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/index.php/Varicose_veins_primary_prevention

# Varicose veins primary prevention Varicose veins are linked to several risk factors. Some of these risk factors can be avoidable while some are not. Age, gender, hormones, family history are unavoidable risk factors. There is not much that can be done about the. However, Obesity, prolonged standing, etc are some risk factors that can be avoided or managed. It has been known that being overweight is a risk factor to not only varicose veins but also a host of other diseases(eg. atherosclerosis , Diabetes , hypertension , several cancers ) as well. Thus, weight loss and having an active lifestyle is one of the best steps can take in the direction of being healthy life. Diet is a crucial part of weight loss, which is often neglected by people. a healthy a balanced diet accompanied by regular exercise can do wonders for our fitness. Being physically active also help us avoid another disk factor which is, standing still for prolonged period of time. Sometimes our work, such as being as salesman, requires us to stand for prolonged periods of time. This can be avoided by taking short breaks/walks at fixed time intervals. It will help take the pressure off of the venous valves by emptying the veins at regular intervals. Sometimes, abdominal masses(such as a tumor) can put pressure on the major veins, thus increasing the pressure in the veins of lower limbs. This, in the long term, can lead to the development of venous incompetence/varicose veins. This can be avoided by getting regular health checkups.

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/index.php/Varicose_veins_risk_factors

# Varicose veins risk factors Varicose veins are associated with multiple risk factors. The most important one is a family history of varicose veins. Other risk factors include increasing age, female sex, prolonged periods of standing, Pregnancy, Obesity. These risk factors can lead to the incompetence of venous valves.

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/index.php/Varicose_veins_screening

# Varicose veins screening Duplex ultrasonography is a cheap and easily accessible technology that can be used to screen for and diagnose varicose veins. Routine testing is not done to screen for varicose veins.

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/index.php/Varicose_veins_secondary_prevention

# Varicose veins secondary prevention Varicose veins usually take a long time before they develop fully and result in complications. If detected early they can be managed relatively easily using conservative measures. The most effective approach to secondary prevention of the varicose veins is risk factor management. This can be done in the following ways -

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/index.php/Varicose_veins_surgery

# Varicose veins surgery Stripping consists of the removal of the saphena vein main trunk from the groin down to the ankle. The complications include deep vein thrombosis (5.3%), pulmonary embolism (0.06%), and wound complications including infection (2.2%). For traditional surgery, reported recurrence rates, which have been tracked for 10 years, range from 5-60%. In addition, since stripping removes the saphenous main trunks, they are no longer available for venous by-pass in the future (coronary and/or leg artery vital disease). CHIVA is the acronym for Conservative and Haemodynamic cure of Incompetent Varicose veins in Ambulatory patients translated from the French cure "Conservatrice et Hémodynamique de l'Insuffisance Veineuse en Ambulatoire" published in France in 1988. CHIVA relies on an hemodynamic impairment assessed by data and evidences depicted through ultrasound dynamic venous investigations. According to this new concept, the clinical symptoms of venous insufficiency are not the cause but the consequence of various abnormalities of the venous system. For example, a varicose vein being overloaded, may be dilated not only because of valvular incompetence (the most frequent) but because of a venous block (thrombosis) or arterio-venous fistulae...and so the treatment has to be tailored according the hemodynamic feature. It generally consists in 1 to 4 small incisions under local anesthesia in order to disconnect the varicose veins from the abnormal flow due to valvular incompetence which dilates them. The patient is dismissed the same day. This method leads to an improvement of the venous function in order to:

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/index.php/Varicose_veins_ultrasound

# Varicose veins ultrasound Due to its cost effectiveness, accuracy and accessibility, Duplex Ultrasound is the investigation of choice for diagnosis and pre-operative assessment of Varicose veins or Chronic Venous Insufficiency . The symptoms of the patients referred for this investigation range from superficial telangiectasias, edema, leg pain to non-healing venous ulcers. Another advantage of Duplex ultrasound is lack of exposure to radiation . Duplex ultrasonography shows us the various structures such as the vessels as well as the direction of blood flow inside them using sound wave pulses . In B-mode scan, the structures that absorb or diffuse the sound waves appear as dark and, the structures that reflect them appear as white. As such, the blood vessels often appear as white rings with dark matter within them. A color doppler can might be done to examine the direction as well as the laminarity of the blood flow. Ultrasonography also helps us examine the patency of the vessel(eg. thrombosis/DVT), condition of the perforators & valves as well as the pliability of the vessels (by applying pressure using the probe). Presence and degree of reflux of blood flow is also examined and helps in planning the treatment of the patient .

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/index.php/Variegate_porphyria

# Variegate porphyria Variegate porphyria is a subtype of porphyria that can have acute (severe but usually not long-lasting) symptoms along with symptoms that affect the skin. The disorder results from low levels of the enzyme responsible for the seventh step in heme production. Heme is a vital molecule for all of the body's organs. It is a component of hemoglobin, the molecule that carries oxygen in the blood. Many people with this disorder never experience symptoms. When symptoms occur, they can include acute attacks (similar to acute intermittent porphyria), skin damage, or both. Acute attacks usually begin in adulthood and cause abdominal pain, vomiting, diarrhea and constipation. During an attack, a person may also experience muscle weakness, seizures, and mental changes such as anxiety and hallucinations. These signs and symptoms are triggered by nongenetic factors such as certain drugs, dieting or fasting, certain hormones and stress. Some people with variegate porphyria have skin that is overly sensitive to sunlight. Areas of skin exposed to the sun develop severe blistering, scarring, changes in pigmentation, and increased hair growth. Exposed skin becomes fragile and is easily damaged. Rarely, the signs and symptoms of variegate porphyria can begin in infancy or early childhood. In such cases, the signs and symptoms are usually more severe than those starting later in life. In addition to the health problems described above, children with this disorder may have mental retardation and grow more slowly than other children. This type of porphyria is most common in the white population of South Africa; about 3 per 1,000 people in this population are diagnosed each year. The disorder occurs much less frequently in other parts of the world. Mutations in the PPOX gene cause variegate porphyria. The PPOX gene makes a membrane bound mitochondrial enzyme called protoporphyrinogen oxidase, which is critical to the chemical process that leads to heme production. The activity of this enzyme is reduced by 50 percent in most people with variegate porphyria. In severe cases that begin early in life, the enzyme is almost completely inactive. Nongenetic factors such as certain drugs, stress, and others listed above can increase the demand for heme and the enzymes required to make heme. The combination of this increased demand and reduced activity of protoporphyrinogen oxidase disrupts heme production and allows byproducts of the process to accumulate in the liver, triggering an acute attack. Variegate porphyria is inherited in an autosomal dominant pattern, which means one copy of the altered gene is sufficient to decrease enzyme activity and cause symptoms. More severe cases result from inheriting two copies of the altered gene. The entire PPOX gene has about 8kb with 13 exon sequences. It was successfully cloned from a cDNA library in 1995 revealing that, after processing, it is 477 nucleotides long. It has previously been thought that the PPOX gene was located on human chromosome 14, however mapping experiments (FISH) have shown that it is near 1q22. An additional aggravating mutation affecting variegate porphyria can be found at 6p21.3 on the HFE gene.

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/index.php/Varrentrapp_reaction

# Varrentrapp reaction The Varrentrapp reaction is an organic reaction involving the chemical decomposition of an α,β-unsaturated acid into two other acid fragments by action of molten alkali. This reaction pioneered by F. Varrentrapp in 1840 has been of some importance in structure elucidation of certain fatty acids but has no practical synthetic use . the reaction conditions are harsh: medium molten potassium hydroxide at temperatures in the range of 250 to 300 °C. Likewise cinnamic acid is converted to benzoic acid. The reaction mechanism for this reaction is outlined below. Although the alkene group in the fatty acid can be located at more than one position in the chain, this does not affect the nature of te reaction products. This is because the double bond always migrates to the position next to the carboxylic acid group prior to cleavage. The next step is nucleophilic addition of a hydroxyl anion to the double bond of 1 followed by proton migration to intermediate 3. The next step is cleavage to enolate 4a and aldehyde 4b. The enolate on acidic workup will form acetic acid. The aldehyde continues to react with another equivalent of base forming carboxylate 7 together with hydrogen. The hydride transfer is akin the Cannizzaro reaction.

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/index.php/Vas_deferens

# Vas deferens There are two such ducts; they are muscular tubes (surrounded by smooth muscle) connecting the left and right epididymis to the ejaculatory ducts in order to move sperm. Each tube is about 30 centimeters long (in humans). During ejaculation the smooth muscle in the walls of the ductus deferens or vas deferens contracts reflexively, thus propelling the sperm forward. This is also known as peristalsis. The sperm is transferred from the vas deferens into the urethra, collecting secretions from the male accessory sex glands such as the seminal vesicles, prostate gland and the bulbourethral glands, which form the bulk of semen. The procedure of deferentectomy, popularly known as a vasectomy, is a method of contraception in which the vasa deferentia (Latin plural) are permanently cut, though in some cases it can be reversed. A modern variation, which is also popularly known as a vasectomy even though it does not include cutting the vas, involves injecting an obstructive material into the ductus to block the flow of sperm. Investigational attempts for male contraception have focused on the vas with the use of the intra vas device and reversible inhibition of sperm under guidance (RISUG). The vas deferens is supplied by an accompanying artery (artery of vas deferens). This artery normally arises from the superior vesical artery, itself a branch of the internal iliac artery.

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/index.php/Vasa_recta

# Vasa recta In the blood supply of the kidney, the vasa recta renis (or straight arteries of kidney, or straight arterioles of kidney) form a series of straight capillaries (recta is from the Latin for "straight") that descend from the cortex into the medulla. These vessels branch off of the efferent arterioles of juxtamedullary nephrons (those nephrons closest to the medulla), enter the medulla, and surround the loop of Henle. Each of the vasa recta has a hairpin turn in the medulla and carries blood at a very slow rate, two factors crucial in the maintenance of countercurrent exchange that prevent washout of the concentration gradients established in the renal medulla. According to Terminologia Anatomica , the term "vasa recta renis" is an alternate name for "arteriolae rectae renis", and a separate term, venulae rectae renis, is used to identify the venous portion. The slow blood flow in vasa recta makes them a likely place of thrombosis in hypercoagulable states, or erythrocyte sickling in sickle cell disease. Ischemia that results may lead to renal papillary necrosis.

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/index.php/Vascular_Closure_Devices

# Vascular closure devices At the very heart of any successful endovascular procedure is successful arterial entry and exit. The first successful cardiac catheterization, according to Andre Cournand, was performed on an equine patient in 1844 utilizing a retrograde approach through both the jugular vein and carotid artery . Human retrograde left heart catheterization was first reported by Zimmerman and Limon-Lason in 1950. Shortly thereafter in 1953, Seldinger developed the percutaneous technique and this technique was quickly adapted to left heart cardiac catheterizations. With the growth of Interventional Cardiology in the years following Grüntzig's introduction of coronary angioplasty in 1977 , the percutaneous approach became, and today remains, by far the most common method of performing catheterization, angiography and endovascular intervention. Within the realm of percutaneous approaches, the majority of the procedures are performed from the femoral approach, with a minority being done from a radial approach. Brachial and axillary are also used in a minority of procedures . Reasons for the continued preference of the femoral route for access includes the vessel size, operator training and equipment, radiation exposure (operator), and the advent of vascular closure devices. Studies have suggested that between 8-10% of all patients selected for a transradial approach will convert to a transfemoral route.

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/index.php/Vascular_Medicine

# Vascular Medicine Vascular medicine is a rapidly advancing discipline that is concerned with the study of the the blood vessels and their diseases. It encompasses the evaluation and treatment of the following disease states:

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/index.php/Vascular_access_steal_syndrome

# Vascular access steal syndrome In nephrology, vascular access steal syndrome, also known less precisely as steal syndrome, refers to vascular insufficiency resulting from a poorly constructed arteriovenous fistula (Cimino fistula, or synthetic vascular graft-AV fistula).

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/index.php/Vascular_disease

# Vascular disease Vascular disease is a class of diseases of the blood vessels – the arteries and veins of the circulatory system of the body. It is a subgroup of cardiovascular disease. Disorders in this vast network of blood vessels, can cause a range of health problems which can be severe or prove fatal. Vascular disease is a pathological state of large and medium muscular arteries and is triggered by endothelial cell dysfunction. Because of factors like pathogens, oxidized LDL particles and other inflammatory stimuli endothelial cells become active. The process causes thickening of the vessel wall, forming a plaque that consists of proliferating smooth muscle cells, macrophages and lymphocytes. The plaque results in a restricted blood flow which will decrease the amount of oxygen and nutrients that reach certain organs, the plaque might rupture causing the formation of clots. It can be difficult to make a Vascular disease diagnosis since there are a variety of symptoms that a person can have, also family history and a physical examination are important. The physical exam may be different depending on the type of vascular disease. In the case of a peripheral vascular disease the physical exam consists in checking the blood flow in the legs. Treatment varies with the each type of Vascular disease, in the case of Renal artery disease information from a meta-analysis indicated that balloon angioplasty results in improvement of diastolic blood pressure and a reduction in antihypertensive drug requirements. In the case of Peripheral artery disease preventing complications is important, without treatment sores or gangrene (tissue death) may occur. Among the treatments are:

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/index.php/Vascular_endothelial_growth_factor

# Vascular endothelial growth factor Vascular endothelial growth factor (VEGF) is an important signaling protein involved in both vasculogenesis (the de novo formation of the embryonic circulatory system) and angiogenesis (the growth of blood vessels from pre-existing vasculature). As its name implies, VEGF activity has been mostly studied on cells of the vascular endothelium, although it does have effects on a number of other cell types (e.g. stimulation monocyte/macrophage migration, neurons, cancer cells, kidney epithelial cells ). In vitro, VEGF has been shown to stimulate endothelial cell mitogenesis and cell migration. VEGF is also a vasodilator and increases microvascular permeability and was originally referred to as vascular permeability factor. The broad term 'VEGF' covers a number of proteins from two families, that result from alternate splicing of mRNA from a single, 8 exon, VEGF gene. The two different familes are referred to according to their terminal exon (exon 8) splice site - the proximal splice site (denoted VEGFxxx) or distal splice site (VEGFxxxb). In addition, alternate splicing of exon 6 and 7 alters their heparin binding affinity, and amino acid number (in humans: VEGF121, VEGF121b, VEGF145, VEGF165, VEGF165b, VEGF189, VEGF206; the rodent orthologs of these proteins contain one fewer amino acid). These domains have important functional consequences for the VEGF splice variants as the terminal (exon 8) splice site determines whether the proteins are pro-angiogenic (proximal splice site, expressed during angiogenesis) or anti-angiogenic (distal splice site, expressed in normal tissues). In addition inclusion or exclusion of exons 6 and 7 mediate interactions with heparan sulfate proteoglycans (HSPGs) and neuropilin co-receptors on the cell surface, enhancing their ability to bind and activate the VEGF signaling receptors (VEGFRs). The VEGF splice variants are released from cells as glycosylated disulfide-bonded dimers. Structurally VEGF belongs to the PDGF family of cystine-knot growth factors. Subsequently, several closely-related proteins were discovered (Placenta growth factor (PlGF), VEGF-B, VEGF-C and VEGF-D) which together comprise the VEGF sub-family of growth factors. VEGF is sometimes referred to as VEGF-A to differentiate it from these related growth factors. A number of VEGF-related proteins have also been discovered encoded by viruses (VEGF-E) and in the venom of some snakes (VEGF-F). All members of the VEGF family stimulate cellular responses by binding to tyrosine kinase receptors (the VEGFRs) on the cell surface, causing them to dimerize and become activated through transphosphorylation, although to different sites, times and extents. The VEGF receptors have an extracellular portion consisting of 7 immunoglobulin-like domains, a single transmembrane spanning region and an intracellular portion containing a split tyrosine-kinase domain. VEGF-A binds to VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1). VEGFR-2 appears to mediate almost all of the known cellular responses to VEGF. The function of VEGFR-1 is less well defined, although it is thought to modulate VEGFR-2 signaling. Another function of VEGFR-1 may be to act as a dummy/decoy receptor, sequestering VEGF from VEGFR-2 binding (this appears to be particularly important during vasculogenesis in the embryo). VEGF-C and VEGF-D, but not VEGF-A, are ligands for a third receptor (VEGFR-3),which mediates lymphangiogenesis. VEGFxxx production can be induced in cells that are not receiving enough oxygen. When a cell is deficient in oxygen, it produces HIF, Hypoxia Inducible Factor, a transcription factor. HIF stimulates the release of VEGFxxx, among other functions (including modulation of erythropoeisis). Circulating VEGFxxx then binds to VEGF Receptors on endothelial cells, triggering a Tyrosine Kinase Pathway leading to angiogenesis. VEGFxxx has been implicated with poor prognosis in breast cancer. Numerous studies show a decreased OS and DFS (Disease-free survival) in those tumors overexpressing VEGF. The overexpression of VEGFxxx may be an early step in the process of metastasis, a step that is involved in the "angiogenic" switch. Although VEGFxxx has been correlated with poor survival, its exact mechanism of action in the progression of tumors remains unclear. VEGFxxx is also important in diabetic retinopathy (DR). The microcirculatory problems in the retina of people with diabetes can cause retinal ischaemia, which results in the release of VEGFxxx, and a switch in the balance of pro-angiogenic VEGFxxx isoforms over the normally expressed VEGFxxxb isoforms. VEGFxxx may then cause the creation of new blood vessels in the retina and elsewhere in the eye, heralding changes which may threaten the sight. VEGFxxx plays a role in the disease pathology of the wet form age-related macular degeneration (AMD), which is the leading cause of blindness for the elderly of the industrialized world. The vascular pathology of AMD shares certain similarities with diabetic retinopathy, although the cause of disease and the typical source of neovascularization differes between the two diseases. Once released, VEGFxxx may elicit several responses. It may cause a cell to survive, move, or further differentiate. Hence, VEGF is a potential target for the treatment of cancer. The first anti-VEGF drug, a monoclonal antibody named bevacizumab, was approved in 2004. Approximately 10-15% of patients benefit from bevacizumab therapy, although biomarkers for bevacizumab efficacy are not yet known. Anti-VEGF therapies are important in the treatment of certain cancers and in age-related macular degeneration. They can involve monoclonal antibodies such as bevacizumab (Avastin), antibody derivatives such as ranibizumab (Lucentis), or orally-available small molecules that inhibit the tyrosine kinases stimulated by VEGF : sunitinib (Sutent), sorafenib (Nexavar), axitinib, and pazopanib. Both antibody-based compounds are commercialized. The first two orally available compounds are commercialized, as well. The latter two are in clinical trials, the results of which were presented (June 07) at ASCO.

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/index.php/Vascular_endothelial_growth_inhibitor

# Vascular endothelial growth inhibitor ## Contents Vascular endothelial growth inhibitor (VEGI), also known as TNF-like ligand 1A (TL1A) and TNF superfamily member 15 (TNFSF15), is protein that in humans is encoded by the TNFSF15 gene. VEGI is an anti-angiogenic protein. It belongs to tumor necrosis factor (ligand) superfamily, where it is member 15. It is the sole known ligand for death receptor 3, and it can also be recognized by decoy receptor 3. ## Function The protein encoded by this gene is a cytokine that belongs to the tumor necrosis factor (TNF) ligand family. This protein is abundantly expressed in endothelial cells, but is not expressed in either B or T cells. The expression of this protein is inducible by TNF-alpha and IL-1 alpha. This cytokine is a ligand for receptor TNFRSF25 (death receptor 3) and TNFRSF6B (decoy receptor 3). It can activate both the NF-κB and MAPK signalling pathways, and acts as an autocrine factor to induce apoptosis in endothelial cells. This cytokine is also found to inhibit endothelial cell proliferation, and thus may function as an angiogenesis inhibitor. An additional isoform encoded by an alternatively spliced transcript variant has been reported but the sequence of this transcript has not been determined.

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/index.php/Vascular_ring

# Vascular ring A vascular ring is a congenital defect in which there is an abnormal formation of the aorta and/or its surrounding blood vessels. The trachea and esophagus are completely encircled and sometimes compressed by a "ring" formed by these vessels, which can lead to breathing and digestive difficulties. Most often this is because of persistence of the double aortic arch after the second month of fetal life. A less common ring is present with a right aortic arch instead of the usual left-sided aortic arch which compresses the esophagus and trachea because of the persistence of a ductal ligament (from fetal circulation) that may connect between the aorta on the front and the left subclavian artery posteriorly going to the left arm.

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/index.php/Vascular_ring_(patient_information)

# Vascular ring (patient information) Vascular rings are unusual congenital anomalies that occur early in the development of the aortic arch and great vessels. The abnormal development of the aorta may cause compression or obstruction of the esophagus or airway. Pressure on the trachea and esophagus can lead to breathing and digestive problems. Usual signs and symptoms include high-pitched cough, repeated pneumonia and respiratory infections, respiratory distress, wheezing, choking, difficulty eating solid foods, and vomiting. Tests such as barium esophagram, chest x-ray, chest CT and MRI can show abnormal compression of the middle part of the esophagus characteristic for a vascular ring. Treatments include medicines and surgery. The prognosis of vascular ring depends on the pressure of the vascular ring putting on the esophagus and trachea, how quickly the infant is diagnosed and treated when symptoms appear. Some children with vascular ring never develop symptoms. However, other cases may show breathing and digestive problems caused by the pressure on the windpipe and esophagus. Vascular ring is rare. It accounts for less than 1% of all congenital heart problems. The condition occurs as often in males as females. Some infants with vascular ring also have another congenital heart problem. Vascular ring occurs very early in the baby's development in the womb. Normally, the aorta develops from one of several curved pieces of tissue (arches). The body breaks down some of the remaining arches, while others form into arteries. Some arteries that should break down do not; this forms vascular rings. With vascular ring, some of the arches and vessels that should have changed into arteries or disappeared are still present when the baby is born. These arches form a ring of blood vessels, which encircles and presses down on the windpipe (trachea) and esophagus. Several different types of vascular ring exist. In some types, the vascular ring only partially encircles the trachea and esophagus, but it still can cause symptoms. Call your health care provider if your baby has symptoms of vascular ring. Getting diagnosed and treated quickly can prevent serious complications such as damage to the trachea and even death. If one emerges the following symptoms, seeking urgent medical care as soon as possible: Treatments for patients with vascular ring are medicines and surgery. Children without symptoms may not need treatment, but need to be carefully observed to make sure the condition doesn't become worse. The goal of medicines, such as antibiotics, is to treat any respiratory tract infections. Surgery is the main treatment for patients with vascular ring. Before treatment starts, talk to your child's doctor about treatment options and your family's preferences on treatment decisions.

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/index.php/Vascular_surgery

# Vascular surgery Vascular surgery is a subspecialty of general surgery in which diseases of the vascular system, or arteries and veins, are managed, largely via surgical intervention, and was originally founded by Dr. Clyde Otis Hagood Jr. The vascular surgeon is trained in the diagnosis and management of diseases affecting all parts of the vascular system except that of the heart and brain. Cardiothoracic surgeons manage surgical disease of the heart and its vessels. Neurosurgeons manage surgical disease of the vessels in the brain (eg intracranial aneurysms). Previously considered a field within general surgery, it is now considered a specialty in its own right. As a result, training has been, or is being re-structured from previously having to complete full general surgery training followed by a period of further vascular surgery training, to being trained in vascular surgery alone from start to finish.

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/index.php/Vasculitis

# Vasculitis Vasculitis means inflammation of a blood vessel. Vasculitis is classified based on the size of vessels which are involved. Large sized-vessel vasculitis mostly happens in major vessels of the body, such as Takayasu's Arteritis and temporal Arteritis. Medium sized-vessel vasculitis includes Kawasaki's Disease and Polyarteritis Nodosa. Small sized-vessel vasculitis commonly manifests as skin lesions and includes Churg-Strauss Syndrome, leukocytoclastic vasculitis, Henoch-Schonlein Purpura, and Wegener's Granulomatosis. Variable sized-vessel vasculitis are Sjogren syndrome and Cogan syndrome. Single organ vasculitis is basically primary central nervous system angiitis. As the affected vessels are vary in size, the affected organs could be different among patients which leads to different disease presentation and severities. This spectrum of diseases could be primary or secondary to another conditions like sepsis. A high degree of level of suspicious is necessary when encounter a patients with appropriate clinical manifestation to lead to final diagnosis. Diagnosis is based on a combination of clinical scenario, lab findings, and imaging findings. Although the definite diagnostic modality is tissue biopsy and microscopic findings. The diseases course could be acute although they usually presents with constitutional symptoms and chronic progression. Treatment of vasculitis depends on the disease severity consists of applying immunosuppressant agents to induce the remission and maintain the the disease course under control. Vasculitis could be a primary disorder or secondary to an underlying condition. Following is a list of common causes of underlying diseases or drugs that may lead to vasculitis syndrome:

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/index.php/Vasculitis_resident_survival_guide

# Vasculitis resident survival guide Vasculitis is the presence of inflammatory leukocytes in the walls of the blood vessels with reactive damage to mural structures leading to compromise of the lumen with downstream ischemia, necrosis, and bleeding. The exact pathogenesis is unknown, and vasculitis can be primary or secondary to underlying disease. Vasculitides are categorized primarily by vessel size, together with etiology, pathogenesis, pathology, demographics, and clinical features The extent and severity of vasculitides may vary from self-limited cutaneous vasculitis to severe fatal vasculitides depending on the degree of systemic involvement. History and clinical findings are non-specific to any type of vasculitis. A high index of clinical suspicion is warranted in considering the diagnosis of vasculitis. Shown below is an step-wise approach summarizing the diagnosis of vasculitis according to the Royal College of Physicians guidelines. The diagnosis of the individual vasculitides is generally based on patterns of organ injury, the size of the vessels affected, histopathological features, and characteristic findings on diagnostic imaging. Treatment regimens are based upon the specific diagnosis and the severity or extent of the disease. The treatment used for specific types of Primary vasculitides is summarized as follows: Shown below is an algorithm summarizing the treatment of ANCA associated vasculitis (AAV) according to The British Society for Rheumatology (BSR) and British Health Professionals in Rheumatology (BHPR) , European League Against Rheumatism (EULAR/ERA-EDTA) recommendations and Canadian Vasculitis Research Network (CanVasc)

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/index.php/Vasectomy

# Vasectomy Vasectomy is a surgical procedure in which the vasa deferentia of a male mammal are cut for the purpose of sterilization. There are some variations on the procedure such as no-scalpel (keyhole) vasectomies, in which a surgical hook, rather than a scalpel, is used to enter the scrotum. After vasectomy, the testes remain in the scrotum where Leydig cells continue to produce testosterone and other male hormones that continue to be secreted into the bloodstream. Some studies find that sexual desire (libido) is unaffected in over 90% of vasectomized men whereas other studies find higher rates of diminished sexual desire. The sperm-filled fluid from the testes contributes about 10% to the volume of an ejaculation (in men who are not vasectomized) and does not significantly affect the appearance, texture, or taste of the ejaculate. When the vasectomy is complete, sperm can no longer exit the body through the penis. They are broken down and absorbed by the body. Much fluid content is absorbed by membranes in the epididymis, and much solid content is broken down by macrophages and re-absorbed via the blood stream. Sperm is matured in the epididymis for about a month once it leaves the testicles. Approximately 50% of the sperm produced never make it to ejaculation in a non-vasectomized man. After vasectomy, the membranes increase in size to absorb more fluid, and more macrophages are recruited to break down and re-absorb more of the solid content. The fraction of sperms that exceed the digestive capabilities of macrophages exit into the scrotum as sperm granulomas. Early failure rates, i.e. pregnancy within a few months after vasectomy, are below 1%, but the effectiveness of the operation and rates of complications vary with the level of experience of the surgeon performing the operation and the surgical technique used. How popular vasectomy is as a birth control method varies by age and nationality. Men in their mid 30s to mid 40s are most likely to have a vasectomy. The rate of vasectomies to tubal ligations worldwide is extremely variable, and the statistics are mostly based on questionnaire studies rather than actual counts of procedures performed. In the U.S. in 2005, the CDC published state by state details of birth control usage by method and age group. Overall, tubal ligation is ahead of vasectomy but not by a large factor. In Britain vasectomy is more popular than tubal ligation, though this statistic may be as a result of the data-gathering methodology. Couples who opt for tubal ligation do so for a number of reasons, including: Animal and human data indicate that vasectomy does not increase atherosclerosis and that increases in circulating immune complexes after vasectomy are transient. Furthermore, the weight of the evidence regarding prostate and testicular cancer suggests that men with vasectomy are not at increased risk of these cancers. Post-Vasectomy Pain Syndrome (PVPS), genital pain of varying intensity that may last for a lifetime, is estimated to appear in between 5% and 33% of vasectomized men, depending on the severity of pain that qualifies for the particular study In one study, vasectomy reversal was found to be 69% effective for reducing the symptoms of chronic post-vasectomy pain. Treatment options for 31% of patients whose pain did not respond to vasectomy reversal were limited. The study was very small, only evaluating 13 patients, making it difficult to draw solid conclusions. In severe cases orchiectomy has been resorted to. Researchers reported in February 2007 that a survey of a small number of men with a rare form of dementia found that more than twice as many as would be expected had undergone vasectomies. The study has not yet been verified by other researchers, and the authors say larger studies are needed to better understand the issue. Although men considering vasectomies should not think of them as reversible, and most men and their spouses are satisfied with the operation, there is a procedure to reverse vasectomies using vasovasostomy (a form of microsurgery first performed by Earl Owen in 1971 ). Vasovasostomy is effective at achieving pregnancy in only 50%-70% of cases, and it is very costly, with total out-of-pocket costs in the United States ranging from $7,000 to more than $35,000. The rate of pregnancy depends on such factors as the method used for the vasectomy and the length of time that has passed since the vasectomy was performed. The reversal procedures are frequently impermanent, with occlusion of the vas recurring two or more years after the operation. Sperm counts are rarely at pre-vasectomy levels. There is evidence that men who have had a vasectomy may produce more abnormal sperm, which would explain why even a mechanically successful reversal does not always restore fertility. The higher rates of aneuploidy and diploidy in the sperms of men who have undergone vasectomy reversal may lead to a higher rate of birth defects .

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/index.php/Vasoactive_intestinal_peptide

# Vasoactive intestinal peptide Vasoactive intestinal peptide, also known as vasoactive intestinal polypeptide or VIP, is a peptide hormone that is vasoactive in the intestine. VIP is a peptide of 28 amino acid residues that belongs to a glucagon/secretin superfamily, the ligand of class II G protein–coupled receptors. VIP is produced in many tissues of vertebrates including the gut, pancreas, and suprachiasmatic nuclei of the hypothalamus in the brain. VIP stimulates contractility in the heart, causes vasodilation, increases glycogenolysis, lowers arterial blood pressure and relaxes the smooth muscle of trachea, stomach and gall bladder. In humans, the vasoactive intestinal peptide is encoded by the VIP gene. The leading hypothesis of VIP function points to the neurons using VIP to communicate with specific postsynaptic targets to regulate circadian rhythm. The depolarization of the VIP expressing neurons by light appears to cause the release of VIP and co-transmitters (including GABA) that can in turn, alter the properties of the next set of neurons with the activation of VPAC2. Another hypothesis supports VIP sending a paracrine signal from a distance rather than the adjacent postsynaptic neuron. With respect to the digestive system, VIP seems to induce smooth muscle relaxation (lower esophageal sphincter, stomach, gallbladder), stimulate secretion of water into pancreatic juice and bile, and cause inhibition of gastric acid secretion and absorption from the intestinal lumen. Its role in the intestine is to greatly stimulate secretion of water and electrolytes, as well as relaxation of enteric smooth muscle, dilating peripheral blood vessels, stimulating pancreatic bicarbonate secretion, and inhibiting gastrin-stimulated gastric acid secretion. These effects work together to increase motility. It also has the function of stimulating pepsinogen secretion by chief cells. It is also found in the heart and has significant effects on the cardiovascular system. It causes coronary vasodilation as well as having a positive inotropic and chronotropic effect. Research is being performed to see if it may have a beneficial role in the treatment of heart failure. VIP provokes vaginal lubrication in normal women, doubling the total volume of lubrication produced. One region includes a specific area of the suprachiasmatic nuclei (SCN), the location of the 'master circadian pacemaker'. See SCN and circadian rhythm below. VIP in the pituitary helps to regulate prolactin secretion; it stimulates prolactin release in the domestic turkey. Additionally, the growth-hormone-releasing hormone (GH-RH) is a member of the VIP family and stimulates growth hormone secretion in the anterior pituitary gland. VIP innervates on both VPAC1 and VPAC2. When VIP binds to VPAC2 receptors, a G-alpha-mediated signalling cascade is triggered. In a number of systems, VIP binding activates adenyl cyclase activity leading to increases in cAMP and PKA. The PKA then activates other intracellular signaling pathways like the phosphorylation of CREB and other transcriptional factors. The mPer1 promoter has CRE domains and thus provides the mechanism for VIP to regulate the molecular clock itself. Then it will activate gene expression pathways such as Per1 and Per2 in circadian rhythm. In addition, GABA levels are connected to VIP in that they are co-released. Sparse GABAergic connections are thought to decrease synchronized firing. While GABA controls the amplitude of SCN neuronal rhythms, it is not critical for maintaining synchrony. However, if GABA release is dynamic, it may mask or amplify synchronizing effects of VIP inappropriately. The SCN coordinates daily timekeeping in the body and VIP plays a key role in communication between individual brain cells within this region. At a cellular level, the SCN expresses different electrical activity in circadian time. Higher activity is observed during the day, while during night there is lower activity. This rhythm is thought to be important feature of SCN to synchronize with each other and control rhythmicity in other regions. VIP acts as a major synchronizing agent among SCN neurons and plays a role in synchronizing the SCN with light cues. The high concentration of VIP and VIP receptor containing neurons are primarily found in the ventrolateral aspect of the SCN, which is also located above the optic chiasm. The neurons in this area receive retinal information from the retinohypothalamic tract and then relay the environmental information to the SCN. Further, VIP is also involved in synchronizing the timing of SCN function with the environmental light-dark cycle. Combined, these roles in the SCN make VIP a crucial component of the mammalian circadian timekeeping machinery. After finding evidence of VIP in the SCN, researchers began contemplating its role within the SCN and how it could affect circadian rhythm. The VIP also plays a pivotal role in modulating oscillations. Previous pharmacological research has established that VIP is needed for normal light-induced synchronization of the circadian systems. Application of VIP also phase shifts the circadian rhythm of vasopressin release and neural activity. The ability of the population to remain synchronized as well as the ability of single cells to generate oscillations is composed in VIP or VIP receptor deficient mice. While not highly studied, there is evidence that levels of VIP and its receptor may vary depending on each circadian oscillation. In SCN, there is an abundant amount of VPAC2. The presence of VPAC2 in ventrolateral side suggests that VIP signals can actually signal back to regulate VIP secreting cells. SCN has neural multiple pathways to control and modulate endocrine activity. VIP and vasopressin are both important for neurons to relay information to different targets and affect neuroendocrine function. They transmit information through such relay nuclei as the SPZ (subparaventricular zone), DMH (dorsomedial hypothalamic nucleus), MPOA (medial preoptic area) and PVN (paraventricular nucleus of hypothalamus). VIP neurons located in the hypothalamus, specifically the dorsal anterior hypothalamus and ventromedial hypothalamus, have an effect on social behaviors in many species of vertebrates. Studies suggest that VIP cascades can be activated in the brain in response to a social situation that stimulates the areas of the brain that are known to regulate behavior. This social circuit includes many areas of the hypothalamus along with the amygdala and the ventral tegmental area. The production and release of the neuropeptide VIP is centralized in the hypothalamic and extrahypothalamic regions of the brain and from there it is able to modulate the release of prolactin secretion. Once secreted from the pituitary gland, prolactin can increase many behaviors such as parental care and aggression. In certain species of birds with a knockout VIP gene there was an observable decrease in overall aggression over nesting territory. In addition to VIPoma, VIP has a role in osteoarthritis (OA). While there is existing conflict in whether down-regulation or up-regulation of VIP contributes to OA, VIP has been shown to prevent cartilage damage in animals.

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/index.php/Vasoconstriction

# Vasoconstriction Vasoconstriction is a procedure of the body that avoids orthostatic hypotension. It is a part of a body negative feed back loop in which the body tries to restore homeostasis. For example, vasoconstriction is a hypothermic preventative in which the blood vessels constrict and blood must move at a higher pressure to actively avoid a hypoxic reaction. ATP is used as a form of energy to increase this pressure to heat the body. Once homeostasis is restored the blood pressure and ATP production regulates. An increase of blood flow in the penis that builds up causes an erection, however if the body is not functioning properly the blood vessels in the penis activate and allow less blood to pool, meaning the erection goes down prematurely or simply fails to completely go up. This does not necessarily mean that the person in question is not aroused, it is a lapse in judgement between the Central Nervous System [CNS] and the Peripheral Nervous System [PNS] . When blood pools in the penis the body reacts to the excessive heat to cool it, resulting in vasoconstriction.

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/index.php/Vasoconstrictors

# Vasoconstrictor A vasoconstrictor, also vasopressor or simply pressor, is any substance that acts to cause vasoconstriction (narrowing of the lumena of blood vessels) and usually results in an increase of the blood pressure. (The opposite process, vasodilation, is the opening of blood vessels. ) Vasoconstrictors are also used clinically to increase blood pressure or to reduce local blood flow. Exposure to moderately high levels of stress also induces vasoconstriction. Vasoconstriction also occurs in superficial blood vessels of warm-blooded animals when their ambient environment is cold; this process diverts the flow of heated blood to the center of the animal, preventing the loss of heat. Vasoconstrictors include systemic and topical. For example, pseudoephedrine is available systemic (i.e. orally ingested tablets like Sudafed), and topical (such as nose sprays like phenylephrine Neo-synephrine, and eye drops for pupil dilation purposes)

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/index.php/Vasodilation

# Vasodilator A vasodilator is a drug or chemical that relaxes the smooth muscle in blood vessels, which causes them to dilate. Dilation of arterial blood vessels (mainly arterioles) lead to a decrease in blood pressure. Vasodilation directly affects the relationship between Mean Arterial Pressure and Cardiac Output and Total Peripheral Resistance (TPR). Mathematically, cardiac output is computed by multiplying the heart rate (in beats/minute) and the stroke volume (the volume of blood ejected during systole). TPR depends on several factors including the length of the vessel, the viscosity of blood (determined by hematocrit), and the diameter of the blood vessel. The latter is the most important variable in determining resistance. An increase in either of these physiological components (cardiac output or TPR) cause a rise in the mean arterial pressure. Vasodilators work to decrease TPR and blood pressure through relaxation of smooth muscle cells in the tunica media layer of large arteries and smaller arterioles. Vasodilation occurs in superficial blood vessels of warm-blooded animals when their ambient environment is hot; this process diverts the flow of heated blood to the skin of the animal, where heat can be more easily released into the atmosphere. The opposite physiological process is vasoconstriction. These processes are naturally modulated by local paracrine agents from endothelial cells (e.g bradykinin, adenosine), as well as an organism's Autonomic Nervous System and adrenal glands, both of which secrete catecholamines such as norepinephrine and epinephrine, respectively. Vasodilation is a result of relaxation in smooth muscle surrounding the blood vessels. This relaxation, in turn, relies on removing the stimulus for contraction, which depends predominately on intracellular calcium ion concentrations and phosphorylation of myosin light chain (MLC). Thus, vasodilation mainly works by either by lowering intracellular calcium concentration or dephosphorylation of MLC. This includes stimulation of myosin light chain phosphatase and induction of calcium symporters and antiporters that pump calcium ions out of the intracellular compartment. This is accomplished through retuptake of ions into the sarcoplasmic reticulum via exchangers and expulsion across the plasma membrane. The specific mechanisms to accomplish these effects varies from vasodilator to vasodilator. Vasodilators are used to treat conditions such as hypertension, where the patient has an abnormally high blood pressure, as well as angina and congestive heart failure, where a maintaining a lower blood pressure reduces the patient's risk of developing other cardiac problems. Flushing may be a physiological response to vasodilators.

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/index.php/Vasopressin

# Vasopressin Vasopressin, also called antidiuretic hormone (ADH), arginine vasopressin (AVP) or argipressin, is a hormone synthesized as a peptide prohormone in neurons in the hypothalamus, and is converted to AVP. It then travels down the axon of that cell, which terminates in the posterior pituitary, and is released from vesicles into the circulation in response to extracellular fluid hypertonicity (hyperosmolality). AVP has two primary functions. First, it increases the amount of solute-free water reabsorbed back into the circulation from the filtrate in the kidney tubules of the nephrons. Second, AVP constricts arterioles, which increases peripheral vascular resistance and raises arterial blood pressure. A third function is possible. Some AVP may be released directly into the brain from the hypothalamus, and may play an important role in social behavior, sexual motivation and pair bonding, and maternal responses to stress. Vasopressin regulates the tonicity of body fluids. It is released from the posterior pituitary in response to hypertonicity and causes the kidneys to reabsorb solute-free water and return it to the circulation from the tubules of the nephron, thus returning the tonicity of the body fluids toward normal. An incidental consequence of this renal reabsorption of water is concentrated urine and reduced urine volume. AVP released in high concentrations may also raise blood pressure by inducing moderate vasoconstriction. AVP also may have a variety of neurological effects on the brain. It may influence pair-bonding in voles. The high-density distributions of vasopressin receptor AVPr1a in prairie vole ventral forebrain regions have been shown to facilitate and coordinate reward circuits during partner preference formation, critical for pair bond formation. The physiologic stimulus for secretion of vasopressin is increased osmolality of the plasma, monitored by the hypothalamus. A decreased arterial blood volume, (such as can occur in cirrhosis, nephrosis and heart failure), stimulates secretion, even in the face of decreased osmolality of the plasma: it supersedes osmolality, but with a milder effect. In other words, vasopressin is secreted in spite of the presence of hypoosmolality (hyponatremia) when the arterial blood volume is low. The AVP that is measured in peripheral blood is almost all derived from secretion from the posterior pituitary gland (except in cases of AVP-secreting tumours). Vasopressin is produced by magnocellular neurosecretory neurons in the Paraventricular nucleus of hypothalamus (PVN) and Supraoptic nucleus (SON). It then travels down the axon through the infundibulum within neurosecretory granules that are found within Herring bodies, localized swellings of the axons and nerve terminals. These carry the peptide directly to the posterior pituitary gland, where it is stored until released into the blood. There are other sources of AVP, beyond the hypothalamic magnocellular neurons. For example, AVP is also synthesized by parvocellular neurosecretory neurons of the PVN, transported and released at the median eminence, from which it travels through the hypophyseal portal system to the anterior pituitary, where it stimulates corticotropic cells synergistically with CRH to produce ACTH (by itself it is a weak secretagogue). Vasopressin is used for measurement of surgical stress at evaluation of surgical techniques. Plasma vasopressin concentration is elevated at noxious stimuli, predominantly during abdominal surgery, especially at gut manipulation and traction of viscera. In a study on dogs, plasma vasopressin concentration increased at removal of both ovaries, with a 15 minute pause between ovary removal. Blood pressure and vasopressin concentrations changed in parallel at use of z‐scores (standard scores) for comparison. In a human study, two different approaches for lumbar spine surgery were compared. An intraoperative increase of vasopressin levels was observed in one of the groups and this group required more postoperative analgesics. The vasopressins are peptides consisting of nine amino acids (nonapeptides). (NB: the value in the table above of 164 amino acids is that obtained before the hormone is activated by cleavage.) The amino acid sequence of arginine vasopressin (argipressin) is Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Arg-Gly-NH2, with the cysteine residues forming a disulfide bond and the C-terminus of the sequence converted to a primary amide. Lysine vasopressin (lypressin) has a lysine in place of the arginine as the eighth amino acid, and is found in pigs and some related animals, whereas arginine vasopressin is found in humans. The structure of oxytocin is very similar to that of the vasopressins: It is also a nonapeptide with a disulfide bridge and its amino acid sequence differs at only two positions (see table below). The two genes are located on the same chromosome separated by a relatively small distance of less than 15,000 bases in most species. The magnocellular neurons that secrete vasopressin are adjacent to magnocellular neurons that secrete oxytocin, and are similar in many respects. The similarity of the two peptides can cause some cross-reactions: oxytocin has a slight antidiuretic function, and high levels of AVP can cause uterine contractions. Vasopressin is used to manage anti-diuretic hormone deficiency. It has off-label uses and is used in the treatment of vasodilatory shock, gastrointestinal bleeding, ventricular tachycardia and ventricular fibrillation. Vasopressin is used to treat diabetes insipidus related to low levels of antiduretic hormone. It is available as Pressyn. Vasopressin agonists are used therapeutically in various conditions, and its long-acting synthetic analogue desmopressin is used in conditions featuring low vasopressin secretion, as well as for control of bleeding (in some forms of von Willebrand disease and in mild haemophilia A) and in extreme cases of bedwetting by children. Terlipressin and related analogues are used as vasoconstrictors in certain conditions. Use of vasopressin analogues for esophageal varices commenced in 1970. Vasopressin infusions are also used as second line therapy for septic shock patients not responding to fluid resuscitation or infusions of catecholamines (e.g., dopamine or norepinephrine) to increase the blood pressure while sparing the use of catecholamines. These argipressins have much shorter elimination half-life (around 20 minutes) comparing to synthetic non-arginine vasopresines with much longer elimination half-life of many hours. Further, argipressins act on V1a, V1b, and V2 reseptors which consequently lead to higher eGFR and lower vascular resistance in the lungs. A number of injectable arginine vasopressins are currently in clinical use in the United States and in Europe. Vasopressin is administered through an intravenous device, intramuscular injection or a subcutaneous injection. The duration of action depends on the mode of administration and ranges from thirty minutes to two hours. It has a half life of ten to twenty minutes. It is widely distributed throughout the body and remains in the extracellular fluid. It is degraded by the liver and excreted through the kidneys. . Arginin vasopressins for use in septic shock are intended for intravenous use only. The most common side effects during treatment with vasopressin are dizziness, angina, chest pain, abdominal cramps, heartburn, nausea, vomiting, trembling, fever, water intoxication, pounding sensation in the head, diarrhea, sweating, paleness, and flatulence. The most severe adverse reactions are myocardial infarction and hypersensitivy. The use of lysine vasopressin is contraindicated in the presence of hypersentivity to beef or pork proteins, increased BUN and chronic renal failure. It is recommended that it be cautiously used in instances of perioperative polyuria, sensitivity to the drug, asthma, seizures, heart failure, a comatose state, migraine headaches, and cardiovascular disease. Decreased AVP release (neurogenic — i.e. due to alcohol intoxication or tumour) or decreased renal sensitivity to AVP (nephrogenic, i.e. by mutation of V2 receptor or AQP) leads to diabetes insipidus, a condition featuring hypernatremia (increased blood sodium concentration), polyuria (excess urine production), and polydipsia (thirst). Syndrome of Inappropriate Antidiuretic Hormone secretion (SIADH) in turn can be caused by a number of problems. Some forms of cancer can cause SIADH, particularly small cell lung carcinoma but also a number of other tumors. A variety of diseases affecting the brain or the lung (infections, bleeding) can be the driver behind SIADH. A number of drugs has been associated with SIADH, such as certain antidepressants (serotonin reuptake inhibitors and tricyclic antidepressants), the anticonvulsant carbamazepine, oxytocin (used to induce and stimulate labor), and the chemotherapy drug vincristine. It has also been associated with fluoroquinolones (including ciprofloxacin and moxifloxacin). Finally, it can occur without a clear explanation. Hyponatremia can be treated pharmaceutically through the use of vasopressin receptor antagonists. Evidence for an effect of AVP on monogamy vs promiscuity comes from experimental studies in several species, which indicate that the precise distribution of vasopressin and vasopressin receptors in the brain is associated with species-typical patterns of social behavior. In particular, there are consistent differences between monogamous species and promiscuous species in the distribution of AVP receptors, and sometimes in the distribution of vasopressin-containing axons, even when closely related species are compared. Vasopressin has shown nootropic effects on pain perception and cognitive function. Vasopressin also plays a role in autism, major depressive disorder, bipolar disorder, and schizophrenia.

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/index.php/Vasospasm

# Vasospasm Vasospasm refers to a condition in which blood vessels spasm, leading to vasoconstriction. This can lead to tissue ischemia and death (necrosis). Cerebral vasospasm may arise in the context of subarachnoid hemorrhage. Symptomatic vasospasm or delayed cerebral ischemia is a major contributor to post-operative stroke and death after aneurysmal subarachnoid hemorrhage. Vasospasm typically appears 4 to 10 days after subarachnoid hemorrhage.

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/index.php/Vasotocin

# Vasotocin ## Sources Vasotocin is an oligopeptide with properties similar to oxytocin and vasopressin, found in birds, fish, and amphibians. It has been found to have effects on the regulation of REM sleep.

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/index.php/Vastus_lateralis_muscle

# Vastus lateralis muscle Template:Infobox Muscle The Vastus lateralis (Vastus externus) is the largest part of the Quadriceps femoris. It arises by a broad aponeurosis, which is attached to the upper part of the intertrochanteric line, to the anterior and inferior borders of the greater trochanter, to the lateral lip of the gluteal tuberosity, and to the upper half of the lateral lip of the linea aspera; this aponeurosis covers the upper three-fourths of the muscle, and from its deep surface many fibers take origin. A few additional fibers arise from the tendon of the Glutæus maximus, and from the lateral intermuscular septum between the Vastus lateralis and short head of the Biceps femoris. The fibers form a large fleshy mass, which is attached to a strong aponeurosis, placed on the deep surface of the lower part of the muscle: this aponeurosis becomes contracted and thickened into a flat tendon inserted into the lateral border of the patella, blending with the Quadriceps femoris tendon, and giving an expansion to the capsule of the knee-joint.

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/index.php/Vat_Yellow_4

# Vat Yellow 4 Vat Yellow 4, also known as Golden Yellow GK, dibenzochrysenedione, dibenzpyrenequinone, Tyrian Yellow I-GOK, and C.I. 59100, is a yellow synthetic anthraquinone vat dye. Chemically it is dibenzo[b,def]chrysene-7,14-dione, or 3,4:8,9-dibenzopyrene-5,10-dione, or C24H12O2. It has the appearance of a viscous orange liquid.

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/index.php/Vault_RNA

# Vault RNA Vault RNAs are an RNA family found as part of the vault ribonucleoprotein complex first discovered in 1986. The complex consists of a major vault protein (MVP), two minor vault proteins (VPARP and TEP1), and several small untranslated RNA molecules. Each vault particle contains 16 vRNA molecules. It has been suggested that the vault complex is involved in drug resistance

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/index.php/VeIP_regimen

# VeIP regimen VeIP regimen refers to a regimen consisting of vinblastine (velban), ifosfamide, mesna and cisplatin (platinol) used for the treatment of advanced-stage germ cell ovarian and testicular cancers

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/index.php/Vector

# Vector In epidemiology, a vector is an organism that does not cause disease itself but which transmits infection by conveying pathogens from one host to another. A classic example is the anopheles mosquito which acts as a vector for the disease malaria by transmitting the malarial parasite plasmodium to humans. In this case plasmodium is harmless to the mosquito (its intermediate host) but causes the disease malaria in humans (its definitive host). A plasmid vector is made by splicing a DNA construct into a plasmid. Various techniques are then used to transfect the plasmid into the cell. There are two types of vector that convey infectious organisms to a host: mechanical and biological. Microbes do not multiply within mechanical vectors - mechanical vectors only physically transport microbes from host to host. In contrast, microbes must propagate within a biological vector before the biological vector can transmit the microbes.

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/index.php/Vegan_Outreach

# Vegan Outreach Vegan Outreach is an American animal advocacy group working to expose and end cruelty to animals through the widespread distribution of printed informational booklets . As of October 2006, over five million hard copies of Vegan Outreach brochures have been handed out by the local members of Vegan Outreach around the world since the group's inception . Template:Animal liberation movement Vegan Outreach founders Matt Ball and Jack Norris met in in Cincinnati, OH in 1990. As members of the Animal Rights Community of Cincinnati, Matt and Jack (along with Phil Murray, now co-owner of Pangea Vegan Products) spent the winter of 1990-1991 holding fur protests outside of cultural events. Their focus turned to vegetarianism in 1992, and the Animal Rights Community of Cincinnati funded the printing and distribution of 10,000 pro-vegetarian flyers entitled "Vegetarianism." In June of 1993, twelve activists -- including Matt and Jack -- held a three-day "Fast for Farm Animals" in front of a Cincinnati slaughterhouse (the logic behind this being that most animals typically go three days without food before slaughter). On the last day of the fast, some of the protestors took a large banner reading "Stop Eating Animals" to the University of Cincinnati campus. Though the fast itself generated some media coverage, many of the people involved felt that holding the banner in the university district was the most effective part of the fast. Following this event, Matt and Jack formed Animal Liberation Action (ALA) and started a campaign of holding "Stop Eating Animals" banners on street corners. This would become the foundation of Vegan Outreach's current tactic of disseminating information on college campuses and in other high-traffic areas. In conjunction with an upswing in civil disobedience relating to the animal rights movement, in 1994 ALA developed a booklet called "And Justice For All." It focused on the reasons to adopt a vegan diet, including the abuse of the animals involved, the impact of industrialized farming on the environment, and the benefits of consuming a plant-based diet. The following year, ALA's name was officially changed to Vegan Outreach, and the campaign to hold banners -- generally poorly received by the public, who did not understand the reasons behind the request -- was set aside in favor of the distribution of printed booklets. Another revision of the booklet, now called "Vegan Outreach," was printed in 1995. The initial 10,000 copy run was stapled, folded, and collated by hand to save money. That autumn, Jack Norris embarked on a tour of the Midwestern United States, distributing the Vegan Outreach brochure at nineteen universities. The first "Why Vegan" was printed in 1996 and distributed at 171 colleges during that year. Jack continued his traveling until funds ran out in 1997. Jack decided to become a Registered Dietitian, which entailed three years of school and an internship. He did this to become educated on the science of nutrition and to figure out what could be done to minimize the number of failed vegetarians in the future. In their June 1998 newsletter, Vegan Outreach published a very long article called "Veganism as the Path to Animal Liberation" (now called "Activism and Veganism Reconsidered" ). This article questioned the priorities of the animal rights movement (in part by pointing out that ~99% of all animals killed in the U.S. died to be eaten, while only a minority of the movement's attention went to exposing factory farms and promoting vegetarianism) and also argued against the movement's focus on trying to get media attention through protests. The essay also questioned the effectiveness of civil disobedience and direct action, and a perceived tendency towards self-delusion and dogmatism in vegetarian and animal rights promotion. Until veganism was more widespread, Matt argued, animal liberation could not succeed on any major front. The essay made a wide impact on activists and shaped Vegan Outreach's guiding principals of advocacy . New booklets were developed in 1999 and 2000, including a Vegetarian Starter Guide (now the "Guide to Cruelty-Free Eating") for people who were interested in following a veterarian diet and "Vegetarian Living" (now "Try Vegetarian") which had none of the graphic photos contained in the "Why Vegan" brochure. In 2001, over 330,000 copies of "Why Vegan" and "Vegetarian Living" were distributed. In the fall of 2003, Vegan Outreach launched its Adopt-A-College program, the animal advocacy movement's first systematic attempt to reach large numbers of students in the U.S. and Canada in an organized way. The program's first year saw 22,000 brochures distributed at 63 schools; most recently, 344,000 brochures were distributed at 385 schools during the fall 2006 semester . Vegan Outreach was able to hire a new employee, Jon Camp, whose focus was entirely on leafleting at colleges. In his first two years of employment with the group, he handed out over 145,000 brochures. Another big change for Vegan Outreach occurred in 2005, when the first copy of their new brochure, "Even If You Like Meat," was printed. The brochure is explained in this way: After many years of leafleting, we realized that students had started to erect a number of mental barriers to prevent them from seriously considering their part in supporting factory farming and slaughterhouses.... One major barrier is that people have convinced themselves that boycotting animal cruelty has to be an all or nothing proposition, and, since they cannot go all the way, they will do nothing. Thus, a big emphasis of EIYLM is to let people know that not supporting cruelty does not have to be an "all or nothing" proposition. Any amount of animal food reduction helps prevent suffering. Another problem we encountered was that people would see the word "vegan" or "vegetarian" on our flyers and assume we were just do-gooder busybodies trying to get them to improve their health, so they would not take a flyer. With EIYLM, we put pictures of factory farms on the front of the brochure so people would immediately see we were talking about a serious social issue in which animals were being treated cruelly. At first, we worried that this might decrease the acceptance rate. But we found that if anything, the reception rate actually increased. The cover pictures also prevent the previous, occasional problem of someone taking a happy looking flyer and then feeling duped when they open it to see graphic photos. Vegan Outreach continues to grow, as an organization, in leaps and bounds. In 2006, Vegan Outreach was able to hire two more full-time leafleters: Victor Tsou covered the western United States while Jenna Calabrese leafleted throughout the northeastern region of the country. Anne Green was hired full-time as Vegan Outreach's vice president in 2007 after many years of unofficially contributing to the planning and management of the organization. Today, Vegan Outreach continues its mission of disseminating this information on college campuses and at other busy venues across the globe. Their brochures have been distributed in all 50 states, Puerto Rico, ten Canadian territories and provinces, Mexico, and numerous other countries (including Australia, Austria, Brazil, Denmark, Egypt, England, Finland, France, Germany, India, Ireland, Italy, Japan, the Netherlands, New Zealand, Norway, Singapore, Slovenia, Slovakia, Spain, Sri Lanka, South Africa, and Taiwan) . Many of Vegan Outreach's pamphlets and articles are available in multiple languages, thanks to the translation efforts of volunteers and supporters. The rate of distribution is increasing every year, limited not by demand -- there are many individuals, student groups, and organizations who would like to distribute as many as possible -- but by availability (i.e., resources for printing and distribution). Vegan Outreach's mission is the reduction of the amount of suffering in the world. They have chosen to focus on people's food choices for three reasons: - The number of animals raised and killed for food each year in the United States alone vastly exceeds any other form of exploitation, involving numbers far greater than the total human population of the entire world. Ninety-nine out of every 100 animals killed in the United States each year are slaughtered for human consumption. - The intensity of farmed animal suffering: the overcrowding and confinement, the stench, the racket, the extremes of heat and cold, the attacks and even cannibalism, the hunger and starvation, the illness, etc. - Exposing factory farms and advocating ethical eating is perhaps the most readily accessible option for reducing animal suffering. Every day, every single person makes decisions that affect the lives of farmed animals. Inspiring someone to change leads to fewer animals suffering on factory farms. By choosing to promote cruelty-free living, every person is a potential major victory. All of Vegan Outreach's printed materials advocate for a reduction and eventual elimination of animal products from one's diet. Furthermore, suggestions for alternative foods, information on staying healthy on a plant-based diet , and tips for advocacy are included in the brochures. Vegan Outreach suggests that one's guide shouldn't be an endless list of vegan ingredients but rather doing his or her absolute best to stop cruelty to animals. Template:Rquote In other words, the focus isn't so much personal beliefs or specific choices but rather the animals and their suffering. Vegan Outreach encourages people to become vegan advocates because if someone believes that being vegan is important, being the most effective advocate for the animals must be seen as even more important. The impact of one's individual veganism -- several hundred animals over the course of a lifetime -- pales in comparison to what he or she can accomplish by being an example to others. For every person inspired to change his or her habits, a vegan's impact on the world multiplies. Conversely, for every person convinced that veganism is overly-demanding by obsessing with an ever-increasing list of ingredients, we do worse than nothing: we turn someone away who could have made a real difference for animals if they hadn't met us. Currently the vast majority of people in our society have no problem eating the actual leg of a chicken. It is not surprising that many people dismiss vegans as unreasonable and irrational when our example includes interrogating waiters, not eating veggie burgers cooked on the same grill with meat, not taking photographs or using medicines, etc. Instead of spending our limited time and resources worrying about the margins (cane sugar, film, medicine, etc.), our focus should be on increasing our impact every day. Helping just one person change leads to hundreds fewer animals suffering in factory farms. By choosing to promote compassionate eating, every person we meet is a potential major victory.... It is not enough to be a righteous vegan, or even a dedicated, knowledgeable vegan advocate. The animals don't need us to be right, they need us to be effective. In other words, we don't want to just win an argument with a meat-eater, we want to open people's hearts and minds to a more compassionate lifestyle. To do this, we have to be the opposite of the vegan stereotype. Regardless of the sorrow and outrage we rightly feel at the cruelties the animals suffer, we must strive to be what others want to be: joyful, respectful individuals, whose fulfilling lives inspire others. Only then can we do our best for the animals. The booklets that Vegan Outreach prints are primarily distributed by individuals and groups through leafleting. This person-to-person, grassroots approach to activism ensures that each person who interacts with a Vegan Outreach distributor is given comprehensive, complete information that they can consider on their own time. The group's major program is called "Adopt-A-College," in which volunteers disseminate the booklets on college campuses. Vegan Outreach has chosen to focus on students (especially college-age), for three main reasons: - The Relative Willingness and Ability to Change: Of course, not every student is willing to stop eating meat. But relative to the population as a whole, college students tend to be more open-minded – even rebellious against the status quo – and in a position where they aren't as restricted by parents, tradition, habits, etc. - The Full Impact of Change: Even if students and senior citizens were equally open to change, over the course of their lives, students can save more animals. Young people not only have more meals ahead of them, but also have more opportunities to influence others. - The Ability to Reach Large Numbers: College students are typically easier to reach in large numbers. For a relatively small investment of time, an activist can hand a copy of "Even If You Like Meat" or "Why Vegan?" to hundreds of students who otherwise might never have viewed a full and compelling case for compassion.

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/index.php/Vegas_Cubanas

# Vegas Cubanas This brand was created by José "Pepin" Garcia and is manufactured at the El Rey de los Habanos factory in Little Havana, Miami, Florida. It was introduced into national distribution in 2005. A Nicaraguan puro, the wrapper is a corojo leaf, colorado maduro in color. It is a mild- to medium-bodied smoke available, uncellophaned, in boxes of 25. Cigars are aged for a minimum of one year before shipping.

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/index.php/Vegetable_oil_used_as_fuel

# Vegetable oil used as fuel Many vegetable oils have similar fuel properties to diesel fuel, except for higher viscosity and lower oxidative stability. If these differences can be overcome, vegetable oil may substitute for #2 Diesel fuel, most significantly as engine fuel or home heating oil. For engines designed to burn #2 diesel fuel, the viscosity of vegetable oil must be lowered to allow for proper atomization of fuel, otherwise incomplete combustion and carbon build up will ultimately damage the engine. Many enthusiasts refer to vegetable oil used as fuel as waste vegetable oil (WVO) if it is oil that was discarded from a restaurant or straight vegetable oil (SVO) to distinguish it from Biodiesel. The first known use of vegetable oil as fuel for a diesel engine was a demonstration of an engine built by the Otto company and designed to burn mineral oil, which was run on pure peanut oil at the 1900 World's Fair. Late in his career, Rudolf Diesel investigated using vegetable oil to fuel engines of his design, and in a 1912 presentation to the British Institute of Mechanical Engineers, he cited a number of efforts in this area and remarked, "The fact that fat oils from vegetable sources can be used may seem insignificant today, but such oils may perhaps become in course of time of the same importance as some natural mineral oils and the tar products are now." Periodic petroleum shortages spurred research into vegetable oil as a diesel substitute during the 30s and 40s, and again in the 70s and early 80s when straight vegetable oil enjoyed its highest level of scientific interest. The 1970s also saw the formation of the first commercial enterprise to allow consumers to run straight vegetable oil in their automobiles, Elsbett of Germany. In the 1990s Bougainville conflict, islanders cut off from oil supplies due to a blockade used coconut oil to fuel their vehicles. Academic research into straight vegetable oil fell off sharply in the 80s with falling petroleum prices and greater interest in biodiesel as an option that did not require extensive vehicle modifications. While engineers and enthusiasts have been experimenting with using vegetable oil as fuel for a diesel engine since at least 1900, in all the literature, only one peer reviewed study exists that compares long term use of vegetable oil and #2 Diesel as fuels which shows no noticeable difference in rate of deterioration of the engine burning vegetable oil, for one particular model of engine, the German Deutz F3l912W . (#1 Diesel has a cold-weather additive to reduce gelling) Most diesel car engines are suitable for the use of SVO, also commonly called Pure Plant Oil (PPO), with suitable modifications. Principally, the viscosity of the SVO/PPO must be reduced by preheating it, typically by using heat from the engine or electricity, otherwise poor atomization, incomplete combustion and carbonization may result. One common solution is to add an additional fuel tank for "normal" diesel fuel (petrodiesel or biodiesel) and a three way valve to switch between this additional tank and the main tank of SVO/PPO. The engine is started on diesel, switched over to vegetable oil as soon as it is warmed up and switched back to diesel shortly before being switched off to ensure it has no vegetable oil in the engine or fuel lines when it is started from cold again. In colder climates it is often necessary to heat the vegetable oil fuel lines and tank as it can become very viscous and even solidify. Single tank conversions have been experimented with but oil analysis reveals significant lube oil contamination caused by blow-by during warm up. While these systems may function for some time in warm climates on IDI engines, they are not viable for most other applications. With unmodified engines the unfavourable effects may be reduced by blending, or "cutting", the SVO with diesel fuel; however, opinions vary as to the efficacy of this. Some WVO mechanics have found higher rates of wear and failure in fuel pumps and piston rings due to partially-combusted WVO/SVO droplets carbonizing in those components[citation needed]. For normal use, without either blending or a second tank and associated modifications in a petrodiesel engine, vegetable oil has to be transesterified to biodiesel. Many cars powered by indirect injection engines supplied by inline injection pumps, or mechanical Bosch injection pumps are capable of running on pure SVO in all but winter temperatures. Turbo diesels tend to run better due to the increased pressure in the injectors. Pre-CDI Mercedes-Benz vehicles and cars featuring the PSA XUD engine tend to perform well too, especially as the latter is normally equipped with a coolant heated fuel filter. The main form of SVO used in the UK is rapeseed oil (also known as canola oil, primarily in the United States and Canada) which has a freezing point of -10°C. However the use of sunflower oil, which freezes at -17°C, is currently being investigated as a means of improving cold weather starting. Unfortunately oils with lower gelling points tend to be less saturated (leading to a higher iodine number) and polymerize more easily in the presence of atmospheric oxygen. Cetane number (combustion quality) is highest with coconut oil, palm stearine, palm kernel, palm oil, palm oleine, lard and tallow. Coconut oil, palm oil, palm stearine, tallow and lard have the lowest iodine numbers. Some Pacific island nations are using coconut oil as fuel to reduce their expenses and their dependence on imported fuels while helping stabilize the coconut oil market. Coconut oil is only usable where temperatures do not drop below 17 degrees Celsius (62 degrees Fahrenheit), unless two-tank SVO/PPO kits or other tank-heating accessories, etc. are used. Fortunately, the same techniques developed to use, for example, Canola and other oils in cold climates can be implemented to make coconut oil usable in temperatures lower than 17 degrees Celsius. With often minimal modification, most residential furnaces and boilers which are designed to burn No. 2 heating oil can be made to burn either biodiesel or filtered, preheated waste vegetable oil. These are generally not as clean-burning as petroleum fuel oil, but if processed at home, by the consumer, can result in considerable savings. Many restaurants will give away their used cooking oil either free or at minimal cost, and processing to biodiesel is fairly simple and inexpensive. Burning filtered WVO directly is somewhat more problematic, since it is much more viscous, but it can be accomplished with suitable preheating. WVO can thus be a very economical heating option for those with the necessary mechanical and experimental aptitude. As of 2000, the United States was producing in excess of 11 billion liters of waste vegetable oil annually, mainly from industrial deep fryers in potato processing plants, snack food factories and fast food restaurants. If all those 11 billion liters could be collected and used to replace the energetically equivalent amount of petroleum (a rather utopian case), almost 1% of US oil consumption could be offset. However, use of waste vegetable oil as a fuel competes with some already established uses. Pure plant oil (PPO) (or Straight Vegetable Oil (SVO)), in contrast to waste vegetable oil, is not a byproduct of other industries, and thus its prospects for use as fuel are not limited by the capacities of other industries. Production of vegetable oils for use as fuels is theoretically limited only by the agricultural capacity of a given economy. The UK exported 280 000 tonnes of rapeseed in 2005. If the UK used just its set aside land it could reach its 5% biofuel target without the need for exotic and environmentally damaging oil crop imports. The conversion of an automobile engine to burn vegetable oil is not legal under US Environmental Protection Agency guidelines. The EPA has not fined anyone for doing so, but certain laws may have to change — or a certification process may need to be established — before VO conversions become more popular in the US. Taxation on SVO as a road fuel varies from country to country, and it is possible the revenue departments in many countries are even unaware of its use, or feel it sufficiently insignificant to legislate. Germany offers 0% taxation, resulting in their leading on most developments of the fuel use. However SVO as a road fuel will be taxed with 0,09 €/liter on January, the 1st of 2008 in Germany. From thereon it will rise up to 0,45 €/liter until 2012. There seems to be no clear taxation system in the USA, however given the low rate of fuel taxation, it is unlikely to face anything unfavourable, although charges could vary from state to state. Production of biodiesel in some US regions may require motor fuel taxes to be paid, which are typically used to fund road construction costs. The Government of Canada exempted biodiesel from the federal excise tax on diesel in the March 2003 budget. In Ireland a pilot scheme is currently running (as of April 2006) whereby eight suppliers have been approved to sell SVO for use as a fuel without the payment of excise duty (Value Added Tax at 21% still applies, SVO from any other source still attracts exise duty at 36.8058 Euro cents per litre plus 21% VAT). Despite its use being common in France, it would appear there has been no legislation to cover this. In the UK, it is legal once duty on the fuel is paid. In the UK, drivers using SVO have been prosecuted for failure to pay duty to Her Majesty's Revenue and Customs. The rate of taxation on SVO was originally set at a reduced rate of 27.1p per litre, but in late 2005, HMRC started to enforce the full diesel excise rate of 47.1p per litre. The tax break has been reconfirmed by HMRC in a recent late 2006 review. HM Revenue & Customs has announced changes regarding the administration and collection of excise duty of biofuels and other fuel subtitutes (Veg Oil). The changes which come into effect on June 30 2007 mean that there is no need to register (enter premises) or pay duty on veg oil used as road fuel if you use less than 2500 litres per year. HMRC argued that SVOs on the market from small producers did not meet the official definition of "biodiesel" in Section 2AA of The Hydrocarbon Oil Duties Act 1979 (HODA), and consequently was merely a "fuel substitute" chargeable at the normal diesel rate. Such a policy seemed to contradict the UK Government's commitments to the Kyoto Protocol and to many EU directives and had many consequences, including an attempt to make the increase retroactive, with one organisation being presented with a £16,000 back tax bill. This change in the rate of excise duty has effectively removed any commercial incentive to use SVO, regardless of its desirability on environmental grounds; unless waste vegetable oil can be obtained free of charge, the combined price of SVO and taxation for its use usually exceeds the price of mineral diesel. HMRC's interpretation is being widely challenged by the SVO industry and the UK pure Plant Oil Association (UKPPOA) has been formed to represent the interests of people using vegetable oil as fuel and to lobby parliament.

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/index.php/Vegetarian_cuisine

# Vegetarian cuisine Vegetarian cuisine refers to food that meets vegetarian standards by excluding meat and animal tissue products. For lacto-ovo vegetarianism (the most common type of vegetarianism in the Western world), dairy products such as eggs, milk, and cheese are permitted. The strictest form of vegetarianism is veganism, which excludes all animal products, including dairy products as well as honey, and even some refined sugars if filtered and whitened with bone char. These are vegetarian versions of popular dishes that non-vegetarians enjoy and are frequently consumed as fast food, comfort food, transition food for new vegetarians, or a way to show non-vegetarians that they can be vegetarians while still enjoying their favorite foods. Many vegetarians just enjoy these dishes as part of a varied diet.

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/index.php/Veggie_burger

# Veggie burger A veggie burger is a vegetarian hamburger. The patty of a veggie burger can be made from vegetables, nuts, dairy, mushrooms, textured vegetable protein (TVP), or a combination of these. They are sometimes vegan. Veggie burgers are available in a growing number of fast-food restaurants in the U.S., but availability may vary geographically or even among particular restaurants of the same franchise. As of April 2005, veggie burgers were available in all Burger King restaurants (although, not vegan : http://www.vegparadise.com/news15.html)[citation needed], and certain Subway restaurants. Many "greasy spoon" cafes as well as top-of-the-range eateries also offer veggie burgers as an option. In places like India where vegetarianism is popular, McDonald's serves veggie burgers as it is one of the primary hot sellers. The first veggie burger was created, in London, by Gregory Sams in 1982, calling it the 'VegeBurger'. Gregory and his brother Craig had run a famous natural food restaurant in Paddington since the 1960s. A Carrefour hypermarket in Southampton sold 2000 packets in three weeks after its launch, which was reported in The Observer newspaper on February 27, 1983.

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/index.php/Vein

# Vein In the circulatory system, a vein is a blood vessel that carries blood toward the heart. The majority of veins in the body carry low-oxygen blood from the tissues back to the heart; the exceptions being the pulmonary and umbilical veins which both carry oxygenated blood. Veins function to return deoxygenated blood to the heart, and are essentially tubes that collapse when their lumens are not filled with blood. The thick, outer-most layer of a vein is comprised of collagen, wrapped in bands of smooth muscle while the interior is lined with endothelial cells. Most veins have one-way flaps called venous valves that prevent blood from backflowing and pooling in the lower extremities due to the effects of gravity. The precise location of veins is much more variable from person to person than that of arteries. The total capacity of the veins is more than sufficient to hold the entire blood volume of the body; this capacity is reduced through the venous tone of the smooth muscles, minimizing the cross-sectional area (and hence volume) of the individual veins and therefore total venous system. The helical bands of smooth muscles which wrap around veins help maintain blood flow to the right atrium. In cases of vasovagal syncope, the smooth muscles relax and the veins of the extremities below the heart fill up with blood, failing to return sufficient volume to maintain cardiac output and blood flow to the brain. Veins serve to return blood from organs to the heart. In systemic circulation oxygenated blood is pumped by the left ventricle through the arteries to the muscles and organs of the body, where its nutrients and gases are exchanged at capillaries, entering the veins filled with cellular waste and carbon dioxide. The de-oxygenated blood is taken by veins to the right atrium of the heart, which transfers the blood to the right ventricle, where it is then pumped to the pulmonary arteries and eventually the lungs. In pulmonary circulation the pulmonary veins return oxygenated blood from the lungs to the left atrium, which empties into the left ventricle, completing the cycle of blood circulation. The return of blood to the heart is assisted by the action of the skeletal-muscle pump which helps maintain the extremely low blood pressure of the venous system. Fainting can be caused by failure of the skeletal-muscular pump. Long periods of standing can result in blood pooling in the legs, with blood pressure too low to return blood to the heart. Neurogenic and hypovolaemic shock can also cause fainting. In these cases the smooth muscles surrounding the veins become slack and the veins fill with blood, absorbing a large portion of the total blood volume, keeping blood away from the brain and causing unconsciousness. Often the generalization is made that arteries carry oxygenated blood to the tissues, the tissues consume the oxygen, and the remaining deoxygenated blood is carried back to the heart for reoxygenation. This is an oversimplification: all veins carry oxygenated blood, although the blood carried by the veins is usually considerably less oxygenated than the blood carried by most arteries. Veins are used medically as points of access to the blood stream, permitting the withdrawal of blood specimens (venipuncture) for testing purposes, and enabling the infusion of fluid, electrolytes, nutrition, and medications. The latter is called intravenous delivery. It can be done by an injection with a syringe, or by inserting a catheter (a flexible tube). In contrast to arterial blood which is uniform throughout the body, the blood removed from veins for testing can vary in its contents depending on the part of the body the vein drains. In example, blood drained from a working muscle will contain significantly less oxygen and glucose than blood drained from the liver. However the more blood from different veins mixes as it returns to the heart, the more homogeneous it becomes. If an intravenous catheter has to be inserted, for most purposes this is done into a peripheral vein (a vein near the surface of the skin in the hand or arm, or less desirably, the leg). Some highly concentrated fluids or irritating medications must flow into the large central veins, which are sometimes used when peripheral access cannot be obtained. Catheters can be threaded into the superior vena cava for these uses: if long term use is thought to be needed, a more permanent access point can be inserted surgically. The most common vein disorder is venous insufficiency, usually manifested by spider veins or varicose veins. A variety of treatments are used depending on the patient's particular type and pattern of veins and on the physician's preferences. Treatment can include radio-frequency ablation, vein stripping, ambulatory phlebectomy, foam sclerotherapy, sclerotherapy, lasers or compression. Deep vein thrombosis is a condition where a blood clot forms in a deep vein, which can lead to pulmonary embolism and chronic venous insufficiency. Phlebology is the medical discipline that involves the diagnosis and treatment of disorders of venous origin. Diagnostic techniques used include the history and physical examination, venous imaging techniques and laboratory evaluation related to venous thromboembolism. The pulmonary veins carry relatively oxygenated blood from the lungs to the heart. The superior and inferior venae cavae carry relatively deoxygenated blood from the upper and lower systemic circulations, respectively. A portal venous system is a series of veins or venules that directly connect two capillary beds. Examples of such systems include the hepatic portal vein and hypophyseal portal system. The blood carried by veins is dark red due to its high percentage of CO2 as it returns to the heart (in contrast to the high levels of O2 in arterial blood, which is bright red). Veins appear blue because the subcutaneous fat in the skin absorbs lower-frequency light, permitting only the highly energetic blue wavelengths to penetrate through to the dark vein and reflect off. This physical effect can also be seen in the iris of blue eyes (pigmentless iris in the front, dark retina in the back) and is called Rayleigh scattering.

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/index.php/Velamentous_cord_insertion

# Velamentous cord insertion In velamentous cord insertion, the umbilical cord inserts in the chorion rather than in the mass of the placenta. The exposed vessels are not protected by Wharton's jelly and hence are vulnerable to rupture.

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/index.php/Vellus_hair

# Vellus hair Vellus hair is short, fine, "peach fuzz" body hair. It is a very soft and short hair that grows in most places on the human body in both sexes. It is usually less than 2 cm long and the follicles are not connected to sebaceous glands. It is most easily observed in women and children, as they have less terminal hair to obscure it. It is also found in pre-adolescents, tanner stage, as well as in male pattern baldness. It should not be confused with lanugo, a much thicker type of hair developed by fetuses and the bodies of anorexics in an attempt to retain bodily heat.

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/index.php/Vemurafenib

# Vemurafenib Vemurafenib is a kinase inhibitor that is FDA approved for the treatment of patients with unresectable or metastatic melanoma with [[BRAF|BRAF V600E mutation]] as detected by an FDA-approved test. Common adverse reactions include arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus, and skin papilloma. Severe dermatologic reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, can occur in patients receiving vemurafenib. Permanently discontinue vemurafenib in patients who experience a severe dermatologic reaction. Concentration-dependent QT prolongation occurred in an uncontrolled, open-label QT sub-study in previously treated patients with BRAF V600E mutation-positive metastatic melanoma. QT prolongation may lead to an increased risk of ventricular arrhythmias, including Torsade de Pointes. Do not start treatment in patients with uncorrectable electrolyte abnormalities, QTc > 500 ms, or long QT syndrome, or in patients who are taking medicinal products known to prolong the QT interval. Prior to and following treatment initiation or after dose modification of vemurafenib for QTc prolongation, evaluate ECG and electrolytes (including potassium, magnesium, and calcium) after 15 days, monthly during the first 3 months, and then every 3 months thereafter or more often as clinically indicated. Withhold vemurafenib in patients who develop QTc > 500 ms (Grade 3). Upon recovery to QTc ≤ 500 ms (Grade ≤ 2), restart at a reduced dose. Permanently discontinue vemurafenib treatment if the QTc interval remains > 500 ms and increased > 60 ms from pre-treatment values after controlling cardiac risk factors for QT prolongation (e.g., electrolyte abnormalities, congestive heart failure, and bradyarrhythmias). Liver injury leading to functional hepatic impairment, including coagulopathy or other organ dysfunction, can occur with vemurafenib. Monitor transaminases, alkaline phosphatase, and bilirubin before initiation of treatment and monthly during treatment, or as clinically indicated. Manage laboratory abnormalities with dose reduction, treatment interruption, or treatment discontinuation. The safety and effectiveness of vemurafenib in combination with Ipilimumab have not been established. In a dose-finding trial, Grade 3 increases in transaminases and bilirubin occurred in a majority of patients who received concurrent Ipilimumab (3 mg/kg) and vemurafenib (960 mg BID or 720 mg BID). Mild to severe photosensitivity can occur in patients treated with vemurafenib. Advise patients to avoid sun exposure, wear protective clothing and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥ 30) when outdoors. Institute dose modifications for intolerable Grade 2 or greater photosensitivity. Uveitis, blurry vision, and photophobia can occur in patients treated with vemurafenib. In Trial 1, uveitis, including iritis, occurred in 2.1% (7/336) of patients receiving vemurafenib compared to no patients in the dacarbazine arm. Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Monitor patients for signs and symptoms of uveitis. vemurafenib can cause fetal harm when administered to a pregnant woman based on its mechanism of action. There are no adequate and well-controlled studies in pregnant women. 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 a fetus. Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in a broader patient population in clinical practice. This section describes adverse drug reactions (ADRs) identified from analyses of Trial 1 and Trial 2. Trial 1 randomized (1:1) 675 treatment-naive patients with unresectable or metastatic melanoma to receive vemurafenib 960 mg orally twice daily or dacarbazine 1000 mg/m2 intravenously every 3 weeks. In Trial 2, 132 patients with metastatic melanoma and failure of at least one prior systemic therapy received treatment with vemurafenib 960 mg orally twice daily. TABLE 1 presents adverse reactions reported in at least 10% of patients treated with vemurafenib. The most common adverse reactions of any grade (≥ 30% in either study) in vemurafenib-treated patients were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus, and skin papilloma. The most common (≥ 5%) Grade 3 adverse reactions were cuSCC and rash. The incidence of Grade 4 adverse reactions was ≤ 4% in both studies. The incidence of adverse events resulting in permanent discontinuation of study medication in Trial 1 was 7% for the vemurafenib arm and 4% for the dacarbazine arm. In Trial 2, the incidence of adverse events resulting in permanent discontinuation of study medication was 3% in vemurafenib-treated patients. The median duration of study treatment was 4.2 months for vemurafenib and 0.8 months for dacarbazine in Trial 1, and 5.7 months for vemurafenib in Trial 2. TABLE 2 shows the incidence of worsening liver laboratory abnormalities in Trial 1 summarized as the proportion of patients who experienced a shift from baseline to Grade 3 or 4. The following adverse reactions have been identified during postapproval use of vemurafenib. 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. Vemurafenib is a substrate of CYP3A4 based on in vitro data; therefore, coadministration of strong CYP3A4 inhibitors or inducers may alter vemurafenib concentrations. Avoid coadministration of vemurafenib with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) or strong inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital), and replace these drugs with alternative drugs when possible. Concomitant use of vemurafenib with drugs with a narrow therapeutic window that are predominantly metabolized by CYP1A2 is not recommended as vemurafenib may increase concentrations of CYP1A2 substrates. If coadministration cannot be avoided, monitor closely for toxicities and consider a dose reduction of concomitant CYP1A2 substrates. Vemurafenib revealed no evidence of teratogenicity in rat embryo/fetuses at doses up to 250 mg/kg/day (approximately 1.3 times the human clinical exposure based on AUC) or rabbit embryo/fetuses at doses up to 450 mg/kg/day (approximately 0.6 times the human clinical exposure based on AUC). Fetal drug levels were 3–5% of maternal levels, indicating that vemurafenib has the potential to be transmitted from the mother to the developing fetus. There are no adequate and well controlled studies in pregnant women. Women of childbearing potential and men should be advised to use appropriate contraceptive measures during vemurafenib therapy and for at least 2 months after discontinuation of vemurafenib. 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 a fetus. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Vemurafenib in women who are pregnant. It is not known whether vemurafenib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from vemurafenib in nursing infants, 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. No formal clinical study has been conducted to evaluate the effect of renal impairment on the pharmacokinetics of vemurafenib. No dose adjustment is recommended for patients with mild and moderate renal impairment based on a population pharmacokinetic analysis. The appropriate dose of vemurafenib has not been established in patients with severe renal impairment. No formal clinical study has been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of vemurafenib. No dose adjustment is recommended for patients with mild and moderate hepatic impairment based on a population pharmacokinetic analysis. The appropriate dose of vemurafenib has not been established in patients with severe hepatic impairment. Vemurafenib is a low molecular weight, orally available inhibitor of some mutated forms of BRAF serine-threonine kinase, including BRAF V600E. Vemurafenib also inhibits other kinases in vitro such as CRAF, ARAF, wild-type BRAF, SRMS, ACK1, MAP4K5, and FGR at similar concentrations. Some mutations in the BRAF gene including V600E result in constitutively activated BRAF proteins, which can cause cell proliferation in the absence of growth factors that would normally be required for proliferation. Vemurafenib has anti-tumor effects in cellular and animal models of melanomas with mutated BRAF V600E. Vemurafenib has the chemical name propane-1-sulfonic acid {3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide. It has the molecular formula C23H18ClF2N3O3S and a molecular weight of 489.9. Vemurafenib has the following chemical structure: In a multi-center, open-label, single-arm study in 132 patients with BRAF V600E mutation-positive metastatic melanoma, patients administered vemurafenib 960 mg orally twice daily did not experience large changes in mean QTc interval (i.e., > 20 ms) from baseline. Vemurafenib is associated with concentration-dependent QTc interval prolongation. The largest mean change from baseline in the first month of treatment occurred at 2 hours post-dose on Day 15—an increase of 12.8 ms (upper boundary of the two-sided 90% confidence interval of 14.9 ms). In the first 6 months of treatment, the largest observed mean change from baseline occurred at a pre-dose time point—an increase of 15.1 ms (upper boundary of the two-sided 90% confidence interval of 17.7 ms). The pharmacokinetics of vemurafenib were determined in patients with BRAF mutation-positive metastatic melanoma following 15 days of 960 mg twice daily with dosing approximately 12 hours apart. The population pharmacokinetic analysis pooled data from 458 patients. At steady-state, vemurafenib exhibits linear pharmacokinetics within the 240 mg to 960 mg dose range. The mean (± SD) Cmax and AUC0-12 were 62 ± 17 µg/mL and 601 ± 170 µg*h/mL, respectively. The median accumulation ratio estimate from the population pharmacokinetic analysis for the twice daily regimen is 7.4, with steady-state achieved at approximately 15 to 22 days. In clinical trials, vemurafenib was administered without regard to food. A food effect study has demonstrated that a single dose of vemurafenib administered with a high-fat meal increased AUC by approximately 5-fold, increased Cmax by 2.5-fold, and delayed Tmax by approximately 4 hours as compared to the fasted state. Vemurafenib is highly bound (> 99%) to human albumin and alpha-1 acid glycoprotein plasma proteins. The population apparent volume of distribution is estimated to be 106 L (with 66% inter-patient variability). Following oral administration of 960 mg of 14C-vemurafenib, mean data showed that vemurafenib and its metabolites represented 95% and 5% of the components in plasma over 48 hours, respectively. Following oral administration of 960 mg of 14C-vemurafenib, approximately 94% of the radioactive dose was recovered in feces and approximately 1% was recovered in the urine. The population apparent clearance is estimated to be 31 L/day (with 32% inter-patient variability). The median elimination half-life estimate for vemurafenib is 57 hours (the 5th and 95th percentile range is 30 to 120 hours). There have been no formal studies conducted assessing the carcinogenic potential of vemurafenib. vemurafenib increased the development of cutaneous squamous cell carcinomas in patients in clinical trials. Vemurafenib did not cause genetic damage when tested in in vitro assays (bacterial mutation [AMES Assay], human lymphocyte chromosome aberration) or in the in vivo rat bone marrow micronucleus test. Consistent with the increased incidence of cutaneous squamous cell carcinomas in patients treated with vemurafenib, the treatment of mice implanted with human cuSCC cells with vemurafenib caused a dose dependent acceleration of the growth of the implanted tumors. Trial 1, an international, open-label, randomized controlled trial, equally allocated 675 patients with treatment-naive, BRAF V600E mutation-positive unresectable or metastatic melanoma, as detected by the cobas® 4800 BRAF V600 Mutation Test, to receive vemurafenib 960 mg by mouth twice daily (n=337) or dacarbazine 1000 mg/m2 intravenously on Day 1 every 3 weeks (n=338). Randomization stratification factors were disease stage, lactate dehydrogenase (LDH), ECOG performance status, and geographic region. Treatment continued until disease progression, unacceptable toxicity, and/or consent withdrawal. The major efficacy outcome measures of the trial were overall survival (OS) and investigator-assessed progression-free survival (PFS). Other outcome measures included confirmed investigator-assessed best overall response rate. Baseline characteristics were balanced between treatment groups. Most patients were male (56%) and caucasian (99%), the median age was 54 years (24% were ≥ 65 years), all patients had ECOG performance status of 0 or 1, and the majority of patients had metastatic disease (95%). Trial 1 demonstrated statistically significant increases in overall survival and progression-free survival in the vemurafenib arm compared to the dacarbazine control arm. TABLE 3 and FIGURE 1 summarize the efficacy results. The confirmed, investigator-assessed best overall response rate was 48.4% (95% CI: 41.6%, 55.2%) in the vemurafenib arm compared to 5.5% (95% CI: 2.8%, 9.3%) in the dacarbazine arm. There were 2 complete responses (0.9%) and 104 partial responses (47.4%) in the vemurafenib arm and all 12 responses were partial responses (5.5%) in the dacarbazine arm. In a single-arm, multicenter, multinational trial (Trial 2), 132 patients with BRAF V600E mutation-positive metastatic melanoma, as detected by the cobas® 4800 BRAF V600 Mutation Test, who had received at least one prior systemic therapy, received vemurafenib 960 mg by mouth twice daily. The median age was 52 years with 19% of patients being older than 65 years. The majority of patients were male (61%) and Caucasian (99%). Forty-nine percent of patients received ≥ 2 prior therapies. The median duration of follow-up was 6.87 months (range, 0.6 to 11.3). The confirmed best overall response rate as assessed by an independent review committee (IRC) was 52% (95% CI: 43%, 61%). There were 3 complete responses (2.3%) and 66 partial responses (50.0%). The median time to response was 1.4 months with 75% of responses occurring by month 1.6 of treatment. The median duration of response by IRC was 6.5 months (95% CI: 5.6, not reached). Health care providers should advise patients of the potential benefits and risks of vemurafenib and instruct their patients to read the MEDICATION GUIDE before starting vemurafenib therapy. Inform patients of the following:

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/index.php/Vena_cavae

# Vena cavae The superior and inferior vena cava are collectively called the venae cavae. They are the veins that return de-oxygenated blood from the body into the heart. They both empty into the right atrium. The superior vena cava (or anterior) is above the heart, and forms from a convergence of the left and right brachiocephalic veins that contain blood from the head and the arms. The vena cavae carry deoxygenated blood from the body to the right atrium of the heart. The venae cavae is the largest blood vessel in the heart.

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/index.php/Venae_cordis_minimae

# Venae cordis minimae Venae cordis minimae (or smallest cardiac veins, Thebesian veins, venae cardiacae minimae, veins of Thebesius) are minute valveless veins in the walls of all four heart chambers and they are often confused with the distinct set of arterial connections, the "vessels of Wearn". They are most abundant in the right atrium and least in the left ventricle. They drain the myocardium and pass through the endocardial layer to empty mostly into the right atrium, but a few empty into the ventricles. The openings of the chambers are called the foramina venarum minimarum. They are named after the German anatomist Adam Christian Thebesius, who described them in a 1708 treatise called Disputatio medica inauguralis de circulo sanguinis in corde.

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/index.php/Venezuelan_hemorrhagic_fever

# Venezuelan hemorrhagic fever Venezuelan hemorrhagic fever (VHF) is a zoonotic human illness first identified in 1989. The disease is most prevalent in several rural areas of central Venezuela and is caused by the Guanarito virus (GTOV) which belongs to the Arenaviridae family. The short-tailed cane mouse (Zygodontomys brevicauda) is the main host for GTOV which is spread mostly by inhalation of aerosolized droplets of saliva, respiratory secretions, urine, or blood from infected rodents. Person-to-person spread is possible, but uncommon. From September 1989 through December 2006, the State of Portuguesa recorded 618 cases of VHF. Nearly all of the cases were individuals who worked or lived in Guanarito during the time they became infected. The case fatality rate was 23.1%. Because the virus is contracted by aerosol dissemination, concern arose shortly after the first cases emerged in 1989 due to fear of biological warfare. Potential biological terrorism agents were identified and categorized in 1999 by the Centers for Disease Control and Prevention (CDC) as part of the Congressional initiative to further response capabilities to biological weapons . Arenaviruses causing hemorrhagic fevers, along with a genus of virus called filoviruses, were categorized in Category A; these are pathogens with the highest potential impact on public health safety. A notable event in the timeline of this virus' scientific knowledge was the unexplained disappearance of a vial of the virus at the University of Texas Medical Branch Galveston National Laboratory, announced 2013 March 24. Arenaviruses are enveloped, single-stranded, bisegmented RNA viruses with ambisense genomes. Based on their antigenic properties, arenaviruses have been classified into two major groups: the Old World arena viruses, and the New World arenaviruses. Old World arena viruses include lymphocytic choriomeningitis virus, and Lassa virus. New world arena viruses are further broken down into three clades, A, B, and C. The Guanarito arena virus belongs to clade B and is the cause of VHF. On the biosafety level scale of one to four, with four causing the most risk, the viruses causing hemorrhagic fevers have been assigned a four by the CDC. The short-tailed cane mouse, the main host of GTOV, is native to western Venezuela and resides in large numbers in tall grass, cultivated agricultural fields, human homes, and outbuildings. It is speculated that demographic and ecological changes in the rural areas increased the frequency of contact between humans and infected rodents such that VHF emerged. VHF has many similarities to Lassa fever and to the arenavirus hemorrhagic fevers that occur in Argentina and Bolivia. It causes fever and malaise followed by hemorrhagic manifestations and convulsions. Some presentations of the virus are also characterized by vascular damage, bleeding diathesis, fever, and multiple organ involvement. Clinical diagnosis of VHF has proven to be difficult based on the nonspecific symptoms. The disease is fatal in 30% of cases and is endemic to Portuguesa state and Barinas state in Venezuela. Treatment and prevention for the VHF virus are limited and there are currently no licensed vaccines available that can act to prevent the disease . However, once infected, Ribavirin, an anti-viral drug given intravenously, is one way to treat VHF.

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/index.php/Venice_treacle

# Venice treacle Venice treacle, also called Andromachi theriaca, Theriacum Andromachi or treacle of Andromachus, in pharmacy, was a honey- or molasses-based alexipharmic composition once thought to be good against venom. It was first developed in Italy, then exported throughout Europe from Venice. The following ingredients for the theriac were taken from d'Amsterdammer Apotheek 1686 and translated from the old Latin names into the Latin names now used where possible. Not all ingredients are known. Roots: Iris, Balsamorhiza deltoidea, Potentilla reptans (creeping cinquefoil), Rheum rhabarbarum (garden rhubarb), Zingiber, Angustafolia odorata, Gentiana, Meum Athamanticum (spignel), Valeriana, Corydalis cava (hollowroot), Agaricus, Cinnamomum zeylanicum (cinnamon), Cinnamomum aromaticum (cassia) Leaves: Teucrium scordium (water germander), Franxinus excelsior, Clinopodium calamintha (lesser calamint), Marrubium vulgare (white or common horehound), Cymbopogon citratus (West-Indian lemongrass), Teucrium chamaedrys (wall germander), Cupressasae, Laurus nobilis (bay laurel), Polium montanum, Piper nigrum (black pepper), Piper longum (long pepper), Juniperus (juniper), Syzygium aromaticum (clove) Seeds: Brassica napus (rapeseed), Petroselinum (parsley), Nigella sativa, Pimpinella anisum (anise), Elettaria cardamomum, Foeniculum vulgare (fennel), Hypericum perforatum (st. john's wort), seseli, thlaspi, Daucus carota (carrot), Lavandula angustifolia (common or English lavender), Papaver somniverum (opium poppy), glycyrrhiza, Cytinus hypocistis, Acaciae (acacia), Styrax benzoin, Gummi arabicum, Sagapeni (wax of an unknown tree probably some kind of Ferula), Gummi Opopanax chironium, Gummi Ferula foetida, Dead sea bitumen, Commiphora (a tree from which myrrh is derived), incense, Turpentine from Cyprus, Boli armen. Verae (some kind of red clay), Chalciditis (copper containing substance), Castoreum, oil from Myristica fragans (nutmeg), Trochisci Viperarum, Magmatis Hedychroi, Canary Island wine, Narbonne white honey

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/index.php/Venki_Ramakrishnan

# Venki Ramakrishnan Venki Ramakrishnan is a structural biologist at the Laboratory of Molecular Biology of the Medical Research Council located in Cambridge, England . In 2000, his laboratory determined the structure of the 30S subunit of the ribosome and its complexes with several antibiotics . This was followed by studies that provided structural insights into the mechanism that ensures the fidelity of protein biosynthesis. More recently, his laboratory has determined the atomic structure of the whole ribosome in complex with its tRNA and mRNA ligands. Ramakrishnan is also known for his past work on histone and chromatin structure. He is a Fellow of the Royal Society, and a member of EMBO and the U.S. National Academy of Sciences.

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/index.php/Venlafaxine_adverse_reactions

# Venlafaxine adverse reactions The information included in the Adverse Findings Observed in Short-Term, Placebo-Controlled Studies with Effexor XR subsection is based on data from a pool of three 8- and 12-week controlled clinical trials in major depressive disorder (includes two U.S. trials and one European trial), on data up to 8 weeks from a pool of five controlled clinical trials in GAD with Effexor XR®, on data up to 12 weeks from a pool of five controlled clinical trials in Social Anxiety Disorder, and on data up to 12 weeks from a pool of four controlled clinical trials in panic disorder. Information on additional adverse events associated with Effexor XR in the entire development program for the formulation and with Effexor (immediate release) is included in the Other Adverse Events Observed During the Premarketing Evaluation of Effexor and Effexor XR subsection (see also WARNINGS and PRECAUTIONS). Approximately 11% of the 357 patients who received Effexor XR (venlafaxine hydrochloride) extended-release capsules in placebo-controlled clinical trials for major depressive disorder discontinued treatment due to an adverse experience, compared with 6% of the 285 placebo-treated patients in those studies. Approximately 18% of the 1381 patients who received Effexor XR capsules in placebo-controlled clinical trials for GAD discontinued treatment due to an adverse experience, compared with 12% of the 555 placebo-treated patients in those studies. Approximately 15% of the 819 patients who received Effexor XR capsules in placebo-controlled clinical trials for Social Anxiety Disorder discontinued treatment due to an adverse experience, compared with 5% of the 695 placebo-treated patients in those studies. Approximately 7% of the 1,001 patients who received Effexor XR capsules in placebo-controlled clinical trials for panic disorder discontinued treatment due to an adverse experience, compared with 6% of the 662 placebo-treated patients in those studies. The most common events leading to discontinuation and considered to be drug-related (ie, leading to discontinuation in at least 1% of the Effexor XR-treated patients at a rate at least twice that of placebo for any indication) are shown in Table 6. Tables 7, 8, 9, and 10 enumerate the incidence, rounded to the nearest percent, of treatment-emergent adverse events that occurred during acute therapy of major depressive disorder (up to 12 weeks; dose range of 75 to 225 mg/day), of GAD (up to 8 weeks; dose range of 37.5 to 225 mg/day), of Social Anxiety Disorder (up to 12 weeks; dose range of 75 to 225 mg/day), and of panic disorder (up to 12 weeks; dose range of 37.5 to 225 mg/day), respectively, in 2% or more of patients treated with Effexor XR (venlafaxine hydrochloride) where the incidence in patients treated with Effexor XR was greater than the incidence for the respective placebo-treated patients. The table shows the percentage of patients in each group who had at least one episode of an event at some time during their treatment. Reported adverse events were classified using a standard COSTART-based Dictionary terminology. The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the population studied. Note in particular the following adverse events that occurred in at least 5% of the Effexor XR patients and at a rate at least twice that of the placebo group for all placebo-controlled trials for the major depressive disorder indication (Table 7): Abnormal ejaculation, gastrointestinal complaints (nausea, dry mouth, and anorexia), CNS complaints (dizziness, somnolence, and abnormal dreams), and sweating. In the two U.S. placebo-controlled trials, the following additional events occurred in at least 5% of Effexor XR-treated patients (n = 192) and at a rate at least twice that of the placebo group: Abnormalities of sexual function (impotence in men, anorgasmia in women, and libido decreased), gastrointestinal complaints (constipation and flatulence), CNS complain c ts (insomnia, nervousness, and tremor), problems of special senses (abnormal vision), cardiovascular effects (hypertension and vasodilatation), and yawning. nervousness Note in particular the following adverse events that occurred in at least 5% of the Effexor XR patients and at a rate at least twice that of the placebo group for all placebo-controlled trials for the GAD indication (Table 8): Abnormalities of sexual function (abnormal ejaculation and impotence), gastrointestinal complaints (nausea, dry mouth, anorexia, and constipation), problems of special senses (abnormal vision), and sweating. Note in particular the following adverse events that occurred in at least 5% of the Effexor XR patients and at a rate at least twice that of the placebo group for the 5 placebo-controlled trials for the Social Anxiety Disorder indication (Table 9): Asthenia, gastrointestinal complaints (anorexia, constipation, dry mouth, nausea), CNS complaints (insomnia, libido decreased, nervousness, somnolence, tremor), abnormalities of sexual function (abnormal ejaculation, impotence), yawn, and sweating. In the 6-month trial, the following adverse events occurred twice as often in the 150–225 mg/day Effexor XR group compared to the 75 mg/day Effexor XR group and placebo: vasodilation, libido decreased, tremor, yawn, abnormal vision, and impotence. Note in particular the following adverse events that occurred in at least 5% of the Effexor XR patients and at a rate at least twice that of the placebo group for 4 placebo-controlled trials for the panic disorder indication (Table 10): gastrointestinal complaints (anorexia, constipation, dry mouth), CNS complaints (somnolence, tremor), abnormalities of sexual function (abnormal ejaculation), and sweating. Effexor XR (venlafaxine hydrochloride) extended-release capsules treatment for up to 12 weeks in premarketing placebo-controlled major depressive disorder trials was associated with a mean final on-therapy increase in pulse rate of approximately 2 beats per minute, compared with 1 beat per minute for placebo. Effexor XR treatment for up to 8 weeks in premarketing placebo-controlled GAD trials was associated with a mean final on-therapy increase in pulse rate of approximately 2 beats per minute, compared with less than 1 beat per minute for placebo. Effexor XR treatment for up to 12 weeks in premarketing placebo-controlled Social Anxiety Disorder trials was associated with a mean final on-therapy increase in pulse rate of approximately 3 beats per minute, compared with an increase of 1 beat per minute for placebo. Effexor XR treatment for up to 12 weeks in premarketing placebo-controlled panic disorder trials was associated with a mean final on-therapy increase in pulse rate of approximately 1 beat per minute, compared with a decrease of less than 1 beat per minute for placebo. (See the Sustained hypertension and Elevations in Systolic and Diastolic Blood Pressure sections of WARNINGS for effects on blood pressure.) In a flexible-dose study, with Effexor (immediate release) doses in the range of 200 to 375 mg/day and mean dose greater than 300 mg/day, the mean pulse was increased by about 2 beats per minute compared with a decrease of about 1 beat per minute for placebo. Effexor XR (venlafaxine hydrochloride) extended-release capsules treatment for up to 12 weeks in premarketing placebo-controlled trials for major depressive disorder was associated with a mean final on-therapy increase in serum cholesterol concentration of approximately 1.5 mg/dL compared with a mean final decrease of 7.4 mg/dL for placebo. Effexor XR treatment for up to 8 weeks and up to 6 months in premarketing placebo-controlled GAD trials was associated with mean final on-therapy increases in serum cholesterol concentration of approximately 1.0 mg/dL and 2.3 mg/dL, respectively while placebo subjects experienced mean final decreases of 4.9 mg/dL and 7.7 mg/dL, respectively. Effexor XR treatment for up to 12 weeks and up to 6 months in premarketing placebo-controlled Social Anxiety Disorder trials was associated with mean final on-therapy increases in serum cholesterol concentration of approximately 7.9 mg/dL and 5.6 mg/dL, respectively, compared with mean final decreases of 2.9 and 4.2 mg/dL, respectively, for placebo. Effexor XR treatment for up to 12 weeks in premarketing placebo-controlled panic disorder trials was associated with mean final on-therapy increases in serum cholesterol concentration of approximately 5.8 mg/dL compared with a mean final decrease of 3.7 mg/dL for placebo. Patients treated with Effexor (immediate release) for at least 3 months in placebo-controlled 12-month extension trials had a mean final on-therapy increase in total cholesterol of 9.1 mg/dL compared with a decrease of 7.1 mg/dL among placebo-treated patients. This increase was duration dependent over the study period and tended to be greater with higher doses. Clinically relevant increases in serum cholesterol, defined as 1) a final on-therapy increase in serum cholesterol ≥50 mg/dL from baseline and to a value ≥261 mg/dL 2) an average on-therapy increase in serum cholesterol ≥50 mg/dL from baseline and to a value ≥261 mg/dL, were recorded in 5.3% of venlafaxine-treated patients and 0.0% of placebo-treated patients (see PRECAUTIONS-General-Serum Cholesterol Elevation). Effexor XR treatment for up to 12 weeks in pooled premarketing Social Anxiety Disorder trials was associated with a mean final on-therapy increase in fasting serum triglyceride concentration of approximately 8.2 mg/dL, compared with a mean final increase of 0.4 mg/dL for placebo. Effexor XR treatment for up to 6 months in a premarketing Social Anxiety Disorder trial was associated with a mean final on-therapy increase in fasting serum triglyceride concentration of approximately 11.8 mg/dL, compared with a mean final on-therapy increase of 1.8 mg/dL for placebo. Effexor XR treatment for up to 12 weeks in pooled premarketing panic disorder trials was associated with a mean final on-therapy increase in fasting serum triglyceride concentration of approximately 5.9 mg/dL, compared with a mean final increase of 0.9 mg/dL for placebo. Effexor XR treatment for up to 6 months in a premarketing panic disorder trial was associated with a mean final on-therapy increase in fasting serum triglyceride concentration of approximately 9.3 mg/dL, compared with a mean final on-therapy decrease of 0.3 mg/dL for placebo. In a flexible-dose study, with Effexor (immediate release) doses in the range of 200 to 375 mg/day and mean dose greater than 300 mg/day, the mean change in heart rate was 8.5 beats per minute compared with 1.7 beats per minute for placebo. During its premarketing assessment, multiple doses of Effexor XR were administered to 705 patients in Phase 3 major depressive disorder studies and Effexor was administered to 96 patients. During its premarketing assessment, multiple doses of Effexor XR were also administered to 1381 patients in Phase 3 GAD studies, 819 patients in Phase 3 Social Anxiety Disorder studies, and 1314 patients in Phase 3 panic disorder studies. In addition, in premarketing assessment of Effexor, multiple doses were administered to 2897 patients in Phase 2 to Phase 3 studies for major depressive disorder. The conditions and duration of exposure to venlafaxine in both development programs varied greatly, and included (in overlapping categories) open and double-blind studies, uncontrolled and controlled studies, inpatient (Effexor only) and outpatient studies, fixed-dose, and titration studies. Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories. In the tabulations that follow, reported adverse events were classified using a standard COSTART-based Dictionary terminology. The frequencies presented, therefore, represent the proportion of the 7212 patients exposed to multiple doses of either formulation of venlafaxine who experienced an event of the type cited on at least one occasion while receiving venlafaxine. All reported events are included except those already listed in Tables 7, 8, 9, and 10 and those events for which a drug cause was remote. If the COSTART term for an event was so general as to be uninformative, it was replaced with a more informative term. It is important to emphasize that, although the events reported occurred during treatment with venlafaxine, they were not necessarily caused by it. Events are further categorized by body system and listed in order of decreasing frequency using the following definitions: Frequent adverse events are defined as those occurring on one or more occasions in at least 1/100 patients; Infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. Body as a whole - Frequent: chest pain substernal, chills, fever, neck pain; Infrequent: face edema, intentional injury, malaise, moniliasis, neck rigidity, pelvic pain, photosensitivity reaction, suicide attempt, withdrawal syndrome; Rare: appendicitis, bacteremia, carcinoma, cellulitis, granuloma. Cardiovascular system - Frequent:migraine, tachycardia; Infrequent: angina pectoris, arrhythmia, bradycardia, extrasystoles, hypotension, peripheral vascular disorder (mainly cold feet and/or cold hands), postural hypotension, syncope; Rare: aortic aneurysm, arteritis, first-degree atrioventricular block, bigeminy, bundle branch block, capillary fragility, cerebral ischemia, coronary artery disease, congestive heart failure, heart arrest, hematoma, cardiovascular disorder (mitral valve and circulatory disturbance), mucocutaneous hemorrhage, myocardial infarct, pallor, sinus arrhythmia, thrombophlebitis. Digestive system - Frequent: increased appetite; Infrequent: bruxism, colitis, dysphagia, tongue edema, eructation, esophagitis, gastritis, gastroenteritis, gastrointestinal ulcer, gingivitis, glossitis, rectal hemorrhage, hemorrhoids, melena, oral moniliasis, stomatitis, mouth ulceration; Rare: abdominal distension, biliary pain, cheilitis, cholecystitis, cholelithiasis, esophageal spasms, duodenitis, hematemesis, gastroesophageal reflux disease, gastrointestinal hemorrhage, gum hemorrhage, hepatitis, ileitis, jaundice, intestinal obstruction, liver tenderness, parotitis, periodontitis, proctitis, rectal disorder, salivary gland enlargement, increased salivation, soft stools, tongue discoloration. Metabolic and nutritional - Frequent: edema, weight gain; Infrequent: alkaline phosphatase increased, dehydration, hypercholesteremia, hyperglycemia, hyperlipidemia, hypokalemia, SGOT (AST) increased, SGPT (ALT) increased, thirst; Rare: alcohol intolerance, bilirubinemia, BUN increased, creatinine increased, diabetes mellitus, glycosuria, gout, healing abnormal, hemochromatosis, hypercalcinuria, hyperkalemia, hyperphosphatemia, hyperuricemia, hypocholesteremia, hypoglycemia, hyponatremia, hypophosphatemia, hypoproteinemia, uremia. Musculoskeletal system - Infrequent: arthritis, arthrosis, bone spurs, bursitis, leg cramps, myAsthenia, tenosynovitis; Rare: bone pain, pathological fracture, muscle cramp, muscle spasms, musculoskeletal stiffness], myopathy, osteoporosis, osteosclerosis, plantar fasciitis, rheumatoid arthritis, tendon rupture. Nervous system - Frequent: amnesia, confusion, depersonalization, hypesthesia,thinking abnormal, trismus, vertigo; Infrequent: akathisia, apathy, ataxia, circumoral paresthesia, CNS stimulation, emotional lability, euphoria, hallucinations, hostility, hyperesthesia, hyperkinesia, hypotonia, incoordination, libido increased, manic reaction, myoclonus, neuralgia, neuropathy, psychosis, seizure, abnormal speech, stupor, suicidal ideation; Rare: abnormal/changed behavior, adjustment disorder, akinesia, alcohol abuse, aphasia, bradykinesia, buccoglossal syndrome, cerebrovascular accident, feeling drunk, loss of consciousness, delusions, dementia, dystonia, energy increased, facial paralysis, abnormal gait, Guillain-Barre Syndrome, homicidal ideation, hyperchlorhydria, hypokinesia, hysteria, impulse control difficulties, motion sickness, neuritis, nystagmus, paranoid reaction, paresis, psychotic depression, reflexes decreased, reflexes increased, torticollis. Respiratory system - Frequent: cough increased, dyspnea; Infrequent: asthma, chest congestion, epistaxis, hyperventilation, laryngismus, laryngitis, pneumonia, voice alteration; Rare: atelectasis, hemoptysis, hypoventilation, hypoxia, larynx edema, pleurisy, pulmonary embolus, sleep apnea. Skin and appendages - Frequent: pruritus; Infrequent: acne, alopecia, contact dermatitis, dry skin, eczema, maculopapular rash, psoriasis, urticaria; Rare: brittle nails, erythema nodosum, exfoliative dermatitis, lichenoid dermatitis, hair discoloration, skin discoloration, furunculosis, hirsutism, leukoderma, miliaria, petechial rash, pruritic rash, pustular rash, vesiculobullous rash, seborrhea, skin atrophy, skin hypertrophy, skin striae, sweating decreased. Special senses - Frequent: abnormality of accommodation, mydriasis, taste perversion; Infrequent: conjunctivitis, diplopia, dry eyes, eye pain, otitis media, parosmia, photophobia, taste loss; Rare: blepharitis, cataract, chromatopsia, conjunctival edema, corneal lesion, deafness, exophthalmos, eye hemorrhage, glaucoma, retinal hemorrhage, subconjunctival hemorrhage, hyperacusis, keratitis, labyrinthitis, miosis, papilledema, decreased pupillary reflex, otitis externa, scleritis, uveitis, visual field defect. Urogenital system - Frequent: albuminuria, urination impaired; Infrequent: amenorrhea,* cystitis, dysuria,hematuria, kidney calculus, kidney pain, leukorrhea,* menorrhagia,* metrorrhagia,* nocturia, breast pain, polyuria, pyuria, prostatic disorder (prostatitis, enlarged prostate, and prostate irritability,* urinary incontinence, urinary retention, urinary urgency, vaginal hemorrhage,* vaginitis*; Rare: abortion,* anuria, breast discharge, breast engorgement, balanitis,* breast enlargement, endometriosis,* female lactation,* fibrocystic breast, calcium crystalluria, cervicitis,* orchitis,* ovarian cyst,*bladder pain, prolonged erection,* gynecomastia (male),* hypomenorrhea,* kidney function abnormal, mastitis, menopause,* pyelonephritis, oliguria, salpingitis,* urolithiasis, uterine hemorrhage,* uterine spasm,* vaginal dryness* Voluntary reports of other adverse events temporally associated with the use of venlafaxine that have been received since market introduction and that may have no causal relationship with the use of venlafaxine include the following: agranulocytosis, anaphylaxis, angioedema, aplastic anemia, catatonia, congenital anomalies, impaired coordination and balance, bone fractures, CPK increased, [deep vein thrombophlebitis, delirium, EKG abnormalities such as QT prolongation; cardiac arrhythmias including atrial fibrillation, supraventricular tachycardia, ventricular extrasystoles, and rare reports of ventricular fibrillation and ventricular tachycardia, including torsade de pointes; toxic epidermal necrolysis/Stevens-Johnson Syndrome, erythema multiforme, extrapyramidal symptoms (including dyskinesia and tardive dyskinesia), angle-closure glaucoma, hemorrhage (including eye and gastrointestinal bleeding), hepatic events (including GGT elevation; abnormalities of unspecified liver function tests; liver damage, necrosis, or failure; and fatty liver), interstitial lung disease, involuntary movements, LDH increased, neutropenia, night sweats,pancreatitis, pancytopenia,panic, prolactin increased, renal failure, rhabdomyolysis, shock-like electrical sensations or tinnitus (in some cases, subsequent to the discontinuation of venlafaxine or tapering of dose), and syndrome of inappropriate antidiuretic hormone secretion (usually in the elderly). There have been reports of elevated clozapine levels that were temporally associated with adverse events, including seizures, following the addition of venlafaxine. There have been reports of increases in prothrombin time, partial thromboplastin time, or INR when venlafaxine was given to patients receiving warfarin therapy.

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# Venlafaxine clinical pharmacology The mechanism of the antidepressant action of venlafaxine in humans is believed to be associated with its potentiation of neurotransmitter activity in the CNS. Preclinical studies have shown that venlafaxine and its active metabolite, O-desmethylvenlafaxine (ODV), are potent inhibitors of neuronal serotonin and norepinephrine reuptake and weak inhibitors of dopamine reuptake. Venlafaxine and ODV have no significant affinity for muscarinic cholinergic, H1-histaminergic, or α1-adrenergic receptors in vitro. Pharmacologic activity at these receptors is hypothesized to be associated with the various anticholinergic, sedative, and cardiovascular effects seen with other psychotropic drugs. Venlafaxine and ODV do not possess monoamine oxidase (MAO) inhibitory activity. Steady-state concentrations of venlafaxine and ODV in plasma are attained within 3 days of oral multiple dose therapy. Venlafaxine and ODV exhibited linear kinetics over the dose range of 75 to 450 mg/day. Mean±SD steady-state plasma clearance of venlafaxine and ODV is 1.3±0.6 and 0.4±0.2 L/h/kg, respectively; apparent elimination half-life is 5±2 and 11±2 hours, respectively; and apparent (steady-state) volume of distribution is 7.5±3.7 and 5.7±1.8 L/kg, respectively. Venlafaxine and ODV are minimally bound at therapeutic concentrations to plasma proteins (27% and 30%, respectively). Venlafaxine is well absorbed and extensively metabolized in the liver. O-desmethylvenlafaxine (ODV) is the only major active metabolite. On the basis of mass balance studies, at least 92% of a single oral dose of venlafaxine is absorbed. The absolute bioavailability of venlafaxine is about 45%. Administration of Effexor XR (150 mg q24 hours) generally resulted in lower Cmax (150 ng/mL for venlafaxine and 260 ng/mL for ODV) and later Tmax (5.5 hours for venlafaxine and 9 hours for ODV) than for Effexor (immediate release) [Cmax's for immediate release 75 mg q12 hours were 225 ng/mL for venlafaxine and 290 ng/mL for ODV; Tmax's were 2 hours for venlafaxine and 3 hours for ODV]. When equal daily doses of venlafaxine were administered as either an immediate release tablet or the extended-release capsule, the exposure to both venlafaxine and ODV was similar for the two treatments, and the fluctuation in plasma concentrations was slightly lower with the Effexor XR capsule. Effexor XR, therefore, provides a slower rate of absorption, but the same extent of absorption compared with the immediate release tablet. Food did not affect the bioavailability of venlafaxine or its active metabolite, ODV. Time of administration (AM vs PM) did not affect the pharmacokinetics of venlafaxine and ODV from the 75 mg Effexor XR capsule. Following absorption, venlafaxine undergoes extensive presystemic metabolism in the liver, primarily to ODV, but also to N-desmethylvenlafaxine, N,O-didesmethylvenlafaxine, and other minor metabolites. In vitro studies indicate that the formation of ODV is catalyzed by CYP2D6; this has been confirmed in a clinical study showing that patients with low CYP2D6 levels ("poor metabolizers") had increased levels of venlafaxine and reduced levels of ODV compared to people with normal CYP2D6 ("extensive metabolizers"). The differences between the CYP2D6 poor and extensive metabolizers, however, are not expected to be clinically important because the sum of venlafaxine and ODV is similar in the two groups and venlafaxine and ODV are pharmacologically approximately equiactive and equipotent. Approximately 87% of a venlafaxine dose is recovered in the urine within 48 hours as unchanged venlafaxine (5%), unconjugated ODV (29%), conjugated ODV (26%), or other minor inactive metabolites (27%). Renal elimination of venlafaxine and its metabolites is thus the primary route of excretion.

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# Venlafaxine clinical studies The efficacy of Effexor XR (venlafaxine hydrochloride) extended-release capsules as a treatment for major depressive disorder was established in two placebo-controlled, short-term, flexible-dose studies in adult outpatients meeting DSM-III-R or DSM-IV criteria for major depressive disorder. A 12-week study utilizing Effexor XR doses in a range 75 to 150 mg/day (mean dose for completers was 136 mg/day) and an 8-week study utilizing Effexor XR doses in a range 75 to 225 mg/day (mean dose for completers was 177 mg/day) both demonstrated superiority of Effexor XR over placebo on the HAM-D total score, HAM-D Depressed Mood Item, the MADRS total score, the Clinical Global Impressions (CGI) Severity of Illness item, and the CGI Global Improvement item. In both studies, Effexor XR was also significantly better than placebo for certain factors of the HAM-D, including the anxiety/somatization factor, the cognitive disturbance factor, and the retardation factor, as well as for the psychic anxiety score. A 4-week study of inpatients meeting DSM-III-R criteria for major depressive disorder with melancholia utilizing Effexor (immediate release) in a range of 150 to 375 mg/day (t.i.d. schedule) demonstrated superiority of Effexor over placebo. The mean dose in completers was 350 mg/day. In one longer-term study, adult outpatients meeting DSM-IV criteria for major depressive disorder who had responded during an 8-week open trial on Effexor XR (75, 150, or 225 mg, qAM) were randomized to continuation of their same Effexor XR dose or to placebo, for up to 26 weeks of observation for relapse. Response during the open phase was defined as a CGI Severity of Illness item score of ≤3 and a HAM-D-21 total score of ≤10 at the day 56 evaluation. Relapse during the double-blind phase was defined as follows: (1) a reappearance of major depressive disorder as defined by DSM-IV criteria and a CGI Severity of Illness item score of ≥4 (moderately ill), (2) 2 consecutive CGI Severity of Illness item scores of ≥4, or (3) a final CGI Severity of Illness item score of ≥4 for any patient who withdrew from the study for any reason. Patients receiving continued Effexor XR treatment experienced significantly lower relapse rates over the subsequent 26 weeks compared with those receiving placebo. In a second longer-term trial, adult outpatients meeting DSM-III-R criteria for major depressive disorder, recurrent type, who had responded (HAM-D-21 total score ≤12 at the day 56 evaluation) and continued to be improved [defined as the following criteria being met for days 56 through 180: (1) no HAM-D-21 total score ≥20; (2) no more than 2 HAM-D-21 total scores >10, and (3) no single CGI Severity of Illness item score ≥4 (moderately ill)] during an initial 26 weeks of treatment on Effexor (immediate release) [100 to 200 mg/day, on a b.i.d. schedule] were randomized to continuation of their same Effexor dose or to placebo. The follow-up period to observe patients for relapse, defined as a CGI Severity of Illness item score ≥4, was for up to 52 weeks. Patients receiving continued Effexor treatment experienced significantly lower relapse rates over the subsequent 52 weeks compared with those receiving placebo. The efficacy of Effexor XR capsules as a treatment for Generalized Anxiety Disorder (GAD) was established in two 8-week, placebo-controlled, fixed-dose studies, one 6-month, placebo-controlled, fixed-dose study, and one 6-month, placebo-controlled, flexible-dose study in adult outpatients meeting DSM-IV criteria for GAD. One 8-week study evaluating Effexor XR doses of 75, 150, and 225 mg/day, and placebo showed that the 225 mg/day dose was more effective than placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score, both the HAM-A anxiety and tension items, and the Clinical Global Impressions (CGI) scale. While there was also evidence for superiority over placebo for the 75 and 150 mg/day doses, these doses were not as consistently effective as the highest dose. A second 8-week study evaluating Effexor XR doses of 75 and 150 mg/day and placebo showed that both doses were more effective than placebo on some of these same outcomes; however, the 75 mg/day dose was more consistently effective than the 150 mg/day dose. A dose-response relationship for effectiveness in GAD was not clearly established in the 75 to 225 mg/day dose range utilized in these two studies. Two 6-month studies, one evaluating Effexor XR doses of 37.5, 75, and 150 mg/day and the other evaluating Effexor XR doses of 75 to 225 mg/day, showed that daily doses of 75 mg or higher were more effective than placebo on the HAM-A total, both the HAM-A anxiety and tension items, and the CGI scale during 6 months of treatment. While there was also evidence for superiority over placebo for the 37.5 mg/day dose, this dose was not as consistently effective as the higher doses. The efficacy of Effexor XR capsules as a treatment for Social Anxiety Disorder (also known as Social Phobia) was established in four double-blind, parallel-group, 12-week, multicenter, placebo-controlled, flexible-dose studies and one double-blind, parallel-group, 6-month, placebo-controlled, fixed/flexible-dose study in adult outpatients meeting DSM-IV criteria for Social Anxiety Disorder. Patients received doses in a range of 75 to 225 mg/day. Efficacy was assessed with the Liebowitz Social Anxiety Scale (LSAS). In these five trials, Effexor XR was significantly more effective than placebo on change from baseline to endpoint on the LSAS total score. There was no evidence for any greater effectiveness of the 150 to 225 mg/day group compared to the 75 mg/day group in the 6-month study. Examination of subsets of the population studied did not reveal any differential responsiveness on the basis of gender. There was insufficient information to determine the effect of age or race on outcome in these studies. The efficacy of Effexor XR capsules as a treatment for panic disorder was established in two double-blind, 12-week, multicenter, placebo-controlled studies in adult outpatients meeting DSM-IV criteria for panic disorder, with or without agoraphobia. Patients received fixed doses of 75 or 150 mg/day in one study and 75 or 225 mg/day in the other study. Efficacy was assessed on the basis of outcomes in three variables: (1) percentage of patients free of full-symptom panic attacks on the Panic and Anticipatory Anxiety Scale (PAAS); (2) mean change from baseline to endpoint on the Panic Disorder Severity Scale (PDSS) total score; and (3) percentage of patients rated as responders (much improved or very much improved) on the Clinical Global Impressions (CGI) Improvement scale. In these two trials, Effexor XR was significantly more effective than placebo in all three variables. In the two 12-week studies described above, one evaluating Effexor XR doses of 75 and 150 mg/day and the other evaluating Effexor XR doses of 75 and 225 mg/day, efficacy was established for each dose. A dose-response relationship for effectiveness in patients with panic disorder was not clearly established in fixed-dose studies. In a longer-term study, adult outpatients meeting DSM-IV criteria for panic disorder who had responded during a 12-week open phase with Effexor XR (75 to 225 mg/day) were randomly assigned to continue the same Effexor XR dose (75, 150, or 225 mg) or switch to placebo for observation for relapse under double-blind conditions. Response during the open phase was defined as ≤ 1 full-symptom panic attack per week during the last 2 weeks of the open phase and a CGI Improvement score of 1 (very much improved) or 2 (much improved). Relapse during the double-blind phase was defined as having 2 or more full-symptom panic attacks per week for 2 consecutive weeks or having discontinued due to loss of effectiveness as determined by the investigators during the study. Randomized patients were in response status for a mean time of 34 days prior to being randomized. In the randomized phase following the 12-week open-label period, patients receiving continued Effexor XR experienced a significantly longer time to relapse.

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# Venlafaxine contraindications The use of MAOIs intended to treat psychiatric disorders with Effexor XR or within 7 days of stopping treatment with Effexor XR is contraindicated because of an increased risk of serotonin syndrome. The use of Effexor XR within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated (seeWARNINGS and DOSAGE AND ADMINISTRATION). Starting Effexor XR in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome (see WARNINGS and DOSAGE AND ADMINISTRATION).

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# Venlafaxine description Effexor XR is an extended-release capsule for oral administration that contains venlafaxine hydrochloride, a structurally novel antidepressant. It is designated (R/S)-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl] cyclohexanol hydrochloride or (±)-1-[α- [(dimethylamino)methyl]-p-methoxybenzyl] cyclohexanol hydrochloride and has the empirical formula of C17H27NO2 HCl. Its molecular weight is 313.87. The structural formula is shown below. Venlafaxine hydrochloride is a white to off-white crystalline solid with a solubility of 572 mg/mL in water (adjusted to ionic strength of 0.2 M with sodium chloride). Its octanol:water (0.2 M sodium chloride) partition coefficient is 0.43. Effexor XR is formulated as an extended-release capsule for once-a-day oral administration. Drug release is controlled by diffusion through the coating membrane on the spheroids and is not pH dependent. Capsules contain venlafaxine hydrochloride equivalent to 37.5 mg, 75 mg, or 150 mg venlafaxine. Inactive ingredients consist of cellulose, ethylcellulose, gelatin, hypromellose, iron oxide, and titanium dioxide.

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# Venlafaxine dosage and administration Effexor XR should be administered in a single dose with food either in the morning or in the evening at approximately the same time each day. Each capsule should be swallowed whole with fluid and not divided, crushed, chewed, or placed in water, or it may be administered by carefully opening the capsule and sprinkling the entire contents on a spoonful of applesauce. This drug/food mixture should be swallowed immediately without chewing and followed with a glass of water to ensure complete swallowing of the pellets. For most patients, the recommended starting dose for Effexor XR is 75 mg/day, administered in a single dose. In the clinical trials establishing the efficacy of Effexor XR in moderately depressed outpatients, the initial dose of venlafaxine was 75 mg/day. For some patients, it may be desirable to start at 37.5 mg/day for 4 to 7 days, to allow new patients to adjust to the medication before increasing to 75 mg/day. While the relationship between dose and antidepressant response for Effexor XR has not been adequately explored, patients not responding to the initial 75 mg/day dose may benefit from dose increases to a maximum of approximately 225 mg/day. Dose increases should be in increments of up to 75 mg/day, as needed, and should be made at intervals of not less than 4 days, since steady state plasma levels of venlafaxine and its major metabolites are achieved in most patients by day 4. In the clinical trials establishing efficacy, upward titration was permitted at intervals of 2 weeks or more; the average doses were about 140 to 180 mg/day (see Clinical Trials under CLINICAL PHARMACOLOGY). It should be noted that, while the maximum recommended dose for moderately depressed outpatients is also 225 mg/day for Effexor (immediate release), more severely depressed inpatients in one study of the development program for that product responded to a mean dose of 350 mg/day (range of 150 to 375 mg/day). Whether or not higher doses of Effexor XR are needed for more severely depressed patients is unknown; however, the experience with Effexor XR doses higher than 225 mg/day is very limited. (See PRECAUTIONS-General-Use in Patients with Concomitant Illness.) For most patients, the recommended starting dose for Effexor XR is 75 mg/day, administered in a single dose. In clinical trials establishing the efficacy of Effexor XR in outpatients with Generalized Anxiety Disorder (GAD), the initial dose of venlafaxine was 75 mg/day. For some patients, it may be desirable to start at 37.5 mg/day for 4 to 7 days, to allow new patients to adjust to the medication before increasing to 75 mg/day. Although a dose-response relationship for effectiveness in GAD was not clearly established in fixed-dose studies, certain patients not responding to the initial 75 mg/day dose may benefit from dose increases to a maximum of approximately 225 mg/day. Dose increases should be in increments of up to 75 mg/day, as needed, and should be made at intervals of not less than 4 days. (See the Use in Patients with Concomitant Illness section of PRECAUTIONS.) The recommended dose is 75 mg/day, administered in a single dose. There was no evidence that higher doses confer any additional benefit. (See the Use in Patients with Concomitant Illness section of PRECAUTIONS.) It is recommended that initial single doses of 37.5 mg/day of Effexor XR be used for 7 days. In clinical trials establishing the efficacy of Effexor XR in outpatients with panic disorder, initial doses of 37.5 mg/day for 7 days were followed by doses of 75 mg/day and subsequent weekly dose increases of 75 mg/day to a maximum dose of 225 mg/day. Although a dose-response relationship for effectiveness in patients with panic disorder was not clearly established in fixed-dose studies, certain patients not responding to 75 mg/day may benefit from dose increases to a maximum of approximately 225 mg/day. Dose increases should be in increments of up to 75 mg/day, as needed, and should be made at intervals of not less than 7 days. (See the Use in Patients with Concomitant Illness section of PRECAUTIONS.) Depressed patients who are currently being treated at a therapeutic dose with Effexor (immediate release) may be switched to Effexor XR at the nearest equivalent dose (mg/day), eg, 37.5 mg venlafaxine two-times-a-day to 75 mg Effexor XR once daily. However, individual dosage adjustments may be necessary. At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with Effexor XR. Conversely, at least 7 days should be allowed after stopping Effexor XR before starting an MAOI intended to treat psychiatric disorders (see CONTRAINDICATIONS). Do not start Effexor XR in a patient who is being treated with linezolid or intravenous methylene blue because there is increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered (see CONTRAINDICATIONS). In some cases, a patient already receiving therapy with Effexor XR may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, Effexor XR should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 7 days or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with Effexor XR may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue (see WARNINGS). The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with Effexor XR is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use (see WARNINGS).

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# Venlafaxine dosage forms and strengths Venlafaxine hydrochloride is a white to off-white crystalline solid with a solubility of 572 mg/mL in water (adjusted to ionic strength of 0.2 M with sodium chloride). Its octanol:water (0.2 M sodium chloride) partition coefficient is 0.43.

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# Venlafaxine drug interactions A single dose of ethanol (0.5 g/kg) had no effect on the pharmacokinetics of venlafaxine or O-desmethylvenlafaxine (ODV) when venlafaxine was administered at 150 mg/day in 15 healthy male subjects. Additionally, administration of venlafaxine in a stable regimen did not exaggerate the psychomotor and psychometric effects induced by ethanol in these same subjects when they were not receiving venlafaxine. Concomitant administration of Cimetidine and venlafaxine in a steady-state study for both drugs resulted in inhibition of first-pass metabolism of venlafaxine in 18 healthy subjects. The oral clearance of venlafaxine was reduced by about 43%, and the exposure (AUC) and maximum concentration (Cmax) of the drug were increased by about 60%. However, coadministration of Cimetidine had no apparent effect on the pharmacokinetics of ODV, which is present in much greater quantity in the circulation than venlafaxine. The overall pharmacological activity of venlafaxine plus ODV is expected to increase only slightly, and no dosage adjustment should be necessary for most normal adults. However, for patients with pre-existing hypertension, and for elderly patients or patients with hepatic dysfunction, the interaction associated with the concomitant use of venlafaxine and Cimetidine is not known and potentially could be more pronounced. Therefore, caution is advised with such patients. Under steady-state conditions for venlafaxine administered at 150 mg/day, a single 10 mg dose of diazepam did not appear to affect the pharmacokinetics of either venlafaxine or ODV in 18 healthy male subjects. Venlafaxine also did not have any effect on the pharmacokinetics of diazepam or its active metabolite, desmethyldiazepam, or affect the psychomotor and psychometric effects induced by diazepam. Venlafaxine administered under steady-state conditions at 150 mg/day in 24 healthy subjects decreased total oral-dose clearance (Cl/F) of a single 2 mg dose of Haloperidol by 42%, which resulted in a 70% increase in Haloperidol AUC. In addition, the Haloperidol Cmax increased 88% when coadministered with venlafaxine, but the Haloperidol elimination half-life (t1/2) was unchanged. The mechanism explaining this finding is unknown. The steady-state pharmacokinetics of venlafaxine administered at 150 mg/day were not affected when a single 600 mg oral dose of Lithium was administered to 12 healthy male subjects. ODV also was unaffected. Venlafaxine had no effect on the pharmacokinetics of Lithium (see also CNS-Active Drugs, below). Venlafaxine is not highly bound to plasma proteins; therefore, administration of Effexor XR to a patient taking another drug that is highly protein bound should not cause increased free concentrations of the other drug. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when Effexor XR is initiated or discontinued. In vitro and in vivo studies indicate that venlafaxine is metabolized to its active metabolite, ODV, by CYP2D6, the isoenzyme that is responsible for the genetic polymorphism seen in the metabolism of many antidepressants. Therefore, the potential exists for a drug interaction between drugs that inhibit CYP2D6-mediated metabolism of venlafaxine, reducing the metabolism of venlafaxine to ODV, resulting in increased plasma concentrations of venlafaxine and decreased concentrations of the active metabolite. CYP2D6 inhibitors such as quinidine would be expected to do this, but the effect would be similar to what is seen in patients who are genetically CYP2D6 poor metabolizers (see Metabolism and Excretion under CLINICAL PHARMACOLOGY). Therefore, no dosage adjustment is required when venlafaxine is coadministered with a CYP2D6 inhibitor. A pharmacokinetic study with ketoconazole 100 mg b.i.d. with a single dose of venlafaxine 50 mg in extensive metabolizers (EM; n = 14) and 25 mg in poor metabolizers (PM; n = 6) of CYP2D6 resulted in higher plasma concentrations of both venlafaxine and O-desmethylvenlafaxine (ODV) in most subjects following administration of ketoconazole. Venlafaxine Cmax increased by 26% in EM subjects and 48% in PM subjects. Cmax values for ODV increased by 14% and 29% in EM and PM subjects, respectively. Venlafaxine AUC increased by 21% in EM subjects and 70% in PM subjects (range in PMs -2% to 206%), and AUC values for ODV increased by 23% and 33% in EM and PM (range in PMs -38% to 105%) subjects, respectively. Combined AUCs of venlafaxine and ODV increased on average by approximately 23% in EMs and 53% in PMs (range in PMs 4% to 134%). Concomitant use of CYP3A4 inhibitors and venlafaxine may increase levels of venlafaxine and ODV. Therefore, caution is advised if a patient's therapy includes a CYP3A4 inhibitor and venlafaxine concomitantly. In vitro studies indicate that venlafaxine is a relatively weak inhibitor of CYP2D6. These findings have been confirmed in a clinical drug interaction study comparing the effect of venlafaxine with that of fluoxetine on the CYP2D6-mediated metabolism of dextromethorphan to dextrorphan. Venlafaxine did not affect the pharmacokinetics of Imipramine and 2-OH-Imipramine. However, desipramine AUC, Cmax, and Cmin increased by about 35% in the presence of venlafaxine. The 2-OH-desipramine AUC's increased by at least 2.5 fold (with venlafaxine 37.5 mg q12h) and by 4.5 fold (with venlafaxine 75 mg q12h). Imipramine did not affect the pharmacokinetics of venlafaxine and ODV. The clinical significance of elevated 2-OH-desipramine levels is unknown. Concomitant administration of venlafaxine (50 mg every 8 hours for 5 days) and Metoprolol (100 mg every 24 hours for 5 days) to 18 healthy male subjects in a pharmacokinetic interaction study for both drugs resulted in an increase of plasma concentrations of Metoprolol by approximately 30–40% without altering the plasma concentrations of its active metabolite, α-hydroxyMetoprolol. Metoprolol did not alter the pharmacokinetic profile of venlafaxine or its active metabolite, O-desmethylvenlafaxine. Venlafaxine appeared to reduce the blood pressure lowering effect of Metoprolol in this study. The clinical relevance of this finding for hypertensive patients is unknown. Caution should be exercised with co-administration of venlafaxine and Metoprolol. Venlafaxine treatment has been associated with dose-related increases in blood pressure in some patients. It is recommended that patients receiving Effexor XR have regular monitoring of blood pressure (see WARNINGS). Venlafaxine administered under steady-state conditions at 150 mg/day slightly inhibited the CYP2D6-mediated metabolism of Risperidone (administered as a single 1 mg oral dose) to its active metabolite, 9-hydroxyRisperidone, resulting in an approximate 32% increase in Risperidone AUC. However, venlafaxine coadministration did not significantly alter the pharmacokinetic profile of the total active moiety (Risperidone plus 9-hydroxyRisperidone). Venlafaxine did not inhibit CYP3A4 in vitro. This finding was confirmed in vivo by clinical drug interaction studies in which venlafaxine did not inhibit the metabolism of several CYP3A4 substrates, including alprazolam, diazepam, and terfenadine. In a study of 9 healthy volunteers, venlafaxine administered under steady-state conditions at 150 mg/day resulted in a 28% decrease in the AUC of a single 800 mg oral dose of indinavir and a 36% decrease in indinavir Cmax. Indinavir did not affect the pharmacokinetics of venlafaxine and ODV. The clinical significance of this finding is unknown. Venlafaxine did not inhibit CYP1A2 in vitro. This finding was confirmed in vivo by a clinical drug interaction study in which venlafaxine did not inhibit the metabolism of caffeine, a CYP1A2 substrate. Venlafaxine did not inhibit CYP2C9 in vitro. In vivo, venlafaxine 75 mg by mouth every 12 hours did not alter the pharmacokinetics of a single 500 mg dose of tolbutamide or the CYP2C9 mediated formation of 4-hydroxy-tolbutamide. The risk of using venlafaxine in combination with other CNS-active drugs has not been systematically evaluated (except in the case of those CNS-active drugs noted above). Consequently, caution is advised if the concomitant administration of venlafaxine and such drugs is required. (See CONTRAINDICATIONS and WARNINGS, Serotonin Syndrome) There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of Effexor XR with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS, Serotonin Syndrome). The risk of QTc prolongation and/or ventricular arrhythmias (e.g., TdP) is increased with concomitant use of other drugs which prolong the QTc interval (e.g., some antipsychotics and antibiotics) (see PRECAUTIONS, Use in Patients With Concomitant Illness). False-positive urine immunoassay screening tests for phencyclidine (PCP) and amphetamine have been reported in patients taking venlafaxine. This is due to lack of specificity of the screening tests. False positive test results may be expected for several days following discontinuation of venlafaxine therapy. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish venlafaxine from PCP and amphetamine.

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# Venlafaxine indications and usage The efficacy of Effexor XR in the treatment of major depressive disorder was established in 8- and 12-week controlled trials of adult outpatients whose diagnoses corresponded most closely to the DSM-III-R or DSM-IV category of major depressive disorder (see Clinical Trials). A major depressive episode (DSM-IV) implies a prominent and relatively persistent (nearly every day for at least 2 weeks) depressed mood or the loss of interest or pleasure in nearly all activities, representing a change from previous functioning, and includes the presence of at least five of the following nine symptoms during the same two-week period: depressed mood, markedly diminished interest or pleasure in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, a suicide attempt or suicidal ideation. The efficacy of Effexor (immediate release) in the treatment of major depressive disorder in adult inpatients meeting diagnostic criteria for major depressive disorder with melancholia was established in a 4-week controlled trial (see Clinical Trials). The safety and efficacy of Effexor XR in hospitalized depressed patients have not been adequately studied. The efficacy of Effexor XR in maintaining a response in major depressive disorder for up to 26 weeks following 8 weeks of acute treatment was demonstrated in a placebo-controlled trial. The efficacy of Effexor (immediate release) in maintaining a response in patients with recurrent major depressive disorder who had responded and continued to be improved during an initial 26 weeks of treatment and were then followed for a period of up to 52 weeks was demonstrated in a second placebo-controlled trial (seeClinical Trials). Nevertheless, the physician who elects to use Effexor/Effexor XR for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION). Effexor XR is indicated for the treatment of Generalized anxiety Disorder (GAD) as defined in DSM-IV. anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic. The efficacy of Effexor XR in the treatment of GAD was established in 8-week and 6-month placebo-controlled trials in adult outpatients diagnosed with GAD according to DSM-IV criteria (see Clinical Trials). Generalized anxiety Disorder (DSM-IV) is characterized by excessive anxiety and worry (apprehensive expectation) that is persistent for at least 6 months and which the person finds difficult to control. It must be associated with at least 3 of the following 6 symptoms: restlessness or feeling keyed up or on edge, being easily fatigued, difficulty concentrating or mind going blank, irritability, muscle tension, sleep disturbance. Although the effectiveness of Effexor XR has been demonstrated in 6-month clinical trials in patients with GAD, the physician who elects to use Effexor XR for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION). Social anxiety Disorder (DSM-IV) is characterized by a marked and persistent fear of 1 or more social or performance situations in which the person is exposed to unfamiliar people or to possible scrutiny by others. Exposure to the feared situation almost invariably provokes anxiety, which may approach the intensity of a panic attack. The feared situations are avoided or endured with intense anxiety or distress. The avoidance, anxious anticipation, or distress in the feared situation(s) interferes significantly with the person's normal routine, occupational or academic functioning, or social activities or relationships, or there is a marked distress about having the phobias. Lesser degrees of performance anxiety or shyness generally do not require psychopharmacological treatment. The efficacy of Effexor XR in the treatment of Social anxiety Disorder was established in four 12-week and one 6-month placebo-controlled trials in adult outpatients with Social anxiety Disorder (DSM-IV) (see Clinical Trials). Although the effectiveness of Effexor XR has been demonstrated in a 6-month clinical trial in patients with Social anxiety Disorder, the physician who elects to use Effexor XR for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION). Effexor XR is indicated for the treatment of panic disorder, with or without agoraphobia, as defined in DSM-IV. Panic disorder is characterized by the occurrence of unexpected panic attacks and associated concern about having additional attacks, worry about the implications or consequences of the attacks, and/or a significant change in behavior related to the attacks. Panic disorder (DSM-IV) is characterized by recurrent, unexpected panic attacks, ie, a discrete period of intense fear or discomfort, in which four (or more) of the following symptoms develop abruptly and reach a peak within 10 minutes: 1) palpitations, pounding heart, or accelerated heart rate; 2) sweating; 3) trembling or shaking; 4) sensations of shortness of breath or smothering; 5) feeling of choking; 6) chest pain or discomfort; 7) nausea or abdominal distress; 8) feeling dizzy, unsteady, lightheaded, or faint; 9) derealization (feelings of unreality) or depersonalization (being detached from oneself); 10) fear of losing control; 11) fear of dying; 12) paresthesias (numbness or tingling sensations); 13) chills or hot flushes. The efficacy of Effexor XR in the treatment of Panic disorder was established in two 12-week placebo-controlled trials in adult outpatients with Panic disorder (DSM-IV). The efficacy of Effexor XR in prolonging time to relapse in Panic disorder among responders following 12 weeks of open-label acute treatment was demonstrated in a placebo-controlled study (see CLINICAL PHARMACOLOGY, Clinical Trials). Nevertheless, the physician who elects to use Effexor XR for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE ANDADMINISTRATION).

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/index.php/Venlafaxine_nonclinical_toxicology

# Venlafaxine nonclinical toxicology Venlafaxine was given by oral gavage to mice for 18 months at doses up to 120 mg/kg per day, which was 1.7 times the maximum recommended human dose on a mg/m2basis. Venlafaxine was also given to rats by oral gavage for 24 months at doses up to 120 mg/kg per day. In rats receiving the 120 mg/kg dose, plasma concentrations of venlafaxine at necropsy were 1 times (male rats) and 6 times (female rats) the plasma concentrations of patients receiving the maximum recommended human dose. Plasma levels of the O-desmethyl metabolite were lower in rats than in patients receiving the maximum recommended dose. Tumors were not increased by venlafaxine treatment in mice or rats. Venlafaxine and the major human metabolite, O-desmethylvenlafaxine (ODV), were not mutagenic in the Ames reverse mutation assay in Salmonella bacteria or the Chinese hamster ovary/HGPRT mammalian cell forward gene mutation assay. Venlafaxine was also not mutagenic or clastogenic in the in vitro BALB/c-3T3 mouse cell transformation assay, the sister chromatid exchange assay in cultured Chinese hamster ovary cells, or in the in vivo chromosomal aberration assay in rat bone marrow. ODV was not clastogenic in the in vitro Chinese hamster ovary cell chromosomal aberration assay, but elicited a clastogenic response in the in vivo chromosomal aberration assay in rat bone marrow. Reproduction and fertility studies of venlafaxine in rats showed no adverse effects on male or female fertility at oral doses of up to 2 times the maximum recommended human dose of 225 mg/day on a mg/m2 basis. However, reduced fertility was observed in a study in which male and female rats were treated with O-desmethylvenlafaxine (ODV), the major human metabolite of venlafaxine, prior to and during mating and gestation. This occurred at an ODV exposure (AUC) approximately 2 to 3 times that associated with a human venlafaxine dose of 225 mg/day.

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/index.php/Venlafaxine_overdosage

# Venlafaxine overdosage Among the patients included in the premarketing evaluation of Effexor XR, there were 2 reports of acute overdosage with Effexor XR in major depressive disorder trials, either alone or in combination with other drugs. One patient took a combination of 6 g of Effexor XR and 2.5 mg of lorazepam. This patient was hospitalized, treated symptomatically, and recovered without any untoward effects. The other patient took 2.85 g of Effexor XR. This patient reported paresthesia of all four limbs but recovered without sequelae. There were 2 reports of acute overdose with Effexor XR in GAD trials. One patient took a combination of 0.75 g of Effexor XR and 200 mg of paroxetine and 50 mg of zolpidem. This patient was described as being alert, able to communicate, and a little sleepy. This patient was hospitalized, treated with activated charcoal, and recovered without any untoward effects. The other patient took 1.2 g of Effexor XR. This patient recovered and no other specific problems were found. The patient had moderate dizziness, nausea, numb hands and feet, and hot-cold spells 5 days after the overdose. These symptoms resolved over the next week. There were 2 reports of acute overdose with Effexor XR in panic disorder trials. One patient took 0.675 g of Effexor XR once, and the other patient took 0.45 g of Effexor XR for 2 days. No signs or symptoms were associated with either overdose, and no actions were taken to treat them. Among the patients included in the premarketing evaluation with Effexor (immediate release), there were 14 reports of acute overdose with venlafaxine, either alone or in combination with other drugs and/or alcohol. The majority of the reports involved ingestion in which the total dose of venlafaxine taken was estimated to be no more than several-fold higher than the usual therapeutic dose. The 3 patients who took the highest doses were estimated to have ingested approximately 6.75 g, 2.75 g, and 2.5 g. The resultant peak plasma levels of venlafaxine for the latter 2 patients were 6.24 and 2.35 μg/mL, respectively, and the peak plasma levels of O-desmethylvenlafaxine were 3.37 and 1.30 μg/mL, respectively. Plasma venlafaxine levels were not obtained for the patient who ingested 6.75 g of venlafaxine. All 14 patients recovered without sequelae. Most patients reported no symptoms. Among the remaining patients, somnolence was the most commonly reported symptom. The patient who ingested 2.75 g of venlafaxine was observed to have 2 generalized convulsions and a prolongation of QTc to 500 msec, compared with 405 msec at baseline. Mild sinus tachycardia was reported in 2 of the other patients. In postmarketing experience, overdose with venlafaxine has occurred predominantly in combination with alcohol and/or other drugs. The most commonly reported events in overdosage include tachycardia, changes in level of consciousness (ranging from somnolence to coma), mydriasis, seizures, and vomiting. Electrocardiogram changes (eg, prolongation of QT interval, bundle branch block, QRS prolongation), ventricular tachycardia, bradycardia, hypotension, rhabdomyolysis, vertigo, liver necrosis, serotonin syndrome, and death have been reported. Published retrospective studies report that venlafaxine overdosage may be associated with an increased risk of fatal outcomes compared to that observed with SSRI antidepressant products, but lower than that for tricyclic antidepressants. Epidemiological studies have shown that venlafaxine-treated patients have a higher pre-existing burden of suicide risk factors than SSRI-treated patients. The extent to which the finding of an increased risk of fatal outcomes can be attributed to the toxicity of venlafaxine in overdosage as opposed to some characteristic(s) of venlafaxine-treated patients is not clear. Prescriptions for Effexor XR should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion or in symptomatic patients. Activated charcoal should be administered. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. No specific antidotes for venlafaxine are known. In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians' Desk Reference® (PDR).

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/index.php/Venlafaxine_patient_counseling_information

# Venlafaxine patient counseling information Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Effexor XR and should counsel them in its appropriate use. A patient Medication Guide about "Antidepressant Medicines, Depression and Other Serious Mental Illness, and Suicidal Thoughts or Actions" is available for Effexor XR. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania,mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication. Clinical studies were performed to examine the effects of venlafaxine on behavioral performance of healthy individuals. The results revealed no clinically significant impairment of psychomotor, cognitive, or complex behavior performance. However, since any psychoactive drug may impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that venlafaxine therapy does not adversely affect their ability to engage in such activities. Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, including herbal preparations and nutritional supplements, since there is a potential for interactions. Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of Effexor XR and triptans, tramadol, tryptophan supplements or other serotonergic agents (see CONTRAINDICATIONS and WARNINGS, Serotonin Syndrome and PRECAUTIONS, Drug Interactions, CNS-Active Drugs, Serotonergic Drugs). Patients should be cautioned about the concomitant use of Effexor XR and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding (see PRECAUTIONS, Abnormal Bleeding). Although venlafaxine has not been shown to increase the impairment of mental and motor skills caused by alcohol, patients should be advised to avoid alcohol while taking venlafaxine. Mydriasis (prolonged dilation of the pupils of the eye) has been reported with venlafaxine. Patients should be advised to notify their physician if they have a history of glaucoma or a history of increased intraocular pressure (see WARNINGS).

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/index.php/Venlafaxine_use_in_specific_populations

# Venlafaxine use in specific populations A population pharmacokinetic analysis of 404 venlafaxine-treated patients from two studies involving both b.i.d. and t.i.d. regimens showed that dose-normalized trough plasma levels of either venlafaxine or ODV were unaltered by age or gender differences. Dosage adjustment based on the age or gender of a patient is generally not necessary (see DOSAGE AND ADMINISTRATION). Plasma concentrations of venlafaxine were higher in CYP2D6 poor metabolizers than extensive metabolizers. Because the total exposure (AUC) of venlafaxine and ODV was similar in poor and extensive metabolizer groups, however, there is no need for different venlafaxine dosing regimens for these two groups. In 9 subjects with hepatic cirrhosis, the pharmacokinetic disposition of both venlafaxine and ODV was significantly altered after oral administration of venlafaxine. Venlafaxine elimination half-life was prolonged by about 30%, and clearance decreased by about 50% in cirrhotic subjects compared to normal subjects. ODV elimination half-life was prolonged by about 60%, and clearance decreased by about 30% in cirrhotic subjects compared to normal subjects. A large degree of intersubject variability was noted. Three patients with more severe cirrhosis had a more substantial decrease in venlafaxine clearance (about 90%) compared to normal subjects. In a second study, venlafaxine was administered orally and intravenously in normal (n = 21) subjects, and in Child-Pugh A (n = 8) and Child-Pugh B (n = 11) subjects (mildly and moderately impaired, respectively). Venlafaxine oral bioavailability was increased 2–3 fold, oral elimination half-life was approximately twice as long and oral clearance was reduced by more than half, compared to normal subjects. In hepatically impaired subjects, ODV oral elimination half-life was prolonged by about 40%, while oral clearance for ODV was similar to that for normal subjects. A large degree of intersubject variability was noted. In a renal impairment study, venlafaxine elimination half-life after oral administration was prolonged by about 50% and clearance was reduced by about 24% in renally impaired patients (GFR=10 to 70 mL/min), compared to normal subjects. In dialysis patients, venlafaxine elimination half-life was prolonged by about 180% and clearance was reduced by about 57% compared to normal subjects. Similarly, ODV elimination half-life was prolonged by about 40% although clearance was unchanged in patients with renal impairment (GFR=10 to 70 mL/min) compared to normal subjects. In dialysis patients, ODV elimination half-life was prolonged by about 142% and clearance was reduced by about 56% compared to normal subjects. A large degree of intersubject variability was noted. Dosage adjustment is necessary in these patients (seeDOSAGE AND ADMINISTRATION).

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/index.php/Venlafaxine_warnings_and_precautions

# Venlafaxine warnings and precautions Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18–24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1. It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION, Discontinuation of Treatment with Effexor XR, for a description of the risks of discontinuation of Effexor XR). Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for Effexor XR should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose. Epidemiological studies show an increased risk of bone fractures in patients receiving serotonin reuptake inhibitors (SRIs) including venlafaxine. The mechanism leading to this risk is not fully understood. A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that Effexor XR is not approved for use in treating bipolar depression. The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including Effexor XR, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John's Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of Serotonin syndrome. The concomitant use of Effexor XR with MAOIs intended to treat psychiatric disorders is contraindicated. Effexor XR should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with a MAOI such as linezolid or intravenous methylene blue in a patient taking Effexor XR. Effexor XR should be discontinued before initiating treatment with the MAOI (see CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION). If concomitant use of Effexor XR with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John's Wort is clinically warranted, patients should be made aware of a potential increased risk for Serotonin syndrome, particularly during treatment initiation and dose increases. Treatment with Effexor XR and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated. Effexor XR treatment is associated with sustained hypertension (defined as treatment-emergent supine diastolic blood pressure (SDBP) ≥90 mm Hg and ≥10 mm Hg above baseline for 3 consecutive on-therapy visits (see Table 2). An analysis for patients in Effexor (immediate release) studies meeting criteria for sustained hypertension revealed a dose-dependent increase in the incidence of sustained hypertension for Effexor (immediate release) (see Table 3). An insufficient number of patients received mean doses of Effexor XR over 300 mg/day to fully evaluate the incidence of sustained increases in blood pressure at these higher doses. In premarketing major depressive disorder studies, 0.7% (5/705) of the Effexor XR-treated patients discontinued treatment because of elevated blood pressure. Among these patients, most of the blood pressure increases were in a modest range (12 to 16 mm Hg, SDBP). In premarketing GAD studies up to 8 weeks and up to 6 months, 0.7% (10/1381) and 1.3% (7/535) of the Effexor XR-treated patients, respectively, discontinued treatment because of elevated blood pressure. Among these patients, most of the blood pressure increases were in a modest range (12 to 25 mm Hg, SDBP up to 8 weeks; 8 to 28 mm Hg up to 6 months). In premarketing Social Anxiety Disorder studies up to 6 months, 0.6% (5/771) of the Effexor XR-treated patients discontinued treatment because of elevated blood pressure. In these patients, the blood pressure increases were modest (1–24 mm Hg, SDBP). In premarketing panic disorder studies up to 12 weeks, 0.5% (5/1001) of the Effexor XR-treated patients discontinued treatment because of elevated blood pressure. In these patients, the blood pressure increases were in a modest range (7 to 19 mm Hg, SDBP). Sustained increases of SDBP could have adverse consequences. Cases of elevated blood pressure requiring immediate treatment have been reported in post marketing experience. Pre-existing hypertension should be controlled before treatment with venlafaxine. It is recommended that patients receiving Effexor XR have regular monitoring of blood pressure. For patients who experience a sustained increase in blood pressure while receiving venlafaxine, either dose reduction or discontinuation should be considered. In placebo-controlled premarketing studies, there were changes in mean blood pressure (see Table 4 for mean changes in supine systolic and supine diastolic blood pressure). Across most indications, a dose-related increase in supine systolic and diastolic blood pressure was evident in Effexor XR-treated patients. Across all clinical trials in MDD, GAD, Social Anxiety Disorder and panic disorder, 1.4% of patients in the Effexor XR-treated groups experienced a ≥15 mm Hg increase in supine diastolic blood pressure with blood pressure ≥105 mm Hg compared to 0.9% of patients in the placebo groups. Similarly, 1% of patients in the Effexor XR-treated groups experienced a ≥20 mm Hg increase in supine systolic blood pressure with blood pressure ≥180 mm Hg compared to 0.3% of patients in the placebo groups. Mydriasis has been reported in association with venlafaxine; therefore patients with raised intraocular pressure or those at risk of acute narrow-angle glaucoma (angle-closure glaucoma) should be monitored (see PRECAUTIONS, Information for Patients). Discontinuation symptoms have been systematically evaluated in patients taking venlafaxine, to include prospective analyses of clinical trials in Generalized Anxiety Disorder and retrospective surveys of trials in major depressive disorder, and Social Anxiety Disorder. Abrupt discontinuation or dose reduction of venlafaxine at various doses has been found to be associated with the appearance of new symptoms, the frequency of which increased with increased dose level and with longer duration of treatment. Reported symptoms include agitation, anorexia, anxiety, confusion, impaired coordination and balance, diarrhea, dizziness, dry mouth, dysphoric mood, fasciculation, fatigue, flu-like symptoms, headaches, hypomania, insomnia, nausea, nervousness, nightmares, sensory disturbances (including shock-like electrical sensations), somnolence, sweating, tremor, vertigo, and vomiting. During marketing of Effexor XR, other SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors), and SSRIs (Selective Serotonin Reuptake Inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g. paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms. Patients should be monitored for these symptoms when discontinuing treatment with Effexor XR. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate (see DOSAGE AND ADMINISTRATION). Treatment-emergent insomnia and nervousness were more commonly reported for patients treated with Effexor XR (venlafaxine hydrochloride) extended-release capsules than with placebo in pooled analyses of short-term major depressive disorder, GAD, [[Social anxiety Disorder]], and panic disorder studies, as shown in Table 5. In GAD trials, insomnia and nervousness led to drug discontinuation in 3% and 2%, respectively, of the patients treated with Effexor XR up to 8 weeks and 2% and 0.7%, respectively, of the patients treated with Effexor XR up to 6 months. In [[Social anxiety Disorder]] trials, insomnia and nervousness led to drug discontinuation in 2% and 1%, respectively, of the patients treated with Effexor XR up to 12 weeks and 2% and 3% respectively, of the patients treated with Effexor XR up to 6 months. In panic disorder trials, insomnia and nervousness led to drug discontinuation in 1% and 0.1%, respectively, of the patients treated with Effexor XR up to 12 weeks. A loss of 5% or more of body weight occurred in 7% of Effexor XR-treated and 2% of placebo-treated patients in the short-term placebo-controlled major depressive disorder trials. The discontinuation rate for weight loss associated with Effexor XR was 0.1% in major depressive disorder studies. In placebo-controlled GAD studies, a loss of 7% or more of body weight occurred in 3% of Effexor XR patients and 1% of placebo patients who received treatment for up to 6 months. The discontinuation rate for weight loss was 0.3% for patients receiving Effexor XR in GAD studies for up to eight weeks. In placebo-controlled [[Social anxiety Disorder]] trials, 4% of the Effexor XR-treated and 1% of the placebo-treated patients sustained a loss of 7% or more of body weight during up to 6 months of treatment. None of the patients receiving Effexor XR in [[Social anxiety Disorder]] studies discontinued for weight loss. In placebo-controlled panic disorder trials, 3% of the Effexor XR-treated and 2% of the placebo-treated patients sustained a loss of 7% or more of body weight during up to 12 weeks of treatment. None of the patients receiving Effexor XR in panic disorder studies discontinued for weight loss. The safety and efficacy of venlafaxine therapy in combination with weight loss agents, including phentermine, have not been established. Co-administration of Effexor XR and weight loss agents is not recommended. Effexor XR is not indicated for weight loss alone or in combination with other products. Weight loss has been observed in pediatric patients (ages 6–17) receiving Effexor XR. In a pooled analysis of four eight-week, double-blind, placebo-controlled, flexible dose outpatient trials for major depressive disorder (MDD) and generalized anxiety disorder (GAD), Effexor XR-treated patients lost an average of 0.45 kg (n = 333), while placebo-treated patients gained an average of 0.77 kg (n = 333). More patients treated with Effexor XR than with placebo experienced a weight loss of at least 3.5% in both the MDD and the GAD studies (18% of Effexor XR-treated patients vs. 3.6% of placebo-treated patients; p<0.001). In a 16-week, double-blind, placebo-controlled, flexible dose outpatient trial for [[Social anxiety Disorder]], Effexor XR-treated patients lost an average of 0.75 kg (n = 137), while placebo-treated patients gained an average of 0.76 kg (n = 148). More patients treated with Effexor XR than with placebo experienced a weight loss of at least 3.5% in the [[Social anxiety Disorder]] study (47% of Effexor XR-treated patients vs. 14% of placebo-treated patients; p<0.001). Weight loss was not limited to patients with treatment-emergent anorexia (seePRECAUTIONS, General, Changes in Appetite). The risks associated with longer-term Effexor XR use were assessed in an open-label MDD study of children and adolescents who received Effexor XR for up to six months. The children and adolescents in the study had increases in weight that were less than expected based on data from age- and sex-matched peers. The difference between observed weight gain and expected weight gain was larger for children (<12 years old) than for adolescents (≥12 years old). During the eight-week, placebo-controlled GAD studies, Effexor XR-treated patients (ages 6–17) grew an average of 0.3 cm (n = 122), while placebo-treated patients grew an average of 1.0 cm (n = 132); p=0.041. This difference in height increase was most notable in patients younger than twelve. During the eight-week placebo-controlled MDD studies, Effexor XR-treated patients grew an average of 0.8 cm (n = 146), while placebo-treated patients grew an average of 0.7 cm (n = 147). During the 16-week, placebo-controlled [[Social anxiety Disorder]] study, both the Effexor XR-treated (n = 109) and the placebo-treated (n = 112) patients each grew an average of 1.0 cm. In the six-month, open-label MDD study, children and adolescents had height increases that were less than expected based on data from age- and sex-matched peers. The difference between observed growth rates and expected growth rates was larger for children (<12 years old) than for adolescents (≥12 years old). Treatment-emergent anorexia was more commonly reported for Effexor XR-treated (8%) than placebo-treated patients (4%) in the pool of short-term, double-blind, placebo-controlled major depressive disorder studies. The discontinuation rate for anorexia associated with Effexor XR was 1.0% in major depressive disorder studies. Treatment-emergent anorexia was more commonly reported for Effexor XR-treated (8%) than placebo-treated patients (2%) in the pool of short-term, double-blind, placebo-controlled GAD studies. The discontinuation rate for anorexia was 0.9% for patients receiving Effexor XR for up to 8 weeks in GAD studies. Treatment-emergent anorexia was more commonly reported for Effexor XR-treated (17%) than placebo-treated patients (2%) in the pool of short-term, double-blind, placebo-controlled [[Social anxiety Disorder]] studies. The discontinuation rate for anorexia was 0.6% for patients receiving Effexor XR for up to 12 weeks in [[Social anxiety Disorder]] studies; no patients discontinued for anorexia between week 12 and month 6. Treatment-emergent anorexia was more commonly reported for Effexor XR-treated (8%) than placebo-treated patients (3%) in the pool of short-term, double-blind, placebo-controlled panic disorder studies. The discontinuation rate for anorexia was 0.4% for patients receiving Effexor XR for up to 12 weeks in panic disorder studies. Decreased appetite has been observed in pediatric patients receiving Effexor XR. In the placebo-controlled trials for GAD and MDD, 10% of patients aged 6-17 treated with Effexor XR for up to eight weeks and 3% of patients treated with placebo reported treatment-emergent anorexia (decreased appetite). None of the patients receiving Effexor XR discontinued for anorexia or weight loss. In the placebo-controlled trial for [[Social anxiety Disorder]], 22% and 3% of patients aged 8-17 treated for up to 16 weeks with Effexor XR and placebo, respectively, reported treatment-emergent anorexia (decreased appetite). The discontinuation rates for anorexia were 0.7% and 0.0% for patients receiving Effexor XR and placebo, respectively; the discontinuation rates for weight loss were 0.7% for patients receiving either Effexor XR or placebo. During premarketing major depressive disorder studies, mania or hypomania occurred in 0.3% of Effexor XR-treated patients and no placebo patients. In premarketing GAD studies, no Effexor XR-treated patients and 0.2% of placebo-treated patients experienced mania or hypomania. In premarketing [[Social anxiety Disorder]] studies, 0.2% Effexor XR-treated patients and no placebo-treated patients experienced mania or hypomania. In premarketing panic disorder studies, 0.1% of Effexor XR-treated patients and no placebo-treated patients experienced mania or hypomania. In all premarketing major depressive disorder trials with Effexor (immediate release), mania or hypomania occurred in 0.5% of venlafaxine-treated patients compared with no placebo patients.Mania/hypomania has also been reported in a small proportion of patients with mood disorders who were treated with other marketed drugs to treat major depressive disorder. As with all drugs effective in the treatment of major depressive disorder, Effexor XR should be used cautiously in patients with a history of mania. Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including Effexor XR. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk (see PRECAUTIONS, Geriatric Use). Discontinuation of Effexor XR should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. During premarketing experience, no seizures occurred among 705 Effexor XR-treated patients in the major depressive disorder studies, among 1381 Effexor XR-treated patients in GAD studies, or among 819 Effexor XR-treated patients in [[Social anxiety Disorder]] studies. In panic disorder studies, 1 seizure occurred among 1,001 Effexor XR-treated patients. In all premarketing major depressive disorder trials with Effexor (immediate release), seizures were reported at various doses in 0.3% (8/3082) of venlafaxine-treated patients. Effexor XR, like many antidepressants, should be used cautiously in patients with a history of seizures and should be discontinued in any patient who develops seizures. SSRIs and SNRIs, including Effexor XR, may increase the risk of bleeding events, ranging from ecchymoses, hematomas, epistaxis, petechiae, and gastrointestinal hemorrhage to life-threatening hemorrhage. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anti-coagulants or other drugs known to affect platelet function may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Patients should be cautioned about the risk of bleeding associated with the concomitant use of Effexor XR and NSAIDs, aspirin, or other drugs that affect coagulation. Clinically relevant increases in serum cholesterol were recorded in 5.3% of venlafaxine-treated patients and 0.0% of placebo-treated patients treated for at least 3 months in placebo-controlled trials (see ADVERSE REACTIONS-Laboratory Changes). Measurement of serum cholesterol levels should be considered during long-term treatment. Interstitial lung disease and eosinophilic pneumonia associated with venlafaxine therapy have been rarely reported. The possibility of these adverse events should be considered in venlafaxine-treated patients who present with progressive dyspnea, cough or chest discomfort. Such patients should undergo a prompt medical evaluation, and discontinuation of venlafaxine therapy should be considered.

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/index.php/Veno-occlusive_disease_medical_therapy

# Veno-occlusive disease medical therapy ## Medical Therapy Treatment for VOD is primarily supportive. In the BMT setting, defibrotide is an investigational treatment that may be promising. Defibrotide is a polydeoxyribonucleotide; its mechanism of benefit in VOD is unclear, but has been attributed to its antithromboitc properties.

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/index.php/Veno-occlusive_disease_natural_history,_complications_and_prognosis

# Veno-occlusive disease natural history, complications and prognosis When associated with bone marrow transplant, VOD is fatal in over 30% of cases. Cases due to plant alkaloids often have a longer and more unpredictable course.

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/index.php/Veno-occlusive_disease_overview

# Veno-occlusive disease overview Veno-occlusive disease (VOD) is a disease of the liver in which the veins in the liver are obstructed or blocked. VOD is a complication that occurs in up to 25% of bone marrow transplantations, and may also occur after ingestion of certain plant alkaloids.

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/index.php/Veno-occlusive_disease_pathophysiology

# Veno-occlusive disease pathophysiology VOD is also known as sinuosoidal obstruction syndrome due to obstruction of the venous system. Following bone marrow transplantation, VOD has been hypothesized to be due to injury to the hepatic venous endothelium from the conditioning regimen.

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/index.php/Venogram

# Venography Venography (also called phlebography) is a procedure in which an x-ray of the veins, a venogram, is taken after a special dye is injected into the vein or even bone marrow. It is the gold standard for diagnosing acute deep venous thrombosis although its use has been largely supplanted by the less invasive Duplex ultrasound scanning. Venography can also be used to distinguish blood clots from obstructions in the veins, to evaluate congenital vein problems, to evaluate veins prior to treatment of chronic venous insufficiency, to see how well the deep leg vein valves are functioning or to identify a vein for coronary artery bypass grafting. In order for the dye to show up on the x-ray it contains iodine. X-rays cannot penetrate iodine and this casts a white shadow on the x-ray film. Because iodine is being injected, you will need let your doctor know if you have had any allergies to iodine in the past. If you have, your doctor may not perform the procedure or your doctor may premedicate you with Benadryl or with steroids. You should also let your doctor know if you are pregnant because the x-ray could harm the fetus. There are certain diseases that put the patient at risk for kidney problems after the procedure. You should let your doctor know if you have any of the following: The night before the procedure, your doctor will ask you to drink plenty of fluids. This is because the dye can be hard on the kidneys and drinking plenty of fluids will help flush the dye out of your body and reduce the concentration of the dye going through the kidneys. Other than this, there is usually very little preparation for a venogram. Prior to the procedure, your doctor will usually shave the area where the catheter will be inserted and will usually create a sterile area for the procedure to be done. Most often dye is injected through the back of the foot to evaluate the veins in the leg. If your doctor is evaluating the veins in your arm, the catheter may be inserted in the back of your hand. Next, your doctor will numb up the area with a local anesthetic. A catheter will then be inserted into the vein under the skin. During the insertion of the catheter you may feel a pinch or something that feels like a bee sting. Your doctor will next inject the dye. During the injection you may feel a sense of warmth in your leg traveling up and going throughout your body. Rarely, some patients become nauseated during this time. Please let your not doctor know if you have any itching, rash, swelling of your common lips or mouth, or difficulty breathing as these may indicate that you have an allergy to the dye. Prompt treatment is necessary for any allergic reaction. It will also be necessary for you to lie very still when the dye is injected so that there is no movement of your leg to blur the image on the x-ray. Once the injection is done, your doctor will remove the catheter, which is painless and will apply pressure for about 10 minutes to stop any bleeding that occurs. You may also be given fluids to clear the dye from your body. In general venography is very safe. There are a few complications that you should be aware of. A blood clot can form at the site of the injection, a blood clot that was already there can be dislodged and travel upstream in your body to the lungs, you can develop an allergic reaction as described above, and your kidney function can decline.

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/index.php/Venom

# Venom Venom (literally, poison of animal origin) is any of a variety of toxins used by certain types of animals, for the purpose of defense and hunting. Generally, venom is injected while other toxins are absorbed by ingestion or through the skin. The animals most widely known to use venom are snakes, some species of which inject venom into their prey through hollow fangs; spiders and centipedes, which also inject venom through fangs; scorpions and stinging insects, which inject venom with a sting (which is a modified egg-laying device - the ovipositor). There are also many caterpillars that have defensive venom glands associated with specialized bristles on the body, known as urticating hairs, some of which can be lethal to humans (e.g., the Lonomia moth). Venom is also found in other reptiles besides snakes such as the gila monster, and mexican beaded lizard. Other insects, such as true bugs , also produce venom. Venom can also be found in some fish, such as the cartilaginous fishes: stingrays, sharks, and chimaeras and the teleost fishes, which include: monognathus eels, catfishes, stonefishes and waspfishes, scorpionfishes and lionfishes, gurnard perches, rabbitfishes, surgeonfishes, scats, stargazers, weevers, carangids, saber-toothed blenny, and toadfish. In fact, recent studies have shown that there are more venomous ray-finned fishes than all other venomous vertebrates combined. Additionally, there are many other venomous invertebrates, including jellyfish, cone snails, bees, wasps and ants. The Box jellyfish is widely considered the most venomous creature in the world. Some mammals are also venomous, including solenodons, shrews, the slow loris, and the male platypus. Because they are tasked to defend their hives and food stores, bees synthesize and employ an acidic venom (apitoxin) to cause pain in those that they sting, whereas wasps use a chemically different venom designed to paralyze prey, so it can be stored alive in the food chambers of their young. The use of venom is much more widespread than just these examples, of course. It is important to note the difference between organisms that are "venomous" and "poisonous", two commonly confused terms with regards to plant and animal life. Venomous, as stated above, refers to animals that inject venom into their prey as a self-defense mechanism. Poisonous, on the other hand, describes plants or animals that are harmful when consumed or touched. One species of bird, the hooded pitohui, although not venomous, is poisonous, secreting a neurotoxin on to its skin and feathers. The slow loris, a primate, blurs the boundary between poisonous and venomous; it has poison secreting patches on the inside of its elbows which it is believed to smear on its young to prevent them from being eaten. However, it will also lick these patches, giving it a venomous bite. Snake venom is produced by glands below the eye and delivered to the victim through tubular or channeled fangs. Snake poisons contain a variety of peptide toxins. Snakes use their venom principally for hunting, though the threat of being bitten serves also as a defense. Snake bites cause a variety of symptoms including pain, swelling, tissue damage, low blood pressure, convulsions, and hemorrhaging (varying by the species of snake). Doctors treat victims of a venomous bite with antivenom, which is created by dosing an animal such as a sheep, horse, goat, or rabbit with a small amount of the targeted venom. The immune system of the subject animal responds to the dose, producing antibodies against the venom's active molecule, which can then be harvested from the animal's blood and applied to treat envenomation in others. This treatment may be effective for a given person only a limited number of times, however, as that person will ultimately develop antibodies to neutralize the foreign animal antibodies injected into him. Even if that person doesn't suffer a serious allergic reaction to the antivenom, his own immune system can destroy the antivenom, before the antivenom can destroy the venom. Though most people never require one treatment of antivenom in their lifetime, let alone several, people who work with snakes or other venomous animals may. Fortunately, these people often develop antibodies of their own against the venom of whatever animals they handle, and thereby are immune without assistance of exogenous antibodies.

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/index.php/Venous_blood

# Venous blood In the circulatory system, venous blood is blood returning to the heart. With one exception (the pulmonary vein) this blood is deoxygenated and high in carbon dioxide, having released oxygen and absorbed CO2 in the tissues. It is also typically warmer than arterial blood, has a lower pH, has lower concentrations of glucose and other nutrients, and has higher concentrations of urea and other waste products. Venous blood can be obtained by venipuncture (also called phlebotomy), or in small quantities by fingerprick. Most medical laboratory tests are conducted on venous blood, with the exception of arterial blood gases. Venous blood is often depicted as blue in color in medical diagrams, and veins sometimes look blue when seen through the skin. However, venous blood is actually a dark red color (but looks purple through the opaque skin), while arterial blood is bright red. The appearance of veins as dark blue is a wavelength phenomenon of light, having to do with the reflection of blue light away from the outside of venous tissue if the vein is @ 0.02in deep or more. This is due to the difference in color between deoxyhemoglobin and oxyhemoglobin; the red color ultimately originates from the iron atom in heme. If blood is drawn for a medical test, the dark red color can be seen; however, if it is exposed to oxygen in the air, it will turn bright red like arterial blood.

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/index.php/Venous_translucence

# Venous translucence Venous translumination or translucence, has been applied in phlebology since 1996 by the surgeon Pedro Fernandes Neto, during ambulatory clinical exams (Brazil). The results were registered in annals of national and international congresses of angiology. It is a process of reflective image visualization of veins by the incidence of light, which reaches up to the superficial venous system. It is an exam of static nature, however it is also a non-invasive method. For being a procedure of easy application and of low cost exam , it can be repeated when it is necessary, what becomes the process useful in the attendance of several pathological situations. Therefore, the use of this process for the obtaining of images with the generation of inconographic files, revealed to be of great importance for the attendance of several stages of venous diseases, beside this facilitating the several treatment conducts, guiding with this, the choice of the best procedure. It is a new diagnostic procedure, still in phase of investigation and a deeper analysis is necessary, in relation to certain technical patterns of this new method. Another aspect is the optical physics. The venous translumination is due to the refraction, absorption and reflection of light, whose principle is the dispersion and absorption of light colors. The color that is not absorbed is reflected and is the one that we can see. Therefore, the venous translumination is based on the incidence of a luminous focus on the vein, where part of the light is absorbed and another reflected, supplying an image of the silhouette of the studied sanguine vase. Some technical considerations, deserve to be described for better understanding of the process that served as a base for this study. Same questions are following related: Certain beginnings of the reflection and refraction of the light are importants, for the understanding the distorted images that can appear during a scanning. Many of these can be due to inappropriate sources, that would provoke light loss similar to luminous pollution. We reminded that when a light ray happens on a surface, it leaves across the reflection and part enters as a ray refracted in the second middle, from where can or not to be absorbed. During the venous translumination, the amount of reflected light depends on the relationship among the indexes of refraction of both means that can be altered as in the venous thrombosis or in the dermatolipoesclerose. Considering this technical parameter, we verified that certain types of lamps process more dispersion than reflection and therefore they favor the formation of artifacts. The luminous pollution in compensation, appears for the use of appropriate components. Focalizing on this question, another aspect that is observed, it the inability to be obtain translumited images with a fiber optic source due to the irradiation frequency being greater than necessary. It is also known that the reflection in an optic fiber source is initially processed, internally. Certain instruments as the venoscopy are not specific for the obtaining of reflected images. The illumination of the skin for distanced infrared light of the area without there being the impression of the source on the skin, doesn't reveal diagnostic images. The handling of the translumination transductor has to be in direct contact with the skin. The process exam should be similar to the accomplished by the doppler ultrasonography. The tissue translumineted by a white light has a refraction index in agreement with its texture. By the impression of the camera on the skin, the red and yellow color is observed. The red color is soon disperses in the skin and the yellow surroundingit begins, to alter its tonality with the change in souce direction. A shade with the change of the direction of the source arises . It is know that the refraction index charge in agreement with the spectrum of transmitted light and when the white light is projected and finds an obstacle, becomes separated in the three elementary colors (RGB). It leaves of this light during the translumination can suffer larger dispersion or reflection depending on the way with that the source is put on the examined area. This handling can define the better image or to harm her interpretation. Everything will depend on the examiner's experience. The skin is opaque the light. In physics light reception, heat or other type of radiant energy on the part of the molecules, is called absorption. In this case when the tissues are illuminated in the process of translumination, it happens that it leaves of this light is absorbed and the other is reflected. It is known that an object that absorbs the whole radiation that happens on him is known as black body and, therefore the pigments that give color to the skin and the other tissues, absorb certain wavelengths of the white light and they contemplate as well as they transmit radiant energy. This is one of the aspects of the color sensation that captured by our vision. However it is not known the mechanism well by the which certain substances absorb more light than other, presumably that process depends on his molecular structure. Another observed fact is that the light when reaching more pigmented areas or in patients with dermolipoesclerose, she disperses and it suffers the reflection more easily, being prejudiced absorption tends in view that in that situation the refraction index and smaller, for the difficulty that the white light has to penetrate to the subdermic plans.Several studies about the distribution of the elastin and of the collagen fibers in the patients bearers of dermal lesions during CIV, they should be analyzed so that she can verify as the same ones come in these situations and the influence of as it is processed those alterations. Considering this aspect is that a study of the tissues consistences using the translumination and the dermatoscopy could supply important data to complement the diagnosis of some collagen diseases of the and to study the aging of the tissues. The interaction and the relationship of skin color during the translumination is important. like this that individuals of white skin has a better venous visualization during the translumination, than the mulatto or black man. The erythrocytes absorb more light because they are oxygenated. Considering that aspect we can deduce that the venous blood has a light absorption different from arterial blood in which sanguine viscosity is greater due to the higher concentration of CO2 and to the factor of the stasis. In that sense the venous circulation has greater power to reflect the light. When we proceeded the translumination in an arterial-venous fistulae, we didn't usually observe reflected images also due to the flow velocity is higher and the fact that the sanguine viscosity in the arterial section is less than in the venous segment. The truth is that it is not possible to visualize arterial vases by translumination, because they don't supply a reflection due to their accelerated inflow. Another considered aspect is that the iron that participates in the composition of hemosiderin and others mine existent in the blood, emit light of several wavelengths when stimulated In the translumination, the spectrum of white light is decomposed of different wavelengths colors, in agreement with the incident area. The histogram represents the graphic visualization of these colors and the luminescence of the obtained images. In a histogram, the intensity of the luminescence is accompanied by the gray baseline that decreases as the source approaches, where the red scale is more intense and it is represented by a line in ascension. The scales of blue and green colors represent in this situations, the refraction indexes of the light in the occasion that the transluminator is positioned in contact with the studied area. In the histogram, when we disable the selection of a scale, for example the green scale, we can map the intensity of luminescence of whole captured images. Bollinger and collaborators remind an exam of their experience, denominated fluorescence videomiscroscopy, based on the video capture of images and study of the luminescence of the same, through the light emission stimulated by the 20% sodium-fluorocein (0.3 ml/l of blood).The principles of spectrographic analysis of this test are similar to that we use to evaluate the intensity of luminescence of captured images by venous translumination, and the histogram that we use also evaluate the scales of red, blue and green (RGB). Finally, we remind that all organic components are composed by several chemical elements that emit light according with its wavelength. This is why the analysis of histogram by the spectrum of colors of transluminated images could be applied, to define a certain organic element in relation to the quality and amount of their components.

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/index.php/Ventilation

# Ventilation (physiology) One of the primary roles of the lungs is to facilitate gas exchange between the circulatory system and the external environment. The lungs are constitute of branching airways that terminate in respiratory bronchioles and alveoli, which participate in gas exchange. The conducting zone of the lung which delivers gas to sites of gas exchange in alveoli is Mostly bronchioles and large airways. Gas exchange happens in the lungs between alveolar air and the blood of the pulmonary capillaries. For sufficient gas exchange to occur, alveoli must be ventilated and perfused. Ventilation (V) refers to the flow of air in and out of the alveoli, compared to perfusion (Q), which refers to the flow of blood to alveolar capillaries. every Individual alveoli have variable degrees of ventilation and perfusion in different regions of the lungs. The ratio of ventilation to perfusion (V/Q) is the Collective changes in ventilation and perfusion in the lungs, for which are measured clinically as V/Q ratio . Changes in the V/Q ratio can affect gas exchange and can contribute to hypoxemia . In respiratory physiology, ventilation (or ventilation rate) is the rate at which gas enters or leaves the lung. It is categorised under the following definitions: Lung volumes and lung capacities refer to the volume of air in the lungs at different phases of the respiratory cycle. The average total lung capacity of an adult human male is about 6 litres of air

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/index.php/Ventilation-perfusion_inequality

# Ventilation-perfusion inequality Ventilation-Perfusion Inequality –also known as Ventilation-Perfusion Mismatch – is when certain groups of alveoli experience a decrease in ventilation which causes a higher concentration of carbon dioxide (CO2) and a lower concentration of oxygen (O2). The inequality refers to the fact that perfusion has remained constant, the amount of blood flowing to and from the healthy alveoli and unhealthy alveoli is still the same. The body's natural reaction to this is to constrict the pulmonary arterioles that lead to the unhealthy alveoli; by doing this, the body increases the amount of blood travelling to healthy alveoli. This is generally caused by hypoxic conditions or asthma.

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/index.php/Ventilation-perfusion_mismatch

# Ventilation-perfusion mismatch In normal lung physiology the V/Q ratio is a measurement used to determine the efficacy and adequacy of ventilation and perfusion of the lung. Ventilation is the amount of air that reaches the lungs and Perfusion is the amount of blood flow to the lung. Any discrepancy between pulmonary blood flow and ventilation is called V/Q mismatch. Ideally ventilation and perfusion should be equal with a V/Q ratio of 1, but the normal lung varies due to multiple factors such as gravity, size and patency of airways, and positioning. There is a higher perfusion at the base of the lung than the apex of the lung. This causes a higher V/Q ratio at the apex compared to the base. The average V/Q ratio in a normal lung is about 0.8, with about 4 liters of oxygen and 5 liters of blood entering the lung per minute. Diseased lung can cause a V/Q mismatch due to decreased blood flow or oxygenation. This results in hypoxemia, which is a decreased oxygen concentration of blood. V/Q mismatch is one of the most common causes of hypoxemia. It can be caused by obstructive lung diseases, pulmonary vascular diseases, and interstitial diseases. Anything that affects the blood flow and oxygenation in the lung can cause a V/Q mismatch. An increased V/Q mismatch is caused by a decrease in blood flow to the lung, for example a pulmonary embolism. A decreased V/Q mismatch is caused by a decrease in ventilation or an airway obstruction, for example Asthma. A V/Q mismatch due to a perfusion defect will improve with 100% oxygen therapy. In normal conditions when there is a low ventilation, the body tries to keep this ratio in a normal range by restricting the perfusion in that specific area of the lung. This unique mechanism is called hypoxic pulmonary vasoconstriction. If this process continues for a long time it can cause pulmonary hypertension. Pulmonary shunts occur when the V/Q ratio is zero. It is formed when there is absent ventilation in one part of the lung with normal perfusion. This deoxygenated blood enters arterial circulation without getting oxygenated in the lung. Absorptive or compressive pulmonary atelectasis is the major reason for shunt formation. Pulmonary AV malformation, hepatopulmonary syndrome , ARDS, and pulmonary edema are less common causes. Shunting is characterized by it poor response to 100% oxygen therapy. Dead space ventilation occurs when V/Q ratio is undefined. When blood supply to part of the lung is cut off, oxygen in the ventilated atmospheric air is not able to enter the bloodstream leading to lesser overall efficiency of the alveolar oxygenation mechanism. Pulmonary Embolism is the most common cause of dead space ventilation. Hypoxemia caused by dead space ventilation will improve with 100% oxygen therapy. If left untreated patients with V/Q mismatch may progress to develop pulmonary hypertension , respiratory failure, and even death. In patients with an decreased V/Q ratio, 100% oxygen can be used as acute treatment while additional diagnostic studies are necessary to determine the underlying cause. Prognosis, mortality and survival rate of patients with V/Q mismatch depend on the underlying cause and early treatment. Patients with V/Q mismatch usually appear distressed. Physical examination of patients with V/Q mismatch depends on the underlying cause. Some common physical examination findings of V/Q mismatch include: Calculations using measurements from Arterial Blood Gas (ABG) and the response of those measures to supplemental oxygen are used to investigate the cause of hypoxia.

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/index.php/Ventilation-perfusion_mismatch_pathophysiology

# Ventilation-perfusion mismatch pathophysiology In normal lung physiology the V/Q ratio is a measurement used to determine the efficacy and adequacy of ventilation and perfusion of the lung. Ventilation is the amount of air that reaches the lungs and Perfusion is the amount of blood flow to the lung. Any discrepancy between pulmonary blood flow and ventilation is called V/Q mismatch. Ideally ventilation and perfusion should be equal with a V/Q ratio of 1, but the normal lung varies due to multiple factors such as gravity, size of airways, and positioning. There is a higher perfusion at the base of the lung than the apex of the lung. This causes a higher V/Q ratio at the apex compared to the base. The average V/Q ratio in a normal lung is about 0.8, with about 4 liters of oxygen and 5 liters of blood entering the lung per minute. Diseased lung can cause a V/Q mismatch due to decreased blood flow or oxygenation. This results in hypoxemia, which is a decreased oxygen concentration of blood. V/Q mismatch is one of the most common causes of hypoxemia. It can be caused by obstructive lung diseases, pulmonary vascular diseases, and interstitial diseases . An increased V/Q mismatch is caused by a decrease in blood flow to the lung, for example a pulmonary embolism. A decreased V/Q mismatch is caused by a decrease in ventilation or an airway obstruction, for example Asthma. A V/Q mismatch due to a perfusion defect will improve with 100% oxygen therapy. In normal conditions when there is a low ventilation, the body tries to keep this ratio in a normal range by restricting the perfusion in that specific area of the lung. This unique mechanism is called hypoxic pulmonary vasoconstriction. If this process continues for a long time it can cause pulmonary hypertension. The microscopic pathology depends on the exact reason for the V/Q mismatch. For example in asthma there are extracellular Charcot-Leyden crystals and increased mucosal goblet cells.

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/index.php/Ventilation/perfusion_ratio

# Ventilation/perfusion ratio Because the lung is centered vertically around the heart, part of the lung is superior to the heart, and part is inferior. This has a major impact on the V/Q ratio: An area with no ventilation (and thus a V/Q of zero) is termed a shunt. An area with no perfusion (and thus a V/Q of infinitiy) is termed "dead space" Ideally, the oxygen provided via ventilation would be just enough to saturate the blood fully. In the typical adult, 1 liter of blood can hold about 200 mL of oxygen; 1 liter of dry air has about 210 mL of oxygen. Therefore, under these conditions, the ideal ventilation perfusion ratio would be about 1.05. If one were to consider humidified air (with less oxygen), then the ideal v/q ratio would be in the vicinity of 1.0, thus leading to concept of ventilation-perfusion equality or ventilation-perfusion matching. This matching may be assessed in the lung as a whole, or in individual or in sub-groups of gas-exchanging units in the lung. On the other side Ventilation-perfusion mismatch is the term used when the ventilation and the perfusion of a gas exchanging unit are not matched. In a subject standing in orthostatic position (upright) the apex of the lung shows higher V/Q ratio, while at the base of the lung the ratio is lower but nearer to the optimal value for reaching adequate blood oxygen concentrations. The main reason for lower V/Q ratios at the base is that both ventilation and perfusion increase when going from the apex to the base, but Q does it more strongly thus lowering the V/Q ratio. The principal factor involved in the genesis of V/Q dishomogeneity between the apex and the base of the lung is gravity (this is why V/Q ratios change in positions other than the orthostatic one). Gravity and lung's weight act on ventilation by increasing pleural pressure at the base (making it less negative) and thus reducing the alveolar volume. The lowest part of the lung in relation to gravity is called the dependent region. At the dependent region smaller volumes mean the alveoli are more compliant (more distensible) and so capable of wider oxygen exchanges with the external environment. The apex, though showing a higher oxygen partial pressure, ventilates less efficiently since its compliance is lower and so smaller volumes are exchanged. The impact of gravity on pulmonary perfusion expresses itself as the hydrostatic pressure of the blood passing through the branches of the pulmonary artery in order to reach the apical and basal district of the lung, acting respectively against or synergistically with the pressure developed by the right ventricle. Thus at the apex of the lung the resulting pressure can be insufficient for developing a flow (which can be sustained only by the negative pressure generated by venous flow towards the left atrium) or even for preventing the collapse of the vascular structures surrounding the alveoli, while the base of the lung shows an intense flow due to the higher resulting pressure.

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/index.php/Ventilation/perfusion_scan

# Ventilation/perfusion scan Ventilation/perfusion scan, also called a V/Q scan, is a medical test to measure the circulation of air and blood within a patient's lungs. The ventilation part of the test evaluates the ability of air to reach all parts of the lungs, while the perfusion part measures how well the blood circulates within the lungs. This test is most commonly done in order to check for the presence of a blood clot or abnormal blood flow inside the lungs (pulmonary embolism or PE), although computed tomography with radiocontrast is now more commonly used for this purpose. A V/Q scan may also be performed in the case of serious lung disorders such as COPD or pneumonia as well as a lung performance quantification tool pre and post lung lobectomy surgery. The ventilation and perfusion segments of a V/Q scan are to be performed together and must include an X-ray of the chest (posterior-anterior projection) in order to properly diagnose. A defect in the perfusion images requires a mismatched ventilation to be indicative of PE. In the ventilation phase of the test, a gaseous radionuclide Xenon or technetium DTPA in an aerosol form is inhaled by the patient through a mouthpiece or mask that covers the nose and mouth. The perfusion phase of the test involves the intravenous injection of radioactive technetium macro aggregated albumin (Tc99m-MAA). The patient lies beneath a gamma camera which allows radioactive agents to be visualized within the lungs. Decreased circulation of the injected MAA (perfusion-ventilation mismatch) indicates a problem with blood flow into or within the lungs. A localized area of decreased uptake, usually in a pie shaped wedge configuration when mismatched with a normal ventilation image suggests a pulmonary embolus or blood clot in the lungs. Although this test uses radioactive materials, total amount of radiation exposure is low. However, this test should still be administered with caution to women who are pregnant, especailly during the first trimester. If breastfeeding, patient must be councelled to refrain from this activity for approximately 24 hours.

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/index.php/Ventilator-associated_lung_injury

# Ventilator-associated lung injury The human lung normally ventilates by using negative pressure in the thorax. Once positive pressure is applied, some degree of VALI is likely to occur. VALI is also caused by use of increased tidal volumes.VALI is also thought to occur more frequently in patients with diseased or inflammed interstitial tissue of lungs. During positive pressure ventilation, atelectatic regions will inflate, however the alveoli will be unstable and will collapse during the expiratory phase of the breath. This repeated alveolar collapse and expansion (RACE) is thought to cause VALI. By opening the lung and keeping the lung open RACE (and VALI) is reduced.

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/index.php/Ventouse

# Ventouse Ventouse is a vacuum device used to assist the delivery of a baby when labour has not progressed adequately. It is an alternative to a forceps delivery. It is not usually used when the baby is in the breech position or for premature births. This technique is also called vacuum-assisted vaginal delivery. The woman is placed in the lithotomy position and assists throughout the process by pushing. A suction cup is placed onto the head of the baby and the suction draws the skin from the scalp into the cup. Most ventouse devices have handles and when the head is born the device can be detached, allowing the woman to complete the delivery of her child.

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/index.php/Ventral_ramus_of_spinal_nerve

# Ventral ramus of spinal nerve The ventral ramus (anterior ramus, anterior branch, anterior divisions of the spinal nerves) supply the antero-lateral parts of the trunk, and the limbs; they are for the most part larger than the posterior divisions. In the thoracic region they run independently of one another, but in the cervical, lumbar, and sacral regions they unite near their origins to form plexuses. The Ventral rami, including the sinuvertebral nerve branches, supply structures anterior to the facet joint, including the vertebral bodies, the discs and their ligaments and joints other spinal nerves to form the lumbo-sacral plexus.

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/index.php/Ventral_respiratory_group

# Ventral respiratory group The ventral respiratory group (VRG) is a column of neurons located in the ventrolateral region of the medulla, extending from the caudal facial nucleus to -400μm obex. The four cell groups of the VRG are the rostral nucleus retrofacialis, caudal nucleus retroambiguus, nucleus para-ambiguus, and the pre-Bötzinger complex. The VRG contains both inspiratory and expiratory neurons. The VRG is secondarily responsible for initiation of inspiratory activity, after the dorsal respiratory group. The nucleus para-ambiguus is active during inspiration, while the nucleus retrofacialis and the nucleus retroambiguus are active during exhalation. The pre-Botzinger complex is the hypothesized location of central respiratory rhythm pattern generation circuitry. It is currently unclear how this system regulates its output to effect motoneuron bursting, which in turn is responsible for inspiratory muscle innervation. Research into the function of the pre-Bötzinger complex is currently being studied by making use of the in vitro slice preparation.

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/index.php/Ventral_tegmentum

# Ventral tegmentum The ventral tegmentum or the ventral tegmental area (VTA) (tegmentum, Latin for covering) is part of the midbrain, lying close to the substantia nigra and the red nucleus. The ventral tegmentum is considered to be part of the pleasure system, or reward circuit, one of the major sources of incentive and behavioural motivation. Activities that produce pleasure tend to activate the ventral tegmentum, and psychostimulant drugs (such as cocaine) directly target this area. Hence, it is widely implicated in neurobiological theories of addiction.

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/index.php/Ventricular_action_potential

# Ventricular action potential The ventricular action potential is composed of four phases: phase 0 is depolarization, phase 1 is early repolarization, phase 2 is a plateau, phase 3 is rapid repolarization and phase 4 is the resting potential. The different phases depend on the opening and/or closure of specific ion channels. At rest, the ventricular myocyte membrane potential is about -90 mV, which is close to the potassium reversal potential. When an action potential is generated, the membrane potential rises above this level in four distinct phases. The beginning of the action potential, phase 1, specialized membrane proteins (voltage-gated sodium channels) in the cell membrane selectively allow sodium ions to enter the cell. This causes the membrane potential to rise at a rate of about 300 V/s. As the membrane voltage rises (to about 40 mV) sodium channels close due to a process called inactivation. The sodium channel opening is followed by inactivation. Sodium inactivation comes with slowly inactivating Ca2+ channels at the same time as a few fast K+ channels open. There is a balance between the centrifugal flow of K+ and the centripetal flow of Ca2+ causing a plateau of length in variables. The delayed opening of more Ca2+-activated K+ channels, which are activated by build-up of Ca2+ in the sarcoplasm, while the Ca2+ channels close, ends the plateau. This leads to repolarisation. The depolarization of the membrane allows calcium channels to open as well. As sodium channels close calcium provides current to maintain the potential around 10 mV. The plateau lasts on the order of 100 ms. At the time that calcium channels are getting activated, channels that mediate the transient outward potassium current open as well. This outward potassium current causes a small dip in membrane potential shortly after depolarization. This current is observed in human and dog action potentials, but not in guinea pig action potentials. Repolarization is accomplished by channels that open slowly and are mostly activated at the end of the action potential (slow delayed-rectifier channels), and channels that open quickly but are inactivated until the end of the action potential (rapid delayed rectifier channels). Fast delayed rectifier channels open quickly but are shut by inactivation at high membrane potentials. As the membrane voltage begins to drop the channels recover from inactivation and carry current.

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/index.php/Ventricular_arrhythmia

# Ventricular arrhythmias A premature ventricular complex is characterized by the premature occurrence of a QRS complex that is bizarre in shape and lasts longer than 120 msec. The T wave is large and usually of opposite polarity to the QRS complex. A premature ventricular complex is usually followed by a full compensatory pause. The term "ventricular bigeminy" refers to alternating normal sinus and premature ventricular complexes. Three or more successive premature ventricular complexes are arbitrarily defined as ventricular tachycardia. Premature ventricular complexes become more prevalent with increasing age and occur in association with a variety of stimuli. It is important to determine whether underlying structural heart disease is present and left ventricular function is impaired.Other common causes include electrolyte abnormalities, stimulants, and some medications. In the absence of heart disease, PVCs are associated with little or no increased risk of developing a dangerous arrhythmia. In this situation, the risk-to-benefit ratio of antiarrhythmic drug therapy does not support routine treatment. It is important to review medications, determine if stimulants are being used, and correct electrolyte abnormalities. If no underlying cause is found, the optimal approach is patient reassurance. Patients should be made aware of the potential dangers of antiarrhythmic drug therapy as determined in the Cardiac Arrhythmia Suppression Trials (CAST and CAST II). CAST showed that the risk of dying increased, rather than decreased, with successful long-term suppression of premature ventricular complexes after myocardial infarction in older patients. At best, CAST II showed no impact on long-term survival from drug treatment that successfully suppressed premature ventricular complexes. If patients with multiple premature ventricular complexes have severe, disabling symptoms, beta blockers are the safest initial choice.Referral to a cardiologist is indicated if beta-blocker therapy is not effective. In this situation, the next agents to be tried would be class I antiarrhythmic drugs, such as flecainide (Tambocor) and amiodarone (Cordarone), although radiofrequency ablation of an ectopic focus may also be an appropriate treatment. The occurrence of premature ventricular complexes in patients with structural heart disease has been shown to significantly increase the risk of subsequent morbidity and mortality. Coronary heart disease, cardiomyopathy, and congestive heart failure are the major cardiac diseases associated with unfavorable outcomes in patients with premature ventricular complexes. Ventricular tachycardia refers to a rhythm originating from a ventricular ectopic focus at a rate >100 bpm. The electrocardiogram shows a wide complex tachycardia with no associated P waves. In patients with bundle branch block,Wolff-Parkinson-White syndrome, or aberrant conduction, supraventricular tachycardia can resemble ventricular tachycardia. Because of the morbidity and mortality associated with untreated ventricular tachycardia, any wide-complex tachycardia should be assumed to be ventricular tachycardia until proved otherwise. Physicians should keep in mind that patients with ventricular tachycardia can have minimal symptoms. The mortality rate within two years is reported to be higher than 30% in patients with non sustained ventricular tachycardia on Holter monitoring and impaired left ventricular function. Two large multicenter trials showed a clear advantage for automatic cardioverter defibrillator implantation over drug therapy in patients who had a malignant ventricular arrhythmia or who had been resuscitated from sudden cardiac death. The selection of high-risk patients for defibrillator implantation should be based on left ventricular function and the findings of electrophysiologic studies. Implantable defibrillators appear to be most beneficial in patients with a low ejection fraction who are noted to have frequent premature ventricular complexes, non sustained ventricular tachycardia on Holter monitoring, and a history of syncope or nearsyncope. It is critical to rule out coronary heart disease and to optimize the treatment of congestive heart failure in these patients. When ventricular tachycardia is diagnosed in relatively asymptomatic patients, medical treatment should be attempted. New recommendations from the American Heart Association emphasize the initial use of 300 mg of iv. administered amiodarone, followed by repeated 150 mg iv. doses every 8-10 minutes, in patients with pulseless VT. Patients with stable ventricular tachycardia should be given 150 mg of amiodarone intravenously over 10 minutes, followed by an infusion at 1 mg/minute for 6 hours and then at 0.5 mg/minute until the VT converts to sinus rhythm or another less dangerous rhythm. The alternative treatment is intravenously administered lidocaine (Xylocaine), given first in a 100 mg bolus (or 1 mg/kg) and then in an infusion at 1-4 mg/minute. Automatic implantable cardioverter defibrillators (ICD) are considered the most effective treatment for patients with life-threatening VT or VF. According to expert recommendations, implantation of an automatic cardioverter defibrillator should be considered in these situations : 1. Zipes DP, Camm AJ, Borggrefe M, et al., ACC/AHA/ESC 2006 Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death A Report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death)Circulation 2006;114;e385-e484

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/index.php/Ventricular_ectopy

# Cardiac ectopy Cardiac ectopy is a disturbance of the electrical conduction system of the heart, in which beats arise from the wrong part of the heart muscle. It can lead to serious arrythmia.

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/index.php/Ventricular_hypertrophy

# Ventricular hypertrophy Although ventricular hypertrophy may occur in either the left or right or both ventricles of the heart, left ventricular hypertrophy (LVH) is more commonly encountered. The ventricles are the chambers in the heart responsible for pumping blood either to the lungs (right ventricle) or the rest of the body (left ventricle). Increased ventricular mass is an adaptation by the ventricle(s) of the heart to increased stress, such as chronically increased volume load (preload) or increased pressure load (afterload). It is a physiological response that enables the heart to adapt to increased stress; however, the response can become pathological and ultimately lead to a deterioration in function. For example, hypertrophy is a normal physiological adaptation to exercise that enables the ventricle to enhance its pumping capacity. Aerobic training results in the heart being able to pump a larger volume of blood through an increase in the size of the ventricles. Anaerobic training results in the thickening of the myocardial wall to push blood through arteries compressed by muscular contraction. This type of physiologic hypertrophy is reversible and non-pathological, increasing the heart's ability to circulate blood. Chronic hypertension causes pathological ventricular hypertrophy. This response enables the heart to maintain a normal stroke volume despite the increase in afterload. However, over time, pathological changes occur in the heart that lead to a functional degradation and heart failure. If the precipitating stress is volume overload (as through aerobic exercise, which increases blood return to the heart through the action of the skeletal-muscle pump), the ventricle responds by adding new sarcomeres in-series with existing sarcomeres (i.e. the sarcomeres lengthen rather than thicken). This results in ventricular dilation while maintaining normal sarcomere lengths - the heart can expand to receive a greater volume of blood. The wall thickness normally increases in proportion to the increase in chamber radius. This type of hypertrophy is termed eccentric hypertrophy. In the case of chronic pressure overload (as through anaerobic exercise, which increases resistance to blood flow by compressing arteries), the chamber radius may not change; however, the wall thickness greatly increases as new sarcomeres are added in-parallel to existing sarcomeres. This is termed concentric hypertrophy. This type of ventricle is capable of generating greater forces and higher pressures, while the increased wall thickness maintains normal wall stress. This type of ventricle becomes "stiff" (i.e., compliance is reduced) which can impair filling and lead to diastolic dysfunction.

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/index.php/Ventricular_remodeling

# Ventricular remodeling The Left Ventricle has an enormous ability to respond to any type of stress or pathological process. Such a response includes a complex of wide range of transcriptional, signaling, structural, electrophysiological and functional events of cardiac myocytes as well as other cells within the ventricle. Ventricular remodeling can be either physiological or pathological. Physiological changes occur in cases of pregnancy, exercise and post-natal growth and considered to be normal, whereas pathological remodeling occur due to cardiac injury and can end up with cardiac arrhythmia and heart failure. Remodeling has three patterns. Concentric remodeling where there is an increase in relative wall thickness (Ventricular wall thickness compared to cavity size) and with or without increase cardiac mass.This change is noticed in cases of pressure overload.Eccentric Hypertrophy where there is an increase in cardiac mass and chamber volume with relative wall thickness varying between being decreased, the same or increased. This change is noticed in cases of volume overload, after infarction and isotonic exercise. Mixed Concentric and Eccentric changes as in Myocardial Infarction (MI), Where there is a combined volume and pressure overload on noninfarcted areas. Recent studies identified some cardiac myocytes in the LV that have the ability to re enter the cell cycle and proliferate. However, the majority of the cardiac cells cannot,and respond to stress by remodeling. Cardiac progenitors are localized to the epicardial surface of the heart and believed to contribute to the formation of coronary blood vessels during embryogenesis. These cells have the ability to express c-Kit,Sca-1 or Islet-1 on their surfaces. As cardiac myocytes stretch there is an increase in the local production or release of Angiotensin II (ANG II), Norepinephrine and endothelin. These neurohormonal proteins stimulate expression of proteins and cardiac myocytes hypertrophy. Increases in ANG II, aldosterone and cytokines stimulate collagen synthesis leading into fibrosis and remodeling of the cardiac extracellular matrix, while reduced nitric oxide will allow more cellular and interstitial growth as it is a negative inhibitor of remodeling. The connective tissue network connecting myocytes together is made from fibrillar collagen. Cardiac fibrosis contributes to morbidity and mortality and the amount of fibrotic tissue in the heart is directly proportional to cardiac arrhythmias and sudden cardiac death. Human and animals models showed that in case of pathological stress, fibroblasts proliferate and differentiate in myofibroblasts that lay down collagen I, collagen III and fibronectin after myocardial infarction and lead to fibrosis ,which in its turn will form a scar and replace injured cardiac myocytes. This scar will prevent ventricular rupture. In contrast, fibrosis arising due to hypertension-induced pressure overload is reactive and can lead to a decrease in compliance and oxygen diffusion capacity. Also, The enzyme collagenase is present in an inactive form in the ventricle and its activation after myocardial injury will lead into collagen degradation and hence an increase in chamber dimensions.MMPs (Matrix Metalloproteinases) is one type of the collagenase enzymes that play a role in remodeling ,where MMP-1 in hypertensive patients with systolic dysfunction lead to heart failure faster than those with diastolic function.Hence it is directly correlated with end-diastolic volume and inversely correlated with Left Ventricular Ejection Fraction. Neurohormonal activation in the form of increased release of Renin, Norepinephrine and antidiuretic hormones plays an important role in the process of remodeling. Although, it is initially a compensatory process and adaptive, such activation will lead into decompensation over the long term. Angiotensin II is one of the hormones that contribute to cardiac remodeling,where it is released from cardiac myocytes due to mechanical stretch as well as it is generated systemically. Angiotensin II binds AT1 receptors on human fibroblasts and promotes collagen synthesis along with protein synthesis and lead to hypertrophic changes. Besides,it enhances the action of aldosterone hormone which binds to mineralocorticoid receptors on cardiac cells and contributes to the process of remodeling. AT2 receptors activated by Angiotensin II leads into vasodilation and blunt cardiac remodeling. This suggests that AT1 & AT2 receptors have opposite effects to each other. Endothelin and Vasopressin are also activated during heart failure, where Vasopressin V1A receptor activation can lead to an increase in Ca2+ level intracellulary and promotes cardiac myocytes hypertrophy and remodeling.Also,the activation of Endothelin-1 increases the contractility and stimulate growth of cardiac myocytes which can lead to cardiac hypertrophy. The cardiac myocyte is the major cell involved. However, the interstium .fibroblasts, collagen, and coronary vasculature also play an important role. Remodeling is mainly affected by hemodynamic load and neurohormonal activation. Remodeling after Myocardial Infarction (MI) usually begins within the first few hours after infarct and progresses over time. The entire heart may be involved as thinning and dilatation in the infarct region is associated with distortion in shape of the entire heart,with volume overload hypertrophy of noninfarcted myocardium.The extent and location of myocardial damage affect the process of remodeling and its enormity. Remodeling after MI occurs in stages. After interruption of blood supply to a certain area, the cardiac myocytes will immediately die either via necrosis, apoptosis or autophagy. These dying cells will release intracellular proteins(cardiac troponins and creatine kinase) into the circulation and trigger an inflammatory response. Neutrophils,macrophages,monocyes and Lymphocytes infiltrate the cardiac tissue to remove cardiac myocytes. Once this inflammatory stage ends, cardiac fibroblasts start proliferating and synthesizing extra cellular proteins such as collagen type I in order to form the scar and replace the dead cardiac cells.Such a process will prevent cardiac rupture. The remodeling here will continue in response to increases in wall stress. Negative T waves can predict post infarction prognosis. lack of negative T waves resolution or late appearance of new negative T-waves are associated with less recovery and more remodeling. Hypertension is the most important factor for heart failure. The pressure overload taking place will shift the heart to increase its wall thickness according to Laplace Law such that the demand on oxygen will decrease. This change is adaptive initially but a persistent high pressure stress will eventually lead into decompensation and heart failure. Atrophic remodeling is also one of the changes that take place in the heart, as the cardiac myocytes are capable of shrinking. Such remodeling can reduce the Left Ventricular (LV) mass, Mechanical unloading (prolonged bed rest and weightlessness during space travel) or increased catabolic state as in cancer are important factors that contribute to atrophic remodeling. Apoptosis is an energy dependent pathway taken by the cells and does not involve the release of any intracellular content that can lead to inflammatory reaction. Metabolic remodeling also plays a crucial role in patients of diabetes mellitus and obesity, where these patients are more prone to develop hypertension ,coronary artery disease and heart failure.Normally,cardiac cells metabolize fatty acids and glucose and to a lesser extent lactate and ketone bodies.However,the onset of insulin resistance and obesity-driven type II diabetes mellitus shift the cardiac cells to utilize fatty acids more than glucose leading to myopathy characterized by ventricular dilatation,cardiac myocytes hypertrophy and death, as well as interstitial fibrosis and dysfunctional changes in diastolic relaxation. Recent studies focused on a paradox termed as obesity paradox where obese patients with heart failure manifest improvements in survival compared to normal weight patients and higher body mass indexes are related to lower mortality risk. Such association is attributed to depression of the neurohormonal system or to an increase in nutritional or metabolic reserve. Electrophysiological Remodeling in patients with LV hypertrophy develop malignant arrhythmias. Sustained ventricular tachycardia or ventricular fibrillation can occur immediately after myocardial infarction, during remodeling and later after injury. Alterations in transmembrane Ca2+ fluxes are believed to contribute to the pathogenesis of hypertrophy and failure by abnormally activating Ca2+ responsive signaling pathway. Ventricular arrhythmia have different mechanisms but they all arise from a disordered electrical currents due to prolongation of ventricular action potentials, and delay in the recovery of excitability, which is observed in cardiac hypertrophy, lead to early and late afterdepolarizations and exacerbate arrhythmias. Premature Ventricular Contractions: The most common type of cardiac arryhytmias, where a premature QRS complex is noted on ECG with abnormal duration and shape.It has no clinical significance in the absence of heart disease. Coronary artery disease which is the leading cause of heart failure with reduced systolic function occurs more in males than females.However, heart failure with preserved systolic function affects females more than males with a ratio of 2:1 Cardiac Remodeling is both an adaptive and maladaptive process during which the heart responds to injury.When the remodeling is adaptive, the heart will be able to maintain function in response to pressure or overload pressure especially during the acute phase of myocardial injury. For instance, the heart has the ability to remodel during mitral insufficiency,where there is an increase in the ventricular load or preload, to keep the flow of blood forward.On the other hand, Progressive remodeling is associated with poor prognosis. The time needed for the transition of any adaptive to maladaptive remodeling is not specific and can vary among patients. Once this transition is established, the remodeling process will contribute to Heart Failure progression. The mortality rate in treated patients with heart failure increases with age as noted by a community-based review of over 5500 persons from the Cardiovascular Health Study and the Framingham study. Also, gender has an effect on the mortality rate, where women has generally a better prognosis than men with 3.2 years median survival rate compared to 1.7 years in men. Cardiomyopathy also has a role in determining the mortality rate where patients with peripartum cardiomyopathy has a better prognosis compared to patients with myocardial disease, particularly amyloidosis or hemochromatosis, HIV infection, doxorubicin therapy, ischemic heart disease, or connective tissue disease.On the other hand, hypertension, myocarditis, sarcoidosis, substance abuse have no effect on the mortality rate of patients with heart failure. Several studies showed that there is a seasonal variation affecting the mortality rate.Deaths from heart failure seems to peak in winter months of January and December more than any other summer month. Left Ventricular Systolic Dysfunction is difficult to be diagnosed solely on the basis of signs and symptoms. Studies showed that remodeling can occur without clinical symptoms. Cardiac remodeling can be assessed using echocardiography and radionuclide imaging. These two imaging studies identify LV systolic Dysfunction. Although echocardiography is reliable in clinical trials, there is still some variations in its readings and good images are easier said than done in obese patients or those with respiratory diseases. Such difficulties make MRI a better method to provide more accurate images .Nevertheless, MRI is considered to be expensive for routine use. Among the biomarkers used to evaluate patients of Heart Failure with Preserved Ejection Fraction are Brain Natriuretic Peptide (BNP) and N-terminal pro-BNP. Other circulating biomarkers used to diagnose Heart Failure with Preserved Ejection Fraction include Procollagen,Interleukin-6,Interleukin-8,Tumor Necrosis Factor-α,matrix metaloproteinase,triiodothyronine,Troponin T,heart-type fatty acid binding proteins and carbohydrate antigen-125.These Biomarkers and their implications still need to be studied more thoroughly. Cardiac Troponin T and I are cardiac enzymes that are released after myocardial injury. These enzymes elevation are used as indicators for progressive decline in left ventricular function in patients of Heart Failure, even in the absence of coronary artery disease. ACE inhibitors and ARBs used to treat hypertension have the ability to target cardiac remodeling and reduce heart failure morbidity and mortality. Recent studies targeted Renin, the rate limiting step of Angiotensin II production, using Aliskiren and showed an ability to blunt cardiac remodeling in infarcted mice hearts. The addition of Mineralocorticoid Receptors Antagonists (MRA) in low doses revealed that there is an improvement in the symptoms of patients with moderately severe or severe heart failure,especially those of recent decompensation or left ventricular dysfunction early after infarction.Spironolactone and Eplerenone are among the MRA drugs used. However, Spironolactone has adverse metabolic and endocrine side effects making eplerenone use to become more convenient.MRA therapy can lead to an increased level of aldosterone,which in its turn can lead to deleterious effects on the heart through non-mineralocorticoid receptors. β-adrenergic receptor blockers are also among drugs used treat hypertension, cardiac arrhythmias and cardiac remodeling. Cardiac myocytes express β1 receptors and respond to β1-selective inhibitors.Nevertheless, fibroblasts express β2-receptors making the mechanism to which β-blockers act to become indefinable. Positive inotropic agents used to control symptoms in decompensated heart failure showed to have an increase in mortality over the long term, and the use of Digoxin did not affect the mortality rate in the long run. However, two new nonglycoside inotropic agents are studied more thoroughly now.One is to deliver cDNA of the sacroplasmic reticulum Ca2+ pump via an Adeno-associated virus in order to refill the downregulated sacroplasmic reticulum Ca2+ levels and showed safety and benefits in advanced heart failure. The second is a Luso-inotropic compound, Istaroxime, which inhibits Na/K ATPase that can lead to accumulation of Na+ intracellulary and decrease the activity of Na-Ca ions exchanger to remove cystolic Ca2+, and hence activates the sacromeric contraction. This process showed a decrease in capillary wedge pressure and heart rate during phase II clinical trial. HMG-CoA reductase inhibitors originally used to lower cholesterol level can provide protection to patients with ischemic heart disease. And anti-remodeling effects can occur when they are added to ACE inhibitors and β-blockers. Vasopressin receptor antagonists such as conivaptan, Lixivaptan, Mozavaptan and Tolvaptan showed no effect on Heart failure long-term mortality and morbidity when used for acute treatment of hospitalized Heart failure patients. However, the addition of Tolvaptan in its oral form to standard therapy improved the symptoms of some Heart failure patients without series cardiac events. Stem cells being considered for myocardial regeneration can be derived from bone marrow , circulating pools of progenitor cells and tissue-resident stem cells derived from adipose tissue, skeletal muscle ,myocardium and epicardium.The majority of clinical trials using stem cells derived from bone marrow showed safety and benefits in the treatment of ischemic heart disease beyond the standard therapy.However,some studies did not show any efficacy as patients receiving autologous adult stem cells are in advanced age and with different comorbidities such as hypertension and diabetes mellitus.Such comorbidities have effects on the viability of stem cells.

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/index.php/Ventricular_remodeling_classification

# Ventricular remodeling classification ## Classification Remodeling has three patterns. Concentric remodeling where there is an increase in relative wall thickness (ventricular wall thickness compared to cavity size) and with or without increase cardiac mass. Eccentric hypertrophy where there is an increase in cardiac mass and chamber volume with relative wall thickness varying between being decreased, the same or increased. This change is noticed in cases of volume overload, after infarction and isotonic exercise. Mixed concentric and eccentric changes as in myocardial infarction (MI), Where there is a combined volume and pressure overload on noninfarcted areas.

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/index.php/Ventricular_remodeling_historical_perspective

# Ventricular remodeling historical perspective Historical terms such as Athelete's Heart, Soldier's Heart, Runner's Heart, and Effort Syndrome referring to cardiac adaptations that occur with prolonged endurance or excessive exertions were initially coined in the 19th century. Sir William Osler described hypertrophy as a compensatory response during the development of the failing heart that precedes the state of broken compensation secondary to degeneration and weakening of the heart muscle. In the 1960s,animal models were investigated for the effects of pressure overload.Such investigations led Meerson to argue that cardiac growth induced by biomechanical stress has a protective role,at least in the short term.In the 1970s and 1980s, patients of valvular heart disease were investigated and their hemodynamic measurements showed that there is an adaptive hypertrophic growth taking place in the heart.Such growth can lead to systolic dysfunction when it is inadequate.

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/index.php/Ventricular_remodeling_overview

# Ventricular remodeling overview Ventricular remodeling refers to the changes in size, shape, and function of the heart after injury to the left ventricle. The injury is typically due to acute myocardial infarction (usually transmural or ST segment elevation infarction), but may be from a number of causes that result in increased pressure or volume overload (forms of strain) on the heart. Chronic hypertension, congenital heart disease with intracardiac shunting, and valvular heart disease may also lead to remodeling. After the insult occurs, a series of histopathological and structural changes occur in the left ventricular myocardium that lead to progressive decline in left ventricular performance. Ultimately, ventricular remodeling may result in diminished contractile (systolic) function and reduced stroke volume. Medically speaking, "ventricular remodeling" implies a decline in function (even though the word "remodeling" usually implies improvement). The term "reverse remodeling" in cardiology implies an improvement in ventricular mechanics and function after a remote injury. The cardiac myocyte is the major cell involved in remodeling. Fibroblasts, collagen, the interstitium, and the coronary vessels to a lesser extent, also play a role. A common scenario for remodeling is after myocardial infarction. There is myocardial necrosis (cell death) and disproportionate thinning of the heart. This thin, weakened area is unable to withstand the pressure and volume load on the heart in the same manner as the other healthy tissue. As a result there is dilatation of the chamber arising from the infarct region. The initial remodeling phase after a myocardial infarction results in repair of the necrotic area and scar formation that may, to some extent, be considered beneficial since there is an improvement in or maintenance of LV function and cardiac output. Over time, however, as the heart undergoes ongoing remodeling, it becomes less elliptical and more spherical. Ventricular mass and volume increase, which together adversely affect cardiac function. Eventually, diastolic function, or the heart's ability to relax between contractions may become impaired, further causing decline. Many factors influence the time course and extent of remodeling, including the severity of the insult, secondary events (recurrent ischemia or infarction),neurohormonal activation, genetic factors and gene expression, and treatment. Medications may attenuate remodeling. Angiotensin-converting enzyme (ACE) inhibitors have been consistently shown to decrease remodeling in animal models or transmural infarction and chronic pressure overload. Clinical trials have shown that ACE inhibitor therapy after myocardial infarction leads to improved myocardial performance, improved ejection fraction, and decreased mortality compared to patients treated with placebo. Early correction of congenital heart defects, if appropriate, may prevent remodeling, as will treatment of chronic hypertension or valvular heart disease. Often, reverse remodeling, or improvement in left ventricular function, will also be seen.

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/index.php/Ventricular_remodeling_pathophysiology

# Ventricular remodeling pathophysiology ## Pathophysiology Ventricular remodeling can be either physiological or pathological. Physiological changes occur in cases of pregnancy, exercise and post-natal growth and are considered to be normal, whereas pathological remodeling occurs secondary to cardiac injury and may result in arrhythmia and heart failure.

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/index.php/Ventricular_septal_defect

# Ventricular septal defect Editor-In-Chief: C. Michael Gibson, M.S., M.D. ; Associate Editors-In-Chief: Priyamvada Singh, MBBS ; Cafer Zorkun, M.D., Ph.D. ;Kalsang Dolma, M.B.B.S. Assistant Editor-In-Chief: Kristin Feeney, B.S. Medical Therapy | Surgery | Ventricular Septal Defect Post-Surgical Prognosis | ACC/AHA Guidelines for Surgical and Catheter Intervention Follow-Up | Prevention | ACC/AHA Guidelines for Reproduction | Cost-Effectiveness of Therapy | Future or Investigational Therapies

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/index.php/Ventriculography

# Left ventriculography With the advancement of noninvasive imaging methods such as echocardiography, less emphasis has recently been placed on the ventriculogram as part of a cardiac catheterization. However, entry into the left ventricle with hemodynamic measurement and visualization of the left ventricle using contrast ventriculography remains an important aspect of a complete angiographic study. In patients presenting acutely with ST elevation myocardial infarction, assessment of myocardial and valvular function with ventriculography may provide important prognostic information and may guide in part the management of the patient. In obese patients with difficult echocardiographic windows, ventriculography may provide diagnostic information that cannot be obtained from the echocardiogram. The operator should keep the left hand on the catheter during injection to change the position as required during the procedure. If the catheter is too far in the apex, pullback of 1-2 cm will usually reposition the catheter for several beats to obtain useful information. Both the RAO and LAO/Cranial projections can be used to identify significant mitral regurgitation. Grading the amount of regurgitation is based on the amount of opacification of the atrium compared to the ventricular opacification, atrial size and the number of cycles required for maximal opacification. Elevation of left atrial pressure in acute regurgitation and dilation of the left atrium from chronic regurgitation can both interfere with the use of this grading system.

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/index.php/Ventriculomegaly

# Ventriculomegaly Ventriculomegaly is a brain condition that occurs when the lateral ventricles become dilated. The most common definition uses a width of the atrium of the lateral ventricle of greater than 10 mm (Cardoza, 1988). This occurs in around 1% of pregnancies (Salomon, 2007). When this measurement is between 10 and 15 mm, the ventriculomegaly may be described as mild to moderate. When the measurement is greater than 15mm, the ventriculomegaly may be classified as more severe (Breeze, 2007). Enlargement of the ventricles may occur for a number of reasons, for example due to loss of brain volume (perhaps due to infection or infarction), or due to impaired outflow or absorption of cerebrospinal fluid from the ventricles. Often, however, there is no identifiable cause. The interventricular foramen may be congenitally malformed, or may have become obstructed by infection, hemorrhage, or rarely tumor, which may impair the drainage of cerebrospinal fluid, and thus accumulation in the ventricles. This diagnosis is generally found in routine fetal anomaly scans at 18–22 weeks gestation. It is one of the commonest abnormal brain findings on prenatal ultrasound, occurring in around 1-2 per 1000 pregnancies (Achiron et al, 1993). In many cases of mild ventriculomegaly, however, there is resolution of ventriculomegaly during the pregnancy. Ventriculomegaly is also known to be associated with other malformations such as agenesis of the corpus callosum, spina bifida, and heart defects. Fetuses with both isolated ventriculomegaly and with other anomalies have an increased risk of having a chromosomal abnormality, including that of Down Syndrome (Breeze, 2007; Gaglioti, 2005). Many conditions associated with ventriculomegaly can be defined prior to birth, but the possibility remains of other anomalies (either structural, chromosomal or genetic) only being identified later in pregnancy or after birth (Breeze, 2005). Ventriculomegaly associated with abnormal findings and other structural malformations, often has an adverse prognosis, which ranges from disability (often mild) to death. However, in cases of mild isolated ventriculomegaly, there is around a 90% chance of a normal outcome (Signorelli, 2004; Gaglioti 2005). Increasingly, fetal magnetic resonance imaging is being considered as part of the assessment of pregnancies complicated by fetal ventriculomegaly (Glenn & Barkovich, 2006), and appears to be important in the postnatal assessment of affected children (Falip, 2007) Achiron R, Schimmel M, Achiron A, Mashiach S. 1993. Fetal mild idiopathic lateral ventriculomegaly: is there a correlation with fetal trisomy? Ultrasound Obstet Gynecol 3: 89–92. Breeze AC, Dey PK, Lees CC, Hackett GA, Smith GCS, Murdoch EM. 2005. Obstetric and neonatal outcomes in apparently isolated mild fetal ventriculomegaly. J Perinat Med 33: 236–240 Abstract Breeze AC, Alexander PM, Murdoch EM, Missfelder-Lobos HH, Hackett GA, Lees CC. 2007. Obstetric and neonatal outcomes in severe fetal ventriculomegaly. Prenat Diagn. 27(2):124-9 Abstract Cardoza JD, Goldstein RB, Filly RA. 1988. Exclusion of fetal ventriculomegaly with a single measurement: the width of the lateral ventricular atrium. Radiology 169: 711–714. Falip C, Blanc N, Maes E, Zaccaria I, Oury JF, Sebag G, Garel C. 2007. Postnatal clinical and imaging follow-up of infants with prenatal isolated mild ventriculomegaly: a series of 101 cases. Pediatr Radiol. 2007 Oct;37(10):981-9. Abstract Glenn OA, Barkovich AJ. 2006. Magnetic resonance imaging of the fetal brain and spine: an increasingly important tool in prenatal diagnosis, part 1. AJNR Am J Neuroradiol. Sep;27(8):1604-11. Signorelli M, Tiberti A, Valseriati D, Molin E, Cerri V, Groli C, Bianchi UA. 2004. Width of the fetal lateral ventricular atrium between 10 and 12 mm: a simple variation of the norm? Ultrasound Obstet Gynecol. Jan;23(1):14-8.

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/index.php/Veralipride

# Veralipride Veralipride (Agreal, Agradil) is a benzamide neuroleptic medicine indicated in the treatment of vasomotor symptoms associated with the menopause. It was first authorised for use in 1979. Veralipride has never gained approval in the United States. On September 2006, it was withdrawn from the Spanish market. As a result, the European Commission referred the matter to the European Medicines Agency (EMA). On July 2007, the EMA recommended the withdrawal of marketing authorisations for veralipride.

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/index.php/Verapamil

# Verapamil Verapamil is a calcium channel blocker that is FDA approved for the treatment of essential hypertension (tablet and capsule), rapid conversion to sinus rhythm of paroxysmal supraventricular tachycardias, and temporary control of rapid ventricular rate in atrial flutter or atrial fibrillation (injection). Common adverse reactions include edema, hypotension, constipation, dizziness, headache, pharyngitis, sinusitis, and influenza-like symptoms. 1-Severe left ventricular dysfunction (see WARNINGS) 2-Hypotension (systolic pressure less than 90 mm Hg) or cardiogenic shock 3-Sick sinus syndrome (except in patients with a functioning artificial ventricular pacemaker) 4-degree AV block or third-degree AV block (except in patients with a functioning artificial ventricular pacemaker) 5-Patients with atrial flutter or atrial fibrillation and an accessory bypass tract (eg, Wolff-Parkinson-White, Lown-Ganong-Levine syndrome) 6-Patients with known hypersensitivity to verapamil hydrochloride 7.Severe congestive heart failure (unless secondary to a supraventricular tachycardia amenable to verapamil therapy). 8.Ventricular tachycardia: Administration of intravenous verapamil to patients with wide-complex ventricular tachycardia (QRS ≥ 0.12 sec) can result in marked hemodynamic deterioration and ventricular fibrillation. Proper pretherapy diagnosis and differentiation from wide-complex supraventricular tachycardia is imperative in the emergency room setting. It has been reported that verapamil decreases neuromuscular transmission in patients with Duchenne's muscular dystrophy, prolongs recovery from the neuromuscular blocking agent vecuronium, and causes a worsening of myasthenia gravis. It may be necessary to decrease the dosage of verapamil when it is administered to patients with attenuated neuromuscular transmission. Relaxation and prevention of coronary artery spasm: Verapamil dilates the main coronary arteries and coronary arterioles, both in normal and ischemic regions, and is a potent inhibitor of coronary artery spasm, whether spontaneous or ergonovine-induced. This property increases myocardial oxygen delivery in patients with coronary artery spasm and is responsible for the effectiveness of Verapamil in vasospastic (Prinzmetal's or variant) as well as unstable angina at rest. Whether this effect plays any role in classical effort angina is not clear, but studies of exercise tolerance have not shown an increase in the maximum exercise rate–pressure product, a widely accepted measure of oxygen utilization. This suggests that, in general, relief of spasm or dilation of coronary arteries is not an important factor in classical angina. Reduction of oxygen utilization: Verapamil regularly reduces the total peripheral resistance (afterload) against which the heart works both at rest and at a given level of exercise by dilating peripheral arterioles. This unloading of the heart reduces myocardial energy consumption and oxygen requirements and probably accounts for the effectiveness of Verapamil in chronic stable effort angina. The chemical name of Verapamil Hydrochloride, USP is benzeneacetonitrile, α-[3-[{2-(3,4-dimethoxyphenyl)ethyl} methylamino] propyl]-3,4-dimethoxy-α-(1-methylethyl) hydrochloride. Verapamil hydrochloride is a white or practically white crystalline powder. It is practically odorless and has a bitter taste. It is soluble in water; freely soluble in chloroform; sparingly soluble in alcohol; practically insoluble in ether. It has the following structural formula: After four weeks of oral dosing (120 mg q.i.d.), verapamil and norverapamil levels were noted in the cerebrospinal fluid with estimated partition coefficient of 0.06 for verapamil and 0.04 for norverapamil.

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/index.php/Veratrum_viride

# Veratrum viride Veratrum viride (Indian Poke, False Hellebore, Green False Hellebore) is a species of Veratrum native to eastern and western (but not central) North America. It is extremely toxic, and is considered a pest plant by farmers with livestock. The species has acquired a large number of common names within its native range, including American False Hellebore, American White Hellebore, Bear Corn, Big Hellebore, Corn Lily, Devils Bite, Duck Retten, Indian Hellebore, Itch-weed, Itchweed, Poor Annie, and Tickleweed. It is a herbaceous perennial plant reaching 0.7-2 m tall, with a solid green stem. The leaves are spirally arranged, 10–35 cm long and 5–20 cm broad, elliptic to broad lanceolate ending in a short point, heavily ribbed and hairy on the underside. The flowers are numerous, produced in a large branched inflorescence 30–70 cm tall; each flower is 5–12 mm long, with six green to yellow-green tepals. The fruit is a capsule 1.5–3 cm long, which splits into three sections at maturity to release the numerous flat 8–10 mm diameter seeds. The plant reproduces through rhizome growth as well as seeds. The related western North American Veratrum californicum (White False Hellebore) can be distinguished from sympatric var. eschscholzianum by its whiter flowers, with erect side branches of the inflorescence. In eastern North America, var. viride occurs from southwestern Labrador and southern Quebec south to northern Georgia. In the west, var. eschscholzianum occurs from Alaska and Northwest Territory south through Yukon, British Columbia, Alberta, Washington, Idaho, Montana, and Oregon to northern California. It is found in wet soils in meadows and open forests, from sea level in the north of the range, up to 1,600 m in the southeast and 2,500 m in the southwest. The plant is highly toxic, causing nausaea and vomiting. If the poison is not evacuated, cold sweat and vertigo appears. Respiration slows, cardiac rhythm and blood pressure falls, eventually leading to death. It is used externally by several Native American nations for external treatment. Although is rarely ever used modern herbalism due to its concentration of various alkaloids, it has been used in the past against high blood pressure and rapid heartbeat. The root contains even higher concentrations than the aerial parts. The plant was used by some tribes to elect a new leader. All the candidates would eat the root, and the last to start vomiting would become the new leader.

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/index.php/Vermiform_appendix

# Vermiform appendix In human anatomy, the vermiform appendix (or appendix, pl. appendices) is a blind ended tube connected to the cecum, from which it develops embryologically. The term "vermiform" comes from Latin and means "wormlike in appearance". The cecum is the first pouch-like structure of the colon. The appendix is near the junction of the small intestine and the large intestine. The appendix averages 100 mm in length, but can range from 20 to 200 mm. The diameter of the appendix is usually between 7 and 8 mm. The longest appendix ever removed was that of a Pakistani man on June 11, 2003, at Pakistan Institute of Medical Sciences, Islamabad, measuring 235 mm (9.2 in) in length. The appendix is located in the lower right quadrant of the abdomen, or more specifically, the right iliac fossa. Its position within the abdomen corresponds to a point on the surface known as McBurney's point (see below). While the base of the appendix is at a fairly constant location, 2 cm below the ileocaecal valve , the location of the tip of the appendix can vary from being retrocaecal (74% ) to being in the pelvis to being extraperitoneal. In rare individuals with situs inversus, the appendix may be located in the lower left side. Medical literature shows that the appendix is not generally credited with significant function. The appendix is rich in infection-fighting lymphoid cells, suggesting that it might play a role in the immune system. Whether or not the appendix has a function, it is routinely removed without any notable ill effects or side effects. Some experts believe that the appendix was used for digesting leaves as primates. Over time, we have eaten fewer vegetables and have evolved, over millions of years, for this organ to be smaller to make room for our stomach. There have been cases of people who have been found, usually on laparoscopy or laparotomy, to have a congenital absence of their appendix. There have been no reports of impaired immune or gastrointestinal function in these people. The most common explanation is that the appendix is a vestigial structure with no absolute purpose. In The Story of Evolution, Joseph McCabe argued thus: The vermiform appendage—in which some recent medical writers have vainly endeavoured to find a utility—is the shrunken remainder of a large and normal intestine of a remote ancestor. This interpretation of it would stand even if it were found to have a certain use in the human body. Vestigial organs are sometimes pressed into a secondary use when their original function has been lost. Loren G. Martin , argues that the appendix has a function in fetuses and adults. Endocrine cells have been found in the appendix of 11 week old fetuses that contribute to "biological control (homeostatic) mechanisms." In adults, Martin argues that the appendix acts as a lymphatic organ. The most common diseases of the appendix (in humans) are appendicitis and carcinoid tumors. Appendix cancer accounts for about 1 in 200 of all gastrointestinal malignancies. Adenomas also (rarely) present. Appendicitis (or epityphlitis) is a condition characterized by inflammation of the appendix. Virtually all cases of Appendicitis require removal of the inflamed appendix, either by laparotomy or laparoscopy. Untreated, the appendix will rupture, leading to peritonitis, then shock, and, if continued untreated, death. Pain often begins in the center of the abdomen where the lining of the stomach is irritated then moves lower right as the condition develops, it is important to note that this makes diagnoses difficult in the early stages that only an MRI can detect. Appendicitis presents as pain in the right lower quadrant with rebound tenderness. In particular, it presents at McBurney's Point, 1/3 of the way along a line drawn from the Anterior Superior Iliac Spine to the Umbilicus. Rebound tenderness is when it does not hurt to press on the point but it hurts greatly when the pressure is released, or when the skin rebounds. Typically, point (skin) pain is not present until the parietal peritoneum is inflamed as well. Fever and immune system response are also characteristic of appendicitis. It is important to see a physician if stomach pain is present. The surgical removal of the vermiform appendix is called an appendicectomy (or appendectomy). This procedure is normally performed as an emergency procedure, when the patient is suffering from acute appendicitis. In the absence of surgical facilities, intravenous antibiotics are used to delay or avoid the onset of sepsis; it is now recognized that many cases will resolve when treated non-operatively. In some cases the appendicitis resolves completely; more often, an inflammatory mass forms around the appendix. This is a relative contraindication to surgery.

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/index.php/Vermox

# Mebendazole Mebendazole is a broad-spectrum anthelmintic that is FDA approved for the treatment of Enterobius vermicularis (pinworm), Trichuris trichiura (whipworm), Ascaris lumbricoides (common roundworm), Ancylostoma duodenale (common hookworm), Necator americanus (American hookworm) in single or mixed infections. Common adverse reactions include rash, abdominal pain, constipation, diarrhea and headache. If the patient is not cured three weeks after treatment, a second course of treatment is advised. No special procedures, such as fasting or purging, are required. There is no evidence that mebendazole, even at high doses, is effective for hydatid disease. There have been rare reports of neutropenia and agranulocytosis when mebendazole was taken for prolonged periods and at dosages substantially above those recommended.

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/index.php/Vernakalant

# Vernakalant | tradename = | licence_EU = Brinavess | licence_US = | pregnancy_AU = | pregnancy_US = | pregnancy_category = | legal_AU = | legal_CA = | legal_UK = | legal_US = | legal_status = Rx-only | routes_of_administration = Intravenous, oral | CAS_number_Ref =  Y | CAS_number = 794466-70-9 | CAS_supplemental = 748810-28-8 (HCl) | ATC_prefix = C01 | ATC_suffix = BG11 | PubChem = 9930049 | DrugBank_Ref =  Y | DrugBank = | UNII_Ref =  Y | UNII = 9G468C8B13 | ChemSpiderID_Ref =  N | ChemSpiderID = 8105680 | smiles = O(c1ccc(cc1OC)CCO[C@@H]3CCCC[C@H]3N2CC[C@@H](O)C2)C | InChI = 1/C20H31NO4/c1-23-19-8-7-15(13-20(19)24-2)10-12-25-18-6-4-3-5-17(18)21-11-9-16(22)14-21/h7-8,13,16-18,22H,3-6,9-12,14H2,1-2H3/t16-,17-,18-/m1/s1 | InChIKey = VBHQKCBVWWUUKN-KZNAEPCWBT | StdInChI_Ref =  N | StdInChI = 1S/C20H31NO4/c1-23-19-8-7-15(13-20(19)24-2)10-12-25-18-6-4-3-5-17(18)21-11-9-16(22)14-21/h7-8,13,16-18,22H,3-6,9-12,14H2,1-2H3/t16-,17-,18-/m1/s1 | StdInChIKey_Ref =  N | StdInChIKey = VBHQKCBVWWUUKN-KZNAEPCWSA-N Vernakalant (INN; codenamed RSD1235, proposed tradenames Kynapid and Brinavess) is an investigational drug under regulatory review for the acute conversion of atrial fibrillation. It was initially developed by Cardiome Pharma, and the intravenous formulation has been bought for further development by Merck in April 2009. On December 11, 2007, the Cardiovascular and Renal Drugs Advisory Committee of the US Food and Drug Administration (FDA) voted to recommend the approval of vernakalant, but in August 2008 the FDA judged that additional information was necessary for approval. The drug was approved in Europe on September 1, 2010. Like other class III antiarrhythmics, vernakalant blocks atrial potassium channels, thereby prolonging repolarization. It differs from typical class III agents by blocking a certain type of potassium channel, the cardiac transient outward potassium current, with increased potency as the heart rate increases. This means that it is more effective at high heart rates, while other class III agents tend to lose effectiveness under these circumstances. It also slightly blocks the hERG potassium channel, leading to a prolonged QT interval. This may theoretically increase the risk of ventricular tachycardia, though this does not seem to be clinically relevant.

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/index.php/Vernanimalcula

# Vernanimalcula Vernanimalcula has been described as the earliest known member of the Bilateria (animals with bilateral symmetry). It lived some 580 to 600 million years ago. It was between 0.1 and 0.2 mm across (roughly the width of one or two human hairs), and probably fed on microbes on the sea floor. It may have moved over the sea floor by flexing its body. Vernanimalcula means "small spring animal", referring to its appearance in the fossil record at the end of the Marinoan Glaciation (see also Snowball Earth). The Vernanimalcula fossils were discovered in the Doushantuo Formation in China. This formation is a Lagerstätte, one of the rare places where soft body parts and very fine details are preserved in the fossil record. The Vernanimalcula fossils show triploblastic structure, a coelom, a differentiated gut, a mouth, an anus, and paired external pits that could be sense organs. The appearance of Vernanimalcula so early in the fossil record has important implications. It greatly reduces the likelihood that animals without coelom (acoelomates), such as flatworms, developed before animals with coeloms. The radiation of animals into many phyla may have occurred before any animal became much larger than microscopic size. The sudden appearance of many animal phyla in the Cambrian Explosion may be an illusion. The Cambrian Explosion may instead represent a (geologically) sudden increase in size and the development of easily fossilized body parts by species in existing phyla. The description of Vernanimalcula was not without controversy. Other workers (Bengtson and Budd) in the field have claimed that it is largely a taphonomic artefact generated by growth of phosphate within a spherical object such as an acritarch. Chen et al. have defended their interpretation of Vernanimalcula against the claims of Bengtson and Budd.

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