants for adverse reactions such as agitation, insomnia, anorexia, and reduced weight gain.
# Precautions with Alcohol
Alcohol-Solriamfetol interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
Sunosi
# Look-Alike Drug Names
There is limited information regarding Solriamfetol Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Solriamfetol | |
000d5f3fda4c10d8d2b39109f338e72c7c27c9fe | wikidoc | Solvent drag | Solvent drag
Solvent drag is a phenomenon in renal physiology. It is when solvents in the ultrafiltrate are transported back from the renal tubule by the flow of water rather than specifically by ion pumps or other membrane transport proteins.
It generally occurs in the paracellular, rather than transcellular, pathway across the tubule cells.
It is seen e.g. in the passive transport in renal sodium reabsorption, renal chloride reabsorption as well as renal urea handling. | Solvent drag
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Solvent drag is a phenomenon in renal physiology. It is when solvents in the ultrafiltrate are transported back from the renal tubule by the flow of water rather than specifically by ion pumps or other membrane transport proteins.[1]
It generally occurs in the paracellular, rather than transcellular, pathway across the tubule cells.
It is seen e.g. in the passive transport in renal sodium reabsorption, renal chloride reabsorption as well as renal urea handling. | https://www.wikidoc.org/index.php/Solvent_drag | |
c73d5151c4b1d8d1486c2929d36bd467f110fbd3 | wikidoc | Somatic cell | Somatic cell
A somatic cell is generally taken to mean any cell forming the body of an organism: the word "somatic" is derived from the Greek word sōma (σώμα), meaning "body". Somatic cells, by definition, are not germline cells. In mammals, germline cells are the spermatozoa and ova (also known as "gametes") which fuse during fertilization to produce a cell called a zygote, from which the entire mammalian embryo develops. Every other cell type in the mammalian body—apart from the sperm and ova, the cells from which they are made (gametocytes) and undifferentiated stem cells—is a somatic cell: internal organs, skin, bones, blood, and connective tissue are all made up of somatic cells.
# Genetics and chromosome content
A simple definition of a somatic cell is that it is a non-sex cell (a very broad and not always accurate description). In humans, somatic cells contain 46 individual chromosomes, organised into 23 pairs of chromosomes. Each pair comprises a chromosome inherited from the father and the mother. Human somatic cells contain twice as many chromosomes as germline cells (sex cells). Germline cells contain only 23 chromosomes. When the germline cells meet during conception, they "fuse" together, creating a zygote. The sex of the child is dependent on the chromosome the germline cells contains (X or Y). Due to the "fusion" of the germline cells, a zygote contains 46 chromosomes (i.e. 23 pairs).
In other species, the situation is more complex. Humans, and other species whose somatic cells contain chromosomes arranged in pairs, are known as "diploid" organisms (their germline cells, which contain only single unpaired chromosomes, are known as "haploid"). However, a large number of species arrange the chromosomes in their somatic cells in fours ("tetraploid") or even sixes ("hexaploid") which means that they can have diploid or even triploid germline cells. An example of this is the modern cultivated species of wheat, Triticum Aestivum L., a hexaploid species whose somatic cells contain six copies of every chromosome. | Somatic cell
A somatic cell is generally taken to mean any cell forming the body of an organism: the word "somatic" is derived from the Greek word sōma (σώμα), meaning "body". Somatic cells, by definition, are not germline cells. In mammals, germline cells are the spermatozoa and ova (also known as "gametes") which fuse during fertilization to produce a cell called a zygote, from which the entire mammalian embryo develops. Every other cell type in the mammalian body—apart from the sperm and ova, the cells from which they are made (gametocytes) and undifferentiated stem cells—is a somatic cell: internal organs, skin, bones, blood, and connective tissue are all made up of somatic cells.
# Genetics and chromosome content
A simple definition of a somatic cell is that it is a non-sex cell (a very broad and not always accurate description). In humans, somatic cells contain 46 individual chromosomes, organised into 23 pairs of chromosomes. Each pair comprises a chromosome inherited from the father and the mother. Human somatic cells contain twice as many chromosomes as germline cells (sex cells). Germline cells contain only 23 chromosomes. When the germline cells meet during conception, they "fuse" together, creating a zygote. The sex of the child is dependent on the chromosome the germline cells contains (X or Y). Due to the "fusion" of the germline cells, a zygote contains 46 chromosomes (i.e. 23 pairs).
In other species, the situation is more complex. Humans, and other species whose somatic cells contain chromosomes arranged in pairs, are known as "diploid" organisms (their germline cells, which contain only single unpaired chromosomes, are known as "haploid"). However, a large number of species arrange the chromosomes in their somatic cells in fours ("tetraploid") or even sixes ("hexaploid") which means that they can have diploid or even triploid germline cells. An example of this is the modern cultivated species of wheat, Triticum Aestivum L., a hexaploid species whose somatic cells contain six copies of every chromosome.
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Somatic_cell | |
272a61035782a0875ada24dd63d70c94380e8de6 | wikidoc | Somatization | Somatization
# Overview
Somatization is currently defined as "a tendency to experience and communicate somatic distress in response to psychosocial stress and to seek medical help for it".
This can be, but not always, related to a psychological condition such as:
- Affective disorders (anxiety and depression)
- Somatoform disorders
The American Psychiatric Association (APA) have classified somatoform disorders in the DSM-IV
and the World Health Organization (WHO) have classified these in the ICD-10.
Both classification systems use similar criteria, though due to limited medical knowledge in psychiatric medicine, differences of opinion are expected. Most current practitioners will use one over the other, though in cases of borderline diagnoses, both may be referred to. | Somatization
Template:Search infobox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Somatization is currently defined as "a tendency to experience and communicate somatic distress in response to psychosocial stress and to seek medical help for it".[1]
This can be, but not always, related to a psychological condition such as:[2]
- Affective disorders (anxiety and depression)
- Somatoform disorders
The American Psychiatric Association (APA) have classified somatoform disorders in the DSM-IV
and the World Health Organization (WHO) have classified these in the ICD-10.
Both classification systems use similar criteria, though due to limited medical knowledge in psychiatric medicine, differences of opinion are expected. Most current practitioners will use one over the other, though in cases of borderline diagnoses, both may be referred to. | https://www.wikidoc.org/index.php/Somatisation | |
b7a5b1edf7ed22c456bbaf4216456084a6c51a70 | wikidoc | Spaceflights | Spaceflights
Manned spaceflight on an individual basis has only been achieved with experimental aircraft such as the X-15.
# Cosmic rays
"Thus far, astronauts have not been exposed to the high doses of radiation that can be received by exposure to SPE radiation , but exposure to SPE radiation will be considerably more likely for astronauts during the exploration class missions (with the necessary extended times in space travel) planned by NASA and other space agencies for the future."
# Protons
"Mice were suspended prior to and after proton radiation exposure (2 Gy dose) and total leukocyte numbers and splenic lymphocyte functionality were evaluated on days 4 or 21 after combined HU and radiation exposure. Total white blood cell (WBC), lymphocyte, neutrophil, and monocyte counts are reduced by approximately 65%, 70%, 55%, and 70%, respectively, compared to the non-treated control group at 4 days after combined exposure. Splenic lymphocyte subpopulations are altered at both time points investigated. At 21 days post-exposure to combined HU and proton radiation, T cell activation and proliferation were assessed in isolated lymphocytes. Cell surface expression of the Early Activation Marker, CD69, is decreased by 30% in the combined treatment group, compared to the non-treated control group and cell proliferation was suppressed by approximately 50%, compared to the non-treated control group. These findings reveal that the combined stressors (HU and proton radiation exposure) result in decreased leukocyte numbers and function, which could contribute to immune system dysfunction in crew members. This investigation is one of the first to report on combined proton radiation and simulated microgravity effects on hematopoietic, specifically immune cells."
"Hematological and immune system effects from ionizing radiation exposure (similar to the expected or estimated spaceflight doses) are established. Previous data indicate a dose-dependent decrease in peripheral blood cell counts, particularly lymphocytes, after whole body proton radiation exposure –. Bone marrow derived lymphocyte numbers are also decreased after whole body proton radiation exposure . Limited studies have been reported on the function and activation of lymphocytes after proton radiation exposure , and there are no available reports on lymphocyte function and activation in response to ground-based microgravity simulation with combined proton radiation exposure."
# Solar cycle effects
"Protons and heavier ions accelerated at the termination shock, after pickup from photo-ionization of interstellar gas neutrals, are called anomalous cosmic rays (ACR)."
"Near solar minimum the ACR ions, including protons, are dominant components of radiation dosage outward from ∼40 AU to the outer heliosphere, while these ions largely disappear at solar maximum. There is a 22-year cycle in the polarity of the solar dipole magnetic field, which is frozen into the solar wind plasma within several radii of the Sun and thereby carried outward into the heliosphere. Due to sign-dependent transport effects, the ACR ions accelerated at the termination shock have larger fluxes, and more positive radial gradients, at 40 to 85 AU near the Ecliptic when the solar dipole moment is directed southward (qA 0 polarity)."
# Theoretical spaceflights
Def. an "act of flight" is called flying.
Def.
- the "act of flying",
- an "instance of flying", or
- a "journey made by an aircraft, eg a balloon, plane or space shuttle, particularly one between two airports, which needs to be reserved in advance" is called a flight.
Def. a flight "into, from or through space" is called a space flight or spaceflight.
Def. any "region of space beyond limits determined with reference to boundaries of a celestial system or body, especially the region of space immediately beyond Earth's atmosphere" is called outer space.
""Flyings" could vary considerably in complexity and lavishness and could involve an actor or property being either lifted from the stage into the flies above or vice versa. As Colin Visser has observed, flyings and sinkings are both "associated with supernatural manifestations of various kinds""
# Bone mineral losses
Def. the "amount of mineral per square centimeter of" bone is called bone density (in clinical practice).
"Actual bone density would be expressed in grams per milliliter."
Areal bone mineral density "BMD (aBMD) measurements by DXA showed that cosmonauts making flights of 4- to 12-month duration on the Soviet/Russian MIR spacecraft lost bone at an average rate of 1%/month from the spine and 1.5%/month from the hip."
From "a study of crewmembers (13 males and 1 female; age range, 40–55 years) on long-duration missions (4–6 months) on the International Space Station (ISS). We used DXA to obtain aBMD of the hip and spine and volumetric QCT (vQCT) to assess integral, cortical, and trabecular volumetric BMD (vBMD) in the hip and spine. In the heel, DXA was used to measure aBMD, and quantitative ultrasound (QUS) was used to measure speed of sound (SOS) and broadband ultrasound attenuation (BUA). aBMD was lost at rates of 0.9%/month at the spine (p < 0.001) and 1.4 –1.5%/month at the hip (p < 0.001). Spinal integral vBMD was lost at a rate of 0.9%/month (p < 0.001), and trabecular vBMD was lost at 0.7%/month (p < 0.05). In contrast to earlier reports, these changes were generalized across the vertebrae and not focused in the posterior elements. In the hip, integral, cortical, and trabecular vBMD was lost at rates of 1.2–1.5%/month (p < 0.0001), 0.4–0.5%/month (p < 0.01), and 2.2–2.7%/month (p < 0.001), respectively. The cortical bone loss in the hip occurred primarily by cortical thinning. Calcaneal aBMD measurements by DXA showed smaller mean losses (0.4%/month) than hip or spine measurements, with SOS and BUA showing no change."
"Long-term spaceflights induce bone loss as a result of profound modifications of bone remodeling"
"We measured intact parathyroid hormone (PTH) and serum calcium; for bone formation, serum concentrations of bone alkaline phosphatase (BAP), intact osteocalcin (iBGP), and type 1 procollagen propeptide (PICP); for resorption, urinary concentrations (normalized by creatinine) of procollagen C-telopeptide (CTX), free and bound deoxypyridinoline (F and B D-Pyr), and Pyr in a 36-year-old cosmonaut (RTO), before (days −180, −60, and −15), during (from days 10 to 178, n = 12), and after (days +7, +15, +25, and +90) a 180-day spaceflight, in another cosmonaut (ASW) before and after the flight. Flight PTH tended to decrease by 48% and postflight PTH increased by 98%. During the flight, BAP, iBGP, and PICP decreased by 27%, 38%, and 28% respectively in CM1, and increased by 54%, 35%, and 78% after the flight. F D-Pyr and CTX increased by 54% and 78% during the flight and decreased by 29% and 40% after the flight, respectively. We showed for the first time in humans that microgravity induced an uncoupling of bone remodeling between formation and resorption that could account for bone loss."
# Carotid baroreceptor-cardiac reflexes
"Spaceflight is associated with decreased orthostatic tolerance after landing. Short-duration spaceflight (4–5 days) impairs one neural mechanism: the carotid baroreceptor-cardiac reflex. To understand the effects of longer-duration spaceflight on baroreflex function, we measured R-R interval power spectra, antecubital vein plasma catecholamine levels, carotid baroreceptor-cardiac reflex responses, responses to Valsalva maneuvers, and orthostatic tolerance in 16 astronauts before and after shuttle missions lasting 8–14 days. We found the following changes between preflight and landing day: 1) orthostatic tolerance decreased; 2) R-R interval spectral power in the 0.05 to 0.15-Hz band increased; 3) plasma norepinephrine and epinephrine levels increased; 4) the slope, range, and operational point of the carotid baroreceptor cardiac reflex response decreased; and 5) blood pressure and heart rate responses to Valsalva maneuvers were altered. Autonomic changes persisted for several days after landing."
# Immune system changes
"The results of immunological analyses before, during and after spaceflight, have established the fact that spaceflight can result in a blunting of the immune mechanisms of human crew members and animal test species. There is some evidence that the immune function changes in short-term flights resemble those occurring after acute stress, while the changes during long-term flights resemble those caused by chronic stress. In addition, this blunting of the immune function occurs concomitant with a relative increase in potentially infectious microorganisms in the space cabin environment. This combination of events results in an increased probability of inflight infectious events. The realization of this probability has been shown to be partially negated by the judicious use of a preflight health stabilization program and other operational countermeasures."
"It is now well established that spaceflight alters immune function – by mechanisms which are poorly understood. The changes in the immunological parameters studied thus far occur within a few days of exposure to the space environment. Factors in the space environment contributing to immune dysregulation during and post-spaceflight include exposure to microgravity, stress, deconditioning (reduced physical activity and shift of fluids), and radiation. Primary immune defense heavily relies on immune cell distribution and function, and is clearly influenced by a combination or synergy of any of the factors described above that exist in the space environment."
"Of the blood cell types, lymphocytes are the most sensitive to ionizing radiation exposure. T cells, or T lymphocytes, processed in the thymus, secrete lymphokines, which orchestrate signaling to lymphocytes and other immune cells to promote cell activation, proliferation, destroy target cells, and incite macrophages. Blood lymphocytes isolated from astronauts upon re-entry after a prolonged spaceflight exhibit decreased responses in mitogen reactivity, T-lymphocyte proliferation, and IL-2 production . Space laboratory studies using rat splenocytes indicate dramatic shifts in T lymphocyte subsets as well as decreased cell division in bone marrow cells post-flight . A follow up study using bone marrow cells isolated from rhesus monkeys upon landing indicated decreased cytokine production and cytokine receptor expression ."
"When human lymphocytes are exposed to microgravity in a rapidly rotating clinostat, Concanavalin A (ConA) stimulated T cell activation is depressed , . During flight, the activation of cultured human lymphocytes is depressed to less than 3% of the ground controls when exposed to ConA . Microarray analysis of T lymphocytes exposed to mitogen in a vectorless gravity environment (using a random positioning machine) revealed that early T cell activation-associated gene expression is in fact, suppressed ."
# Muscle mass losses
"Muscle strength and limb girth measurements during Skylab and Apollo missions suggested that loss of muscle mass may occur as a result of spaceflight. Extended duration spaceflight is important for the economical and practical use of space. The loss of muscle mass during spaceflight is a medical concern for long duration flights to the planets or extended stays aboard space stations. Understanding the extent and temporal relationships of muscle loss is important for the development of effective spaceflight countermeasures."
"Statistical analyses demonstrated that the soleus-gastrocnemius (-6.3%), anterior calf (-3.9%), hamstrings (-8.3%), quadriceps (-6.0%) and intrinsic back (-10.3%) muscles were decreased, p < 0.05, compared to baseline, 24 h after landing. At 2 weeks post recovery, the hamstrings and intrinsic lower back muscles were still below baseline, p < 0.05."
# Orthostatic intolerances
Def. symptoms "of cerebral hypoperfusion or autonomic overaction which develop while the subject is standing, but are relieved on recumbency" are called orthostatic intolerance.
The types of orthostatic intolerance "include NEUROCARDIOGENIC SYNCOPE; POSTURAL ORTHOSTATIC TACHYCARDIA SYNDROME; and neurogenic ORTHOSTATIC HYPOTENSION."
Def. a "transient loss of consciousness and postural tone caused by diminished blood flow to the brain" is called a syncope.
Def. loss "of consciousness due to a reduction in blood pressure that is associated with an increase in vagal tone and peripheral vasodilation" is called vasovagal syncope or neurocardiogenic syncope.
Def. a "syndrome of ORTHOSTATIC INTOLERANCE combined with excessive upright TACHYCARDIA, and usually without associated ORTHOSTATIC HYPOTENSION" is called Postural Orthostatic Tachycardia Syndrome.
"All variants have in common an excessively reduced venous return to the heart (central HYPOVOLEMIA) while upright."
Def. "a 20-mm Hg decrease in systolic pressure or a 10-mm Hg decrease in diastolic pressure 3 minutes after the person has risen from supine to standing" is called orthostatic hypotension.
"Symptoms generally include DIZZINESS, blurred vision, and SYNCOPE."
"Orthostatic intolerance occurs commonly after spaceflight, and important aspects of the underlying mechanisms remain unclear."
"After spaceflight, 9 of the 14 (64%) crew members could not complete a 10-min stand test that all completed preflight."
The "postural vasoconstrictor response was significantly greater among the finishers (P < 0.01)."
# Hypotheses
- A method to place a 5,000 kg object in orbit by using the natural electric field of the Earth may be possible.
# Acknowledgements
The content on this page was first contributed by: Henry A. Hoff.
Initial content for this page in some instances came from Wikiversity. | Spaceflights
Editor-In-Chief: Henry A. Hoff
Manned spaceflight on an individual basis has only been achieved with experimental aircraft such as the X-15.
# Cosmic rays
"Thus far, astronauts have not been exposed to the high doses of radiation that can be received by exposure to SPE radiation [47], but exposure to [solar particle event] SPE radiation will be considerably more likely for astronauts during the exploration class missions (with the necessary extended times in space travel) planned by NASA and other space agencies for the future."[1]
# Protons
"Mice were suspended prior to and after proton radiation exposure (2 Gy dose) and total leukocyte numbers and splenic lymphocyte functionality were evaluated on days 4 or 21 after combined HU and radiation exposure. Total white blood cell (WBC), lymphocyte, neutrophil, and monocyte counts are reduced by approximately 65%, 70%, 55%, and 70%, respectively, compared to the non-treated control group at 4 days after combined exposure. Splenic lymphocyte subpopulations are altered at both time points investigated. At 21 days post-exposure to combined HU and proton radiation, T cell activation and proliferation were assessed in isolated lymphocytes. Cell surface expression of the Early Activation Marker, CD69, is decreased by 30% in the combined treatment group, compared to the non-treated control group and cell proliferation was suppressed by approximately 50%, compared to the non-treated control group. These findings reveal that the combined stressors (HU and proton radiation exposure) result in decreased leukocyte numbers and function, which could contribute to immune system dysfunction in crew members. This investigation is one of the first to report on combined proton radiation and simulated microgravity effects on hematopoietic, specifically immune cells."[1]
"Hematological and immune system effects from ionizing radiation exposure (similar to the expected or estimated spaceflight doses) are established. Previous data indicate a dose-dependent decrease in peripheral blood cell counts, particularly lymphocytes, after whole body proton radiation exposure [14]–[16]. Bone marrow derived lymphocyte numbers are also decreased after whole body proton radiation exposure [17]. Limited studies have been reported on the function and activation of lymphocytes after proton radiation exposure [18], and there are no available reports on lymphocyte function and activation in response to ground-based microgravity simulation with combined proton radiation exposure."[1]
# Solar cycle effects
"Protons and heavier ions accelerated at the termination shock, after pickup from photo-ionization of interstellar gas neutrals, are called anomalous cosmic rays (ACR)."[2]
"Near solar minimum the ACR ions, including protons, are dominant components of radiation dosage outward from ∼40 AU to the outer heliosphere, while these ions largely disappear at solar maximum. There is a 22-year cycle in the polarity of the solar dipole magnetic field, which is frozen into the solar wind plasma within several radii of the Sun and thereby carried outward into the heliosphere. Due to sign-dependent transport effects, the ACR ions accelerated at the termination shock have larger fluxes, and more positive radial gradients, at 40 to 85 AU near the Ecliptic when the solar dipole moment is directed southward (qA < 0 polarity) than when it is northward (qA > 0 polarity)."[2]
# Theoretical spaceflights
Def. an "act of flight"[3] is called flying.
Def.
- the "act of flying",[4]
- an "instance of flying",[4] or
- a "journey made by an aircraft, eg a balloon, plane or space shuttle, particularly one between two airports, which needs to be reserved in advance"[4] is called a flight.
Def. a flight "into, from or through space"[5] is called a space flight or spaceflight.
Def. any "region of space beyond limits determined with reference to boundaries of a celestial system or body, especially the region of space immediately beyond Earth's atmosphere"[6] is called outer space.
""Flyings" could vary considerably in complexity and lavishness and could involve an actor or property being either lifted from the stage into the flies above or vice versa. As Colin Visser has observed, flyings and sinkings are both "associated with supernatural manifestations of various kinds""[7]
# Bone mineral losses
Def. the "amount of mineral per square centimeter of"[8] bone is called bone density (in clinical practice).
"Actual bone density would be expressed in grams per milliliter."[8]
Areal bone mineral density "BMD (aBMD) measurements by [dual energy X-ray absorptiometry] DXA showed that cosmonauts making flights of 4- to 12-month duration on the Soviet/Russian MIR spacecraft lost bone at an average rate of 1%/month from the spine and 1.5%/month from the hip."[9]
From "a study of crewmembers (13 males and 1 female; age range, 40–55 years) on long-duration missions (4–6 months) on the International Space Station (ISS). We used DXA to obtain aBMD of the hip and spine and volumetric QCT (vQCT) to assess integral, cortical, and trabecular volumetric BMD (vBMD) in the hip and spine. In the heel, DXA was used to measure aBMD, and quantitative ultrasound (QUS) was used to measure speed of sound (SOS) and broadband ultrasound attenuation (BUA). [...] aBMD was lost at rates of 0.9%/month at the spine (p < 0.001) and 1.4 –1.5%/month at the hip (p < 0.001). Spinal integral vBMD was lost at a rate of 0.9%/month (p < 0.001), and trabecular vBMD was lost at 0.7%/month (p < 0.05). In contrast to earlier reports, these changes were generalized across the vertebrae and not focused in the posterior elements. In the hip, integral, cortical, and trabecular vBMD was lost at rates of 1.2–1.5%/month (p < 0.0001), 0.4–0.5%/month (p < 0.01), and 2.2–2.7%/month (p < 0.001), respectively. The cortical bone loss in the hip occurred primarily by cortical thinning. Calcaneal aBMD measurements by DXA showed smaller mean losses (0.4%/month) than hip or spine measurements, with SOS and BUA showing no change."[9]
"Long-term spaceflights induce bone loss as a result of profound modifications of bone remodeling"[10]
"We measured intact parathyroid hormone (PTH) and serum calcium; for bone formation, serum concentrations of bone alkaline phosphatase (BAP), intact osteocalcin (iBGP), and type 1 procollagen propeptide (PICP); for resorption, urinary concentrations (normalized by creatinine) of procollagen C-telopeptide (CTX), free and bound deoxypyridinoline (F and B D-Pyr), and Pyr in a 36-year-old cosmonaut (RTO), before (days −180, −60, and −15), during (from days 10 to 178, n = 12), and after (days +7, +15, +25, and +90) a 180-day spaceflight, in another cosmonaut (ASW) before and after the flight. Flight PTH tended to decrease by 48% and postflight PTH increased by 98%. During the flight, BAP, iBGP, and PICP decreased by 27%, 38%, and 28% respectively in CM1, and increased by 54%, 35%, and 78% after the flight. F D-Pyr and CTX increased by 54% and 78% during the flight and decreased by 29% and 40% after the flight, respectively. We showed for the first time in humans that microgravity induced an uncoupling of bone remodeling between formation and resorption that could account for bone loss."[10]
# Carotid baroreceptor-cardiac reflexes
"Spaceflight is associated with decreased orthostatic tolerance after landing. Short-duration spaceflight (4–5 days) impairs one neural mechanism: the carotid baroreceptor-cardiac reflex. To understand the effects of longer-duration spaceflight on baroreflex function, we measured R-R interval power spectra, antecubital vein plasma catecholamine levels, carotid baroreceptor-cardiac reflex responses, responses to Valsalva maneuvers, and orthostatic tolerance in 16 astronauts before and after shuttle missions lasting 8–14 days. We found the following changes between preflight and landing day: 1) orthostatic tolerance decreased; 2) R-R interval spectral power in the 0.05 to 0.15-Hz band increased; 3) plasma norepinephrine and epinephrine levels increased; 4) the slope, range, and operational point of the carotid baroreceptor cardiac reflex response decreased; and 5) blood pressure and heart rate responses to Valsalva maneuvers were altered. Autonomic changes persisted for several days after landing."[11]
# Immune system changes
"The results of immunological analyses before, during and after spaceflight, have established the fact that spaceflight can result in a blunting of the immune mechanisms of human crew members and animal test species. There is some evidence that the immune function changes in short-term flights resemble those occurring after acute stress, while the changes during long-term flights resemble those caused by chronic stress. In addition, this blunting of the immune function occurs concomitant with a relative increase in potentially infectious microorganisms in the space cabin environment. This combination of events results in an increased probability of inflight infectious events. The realization of this probability has been shown to be partially negated by the judicious use of a preflight health stabilization program and other operational countermeasures."[12]
"It is now well established that spaceflight alters immune function [1]–[6] by mechanisms which are poorly understood. The changes in the immunological parameters studied thus far occur within a few days of exposure to the space environment. Factors in the space environment contributing to immune dysregulation during and post-spaceflight include exposure to microgravity, stress, deconditioning (reduced physical activity and shift of fluids), and radiation. Primary immune defense heavily relies on immune cell distribution and function, and is clearly influenced by a combination or synergy of any of the factors described above that exist in the space environment."[1]
"Of the blood cell types, lymphocytes are the most sensitive to ionizing radiation exposure. T cells, or T lymphocytes, processed in the thymus, secrete lymphokines, which orchestrate signaling to lymphocytes and other immune cells to promote cell activation, proliferation, destroy target cells, and incite macrophages. Blood lymphocytes isolated from astronauts upon re-entry after a prolonged spaceflight exhibit decreased responses in mitogen reactivity, T-lymphocyte proliferation, and IL-2 production [7]. Space laboratory studies using rat splenocytes indicate dramatic shifts in T lymphocyte subsets as well as decreased cell division in bone marrow cells post-flight [8]. A follow up study using bone marrow cells isolated from rhesus monkeys upon landing indicated decreased cytokine production and cytokine receptor expression [9]."[1]
"When human lymphocytes are exposed to microgravity in a rapidly rotating clinostat, Concanavalin A (ConA) stimulated T cell activation is depressed [10], [11]. During flight, the activation of cultured human lymphocytes is depressed to less than 3% of the ground controls when exposed to ConA [12]. Microarray analysis of T lymphocytes exposed to mitogen in a vectorless gravity environment (using a random positioning machine) revealed that early T cell activation-associated gene expression is in fact, suppressed [13]."[1]
# Muscle mass losses
"Muscle strength and limb girth measurements during Skylab and Apollo missions suggested that loss of muscle mass may occur as a result of spaceflight. Extended duration spaceflight is important for the economical and practical use of space. The loss of muscle mass during spaceflight is a medical concern for long duration flights to the planets or extended stays aboard space stations. Understanding the extent and temporal relationships of muscle loss is important for the development of effective spaceflight countermeasures."[13]
"Statistical analyses demonstrated that [after 8 d shuttle flight] the soleus-gastrocnemius (-6.3%), anterior calf (-3.9%), hamstrings (-8.3%), quadriceps (-6.0%) and intrinsic back (-10.3%) muscles were decreased, p < 0.05, compared to baseline, 24 h after landing. At 2 weeks post recovery, the hamstrings and intrinsic lower back muscles were still below baseline, p < 0.05."[13]
# Orthostatic intolerances
Def. symptoms "of cerebral hypoperfusion or autonomic overaction which develop while the subject is standing, but are relieved on recumbency"[8] are called orthostatic intolerance.
The types of orthostatic intolerance "include NEUROCARDIOGENIC SYNCOPE; POSTURAL ORTHOSTATIC TACHYCARDIA SYNDROME; and neurogenic ORTHOSTATIC HYPOTENSION."[8]
Def. a "transient loss of consciousness and postural tone caused by diminished blood flow to the brain"[8] is called a syncope.
Def. loss "of consciousness due to a reduction in blood pressure that is associated with an increase in vagal tone and peripheral vasodilation"[8] is called vasovagal syncope or neurocardiogenic syncope.
Def. a "syndrome of ORTHOSTATIC INTOLERANCE combined with excessive upright TACHYCARDIA, and usually without associated ORTHOSTATIC HYPOTENSION"[8] is called Postural Orthostatic Tachycardia Syndrome.
"All variants have in common an excessively reduced venous return to the heart (central HYPOVOLEMIA) while upright."[8]
Def. "a 20-mm Hg decrease in systolic pressure or a 10-mm Hg decrease in diastolic pressure 3 minutes after the person has risen from supine to standing"[8] is called orthostatic hypotension.
"Symptoms generally include DIZZINESS, blurred vision, and SYNCOPE."[8]
"Orthostatic intolerance occurs commonly after spaceflight, and important aspects of the underlying mechanisms remain unclear."[14]
"After spaceflight, 9 of the 14 (64%) crew members could not complete a 10-min stand test that all completed preflight."[14]
The "postural vasoconstrictor response was significantly greater among the finishers (P < 0.01)."[14]
# Hypotheses
- A method to place a 5,000 kg object in orbit by using the natural electric field of the Earth may be possible.
# 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/Spaceflights | |
fa520baec2472d216dda352ab2aee36b42a46fb6 | wikidoc | Sparfloxacin | Sparfloxacin
# Overview
Sparfloxacin (spar FLOX a sin), trade names Spacin in Bangladesh, Zagam and Zagam Respipac, is a fluoroquinolone antibiotic used in the treatment of bacterial infections. It has a controversial safety profile. Zagam is no longer available in the United States.
# Pharmacological properties
Sparfloxacin is about 37-45% bound to proteins in the blood.
- Sparfloxacin achieves a high degree of penetration into most tissues, except for the central nervous system.
- Following a single 400 mg oral dose of sparfloxacin, the mean peak concentration in cantharides-induced inflammatory fluid is 1.3 lA-g per ml after a mean duration of 5 h post-dose. Thus(overall sparfloxacin penetration into inflammatory fluid is 117% and the mean elimination half-life from this fluid is 19.7 h.
- Skin penetration of sparfloxacin is good with skin:plasma ratios of 1.00 at 4 h (time of peak plasma concentration) and 1.39 at 5 h. Following single oral doses of 100 or 200 mg, concentrations in skin of 0.56 and 0.82-1.31 lA-g per g, respectively, can be expected. Sparfloxacin achieves excellent penetration into human polymorphonuclear leukocytes in vitro.
- Sparfloxacin achieves high concentrations in respiratory and sinus tissues. Following an oral loading dose of 400 mg followed by 200 mg daily, mean concentrations of sparfloxacin (2.5 to 5 h after dosing) in bronchial mucosa, epithelial lining fluid and alveolar macrophages are 4.4 µg/g, 15.0 µg/ml and 53.7 µg/g, respectively. The mean sparfloxacin concentration in maxillary sinus mucosa, 2-5 h after a single 400 mg dose, is 5.8 µg/g.
Shimada et al. ( 1993) has summarized many of the studies published in Japanese regarding the tissue distribution of sparfloxacin. (high concentrations are achieved in sputum, pleural fluid, skin, lung, prostate, gynecological tissues, breast milk and otolaryngological tissues. *Salivary concentrations are 66-70% of plasma levels, while CSF penetration appears to be somewhat limited with CSF:plasma concentration ratios of only 0.25-0.35.
- Sparfloxacin achieves concentrations in bile and gallbladder of 7.1- to 83-fold the concurrent serum levels.
In rabbits, sparfloxacin achieves very good penetration into the ocular vitreous (54%), cornea (76%) and lens (36%).
# Medical uses
The compound is indicated for treating community-acquired lower respiratory tract infections (acute sinusitis, exacerbations of chronic bronchitis caused by susceptible bacteria, community-acquired pneumonia).
# Adverse drug reactions
- In a review of 2081 adult patients participating in a Phase III clinical trial of sparfloxacin in community-acquired, lower respiratory tract infections, sparfloxacin (200- or 400 mg loading dose then 100 or 200 mg daily; i.e. 200/100 mg and 400/200 mg) had a similar incidence of adverse events as the comparator agents (Rubinstein, 1996). The overall rates of drug-related adverse reactions for sparfloxacin 400/200 mg versus comparators and 200/100 mg versus the comparator (amoxycillin/clavulanic acid) were 13.7 versus 17.7%, and 9.5 versus 13.2%, respectively. However, many of these reported reactions were very minor; discontinua- tion of the antibacterial agent because of drug-related adverse reactions occurred in 1.6 versus 1.6%, and 1) versus 1.1%, respectively. Adverse reactions affecting the nervous system were reported in 5.7% of the sparfloxacin group, with insomnia and other sleep disorders the most common events.
- Phototoxicity was noted in 2.0% of sparfloxacin recipients, with the average delay in onset being 6.3 :t 4.5 days (range 1–14 days) after commencing sparfloxacin. Mostly this consisted of erythema on the face and hands which lasted an average of 6.4 :t 4.2 days. The incidence of phototoxicity associated with sparfloxacin appears to be higher than that observed with ciprofloxacin and ofloxacin but less than that reported for fleroxacin, pefloxacin, enoxacin and nalidixic acid.
- Most importantly, features of the hemolytic-uremic syndrome such as that associated with temafloxacin have not been reported.
# Mechanism of action
Sparfloxacin, like other quinolones and fluoroquinolones, are bactericidal drugs, actively killing bacteria. Quinolones inhibit the bacterial DNA gyrase or the topoisomerase IV enzyme, thereby inhibiting DNA replication and transcription. Quinolones can enter cells easily and therefore are often used to treat intracellular pathogens such as Legionella pneumophila and Mycoplasma pneumoniae. For many gram-negative bacteria DNA gyrase is the target, whereas topoisomerase IV is the target for many gram-positive bacteria. Eukaryotic cells do not contain DNA gyrase or topoisomerase IV. | Sparfloxacin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Sparfloxacin (spar FLOX a sin), trade names Spacin in Bangladesh, Zagam and Zagam Respipac, is a fluoroquinolone antibiotic used in the treatment of bacterial infections. It has a controversial safety profile.[1] Zagam is no longer available in the United States.
# Pharmacological properties
Sparfloxacin is about 37-45% bound to proteins in the blood.[2][3]
- Sparfloxacin achieves a high degree of penetration into most tissues, except for the central nervous system.
- Following a single 400 mg oral dose of sparfloxacin, the mean peak concentration in cantharides-induced inflammatory fluid is 1.3 lA-g per ml after a mean duration of 5 h post-dose. Thus(overall sparfloxacin penetration into inflammatory fluid is 117% and the mean elimination half-life from this fluid is 19.7 h.[4]
- Skin penetration of sparfloxacin is good with skin:plasma ratios of 1.00 at 4 h (time of peak plasma concentration) and 1.39 at 5 h. Following single oral doses of 100 or 200 mg, concentrations in skin of 0.56 and 0.82-1.31 lA-g per g, respectively, can be expected.[5] Sparfloxacin achieves excellent penetration into human polymorphonuclear leukocytes in vitro.[6]
- Sparfloxacin achieves high concentrations in respiratory and sinus tissues. Following an oral loading dose of 400 mg followed by 200 mg daily, mean concentrations of sparfloxacin (2.5 to 5 h after dosing) in bronchial mucosa, epithelial lining fluid and alveolar macrophages are 4.4 µg/g, 15.0 µg/ml and 53.7 µg/g, respectively. The mean sparfloxacin concentration in maxillary sinus mucosa, 2-5 h after a single 400 mg dose, is 5.8 µg/g.[7]
Shimada et al. ( 1993) has summarized many of the studies published in Japanese regarding the tissue distribution of sparfloxacin. (high concentrations are achieved in sputum, pleural fluid, skin, lung, prostate, gynecological tissues, breast milk and otolaryngological tissues. *Salivary concentrations are 66-70% of plasma levels, while CSF penetration appears to be somewhat limited with CSF:plasma concentration ratios of only 0.25-0.35.
- Sparfloxacin achieves concentrations in bile and gallbladder of 7.1- to 83-fold the concurrent serum levels.
In rabbits, sparfloxacin achieves very good penetration into the ocular vitreous (54%), cornea (76%) and lens (36%).[8]
# Medical uses
The compound is indicated for treating community-acquired lower respiratory tract infections (acute sinusitis, exacerbations of chronic bronchitis caused by susceptible bacteria, community-acquired pneumonia).[9][10][11][12]
# Adverse drug reactions
- In a review of 2081 adult patients participating in a Phase III clinical trial of sparfloxacin in community-acquired, lower respiratory tract infections, sparfloxacin (200- or 400 mg loading dose then 100 or 200 mg daily; i.e. 200/100 mg and 400/200 mg) had a similar incidence of adverse events as the comparator agents (Rubinstein, 1996). The overall rates of drug-related adverse reactions for sparfloxacin 400/200 mg versus comparators and 200/100 mg versus the comparator (amoxycillin/clavulanic acid) were 13.7 versus 17.7%, and 9.5 versus 13.2%, respectively. However, many of these reported reactions were very minor; discontinua- tion of the antibacterial agent because of drug-related adverse reactions occurred in 1.6 versus 1.6%, and 1) versus 1.1%, respectively. Adverse reactions affecting the nervous system were reported in 5.7% of the sparfloxacin group, with insomnia and other sleep disorders the most common events.
- Phototoxicity was noted in 2.0% of sparfloxacin recipients, with the average delay in onset being 6.3 :t 4.5 days (range 1–14 days) after commencing sparfloxacin. Mostly this consisted of erythema on the face and hands which lasted an average of 6.4 :t 4.2 days. The incidence of phototoxicity associated with sparfloxacin appears to be higher than that observed with ciprofloxacin and ofloxacin but less than that reported for fleroxacin, pefloxacin, enoxacin and nalidixic acid.
- Most importantly, features of the hemolytic-uremic syndrome such as that associated with temafloxacin[13] have not been reported.[14][15][16][17][18]
# Mechanism of action
Sparfloxacin, like other quinolones and fluoroquinolones, are bactericidal drugs, actively killing bacteria. Quinolones inhibit the bacterial DNA gyrase or the topoisomerase IV enzyme, thereby inhibiting DNA replication and transcription. Quinolones can enter cells easily and therefore are often used to treat intracellular pathogens such as Legionella pneumophila and Mycoplasma pneumoniae. For many gram-negative bacteria DNA gyrase is the target, whereas topoisomerase IV is the target for many gram-positive bacteria. Eukaryotic cells do not contain DNA gyrase or topoisomerase IV. | https://www.wikidoc.org/index.php/Sparfloxacin | |
6435336fd417a9be2a57e2a5af38021c6cdb391c | wikidoc | Spectrometer | Spectrometer
A spectrometer is an optical instrument used to measure properties of light over a specific portion of the electromagnetic spectrum, typically used in spectroscopic analysis to identify materials. The variable measured is most often the light's intensity but could also, for instance, be the polarization state. The independent variable is usually the wavelength of the light, normally expressed as some fraction of a meter, but sometimes expressed as some unit directly proportional to the photon energy, such as wavenumber or electron volts, which has a reciprocal relationship to wavelength. A spectrometer is used in spectroscopy for producing spectral lines and measuring their wavelengths and intensities. Spectrometer is a term that is applied to instruments that operate over a very wide range of wavelengths, from gamma rays and X-rays into the far infrared. If the region of interest is restricted to near the visible spectrum, the study is called spectrophotometry.
In general, any particular instrument will operate over a small portion of this total range because of the different techniques used to measure different portions of the spectrum. Below optical frequencies (that is, at microwave and radio frequencies), the spectrum analyzer is a closely related electronic device.
# Spectroscopes
They are used often in astronomy and some branches of chemistry. Early spectroscopes were simply a prism with graduations marking wavelengths of light. Modern spectroscopes, such as monochromators, generally use a diffraction grating, a movable slit, and some kind of photodetector, all automated and controlled by a computer. The spectroscope was invented by both Gustav Robert Georg Kirchhoff and Robert Wilhelm Bunsen.
When a material is heated to incandescence it emits light that is characteristic of the atomic makeup of the material.
Particular light frequencies give rise to sharply defined bands on the scale which can be thought of as fingerprints. For example, the element sodium has a very characteristic double yellow band known as the Sodium D-lines at 588.9950 and 589.5924 nanometers, the colour of which will be familiar to anyone who has seen a low pressure sodium vapor lamp.
In the original spectroscope design in the early 19th century, light entered a slit and a collimating lens transformed the light into a thin beam of parallel rays. The light was then passed through a prism (in hand-held spectroscopes, usually an Amici prism) that refracted the beam into a spectrum because different wavelengths were refracted different amounts due to dispersion. This image was then viewed through a tube with a scale that was transposed upon the spectral image, enabling its direct measurement.
With the development of photographic film, the more accurate spectrograph was created. It was based on the same principle as the spectroscope, but it had a camera in place of the viewing tube. In recent years the electronic circuits built around the photomultiplier tube have replaced the camera, allowing real-time spectrographic analysis with far greater accuracy. Arrays of photosensors are also used in place of film in spectrographic systems. Such spectral analysis, or spectroscopy, has become an important scientific tool for analyzing the composition of unknown material and for studying astronomical phenomena and testing astronomical theories. The wavelengths are measured with the spectrometer.
# Spectrographs
A spectrograph is an instrument that transforms an incoming time-domain waveform into a frequency spectrum, or generally a sequence of such spectra. There are several kinds of machines referred to as spectrographs, depending on the precise nature of the waves. The first spectrographs used photographic paper as the detector. The star spectral classification and discovery of the main sequence, Hubble's law and the Hubble sequence were all made with
spectrographs that used photographic paper. The plant pigment phytochrome was discovered using a spectrograph that used living plants as the detector. More recent spectrographs use electronic detectors, such as CCDs which can be used for both visible and UV light. The exact choice of detector depends on the wavelengths of light to be recorded.
The forthcoming James Webb Space Telescope will contain both a near-infrared spectrograph (NIRSpec) and a mid-infrared spectrometer (MIRI).
An echelle spectrograph uses two diffraction gratings, rotated 90 degrees with respect to each other and placed close to one another. Therefore an entrance point and not a slit is used and a 2d CCD-chip records the spectrum. Usually one would guess to retrieve a spectrum on the diagonal, but when both grating have a wide spacing and one is blazed so that only the first order is visible and the other is blazed that a lot of higher orders are visible, one gets a very fine spectrum nicely folded onto a small common CCD-chip. The small chip also means that the collimating optics need not to be optimized for coma or astigmatism, but the spherical aberration can be set to zero.
A spectrograph is sometimes called polychromator, as an analogy to monochromator. | Spectrometer
Template:Otheruses4
Template:Infobox Laboratory equipment
A spectrometer is an optical instrument used to measure properties of light over a specific portion of the electromagnetic spectrum, typically used in spectroscopic analysis to identify materials. The variable measured is most often the light's intensity but could also, for instance, be the polarization state. The independent variable is usually the wavelength of the light, normally expressed as some fraction of a meter, but sometimes expressed as some unit directly proportional to the photon energy, such as wavenumber or electron volts, which has a reciprocal relationship to wavelength. A spectrometer is used in spectroscopy for producing spectral lines and measuring their wavelengths and intensities. Spectrometer is a term that is applied to instruments that operate over a very wide range of wavelengths, from gamma rays and X-rays into the far infrared. If the region of interest is restricted to near the visible spectrum, the study is called spectrophotometry.
In general, any particular instrument will operate over a small portion of this total range because of the different techniques used to measure different portions of the spectrum. Below optical frequencies (that is, at microwave and radio frequencies), the spectrum analyzer is a closely related electronic device.
# Spectroscopes
They are used often in astronomy and some branches of chemistry. Early spectroscopes were simply a prism with graduations marking wavelengths of light. Modern spectroscopes, such as monochromators, generally use a diffraction grating, a movable slit, and some kind of photodetector, all automated and controlled by a computer. The spectroscope was invented by both Gustav Robert Georg Kirchhoff and Robert Wilhelm Bunsen.
When a material is heated to incandescence it emits light that is characteristic of the atomic makeup of the material.
Particular light frequencies give rise to sharply defined bands on the scale which can be thought of as fingerprints. For example, the element sodium has a very characteristic double yellow band known as the Sodium D-lines at 588.9950 and 589.5924 nanometers, the colour of which will be familiar to anyone who has seen a low pressure sodium vapor lamp.
In the original spectroscope design in the early 19th century, light entered a slit and a collimating lens transformed the light into a thin beam of parallel rays. The light was then passed through a prism (in hand-held spectroscopes, usually an Amici prism) that refracted the beam into a spectrum because different wavelengths were refracted different amounts due to dispersion. This image was then viewed through a tube with a scale that was transposed upon the spectral image, enabling its direct measurement.
With the development of photographic film, the more accurate spectrograph was created. It was based on the same principle as the spectroscope, but it had a camera in place of the viewing tube. In recent years the electronic circuits built around the photomultiplier tube have replaced the camera, allowing real-time spectrographic analysis with far greater accuracy. Arrays of photosensors are also used in place of film in spectrographic systems. Such spectral analysis, or spectroscopy, has become an important scientific tool for analyzing the composition of unknown material and for studying astronomical phenomena and testing astronomical theories. The wavelengths are measured with the spectrometer.
# Spectrographs
A spectrograph is an instrument that transforms an incoming time-domain waveform into a frequency spectrum, or generally a sequence of such spectra. There are several kinds of machines referred to as spectrographs, depending on the precise nature of the waves. The first spectrographs used photographic paper as the detector. The star spectral classification and discovery of the main sequence, Hubble's law and the Hubble sequence were all made with
spectrographs that used photographic paper. The plant pigment phytochrome was discovered using a spectrograph that used living plants as the detector. More recent spectrographs use electronic detectors, such as CCDs which can be used for both visible and UV light. The exact choice of detector depends on the wavelengths of light to be recorded.
The forthcoming James Webb Space Telescope will contain both a near-infrared spectrograph (NIRSpec) and a mid-infrared spectrometer (MIRI).
An echelle spectrograph uses two diffraction gratings, rotated 90 degrees with respect to each other and placed close to one another. Therefore an entrance point and not a slit is used and a 2d CCD-chip records the spectrum. Usually one would guess to retrieve a spectrum on the diagonal, but when both grating have a wide spacing and one is blazed so that only the first order is visible and the other is blazed that a lot of higher orders are visible, one gets a very fine spectrum nicely folded onto a small common CCD-chip. The small chip also means that the collimating optics need not to be optimized for coma or astigmatism, but the spherical aberration can be set to zero.
A spectrograph is sometimes called polychromator, as an analogy to monochromator. | https://www.wikidoc.org/index.php/Spectrograph | |
fe51e4a64fa0257d7235ef0f8424f8f1ea954d29 | wikidoc | Spectroscopy | Spectroscopy
# Overview
Spectroscopy was originally the study of the interaction between radiation and matter as a function of wavelength λ. In fact, historically, spectroscopy referred to the use of visible light dispersed according to its wavelength, e.g. by a prism. Later the concept was expanded greatly to comprise any measurement of a quantity as function of either wavelength or frequency. Thus it also can refer to interactions with particle radiation or to a response to an alternating field or varying frequency ν. An further extension of the scope of the definition added energy E as a variable, once the very close relationship E=hν for photons was realized. A plot of the response as a function of wavelength — or more commonly frequency — is referred to as a spectrum.
Spectrometry is the measurement of these responses and an instrument which performs such measurements is a spectrometer or spectrograph, although these terms are more limited in use to the orginal field of optics from which the concept sprang.
Spectroscopy is often used in physical and analytical chemistry for the identification of substances through the spectrum emitted from or absorbed by them. Spectroscopy is also heavily used in astronomy and remote sensing. Most large telescopes have spectrometers, which are used either to measure the chemical composition and physical properties of astronomical objects or to measure their velocities from the Doppler shift of their spectral lines.
# Classification of methods
## Nature of excitation measured
The type of spectroscopy depends on the physical quantity measured. Normally, the quantity that is measured is an intensity, either of energy absorbed or produced.
- Optical Spectroscopy (Electromagnetic Spectroscopy) involves interactions of matter with electromagnetic radiation or light. Ultraviolet-visible spectroscopy is an example.
- Electron Spectroscopy involves interactions with electron beams. Auger spectroscopy involves inducing the Auger effect with an electron beam. In this case the measurement typically involves the kinetic energy of the electron as variable.
- Mass spectroscopy involves the interaction of charged species with magnetic and/or electric fields, giving rise to a mass spectrum. The term "mass spectroscopy" is deprecated in favor of mass spectrometry, for the technique is primarily a form of measurement, though it does produce a spectrum for observation. This spectrum has the mass m as variable, but the measurement is essentially one of the kinetic energy of the particle.
- Acoustic spectroscopy involves the frequency of sound.
- Dielectric spectroscopy involves the frequency of an external electrical field
- Mechanical spectroscopy involves the frequency of an external mechanical stress, e.g. a torsion applied to a piece of material.
## Measurement process
Most spectroscopic methods are differentiated as either atomic or molecular based on whether or not they apply to atoms or molecules. Along with that distinction, they can be classified on the nature of their interaction:
- Absorption spectroscopy uses the range of the electromagnetic spectra in which a substance absorbs. This includes atomic absorption spectroscopy and various molecular techniques, such as infrared spectroscopy in that region and nuclear magnetic resonance (NMR) spectroscopy in the radio region.
- Emission spectroscopy uses the range of electromagnetic spectra in which a substance radiates (emits). The substance first must absorb energy. This energy can be from a variety of sources, which determines the name of the subsequent emission, like luminescence. Molecular luminescence techniques include spectrofluorimetry.
- Scattering spectroscopy measures the amount of light that a substance scatters at certain wavelengths, incident angles, and polarization angles. The scattering process is much faster than the absorption/emission process. One of the most useful applications of light scattering spectroscopy is Raman spectroscopy.
# Common types
## Fluorescence
Fluorescence spectroscopy uses higher energy photons to excite a sample, which will then emit lower energy photons. This technique has become popular for its biochemical and medical applications, and can be used for confocal microscopy, fluorescence resonance energy transfer, and fluorescence lifetime imaging.
## X-ray
When X-rays of sufficient frequency (energy) interact with a substance, inner shell electrons in the atom are excited to outer empty orbitals, or they may be removed completely, ionizing the atom. The inner shell "hole" will then be filled by electrons from outer orbitals. The energy available in this de-excitation process is emitted as radiation (fluorescence) or will remove other less-bound electrons from the atom (Auger effect). The absorption or emission frequencies (energies) are characteristic of the specific atom. In addition, for a specific atom small frequency (energy) variations occur which are characteristic of the chemical bonding. With a suitable apparatus, these characteristic X-ray frequencies or Auger electron energies can be measured. X-ray absorption and emission spectroscopy is used in chemistry and material sciences to determine elemental composition and chemical bonding.
X-ray crystallography is a scattering process; crystalline materials scatter X-rays at well-defined angles. If the wavelength of the incident X-rays is known, this allows calculation of the distances between planes of atoms within the crystal. The intensities of the scattered X-rays give information about the atomic positions and allow the arrangement of the atoms within the crystal structure to be calculated.
## Flame
Liquid solution samples are aspirated into a burner or nebulizer/burner combination, desolvated, atomized, and sometimes excited to a higher energy electronic state. The use of a flame during analysis requires fuel and oxidant, typically in the form of gases. Common fuel gases used are acetylene (ethyne) or hydrogen. Common oxidant gases used are oxygen, air, or nitrous oxide. These methods are often capable of analyzing metallic element analytes in the part per million, billion, or possibly lower concentration ranges. Light detectors are needed to detect light with the analysis information coming from the flame.
- Atomic Emission Spectroscopy - This method uses flame excitation; atoms are excited from the heat of the flame to emit light. This method commonly uses a total consumption burner with a round burning outlet. A higher temperature flame than atomic absorption spectroscopy (AA) is typically used to produce excitation of analyte atoms. Since analyte atoms are excited by the heat of the flame, no special elemental lamps to shine into the flame are needed. A high resolution polychromator can be used to produce an emission intensity vs. wavelength spectrum over a range of wavelengths showing multiple element excitation lines, meaning multiple elements can be detected in one run. Alternatively, a monochromator can be set at one wavelength to concentrate on analysis of a single element at a certain emission line. Plasma emission spectroscopy is a more modern version of this method. See Flame emission spectroscopy for more details.
- Atomic absorption spectroscopy (often called AA) - This method commonly uses a pre-burner nebulizer (or nebulizing chamber) to create a sample mist and a slot-shaped burner which gives a longer pathlength flame. The temperature of the flame is low enough that the flame itself does not excite sample atoms from their ground state. The nebulizer and flame are used to desolvate and atomize the sample, but the excitation of the analyte atoms is done by the use of lamps shining through the flame at various wavelengths for each type of analyte. In AA, the amount of light absorbed after going through the flame determines the amount of analyte in the sample. A graphite furnace for heating the sample to desolvate and atomize is commonly used for greater sensitivity. The graphite furnace method can also analyze some solid or slurry samples. Because of its good sensitivity and selectivity, it is still a commonly used method of analysis for certain trace elements in aqueous (and other liquid) samples.
- Atomic Fluorescence Spectroscopy - This method commonly uses a burner with a round burning outlet. The flame is used to solvate and atomize the sample, but a lamp shines light at a specific wavelength into the flame to excite the analyte atoms in the flame. The atoms of certain elements can then fluoresce emitting light in a different direction. The intensity of this fluorescing light is used for quantifying the amount of analyte element in the sample. A graphite furnace can also be used for atomic fluorescence spectroscopy. This method is not as commonly used as atomic absorption or plasma emission spectroscopy.
Plasma Emission Spectroscopy
In some ways similar to flame atomic emission spectroscopy, it has largely replaced it.
- Direct-current plasma (DCP)
A direct-current plasma (DCP) is created by an electrical discharge between two electrodes.
A plasma support gas is necessary, and Ar is common. Samples can be deposited on one of the electrodes, or if conducting can make up one electrode.
- Glow discharge-optical emission spectrometry (GD-OES)
- Inductively coupled plasma-atomic emission spectrometry (ICP-AES)
- Laser Induced Breakdown Spectroscopy (LIBS) (LIBS), also called Laser-induced plasma spectrometry (LIPS)
- Microwave-induced plasma (MIP)
Spark or arc (emission) spectroscopy - is used for the analysis of metallic elements in solid samples. For non-conductive materials, a sample is ground with graphite powder to make it conductive. In traditional arc spectroscopy methods, a sample of the solid was commonly ground up and destroyed during analysis. An electric arc or spark is passed through the sample, heating the sample to a high temperature to excite the atoms in it. The excited analyte atoms glow emitting light at various wavelengths which could be detected by common spectroscopic methods. Since the conditions producing the arc emission typically are not controlled quantitatively, the analysis for the elements is qualitative.
Nowadays, the spark sources with controlled discharges under an argon atmosphere allow that this method can be considered eminently quantitative, and its use is widely expanded worldwide through production control laboratories of foundries and steel mills.
## Visible
Many atoms emit or absorb visible light. In order to obtain a fine line spectrum, the atoms must be in a gas phase. This means that the substance has to be vaporised. The spectrum is studied in absorption or emission. Visible absorption spectroscopy is often combined with UV absorption spectroscopy in UV/Vis spectroscopy.
## Ultraviolet
All atoms absorb in the Ultraviolet (UV) region because these photons are energetic enough to excite outer electrons. If the frequency is high enough, photoionisation takes place. UV spectroscopy is also used in quantifying protein and DNA concentration as well as the ratio of protein to DNA concentration in a solution. Several amino acids usually found in protein, such as tryptophan, absorb light in the 280nm range and DNA absorbs light in the 260nm range. For this reason, the ratio of 260/280nm absorbance is a good general indicator of the relative purity of a solution in terms of these two macromolecules. Reasonable estimates of protein or DNA concentration can also be made this way using Beer's law.
## Infrared
Infrared spectroscopy offers the possibility to measure different types of inter atomic bond vibrations at different frequencies. Especially in organic chemistry the analysis of IR absorption spectra shows what type of bonds are present in the sample.
## Raman
Raman spectroscopy uses the inelastic scattering of light to analyse vibrational and rotational modes of molecules. The resulting 'fingerprints' are an aid to analysis.
## Nuclear magnetic resonance
Nuclear magnetic resonance spectroscopy analyzes the magnetic properties of certain atomic nuclei to determine different electronic local environments of hydrogen, carbon, or other atoms in an organic compound or other compound. This is used to help determine the structure of the compound.
## Photoemission
## Mössbauer
Transmission or conversion-electron (CEMS) modes of Mössbauer spectroscopy probe the properties of specific isotope nuclei in different atomic environments by analyzing the resonant absorption of characteristic energy gamma-rays known as the Mössbauer effect.
# Other types
- Photoacoustic spectroscopy measures the sound waves produced upon the absorption of radiation.
- Photothermal spectroscopy measures heat evolved upon absorption of radiation.
- Circular Dichroism spectroscopy
- Raman optical activity spectroscopy exploits Raman scattering and optical activity effects to reveal detailed information on chiral centers in molecules.
- Terahertz spectroscopy uses wavelengths above infrared spectroscopy and below microwave or millimeter wave measurements.
- Inelastic neutron scattering works like Raman spectroscopy, with neutrons instead of photons.
- Inelastic electron tunneling spectroscopy uses the changes in current due to inelastic electron-vibration interaction at specific energies which can also measure optically forbidden transitions.
- Auger Spectroscopy is a method used to study surfaces of materials on a micro-scale. It is often used in connection with electron microscopy.
- Cavity ring down spectroscopy
- Fourier transform is an efficient method for processing spectra data obtained using interferometers. The use of Fourier transform in spectroscopy is called Fourier transform spectroscopy. Nearly all infrared spectroscopy (FTIR) and Nuclear Magnetic Resonance (NMR) spectroscopy are performed with Fourier transforms.
- Spectroscopy of matter in situations where the properties are changing with time is called Time-resolved spectroscopy.
- Mechanical spectroscopy involves interactions with macroscopic vibrations, such as phonons. An example is acoustic spectroscopy, involving sound waves.
- Time-resolved spectroscopy
- Spectroscopy using an AFM-based analytical technique is called Force spectroscopy.
- Dielectric spectroscopy
- Thermal infrared spectroscopy measures thermal radiation emitted from materials and surfaces and is used to determine the type of bonds present in a sample as well as their lattice environment. The techniques are widely used by organic chemists, mineralogists, and planetary scientists.
# Background subtraction
Background subtraction is a term typically used in spectroscopy when one explains the process of acquiring a background radiation level (or ambient radiation level) and then makes an algorithmic adjustment to the data to obtain qualitative information about any deviations from the background, even when they are an order of magnitude less decipherable than the background itself.
Background subtraction can effect a number of statistical calculations (Continuum, Compton, Bremsstrahlung) leading to improved overall system performance. | Spectroscopy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Spectroscopy was originally the study of the interaction between radiation and matter as a function of wavelength λ. In fact, historically, spectroscopy referred to the use of visible light dispersed according to its wavelength, e.g. by a prism. Later the concept was expanded greatly to comprise any measurement of a quantity as function of either wavelength or frequency. Thus it also can refer to interactions with particle radiation or to a response to an alternating field or varying frequency ν. An further extension of the scope of the definition added energy E as a variable, once the very close relationship E=hν for photons was realized. A plot of the response as a function of wavelength — or more commonly frequency — is referred to as a spectrum.
Spectrometry is the measurement of these responses and an instrument which performs such measurements is a spectrometer or spectrograph, although these terms are more limited in use to the orginal field of optics from which the concept sprang.
Spectroscopy is often used in physical and analytical chemistry for the identification of substances through the spectrum emitted from or absorbed by them. Spectroscopy is also heavily used in astronomy and remote sensing. Most large telescopes have spectrometers, which are used either to measure the chemical composition and physical properties of astronomical objects or to measure their velocities from the Doppler shift of their spectral lines.
# Classification of methods
## Nature of excitation measured
The type of spectroscopy depends on the physical quantity measured. Normally, the quantity that is measured is an intensity, either of energy absorbed or produced.
- Optical Spectroscopy (Electromagnetic Spectroscopy) involves interactions of matter with electromagnetic radiation or light. Ultraviolet-visible spectroscopy is an example.
- Electron Spectroscopy involves interactions with electron beams. Auger spectroscopy involves inducing the Auger effect with an electron beam. In this case the measurement typically involves the kinetic energy of the electron as variable.
- Mass spectroscopy involves the interaction of charged species with magnetic and/or electric fields, giving rise to a mass spectrum. The term "mass spectroscopy" is deprecated in favor of mass spectrometry, for the technique is primarily a form of measurement, though it does produce a spectrum for observation. This spectrum has the mass m as variable, but the measurement is essentially one of the kinetic energy of the particle.
- Acoustic spectroscopy involves the frequency of sound.
- Dielectric spectroscopy involves the frequency of an external electrical field
- Mechanical spectroscopy involves the frequency of an external mechanical stress, e.g. a torsion applied to a piece of material.
## Measurement process
Most spectroscopic methods are differentiated as either atomic or molecular based on whether or not they apply to atoms or molecules. Along with that distinction, they can be classified on the nature of their interaction:
- Absorption spectroscopy uses the range of the electromagnetic spectra in which a substance absorbs. This includes atomic absorption spectroscopy and various molecular techniques, such as infrared spectroscopy in that region and nuclear magnetic resonance (NMR) spectroscopy in the radio region.
- Emission spectroscopy uses the range of electromagnetic spectra in which a substance radiates (emits). The substance first must absorb energy. This energy can be from a variety of sources, which determines the name of the subsequent emission, like luminescence. Molecular luminescence techniques include spectrofluorimetry.
- Scattering spectroscopy measures the amount of light that a substance scatters at certain wavelengths, incident angles, and polarization angles. The scattering process is much faster than the absorption/emission process. One of the most useful applications of light scattering spectroscopy is Raman spectroscopy.
# Common types
## Fluorescence
Fluorescence spectroscopy uses higher energy photons to excite a sample, which will then emit lower energy photons. This technique has become popular for its biochemical and medical applications, and can be used for confocal microscopy, fluorescence resonance energy transfer, and fluorescence lifetime imaging.
## X-ray
When X-rays of sufficient frequency (energy) interact with a substance, inner shell electrons in the atom are excited to outer empty orbitals, or they may be removed completely, ionizing the atom. The inner shell "hole" will then be filled by electrons from outer orbitals. The energy available in this de-excitation process is emitted as radiation (fluorescence) or will remove other less-bound electrons from the atom (Auger effect). The absorption or emission frequencies (energies) are characteristic of the specific atom. In addition, for a specific atom small frequency (energy) variations occur which are characteristic of the chemical bonding. With a suitable apparatus, these characteristic X-ray frequencies or Auger electron energies can be measured. X-ray absorption and emission spectroscopy is used in chemistry and material sciences to determine elemental composition and chemical bonding.
X-ray crystallography is a scattering process; crystalline materials scatter X-rays at well-defined angles. If the wavelength of the incident X-rays is known, this allows calculation of the distances between planes of atoms within the crystal. The intensities of the scattered X-rays give information about the atomic positions and allow the arrangement of the atoms within the crystal structure to be calculated.
## Flame
Liquid solution samples are aspirated into a burner or nebulizer/burner combination, desolvated, atomized, and sometimes excited to a higher energy electronic state. The use of a flame during analysis requires fuel and oxidant, typically in the form of gases. Common fuel gases used are acetylene (ethyne) or hydrogen. Common oxidant gases used are oxygen, air, or nitrous oxide. These methods are often capable of analyzing metallic element analytes in the part per million, billion, or possibly lower concentration ranges. Light detectors are needed to detect light with the analysis information coming from the flame.
- Atomic Emission Spectroscopy - This method uses flame excitation; atoms are excited from the heat of the flame to emit light. This method commonly uses a total consumption burner with a round burning outlet. A higher temperature flame than atomic absorption spectroscopy (AA) is typically used to produce excitation of analyte atoms. Since analyte atoms are excited by the heat of the flame, no special elemental lamps to shine into the flame are needed. A high resolution polychromator can be used to produce an emission intensity vs. wavelength spectrum over a range of wavelengths showing multiple element excitation lines, meaning multiple elements can be detected in one run. Alternatively, a monochromator can be set at one wavelength to concentrate on analysis of a single element at a certain emission line. Plasma emission spectroscopy is a more modern version of this method. See Flame emission spectroscopy for more details.
- Atomic absorption spectroscopy (often called AA) - This method commonly uses a pre-burner nebulizer (or nebulizing chamber) to create a sample mist and a slot-shaped burner which gives a longer pathlength flame. The temperature of the flame is low enough that the flame itself does not excite sample atoms from their ground state. The nebulizer and flame are used to desolvate and atomize the sample, but the excitation of the analyte atoms is done by the use of lamps shining through the flame at various wavelengths for each type of analyte. In AA, the amount of light absorbed after going through the flame determines the amount of analyte in the sample. A graphite furnace for heating the sample to desolvate and atomize is commonly used for greater sensitivity. The graphite furnace method can also analyze some solid or slurry samples. Because of its good sensitivity and selectivity, it is still a commonly used method of analysis for certain trace elements in aqueous (and other liquid) samples.
- Atomic Fluorescence Spectroscopy - This method commonly uses a burner with a round burning outlet. The flame is used to solvate and atomize the sample, but a lamp shines light at a specific wavelength into the flame to excite the analyte atoms in the flame. The atoms of certain elements can then fluoresce emitting light in a different direction. The intensity of this fluorescing light is used for quantifying the amount of analyte element in the sample. A graphite furnace can also be used for atomic fluorescence spectroscopy. This method is not as commonly used as atomic absorption or plasma emission spectroscopy.
Plasma Emission Spectroscopy
In some ways similar to flame atomic emission spectroscopy, it has largely replaced it.
- Direct-current plasma (DCP)
A direct-current plasma (DCP) is created by an electrical discharge between two electrodes.
A plasma support gas is necessary, and Ar is common. Samples can be deposited on one of the electrodes, or if conducting can make up one electrode.
- Glow discharge-optical emission spectrometry (GD-OES)
- Inductively coupled plasma-atomic emission spectrometry (ICP-AES)
- Laser Induced Breakdown Spectroscopy (LIBS) (LIBS), also called Laser-induced plasma spectrometry (LIPS)
- Microwave-induced plasma (MIP)
Spark or arc (emission) spectroscopy - is used for the analysis of metallic elements in solid samples. For non-conductive materials, a sample is ground with graphite powder to make it conductive. In traditional arc spectroscopy methods, a sample of the solid was commonly ground up and destroyed during analysis. An electric arc or spark is passed through the sample, heating the sample to a high temperature to excite the atoms in it. The excited analyte atoms glow emitting light at various wavelengths which could be detected by common spectroscopic methods. Since the conditions producing the arc emission typically are not controlled quantitatively, the analysis for the elements is qualitative.
Nowadays, the spark sources with controlled discharges under an argon atmosphere allow that this method can be considered eminently quantitative, and its use is widely expanded worldwide through production control laboratories of foundries and steel mills.
## Visible
Many atoms emit or absorb visible light. In order to obtain a fine line spectrum, the atoms must be in a gas phase. This means that the substance has to be vaporised. The spectrum is studied in absorption or emission. Visible absorption spectroscopy is often combined with UV absorption spectroscopy in UV/Vis spectroscopy.
## Ultraviolet
All atoms absorb in the Ultraviolet (UV) region because these photons are energetic enough to excite outer electrons. If the frequency is high enough, photoionisation takes place. UV spectroscopy is also used in quantifying protein and DNA concentration as well as the ratio of protein to DNA concentration in a solution. Several amino acids usually found in protein, such as tryptophan, absorb light in the 280nm range and DNA absorbs light in the 260nm range. For this reason, the ratio of 260/280nm absorbance is a good general indicator of the relative purity of a solution in terms of these two macromolecules. Reasonable estimates of protein or DNA concentration can also be made this way using Beer's law.
## Infrared
Infrared spectroscopy offers the possibility to measure different types of inter atomic bond vibrations at different frequencies. Especially in organic chemistry the analysis of IR absorption spectra shows what type of bonds are present in the sample.
## Raman
Raman spectroscopy uses the inelastic scattering of light to analyse vibrational and rotational modes of molecules. The resulting 'fingerprints' are an aid to analysis.
## Nuclear magnetic resonance
Nuclear magnetic resonance spectroscopy analyzes the magnetic properties of certain atomic nuclei to determine different electronic local environments of hydrogen, carbon, or other atoms in an organic compound or other compound. This is used to help determine the structure of the compound.
## Photoemission
## Mössbauer
Transmission or conversion-electron (CEMS) modes of Mössbauer spectroscopy probe the properties of specific isotope nuclei in different atomic environments by analyzing the resonant absorption of characteristic energy gamma-rays known as the Mössbauer effect.
# Other types
- Photoacoustic spectroscopy measures the sound waves produced upon the absorption of radiation.
- Photothermal spectroscopy measures heat evolved upon absorption of radiation.
- Circular Dichroism spectroscopy
- Raman optical activity spectroscopy exploits Raman scattering and optical activity effects to reveal detailed information on chiral centers in molecules.
- Terahertz spectroscopy uses wavelengths above infrared spectroscopy and below microwave or millimeter wave measurements.
- Inelastic neutron scattering works like Raman spectroscopy, with neutrons instead of photons.
- Inelastic electron tunneling spectroscopy uses the changes in current due to inelastic electron-vibration interaction at specific energies which can also measure optically forbidden transitions.
- Auger Spectroscopy is a method used to study surfaces of materials on a micro-scale. It is often used in connection with electron microscopy.
- Cavity ring down spectroscopy
- Fourier transform is an efficient method for processing spectra data obtained using interferometers. The use of Fourier transform in spectroscopy is called Fourier transform spectroscopy. Nearly all infrared spectroscopy (FTIR) and Nuclear Magnetic Resonance (NMR) spectroscopy are performed with Fourier transforms.
- Spectroscopy of matter in situations where the properties are changing with time is called Time-resolved spectroscopy.
- Mechanical spectroscopy involves interactions with macroscopic vibrations, such as phonons. An example is acoustic spectroscopy, involving sound waves.
- Time-resolved spectroscopy
- Spectroscopy using an AFM-based analytical technique is called Force spectroscopy.
- Dielectric spectroscopy
- Thermal infrared spectroscopy measures thermal radiation emitted from materials and surfaces and is used to determine the type of bonds present in a sample as well as their lattice environment. The techniques are widely used by organic chemists, mineralogists, and planetary scientists.
# Background subtraction
Background subtraction is a term typically used in spectroscopy when one explains the process of acquiring a background radiation level (or ambient radiation level) and then makes an algorithmic adjustment to the data to obtain qualitative information about any deviations from the background, even when they are an order of magnitude less decipherable than the background itself.
Background subtraction can effect a number of statistical calculations (Continuum, Compton, Bremsstrahlung) leading to improved overall system performance. | https://www.wikidoc.org/index.php/Spectrometry | |
4deef53ed3af2e3cc350028ee71cf61fdd89816b | wikidoc | Spermatozoon | Spermatozoon
A spermatozoon or spermatozoan (pl. spermatozoa), from the ancient Greek σπέρμα (seed) and Template:Unicode (living being) and more commonly known as a sperm cell, is the haploid cell that is the male gamete. It joins an ovum to form a zygote. A zygote is a single cell, with a complete set of chromosomes, that normally develops into an embryo.
Sperm cells contribute half of the genetic information to the diploid offspring. In mammals, the sex of the offspring is determined by the sperm cells: a spermatozoon bearing a Y chromosome will lead to a male (XY) offspring, while one bearing an X chromosome will lead to a female (XX) offspring (the ovum always provides an X chromosome). Sperm cells were first observed by a student of Anton van Leeuwenhoek in 1677.
# Mammalian spermatozoan structure, function, and size
## Humans
The human sperm cell is the reproductive cell in males. Sperm cells come in two types; "male" and "female." Sperm cells that give rise to female (XX) offspring after fertilization differ in that they carry an X chromosome, while sperm cells that give rise to male (XY) offspring carry a Y chromosome. The "female" sperm cell also differs phenotypically in that it has a larger head in comparison to the "male" sperm cell.
In male humans, sperm cells consists of a head 5 µm by 3 µm and a tail 50 µm long. The Reynolds number associated with spermatozoa is in the order of 1Template:E, so it is known that the spermatozoa exhibit laminar flow. Spermatozoan stream lines are straight and parallel. The tail flagellates, which propels the sperm cell (at about 1-3 mm/minute in humans) by whipping in an elliptical cone.
. Semen has an alkaline nature, and they do not reach full motility (hypermotility) until they reach the vagina where the alkaline pH is neutralized by acidic vaginal fluids. This gradual process takes 20-30 minutes. In this time, fibrinogen from the seminal vesicles forms a clot, securing and protecting the sperm. Just as they become hypermotile, fibrinolysin from the prostate dissolves the clot, allowing the sperm to progress optimally.
The spermatozoon is characterized by a minimum of cytoplasm and the most densely packed DNA known in eukaryotes. Compared to mitotic chromosomes in somatic cells, sperm DNA is at least sixfold more highly condensed.
During fertilization, the sperm's mitochondria are destroyed by the egg cell, and this means only the mother is able to
provide the baby's mitochondria and mitochondrial DNA, which have an important application in tracing maternal ancestry. However it has been recently discovered that mitochondrial DNA can be recombinant
## Avoidance of immune system response
Glycoprotein molecules on the surface of sperm cells are recognised by all human immune systems, and interpreted as a signal that the cell should not be rejected. The male immune system might otherwise attack sperm whilst in the testes, and the female immune system would attack sperm in the reproductive tract. The specific glycoproteins coating sperm cells are also utilized by some cancerous and bacterial cells, some parasitic worms, and HIV-infected white blood cells, in order to avoid an immune response from the host organism.
# Spermatozoa production in mammals
Spermatozoa are produced in the seminiferous tubules of the testes in a process called spermatogenesis. Round cells called spermatogonia divide and differentiate eventually to become spermatozoa. During copulation the cloaca or vagina gets inseminated, and then the spermatozoa move through chemotaxis to the ovum inside a Fallopian tube or the uterus.
# Spermatozoa Activation
Mammalian sperm cells become even more active when they approach an egg cell in a process called sperm activation. Sperm activation has been shown to be caused by calcium ionophores in vitro, progesterone released by nearby cumulus cells and binding to ZP3 of the zona pellucida.
The intiial change is called "hyperactivation", which causes a change in spermatozoa motility. They swim faster and their tail movements become more forceful and erratic.
A recent discovery links hyperactivation to a sudden influx of calcium ion into the tails. The whip-like tail (flagellum) of the sperm is studded with ion channels formed by proteins called CatSper. These channels are selective, allowing only calcium ion to pass. The opening of CatSper channels is responsible for the influx of calcium. The sudden rise in calcium levels causes the flagellum to form deeper bends, propelling the sperm more forcefully through the viscous environment. Sperm hyperactivity is necessary for breaking through two physical barriers that protect the egg from fertilization.
The second process in sperm activation is the acrosome reaction. This involves releasing hyaluronidase to digest cumulus cells surrounding the oocyte and exposing acorsin attatched to the inner membrane of the sperm. The cumulus cells are embedded in a gel-like substance made primarily of hyaluronic acid, and developed in the ovary with the egg and support it as it grows.
Acrosin digests the zona pellucida and membrane of the oocyte. Part of the sperm's cell membrane then fuses with the egg cell's membrane, and the contents of the head sink into the egg. ZP3, one of the proteins that make up the zona pellucida, binds to a partner molecule on the sperm. This lock-and-key type mechanism is species-specific and prevents the sperm and egg of different species from fusing. There is some evidence that this binding is what triggers the acrosome to release the enzymes that allow the sperm to fuse with the egg.
Upon penetration, the oocyte is said to have become activated. It undergoes its secondary meiotic division, and the two haploid nuclei (paternal and maternal) fuse to form a zygote. In order to prevent polyspermy and minimise the possibility of producing a triploid zygote, several changes to the egg's cell membranes renders them impenetrable shortly after the first sperm enters the egg. | Spermatozoon
Template:Infobox Anatomy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [3]
A spermatozoon or spermatozoan (pl. spermatozoa), from the ancient Greek σπέρμα (seed) and Template:Unicode (living being) and more commonly known as a sperm cell, is the haploid cell that is the male gamete. It joins an ovum to form a zygote. A zygote is a single cell, with a complete set of chromosomes, that normally develops into an embryo.
Sperm cells contribute half of the genetic information to the diploid offspring. In mammals, the sex of the offspring is determined by the sperm cells: a spermatozoon bearing a Y chromosome will lead to a male (XY) offspring, while one bearing an X chromosome will lead to a female (XX) offspring (the ovum always provides an X chromosome). Sperm cells were first observed by a student of Anton van Leeuwenhoek in 1677.[1]
# Mammalian spermatozoan structure, function, and size
## Humans
The human sperm cell is the reproductive cell in males. Sperm cells come in two types; "male" and "female." Sperm cells that give rise to female (XX) offspring after fertilization differ in that they carry an X chromosome, while sperm cells that give rise to male (XY) offspring carry a Y chromosome. The "female" sperm cell also differs phenotypically in that it has a larger head in comparison to the "male" sperm cell.
In male humans, sperm cells consists of a head 5 µm by 3 µm and a tail 50 µm long. The Reynolds number associated with spermatozoa is in the order of 1Template:E, so it is known that the spermatozoa exhibit laminar flow. Spermatozoan stream lines are straight and parallel. The tail flagellates, which propels the sperm cell (at about 1-3 mm/minute in humans) by whipping in an elliptical cone.
[2]. Semen has an alkaline nature, and they do not reach full motility (hypermotility) until they reach the vagina where the alkaline pH is neutralized by acidic vaginal fluids. This gradual process takes 20-30 minutes. In this time, fibrinogen from the seminal vesicles forms a clot, securing and protecting the sperm. Just as they become hypermotile, fibrinolysin from the prostate dissolves the clot, allowing the sperm to progress optimally.
The spermatozoon is characterized by a minimum of cytoplasm and the most densely packed DNA known in eukaryotes. Compared to mitotic chromosomes in somatic cells, sperm DNA is at least sixfold more highly condensed.[3]
During fertilization, the sperm's mitochondria are destroyed by the egg cell, and this means only the mother is able to
provide the baby's mitochondria and mitochondrial DNA, which have an important application in tracing maternal ancestry. However it has been recently discovered that mitochondrial DNA can be recombinant
[4].
## Avoidance of immune system response
Glycoprotein molecules on the surface of sperm cells are recognised by all human immune systems, and interpreted as a signal that the cell should not be rejected. The male immune system might otherwise attack sperm whilst in the testes, and the female immune system would attack sperm in the reproductive tract. The specific glycoproteins coating sperm cells are also utilized by some cancerous and bacterial cells, some parasitic worms, and HIV-infected white blood cells, in order to avoid an immune response from the host organism.[5]
# Spermatozoa production in mammals
Spermatozoa are produced in the seminiferous tubules of the testes in a process called spermatogenesis. Round cells called spermatogonia divide and differentiate eventually to become spermatozoa. During copulation the cloaca or vagina gets inseminated, and then the spermatozoa move through chemotaxis to the ovum inside a Fallopian tube or the uterus.
# Spermatozoa Activation
Mammalian sperm cells become even more active when they approach an egg cell in a process called sperm activation. Sperm activation has been shown to be caused by calcium ionophores in vitro, progesterone released by nearby cumulus cells and binding to ZP3 of the zona pellucida.
The intiial change is called "hyperactivation", which causes a change in spermatozoa motility. They swim faster and their tail movements become more forceful and erratic.
A recent discovery links hyperactivation to a sudden influx of calcium ion into the tails. The whip-like tail (flagellum) of the sperm is studded with ion channels formed by proteins called CatSper. These channels are selective, allowing only calcium ion to pass. The opening of CatSper channels is responsible for the influx of calcium. The sudden rise in calcium levels causes the flagellum to form deeper bends, propelling the sperm more forcefully through the viscous environment. Sperm hyperactivity is necessary for breaking through two physical barriers that protect the egg from fertilization.
The second process in sperm activation is the acrosome reaction. This involves releasing hyaluronidase to digest cumulus cells surrounding the oocyte and exposing acorsin attatched to the inner membrane of the sperm. The cumulus cells are embedded in a gel-like substance made primarily of hyaluronic acid, and developed in the ovary with the egg and support it as it grows.
Acrosin digests the zona pellucida and membrane of the oocyte. Part of the sperm's cell membrane then fuses with the egg cell's membrane, and the contents of the head sink into the egg. ZP3, one of the proteins that make up the zona pellucida, binds to a partner molecule on the sperm. This lock-and-key type mechanism is species-specific and prevents the sperm and egg of different species from fusing. There is some evidence that this binding is what triggers the acrosome to release the enzymes that allow the sperm to fuse with the egg.
Upon penetration, the oocyte is said to have become activated. It undergoes its secondary meiotic division, and the two haploid nuclei (paternal and maternal) fuse to form a zygote. In order to prevent polyspermy and minimise the possibility of producing a triploid zygote, several changes to the egg's cell membranes renders them impenetrable shortly after the first sperm enters the egg. | https://www.wikidoc.org/index.php/Spermatazoa | |
b168caa8207f140fbae4335ab21b32393ec4e8b2 | wikidoc | Spermatocyte | Spermatocyte
A spermatocyte is a male gametocyte which is derived from a spermatogonium. Initially in spermatogenesis, a spermatogonium divides by mitosis into two so-called primary spermatocytes. A primary spermatocyte is also diploid, and, in turn, gives place by meiosis to two secondary spermatocytes, which this time are haploid.
# Additional images
- Histological section through testicular parenchyma of a boar. 1 Lumen of Tubulus seminiferus contortus, 2 spermatids, 3 spermatocytes, 4 spermatogonia, 5 Sertoli cell, 6 Myofibroblasts, 7 Leydig cells, 8 capillaries
Histological section through testicular parenchyma of a boar. 1 Lumen of Tubulus seminiferus contortus, 2 spermatids, 3 spermatocytes, 4 spermatogonia, 5 Sertoli cell, 6 Myofibroblasts, 7 Leydig cells, 8 capillaries | Spermatocyte
Template:Infobox Anatomy
A spermatocyte is a male gametocyte which is derived from a spermatogonium. Initially in spermatogenesis, a spermatogonium divides by mitosis into two so-called primary spermatocytes. A primary spermatocyte is also diploid, and, in turn, gives place by meiosis to two secondary spermatocytes, which this time are haploid.
# Additional images
- Histological section through testicular parenchyma of a boar. 1 Lumen of Tubulus seminiferus contortus, 2 spermatids, 3 spermatocytes, 4 spermatogonia, 5 Sertoli cell, 6 Myofibroblasts, 7 Leydig cells, 8 capillaries
Histological section through testicular parenchyma of a boar. 1 Lumen of Tubulus seminiferus contortus, 2 spermatids, 3 spermatocytes, 4 spermatogonia, 5 Sertoli cell, 6 Myofibroblasts, 7 Leydig cells, 8 capillaries
Template:Male reproductive system
Template:WH
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Spermatocyte | |
e63b7d1530f0116e0bb32cce2e6cbcf6b7fd46bf | wikidoc | Spinal tumor | Spinal tumor
# Overview
Spinal tumors are neoplasms located in the spinal cord. They are mostly metastases from primary cancers elsewhere (commonly breast, prostate and lung cancer). Primary tumors may be benign (e.g. hemangioma) or malignant in nature.
Depending on their location, the spinal cord tumors can be:
- Extradural - outside the dura mater lining
- Intradural - part of the dura
- Intramedullary - inside the spinal cord
The symptoms seen are due to spinal nerve compression and weakening of the vertebral structure. Incontinence and decreased sensitivity in the saddle area (buttocks) are generally considered warning signs of spinal cord compression by the tumor. Back pain in a patient with known malignancy may prompt a bone scan to confirm or exclude spinal metastasis.
# Diagnosis
MRI and bone scanning are used for diagnostic purposes. This assesses not only the location of the tumor(s) but also their relationship with the spinal cord and the risk of cord compression.
# Treatment
- Steroids may be administered if there is evidence of spinal cord compression. These do not affect the tumoral mass itself, but tend to reduce the inflammatory reaction around it, and thus decrease the overall volume of the mass impinging on the spinal cord.
- Radiotherapy
- Surgery is sometimes possible | Spinal tumor
Template:DiseaseDisorder infobox
# Overview
Spinal tumors are neoplasms located in the spinal cord. They are mostly metastases from primary cancers elsewhere (commonly breast, prostate and lung cancer). Primary tumors may be benign (e.g. hemangioma) or malignant in nature.
Depending on their location, the spinal cord tumors can be:
- Extradural - outside the dura mater lining
- Intradural - part of the dura
- Intramedullary - inside the spinal cord
The symptoms seen are due to spinal nerve compression and weakening of the vertebral structure. Incontinence and decreased sensitivity in the saddle area (buttocks) are generally considered warning signs of spinal cord compression by the tumor. Back pain in a patient with known malignancy may prompt a bone scan to confirm or exclude spinal metastasis.
# Diagnosis
MRI and bone scanning are used for diagnostic purposes. This assesses not only the location of the tumor(s) but also their relationship with the spinal cord and the risk of cord compression.
# Treatment
- Steroids may be administered if there is evidence of spinal cord compression. These do not affect the tumoral mass itself, but tend to reduce the inflammatory reaction around it, and thus decrease the overall volume of the mass impinging on the spinal cord.
- Radiotherapy
- Surgery is sometimes possible
# External links
- Malia's Cord Foundation: An Organization Seeking a Cure for primary Spinal Cord Tumors
- Spinal Cord Tumor Association: Non-profit on line support group and research library for those suffering with spinal cord tumors
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Spinal_cord_neoplasm | |
ae5d9261afca8c6021b6e3f70c2a5125c8b4243b | wikidoc | Spinal shock | Spinal shock
# Overview
Spinal shock was first defined by Whytt in 1750 as a loss of sensation accompanied by motor paralysis with initial loss but gradual recovery of reflexes, following a spinal cord injury (SCI) -- most often a complete transection. Reflexes in the spinal cord caudal to the SCI are depressed (dysreflexia) or absent (areflexia), while those rostral to the SCI remain unaffected. Note that the 'shock' in spinal shock does not refer to circulatory collapse.
# Phases of Spinal Shock
## Explanation of Phases
Ditunno proposed a four-phase model for spinal shock in 2004.
Phase 1 is characterized by a complete loss -- or weakening -- of all reflexes below the SCI. This phase lasts for a day. The neurons involved in various reflex arcs normally receive a basal level of excitatory stimulation from the brain. After an SCI, these cells lose this input, and the neurons involved become hyperpolarized and therefore less responsive to stimuli.
Phase 2 occurs over the next two days, and is characterized by the return of some, but not all, reflexes below the SCI. The first reflexes to reappear are polysynaptic in nature, such as the bulbocavernosus reflex. Monosynaptic reflexes, such as the deep tendon reflexes, are not restored until Phase 3. Note that restoration of reflexes is not rostral to caudal as previously (and commonly) believed, but instead proceeds from polysynaptic to monosynaptic. The reason reflexes return is the hypersensitivity of reflex muscles following denervation -- more receptors for neurotransmitters are expressed and are therefore easier to stimulate.
Phases 3 and 4 are characterized by hyperreflexia, or abnormally strong reflexes usually produced with minimal stimulation. Interneurons and lower motor neurons below the SCI begin sprouting, attempting to re-establish synapses. The first synapses to form are from shorter axons, usually from interneurons; this is Phase 3. Phase 4, on the other hand, is soma-mediated, and as it takes longer for axonal transport to push growth factors and proteins from soma to the end of the axon, it takes longer.
# Autonomic Effects
In spinal cord injuries above T6, autonomic dysreflexia may occur, from the loss of autonomic innervation from the brain. Sacral parasympathetics (S2-S4) are lost, as are many sympathetic levels, depending on the level of the SCI. Cervical lesions cause total loss of sympathetic innervation and lead to vasovagal hypotension and bradyarrythmias -- which resolve in 3-6 weeks. Autonomic dysreflexia is permanent, and occurs from Phase 4 onwards. It is characterized by unchecked sympathetic stimulation below the SCI (from a loss of cranial regulation), leading to oftentimes extreme hypertension, loss of bladder/bowel control, sweating, headaches, and other sympathetic effects.
# Reference
- Ditunno JF, Little JW, Tessler A, Burns AS. Spinal shock revisited: a four-phase model. Spinal Cord. 2004 Jul;42(7):383-95. | Spinal shock
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Spinal shock was first defined by Whytt in 1750 as a loss of sensation accompanied by motor paralysis with initial loss but gradual recovery of reflexes, following a spinal cord injury (SCI) -- most often a complete transection. Reflexes in the spinal cord caudal to the SCI are depressed (dysreflexia) or absent (areflexia), while those rostral to the SCI remain unaffected. Note that the 'shock' in spinal shock does not refer to circulatory collapse.
# Phases of Spinal Shock
## Explanation of Phases
Ditunno proposed a four-phase model for spinal shock in 2004.
Phase 1 is characterized by a complete loss -- or weakening -- of all reflexes below the SCI. This phase lasts for a day. The neurons involved in various reflex arcs normally receive a basal level of excitatory stimulation from the brain. After an SCI, these cells lose this input, and the neurons involved become hyperpolarized and therefore less responsive to stimuli.
Phase 2 occurs over the next two days, and is characterized by the return of some, but not all, reflexes below the SCI. The first reflexes to reappear are polysynaptic in nature, such as the bulbocavernosus reflex. Monosynaptic reflexes, such as the deep tendon reflexes, are not restored until Phase 3. Note that restoration of reflexes is not rostral to caudal as previously (and commonly) believed, but instead proceeds from polysynaptic to monosynaptic. The reason reflexes return is the hypersensitivity of reflex muscles following denervation -- more receptors for neurotransmitters are expressed and are therefore easier to stimulate.
Phases 3 and 4 are characterized by hyperreflexia, or abnormally strong reflexes usually produced with minimal stimulation. Interneurons and lower motor neurons below the SCI begin sprouting, attempting to re-establish synapses. The first synapses to form are from shorter axons, usually from interneurons; this is Phase 3. Phase 4, on the other hand, is soma-mediated, and as it takes longer for axonal transport to push growth factors and proteins from soma to the end of the axon, it takes longer.
# Autonomic Effects
In spinal cord injuries above T6, autonomic dysreflexia may occur, from the loss of autonomic innervation from the brain. Sacral parasympathetics (S2-S4) are lost, as are many sympathetic levels, depending on the level of the SCI. Cervical lesions cause total loss of sympathetic innervation and lead to vasovagal hypotension and bradyarrythmias -- which resolve in 3-6 weeks. Autonomic dysreflexia is permanent, and occurs from Phase 4 onwards. It is characterized by unchecked sympathetic stimulation below the SCI (from a loss of cranial regulation), leading to oftentimes extreme hypertension, loss of bladder/bowel control, sweating, headaches, and other sympathetic effects.
# Reference
- Ditunno JF, Little JW, Tessler A, Burns AS. Spinal shock revisited: a four-phase model. Spinal Cord. 2004 Jul;42(7):383-95.
Template:Med-stub | https://www.wikidoc.org/index.php/Spinal_shock | |
b43bbebde5c6f699ebb989c85f9d90be1b752371 | wikidoc | Spinal veins | Spinal veins
The veins of the medulla spinalis (spinal veins, veins of the spinal cord) are situated in the pia mater and form a minute, tortuous, venous plexus.
They emerge chiefly from the median fissures of the medulla spinalis and are largest in the lumbar region.
In this plexus there are:
- (1) two median longitudinal veins, one in front of the anterior fissure, and the other behind the posterior sulcus of the cord.
- (2) four lateral longitudinal veins which run behind the nerve roots.
They end in the intervertebral veins.
Near the base of the skull they unite, and form two or three small trunks, which communicate with the vertebral veins, and then end in the inferior cerebellar veins, or in the inferior petrosal sinuses. | Spinal veins
Template:Infobox Vein
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
The veins of the medulla spinalis (spinal veins, veins of the spinal cord) are situated in the pia mater and form a minute, tortuous, venous plexus.
They emerge chiefly from the median fissures of the medulla spinalis and are largest in the lumbar region.
In this plexus there are:
- (1) two median longitudinal veins, one in front of the anterior fissure, and the other behind the posterior sulcus of the cord.
- (2) four lateral longitudinal veins which run behind the nerve roots.
They end in the intervertebral veins.
Near the base of the skull they unite, and form two or three small trunks, which communicate with the vertebral veins, and then end in the inferior cerebellar veins, or in the inferior petrosal sinuses.
# External links
- Template:EMedicineDictionary
Template:Gray's
Template:Veins
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Spinal_veins | |
dbe29e78e1601b9ed97e710284d3376e7f45e779 | wikidoc | Spinnbarkeit | Spinnbarkeit
Spinnbarkeit is a medical term and refers to the stringy and/or stretchy quality found to varying degrees in mucus, saliva, and similar fluids. The term is used especially with reference to cervical mucus at the time just prior to or during ovulation.
Under the influence of estrogens this mucus becomes abundant, clear, and stretchable, somewhat like egg white. The stretchability of the mucus is termed spinnbarkeit, meaning in German that it has the ability to be spun. Only such mucus appears to be able to be penetrated by sperm. After ovulation, the character of cervical mucus changes, and under the influence of progesterone it becomes thick, scant, and tacky. Sperm typically cannot penetrate it.
Saliva does not always exhibit spinnbarkeit, but it can under certain circumstances. The thickness and spinnbarkeit of nasal mucus are factors in whether or not the nose seems to be blocked.
# External link
- Natural Family Planning Instructions: Cervical Mucus Method - mjbovo.com. | Spinnbarkeit
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Spinnbarkeit is a medical term and refers to the stringy and/or stretchy quality found to varying degrees in mucus, saliva, and similar fluids. The term is used especially with reference to cervical mucus at the time just prior to or during ovulation.
Under the influence of estrogens this mucus becomes abundant, clear, and stretchable, somewhat like egg white. The stretchability of the mucus is termed spinnbarkeit, meaning in German that it has the ability to be spun. Only such mucus appears to be able to be penetrated by sperm. After ovulation, the character of cervical mucus changes, and under the influence of progesterone it becomes thick, scant, and tacky. Sperm typically cannot penetrate it.
Saliva does not always exhibit spinnbarkeit, but it can under certain circumstances. The thickness and spinnbarkeit of nasal mucus are factors in whether or not the nose seems to be blocked.
# External link
- Natural Family Planning Instructions: Cervical Mucus Method - mjbovo.com.
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Spinnbarkeit | |
725dc8593a23e5e156ee6069d1cd563a2bcafd9a | wikidoc | Splenic cyst | Splenic cyst
# Overview
Splenic cyst is developmental in origin.
True nonparasitic splenic cyst, also called congenital cyst and epidermoid cyst, is defined by the presence of an inner endotheial lining.
# Differentiating Splenic cyst from Other Diseases
- Inflammatory (abscesses, hydatid cyst)
- Vascular (infarction], peliosis)
- Posttraumatic (hematoma, false cyst)
- Neoplastic (hemangioma, lymphangioma, lymphoma, metastasis)
# Diagnosis
## Ultrasound
- Anechoic well-defined, round mass.
## CT
- CT typically shows a large, low-attenuation,unilocular mass with imperceptible walls;
- HU are in the range of that of water.
- No enhancement is seen after the administration of contrast material
## MRI
- Magnetic resonance (MR) images show a well-defined, round mass.
- On T2-weighted images, the mass has markedly high signal intensity, a characteristic finding of a cyst. | Splenic cyst
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Splenic cyst is developmental in origin.
True nonparasitic splenic cyst, also called congenital cyst and epidermoid cyst, is defined by the presence of an inner endotheial lining.
# Differentiating Splenic cyst from Other Diseases
- Inflammatory (abscesses, hydatid cyst)
- Vascular (infarction], peliosis)
- Posttraumatic (hematoma, false cyst)
- Neoplastic (hemangioma, lymphangioma, lymphoma, metastasis)
# Diagnosis
## Ultrasound
- Anechoic well-defined, round mass.
## CT
- CT typically shows a large, low-attenuation,unilocular mass with imperceptible walls;
- HU are in the range of that of water.
- No enhancement is seen after the administration of contrast material
## MRI
- Magnetic resonance (MR) images show a well-defined, round mass.
- On T2-weighted images, the mass has markedly high signal intensity, a characteristic finding of a cyst.
-
-
- | https://www.wikidoc.org/index.php/Splenic_cyst | |
100d5cd7e270a54a2a65e7cf67ad11f079e2e6d7 | wikidoc | Spoon theory | Spoon theory
The Spoon Theory was developed by Christine Miserandino, a lupus sufferer from New York and founder of the website "But You Don't Look Sick." Miserandino was searching for a way to illustrate to her best friend what she endures every day in order to function with a chronic illness.
The theory uses spoons as units of measurement for personal energy, with the idea being that once the patient has depleted their supply of spoons for the day, they are too exhausted to continue with the necessities of life.
The creation of the theory led to the founding of ButYouDontLookSick.com and remains the single most widely-read article on the website today.
Miserandino went on from the creation of the Spoon Theory to found the website and continue her work as a writer and patient advocate. In 2008 she and her family will be honored by the Lupus Alliance of America for their ongoing efforts to assist the chronically ill. | Spoon theory
The Spoon Theory was developed by Christine Miserandino, a lupus sufferer from New York and founder of the website "But You Don't Look Sick." Miserandino was searching for a way to illustrate to her best friend what she endures every day in order to function with a chronic illness.
The theory uses spoons as units of measurement for personal energy, with the idea being that once the patient has depleted their supply of spoons for the day, they are too exhausted to continue with the necessities of life.[1]
The creation of the theory led to the founding of ButYouDontLookSick.com and remains the single most widely-read article on the website today.[2]
Miserandino went on from the creation of the Spoon Theory to found the website and continue her work as a writer and patient advocate. In 2008 she and her family will be honored by the Lupus Alliance of America for their ongoing efforts to assist the chronically ill.[3] | https://www.wikidoc.org/index.php/Spoon_theory | |
dd00ede75b60297a3f7770c9187aeefeb69c23ce | wikidoc | Sports drink | Sports drink
A sports drink is a beverage designed to help athletes rehydrate, as well as replenish electrolytes, sugar, and other nutrients, which can be depleted after strenuous training or competition. Companies marketing these products point out the fact that plain water, despite its association with good health, can actually be toxic if consumed in large amounts (cf. water intoxication). This can happen because overconsumption of water reduces levels of electrolytes such as sodium and potassium in the body by dilution, interfering with the nervous system. An example of a sport drink is Powerade, or what is possibly the best known sports drink in the United States, Gatorade, which was introduced in 1966.
Currently the largest growing segment of the sports drink market is non-athletes.
This market shift has led some sports drinks manufacturers to specifically target and develop products aimed at non-athletes, such as low-sodium or low-calorie sports drinks. Non-athletes who use sports drinks should also be aware that sports drinks for athletes typically contain high levels of carbohydrates which will result in weight gain if consumed without a corresponding increase in exercise activity.
Sports drinks are not to be confused with energy drinks (e.g. Full Throttle, Lucozade, Mountain Dew AMP, or Monster Energy). Sports drinks are intended to replenish electrolytes, sugar, water, and other nutrients, and are usually isotonic (containing the same proportions as found in the human body). Energy drinks, on the other hand, simply provide lots of sugar and caffeine.
The sports drinks on the market today include Gatorade by PepsiCo, Inc., All Sport by Monarch Beverage Co., Powerade by Coca Cola, Accelerade by PacificHealth Laboratories, Lucozade Sport by GlaxoSmithKline, Cera Sport by Cera Products, and many others such as Pocari Sweat. | Sports drink
A sports drink is a beverage designed to help athletes rehydrate, as well as replenish electrolytes, sugar, and other nutrients, which can be depleted after strenuous training or competition. Companies marketing these products point out the fact that plain water, despite its association with good health, can actually be toxic if consumed in large amounts (cf. water intoxication). This can happen because overconsumption of water reduces levels of electrolytes such as sodium and potassium in the body by dilution, interfering with the nervous system. An example of a sport drink is Powerade, or what is possibly the best known sports drink in the United States, Gatorade, which was introduced in 1966.
Currently the largest growing segment of the sports drink market is non-athletes.[1]
This market shift has led some sports drinks manufacturers to specifically target and develop products aimed at non-athletes, such as low-sodium or low-calorie sports drinks. Non-athletes who use sports drinks should also be aware that sports drinks for athletes typically contain high levels of carbohydrates which will result in weight gain if consumed without a corresponding increase in exercise activity.[2]
Sports drinks are not to be confused with energy drinks (e.g. Full Throttle, Lucozade, Mountain Dew AMP, or Monster Energy). Sports drinks are intended to replenish electrolytes, sugar, water, and other nutrients, and are usually isotonic (containing the same proportions as found in the human body). Energy drinks, on the other hand, simply provide lots of sugar and caffeine.
The sports drinks on the market today include Gatorade by PepsiCo, Inc., All Sport by Monarch Beverage Co., Powerade by Coca Cola, Accelerade by PacificHealth Laboratories, Lucozade Sport by GlaxoSmithKline, Cera Sport by Cera Products, and many others such as Pocari Sweat. | https://www.wikidoc.org/index.php/Sports_drink | |
581b348bbb51d73a7c6a7449951174f373353a5c | wikidoc | Stage fright | Stage fright
# Background
Stage fright or performance anxiety refers to an anxiety, fear or persistent phobia related to performance in front of an audience or camera. This form of anxiety can precede or accompany participation in any activity involving public self-presentation.
# Explanation
Often the term "stage fright" or topophobia is conflated with glossophobia, a fear of speaking in public. Jugglers and mimes are the simplest examples of the difference in notions.
Performance anxiety is also observed in sportsmen. In the latter case it is interpreted as a fear to underperform (in view of the actual public or implied publicity).
Quite often stage fright arises in a mere anticipation of a performance, often long time ahead. It has numerous manifestations: fluttering or pounding heart, tremor in hands and legs, diarrhea, facial nerve tics, dry mouth.
Stage fright may be observed in ordinary people, beginning artists, as well as in accomplished ones.
Some musicians use beta blockers to avoid stage fright during auditions, and performances. In other cases, performers use alcoholic beverages to ease their stage fright. There have been many cases in which this habit has led to alcoholism.
# Footnotes
- ↑ Better Playing Through Chemistry by Blair Tindall, New York Times October 17, 2004.
de:Lampenfieber
id:Demam panggung
nl:Plankenkoorts
sv:Scenskräck | Stage fright
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Background
Stage fright or performance anxiety refers to an anxiety, fear or persistent phobia related to performance in front of an audience or camera. This form of anxiety can precede or accompany participation in any activity involving public self-presentation.
# Explanation
Often the term "stage fright" or topophobia is conflated with glossophobia, a fear of speaking in public. Jugglers and mimes are the simplest examples of the difference in notions.
Performance anxiety is also observed in sportsmen. In the latter case it is interpreted as a fear to underperform (in view of the actual public or implied publicity).
Quite often stage fright arises in a mere anticipation of a performance, often long time ahead. It has numerous manifestations: fluttering or pounding heart, tremor in hands and legs, diarrhea, facial nerve tics, dry mouth.
Stage fright may be observed in ordinary people, beginning artists, as well as in accomplished ones.
Some musicians use beta blockers to avoid stage fright during auditions, and performances.[1] In other cases, performers use alcoholic beverages to ease their stage fright. There have been many cases in which this habit has led to alcoholism.
# Footnotes
- ↑ Better Playing Through Chemistry by Blair Tindall, New York Times October 17, 2004.
de:Lampenfieber
id:Demam panggung
nl:Plankenkoorts
sv:Scenskräck | https://www.wikidoc.org/index.php/Stage_fright | |
18496eb62903c7583ec14c00d22f942970ede4eb | wikidoc | Stapedectomy | Stapedectomy
A stapedectomy is a surgical procedure of the middle ear performed to improve hearing. The world's first stapedectomy is credited to Dr. John J. Shea, Jr., performed in May, 1956, the first patient being a 54 year-old housewife who could no longer hear even with a hearing aid.
If the stapes footplate is fixed in position, rather than being normally mobile, then a conductive hearing loss results. There are two major causes of stapes fixation. The first is a disease process of abnormal mineralization of the temporal bone called otosclerosis. The second is a congenital malformation of the stapes.
In both of these situations, it is possible to improve hearing by removing the stapes bone and replacing it with a micro prosthesis - a stapedectomy, or creating a small hole in the fixed stapes footplace and inserting a tiny, piston-like prothesis - a stapedotomy.
The results of this surgery are generally most reliable in patients whose stapes has lost mobility because of otosclerosis. Nine out of ten patients who undergo the procedure will come out with significantly improved hearing while less than 1% will experience worsened hearing ability or deafness. Successful surgery usually provides an increase in hearing ability of about 20 dB. That is as much difference as having your hands over both ears, or not. The relative success rate for this surgery varies considerably between surgeons. As for any surgical procedure, all other variables fixed, the more experience the surgeon has with the surgery, the better the outcome. Since stapes surgery is fairly rare, significantly better success rates are found at facilities that specialize in this procedure.
# Indications
Indications of stapedectomy:
- Conductive deafness due to fixation of stapes.
- Air bone gap of at least 40 dB.
- Presence of Carhart's notch in the audiogram of a patient with conductive deafness.
- Good cochlear reserve as assessed by the presence of good speech discrimination.
# Contraindications
Contraindications for stapedectomy:
- Poor general condition of the patient.
- Only hearing ear.
- Poor cochlear reserve as shown by poor speech discrimination scores
- Patient with tinnitus and vertigo
- Presence of active otosclerotic foci (otospongiosis) as evidenced by a positive flemmingo sign.
- Conductive deafness due to Ehlers-Danlos Syndrome (EDS)
# Complications
Complications of stapedectomy:
- Facial palsy
- Vertigo in the immediate post op period
- Vomiting
- Perilymph gush
- Floating foot plate
- Tympanic membrane tear
- Dead labyrinth
- Perilymph fistula
- Labyrinthitis
When a stapedectomy is done in a middle ear with a congenitally fixed footplate, the results may be excellent but the risk of hearing damage is greater than when the stapes bone is removed and replaced (for otosclerosis). This is primarily due to the risk of additional anomalies being present in the congenitally abnormal ear. If high pressure within the fluid compartment that lies just below the stapes footplate exists, then a perilymphatic gusher may occur when the stapes is removed. Even without immediate complications during surgery, there is always concern of a perilymph fistula forming postoperatively.
# Stapedotomy
A modified stapes operation, called a stapedotomy, is thought by many otologic surgeons to be safer and reduce the chances of postoperative complications. In stapedotomy, instead of removing the whole stapes footplace, a tiny hole is made in the footplate - either with a microdrill or with a laser, and a prosthesis is placed to touch this area with movement of the tympanic membrane. This procedure greatly reduces the chance of a perilymph fistula (leakage of cochlear fluid) and can be further improved by the use of a tissue graft seal of the fenestra.
# Footnotes
- ↑ "John J. Shea, Jr". Shea Ear Clinic. Retrieved 2007-07-03..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}
- ↑ Perkins, Rodney C. (1980), "Laser Stapedotomy for Otosclerosis", Laryngoscope, 90 (2): 228–241
- ↑ de Souza; Glassock (2004), Otosclerosis and Stapedectomy, ISBN 1588901696 | Stapedectomy
Template:Interventions infobox
A stapedectomy is a surgical procedure of the middle ear performed to improve hearing. The world's first stapedectomy is credited to Dr. John J. Shea, Jr., performed in May, 1956, the first patient being a 54 year-old housewife who could no longer hear even with a hearing aid.[1]
If the stapes footplate is fixed in position, rather than being normally mobile, then a conductive hearing loss results. There are two major causes of stapes fixation. The first is a disease process of abnormal mineralization of the temporal bone called otosclerosis. The second is a congenital malformation of the stapes.
In both of these situations, it is possible to improve hearing by removing the stapes bone and replacing it with a micro prosthesis - a stapedectomy, or creating a small hole in the fixed stapes footplace and inserting a tiny, piston-like prothesis - a stapedotomy.
The results of this surgery are generally most reliable in patients whose stapes has lost mobility because of otosclerosis. Nine out of ten patients who undergo the procedure will come out with significantly improved hearing while less than 1% will experience worsened hearing ability or deafness. Successful surgery usually provides an increase in hearing ability of about 20 dB. That is as much difference as having your hands over both ears, or not. The relative success rate for this surgery varies considerably between surgeons. As for any surgical procedure, all other variables fixed, the more experience the surgeon has with the surgery, the better the outcome. Since stapes surgery is fairly rare, significantly better success rates are found at facilities that specialize in this procedure.
# Indications
Indications of stapedectomy:
- Conductive deafness due to fixation of stapes.
- Air bone gap of at least 40 dB.
- Presence of Carhart's notch in the audiogram of a patient with conductive deafness.
- Good cochlear reserve as assessed by the presence of good speech discrimination.
# Contraindications
Contraindications for stapedectomy:
- Poor general condition of the patient.
- Only hearing ear.
- Poor cochlear reserve as shown by poor speech discrimination scores
- Patient with tinnitus and vertigo
- Presence of active otosclerotic foci (otospongiosis) as evidenced by a positive flemmingo sign.
- Conductive deafness due to Ehlers-Danlos Syndrome (EDS)
# Complications
Complications of stapedectomy:
- Facial palsy
- Vertigo in the immediate post op period
- Vomiting
- Perilymph gush
- Floating foot plate
- Tympanic membrane tear
- Dead labyrinth
- Perilymph fistula
- Labyrinthitis
When a stapedectomy is done in a middle ear with a congenitally fixed footplate, the results may be excellent but the risk of hearing damage is greater than when the stapes bone is removed and replaced (for otosclerosis). This is primarily due to the risk of additional anomalies being present in the congenitally abnormal ear. If high pressure within the fluid compartment that lies just below the stapes footplate exists, then a perilymphatic gusher may occur when the stapes is removed. Even without immediate complications during surgery, there is always concern of a perilymph fistula forming postoperatively.
# Stapedotomy
A modified stapes operation, called a stapedotomy, is thought by many otologic surgeons to be safer and reduce the chances of postoperative complications. In stapedotomy, instead of removing the whole stapes footplace, a tiny hole is made in the footplate - either with a microdrill or with a laser,[5] and a prosthesis is placed to touch this area with movement of the tympanic membrane. This procedure greatly reduces the chance of a perilymph fistula (leakage of cochlear fluid) and can be further improved by the use of a tissue graft seal of the fenestra.[6]
# Footnotes
- ↑ "John J. Shea, Jr". Shea Ear Clinic. Retrieved 2007-07-03..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}
- ↑ http://www.ghorayeb.com
- ↑ http://www.ghorayeb.com
- ↑ http://www.ghorayeb.com
- ↑ Perkins, Rodney C. (1980), "Laser Stapedotomy for Otosclerosis", Laryngoscope, 90 (2): 228–241
- ↑ de Souza; Glassock (2004), Otosclerosis and Stapedectomy, ISBN 1588901696
# External links
- Balasubramanian T (2006). "Stapedectomy". Retrieved 2007-07-03. - details of the procedure with pictures
- Amanda Jenner, Lynne Shields PhD ccc-slp "Speech and Language Issues" [1]
- M. Hawthorne, FRCS-ENT Surgeon. "Hearing Impairment and EDS" [2]
Template:Operations and other procedures on the ear
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Stapedectomy | |
7bde904b4bb0ecb7d7922f4c26befb6855f08fad | wikidoc | Stark effect | Stark effect
The Stark effect is the shifting and splitting of spectral lines of atoms and molecules due to the presence of an external static electric field. The amount of splitting and or shifting is called the Stark splitting or Stark shift. In general one distinguishes first- and second-order Stark effects. The first-order effect is linear in the applied electric field, while the second-order effect is quadratic in the field.
The Stark effect is responsible for the pressure broadening (Stark broadening) of spectral lines by charged particles. When the split/shifted lines appear in absorption, the effect is called the inverse Stark effect.
The Stark effect is the electric analogue of the Zeeman effect where a spectral line is split into several components due to the presence of a magnetic field.
# History
The effect is named after Johannes Stark, who discovered it in 1913. It was independently discovered in the same year by the Italian physicist Antonino Lo Surdo, and in Italy it is thus sometimes called the Stark-Lo Surdo effect. The discovery of this effect contributed importantly to the development of quantum theory. Ironically, soon after their discoveries, both Stark and Lo Surdo rejected developments in modern physics and allied themselves with the political and racial programs of Hitler and Mussolini.
Inspired by the magnetic Zeeman effect, and especially by Lorentz' explanation of it, Woldemar Voigt performed classical mechanical calculations of quasi-elastically bound electrons in an electric field. By using experimental indices of refraction he gave an estimate of the Stark splittings. This estimate was a few orders of magnitude too low. Not deterred by this prediction, Stark undertook measurements on excited states of the hydrogen atom and succeeded in observing splittings.
By the use of the Bohr-Sommerfeld ("old") quantum theory Paul Epstein and Karl Schwarzschild were independently able to derive equations for the linear and quadratic Stark effect in hydrogen. Four years later, Hendrik Kramers derived formulas for intensities of spectral transitions. Kramers also included the effect of fine structure, which includes corrections for relativistic kinetic energy and coupling between electron spin and orbit. The first quantum mechanical treatment (in the framework of Heisenberg's matrix mechanics) was by Wolfgang Pauli. Erwin Schrödinger discussed at length the Stark effect in his third paper on quantum theory (in which he introduced his perturbation theory), once in the manner of the 1916 work of Epstein (but generalized from the old to the new quantum theory) and once by his (first-order) perturbation approach.
Finally, Epstein reconsidered the linear and quadratic Stark effect from the point of view of the new quantum theory. He derived equations for the line intensities which were a decided improvement over Kramers' results obtained by the old quantum theory.
# Mechanism
## Classical electrostatics
The Stark effect originates from the interaction between a charge distribution (atom or molecule) and an external electric field. Before turning to quantum mechanics we describe the interaction
classically and consider a continuous charge distribution ρ(r).
If this charge distribution is non-polarizable its interaction energy with an external electrostatic potential V(r) is
If the electric field is of macroscopic origin and the charge distribution is microscopic, it is reasonable to assume that the electric field is uniform over the charge distribution. That is, V is given by a two-term Taylor expansion,
V(\mathbf{r}) = V(\mathbf{0}) - \sum_{i=1}^3 r_i F_i \quad \hbox{with the electric field:}\quad
F_i \equiv -\left. \left(\frac{\partial V}{\partial r_i} \right)\right|_{\mathbf{0}},
where we took the origin 0 somewhere within ρ.
With V(\mathbf{0})\int \rho(\mathbf{r}) d\mathbf{r} as the zero energy, the interaction becomes
E_{\mathrm{int}} = - \sum_{i=1}^3 F_i \int \rho(\mathbf{r}) r_i d\mathbf{r} \equiv
- \sum_{i=1}^3 F_i \mu_i = - \mathbf{F}\cdot \boldsymbol{\mu}.
Here we have introduced the dipole moment μ of ρ as an integral over the charge distribution. In case ρ consists of N point charges qj this definition becomes a sum
\boldsymbol{\mu} \equiv \sum_{j=1}^N q_j \mathbf{r}_j.
## Perturbation theory
Turning now to quantum mechanics we see an atom or a molecule as a collection of point charges (electrons and nuclei), so that the second definition of the dipole applies. The interaction of atom or molecule with a uniform external field is described by the operator
This operator is used as a perturbation in first- and second-order perturbation theory to account for the first- and second-order Stark effect.
### First order
Let the unperturbed atom or molecule be in a g-fold degenerate state with orthonormal zeroth-order state functions \psi^0_1, \ldots, \psi^0_g . (Non-degeneracy is the special case g = 1). According to perturbation theory the first-order energies are the eigenvalues of the g x g matrix with general element
(\mathbf{V}_{\mathrm{int}})_{kl} = \langle \psi^0_k | V_{\mathrm{int}} | \psi^0_l \rangle =
-\mathbf{F}\cdot \langle \psi^0_k | \boldsymbol{\mu} | \psi^0_l \rangle,
\qquad k,l=1,\ldots, g.
If g = 1 (as is often the case for electronic states of molecules) the first-order energy becomes proportional to the expectation (average) value of the dipole operator \boldsymbol{\mu},
E^{(1)} = -\mathbf{F}\cdot \langle \psi^0_1 | \boldsymbol{\mu} | \psi^0_1 \rangle =
-\mathbf{F}\cdot \langle \boldsymbol{\mu} \rangle.
Because a dipole moment is a polar vector, the diagonal elements of the perturbation matrix Vint vanish for systems with an inversion center (such as atoms). Molecules with an inversion center in a non-degenerate electronic state do not have a (permanent) dipole and hence do not show a linear Stark effect.
In order to obtain a non-zero matrix Vint for systems with an inversion center it is necessary that some of the unperturbed functions \psi^0_i have opposite parity (obtain plus and minus under inversion), because only functions of opposite parity give non-vanishing matrix elements. Degenerate zeroth-order states of opposite parity occur for excited hydrogen-like (one-electron) atoms. Such atoms have the principal quantum number n among their quantum numbers. The excited state of hydrogen-like atoms with principal quantum number n is n2-fold degenerate and
n^2 = \sum_{\ell=0}^{n-1} (2 \ell + 1),
where \ell is the azimuthal (angular momentum) quantum number. For instance, the excited n = 4 state contains the following \ell states,
16 = 1 + 3 + 5 +7 \;\; \Longrightarrow\;\; n=4\;\hbox{contains}\; s\oplus p\oplus d\oplus f.
The one-electron states with even \ell are even under parity, while those with odd \ell are odd under parity. Hence hydrogen-like atoms with n>1 show first-order Stark effect.
The first-order Stark effect occurs in rotational transitions of symmetric top molecules (but not for linear and asymmetric molecules). In first approximation a molecule may be seen as a rigid rotor. A symmetric top rigid rotor has the unperturbed eigenstates
with 2(2J+1)-fold degenerate energy for |K| > 0 and (2J+1)-fold degenerate energy for K=0.
Here DJMK is an element of the Wigner D-matrix. The first-order perturbation matrix on basis of the unperturbed rigid rotor function is non-zero and can be diagonalized. This gives shifts and splittings
in the rotational spectrum. Quantitative analysis of these Stark shift yields the permanent electric dipole moment of the symmetric top molecule.
### Second order
As stated, the quadratic Stark effect is described by second-order perturbation theory.
The zeroth-order problems
H^{(0)} \psi^0_k = E^{(0)}_k \psi^0_k, \quad k=0,1, \ldots, \quad E^{(0)}_0 < E^{(0)}_1 \le E^{(0)}_2, \dots
are assumed to be solved. It is usual to assume that the zeroth-order state to be perturbed is non-degenerate. If we take the ground state as the non-degenerate state under consideration (for hydrogen-like atoms: n = 1), perturbation theory gives
E^{(2)} = \sum_{k>0} \frac{\langle \psi^0_0 | V_\mathrm{int} | \psi^0_k \rangle \langle \psi^0_k | V_\mathrm{int} | \psi^0_0 \rangle}{E^{(0)}_0 - E^{(0)}_k}
=- \frac{1}{2} \sum_{i,j=1}^3 F_i \alpha_{ij} F_j
with the components of the polarizability tensor α defined by
\alpha_{ij}\equiv -2\sum_{k>0} \frac{\langle \psi^0_0 | \mu_i | \psi^0_k \rangle \langle \psi^0_k | \mu_j | \psi^0_0\rangle}{E^{(0)}_0 - E^{(0)}_k}.
The energy E(2) gives the quadratic Stark effect.
Because of their spherical symmetry the polarizability tensor of atoms is isotropic,
\alpha_{ij} = \alpha_0 \delta_{ij} \Longrightarrow E^{(2)} = -\frac{1}{2} \alpha_0 F^2,
which is the quadratic Stark shift for atoms. For many molecules this expression is not too bad an approximation, because molecular tensors are often reasonably isotropic.
### Problems
The perturbative treatment of the Stark effect has some problems. In the presence of an electric field, states of atoms and molecules that were previously bound (square-integrable), become formally (non-square-integrable) resonances of finite width.
These resonances may decay in finite time via field ionization. For low lying states and not too strong fields the decay times are so long, however, that for all practical purposes the system can be regarded as bound. For highly excited states and very strong fields ionization may have to be accounted for. (See also the article on the Rydberg atom).
# Quantum-Confined Stark Effect
In a semiconductor heterostructure, where a small bandgap material is sandwiched between two layers of a larger bandgap material, the Stark effect can be dramatically enhanced by bound excitons. This is due to the fact that the electron and hole which form the exciton are pulled in opposite directions by the applied electric field, but they remain confined in the smaller bandgap material, so the exciton is not merely pulled apart by the field. The quantum-confined Stark effect is widely used for semiconductor-based optical modulators, particularly for optical fiber communications. | Stark effect
The Stark effect is the shifting and splitting of spectral lines of atoms and molecules due to the presence of an external static electric field. The amount of splitting and or shifting is called the Stark splitting or Stark shift. In general one distinguishes first- and second-order Stark effects. The first-order effect is linear in the applied electric field, while the second-order effect is quadratic in the field.
The Stark effect is responsible for the pressure broadening (Stark broadening) of spectral lines by charged particles. When the split/shifted lines appear in absorption, the effect is called the inverse Stark effect.
The Stark effect is the electric analogue of the Zeeman effect where a spectral line is split into several components due to the presence of a magnetic field.
# History
The effect is named after Johannes Stark, who discovered it in 1913. It was independently discovered in the same year by the Italian physicist Antonino Lo Surdo, and in Italy it is thus sometimes called the Stark-Lo Surdo effect. The discovery of this effect contributed importantly to the development of quantum theory. Ironically, soon after their discoveries, both Stark and Lo Surdo rejected developments in modern physics and allied themselves with the political and racial programs of Hitler and Mussolini.[1]
Inspired by the magnetic Zeeman effect, and especially by Lorentz' explanation of it, Woldemar Voigt[2] performed classical mechanical calculations of quasi-elastically bound electrons in an electric field. By using experimental indices of refraction he gave an estimate of the Stark splittings. This estimate was a few orders of magnitude too low. Not deterred by this prediction, Stark [3] undertook measurements on excited states of the hydrogen atom and succeeded in observing splittings.
By the use of the Bohr-Sommerfeld ("old") quantum theory Paul Epstein[4] and Karl Schwarzschild[5] were independently able to derive equations for the linear and quadratic Stark effect in hydrogen. Four years later, Hendrik Kramers[6] derived formulas for intensities of spectral transitions. Kramers also included the effect of fine structure, which includes corrections for relativistic kinetic energy and coupling between electron spin and orbit. The first quantum mechanical treatment (in the framework of Heisenberg's matrix mechanics) was by Wolfgang Pauli[7]. Erwin Schrödinger discussed at length the Stark effect in his third paper[8] on quantum theory (in which he introduced his perturbation theory), once in the manner of the 1916 work of Epstein (but generalized from the old to the new quantum theory) and once by his (first-order) perturbation approach.
Finally, Epstein[9] reconsidered the linear and quadratic Stark effect from the point of view of the new quantum theory. He derived equations for the line intensities which were a decided improvement over Kramers' results obtained by the old quantum theory.
# Mechanism
## Classical electrostatics
The Stark effect originates from the interaction between a charge distribution (atom or molecule) and an external electric field. Before turning to quantum mechanics we describe the interaction
classically and consider a continuous charge distribution ρ(r).
If this charge distribution is non-polarizable its interaction energy with an external electrostatic potential V(r) is
If the electric field is of macroscopic origin and the charge distribution is microscopic, it is reasonable to assume that the electric field is uniform over the charge distribution. That is, V is given by a two-term Taylor expansion,
V(\mathbf{r}) = V(\mathbf{0}) - \sum_{i=1}^3 r_i F_i \quad \hbox{with the electric field:}\quad
F_i \equiv -\left. \left(\frac{\partial V}{\partial r_i} \right)\right|_{\mathbf{0}},
</math>
where we took the origin 0 somewhere within ρ.
With <math>V(\mathbf{0})\int \rho(\mathbf{r}) d\mathbf{r}</math> as the zero energy, the interaction becomes
E_{\mathrm{int}} = - \sum_{i=1}^3 F_i \int \rho(\mathbf{r}) r_i d\mathbf{r} \equiv
- \sum_{i=1}^3 F_i \mu_i = - \mathbf{F}\cdot \boldsymbol{\mu}.
</math>
Here we have introduced the dipole moment μ of ρ as an integral over the charge distribution. In case ρ consists of N point charges qj this definition becomes a sum
\boldsymbol{\mu} \equiv \sum_{j=1}^N q_j \mathbf{r}_j.
</math>
## Perturbation theory
Turning now to quantum mechanics we see an atom or a molecule as a collection of point charges (electrons and nuclei), so that the second definition of the dipole applies. The interaction of atom or molecule with a uniform external field is described by the operator
</math>
This operator is used as a perturbation in first- and second-order perturbation theory to account for the first- and second-order Stark effect.
### First order
Let the unperturbed atom or molecule be in a g-fold degenerate state with orthonormal zeroth-order state functions <math> \psi^0_1, \ldots, \psi^0_g </math>. (Non-degeneracy is the special case g = 1). According to perturbation theory the first-order energies are the eigenvalues of the g x g matrix with general element
(\mathbf{V}_{\mathrm{int}})_{kl} = \langle \psi^0_k | V_{\mathrm{int}} | \psi^0_l \rangle =
-\mathbf{F}\cdot \langle \psi^0_k | \boldsymbol{\mu} | \psi^0_l \rangle,
\qquad k,l=1,\ldots, g.
</math>
If g = 1 (as is often the case for electronic states of molecules) the first-order energy becomes proportional to the expectation (average) value of the dipole operator <math>\boldsymbol{\mu}</math>,
E^{(1)} = -\mathbf{F}\cdot \langle \psi^0_1 | \boldsymbol{\mu} | \psi^0_1 \rangle =
-\mathbf{F}\cdot \langle \boldsymbol{\mu} \rangle.
</math>
Because a dipole moment is a polar vector, the diagonal elements of the perturbation matrix Vint vanish for systems with an inversion center (such as atoms). Molecules with an inversion center in a non-degenerate electronic state do not have a (permanent) dipole and hence do not show a linear Stark effect.
In order to obtain a non-zero matrix Vint for systems with an inversion center it is necessary that some of the unperturbed functions <math> \psi^0_i</math> have opposite parity (obtain plus and minus under inversion), because only functions of opposite parity give non-vanishing matrix elements. Degenerate zeroth-order states of opposite parity occur for excited hydrogen-like (one-electron) atoms. Such atoms have the principal quantum number n among their quantum numbers. The excited state of hydrogen-like atoms with principal quantum number n is n2-fold degenerate and
n^2 = \sum_{\ell=0}^{n-1} (2 \ell + 1),
</math>
where <math>\ell </math> is the azimuthal (angular momentum) quantum number. For instance, the excited n = 4 state contains the following <math>\ell</math> states,
16 = 1 + 3 + 5 +7 \;\; \Longrightarrow\;\; n=4\;\hbox{contains}\; s\oplus p\oplus d\oplus f.
</math>
The one-electron states with even <math>\ell</math> are even under parity, while those with odd <math>\ell</math> are odd under parity. Hence hydrogen-like atoms with n>1 show first-order Stark effect.
The first-order Stark effect occurs in rotational transitions of symmetric top molecules (but not for linear and asymmetric molecules). In first approximation a molecule may be seen as a rigid rotor. A symmetric top rigid rotor has the unperturbed eigenstates
</math>
with 2(2J+1)-fold degenerate energy for |K| > 0 and (2J+1)-fold degenerate energy for K=0.
Here DJMK is an element of the Wigner D-matrix. The first-order perturbation matrix on basis of the unperturbed rigid rotor function is non-zero and can be diagonalized. This gives shifts and splittings
in the rotational spectrum. Quantitative analysis of these Stark shift yields the permanent electric dipole moment of the symmetric top molecule.
### Second order
As stated, the quadratic Stark effect is described by second-order perturbation theory.
The zeroth-order problems
H^{(0)} \psi^0_k = E^{(0)}_k \psi^0_k, \quad k=0,1, \ldots, \quad E^{(0)}_0 < E^{(0)}_1 \le E^{(0)}_2, \dots
</math>
are assumed to be solved. It is usual to assume that the zeroth-order state to be perturbed is non-degenerate. If we take the ground state as the non-degenerate state under consideration (for hydrogen-like atoms: n = 1), perturbation theory gives
E^{(2)} = \sum_{k>0} \frac{\langle \psi^0_0 | V_\mathrm{int} | \psi^0_k \rangle \langle \psi^0_k | V_\mathrm{int} | \psi^0_0 \rangle}{E^{(0)}_0 - E^{(0)}_k}
=- \frac{1}{2} \sum_{i,j=1}^3 F_i \alpha_{ij} F_j
</math>
with the components of the polarizability tensor α defined by
\alpha_{ij}\equiv -2\sum_{k>0} \frac{\langle \psi^0_0 | \mu_i | \psi^0_k \rangle \langle \psi^0_k | \mu_j | \psi^0_0\rangle}{E^{(0)}_0 - E^{(0)}_k}.
</math>
The energy E(2) gives the quadratic Stark effect.
Because of their spherical symmetry the polarizability tensor of atoms is isotropic,
\alpha_{ij} = \alpha_0 \delta_{ij} \Longrightarrow E^{(2)} = -\frac{1}{2} \alpha_0 F^2,
</math>
which is the quadratic Stark shift for atoms. For many molecules this expression is not too bad an approximation, because molecular tensors are often reasonably isotropic.
### Problems
The perturbative treatment of the Stark effect has some problems. In the presence of an electric field, states of atoms and molecules that were previously bound (square-integrable), become formally (non-square-integrable) resonances of finite width.
These resonances may decay in finite time via field ionization. For low lying states and not too strong fields the decay times are so long, however, that for all practical purposes the system can be regarded as bound. For highly excited states and very strong fields ionization may have to be accounted for. (See also the article on the Rydberg atom).
# Quantum-Confined Stark Effect
In a semiconductor heterostructure, where a small bandgap material is sandwiched between two layers of a larger bandgap material, the Stark effect can be dramatically enhanced by bound excitons. This is due to the fact that the electron and hole which form the exciton are pulled in opposite directions by the applied electric field, but they remain confined in the smaller bandgap material, so the exciton is not merely pulled apart by the field. The quantum-confined Stark effect is widely used for semiconductor-based optical modulators, particularly for optical fiber communications. | https://www.wikidoc.org/index.php/Stark_effect | |
8f169aff9c42350b756ea2279cee688c5e75ed4f | wikidoc | Stasis ulcer | Stasis ulcer
Synonyms and keywords: Venous insufficiency ulceration, stasis ulcer, stasis dermatitis, varicose ulcer, ulcus cruris.
# Overview
Venous ulcers (venous insufficiency ulceration, stasis ulcers, stasis dermatitis, varicose ulcers, or ulcus cruris) are wounds that are thought to occur due to improper functioning of venous valves, usually of the legs (hence leg ulcers).:846 They are the major occurrence of chronic wounds, occurring in 70% to 90% of leg ulcer cases. Venous ulcers develop mostly along the medial distal leg, and can be very painful.
Two layers of skin created from animal sources as a skin graft has been found to be useful in venous leg ulcers.
# Pathophysiology
The exact etiology of venous ulcers is not certain, but they are thought to arise when venous valves that exist to prevent backflow of blood do not function properly, causing the pressure in veins to increase. The body needs the pressure gradient between arteries and veins in order for the heart to pump blood forward through arteries and into veins. When venous hypertension exists, arteries no longer have significantly higher pressure than veins, and blood is not pumped as effectively into or out of the area.
Venous hypertension may also stretch veins and allow blood proteins to leak into the extravascular space, isolating extracellular matrix (ECM) molecules and growth factors, preventing them from helping to heal the wound. Leakage of fibrinogen from veins as well as deficiencies in fibrinolysis may also cause fibrin to build up around the vessels, preventing oxygen and nutrients from reaching cells. Venous insufficiency may also cause white blood cells (leukocytes) to accumulate in small blood vessels, releasing inflammatory factors and reactive oxygen species (ROS, free radicals) and further contributing to chronic wound formation. Buildup of white blood cells in small blood vessels may also plug the vessels, further contributing to ischemia. This blockage of blood vessels by leukocytes may be responsible for the "no reflow phenomenon," in which ischemic tissue is never fully reperfused. Allowing blood to flow back into the limb, for example by elevating it, is necessary but also contributes to reperfusion injury. Other comorbidities may also be the root cause of venous ulcers.
It is in the crus that the classic venous stasis ulcer occurs. Venous stasis results from damage to the vein valvular system in the lower extremity and in extreme cases allows the pressure in the veins to be higher than the pressure in the arteries. This pressure results in transudation of inflammatory mediators into the subcutaneous tissues of the lower extremity and subsequent breakdown of the tissue including the skin.
Wounds of the distal lower extremities arising from causes not directly related to venous insufficiency (e.g., scratch, bite, burn, or surgical incision) may ultimately fail to heal if underlying (often undiagnosed) venous disease is not properly addressed.
# Characteristics
Edema and fibrinous exudate leads to fibrosis of subcutaneous tissues with localized pigment loss and dilation of capillary loops. This is called atrophic blanche. This can occur around ankles and gives an appearance of inverted champagne bottle to legs. Large ulcers may encircle the leg.
Lymphoedema results from obliteration of superficial lymphatics. There is hypertrophy of overlying epidermis giving polypoid appearance, known as lipodermatosclerosis.
# Physical examination
## Gallery
### Head
- url = >
- url = >
- url = >
- url = >
# Diagnosis
## Classification
A clinical severity score has been developed to assess chronic venous ulcers. It is based on the CEAP (clinical, etiology, anatomy, and pathophysiology) classification system developed by an expert panel. A high score gives a poor prognosis.
## Distinction from arterial ulcer
An arterial ulcer tends to occur on lateral side of distal leg and leg is pulseless and cool. Venous ulceration is typically seen just above the medial malleolus. Arterial ulcers are seen distally and over bony prominences.
# Treatment
The main aim of the treatment is to create such an environment that allows skin to grow across an ulcer. In the majority of cases this requires finding and treating underlying venous reflux and NICE (National Institute for Health and Care Excellence) Clinical Guidelines CG 168 recommend referral to a Vascular Service for anyone with a leg ulcer that has not healed within 2 weeks or anyone with a healed leg ulcer.
## Bisgaard regimen
Most venous ulcers respond to a regimen called Bisgaard regimen for treating ulcers. It has four components: Patient education, elevation of foot, elastic compression and evaluation.
## Compression therapy
Non-elastic, ambulatory, below knee (BK) compression aggressively counters the impact of reflux on venous pump failure. Compression therapy is used for venous leg ulcers and can decrease blood vessel diameter and pressure, which increases their effectiveness, preventing blood from flowing backwards. Compression is also used to decrease release of inflammatory cytokines, lower the amount of fluid leaking from capillaries and therefore prevent swelling, and prevent clotting by decreasing activation of thrombin and increasing that of plasmin. Compression is applied using elastic bandages or boots specifically designed for the purpose.
Regarding effectiveness, compression dressings improve healing. It is not clear whether non-elastic systems are better than a multilayer elastic system. Patients should wear as much compression as is comfortable. The type of dressing applied beneath the compression does not seem to matter, and hydrocolloid is not better than simple low adherent dressings. Recently there have been clinical studies on a multi-functional botanical-based ointment in combination with compression therapy in the treatment of difficult-to-heal wounds, including venous leg ulcers.
Intermittent pneumatic compression devices may be used, but it is not clear that they are superior to simple compression dressings.
## Pentoxifylline
A meta-analysis of randomized controlled trials by the Cochrane Collaboration found that "Pentoxifylline is an effective adjunct to compression bandaging for treating venous ulcers and may be effective in the absence of compression". It works by reducing platelet aggregation and thrombus formation.
## Artificial skin
Artificial skin, made of collagen and cultured skin cells, is also used to cover venous ulcers and excrete growth factors to help them heal. A Systematic review of 17 Randomized trials found that Bilayer Artificial Skin with compression bandaging is useful in the healing of venous ulcers when compared to simple dressings.
## Surgical correction of superficial venous reflux
A randomized controlled trial found that surgery "reduces the recurrence of ulcers at four years and results in a greater proportion of ulcer free time".
## Local Anaesthetic Endovenous correction of superficial venous reflux
Local anaesthetic endovenous surgery using the thermoablation (endovenous laser ablation or radiofrequency), perforator closure (TRLOP) and foam sclerotherapy showed an 85% success rate of healing, with no recurrence of healed ulcers at an average of 3.1 years, and a clinical improvement in 98% in a selected group of venous leg ulcers.
## TIRS Technique
Terminal Interruption of Reflux Source Technique entails blocking off the veins that drain the ulcer bed using Sotradecol or Polidocanol foam, administered by ultrasound guidance.
# Prognosis
Venous ulcers are costly to treat, and there is a significant chance that they will recur after healing; one study found that up to 48% of venous ulcers had recurred by the fifth year after healing. However treatment with local anaesthetic endovenous techniques suggests a reduction of this high recurrence rate is possible.
Without proper care, the ulcer may get infected leading to cellulitis or gangrene and eventually may need amputation of the part of limb in future.
Some topical drugs used to treat venous ulcer may cause venous eczema.
# Current research
The current ‘best’ practice in the UK is to treat the underlying venous reflux once an ulcer has healed. It is questionable as to whether endovenous treatment should be offered before ulcer healing, as current evidence would not support this approach as standard care. EVRA (Early Venous Reflux Ablation) ulcer trial - A UK NIHR HTA funded randomised clinical trial to compare early versus delayed endovenous treatment of superficial venous reflux in patients with chronic venous ulceration opened for recruitment in October 2013. The study hopes to show an increase in healing rates from 60% to 75% at 24 weeks.
Research from the University of Surrey and funded by the Leg Ulcer Charity is currently looking at the effects that having a leg ulcer has on the relatives and friends of the affected person - and how this changes if the ulcer is permanently cured by endovenous surgery. | Stasis ulcer
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Jesus Rosario Hernandez, M.D. [2].
Synonyms and keywords: Venous insufficiency ulceration, stasis ulcer, stasis dermatitis, varicose ulcer, ulcus cruris.
# Overview
Venous ulcers (venous insufficiency ulceration, stasis ulcers, stasis dermatitis, varicose ulcers, or ulcus cruris) are wounds that are thought to occur due to improper functioning of venous valves, usually of the legs (hence leg ulcers).[1]:846 They are the major occurrence of chronic wounds, occurring in 70% to 90% of leg ulcer cases.[2] Venous ulcers develop mostly along the medial distal leg, and can be very painful.
Two layers of skin created from animal sources as a skin graft has been found to be useful in venous leg ulcers.[3]
# Pathophysiology
The exact etiology of venous ulcers is not certain, but they are thought to arise when venous valves that exist to prevent backflow of blood do not function properly, causing the pressure in veins to increase.[4][5][6][7] The body needs the pressure gradient between arteries and veins in order for the heart to pump blood forward through arteries and into veins. When venous hypertension exists, arteries no longer have significantly higher pressure than veins, and blood is not pumped as effectively into or out of the area.[4][5][6][7]
Venous hypertension may also stretch veins and allow blood proteins to leak into the extravascular space, isolating extracellular matrix (ECM) molecules and growth factors, preventing them from helping to heal the wound.[4][7] Leakage of fibrinogen from veins as well as deficiencies in fibrinolysis may also cause fibrin to build up around the vessels, preventing oxygen and nutrients from reaching cells.[4] Venous insufficiency may also cause white blood cells (leukocytes) to accumulate in small blood vessels, releasing inflammatory factors and reactive oxygen species (ROS, free radicals) and further contributing to chronic wound formation.[4][7] Buildup of white blood cells in small blood vessels may also plug the vessels, further contributing to ischemia.[8] This blockage of blood vessels by leukocytes may be responsible for the "no reflow phenomenon," in which ischemic tissue is never fully reperfused.[8] Allowing blood to flow back into the limb, for example by elevating it, is necessary but also contributes to reperfusion injury.[5] Other comorbidities may also be the root cause of venous ulcers.[6]
It is in the crus that the classic venous stasis ulcer occurs. Venous stasis results from damage to the vein valvular system in the lower extremity and in extreme cases allows the pressure in the veins to be higher than the pressure in the arteries. This pressure results in transudation of inflammatory mediators into the subcutaneous tissues of the lower extremity and subsequent breakdown of the tissue including the skin.
Wounds of the distal lower extremities arising from causes not directly related to venous insufficiency (e.g., scratch, bite, burn, or surgical incision) may ultimately fail to heal if underlying (often undiagnosed) venous disease is not properly addressed.
# Characteristics
Edema and fibrinous exudate leads to fibrosis of subcutaneous tissues with localized pigment loss and dilation of capillary loops. This is called atrophic blanche. This can occur around ankles and gives an appearance of inverted champagne bottle to legs. Large ulcers may encircle the leg.
Lymphoedema results from obliteration of superficial lymphatics. There is hypertrophy of overlying epidermis giving polypoid appearance, known as lipodermatosclerosis.
# Physical examination
## Gallery
### Head
- url = http://www.atlasdermatologico.com.br/disease.jsf?diseaseId=433>
- url = http://www.atlasdermatologico.com.br/disease.jsf?diseaseId=433>
- url = http://www.atlasdermatologico.com.br/disease.jsf?diseaseId=433>
- url = http://www.atlasdermatologico.com.br/disease.jsf?diseaseId=433>
# Diagnosis
## Classification
A clinical severity score has been developed to assess chronic venous ulcers. It is based on the CEAP (clinical, etiology, anatomy, and pathophysiology) classification system developed by an expert panel. A high score gives a poor prognosis.[9]
## Distinction from arterial ulcer
An arterial ulcer tends to occur on lateral side of distal leg and leg is pulseless and cool. Venous ulceration is typically seen just above the medial malleolus. Arterial ulcers are seen distally and over bony prominences.
# Treatment
The main aim of the treatment is to create such an environment that allows skin to grow across an ulcer. In the majority of cases this requires finding and treating underlying venous reflux and NICE (National Institute for Health and Care Excellence) Clinical Guidelines CG 168 recommend referral to a Vascular Service for anyone with a leg ulcer that has not healed within 2 weeks or anyone with a healed leg ulcer.[10]
## Bisgaard regimen
Most venous ulcers respond to a regimen called Bisgaard regimen for treating ulcers.[11] It has four components: Patient education, elevation of foot, elastic compression and evaluation.
## Compression therapy
Non-elastic, ambulatory, below knee (BK) compression aggressively counters the impact of reflux on venous pump failure. Compression therapy is used for venous leg ulcers and can decrease blood vessel diameter and pressure, which increases their effectiveness, preventing blood from flowing backwards.[4] Compression is also used [4][12] to decrease release of inflammatory cytokines, lower the amount of fluid leaking from capillaries and therefore prevent swelling, and prevent clotting by decreasing activation of thrombin and increasing that of plasmin.[2] Compression is applied using elastic bandages or boots specifically designed for the purpose.[4]
Regarding effectiveness, compression dressings improve healing.[13] It is not clear whether non-elastic systems are better than a multilayer elastic system.[13] Patients should wear as much compression as is comfortable.[14] The type of dressing applied beneath the compression does not seem to matter, and hydrocolloid is not better than simple low adherent dressings.[15][16] Recently there have been clinical studies on a multi-functional botanical-based ointment in combination with compression therapy in the treatment of difficult-to-heal wounds, including venous leg ulcers.[17]
Intermittent pneumatic compression devices may be used, but it is not clear that they are superior to simple compression dressings.[18]
## Pentoxifylline
A meta-analysis of randomized controlled trials by the Cochrane Collaboration found that "Pentoxifylline is an effective adjunct to compression bandaging for treating venous ulcers and may be effective in the absence of compression".[19] It works by reducing platelet aggregation and thrombus formation.
## Artificial skin
Artificial skin, made of collagen and cultured skin cells, is also used to cover venous ulcers and excrete growth factors to help them heal.[20] A Systematic review of 17 Randomized trials found that Bilayer Artificial Skin with compression bandaging is useful in the healing of venous ulcers when compared to simple dressings.[3]
## Surgical correction of superficial venous reflux
A randomized controlled trial found that surgery "reduces the recurrence of ulcers at four years and results in a greater proportion of ulcer free time".[21]
## Local Anaesthetic Endovenous correction of superficial venous reflux
Local anaesthetic endovenous surgery using the thermoablation (endovenous laser ablation or radiofrequency), perforator closure (TRLOP) and foam sclerotherapy showed an 85% success rate of healing, with no recurrence of healed ulcers at an average of 3.1 years, and a clinical improvement in 98% in a selected group of venous leg ulcers.[22]
## TIRS Technique
Terminal Interruption of Reflux Source Technique entails blocking off the veins that drain the ulcer bed using Sotradecol or Polidocanol foam, administered by ultrasound guidance.[23]
# Prognosis
Venous ulcers are costly to treat, and there is a significant chance that they will recur after healing;[2][4] one study found that up to 48% of venous ulcers had recurred by the fifth year after healing.[4] However treatment with local anaesthetic endovenous techniques suggests a reduction of this high recurrence rate is possible.[22]
Without proper care, the ulcer may get infected leading to cellulitis or gangrene and eventually may need amputation of the part of limb in future.
Some topical drugs used to treat venous ulcer may cause venous eczema.[24]
# Current research
The current ‘best’ practice in the UK is to treat the underlying venous reflux once an ulcer has healed. It is questionable as to whether endovenous treatment should be offered before ulcer healing, as current evidence would not support this approach as standard care. EVRA (Early Venous Reflux Ablation) ulcer trial - A UK NIHR HTA funded randomised clinical trial to compare early versus delayed endovenous treatment of superficial venous reflux in patients with chronic venous ulceration opened for recruitment in October 2013. The study hopes to show an increase in healing rates from 60% to 75% at 24 weeks.[25]
Research from the University of Surrey and funded by the Leg Ulcer Charity is currently looking at the effects that having a leg ulcer has on the relatives and friends of the affected person - and how this changes if the ulcer is permanently cured by endovenous surgery.[26] | https://www.wikidoc.org/index.php/Stasis_ulcer | |
6b13896a17b8281fdc91c8227e788a0233915f53 | wikidoc | Statistician | Statistician
Statisticians work with theoretical and applied statistics in both the private and public sectors. The core of that work is to measure, interpret, and describe the world and human activity patterns within it.
It is common to combine statistical knowledge with expertise in other subjects. The applications are varied. Statisticians apply their knowledge to production, research, finances, medicine, insurance, and government. They often are employed to support managerial decisions or to supervise quality control in manufacturing.
# Nature of the work
According to the United States Bureau of Labor Statistics, as of 2006, there were 19,000 jobs classified as statistician in the United States. Of these people, 41 percent worked for governments (federal, state, or local). Additionally, there are substantial numbers of persons who use statistics in their work but have other job titles than statistician.. The job of statistician is considered a profession. Most statisticians work in offices and have regular working hours.
Most employment as a statistician requires a minimum of a masters degree in statistics or a related field. Many professional statisticians have a PhD.
# History
Civilizations have used the work of statisticians for thousands of years. Statistics was employed in ancient Egypt in censuses of population and cattle. Typical work might involve developing a model and sampling plans, analyzing survey results, or contributing to agricultural or econometric forecasts. | Statistician
Statisticians work with theoretical and applied statistics in both the private and public sectors. The core of that work is to measure, interpret, and describe the world and human activity patterns within it.
It is common to combine statistical knowledge with expertise in other subjects. The applications are varied. Statisticians apply their knowledge to production, research, finances, medicine, insurance, and government. They often are employed to support managerial decisions or to supervise quality control in manufacturing.
# Nature of the work
According to the United States Bureau of Labor Statistics, as of 2006, there were 19,000 jobs classified as statistician in the United States. Of these people, 41 percent worked for governments (federal, state, or local). Additionally, there are substantial numbers of persons who use statistics in their work but have other job titles than statistician.[1]. The job of statistician is considered a profession. Most statisticians work in offices and have regular working hours.
Most employment as a statistician requires a minimum of a masters degree in statistics or a related field. Many professional statisticians have a PhD.
# History
Civilizations have used the work of statisticians for thousands of years. Statistics was employed in ancient Egypt in censuses of population and cattle. Typical work might involve developing a model and sampling plans, analyzing survey results, or contributing to agricultural or econometric forecasts. | https://www.wikidoc.org/index.php/Statistician | |
36e0390d8a5db525b62dd31a321e3a9ad82a8449 | wikidoc | Steeple sign | Steeple sign
# Overview
In radiology, the steeple sign is a sign on a frontal X-ray of tracheal narrowing and suggestive of the diagnosis of croup.
# X Ray
- The steeple sign is seen on anteroposterior radiographs of the soft tissues of the neck.
Normal lateral convexities of the subglottic trachea are lost, and narrowing of the subglottic lumen produces an inverted V configuration in this area.
Point of the inverted V is at the level of the inferior margin of the true vocal cords.
Narrowing of the subglottic lumen alters the radiographic appearance of the tracheal air column, which resembles a steeply pitched roof or a church steeple.
- Normal lateral convexities of the subglottic trachea are lost, and narrowing of the subglottic lumen produces an inverted V configuration in this area.
- Point of the inverted V is at the level of the inferior margin of the true vocal cords.
- Narrowing of the subglottic lumen alters the radiographic appearance of the tracheal air column, which resembles a steeply pitched roof or a church steeple.
- The lateral radiograph of the upper airway will show a normal epiglottis and narrowing of the subglottic region. | Steeple sign
Template:Search infobox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
In radiology, the steeple sign is a sign on a frontal X-ray of tracheal narrowing and suggestive of the diagnosis of croup.[1]
# X Ray
- The steeple sign is seen on anteroposterior radiographs of the soft tissues of the neck.
Normal lateral convexities of the subglottic trachea are lost, and narrowing of the subglottic lumen produces an inverted V configuration in this area.
Point of the inverted V is at the level of the inferior margin of the true vocal cords.
Narrowing of the subglottic lumen alters the radiographic appearance of the tracheal air column, which resembles a steeply pitched roof or a church steeple.
- Normal lateral convexities of the subglottic trachea are lost, and narrowing of the subglottic lumen produces an inverted V configuration in this area.
- Point of the inverted V is at the level of the inferior margin of the true vocal cords.
- Narrowing of the subglottic lumen alters the radiographic appearance of the tracheal air column, which resembles a steeply pitched roof or a church steeple.
- The lateral radiograph of the upper airway will show a normal epiglottis and narrowing of the subglottic region.
-
- | https://www.wikidoc.org/index.php/Steeple_sign | |
7f31ba3c75dba7c227bebd02c85ccb4bf7b773ba | wikidoc | White spirit | White spirit
White spirit, also known as Stoddard solvent, is a paraffin-derived clear, transparent liquid which is a common organic solvent used in painting and decorating. In 1924, an Atlanta dry cleaner named W. J. Stoddard worked with Lloyd E. Jackson of the Mellon Research Institute to develop specifications for a less volatile dry cleaning solvent as an alternative to more volatile petroleum solvents. Dry cleaners began using it in 1928 and it was the predominant dry cleaning solvent in the United States from the late 1920s until the late 1950s.
It is a mixture of saturated aliphatic and alicyclic C7 to C12 hydrocarbons with a maximum content of 25% of C7 to C12 alkyl aromatic hydrocarbons.
White spirit is used as an extraction solvent, as a cleaning solvent, as a degreasing solvent and as a solvent in aerosols, paints, wood preservatives, lacquers, varnishes, and asphalt products. In western Europe about 60% of the total white spirit consumption is used in paints, lacquers and varnishes. White spirit is the most widely used solvent in the paint industry. In households, white spirit is commonly used to clean paint brushes after decorating. Its paint thinning properties enable brushes to be properly cleaned (by preventing the paint from hardening and ruining the bristles) and therefore enabling them to be re-used.
Three different types and three different grades of white spirit exist. The type refers to whether the solvent has been subjected to hydrodesulfurization (removal of sulfur) alone (type 1), solvent extraction (type 2) or hydrogenation (type 3). Each type comprises three different grades: low flash grade, regular grade, and high flash grade. The grade is determined by the crude oil used as the starting material and the conditions of distillation.
In addition there is type 0, which is defined as distillation fraction with no further treatment, consisting predominantly of saturated C9 to C12 hydrocarbons with a boiling range of 140-200 °C.
# Physical properties
The physical properties of the three types of white spirit are:
# Toxicity
White spirit is mainly classed as an Irritant.
White spirit has a fairly low acute toxicity by inhalation of the vapour, dermal (touching the skin) and oral routes (ingestion). However, acute exposure can lead to central nervous system depression resulting in lack of coordination and slowed reactions. Exposure to very high concentrations in enclosed spaces can lead to general narcotic effects (drowsiness, dizziness, nausea etc...) and can eventually lead to unconsciousness. Oral ingestion presents a high aspiration hazard. Prolonged or repeated skin exposure over a long period of time can result in severe irritant dermatitis, also called contact dermatitis. It is highly recommended that skin exposure is kept to a minimum by use of gloves and that hands are washed after coming into contact with it. Occasional exposure to skin is highly unlikely to cause any problems.
Exposure to an average white spirit concentration of 240 mg/m3(40 ppm) for more than 13 years could lead to chronic Central nervous system effects. White spirit is implicated in the development of "chronic toxic encephalopathy" among house painters.
Owing to the volatility and low bioavailability of its constituents, white spirit, although it is moderately toxic to aquatic organisms, is unlikely to present significant hazards to the environment. It should not however, be purposely poured down the sink or freshwater drain if avoidable. It should be disposed of correctly wherever possible. | White spirit
Template:Other
White spirit, also known as Stoddard solvent, is a paraffin-derived clear, transparent liquid which is a common organic solvent used in painting and decorating. In 1924, an Atlanta dry cleaner named W. J. Stoddard worked with Lloyd E. Jackson of the Mellon Research Institute to develop specifications for a less volatile dry cleaning solvent as an alternative to more volatile petroleum solvents. Dry cleaners began using it in 1928 and it was the predominant dry cleaning solvent in the United States from the late 1920s until the late 1950s.
It is a mixture of saturated aliphatic and alicyclic C7 to C12 hydrocarbons with a maximum content of 25% of C7 to C12 alkyl aromatic hydrocarbons.
White spirit is used as an extraction solvent, as a cleaning solvent, as a degreasing solvent and as a solvent in aerosols, paints, wood preservatives, lacquers, varnishes, and asphalt products. In western Europe about 60% of the total white spirit consumption is used in paints, lacquers and varnishes. White spirit is the most widely used solvent in the paint industry. In households, white spirit is commonly used to clean paint brushes after decorating. Its paint thinning properties enable brushes to be properly cleaned (by preventing the paint from hardening and ruining the bristles) and therefore enabling them to be re-used.
Three different types and three different grades of white spirit exist. The type refers to whether the solvent has been subjected to hydrodesulfurization (removal of sulfur) alone (type 1), solvent extraction (type 2) or hydrogenation (type 3). Each type comprises three different grades: low flash grade, regular grade, and high flash grade. The grade is determined by the crude oil used as the starting material and the conditions of distillation.
In addition there is type 0, which is defined as distillation fraction with no further treatment, consisting predominantly of saturated C9 to C12 hydrocarbons with a boiling range of 140-200 °C.
# Physical properties
The physical properties of the three types of white spirit are:
# Toxicity
White spirit is mainly classed as an Irritant.
White spirit has a fairly low acute toxicity by inhalation of the vapour, dermal (touching the skin) and oral routes (ingestion). However, acute exposure can lead to central nervous system depression resulting in lack of coordination and slowed reactions. Exposure to very high concentrations in enclosed spaces can lead to general narcotic effects (drowsiness, dizziness, nausea etc...) and can eventually lead to unconsciousness. Oral ingestion presents a high aspiration hazard. Prolonged or repeated skin exposure over a long period of time can result in severe irritant dermatitis, also called contact dermatitis. It is highly recommended that skin exposure is kept to a minimum by use of gloves and that hands are washed after coming into contact with it. Occasional exposure to skin is highly unlikely to cause any problems.
Exposure to an average white spirit concentration of 240 mg/m3(40 ppm) for more than 13 years could lead to chronic Central nervous system effects. White spirit is implicated in the development of "chronic toxic encephalopathy" among house painters.
Owing to the volatility and low bioavailability of its constituents, white spirit, although it is moderately toxic to aquatic organisms, is unlikely to present significant hazards to the environment. It should not however, be purposely poured down the sink or freshwater drain if avoidable. It should be disposed of correctly wherever possible. | https://www.wikidoc.org/index.php/Stoddard_solvent | |
6ef612a0adefdab1a3636caf7b22e2f32fae8e01 | wikidoc | Stop Smoking | Stop Smoking
Stop Smoking is a cognitive project launched in April 2007 within Qoach (Question Oriented Approach for Common Health) and aiming to replace smoking habits with new learning habits.
The idea of Dr Alexandre-Pierre Gaspar was both to replace and to use the energy of smoking to gain something new.
The first method developed within the Stop Smoking project is simple: instead of a cigarette, the potential smoker will have to remember some piece of art, of music, of culture. He may get a random piece online each time he feels like having a cigarette and wants to learn something new. Soon the pleasure of learning will replace the pleasure of smoking.
Various forms of this method are presently being developed to suit different contexts and personality types.
# Resources
- Stop Smoking: Instead Of A Cigarette
- QOACH Health information system | Stop Smoking
Stop Smoking is a cognitive project launched in April 2007 within Qoach (Question Oriented Approach for Common Health) and aiming to replace smoking habits with new learning habits.
The idea of Dr Alexandre-Pierre Gaspar was both to replace and to use the energy of smoking to gain something new.
The first method developed within the Stop Smoking project is simple: instead of a cigarette, the potential smoker will have to remember some piece of art, of music, of culture. He may get a random piece online each time he feels like having a cigarette and wants to learn something new. Soon the pleasure of learning will replace the pleasure of smoking.
Various forms of this method are presently being developed to suit different contexts and personality types.
# Resources
- Stop Smoking: Instead Of A Cigarette
- QOACH Health information system | https://www.wikidoc.org/index.php/Stop_Smoking | |
d4c31e5f06f47d028cf5e819972eb3029d9b77c2 | wikidoc | Stramenopile | Stramenopile
The Stramenopile group is a recently recognised informal monophyletic grouping into which a number of microscopic parasitic organisms from the superkingdom Protista and a number of diatoms and brown seaweeds are placed.
Labyrinthulomycota, Hyphochytriomycota, Phytophthora, Aphanomyces, Bremia, Pernospora and the Oomycetes are also protists that form part of the Stramenopile group. The Stramenopile group (or clade) is a sister group of another multicellular clade which includes Plantae, Animalia and Fungi.
# Notes
- ↑ An all-taxa biodiversity inventory of the Huron Mountain Club retrieved June 6 2007
- ↑ Genescope Blastocystis hominis: Whole genome shotgun retrieved June 6 2007
- ↑ An all-taxa biodiversity inventory of the Huron Mountain Club retrieved June 6 2007 | Stramenopile
The Stramenopile group is a recently recognised[1] informal monophyletic grouping into which a number of microscopic parasitic organisms from the superkingdom Protista and a number of diatoms and brown seaweeds are placed.
Labyrinthulomycota, Hyphochytriomycota, Phytophthora, Aphanomyces, Bremia, Pernospora and the Oomycetes are also protists that form part of the Stramenopile group.[2] The Stramenopile group (or clade) is a sister group of another multicellular clade which includes Plantae, Animalia and Fungi.[3]
# Notes
- ↑ An all-taxa biodiversity inventory of the Huron Mountain Club retrieved June 6 2007
- ↑ Genescope Blastocystis hominis: Whole genome shotgun retrieved June 6 2007
- ↑ An all-taxa biodiversity inventory of the Huron Mountain Club retrieved June 6 2007
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Stramenopile | |
6ba9df5cd9e979363f77183e253f625b11c190fa | wikidoc | Streptomyces | Streptomyces
# Overview
Streptomyces, the largest genus of Actinobacteria, is a group of Gram-positive and generally high GC-content bacteria. Streptomycetes are found predominantly in soil and in decaying vegetation, and most produce spores. Streptomycetes are noted for their distinct "earthy" odor which results from production of a volatile metabolite, geosmin.
Streptomycetes are characterised by a complex secondary metabolism. They produce over two thirds of the clinically useful antibiotics of natural
-rigin antibiotics , (Neomycin, Chloramphenicol) to name but a few; the now rarely used streptomycin takes its name directly from Streptomyces. Streptomycetes are infrequent pathogens, though infections in human such as mycetoma can be caused by S. somaliensis and S. sudanensis and in plants such as scabies can be caused by S. caviscabies and S. scabies.
# Genomics
The complete genome of one of the strain, "S. coelicolor" A3(2), was published in 2002. At the time, the "S. coelicolor" genome contained the largest number of genes of any bacterium. The genome sequence of S. avermitilis was completed in 2003. This is the first complete genome sequence of the industrial microorganism. Both of these genomes comprise a single chromosome that is linear, unlike most bacterial genomes which comprise a circular chromosome. The genome sequence of S. scabies, a member of the genus with the ability to cause potato scab disease, has been determined at the Wellcome Trust Sanger Institute and is currently in annotation, with publication scheduled for 2007.
Taxonomically, "S. coelicolor" A3(2) belongs to the species of S. violaceoruber and not a validly described separate species; don't mistake S. coelicolor A3(2) for S. coelicolor (Müller) (ATCC 23899).
# Biotechnology
In recent years, biotechnology researchers have begun to use Streptomyces spp. for production of recombinant human proteins. Traditionally, Escherichia coli was the species of choice to host eukaryotic genes since it was well understood and easy to work with. However, E. coli introduces problems such as incorrect (or lack of) glycosylation and incorrect protein folding, resulting in insolubility and loss of bioactivity of the product. Streptomyces spp. on the other hand have the ability to secrete correctly folded recombinant proteins into the medium after production simplifying the subsequent purification steps. These properties among others make Streptomyces spp. an attractive alternative to other bacteria such as E. coli and Bacillus subtilis.
# Medicine
Streptomyces is the largest antibiotic producing genus (), producing both antibacterials and antifungals, and also a wide range of other bioactive compounds such as immunosuppressants
## Some of the antifungals produced by Streptomyces spp.
- Nystatin (from S. noursei)
- Amphotericin B (from S. nodosus)
- Natamycin (from S. natalensis)
## Some of the antibiotics produced by Streptomyces spp.
- Erythromycin (from S. erythreus)
- Neomycin (from S. fradiae)
- Streptomycin (from S. griseus)
- Tetracycline (from S. rimosus)
- Vancomycin (from S. orientalis)
- Rifamycin (from S. mediterranei)
- Chloramphenicol (from S. venezuelae)
## Some of the anti-cancer compounds produced by Streptomyces spp.
- Migrastatin (from S. platensis) | Streptomyces
# Overview
Streptomyces, the largest genus of Actinobacteria, is a group of Gram-positive and generally high GC-content bacteria.[1] Streptomycetes are found predominantly in soil and in decaying vegetation, and most produce spores. Streptomycetes are noted for their distinct "earthy" odor which results from production of a volatile metabolite, geosmin.
Streptomycetes are characterised by a complex secondary metabolism.[1] They produce over two thirds of the clinically useful antibiotics of natural
origin antibiotics , (Neomycin, Chloramphenicol) to name but a few[2]; the now rarely used streptomycin takes its name directly from Streptomyces. Streptomycetes are infrequent pathogens, though infections in human such as mycetoma can be caused by S. somaliensis and S. sudanensis and in plants such as scabies can be caused by S. caviscabies and S. scabies.
# Genomics
The complete genome of one of the strain, "S. coelicolor" A3(2), was published in 2002.[3] At the time, the "S. coelicolor" genome contained the largest number of genes of any bacterium. The genome sequence of S. avermitilis was completed in 2003.[4] This is the first complete genome sequence of the industrial microorganism. Both of these genomes comprise a single chromosome that is linear, unlike most bacterial genomes which comprise a circular chromosome. The genome sequence of S. scabies, a member of the genus with the ability to cause potato scab disease, has been determined at the Wellcome Trust Sanger Institute and is currently in annotation, with publication scheduled for 2007.
Taxonomically, "S. coelicolor" A3(2) belongs to the species of S. violaceoruber and not a validly described separate species; don't mistake S. coelicolor A3(2) for S. coelicolor (Müller) (ATCC 23899).
# Biotechnology
In recent years, biotechnology researchers have begun to use Streptomyces spp. for production of recombinant human proteins. Traditionally, Escherichia coli was the species of choice to host eukaryotic genes since it was well understood and easy to work with.[5][6] However, E. coli introduces problems such as incorrect (or lack of) glycosylation and incorrect protein folding, resulting in insolubility and loss of bioactivity of the product.[7] Streptomyces spp. on the other hand have the ability to secrete correctly folded recombinant proteins into the medium after production simplifying the subsequent purification steps. These properties among others make Streptomyces spp. an attractive alternative to other bacteria such as E. coli and Bacillus subtilis.
# Medicine
Streptomyces is the largest antibiotic producing genus ([1]), producing both antibacterials and antifungals, and also a wide range of other bioactive compounds such as immunosuppressants
## Some of the antifungals produced by Streptomyces spp.
- Nystatin (from S. noursei)
- Amphotericin B (from S. nodosus)
- Natamycin (from S. natalensis)
## Some of the antibiotics produced by Streptomyces spp.
- Erythromycin (from S. erythreus)
- Neomycin (from S. fradiae)
- Streptomycin (from S. griseus)
- Tetracycline (from S. rimosus)
- Vancomycin (from S. orientalis)
- Rifamycin (from S. mediterranei)
- Chloramphenicol (from S. venezuelae)
## Some of the anti-cancer compounds produced by Streptomyces spp.
- Migrastatin (from S. platensis) | https://www.wikidoc.org/index.php/Streptomyces | |
90ab93b0fd38752756cf805aee6012ced44c1c4e | wikidoc | Streptomycin | Streptomycin
# 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
Streptomycin is an aminoglycosides and antitubercular antibiotic that is FDA approved for the treatment of Mycobacterium tuberculosis and Non-tuberculosis infections like plague, tularemia, Brucella, donovanosis, granuloma inguinale, chancroid, H. influenzae (in respiratory, endocardial, and meningeal infections-concomitantly with another antibacterial agent), K. pneumoniae pneumonia (concomitantly with another antibacterial agent), E.coli, Proteus, A. aerogenes, K. pneumoniae, and Enterococcus faecalis in urinary tract infections. Streptococcus viridans, Enterococcus faecalis (in endocardial infections -concomitantly with penicillin), Gram-negative bacillary bacteremia (concomitantly with another antibacterial agent). There is a Black Box Warning for this drug as shown here. Common adverse reactions include vestibular ototoxicity, nausea, vomiting, vertigo, paresthesia of face, rash, fever, urticaria, angioneurotic edema and eosinophilia..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Streptomycin is indicated for the treatment of individuals with moderate to severe infections caused by susceptibile strains of microorganisms in the specific conditions listed below:
- The Advisory Council for the Elimination of tuberculosis, the American Thoracic Society, and the Center for Disease Control recommend that either streptomycin or ethambutol be added as a fourth drug in a regimen containing isoniazid (INH), rifampin and pyrazinamide for initial treatment of tuberculosis unless the likelihood of INH or rifampin resistance is very low. The need for a fourth drug should be reassessed when the results of susceptibility testing are known. In the past when the national rate of primary drug resistance to isoniazid was known to be less than 4% and was either stable or declining, therapy with two and three drug regimens was considered adequate. If community rates of INH resistance are currently less than 4%, an initial treatment regimen with less than four drugs may be considered.
- Streptomycin is also indicated for therapy of tuberculosis when one or more of the above drugs is contraindicated because of toxicity or intolerance. The management of tuberculosis has become more complex as a consequence of increasing rates of drug resistance and concomitant HIV infection. Additional consultation from experts in the treatment of tuberculosis may be desirable in those settings.
- The use of streptomycin should be limited to the treatment of infections caused by bacteria which have been shown to be susceptible to the antibacterial effects of streptomycin and which are not amenable to therapy with less potentially toxic agents.
- Pasteurella pestis (plague)
- Francisella tularensis (tularemia)
- Brucella
- Calymmatobacterium granulomatis (donovanosis, granuloma inguinale)
- H. ducreyi (chancroid)
- H. influenzae (in respiratory, endocardial, and meningeal infections-concomitantly with another antibacterial agent)
- K. pneumoniae pneumonia (concomitantly with another antibacterial agent)
- E.coli, Proteus, A. aerogenes, K. pneumoniae, and Enterococcus faecalis in urinary tract infections
- Streptococcus viridans, Enterococcus faecalis (in endocardial infections -concomitantly with penicillin)
- Gram-negative bacillary bacteremia (concomitantly with another antibacterial agent).
- To reduce the development of drug-resistant bacteria and maintain the effectiveness of streptomycin and other antibacterial drugs, streptomycin should be used only 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.
- Intramuscular Route Only
- Adults: The preferred site is the upper outer quadrant of the buttock, (i.e., gluteus maximus), or the mid-lateral thigh.
- The deltoid area should be used only if well developed such as in certain adults and older children, and then only with caution to avoid radial nerve injury. Intramuscular injections should not be made into the lower and mid-third of the upper arm. As with all intramuscular injections, aspiration is necessary to help avoid inadvertent injection into a blood vessel.
- Injection sites should be alternated. As higher doses or more prolonged therapy with streptomycin may be indicated for more severe or fulminating infections (endocarditis, meningitis, etc.), the physician should always take adequate measures to be immediately aware of any toxic signs or symptoms occurring in the patient as a result of streptomycin therapy.
- Tuberculosis:
- The standard regimen for the treatment of drug susceptible tuberculosis has been two months of INH, rifampin and pyrazinamide followed by four months of INH and rifampin (patients with concomitant infection with tuberculosis and HIV may require treatment for a longer period). When streptomycin is added to this regimen because of suspected or proven drug resistance, the recommended dosing for streptomycin is as follows:
- Streptomycin is usually administered daily as a single intramuscular injection. A total dose of not more than 120 g over the course of therapy should be given unless there are no other therapeutic options. In patients older than 60 years of age the drug should be used at a reduced dosage due to the risk of increased toxicity.
- Therapy with streptomycin may be terminated when toxic symptoms have appeared, when impending toxicity is feared, when organisms become resistant, or when full treatment effect has been obtained. The total period of drug treatment of tuberculosis is a minimum of 1 year; however, indications for terminating therapy with streptomycin may occur at any time as noted above.
- TULAREMIA:
- One to 2 g daily in divided doses for 7 to 14 days until the patient is afebrile for 5 to 7 days.
- PLAGUE:
- Two grams of streptomycin daily in two divided doses should be administered intramuscularly. :- A minimum of 10 days of therapy is recommended.
- BACTERIAL ENDOCARDITIS:
- Streptococcal Endocarditis
In penicillin-sensitive alpha and non-hemolytic streptococcal endocarditis (penicillin MIC<0.1 mcg/mL), streptomycin may be used for 2-week treatment concomitantly with penicillin. The streptomycin regimen is 1 g b.i.d. for the first week, and 500 mg b.i.d. for the second week. If the patient is over 60 years of age, the dosage should be 500 mg b.i.d. for the entire 2- week period.
- In penicillin-sensitive alpha and non-hemolytic streptococcal endocarditis (penicillin MIC<0.1 mcg/mL), streptomycin may be used for 2-week treatment concomitantly with penicillin. The streptomycin regimen is 1 g b.i.d. for the first week, and 500 mg b.i.d. for the second week. If the patient is over 60 years of age, the dosage should be 500 mg b.i.d. for the entire 2- week period.
- Enterococcal Endocarditis
Streptomycin in doses of 1 g b.i.d. for 2 weeks and 500 mg b.i.d. for an additional 4 weeks is given in combination with penicillin. Ototoxicity may require termination of the streptomycin prior to completion of the 6-week course of treatment.
- Streptomycin in doses of 1 g b.i.d. for 2 weeks and 500 mg b.i.d. for an additional 4 weeks is given in combination with penicillin. Ototoxicity may require termination of the streptomycin prior to completion of the 6-week course of treatment.
- CONCOMITANT USE WITH OTHER AGENTS:
- For concomitant use with other agents to which the infecting organism is also sensitive:
- Streptomycin is considered a secondline agent for the treatment of gram-negative bacillary bactermia, meningitis, and pneumonia; brucellosis; granuloma inguinale; chancroid, and urinary tract infection.
- For adults: 1 to 2 grams in divided doses every six to twelve hours for moderate to severe infections. Doses should generally not exceed 2 grams per day.
- For children: 20 to 40 mg/kg/day (8 to 20 mg/lb/day) in divided doses every 6 to 12 hours. (Particular care should be taken to avoid excessive dosage in children).
- The dry lyophillized cake is dissolved by adding Water for Injection USP in an amount to yield the desired concentration as indicated in the following table:
- Sterile reconstituted solutions should be protected from light and may be stored at room temperature for one week without significant loss of potency.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Streptomycin in adult patients.
### Non–Guideline-Supported Use
- Glanders
- Mycobacterium avium complex infection, Lung disease
- Rat bite fever
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- It is recommended that intramuscular injections be given preferably in the mid-lateral muscles of the thigh. In infants and small children the periphery of the upper outer quadrant of the gluteal region should be used only when necessary, such as in burn patients, in order to minimize the possibility of damage to the sciatic nerve.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Streptomycin sulfate in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Streptomycin sulfate in pediatric patients.
# Contraindications
- A history of clinically significant hypersensitivity to streptomycin is a contraindication to its use. Clinically significant hypersensitivity to other aminoglycosides may contraindicate the use of streptomycin because of the known cross-sensitivity of patients to drugs in this class.
# Warnings
### Ototoxicity=
- Both vestibular and auditory dysfunction can follow the administration of streptomycin. The degree of impairment is directly proportional to the dose and duration of streptomycin administration, to the age of the patient, to the level of renal function and to the amount of underlying existing uditory dysfunction. The ototoxic effects of the aminoglycosides, including streptomycin, are potentiated by the co-administration of ethacrynic acid, mannitol, furosemide and possibly other diuretics.
- The vestibulotoxic potential of streptomycin exceeds that of its capacity for cochlear toxicity. Vestibular damage is heralded by headache, nausea, vomiting and disequilibrium. Early cochlear injury is demonstrated by the loss of high frequency hearing. Appropriate monitoring and early discontinuation of the drug may permit recovery prior to irreversible damage to the sensorineural cells.
- Streptomycin can cause fetal harm when administered to a pregnant woman. Because streptomycin readily crosses the placental barrier, caution in use of the drug is important to prevent ototoxicity in the fetus. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
- Clostridium difficile associated diarrhea (CDAD) as been reported with use of nearly all antibacterial agents, including Streptomycin for Injection, 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.
- General
- Prescribing streptomycin in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
- Baseline and periodic caloric stimulation tests and audiometric tests are advisable with extended streptomycin therapy. Tinnitus, roaring noises, or a sense of fullness in the ears indicates need for audiometric examination or termination of streptomycin therapy or both.
- Care should be taken by individuals handling streptomycin for injection to avoid skin sensitivity reactions. As with all intramuscular preparations, Streptomycin Sulfate Injection should be injected well within the body of a relatively large muscle and care should be taken to minimize the possibility of damage to peripheral nerves.
- Extreme caution must be exercised in selecting a dosage regimen in the presence of pre-existing renal insufficiency. In severely uremic patients a single dose may produce high blood levels for several days and the cumulative effect may produce ototoxic sequelae. When streptomycin must be given for prolonged periods of time alkalinization of the urine may minimize or prevent renal irritation.
- A syndrome of apparent central nervous system depression, characterized by stupor and flaccidity, occasionally coma and deep respiratory depression, has been reported in very young infants in whom streptomycin dosage had exceeded the recommended limits. Thus, infants should not receive streptomycin in excess of the recommended dosage.
- In the treatment of venereal infections such as granuloma inguinale, and chancroid, if concomitant syphilis is suspected, suitable laboratory procedures such as a dark field examination should be performed before the start of treatment, and monthly serologic tests should be done for at least four months.
- As with other antibiotics, use of this drug may result in overgrowth of nonsusceptible organisms, including fungi. If superinfection occurs, appropriate therapy should be instituted.
# Adverse Reactions
## Clinical Trials Experience
- The following reactions are common: vestibular ototoxicity (nausea, vomiting, and vertigo); paresthesia of face; rash; fever; urticaria; angioneurotic edema; and eosinophilia.
- The following reactions are less frequent: cochlear ototoxicity (deafness); exfoliative dermatitis; anaphylaxis; azotemia; leucopenia; thrombocytopenia; pancytopenia; hemolytic anemia; muscular weakness; and amblyopia.
- Vestibular dysfunction resulting from the parenteral administration of streptomycin is cumulatively related to the total daily dose. When 1.8 to 2 g/day are given, symptoms are likely to develop in the large percentage of patients - especially in the elderly or patients with impaired renal function - within four weeks. Therefore, it is recommended that caloric and audiometric tests be done prior to, during, and following intensive therapy with streptomycin in order to facilitate detection of any vestibular dysfunction and/or impairment of hearing which may occur.
- Vestibular symptoms generally appear early and usually are reversible with early detection and cessation of streptomycin administration. Two to three months after stopping the drug, gross Vestibular symptoms usually disappear, except from the relative inability to walk in total darkness or on very rough terrain.
- Although streptomycin is the least nephrotoxic of the aminoglycosides, nephrotoxicity does occur rarely.
- Clinical judgment as to termination of therapy must be exercised when side effects occur.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Streptomycin sulfate in the drug label.
# Drug Interactions
- The ototoxic effects of the aminoglycosides, including streptomycin, are potentiated by the co-administration of ethacrynic acid, furosemide, mannitol and possibly other diuretics.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
- Streptomycin can cause fetal harm when administered to a pregnant woman. Because streptomycin readily crosses the placental barrier, caution in use of the drug is important to prevent ototoxicity in the fetus. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Streptomycin sulfate in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Streptomycin sulfate during labor and delivery.
### Nursing Mothers
- Because of the potential for serious adverse reactions in nursing infants from streptomycin, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
There is no FDA guidance on the use of Streptomycin sulfate with respect to pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of Streptomycin sulfate with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Streptomycin sulfate with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Streptomycin sulfate with respect to specific racial populations.
### Renal Impairment
- The risk of severe neurotoxic reactions is sharply increased in patients with impaired renal function or pre-renal azotemia. These include disturbances of vestibular and cochlear function, optic nerve dysfunction, peripheral neuritis, arachnoiditis, and encephalopathy may also occur. The incidence of clinically detectable, irreversible vestibular damage is particularly high in patients treated with streptomycin.
- Renal function should be monitored carefully; patients with renal impairment and/or nitrogen retention should receive reduced doses. The peak serum concentration in individuals with kidney damage should not exceed 20 to 25 mcg/ml.
- The concurrent or sequential use of other neurotoxic and/or nephrotoxic drugs with streptomycin sulfate, including neomycin, kanamycin, gentamicin, cephaloridine, paromomycin, viomycin, polymyxin b, colistin, tobramycin and cyclosporine should be avoided.
- Renal function should be monitored carefully; patients with renal impairment and/or nitrogen retention should receive reduced doses. The peak serum concentration in individuals with kidney damage should not exceed 20 to 25 mcg/ml.
### Hepatic Impairment
There is no FDA guidance on the use of Streptomycin sulfate in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Streptomycin sulfate in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Streptomycin sulfate in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intramuscular
- Intravenous
### Monitoring
- The risk of severe neurotoxic reactions is sharply increased in patients with impaired renal function or pre-renal azotemia. These include disturbances of vestibular and cochlear function, optic nerve dysfunction, peripheral neuritis, arachnoiditis, and encephalopathy may also occur. The incidence of clinically detectable, irreversible vestibular damage is particularly high in patients treated with streptomycin.
- Renal function should be monitored carefully; patients with renal impairment and/or nitrogen retention should receive reduced doses. The peak serum concentration in individuals with kidney damage should not exceed 20 to 25 mcg/ml.
- Both vestibular and auditory dysfunction can follow the administration of streptomycin. The degree of impairment is directly proportional to the dose and duration of streptomycin administration, to the age of the patient, to the level of renal function and to the amount of underlying existing auditory dysfunction. The ototoxic effects of the aminoglycosides, including streptomycin, are potentiated by the co-administration of ethacrynic acid, mannitol, furosemide and possibly other diuretics.
- The vestibulotoxic potential of streptomycin exceeds that of its capacity for cochlear toxicity. Vestibular damage is heralded by headache, nausea, vomiting and disequilibrium. Early cochlear injury is demonstrated by the loss of high frequency hearing. Appropriate monitoring and early discontinuation of the drug may permit recovery prior to irreversible damage to the sensorineural cells.
# IV Compatibility
There is limited information regarding IV Compatibility of Streptomycin sulfate in the drug label.
# Overdosage
There is limited information regarding Chronic Overdose of Streptomycin sulfate in the drug label.
# Pharmacology
## Mechanism of Action
- Streptomycin sulfate is a bactericidal antibiotic. It acts by interfering with normal protein synthesis.
## Structure
- Streptomycin is a water-soluble aminoglycoside derived from Streptomyces griseus. It is marketed as the sulfate salt of streptomycin. The chemical name of streptomycin sulfate is D-Streptamine, O-2-deoxy-2-(methylamino)-α-L-glucopyranosyl-(1→2)-O-5-deoxy-3-C-formyl-α-L-lyxofuranosyl-(1→4)-N,N1-bis(aminoiminomethyl)-,sulfate (2:3) (salt). The molecular formula for Streptomycin Sulfate is (C21H39N7O12)2 -3H2SO4 and the molecular weight is 1457.41. It has the following structural formula:
## Pharmacodynamics
### Microbiology
- Streptomycin sulfate is a bactericidal antibiotic. It acts by interfering with normal protein synthesis.
- Streptomycin has been shown to be active against most strains of the following organisms both in vitro and in clinical infection.
- Brucella (brucellosis),
- Calymmatobacterium granulomatis (donovanosis, granuloma inguinale),
- Escherichia coli, Proteus spp., Aerobacter aerogenes, Klebsiella pneumoniae, and
- Enterococcus faecalis in urinary tract infections,
- Francisella tularensis,
- Haemophilus ducreyi (chancroid),
- Haemophilus influenzae (in respiratory, endocardial, and meningeal infections - concomitantly with another antibacterial agent),
- Klebsiella pneumoniae pneumonia (concomitantly with another antibacterial drugs),
- tuberculosis
## Pharmacokinetics
- Following intramuscular injection of 1 g of streptomycin as the sulfate, a peak serum level of 25 to 50 mcg/mL is reached within 1 hour, diminishing slowly to about 50 percent after 5 to 6 hours.
- Appreciable concentrations are found in all organ tissues except the brain. Significant amounts have been found in pleural fluid and tuberculous cavities. Streptomycin passes through the placenta with serum levels in the cord blood similar to maternal levels. Small amounts are excreted in milk, saliva, and sweat.
- Streptomycin is excreted by glomerular filtration. In patients with normal kidney function, between 29% and 89% of a single 400 mg dose is excreted in the urine within 24 hours. Any reduction of glomerular function results in decreased excretion of the drug and concurrent rise in serum and tissue levels.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Streptomycin sulfate in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Streptomycin sulfate in the drug label.
# How Supplied
- Streptomycin for Injection USP is available in single vials containing 1 gram NDC 39822-0706-1 packaged as boxes of ten vials NDC 39822-0706-2.
## Storage
- Store dry powder under controlled room temperature 15° to 30°C (59° to 86°F)
# Images
## Drug Images
## Package and Label Display Panel
NDC 39822-0706-1
Streptomycin for Injection, USP
1 gram*/ vial
For Intramuscular Use
Rx Only
1 Vial
X-GEN Pharmaceuticals, Inc.
NDC 39822-0706-2
Streptomycin for Injection, USP
1 gram*/ vial
For Intramuscular Use
Rx Only
10 Vial carton
X-GEN Pharmaceuticals, Inc.
# Patient Counseling Information
- Patients should be counseled that antibacterial drugs including streptomycin should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When streptomycin is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by streptomycin or other antibacterial drugs in the future.
- Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.
# Precautions with Alcohol
- Alcohol-Streptomycin sulfate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
There is limited information regarding Streptomycin Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Streptomycin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Streptomycin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Adeel Jamil, M.D. [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Streptomycin is an aminoglycosides and antitubercular antibiotic that is FDA approved for the treatment of Mycobacterium tuberculosis and Non-tuberculosis infections like plague, tularemia, Brucella, donovanosis, granuloma inguinale, chancroid, H. influenzae (in respiratory, endocardial, and meningeal infections-concomitantly with another antibacterial agent), K. pneumoniae pneumonia (concomitantly with another antibacterial agent), E.coli, Proteus, A. aerogenes, K. pneumoniae, and Enterococcus faecalis in urinary tract infections. Streptococcus viridans, Enterococcus faecalis (in endocardial infections -concomitantly with penicillin), Gram-negative bacillary bacteremia (concomitantly with another antibacterial agent). There is a Black Box Warning for this drug as shown here. Common adverse reactions include vestibular ototoxicity, nausea, vomiting, vertigo, paresthesia of face, rash, fever, urticaria, angioneurotic edema and eosinophilia..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Streptomycin is indicated for the treatment of individuals with moderate to severe infections caused by susceptibile strains of microorganisms in the specific conditions listed below:
- The Advisory Council for the Elimination of tuberculosis, the American Thoracic Society, and the Center for Disease Control recommend that either streptomycin or ethambutol be added as a fourth drug in a regimen containing isoniazid (INH), rifampin and pyrazinamide for initial treatment of tuberculosis unless the likelihood of INH or rifampin resistance is very low. The need for a fourth drug should be reassessed when the results of susceptibility testing are known. In the past when the national rate of primary drug resistance to isoniazid was known to be less than 4% and was either stable or declining, therapy with two and three drug regimens was considered adequate. If community rates of INH resistance are currently less than 4%, an initial treatment regimen with less than four drugs may be considered.
- Streptomycin is also indicated for therapy of tuberculosis when one or more of the above drugs is contraindicated because of toxicity or intolerance. The management of tuberculosis has become more complex as a consequence of increasing rates of drug resistance and concomitant HIV infection. Additional consultation from experts in the treatment of tuberculosis may be desirable in those settings.
- The use of streptomycin should be limited to the treatment of infections caused by bacteria which have been shown to be susceptible to the antibacterial effects of streptomycin and which are not amenable to therapy with less potentially toxic agents.
- Pasteurella pestis (plague)
- Francisella tularensis (tularemia)
- Brucella
- Calymmatobacterium granulomatis (donovanosis, granuloma inguinale)
- H. ducreyi (chancroid)
- H. influenzae (in respiratory, endocardial, and meningeal infections-concomitantly with another antibacterial agent)
- K. pneumoniae pneumonia (concomitantly with another antibacterial agent)
- E.coli, Proteus, A. aerogenes, K. pneumoniae, and Enterococcus faecalis in urinary tract infections
- Streptococcus viridans, Enterococcus faecalis (in endocardial infections -concomitantly with penicillin)
- Gram-negative bacillary bacteremia (concomitantly with another antibacterial agent).
- To reduce the development of drug-resistant bacteria and maintain the effectiveness of streptomycin and other antibacterial drugs, streptomycin should be used only 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.
- Intramuscular Route Only
- Adults: The preferred site is the upper outer quadrant of the buttock, (i.e., gluteus maximus), or the mid-lateral thigh.
- The deltoid area should be used only if well developed such as in certain adults and older children, and then only with caution to avoid radial nerve injury. Intramuscular injections should not be made into the lower and mid-third of the upper arm. As with all intramuscular injections, aspiration is necessary to help avoid inadvertent injection into a blood vessel.
- Injection sites should be alternated. As higher doses or more prolonged therapy with streptomycin may be indicated for more severe or fulminating infections (endocarditis, meningitis, etc.), the physician should always take adequate measures to be immediately aware of any toxic signs or symptoms occurring in the patient as a result of streptomycin therapy.
- Tuberculosis:
- The standard regimen for the treatment of drug susceptible tuberculosis has been two months of INH, rifampin and pyrazinamide followed by four months of INH and rifampin (patients with concomitant infection with tuberculosis and HIV may require treatment for a longer period). When streptomycin is added to this regimen because of suspected or proven drug resistance, the recommended dosing for streptomycin is as follows:
- Streptomycin is usually administered daily as a single intramuscular injection. A total dose of not more than 120 g over the course of therapy should be given unless there are no other therapeutic options. In patients older than 60 years of age the drug should be used at a reduced dosage due to the risk of increased toxicity.
- Therapy with streptomycin may be terminated when toxic symptoms have appeared, when impending toxicity is feared, when organisms become resistant, or when full treatment effect has been obtained. The total period of drug treatment of tuberculosis is a minimum of 1 year; however, indications for terminating therapy with streptomycin may occur at any time as noted above.
- TULAREMIA:
- One to 2 g daily in divided doses for 7 to 14 days until the patient is afebrile for 5 to 7 days.
- PLAGUE:
- Two grams of streptomycin daily in two divided doses should be administered intramuscularly. :* A minimum of 10 days of therapy is recommended.
- BACTERIAL ENDOCARDITIS:
- Streptococcal Endocarditis
In penicillin-sensitive alpha and non-hemolytic streptococcal endocarditis (penicillin MIC<0.1 mcg/mL), streptomycin may be used for 2-week treatment concomitantly with penicillin. The streptomycin regimen is 1 g b.i.d. for the first week, and 500 mg b.i.d. for the second week. If the patient is over 60 years of age, the dosage should be 500 mg b.i.d. for the entire 2- week period.
- In penicillin-sensitive alpha and non-hemolytic streptococcal endocarditis (penicillin MIC<0.1 mcg/mL), streptomycin may be used for 2-week treatment concomitantly with penicillin. The streptomycin regimen is 1 g b.i.d. for the first week, and 500 mg b.i.d. for the second week. If the patient is over 60 years of age, the dosage should be 500 mg b.i.d. for the entire 2- week period.
- Enterococcal Endocarditis
Streptomycin in doses of 1 g b.i.d. for 2 weeks and 500 mg b.i.d. for an additional 4 weeks is given in combination with penicillin. Ototoxicity may require termination of the streptomycin prior to completion of the 6-week course of treatment.
- Streptomycin in doses of 1 g b.i.d. for 2 weeks and 500 mg b.i.d. for an additional 4 weeks is given in combination with penicillin. Ototoxicity may require termination of the streptomycin prior to completion of the 6-week course of treatment.
- CONCOMITANT USE WITH OTHER AGENTS:
- For concomitant use with other agents to which the infecting organism is also sensitive:
- Streptomycin is considered a secondline agent for the treatment of gram-negative bacillary bactermia, meningitis, and pneumonia; brucellosis; granuloma inguinale; chancroid, and urinary tract infection.
- For adults: 1 to 2 grams in divided doses every six to twelve hours for moderate to severe infections. Doses should generally not exceed 2 grams per day.
- For children: 20 to 40 mg/kg/day (8 to 20 mg/lb/day) in divided doses every 6 to 12 hours. (Particular care should be taken to avoid excessive dosage in children).
- The dry lyophillized cake is dissolved by adding Water for Injection USP in an amount to yield the desired concentration as indicated in the following table:
- Sterile reconstituted solutions should be protected from light and may be stored at room temperature for one week without significant loss of potency.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Streptomycin in adult patients.
### Non–Guideline-Supported Use
- Glanders
- Mycobacterium avium complex infection, Lung disease
- Rat bite fever
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- It is recommended that intramuscular injections be given preferably in the mid-lateral muscles of the thigh. In infants and small children the periphery of the upper outer quadrant of the gluteal region should be used only when necessary, such as in burn patients, in order to minimize the possibility of damage to the sciatic nerve.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Streptomycin sulfate in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Streptomycin sulfate in pediatric patients.
# Contraindications
- A history of clinically significant hypersensitivity to streptomycin is a contraindication to its use. Clinically significant hypersensitivity to other aminoglycosides may contraindicate the use of streptomycin because of the known cross-sensitivity of patients to drugs in this class.
# Warnings
### Ototoxicity=
- Both vestibular and auditory dysfunction can follow the administration of streptomycin. The degree of impairment is directly proportional to the dose and duration of streptomycin administration, to the age of the patient, to the level of renal function and to the amount of underlying existing uditory dysfunction. The ototoxic effects of the aminoglycosides, including streptomycin, are potentiated by the co-administration of ethacrynic acid, mannitol, furosemide and possibly other diuretics.
- The vestibulotoxic potential of streptomycin exceeds that of its capacity for cochlear toxicity. Vestibular damage is heralded by headache, nausea, vomiting and disequilibrium. Early cochlear injury is demonstrated by the loss of high frequency hearing. Appropriate monitoring and early discontinuation of the drug may permit recovery prior to irreversible damage to the sensorineural cells.
- Streptomycin can cause fetal harm when administered to a pregnant woman. Because streptomycin readily crosses the placental barrier, caution in use of the drug is important to prevent ototoxicity in the fetus. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
- Clostridium difficile associated diarrhea (CDAD) as been reported with use of nearly all antibacterial agents, including Streptomycin for Injection, 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.
- General
- Prescribing streptomycin in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
- Baseline and periodic caloric stimulation tests and audiometric tests are advisable with extended streptomycin therapy. Tinnitus, roaring noises, or a sense of fullness in the ears indicates need for audiometric examination or termination of streptomycin therapy or both.
- Care should be taken by individuals handling streptomycin for injection to avoid skin sensitivity reactions. As with all intramuscular preparations, Streptomycin Sulfate Injection should be injected well within the body of a relatively large muscle and care should be taken to minimize the possibility of damage to peripheral nerves.
- Extreme caution must be exercised in selecting a dosage regimen in the presence of pre-existing renal insufficiency. In severely uremic patients a single dose may produce high blood levels for several days and the cumulative effect may produce ototoxic sequelae. When streptomycin must be given for prolonged periods of time alkalinization of the urine may minimize or prevent renal irritation.
- A syndrome of apparent central nervous system depression, characterized by stupor and flaccidity, occasionally coma and deep respiratory depression, has been reported in very young infants in whom streptomycin dosage had exceeded the recommended limits. Thus, infants should not receive streptomycin in excess of the recommended dosage.
- In the treatment of venereal infections such as granuloma inguinale, and chancroid, if concomitant syphilis is suspected, suitable laboratory procedures such as a dark field examination should be performed before the start of treatment, and monthly serologic tests should be done for at least four months.
- As with other antibiotics, use of this drug may result in overgrowth of nonsusceptible organisms, including fungi. If superinfection occurs, appropriate therapy should be instituted.
# Adverse Reactions
## Clinical Trials Experience
- The following reactions are common: vestibular ototoxicity (nausea, vomiting, and vertigo); paresthesia of face; rash; fever; urticaria; angioneurotic edema; and eosinophilia.
- The following reactions are less frequent: cochlear ototoxicity (deafness); exfoliative dermatitis; anaphylaxis; azotemia; leucopenia; thrombocytopenia; pancytopenia; hemolytic anemia; muscular weakness; and amblyopia.
- Vestibular dysfunction resulting from the parenteral administration of streptomycin is cumulatively related to the total daily dose. When 1.8 to 2 g/day are given, symptoms are likely to develop in the large percentage of patients - especially in the elderly or patients with impaired renal function - within four weeks. Therefore, it is recommended that caloric and audiometric tests be done prior to, during, and following intensive therapy with streptomycin in order to facilitate detection of any vestibular dysfunction and/or impairment of hearing which may occur.
- Vestibular symptoms generally appear early and usually are reversible with early detection and cessation of streptomycin administration. Two to three months after stopping the drug, gross Vestibular symptoms usually disappear, except from the relative inability to walk in total darkness or on very rough terrain.
- Although streptomycin is the least nephrotoxic of the aminoglycosides, nephrotoxicity does occur rarely.
- Clinical judgment as to termination of therapy must be exercised when side effects occur.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Streptomycin sulfate in the drug label.
# Drug Interactions
- The ototoxic effects of the aminoglycosides, including streptomycin, are potentiated by the co-administration of ethacrynic acid, furosemide, mannitol and possibly other diuretics.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
- Streptomycin can cause fetal harm when administered to a pregnant woman. Because streptomycin readily crosses the placental barrier, caution in use of the drug is important to prevent ototoxicity in the fetus. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Streptomycin sulfate in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Streptomycin sulfate during labor and delivery.
### Nursing Mothers
- Because of the potential for serious adverse reactions in nursing infants from streptomycin, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
There is no FDA guidance on the use of Streptomycin sulfate with respect to pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of Streptomycin sulfate with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Streptomycin sulfate with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Streptomycin sulfate with respect to specific racial populations.
### Renal Impairment
- The risk of severe neurotoxic reactions is sharply increased in patients with impaired renal function or pre-renal azotemia. These include disturbances of vestibular and cochlear function, optic nerve dysfunction, peripheral neuritis, arachnoiditis, and encephalopathy may also occur. The incidence of clinically detectable, irreversible vestibular damage is particularly high in patients treated with streptomycin.
- Renal function should be monitored carefully; patients with renal impairment and/or nitrogen retention should receive reduced doses. The peak serum concentration in individuals with kidney damage should not exceed 20 to 25 mcg/ml.
- The concurrent or sequential use of other neurotoxic and/or nephrotoxic drugs with streptomycin sulfate, including neomycin, kanamycin, gentamicin, cephaloridine, paromomycin, viomycin, polymyxin b, colistin, tobramycin and cyclosporine should be avoided.
- Renal function should be monitored carefully; patients with renal impairment and/or nitrogen retention should receive reduced doses. The peak serum concentration in individuals with kidney damage should not exceed 20 to 25 mcg/ml.
### Hepatic Impairment
There is no FDA guidance on the use of Streptomycin sulfate in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Streptomycin sulfate in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Streptomycin sulfate in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intramuscular
- Intravenous
### Monitoring
- The risk of severe neurotoxic reactions is sharply increased in patients with impaired renal function or pre-renal azotemia. These include disturbances of vestibular and cochlear function, optic nerve dysfunction, peripheral neuritis, arachnoiditis, and encephalopathy may also occur. The incidence of clinically detectable, irreversible vestibular damage is particularly high in patients treated with streptomycin.
- Renal function should be monitored carefully; patients with renal impairment and/or nitrogen retention should receive reduced doses. The peak serum concentration in individuals with kidney damage should not exceed 20 to 25 mcg/ml.
- Both vestibular and auditory dysfunction can follow the administration of streptomycin. The degree of impairment is directly proportional to the dose and duration of streptomycin administration, to the age of the patient, to the level of renal function and to the amount of underlying existing auditory dysfunction. The ototoxic effects of the aminoglycosides, including streptomycin, are potentiated by the co-administration of ethacrynic acid, mannitol, furosemide and possibly other diuretics.
- The vestibulotoxic potential of streptomycin exceeds that of its capacity for cochlear toxicity. Vestibular damage is heralded by headache, nausea, vomiting and disequilibrium. Early cochlear injury is demonstrated by the loss of high frequency hearing. Appropriate monitoring and early discontinuation of the drug may permit recovery prior to irreversible damage to the sensorineural cells.
# IV Compatibility
There is limited information regarding IV Compatibility of Streptomycin sulfate in the drug label.
# Overdosage
There is limited information regarding Chronic Overdose of Streptomycin sulfate in the drug label.
# Pharmacology
## Mechanism of Action
- Streptomycin sulfate is a bactericidal antibiotic. It acts by interfering with normal protein synthesis.
## Structure
- Streptomycin is a water-soluble aminoglycoside derived from Streptomyces griseus. It is marketed as the sulfate salt of streptomycin. The chemical name of streptomycin sulfate is D-Streptamine, O-2-deoxy-2-(methylamino)-α-L-glucopyranosyl-(1→2)-O-5-deoxy-3-C-formyl-α-L-lyxofuranosyl-(1→4)-N,N1-bis(aminoiminomethyl)-,sulfate (2:3) (salt). The molecular formula for Streptomycin Sulfate is (C21H39N7O12)2 -3H2SO4 and the molecular weight is 1457.41. It has the following structural formula:
## Pharmacodynamics
### Microbiology
- Streptomycin sulfate is a bactericidal antibiotic. It acts by interfering with normal protein synthesis.
- Streptomycin has been shown to be active against most strains of the following organisms both in vitro and in clinical infection.
- Brucella (brucellosis),
- Calymmatobacterium granulomatis (donovanosis, granuloma inguinale),
- Escherichia coli, Proteus spp., Aerobacter aerogenes, Klebsiella pneumoniae, and
- Enterococcus faecalis in urinary tract infections,
- Francisella tularensis,
- Haemophilus ducreyi (chancroid),
- Haemophilus influenzae (in respiratory, endocardial, and meningeal infections - concomitantly with another antibacterial agent),
- Klebsiella pneumoniae pneumonia (concomitantly with another antibacterial drugs),
- tuberculosis
## Pharmacokinetics
- Following intramuscular injection of 1 g of streptomycin as the sulfate, a peak serum level of 25 to 50 mcg/mL is reached within 1 hour, diminishing slowly to about 50 percent after 5 to 6 hours.
- Appreciable concentrations are found in all organ tissues except the brain. Significant amounts have been found in pleural fluid and tuberculous cavities. Streptomycin passes through the placenta with serum levels in the cord blood similar to maternal levels. Small amounts are excreted in milk, saliva, and sweat.
- Streptomycin is excreted by glomerular filtration. In patients with normal kidney function, between 29% and 89% of a single 400 mg dose is excreted in the urine within 24 hours. Any reduction of glomerular function results in decreased excretion of the drug and concurrent rise in serum and tissue levels.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Streptomycin sulfate in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Streptomycin sulfate in the drug label.
# How Supplied
- Streptomycin for Injection USP is available in single vials containing 1 gram NDC 39822-0706-1 packaged as boxes of ten vials NDC 39822-0706-2.
## Storage
- Store dry powder under controlled room temperature 15° to 30°C (59° to 86°F)
# Images
## Drug Images
## Package and Label Display Panel
NDC 39822-0706-1
Streptomycin for Injection, USP
1 gram*/ vial
For Intramuscular Use
Rx Only
1 Vial
X-GEN Pharmaceuticals, Inc.
NDC 39822-0706-2
Streptomycin for Injection, USP
1 gram*/ vial
For Intramuscular Use
Rx Only
10 Vial carton
X-GEN Pharmaceuticals, Inc.
# Patient Counseling Information
- Patients should be counseled that antibacterial drugs including streptomycin should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When streptomycin is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by streptomycin or other antibacterial drugs in the future.
- Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.
# Precautions with Alcohol
- Alcohol-Streptomycin sulfate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
There is limited information regarding Streptomycin Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Streptomycin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Streptomycin | |
38f289ddd01519168bad0cb7e8297c32d7ac7ce8 | wikidoc | Streptozocin | Streptozocin
# 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
Streptozocin is an alkylating agent, antineoplastic agent and nitrosourea that is FDA approved for the treatment of metastatic islet cell carcinoma of the pancreas. There is a Black Box Warning for this drug as shown here. Common adverse reactions include nausea, confusion, lethargy and depression.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Streptozocin sterile powder should be administered intravenously by rapid injection or short/prolonged infusion. It is not active orally. Although it has been administered intraarterially, this is not recommended pending further evaluation of the possibility that adverse renal effects may be evoked more rapidly by this route of administration.
## Two different dosage schedules have been employed successfully with Streptozocin.
### Daily Schedule
- The recommended dose for daily intravenous administration is 500 mg/m2 of body surface area for five consecutive days every six weeks until maximum benefit or until treatment-limiting toxicity is observed. Dose escalation on this schedule is not recommended.
### Weekly Schedule
- The recommended initial dose for weekly intravenous administration is 1000 mg/m2 of body surface area at weekly intervals for the first two courses (weeks). In subsequent courses, drug doses may be escalated in patients who have not achieved a therapeutic response and who have not experienced significant toxicity with the previous course of treatment. However, A SINGLE DOSE OF 1500 mg/m2 BODY SURFACE AREA SHOULD NOT BE EXCEEDED as a greater dose may cause azotemia. When administered on this schedule, the median time to onset of response is about 17 days and the median time to maximum response is about 35 days. The median total dose to onset of response is about 2000 mg/m2 body surface area and the median total dose to maximum response is about 4000 mg/m2 body surface area.
- The ideal duration of maintenance therapy with Streptozocin has not yet been clearly established for either of the above schedules.
- For patients with functional tumors, serial monitoring of fasting insulin levels allows a determination of biochemical response to therapy. For patients with either functional or nonfunctional tumors, response to therapy can be determined by measurable reductions of tumor size (reduction of organomegaly, masses, or lymph nodes).
- Reconstitute Streptozocin with 9.5 mL of dextrose injection, USP, or 0.9% sodium chloride injection, USP. The resulting pale-gold solution will contain 100 mg of streptozocin and 22 mg of citric acid per mL. Where more dilute infusion solutions are desirable, further dilution in the above vehicles is recommended. The total storage time for streptozocin after it has been placed in solution should not exceed 12 hours. This product contains no preservatives and is not intended as a multiple-dose vial.
Caution in the handling and preparation of the powder and solution should be exercised, and the use of gloves is recommended. If the sterile powder of Streptozocin or a solution prepared from Streptozocin contacts the skin or mucosae, immediately wash the affected area with soap and water. Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1–7 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Streptozocin in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Streptozocin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Streptozocin 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 Streptozocin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Streptozocin in pediatric patients.
# Contraindications
There is limited information regarding Streptozocin Contraindications in the drug label.
# Warnings
### Renal Toxicity
- Many patients treated with Streptozocin have experienced renal toxicity, as evidenced by azotemia, anuria, hypophosphatemia, glycosuria and renal tubular acidosis. Such toxicity is dose-related and cumulative and may be severe or fatal.
- Renal function must be monitored before and after each course of therapy. Serial urinalysis, blood urea nitrogen, plasma creatinine, serum electrolytes and creatinine clearance should be obtained prior to, at least weekly during, and for four weeks after drug administration. Serial urinalysis is particularly important for the early detection of proteinuria and should be quantitated with a 24 hour collection when proteinuria is detected. Mild proteinuria is one of the first signs of renal toxicity and may herald further deterioration of renal function. Reduction of the dose of Streptozocin or discontinuation of treatment is suggested in the presence of significant renal toxicity. Adequate hydration may help reduce the risk of nephrotoxicity to renal tubular epithelium by decreasing renal and urinary concentration of the drug and its metabolites.
- Use of Streptozocin in patients with preexisting renal disease requires a judgment by the physician of potential benefit as opposed to the known risk of serious renal damage.
- This drug should not be used in combination with or concomitantly with other potential nephrotoxins.
- When exposed dermally, some rats developed benign tumors at the site of application of streptozocin. Consequently, streptozocin may pose a carcinogenic hazard following topical exposure if not properly handled.
# Adverse Reactions
## Clinical Trials Experience
### Renal
- See warnings.
### Gastrointestinal
- Most patients treated with Streptozocin have experienced severe nausea and vomiting, occasionally requiring discontinuation of drug therapy. Some patients experienced diarrhea. A number of patients have experienced hepatic toxicity, as characterized by elevated liver enzyme (SGOT and LDH) levels and hypoalbuminemia.
### Hematological
- Hematological toxicity has been rare, most often involving mild decreases in hematocrit values. However, fatal hematological toxicity with substantial reductions in leukocyte (Leukopenia) and platelet (Thrombocytopenia) count has been observed.
### Metabolic
- Mild to moderate abnormalities of glucose tolerance have been noted in some patients treated with Streptozocin. These have generally been reversible, but insulin shock with hypoglycemia has been observed.
### Genitourinary
- Two cases of nephrogenic diabetes insipidus following therapy with Streptozocin have been reported. One had spontaneous recovery and the second responded to indomethacin.
## Postmarketing Experience
- Spontaneous reports have been received of local inflammation (i.e., edema, erythema, burning, tenderness) following extravasation of the product. In most cases, these events resolved the same day or within a few days.
# Drug Interactions
There is limited information regarding Streptozocin Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
- Reproduction studies revealed that streptozocin is teratogenic in the rat and has abortifacient effects in rabbits. When administered intravenously to pregnant monkeys, it appears rapidly in the fetal circulation. There are no studies in pregnant women. Streptozocin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Streptozocin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Streptozocin during labor and delivery.
### Nursing Mothers
- It is not known whether streptozocin 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, nursing should be discontinued in patients receiving Streptozocin.
### Pediatric Use
There is no FDA guidance on the use of Streptozocin in pediatric settings.
### Geriatic Use
- Clinical studies of streptozocin did not include sufficient numbers of patients aged 65 years and older to determine whether there was a difference in either efficacy or toxicity as compared to younger patients. Other reported clinical experience has not identified differences in efficacy or safety between the elderly and younger patient populations. In general, dose selection for elderly patients 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.
### Gender
There is no FDA guidance on the use of Streptozocin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Streptozocin with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Streptozocin in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Streptozocin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Streptozocin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Streptozocin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Streptozocin Administration in the drug label.
### Monitoring
There is limited information regarding Streptozocin Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Streptozocin and IV administrations.
# Overdosage
No specific antidote for Streptozocin is known.
# Pharmacology
## Mechanism of Action
- Streptozocin inhibits DNA synthesis in bacterial and mammalian cells. In bacterial cells, a specific interaction with cytosine moieties leads to degradation of DNA. The biochemical mechanism leading to mammalian cell death has not been definitely established; streptozocin inhibits cell proliferation at a considerably lower level than that needed to inhibit precursor incorporation into DNA or to inhibit several of the enzymes involved in DNA synthesis. Although streptozocin inhibits the progression of cells into mitosis, no specific phase of the cell cycle is particularly sensitive to its lethal effects.
## Structure
The structural formula is represented below:
## Pharmacodynamics
There is limited information regarding Streptozocin Pharmacodynamics in the drug label.
## Pharmacokinetics
- Streptozocin is active in the L1210 leukemic mouse over a fairly wide range of parenteral dosage schedules. In experiments in many animal species, streptozocin induced a diabetes that resembles human hyperglycemic nonketotic diabetes mellitus. This phenomenon, which has been extensively studied, appears to be mediated through a lowering of beta cell nicotinamide adenine dinucleotide (NAD) and consequent histopathologic alteration of pancreatic islet beta cells.
- The metabolism and the chemical dissociation of streptozocin that occurs under physiologic conditions has not been extensively studied. When administered intravenously to a variety of experimental animals, streptozocin disappears from the blood very rapidly. In all species tested, it was found to concentrate in the liver and kidney. As much as 20% of the drug (or metabolites containing an N-nitrosourea group) is metabolized and/or excreted by the kidney. Metabolic products have not yet been identified.
## Nonclinical Toxicology
There is limited information regarding Streptozocin Nonclinical Toxicology in the drug label.
# Clinical Studies
There is limited information regarding Streptozocin Clinical Studies in the drug label.
# How Supplied
## Storage
Unopened vials of Streptozocin should be stored at refrigeration temperatures (2° to 8°C) and protected from light (preferably stored in carton).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Streptozocin Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Streptozocin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Zanosar
# Look-Alike Drug Names
There is limited information regarding Streptozocin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Streptozocin
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.
# Black Box Warning
# Overview
Streptozocin is an alkylating agent, antineoplastic agent and nitrosourea that is FDA approved for the treatment of metastatic islet cell carcinoma of the pancreas. There is a Black Box Warning for this drug as shown here. Common adverse reactions include nausea, confusion, lethargy and depression.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Streptozocin sterile powder should be administered intravenously by rapid injection or short/prolonged infusion. It is not active orally. Although it has been administered intraarterially, this is not recommended pending further evaluation of the possibility that adverse renal effects may be evoked more rapidly by this route of administration.
## Two different dosage schedules have been employed successfully with Streptozocin.
### Daily Schedule
- The recommended dose for daily intravenous administration is 500 mg/m2 of body surface area for five consecutive days every six weeks until maximum benefit or until treatment-limiting toxicity is observed. Dose escalation on this schedule is not recommended.
### Weekly Schedule
- The recommended initial dose for weekly intravenous administration is 1000 mg/m2 of body surface area at weekly intervals for the first two courses (weeks). In subsequent courses, drug doses may be escalated in patients who have not achieved a therapeutic response and who have not experienced significant toxicity with the previous course of treatment. However, A SINGLE DOSE OF 1500 mg/m2 BODY SURFACE AREA SHOULD NOT BE EXCEEDED as a greater dose may cause azotemia. When administered on this schedule, the median time to onset of response is about 17 days and the median time to maximum response is about 35 days. The median total dose to onset of response is about 2000 mg/m2 body surface area and the median total dose to maximum response is about 4000 mg/m2 body surface area.
- The ideal duration of maintenance therapy with Streptozocin has not yet been clearly established for either of the above schedules.
- For patients with functional tumors, serial monitoring of fasting insulin levels allows a determination of biochemical response to therapy. For patients with either functional or nonfunctional tumors, response to therapy can be determined by measurable reductions of tumor size (reduction of organomegaly, masses, or lymph nodes).
- Reconstitute Streptozocin with 9.5 mL of dextrose injection, USP, or 0.9% sodium chloride injection, USP. The resulting pale-gold solution will contain 100 mg of streptozocin and 22 mg of citric acid per mL. Where more dilute infusion solutions are desirable, further dilution in the above vehicles is recommended. The total storage time for streptozocin after it has been placed in solution should not exceed 12 hours. This product contains no preservatives and is not intended as a multiple-dose vial.
Caution in the handling and preparation of the powder and solution should be exercised, and the use of gloves is recommended. If the sterile powder of Streptozocin or a solution prepared from Streptozocin contacts the skin or mucosae, immediately wash the affected area with soap and water. Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1–7 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Streptozocin in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Streptozocin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Streptozocin 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 Streptozocin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Streptozocin in pediatric patients.
# Contraindications
There is limited information regarding Streptozocin Contraindications in the drug label.
# Warnings
### Renal Toxicity
- Many patients treated with Streptozocin have experienced renal toxicity, as evidenced by azotemia, anuria, hypophosphatemia, glycosuria and renal tubular acidosis. Such toxicity is dose-related and cumulative and may be severe or fatal.
- Renal function must be monitored before and after each course of therapy. Serial urinalysis, blood urea nitrogen, plasma creatinine, serum electrolytes and creatinine clearance should be obtained prior to, at least weekly during, and for four weeks after drug administration. Serial urinalysis is particularly important for the early detection of proteinuria and should be quantitated with a 24 hour collection when proteinuria is detected. Mild proteinuria is one of the first signs of renal toxicity and may herald further deterioration of renal function. Reduction of the dose of Streptozocin or discontinuation of treatment is suggested in the presence of significant renal toxicity. Adequate hydration may help reduce the risk of nephrotoxicity to renal tubular epithelium by decreasing renal and urinary concentration of the drug and its metabolites.
- Use of Streptozocin in patients with preexisting renal disease requires a judgment by the physician of potential benefit as opposed to the known risk of serious renal damage.
- This drug should not be used in combination with or concomitantly with other potential nephrotoxins.
- When exposed dermally, some rats developed benign tumors at the site of application of streptozocin. Consequently, streptozocin may pose a carcinogenic hazard following topical exposure if not properly handled.
# Adverse Reactions
## Clinical Trials Experience
### Renal
- See warnings.
### Gastrointestinal
- Most patients treated with Streptozocin have experienced severe nausea and vomiting, occasionally requiring discontinuation of drug therapy. Some patients experienced diarrhea. A number of patients have experienced hepatic toxicity, as characterized by elevated liver enzyme (SGOT and LDH) levels and hypoalbuminemia.
### Hematological
- Hematological toxicity has been rare, most often involving mild decreases in hematocrit values. However, fatal hematological toxicity with substantial reductions in leukocyte (Leukopenia) and platelet (Thrombocytopenia) count has been observed.
### Metabolic
- Mild to moderate abnormalities of glucose tolerance have been noted in some patients treated with Streptozocin. These have generally been reversible, but insulin shock with hypoglycemia has been observed.
### Genitourinary
- Two cases of nephrogenic diabetes insipidus following therapy with Streptozocin have been reported. One had spontaneous recovery and the second responded to indomethacin.
## Postmarketing Experience
- Spontaneous reports have been received of local inflammation (i.e., edema, erythema, burning, tenderness) following extravasation of the product. In most cases, these events resolved the same day or within a few days.
# Drug Interactions
There is limited information regarding Streptozocin Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
- Reproduction studies revealed that streptozocin is teratogenic in the rat and has abortifacient effects in rabbits. When administered intravenously to pregnant monkeys, it appears rapidly in the fetal circulation. There are no studies in pregnant women. Streptozocin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Streptozocin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Streptozocin during labor and delivery.
### Nursing Mothers
- It is not known whether streptozocin 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, nursing should be discontinued in patients receiving Streptozocin.
### Pediatric Use
There is no FDA guidance on the use of Streptozocin in pediatric settings.
### Geriatic Use
- Clinical studies of streptozocin did not include sufficient numbers of patients aged 65 years and older to determine whether there was a difference in either efficacy or toxicity as compared to younger patients. Other reported clinical experience has not identified differences in efficacy or safety between the elderly and younger patient populations. In general, dose selection for elderly patients 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.
### Gender
There is no FDA guidance on the use of Streptozocin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Streptozocin with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Streptozocin in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Streptozocin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Streptozocin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Streptozocin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Streptozocin Administration in the drug label.
### Monitoring
There is limited information regarding Streptozocin Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Streptozocin and IV administrations.
# Overdosage
No specific antidote for Streptozocin is known.
# Pharmacology
## Mechanism of Action
- Streptozocin inhibits DNA synthesis in bacterial and mammalian cells. In bacterial cells, a specific interaction with cytosine moieties leads to degradation of DNA. The biochemical mechanism leading to mammalian cell death has not been definitely established; streptozocin inhibits cell proliferation at a considerably lower level than that needed to inhibit precursor incorporation into DNA or to inhibit several of the enzymes involved in DNA synthesis. Although streptozocin inhibits the progression of cells into mitosis, no specific phase of the cell cycle is particularly sensitive to its lethal effects.
## Structure
The structural formula is represented below:
## Pharmacodynamics
There is limited information regarding Streptozocin Pharmacodynamics in the drug label.
## Pharmacokinetics
- Streptozocin is active in the L1210 leukemic mouse over a fairly wide range of parenteral dosage schedules. In experiments in many animal species, streptozocin induced a diabetes that resembles human hyperglycemic nonketotic diabetes mellitus. This phenomenon, which has been extensively studied, appears to be mediated through a lowering of beta cell nicotinamide adenine dinucleotide (NAD) and consequent histopathologic alteration of pancreatic islet beta cells.
- The metabolism and the chemical dissociation of streptozocin that occurs under physiologic conditions has not been extensively studied. When administered intravenously to a variety of experimental animals, streptozocin disappears from the blood very rapidly. In all species tested, it was found to concentrate in the liver and kidney. As much as 20% of the drug (or metabolites containing an N-nitrosourea group) is metabolized and/or excreted by the kidney. Metabolic products have not yet been identified.
## Nonclinical Toxicology
There is limited information regarding Streptozocin Nonclinical Toxicology in the drug label.
# Clinical Studies
There is limited information regarding Streptozocin Clinical Studies in the drug label.
# How Supplied
## Storage
Unopened vials of Streptozocin should be stored at refrigeration temperatures (2° to 8°C) and protected from light (preferably stored in carton).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Streptozocin Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Streptozocin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Zanosar
# Look-Alike Drug Names
There is limited information regarding Streptozocin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Streptozocin | |
4e465feb88c17cc4c30040870824427116bce7a3 | wikidoc | Stress ulcer | Stress ulcer
# Overview
Stress ulcers are single or multiple mucosal defects which can become complicated by upper gastrointestinal bleeding during the physiologic stress of serious illness. Ordinary peptic ulcers are found commonly in the gastric antrum and the duodenum whereas stress ulcers are found commonly in fundic mucosa and can be located anywhere within the stomach and proximal duodenum.
# Incidence/Significance
Stress ulcers, as defined by overt bleeding and hemodynamic instability, decreased hemoglobin, and/or need for transfusion, was seen in 1.5% of patients in the 2252 patients in the Canadian Critical Care Trials group study. Patients with stress ulcers have a longer ICU length of stay (upto 8 days) and a higher mortality (upto 4 fold) than compared to patients who do not have stress ulceration and bleeding . While the bleeding and transfusions associated with the stress ulcerations contribute to the increased mortality, the contribution of factors like hypotension, sepsis and respiratory failure to the mortality independently of the stress ulceration cannot be ignored.
# Risk Factors
Risk factors for stress ulcer formation that have been identified are numerous and varied. However, two landmark studies and one position paper exist that addresses the topic of risk factors for stress ulcer formation:
- Non-critically ill medical patients with 2 or more of the following: respiratory failure, sepsis, heart failure, hepatic encephalopathy, jaundice, renal failure, stroke, hypotension, previous gastrointestinal disease and treatment with corticosteroids, NSAIDS, heparin, or warfarin.
- In surgical critically ill patients, only those patients who are on a mechanical ventilator for more than 48 hours and/or those with a coagulopathy.
- The American Society of Health-System Pharmacists guideline recommends against the practice of stress ulcer prophylaxis in non-critically ill patients.
# Diagnosis
Stress ulcer is suspected when there is upper gastrointestinal bleeding in the appropriate clinical setting, for example, when there is upper gastrointestinal bleeding in elderly patients in a surgical intensive care unit (ICU) with heart and lung disease, or when there is upper gastrointestinal bleeding in patients in a medical ICU who require respirators.
Stress ulcer can be diagnosed after the initial management of gastrointestinal bleeding, the diagnosis can be confirmed by upper GI endoscopy.
# The site of ulcerations
The ulcerations may be superficial and confined to the mucosa, in which case they are more appropriately called erosions, or they may penetrate deeper into the submucosa. The former may cause diffuse mucosal oozing of blood, whereas the latter may erode into a submucosal vessel and produce frank hemorrhage.
# Lesion of stress ulcers
The characteristic lesions may be multiple, superficial mucosal erosions similar to erosive gastroduodenitis. Occasionally, there may be a large acute ulcer in the duodenum (Curling’s ulcer).
Generally, there are multiple lesions located mainly in the stomach and occasionally in the duodenum. They range in depth from mere shedding of the superficial epithelium (erosion) to deeper lesions that involve the entire mucosal thickness (ulceration).
# Stress Ulcer formation
The pathogenic mechanisms are similar to those of erosive gastritis.”
The pathogenesis of stress ulcer is unclear but probably is related to a reduction in mucosal blood flow or a breakdown in other normal mucosal defense mechanisms in conjunction with the injurious effects of acid and pepsin on the gastroduodenal mucosa.
# Stress Ulcer Prophylaxis (SUP)
Clinical practice guidelines inform prophylaxis decisions.
## Who should be on stress ulcer prophylaxis?
Not every patient who enters the hospital needs SUP. Cook et al demonstrated that in surgical critically-ill patients the only risk factors associated with clinically significant bleeding from stress ulcers were mechanical ventilation for more than 48 hours and coagulopathy (OR 15.6 and 4.3, respectively).
## Drug classes and options available
Prophylactic agents include antacids, H2-receptor blockers, sucralfate, proton pump inhibitors (PPIs), prostaglandin analogs, and nutrition.
Among recent comparisons of prophylactic agents:
- Systematic reviews find inconsiatent results between proton pump inhibitors and H2-receptor blockers.
- A more recent randomized controlled trial of proton pump inhibitors versus H2-receptor blockers found no difference but a borderling increase in mortality with PPIs.
### Proton pump inhibitors
PPIs are also widely used in SUP. "Data regarding the efficacy and potential adverse effects of these drugs in the prevention of stress ulceration are less extensive than for antacids, H2 blockers, or sucralfate." In one study looking at omeprazole, patients were given an oral suspension by mouth followed by nasogastric tube and there were no episodes of bleeding or signs of toxicity. Similar results were reproduced in another study.
### H2 Receptor antagonists
In contrast, H2-receptor blockers are widely used in SUP. Most trials, but not all, have demonstrated their effectiveness in preventing stress ulcer formation.
### Sucralfate
Sucralfate has not been shown to effectively decrease the incidence of stress ulcer formation. This was demonstrated in a large randomized, double-blinded, control trial of 1200 patients and compared sucralfate to the H2-receptor blocker, ranitidine.
### Prostaglandin analogues
This class includes Misoprostol and the likes. Significant side effects including diarrhea, drug interactions, lack of overall efficacy and availability of much better alternatives preclude its use in current medical practice.
### Antacids
Antacids have been used in SUP. Numerous studies have shown them to be as effective in prevention when compared to H2-receptor blockers. One study did show them to be no more effective than placebo. Overall, all the studies show a trend towards effectiveness when compared to placebo but the effect is not as strong as other H2 receptor antagonists. Additionally, these drugs have other drawbacks such as the need for frequent administration (sometimes as often as every 2-3 hours), electrolyte imbalance, diarrhea, constipation and other important drug interactions. For these reasons, these drugs are no longer used for stress ulcer prophylaxis.
# Treatment
The principles of management are the same as for the chronic ulcer. The steps of management are similar as in erosive gastritis.
Endoscopic means of treating stress ulceration may be ineffective and operation required. It is believed that shunting of blood away from the mucosa makes the mucous membrane ischaemic and more susceptible to injury.
Treatment of stress ulceration usually begins with prevention. Careful attention to respiratory status, acid-base balance, and treatment of other illnesses helps prevent the conditions under which stress ulcers occur. Patients who develop stress ulcers typically do not secrete large quantities of gastric acid; however, acid does appear to be involved in the pathogenesis of the lesions. Thus it is reasonable either to neutralize acid or to inhibit its secretion in patients at high risk.
In case of severe hemorrhagic or erosive gastritis and stress ulcers, a combination of antacids and H2-blockers may stop active bleeding and prevent re bleeding. In selected patients, either endoscopic therapy or selective infusion of vasopressin into the left gastric artery may help control the hemorrhage.
# Footnote
- ↑ Jump up to: 1.0 1.1 Cook, DJ, Fuller, HD, Guyatt, GH, et al. Risk factors for gastrointestinal bleeding in critically ill patients. N Engl J Med 1994; 330:377.PMID 8284001
- ↑ Cook DJ, Griffith LE et al. The attributable mortality and length of intensive care unit stay of clinically important gastrointestinal bleeding in critically ill patients. Critical Care 2001 Dec;5(6):368-75. Epub 2001 Oct 5 PMID 11737927
- ↑ Manual of Gastroenterology by Gregory L. Eastwood, M.D. &Canan Avunduk, M.D., Ph.D.(1994)
- ↑ TEXTBOOK OF SURGERY ISBN 0-07-4621-149-1 page 409
- ↑ Robbins PATHOLOGIC BASIS OF DISEASE 6TH Edition ISBN 81-7867-052-6 page 796
- ↑ Robbins PATHOLOGIC BASIS OF DISEASE 6TH Edition ISBN 81-7867-052-6 page 796
- ↑ Manual of Gastroenterology
Gregory L. Eastwood, M.D.& Canan Avunduk, M.D., Ph.D.(1994)
- ↑ Ye Z, Reintam Blaser A, Lytvyn L, Wang Y, Guyatt GH, Mikita JS; et al. (2020). "Gastrointestinal bleeding prophylaxis for critically ill patients: a clinical practice guideline". BMJ. 368: l6722. doi:10.1136/bmj.l6722. PMID 31907223.CS1 maint: Multiple names: authors list (link) .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}
- ↑ Cook, DJ, Fuller, HD, Guyatt, GH, et al. Risk factors for gastrointestinal bleeding in critically ill patients. N Engl J Med 1994; 330:377.
- ↑ Wang Y, Ye Z, Ge L, Siemieniuk RAC, Wang X, Wang Y; et al. (2020). "Efficacy and safety of gastrointestinal bleeding prophylaxis in critically ill patients: systematic review and network meta-analysis". BMJ. 368: l6744. doi:10.1136/bmj.l6744. PMID 31907166.CS1 maint: Multiple names: authors list (link)
- ↑ Toews I, George AT, Peter JV, Kirubakaran R, Fontes LES, Ezekiel JPB; et al. (2018). "Interventions for preventing upper gastrointestinal bleeding in people admitted to intensive care units". Cochrane Database Syst Rev. 6: CD008687. doi:10.1002/14651858.CD008687.pub2. PMC 6513395 Check |pmc= value (help). PMID 29862492.CS1 maint: Multiple names: authors list (link)
- ↑ PEPTIC Investigators for the Australian and New Zealand Intensive Care Society Clinical Trials Group, Alberta Health Services Critical Care Strategic Clinical Network, and the Irish Critical Care Trials Group. Young PJ, Bagshaw SM, Forbes AB, Nichol AD, Wright SE; et al. (2020). "Effect of Stress Ulcer Prophylaxis With Proton Pump Inhibitors vs Histamine-2 Receptor Blockers on In-Hospital Mortality Among ICU Patients Receiving Invasive Mechanical Ventilation: The PEPTIC Randomized Clinical Trial". JAMA. doi:10.1001/jama.2019.22190. PMID 31950977.CS1 maint: Multiple names: authors list (link)
- ↑ Phillips, JO, Metzler, MH, Palmieri, MT, et al. A prospective study of simplified omeprazole suspension for the prophylaxis of stress-related mucosal damage. Crit Care Med 1996; 24:1793.
- ↑ Lasky, MR, Metzler, MH, Phillips, JO. A prospective study of omeprazole suspension to prevent clinically significant gastrointestinal bleeding from stress ulcers in mechanically ventilated trauma patients. J Trauma 1998; 44:527.
- ↑ Shuman, RB, Schuster, DP, Zuckerman, GR. Prophylactic therapy for stress ulcer bleeding: A reappraisal. Ann Intern Med 1987; 106:562.
- ↑ Messori, A, Trippoli, S, Vaiani, M, et al. Bleeding and pneumonia in intensive care patients given ranitidine and sucralfate for prevention of stress ulcer: meta-analysis of randomised controlled trials. BMJ 2000; 321:1103.
- ↑ Cook, D, Guyatt, G, Marshall, J, et al. A comparison of sucralfate and ranitidine for the prevention of upper gastrointestinal bleeding in patients requiring mechanical ventilation. N Engl J Med 1998; 338:791.
- ↑ Shuman, RB, Schuster, DP, Zuckerman, GR. Prophylactic therapy for stress ulcer bleeding: A reappraisal. Ann Intern Med 1987; 106:562.
- ↑ Cook, DJ, Reeve, BK, Guyatt, GH, et al. Stress ulcer prophylaxis in critically ill patients. Resolving discordant meta-analyses. JAMA 1996; 275:308.
- ↑ Bailey & Love’s SHORT PRACTICE OF SURGERY 23rd Edition ISBN 0 340 75949 6 page 916
- ↑ TEXTBOOK OF SURGERY ISBN 0-07-4621-149-1 page 409
- ↑ Bailey & Love’s SHORT PRACTICE OF SURGERY 23rd Edition ISBN 0 340 75949 6 page 916
- ↑ TEXTBOOK OF SURGERY ISBN 0-07-4621-149-1 page 409
- ↑ Manual of Gastroenterology priyank sinha
Gregory L. Eastwood, M.D. & Canan Avunduk, M.D., Ph.D.(1994)
- ↑ A Practical Approach to Emergency Medicine by Robert J. Stine, M.D., Carl R. Chudnofsky, M.D., Cynthia K. Aaron, M.D. (1994)
Bailey & Love's, Short Practice of Surgery (23rd ed.), New York, USA: Arnold, Co-published in the USA by Oxford University press Inc., New York 2000 Unknown parameter |coauthors= ignored (help)
# Selected Readings
- Cheung, L. Y. Pathogenesis, prophylaxis and treatment of stress gastritis. Am. J. Surg. 156:437, 1988.
- Craven, D. E., et al. Risk factors for pneumonia and fatality in patients receiving continuous mechanical ventilation. Am. Rev. Respir. Dis. 133:792, 1986.
- Driks, M. R., et al. Nosocomial pneumonia in intubated patients given sucralfate as compared with antacids or histamine type 2 blockers. N. Engl. J. Med. 317:1376, 1987.
- DuMoulin, G. C., et al. Aspiration of gastric bacteria in antacid-treated patients: A frequent cause of postoperative colonisation of the airway. Lancet 1:242, 1982.
- Lamothe, P. H., et al. Comparative efficacy of cimetidine, famotidine, ranitidine, and Mylanta in postoperative stress ulcers: Gastric pH control and ulcer prevention in patients undergoing coronary artery bypass graft surgery. Gastroenterology 100:1515, 1991.
- Priebe, H. J., et al. Antacid versus cimetidine in preventing acute gastrointestinal bleeding: A randomized trial in 75 ill patients. N. Engl. J. Med. 302:426, 1980.
- Shuman, R. B., Schuster, D. P., and Zuckerman, G. R. Prophylactic therapy for stress ulcer bleeding: A reappraisal. Ann Intern. Med. 106:562, 1987.
- Tryba, M. Stress bleeding prophylaxis with sucralfate: Pathophysiologic basis and clinical use. Scand. J. Gastroenterol. 25:22, 1990. | Stress ulcer
# Overview
Stress ulcers are single or multiple mucosal defects which can become complicated by upper gastrointestinal bleeding during the physiologic stress of serious illness. Ordinary peptic ulcers are found commonly in the gastric antrum and the duodenum whereas stress ulcers are found commonly in fundic mucosa and can be located anywhere within the stomach and proximal duodenum.
# Incidence/Significance
Stress ulcers, as defined by overt bleeding and hemodynamic instability, decreased hemoglobin, and/or need for transfusion, was seen in 1.5% of patients in the 2252 patients in the Canadian Critical Care Trials group study.[1] Patients with stress ulcers have a longer ICU length of stay (upto 8 days) and a higher mortality (upto 4 fold) than compared to patients who do not have stress ulceration and bleeding [2]. While the bleeding and transfusions associated with the stress ulcerations contribute to the increased mortality, the contribution of factors like hypotension, sepsis and respiratory failure to the mortality independently of the stress ulceration cannot be ignored.
# Risk Factors
Risk factors for stress ulcer formation that have been identified are numerous and varied. However, two landmark studies and one position paper exist that addresses the topic of risk factors for stress ulcer formation:
- Non-critically ill medical patients with 2 or more of the following: respiratory failure, sepsis, heart failure, hepatic encephalopathy, jaundice, renal failure, stroke, hypotension, previous gastrointestinal disease and treatment with corticosteroids, NSAIDS, heparin, or warfarin.
- In surgical critically ill patients, only those patients who are on a mechanical ventilator for more than 48 hours and/or those with a coagulopathy.[1]
- The American Society of Health-System Pharmacists guideline recommends against the practice of stress ulcer prophylaxis in non-critically ill patients.
# Diagnosis
Stress ulcer is suspected when there is upper gastrointestinal bleeding in the appropriate clinical setting, for example, when there is upper gastrointestinal bleeding in elderly patients in a surgical intensive care unit (ICU) with heart and lung disease, or when there is upper gastrointestinal bleeding in patients in a medical ICU who require respirators.
Stress ulcer can be diagnosed after the initial management of gastrointestinal bleeding, the diagnosis can be confirmed by upper GI endoscopy.
# The site of ulcerations
The ulcerations may be superficial and confined to the mucosa, in which case they are more appropriately called erosions, or they may penetrate deeper into the submucosa. The former may cause diffuse mucosal oozing of blood, whereas the latter may erode into a submucosal vessel and produce frank hemorrhage. [3]
# Lesion of stress ulcers
The characteristic lesions may be multiple, superficial mucosal erosions similar to erosive gastroduodenitis. Occasionally, there may be a large acute ulcer in the duodenum (Curling’s ulcer). [4]
Generally, there are multiple lesions located mainly in the stomach and occasionally in the duodenum. They range in depth from mere shedding of the superficial epithelium (erosion) to deeper lesions that involve the entire mucosal thickness (ulceration). [5]
# Stress Ulcer formation
The pathogenic mechanisms are similar to those of erosive gastritis.” [6]
The pathogenesis of stress ulcer is unclear but probably is related to a reduction in mucosal blood flow or a breakdown in other normal mucosal defense mechanisms in conjunction with the injurious effects of acid and pepsin on the gastroduodenal mucosa. [7]
# Stress Ulcer Prophylaxis (SUP)
Clinical practice guidelines inform prophylaxis decisions[8].
## Who should be on stress ulcer prophylaxis?
Not every patient who enters the hospital needs SUP. Cook et al demonstrated that in surgical critically-ill patients the only risk factors associated with clinically significant bleeding from stress ulcers were mechanical ventilation for more than 48 hours and coagulopathy (OR 15.6 and 4.3, respectively). [9]
## Drug classes and options available
Prophylactic agents include antacids, H2-receptor blockers, sucralfate, proton pump inhibitors (PPIs), prostaglandin analogs, and nutrition.
Among recent comparisons of prophylactic agents:
- Systematic reviews find inconsiatent results between proton pump inhibitors and H2-receptor blockers[10].
- A more recent randomized controlled trial of proton pump inhibitors versus H2-receptor blockers found no difference but a borderling increase in mortality with PPIs[11][12].
### Proton pump inhibitors
PPIs are also widely used in SUP. "Data regarding the efficacy and potential adverse effects of these drugs in the prevention of stress ulceration are less extensive than for antacids, H2 blockers, or sucralfate." [13] In one study looking at omeprazole, patients were given an oral suspension by mouth followed by nasogastric tube and there were no episodes of bleeding or signs of toxicity. [14] Similar results were reproduced in another study. [15]
### H2 Receptor antagonists
In contrast, H2-receptor blockers are widely used in SUP. Most trials, but not all, have demonstrated their effectiveness in preventing stress ulcer formation. [16] [17]
### Sucralfate
Sucralfate has not been shown to effectively decrease the incidence of stress ulcer formation. This was demonstrated in a large randomized, double-blinded, control trial of 1200 patients and compared sucralfate to the H2-receptor blocker, ranitidine. [18]
### Prostaglandin analogues
This class includes Misoprostol and the likes. Significant side effects including diarrhea, drug interactions, lack of overall efficacy and availability of much better alternatives preclude its use in current medical practice.
### Antacids
Antacids have been used in SUP. Numerous studies have shown them to be as effective in prevention when compared to H2-receptor blockers. [19] One study did show them to be no more effective than placebo. [20] Overall, all the studies show a trend towards effectiveness when compared to placebo but the effect is not as strong as other H2 receptor antagonists. Additionally, these drugs have other drawbacks such as the need for frequent administration (sometimes as often as every 2-3 hours), electrolyte imbalance, diarrhea, constipation and other important drug interactions. For these reasons, these drugs are no longer used for stress ulcer prophylaxis.
# Treatment
The principles of management are the same as for the chronic ulcer. [21] The steps of management are similar as in erosive gastritis.[22]
Endoscopic means of treating stress ulceration may be ineffective and operation required. [23] It is believed that shunting of blood away from the mucosa makes the mucous membrane ischaemic and more susceptible to injury. [24]
Treatment of stress ulceration usually begins with prevention. Careful attention to respiratory status, acid-base balance, and treatment of other illnesses helps prevent the conditions under which stress ulcers occur. Patients who develop stress ulcers typically do not secrete large quantities of gastric acid; however, acid does appear to be involved in the pathogenesis of the lesions. Thus it is reasonable either to neutralize acid or to inhibit its secretion in patients at high risk. [25]
In case of severe hemorrhagic or erosive gastritis and stress ulcers, a combination of antacids and H2-blockers may stop active bleeding and prevent re bleeding. In selected patients, either endoscopic therapy or selective infusion of vasopressin into the left gastric artery may help control the hemorrhage. [26]
# Footnote
- ↑ Jump up to: 1.0 1.1 Cook, DJ, Fuller, HD, Guyatt, GH, et al. Risk factors for gastrointestinal bleeding in critically ill patients. N Engl J Med 1994; 330:377.PMID 8284001
- ↑ Cook DJ, Griffith LE et al. The attributable mortality and length of intensive care unit stay of clinically important gastrointestinal bleeding in critically ill patients. Critical Care 2001 Dec;5(6):368-75. Epub 2001 Oct 5 PMID 11737927
- ↑ Manual of Gastroenterology by Gregory L. Eastwood, M.D. &Canan Avunduk, M.D., Ph.D.(1994)
- ↑ TEXTBOOK OF SURGERY ISBN 0-07-4621-149-1 page 409
- ↑ Robbins PATHOLOGIC BASIS OF DISEASE 6TH Edition ISBN 81-7867-052-6 page 796
- ↑ Robbins PATHOLOGIC BASIS OF DISEASE 6TH Edition ISBN 81-7867-052-6 page 796
- ↑ Manual of Gastroenterology
Gregory L. Eastwood, M.D.& Canan Avunduk, M.D., Ph.D.(1994)
- ↑ Ye Z, Reintam Blaser A, Lytvyn L, Wang Y, Guyatt GH, Mikita JS; et al. (2020). "Gastrointestinal bleeding prophylaxis for critically ill patients: a clinical practice guideline". BMJ. 368: l6722. doi:10.1136/bmj.l6722. PMID 31907223.CS1 maint: Multiple names: authors list (link) .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}
- ↑ Cook, DJ, Fuller, HD, Guyatt, GH, et al. Risk factors for gastrointestinal bleeding in critically ill patients. N Engl J Med 1994; 330:377.
- ↑ Wang Y, Ye Z, Ge L, Siemieniuk RAC, Wang X, Wang Y; et al. (2020). "Efficacy and safety of gastrointestinal bleeding prophylaxis in critically ill patients: systematic review and network meta-analysis". BMJ. 368: l6744. doi:10.1136/bmj.l6744. PMID 31907166.CS1 maint: Multiple names: authors list (link)
- ↑ Toews I, George AT, Peter JV, Kirubakaran R, Fontes LES, Ezekiel JPB; et al. (2018). "Interventions for preventing upper gastrointestinal bleeding in people admitted to intensive care units". Cochrane Database Syst Rev. 6: CD008687. doi:10.1002/14651858.CD008687.pub2. PMC 6513395 Check |pmc= value (help). PMID 29862492.CS1 maint: Multiple names: authors list (link)
- ↑ PEPTIC Investigators for the Australian and New Zealand Intensive Care Society Clinical Trials Group, Alberta Health Services Critical Care Strategic Clinical Network, and the Irish Critical Care Trials Group. Young PJ, Bagshaw SM, Forbes AB, Nichol AD, Wright SE; et al. (2020). "Effect of Stress Ulcer Prophylaxis With Proton Pump Inhibitors vs Histamine-2 Receptor Blockers on In-Hospital Mortality Among ICU Patients Receiving Invasive Mechanical Ventilation: The PEPTIC Randomized Clinical Trial". JAMA. doi:10.1001/jama.2019.22190. PMID 31950977.CS1 maint: Multiple names: authors list (link)
- ↑ [www.Uptodate.com]
- ↑ Phillips, JO, Metzler, MH, Palmieri, MT, et al. A prospective study of simplified omeprazole suspension for the prophylaxis of stress-related mucosal damage. Crit Care Med 1996; 24:1793.
- ↑ Lasky, MR, Metzler, MH, Phillips, JO. A prospective study of omeprazole suspension to prevent clinically significant gastrointestinal bleeding from stress ulcers in mechanically ventilated trauma patients. J Trauma 1998; 44:527.
- ↑ Shuman, RB, Schuster, DP, Zuckerman, GR. Prophylactic therapy for stress ulcer bleeding: A reappraisal. Ann Intern Med 1987; 106:562.
- ↑ Messori, A, Trippoli, S, Vaiani, M, et al. Bleeding and pneumonia in intensive care patients given ranitidine and sucralfate for prevention of stress ulcer: meta-analysis of randomised controlled trials. BMJ 2000; 321:1103.
- ↑ Cook, D, Guyatt, G, Marshall, J, et al. A comparison of sucralfate and ranitidine for the prevention of upper gastrointestinal bleeding in patients requiring mechanical ventilation. N Engl J Med 1998; 338:791.
- ↑ Shuman, RB, Schuster, DP, Zuckerman, GR. Prophylactic therapy for stress ulcer bleeding: A reappraisal. Ann Intern Med 1987; 106:562.
- ↑ Cook, DJ, Reeve, BK, Guyatt, GH, et al. Stress ulcer prophylaxis in critically ill patients. Resolving discordant meta-analyses. JAMA 1996; 275:308.
- ↑ Bailey & Love’s SHORT PRACTICE OF SURGERY 23rd Edition ISBN 0 340 75949 6 page 916
- ↑ TEXTBOOK OF SURGERY ISBN 0-07-4621-149-1 page 409
- ↑ Bailey & Love’s SHORT PRACTICE OF SURGERY 23rd Edition ISBN 0 340 75949 6 page 916
- ↑ TEXTBOOK OF SURGERY ISBN 0-07-4621-149-1 page 409
- ↑ Manual of Gastroenterology priyank sinha
Gregory L. Eastwood, M.D. & Canan Avunduk, M.D., Ph.D.(1994)
- ↑ A Practical Approach to Emergency Medicine by Robert J. Stine, M.D., Carl R. Chudnofsky, M.D., Cynthia K. Aaron, M.D. (1994)
Bailey & Love's, Short Practice of Surgery (23rd ed.), New York, USA: Arnold, Co-published in the USA by Oxford University press Inc., New York 2000 Unknown parameter |coauthors= ignored (help)
# Selected Readings
- Cheung, L. Y. Pathogenesis, prophylaxis and treatment of stress gastritis. Am. J. Surg. 156:437, 1988.
- Craven, D. E., et al. Risk factors for pneumonia and fatality in patients receiving continuous mechanical ventilation. Am. Rev. Respir. Dis. 133:792, 1986.
- Driks, M. R., et al. Nosocomial pneumonia in intubated patients given sucralfate as compared with antacids or histamine type 2 blockers. N. Engl. J. Med. 317:1376, 1987.
- DuMoulin, G. C., et al. Aspiration of gastric bacteria in antacid-treated patients: A frequent cause of postoperative colonisation of the airway. Lancet 1:242, 1982.
- Lamothe, P. H., et al. Comparative efficacy of cimetidine, famotidine, ranitidine, and Mylanta in postoperative stress ulcers: Gastric pH control and ulcer prevention in patients undergoing coronary artery bypass graft surgery. Gastroenterology 100:1515, 1991.
- Priebe, H. J., et al. Antacid versus cimetidine in preventing acute gastrointestinal bleeding: A randomized trial in 75 ill patients. N. Engl. J. Med. 302:426, 1980.
- Shuman, R. B., Schuster, D. P., and Zuckerman, G. R. Prophylactic therapy for stress ulcer bleeding: A reappraisal. Ann Intern. Med. 106:562, 1987.
- Tryba, M. Stress bleeding prophylaxis with sucralfate: Pathophysiologic basis and clinical use. Scand. J. Gastroenterol. [Suppl. 173] 25:22, 1990.
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Stress_ulcer | |
eb0ebf0102be58d1265bc145c99845f181cd6750 | wikidoc | Study design | Study design
A study design is an analytic approach to conduct an epidemiological investigation, such as a clinical trial.
# Types of design
Some of the most popular designs are sorted below, with the ones at the top being the most powerful at reducing observer-expectancy effect but also most expensive, and in some cases introducing ethical concerns. The ones at the bottom are the most affordable, and are frequently used earlier in the research cycle, to develop strong hypotheses worth testing with the more expensive research approaches.
File:Studydesigns.GIF
## Experimental
- Randomized controlled trial
Double-blind
Single-blind
Non-blind
Adaptive designs
- Double-blind
- Single-blind
- Non-blind
- Adaptive designs
- Nonrandomized controlled trial
- Stepped-wedge trial is usually randomized but can also be non-randomized.. Difficulties in executing stepped-wedge designs have been documented.
- Randomized database studies
## Nonexperimental
- Cohort study
Prospective cohort
Retrospective cohort
Nested cohort
Time-trend study
- Prospective cohort
- Retrospective cohort
- Nested cohort
- Time-trend study
- Case-cohort study
- Case-control study (case series)
Nested case-control study
- Nested case-control study
- Cross-sectional study
## Descriptive
- Community survey
# Important considerations
When choosing a study design, many factors must be taken into account. Different types of studies are subject to different types of bias. For example, recall bias is likely to occur in cross-sectional or case-control studies where subjects are asked to recall exposure to risk factors. Subjects with the relevant condition (e.g. breast cancer) may be more likely to recall the relevant exposures that they had undergone (e.g. hormone replacement therapy) than subjects who don't have the condition.
The ecological fallacy may occur when analyses are done on ecological (group-based) data rather than individual data. The nature of this type of analysis tends to overestimate the degree of association between variables.
# Other terms
- A "retrospective study" looks at past behavior, while a "prospective study" looks at future behavior.
- "Superiority trials" are designed to demonstrate that one treatment is more effective than another.
- "Non-inferiority trials" are designed to demonstrate that a treatment is at least not appreciably worse than another.
- "Equivalence trials" are designed to demonstrate that one treatment is as effective as another.
- When using "parallel groups", each patient receives one treatment; in a "crossover study", each patient receives several treatments.
- A longitudinal study studies a few subjects for a long period of time, while a cross-sectional study involves many subjects measured at once. | Study design
A study design is an analytic approach to conduct an epidemiological investigation, such as a clinical trial.
# Types of design
Some of the most popular designs are sorted below, with the ones at the top being the most powerful at reducing observer-expectancy effect but also most expensive, and in some cases introducing ethical concerns. The ones at the bottom are the most affordable, and are frequently used earlier in the research cycle, to develop strong hypotheses worth testing with the more expensive research approaches.
File:Studydesigns.GIF
## Experimental
- Randomized controlled trial
Double-blind
Single-blind
Non-blind
Adaptive designs[1]
- Double-blind
- Single-blind
- Non-blind
- Adaptive designs[1]
- Nonrandomized controlled trial
- Stepped-wedge trial is usually randomized[2] but can also be non-randomized.[3]. Difficulties in executing stepped-wedge designs have been documented.[4][5][6]
- Randomized database studies
## Nonexperimental
- Cohort study
Prospective cohort
Retrospective cohort
Nested cohort
Time-trend study
- Prospective cohort
- Retrospective cohort
- Nested cohort
- Time-trend study
- Case-cohort study
- Case-control study (case series)
Nested case-control study
- Nested case-control study
- Cross-sectional study
## Descriptive
- Community survey
# Important considerations
When choosing a study design, many factors must be taken into account. Different types of studies are subject to different types of bias. For example, recall bias is likely to occur in cross-sectional or case-control studies where subjects are asked to recall exposure to risk factors. Subjects with the relevant condition (e.g. breast cancer) may be more likely to recall the relevant exposures that they had undergone (e.g. hormone replacement therapy) than subjects who don't have the condition.
The ecological fallacy may occur when analyses are done on ecological (group-based) data rather than individual data. The nature of this type of analysis tends to overestimate the degree of association between variables.
# Other terms
- A "retrospective study" looks at past behavior, while a "prospective study" looks at future behavior.
- "Superiority trials" are designed to demonstrate that one treatment is more effective than another.
- "Non-inferiority trials" are designed to demonstrate that a treatment is at least not appreciably worse than another.
- "Equivalence trials" are designed to demonstrate that one treatment is as effective as another.
- When using "parallel groups", each patient receives one treatment; in a "crossover study", each patient receives several treatments.
- A longitudinal study studies a few subjects for a long period of time, while a cross-sectional study involves many subjects measured at once. | https://www.wikidoc.org/index.php/Study_design | |
73d38e7608780ff488daf7e50972aebc8ae23d66 | wikidoc | Subspecialty | Subspecialty
A subspecialty is narrow field within a specialty such as forensic pathology, which is a subspecialty of anatomical pathology.
In medicine subspecialization is particularily common in internal medicine and has grown as medicine has:
- become more complex and
- it has become clear that a physician's case volume is negatively associated with their complication rate; that is, complications tend decrease as volume of cases goes up. | Subspecialty
A subspecialty is narrow field within a specialty such as forensic pathology, which is a subspecialty of anatomical pathology.
In medicine subspecialization is particularily common in internal medicine and has grown as medicine has:
- become more complex and
- it has become clear that a physician's case volume is negatively associated with their complication rate; that is, complications tend decrease as volume of cases goes up.[1][2] | https://www.wikidoc.org/index.php/Subspecialty | |
e935c2172188de80f3a17207d54cc32641a431bd | wikidoc | Succinyl-CoA | Succinyl-CoA
Succinyl-Coenzyme A, generally abbreviated as Succinyl-CoA or SucCoA is a combination of succinic acid and coenzyme A.
# Source
It is an important intermediate in the citric acid cycle, where it is synthesized from α-Ketoglutarate by α-ketoglutarate dehydrogenase through decarboxylation. During the process, coenzyme A is added.
It is also synthesized from propionyl CoA, the odd numbered fatty acid which cannot undergo beta-oxidation. Propionyl-CoA is carboxylated to D-methylmalonyl-CoA, isomerized to L-methylmalonyl-CoA, and rearranged to yield succinyl-CoA via a vitamin B12-dependent enzyme. Succinyl-CoA is an intermediate of the citric acid cycle and can be readily incorporated there.
# Fate
It is converted into succinate through the hydrolytic release of coenzyme A by succinyl-CoA synthetase (succinate thiokinase).
Another fate of succinyl-CoA is porphyrin synthesis, where succinyl-CoA and glycine are combined by ALA synthase to form δ-aminolevulinic acid (dALA).
# Formation
Succinyl CoA can be formed from methylmalonyl CoA through the utilization of deoxyadenosyl-B12 (deoxyadenosylcobalamin) by methylmalonyl CoA Mutase. This reaction, which requires vitamin B12 to occur, is important in the catabolism of some branched-chain amino acids as well as odd-chain fatty acids. | Succinyl-CoA
Template:Chembox new
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Succinyl-Coenzyme A, generally abbreviated as Succinyl-CoA or SucCoA is a combination of succinic acid and coenzyme A.
# Source
It is an important intermediate in the citric acid cycle, where it is synthesized from α-Ketoglutarate by α-ketoglutarate dehydrogenase through decarboxylation. During the process, coenzyme A is added.
It is also synthesized from propionyl CoA, the odd numbered fatty acid which cannot undergo beta-oxidation. Propionyl-CoA is carboxylated to D-methylmalonyl-CoA, isomerized to L-methylmalonyl-CoA, and rearranged to yield succinyl-CoA via a vitamin B12-dependent enzyme. Succinyl-CoA is an intermediate of the citric acid cycle and can be readily incorporated there.
# Fate
It is converted into succinate through the hydrolytic release of coenzyme A by succinyl-CoA synthetase (succinate thiokinase).
Another fate of succinyl-CoA is porphyrin synthesis, where succinyl-CoA and glycine are combined by ALA synthase to form δ-aminolevulinic acid (dALA).
# Formation
Succinyl CoA can be formed from methylmalonyl CoA through the utilization of deoxyadenosyl-B12 (deoxyadenosylcobalamin) by methylmalonyl CoA Mutase. This reaction, which requires vitamin B12 to occur, is important in the catabolism of some branched-chain amino acids as well as odd-chain fatty acids. | https://www.wikidoc.org/index.php/Succinyl-CoA | |
ebcb67ff8ce8e6b133d048cfaa03955b59220ba0 | wikidoc | Sulfadiazine | Sulfadiazine
# 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
Sulfadiazine is a anti-infective, anti-parasitic agent that is FDA approved for the treatment of chancroid, trachoma, inclusion conjunctivitis, nocardiosis, urinary tract infections (primarily pyelonephritis, pyelitis and cystitis), toxoplasmosis encephalitis in patients with and without acquired immunodeficiency syndrome, malaria due to chloroquine-resistant strains of plasmodium falciparum, prophylaxis of meningococcal meningitis, meningococcal meningitis, acute otitis media due to haemophilus influenzae, prophylaxis against recurrences of rheumatic fever, H. influenzae meningitis, as an adjunctive therapy. Common adverse reactions include rash, abdominal pain, diarrhea, nausea, vomiting.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- Initial, 2 to 4 g ORALLY
- Maintenance, 2 to 4 g ORALLY divided into 3 to 6 doses, every 24 hours
- Dosing Information
- Initial, 2 to 4 g ORALLY
- Maintenance, 2 to 4 g ORALLY divided into 3 to 6 doses, every 24 hours
- Dosing Information
- Initial, 2 to 4 g ORALLY
- Maintenance, 2 to 4 g ORALLY divided into 3 to 6 doses, every 24 hours
### Inclusion conjunctivitis
- Dosing Information
- Initial, 2 to 4 g ORALLY
- Maintenance, 2 to 4 g ORALLY divided into 3 to 6 doses, every 24 hours
### Malaria, due to chloroquine-resistant strains of Plasmodium falciparum; Adjunct
- Dosing Information
- Initial, 2 to 4 g ORALLY
- Maintenance, 2 to 4 g ORALLY divided into 3 to 6 doses, every 24 hours
### Meningococcal meningitis; Treatment and Prophylaxis
- Dosing Information
- Initial, 2 to 4 g ORALLY
- Maintenance, 2 to 4 g ORALLY divided into 3 to 6 doses, every 24 hours
### Nocardiosis
- Dosing Information
- Initial, 2 to 4 g ORALLY
- Maintenance, 2 to 4 g ORALLY divided into 3 to 6 doses, every 24 hours
### Rheumatic fever, Recurrent; Prophylaxis
- Dosing Information
- Greater than 27 kg: 1 g ORALLY once a day; (27 kg or less) 500 mg ORALLY once a day (guideline dosing)
- Initial, 2 to 4 g ORALLY (manufacturer dosing)
- Maintenance, 2 to 4 g ORALLY divided into 3 to 6 doses, every 24 hours (manufacturer dosing)
### Toxoplasma encephalitis
- Dosing Information
- Initial 2 to 4 g ORALLY (manufacturer dosing)
- Maintenance, 2 to 4 g ORALLY divided into 3 to 6 doses, every 24 hours (manufacturer dosing)
- Less than 60 kg: 1000 mg ORALLY every 6 hour plus pyrimethamine 200 mg ORALLY for 1 dose, then 50 mg ORALLY daily plus leucovorin 10 to 25 mg (can increase to 50 mg) ORALLY daily for at least 6 week (guideline dosing)
- 60 kg or greater: 1500 mg ORALLY every 6 hour plus pyrimethamine 200 mg ORALLY for 1 dose, then 75 mg ORALLY daily plus leucovorin 10 to 25 mg (can increase to 50 mg) ORALLY daily for at least 6 week (guideline dosing)
- 1000 to 1500 mg ORALLY every 6 hour plus atovaquone 1500 mg orally twice daily for at least 6 week (guideline dosing)
### Trachoma
- Dosing Information
- Initial, 2 to 4 g ORALLY
- Maintenance, 2 to 4 g ORALLY divided into 3 to 6 doses, every 24 hours
### Urinary tract infectious disease
- Dosing Information
- Initial, 2 to 4 g ORALLY
- Maintenance, 2 to 4 g ORALLY divided into 3 to 6 doses, every 24 hours
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Sulfadiazine in adult patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Sulfadiazine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- 2 months and older: Initial 75 mg/kg or 2 g/m(2) ORALLY
- 2 months and older: Maintenance, 150 mg/kg/day or 4 g/m(2)/day ORALLY divided into 4 to 6 doses, every 24 hours; MAX 6 g every 24 hours
- Dosing Information
- (2 months and older) initial 75 mg/kg or 2 g/m(2) ORALLY
- (2 months and older) maintenance, 150 mg/kg/day or 4 g/m(2)/day ORALLY divided into 4 to 6 doses, every 24 hours; MAX 6 g every 24 hours
- Dosing Information
- 2 months and older: Initial 75 mg/kg or 2 g/m(2) ORALLY (manufacturer dosing)
- 2 months and older: Maintenance, 150 mg/kg/day or 4 g/m(2)/day ORALLY divided into 4 to 6 doses, every 24 hours; MAX 6 g every 24 hours (manufacturer dosing)
- (HIV) 50 mg/kg per dose ORALLY twice daily PLUS pyrimethamine 2 mg/kg ORALLY once daily for 2 days, then 1 mg/kg ORALLY once daily for 2 to 6 months, then 1 mg/kg ORALLY 3 times weekly PLUS leucovorin 10 mg ORALLY or IM with each dose of pyrimethamine; total treatment duration is 12 months (guideline dosing)
### Haemophilus influenzae meningitis, In combination with parenteral streptomycin; Adjunct
- Dosing Information
- (2 months and older) Initial 75 mg/kg or 2 g/m(2) ORALLY
- (2 months and older) Maintenance, 150 mg/kg/day or 4 g/m(2)/day ORALLY divided into 4 to 6 doses, every 24 hours; MAX 6 g every 24 hours
### Inclusion conjunctivitis
- Dosing Information
- (2 months and older) initial 75 mg/kg or 2 g/m(2) ORALLY
- (2 months and older) maintenance, 150 mg/kg/day or 4 g/m(2)/day ORALLY divided into 4 to 6 doses, every 24 hours; MAX 6 g every 24 hours
### Malaria, due to chloroquine-resistant strains of Plasmodium falciparum; Adjunct
- Dosing Information
- (2 months and older) initial 75 mg/kg or 2 g/m(2) ORALLY
- (2 months and older) maintenance, 150 mg/kg/day or 4 g/m(2)/day ORALLY divided into 4 to 6 doses, every 24 hours; MAX 6 g every 24 hours
### Meningococcal meningitis; Treatment and Prophylaxis
- Dosing Information
- (2 months and older) initial 75 mg/kg or 2 g/m(2) ORALLY
- (2 months and older) maintenance, 150 mg/kg/day or 4 g/m(2)/day ORALLY divided into 4 to 6 doses, every 24 hours; MAX 6 g every 24 hours
### Nocardiosis
- Dosing Information
- (2 months and older) initial 75 mg/kg or 2 g/m(2) ORALLY
- (2 months and older) maintenance, 150 mg/kg/day or 4 g/m(2)/day ORALLY divided into 4 to 6 doses, every 24 hours; MAX 6 g every 24 hours
### Rheumatic fever, Recurrent; Prophylaxis
- Dosing Information
- (27 kg or less) 500 mg ORALLY once a day (guideline dosing)
- (greater than 27 kg) 1 g ORALLY once a day (guideline dosing)
- (less than 30 kg) 500 mg ORALLY every 24 hours (manufacturer dosing)
- (greater than 30 kg) 1 g ORALLY every 24 hours (manufacturer dosing)
### Toxoplasma encephalitis
- Dosing Information
- (2 months and older) initial 75 mg/kg or 2 g/m(2) ORALLY (manufacturer dosing)
- (2 months and older) maintenance, 150 mg/kg/day or 4 g/m(2)/day ORALLY divided into 4 to 6 doses, every 24 hours; MAX 6 g every 24 hours (manufacturer dosing)
- (acquired toxoplasmosis in children with HIV) 25 to 50 mg/kg (MAX 1000 to 1500 mg/dose) ORALLY 4 times daily plus pyrimethamine 2 mg/kg (MAX 50 mg) ORALLY once daily for 3 days, then 1 mg/kg (MAX 25 mg) ORALLY once daily PLUS leucovorin 10 to 25 mg ORALLY daily; continue for at least 6 weeks, followed by secondary prophylaxis (guideline dosing)
### Trachoma
- Dosing Information
- (2 months and older) initial 75 mg/kg or 2 g/m(2) ORALLY
- (2 months and older) maintenance, 150 mg/kg/day or 4 g/m(2)/day ORALLY divided into 4 to 6 doses, every 24 hours; MAX 6 g every 24 hours
### Urinary tract infectious disease
- Dosing Information
- (2 months and older) initial 75 mg/kg or 2 g/m(2) ORALLY
- (2 months and older) maintenance, 150 mg/kg/day or 4 g/m(2)/day ORALLY divided into 4 to 6 doses, every 24 hours; MAX 6 g every 24 hours
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Sulfadiazine in pediatric patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Sulfadiazine in pediatric patients.
# Contraindications
- Sulfadiazine is contraindicated in the following circumstances: Hypersensitivity to sulfonamides.
- In infants less than 2 months of age (except as adjunctive therapy with pyrimethamine in the treatment of congenital toxoplasmosis).
- In pregnancy at term and during the nursing period, because sulfonamides cross the placenta and are excreted in breast milk and may cause kernicterus.
# Warnings
- The sulfonamides should not be used for the treatment of group A betahemolytic streptococcal infections. In an established infection, they will not eradicate the streptococcus and, therefore, will not prevent sequelae such as rheumatic fever and glomerulonephritis.
- Deaths associated with the administration of sulfonamides have been reported from hypersensitivity reactions, agranulocytosis, aplastic anemia and other blood dyscrasias.
- The presence of such clinical signs as sore throat, fever, pallor, purpura or jaundice may be early indications of serious blood disorders.
- The frequency of renal complications is considerably lower in patients receiving the more soluble sulfonamides.
### Precautions
General
- Sulfonamides should be given with caution to patients with impaired renal or hepatic function and to those with severe allergy or bronchial asthma.
- Hemolysis may occur in individuals deficient in glucose-6-phosphate dehydrogenase. This reaction is dose related.
- Adequate fluid intake must be maintained in order to prevent crystalluria and stone formation.
Laboratory Tests
- Complete blood counts and urinalyses with careful microscopic examinations should be done frequently in patients receiving sulfonamides.
# Adverse Reactions
## Clinical Trials Experience
Blood Dyscrasias
- Agranulocytosis, aplastic anemia, thrombocytopenia, leukopenia, hemolytic anemia, purpura, hypoprothrombinemia and methemoglobinemia.
Allergic Reactions
- Erythema multiforme (Stevens-Johnson syndrome), generalized skin eruptions, epidermal necrolysis, urticaria, serum sickness, pruritus, exfoliative dermatitis, anaphylactoid reactions, periorbital edema, conjunctival and scleral injection, photosensitization, arthralgia, allergic myocarditis, drug fever and chills.
Gastrointestinal Reactions
- Nausea, emesis, abdominal pains, hepatitis, diarrhea, anorexia, pancreatitis and stomatitis.
C.N.S. Reactions
- Headache, peripheral neuritis, mental depression, convulsions, ataxia, hallucinations, tinnitus, vertigo and insomnia.
Renal
- Crystalluria, stone formation, toxic nephrosis with oliguria and anuria; periarteritis nodosa and lupus erythematosus phenomenon have been noted.
Miscellaneous Reactions
- The sulfonamides bear certain chemical similarities to some goitrogens, diuretics (acetazolamide and the thiazides) and oral hypoglycemic agents. Goiter production, diuresis, and hypoglycemia have occurred rarely in patients receiving sulfonamides. Cross-sensitivity may exist with these agents.
## Postmarketing Experience
- There is limited information regarding Postmarketing Experience of Sulfadiazine in the drug label.
# Drug Interactions
- Administration of a sulfonamide may increase the effect of oral anticoagulants and methotrexate, probably by displacement of these drugs from binding sites on plasma albumin. Potentiation of the action of sulfonylurea hypoglycemic agents, thiazide diuretics and uricosuric agents may also be noted. This may also be due to displacement of the drugs from albumin or a pharmacodynamic mechanism may play a role. Conversely, agents such as indomethacin, probenecid and salicylates may displace sulfonamides from plasma albumin and increase the concentrations of free drug in plasma.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
Teratogenic Effects
Pregnancy Category C
- The safe use of sulfonamides in pregnancy has not been established. The teratogenic potential of most sulfonamides has not been thoroughly investigated in either animals or humans. However, a significant increase in the incidence of cleft palate and other bony abnormalities in offspring has been observed when certain sulfonamides of the short, intermediate and long acting types were given to pregnant rats and mice in high oral doses (7 to 25 times the human therapeutic dose).
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
- There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Sulfadiazine in women who are pregnant.
### Labor and Delivery
- There is no FDA guidance on use of Sulfadiazine during labor and delivery.
### Nursing Mothers
- Sulfadiazine is contraindicated for use in nursing mothers because the sulfonamides cross the placenta, are excreted in breast milk and may cause kernicterus.
- Because of the potential for serious adverse reactions in nursing infants from sulfadiazine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. See CONTRAINDICATIONS.
### Pediatric Use
- Sulfadiazine is contraindicated in infants less than 2 months of age (except as adjunctive therapy with pyrimethamine in the treatment of congenital toxoplasmosis). See CONTRAINDICATIONSand DOSAGE AND ADMINISTRATION.
### Geriatic Use
- There is no FDA guidance on the use of Sulfadiazine with respect to geriatric patients.
### Gender
- There is no FDA guidance on the use of Sulfadiazine with respect to specific gender populations.
### Race
- There is no FDA guidance on the use of Sulfadiazine with respect to specific racial populations.
### Renal Impairment
- There is no FDA guidance on the use of Sulfadiazine in patients with renal impairment.
### Hepatic Impairment
- There is no FDA guidance on the use of Sulfadiazine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
- There is no FDA guidance on the use of Sulfadiazine in women of reproductive potentials and males.
### Immunocompromised Patients
- There is no FDA guidance one the use of Sulfadiazine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- SYSTEMIC SULFONAMIDES ARE CONTRAINDICATED IN INFANTS UNDER 2 MONTHS OF AGE except as adjunctive therapy with pyrimethamine in the treatment of congenital toxoplasmosis.
- Usual Dosage for Infants over 2 Months of Age and Children
- Initially, one-half the 24-hour dose. Maintenance, 150 mg/kg or 4 g/m2, divided into 4 to 6 doses, every 24 hours, with a maximum of 6 g every 24 hours. Rheumatic fever prophylaxis, under 30 kg (66 pounds), 500 mg every 24 hours; over 30 kg (66 pounds), 1 g every 24 hours.
Usual Adult Dosage
- Initially, 2 g to 4 g. Maintenance, 2 g to 4 g, divided into 3 to 6 doses, every 24 hours.
### Monitoring
- There is limited information regarding Monitoring of Sulfadiazine in the drug label.
# IV Compatibility
- There is limited information regarding IV Compatibility of Sulfadiazine in the drug label.
# Overdosage
- There is limited information regarding Chronic Overdose of Sulfadiazine in the drug label.
# Pharmacology
## Mechanism of Action
- The systemic sulfonamides are bacteriostatic agents having a similar spectrum of activity. Sulfonamides competitively inhibit bacterial synthesis of folic acid (pteroylglutamic acid) from aminobenzoic acid. Resistant strains are capable of utilizing folic acid precursors or preformed folic acid.
## Structure
- Sulfadiazine is an oral sulfonamide anti-bacterial agent.
- Each tablet, for oral administration, contains 500 mg sulfadiazine. In addition, each tablet contains the following inactive ingredients: croscarmellose sodium, docusate sodium, microcrystalline cellulose, povidone, sodium benzoate, sodium starch glycolate and stearic acid.
- Sulfadiazine occurs as a white or slightly yellow powder. It is odorless or nearly so and slowly darkens on exposure to light. It is practically insoluble in water and slightly soluble in alcohol. The chemical name of sulfadiazine is N1-2-pyrimidinylsulfanilamide. The molecular formula is C10H10N4O2S. It has a molecular weight of 250.27. The structural formula is shown below:
- Most sulfonamides slowly darken on exposure to light.
## Pharmacodynamics
- There is limited information regarding Pharmacodynamics of Sulfadiazine in the drug label.
## Pharmacokinetics
- Sulfonamides exist in the blood in 3 forms - free, conjugated (acetylated and possibly others) and protein bound. The free form is considered to be the therapeutically active one.
- Sulfadiazine given orally is readily absorbed from the gastrointestinal tract. After a single 2 g oral dose, a peak of 6.04 mg/100 mL is reached in 4 hours; of this, 4.65 mg/100 mL is free drug.
- When a dose of 100 mg/kg of body weight is given initially and followed by 50 mg/kg every 6 hours, blood levels of free sulfadiazine are about 7 mg/100mL. Protein binding is 38% to 48%. Sulfadiazine diffuses into the cerebrospinal fluid; free drug reaches 32% to 65% of blood levels and total drug 40% to 60%.
- Sulfadiazine is excreted largely in the urine, where concentrations are 10 to 25 times greater than serum levels. Approximately 10% of a single oral dose is excreted in the first 6 hours, 50% within 24 hours and 60% to 85% in 48 to 72 hours. Of the amount excreted in the urine, 15% to 40% is in the acetyl form.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
- The sulfonamides bear certain chemical similarities to some goitrogens. Rats appear to be especially susceptible to the goitrogenic effects of sulfonamides and long-term administration has produced thyroid malignancies in rats.
# Clinical Studies
- There is limited information regarding Clinical Studies of Sulfadiazine in the drug label.
# How Supplied
- SulfADIAZine Tablets USP for oral administration are available as:
- 500 mg: white, unscored, capsule-shaped tablets, debossed “E 757” on one face and supplied as:
- NDC 0185-0757-30 bottles of 30
- NDC 0185-0757-01 bottles of 100
- NDC 0185-0757-10 bottles of 1000
## Storage
- Storage: Store at 20° to 25°C (68° to 77°F) .
- Dispense in a tight, light-resistant container as defined in the USP with a child-resistant closure, as required.
- To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Information for Patients
- Patients should be instructed to drink an eight ounce glass of water with each dose of medication and at frequent intervals throughout the day. Caution patients to report promptly the onset of sore throat, fever, pallor, purpura or jaundice when taking this drug, since these may be early indications of serious blood disorders.
# Precautions with Alcohol
- Alcohol-Sulfadiazine 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 | Sulfadiazine
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
Sulfadiazine is a anti-infective, anti-parasitic agent that is FDA approved for the treatment of chancroid, trachoma, inclusion conjunctivitis, nocardiosis, urinary tract infections (primarily pyelonephritis, pyelitis and cystitis), toxoplasmosis encephalitis in patients with and without acquired immunodeficiency syndrome, malaria due to chloroquine-resistant strains of plasmodium falciparum, prophylaxis of meningococcal meningitis, meningococcal meningitis, acute otitis media due to haemophilus influenzae, prophylaxis against recurrences of rheumatic fever, H. influenzae meningitis, as an adjunctive therapy. Common adverse reactions include rash, abdominal pain, diarrhea, nausea, vomiting.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- Initial, 2 to 4 g ORALLY
- Maintenance, 2 to 4 g ORALLY divided into 3 to 6 doses, every 24 hours
- Dosing Information
- Initial, 2 to 4 g ORALLY
- Maintenance, 2 to 4 g ORALLY divided into 3 to 6 doses, every 24 hours
- Dosing Information
- Initial, 2 to 4 g ORALLY
- Maintenance, 2 to 4 g ORALLY divided into 3 to 6 doses, every 24 hours
### Inclusion conjunctivitis
- Dosing Information
- Initial, 2 to 4 g ORALLY
- Maintenance, 2 to 4 g ORALLY divided into 3 to 6 doses, every 24 hours
### Malaria, due to chloroquine-resistant strains of Plasmodium falciparum; Adjunct
- Dosing Information
- Initial, 2 to 4 g ORALLY
- Maintenance, 2 to 4 g ORALLY divided into 3 to 6 doses, every 24 hours
### Meningococcal meningitis; Treatment and Prophylaxis
- Dosing Information
- Initial, 2 to 4 g ORALLY
- Maintenance, 2 to 4 g ORALLY divided into 3 to 6 doses, every 24 hours
### Nocardiosis
- Dosing Information
- Initial, 2 to 4 g ORALLY
- Maintenance, 2 to 4 g ORALLY divided into 3 to 6 doses, every 24 hours
### Rheumatic fever, Recurrent; Prophylaxis
- Dosing Information
- Greater than 27 kg: 1 g ORALLY once a day; (27 kg or less) 500 mg ORALLY once a day (guideline dosing)
- Initial, 2 to 4 g ORALLY (manufacturer dosing)
- Maintenance, 2 to 4 g ORALLY divided into 3 to 6 doses, every 24 hours (manufacturer dosing)
### Toxoplasma encephalitis
- Dosing Information
- Initial 2 to 4 g ORALLY (manufacturer dosing)
- Maintenance, 2 to 4 g ORALLY divided into 3 to 6 doses, every 24 hours (manufacturer dosing)
- Less than 60 kg: 1000 mg ORALLY every 6 hour plus pyrimethamine 200 mg ORALLY for 1 dose, then 50 mg ORALLY daily plus leucovorin 10 to 25 mg (can increase to 50 mg) ORALLY daily for at least 6 week (guideline dosing)
- 60 kg or greater: 1500 mg ORALLY every 6 hour plus pyrimethamine 200 mg ORALLY for 1 dose, then 75 mg ORALLY daily plus leucovorin 10 to 25 mg (can increase to 50 mg) ORALLY daily for at least 6 week (guideline dosing)
- 1000 to 1500 mg ORALLY every 6 hour plus atovaquone 1500 mg orally twice daily for at least 6 week (guideline dosing)
### Trachoma
- Dosing Information
- Initial, 2 to 4 g ORALLY
- Maintenance, 2 to 4 g ORALLY divided into 3 to 6 doses, every 24 hours
### Urinary tract infectious disease
- Dosing Information
- Initial, 2 to 4 g ORALLY
- Maintenance, 2 to 4 g ORALLY divided into 3 to 6 doses, every 24 hours
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Sulfadiazine in adult patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Sulfadiazine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- 2 months and older: Initial 75 mg/kg or 2 g/m(2) ORALLY
- 2 months and older: Maintenance, 150 mg/kg/day or 4 g/m(2)/day ORALLY divided into 4 to 6 doses, every 24 hours; MAX 6 g every 24 hours
- Dosing Information
- (2 months and older) initial 75 mg/kg or 2 g/m(2) ORALLY
- (2 months and older) maintenance, 150 mg/kg/day or 4 g/m(2)/day ORALLY divided into 4 to 6 doses, every 24 hours; MAX 6 g every 24 hours
- Dosing Information
- 2 months and older: Initial 75 mg/kg or 2 g/m(2) ORALLY (manufacturer dosing)
- 2 months and older: Maintenance, 150 mg/kg/day or 4 g/m(2)/day ORALLY divided into 4 to 6 doses, every 24 hours; MAX 6 g every 24 hours (manufacturer dosing)
- (HIV) 50 mg/kg per dose ORALLY twice daily PLUS pyrimethamine 2 mg/kg ORALLY once daily for 2 days, then 1 mg/kg ORALLY once daily for 2 to 6 months, then 1 mg/kg ORALLY 3 times weekly PLUS leucovorin 10 mg ORALLY or IM with each dose of pyrimethamine; total treatment duration is 12 months (guideline dosing)
### Haemophilus influenzae meningitis, In combination with parenteral streptomycin; Adjunct
- Dosing Information
- (2 months and older) Initial 75 mg/kg or 2 g/m(2) ORALLY
- (2 months and older) Maintenance, 150 mg/kg/day or 4 g/m(2)/day ORALLY divided into 4 to 6 doses, every 24 hours; MAX 6 g every 24 hours
### Inclusion conjunctivitis
- Dosing Information
- (2 months and older) initial 75 mg/kg or 2 g/m(2) ORALLY
- (2 months and older) maintenance, 150 mg/kg/day or 4 g/m(2)/day ORALLY divided into 4 to 6 doses, every 24 hours; MAX 6 g every 24 hours
### Malaria, due to chloroquine-resistant strains of Plasmodium falciparum; Adjunct
- Dosing Information
- (2 months and older) initial 75 mg/kg or 2 g/m(2) ORALLY
- (2 months and older) maintenance, 150 mg/kg/day or 4 g/m(2)/day ORALLY divided into 4 to 6 doses, every 24 hours; MAX 6 g every 24 hours
### Meningococcal meningitis; Treatment and Prophylaxis
- Dosing Information
- (2 months and older) initial 75 mg/kg or 2 g/m(2) ORALLY
- (2 months and older) maintenance, 150 mg/kg/day or 4 g/m(2)/day ORALLY divided into 4 to 6 doses, every 24 hours; MAX 6 g every 24 hours
### Nocardiosis
- Dosing Information
- (2 months and older) initial 75 mg/kg or 2 g/m(2) ORALLY
- (2 months and older) maintenance, 150 mg/kg/day or 4 g/m(2)/day ORALLY divided into 4 to 6 doses, every 24 hours; MAX 6 g every 24 hours
### Rheumatic fever, Recurrent; Prophylaxis
- Dosing Information
- (27 kg or less) 500 mg ORALLY once a day (guideline dosing)
- (greater than 27 kg) 1 g ORALLY once a day (guideline dosing)
- (less than 30 kg) 500 mg ORALLY every 24 hours (manufacturer dosing)
- (greater than 30 kg) 1 g ORALLY every 24 hours (manufacturer dosing)
### Toxoplasma encephalitis
- Dosing Information
- (2 months and older) initial 75 mg/kg or 2 g/m(2) ORALLY (manufacturer dosing)
- (2 months and older) maintenance, 150 mg/kg/day or 4 g/m(2)/day ORALLY divided into 4 to 6 doses, every 24 hours; MAX 6 g every 24 hours (manufacturer dosing)
- (acquired toxoplasmosis in children with HIV) 25 to 50 mg/kg (MAX 1000 to 1500 mg/dose) ORALLY 4 times daily plus pyrimethamine 2 mg/kg (MAX 50 mg) ORALLY once daily for 3 days, then 1 mg/kg (MAX 25 mg) ORALLY once daily PLUS leucovorin 10 to 25 mg ORALLY daily; continue for at least 6 weeks, followed by secondary prophylaxis (guideline dosing)
### Trachoma
- Dosing Information
- (2 months and older) initial 75 mg/kg or 2 g/m(2) ORALLY
- (2 months and older) maintenance, 150 mg/kg/day or 4 g/m(2)/day ORALLY divided into 4 to 6 doses, every 24 hours; MAX 6 g every 24 hours
### Urinary tract infectious disease
- Dosing Information
- (2 months and older) initial 75 mg/kg or 2 g/m(2) ORALLY
- (2 months and older) maintenance, 150 mg/kg/day or 4 g/m(2)/day ORALLY divided into 4 to 6 doses, every 24 hours; MAX 6 g every 24 hours
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Sulfadiazine in pediatric patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Sulfadiazine in pediatric patients.
# Contraindications
- Sulfadiazine is contraindicated in the following circumstances: Hypersensitivity to sulfonamides.
- In infants less than 2 months of age (except as adjunctive therapy with pyrimethamine in the treatment of congenital toxoplasmosis).
- In pregnancy at term and during the nursing period, because sulfonamides cross the placenta and are excreted in breast milk and may cause kernicterus.
# Warnings
- The sulfonamides should not be used for the treatment of group A betahemolytic streptococcal infections. In an established infection, they will not eradicate the streptococcus and, therefore, will not prevent sequelae such as rheumatic fever and glomerulonephritis.
- Deaths associated with the administration of sulfonamides have been reported from hypersensitivity reactions, agranulocytosis, aplastic anemia and other blood dyscrasias.
- The presence of such clinical signs as sore throat, fever, pallor, purpura or jaundice may be early indications of serious blood disorders.
- The frequency of renal complications is considerably lower in patients receiving the more soluble sulfonamides.
### Precautions
General
- Sulfonamides should be given with caution to patients with impaired renal or hepatic function and to those with severe allergy or bronchial asthma.
- Hemolysis may occur in individuals deficient in glucose-6-phosphate dehydrogenase. This reaction is dose related.
- Adequate fluid intake must be maintained in order to prevent crystalluria and stone formation.
Laboratory Tests
- Complete blood counts and urinalyses with careful microscopic examinations should be done frequently in patients receiving sulfonamides.
# Adverse Reactions
## Clinical Trials Experience
Blood Dyscrasias
- Agranulocytosis, aplastic anemia, thrombocytopenia, leukopenia, hemolytic anemia, purpura, hypoprothrombinemia and methemoglobinemia.
Allergic Reactions
- Erythema multiforme (Stevens-Johnson syndrome), generalized skin eruptions, epidermal necrolysis, urticaria, serum sickness, pruritus, exfoliative dermatitis, anaphylactoid reactions, periorbital edema, conjunctival and scleral injection, photosensitization, arthralgia, allergic myocarditis, drug fever and chills.
Gastrointestinal Reactions
- Nausea, emesis, abdominal pains, hepatitis, diarrhea, anorexia, pancreatitis and stomatitis.
C.N.S. Reactions
- Headache, peripheral neuritis, mental depression, convulsions, ataxia, hallucinations, tinnitus, vertigo and insomnia.
Renal
- Crystalluria, stone formation, toxic nephrosis with oliguria and anuria; periarteritis nodosa and lupus erythematosus phenomenon have been noted.
Miscellaneous Reactions
- The sulfonamides bear certain chemical similarities to some goitrogens, diuretics (acetazolamide and the thiazides) and oral hypoglycemic agents. Goiter production, diuresis, and hypoglycemia have occurred rarely in patients receiving sulfonamides. Cross-sensitivity may exist with these agents.
## Postmarketing Experience
- There is limited information regarding Postmarketing Experience of Sulfadiazine in the drug label.
# Drug Interactions
- Administration of a sulfonamide may increase the effect of oral anticoagulants and methotrexate, probably by displacement of these drugs from binding sites on plasma albumin. Potentiation of the action of sulfonylurea hypoglycemic agents, thiazide diuretics and uricosuric agents may also be noted. This may also be due to displacement of the drugs from albumin or a pharmacodynamic mechanism may play a role. Conversely, agents such as indomethacin, probenecid and salicylates may displace sulfonamides from plasma albumin and increase the concentrations of free drug in plasma.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
Teratogenic Effects
Pregnancy Category C
- The safe use of sulfonamides in pregnancy has not been established. The teratogenic potential of most sulfonamides has not been thoroughly investigated in either animals or humans. However, a significant increase in the incidence of cleft palate and other bony abnormalities in offspring has been observed when certain sulfonamides of the short, intermediate and long acting types were given to pregnant rats and mice in high oral doses (7 to 25 times the human therapeutic dose).
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
- There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Sulfadiazine in women who are pregnant.
### Labor and Delivery
- There is no FDA guidance on use of Sulfadiazine during labor and delivery.
### Nursing Mothers
- Sulfadiazine is contraindicated for use in nursing mothers because the sulfonamides cross the placenta, are excreted in breast milk and may cause kernicterus.
- Because of the potential for serious adverse reactions in nursing infants from sulfadiazine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. See CONTRAINDICATIONS.
### Pediatric Use
- Sulfadiazine is contraindicated in infants less than 2 months of age (except as adjunctive therapy with pyrimethamine in the treatment of congenital toxoplasmosis). See CONTRAINDICATIONSand DOSAGE AND ADMINISTRATION.
### Geriatic Use
- There is no FDA guidance on the use of Sulfadiazine with respect to geriatric patients.
### Gender
- There is no FDA guidance on the use of Sulfadiazine with respect to specific gender populations.
### Race
- There is no FDA guidance on the use of Sulfadiazine with respect to specific racial populations.
### Renal Impairment
- There is no FDA guidance on the use of Sulfadiazine in patients with renal impairment.
### Hepatic Impairment
- There is no FDA guidance on the use of Sulfadiazine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
- There is no FDA guidance on the use of Sulfadiazine in women of reproductive potentials and males.
### Immunocompromised Patients
- There is no FDA guidance one the use of Sulfadiazine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- SYSTEMIC SULFONAMIDES ARE CONTRAINDICATED IN INFANTS UNDER 2 MONTHS OF AGE except as adjunctive therapy with pyrimethamine in the treatment of congenital toxoplasmosis.
- Usual Dosage for Infants over 2 Months of Age and Children
- Initially, one-half the 24-hour dose. Maintenance, 150 mg/kg or 4 g/m2, divided into 4 to 6 doses, every 24 hours, with a maximum of 6 g every 24 hours. Rheumatic fever prophylaxis, under 30 kg (66 pounds), 500 mg every 24 hours; over 30 kg (66 pounds), 1 g every 24 hours.
Usual Adult Dosage
- Initially, 2 g to 4 g. Maintenance, 2 g to 4 g, divided into 3 to 6 doses, every 24 hours.
### Monitoring
- There is limited information regarding Monitoring of Sulfadiazine in the drug label.
# IV Compatibility
- There is limited information regarding IV Compatibility of Sulfadiazine in the drug label.
# Overdosage
- There is limited information regarding Chronic Overdose of Sulfadiazine in the drug label.
# Pharmacology
## Mechanism of Action
- The systemic sulfonamides are bacteriostatic agents having a similar spectrum of activity. Sulfonamides competitively inhibit bacterial synthesis of folic acid (pteroylglutamic acid) from aminobenzoic acid. Resistant strains are capable of utilizing folic acid precursors or preformed folic acid.
## Structure
- Sulfadiazine is an oral sulfonamide anti-bacterial agent.
- Each tablet, for oral administration, contains 500 mg sulfadiazine. In addition, each tablet contains the following inactive ingredients: croscarmellose sodium, docusate sodium, microcrystalline cellulose, povidone, sodium benzoate, sodium starch glycolate and stearic acid.
- Sulfadiazine occurs as a white or slightly yellow powder. It is odorless or nearly so and slowly darkens on exposure to light. It is practically insoluble in water and slightly soluble in alcohol. The chemical name of sulfadiazine is N1-2-pyrimidinylsulfanilamide. The molecular formula is C10H10N4O2S. It has a molecular weight of 250.27. The structural formula is shown below:
- Most sulfonamides slowly darken on exposure to light.
## Pharmacodynamics
- There is limited information regarding Pharmacodynamics of Sulfadiazine in the drug label.
## Pharmacokinetics
- Sulfonamides exist in the blood in 3 forms - free, conjugated (acetylated and possibly others) and protein bound. The free form is considered to be the therapeutically active one.
- Sulfadiazine given orally is readily absorbed from the gastrointestinal tract. After a single 2 g oral dose, a peak of 6.04 mg/100 mL is reached in 4 hours; of this, 4.65 mg/100 mL is free drug.
- When a dose of 100 mg/kg of body weight is given initially and followed by 50 mg/kg every 6 hours, blood levels of free sulfadiazine are about 7 mg/100mL. Protein binding is 38% to 48%. Sulfadiazine diffuses into the cerebrospinal fluid; free drug reaches 32% to 65% of blood levels and total drug 40% to 60%.
- Sulfadiazine is excreted largely in the urine, where concentrations are 10 to 25 times greater than serum levels. Approximately 10% of a single oral dose is excreted in the first 6 hours, 50% within 24 hours and 60% to 85% in 48 to 72 hours. Of the amount excreted in the urine, 15% to 40% is in the acetyl form.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
- The sulfonamides bear certain chemical similarities to some goitrogens. Rats appear to be especially susceptible to the goitrogenic effects of sulfonamides and long-term administration has produced thyroid malignancies in rats.
# Clinical Studies
- There is limited information regarding Clinical Studies of Sulfadiazine in the drug label.
# How Supplied
- SulfADIAZine Tablets USP for oral administration are available as:
- 500 mg: white, unscored, capsule-shaped tablets, debossed “E 757” on one face and supplied as:
- NDC 0185-0757-30 bottles of 30
- NDC 0185-0757-01 bottles of 100
- NDC 0185-0757-10 bottles of 1000
## Storage
- Storage: Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].
- Dispense in a tight, light-resistant container as defined in the USP with a child-resistant closure, as required.
- To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Information for Patients
- Patients should be instructed to drink an eight ounce glass of water with each dose of medication and at frequent intervals throughout the day. Caution patients to report promptly the onset of sore throat, fever, pallor, purpura or jaundice when taking this drug, since these may be early indications of serious blood disorders.
# Precautions with Alcohol
- Alcohol-Sulfadiazine 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/Sulfadiazine | |
509af5d450151f941853f3f2bdd85422b6a67075 | wikidoc | Sulfonylurea | Sulfonylurea
# Overview
Sulfonylurea derivatives are a class of antidiabetic drugs that are used in the management of diabetes mellitus type 2 ("adult-onset"). They act by increasing insulin release from the beta cells in the pancreas.
# Drugs in this class
First generation:
- Acetohexamide
- Chlorpropamide
- Tolbutamide
- Tolazamide
Second generation:
- Glipizide
- Gliclazide
- Glibenclamide (glyburide)
- Gliquidone
Third generation:
- Glimepiride
# Chemistry
All sulfonylureas have a central phenyl ring with two branching chains
# Pharmacology
## Mechanism of action
Sulfonylureas bind to an ATP-dependent K+ (KATP) channel on the cell membrane of pancreatic beta cells. This inhibits a tonic, hyperpolarizing outflux of potassium, which causes the electric potential over the membrane to become more positive. This depolarization opens voltage-gated Ca2+ channels. The rise in intracellular calcium leads to increased fusion of insulin granulae with the cell membrane, and therefore increased secretion of (pro)insulin.
There is some evidence that sulfonylureas also sensitize β-cells to glucose, that they limit glucose production in the liver, that they decrease lipolysis (breakdown and release of fatty acids by adipose tissue) and decrease clearance of insulin by the liver.
The KATP channel in turn is a complex of the inward-rectifier potassium ion channel Kir6.2 and sulfonylurea receptor SUR1 which associate with a stoichiometry of Kir6.24/SUR14.
## Pharmacokinetics
Various sulfonylureas have different pharmacokinetics. The choice depends on the propensity of the patient to develop hypoglycemia - long-acting sulfonylureas with active metabolites can induce hypoglycemia. They can, however, help achieve glycemic control when tolerated by the patient. The shorter-acting agents may not control blood sugar levels adequately.
Due to varying half-life, some drugs have to be taken twice (e.g. tolbutamide) or three times a day rather than once (e.g. glimepiride). The short-acting agents may have to be taken about 30 minutes before the meal, to ascertain maximum efficacy when the food leads to increased blood glucose levels.
Some sulfonylureas are metabolised by liver metabolic enzymes (cytochrome P450) and inducers of this enzyme system (such as the antibiotic rifampicin) can therefore increase the clearance of sulfonylureas. In addition, because some sulfonylureas are bound to plasma proteins, use of drugs that also bind to plasma proteins can release the sulfonylureas from their binding places, leading to increased clearance.
# Uses
Sulfonylureas are used almost exclusively in diabetes mellitus type 2. Sulfonylureas are ineffective where there is absolute deficiency of insulin production such as in type 1 diabetes or post-pancreatectomy.
Although for many years sulfonylureas were the first drugs to be used in new cases of diabetes, in the 1990s it was discovered that obese patients might benefit more from metformin.
In about 10% of patients, sulfonylureas alone are ineffective in controlling blood glucose levels. Addition of metformin or a thiazolidinedione may be necessary, or (ultimately) insulin. Triple therapy of sulfonylureas, a biguanide (metformin) and a thiazolidinedione is generally discouraged, but some doctors prefer this combination over resorting to insulin.
# Side-effects and cautions
Sulfonylureas, as opposed to metformin and the thiazolidinediones, can induce hypoglycemia when insulin production overshoots. It is treated with sugary food, or (in the case of hypoglycemic coma) with intravenous dextrose. The best way to prevent this side-effect is to choose the lowest possible dose that adequately controls glucose levels.
Like insulin, sulfonylureas can induce weight gain, mainly as a result of edema and reduction of the osmotic diuresis caused by hyperglycemia. Other side-effects are: abdominal upset, headache and hypersensitivity reactions.
Sulfonylureas are potentially teratogenic and cannot be used in pregnancy or in patients who intend to get pregnant. Impairment of liver or kidney function increase the risk of hypoglycemia, and are contraindications. As other anti-diabetic drugs cannot be used either under these circumstances, insulin therapy is the only option in pregnancy and hepatic and renal failure.
Second-generation sulfonylureas have increased potency by weight, compared to first-generation sulfonylureas. They have decreased side effects but are more expensive.
# History
Sulfonylureas were discovered by the chemist Marcel Janbon and co-workers, who were studying sulfonamide antibiotics and discovered that the compound sulfonylurea induced hypoglycemia in animals. | Sulfonylurea
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Sulfonylurea derivatives are a class of antidiabetic drugs that are used in the management of diabetes mellitus type 2 ("adult-onset"). They act by increasing insulin release from the beta cells in the pancreas.
# Drugs in this class
First generation:
- Acetohexamide
- Chlorpropamide
- Tolbutamide
- Tolazamide
Second generation:
- Glipizide
- Gliclazide
- Glibenclamide (glyburide)
- Gliquidone
Third generation:
- Glimepiride
# Chemistry
All sulfonylureas have a central phenyl ring with two branching chains
# Pharmacology
## Mechanism of action
Sulfonylureas bind to an ATP-dependent K+ (KATP) channel on the cell membrane of pancreatic beta cells. This inhibits a tonic, hyperpolarizing outflux of potassium, which causes the electric potential over the membrane to become more positive. This depolarization opens voltage-gated Ca2+ channels. The rise in intracellular calcium leads to increased fusion of insulin granulae with the cell membrane, and therefore increased secretion of (pro)insulin.
There is some evidence that sulfonylureas also sensitize β-cells to glucose, that they limit glucose production in the liver, that they decrease lipolysis (breakdown and release of fatty acids by adipose tissue) and decrease clearance of insulin by the liver.
The KATP channel in turn is a complex of the inward-rectifier potassium ion channel Kir6.2 and sulfonylurea receptor SUR1 which associate with a stoichiometry of Kir6.24/SUR14.
## Pharmacokinetics
Various sulfonylureas have different pharmacokinetics. The choice depends on the propensity of the patient to develop hypoglycemia - long-acting sulfonylureas with active metabolites can induce hypoglycemia. They can, however, help achieve glycemic control when tolerated by the patient. The shorter-acting agents may not control blood sugar levels adequately.
Due to varying half-life, some drugs have to be taken twice (e.g. tolbutamide) or three times a day rather than once (e.g. glimepiride). The short-acting agents may have to be taken about 30 minutes before the meal, to ascertain maximum efficacy when the food leads to increased blood glucose levels.
Some sulfonylureas are metabolised by liver metabolic enzymes (cytochrome P450) and inducers of this enzyme system (such as the antibiotic rifampicin) can therefore increase the clearance of sulfonylureas. In addition, because some sulfonylureas are bound to plasma proteins, use of drugs that also bind to plasma proteins can release the sulfonylureas from their binding places, leading to increased clearance.
# Uses
Sulfonylureas are used almost exclusively in diabetes mellitus type 2. Sulfonylureas are ineffective where there is absolute deficiency of insulin production such as in type 1 diabetes or post-pancreatectomy.
Although for many years sulfonylureas were the first drugs to be used in new cases of diabetes, in the 1990s it was discovered that obese patients might benefit more from metformin.
In about 10% of patients, sulfonylureas alone are ineffective in controlling blood glucose levels. Addition of metformin or a thiazolidinedione may be necessary, or (ultimately) insulin. Triple therapy of sulfonylureas, a biguanide (metformin) and a thiazolidinedione is generally discouraged, but some doctors prefer this combination over resorting to insulin.
# Side-effects and cautions
Sulfonylureas, as opposed to metformin and the thiazolidinediones, can induce hypoglycemia when insulin production overshoots. It is treated with sugary food, or (in the case of hypoglycemic coma) with intravenous dextrose. The best way to prevent this side-effect is to choose the lowest possible dose that adequately controls glucose levels.
Like insulin, sulfonylureas can induce weight gain, mainly as a result of edema and reduction of the osmotic diuresis caused by hyperglycemia. Other side-effects are: abdominal upset, headache and hypersensitivity reactions.
Sulfonylureas are potentially teratogenic and cannot be used in pregnancy or in patients who intend to get pregnant. Impairment of liver or kidney function increase the risk of hypoglycemia, and are contraindications. As other anti-diabetic drugs cannot be used either under these circumstances, insulin therapy is the only option in pregnancy and hepatic and renal failure.
Second-generation sulfonylureas have increased potency by weight, compared to first-generation sulfonylureas. They have decreased side effects but are more expensive.
# History
Sulfonylureas were discovered by the chemist Marcel Janbon and co-workers,[1] who were studying sulfonamide antibiotics and discovered that the compound sulfonylurea induced hypoglycemia in animals.[2] | https://www.wikidoc.org/index.php/Sulfonylurea | |
74e1570ea3d27c8d324fcc591279d7c20d7d2b2b | wikidoc | Sulforaphane | Sulforaphane
# Overview
Sulforaphane is an anticancer and antimicrobial compound that can be obtained by eating cruciferous vegetables such as brussel sprouts, broccoli, cabbage, cauliflower, bok choy, kale, collards, broccoli sprouts, chinese broccoli, broccoli raab, kohlrabi, mustard, turnip, radish, rocket, and watercress. The enzyme myrosinase transforms glucoraphanin (a glucosinolate) into sulforaphane upon damage to the plant (such as from chewing). The young sprouts of broccoli and cauliflower are particularly rich in glucoraphanin.
The anticancer activity of sulforaphane is thought to be related to the induction of phase-II enzymes of xenobiotic transformation (such as quinone reductase and glutathione S-transferase), and enhancing the transcription of tumor suppressor proteins.
Researchers at the Johns Hopkins University School of Medicine in Baltimore MD first identified sulforaphane in broccoli sprouts which, of the cruciferous vegetables, have the highest concentration of sulforaphane. Consumption of broccoli sprouts has shown to be effective at inhibiting Helicobacter pylori growth with sulforaphane being at least one of the active agents.
Sulforaphane and Diindolylmethane (another compound from Brassica vegetables) have recently been shown to synergize together in the inhibition of cancer growth.
In terms of dosage, optimal levels have not yet been determined but some doctors recommend 200 - 400 mcg of sulforaphane daily from broccoli-sprout extracts. Despite that no side effects or drug interactions have been reported yet, people taking prescription drugs are still advised to consult a doctor before taking sulforaphane or broccoli-sprout extracts. Sulforaphane and dietary consumption of cruciferous vegetables are known to affect the action of drug-detoxifying enzymes.
Sulforaphane seems to protect skin against UV radiation damage, and thus potentially against cancer, when applied topically.
# Notes
- ↑ Zhang Y, Talalay P, Cho CG, Posner GH. A major inducer of anticarcinogenic protective enzymes from broccoli: isolation and elucidation of structure. Proc Natl Acad Sci 1992;89:2399–403
- ↑ Galan MV, Kishan AA, Silverman AL (2004). "Oral broccoli sprouts for the treatment of Helicobacter pylori infection: a preliminary report". Dig Dis Sci. 49 (7–8): 1088–90. PMID 15387326. Unknown parameter |month= ignored (help)CS1 maint: Multiple names: authors list (link) .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}
- ↑ Fahey JW, Haristoy X, Dolan PM, Kensler TW, Scholtus I, Stephenson KK, Talalay P, Lozniewski A (2002). "Sulforaphane inhibits extracellular, intracellular, and antibiotic-resistant strains of Helicobacter pylori and prevents benzopyrene-induced stomach tumors". PMID 12032331. Unknown parameter |month= ignored (help)CS1 maint: Multiple names: authors list (link)
- ↑ Kall MA, Vang O, Clausen J. Effects of dietary broccoli on human drug metabolising activity. Cancer Lett 1997;114:169–70.
- ↑ Talalay P, Fahey JW, Healy ZR, Wehage SL, Benedict AL, Min C, Dinkova-Kostova AT. Sulforaphane mobilizes cellular defenses that protect skin against damage by UV radiation. Proc Natl Acad Sci U S A. 2007 Oct 23; .
de:Sulforaphan
nl:Sulforafaan
sl:Sulforafan | Sulforaphane
Template:Chembox new
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Sulforaphane is an anticancer and antimicrobial compound that can be obtained by eating cruciferous vegetables such as brussel sprouts, broccoli, cabbage, cauliflower, bok choy, kale, collards, broccoli sprouts, chinese broccoli, broccoli raab, kohlrabi, mustard, turnip, radish, rocket, and watercress. The enzyme myrosinase transforms glucoraphanin (a glucosinolate) into sulforaphane upon damage to the plant (such as from chewing). The young sprouts of broccoli and cauliflower are particularly rich in glucoraphanin.
The anticancer activity of sulforaphane is thought to be related to the induction of phase-II enzymes of xenobiotic transformation (such as quinone reductase and glutathione S-transferase), and enhancing the transcription of tumor suppressor proteins.[citation needed]
Researchers at the Johns Hopkins University School of Medicine in Baltimore MD first identified sulforaphane in broccoli sprouts [1] which, of the cruciferous vegetables, have the highest concentration of sulforaphane. Consumption of broccoli sprouts has shown to be effective at inhibiting Helicobacter pylori growth[2] with sulforaphane being at least one of the active agents[3].
Sulforaphane and Diindolylmethane (another compound from Brassica vegetables) have recently been shown to synergize together in the inhibition of cancer growth.
In terms of dosage, optimal levels have not yet been determined but some doctors recommend 200 - 400 mcg of sulforaphane daily from broccoli-sprout extracts. Despite that no side effects or drug interactions have been reported yet, people taking prescription drugs are still advised to consult a doctor before taking sulforaphane or broccoli-sprout extracts. Sulforaphane and dietary consumption of cruciferous vegetables are known to affect the action of drug-detoxifying enzymes.[4]
Sulforaphane seems to protect skin against UV radiation damage, and thus potentially against cancer, when applied topically. [5]
# Notes
- ↑ Zhang Y, Talalay P, Cho CG, Posner GH. A major inducer of anticarcinogenic protective enzymes from broccoli: isolation and elucidation of structure. Proc Natl Acad Sci 1992;89:2399–403
- ↑ Galan MV, Kishan AA, Silverman AL (2004). "Oral broccoli sprouts for the treatment of Helicobacter pylori infection: a preliminary report". Dig Dis Sci. 49 (7–8): 1088–90. PMID 15387326. Unknown parameter |month= ignored (help)CS1 maint: Multiple names: authors list (link) .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}
- ↑ Fahey JW, Haristoy X, Dolan PM, Kensler TW, Scholtus I, Stephenson KK, Talalay P, Lozniewski A (2002). "Sulforaphane inhibits extracellular, intracellular, and antibiotic-resistant strains of Helicobacter pylori and prevents benzo[a]pyrene-induced stomach tumors". PMID 12032331. Unknown parameter |month= ignored (help)CS1 maint: Multiple names: authors list (link)
- ↑ Kall MA, Vang O, Clausen J. Effects of dietary broccoli on human drug metabolising activity. Cancer Lett 1997;114:169–70.
- ↑ Talalay P, Fahey JW, Healy ZR, Wehage SL, Benedict AL, Min C, Dinkova-Kostova AT. Sulforaphane mobilizes cellular defenses that protect skin against damage by UV radiation. Proc Natl Acad Sci U S A. 2007 Oct 23; [Epub ahead of print].
Template:Glycosides
de:Sulforaphan
nl:Sulforafaan
sl:Sulforafan
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Sulforaphane | |
8574242bf22837d166a90a92db90f4382291f341 | wikidoc | Superantigen | Superantigen
Superantigens (SAgs) are secreted proteins (exotoxins) that exhibit highly potent lymphocyte-transforming (mitogenic) activity directed towards T lymphocytes . Compared to a normal antigen-induced T-cell response where .001-.0001% of the body’s T-cells are activated, SAgs are capable of activating up to 20% of the body’s T-cells . This causes a massive immune response that is not specific to any particular epitope on the SAg. Since one of the fundamental strengths of the adaptive immune system is its ability to target antigens with high specificity, SAgs produce an immune response that is effectively useless. Microbes (including viruses, mycoplasma, and bacteria ) produce SAgs as a defense mechanism to aid them in evading the immune system .
# Types of Superantigens
The most well characterized superantigens are secreted by the bacteria Staphylococcus aureus, and Streptococcus pyogenes . These bacteria produce more than 20 different SAgs . Five groups have been proposed for classifying these toxins based on the specific variable region of the β chain of the human T cell receptor (TCR) to which they bind. Group I, for example, contains Toxic Shock Syndrome Toxin 1 (TSST-1) . Other non-bacterial SAgs have been discovered and are discussed in the section on endogenous superantigens.
Most of the genes encoding SAgs are located in close proximity to each other on mobile elements of bacterial genomes such as plasmids or “pathogenicity islands” . An operon known as the enterotoxin gene cluster was found to be common in most SAg-producing bacterial strains . Table 1 illustrates the main groups of enterotoxins and nomenclature used to describe them.
# Structure
SAgs are produced intracellularly by bacteria and are released upon infection as extracellular mature toxins . The sequences of these toxins are relatively conserved among the different subgroups. More important than sequence homology, the 3D structure is very similar among different SAgs resulting in similar functional effects among different groups . Crystal structures of the enterotoxins reveals that they are compact, ellipsoidal proteins sharing a characteristic two-domain folding pattern comprising an NH2-terminal β barrel globular domain known as the oligosaccharide / oligonucleotide fold, a long α-helix that diagonally spans the center of the molecule, and a COOH terminal globular domain . The domains have binding regions for the Major Histocompatibility Complex Class II (MHC Class II) and the T-cell Receptor (TCR), respectively (see Figure 2) .
# Binding
Superantigens bind first to the MHC Class II and then coordinate to a T-cell Receptor (TCR) with a specific Variable β motif .
## MHC Class II
Binding to the MHC class II can involve interactions between the SAg and the peptide in the cleft of the MHC, as is the case with TSST-1 of the Group I SAgs. Group II SAgs exhibit peptide independent binding. Most SAgs bind preferentially to the α-chain of MHC class II molecules in the NH2-terminal domain . There are several different forms of the Human Leukocyte Antigen (HLA) that exhibit some variation on the heavy chains, and most SAgs show preference for the HLA-DQ form of the molecule . Binding to the α-chain puts the SAg in the appropriate position to coordinate to the TCR.
Less commonly, SAgs attach to the polymorphic MHC class II β-chain in an interaction mediated by a zinc ion coordination complex between three SAg residues and a highly conserved region of the HLA-DR β chain . The use of a zinc ion in binding leads to a higher affinity interaction . Several staphylococcal SAgs are capable of cross-linking MHC molecules by binding to both the α and β chains . This mechanism stimulates cytokine expression and release in antigen presenting cells as well as inducing the production of costimulatory molecules that allow the cell to bind to and activate T cells more effectively .
## T-cell Receptor
The T-cell binding region of the SAg interacts with the Variable region on the Beta chain of the T-cell Receptor. A given SAg can activate a large proportion of the T-cell population because the human T-cell repertoire comprises only about 50 types of Vβ elements and some SAgs are capable of binding to multiple types of VB regions. This interaction varies slightly among the different groups of SAgs . Variability among different people in the types of T-cell regions that are prevalent explains why some people respond more strongly to certain SAgs. Group I SAgs contact the Vβ at the CDR2 and framework region of the molecule . SAgs of Group II interact with the Vβ region using mechanisms that are conformation-dependent. These interactions are for the most part independent of specific Vβ amino acid side-chains. Group IV SAgs have been shown to engage all three CDR loops of certain Vβ forms . The interaction takes place in a cleft between the small and large domains of the SAg and allows the SAg to act as a wedge between the TCR and MHC. This displaces the antigenic peptide away from the TCR and circumvents the normal mechanism for T-cell activation .
The biological strength of the SAg (its ability to stimulate) is determined by its affinity for the TCR. SAgs with the highest affinity for the TCR elicit the strongest response . SPMEZ-2 is the most potent SAg discovered to date .
# T-cell Signaling
The SAg cross-links the MHC and the TCR inducing a signaling pathway that results in the proliferation of the cell and production of cytokines. Low levels of Zap-70 have been found in T-cells activated by SAgs, indicating that the normal signaling pathway of T-cell activation is impaired . It is hypothesized that Fyn rather than Lck is activated by a tyrosine kinase, leading to the adaptive induction of anergy . Both the protein kinase C pathway and the protein tyrosine kinase pathways are activated, resulting in upregulating production of proinflammatory cytokines . This alternative signaling pathway impairs the calcium/calcineurin and Ras/MAPkinase pathways slightly , but allows for a focused inflammatory response.
# Direct Effects
SAg stimulation of antigen presenting cells and T-cells elicits a response that is mainly inflammatory, focused on the action of Th1 T-helper cells. Some of the major products are IL-1, IL-2, IL-6, TNF-α, gamma interferon (IFN-γ), macrophage inflammatory protein 1α (MIP-1α), MIP-1β, and monocyte chemoattractant protein 1 (MCP-1) . This excessive uncoordinated release of cytokines, (especially TNF-α), overloads the body and results in to rashes, fever, and can lead to multi-organ failure, coma and death . Deletion or anergy of activated T-cells follows infection. This results from production of IL-10 from prolonged exposure to the toxin. IL-10 downregulates production of IL-2, MHC Class II, and costimulatory molecules on the surface of APCs. These effects produce memory cells that are unresponsive to antigen stimulation . One mechanism by which this is possible involves cytokine-mediated suppression of T-cells. MHC crosslinking also activates a signaling pathway that suppresses hematopoiesis and upregulates Fas-mediated apoptosis . IFN-α is another product of prolong SAg exposure. This cytokine is closely linked with induction of autoimmunity , and the autoimmune disease Kawasaki Disease is known to be caused by SAg infection . SAg activation in T-cells leads to production of CD40 ligand which activates isotype switching in B cells from to IgG and IgM and IgE . To summarize, the T-cells are stimulated and produce excess amounts of cytokine resulting in cytokine-mediated suppression of T-cells and deletion of the activated cells as the body returns to homeostasis. The toxic effects of the microbe and SAg also damage tissue and organ systems, a condition known as Toxic Shock Syndrome . If the initial inflammation is survived, the host cells become anergic or are deleted, resulting in a severely compromised immune system.
# Superantigenicity independent Effects (Indirect Effects)
Apart from their mitogenic activity, SAgs are able to cause symptoms that are characteristic of infection .
One such effect is emesis. This effect is felt in cases of food poisoning, when SAg-producing bacteria release the toxin, which is highly resistant to heat. There is a distinct region of the molecule that is active in inducing gastrointestinal toxicity . This activity is also highly potent, and quantities as small as 20-35ug of SAg are able to induce vomiting .
SAgs are able to stimulate recruitment of neutrophils to the site of infection in a way that is independent of T-cell stimulation. This effect is due to the ability of SAgs to activate monocytic cells, stimulating the release of the cytokine TNF-α, leading to increased expression of adhesion molecules that recruit leukocytes to infected regions. This causes inflammation in the lungs, intestinal tissue, and any place that the bacteria have colonized . While small amounts of inflammation are natural and helpful, excessive inflammation can lead to tissue destruction.
One of the more dangerous indirect effects of SAg infection concerns the ability of SAgs to augment the effects of endotoxins in the body. This is accomplished by reducing the threshold for endotoxicity. Schlievert demonstrated that, when administered conjunctively, the effects of SAg and endotoxin are magnified as much as 50 000 times . This could be due to the reduced immune system efficiency induced by SAg infection. Aside from the synergistic relationship between endotoxin and SAg, the “double hit” effect of the activity of the endotoxin and the SAg result in effects more deleterious that those seen in a typical bacterial infection. This also implicates SAgs in the progression of sepsis in patients with bacterial infections .
# Diseases Associated with Superantigen production
- Toxic Shock Syndrome
- Kawasaki Disease
- Eczema
- Guttate psoriasis
- Rheumatoid arthritis
- Diabetes mellitus
- Scarlet fever
# Treatment
The primary goal of medical treatment is to eliminate the microbe that is producing the SAgs. This is accomplished through the use of vasopressors, fluid resuscitation and antibiotics . The body naturally produces antibodies to some SAgs, and this effect can be augmented by stimulating B-cell production of these antibodies . Immunoglobulin pools are able to neutralize specific antibodies and prevent T-cell activation. Synthetic antibodies and peptides have been created to mimic SAg-binding regions on the MHC class II, blocking the interaction and preventing T cell activation . Immunosuppressants are also employed to prevent T-cell activation and the release of cytokines. Corticosteroids are used to reduce inflammatory effects .
# Evolution of Superantigen Production
SAg production effectively corrupts the immune response, allowing the microbe secreting the SAg to be carried and transmitted unchecked. One mechanism by which this is done system is through inducing anergy of the T-cells to antigens and SAgs . Lussow and MacDonald demonstrated this by systematically exposing animals to a streptococcal antigen. They found that exposure to other antigens after SAg infection failed to elicit an immune response . In another experiment, Watson and Lee discovered that memory T-cells created by normal antigen stimulation were anergic to SAg stimulation and that memory T-cells created after a SAg infection were anergic to all antigen stimulation. The mechanism by which this occurred was undetermined . The genes that regulate SAg expression also regulate mechanisms of immune evasion such as M protein and capsule expression, supporting the hypothesis that SAg production evolved primarily as a mechanism of immune evasion .
When the structure of individual SAg domains has been compared to other immunoglobulin-binding streptococcal proteins (such as those toxins produced by ''E. coli'') it was found that the domains separately resemble members of these families. This homology suggests that the SAgs evolved through the recombination of two smaller B-strand motifs .
# Endogenous SAgs
Minor lymphocyte stimulating (Mls) exotoxins were originally discovered in the thymic stromal cells of mice. These toxins are encoded by SAg genes that were incorporated into the mouse genome from the mouse mammary tumour virus (MMTV). The presence of these genes in the mouse genome allows the mouse to express the antigen in the thymus as a means of negatively selecting for lymphocytes with a variable Beta region that is susceptible to stimulation by the viral SAg. The result is that these mice are immune to infection by the virus later in life .
Similar endogenous SAg-dependent selection has yet to be identified in the human genome, but endogenous SAgs have been discovered and are suspected of playing an integral role in viral infection. Infection by theEpstein-Barr virus, for example, is known to cause production of a SAg in infected cells, yet no gene for the toxin has been found on the genome of the virus. The virus manipulates the infected cell to express its own SAg genes, and this helps it to evade the host immune system. Similar results have been found with rabies, cytomegalovirus, and HIV .
# Conclusion
Much detailed research has been conducted to determine the specific structures and binding mechanisms of each type of SAg. This paper presents a general overview of some of these that are more common and well-understood mechanisms of SAg infection. Recent research attempts to harness the immunostimulatory properties of these molecules by using specific SAgs to induce inflammatory cytokines that could target and prevent tumour growth . As the microbial population develops more effective ways of infecting other organisms the human population uses intelligence to combat the advancing lines | Superantigen
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Superantigens (SAgs) are secreted proteins (exotoxins) that exhibit highly potent lymphocyte-transforming (mitogenic) activity directed towards T lymphocytes [2,4,6]. Compared to a normal antigen-induced T-cell response where .001-.0001% of the body’s T-cells are activated, SAgs are capable of activating up to 20% of the body’s T-cells [23]. This causes a massive immune response that is not specific to any particular epitope on the SAg. Since one of the fundamental strengths of the adaptive immune system is its ability to target antigens with high specificity, SAgs produce an immune response that is effectively useless. Microbes (including viruses, mycoplasma, and bacteria [2]) produce SAgs as a defense mechanism to aid them in evading the immune system [4].
# Types of Superantigens
The most well characterized superantigens are secreted by the bacteria Staphylococcus aureus, and Streptococcus pyogenes [1]. These bacteria produce more than 20 different SAgs [9, 15]. Five groups have been proposed for classifying these toxins based on the specific variable region of the β chain of the human T cell receptor (TCR) to which they bind. Group I, for example, contains Toxic Shock Syndrome Toxin 1 (TSST-1) [1, 2]. Other non-bacterial SAgs have been discovered and are discussed in the section on endogenous superantigens.
Most of the genes encoding SAgs are located in close proximity to each other on mobile elements of bacterial genomes such as plasmids or “pathogenicity islands” [15]. An operon known as the enterotoxin gene cluster was found to be common in most SAg-producing bacterial strains [15]. Table 1 illustrates the main groups of enterotoxins and nomenclature used to describe them.
# Structure
SAgs are produced intracellularly by bacteria and are released upon infection as extracellular mature toxins [5]. The sequences of these toxins are relatively conserved among the different subgroups. More important than sequence homology, the 3D structure is very similar among different SAgs resulting in similar functional effects among different groups [12, 14]. Crystal structures of the enterotoxins reveals that they are compact, ellipsoidal proteins sharing a characteristic two-domain folding pattern comprising an NH2-terminal β barrel globular domain known as the oligosaccharide / oligonucleotide fold, a long α-helix that diagonally spans the center of the molecule, and a COOH terminal globular domain [12]. The domains have binding regions for the Major Histocompatibility Complex Class II (MHC Class II) and the T-cell Receptor (TCR), respectively (see Figure 2) [13].
# Binding
Superantigens bind first to the MHC Class II and then coordinate to a T-cell Receptor (TCR) with a specific Variable β motif [4,14,15].
## MHC Class II
Binding to the MHC class II can involve interactions between the SAg and the peptide in the cleft of the MHC, as is the case with TSST-1 of the Group I SAgs. Group II SAgs exhibit peptide independent binding. Most SAgs bind preferentially to the α-chain of MHC class II molecules in the NH2-terminal domain [1, 15]. There are several different forms of the Human Leukocyte Antigen (HLA) that exhibit some variation on the heavy chains, and most SAgs show preference for the HLA-DQ form of the molecule [15]. Binding to the α-chain puts the SAg in the appropriate position to coordinate to the TCR.
Less commonly, SAgs attach to the polymorphic MHC class II β-chain in an interaction mediated by a zinc ion coordination complex between three SAg residues and a highly conserved region of the HLA-DR β chain [14]. The use of a zinc ion in binding leads to a higher affinity interaction [12]. Several staphylococcal SAgs are capable of cross-linking MHC molecules by binding to both the α and β chains [12,14]. This mechanism stimulates cytokine expression and release in antigen presenting cells as well as inducing the production of costimulatory molecules that allow the cell to bind to and activate T cells more effectively [14].
## T-cell Receptor
The T-cell binding region of the SAg interacts with the Variable region on the Beta chain of the T-cell Receptor. A given SAg can activate a large proportion of the T-cell population because the human T-cell repertoire comprises only about 50 types of Vβ elements and some SAgs are capable of binding to multiple types of VB regions. This interaction varies slightly among the different groups of SAgs [13]. Variability among different people in the types of T-cell regions that are prevalent explains why some people respond more strongly to certain SAgs. Group I SAgs contact the Vβ at the CDR2 and framework region of the molecule [1,9]. SAgs of Group II interact with the Vβ region using mechanisms that are conformation-dependent. These interactions are for the most part independent of specific Vβ amino acid side-chains. Group IV SAgs have been shown to engage all three CDR loops of certain Vβ forms [1,9]. The interaction takes place in a cleft between the small and large domains of the SAg and allows the SAg to act as a wedge between the TCR and MHC. This displaces the antigenic peptide away from the TCR and circumvents the normal mechanism for T-cell activation [14, 23].
The biological strength of the SAg (its ability to stimulate) is determined by its affinity for the TCR. SAgs with the highest affinity for the TCR elicit the strongest response [22]. SPMEZ-2 is the most potent SAg discovered to date [22].
# T-cell Signaling
The SAg cross-links the MHC and the TCR inducing a signaling pathway that results in the proliferation of the cell and production of cytokines. Low levels of Zap-70 have been found in T-cells activated by SAgs, indicating that the normal signaling pathway of T-cell activation is impaired [10]. It is hypothesized that Fyn rather than Lck is activated by a tyrosine kinase, leading to the adaptive induction of anergy [18]. Both the protein kinase C pathway and the protein tyrosine kinase pathways are activated, resulting in upregulating production of proinflammatory cytokines [11]. This alternative signaling pathway impairs the calcium/calcineurin and Ras/MAPkinase pathways slightly [18], but allows for a focused inflammatory response.
# Direct Effects
SAg stimulation of antigen presenting cells and T-cells elicits a response that is mainly inflammatory, focused on the action of Th1 T-helper cells. Some of the major products are IL-1, IL-2, IL-6, TNF-α, gamma interferon (IFN-γ), macrophage inflammatory protein 1α (MIP-1α), MIP-1β, and monocyte chemoattractant protein 1 (MCP-1) [11]. This excessive uncoordinated release of cytokines, (especially TNF-α), overloads the body and results in to rashes, fever, and can lead to multi-organ failure, coma and death [9, 15]. Deletion or anergy of activated T-cells follows infection. This results from production of IL-10 from prolonged exposure to the toxin. IL-10 downregulates production of IL-2, MHC Class II, and costimulatory molecules on the surface of APCs. These effects produce memory cells that are unresponsive to antigen stimulation [8, 19]. One mechanism by which this is possible involves cytokine-mediated suppression of T-cells. MHC crosslinking also activates a signaling pathway that suppresses hematopoiesis and upregulates Fas-mediated apoptosis [21]. IFN-α is another product of prolong SAg exposure. This cytokine is closely linked with induction of autoimmunity [20], and the autoimmune disease Kawasaki Disease is known to be caused by SAg infection [22]. SAg activation in T-cells leads to production of CD40 ligand which activates isotype switching in B cells from to IgG and IgM and IgE [17]. To summarize, the T-cells are stimulated and produce excess amounts of cytokine resulting in cytokine-mediated suppression of T-cells and deletion of the activated cells as the body returns to homeostasis. The toxic effects of the microbe and SAg also damage tissue and organ systems, a condition known as Toxic Shock Syndrome [17]. If the initial inflammation is survived, the host cells become anergic or are deleted, resulting in a severely compromised immune system.
# Superantigenicity independent Effects (Indirect Effects)
Apart from their mitogenic activity, SAgs are able to cause symptoms that are characteristic of infection [as cited by 2].
One such effect is emesis. This effect is felt in cases of food poisoning, when SAg-producing bacteria release the toxin, which is highly resistant to heat. There is a distinct region of the molecule that is active in inducing gastrointestinal toxicity [as cited by 2]. This activity is also highly potent, and quantities as small as 20-35ug of SAg are able to induce vomiting [15].
SAgs are able to stimulate recruitment of neutrophils to the site of infection in a way that is independent of T-cell stimulation. This effect is due to the ability of SAgs to activate monocytic cells, stimulating the release of the cytokine TNF-α, leading to increased expression of adhesion molecules that recruit leukocytes to infected regions. This causes inflammation in the lungs, intestinal tissue, and any place that the bacteria have colonized [3]. While small amounts of inflammation are natural and helpful, excessive inflammation can lead to tissue destruction.
One of the more dangerous indirect effects of SAg infection concerns the ability of SAgs to augment the effects of endotoxins in the body. This is accomplished by reducing the threshold for endotoxicity. Schlievert demonstrated that, when administered conjunctively, the effects of SAg and endotoxin are magnified as much as 50 000 times [4]. This could be due to the reduced immune system efficiency induced by SAg infection. Aside from the synergistic relationship between endotoxin and SAg, the “double hit” effect of the activity of the endotoxin and the SAg result in effects more deleterious that those seen in a typical bacterial infection. This also implicates SAgs in the progression of sepsis in patients with bacterial infections [17].
# Diseases Associated with Superantigen production [2]
- Toxic Shock Syndrome
- Kawasaki Disease
- Eczema
- Guttate psoriasis
- Rheumatoid arthritis
- Diabetes mellitus
- Scarlet fever [15]
# Treatment
The primary goal of medical treatment is to eliminate the microbe that is producing the SAgs. This is accomplished through the use of vasopressors, fluid resuscitation and antibiotics [2]. The body naturally produces antibodies to some SAgs, and this effect can be augmented by stimulating B-cell production of these antibodies [16]. Immunoglobulin pools are able to neutralize specific antibodies and prevent T-cell activation. Synthetic antibodies and peptides have been created to mimic SAg-binding regions on the MHC class II, blocking the interaction and preventing T cell activation [as cited by 2]. Immunosuppressants are also employed to prevent T-cell activation and the release of cytokines. Corticosteroids are used to reduce inflammatory effects [17].
# Evolution of Superantigen Production
SAg production effectively corrupts the immune response, allowing the microbe secreting the SAg to be carried and transmitted unchecked. One mechanism by which this is done system is through inducing anergy of the T-cells to antigens and SAgs [8, 10]. Lussow and MacDonald demonstrated this by systematically exposing animals to a streptococcal antigen. They found that exposure to other antigens after SAg infection failed to elicit an immune response [8]. In another experiment, Watson and Lee discovered that memory T-cells created by normal antigen stimulation were anergic to SAg stimulation and that memory T-cells created after a SAg infection were anergic to all antigen stimulation. The mechanism by which this occurred was undetermined [10]. The genes that regulate SAg expression also regulate mechanisms of immune evasion such as M protein and capsule expression, supporting the hypothesis that SAg production evolved primarily as a mechanism of immune evasion [6].
When the structure of individual SAg domains has been compared to other immunoglobulin-binding streptococcal proteins (such as those toxins produced by ''E. coli'') it was found that the domains separately resemble members of these families. This homology suggests that the SAgs evolved through the recombination of two smaller B-strand motifs [24].
# Endogenous SAgs
Minor lymphocyte stimulating (Mls) exotoxins were originally discovered in the thymic stromal cells of mice. These toxins are encoded by SAg genes that were incorporated into the mouse genome from the mouse mammary tumour virus (MMTV). The presence of these genes in the mouse genome allows the mouse to express the antigen in the thymus as a means of negatively selecting for lymphocytes with a variable Beta region that is susceptible to stimulation by the viral SAg. The result is that these mice are immune to infection by the virus later in life [as cited by 2].
Similar endogenous SAg-dependent selection has yet to be identified in the human genome, but endogenous SAgs have been discovered and are suspected of playing an integral role in viral infection. Infection by theEpstein-Barr virus, for example, is known to cause production of a SAg in infected cells, yet no gene for the toxin has been found on the genome of the virus. The virus manipulates the infected cell to express its own SAg genes, and this helps it to evade the host immune system. Similar results have been found with rabies, cytomegalovirus, and HIV [as cited by 2].
# Conclusion
Much detailed research has been conducted to determine the specific structures and binding mechanisms of each type of SAg. This paper presents a general overview of some of these that are more common and well-understood mechanisms of SAg infection. Recent research attempts to harness the immunostimulatory properties of these molecules by using specific SAgs to induce inflammatory cytokines that could target and prevent tumour growth [16]. As the microbial population develops more effective ways of infecting other organisms the human population uses intelligence to combat the advancing lines | https://www.wikidoc.org/index.php/Super-antigens | |
3f07338218dca94948c1d6b9bdbd40ebecf0c995 | wikidoc | Supercooling | Supercooling
Supercooling is the process of chilling a liquid below its freezing point, without it becoming solid.
A liquid below its freezing point will crystallize in the presence of a seed crystal or nucleus around which a crystal structure can form. However, lacking any such nucleus, the liquid phase can be maintained all the way down to the temperature at which crystal homogeneous nucleation occurs. The homogeneous nucleation can occur above the glass transition where the system is an amorphous—that is, non-crystalline—solid.
Water has a freezing point of 273.15 K (0 °C or 32 °F) but can be supercooled at standard pressure down to its crystal homogeneous nucleation at almost 231 K (−42 °C). If cooled at a rate on the order of 106 K/s, the crystal nucleation can be avoided and water becomes a glass. Its glass transition temperature is much colder and harder to determine, but studies estimate it at about 165 K (−108 °C).
Glassy water can be heated up to approximately 150 K (−123 °C).
In the range of temperatures between 231 K (−42 °C) and 150 K (−123 °C) experiments find only crystal ice.
Droplets of supercooled water often exist in stratiform and cumulus clouds. They form into ice when they are struck by the wings of passing airplanes and abruptly crystallize. (This causes problems with lift, so aircraft that are expected to fly in such conditions are equipped with a deicing system.) Freezing rain is also caused by supercooled droplets.
The process opposite to supercooling, the melting of a solid above the freezing point, is much more difficult, and a solid will almost always melt at the same temperature for a given pressure. It is, however, possible to superheat a liquid above its boiling point without it becoming gaseous.
# Constitutional supercooling
Constitutional supercooling occurs during solidification, is due to compositional changes, and results in cooling a liquid below the freezing point ahead of the solid-liquid interface. When solidifying a liquid, the interface is often unstable, and the velocity of the solid-liquid interface must be small in order to avoid constitutional supercooling.
Supercooled zones are observed when the liquidus temperature gradient at the interface is larger than the temperature gradient.
-r
The slope of the liquidus phase boundary on the phase diagram is m = \partial T_L / \partial C_L
The concentration gradient is related to points, C^{LS} and C^{SL}, on the phase diagram:
The minimum thermal gradient necessary to create a stable solid front is as expressed below. | Supercooling
Supercooling is the process of chilling a liquid below its freezing point, without it becoming solid.
A liquid below its freezing point will crystallize in the presence of a seed crystal or nucleus around which a crystal structure can form. However, lacking any such nucleus, the liquid phase can be maintained all the way down to the temperature at which crystal homogeneous nucleation occurs. The homogeneous nucleation can occur above the glass transition where the system is an amorphous—that is, non-crystalline—solid.
Water has a freezing point of 273.15 K (0 °C or 32 °F) but can be supercooled at standard pressure down to its crystal homogeneous nucleation at almost 231 K (−42 °C).[1] If cooled at a rate on the order of 106 K/s, the crystal nucleation can be avoided and water becomes a glass. Its glass transition temperature is much colder and harder to determine, but studies estimate it at about 165 K (−108 °C).[2]
Glassy water can be heated up to approximately 150 K (−123 °C).[1]
In the range of temperatures between 231 K (−42 °C) and 150 K (−123 °C) experiments find only crystal ice.
Droplets of supercooled water often exist in stratiform and cumulus clouds. They form into ice when they are struck by the wings of passing airplanes and abruptly crystallize. (This causes problems with lift, so aircraft that are expected to fly in such conditions are equipped with a deicing system.) Freezing rain is also caused by supercooled droplets.
The process opposite to supercooling, the melting of a solid above the freezing point, is much more difficult, and a solid will almost always melt at the same temperature for a given pressure. It is, however, possible to superheat a liquid above its boiling point without it becoming gaseous.
# Constitutional supercooling
Constitutional supercooling occurs during solidification, is due to compositional changes, and results in cooling a liquid below the freezing point ahead of the solid-liquid interface. When solidifying a liquid, the interface is often unstable, and the velocity of the solid-liquid interface must be small in order to avoid constitutional supercooling.
Supercooled zones are observed when the liquidus temperature gradient at the interface is larger than the temperature gradient.
or
The slope of the liquidus phase boundary on the phase diagram is <math>m = \partial T_L / \partial C_L</math>
The concentration gradient is related to points, <math>C^{LS}</math> and <math>C^{SL}</math>, on the phase diagram:
The minimum thermal gradient necessary to create a stable solid front is as expressed below. | https://www.wikidoc.org/index.php/Supercooling | |
218021bd9b65c9cea7034163bc1de68db09fd341 | wikidoc | Surface area | Surface area
Surface area is how much exposed area an object has. It is expressed in square units. If an object has flat faces, its surface area can be calculated by adding together the areas of its faces. Even objects with smooth surfaces, such as spheres, have surface area.
# Formula
### Sphere
a surface area of a sphere is the integral of infinitesimal circular rings of width dx
The radius of the circular ring is f(x) = \sqrt{r^2-x^2}. The length of the circular ring is equal to 2\pi\cdot f(x)
The width of the ring can be determined by using Pythagoras' formula for a rectangular triangle with side lengths dx and f'(x) \cdot dx, which leads to \sqrt{1+f'(x)^2}\,dx
The infinitesimal surface area of the circular ring thus is equal to 2\pi f(x)\cdot \sqrt{1+f'(x)^2}\,dx
The derivative of f(x) is equal to f'(x) = \frac{-x}{\sqrt{r^2-x^2}}
The surface area of the sphere can be calculated as
\int_{-r}^r 2\pi f(x)\cdot \sqrt{1+f'(x)^2}\,dx = \int_{-r}^r 2\pi \sqrt{r^2-x^2} \cdot \sqrt{1+\frac{x^2}{r^2-x^2}}\,dx = \int_{-r}^r 2\pi \sqrt {r^2}\,dx = 2\pi r \int_{-r}^r 1\,dx
The antiderivative needed is the simple linear function x
Thus, the sphere surface area amounAsphere = 2\pi r = 4\pi r^2 \
### Cylinder
The surface area of a (circular) cylinder of radius r and height h is
where the second term shows the contributions of the top and bottom of the cylinder.
# Surfaces whose area cannot be defined
While areas of many simple surfaces have been known since antiquity, a rigorous mathematical definition of area requires much care. Various approaches to defining the surface area were developed in the late nineteenth and the early twentieth century by Henri Lebesgue and Hermann Minkowski. For a very wide class of geometric surfaces called piecewise-smooth all these approaches result in the same notion of area. However, if a surface is very irregular or rough, then it may not be possible to assign any area at all to it. A typical example is given by a surface with spikes spread throughout in a dense fashion. Many surfaces of this type occur in the theory of fractals. Extensions of the notion of area which partially fulfill its function and may be defined even for very badly irregular surfaces are studied in the geometric measure theory. A specific example of such an extension is the Minkowski content of a surface.
# In chemistry
Surface area is important in chemical kinetics. Increasing the surface area of a substance generally increases the rate of a chemical reaction. For example, iron in a fine powder will combust, while in solid blocks it is stable enough to use in structures. For different applications a minimal or maximal surface area may be desired.
# In biology
The surface area-to-volume ratio (SA:V) of a cell imposes upper limits on size, as the volume increases much faster than does the surface area, thus limiting the rate at which substances diffuse from the interior across the cell membrane to interstitial spaces or to other cells. If you consider the math, you'll see the relation between SA and V much more intuitively: V = 4/3 π r3; SA = 4 π r2, where r is the radius of the cell. Do the math and the resulting ratio becomes 3/r. If a cell has a radius of 1 μm, the SA:V ratio is 3. Increase the cell's radius to 10 μm and the SA:V ratio becomes 0.3. With a cell radius of 100, SA:V ratio is 0.03. Using the previous simple example, we can see how the surface area falls off steeply with increasing volume.
What limitations does this place on a living cell? For small cells, SA:V ratio allows for relatively good exchange of nutrients and wastes. For larger cells and organisms, SA:V ratio forces the cell or organism to find more efficient ways to exchange nutrients and waste products, e.g. specific conduits that carry blood, hormones, lymph, etc. from deep regions to the surface of an organism. | Surface area
Surface area is how much exposed area an object has. It is expressed in square units. If an object has flat faces, its surface area can be calculated by adding together the areas of its faces. Even objects with smooth surfaces, such as spheres, have surface area.
# Formula
### Sphere
a surface area of a sphere is the integral of infinitesimal circular rings of width <math>dx</math>
The radius of the circular ring is <math> f(x) = \sqrt{r^2-x^2}</math>. The length of the circular ring is equal to <math>2\pi\cdot f(x)</math>
The width of the ring can be determined by using Pythagoras' formula for a rectangular triangle with side lengths <math>dx</math> and <math>f'(x) \cdot dx</math>, which leads to <math>\sqrt{1+f'(x)^2}\,dx</math>
The infinitesimal surface area of the circular ring thus is equal to <math>2\pi f(x)\cdot \sqrt{1+f'(x)^2}\,dx</math>
The derivative of <math>f(x)</math> is equal to <math>f'(x) = \frac{-x}{\sqrt{r^2-x^2}}</math>
The surface area of the sphere can be calculated as
<math> \int_{-r}^r 2\pi f(x)\cdot \sqrt{1+f'(x)^2}\,dx</math> = <math> \int_{-r}^r 2\pi \sqrt{r^2-x^2} \cdot \sqrt{1+\frac{x^2}{r^2-x^2}}\,dx = \int_{-r}^r 2\pi \sqrt {r^2}\,dx = 2\pi r \int_{-r}^r 1\,dx</math>
The antiderivative needed is the simple linear function <math>x</math>
Thus, the sphere surface area amounAsphere = <math>2\pi r[r-(-r)] = 4\pi r^2 \ </math>
[1]
### Cylinder
The surface area of a (circular) cylinder of radius r and height h is
where the second term shows the contributions of the top and bottom of the cylinder.
# Surfaces whose area cannot be defined
While areas of many simple surfaces have been known since antiquity, a rigorous mathematical definition of area requires much care. Various approaches to defining the surface area were developed in the late nineteenth and the early twentieth century by Henri Lebesgue and Hermann Minkowski. For a very wide class of geometric surfaces called piecewise-smooth all these approaches result in the same notion of area. However, if a surface is very irregular or rough, then it may not be possible to assign any area at all to it. A typical example is given by a surface with spikes spread throughout in a dense fashion. Many surfaces of this type occur in the theory of fractals. Extensions of the notion of area which partially fulfill its function and may be defined even for very badly irregular surfaces are studied in the geometric measure theory. A specific example of such an extension is the Minkowski content of a surface.
# In chemistry
Surface area is important in chemical kinetics. Increasing the surface area of a substance generally increases the rate of a chemical reaction. For example, iron in a fine powder will combust, while in solid blocks it is stable enough to use in structures. For different applications a minimal or maximal surface area may be desired.
# In biology
The surface area-to-volume ratio (SA:V) of a cell imposes upper limits on size, as the volume increases much faster than does the surface area, thus limiting the rate at which substances diffuse from the interior across the cell membrane to interstitial spaces or to other cells. If you consider the math, you'll see the relation between SA and V much more intuitively: V = 4/3 π r3; SA = 4 π r2, where r is the radius of the cell. Do the math and the resulting ratio becomes 3/r. If a cell has a radius of 1 μm, the SA:V ratio is 3. Increase the cell's radius to 10 μm and the SA:V ratio becomes 0.3. With a cell radius of 100, SA:V ratio is 0.03. Using the previous simple example, we can see how the surface area falls off steeply with increasing volume.
What limitations does this place on a living cell? For small cells, SA:V ratio allows for relatively good exchange of nutrients and wastes. For larger cells and organisms, SA:V ratio forces the cell or organism to find more efficient ways to exchange nutrients and waste products, e.g. specific conduits that carry blood, hormones, lymph, etc. from deep regions to the surface of an organism. | https://www.wikidoc.org/index.php/Surface_area | |
9ebd3b43fb1cfdbc8565461bcb15145356e70c37 | wikidoc | Surfer's Ear | Surfer's Ear
# Overview
Surfer's Ear is the common name for exostosis, abnormal bone growth, within the ear canal. Surfer's ear is not the same as swimmer's ear.
Irritation from cold wind and water exposure causes the bone surrounding the ear canal to develop lumps of new bony growth which constrict the ear canal. The condition is so named due to its prevalence among cold water surfers. Cold water surfers experience surfer's ear at about six times the rate of warm water surfers.
The condition is not limited to surfing and can occur in any activity with cold, wet, windy conditions such as kayaking, sailing,diving. Most avid surfers have at least some mild bone growths (exostoses), causing little to no problems. The condition is progressive, making it important to take preventative measures early, preferably whenever surfing.
# Etiology
# Symptoms
In general one ear will be much worse than the other due to the areas prevailing wind direction or the side that most often strikes the wave first.
- Decreased hearing or hearing loss, temporary or ongoing
- Increased prevalence of ear infections, causing ear pain
- Difficulty evacuating debris or water from the ear causing a plugging sensation
- Normal Ear Canal
Normal Ear Canal
- Normal Ear Canal
Normal Ear Canal
- Exostosis in Ear Canal
Exostosis in Ear Canal
- Exostosis in Ear Canal
Exostosis in Ear Canal
# Treatment
Traditionally surfer's ear has been treated by exostectomy wherein a small incision is opened behind the ear and the bone growth is removed using a surgical drill. When exostoses are completely removed there is little chance of recurrence requiring repeat surgery in the future. The postauricular approach minimizes complications by providing a proper operative trajectory to the exostoses.
During recuperation it is extremely important not to return to the water for at least four weeks to avoid infection or complications. The operation is performed under general anesthesia.
Some doctors now use extremely small chisels and enter directly through the ear canal. While not requiring an incision behind the ear, this procedure has resulted in accidental mobilization of the ear canal in several cases, and still requires use of a drill near the eardrum.
Unprotected exposure of ear canals to cold water and wind after treatment can lead to regrowth of bone and the need for repeated operations on the same ear.
# Prevention
Just as it iss possible that motorcycle helmets increase nonhead related injuries due to increased risk-taking , the widespread use of wetsuit hoods, caps, and neoprene bands has allowed people to surf in much colder waters, which probably has increased the incidence and severity of surfer's ear for those that don't properly protect their ears.
Other recommendations:
- Avoid activity during extremely cold or windy conditions.
- Keep the ear canal as warm and dry as possible.
Ear plugs
Neoprene hood
swim cap
- Ear plugs
- Neoprene hood
- swim cap | Surfer's Ear
# Overview
Surfer's Ear is the common name for exostosis, abnormal bone growth, within the ear canal. Surfer's ear is not the same as swimmer's ear.
Irritation from cold wind and water exposure causes the bone surrounding the ear canal to develop lumps of new bony growth which constrict the ear canal. The condition is so named due to its prevalence among cold water surfers. Cold water surfers experience surfer's ear at about six times the rate of warm water surfers.
The condition is not limited to surfing and can occur in any activity with cold, wet, windy conditions such as kayaking, sailing,diving. Most avid surfers have at least some mild bone growths (exostoses), causing little to no problems.[1] The condition is progressive, making it important to take preventative measures early, preferably whenever surfing.
# Etiology
# Symptoms
In general one ear will be much worse than the other due to the areas prevailing wind direction or the side that most often strikes the wave first.
- Decreased hearing or hearing loss, temporary or ongoing
- Increased prevalence of ear infections, causing ear pain
- Difficulty evacuating debris or water from the ear causing a plugging sensation
- Normal Ear Canal
Normal Ear Canal
- Normal Ear Canal
Normal Ear Canal
- Exostosis in Ear Canal
Exostosis in Ear Canal
- Exostosis in Ear Canal
Exostosis in Ear Canal
# Treatment
Traditionally surfer's ear has been treated by exostectomy wherein a small incision is opened behind the ear and the bone growth is removed using a surgical drill. When exostoses are completely removed there is little chance of recurrence requiring repeat surgery in the future. The postauricular approach minimizes complications by providing a proper operative trajectory to the exostoses.[2]
During recuperation it is extremely important not to return to the water for at least four weeks to avoid infection or complications. The operation is performed under general anesthesia.
Some doctors now use extremely small chisels and enter directly through the ear canal. While not requiring an incision behind the ear, this procedure has resulted in accidental mobilization of the ear canal in several cases, and still requires use of a drill near the eardrum.[3]
Unprotected exposure of ear canals to cold water and wind after treatment can lead to regrowth of bone and the need for repeated operations on the same ear.
# Prevention
Just as it iss possible that motorcycle helmets increase nonhead related injuries due to increased risk-taking , the widespread use of wetsuit hoods, caps, and neoprene bands has allowed people to surf in much colder waters, which probably has increased the incidence and severity of surfer's ear for those that don't properly protect their ears.
Other recommendations:
- Avoid activity during extremely cold or windy conditions.
- Keep the ear canal as warm and dry as possible.
Ear plugs
Neoprene hood
swim cap
- Ear plugs
- Neoprene hood
- swim cap | https://www.wikidoc.org/index.php/Surfer%27s_Ear | |
e2c0cbb05251aa734aad963078221e8a74368ccb | wikidoc | Susan Nelles | Susan Nelles
Susan Marguerite Nelles (born in Belleville, Ontario) was charged with murdering four babies in 1981, when she worked as a nurse at Toronto's Hospital for Sick Children. She was ultimately exonerated.
The hospital investigated the cause of infant deaths in the cardiac unit, using an experimental, inappropriate testing method. The test indicated that as many as 43 babies were poisoned with the heart medication digoxin. Police determined that Susan Nelles had been scheduled to work at the times that 23 of the deaths occurred. They arrested and charged her with the deaths of four babies. The deaths then stopped.
However, Nelles had not been on duty for several of the infant deaths, because she swapped shifts with other nurses – who had access to the same medication. Although the deaths ended after Nelles's arrest, the hospital had introduced restrictions for access to digoxin and had implemented a policy that kept infants in intensive care longer. Total deaths between the two units remained identical.
Nelles asked for legal counsel when she was arrested. This was interpreted by the investigating police officers to be an indication of her guilt, but the court later ruled that this should not be interpreted as evidence of guilt. The court also ruled that the Crown lacked evidence to convict Nelles. The government eventually paid for Nelles's legal costs after she sued the province's Attorney-General, Roy McMurtry for malicious prosecution.
A Royal Commission, led by Justice Samuel Grange, found that eight infants had been murdered. Although another nurse, Phyllis Trainor, fell under scrutiny, no one was charged. Moreover, the experimental test that detected digoxin may have given false results for other chemicals.
In 1999, she received an honorary degree from Queen's University in Kingston, Ontario at which she graduated with a Bachelor of Nursing Science degree in 1978. This honour, presented under her married name Susan Pine, was for her work in promoting integrity in the nursing field. | Susan Nelles
Susan Marguerite Nelles (born in Belleville, Ontario)[1] was charged with murdering four babies in 1981, when she worked as a nurse at Toronto's Hospital for Sick Children. She was ultimately exonerated.
The hospital investigated the cause of infant deaths in the cardiac unit, using an experimental, inappropriate testing method. The test indicated that as many as 43 babies were poisoned with the heart medication digoxin. Police determined that Susan Nelles had been scheduled to work at the times that 23 of the deaths occurred. They arrested and charged her with the deaths of four babies. The deaths then stopped.
However, Nelles had not been on duty for several of the infant deaths, because she swapped shifts with other nurses – who had access to the same medication. Although the deaths ended after Nelles's arrest, the hospital had introduced restrictions for access to digoxin and had implemented a policy that kept infants in intensive care longer. Total deaths between the two units remained identical.
Nelles asked for legal counsel when she was arrested. This was interpreted by the investigating police officers to be an indication of her guilt, but the court later ruled that this should not be interpreted as evidence of guilt. The court also ruled that the Crown lacked evidence to convict Nelles. The government eventually paid for Nelles's legal costs after she sued the province's Attorney-General, Roy McMurtry for malicious prosecution.
A Royal Commission, led by Justice Samuel Grange, found that eight infants had been murdered. Although another nurse, Phyllis Trainor, fell under scrutiny, no one was charged. Moreover, the experimental test that detected digoxin may have given false results for other chemicals.
In 1999, she received an honorary degree from Queen's University in Kingston, Ontario at which she graduated with a Bachelor of Nursing Science degree in 1978. This honour, presented under her married name Susan Pine, was for her work in promoting integrity in the nursing field.[1] | https://www.wikidoc.org/index.php/Susan_Nelles | |
1b4a5be4b375e749e3e2cfbaf1268f852bf1d994 | wikidoc | Suzanna Hupp | Suzanna Hupp
Dr. Suzanna Gratia Hupp (born January 1, 1959) is a former Republican Party member of the Texas House of Representatives, who represented traditionally Democratic Party (Bell County, Texas, Burnet County, and Lampasas County, Texas) for ten years from 1997-2007. Hupp is recognized as a leading advocate for the Second Amendment to the United States Constitution and an individual's right to carry a concealed weapon. She was elected to her first term in 1996 but did not seek a sixth two-year term in 2006.
Hupp was reared in Friendswood, Texas, a city partly in Harris County, Texas and Galveston County, Texas counties. She has an older brother, Allan, and a younger sister, Erika. She attended the University of Texas at El Paso and Texas Chiropractic College, from which she received the doctor of chiropractic degree in 1985. Hupp moved first to Houston, Texas to practice chiropractic and then to central Texas in 1987. She owned and operated the Cove Physical Rehab Clinic from 1987 until 2000, when she sold the facility.
# Death of parents
On Wednesday, October 16, 1991, Hupp and her parents were having lunch at the Luby's Cafeteria in Killeen, Texas. She had left her gun in her car to comply with Texas state law at the time which forbade carrying a concealed weapon. When George Hennard drove his truck into the cafeteria and opened fire on the patrons, Hupp instinctively reached into her purse for her weapon, but it was in her vehicle. Her father, Al Gratia, tried to rush Hennard and was shot in the chest. As the gunman reloaded, Hupp escaped through a broken window and believed that her mother, Ursula Gratia, was behind her. Hennard put a gun to her mother's head as she cradled her mortally wounded husband. Hupp's mother and father were killed along with twenty-one other persons. Hennard also wounded some twenty others. As a survivor of the "Luby's massacre", Hupp testified across the country in support of concealed-handgun laws. She said that had there been a second chance to prevent the slaughter, she would have violated the Texas law and carried the handgun inside her purse into the restaurant.
# Election returns, 1996-2004
In the 1996 legislative election, the incumbent Democrat in the district, Layton Black, did not run again. Hupp defeated Democratic nominee Dick Miller, 17,620 votes (52.8 percent) to 15,757 ballots (47.2 percent). At the time, the district included Bell and Lampasas counties but also the small populated counties of McCulloch County, Texas, Mills County, Texas, and San Saba, Texas. In 1998, Hupp defeated Democrat Don Armstrong, 11,954 votes (54.8 percent) to 9,866 ballots (45.2 percent). In 2000, she again defeated Armstrong, 23,139 (62.2 percent) to 14,084 (37.8 percent). The higher turnout reflected the presidential election year. Hupp was unopposed in 2002. In 2004, Hupp defeated the Democrat Edward Lindsay of Killeen, 28,907 votes (60.9 percent) to 18,594 ballots (39.1 percent).
# Hupp in the limelight
Hupp has been quoted in such publications as U.S. News & World Report, The Wall Street Journal, Texas Monthly, and Time (magazine) and People (magazine) magazines. She was featured on CBS's 48 Hours (TV series), American Broadcasting Company's World News with Charles Gibson and season 3 episode 9 of Penn & Teller: Bullshit!. Hupp can be heard in episode 81 of This American Life, giving a first-hand account of her experience in the Luby's massacre of Killeen, TX in 1991.
Hupp has authored a book regarding her experiences: "From Luby's to the Legislature: One Woman's Fight Against Gun Control". Now available for $22.95 from Privateer Publications, San Antonio, Texas, SuzannaHupp.com or free with paid membership from CHL Protection Plan, Dallas, Texas
Hupp was awarded the Sybil Ludington Women's Freedom Award by the National Rifle Association. In 1998, Charlton Heston honored Hupp as the first Texan awarded a lifetime NRA membership.
In the state House, Hupp was a member of the House Rural Caucus and the House Veterans and Military Affairs Caucus. In November 2003, Speaker (politics) Tom Craddick appointed Hupp as chair of the House select committee on child welfare and foster care. Craddick also named her to chair the Human Services Committee in the Seventy-ninth Texas Legislature. She also served on the House Law Enforcement Committee.
Hupp has been recognized by many Conservatism interest groups: the American Family Association, Free Market Foundation, the Texas Association of Business, the Chamber of Commerce, Texas Alliance For Life, Texas Eagle Forum, and the Young Conservatives of Texas. She was rated 100 percent pro-life by the Texas Right to Life Committee.
Hupp is quoted as having said, "How a politician stands on the Second Amendment tells you how he or she views you as an individual... as a trustworthy and productive citizen, or as part of an unruly crowd that needs to be lorded over, controlled, supervised, and taken care of."
Hupp has hosted a radio talk program in the Greater Austin, Texas area. She is a co-founder of the Civil Liberties Defense Foundation, a non-profit legal foundation dedicated to providing educational information relating to the preservation of civil liberties guaranteed by the United States Bill of Rights to the United States Constitution and to providing legal services to protect those rights.
She is married to Greg Hupp, who has served as her campaign manager. They have two sons, Alexander and Ethan. The Hupps have a small Arabian horse ranch near Kempner, Texas in Lampasas County.
# Election history
Hupp did not seek a sixth term in 2006.
# Notes
- ↑ Net Detective, People Search
- ↑ Video of Hupp testifying before Congress | Suzanna Hupp
Template:Infobox State Representative
Dr. Suzanna Gratia Hupp (born January 1, 1959)[1] is a former Republican Party member of the Texas House of Representatives, who represented traditionally Democratic Party (Bell County, Texas, Burnet County, and Lampasas County, Texas) for ten years from 1997-2007. Hupp is recognized as a leading advocate for the Second Amendment to the United States Constitution and an individual's right to carry a concealed weapon. She was elected to her first term in 1996 but did not seek a sixth two-year term in 2006.
Hupp was reared in Friendswood, Texas, a city partly in Harris County, Texas and Galveston County, Texas counties. She has an older brother, Allan, and a younger sister, Erika. She attended the University of Texas at El Paso and Texas Chiropractic College, from which she received the doctor of chiropractic degree in 1985. Hupp moved first to Houston, Texas to practice chiropractic and then to central Texas in 1987. She owned and operated the Cove Physical Rehab Clinic from 1987 until 2000, when she sold the facility.
# Death of parents
On Wednesday, October 16, 1991, Hupp and her parents were having lunch at the Luby's Cafeteria in Killeen, Texas. She had left her gun in her car to comply with Texas state law at the time which forbade carrying a concealed weapon. When George Hennard drove his truck into the cafeteria and opened fire on the patrons, Hupp instinctively reached into her purse for her weapon, but it was in her vehicle. Her father, Al Gratia, tried to rush Hennard and was shot in the chest. As the gunman reloaded, Hupp escaped through a broken window and believed that her mother, Ursula Gratia, was behind her. Hennard put a gun to her mother's head as she cradled her mortally wounded husband. Hupp's mother and father were killed along with twenty-one other persons. Hennard also wounded some twenty others. As a survivor of the "Luby's massacre", Hupp testified across the country in support of concealed-handgun laws. She said that had there been a second chance to prevent the slaughter, she would have violated the Texas law and carried the handgun inside her purse into the restaurant[2].
# Election returns, 1996-2004
In the 1996 legislative election, the incumbent Democrat in the district, Layton Black, did not run again. Hupp defeated Democratic nominee Dick Miller, 17,620 votes (52.8 percent) to 15,757 ballots (47.2 percent). At the time, the district included Bell and Lampasas counties but also the small populated counties of McCulloch County, Texas, Mills County, Texas, and San Saba, Texas. In 1998, Hupp defeated Democrat Don Armstrong, 11,954 votes (54.8 percent) to 9,866 ballots (45.2 percent). In 2000, she again defeated Armstrong, 23,139 (62.2 percent) to 14,084 (37.8 percent). The higher turnout reflected the presidential election year. Hupp was unopposed in 2002. In 2004, Hupp defeated the Democrat Edward Lindsay of Killeen, 28,907 votes (60.9 percent) to 18,594 ballots (39.1 percent).
# Hupp in the limelight
Hupp has been quoted in such publications as U.S. News & World Report, The Wall Street Journal, Texas Monthly, and Time (magazine) and People (magazine) magazines. She was featured on CBS's 48 Hours (TV series), American Broadcasting Company's World News with Charles Gibson and season 3 episode 9 of Penn & Teller: Bullshit!. Hupp can be heard in episode 81 of This American Life, giving a first-hand account of her experience in the Luby's massacre of Killeen, TX in 1991.
Hupp has authored a book regarding her experiences: "From Luby's to the Legislature: One Woman's Fight Against Gun Control". Now available for $22.95 from Privateer Publications, San Antonio, Texas[3], SuzannaHupp.com[4] or free with paid membership from CHL Protection Plan, Dallas, Texas[5]
Hupp was awarded the Sybil Ludington Women's Freedom Award by the National Rifle Association. In 1998, Charlton Heston honored Hupp as the first Texan awarded a lifetime NRA membership.
In the state House, Hupp was a member of the House Rural Caucus and the House Veterans and Military Affairs Caucus. In November 2003, Speaker (politics) Tom Craddick appointed Hupp as chair of the House select committee on child welfare and foster care. Craddick also named her to chair the Human Services Committee in the Seventy-ninth Texas Legislature. She also served on the House Law Enforcement Committee.
Hupp has been recognized by many Conservatism interest groups: the American Family Association, Free Market Foundation, the Texas Association of Business, the Chamber of Commerce, Texas Alliance For Life, Texas Eagle Forum, and the Young Conservatives of Texas. She was rated 100 percent pro-life by the Texas Right to Life Committee.
Hupp is quoted as having said, "How a politician stands on the Second Amendment tells you how he or she views you as an individual... as a trustworthy and productive citizen, or as part of an unruly crowd that needs to be lorded over, controlled, supervised, and taken care of."[6]
Hupp has hosted a radio talk program in the Greater Austin, Texas area. She is a co-founder of the Civil Liberties Defense Foundation, a non-profit legal foundation dedicated to providing educational information relating to the preservation of civil liberties guaranteed by the United States Bill of Rights to the United States Constitution and to providing legal services to protect those rights.
She is married to Greg Hupp, who has served as her campaign manager. They have two sons, Alexander and Ethan. The Hupps have a small Arabian horse ranch near Kempner, Texas in Lampasas County.
# Election history
Hupp did not seek a sixth term in 2006.
### 2004
Template:Election box begin
Template:Election box candidate with party link
Template:Election box majority
Template:Election box turnout
Template:Election box hold with party link no swing
Template:Election box end
### 2002
Template:Election box begin
Template:Election box candidate with party link
Template:Election box majority
Template:Election box turnout
Template:Election box hold with party link no swing
Template:Election box end
### 2000
Template:Election box begin
Template:Election box candidate with party link
Template:Election box candidate with party link
Template:Election box majority
Template:Election box turnout
Template:Election box hold with party link no swing
Template:Election box end
### 1998
Template:Election box begin
Template:Election box candidate with party link
Template:Election box candidate with party link
Template:Election box majority
Template:Election box turnout
Template:Election box hold with party link no swing
Template:Election box end
### 1996
Template:Election box begin
Template:Election box candidate with party link
Template:Election box candidate with party link
Template:Election box majority
Template:Election box turnout
Template:Election box hold with party link no swing
Template:Election box end
Template:Election box begin
Template:Election box candidate with party link
Template:Election box candidate with party link
Template:Election box majority
Template:Election box turnout
Template:Election box gain with party link no swing
Template:Election box end
# Notes
- ↑ Net Detective, People Search
- ↑ http://video.google.com/videoplay?docid=-4069761537893819675&hl=en Video of Hupp testifying before Congress
- ↑ http://www.privateerpublications.com
- ↑ http://www.suzannahupp.com
- ↑ http://www.chlpp.com
- ↑ http://www.youtube.com/watch?v=M1u0Byq5Qis | https://www.wikidoc.org/index.php/Suzanna_Hupp | |
d27c4058f58fbd48b4e8fc73343ec371a0d14830 | wikidoc | Sweet violet | Sweet violet
(Viola odorata) is a species of the genus Viola native to Europe and Asia, but has also been introduced in North America. It is also called the Garden Violet.
Viola odorata is quite similar to other species of violet, but can be distinguished by the following characteristics:
- the flowers have a sweet scent,
- the flowers are normally either dark violet or white,
- the leaves and flowers are all in a basal rosette,
- the style is hooked (and does not end with a rounded appendage),
- the leaf-stalks have hairs which point downwards, and
- the plant spreads with stolons (above-ground shoots).
The Sweet Violet can be found near the edges of forests or in clearings; it is also a common "uninvited guest" in shaded lawns or elsewhere in gardens. The flowers appear as early as February and last until the end of April.
- File:Sweetviolet4.jpg
- File:Sweetviolet.jpg
- File:Sweetviolet2.jpg
- File:Sweetviolet3.jpg
- File:Sweet violet.jpg
- File:Viola odorata flower - purple with white center - front P.2005.04.04.jpg
- File:Violet toporas.jpg
- File:Viola odorata1.jpg
ang:Æppellēaf
cs:Violka vonná
da:Marts-Viol
de:Duftveilchen
lt:Kvapioji našlaitė
hu:Illatos ibolya
nl:Maarts viooltje
no:Marsfiol
nn:Marsfiol
sk:Fialka voňavá
sv:Luktviol
uk:Фіалка запашна | Sweet violet
(Viola odorata) is a species of the genus Viola native to Europe and Asia, but has also been introduced in North America. It is also called the Garden Violet.
Viola odorata is quite similar to other species of violet, but can be distinguished by the following characteristics:
- the flowers have a sweet scent,
- the flowers are normally either dark violet or white,
- the leaves and flowers are all in a basal rosette,
- the style is hooked (and does not end with a rounded appendage),
- the leaf-stalks have hairs which point downwards, and
- the plant spreads with stolons (above-ground shoots).
The Sweet Violet can be found near the edges of forests or in clearings; it is also a common "uninvited guest" in shaded lawns or elsewhere in gardens. The flowers appear as early as February and last until the end of April.
- File:Sweetviolet4.jpg
- File:Sweetviolet.jpg
- File:Sweetviolet2.jpg
- File:Sweetviolet3.jpg
- File:Sweet violet.jpg
- File:Viola odorata flower - purple with white center - front P.2005.04.04.jpg
- File:Violet toporas.jpg
- File:Viola odorata1.jpg
Template:Malpighiales-stub
ang:Æppellēaf
cs:Violka vonná
da:Marts-Viol
de:Duftveilchen
lt:Kvapioji našlaitė
hu:Illatos ibolya
nl:Maarts viooltje
no:Marsfiol
nn:Marsfiol
sk:Fialka voňavá
sv:Luktviol
uk:Фіалка запашна | https://www.wikidoc.org/index.php/Sweet_violet | |
3d011c64a22b956ba8af1046ea04f46c8aaaf6fd | wikidoc | Synaptojanin | Synaptojanin
Synaptojanin is a protein involved in vesicle uncoating in neurons. This is an important regulatory lipid phosphatase. It dephosphorylates the D-5 position phosphate from phosphatidylinositol (3,4,5)-trisphosphate (PIP3) and Phosphatidylinositol (4,5)-bisphosphate(PIP2). It belongs to family of 5-phosphatases, which are structurally unrelated to D-3 inositol phosphatases like PTEN. Other members of the family of 5'phosphoinositide phosphatases include OCRL, SHIP1, SHIP2, INPP5J, INPP5E, INPP5B, INPP5A and SKIP.
# Synaptojanin Family
The synaptojanin family comprises proteins that are key players in the synaptic vesicle recovery at the synapse. In general, vesicles containing neurotransmitters fuse with the presynaptic cell in order to release neurotransmitter into the synaptic cleft. It is the release of neurotransmitters that allows neuron to neuron communication in the nervous system. The recovery of the vesicle is referred to as endocytosis and is important to reset the presynaptic cell with new neurotransmitter.
Synaptojanin 1 and Synaptojanin 2 are the two main proteins in the synaptojanin family. Synaptojanin 2 can be further subdivided into synaptojanin 2a and synaptojanin 2b.
The mechanism by which vesicles are recovered is thought to involve the synaptojanin attracting the protein clathrin, which coats the vesicle and initiates vesicle endocytosis.
Synaptojanins are composed to three domains. The first is a central inositol 5-phosphatase domain, which can act on both PIP2 and PIP3. The second is an N-terminal Sac1-like inositol phosphatase domain, which can hydrolyze to PI in vitro PIP, PIP2. The third is a C-terminal domain that is rich in the amino acid proline and interacts with several proteins also involved in vesicle endocytosis. Specifically, the c-terminal domain interacts with amphiphysin, endophilin, DAP160/intersectin, syndapin and Eps15. The function of endophilin appears to be a binding partner for synaptojanin such that it can interact with other proteins and is involved in the initiation of shallow clathrin coated pits. Dap160 is a molecular scaffolding protein and functions in actin recruitment. Dynamin is a GTPase involved in vesicle budding, specifically modulating the severance of the vesicle from the neuronal membrane. Dynamin appears to be playing a larger role in neurite formation because its vesicle pinching role and the possibility of it recycling plasma membrane and growth factor receptor proteins.
Mutation in this gene have been associated with autosomal recessive, early-onset parkinsonism.
# Role in Development
Synaptojanin, through its interactions with a variety of proteins and molecules is thought to play a role in the development of nervous systems.
## Ephrin
Synaptojanin 1 has been found to be influenced by the protein ephrin. Ephrin is a chemorepulsant meaning that its interactions with proteins results in an inactivation or retraction of processes when referring to neuronal migration. Ephrin's receptor is called Eph and is a receptor tyrosine kinase. Upon activation of the Eph receptor, synaptojanin 1 becomes phosphorylated at the proline rich domain and is inhibited from binding with any of its natural binding partners. Therefore, the presence of ephrin inactivates vesicle endocytosis.
## Calcium
The influx of calcium in the neuron has been shown to activate a variety of molecules including some calcium dependent phosphatases that activate synaptojanin.
## Membranes
Neuronal migration during development involves the extension of a neurite along the extracellular matrix. This extension is guided by the growth cone. However the actual extension of the neurite involves the insertion of membrane lipids immediately behind the growth one. In fact, membranes can be trafficked from degenerating extensions to elongating ones. Synaptojanin has been proposed as the mechanism by which membrane lipids can be trafficked around the developing neuron.
## Receptors
During development, receptors are trafficked around the growth cone. This trafficking involves vesicle endocytosis. In the presence of nerve growth factor (NGF), TrkA receptors are trafficked to the stimulated side of the growth cone. Additionally, calcium and glutamate stimulate the trafficking of AMPA receptors to the stimulated side of the growth cone. Both of these receptors are trafficked via synaptojanin.
# Model organisms
Model organisms have been used in the study of Synaptojanin function. A conditional knockout mouse line of synaptojanin 2, called Synj2tm1a(EUCOMM)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty two tests were carried out on mutant mice, but no significant abnormalities were observed. | Synaptojanin
Synaptojanin is a protein involved in vesicle uncoating in neurons. This is an important regulatory lipid phosphatase. It dephosphorylates the D-5 position phosphate from phosphatidylinositol (3,4,5)-trisphosphate (PIP3) and Phosphatidylinositol (4,5)-bisphosphate(PIP2). It belongs to family of 5-phosphatases, which are structurally unrelated to D-3 inositol phosphatases like PTEN. Other members of the family of 5'phosphoinositide phosphatases include OCRL, SHIP1, SHIP2, INPP5J, INPP5E, INPP5B, INPP5A and SKIP.
# Synaptojanin Family
The synaptojanin family comprises proteins that are key players in the synaptic vesicle recovery at the synapse.[1] In general, vesicles containing neurotransmitters fuse with the presynaptic cell in order to release neurotransmitter into the synaptic cleft. It is the release of neurotransmitters that allows neuron to neuron communication in the nervous system. The recovery of the vesicle is referred to as endocytosis and is important to reset the presynaptic cell with new neurotransmitter.
Synaptojanin 1 and Synaptojanin 2 are the two main proteins in the synaptojanin family. Synaptojanin 2 can be further subdivided into synaptojanin 2a and synaptojanin 2b.[2]
The mechanism by which vesicles are recovered is thought to involve the synaptojanin attracting the protein clathrin, which coats the vesicle and initiates vesicle endocytosis.
Synaptojanins are composed to three domains. The first is a central inositol 5-phosphatase domain, which can act on both PIP2 and PIP3. The second is an N-terminal Sac1-like inositol phosphatase domain, which can hydrolyze to PI in vitro PIP, PIP2. The third is a C-terminal domain that is rich in the amino acid proline and interacts with several proteins also involved in vesicle endocytosis.[1] Specifically, the c-terminal domain interacts with amphiphysin, endophilin, DAP160/intersectin, syndapin and Eps15. The function of endophilin appears to be a binding partner for synaptojanin such that it can interact with other proteins and is involved in the initiation of shallow clathrin coated pits. Dap160 is a molecular scaffolding protein and functions in actin recruitment. Dynamin is a GTPase involved in vesicle budding, specifically modulating the severance of the vesicle from the neuronal membrane.[3] Dynamin appears to be playing a larger role in neurite formation because its vesicle pinching role and the possibility of it recycling plasma membrane and growth factor receptor proteins.[4]
Mutation in this gene have been associated with autosomal recessive, early-onset parkinsonism.[5]
# Role in Development
Synaptojanin, through its interactions with a variety of proteins and molecules is thought to play a role in the development of nervous systems.
## Ephrin
Synaptojanin 1 has been found to be influenced by the protein ephrin.[6] Ephrin is a chemorepulsant meaning that its interactions with proteins results in an inactivation or retraction of processes when referring to neuronal migration. Ephrin's receptor is called Eph and is a receptor tyrosine kinase.[6] Upon activation of the Eph receptor, synaptojanin 1 becomes phosphorylated at the proline rich domain and is inhibited from binding with any of its natural binding partners.[7] Therefore, the presence of ephrin inactivates vesicle endocytosis.
## Calcium
The influx of calcium in the neuron has been shown to activate a variety of molecules including some calcium dependent phosphatases that activate synaptojanin.[8]
## Membranes
Neuronal migration during development involves the extension of a neurite along the extracellular matrix. This extension is guided by the growth cone. However the actual extension of the neurite involves the insertion of membrane lipids immediately behind the growth one.[9] In fact, membranes can be trafficked from degenerating extensions to elongating ones.[10] Synaptojanin has been proposed as the mechanism by which membrane lipids can be trafficked around the developing neuron.[9]
## Receptors
During development, receptors are trafficked around the growth cone. This trafficking involves vesicle endocytosis. In the presence of nerve growth factor (NGF), TrkA receptors are trafficked to the stimulated side of the growth cone.[8] Additionally, calcium and glutamate stimulate the trafficking of AMPA receptors to the stimulated side of the growth cone.[11] Both of these receptors are trafficked via synaptojanin.
# Model organisms
Model organisms have been used in the study of Synaptojanin function. A conditional knockout mouse line of synaptojanin 2, called Synj2tm1a(EUCOMM)Wtsi[16][17] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute.[18][19][20]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[14][21] Twenty two tests were carried out on mutant mice, but no significant abnormalities were observed.[14] | https://www.wikidoc.org/index.php/Synaptojanin | |
cfdc96388ea8c3c33c2e65d43aededef1d188b9d | wikidoc | Synarthrosis | Synarthrosis
# Overview
A synarthrosis is a type of joint which permits little or no mobility. Most synarthrosis joints are fibrous.
Suture joints and synchondroses are synarthroses.
# Types
They can be categorised by how the two bones are joined together:
- Synchondroses are joints where the two bones are connected by a piece of cartilage.
- Synostoses are where two bones that are initially separted eventually fuse together, essentially becoming one bone. In humans the plates of the cranium fuse together as a child approaches adulthood. Children whose craniums fuse too early may suffer deformities and brain damage as the skull does not expand properly to accommodate the growing brain, a condition known as craniostenosis. | Synarthrosis
Template:Infobox Anatomy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
A synarthrosis is a type of joint which permits little or no mobility. Most synarthrosis joints are fibrous.
Suture joints and synchondroses are synarthroses.[1]
# Types
They can be categorised by how the two bones are joined together:
- Synchondroses are joints where the two bones are connected by a piece of cartilage.
- Synostoses are where two bones that are initially separted eventually fuse together, essentially becoming one bone. In humans the plates of the cranium fuse together as a child approaches adulthood. Children whose craniums fuse too early may suffer deformities and brain damage as the skull does not expand properly to accommodate the growing brain, a condition known as craniostenosis. | https://www.wikidoc.org/index.php/Synarthrodial | |
1567193f30ced6886c831ca959b3b9307c170492 | wikidoc | TAR syndrome | TAR syndrome
# Overview
TAR Syndrome (Thrombocytopenia with Absent radius) is a rare genetic disorder which is characterized by the absence of the radius bone in the forearm, and a dramatically reduced platelet count.
# Historical Perspective
TAR was first identified in 1956, and was named almost thirteen years later when severe bruising (along with abnormally short forearms) was present in three families with nine newborns.
# Pathophysiology
## Genetics
A region of chromosome 1, 1q21.1, containing 11 genes, is mutated in thirty of thirty patients with TAR. This mutation was also found in 32% of unaffected family members, so there are likely other genetic components of the syndrome besides this one, hence when a child has the condition any future siblings are likely to have a 25% chance of also having it.
## Associated Conditions
Other common links between people with TAR seem to include heart problems such as secundum atrial septal defect, kidney problems, knee joint problems and frequently lactose intolerance.
# Epidemiology and Demographics
The incidence is 0.42 per 100,000 live births.
# Natural History, Complications and Prognosis
The critical period is the first year of life. For most people with TAR, platelet counts improve as they grow out of childhood.
# Diagnosis
## Symptoms
Symptoms of thrombocytopenia, or a lowered platelet count, leads to bruising and potentially life-threatening haemorrhage.
# Treatment
Treatments range from platelet transfusions through to surgery aimed at 'normalizing' the appearance of the arm, which is much shorter and 'clubbed.' There is some controversy surrounding the role of surgery. The infant mortality rate has been curbed by new technology, including platelet transfusions, which can even be performed in utero. | TAR syndrome
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
TAR Syndrome (Thrombocytopenia with Absent radius) is a rare genetic disorder which is characterized by the absence of the radius bone in the forearm, and a dramatically reduced platelet count.
# Historical Perspective
TAR was first identified in 1956, and was named almost thirteen years later when severe bruising (along with abnormally short forearms) was present in three families with nine newborns.
# Pathophysiology
## Genetics
A region of chromosome 1, 1q21.1, containing 11 genes, is mutated in thirty of thirty patients with TAR.[1] This mutation was also found in 32% of unaffected family members, so there are likely other genetic components of the syndrome besides this one, hence when a child has the condition any future siblings are likely to have a 25% chance of also having it.
## Associated Conditions
Other common links between people with TAR seem to include heart problems such as secundum atrial septal defect, kidney problems, knee joint problems and frequently lactose intolerance.
# Epidemiology and Demographics
The incidence is 0.42 per 100,000 live births.
# Natural History, Complications and Prognosis
The critical period is the first year of life. For most people with TAR, platelet counts improve as they grow out of childhood.
# Diagnosis
## Symptoms
Symptoms of thrombocytopenia, or a lowered platelet count, leads to bruising and potentially life-threatening haemorrhage.
# Treatment
Treatments range from platelet transfusions through to surgery aimed at 'normalizing' the appearance of the arm, which is much shorter and 'clubbed.' There is some controversy surrounding the role of surgery. The infant mortality rate has been curbed by new technology, including platelet transfusions, which can even be performed in utero. | https://www.wikidoc.org/index.php/TAR_syndrome | |
5af6fd5d412b85a65ccd2ee55f2a118cf6dbab53 | wikidoc | TAVR imaging | TAVR imaging
# Overview
Transthoracic Echocardiography (TTE) is the best initial imaging modality for evaluating AS severity. Although, multimodality imaging is needed for preprocedural planning and intraoperative decision making given the complex 3D anatomy of the aortic valve, sinuses, and annulus.
Multi-Detector CT (MDCT) is a core element of the standard imaging pathway for the preprocedural planning of TAVR.
In patients being evaluated for TAVR, MDCT systems with at least 64 detectors and a spatial resolution of 0.5 to 0.6 mm are recommended.
Evaluation of kidney function to avoid contrast induced nephropathy must be taken in to consideration.
# Definition
AS severity is defined based on imaging findings.
Severe symptomatic (Stage D) AS is considered as TAVR candidate.
Abbreviations:
ΔP: mean gradient, Vmax: maximum aortic velocity, AVA: aortic valve area. AS: aortic stenosis, AR: aortic regurgitation.
# TAVR imaging checklist
Abbreviations:
CV: Cardiovascular, AVR: Aortic valve replacement, AS: Aortic Stenosis, MR: Mitral Regurgitation, AR: Aortic Regurgitation, PAP: Pulmonary Artery Pressure, RV: Right Ventricle, CTA: CT angiography, PA: Pulmonary Artery, TEE: Trans Esophageal Echocardiography, TTE: Trans Thoracic Echocardiography
AVA: Aortic Valve Area; CMR: Cardiovascular Magnetic Resonance Imaging; CT: Computed Tomography; ECG: Electrocardiogram; EF: Ejection Fraction; DSE: Dobutamine Stress Echocardiography; ESRD: End-Stage Renal Disease; GFR: Glomerular Filtration Rate; LFLG: Low-Flow Low-Gradient; LV: Left Ventricular; LVEF: Left Ventricular Ejection Fraction; MAC: Mitral Annular Calcification; MDCT: Multi Detector Computed Tomography; MRA: Magnetic Resonance Angiogram;
MRI: Magnetic Resonance Imaging; MS: Mitral Stenosis; PET: Positron Emission Tomography; TAVR: Trans-catheter Aortic Valve Replacement
## Specific CT measurements for TAVR | TAVR imaging
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1],Associate Editor(s)-in-Chief: Seyedmahdi Pahlavani, M.D. [2]
# Overview
Transthoracic Echocardiography (TTE) is the best initial imaging modality for evaluating AS severity.[1] Although, multimodality imaging is needed for preprocedural planning and intraoperative decision making given the complex 3D anatomy of the aortic valve, sinuses, and annulus.[2]
Multi-Detector CT (MDCT) is a core element of the standard imaging pathway for the preprocedural planning of TAVR.[3]
In patients being evaluated for TAVR, MDCT systems with at least 64 detectors and a spatial resolution of 0.5 to 0.6 mm are recommended.
Evaluation of kidney function to avoid contrast induced nephropathy must be taken in to consideration.
# Definition
AS severity is defined based on imaging findings.
Severe symptomatic (Stage D) AS is considered as TAVR candidate.
Abbreviations:
ΔP: mean gradient, Vmax: maximum aortic velocity, AVA: aortic valve area. AS: aortic stenosis, AR: aortic regurgitation.
# TAVR imaging checklist
Abbreviations:
CV: Cardiovascular, AVR: Aortic valve replacement, AS: Aortic Stenosis, MR: Mitral Regurgitation, AR: Aortic Regurgitation, PAP: Pulmonary Artery Pressure, RV: Right Ventricle, CTA: CT angiography, PA: Pulmonary Artery, TEE: Trans Esophageal Echocardiography, TTE: Trans Thoracic Echocardiography
AVA: Aortic Valve Area; CMR: Cardiovascular Magnetic Resonance Imaging; CT: Computed Tomography; ECG: Electrocardiogram; EF: Ejection Fraction; DSE: Dobutamine Stress Echocardiography; ESRD: End-Stage Renal Disease; GFR: Glomerular Filtration Rate; LFLG: Low-Flow Low-Gradient; LV: Left Ventricular; LVEF: Left Ventricular Ejection Fraction; MAC: Mitral Annular Calcification; MDCT: Multi Detector Computed Tomography; MRA: Magnetic Resonance Angiogram;
MRI: Magnetic Resonance Imaging; MS: Mitral Stenosis; PET: Positron Emission Tomography; TAVR: Trans-catheter Aortic Valve Replacement
## Specific CT measurements for TAVR | https://www.wikidoc.org/index.php/TAVR_imaging | |
e1323ecf4585f653ff49540f71ab905da1e9180a | wikidoc | TAVR vs SAVR | TAVR vs SAVR
# Overview
Until recently, aortic valve replacement (AVR) was the only effective treatment for severe symptomatic aortic stenosis. Global aging has raised concerns about safety and possibility of surgical procedure in old patients with associated comorbidities. Transcatheter aortic valve replacement (TAVR) created a new era of safety for this population and enabled physicians to replace the stenotic valve with more certainty. In TAVR, also known as Percutaneous Aortic Valve Replacement (PAVR), a synthetic valve is advanced to the heart through a small hole made in groin. This procedure is similar in its mechanism to the insertion of a stent, or performing balloon angioplasty albeit with much larger equipment. Traditional aortic valve replacement is an invasive surgical procedure, with considerable mortality and morbidity, especially in more fragile patients. In the newly developed TAVR procedure, the dysfunctional aortic valve is replaced percutaneously, which obviates the need for open heart surgery.Patient selection, selecting the appropriate imaging modality, preprocedure evaluation, selecting the appropriate valve type and valve size, post procedure complications and long term follow-up are the main areas of focused importance.
# Comparing TAVR and SAVR
- Surgical Aortic Valve Repair (SAVR) is the traditional way of treating a stenotic aortic valve.
- In the last decade, TAVR has emerged as a viable option for patients at high surgical risk or at high risk for post-surgical complications.
## Evidence
Systematic reviews have addressed this comparison in patients deemed to be low-risk (Society of Thoracic Surgery (STS) risk score uropean System for Cardiac Operative Risk Evaluation (EuroSCORE) II less than 4%.):
- "In patients with severe aortic stenosis and coronary artery disease, TAVR + PCI was associated with greater all-cause mortality at follow-up compared with SAVR + CABG."
- "Among older low-risk patients with severe aortic stenosis, TAVR is associated with a lower rate of death or disabling stroke compared with SAVR"
The Cochrane Collaboration reviewed the following trials of low-risk patients in 2019:
- Popma (Evolut) 1468 patients
- Thyregod (NOTION) 280 patients
- Mack (PARTNER 3). 1000 patients
After the Cochrane review, a systematic review by Kheiri in 2020 of low risk patients included the same three trials and added:
- Nielsen (STACCATO), 2012 The Cochrane had handled this trial separately due to the trial having "utilised the less contemporary transapical TAVI and was prematurely terminated due to an excess of adverse events in the TAVI group." The Cochrane had excluded this trial because "all study participants were deemed intermediate risk according to the study investigators."
- Serruys (SURTAVI) 2018
Other randomized controlled trials with increased surgical risk:
- Leon (PARTNER 2)
- Adams (US PIVOTAL - CoveValve)
Non-randomized studies:
- Thourani (SAPIEN 3)
## 2014 AHA/ACC Guidelines for the Management of Patients With Valvular Heart Disease Recommend the Following:
- In the recent years, terminology has arose to define patients who qualify for TAVR as "inoperable patients" who are at > 50% risk of mortality at 30 days after a potential SAVR procedure.
- There is much debate regarding the subjective nature of defining a patient as "inoperable"; however, the heart valve team should collaborate to determine the optimal procedure for the patient.
- TAVR has demonstrated up to a 20% risk reduction in all-cause-mortality at 12 months which is sustained for up to 5 years post-procedure, when compared to SAVR.
- In high risk patients such as the elderly and those with a NYHA III or IV functional status, TAVR has shown non-inferiority to the traditional SAVR procedure and regardless of the procedure undertaken, patients maintained a NYHA I or II functionality for up to 5 years post-procedure.
- It is noteworthy to say that TAVR is associated with a significant and sustained reduction in risk of ischemic stroke for 30 days and up to 2 years after the procedure compared to surgery.
- Nevertheless, SAVR continues to play a role in patients who require an aortic valve replacement with lower surgical risk.
## 2017 ESC/EACTS Guidelines for the Management of Patients With Valvular Heart Disease Recommend the Following:
# Future Perspectives
- TAVR has transformed the treatment and the way of dealing with symptomatic patients suffering from aortic stenosis, particularly in those who are at high risk or inoperable for surgical aortic valve replacement (SAVR).
- When it successfully performed, TAVR returns the patient to a good prognosis and favorable life style.
- It is estimated that 25,000 TAVR procedures were done in the U.S in 2015 and an increase in this number is anticipated because of increase in the number of the elderly population.
- In the United States, the elderly population will reach 50 million by 2019 and this old population is highly vulnerable to degenerative valve disease.
- The future of TAVR will be focusing on more technical aspects; trying to reduce the device profile, enhancing it's positioning, retrievability and promoting valve durability with anticalcification treatments.
- In the last decade, clinicians remained focused on demonstrating efficacy and safety of the procedure. In latter years, the minimalist approach to the deployment of the valves has become the mainstay of advancements in the TAVR procedure.
- Examples include the avoidance of general anesthesia and the utilization of conscious sedation whenever possible, the reduction of reliance or use of transesophageal echocardiography (TEE), the reduction or elimination of balloon pre-dilatation of the stenosed valve, as well as early discharge programs.
- With ongoing clinical trials and further advancements in valve technology, TAVR will establish an expanded indication in patients with moderate to severe aortic stenosis. | TAVR vs SAVR
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1],Associate Editor(s)-in-Chief: Seyedmahdi Pahlavani, M.D. [2],Tarek Nafee, M.D. [3],Sabawoon Mirwais, M.B.B.S, M.D.[4]
# Overview
Until recently, aortic valve replacement (AVR) was the only effective treatment for severe symptomatic aortic stenosis. Global aging has raised concerns about safety and possibility of surgical procedure in old patients with associated comorbidities.[1] Transcatheter aortic valve replacement (TAVR) created a new era of safety for this population and enabled physicians to replace the stenotic valve with more certainty. In TAVR, also known as Percutaneous Aortic Valve Replacement (PAVR), a synthetic valve is advanced to the heart through a small hole made in groin. This procedure is similar in its mechanism to the insertion of a stent, or performing balloon angioplasty albeit with much larger equipment. Traditional aortic valve replacement is an invasive surgical procedure, with considerable mortality and morbidity, especially in more fragile patients. In the newly developed TAVR procedure, the dysfunctional aortic valve is replaced percutaneously, which obviates the need for open heart surgery.[2]Patient selection, selecting the appropriate imaging modality, preprocedure evaluation, selecting the appropriate valve type and valve size, post procedure complications and long term follow-up are the main areas of focused importance.
# Comparing TAVR and SAVR
- Surgical Aortic Valve Repair (SAVR) is the traditional way of treating a stenotic aortic valve.
- In the last decade, TAVR has emerged as a viable option for patients at high surgical risk or at high risk for post-surgical complications.
## Evidence
Systematic reviews have addressed this comparison in patients deemed to be low-risk (Society of Thoracic Surgery (STS) risk score uropean System for Cardiac Operative Risk Evaluation (EuroSCORE) II less than 4%.)[3][4]:
- "In patients with severe aortic stenosis and coronary artery disease, TAVR + PCI was associated with greater all-cause mortality at follow-up compared with SAVR + CABG."[3]
- "Among older low-risk patients with severe aortic stenosis, TAVR is associated with a lower rate of death or disabling stroke compared with SAVR"[4]
The Cochrane Collaboration reviewed the following trials of low-risk patients in 2019[5]:
- Popma (Evolut) [6] 1468 patients
- Thyregod (NOTION)[7] 280 patients
- Mack (PARTNER 3)[8]. 1000 patients
After the Cochrane review, a systematic review by Kheiri in 2020 of low risk patients[4] included the same three trials and added:
- Nielsen (STACCATO), 2012[9] The Cochrane had handled this trial separately due to the trial having "utilised the less contemporary transapical TAVI and was prematurely terminated due to an excess of adverse events in the TAVI group." The Cochrane had excluded this trial because "all study participants were deemed intermediate risk according to the study investigators."
- Serruys (SURTAVI) 2018[10]
Other randomized controlled trials with increased surgical risk:
- Leon (PARTNER 2)[11]
- Adams (US PIVOTAL - CoveValve)[12]
Non-randomized studies:
- Thourani (SAPIEN 3)
## 2014 AHA/ACC Guidelines for the Management of Patients With Valvular Heart Disease Recommend the Following:[2]
- In the recent years, terminology has arose to define patients who qualify for TAVR as "inoperable patients" who are at > 50% risk of mortality at 30 days after a potential SAVR procedure.
- There is much debate regarding the subjective nature of defining a patient as "inoperable"; however, the heart valve team should collaborate to determine the optimal procedure for the patient.
- TAVR has demonstrated up to a 20% risk reduction in all-cause-mortality at 12 months which is sustained for up to 5 years post-procedure, when compared to SAVR.
- In high risk patients such as the elderly and those with a NYHA III or IV functional status, TAVR has shown non-inferiority to the traditional SAVR procedure and regardless of the procedure undertaken, patients maintained a NYHA I or II functionality for up to 5 years post-procedure.
- It is noteworthy to say that TAVR is associated with a significant and sustained reduction in risk of ischemic stroke for 30 days and up to 2 years after the procedure compared to surgery.
- Nevertheless, SAVR continues to play a role in patients who require an aortic valve replacement with lower surgical risk.
## 2017 ESC/EACTS Guidelines for the Management of Patients With Valvular Heart Disease Recommend the Following:
# Future Perspectives
- TAVR has transformed the treatment and the way of dealing with symptomatic patients suffering from aortic stenosis, particularly in those who are at high risk or inoperable for surgical aortic valve replacement (SAVR).[13]
- When it successfully performed, TAVR returns the patient to a good prognosis and favorable life style.
- It is estimated that 25,000 TAVR procedures were done in the U.S in 2015 and an increase in this number is anticipated because of increase in the number of the elderly population.
- In the United States, the elderly population will reach 50 million by 2019 [14]and this old population is highly vulnerable to degenerative valve disease.
- The future of TAVR will be focusing on more technical aspects; trying to reduce the device profile, enhancing it's positioning, retrievability and promoting valve durability with anticalcification treatments.
- In the last decade, clinicians remained focused on demonstrating efficacy and safety of the procedure. In latter years, the minimalist approach to the deployment of the valves has become the mainstay of advancements in the TAVR procedure.
- Examples include the avoidance of general anesthesia and the utilization of conscious sedation whenever possible, the reduction of reliance or use of transesophageal echocardiography (TEE), the reduction or elimination of balloon pre-dilatation of the stenosed valve, as well as early discharge programs.
- With ongoing clinical trials and further advancements in valve technology, TAVR will establish an expanded indication in patients with moderate to severe aortic stenosis. | https://www.wikidoc.org/index.php/TAVR_vs_SAVR | |
9fd19492142bd006be4296a1ddc93219611a7370 | wikidoc | TCF21 (gene) | TCF21 (gene)
Transcription factor 21 (TCF21), also known as pod-1, capsulin, or epicardin, is a protein that in humans is encoded by the TCF21 gene on chromosome 6. It is ubiquitously expressed in many tissues and cell types and highly significantly expressed in lung and placenta. TCF21 is crucial for the development of a number of cell types during embryogenesis of the heart, lung, kidney, and spleen. TCF21 is also deregulated in several types of cancers, and thus known to function as a tumor suppressor. The TCF21 gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.
# Discovery
TCF21 was discovered in 1998 when search for novel cell-type-specific bHLH proteins expressed in human and mouse kidneys by performing a search of the expressed sequence tag (EST) databases. Because the transcript they found was highly expressed in visceral glomerular epithelial cells (podocytes), TCF21 was initialled named Pod-1. Comparison of Pod-1 with previously characterized bHLH proteins identified Pod-1 as a novel member of a subfamily of bHLH proteins with important roles in mesodermal development. The chromosomal location of Pod-1 in the mouse was then determined using an interspecific backcross panel along with genomic southern blot analysis to identify restriction fragment length polymorphisms (RFLPs) between inbred mouse strains. Analysis showed Pod-1 to map to a region of mouse chromosome 10 that is syntenic with human chromosome 6q23-q24.
The tissue distribution of Pod-1 was determined by hybridization of a human multiple tissue northern blot with a Pod-1 cDNA. A probe lacking the bHLH domain was used to minimize cross-reactivity along with high stringency hybridization and washing. Results showed that in humans and mice, Pod-1 was most highly expressed in the kidney, lung and heart, with selective expression at sites of epithelial-mesenchymal interaction in the kidney, lung, intestine and pancreas of developing mouse embryos. RNA in situ hybridization using 33P-labeled riboprobes was used to identify the cell types that expressed Pod-1 in the developing kidney and other tissues. This revealed Pod-1 expression in mesenchymal cells and podocytes, with expression coinciding with the onset of podocyte differentiation. It was found that expression of Pod-1 in embryonic kidney explants was inhibited through antisense oligonucleotides. This inhibition resulted in decreased mesenchymal cell condensation around the ureteric bud and a significant decrease in ureteric branching. Pod-1 was the first tissue-restricted bHLH protein to be identified in the developing kidney and tied to regulation of morphogenetic events.
In an effort to identify novel bHLH factors related to dHAND and eHAND (a novel subclass of cell type-restricted bHLH factors shown to play important roles in cardiac morphogenesis), they screened expressed sequence tag (EST) databases for sequences with homology to the bHLH regions of these factors. The novel bHLH protein they identified in their search was also Pod-1, but they used the name capsulin.
Whole-mount in situ hybridization of Capsulin transcripts were used to define sites of expression, which showed to be specific to mesodermal precursor cells that surround the epithelium of the developing gastrointestinal, genitourinary and respiratory systems during mouse embryogenesis. Expression patterns of capsulin mRNA in adult mouse tissues by Northern blot detected highest levels in the lungs, with lower levels in kidneys, heart and spleen. Capsulin transcripts were also found to mark the spiral septum of the heart and progenitor cells that give rise to the pericardium and coronary arteries.
Capsulin was translated in a rabbit reticulocyte lysate in the presence and absence of the widely expressed bHLH protein E12 and performed gel mobility shift assays with several E-box sequences as probes to test the protein's DNA binding activity. Capsulin alone failed to bind any of the sequences tested. However, in the presence of E12 plus capsulin, a DNA complex was generated with the probe that migrated faster than the E12 homodimeric complex alone, representing the binding of capsulin/E12 heterodimers. It was concluded that capsulin heterodimerizes with E12 and binds the specific E-box consensus sequence (CANNTG), though not activating transcription through this sequence on its own. Its restricted expression pattern and DNA binding activity identified Capsulin as a regulator of gene expression in specific subtypes of visceral mesodermal cells involved in organogenesis and in precursor cells that contribute to the pericardium, coronary arteries and regions of the heart.
# Structure
## Gene
The TCF21 gene resides on chromosome 6 at the band 6q23.2 and includes 3 exons. These three exons are associated with CpG islands CGI1, CGI2, and CGI3. DNA methylation analysis revealed hypermethylation at CGI1 and CGI3, but not CGI2 in samples from various cancer tissues. Luciferase reporter assays with constructs covering CGI3 sequences in sense and antisense orientation demonstrated that CGI3 harbors a promoter that directs the synthesis of a previously unknown long non-coding RNAs (lncRNAs) in antisense orientation to TCF21. This lncRNA has been named TARID (for TCF21 antisense RNA inducing demethylation).
## Protein
TCF21 is a member of the bHLH (basic helix-loop-helix) family of transcription factors. This protein is predicted to span 179 amino acid residues and contains a bHLH domain and an arginine-rich sequence that may facilitate DNA binding.
# Function
TCF21 encodes a transcription factor of the basic helix-loop-helix (bHLH) family, which manages cell-fate specification, commitment and differentiation in various cell lineages during development. The TCF21 product is mesoderm-specific and expressed in embryonic epicardium, mesenchyme-derived tissues of lung, gut, gonad, and both mesenchymal and glomerular epithelial cells in the kidney.
TCF21 is essential for regulating properties of the mesenchyme that are critically important for several aspects of lung and kidney morphogenesis. TCF21 is also essential for cardiac fibroblast cell fate, as demonstrated by the failed development of cardiac fibroblasts in mice lacking TCF21. In the absence of TCF21, these fibroblast progenitor cells do not undergo epithelial-to-mesenchymal transition (EMT). While TCF21-expressing epicardial cells are initially multipotent, they become committed to the fibroblast lineage over time. Those TCF21-expressing cells that do not commit to the fibroblast lineage lose this expression and remain undifferentiated epicardial cells or coronary vascular smooth muscle cells. TCF21 is expressed in mesodermal cells in the proepicardial organ that give rise to coronary artery smooth muscle cells (SMC) and loss of TCF21 results in increased expression of smooth muscle markers by cells on the heart surface consistent with premature SMC differentiation. This suggests that early expression of TCF21 is important for expansion of the SMC compartment of the coronary circulation, with persistent TCF21 expression being required for cardiac fibroblast development.
TCF21 activation is directed by an antisense long non-coding RNA, TARID (TCF21 antisense RNA inducing demethylation). TARID activates TCF21 expression by inducing promoter demethylation and affects expression levels of target genes by functioning as epigenetic regulators of chromatin structure through interactions with histone modifiers, chromatin remodeling complexes, transcriptional regulators, and/or DNA methylation machinery.
## Role in development
Since the identification of Tcf21 significance in various cell lineages, further research has expanded understanding of the essential roles of this gene.
TCF21 is essential for regulating properties of the mesenchyme that are critically important for several aspects of lung and kidney morphogenesis. Null TCF21 mutant mice are born but die shortly after due to severely hypoplastic lungs and kidneys that lack alveoli and mature glomeruli. While TCF21 is exclusively expressed in the mesenchyme and podocytes, major defects are observed in adjacent epithelia of TCF21 mutant mice. In the kidney, TCF21 is required for conversion of condensing mesenchyme to epithelium of the nephron, branching morphogenesis and terminal differentiation of tubular epithelium. In the lung, TCF21 is required to correctly pattern the proximodistal axis of airway epithelium and for normal branching to occur.
TCF21 null mice also fail to form a spleen, as TCF21 acts after splenic specification to control morphogenetic expansion of the splenic anlage and in its absence, splenic precursor cells undergo apoptosis. Since this splenic phenotype resembles that of mice lacking the homeobox genes Hox11 and Bapx1, it is possible that TCF21, together with Hox11, and Bapx1 control a common essential early step in the developmental pathway for spleen organogenesis.
TCF21 is essential for cardiac fibroblast cell fate, as demonstrated by the failed development of cardiac fibroblasts in mice lacking TCF21. In the absence of TCF21, these fibroblast progenitor cells do not undergo epithelial-to-mesenchymal transition (EMT). While TCF21-expressing epicardial cells are initially multipotent, they become committed to the fibroblast lineage over time. Those TCF21-expressing cells that do not commit to the fibroblast lineage lose this expression and remain undifferentiated epicardial cells or coronary vascular smooth muscle cells. TCF21 is expressed in mesodermal cells in the proepicardial organ that give rise to coronary artery smooth muscle cells (SMC) and loss of TCF21 results in increased expression of smooth muscle markers by cells on the heart surface consistent with premature SMC differentiation. This suggests that early expression of TCF21 is important for expansion of the SMC compartment of the coronary circulation, with persistent TCF21 expression being required for cardiac fibroblast development.
Male TCF21 knockout mice, which die at birth due to respiratory failure, are reported to have feminized genitalia, implicating TCF21 in mouse gonadal development/differentiation. TCF21 transcriptionally represses steroidogenic factor 1 (Sf1), a gene expression regulator that mediates sexual differentiation and is involved in coordinating cell fate decisions in gonadal progenitors. Without TCF21, normal gonad development is disrupted as a result of ectopic expression of Sf1, which leads to abnormal committing of urogenital progenitor cells to steroidogenic cell fates. In the XY gonad, this disruption in organization contributes to changes in testicular structure and vasculature.
# Clinical significance
## As a cancer suppressor
In humans, TCF21 has been identified as a candidate tumor suppressor gene and is frequently epigenetically silenced in various human cancers.
Restriction landmark genomic scanning (RLGS) along a region of recurrent loss of heterozygosity (LOH) at chromosome 6q23-q24 to profile DNA methylation was used to test the hypothesis that abnormal promoter methylation could help pinpoint the location of a candidate tumor suppressor in regions of LOH. 6q23-q24 was the chosen chromosomal region due to frequently described LOH in human head and neck squamous cell carcinomas (HNSCC) and non-small-cell lung cancers (NSCLC) as well as in other tumor types, but with no identified tumor suppressor. Hypermethylation was found to occur frequently in the same RLGS loci in HNSCC and NSCLC. Sodium bisulfite sequencing further identified tumor-specific methylation of TCF21 when compared to normal controls. RNA samples were isolated from tumor tissues and analyzed to correlate the amount of TCF21 mRNA and DNA methylation in the samples. Overall, tumor samples with higher levels of CpG island hypermethylation had decreased TCF21 expression than normal controls. Exogenous expression of TCF21 in cells with silenced endogenous TCF21 loci resulted in a reductions in tumor properties both in vitro and in vivo. Based on these results, it was concluded that TCF21 is a tumor suppressor gene, often silenced by hypermethylation in cancer.
TCF21 has also been linked to metastatic melanoma progression through the inhibition of the KISS1 metastasis-suppressor gene. DNA methylation analysis in melanoma patient biopsies has demonstrated downregulation of TCF21 due to promoter hypermethylation, which also correlates with decreased survival in patients suffering from metastatic skin melanoma. TCF21, together with E12 and TCF12, bind the KISS1 promoter, sustaining its activity. Without TCF21 to interact with the KISS1 promoter, KISS1 expression is lost. Melanoma cells overexpressing TCF21 have also been found to display reduced motility compared with vector-only control cells.
Tobacco-induced lung cancer research has found TCF21 to be among the genes identified as highly methylated at both high and low concentrations of cigarette smoke condensate (CSC). In the presence genistein, one of the soy-derived bioactive isoflavones, methylation of TCF21 is significantly reduced. Genistein has been known to affect tumorigenesis through epigenetic regulation, such as chromatin configuration and DNA methylation, activating other tumor suppressor genes that affect cancer cell survival. These findings support the hypothesis that increasing hypermethylated tumor suppressor genes such as TCF21 is a potential chemopreventative pathway in tobacco-induced lung cancer.
TCF21 may have also therapeutic potential for breast cancer treatment, as downregulation of TCF21 has been implicated in breast cancer tumorigenesis and proliferation. TCF21 mRNA expression is very low in breast cancer cells compared with normal breast epithelial cells. This low expression is also associated with large tumor size and lymph node metastasis. Breast cancer tissues exhibit significantly downregulated expression of TCF21 mRNA and TCF21 mRNA overexpression has been found to inhibit cancerous cell proliferation.
## Clinical marker
TCF21 methylation has been considered as a potential clinical marker in the diagnosis of renal cell carcinoma. Accordingly, TCF21 methylation levels in urine samples may be a useful means of diagnosing renal cell carcinoma. Also TCF21 rs12190287 polymorphism can regulate TCF21 expression and may serve as a potential marker for genetic susceptibility to breast cancer.
Additionally, a multi-locus genetic risk score study based on a combination of 27 loci, including the TCF21 gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy. The study was based on a community cohort study (the Malmo Diet and Cancer study) and four additional randomized controlled trials of primary prevention cohorts (JUPITER and ASCOT) and secondary prevention cohorts (CARE and PROVE IT-TIMI 22). | TCF21 (gene)
Transcription factor 21 (TCF21), also known as pod-1, capsulin, or epicardin, is a protein that in humans is encoded by the TCF21 gene on chromosome 6.[1][2] It is ubiquitously expressed in many tissues and cell types and highly significantly expressed in lung and placenta.[3] TCF21 is crucial for the development of a number of cell types during embryogenesis of the heart,[4] lung,[5] kidney,[5] and spleen.[6] TCF21 is also deregulated in several types of cancers, and thus known to function as a tumor suppressor.[7] The TCF21 gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.[8]
# Discovery
TCF21 was discovered in 1998 when search for novel cell-type-specific bHLH proteins expressed in human and mouse kidneys by performing a search of the expressed sequence tag (EST) databases.[1] Because the transcript they found was highly expressed in visceral glomerular epithelial cells (podocytes), TCF21 was initialled named Pod-1. Comparison of Pod-1 with previously characterized bHLH proteins identified Pod-1 as a novel member of a subfamily of bHLH proteins with important roles in mesodermal development.[1] The chromosomal location of Pod-1 in the mouse was then determined using an interspecific backcross panel along with genomic southern blot analysis to identify restriction fragment length polymorphisms (RFLPs) between inbred mouse strains. Analysis showed Pod-1 to map to a region of mouse chromosome 10 that is syntenic with human chromosome 6q23-q24.[1]
The tissue distribution of Pod-1 was determined by hybridization of a human multiple tissue northern blot with a Pod-1 cDNA. A probe lacking the bHLH domain was used to minimize cross-reactivity along with high stringency hybridization and washing. Results showed that in humans and mice, Pod-1 was most highly expressed in the kidney, lung and heart, with selective expression at sites of epithelial-mesenchymal interaction in the kidney, lung, intestine and pancreas of developing mouse embryos.[1] RNA in situ hybridization using 33P-labeled riboprobes was used to identify the cell types that expressed Pod-1 in the developing kidney and other tissues. This revealed Pod-1 expression in mesenchymal cells and podocytes, with expression coinciding with the onset of podocyte differentiation.[1] It was found that expression of Pod-1 in embryonic kidney explants was inhibited through antisense oligonucleotides. This inhibition resulted in decreased mesenchymal cell condensation around the ureteric bud and a significant decrease in ureteric branching. Pod-1 was the first tissue-restricted bHLH protein to be identified in the developing kidney and tied to regulation of morphogenetic events.[1]
In an effort to identify novel bHLH factors related to dHAND and eHAND (a novel subclass of cell type-restricted bHLH factors shown to play important roles in cardiac morphogenesis), they screened expressed sequence tag (EST) databases for sequences with homology to the bHLH regions of these factors.[9] The novel bHLH protein they identified in their search was also Pod-1, but they used the name capsulin.
Whole-mount in situ hybridization of Capsulin transcripts were used to define sites of expression, which showed to be specific to mesodermal precursor cells that surround the epithelium of the developing gastrointestinal, genitourinary and respiratory systems during mouse embryogenesis.[10] Expression patterns of capsulin mRNA in adult mouse tissues by Northern blot detected highest levels in the lungs, with lower levels in kidneys, heart and spleen. Capsulin transcripts were also found to mark the spiral septum of the heart and progenitor cells that give rise to the pericardium and coronary arteries.[10]
Capsulin was translated in a rabbit reticulocyte lysate in the presence and absence of the widely expressed bHLH protein E12 and performed gel mobility shift assays with several E-box sequences as probes to test the protein's DNA binding activity.[10] Capsulin alone failed to bind any of the sequences tested. However, in the presence of E12 plus capsulin, a DNA complex was generated with the probe that migrated faster than the E12 homodimeric complex alone, representing the binding of capsulin/E12 heterodimers.[10] It was concluded that capsulin heterodimerizes with E12 and binds the specific E-box consensus sequence (CANNTG), though not activating transcription through this sequence on its own. Its restricted expression pattern and DNA binding activity identified Capsulin as a regulator of gene expression in specific subtypes of visceral mesodermal cells involved in organogenesis and in precursor cells that contribute to the pericardium, coronary arteries and regions of the heart.[10]
# Structure
## Gene
The TCF21 gene resides on chromosome 6 at the band 6q23.2 and includes 3 exons.[2] These three exons are associated with CpG islands CGI1, CGI2, and CGI3. DNA methylation analysis revealed hypermethylation at CGI1 and CGI3, but not CGI2 in samples from various cancer tissues.[11] Luciferase reporter assays with constructs covering CGI3 sequences in sense and antisense orientation demonstrated that CGI3 harbors a promoter that directs the synthesis of a previously unknown long non-coding RNAs (lncRNAs) in antisense orientation to TCF21. This lncRNA has been named TARID (for TCF21 antisense RNA inducing demethylation).[12]
## Protein
TCF21 is a member of the bHLH (basic helix-loop-helix) family of transcription factors.[13] This protein is predicted to span 179 amino acid residues and contains a bHLH domain and an arginine-rich sequence that may facilitate DNA binding.[14]
# Function
TCF21 encodes a transcription factor of the basic helix-loop-helix (bHLH) family, which manages cell-fate specification, commitment and differentiation in various cell lineages during development.[4] The TCF21 product is mesoderm-specific and expressed in embryonic epicardium, mesenchyme-derived tissues of lung, gut, gonad, and both mesenchymal and glomerular epithelial cells in the kidney.[2]
TCF21 is essential for regulating properties of the mesenchyme that are critically important for several aspects of lung and kidney morphogenesis.[5] TCF21 is also essential for cardiac fibroblast cell fate, as demonstrated by the failed development of cardiac fibroblasts in mice lacking TCF21.[4] In the absence of TCF21, these fibroblast progenitor cells do not undergo epithelial-to-mesenchymal transition (EMT). While TCF21-expressing epicardial cells are initially multipotent, they become committed to the fibroblast lineage over time. Those TCF21-expressing cells that do not commit to the fibroblast lineage lose this expression and remain undifferentiated epicardial cells or coronary vascular smooth muscle cells.[4] TCF21 is expressed in mesodermal cells in the proepicardial organ that give rise to coronary artery smooth muscle cells (SMC) and loss of TCF21 results in increased expression of smooth muscle markers by cells on the heart surface consistent with premature SMC differentiation. This suggests that early expression of TCF21 is important for expansion of the SMC compartment of the coronary circulation, with persistent TCF21 expression being required for cardiac fibroblast development.[15]
TCF21 activation is directed by an antisense long non-coding RNA, TARID (TCF21 antisense RNA inducing demethylation). TARID activates TCF21 expression by inducing promoter demethylation and affects expression levels of target genes by functioning as epigenetic regulators of chromatin structure through interactions with histone modifiers, chromatin remodeling complexes, transcriptional regulators, and/or DNA methylation machinery.[12]
## Role in development
Since the identification of Tcf21 significance in various cell lineages, further research has expanded understanding of the essential roles of this gene.
TCF21 is essential for regulating properties of the mesenchyme that are critically important for several aspects of lung and kidney morphogenesis. Null TCF21 mutant mice are born but die shortly after due to severely hypoplastic lungs and kidneys that lack alveoli and mature glomeruli.[5] While TCF21 is exclusively expressed in the mesenchyme and podocytes, major defects are observed in adjacent epithelia of TCF21 mutant mice. In the kidney, TCF21 is required for conversion of condensing mesenchyme to epithelium of the nephron, branching morphogenesis and terminal differentiation of tubular epithelium. In the lung, TCF21 is required to correctly pattern the proximodistal axis of airway epithelium and for normal branching to occur.[5]
TCF21 null mice also fail to form a spleen, as TCF21 acts after splenic specification to control morphogenetic expansion of the splenic anlage and in its absence, splenic precursor cells undergo apoptosis.[6] Since this splenic phenotype resembles that of mice lacking the homeobox genes Hox11 and Bapx1, it is possible that TCF21, together with Hox11, and Bapx1 control a common essential early step in the developmental pathway for spleen organogenesis.[6]
TCF21 is essential for cardiac fibroblast cell fate, as demonstrated by the failed development of cardiac fibroblasts in mice lacking TCF21.[4] In the absence of TCF21, these fibroblast progenitor cells do not undergo epithelial-to-mesenchymal transition (EMT). While TCF21-expressing epicardial cells are initially multipotent, they become committed to the fibroblast lineage over time. Those TCF21-expressing cells that do not commit to the fibroblast lineage lose this expression and remain undifferentiated epicardial cells or coronary vascular smooth muscle cells.[4] TCF21 is expressed in mesodermal cells in the proepicardial organ that give rise to coronary artery smooth muscle cells (SMC) and loss of TCF21 results in increased expression of smooth muscle markers by cells on the heart surface consistent with premature SMC differentiation. This suggests that early expression of TCF21 is important for expansion of the SMC compartment of the coronary circulation, with persistent TCF21 expression being required for cardiac fibroblast development.[15]
Male TCF21 knockout mice, which die at birth due to respiratory failure, are reported to have feminized genitalia, implicating TCF21 in mouse gonadal development/differentiation.[16] TCF21 transcriptionally represses steroidogenic factor 1 (Sf1), a gene expression regulator that mediates sexual differentiation and is involved in coordinating cell fate decisions in gonadal progenitors.[16] Without TCF21, normal gonad development is disrupted as a result of ectopic expression of Sf1, which leads to abnormal committing of urogenital progenitor cells to steroidogenic cell fates. In the XY gonad, this disruption in organization contributes to changes in testicular structure and vasculature.[16]
# Clinical significance
## As a cancer suppressor
In humans, TCF21 has been identified as a candidate tumor suppressor gene and is frequently epigenetically silenced in various human cancers.
Restriction landmark genomic scanning (RLGS) along a region of recurrent loss of heterozygosity (LOH) at chromosome 6q23-q24 to profile DNA methylation was used to test the hypothesis that abnormal promoter methylation could help pinpoint the location of a candidate tumor suppressor in regions of LOH. 6q23-q24 was the chosen chromosomal region due to frequently described LOH in human head and neck squamous cell carcinomas (HNSCC) and non-small-cell lung cancers (NSCLC) as well as in other tumor types, but with no identified tumor suppressor.[7] Hypermethylation was found to occur frequently in the same RLGS loci in HNSCC and NSCLC. Sodium bisulfite sequencing further identified tumor-specific methylation of TCF21 when compared to normal controls. RNA samples were isolated from tumor tissues and analyzed to correlate the amount of TCF21 mRNA and DNA methylation in the samples. Overall, tumor samples with higher levels of CpG island hypermethylation had decreased TCF21 expression than normal controls.[7] Exogenous expression of TCF21 in cells with silenced endogenous TCF21 loci resulted in a reductions in tumor properties both in vitro and in vivo. Based on these results, it was concluded that TCF21 is a tumor suppressor gene, often silenced by hypermethylation in cancer.[7]
TCF21 has also been linked to metastatic melanoma progression through the inhibition of the KISS1 metastasis-suppressor gene.[17] DNA methylation analysis in melanoma patient biopsies has demonstrated downregulation of TCF21 due to promoter hypermethylation, which also correlates with decreased survival in patients suffering from metastatic skin melanoma.[17] TCF21, together with E12 and TCF12, bind the KISS1 promoter, sustaining its activity. Without TCF21 to interact with the KISS1 promoter, KISS1 expression is lost. Melanoma cells overexpressing TCF21 have also been found to display reduced motility compared with vector-only control cells.[17]
Tobacco-induced lung cancer research has found TCF21 to be among the genes identified as highly methylated at both high and low concentrations of cigarette smoke condensate (CSC). In the presence genistein, one of the soy-derived bioactive isoflavones, methylation of TCF21 is significantly reduced.[18] Genistein has been known to affect tumorigenesis through epigenetic regulation, such as chromatin configuration and DNA methylation, activating other tumor suppressor genes that affect cancer cell survival.[19] These findings support the hypothesis that increasing hypermethylated tumor suppressor genes such as TCF21 is a potential chemopreventative pathway in tobacco-induced lung cancer.[18]
TCF21 may have also therapeutic potential for breast cancer treatment, as downregulation of TCF21 has been implicated in breast cancer tumorigenesis and proliferation.[10] TCF21 mRNA expression is very low in breast cancer cells compared with normal breast epithelial cells. This low expression is also associated with large tumor size and lymph node metastasis. Breast cancer tissues exhibit significantly downregulated expression of TCF21 mRNA and TCF21 mRNA overexpression has been found to inhibit cancerous cell proliferation.[10]
## Clinical marker
TCF21 methylation has been considered as a potential clinical marker in the diagnosis of renal cell carcinoma.[20] Accordingly, TCF21 methylation levels in urine samples may be a useful means of diagnosing renal cell carcinoma. Also TCF21 rs12190287 polymorphism can regulate TCF21 expression and may serve as a potential marker for genetic susceptibility to breast cancer.[21]
Additionally, a multi-locus genetic risk score study based on a combination of 27 loci, including the TCF21 gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy. The study was based on a community cohort study (the Malmo Diet and Cancer study) and four additional randomized controlled trials of primary prevention cohorts (JUPITER and ASCOT) and secondary prevention cohorts (CARE and PROVE IT-TIMI 22).[22] | https://www.wikidoc.org/index.php/TCF21_(gene) | |
884ced0f1364f9bb147d72878958d0442c633d88 | wikidoc | Tenecteplase | Tenecteplase
# 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
Tenecteplase is a tissue plasminogen activator that is FDA approved for the {{{indicationType}}} of acute myocardial infarction. Common adverse reactions include hematoma, gastrointestinal bleeding, bleeding.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Acute Myocardial Infarction
- The recommended total dose should not exceed 50 mg and is based upon patient weight.
- A single bolus dose should be administered over 5 seconds based on patient weight.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Tenecteplase in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tenecteplase in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Tenecteplase 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 Tenecteplase in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tenecteplase in pediatric patients.
# Contraindications
Tenecteplase therapy in patients with acute myocardial infarction is contraindicated in the following situations because of an increased risk of bleeding:
- Active internal bleeding
- History of cerebrovascular accident
- Intracranial or intraspinal surgery or trauma within 2 months
- Intracranial neoplasm, arteriovenous malformation, or aneurysm
- Known bleeding diathesis
- Severe uncontrolled hypertension
# Warnings
### Bleeding
The most common complication encountered during Tenecteplase therapy is bleeding. The type of bleeding associated with thrombolytic therapy can be divided into two broad categories:
- Internal bleeding, involving intracranial and retroperitoneal sites, or the gastrointestinal, genitourinary, or respiratory tracts.
- Superficial or surface bleeding, observed mainly at vascular puncture and access sites (e.g., venous cutdowns, arterial punctures) or sites of recent surgical intervention.
Should serious bleeding (not controlled by local pressure) occur, any concomitant heparin or antiplatelet agents should be discontinued immediately.
In clinical studies of Tenecteplase, patients were treated with both aspirin and heparin. heparin may contribute to the bleeding risks associated with Tenecteplase. The safety of the use of Tenecteplase with other antiplatelet agents has not been adequately studied. Intramuscular injections and nonessential handling of the patient should be avoided for the first few hours following treatment with Tenecteplase. Venipunctures should be performed and monitored carefully.
Should an arterial puncture be necessary during the first few hours following Tenecteplase therapy, it is preferable to use an upper extremity vessel that is accessible to manual compression. Pressure should be applied for at least 30 minutes, a pressure dressing applied, and the puncture site checked frequently for evidence of bleeding.
Each patient being considered for therapy with Tenecteplase should be carefully evaluated and anticipated benefits weighed against potential risks associated with therapy. In the following conditions, the risk of Tenecteplase therapy may be increased and should be weighed against the anticipated benefits:
- Recent major surgery, e.g., coronary artery bypass graft, obstetrical delivery, organ biopsy, previous puncture of noncompressible vessels
- Cerebrovascular disease
- Recent gastrointestinal or genitourinary bleeding
- Recent trauma
- hypertension: systolic BP ≥180 mm Hg and/or diastolic BP ≥110 mm Hg
- High likelihood of left heart thrombus, e.g., mitral stenosis with atrial fibrillation
- Acute pericarditis
- Subacute bacterial endocarditis
- Hemostatic defects, including those secondary to severe hepatic or renal disease
- Severe hepatic dysfunction
- Pregnancy
- Diabetic hemorrhagic retinopathy or other hemorrhagic ophthalmic conditions
- Septic thrombophlebitis or occluded AV cannula at seriously infected site
- Advanced age
- Patients currently receiving oral anticoagulants, e.g., warfarin sodium
- Recent administration of GP IIb/IIIa inhibitors
- Any other condition in which bleeding constitutes a significant hazard or would be particularly difficult to manage because of its location
### Cholesterol Embolization
Cholesterol embolism has been reported rarely in patients treated with all types of thrombolytic agents; the true incidence is unknown. This serious condition, which can be lethal, is also associated with invasive vascular procedures (e.g., cardiac catheterization, angiography, vascular surgery) and/or anticoagulant therapy. Clinical features of cholesterol embolism may include livedo reticularis, "purple toe" syndrome, acute renal failure, gangrenous digits, hypertension, pancreatitis, myocardial infarction, cerebral infarction, spinal cord infarction, retinal artery occlusion, bowel infarction, and rhabdomyolysis.
### Arrhythmias
Coronary thrombolysis may result in arrhythmias associated with reperfusion. These arrhythmias (such as sinus bradycardia, accelerated idioventricular rhythm, ventricular premature depolarizations, ventricular tachycardia) are not different from those often seen in the ordinary course of acute myocardial infarction and may be managed with standard anti‑arrhythmic measures. It is recommended that anti‑arrhythmic therapy for bradycardia and/or ventricular irritability be available when Tenecteplase is administered.
### Use with Percutaneous Coronary Intervention (PCI)
In patients with large ST segment elevation myocardial infarction, physicians should choose either thrombolysis or PCI as the primary treatment strategy for reperfusion. Rescue PCI or subsequent elective PCI may be performed after administration of thrombolytic therapies if medically appropriate; however, the optimal use of adjunctive antithrombotic and antiplatelet therapies in this setting is unknown.
# Adverse Reactions
## Clinical Trials Experience
# Adverse Reactions
## Bleeding
The most frequent adverse reaction associated with Tenecteplase is bleeding.
Should serious bleeding occur, concomitant heparin and antiplatelet therapy should be discontinued. Death or permanent disability can occur in patients who experience stroke or serious bleeding episodes.
For Tenecteplase-treated patients in ASSENT-2, the incidence of intracranial hemorrhage was 0.9% and any stroke was 1.8%. The incidence of all strokes, including intracranial bleeding, increases with increasing age.
In the ASSENT-2 study, the following bleeding events were reported (see Table 3).
Non-intracranial major bleeding and the need for blood transfusions were lower in patients treated with Tenecteplase.
Types of major bleeding reported in 1% or more of the patients were hematoma (1.7%) and gastrointestinal tract (1%). Types of major bleeding reported in less than 1% of the patients were urinary tract, puncture site (including cardiac catheterization site), retroperitoneal, respiratory tract, and unspecified. Types of minor bleeding reported in 1% or more of the patients were hematoma (12.3%), urinary tract (3.7%), puncture site (including cardiac catheterization site) (3.6%), pharyngeal (3.1%), gastrointestinal tract (1.9%), epistaxis (1.5%), and unspecified (1.3%).
## Allergic Reactions
Allergic-type reactions (e.g., anaphylaxis, angioedema, laryngeal edema, rash, and urticaria) have rarely (< 1%) been reported in patients treated with Tenecteplase. Anaphylaxis was reported in < 0.1% of patients treated with Tenecteplase; however, causality was not established. When such reactions occur, they usually respond to conventional therapy.
## Other Adverse Reactions
The following adverse reactions have been reported among patients receiving Tenecteplase in clinical trials. These reactions are frequent sequelae of the underlying disease, and the effect of Tenecteplase on the incidence of these events is unknown.
These events include cardiogenic shock, arrhythmias, atrioventricular block, pulmonary edema, heart failure, cardiac arrest, recurrent myocardial ischemia, myocardial reinfarction, myocardial rupture, cardiac tamponade, pericarditis, pericardial effusion, mitral regurgitation, thrombosis, embolism, and electromechanical dissociation. These events can be life-threatening and may lead to death. Nausea and/or vomiting,hypotension, and fever have also been reported.
## Postmarketing Experience
There is limited information regarding Tenecteplase Postmarketing Experience in the drug label.
# Drug Interactions
Formal interaction studies of Tenecteplase with other drugs have not been performed. Patients studied in clinical trials of Tenecteplase were routinely treated with heparin and aspirin. Anticoagulants (such as heparin and vitamin K antagonists) and drugs that alter platelet function (such as acetylsalicylic acid, dipyridamole, and GP IIb/IIIa inhibitors) may increase the risk of bleeding if administered prior to, during, or after Tenecteplase therapy.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
Tenecteplase has been shown to elicit maternal and embryo toxicity in rabbits given multiple IV administrations. In rabbits administered 0.5, 1.5, and 5.0 mg/kg/day, vaginal hemorrhageresulted in maternal deaths. Subsequent embryonic deaths were secondary to maternal hemorrhage and no fetal anomalies were observed. Tenecteplase does not elicit maternal and embryo toxicity in rabbits following a single IV administration. Thus, in developmental toxicity studies conducted in rabbits, the no observable effect level (NOEL) of a single IV administration of Tenecteplase on maternal or developmental toxicity was 5 mg/kg (approximately 8–10 times the human dose). There are no adequate and well‑controlled studies in pregnant women. Tenecteplase should be given to pregnant women only if the potential benefits justify the potential risk to the fetus.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tenecteplase in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Tenecteplase during labor and delivery.
### Nursing Mothers
It is not known if Tenecteplase is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Tenecteplase is administered to a nursing woman.
### Pediatric Use
The safety and effectiveness of Tenecteplase in pediatric patients have not been established.
### Geriatic Use
Of the patients in ASSENT-2 who received Tenecteplase, 4,958 (59%) were under the age of 65; 2,256 (27%) were between the ages of 65 and 74; and 1,244 (15%) were 75 and over. The 30-day mortality rates by age were 2.5% in patients under the age of 65, 8.5% in patients between the ages of 65 and 74, and 16.2% in patients age 75 and over. The ICH rates were 0.4% in patients under the age of 65, 1.6% in patients between the ages of 65 and 74, and 1.7% in patients age 75 and over. The rates of any stroke were 1.0% in patients under the age of 65, 2.9% in patients between the ages of 65 and 74, and 3.0% in patients age 75 and over. Major bleeding rates, defined as bleeding requiring blood transfusion or leading to hemodynamic compromise, were 3.1% in patients under the age of 65, 6.4% in patients between the ages of 65 and 74, and 7.7% in patients age 75 and over. In elderly patients, the benefits of Tenecteplase on mortality should be carefully weighed against the risk of increased adverse events, including bleeding.
### Gender
There is no FDA guidance on the use of Tenecteplase with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Tenecteplase with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Tenecteplase in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Tenecteplase in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Tenecteplase in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Tenecteplase in patients who are immunocompromised.
# Administration and Monitoring
### Administration
1.The product should be visually inspected prior to administration for particulate matter and discoloration. Tenecteplase may be administered as reconstituted at 5 mg/mL.
2.Precipitation may occur when Tenecteplase is administered in an IV line containing dextrose. Dextrose-containing lines should be flushed with a saline-containing solution prior to and following single bolus administration of Tenecteplase.
3.Reconstituted Tenecteplase should be administered as a single IV bolus over 5 seconds.
4.Because Tenecteplase contains no antibacterial preservatives, it should be reconstituted immediately before use. If the reconstituted Tenecteplase is not used immediately, refrigerate the Tenecteplase vial at 2–8°C (36–46°F) and use within 8 hours.
5.Although the supplied syringe is compatible with a conventional needle, this syringe is designed to be used with needleless IV systems. From the information below, follow the instructions applicable to the IV system in use.
6.Dispose of the syringe, cannula and shield per established procedures.
The safety and efficacy of Tenecteplase have only been investigated with concomitant administration of heparin and aspirin.
### Reconstitution
NOTE: Read all instructions completely before beginning reconstitution and administration.
1.Remove the shield assembly from the supplied B-D® 10 mL syringe with TwinPak™ Dual Cannula Device (see figure) and aseptically withdraw 10 mL of Sterile Water for Injection (SWFI), USP, from the supplied diluent vial using the red hub cannula syringe filling device. Do not use Bacteriostatic Water for Injection, USP.
Note: Do not discard the shield assembly.
2.Inject the entire contents of the syringe (10 mL) into the Tenecteplase vial directing the diluent stream into the powder. Slight foaming upon reconstitution is not unusual; any large bubbles will dissipate if the product is allowed to stand undisturbed for several minutes.
3.Gently swirl until contents are completely dissolved. DO NOT SHAKE. The reconstituted preparation results in a colorless to pale yellow transparent solution containing Tenecteplase at 5 mg/mL at a pH of approximately 7.3. The osmolality of this solution is approximately 290 mOsm/kg.
4.Determine the appropriate dose of Tenecteplase (see Dose Information Table) and withdraw this volume (in milliliters) from the reconstituted vial with the syringe. Any unused solution should be discarded.
5.Once the appropriate dose of Tenecteplase is drawn into the syringe, stand the shield vertically on a flat surface (with green side down) and passively recap the red hub cannula.
6.Remove the entire shield assembly, including the red hub cannula, by twisting counterclockwise. Note: The shield assembly also contains the clear-ended blunt plastic cannula; retain for split septum IV access.
### Readministration
Readministration of plasminogen activators, including tenecteplase, to patients who have received prior plasminogen activator therapy has not been systematically studied. Three of 487 patients tested for antibody formation to tenecteplase had a positive antibody titer at 30 days. The data reflect the percentage of patients whose test results were considered positive for antibodies to tenecteplase in a radioimmunoprecipitation assay, and are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors including sample handling, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to tenecteplase with the incidence of antibodies to other products may be misleading. Although sustained antibody formation in patients receiving one dose of tenecteplase has not been documented, readministration should be undertaken with caution. If an anaphylactic reaction occurs, appropriate therapy should be administered.
### Monitoring
There is limited information regarding Monitoring of Tenecteplase in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Tenecteplase and IV administrations.
# Overdosage
There is limited information regarding Tenecteplase overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
Tenecteplase is a modified form of human tissue plasminogen activator (tPA) that binds to fibrin and converts plasminogen to plasmin. In the presence of fibrin, in vitro studies demonstrate that Tenecteplase conversion of plasminogen to plasmin is increased relative to its conversion in the absence of fibrin. This fibrin specificity decreases systemic activation of plasminogen and the resulting degradation of circulating fibrinogen as compared to a molecule lacking this property. Following administration of 30, 40, or 50 mg of Tenecteplase, there are decreases in circulating fibrinogen (4%–15%) and plasminogen (11%–24%). The clinical significance of fibrin-specificity on safety (e.g., bleeding) or efficacy has not been established. Biological potency is determined by an in vitro clot lysis assay and is expressed in Tenecteplase-specific units. The specific activity of Tenecteplase has been defined as 200 units/mg.
## Structure
Tenecteplase is a tissue plasminogen activator (tPA) produced by recombinant DNA technology using an established mammalian cell line (Chinese Hamster Ovary cells). Tenecteplase is a 527 amino acid glycoprotein developed by introducing the following modifications to the complementary DNA (cDNA) for natural human tPA: a substitution of threonine 103 with asparagine, and a substitution of asparagine 117 with glutamine, both within the kringle 1 domain, and a tetra-alanine substitution at amino acids 296–299 in the protease domain.
## Pharmacodynamics
In patients with acute myocardial infarction (AMI), Tenecteplase administered as a single bolus exhibits a biphasic disposition from the plasma. Tenecteplase was cleared from the plasma with an initial half-life of 20 to 24 minutes. The terminal phase half-life of Tenecteplase was 90 to 130 minutes. In 99 of 104 patients treated with Tenecteplase, mean plasma clearance ranged from 99 to 119 mL/min.
The initial volume of distribution is weight related and approximates plasma volume. Liver metabolism is the major clearance mechanism for Tenecteplase
## Pharmacokinetics
There is limited information regarding Pharmacokinetics of Tenecteplase in the drug label.
## Nonclinical Toxicology
Studies in animals have not been performed to evaluate the carcinogenic potential, mutagenicity, or the effect on fertility.
# Clinical Studies
ASSENT-2 was an international, randomized, double-blind trial that compared 30-day mortality rates in 16,949 patients assigned to receive an IV bolus dose of Tenecteplase or an accelerated infusion of Activase® (alteplase). Eligibility criteria included onset of chest pain within 6 hours of randomization and ST-segment elevation or left bundle branch block on electrocardiogram (ECG). Patients were to be excluded from the trial if they received GP IIb/IIIainhibitors within the previous 12 hours. Tenecteplase was dosed using actual or estimated weight in a weight-tiered fashion. All patients were to receive 150–325 mg of aspirin administered as soon as possible, followed by 150–325 mg daily. Intravenous heparin was to be administered as soon as possible: for patients weighing ≤67 kg, heparin was administered as a 4000 unit IV bolus followed by infusion at 800 U/hr; for patients weighing >67 kg, heparin was administered as a 5000 unit IV bolus followed by infusion at 1000 U/hr. heparin was continued for 48 to 72 hours with infusion adjusted to maintain aPTT at 50–75 seconds. The use of GP IIb/IIIa inhibitors was discouraged for the first 24 hours following randomization. The results of the primary endpoint (30-day mortality rates with non-parametric adjustment for the covariates of age, Killip class, heart rate, systolic blood pressure and infarct location) along with selected other 30-day endpoints are shown in Table 1.
Rates of mortality and the combined endpoint of death or stroke among pre-specified subgroups, including age, gender, time to treatment, infarct location, and history of previousmyocardial infarction, demonstrate consistent relative risks across these subgroups. There was insufficient enrollment of non-Caucasian patients to draw any conclusions regarding relative efficacy in racial subsets.
Rates of in-hospital procedures, including percutaneous transluminal coronary angioplasty (PTCA), stent placement, intra-aortic balloon pump(IABP) use, and coronary artery bypass graft (CABG) surgery, were similar between the Tenecteplase and Activase®(Alteplase) groups.
TIMI 10B was an open-label, controlled, randomized, dose-ranging, angiography study which utilized a blinded core laboratory for review of coronary arteriograms. Patients (n = 837) presenting within 12 hours of symptom onset were treated with fixed doses of 30, 40, or 50 mg of Tenecteplase or the accelerated infusion of activase and underwent coronary arteriography at 90 minutes. The results showed that the 40 mg and 50 mg doses were similar to accelerated infusion of activase in restoring patency. TIMI Grade 3 flow and TIMI Grade 2/3 flow at 90 minutes are shown in Table 2. The exact relationship between coronary artery patency and clinical activity has not been established.
The angiographic results from TIMI 10B and the safety data from ASSENT-1, an additional uncontrolled safety study of 3,235 Tenecteplase-treated patients, provided the framework to develop a weight-tiered Tenecteplase dose regimen.3 Exploratory analyses suggested that a weight-adjusted dose of 0.5 mg/kg to 0.6 mg/kg of Tenecteplase resulted in a better patency to bleeding relationship than fixed doses of Tenecteplase across a broad range of patient weights.
The Assessment of the Safety and Efficacy of a New Treatment Strategy with Percutaneous Coronary Intervention (ASSENT 4 PCI) was a Phase IIIb/IV study designed to assess the safety and effectiveness of a strategy of administering full dose Tenecteplase with a single bolus of 4000 U of unfractionated heparin in patients with ST segment elevation AMI, in whom primary percutaneous coronary intervention (PCI) was planned, but in whom a delay of 1–3 hours was anticipated before PCI. The trial was prematurely terminated with 1667 randomized patients (75 of whom were treated in the United States) due to a numerically higher mortality in the patients receiving Tenecteplase prior to primary PCI versus PCI without Tenecteplase (median time from randomization to balloon of 115 minutes). The incidence of the 90‑day primary endpoint, a composite of death or cardiogenic shock or congestive heart failure (CHF) within 90 days, was 18.6% in patients treated with Tenecteplase plus PCI versus 13.4% in those treated with PCI alone (p=0.0055; OR 1.39 (95% C.I. 1.11–1.74)).
There were trends toward worse outcomes in the individual components of the primary endpoint between Tenecteplase plus PCI versus PCI alone (mortality 6.7% vs. 5.0%, respectively; cardiogenic shock 6.1% vs. 4.8%, respectively; and CHF 12.1% vs. 9.4%, respectively). In addition, there were trends towards worse outcomes in recurrent MI (6.1% vs. 3.5%, respectively; p=0.03) and repeat target vessel revascularization (6.6% vs. 3.6%, respectively; p=0.005) in patients receiving Tenecteplase plus PCI versus PCI alone.
There was no difference in in‑hospital major bleeding between the two groups (5.6% vs. 4.4% for Tenecteplase plus PCI vs. PCI alone, respectively). For patients treated with Tenecteplase plus PCI, in‑hospital rates of intracranial hemorrhage and total stroke were similar to those observed in previous trials (0.97% and 1.8%, respectively); however, none of the patients treated with PCI alone experienced a stroke (ischemic, hemorrhagic or other).
# How Supplied
Tenecteplase is supplied as a sterile, lyophilized powder in a 50 mg vial under partial vacuum. Each 50 mg vial of Tenecteplase is packaged with one 10 mL vial of Sterile Water for Injection, USP for reconstitution, the B-D® 10 mL syringe with TwinPak™ Dual Cannula Device, and three alcohol prep pads. NDC 50242-038-61.
## Storage
Store lyophilized Tenecteplase at controlled room temperature not to exceed 30°C (86°F) or under refrigeration 2–8°C (36–46°F). Do not use beyond the expiration date stamped on the vial.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Tenecteplase in the drug label.
# Precautions with Alcohol
Alcohol-Tenecteplase interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
TNKase®
# Look-Alike Drug Names
There is limited information regarding Tenecteplase Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Tenecteplase
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alejandro Lemor, M.D. [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Tenecteplase is a tissue plasminogen activator that is FDA approved for the {{{indicationType}}} of acute myocardial infarction. Common adverse reactions include hematoma, gastrointestinal bleeding, bleeding.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Acute Myocardial Infarction
- The recommended total dose should not exceed 50 mg and is based upon patient weight.
- A single bolus dose should be administered over 5 seconds based on patient weight.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Tenecteplase in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tenecteplase in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Tenecteplase 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 Tenecteplase in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tenecteplase in pediatric patients.
# Contraindications
Tenecteplase therapy in patients with acute myocardial infarction is contraindicated in the following situations because of an increased risk of bleeding:
- Active internal bleeding
- History of cerebrovascular accident
- Intracranial or intraspinal surgery or trauma within 2 months
- Intracranial neoplasm, arteriovenous malformation, or aneurysm
- Known bleeding diathesis
- Severe uncontrolled hypertension
# Warnings
### Bleeding
The most common complication encountered during Tenecteplase therapy is bleeding. The type of bleeding associated with thrombolytic therapy can be divided into two broad categories:
- Internal bleeding, involving intracranial and retroperitoneal sites, or the gastrointestinal, genitourinary, or respiratory tracts.
- Superficial or surface bleeding, observed mainly at vascular puncture and access sites (e.g., venous cutdowns, arterial punctures) or sites of recent surgical intervention.
Should serious bleeding (not controlled by local pressure) occur, any concomitant heparin or antiplatelet agents should be discontinued immediately.
In clinical studies of Tenecteplase, patients were treated with both aspirin and heparin. heparin may contribute to the bleeding risks associated with Tenecteplase. The safety of the use of Tenecteplase with other antiplatelet agents has not been adequately studied. Intramuscular injections and nonessential handling of the patient should be avoided for the first few hours following treatment with Tenecteplase. Venipunctures should be performed and monitored carefully.
Should an arterial puncture be necessary during the first few hours following Tenecteplase therapy, it is preferable to use an upper extremity vessel that is accessible to manual compression. Pressure should be applied for at least 30 minutes, a pressure dressing applied, and the puncture site checked frequently for evidence of bleeding.
Each patient being considered for therapy with Tenecteplase should be carefully evaluated and anticipated benefits weighed against potential risks associated with therapy. In the following conditions, the risk of Tenecteplase therapy may be increased and should be weighed against the anticipated benefits:
- Recent major surgery, e.g., coronary artery bypass graft, obstetrical delivery, organ biopsy, previous puncture of noncompressible vessels
- Cerebrovascular disease
- Recent gastrointestinal or genitourinary bleeding
- Recent trauma
- hypertension: systolic BP ≥180 mm Hg and/or diastolic BP ≥110 mm Hg
- High likelihood of left heart thrombus, e.g., mitral stenosis with atrial fibrillation
- Acute pericarditis
- Subacute bacterial endocarditis
- Hemostatic defects, including those secondary to severe hepatic or renal disease
- Severe hepatic dysfunction
- Pregnancy
- Diabetic hemorrhagic retinopathy or other hemorrhagic ophthalmic conditions
- Septic thrombophlebitis or occluded AV cannula at seriously infected site
- Advanced age
- Patients currently receiving oral anticoagulants, e.g., warfarin sodium
- Recent administration of GP IIb/IIIa inhibitors
- Any other condition in which bleeding constitutes a significant hazard or would be particularly difficult to manage because of its location
### Cholesterol Embolization
Cholesterol embolism has been reported rarely in patients treated with all types of thrombolytic agents; the true incidence is unknown. This serious condition, which can be lethal, is also associated with invasive vascular procedures (e.g., cardiac catheterization, angiography, vascular surgery) and/or anticoagulant therapy. Clinical features of cholesterol embolism may include livedo reticularis, "purple toe" syndrome, acute renal failure, gangrenous digits, hypertension, pancreatitis, myocardial infarction, cerebral infarction, spinal cord infarction, retinal artery occlusion, bowel infarction, and rhabdomyolysis.
### Arrhythmias
Coronary thrombolysis may result in arrhythmias associated with reperfusion. These arrhythmias (such as sinus bradycardia, accelerated idioventricular rhythm, ventricular premature depolarizations, ventricular tachycardia) are not different from those often seen in the ordinary course of acute myocardial infarction and may be managed with standard anti‑arrhythmic measures. It is recommended that anti‑arrhythmic therapy for bradycardia and/or ventricular irritability be available when Tenecteplase is administered.
### Use with Percutaneous Coronary Intervention (PCI)
In patients with large ST segment elevation myocardial infarction, physicians should choose either thrombolysis or PCI as the primary treatment strategy for reperfusion. Rescue PCI or subsequent elective PCI may be performed after administration of thrombolytic therapies if medically appropriate; however, the optimal use of adjunctive antithrombotic and antiplatelet therapies in this setting is unknown.
# Adverse Reactions
## Clinical Trials Experience
# Adverse Reactions
## Bleeding
The most frequent adverse reaction associated with Tenecteplase is bleeding.
Should serious bleeding occur, concomitant heparin and antiplatelet therapy should be discontinued. Death or permanent disability can occur in patients who experience stroke or serious bleeding episodes.
For Tenecteplase-treated patients in ASSENT-2, the incidence of intracranial hemorrhage was 0.9% and any stroke was 1.8%. The incidence of all strokes, including intracranial bleeding, increases with increasing age.
In the ASSENT-2 study, the following bleeding events were reported (see Table 3).
Non-intracranial major bleeding and the need for blood transfusions were lower in patients treated with Tenecteplase.
Types of major bleeding reported in 1% or more of the patients were hematoma (1.7%) and gastrointestinal tract (1%). Types of major bleeding reported in less than 1% of the patients were urinary tract, puncture site (including cardiac catheterization site), retroperitoneal, respiratory tract, and unspecified. Types of minor bleeding reported in 1% or more of the patients were hematoma (12.3%), urinary tract (3.7%), puncture site (including cardiac catheterization site) (3.6%), pharyngeal (3.1%), gastrointestinal tract (1.9%), epistaxis (1.5%), and unspecified (1.3%).
## Allergic Reactions
Allergic-type reactions (e.g., anaphylaxis, angioedema, laryngeal edema, rash, and urticaria) have rarely (< 1%) been reported in patients treated with Tenecteplase. Anaphylaxis was reported in < 0.1% of patients treated with Tenecteplase; however, causality was not established. When such reactions occur, they usually respond to conventional therapy.
## Other Adverse Reactions
The following adverse reactions have been reported among patients receiving Tenecteplase in clinical trials. These reactions are frequent sequelae of the underlying disease, and the effect of Tenecteplase on the incidence of these events is unknown.
These events include cardiogenic shock, arrhythmias, atrioventricular block, pulmonary edema, heart failure, cardiac arrest, recurrent myocardial ischemia, myocardial reinfarction, myocardial rupture, cardiac tamponade, pericarditis, pericardial effusion, mitral regurgitation, thrombosis, embolism, and electromechanical dissociation. These events can be life-threatening and may lead to death. Nausea and/or vomiting,hypotension, and fever have also been reported.
## Postmarketing Experience
There is limited information regarding Tenecteplase Postmarketing Experience in the drug label.
# Drug Interactions
Formal interaction studies of Tenecteplase with other drugs have not been performed. Patients studied in clinical trials of Tenecteplase were routinely treated with heparin and aspirin. Anticoagulants (such as heparin and vitamin K antagonists) and drugs that alter platelet function (such as acetylsalicylic acid, dipyridamole, and GP IIb/IIIa inhibitors) may increase the risk of bleeding if administered prior to, during, or after Tenecteplase therapy.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
Tenecteplase has been shown to elicit maternal and embryo toxicity in rabbits given multiple IV administrations. In rabbits administered 0.5, 1.5, and 5.0 mg/kg/day, vaginal hemorrhageresulted in maternal deaths. Subsequent embryonic deaths were secondary to maternal hemorrhage and no fetal anomalies were observed. Tenecteplase does not elicit maternal and embryo toxicity in rabbits following a single IV administration. Thus, in developmental toxicity studies conducted in rabbits, the no observable effect level (NOEL) of a single IV administration of Tenecteplase on maternal or developmental toxicity was 5 mg/kg (approximately 8–10 times the human dose). There are no adequate and well‑controlled studies in pregnant women. Tenecteplase should be given to pregnant women only if the potential benefits justify the potential risk to the fetus.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tenecteplase in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Tenecteplase during labor and delivery.
### Nursing Mothers
It is not known if Tenecteplase is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Tenecteplase is administered to a nursing woman.
### Pediatric Use
The safety and effectiveness of Tenecteplase in pediatric patients have not been established.
### Geriatic Use
Of the patients in ASSENT-2 who received Tenecteplase, 4,958 (59%) were under the age of 65; 2,256 (27%) were between the ages of 65 and 74; and 1,244 (15%) were 75 and over. The 30-day mortality rates by age were 2.5% in patients under the age of 65, 8.5% in patients between the ages of 65 and 74, and 16.2% in patients age 75 and over. The ICH rates were 0.4% in patients under the age of 65, 1.6% in patients between the ages of 65 and 74, and 1.7% in patients age 75 and over. The rates of any stroke were 1.0% in patients under the age of 65, 2.9% in patients between the ages of 65 and 74, and 3.0% in patients age 75 and over. Major bleeding rates, defined as bleeding requiring blood transfusion or leading to hemodynamic compromise, were 3.1% in patients under the age of 65, 6.4% in patients between the ages of 65 and 74, and 7.7% in patients age 75 and over. In elderly patients, the benefits of Tenecteplase on mortality should be carefully weighed against the risk of increased adverse events, including bleeding.
### Gender
There is no FDA guidance on the use of Tenecteplase with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Tenecteplase with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Tenecteplase in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Tenecteplase in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Tenecteplase in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Tenecteplase in patients who are immunocompromised.
# Administration and Monitoring
### Administration
1.The product should be visually inspected prior to administration for particulate matter and discoloration. Tenecteplase may be administered as reconstituted at 5 mg/mL.
2.Precipitation may occur when Tenecteplase is administered in an IV line containing dextrose. Dextrose-containing lines should be flushed with a saline-containing solution prior to and following single bolus administration of Tenecteplase.
3.Reconstituted Tenecteplase should be administered as a single IV bolus over 5 seconds.
4.Because Tenecteplase contains no antibacterial preservatives, it should be reconstituted immediately before use. If the reconstituted Tenecteplase is not used immediately, refrigerate the Tenecteplase vial at 2–8°C (36–46°F) and use within 8 hours.
5.Although the supplied syringe is compatible with a conventional needle, this syringe is designed to be used with needleless IV systems. From the information below, follow the instructions applicable to the IV system in use.
6.Dispose of the syringe, cannula and shield per established procedures.
The safety and efficacy of Tenecteplase have only been investigated with concomitant administration of heparin and aspirin.
### Reconstitution
NOTE: Read all instructions completely before beginning reconstitution and administration.
1.Remove the shield assembly from the supplied B-D® 10 mL syringe with TwinPak™ Dual Cannula Device (see figure) and aseptically withdraw 10 mL of Sterile Water for Injection (SWFI), USP, from the supplied diluent vial using the red hub cannula syringe filling device. Do not use Bacteriostatic Water for Injection, USP.
Note: Do not discard the shield assembly.
2.Inject the entire contents of the syringe (10 mL) into the Tenecteplase vial directing the diluent stream into the powder. Slight foaming upon reconstitution is not unusual; any large bubbles will dissipate if the product is allowed to stand undisturbed for several minutes.
3.Gently swirl until contents are completely dissolved. DO NOT SHAKE. The reconstituted preparation results in a colorless to pale yellow transparent solution containing Tenecteplase at 5 mg/mL at a pH of approximately 7.3. The osmolality of this solution is approximately 290 mOsm/kg.
4.Determine the appropriate dose of Tenecteplase (see Dose Information Table) and withdraw this volume (in milliliters) from the reconstituted vial with the syringe. Any unused solution should be discarded.
5.Once the appropriate dose of Tenecteplase is drawn into the syringe, stand the shield vertically on a flat surface (with green side down) and passively recap the red hub cannula.
6.Remove the entire shield assembly, including the red hub cannula, by twisting counterclockwise. Note: The shield assembly also contains the clear-ended blunt plastic cannula; retain for split septum IV access.
### Readministration
Readministration of plasminogen activators, including tenecteplase, to patients who have received prior plasminogen activator therapy has not been systematically studied. Three of 487 patients tested for antibody formation to tenecteplase had a positive antibody titer at 30 days. The data reflect the percentage of patients whose test results were considered positive for antibodies to tenecteplase in a radioimmunoprecipitation assay, and are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors including sample handling, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to tenecteplase with the incidence of antibodies to other products may be misleading. Although sustained antibody formation in patients receiving one dose of tenecteplase has not been documented, readministration should be undertaken with caution. If an anaphylactic reaction occurs, appropriate therapy should be administered.
### Monitoring
There is limited information regarding Monitoring of Tenecteplase in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Tenecteplase and IV administrations.
# Overdosage
There is limited information regarding Tenecteplase overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
Tenecteplase is a modified form of human tissue plasminogen activator (tPA) that binds to fibrin and converts plasminogen to plasmin. In the presence of fibrin, in vitro studies demonstrate that Tenecteplase conversion of plasminogen to plasmin is increased relative to its conversion in the absence of fibrin. This fibrin specificity decreases systemic activation of plasminogen and the resulting degradation of circulating fibrinogen as compared to a molecule lacking this property. Following administration of 30, 40, or 50 mg of Tenecteplase, there are decreases in circulating fibrinogen (4%–15%) and plasminogen (11%–24%). The clinical significance of fibrin-specificity on safety (e.g., bleeding) or efficacy has not been established. Biological potency is determined by an in vitro clot lysis assay and is expressed in Tenecteplase-specific units. The specific activity of Tenecteplase has been defined as 200 units/mg.
## Structure
Tenecteplase is a tissue plasminogen activator (tPA) produced by recombinant DNA technology using an established mammalian cell line (Chinese Hamster Ovary cells). Tenecteplase is a 527 amino acid glycoprotein developed by introducing the following modifications to the complementary DNA (cDNA) for natural human tPA: a substitution of threonine 103 with asparagine, and a substitution of asparagine 117 with glutamine, both within the kringle 1 domain, and a tetra-alanine substitution at amino acids 296–299 in the protease domain.
## Pharmacodynamics
In patients with acute myocardial infarction (AMI), Tenecteplase administered as a single bolus exhibits a biphasic disposition from the plasma. Tenecteplase was cleared from the plasma with an initial half-life of 20 to 24 minutes. The terminal phase half-life of Tenecteplase was 90 to 130 minutes. In 99 of 104 patients treated with Tenecteplase, mean plasma clearance ranged from 99 to 119 mL/min.
The initial volume of distribution is weight related and approximates plasma volume. Liver metabolism is the major clearance mechanism for Tenecteplase
## Pharmacokinetics
There is limited information regarding Pharmacokinetics of Tenecteplase in the drug label.
## Nonclinical Toxicology
Studies in animals have not been performed to evaluate the carcinogenic potential, mutagenicity, or the effect on fertility.
# Clinical Studies
ASSENT-2 was an international, randomized, double-blind trial that compared 30-day mortality rates in 16,949 patients assigned to receive an IV bolus dose of Tenecteplase or an accelerated infusion of Activase® (alteplase). Eligibility criteria included onset of chest pain within 6 hours of randomization and ST-segment elevation or left bundle branch block on electrocardiogram (ECG). Patients were to be excluded from the trial if they received GP IIb/IIIainhibitors within the previous 12 hours. Tenecteplase was dosed using actual or estimated weight in a weight-tiered fashion. All patients were to receive 150–325 mg of aspirin administered as soon as possible, followed by 150–325 mg daily. Intravenous heparin was to be administered as soon as possible: for patients weighing ≤67 kg, heparin was administered as a 4000 unit IV bolus followed by infusion at 800 U/hr; for patients weighing >67 kg, heparin was administered as a 5000 unit IV bolus followed by infusion at 1000 U/hr. heparin was continued for 48 to 72 hours with infusion adjusted to maintain aPTT at 50–75 seconds. The use of GP IIb/IIIa inhibitors was discouraged for the first 24 hours following randomization. The results of the primary endpoint (30-day mortality rates with non-parametric adjustment for the covariates of age, Killip class, heart rate, systolic blood pressure and infarct location) along with selected other 30-day endpoints are shown in Table 1.
Rates of mortality and the combined endpoint of death or stroke among pre-specified subgroups, including age, gender, time to treatment, infarct location, and history of previousmyocardial infarction, demonstrate consistent relative risks across these subgroups. There was insufficient enrollment of non-Caucasian patients to draw any conclusions regarding relative efficacy in racial subsets.
Rates of in-hospital procedures, including percutaneous transluminal coronary angioplasty (PTCA), stent placement, intra-aortic balloon pump(IABP) use, and coronary artery bypass graft (CABG) surgery, were similar between the Tenecteplase and Activase®(Alteplase) groups.
TIMI 10B was an open-label, controlled, randomized, dose-ranging, angiography study which utilized a blinded core laboratory for review of coronary arteriograms. Patients (n = 837) presenting within 12 hours of symptom onset were treated with fixed doses of 30, 40, or 50 mg of Tenecteplase or the accelerated infusion of activase and underwent coronary arteriography at 90 minutes. The results showed that the 40 mg and 50 mg doses were similar to accelerated infusion of activase in restoring patency. TIMI Grade 3 flow and TIMI Grade 2/3 flow at 90 minutes are shown in Table 2. The exact relationship between coronary artery patency and clinical activity has not been established.
The angiographic results from TIMI 10B and the safety data from ASSENT-1, an additional uncontrolled safety study of 3,235 Tenecteplase-treated patients, provided the framework to develop a weight-tiered Tenecteplase dose regimen.3 Exploratory analyses suggested that a weight-adjusted dose of 0.5 mg/kg to 0.6 mg/kg of Tenecteplase resulted in a better patency to bleeding relationship than fixed doses of Tenecteplase across a broad range of patient weights.
The Assessment of the Safety and Efficacy of a New Treatment Strategy with Percutaneous Coronary Intervention (ASSENT 4 PCI) was a Phase IIIb/IV study designed to assess the safety and effectiveness of a strategy of administering full dose Tenecteplase with a single bolus of 4000 U of unfractionated heparin in patients with ST segment elevation AMI, in whom primary percutaneous coronary intervention (PCI) was planned, but in whom a delay of 1–3 hours was anticipated before PCI. The trial was prematurely terminated with 1667 randomized patients (75 of whom were treated in the United States) due to a numerically higher mortality in the patients receiving Tenecteplase prior to primary PCI versus PCI without Tenecteplase (median time from randomization to balloon of 115 minutes). The incidence of the 90‑day primary endpoint, a composite of death or cardiogenic shock or congestive heart failure (CHF) within 90 days, was 18.6% in patients treated with Tenecteplase plus PCI versus 13.4% in those treated with PCI alone (p=0.0055; OR 1.39 (95% C.I. 1.11–1.74)).
There were trends toward worse outcomes in the individual components of the primary endpoint between Tenecteplase plus PCI versus PCI alone (mortality 6.7% vs. 5.0%, respectively; cardiogenic shock 6.1% vs. 4.8%, respectively; and CHF 12.1% vs. 9.4%, respectively). In addition, there were trends towards worse outcomes in recurrent MI (6.1% vs. 3.5%, respectively; p=0.03) and repeat target vessel revascularization (6.6% vs. 3.6%, respectively; p=0.005) in patients receiving Tenecteplase plus PCI versus PCI alone.
There was no difference in in‑hospital major bleeding between the two groups (5.6% vs. 4.4% for Tenecteplase plus PCI vs. PCI alone, respectively). For patients treated with Tenecteplase plus PCI, in‑hospital rates of intracranial hemorrhage and total stroke were similar to those observed in previous trials (0.97% and 1.8%, respectively); however, none of the patients treated with PCI alone experienced a stroke (ischemic, hemorrhagic or other).
# How Supplied
Tenecteplase is supplied as a sterile, lyophilized powder in a 50 mg vial under partial vacuum. Each 50 mg vial of Tenecteplase is packaged with one 10 mL vial of Sterile Water for Injection, USP for reconstitution, the B-D® 10 mL syringe with TwinPak™ Dual Cannula Device, and three alcohol prep pads. NDC 50242-038-61.
## Storage
Store lyophilized Tenecteplase at controlled room temperature not to exceed 30°C (86°F) or under refrigeration 2–8°C (36–46°F). Do not use beyond the expiration date stamped on the vial.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Tenecteplase in the drug label.
# Precautions with Alcohol
Alcohol-Tenecteplase interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
TNKase®
# Look-Alike Drug Names
There is limited information regarding Tenecteplase Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/TNK | |
d2b305340ea3543d6f1d51ca958bf7c646fef198 | wikidoc | Trk receptor | Trk receptor
# Overview
Trk receptors are a family of tyrosine kinases that regulates synaptic strength and plasticity in the mammalian nervous system. Trk receptors affect neuronal survival and differentiation through several signal cascades. However, the activation of these receptors also has significant effects on functional properties of neurons.
The common ligands of trk receptors are neurotrophins, a family of growth factors critical to the functioning of the nervous system. The binding of these molecules is highly specific. Each type of neurotrophin has different binding affinity toward its corresponding trk receptor. The activation of Trk receptors by neurotrophin binding may lead to activation of signal cascades resulting in promoting survival and other functional regulation of cells.
# Origin of the name trk
The abbreviation trk (often pronounced 'track') stands for tropomyosin-receptor-kinase (and not tyrosine kinase nor tropomyosin-related kinase, as has been commonly mistaken).
The family of Trk receptors is named for the oncogene trk, whose identifical led to the discovery of its first member, TrkA. trk, initially identified in a colon carcinoma, is frequently (25%) activated in thyroid papillary carcinomas . The oncogene was generated by a mutation in chromosome 1 that resulted in the fusion of the first seven exons of tropomyosin to the transmembrane and cytoplasmic domains of the then-unknown TrkA receptor . Normal Trk receptors do not contain amino acid or DNA sequences related to tropomyosin.
# Trk receptor types and corresponding ligands
The three most common types of trk receptors are trkA, trkB, and trkC. Each of these receptors types has different binding affinity to certain types of neurotrophins. The differences in the signaling initiated by these distinct types of receptors are important for generating diverse of biological responses.
Neurotrophin ligands of Trk receptors are processed ligands, meaning that they are synthesized in immature forms and then transformed by protease cleavage. Immature neurotrophins are specific only to one common p75NTR receptor. However, protease cleavage generates neurotrophins that have higher affinity to their corresponding Trk receptors. These processed neurotrophins can still bind to p75NTR, but at a much lower affinity.
## TrkA
TrkA has the highest affinity to the binding nerve growth factor (NGF). NGF is important in both local and nuclear actions, regulating growth cones, motility, and expression of genes encoding the biosynthesis enzymes for neurotransmitters. Nocireceptive sensory neurons express mostly trkA and not trkB or trkC.
## TrkB
TrkB has the highest affinity to the binding brain-derived neurotrophic factor (BDNF) and NT-4. BDNF is growth factor that has important roles in the survival and function of neurons in the central nervous system. The binding of BDNF to TrkB receptor causes many intercellular cascades be activated, which regulate neuronal development and plasticity, long-term potentiation, and apoptosis.
Although both BDNF and NT-4 have high specificity to TrkB, they are not interchangeable. In a mouse model study where BDNF expression was replaced by NT-4, the mouse with NT4 expression appeared to be smaller and exhibited decreased fertility.
Recently, studies have also indicated that TrkB receptor is associated with Alzheimer's disease.
## TrkC
TrkC is ordinarily activated by binding with NT-3 and has little activation by other ligands. (TrkA and TrkB also bind NT-3, but to a lesser extent.) TrkC is mostly expressed by proprioceptive sensory neurons. The axons of these proprioceptive sensory neurons are much thicker than those of nocireceptive sensory neurons, which express trkA.
# Regulation by P75NTR
p75NTR (p75 neurotrophin receptor) affects the binding affinity and specificity of Trk receptor activation by neurotrophins. The presence of p75NTR is especially important in increasing the binding affinity of NGF to TrkA. Although the dissociation constants of p75NTR and TrkA are remarkably similar, their kinetics are quite different. Reduction and mutation of cytoplasmic and transmembrane domains of either TrkA or P75NTR prevent the formation of high-affinity binding sites on TrkA. However, the binding of ligands in p75NTR is not required to promote high-affinity binding. Therefore, the data suggest that the presence of p75NTR affects the conformation of TrkA, preferentially the state with high-affinity binding site for NGF. Surprisingly, although the presence of p75NTR is essential to promote high-affinity binding, the NT3 binding to the receptor is not required.
Apart from affecting the affinity and specificity for Trk receptor, P75 neurotropins receptor (P75NTR) can also reduce ligand-induced receptor ubiquitination, delays receptor internalization, and degradation. In an experiment by Makkerh in 2005, both TrkA and TrkB receptors were tested using similar method. The only difference is that NGF was used to activate the TrkA receptor whereas BDNF was used for TrkB receptor.
To test if TrkA and TrkB receptors activity are ligand-dependant, the receptors are treated with NGF and BDNF correspondingly. In vivo, the activity of these receptors is regulated by ubiquitination, the process in which protein undergoes modification by attachment of ubiquitin monomers. These molecules usually have main function of labeling proteins for proteasomal degradation. After being activated, Trk receptors may undergo endocytosis and will be either recycled or degraded. Two types of cells were used to test the protocol, P12 cells and E16 mouse cortices. An E16 mouse cortex was used in conjunction with BDNF, since it expresses abundant TrkB and lesser p75NTR. On the other hands, P12 cells were treated with NGF, since it expresses more TrkA and p75NTR but not TrkB and TrkC. The treated receptors were then immunoprecipitated and immunoblotted to be analyzed. The result shows that TrkB phosphotyrosine (activated TrkB) content increased rapidly with the presence of BDNF compared with control (absence of BDNF) whereas TrkA phosphotyrosine content increased modestly when treated with NGF.
To test if p75NTR reduces Trk ubiquitination, HEK293 (human embryonic kidney 293 cells) were co-tranfected with plasmids encoding TrkA and Myc-tagged ubiquitin with the presence and absence of plasmid encoding P25NTR. When treated with their corresponding neurotrophins, lower levels of ubiquitinated TrkA and TrkB are present in presence of p75NTR. Vice versa, in the absence of p75NTR, ubiquitination content increases decreases significantly.
To test the hypothesis, HEK93 cells were subjected to biotinylation with the presence and absence of P25NTR. Each samples were taken at different time points (0, 2, 5, and 15 mins), immunoblotted, and screened for the level of tyrosine-phosphorylated molecules. The result shows increases in the level of tyrosine-phosphorylated molecules with the presence of p75NTR. In absence of P25NTR, tyrosine-phosphorylated level fell below detection limit in 5 min. The biotinylated protein complexes were lysed to show both tyrosine-phosphorylated molecules in the surface and those that been internalized.
# Essential roles in differentiation and function
### Precursor cell survival and proliferation
Numerous studies, both in vivo and in vitro, have shown that neurotrophins have proliferation and differentiation effects on CNS neuro-epithelial precursors, neural crest cells, or precursors of the enteric nervous system. TrkA that expresses NGF not only increase the survival of both C and A delta classes of nocireceptor neurons, but also affect the functional properties of these neurons.4 As mentioned before, BDNF improves the survival and function of neurons in CNS, particularly cholinergic neurons of the basal forebrain, as well as neurons in the hippocampus and cortex.
BDNF belongs to the neurotrophin family of growth factors and affects the survival and function of neurons in the central nervous system, particularly in brain regions susceptible to degeneration in AD. BDNF improves survival of cholinergic neurons of the basal forebrain, as well as neurons in the hippocampus and cortex.
TrkC that expresses NT3 has been shown to promote proliferation and survival of cultured neural crest cells, oligodendrocyte precursors, and differentiation of hippocampal neuron precursors.
### Control of target innervation
Each of the neurotrophins mentioned aboveTemplate:Vague promotes neurite outgrowth. NGF/TrkA signaling regulates the advance of sympathetic neuron growth cones; even when neurons received adequate trophic (sustaining and nourishing) support, one experiment showed they did not grow into relating compartments without NGF.Template:Vague NGF increases the innervation of tissues that receive sympathetic or sensory innervation and induces aberrant innervation in tissues that are normally not innervated.
NGF/TrkA signaling upregulates BDNF, which is transported to both peripheral and central terminals of nocireceptive sensory neurons. In the periphery, TrkB/BDNF binding and TrkB/NT-4 binding acutely sensitizing nocireceptive pathway that require the presence of mast cells.
### Sensory neuron function
Trk receptors and their ligands (neurotrophins) also affect neurons' functional properties. Both NT-3 and BDNF are important in the regulation and development of synapses formed between afferent neurons and motor neurons. Increased NT-3/trkC binding results in larger monosynaptic excitatory postsynaptic potentials (EPSPs) and reduced polysynaptic components. On the other hand, increased NT-3 binding to trkB to BDNFTemplate:Vague has the opposite effect, reducing the size of monosynaptic excitatory postsynaptic potentials (EPSPs) and increasing polysynaptic signaling.
### Formation of ocular dominance column
In the development of mammalian visual system, axons from each eyes crosses through the lateral geniculate nucleus (LGN) and terminate in separate layers of striate cortex. However, axons from each LGN can only be driven by one side of the eye, but not both together. tThese axons that terminate in layer IV of the striate cortex result in ocular dominance columns. A study shows that The density of innervating axons in layer IV from LGN can be increased by exogenous BDNF and reduced by a scavenger of endogenous BDNF. Therefore, it raises the possibility that both of these agents are involved in some sorting mechanism that is not well comprehended yet. Previous studies with cat model has shown that monocular deprivation occurs when input to one of the mammalian eyes is absent during the critical period (critical window). However, A study demonstrated that the infusion of NT-4 (a ligand of trkB) into the visual cortex during the critical period has been shown to prevent many consequences of monocular deprivation. Surprisingly, even after losing responses during the critical period, the infusion of NT-4 has been shown to be able to restore them.
### Synaptic strength and plasticity
In mammalian hippocampus, the axons of the CA3 pyramidal cells project into CA1 cells through the Schaffer collaterals. The long-term potentiation (LTP) may induce in either of these pathways, but it is specific only to the one that is stimulated with tetanus.Template:Vague The stimulated axon does not impact spill over to the other pathway. TrkB receptors are expressed in most of these hippocampal neurons, including dentate granule cells, CA3 and CA1 pyramidal cells, and inhibitory interneurons. Interestingly, LTP can be greatly reduced by BDNF mutants. In a similar study on a mouse mutant with reduced expression of trkB receptors, LTP of CA1 cells reduced significantly. TrkB loss has also been linked to interfere with the memory acquisition and consolidation in many learning paradigm.
# Activation pathway
Trk receptors dimerize in response to ligand, as do other tyrosine kinase receptors. These dimers phosphorylate each other and enhance catalytic activity of the kinase. Trk receptors affect neuronal growth and differentiation through the activation of different signaling cascades. The three known pathways are PLC, Ras/MAPK (mitogen-activated protein kinase) and the PI3K (phosphatidylinositol 3-kinase) pathways. These pathways involve the interception of nuclear and mitochondrial cell-death programs. These signaling cascades eventually led to the activation of a transcription factor, CREB (cAMP response element-binding), which in turn the activate target genes.
### PKC pathways
The binding of neutrophin will lead to the phosphorylation PLC by trk receptor. The phosphorylation of PLC induces an enzyme to catalyze the breakdown of lipids to diacyglycerol and inositol (1,4, 5). Diacyglycerol may indirectly activate PI3 kinase or several protein kinases C isoform, whereas inositol (1,4, 5) promotes release of calcium from intracellular stores.
### Ras/MAPK pathway
The signaling through Ras/MAPK pathway is important for the neurotrophin-induced differentiation of neuronal and neuroblastoma cells. Phosphorylation of tyrosine residues in the Trk receptors led to the activation of Ras molecules, H-Ras and K-Ras. H-ras is found in lipid rafts, embedded within the plasma membrane, while K-Ras is predominantly found in disordered region of the membrane. RAP, a vesicle bounded molecule that also takes part in the cascading, is localized in the intracellular region.
The activation of these molecules result in two alternative MAP kinase pathways. Erk 1,2 can be stimulated through the activation cascades of K-Ras, Raf1, and MEK 1,2, whereas ERK 5 is stimulated through the activation cascades of B-Raf, MEK5, and Erk 5. However, whether PKC (protein kinase C) could activate MEK5 is not yet known.
### PI3 pathway
PI3 pathway signaling is critical for both mediation of neurotrophin-induced survival and regulation of vesicular trafficking. The trk receptor stimulates P13 heterodimers, which causes the activation of kinases PDK-1 and Akt. Akt in turn stimulates FRK (Forkhead family transcription factor), BAD, and GSK-3.
Some studies have suggested that NGF/TrkA coupling causes preferential activation of the Ras/MAPK pathway, whereas NT3/TrkC coupling causes preferential activation of the PI3 pathway. | Trk receptor
# Overview
Trk receptors are a family of tyrosine kinases that regulates synaptic strength and plasticity in the mammalian nervous system.[1] Trk receptors affect neuronal survival and differentiation through several signal cascades. However, the activation of these receptors also has significant effects on functional properties of neurons.
The common ligands of trk receptors are neurotrophins, a family of growth factors critical to the functioning of the nervous system.[2] The binding of these molecules is highly specific. Each type of neurotrophin has different binding affinity toward its corresponding trk receptor. The activation of Trk receptors by neurotrophin binding may lead to activation of signal cascades resulting in promoting survival and other functional regulation of cells.
# Origin of the name trk
The abbreviation trk (often pronounced 'track') stands for tropomyosin-receptor-kinase [3] (and not tyrosine kinase nor tropomyosin-related kinase, as has been commonly mistaken).
The family of Trk receptors is named for the oncogene trk, whose identifical led to the discovery of its first member, TrkA[1]. trk, initially identified in a colon carcinoma, is frequently (25%) activated in thyroid papillary carcinomas [4]. The oncogene was generated by a mutation in chromosome 1 that resulted in the fusion of the first seven exons of tropomyosin to the transmembrane and cytoplasmic domains of the then-unknown TrkA receptor [3]. Normal Trk receptors do not contain amino acid or DNA sequences related to tropomyosin.
# Trk receptor types and corresponding ligands
The three most common types of trk receptors are trkA, trkB, and trkC. Each of these receptors types has different binding affinity to certain types of neurotrophins. The differences in the signaling initiated by these distinct types of receptors are important for generating diverse of biological responses.
Neurotrophin ligands of Trk receptors are processed ligands,[2] meaning that they are synthesized in immature forms and then transformed by protease cleavage. Immature neurotrophins are specific only to one common p75NTR receptor. However, protease cleavage generates neurotrophins that have higher affinity to their corresponding Trk receptors. These processed neurotrophins can still bind to p75NTR, but at a much lower affinity.
## TrkA
TrkA has the highest affinity to the binding nerve growth factor (NGF). NGF is important in both local and nuclear actions, regulating growth cones, motility, and expression of genes encoding the biosynthesis enzymes for neurotransmitters. Nocireceptive sensory neurons express mostly trkA and not trkB or trkC.
## TrkB
TrkB has the highest affinity to the binding brain-derived neurotrophic factor (BDNF) and NT-4. BDNF is growth factor that has important roles in the survival and function of neurons in the central nervous system. The binding of BDNF to TrkB receptor causes many intercellular cascades be activated, which regulate neuronal development and plasticity, long-term potentiation, and apoptosis.[5]
Although both BDNF and NT-4 have high specificity to TrkB, they are not interchangeable.[6] In a mouse model study where BDNF expression was replaced by NT-4, the mouse with NT4 expression appeared to be smaller and exhibited decreased fertility.[6]
Recently, studies have also indicated that TrkB receptor is associated with Alzheimer's disease.[5]
## TrkC
TrkC is ordinarily activated by binding with NT-3 and has little activation by other ligands. (TrkA and TrkB also bind NT-3, but to a lesser extent.[2]) TrkC is mostly expressed by proprioceptive sensory neurons.[2] The axons of these proprioceptive sensory neurons are much thicker than those of nocireceptive sensory neurons, which express trkA.[2]
# Regulation by P75NTR
p75NTR (p75 neurotrophin receptor) affects the binding affinity and specificity of Trk receptor activation by neurotrophins. The presence of p75NTR is especially important in increasing the binding affinity of NGF to TrkA.[2] Although the dissociation constants of p75NTR and TrkA are remarkably similar, their kinetics are quite different.[2] Reduction and mutation of cytoplasmic and transmembrane domains of either TrkA or P75NTR prevent the formation of high-affinity binding sites on TrkA.[2] However, the binding of ligands in p75NTR is not required to promote high-affinity binding.[2] Therefore, the data suggest that the presence of p75NTR affects the conformation of TrkA, preferentially the state with high-affinity binding site for NGF.[2] Surprisingly, although the presence of p75NTR is essential to promote high-affinity binding, the NT3 binding to the receptor is not required.[2]
Apart from affecting the affinity and specificity for Trk receptor, P75 neurotropins receptor (P75NTR) can also reduce ligand-induced receptor ubiquitination, delays receptor internalization, and degradation.[7] In an experiment by Makkerh in 2005, both TrkA and TrkB receptors were tested using similar method.[7] The only difference is that NGF was used to activate the TrkA receptor whereas BDNF was used for TrkB receptor.[7]
To test if TrkA and TrkB receptors activity are ligand-dependant, the receptors are treated with NGF and BDNF correspondingly.[7] In vivo, the activity of these receptors is regulated by ubiquitination, the process in which protein undergoes modification by attachment of ubiquitin monomers.[7] These molecules usually have main function of labeling proteins for proteasomal degradation.[7] After being activated, Trk receptors may undergo endocytosis and will be either recycled or degraded.[7] Two types of cells were used to test the protocol, P12 cells and E16 mouse cortices.[7] An E16 mouse cortex was used in conjunction with BDNF, since it expresses abundant TrkB and lesser p75NTR.[7] On the other hands, P12 cells were treated with NGF, since it expresses more TrkA and p75NTR but not TrkB and TrkC.[7] The treated receptors were then immunoprecipitated and immunoblotted to be analyzed.[7] The result shows that TrkB phosphotyrosine (activated TrkB) content increased rapidly with the presence of BDNF compared with control (absence of BDNF) whereas TrkA phosphotyrosine content increased modestly when treated with NGF.[7]
To test if p75NTR reduces Trk ubiquitination, HEK293 (human embryonic kidney 293 cells) were co-tranfected with plasmids encoding TrkA and Myc-tagged ubiquitin with the presence and absence of plasmid encoding P25NTR.[7] When treated with their corresponding neurotrophins, lower levels of ubiquitinated TrkA and TrkB are present in presence of p75NTR.[7] Vice versa, in the absence of p75NTR, ubiquitination content increases decreases significantly.[7]
To test the hypothesis, HEK93 cells were subjected to biotinylation with the presence and absence of P25NTR.[7] Each samples were taken at different time points (0, 2, 5, and 15 mins), immunoblotted, and screened for the level of tyrosine-phosphorylated molecules.[7] The result shows increases in the level of tyrosine-phosphorylated molecules with the presence of p75NTR.[7] In absence of P25NTR, tyrosine-phosphorylated level fell below detection limit in 5 min.[7] The biotinylated protein complexes were lysed to show both tyrosine-phosphorylated molecules in the surface and those that been internalized.[7]
# Essential roles in differentiation and function
### Precursor cell survival and proliferation
Numerous studies, both in vivo and in vitro, have shown that neurotrophins have proliferation and differentiation effects on CNS neuro-epithelial precursors, neural crest cells, or precursors of the enteric nervous system.[8] TrkA that expresses NGF not only increase the survival of both C and A delta classes of nocireceptor neurons, but also affect the functional properties of these neurons.4 As mentioned before, BDNF improves the survival and function of neurons in CNS, particularly cholinergic neurons of the basal forebrain, as well as neurons in the hippocampus and cortex.[9]
BDNF belongs to the neurotrophin family of growth factors and affects the survival and function of neurons in the central nervous system, particularly in brain regions susceptible to degeneration in AD. BDNF improves survival of cholinergic neurons of the basal forebrain, as well as neurons in the hippocampus and cortex.[9]
TrkC that expresses NT3 has been shown to promote proliferation and survival of cultured neural crest cells, oligodendrocyte precursors, and differentiation of hippocampal neuron precursors.[8]
### Control of target innervation
Each of the neurotrophins mentioned aboveTemplate:Vague promotes neurite outgrowth.[8] NGF/TrkA signaling regulates the advance of sympathetic neuron growth cones; even when neurons received adequate trophic (sustaining and nourishing) support, one experiment showed they did not grow into relating compartments without NGF.Template:Vague[8] NGF increases the innervation of tissues that receive sympathetic or sensory innervation and induces aberrant innervation in tissues that are normally not innervated.[8]
NGF/TrkA signaling upregulates BDNF, which is transported to both peripheral and central terminals of nocireceptive sensory neurons.[8] In the periphery, TrkB/BDNF binding and TrkB/NT-4 binding acutely sensitizing nocireceptive pathway that require the presence of mast cells.[8]
### Sensory neuron function
Trk receptors and their ligands (neurotrophins) also affect neurons' functional properties.[8] Both NT-3 and BDNF are important in the regulation and development of synapses formed between afferent neurons and motor neurons.[8] Increased NT-3/trkC binding results in larger monosynaptic excitatory postsynaptic potentials (EPSPs) and reduced polysynaptic components.[8] On the other hand, increased NT-3 binding to trkB to BDNFTemplate:Vague has the opposite effect, reducing the size of monosynaptic excitatory postsynaptic potentials (EPSPs) and increasing polysynaptic signaling.[8]
### Formation of ocular dominance column
In the development of mammalian visual system, axons from each eyes crosses through the lateral geniculate nucleus (LGN) and terminate in separate layers of striate cortex. However, axons from each LGN can only be driven by one side of the eye, but not both together. tThese axons that terminate in layer IV of the striate cortex result in ocular dominance columns. A study shows that The density of innervating axons in layer IV from LGN can be increased by exogenous BDNF and reduced by a scavenger of endogenous BDNF.[8] Therefore, it raises the possibility that both of these agents are involved in some sorting mechanism that is not well comprehended yet.[8] Previous studies with cat model has shown that monocular deprivation occurs when input to one of the mammalian eyes is absent during the critical period (critical window). However, A study demonstrated that the infusion of NT-4 (a ligand of trkB) into the visual cortex during the critical period has been shown to prevent many consequences of monocular deprivation.[8] Surprisingly, even after losing responses during the critical period, the infusion of NT-4 has been shown to be able to restore them.[8]
### Synaptic strength and plasticity
In mammalian hippocampus, the axons of the CA3 pyramidal cells project into CA1 cells through the Schaffer collaterals. The long-term potentiation (LTP) may induce in either of these pathways, but it is specific only to the one that is stimulated with tetanus.Template:Vague The stimulated axon does not impact spill over to the other pathway. TrkB receptors are expressed in most of these hippocampal neurons, including dentate granule cells, CA3 and CA1 pyramidal cells, and inhibitory interneurons.[8] Interestingly, LTP can be greatly reduced by BDNF mutants.[8] In a similar study on a mouse mutant with reduced expression of trkB receptors, LTP of CA1 cells reduced significantly.[8] TrkB loss has also been linked to interfere with the memory acquisition and consolidation in many learning paradigm.[8]
# Activation pathway
Trk receptors dimerize in response to ligand, as do other tyrosine kinase receptors.[2] These dimers phosphorylate each other and enhance catalytic activity of the kinase.[2] Trk receptors affect neuronal growth and differentiation through the activation of different signaling cascades. The three known pathways are PLC, Ras/MAPK (mitogen-activated protein kinase) and the PI3K (phosphatidylinositol 3-kinase) pathways.[2] These pathways involve the interception of nuclear and mitochondrial cell-death programs.[2] These signaling cascades eventually led to the activation of a transcription factor, CREB (cAMP response element-binding), which in turn the activate target genes.[2]
### PKC pathways
The binding of neutrophin will lead to the phosphorylation PLC by trk receptor. The phosphorylation of PLC induces an enzyme to catalyze the breakdown of lipids to diacyglycerol and inositol (1,4, 5).[2] Diacyglycerol may indirectly activate PI3 kinase or several protein kinases C isoform, whereas inositol (1,4, 5) promotes release of calcium from intracellular stores.[2]
### Ras/MAPK pathway
The signaling through Ras/MAPK pathway is important for the neurotrophin-induced differentiation of neuronal and neuroblastoma cells.[2] Phosphorylation of tyrosine residues in the Trk receptors led to the activation of Ras molecules, H-Ras and K-Ras.[2] H-ras is found in lipid rafts, embedded within the plasma membrane, while K-Ras is predominantly found in disordered region of the membrane.[2] RAP, a vesicle bounded molecule that also takes part in the cascading, is localized in the intracellular region.[2]
The activation of these molecules result in two alternative MAP kinase pathways.[2] Erk 1,2 can be stimulated through the activation cascades of K-Ras, Raf1, and MEK 1,2, whereas ERK 5 is stimulated through the activation cascades of B-Raf, MEK5, and Erk 5.[2] However, whether PKC (protein kinase C) could activate MEK5 is not yet known.[2]
### PI3 pathway
PI3 pathway signaling is critical for both mediation of neurotrophin-induced survival and regulation of vesicular trafficking.[2] The trk receptor stimulates P13 heterodimers, which causes the activation of kinases PDK-1 and Akt.[2] Akt in turn stimulates FRK (Forkhead family transcription factor), BAD, and GSK-3.
Some studies have suggested that NGF/TrkA coupling causes preferential activation of the Ras/MAPK pathway, whereas NT3/TrkC coupling causes preferential activation of the PI3 pathway.[2] | https://www.wikidoc.org/index.php/TRK | |
9645663d5d800645a171bd266a5efd33d3a16e11 | wikidoc | Tanner stage | Tanner stage
# Overview
The Tanner stages (also known as the Tanner scale) are stages of physical development in children, adolescents and adults. The stages define physical measurements of development based on external primary and secondary sex characteristics, such as the size of the breasts, genitalia, and development of pubic hair.
Due to natural variation, individuals pass through the Tanner stages at different rates, depending in particular on the timing of puberty.
In HIV treatment, Tanner staging is used to determine which treatment regimen to follow (adult, adolescent, or pediatric).
The Tanner stages were first identified by James Mourilyan Tanner and thus bear his name.
# Definitions of stages
Adapted from text by Lawrence Neinstein, MD.
## Pubic hair (both male and female)
## Genitals (male)
## Breasts (female) | Tanner stage
# Overview
The Tanner stages (also known as the Tanner scale) are stages of physical development in children, adolescents and adults. The stages define physical measurements of development based on external primary and secondary sex characteristics, such as the size of the breasts, genitalia, and development of pubic hair.
Due to natural variation, individuals pass through the Tanner stages at different rates, depending in particular on the timing of puberty.
In HIV treatment, Tanner staging is used to determine which treatment regimen to follow (adult, adolescent, or pediatric).
The Tanner stages were first identified by James Mourilyan Tanner and thus bear his name.
# Definitions of stages
Adapted from text by Lawrence Neinstein, MD.[1]
## Pubic hair (both male and female)
## Genitals (male)
## Breasts (female) | https://www.wikidoc.org/index.php/Tanner_stage | |
13d15f2e2356a77b64cbc9e9dbd190853613cea3 | wikidoc | Taurodontism | Taurodontism
# Overview
Taurodontism is a condition found in teeth where the body of the tooth and pulp chamber is enlarged. As a result, the floor of the pulp and the furcation of the tooth is moved apically down the root.
The term means "bull like" teeth derived from similarity of these teeth to those of ungulate or cud chewing animals.
According to Shaw these can be classified as hypotaurodont, hypertaurodont and mesotaurodont.
According to Mangion taurodontism may be:
1. A retrograde character
2. A primitive pattern
3. Mendalian recessive character
4. Atavistic feature
5. A mutation
The condition is of anthropological importance as it was seen in Neanderthals. It has also been reported in Klinefelter's syndrome.
The teeth involved are invariably molars, sometimes single and at the other times multiple teeth may be involved. The teeth themselves may look normal and do not have any paricular anatomical character on clinical examination.
On dental radiograph, the involved tooth looks rectangular in shape without apical taper. The pulp chamber is extremely large and the furcations may be only a few millimeters long at times. | Taurodontism
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Taurodontism is a condition found in teeth where the body of the tooth and pulp chamber is enlarged. As a result, the floor of the pulp and the furcation of the tooth is moved apically down the root.
The term means "bull like" teeth derived from similarity of these teeth to those of ungulate or cud chewing animals.
According to Shaw these can be classified as hypotaurodont, hypertaurodont and mesotaurodont.
According to Mangion taurodontism may be:
1. A retrograde character
2. A primitive pattern
3. Mendalian recessive character
4. Atavistic feature
5. A mutation
The condition is of anthropological importance as it was seen in Neanderthals. It has also been reported in Klinefelter's syndrome.
The teeth involved are invariably molars, sometimes single and at the other times multiple teeth may be involved. The teeth themselves may look normal and do not have any paricular anatomical character on clinical examination.
On dental radiograph, the involved tooth looks rectangular in shape without apical taper. The pulp chamber is extremely large and the furcations may be only a few millimeters long at times. | https://www.wikidoc.org/index.php/Taurodontism | |
690dfcea301276d8895d56723f9f0f39a3712ab0 | wikidoc | Tea tree oil | Tea tree oil
# Overview
Tea tree oil is an extraction from the Melaleuca tree. Tea tree oil should not be confused with tea oil, the sweet seasoning and cooking oil from pressed seeds of the tea plant (drinking tea) Camellia sinensis or the tea oil plant Camellia oleifera.
The term "tea tree oil" is also somewhat of a misnomer since Melaleuca alternifolia is a paperbark rather than a tea tree (genus Leptospermum).
Tea tree oil or melaleuca oil is a clear to very pale golden color essential oil with a fresh camphoraceous odour. It is taken from the leaves of the Melaleuca alternifolia which is native to the northeast coast of New South Wales, Australia. The oil is believed to have beneficial cosmetic and medical properties (including antiseptic and antifungal action).
# History and extraction
The indigenous Bundjalung people of eastern Australia use “tea trees” as a traditional medicine by inhaling the oils from the crushed leaves to treat coughs and colds. They also sprinkle leaves on wounds, after which a poultice is applied. In addition, tea tree leaves are soaked to make an infusion to treat sore throats or skin ailments.
Use of the oil itself, as opposed to the unextracted plant material, did not become common practice until researcher, Arthur Penfold, published the first reports of its antimicrobial activity in a series of papers in the 1920s and 1930s. In evaluating the antimicrobial activity of M. alternifolia, tea tree oil was rated as 11 times more active than phenol.
The commercial tea tree oil industry was born after the medicinal properties of the oil were first reported by Penfold in the 1920s. It was produced from natural bush stands of M. alternifolia that produced oil with the appropriate chemotype. The plant material was hand cut and often distilled on the spot in makeshift, mobile, wood-fired bush stills.
Production ebbed after World War II as demand for the oil declined, presumably due to the development of effective antibiotics and the waning image of natural products. Interest in the oil was rekindled in the 1970s as part of the general renaissance of interest in natural products. Commercial plantations were established in the 1970s and 1980s, which lead to mechanization and large-scale production of a consistent essential oil product.
Among over 98 compounds contained in the oil, terpinen-4-ol is responsible for most of the antimicrobial actions.
Although tea tree oil is normally extracted from Melaleuca alternifolia commercially, it can also be extracted from Melaleuca dissitiflora and Melaleuca linariifolia. Tea tree oil is defined by international standard ISO 4730 ("Oil of Melaleuca, Terpinen-4-ol type"), which specifies levels of 14 components which are needed to define the oil as "tea tree oil."
# Medicinal use
Tea tree oil has been recognized as a potent antiseptic in Australia anecdotally for much longer than there has been scientific evidence. However, recent studies support a role for tea tree oil in skin care and treatment of various ailments.
Tea tree oil is a known antifungal agent, effective in vitro against multiple dermatophytes found on the skin. In vivo, shampoo with 5% tea tree oil has been shown to be an effective treatment for dandruff due to its ability to treat Malassezia furfur, the most common cause of the condition.
Tea Tree Oil is used in medically used cosmetic products also. Some references are there to suggest its role as antiviral.
Effectiveness of topical tea tree oil preparations for Candidiasis is supported by their ability to kill Candida in vitro.
In the treatment of moderate acne, topical application of 5% tea tree oil has shown an effect comparable to 5% benzoyl peroxide, albeit with slower onset of action. Another study in 2007 5% strength gel was compared against a placebo, with statistically significant results.
Tea tree oil is also effective for treating insect bites, boils and minor wounds. It has also been known to help soothe sunburns, poison ivy, ear infections, and bee stings.
Diluted solutions of tea tree oil are sold as remedies which claim to treat bacterial and fungal infection in pet fish.
Pets: Skin problems, wounds, insect bites and stings, and ringworm can all be treated with tea tree oil or products made with tea tree oil. There are some cases where pure tea tree oil placed on the skin of the animal can cause irritation (recovering quickly after discontinuing). Therefore, test the treatment first by applying only to a small area of the animal's skin.
Toothpastes and mouthwashes containing tea tree oil are shown to be effective for a number of oral problems. Some of these include, halitosis (bad breath), gum disease, and canker sores.
There is some limited research that has shown that tea tree oil may have anti-viral activity, especially with the Herpes virus (cold sores, chicken pox and shingles blisters, warts, etc.)
# Safety
Melaleuca oil is used almost exclusively externally.
Data on oral use of tea tree oil in humans in large quantities is sparse aside from several anecdotal reports of side effects following oral ingestion. Symptoms may include ataxia and drowsiness. A relatively small number of people report an allergic reaction to tea tree oil which could consist of a minor skin irritation. In a study of 725 consecutive patients, patients were patch tested with undiluted, 1% and
0.1% Tea Tree Oil. For pure undiluted tea tree oil, less than 6% of the patients observed positive reactions of skin irritation.
Only 1 of 725 patients observed a positive reaction of skin irritation with the 1% dilution. None of the 725 patients observed adverse reactions with the 0.1% dilution.
A case study reported in a recent publication showed a possible association between repeated topical application of products containing lavender oil with prepubertal gynecomastia (abnormal breast development in young boys). The study involved just three individuals. All three cases included the use of lavender oil. In one of the three cases, a product was used that contained lavender oil as well as tea tree oil, and other ingredients. The prepubertal gynecomastia reversed after discontinuing use of products containing lavender oil. In the same paper, results from cell culture assays indicated that both essential oils exhibit weak estrogenic properties. Researchers indicated that other components in these products may also have contributed to the gynecomastia, but those components were not yet tested. Researchers also noted that estrogenic activities have also been reported for many other commonly used essential oils as well as foods such as almonds and peanuts. Other articles have cast doubt as to the conclusions of the article and dismissed the study as having used "poor methodology".
As with many antibiotics, if used in 4% concentrations or below it may activate stress reactions in bacteria which can cause them to become less sensitive to antibiotics in vitro. Tea tree oil is not recommended for use in the ears. | Tea tree oil
# Overview
Tea tree oil is an extraction from the Melaleuca tree. Tea tree oil should not be confused with tea oil, the sweet seasoning and cooking oil from pressed seeds of the tea plant (drinking tea) Camellia sinensis or the tea oil plant Camellia oleifera.
The term "tea tree oil" is also somewhat of a misnomer since Melaleuca alternifolia is a paperbark rather than a tea tree (genus Leptospermum).
Tea tree oil or melaleuca oil is a clear to very pale golden color essential oil with a fresh camphoraceous odour. It is taken from the leaves of the Melaleuca alternifolia which is native to the northeast coast of New South Wales, Australia. The oil is believed to have beneficial cosmetic and medical properties (including antiseptic and antifungal action).
# History and extraction
The indigenous Bundjalung people of eastern Australia use “tea trees” as a traditional medicine by inhaling the oils from the crushed leaves to treat coughs and colds. They also sprinkle leaves on wounds, after which a poultice is applied. In addition, tea tree leaves are soaked to make an infusion to treat sore throats or skin ailments.[1][2]
Use of the oil itself, as opposed to the unextracted plant material, did not become common practice until researcher, Arthur Penfold, published the first reports of its antimicrobial activity in a series of papers in the 1920s and 1930s. In evaluating the antimicrobial activity of M. alternifolia, tea tree oil was rated as 11 times more active than phenol.[3]
The commercial tea tree oil industry was born after the medicinal properties of the oil were first reported by Penfold in the 1920s. It was produced from natural bush stands of M. alternifolia that produced oil with the appropriate chemotype. The plant material was hand cut and often distilled on the spot in makeshift, mobile, wood-fired bush stills.
Production ebbed after World War II as demand for the oil declined, presumably due to the development of effective antibiotics and the waning image of natural products. Interest in the oil was rekindled in the 1970s as part of the general renaissance of interest in natural products. Commercial plantations were established in the 1970s and 1980s, which lead to mechanization and large-scale production of a consistent essential oil product.[4]
Among over 98 compounds contained in the oil, terpinen-4-ol is responsible for most of the antimicrobial actions.
Although tea tree oil is normally extracted from Melaleuca alternifolia commercially, it can also be extracted from Melaleuca dissitiflora and Melaleuca linariifolia. Tea tree oil is defined by international standard ISO 4730 ("Oil of Melaleuca, Terpinen-4-ol type"), which specifies levels of 14 components which are needed to define the oil as "tea tree oil."
# Medicinal use
Tea tree oil has been recognized as a potent antiseptic in Australia anecdotally for much longer than there has been scientific evidence. However, recent studies support a role for tea tree oil in skin care and treatment of various ailments.
Tea tree oil is a known antifungal agent, effective in vitro against multiple dermatophytes found on the skin.[5] In vivo, shampoo with 5% tea tree oil has been shown to be an effective treatment for dandruff due to its ability to treat Malassezia furfur, the most common cause of the condition.[6]
Tea Tree Oil is used in medically used cosmetic products also. Some references are there to suggest its role as antiviral.
Effectiveness of topical tea tree oil preparations for Candidiasis is supported by their ability to kill Candida in vitro.[7]
In the treatment of moderate acne, topical application of 5% tea tree oil has shown an effect comparable to 5% benzoyl peroxide, albeit with slower onset of action.[8] Another study in 2007 5% strength gel was compared against a placebo, with statistically significant results.[9]
Tea tree oil is also effective for treating insect bites, boils and minor wounds.[10] It has also been known to help soothe sunburns, poison ivy, ear infections, and bee stings.[11]
Diluted solutions of tea tree oil are sold as remedies which claim to treat bacterial and fungal infection in pet fish.
Pets: Skin problems, wounds, insect bites and stings, and ringworm can all be treated with tea tree oil or products made with tea tree oil. There are some cases where pure tea tree oil placed on the skin of the animal can cause irritation (recovering quickly after discontinuing). Therefore, test the treatment first by applying only to a small area of the animal's skin.[12]
Toothpastes and mouthwashes containing tea tree oil are shown to be effective for a number of oral problems. Some of these include, halitosis (bad breath), gum disease, and canker sores.[13][14][15]
There is some limited research that has shown that tea tree oil may have anti-viral activity, especially with the Herpes virus (cold sores, chicken pox and shingles blisters, warts, etc.)[16]
# Safety
Melaleuca oil is used almost exclusively externally.
Data on oral use of tea tree oil in humans in large quantities is sparse aside from several anecdotal reports of side effects following oral ingestion.[17] Symptoms may include ataxia and drowsiness. A relatively small number of people report an allergic reaction to tea tree oil which could consist of a minor skin irritation. In a study of 725 consecutive patients, patients were patch tested with undiluted, 1% and
0.1% Tea Tree Oil. For pure undiluted tea tree oil, less than 6% of the patients observed positive reactions of skin irritation.
Only 1 of 725 patients observed a positive reaction of skin irritation with the 1% dilution. None of the 725 patients observed adverse reactions with the 0.1% dilution.[18]
A case study reported in a recent publication showed a possible association between repeated topical application of products containing lavender oil with prepubertal gynecomastia (abnormal breast development in young boys). The study involved just three individuals. All three cases included the use of lavender oil. In one of the three cases, a product was used that contained lavender oil as well as tea tree oil, and other ingredients. The prepubertal gynecomastia reversed after discontinuing use of products containing lavender oil. In the same paper, results from cell culture assays indicated that both essential oils exhibit weak estrogenic properties. Researchers indicated that other components in these products may also have contributed to the gynecomastia, but those components were not yet tested. Researchers also noted that estrogenic activities have also been reported for many other commonly used essential oils as well as foods such as almonds and peanuts.[19] Other articles have cast doubt as to the conclusions of the article and dismissed the study as having used "poor methodology".[20][21]
As with many antibiotics, if used in 4% concentrations or below it may activate stress reactions in bacteria which can cause them to become less sensitive to antibiotics in vitro.[22] Tea tree oil is not recommended for use in the ears.[23] | https://www.wikidoc.org/index.php/Tea_tree_oil | |
a291241ff67081d6b311cff6bcb169fd59bc8a35 | wikidoc | Team nursing | Team nursing
Assistant Editor-In-Chief: Michelle Lew
# Overview
Team nursing is an historical method of nursing practice which utilized the "economy of scale" philosophy by having one nurse or nursing assistant do one specialized function for all the inpatients within a nursing unit of a hospital. For example, one nurse may administer and record all the medications, while another checks and records the vital signs of those same inpatients.
Team nursing was developed in 1950’s (under grant from W.K. Kellogg Foundation) directed by Eleanor Lambertson at Teachers college, Columbia University in New York. Because the functional method received criticism, a new system of nursing was devised to improve patient satisfaction. “Care through others” became the hallmark of team nursing. It has been developed in an effort to decrease the problems associated with the functional organization of patient care majority of people felt that despite a continued shortage of professional nursing staff, a patient care system has to be developed that reduce the fragmented care that accompanied functional nursing.
Team nursing was developed because of social and technological changes in World War II drew many nurses away from hospitals, learning haps, services, procedures and equipments became more expensive and complicated, requiring specialization at every turn. It is an attempt to meet increased demands of nursing services and better use of knowledge and skills of professional nurses.
# Definitions
Team nursing is based on philosophy in which groups of professional and non-professional personnel work together to identify, plan, implement and evaluate comprehensive client-centred care. The key concept is a group that work’s together toward common goal, providing qualitative comprehensive nursing care (Kron 1978).
Team nursing was designed to accommodate several categories of personnel in meeting the comprehensive nursing needs of a group of clients (Donavan 1975).
# Objective of team nursing
The objective of team nursing is to give the best possible quality of patient care by utilizing the abilities of every member of the staff to the fullest extent and by providing close supervision both of patient care and of the individual who give it.
# Line of organization of team nursing
A clear line of organization structure is needed for team nursing to provide a mechanism for horizontal and vertical communication, and an organized pattern is employed.
# Functioning of team nursing
The two important points of functioning are:
- The head nurse must know at all times the condition of the patients and the plan for their care and must be assured that assignments and workmanship contribute to quality nursing
- The team leader must have freedom to use her initiative and the opportunity to nurse, to supervise and to teach unencumbered by the responsibility for administrative detail
# Functions of Registered Nurses
In the team nursing registered nurse (RN) functions as a team leader and coordinates the small group (no more than four or five) of ancillary personnel to provide care to a small group of patients.
As coordinator of the team, the RN must know the condition and needs of all patients assigned to the team and plan for the individualized care for each patient. (Marquis and Huston, 2003)
The team leader is also responsible for encouraging a cooperative environment and maintaining clear communication among all team members.
The team leader’s duties include planning care, assigning duties, directing and assisting team members, giving direct patient care, teaching and coordinating patient activities.
The team leader assigns each member specific responsibilities dependent on the role.
The members of the team report directly to the team leader, who then reports to the charge nurse or unit manager.
Communication is enhanced through the use of written patient assignments, the development of nursing care plans, and the use of regularly scheduled team conferences to discuss the patient status and formulate revisions to the plan of care.
However, for team nursing to succeed, the team leader must have strong clinical skills, good communication skills, delegation ability, decision-making ability, and the ability to create a cooperative working environment.
# Channels of communication in team nursing
- Reports
- Work or assignment conference
- Patient care conference
- Written nursing care plan
# Team conference
The greatest single distinguishing feature of team nursing is the team conference. In general, there are three parts to the conference;
- Report by each team member on her patients.
- Planning for new patients and changing plans as needed for others.
- Planning the next day’s assessment.
It is essential that the conference be well planned, brief but comprehensive and interesting. The team leader is the chair person for the conference. They offer opportunity for all personnel to evaluate patient care and solve the problems through team discussion.
# Advantages: (Marquis and Huston, 2003)
- High quality comprehensive care can be provided with a relative high proportion of ancillary staff.
- Each member of the team is able to participate in decision making and problem solving.
- Each team member is able to contribute his or her own special expertise or skills in caring for the patient.
- Improved patient satisfaction.
- Organizational decision making occurring at the lower level.
- Cost-effective system because it works with expected ratio of unlicensed to licensed personnel.
- Team nursing is an effective method of patient care delivery and has been used in most inpatient and outpatient health care settings.
## Other advantages
- Feeling of participation and belonging are facilitated with team members.
- Work load can be balanced and shared.
- Division of labour allows members the opportunity to develop leadership skills.
- Every team member has the opportunity to learn from and teach colleagues
- There is a variety in the daily assignment.
- Interest in client’s wellbeing and care is shared by several people, reliability of decisions is increased.
- Nursing care hours are usually cost effective.
- The client is able to identify personnel who are responsible for his care.
- Continuity of care is facilitated, especially if teams are constant.
- Barriers between professional and non-professional workers can be minimized, the group efforts prevail.
- Everyone has the opportunity to contribute to the care plan.
# Disadvantages
- Establishing a team concept takes time, effort and constancy of personnel. Merely assigning people to a group does not make them a ‘group’ or ‘team’.
- Unstable staffing pattern make team nursing difficult.
- All personnel must be client centered.
- There is less individual responsibility and independence regarding nursing functions.
- Continuity of care may suffer if the daily team assignments vary and the patient is confronted with many different caregivers.
- The team leader may not have the leadership skills required to effectively direct the team and create a “team spirit”.
- Insufficient time for care planning and communication may lead to unclear goals. Therefore responsibilities and care may become fragmented.
# Modifications
In an attempt to overcome some of its disadvantages, the team nursing design has been modified many times since its original inception, and variations of the model are evident in other methods of nursing care delivery such, as modular nursing.
# Modular Nursing
Modular nursing is a modification of team nursing and focuses on the patient’s geographic location for staff assignments. (Magargal 1980)
- The patient unit is divided into modules or districts, and the same team of caregivers is assigned consistently to the same geographic location.
- Each location, or module, has an RN assigned as the team leader, and the other team members may include LVN/LPN or UAP. (Yoder Wise 2003)
- Just as in the team nursing, the team leader in the modular nursing is accountable for all patient care and is responsible for providing leadership for team members and creating a cooperative work environment.
- The concept of modular nursing calls for a smaller group of staff providing care for a smaller group of patients.
- The goal is to increase the involvement of the RN in planning and coordinating care.
- Communication is more efficient among a smaller group of team members. (Marquis and Huston, 2003)
- The success of the modular nursing depends greatly on the leadership abilities of the team leader.
# Advantages: (Yoder Wise 2003)
- Continuity of care is improved when staff members are consistently assigned to the same module
- The RN as team leader is able to be more involved in planning and coordinating care.
- Geographic closeness and more efficient communication save staff time.
# Disadvantages: (Yoder Wise 2003)
- Costs may be increased to stock each module with the necessary patient care supplies (medication cart, linens and dressings).
- Long corridors, common in many hospitals, are not condusive to modular nursing. | Team nursing
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Assistant Editor-In-Chief: Michelle Lew
# Overview
Team nursing is an historical method of nursing practice which utilized the "economy of scale" philosophy by having one nurse or nursing assistant do one specialized function for all the inpatients within a nursing unit of a hospital. For example, one nurse may administer and record all the medications, while another checks and records the vital signs of those same inpatients.
Team nursing was developed in 1950’s (under grant from W.K. Kellogg Foundation) directed by Eleanor Lambertson at Teachers college, Columbia University in New York. Because the functional method received criticism, a new system of nursing was devised to improve patient satisfaction. “Care through others” became the hallmark of team nursing. It has been developed in an effort to decrease the problems associated with the functional organization of patient care majority of people felt that despite a continued shortage of professional nursing staff, a patient care system has to be developed that reduce the fragmented care that accompanied functional nursing.
Team nursing was developed because of social and technological changes in World War II drew many nurses away from hospitals, learning haps, services, procedures and equipments became more expensive and complicated, requiring specialization at every turn. It is an attempt to meet increased demands of nursing services and better use of knowledge and skills of professional nurses.
# Definitions
Team nursing is based on philosophy in which groups of professional and non-professional personnel work together to identify, plan, implement and evaluate comprehensive client-centred care. The key concept is a group that work’s together toward common goal, providing qualitative comprehensive nursing care (Kron 1978).
Team nursing was designed to accommodate several categories of personnel in meeting the comprehensive nursing needs of a group of clients (Donavan 1975).
# Objective of team nursing
The objective of team nursing is to give the best possible quality of patient care by utilizing the abilities of every member of the staff to the fullest extent and by providing close supervision both of patient care and of the individual who give it.
# Line of organization of team nursing
A clear line of organization structure is needed for team nursing to provide a mechanism for horizontal and vertical communication, and an organized pattern is employed.
# Functioning of team nursing
The two important points of functioning are:
- The head nurse must know at all times the condition of the patients and the plan for their care and must be assured that assignments and workmanship contribute to quality nursing
- The team leader must have freedom to use her initiative and the opportunity to nurse, to supervise and to teach unencumbered by the responsibility for administrative detail
# Functions of Registered Nurses
In the team nursing registered nurse (RN) functions as a team leader and coordinates the small group (no more than four or five) of ancillary personnel to provide care to a small group of patients.
As coordinator of the team, the RN must know the condition and needs of all patients assigned to the team and plan for the individualized care for each patient. (Marquis and Huston, 2003)
The team leader is also responsible for encouraging a cooperative environment and maintaining clear communication among all team members.
The team leader’s duties include planning care, assigning duties, directing and assisting team members, giving direct patient care, teaching and coordinating patient activities.
The team leader assigns each member specific responsibilities dependent on the role.
The members of the team report directly to the team leader, who then reports to the charge nurse or unit manager.
Communication is enhanced through the use of written patient assignments, the development of nursing care plans, and the use of regularly scheduled team conferences to discuss the patient status and formulate revisions to the plan of care.
However, for team nursing to succeed, the team leader must have strong clinical skills, good communication skills, delegation ability, decision-making ability, and the ability to create a cooperative working environment.
# Channels of communication in team nursing
- Reports
- Work or assignment conference
- Patient care conference
- Written nursing care plan
# Team conference
The greatest single distinguishing feature of team nursing is the team conference. In general, there are three parts to the conference;
- Report by each team member on her patients.
- Planning for new patients and changing plans as needed for others.
- Planning the next day’s assessment.
It is essential that the conference be well planned, brief but comprehensive and interesting. The team leader is the chair person for the conference. They offer opportunity for all personnel to evaluate patient care and solve the problems through team discussion.
# Advantages: (Marquis and Huston, 2003)
- High quality comprehensive care can be provided with a relative high proportion of ancillary staff.
- Each member of the team is able to participate in decision making and problem solving.
- Each team member is able to contribute his or her own special expertise or skills in caring for the patient.
- Improved patient satisfaction.
- Organizational decision making occurring at the lower level.
- Cost-effective system because it works with expected ratio of unlicensed to licensed personnel.
- Team nursing is an effective method of patient care delivery and has been used in most inpatient and outpatient health care settings.
## Other advantages
- Feeling of participation and belonging are facilitated with team members.
- Work load can be balanced and shared.
- Division of labour allows members the opportunity to develop leadership skills.
- Every team member has the opportunity to learn from and teach colleagues
- There is a variety in the daily assignment.
- Interest in client’s wellbeing and care is shared by several people, reliability of decisions is increased.
- Nursing care hours are usually cost effective.
- The client is able to identify personnel who are responsible for his care.
- Continuity of care is facilitated, especially if teams are constant.
- Barriers between professional and non-professional workers can be minimized, the group efforts prevail.
- Everyone has the opportunity to contribute to the care plan.
# Disadvantages
- Establishing a team concept takes time, effort and constancy of personnel. Merely assigning people to a group does not make them a ‘group’ or ‘team’.
- Unstable staffing pattern make team nursing difficult.
- All personnel must be client centered.
- There is less individual responsibility and independence regarding nursing functions.
- Continuity of care may suffer if the daily team assignments vary and the patient is confronted with many different caregivers.
- The team leader may not have the leadership skills required to effectively direct the team and create a “team spirit”.
- Insufficient time for care planning and communication may lead to unclear goals. Therefore responsibilities and care may become fragmented.
# Modifications
In an attempt to overcome some of its disadvantages, the team nursing design has been modified many times since its original inception, and variations of the model are evident in other methods of nursing care delivery such, as modular nursing.
# Modular Nursing
Modular nursing is a modification of team nursing and focuses on the patient’s geographic location for staff assignments. (Magargal 1980)
- The patient unit is divided into modules or districts, and the same team of caregivers is assigned consistently to the same geographic location.
- Each location, or module, has an RN assigned as the team leader, and the other team members may include LVN/LPN or UAP. (Yoder Wise 2003)
- Just as in the team nursing, the team leader in the modular nursing is accountable for all patient care and is responsible for providing leadership for team members and creating a cooperative work environment.
- The concept of modular nursing calls for a smaller group of staff providing care for a smaller group of patients.
- The goal is to increase the involvement of the RN in planning and coordinating care.
- Communication is more efficient among a smaller group of team members. (Marquis and Huston, 2003)
- The success of the modular nursing depends greatly on the leadership abilities of the team leader.
# Advantages: (Yoder Wise 2003)
- Continuity of care is improved when staff members are consistently assigned to the same module
- The RN as team leader is able to be more involved in planning and coordinating care.
- Geographic closeness and more efficient communication save staff time.
# Disadvantages: (Yoder Wise 2003)
- Costs may be increased to stock each module with the necessary patient care supplies (medication cart, linens and dressings).
- Long corridors, common in many hospitals, are not condusive to modular nursing. | https://www.wikidoc.org/index.php/Team_nursing | |
ed93594a5b109763d8c73f10137e34e9d83bc652 | wikidoc | Teddy Infuhr | Teddy Infuhr
Teddy Infuhr (born Theodore Edward Infuhr on November 9, 1936 – died May 12, 2007), was an American child actor.
# Biography
Missouri-born child actor Teddy Infuhr, youngest of four, moved with his family to Los Angeles when he was three and was initially prodded into acting by his mother. A young student at the Rainbow Studios, he was spotted by a talent agent and booked the very first film he went out on with The Tuttles of Tahiti (1942) at the age of 5. Throughout the rest of the 1940s he would find steady roles as mean-spirited tykes, trouble-makers or bullying types, never settling down to one specific studio.
A good portion of his work was noticeable yet he also appeared unbilled much of the time. Unable to move into the major child star leagues, he was cast in some of the biggest pictures Hollywood had to offer including A Tree Grows in Brooklyn, Spellbound (1945 film) and The Best Years of Our Lives. One of his more oddball roles included the role of Gale Sondergaard fly-swallowing nephew in The Spider Woman.
Ted found a recurring role in the "Rusty" canine adventure series, beginning with The Return of Rusty and finishing with Rusty's Birthday. He was also one of the bucolic brood in the Ma and Pa Kettle series that was introduced with the classic The Egg and I. He appeared more times in that series than any other of the regular child stars. After the war, he had larger parts in The Boy with Green Hair, Fighting Fools, West of El Dorado and Blondie's Hero and appeared with Gene Autry a few times.
# Personal life
One of the few child actors that Natalie Wood's mother allowed her to socialize with on the set.
For his role in The North Star (1943 film), Teddy had to shave his head bald. The embarrassed 7-year-old returned to school wearing a hat and refused to remove it to the dismay of his teachers until they found out the reason.
Unfortunately, he did not survive the transition from awkward adolescent to adult, ending his career unbilled as a troubled teen in Blackboard Jungle. Luckily, Teddy played it smart, and found a vocation, graduating from chiropractic school in 1958. Long married to wife Rita, with whom he had two sons, he has had no qualms or regrets about leaving show business. Until his death in Thousand Oaks on May 12, 2007, he attended nostalgia conventions.
# Filmography
- The Tuttles of Tahiti (1942)
- The North Star (1943 film) (1943) (uncredited)
- The Spider Woman (1944)
- Spellbound (1945 film) (1945) (uncredited)
- The Egg and I (1947)
- The Bishop's Wife (1947)
- Ma and Pa Kettle (1949)
- Ma and Pa Kettle Go to Town (1950)
- The Gene Autry Show (1951) (1 episode)
- Ma and Pa Kettle Back on the Farm (1951)
- The Cisco Kid (1952) (2 episodes)
- The Abbott and Costello Show (1953) (1 episode) | Teddy Infuhr
Template:Infobox officeholder
Teddy Infuhr (born Theodore Edward Infuhr on November 9, 1936 – died May 12, 2007), was an American child actor.
# Biography
Missouri-born child actor Teddy Infuhr, youngest of four, moved with his family to Los Angeles when he was three and was initially prodded into acting by his mother. A young student at the Rainbow Studios, he was spotted by a talent agent and booked the very first film he went out on with The Tuttles of Tahiti (1942) at the age of 5. Throughout the rest of the 1940s he would find steady roles as mean-spirited tykes, trouble-makers or bullying types, never settling down to one specific studio.
A good portion of his work was noticeable yet he also appeared unbilled much of the time. Unable to move into the major child star leagues, he was cast in some of the biggest pictures Hollywood had to offer including A Tree Grows in Brooklyn, Spellbound (1945 film) and The Best Years of Our Lives. One of his more oddball roles included the role of Gale Sondergaard fly-swallowing nephew in The Spider Woman.
Ted found a recurring role in the "Rusty" canine adventure series, beginning with The Return of Rusty and finishing with Rusty's Birthday. He was also one of the bucolic brood in the Ma and Pa Kettle series that was introduced with the classic The Egg and I. He appeared more times in that series than any other of the regular child stars. After the war, he had larger parts in The Boy with Green Hair, Fighting Fools, West of El Dorado and Blondie's Hero and appeared with Gene Autry a few times.
# Personal life
One of the few child actors that Natalie Wood's mother allowed her to socialize with on the set.
For his role in The North Star (1943 film), Teddy had to shave his head bald. The embarrassed 7-year-old returned to school wearing a hat and refused to remove it to the dismay of his teachers until they found out the reason.
Unfortunately, he did not survive the transition from awkward adolescent to adult, ending his career unbilled as a troubled teen in Blackboard Jungle. Luckily, Teddy played it smart, and found a vocation, graduating from chiropractic school in 1958. Long married to wife Rita, with whom he had two sons, he has had no qualms or regrets about leaving show business. Until his death in Thousand Oaks on May 12, 2007, he attended nostalgia conventions.
# Filmography
- The Tuttles of Tahiti (1942)
- The North Star (1943 film) (1943) (uncredited)
- The Spider Woman (1944)
- Spellbound (1945 film) (1945) (uncredited)
- The Egg and I (1947)
- The Bishop's Wife (1947)
- Ma and Pa Kettle (1949)
- Ma and Pa Kettle Go to Town (1950)
- The Gene Autry Show (1951) (1 episode)
- Ma and Pa Kettle Back on the Farm (1951)
- The Cisco Kid (1952) (2 episodes)
- The Abbott and Costello Show (1953) (1 episode)
# External links
- Template:Imdb name
- Template:Tvtome person
Template:ATTRIB | https://www.wikidoc.org/index.php/Teddy_Infuhr | |
2025debbca520b61d596a67b8cb29d2faed7efe8 | wikidoc | Telemedicine | Telemedicine
Should this page be merged with telehealth? These are synonymous per the National Library of Medicine
Telemedicine may be as simple as two health professionals discussing a case over the telephone, or as complex as using satellite technology and video-conferencing equipment to conduct a real-time consultation between medical specialists in two different countries. Telemedicine generally refers to the use of communications and information technologies for the delivery of clinical care.
Care at a distance (also called in absentia care), is an old practice which was often conducted via post; there has been a long and successful history of in absentia health care, which - thanks to modern communication technology - has metamorphosed into what we know as modern telemedicine.
In its early manifestations, African villagers used smoke signals to warn people to stay away from the village in case of serious disease. In the early 1900s, people living in remote areas in Australia used two-way radios, powered by a dynamo driven by a set of bicycle pedals, to communicate with the Royal Flying Doctor Service of Australia.
The terms e-health and telehealth are at times wrongly interchanged with telemedicine. Like the terms "medicine" and "health care", telemedicine often refers only to the provision of clinical services while the term telehealth can refer to clinical and non-clinical services such as medical education, administration, and research. The term e-health is often, particularly in the UK and Europe, used as an umbrella term that includes telehealth, electronic medical records, and other components of health IT.
# Types of telemedicine
Telemedicine is practiced on the basis of two concepts: real time (synchronous) and store-and-forward (asynchronous).
Real time telemedicine could be as simple as a telephone call or as complex as robotic surgery. It requires the presence of both parties at the same time and a communications link between them that allows a real-time interaction to take place. Video-conferencing equipment is one of the most common forms of technologies used in synchronous telemedicine. There are also peripheral devices which can be attached to computers or the video-conferencing equipment which can aid in an interactive examination. For instance, a tele-otoscope allows a remote physician to 'see' inside a patient's ear; a tele-stethoscope allows the consulting remote physician to hear the patient's heartbeat. Medical specialties conducive to this kind of consultation include psychiatry, internal medicine, rehabilitation, cardiology, pediatrics, obstetrics and gynecology and neurology.
Store-and-forward telemedicine involves acquiring medical data (like medical images, biosignals etc) and then transmitting this data to a doctor or medical specialist at a convenient time for assessment offline. It does not require the presence of both parties at the same time. Dermatology, radiology, and pathology are common specialties that are conducive to asynchronous telemedicine. A properly structured Medical Record preferably in electronic form should be a component of this transfer.
Telemedicine is most beneficial for populations living in isolated communities and remote regions and is currently being applied in virtually all medical domains. Specialties that use telemedicine often use a "tele-" prefix; for example, telemedicine as applied by radiologists is called Teleradiology. Similarly telemedicine as applied by cardiologists is termed as telecardiology, etc.
Telemedicine is also useful as a communication tool between a general practitioner and a specialist available at a remote location.
The focus of telemedicine has mainly been consultative, meaning a general practitioner consulting a specialist or a specialist consulting another specialist. Monitoring a patient at home using known devices like blood pressure monitors and transferring the information to a caregiver is a fast growing emerging service. These remote monitoring solutions have a focus on current high morbidity chronic diseases and are mainly deployed for the First World. In developing countries a new way of practicing telemedicine is emerging better known as Primary Remote Diagnostic Visits whereby devices examine a patient whereby a connected doctor residing in another location virtually examines the patient and treat him. This new technology and principle of practicing medicine holds big promises to solving major health care delivery problems in for instance Southern Africa because Primary Remote Diagnostic Consultations not only monitors an already diagnosed chronic disease, but has the promise to diagnosing and managing the diseases a patient will typically visit a general practitioner for.
# Teleradiology
Teleradiology is the ability to send radiographic images (x-rays) from one location to another. For this process to be implemented, three essential components are required, an image sending station, a transmission network, and a receiving / image review station.
The teleradiology process begins at the image sending station. The radiographic image and a modem are required for this first step. The image is scanned and then sent to the modem.
The transmission network can be wire, fiber optics, or microwave. After the digital information has been sent to the modem, electrical impulses are sent along to the transmission network to the receiving / image review station.
The receiving / image review station consists of a modem, a computer with sufficient storage capabilities, a display, and sometimes a printer to provide hard copies to the end user. The electrical impulses created through the transmission network are received by the modem on the review station. These impulses are converted back to the original digital image once it reaches the review station. This image is then stored and can be viewed on the display for diagnostic purposes. A hard copy can be printed for more convenience.
Clearly with the number of companies focusing on telemedical devices and the specialization of these companies one can expect telemedicine to become a significant way that physicians, hospitals, and veterinarian offices operate in the near future.
bith place of telemedicine is southasia.
de:Telemedizin
it:Telemedicina
nl:Telegeneeskunde | Telemedicine
Should this page be merged with telehealth? These are synonymous per the National Library of Medicine[1]
Telemedicine may be as simple as two health professionals discussing a case over the telephone, or as complex as using satellite technology and video-conferencing equipment to conduct a real-time consultation between medical specialists in two different countries. Telemedicine generally refers to the use of communications and information technologies for the delivery of clinical care.
Care at a distance (also called in absentia care), is an old practice which was often conducted via post; there has been a long and successful history of in absentia health care, which - thanks to modern communication technology - has metamorphosed into what we know as modern telemedicine.
In its early manifestations, African villagers used smoke signals to warn people to stay away from the village in case of serious disease. In the early 1900s, people living in remote areas in Australia used two-way radios, powered by a dynamo driven by a set of bicycle pedals, to communicate with the Royal Flying Doctor Service of Australia.
The terms e-health and telehealth are at times wrongly interchanged with telemedicine. Like the terms "medicine" and "health care", telemedicine often refers only to the provision of clinical services while the term telehealth can refer to clinical and non-clinical services such as medical education, administration, and research. The term e-health is often, particularly in the UK and Europe, used as an umbrella term that includes telehealth, electronic medical records, and other components of health IT.
# Types of telemedicine
Telemedicine is practiced on the basis of two concepts: real time (synchronous) and store-and-forward (asynchronous).
Real time telemedicine could be as simple as a telephone call or as complex as robotic surgery. It requires the presence of both parties at the same time and a communications link between them that allows a real-time interaction to take place. Video-conferencing equipment is one of the most common forms of technologies used in synchronous telemedicine. There are also peripheral devices which can be attached to computers or the video-conferencing equipment which can aid in an interactive examination. For instance, a tele-otoscope allows a remote physician to 'see' inside a patient's ear; a tele-stethoscope allows the consulting remote physician to hear the patient's heartbeat. Medical specialties conducive to this kind of consultation include psychiatry, internal medicine, rehabilitation, cardiology, pediatrics, obstetrics and gynecology and neurology.
Store-and-forward telemedicine involves acquiring medical data (like medical images, biosignals etc) and then transmitting this data to a doctor or medical specialist at a convenient time for assessment offline. It does not require the presence of both parties at the same time. Dermatology, radiology, and pathology are common specialties that are conducive to asynchronous telemedicine. A properly structured Medical Record preferably in electronic form should be a component of this transfer.
Telemedicine is most beneficial for populations living in isolated communities and remote regions and is currently being applied in virtually all medical domains. Specialties that use telemedicine often use a "tele-" prefix; for example, telemedicine as applied by radiologists is called Teleradiology. Similarly telemedicine as applied by cardiologists is termed as telecardiology, etc.
Telemedicine is also useful as a communication tool between a general practitioner and a specialist available at a remote location.
The focus of telemedicine has mainly been consultative, meaning a general practitioner consulting a specialist or a specialist consulting another specialist. Monitoring a patient at home using known devices like blood pressure monitors and transferring the information to a caregiver is a fast growing emerging service. These remote monitoring solutions have a focus on current high morbidity chronic diseases and are mainly deployed for the First World. In developing countries a new way of practicing telemedicine is emerging better known as Primary Remote Diagnostic Visits whereby devices examine a patient whereby a connected doctor residing in another location virtually examines the patient and treat him. This new technology and principle of practicing medicine holds big promises to solving major health care delivery problems in for instance Southern Africa because Primary Remote Diagnostic Consultations not only monitors an already diagnosed chronic disease, but has the promise to diagnosing and managing the diseases a patient will typically visit a general practitioner for.
# Teleradiology
Teleradiology is the ability to send radiographic images (x-rays) from one location to another. For this process to be implemented, three essential components are required, an image sending station, a transmission network, and a receiving / image review station.
The teleradiology process begins at the image sending station. The radiographic image and a modem are required for this first step. The image is scanned and then sent to the modem.
The transmission network can be wire, fiber optics, or microwave. After the digital information has been sent to the modem, electrical impulses are sent along to the transmission network to the receiving / image review station.
The receiving / image review station consists of a modem, a computer with sufficient storage capabilities, a display, and sometimes a printer to provide hard copies to the end user. The electrical impulses created through the transmission network are received by the modem on the review station. These impulses are converted back to the original digital image once it reaches the review station. This image is then stored and can be viewed on the display for diagnostic purposes. A hard copy can be printed for more convenience.
Clearly with the number of companies focusing on telemedical devices and the specialization of these companies one can expect telemedicine to become a significant way that physicians, hospitals, and veterinarian offices operate in the near future.
bith place of telemedicine is southasia.
de:Telemedizin
it:Telemedicina
nl:Telegeneeskunde | https://www.wikidoc.org/index.php/Telemedicine | |
7a009554a083175d4cbc98019553cbf8047625c4 | wikidoc | Temafloxacin | Temafloxacin
# Overview
Temafloxacin (marketed by Abbott Laboratories as Omniflox) is a fluoroquinolone antibiotic drug which was withdrawn from sale in the United States shortly after its approval in 1992 because of serious adverse effects resulting in three deaths.
# History
Omniflox was approved to treat lower respiratory tract infections, genital and urinary infections like prostatitis, and skin infections in the United States by the Food and Drug Administration in January 1992. Severe adverse reactions, including allergic reactions and hemolytic anemia, developed in about fifty patients during the first four months of its use, leading to three patient deaths. Abbott withdrew the drug from sale in June 1992.
# Pharmacokinetic
Following oral administration the compound is well absorbed from the gastrointestinal tract. The oral bioavailability is greater than 90%. Temafloxacin has a good tissue penetration in various biological fluids and tissues, particularly in the respiratory tissues, nasal secretions, tonsils, prostate and bone. In these districts the concentrations achieved are equal to or higher than those in serum. The fluoroquinolone has a 7-8 hour half-life.
The penetration into the central nervous system (CNS)is less pronounced.The escretion from the body is primarily due to the glomerular filtration.
# Clinical uses
The compound is indicated for treating lower respiratory tract infections (community-acquired pneumonia, exacerbations of chronic bronchitis), genital and urinary tract infections (prostatitis, gonococcal and non-gonococcal urethritis, cervicitis), skin and soft tissue infections. | Temafloxacin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Temafloxacin (marketed by Abbott Laboratories as Omniflox) is a fluoroquinolone antibiotic drug which was withdrawn from sale in the United States shortly after its approval in 1992 because of serious adverse effects resulting in three deaths.[1][2]
# History
Omniflox was approved to treat lower respiratory tract infections, genital and urinary infections like prostatitis, and skin infections in the United States by the Food and Drug Administration in January 1992. Severe adverse reactions, including allergic reactions and hemolytic anemia,[3] developed in about fifty patients during the first four months of its use, leading to three patient deaths. Abbott withdrew the drug from sale in June 1992.
# Pharmacokinetic
Following oral administration the compound is well absorbed from the gastrointestinal tract. The oral bioavailability is greater than 90%. Temafloxacin has a good tissue penetration in various biological fluids and tissues, particularly in the respiratory tissues, nasal secretions, tonsils, prostate and bone.[4] In these districts the concentrations achieved are equal to or higher than those in serum.[5] The fluoroquinolone has a 7-8 hour half-life.[6]
The penetration into the central nervous system (CNS)is less pronounced.[6]The escretion from the body is primarily due to the glomerular filtration.[7][8][9]
# Clinical uses
The compound is indicated for treating lower respiratory tract infections (community-acquired pneumonia, exacerbations of chronic bronchitis), genital and urinary tract infections (prostatitis, gonococcal and non-gonococcal urethritis, cervicitis), skin and soft tissue infections.[6][10][11][12] | https://www.wikidoc.org/index.php/Temafloxacin |
Subsets and Splits