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Statin

Statins (or HMG-CoA reductase inhibitors) are a class of medications that reduce illness and mortality in people who are at high risk of cardiovascular disease. They are the most commonly prescribed cholesterol-lowering drugs.

Low-density lipoprotein (LDL) carriers of cholesterol play a key role in the development of atherosclerosis and coronary heart disease via the mechanisms described by the lipid hypothesis. As lipid-lowering medications, statins are effective in lowering LDL cholesterol; they are widely used for primary prevention in people at high risk of cardiovascular disease, as well as in secondary prevention for those who have developed cardiovascular disease.

Side effects of statins include muscle pain, increased risk of diabetes, and abnormal blood levels of certain liver enzymes. Additionally, they have rare but severe adverse effects, particularly muscle damage, and very rarely rhabdomyolysis.

They act by inhibiting the enzyme HMG-CoA reductase, which plays a central role in the production of cholesterol. High cholesterol levels have been associated with cardiovascular disease.

There are various forms of statins, some of which include atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin. Combination preparations of a statin and another agent, such as ezetimibe/simvastatin, are also available. The class is on the World Health Organization's List of Essential Medicines with simvastatin being the listed medicine. In 2005, sales were estimated at US$18.7 billion in the United States. The best-selling statin is atorvastatin, also known as Lipitor, which in 2003 became the best-selling pharmaceutical in history. The manufacturer Pfizer reported sales of US$12.4 billion in 2008.

Patient compliance with statin usage has been problematic for many medical practitioners, despite robust evidence of the benefits to the majority of patients.

Medical uses
Statins are usually used to lower blood cholesterol levels and reduce risk for illnesses related to atherosclerosis, with a varying degree of effect depending on underlying risk factors and history of cardiovascular disease. Clinical practice guidelines generally recommend people start with lifestyle modification through a cholesterol-lowering diet and physical exercise. For those unable to meet their lipid-lowering goals through such methods, statins can be helpful. The medication appears to work equally well regardless of sex, although some sex-related differences in treatment response were described.

If there is an underlying history of cardiovascular disease, it has a significant impact on the effects of statin. This can be used to divide medication usage into broad categories of primary and secondary prevention.

Primary prevention
For the primary prevention of cardiovascular disease, the United States Preventive Services Task Force (USPSTF) 2016 guidelines recommend statins for those who have at least one risk factor for coronary heart disease, are between 40 and 75 years old, and have at least a 10% 10-year risk of heart disease, as calculated by the 2013 ACC/AHA Pooled Cohort algorithm. Risk factors for coronary heart disease included abnormal lipid levels in the blood, diabetes mellitus, high blood pressure, and smoking. They recommended selective use of low-to-moderate doses statins in the same adults who have a calculated 10-year cardiovascular disease event risk of 7.5–10% or greater. In people over the age of 70, statins decrease the risk of cardiovascular disease but only in those with a history of heavy cholesterol blockage in their arteries.

Most evidence suggests that statins are also effective in preventing heart disease in those with high cholesterol but no history of heart disease. A 2013 Cochrane review found a decrease in risk of death and other poor outcomes without any evidence of harm. For every 138 people treated for 5 years, one fewer dies; for every 49 treated, one fewer has an episode of heart disease. A 2011 review reached similar conclusions, and a 2012 review found benefits in both women and men. A 2010 review concluded that treatment without history of cardiovascular disease reduces cardiovascular events in men but not women, and provides no mortality benefit in either sex. Two other meta-analyses published that year, one of which used data obtained exclusively from women, found no mortality benefit in primary prevention.

The National Institute for Health and Clinical Excellence (NICE) recommends statin treatment for adults with an estimated 10 year risk of developing cardiovascular disease that is greater than 10%. Guidelines by the American College of Cardiology and the American Heart Association recommend statin treatment for primary prevention of cardiovascular disease in adults with LDL cholesterol ≥ 190 mg/dL (4.9 mmol/L) or those with diabetes, age 40–75 with LDL-C 70–190 mg/dL (1.8–4.9 mmol/dL); or in those with a 10-year risk of developing heart attack or stroke of 7.5% or more. In this latter group, statin assignment was not automatic, but was recommended to occur only after a clinician-patient risk discussion with shared decision making where other risk factors and lifestyle are addressed, the potential for benefit from a statin is weighed against the potential for adverse effects or drug interactions and informed patient preference is elicited. Moreover, if a risk decision was uncertain, factors such as family history, coronary calcium score, ankle-brachial index, and an inflammation test (hs-CRP ≥ 2.0 mg/L) were suggested to inform the risk decision. Additional factors that could be used were an LDL-C ≥ 160 mg/dL (4.14 mmol/L) or a very high lifetime risk. However, critics such as Steven E. Nissen say that the AHA/ACC guidelines were not properly validated, overestimate the risk by at least 50%, and recommend statins for people who will not benefit, based on populations whose observed risk is lower than predicted by the guidelines. The European Society of Cardiology and the European Atherosclerosis Society recommend the use of statins for primary prevention, depending on baseline estimated cardiovascular score and LDL thresholds.

Secondary prevention
Statins are effective in decreasing mortality in people with pre-existing cardiovascular disease. Pre-existing disease can have many manifestations. Defining illnesses include a prior heart attack, stroke, stable or unstable angina, aortic aneurysm, or other arterial ischemic disease, in the presence of atherosclerosis. They are also advocated for use in people at high risk of developing coronary heart disease. On average, statins can lower LDL cholesterol by 1.8 mmol/L (70 mg/dL), which translates into an estimated 60% decrease in the number of cardiac events (heart attack, sudden cardiac death) and a 17% reduced risk of stroke after long-term treatment. A greater benefit is observed with high-intensity statin therapy. They have less effect than the fibrates or niacin in reducing triglycerides and raising HDL-cholesterol ("good cholesterol").

No studies have examined the effect of statins on cognition in patients with prior stroke. However, two large studies (HPS and PROSPER) that included people with vascular diseases reported that simvastatin and pravastatin did not impact cognition.

Statins have been studied for improving operative outcomes in cardiac and vascular surgery. Mortality and adverse cardiovascular events were reduced in statin groups.

Older adults who receive statin therapy at time of discharge from the hospital after an inpatient stay have been studied. People with cardiac ischemia not previously on statins at the time of admission have a lower risk of major cardiac adverse events and hospital readmission two years post-hospitalization.

Statin product offerings - comparative effectiveness
All statins appear effective regardless of potency or degree of cholesterol reduction. Simvastatin and pravastatin appear to have a reduced incidence of side-effects.

Women and children
According to the 2015 Cochrane systematic review, atorvastatin showed greater cholesterol-lowering effect in women than in men compared to rosuvastatin.

In children, statins are effective at reducing cholesterol levels in those with familial hypercholesterolemia. Their long term safety is, however, unclear. Some recommend that if lifestyle changes are not enough statins should be started at 8 years old.

Familial hypercholesterolemia
Statins may be less effective in reducing LDL cholesterol in people with familial hypercholesterolemia, especially those with homozygous deficiencies. These people have defects usually in either the LDL receptor or apolipoprotein B genes, both of which are responsible for LDL clearance from the blood. Statins remain a first-line treatment in familial hypercholesterolemia, although other cholesterol-reducing measures may be required. In people with homozygous deficiencies, statins may still prove helpful, albeit at high doses and in combination with other cholesterol-reducing medications.

Contrast-induced nephropathy
A 2014 meta-analysis found that statins could reduce the risk of contrast-induced nephropathy by 53% in people undergoing coronary angiography/percutaneous interventions. The effect was found to be stronger among those with preexisting kidney dysfunction or diabetes mellitus.

Chronic kidney disease
The risk of cardiovascular disease is similar in people with chronic kidney disease and coronary artery disease and statins are often suggested. There is some evidence that appropriate use of statin medications in people with chronic kidney disease who do not require dialysis may reduce mortality and the incidence of major cardiac events by up to 20% and are not that likely to increase the risk of stroke or kidney failure.

 Asthma

Statins have been identified as having a possible adjunct role in the treatment of asthma though anti-inflammatory pathways. There is low quality evidence for the use of statins in treating asthma, however further research is required to determine the effectiveness and safety of this therapy in those with asthma.

Adverse effects
The most important adverse side effects are muscle problems, an increased risk of diabetes mellitus, and increased liver enzymes in the blood due to liver damage. Over 5 years of treatment statins result in 75 cases of diabetes, 7.5 cases of bleeding stroke, and 5 cases of muscle damage per 10,000 people treated. This could be due to the statins inhibiting the enzyme (HMG-CoA reductase), which is necessary to make cholesterol, but also for other processes, such as CoQ10 production, which is important for muscle function and sugar regulation.

Other possible adverse effects include neuropathy, pancreatic and liver dysfunction, and sexual dysfunction. The rate at which such events occur has been widely debated, in part because the risk/benefit ratio of statins in low-risk populations is highly dependent on the rate of adverse events. A Cochrane meta-analysis of statin clinical trials in primary prevention found no evidence of excess adverse events among those treated with statins compared to placebo. Another meta-analysis found a 39% increase in adverse events in statin treated people relative to those receiving placebo, but no increase in serious adverse events. The author of one study argued that adverse events are more common in clinical practice than in randomized clinical trials. A systematic review concluded that while clinical trial meta-analyses underestimate the rate of muscle pain associated with statin use, the rates of rhabdomyolysis are still "reassuringly low" and similar to those seen in clinical trials (about 1–2 per 10,000 person years). Another systematic review from the International Centre for Circulatory Health of the National Heart and Lung Institute in London concluded that only a small fraction of side effects reported by people on statins are actually attributable to the statin.

Cognitive effects
Multiple systematic reviews and meta-analyses have concluded that the available evidence does not support an association between statin use and cognitive decline. A 2010 meta-review of medical trials involving over 65,000 people concluded that Statins decreased the risk of dementia, Alzheimer's disease, and even improved cognitive impairment in some cases. Additionally, both the Patient-Centered Research into Outcomes Stroke Patients Prefer and Effectiveness Research (PROSPER) study and the Health Protection Study (HPS) demonstrated that simvastatin and pravastatin did not affect cognition for patients with risk factors for, or a history of, vascular diseases.

There are reports of reversible cognitive impairment with statins. The U.S. Food and Drug Administration (FDA) package insert on statins includes a warning about the potential for non-serious and reversible cognitive side effects with the medication (memory loss, confusion).

Muscles
In observational studies 10–15% of people who take statins experience muscle problems; in most cases these consist of muscle pain. These rates, which are much higher than those seen in randomized clinical trials have been the topic of extensive debate and discussion.

Muscle and other symptoms often cause patients to stop taking a statin. This is known as statin intolerance. A 2021 double-blind multiple crossover randomized controlled trial (RCT) in statin-intolerant patients found that adverse effects, including muscle pain, were similar between atorvastatin and placebo. A smaller double-blind RCT obtained similar results. The results of these studies help explain why statin symptom rates in observational studies are so much higher than in double-blind RCTs and support the notion that the difference results from the nocebo effect; that the symptoms are caused by expectations of harm.

Media reporting on statins is often negative, and patient leaflets inform patients that rare but potentially serious muscle problems can occur during statin treatment. These create expectations of harm. Nocebo symptoms are real and bothersome and are a major barrier to treatment. Because of this, many people stop taking statins, which have been proven in numerous large-scale RCTs to reduce heart attacks, stroke, and deaths – as long as people continue to take them.

Serious muscle problems such as rhabdomyolysis (destruction of muscle cells) and statin-associated autoimmune myopathy occur in less than 0.1% of treated people. Rhabdomyolysis can in turn result in life-threatening kidney injury. The risk of statin-induced rhabdomyolysis increases with older age, use of interacting medications such as fibrates, and hypothyroidism. Coenzyme Q10 (ubiquinone) levels are decreased in statin use; CoQ10 supplements are sometimes used to treat statin-associated myopathy, though evidence of their efficacy is lacking. The gene SLCO1B1 (Solute carrier organic anion transporter family member 1B1) codes for an organic anion-transporting polypeptide that is involved in the regulation of the absorption of statins. A common variation in this gene was found in 2008 to significantly increase the risk of myopathy.

Records exist of over 250,000 people treated from 1998 to 2001 with the statin drugs atorvastatin, cerivastatin, fluvastatin, lovastatin, pravastatin, and simvastatin. The incidence of rhabdomyolysis was 0.44 per 10,000 patients treated with statins other than cerivastatin. However, the risk was over 10-fold greater if cerivastatin was used, or if the standard statins (atorvastatin, fluvastatin, lovastatin, pravastatin, or simvastatin) were combined with a fibrate (fenofibrate or gemfibrozil) treatment. Cerivastatin was withdrawn by its manufacturer in 2001.

Some researchers have suggested hydrophilic statins, such as fluvastatin, rosuvastatin, and pravastatin, are less toxic than lipophilic statins, such as atorvastatin, lovastatin, and simvastatin, but other studies have not found a connection. Lovastatin induces the expression of gene atrogin-1, which is believed to be responsible in promoting muscle fiber damage. Tendon rupture does not appear to occur.

Diabetes
The relationship between statin use and risk of developing diabetes remains unclear and the results of reviews are mixed. Higher doses have a greater effect, but the decrease in cardiovascular disease outweighs the risk of developing diabetes. Use in postmenopausal women is associated with an increased risk for diabetes. The exact mechanism responsible for the possible increased risk of diabetes mellitus associated with statin use is unclear. However, recent findings have indicated the inhibition of HMGCoAR as a key mechanism. Statins are thought to decrease cells' uptake of glucose from the bloodstream in response to the hormone insulin. One way this is thought to occur is by interfering with cholesterol synthesis which is necessary for the production of certain proteins responsible for glucose uptake into cells such as GLUT1.

Cancer
Several meta-analyses have found no increased risk of cancer, and some meta-analyses have found a reduced risk. Specifically, statins may reduce the risk of esophageal cancer, colorectal cancer, gastric cancer, hepatocellular carcinoma, and possibly prostate cancer. They appear to have no effect on the risk of lung cancer, kidney cancer, breast cancer, pancreatic cancer, or bladder cancer.

Drug interactions
Combining any statin with a fibrate or niacin (other categories of lipid-lowering drugs) increases the risks for rhabdomyolysis to almost 6.0 per 10,000 person-years. Monitoring liver enzymes and creatine kinase is especially prudent in those on high-dose statins or in those on statin/fibrate combinations, and mandatory in the case of muscle cramps or of deterioration in kidney function.

Consumption of grapefruit or grapefruit juice inhibits the metabolism of certain statins, and bitter oranges may have a similar effect. Furanocoumarins in grapefruit juice (i.e. bergamottin and dihydroxybergamottin) inhibit the cytochrome P450 enzyme CYP3A4, which is involved in the metabolism of most statins (however, it is a major inhibitor of only lovastatin, simvastatin, and to a lesser degree, atorvastatin) and some other medications (flavonoids (i.e. naringin) were thought to be responsible). This increases the levels of the statin, increasing the risk of dose-related adverse effects (including myopathy/rhabdomyolysis). The absolute prohibition of grapefruit juice consumption for users of some statins is controversial.

The U.S. Food and Drug Administration (FDA) notified healthcare professionals of updates to the prescribing information concerning interactions between protease inhibitors and certain statin drugs. Protease inhibitors and statins taken together may increase the blood levels of statins and increase the risk for muscle injury (myopathy). The most serious form of myopathy, rhabdomyolysis, can damage the kidneys and lead to kidney failure, which can be fatal.

Osteoporosis and fractures
Studies have found that the use of statins may protect against getting osteoporosis and fractures or may induce osteoporosis and fractures. A cross-sectional retrospective analysis of the entire Austrian population found that the risk of getting osteoporosis is dependent on the dose used.

Mechanism of action

Statins act by competitively inhibiting HMG-CoA reductase, the rate-limiting enzyme of the mevalonate pathway. Because statins are similar in structure to HMG-CoA on a molecular level, they will fit into the enzyme's active site and compete with the native substrate (HMG-CoA). This competition reduces the rate by which HMG-CoA reductase is able to produce mevalonate, the next molecule in the cascade that eventually produces cholesterol. A variety of natural statins are produced by Penicillium and Aspergillus fungi as secondary metabolites. These natural statins probably function to inhibit HMG-CoA reductase enzymes in bacteria and fungi that compete with the producer.

Inhibiting cholesterol synthesis
By inhibiting HMG-CoA reductase, statins block the pathway for synthesizing cholesterol in the liver. This is significant because most circulating cholesterol comes from internal manufacture rather than the diet. When the liver can no longer produce cholesterol, levels of cholesterol in the blood will fall. Cholesterol synthesis appears to occur mostly at night, so statins with short half-lives are usually taken at night to maximize their effect. Studies have shown greater LDL and total cholesterol reductions in the short-acting simvastatin taken at night rather than the morning, but have shown no difference in the long-acting atorvastatin.

Increasing LDL uptake
In rabbits, liver cells sense the reduced levels of liver cholesterol and seek to compensate by synthesizing LDL receptors to draw cholesterol out of the circulation. This is accomplished via proteases that cleave membrane-bound sterol regulatory element binding proteins, which then migrate to the nucleus and bind to the sterol response elements. The sterol response elements then facilitate increased transcription of various other proteins, most notably, LDL receptor. The LDL receptor is transported to the liver cell membrane and binds to passing LDL and VLDL particles, mediating their uptake into the liver, where the cholesterol is reprocessed into bile salts and other byproducts. This results in a net effect of less LDL circulating in blood.

Decreasing of specific protein prenylation
Statins, by inhibiting the HMG CoA reductase pathway, inhibit downstream synthesis of isoprenoids, such as farnesyl pyrophosphate and geranylgeranyl pyrophosphate. Inhibition of protein prenylation for proteins such as RhoA (and subsequent inhibition of Rho-associated protein kinase) may be involved, at least partially, in the improvement of endothelial function, modulation of immune function, and other pleiotropic cardiovascular benefits of statins,   as well as in the fact that a number of other drugs that lower LDL have not shown the same cardiovascular risk benefits in studies as statins, and may also account for some of the benefits seen in cancer reduction with statins. In addition, the inhibitory effect on protein prenylation may also be involved in a number of unwanted side effects associated with statins, including muscle pain (myopathy) and elevated blood sugar (diabetes).

Other effects
As noted above, statins exhibit action beyond lipid-lowering activity in the prevention of atherosclerosis through so-called "pleiotropic effects of statins". The pleiotropic effects of statins remain controversial. The ASTEROID trial showed direct ultrasound evidence of atheroma regression during statin therapy. Researchers hypothesize that statins prevent cardiovascular disease via four proposed mechanisms (all subjects of a large body of biomedical research):

 * 1) Improve endothelial function
 * 2) Modulate inflammatory responses
 * 3) Maintain plaque stability
 * 4) Prevent blood clot formation

In 2008, the JUPITER trial showed statins provided benefit in those who had no history of high cholesterol or heart disease, but only in those with elevated high-sensitivity C-reactive protein (hsCRP) levels, an indicator for inflammation. The study has been criticized due to perceived flaws in the study design,  although Paul M. Ridker, lead investigator of the JUPITER trial, has responded to these criticisms at length.

As the target of statins, the HMG-CoA reductase, is highly similar between eukaryota and archaea, statins also act as antibiotics against archaea by inhibiting archaeal mevalonate biosynthesis. This has been shown in vivo and in vitro. Since patients with a constipation phenotype present with higher abundance of methanogenic archaea in the gut, the use of statins for management of irritable bowel syndrome has been proposed and may actually be one of the hidden benefits of statin use.

Available forms
The statins are divided into two groups: fermentation-derived and synthetic. Some specific types are listed in the table below. Note that the associated brand names may vary between countries.

LDL-lowering potency varies between agents. Cerivastatin is the most potent (withdrawn from the market in August 2001 due to risk of serious rhabdomyolysis), followed by (in order of decreasing potency) rosuvastatin, atorvastatin, simvastatin, lovastatin, pravastatin, and fluvastatin. The relative potency of pitavastatin has not yet been fully established, but preliminary studies indicate a potency similar to rosuvastatin.

Some types of statins are naturally occurring, and can be found in such foods as oyster mushrooms and red yeast rice. Randomized controlled trials have found these foodstuffs to reduce circulating cholesterol, but the quality of the trials has been judged to be low. Due to patent expiration, most of the block-buster branded statins have been generic since 2012, including atorvastatin, the largest-selling branded drug.

History
The role of cholesterol in the development of cardiovascular disease was elucidated in the second half of the 20th century. This lipid hypothesis prompted attempts to reduce cardiovascular disease burden by lowering cholesterol. Treatment consisted mainly of dietary measures, such as a low-fat diet, and poorly tolerated medicines, such as clofibrate, cholestyramine, and nicotinic acid. Cholesterol researcher Daniel Steinberg writes that while the Coronary Primary Prevention Trial of 1984 demonstrated cholesterol lowering could significantly reduce the risk of heart attacks and angina, physicians, including cardiologists, remained largely unconvinced. Scientists in academic settings and the pharmaceutical industry began trying to develop a drug to reduce cholesterol more effectively. There were several potential targets, with 30 steps in the synthesis of cholesterol from acetyl-coenzyme A.

In 1971, Akira Endo, a Japanese biochemist working for the pharmaceutical company Sankyo, began to investigate this problem. Research had already shown cholesterol is mostly manufactured by the body in the liver with the enzyme HMG-CoA reductase. Endo and his team reasoned that certain microorganisms may produce inhibitors of the enzyme to defend themselves against other organisms, as mevalonate is a precursor of many substances required by organisms for the maintenance of their cell walls or cytoskeleton (isoprenoids). The first agent they identified was mevastatin (ML-236B), a molecule produced by the fungus Penicillium citrinum.

A British group isolated the same compound from Penicillium brevicompactum, named it compactin, and published their report in 1976. The British group mentions antifungal properties, with no mention of HMG-CoA reductase inhibition. Mevastatin was never marketed, because of its adverse effects of tumors, muscle deterioration, and sometimes death in laboratory dogs. P. Roy Vagelos, chief scientist and later CEO of Merck & Co, was interested, and made several trips to Japan starting in 1975. By 1978, Merck had isolated lovastatin (mevinolin, MK803) from the fungus Aspergillus terreus, first marketed in 1987 as Mevacor.

In the 1990s, as a result of public campaigns, people in the United States became familiar with their cholesterol numbers and the difference between HDL and LDL cholesterol, and various pharmaceutical companies began producing their own statins, such as pravastatin (Pravachol), manufactured by Sankyo and Bristol-Myers Squibb. In April 1994, the results of a Merck-sponsored study, the Scandinavian Simvastatin Survival Study, were announced. Researchers tested simvastatin, later sold by Merck as Zocor, on 4,444 patients with high cholesterol and heart disease. After five years, the study concluded the patients saw a 35% reduction in their cholesterol, and their chances of dying of a heart attack were reduced by 42%. In 1995, Zocor and Mevacor both made Merck over US$1 billion.

Though he did not profit from his original discovery, Endo was awarded the 2006 Japan Prize, and the Lasker-DeBakey Clinical Medical Research Award in 2008, for his pioneering research. Endo was also inducted into the National Inventors Hall of Fame in Alexandria, Virginia in 2012. Michael S. Brown and Joseph Goldstein, who won the Nobel Prize for related work on cholesterol, said of Endo: "The millions of people whose lives will be extended through statin therapy owe it all to Akira Endo."

misleading claims exaggerating the adverse effects of statins had received widespread media coverage, with a consequent negative impact to public health. Controversy over the effectiveness of statins in the medical literature was amplified in popular media in the early 2010s, leading an estimated 200,000 people in the UK to stop using statins over a six-month period to mid 2016, according to the authors of a study funded by the British Heart Foundation. They estimated that there could be up to 2,000 extra heart attacks or strokes over the following 10 years as a consequence. An unintended effect of the academic statin controversy has been the spread of scientifically questionable alternative therapies. Cardiologist Steven Nissen at Cleveland Clinic commented "We are losing the battle for the hearts and minds of our patients to Web sites..." promoting unproven medical therapies. Harriet Hall sees a spectrum of "statin denialism" ranging from pseudoscientific claims to the understatement of benefits and overstatement of side effects, all of which is contrary to the scientific evidence.

Several statins have been approved as generic drugs in the United States:
 * Lovastatin (Mevacor) in December 2001
 * Pravastatin (Pravachol) in April 2006
 * Simvastatin (Zocor) in June 2006
 * Atorvastatin (Lipitor) in November 2011
 * Fluvastatin (Lescol) in April 2012
 * Pitavastatin (Livalo) and rosuvastatin (Crestor) in 2016
 * Ezetimibe/simvastatin (Vytorin) and ezetimibe/atorvastatin (Liptruzet) in 2017

Research
Clinical studies have been conducted on the use of statins in dementia, lung cancer, nuclear cataracts, hypertension, and prostate cancer and breast cancer. There is no high quality evidence that statins are useful for pneumonia. The small number of available trials do not support the use of statins as an adjunctive therapy or as a monotherapy in multiple sclerosis.

title: Statin


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Antiplatelet drug

An antiplatelet drug (antiaggregant), also known as a platelet agglutination inhibitor or platelet aggregation inhibitor, is a member of a class of pharmaceuticals that decrease platelet aggregation and inhibit thrombus formation. They are effective in the arterial circulation where classical Vitamin K antagonist anticoagulants have minimal effect. Antiplatelet drugs are widely used in primary and secondary prevention of thrombotic disease, especially myocardial infarction and ischemic stroke.

Antiplatelet therapy with one or more of these drugs decreases the ability of blood clots to form by interfering with the platelet activation process in primary hemostasis. Antiplatelet drugs can reversibly or irreversibly inhibit the process involved in platelet activation resulting in decreased tendency of platelets to adhere to one another and to damaged blood vessels' endothelium.

Choice
Antiplatelet medications are one of the primary recommendations for treatment of both stable and unstable ischemic heart disease. Most commonly, aspirin is used as a single medication in cases of uncomplicated stable angina, and in some cases of unstable angina. If a patient does not tolerate aspirin, ADP/P2Y inhibitors may be used as single-drug therapy instead. More severe and complicated cases are treated with dual antiplatelet therapy, or in some cases triple therapy that includes direct oral anticoagulants. Clinicians must make a choice that balances patient risk with the increased risks of bleeding associated with combination therapy.

Dual antiplatelet therapy
Often a combination of aspirin plus an ADP/P2Y inhibitor (such as clopidogrel, prasugrel, ticagrelor, or another) is used to obtain greater effectiveness than with either agent alone. This is known as "dual antiplatelet therapy" (or DAPT). DAPT is used in patients who have, or are at high risk of developing, unstable angina, NSTEMI myocardial infarctions, and other high-risk thrombotic conditions. Dual antiplatelet therapy has been found to significantly reduce rates of heart attacks, strokes, and overall cardiovascular death, but is not used in low-risk patients because it significantly increases the risks of major bleeding.

Classification
Classes of antiplatelet drugs include:
 * Adenosine diphosphate (ADP) receptor inhibitors
 * Cangrelor (Kengreal)
 * Clopidogrel (Plavix)
 * Prasugrel (Effient)
 * Ticagrelor (Brilinta)
 * Ticlopidine (Ticlid)
 * Adenosine reuptake inhibitors
 * Dipyridamole (Persantine)
 * Glycoprotein IIB/IIIA inhibitors (intravenous use only)
 * Abciximab (ReoPro)
 * Eptifibatide (Integrilin)
 * Tirofiban (Aggrastat)
 * Irreversible cyclooxygenase inhibitors
 * Aspirin
 * Triflusal (Disgren)
 * Phosphodiesterase inhibitors
 * Cilostazol (Pletaal)
 * Protease-activated receptor-1 antagonists (which inhibit the protease-activated receptor 1 a.k.a. PAR-1)
 * Vorapaxar (Zontivity)
 * Thromboxane inhibitors
 * Thromboxane receptor antagonists
 * Terutroban
 * Thromboxane synthase inhibitors

Prevention and treatment of arterial thrombosis
Prevention and treatment of arterial thrombosis is essential in patients with certain medical conditions whereby the risk of thrombosis or thromboembolism may result in disastrous consequences such as heart attack, pulmonary embolism or stroke. Patients who require the use of antiplatelet drugs are: stroke with or without atrial fibrillation, any heart surgery (especially prosthetic replacement heart valve), Coronary Heart Disease such as stable angina, unstable angina and heart attack, patients with coronary stent, Peripheral Vascular Disease/Peripheral Arterial Disease and apical/ventricular/mural thrombus.

Treatment of established arterial thrombosis includes the use of antiplatelet drugs and thrombolytic therapy. Antiplatelet drugs alter the platelet activation at the site of vascular damage crucial to the development of arterial thrombosis.

 * Aspirin and Triflusal irreversibly inhibits the enzyme COX, resulting in reduced platelet production of TXA2 (thromboxane – powerful vasoconstrictor that lowers cyclic AMP and initiates the platelet release reaction).
 * Clopidogrel affects the ADP-dependent activation of IIb/IIIa complex
 * Dipyridamole inhibits platelet phosphodiesterase, causing an increase in cyclic AMP with potentiation of the action of PGI2 – opposes actions of TXA2
 * Epoprostenol is a prostacyclin that is used to inhibit platelet aggregation during renal dialysis (with or without heparin) and is also used in primary pulmonary hypertension.
 * Glycoprotein IIb/IIIa receptor antagonists block a receptor on the platelet for fibrinogen and von Willebrand factor. 3 classes:
 * Murine-human chimeric antibodies (e.g., abciximab)
 * Synthetic non-peptides (e.g., tirofiban)
 * Synthetic peptides (e.g., eptifibatide)

Management in the perioperative period
Antiplatelet therapy may increase the risk of a bleed during surgery, however, stopping therapy may increase the risk of other thrombotic problems including myocardial infarction. When considering these medications and the risk-benefit ratio in the perioperative period, one must consider the risk of stopping the medication and a clot forming versus the risk of bleeding during or after the surgery if medication is continued. A 2018 Cochrane Review that included five randomized controlled trials found low-certainty evidence to suggest that continuing or discontinuing antiplatelet therapy for a non-cardiac surgery does not make a difference in mortality, major bleeds that require surgery, or ischaemic events. The same review found moderate certainty evidence that continuing or discontinuing therapy also did not have a big difference on the incidence of bleeds requiring a blood transfusion.

 * Balloon angioplasty in the preoperative period——patients can proceed to surgery two weeks after the procedure.
 * Bare metal stents required at least one month of DAPT
 * CABG: Patients may proceed with surgery as soon as they are healed from the coronary artery bypass procedure and they do not need any specific amount of time on DAPT
 * In patients with truly time-sensitive disease (defined in the 2014 ACC/AHA guidelines as needing to proceed in 2–6 weeks), DAPT can be stopped 3 (three) months (90 days) after a coronary stent is placed if postponing surgery any longer would result in significant morbidity. Examples of these types of surgeries include some cancer surgery and possibly some orthopedic surgery (non-urgent/emergent fracture management). Preferably 6 to 12 months of DAPT should be continued in patients having elective surgery.

Dental management of patients on antiplatelet drugs
Dentists should be aware of the risk of prolonged bleeding time in patients taking antiplatelet drugs when planning dental treatments that are likely to cause bleeding. Therefore, it is important for dentists to know how to assess patient's bleeding risk and how to manage them.

Assess bleeding risk
Identify the likelihood and risk of dental treatment causing bleeding complications.

Drug toxicity
Antiplatelet drugs effect may be affected by patient's medications, current medical conditions, food and supplements taken. Antiplatelet drugs effect may be increased or decreased. An increase in antiplatelet effect would increase the risk of bleeding and could cause prolonged or excessive bleeding. A decrease in antiplatelet effect would reduce the risk of bleeding, but increase the thromboembolic risk. Drug toxicity may increase when multiple antiplatelet drugs are used. Gastrointestinal bleeding is a common adverse event seen in many patients.

Medications
Medications that may increase antiplatelet drug effect: Medications that may decrease antiplatelet drug effect: Use of NSAIDs as part of dental management of patients with vascular disease should be discouraged as NSAIDs have antiplatelet effect. Instead, simple analgesics such as paracetamol or co-codamol should be of first choice. If NSAIDs are required, the risk of bleeding increases with duration of dental treatment.
 * Cytotoxic drugs or drugs associated with bone marrow suppression (e.g.: leflunomide, hydroxychloroquine, adalimumab, infliximab, etanercept, sulfasalazine, penicillamine, gold, methotrexate, azathioprine, mycophenolate)
 * Drugs affecting the nervous system (e.g.: Selective serotonin reuptake inhibitors (SSRIs))
 * NSAIDS (e.g.: aspirin, ibuprofen, diclofenac, naproxen)
 * Other anticoagulants or antiplatelet drugs
 * Carbamazepine
 * Erythromycin
 * Fluconazole
 * Omeprazole

Medical conditions
Medical conditions that may increase antiplatelet drugs' effect include:

Chronic kidney failure, liver disease, haematological malignancy, recent or current chemotherapy, advanced heart failure, mild forms of inherited bleeding disorders (e.g. haemophilia, Von Willebrand's disease) and idiopathic thrombocytopenic purpura.

Food and supplements
Food and supplements that may increase antiplatelet drugs' effect:

St. John's wort, ginkgo biloba, garlic.

license: Creative Commons - Attribution Share-Alike - https://creativecommons.org/licenses/by-sa/4.0/

title: Antiplatelet drug


text:
August Tholuck

Friedrich August Gotttreu Tholuck (30 March 1799 – 10 June 1877), known as August Tholuck, was a German Protestant theologian, pastor, and historian, and church leader.

Biography
Tholuck was born at Breslau, and educated at the gymnasium and university there. He distinguished himself by his ability to learn languages. A love of Oriental languages and literature led him to exchange the University of Breslau for that of Berlin, in order to study to greater advantage, and there he was received into the house of the Orientalist Heinrich Friedrich von Diez (1750–1817). He was introduced to pietistic circles in Berlin, and came under the influence of Baron Hans Ernst von Kottwitz, who became his "spiritual father," and of the historian Neander. Before deciding on the career of theological professor, he had in view that of a missionary in the East. Meanwhile, he was feeling the influence to a certain degree of the romantic school, and of Schleiermacher and G. W. F. Hegel too, though he never sounded the depths of their systems.

At length, in his twenty-first year, he finally decided to adopt the academical calling. In 1821 he was Privatdozent and in 1823 became professor extraordinarius of theology in Berlin, though he was at the same time active in the work of home and foreign missions. He lectured on the Old and New Testaments, theology, apologetics and the history of the church in the 18th century. In 1821 appeared his first work, Sufismus, sive theosophia Persarum pantheistica; following the same line of study he published Blütensammlung aus der morgenlandischen Mystik (1825) and Speculative Trinitätslehre des späteren Orients (1826). His well-known essay on the nature and moral influence of heathenism (1822) was published by Neander, with high commendation, in his Denkwürdigkeiten; and his Commentary on the Epistle to the Romans (1824) secured him a foremost place amongst the most suggestive, if not the most accurate, Biblical interpreters of that time.

Another work, soon translated into all the principal European languages, Die wahre Weihe des Zweiflers (1823), the outcome of his own religious history, obtained for him the permanent position of the modern Pietistic apologist of Evangelical Christianity. In 1825, with the aid of the Prussian government, he visited the libraries of England and the Netherlands, and on his return was appointed (in 1826) professor ordinarius of theology at the University of Halle, the centre of German rationalism, where he afterwards became preacher and member of the supreme consistorial council of the Evangelical State Church in Prussia. Here he made it his aim to combine in a higher unity the learning and to some extent the rationalism of Johann Salomo Semler with the devout and active pietism of A H Francke; and, in spite of the opposition of the theological faculty of the university, he succeeded in changing the character of its theology.

This he achieved partly by his lectures, but above all by his personal influence on the students, and, after 1833, by his preaching. His theological position was orthodox, but laid more stress upon Christian experience than upon rigid dogmatic belief. On the two great questions of miracles and inspiration he made great concessions to modern criticism and philosophy. His lifelong battle was on behalf of personal religious experience, in opposition to the externality of rationalism, orthodoxy or sacramentarianism. Karl Schwarz happily remarks that, as the English apologists of the 18th century were themselves infected with the poison of the deists whom they endeavoured to refute, so Tholuck absorbed some of the heresies of the rationalists whom he tried to overthrow. He was also one of the prominent members of the Evangelical Alliance, and few men were more widely known or more beloved throughout the Protestant churches of Europe and America than him. He died at Halle. As a preacher, Tholuck ranked among the foremost of his time. As a teacher, he showed remarkable sympathy and won great success. As a thinker he can hardly be said to have been endowed with great creative power.

After his commentaries (on Romans, the Gospel of John, the Sermon on the Mount and the Epistle to the Hebrews) and several volumes of sermons, his best-known books are Stunden christlicher Andacht (1839; 8th ed., 1870), intended to take the place of J H D Zschokke's standard rationalistic work with the same title, and his reply to David Strauss's Life of Jesus (Glaubwürdigkeit der evangelischen Geschichte, 1837).

He published at various times valuable contributions towards a history of rationalism--Vorgeschichte des Rationalismus (1853–1862), Geschichte des Rationalismus (1865), and a number of essays connected with the history of theology and especially of apologetics. His views on inspiration were indicated in his work Die Propheten und ihre Weissagungen (1860), in his essay on the "Alte Inspirationslehre," in Deutsche Zeitschrift für christliche Wissenschaft (1850), and in his Gespräche über die vornehmsten Glaubensfragen der Zeit (1846; 2nd ed., 1867).

He also contributed many articles to Herzog's Realencyklopädie, and for several years edited a journal (1830–1849), Literarischer Anzeiger.

In 1864, he was elected as a member to the American Philosophical Society.

Tholuck had an international influence. Philip Schaff says, "Next to Neander, no German divine of the present century is more extensively known in the Protestant churches of ... America than Dr. Frederick Augustus Tholuck." In the nineteenth century, many of his books were translated into English. His popular works, such as his sermons, were also translated. American scholars were especially interested in his biblical commentaries. Several Americans, like Charles Hodge and Edward Robinson, studied with Tholuck in Halle.

title: August Tholuck


text:
Progress (spacecraft)

The Progress (Прогресс) is a Russian expendable cargo spacecraft. Its purpose is to deliver the supplies needed to sustain a human presence in orbit. While it does not carry a crew, it can be boarded by astronauts when docked to a space station, hence it is classified as crewed by its manufacturer. Progress is derived from the crewed Soyuz spacecraft and launches on the same launch vehicle, a Soyuz rocket.

Progress has supported space stations as early as Salyut 6 and as recently as the International Space Station (ISS). Each year there are between three and four Progress flights to the ISS. A Progress remains docked until shortly before being replaced with a new one or a Soyuz (which will use the same docking port). Then it is filled with waste, disconnected, and de-orbited, at which point it burns up in the atmosphere. Due to the variation in Progress vehicles flown to the ISS, NASA uses its own nomenclature where "ISS 1P" means the first Progress spacecraft to ISS.

Progress was developed because of the need for a constant source of supplies to make long duration space missions possible. It was determined that cosmonauts needed an inflow of consumables (food, water, air, etc.), plus there was a need for maintenance items and scientific payloads that necessitated a dedicated cargo carrier. Such payloads were impractical to launch with passengers in the restricted space of a Soyuz. As of 15 February 2021, there have been 168 Progress flights with three failures. All three failures have occurred between 2011 and 2016.

Design
Progress is of much the same size and shape as Soyuz. It consists of three modules:

 * A pressurized forward module. This carries the supplies for the crew such as scientific equipment, clothes, prepackaged and fresh food, and letters from home. The docking drogue is similar to that of the Soyuz but features ducting for the Unsymmetrical dimethylhydrazine (UDMH) fuel and N2O4 oxidiser.
 * A fuel compartment. The reentry module of the Soyuz was replaced with an unpressurized propellant and refueling compartment with ducting along the outside of the spacecraft. This meant that if a leak occurred, the poisonous gas would not enter the station's atmosphere. The fuel is carried in two tanks.
 * A propulsion module. The propulsion module, at the rear of the spacecraft, remained unchanged from the Soyuz and contains the orientation engines used for the automatic docking. It may be used to boost the orbit of the station once docked.

Reduction in mass was possible because the Progress was designed to be uncrewed and disposable. This means that there is no need for bulky life support systems and heat shields. A small amount of weight is saved due to the lack of automatic crew rescue systems and the lack of parachutes. The spacecraft also has no ability to split into separate modules. After undocking, the spacecraft performs a retrofire and burns up in the atmosphere.

Versions
There were many small variations between the different flights, but the major upgrades are reflected in the change of name.

Progress (1978–1990)

There were 42 spacecraft built using the initial Progress design, the last one being launched in May 1990.

The bureau in charge of designing the freighter was TsKBEM (now RKK Energia). They began work on the design in mid-1973, assigning Progress the GRAU index 11F615A15. The design was complete by February 1974, and the first production model was ready for launch in November 1977. Progress 1 launched on 20 January 1978 aboard the same rocket used to launch the Soyuz. It still featured the same launch shroud as the Soyuz, though this was purely for aerodynamic purposes as the launch escape system had been deactivated.

This first version of Progress had a mass of 7020 kg and carried 2300 kg of cargo, or 30% of its launch mass. It had the same diameter as the Soyuz at 2.2 m, but was 8 m in length – slightly longer. The autonomous flight time was 3 days, the same time as that of the Soyuz ferry. It could spend 30 days docked. Progress always docked to the aft port of the station it was resupplying (the aft being where the main rocket engines of the station and their tankage, for refueling by the Progress, are located).

 * Launch mass: 7020 - 7249 kg
 * Mass of cargo:
 * ~2300 kg (before Progress-24)
 * ~2500 kg (from Progress-24)
 * Length: 7.94 m
 * Diameter of cargo modules: 2.2 m
 * Maximum diameter: 2.72 m
 * Volume of cargo compartment: 6.6 m3

Progress-M 11F615A55 (1989–2021)

The upgraded Progress M (GRAU: 11F615A55, manufacturer's designation: 7K-TGM) was first launched in August 1989. The first 43 flights all went to Mir; following Mir's re-entry, Progress was used as the resupply vehicle for the International Space Station. As of December 2020, there have been over 80 flights (over different configurations) to the ISS and more are scheduled.

The Progress M is essentially the same spacecraft as the Progress, but it features improvements based on the Soyuz-T and Soyuz-TM designs. It can spend up to 30 days in autonomous flight and is able to carry 100 kg more. Also, unlike the old Progress crafts, it can return items to Earth. This is accomplished by using the VBK-Raduga capsule, which can carry up to 150 kg of cargo. It is 1.5 m long and 60 cm in diameter and has a "dry mass" of 350 kg. Progress M can also dock to the forward port of the station and still transfer fuel. It uses the same rendezvous system as the Soyuz, and it features solar panels for the first time. The last launch was of Progress M-UM on 24 November 2021.

 * Launch mass: 7130 kg
 * Cargo mass: 2600 kg
 * Dry cargo mass: 1500 kg
 * Liquid cargo mass: 1540 kg
 * Length: 7.23 m
 * Diameter of cargo modules: 2.2 m
 * Maximum diameter: 2.72 m
 * Dry cargo compartment volume: 7.6 m3
 * Solar array span: 10.6 m

Progress-М 11F615A60 (2008–2015)
A new modification of the Progress spacecraft, with new TsVM-101 digital flight computer and MBITS digital telemetry system, was first launched on 26 November 2008, at 12:38 UTC from the Kazakhstan's Baikonur Cosmodrome spaceport aboard a Russian Soyuz rocket. The first spacecraft of this series was Progress M-01M.

The spacecraft belongs to the so-called 400 series (GRAU: 11F615A60), and all modifications applied to it were subsequently used in the production of new Soyuz TMA-01M crewed spacecraft.

Progress M-27M was launched on 28 April 2015, but communication with the vessel was lost soon after, and it was destroyed as it re-entered the atmosphere on 8 May 2015. The last launch was Progress M-29M.

Progress M1 (2000–2004)
Progress M1 is another variant, capable of carrying more propellant (but less total cargo) to the space station. There have been 11 of these flights.

 * Mass: 7150 kg
 * Capacity cargo: 2230 kg
 * Capacity dry cargo: 1800 kg
 * Capacity propellant: 1950 kg

Progress M2
Progress M2 was a planned variant, which was a proposed design for the proposed Mir-2 space station, but was dropped due to financial issues. The M2 variant would have a larger service module for larger cargo or space station modules and would have been launched on a Zenit rocket as the spacecraft is bigger.

Progress MS (2015–present)
Progress MS is an improved variant which first launched on 21 December 2015. It has the following improvements:

 * New external compartment that enables it to deploy satellites. Each compartment can hold up to four launch containers. First time installed on Progress MS-03.
 * Enhanced redundancy thanks to the addition of a backup system of electrical motors for the docking and sealing mechanism.
 * Improved Micrometeoroid (MMOD) protection with additional panels in the cargo compartment.
 * Luch Russian relay satellites link capabilities enable telemetry and control even when not in direct view of ground radio stations.
 * GNSS autonomous navigation enables real time determination of the status vector and orbital parameters dispensing with the need of ground station orbit determination.
 * Real time relative navigation thanks to direct radio data exchange capabilities with the space station.
 * New digital radio that enables enhanced TV camera view for the docking operations.
 * The Ukrainian Chezara Kvant-V on board radio system and antenna/feeder system has been replaced with a Unified Command Telemetry System (UCTS).
 * Replacement of the Kurs A with Kurs NA digital system.

Current status
Progress spacecraft are used to resupply the International Space Station (ISS) as of 2021. Between 1 February 2003 and 26 July 2005, they were the only spacecraft available to transport large quantities of supplies to the station, as the Space Shuttle fleet was grounded after the breakup of Columbia at the end of STS-107. For ISS missions, the Progress M1 variant is used, which moves the water tanks from the propellant and refueling module to the pressurized section, and as a result is able to carry more propellant. Progress M-UM, the final flight of a Progress-M spacecraft, was launched 24 November 2021 on a Soyuz 2.1b. As of 7/1/2021, there have been 170 Progress flights to the ISS.

On 9 July 2018, Progress MS-09 broke a previous record by reaching the ISS in 3 hours and 48 minutes, carrying about 2450 kg of cargo and supplies. It delivered food, fuel and supplies, including 705 kg of propellant, 50 kg of oxygen and air, 420 kg of water.

The European Space Agency (ESA) operated its own type of robotic supply freighter, the Automated Transfer Vehicle (ATV). The first of these, named Jules Verne, was launched at 04:03 UTC on 9 March 2008. ATVs can carry up to 8.85 tonnes of cargo into space, roughly three times as much as the Progress, and were launched annually by Ariane 5 rockets from 2011-2014 as part of ESA contribution to ISS upkeep. The design is adopted as the Service Module of the Orion spacecraft.

NASA's planned Orion spacecraft was initially designed to have an uncrewed variant of the Crew module similar to Progress; however, this capability was removed in 2009. As of 2023, SpaceX's Dragon spacecraft and Northrop Grumman's Cygnus spacecraft handle American logistics to the International Space Station.

title: Progress (spacecraft)


text:
Progress (disambiguation)

Progress is advancement to a higher or more developed state.

Progress or PROGRESS may also refer to:

Architecture

 * Progress Energy Center for the Performing Arts, in Raleigh, North Carolina
 * Progress Energy Park, a baseball stadium in St. Petersburg, Florida
 * Progress Theatre, a theatre in Berkshire, England

Books

 * Progress, a 2015 book by Fran Lebowitz
 * Progress: Ten Reasons to Look Forward to the Future, 2016 book by Johan Norberg

Albums

 * Progress (Big Youth album), 1979
 * Progress (EP), an EP by Pedro the Lion
 * Progress (Michael Giles album)
 * Progress (Rx Bandits album), 2001
 * Progress (Show-Ya album)
 * Progress (Take That album)
 * Progress (Ultraspank album)

Songs

 * "Progress" (song), a 2011 song by Ayumi Hamasaki
 * "Progress", a 1967 song by The Pretty Things recorded for Emotions
 * "Progress", a 1980 song by Orchestral Manoeuvres in the Dark from Organisation
 * "Progress", a 1984 song by Angelic Upstarts from Last Tango in Moscow
 * "Progress", a 1984 song by Nik Kershaw included on The Best of Nik Kershaw
 * "Progress", a 1987 song by Neurosis from Pain of Mind
 * "Progress", a 1990 song by Midnight Oil from Essential Oils
 * "Progress", a song by Kokua from "Progress" single (2006) and Progress album (2016)

Other arts, entertainment and media

 * "Progress" (Star Trek: Deep Space Nine), a TV series episode
 * "Progress" (Agents of S.H.I.E.L.D.: Slingshot)
 * Progress Wrestling, an English professional wrestling promotion
 * Progress, a 1984 play by Doug Lucie

Business

 * PROGRESS, a German film distributor
 * Progress Energy Inc, an American power generation and distribution company
 * Progress Energy Resources, a Canadian subsidiary of Malaysian oil and gas company Petronas
 * Progress Publishers, a Moscow-based Soviet publisher
 * Progress Software Corporation, the creator of Progress 4GL
 * Progress State Research and Production Rocket Space Center, a Samara-based Russian space company
 * Ivchenko-Progress, a Ukrainian aero-engine manufacturer

Computer science

 * Progress 4GL, now known as OpenEdge Advanced Business Language, a programming language developed by Progress Software
 * Progress indicator, a component in a user interface to convey the progress of a task

United States

 * Progress, Indiana
 * Progress, Mississippi
 * Progress, Oregon
 * Progress, Pennsylvania
 * Progress, Texas
 * Progress Village, Florida

Elsewhere

 * Progress Station, Antarctica
 * Rural Municipality of Progress No. 351, Saskatchewan, Canada
 * Progress, Chüy, Kyrgyzstan
 * Progress, Russia, several inhabited localities in Russia

Politics and government

 * Progressive Britain, formerly known as Progress (organisation), a political think-tank associated with the right-wing of the British Labour Party
 * Progress Party (disambiguation)
 * Royal progress, a formal tour of the state by its monarch

Transportation

 * Progress (spacecraft), a Russian expendable unmanned freighter spacecraft
 * Progress (train), which ran between Prague, Czechoslovakia, and the German Democratic Republic
 * Progress D-27, a 1980s propfan engine developed in the USSR
 * Progress, formerly known as Sea Serpent clippership (1850–1891, lost at sea)

Other uses

 * Progress (evolution), the idea that there is a largest-scale trend in evolution of organisms and that the trend is toward improvement or adaptation to changing environmental conditions
 * PROGRESS (study), a trial study of perindopril and indapamide

title: Progress (disambiguation)


text:
Angus Wilson

Sir Angus Frank Johnstone-Wilson, CBE (11 August 1913 – 31 May 1991) was an English novelist and short story writer. He was one of England's first openly gay authors. He was awarded the 1958 James Tait Black Memorial Prize for The Middle Age of Mrs Eliot and later received a knighthood for his services to literature.

Biography
Wilson was born in Bexhill, Sussex, England, to an English father, William Johnstone-Wilson, and South African mother, Maude (née Caney), of a wealthy merchant family of Durban. Wilson's grandfather had served in a prestigious Scottish army regiment, and owned an estate in Dumfriesshire, where William Johnstone-Wilson (despite being born at Haymarket) was raised, and where he subsequently lived.

Wilson was educated at Westminster School and Merton College, Oxford, and in 1937 became a librarian in the British Museum's Department of Printed Books, working on the new General Catalogue. Previous employment included tutoring, catering, and co-managing a restaurant with his brother.

During World War II, he worked in the Naval section at the code-breaking establishment, Bletchley Park, translating Italian Naval codes. A wearer of large, brightly coloured bow-ties and shirts, Sinclair McKay described him as one of the "famous homosexuals" at Bletchley. He was billeted with a "kind family" in the village of Simpson, who worried about his "prodigious consumption" of cigarettes by coughing theatrically. They only read (and re-read) John Bunyan's The Holy War. The "claustrophobia" of the billet may have contributed to his increasing depression and his "Pompeiian mood swings". The work situation was stressful and led to a nervous breakdown, for which he was treated by Rolf-Werner Kosterlitz. A colleague said when he threw an inkpot at a Wren that "Angus isn't really mad. He threw inkpots at all the right people!"

A Wren, Dorothy Robertson, was taught traffic analysis by Wilson and another instructor. She recalled him as:

"a brilliant young homosexual .... He used to mince into the room wearing, in those days, outrageous clothes in all colours; he chain-smoked; his nails were bitten down to the quick and he had a rather hysterical laugh."

Wilson returned to the Museum after the end of the war, and it was there that he met Tony Garrett (born 1929), who was to be his companion for the rest of his life. Years later their life together was sympathetically portrayed in the BBC2 film "Angus and Tony" (1984), directed by Jonathan Gili. It was one of the first depictions of the life of a gay couple on British television.

Wilson's first publication was a collection of short stories, The Wrong Set (1949), followed quickly by the daring novel Hemlock and After, which was a great success, prompting invitations to lecture in Europe.

Wilson worked as a reviewer, and in 1955 he resigned from the British Museum to write full-time (although his financial situation did not justify doing so) and moved to Suffolk.

He was instrumental in getting Colin Wilson's first novel published in 1956 and from 1957 he gave lectures further afield, in Japan, Switzerland, Australia, and the USA. He was appointed a Commander of the Order of the British Empire (CBE) in the 1968 New Year Honours, and received many literary honours in succeeding years. He was made a Knight Bachelor in the 1980 Birthday Honours, and was President of the Royal Society of Literature from 1982 to 1988. His remaining years were affected by ill health, and he died of a stroke at a nursing home in Bury St Edmunds, Suffolk, on 31 May 1991, aged 77.

Wilson's writing, which has a strongly satirical vein, expresses his concern with preserving a liberal humanistic outlook in the face of fashionable doctrinaire temptations. Several of his works were adapted for television. He was Professor of English Literature at the University of East Anglia from 1966 to 1978, and jointly helped to establish their creative writing course at masters level in 1970, which was then a groundbreaking initiative in the United Kingdom.

Wilson's medals, then in private ownership, were shown on the BBC Television programme Antiques Roadshow in August 2018.

Novels

 * Hemlock and After (1952)
 * Anglo-Saxon Attitudes (1956)
 * The Middle Age of Mrs Eliot (1958)
 * The Old Men at the Zoo (1961)
 * Late Call (1964)
 * No Laughing Matter (1967)
 * As if by Magic (1973)
 * Setting the World on Fire (1980)

Short story collections

 * The Wrong Set (1949)
 * Such Darling Dodos (1950)
 * A Bit Off the Map (1957)
 * Death Dance (selected stories, 1969)

Play

 * The Mulberry Bush (1955)

Others

 * Emile Zola: An Introductory Study of his Novels (1952)
 * For Whom the Cloche Tolls: a Scrapbook of the Twenties (1953)
 * The Wild Garden or Speaking of Writing (1963)
 * The World of Charles Dickens (1970)
 * The Mystery of Edwin Drood: Penguin Classics (1974) Introduction
 * The Naughty Nineties (1976)
 * The Strange Ride of Rudyard Kipling: His Life and Works (1977)
 * Diversity and Depth in Fiction: Selected Critical Writings of Angus Wilson (1983)
 * Reflections In A Writer's Eye: travel pieces by Angus Wilson (1986)

title: Angus Wilson


text:
Julius Wegscheider

Julius August Ludwig Wegscheider (27 September 1771 – 27 January 1849), was a German Protestant theologian.

Life
Wegscheider was born at Küblingen (now a part of Schöppenstedt, Lower Saxony). He studied theology at the University of Helmstedt, where he was a pupil of Heinrich Philipp Konrad Henke. From 1795 to 1805, he worked as a tutor to the family of a wealthy Hamburg merchant. In 1805 he presented a dissertation titled Graecorum mysteriis religioni non obtrudendis at the University of Göttingen. He then served as a professor of theology at the University of Rinteln (1806–1810), and at the University of Halle from 1810 onwards.

Wegscheider was a leading figure of dogmatic theological rationalism—for instance, he considered supernatural revelation to be an impossibility. Because of his rationalist teachings, he, along with his colleague Wilhelm Gesenius, were attacked by followers of Supernaturalism, creating a situation that led to a government investigation (1830). Ultimately, he retained his office at Halle, but lost his former influence.

Principal works

 * Über die von der neuesten Philosophie geforderte Trennung der Moral von der Religion, 1804 – On the latest philosophy requiring separation of morality from religion.
 * Versuch einer vollständigen Einleitung in das Evangelium Johannis, 1806 – Attempt of a complete introduction to the Gospel of John.
 * Institutiones theologicae dogmaticae, 1815; to which Wilhelm Steiger's Kritik des Rationalismus in Wegscheiders Dogmatik (1830) was a reply.

Books about Wegscheider

 * "Leben und Werk des Hallenser Theologen Julius Wegscheider (1771–1849) : mit unveröffentlichten Briefen an Eduard Reuss"; by Jean Marcel Vincent, Waltrop : Spenner, 1997.  Series:	Wissen und Kritik, Bd. 13.

title: Julius Wegscheider


text:
Lipid-lowering agent

Lipid-lowering agents, also sometimes referred to as hypolipidemic agents, cholesterol-lowering drugs, or antihyperlipidemic agents are a diverse group of pharmaceuticals that are used to lower the level of lipids and lipoproteins, such as cholesterol, in the blood (hyperlipidemia). The American Heart Association recommends the descriptor 'lipid lowering agent' be used for this class of drugs rather than the term 'hypolipidemic'.

Classes
The several classes of lipid lowering drugs may differ in both their impact on the cholesterol profile and adverse effects. For example, some may lower low density lipoprotein (LDL) levels more so than others, while others may preferentially increase high density lipoprotein (HDL). Clinically, the choice of an agent depends on the patient's cholesterol profile, cardiovascular risk, and the liver and kidney functions of the patient, evaluated against the balancing of risks and benefits of the medications. In the United States, this is guided by the evidence-based guideline most recently updated in 2018 by the American College of Cardiology & American Heart Association.

Established

 * Statins (HMG-CoA reductase inhibitors) are particularly well suited for lowering LDL, the cholesterol with the strongest links to vascular diseases. In studies using standard doses, statins have been found to lower LDL-C by 18% to 55%, depending on the specific statin being used. A risk exists of muscle damage (myopathy and rhabdomyolysis) with statins. Hypercholesterolemia is not a risk factor for mortality in persons older than 70 years and risks from statin drugs are more increased after age 85.
 * Fibrates are indicated for hypertriglyceridemia. Fibrates typically lower triglycerides by 20% to 50%. Level of the good cholesterol HDL is also increased. Fibrates may decrease LDL, though generally to a lesser degree than statins. Similar to statins, the risk of muscle damage exists.
 * Niacin, like fibrates, is also well suited for lowering triglycerides by 20–50%. It may also lower LDL by 5–25% and increase HDL by 15–35%. Niacin may cause hyperglycemia and may also cause liver damage. The niacin derivative acipimox is also associated with a modest decrease in LDL.
 * Bile acid sequestrants (resins, e.g. cholestyramine) are particularly effective for lowering LDL-C by sequestering the cholesterol-containing bile acids released into the intestine and preventing their reabsorption from the intestine. It decreases LDL by 15–30% and raises HDL by 3–5%, with little effect on triglycerides, but can cause a slight increase. Bile acid sequestrants may cause gastrointestinal problems and may also reduce the absorption of other drugs and vitamins from the gut.
 * Ezetimibe is a selective inhibitor of dietary cholesterol absorption.
 * Lomitapide is a microsomal triglyceride transfer protein inhibitor.
 * PCSK9 inhibitors are monoclonal antibodies for refractory cases. (e.g. Evolocumab, Inclisiran) They are used in combination with statins.
 * Probucol (withdrawn in several countries)

Alternative

 * Lecithin has been shown to effectively decrease cholesterol concentration by 33%, lower LDL by 38% and increase HDL by 46%.
 * Phytosterols may be found naturally in plants. Similar to ezetimibe, phytosterols reduce the absorption of cholesterol in the gut, so they are most effective when consumed with meals. However, their precise mechanism of action differs from ezetimibe.
 * Omega-3 supplements taken at high doses can reduce levels of triglycerides. They are associated with a very modest increase in LDL (~5%).
 * Choline
 * Pycnogenol
 * Berberine
 * Red yeast rice is the natural source from which statins were discovered, but the FDA currently disallows any RYR with significant amounts of statin to be sold as a dietary supplement
 * Boswellia serrata
 * L-arginine may enhance the effects of a Statin, but will not lead to a reduction in cholesterol alone.
 * Flaxseed oil

Research
Investigational classes of hypolipidemic agents:
 * CETP inhibitors (cholesteryl ester transfer protein), 1 candidate is in trials. (Anacetrapib) It is expected that these drugs will mainly increase HDL while lowering LDL
 * Squalene synthase inhibitor
 * ApoA-1 Milano
 * Succinobucol (AGI-1067), a novel antioxidant, failed a phase-III trial.
 * Apoprotein-B inhibitor mipomersen (approved by the FDA in 2013 homozygous familial hypercholesterolemia. ).
 * Bempedoic acid, an ATP citrate lyase inhibitor

title: Lipid-lowering agent


text:
Anticoagulant

An anticoagulant, commonly known as a blood thinner, is a chemical substance that prevents or reduces the coagulation of blood, prolonging the clotting time. Some occur naturally in blood-eating animals, such as leeches and mosquitoes, which help keep the bite area unclotted long enough for the animal to obtain blood.

As a class of medications, anticoagulants are used in therapy for thrombotic disorders. Oral anticoagulants (OACs) are taken by many people in pill or tablet form, and various intravenous anticoagulant dosage forms are used in hospitals. Some anticoagulants are used in medical equipment, such as sample tubes, blood transfusion bags, heart–lung machines, and dialysis equipment. One of the first anticoagulants, warfarin, was initially approved as a rodenticide.

Anticoagulants are closely related to antiplatelet drugs and thrombolytic drugs by manipulating the various pathways of blood coagulation. Specifically, antiplatelet drugs inhibit platelet aggregation (clumping together), whereas anticoagulants inhibit specific pathways of the coagulation cascade, which happens after the initial platelet aggregation but before the formation of fibrin and stable aggregated platelet products.

Common anticoagulants include warfarin and heparin.

Medical uses
The use of anticoagulants is a decision based on the risks and benefits of anticoagulation. The biggest risk of anticoagulation therapy is the increased risk of bleeding. In otherwise healthy people, the increased risk of bleeding is minimal, but those who have had recent surgery, cerebral aneurysms, and other conditions may have too great a risk of bleeding. Generally, the benefit of anticoagulation is preventing or reducing the progression of a thromboembolic disease. Some indications for anticoagulant therapy that are known to have benefit from therapy include:
 * Atrial fibrillation — commonly forms an atrial appendage clot
 * Coronary artery disease
 * Deep vein thrombosis — can lead to pulmonary embolism
 * Ischemic stroke
 * Hypercoagulable states (e.g., Factor V Leiden) — can lead to deep vein thrombosis
 * Mechanical heart valves
 * Myocardial infarction
 * Pulmonary embolism
 * Restenosis from stents
 * Cardiopulmonary bypass (or any other surgeries requiring temporary aortic occlusion)
 * Heart failure

In these cases, anticoagulation therapy prevents the formation or growth of dangerous clots.

The decision to begin therapeutic anticoagulation often involves the use of multiple bleeding risk predictable outcome tools as non-invasive pre-test stratifications due to the potential for bleeding while on blood thinning agents. Among these tools are HAS-BLED, ATRIA, HEMORR2HAGES, and CHA2DS2-VASc. The risk of bleeding using the risk assessment tools above must then be weighed against thrombotic risk to formally determine the patient's overall benefit in starting anticoagulation therapy.

There is no evidence to indicate that adding anticoagulant therapy to standard treatment has a benefit for people with cerebral small vessel disease but not dementia, and there is an increased risk of a person with this disease experiencing a bleed with this approach.

Adverse effects
The most serious and common adverse side effects associated with anticoagulants are increased risk of bleeding, both nonmajor and major bleeding events. The bleeding risk depends on the class of anticoagulant agent used, the patient's age, and pre-existing health conditions. Warfarin has an estimated incidence of bleeding of 15-20% per year and a life-threatening bleeding rate of 1-3% per year. Newer non-vitamin K antagonist oral anticoagulants appear to have fewer life-threatening bleeding events than warfarin. Additionally, patients aged 80 years or more may be especially susceptible to bleeding complications, with a rate of 13 bleeds per 100 person-years. Bleeding risk is especially important to consider in patients with renal impairment and NOAC therapy because all NOACs, to some extent, are excreted by the kidneys. Thus, patients with renal impairment may be at higher risk of increased bleeding.

In people with cancer, a systematic review has found warfarin had no effect on death rate or the risk of blood clots. However, it did increase the risk of major bleeding in 107 more people per 1000 population and minor bleeding in 167 more people per 1000 population. Apixaban had no effect on mortality, recurrence of blood clots in blood vessels, or major or minor bleeding. However, this finding comes only from one study.

Nonhemorrhagic adverse events are less common than hemorrhagic adverse events but should still be monitored closely. Nonhemorrhagic adverse events of warfarin include skin necrosis, limb gangrene, and purple toe syndrome. Skin necrosis and limb gangrene are most commonly observed on the third to eighth day of therapy. The exact pathogenesis of skin necrosis and limb gangrene is not completely understood but it is believed to be associated with warfarin's effect on inhibiting the production of protein C and protein S. Purple toe syndrome typically develops three to eight weeks after initiation of warfarin therapy. Other adverse effects of warfarin are associated with depletion of vitamin K, which can lead to inhibition of G1a proteins and growth arrest-specific gene 6, which can lead to increased risk of arterial calcification and heart valve, especially if too much Vitamin D is present. Warfarin's interference with G1a proteins has also been linked to abnormalities in fetal bone development in mothers who were treated with warfarin during pregnancy. Long-term warfarin and heparin usage have also been linked to osteoporosis.

Another potentially severe complication associated with heparin use is called heparin-induced thrombocytopenia (HIT). There are two distinct types: HIT 1) immune-mediated and 2) non-immune-mediated. Immune-mediated HIT most commonly arises five to ten days after exposure to heparin. Pathogenesis of immune-mediated HIT is believed to be caused by heparin-dependent immunoglobulin antibodies binding to platelet factor 4/heparin complexes on platelets, leading to widespread platelet activation.

Interactions
Foods and food supplements with blood-thinning effects include nattokinase, lumbrokinase, beer, bilberry, celery, cranberries, fish oil, garlic, ginger, ginkgo, ginseng, green tea, horse chestnut, licorice, niacin, onion, papaya, pomegranate, red clover, soybean, St. John's wort, turmeric, wheatgrass, and willow bark. Many herbal supplements have blood-thinning properties, such as danshen and feverfew. Multivitamins that do not interact with clotting are available for patients on anticoagulants.

However, some foods and supplements encourage clotting. These include alfalfa, avocado, cat's claw, coenzyme Q10, and dark leafy greens such as spinach. Excessive intake of the food mentioned above should be avoided while taking anticoagulants, or if coagulability is being monitored, their intake should be kept approximately constant so that anticoagulant dosage can be maintained at a level high enough to counteract this effect without fluctuations in coagulability.

Grapefruit interferes with some anticoagulant drugs, increasing the time it takes for them to be metabolized out of the body, and should be eaten with caution when on anticoagulant drugs.

Anticoagulants are often used to treat acute deep-vein thrombosis. People using anticoagulants to treat this condition should avoid using bed rest as a complementary treatment because there are clinical benefits to continuing to walk and remaining mobile while using anticoagulants in this way. Bed rest while using anticoagulants can harm patients in circumstances in which it is not medically necessary.

Types
Several anticoagulants are available. Warfarin, other coumarins, and heparins have long been used. Since the 2000s, several agents have been introduced that are collectively referred to as direct oral anticoagulants (DOACs), previously named novel oral anticoagulants (NOACs) or non-vitamin K antagonist oral anticoagulants. These agents include direct thrombin inhibitor (dabigatran) and factor Xa inhibitor (rivaroxaban, apixaban, betrixaban and edoxaban), and they have been shown to be as good or possibly better than the coumarins with less serious side effects. The newer anticoagulants (NOACs/DOACs) are more expensive than the traditional ones and should be used in caring for patients with kidney problems.

Coumarins (vitamin K antagonists)
These oral anticoagulants are derived from coumarin found in many plants. A prominent member of this class, warfarin (Coumadin), was found to be the anticoagulant most prescribed in a large multispecialty practice. The anticoagulant effect takes at least 48 to 72 hours to develop. Where an immediate effect is required, heparin is given concomitantly. These anticoagulants are used to treat patients with deep-vein thrombosis (DVT) and pulmonary embolism (PE) and to prevent emboli in patients with atrial fibrillation (AF), and mechanical prosthetic heart valves. Other examples are acenocoumarol, phenprocoumon, atromentin, and phenindione.

The coumarins brodifacoum and difenacoum are used as mammalicides (particularly as rodenticides) but are not used medically.

Heparin and derivative substances
Heparin is the most widely used intravenous clinical anticoagulant worldwide. Heparin is a naturally occurring glycosaminoglycan. There are three major categories of heparin: unfractionated heparin (UFH), low molecular weight heparin (LMWH), and ultra-low-molecular weight heparin (ULMWH). Unfractionated heparin is usually derived from pig intestines and bovine lungs. UFH binds to the enzyme inhibitor antithrombin III (AT), causing a conformational change that results in its activation. The activated AT then inactivates factor Xa, thrombin, and other coagulation factors. Heparin can be used in vivo (by injection), and also in vitro to prevent blood or plasma clotting in or on medical devices. In venipuncture, Vacutainer brand blood collecting tubes containing heparin usually have a green cap.

Low molecular weight heparin (LMWH)
Low molecular weight heparin (LMWH) is produced through a controlled depolymerization of unfractionated heparin. LMWH exhibits a higher anti-Xa/anti-IIa activity ratio and is useful as it does not require monitoring of the APTT coagulation parameter and has fewer side effects.

Synthetic pentasaccharide inhibitors of factor Xa

 * Fondaparinux is a synthetic sugar composed of the five sugars (pentasaccharides) in heparin that bind to antithrombin. It is a smaller molecule than low molecular-weight heparin.
 * Idraparinux
 * Idrabiotaparinux

Direct oral
The direct oral anticoagulants (DOACs) were introduced in and after 2008. There are five DOACs currently on the market: dabigatran, rivaroxaban, apixaban, edoxaban and betrixaban. They were also previously referred to as "new/novel" and "non-vitamin K antagonist" oral anticoagulants (NOACs).

Compared to warfarin, DOACs have a rapid onset action and relatively short half-lives; hence, they carry out their function more rapidly and effectively, allowing drugs to reduce their anticoagulation effects quickly. Routine monitoring and dose adjustments of DOACs are less important than for warfarin, as they have better predictable anticoagulation activity. DOAC monitoring, including laboratory monitoring and a complete medication review, should generally be conducted before initiation of a DOAC, 1–3 months after initiation, and then every 6–12 months afterwards.

Both DOACs and warfarin are equivalently effective, but compared to warfarin, DOACs have fewer drug interactions, no known dietary interactions, a wider therapeutic index, and have conventional dosing that does not require dose adjustments with constant monitoring. However, there is no countermeasure for most DOACs, unlike for warfarin; nonetheless, the short half-lives of DOACs will allow their effects to recede swiftly. A reversal agent for dabigatran, idarucizumab, is currently available and approved for use by the FDA. Rates of adherence to DOACs are only modestly higher than adherence to warfarin among patients prescribed these drugs. Thus, adherence to anticoagulation is often poor despite hopes that DOACs would lead to higher adherence rates.

DOACs are significantly more expensive than warfarin, but the patients on DOACs may experience reduced lab costs as they do not need to monitor their INR.

Direct factor Xa inhibitors
Drugs such as rivaroxaban, apixaban and edoxaban work by inhibiting factor Xa directly (unlike heparins and fondaparinux, which work via antithrombin activation). Also included in this category are betrixaban from Portola Pharmaceuticals, the discontinued darexaban (YM150) from Astellas, and, more recently, the discontinued letaxaban (TAK-442) from Takeda and eribaxaban (PD0348292) from Pfizer. Betrixaban is significant as it was in 2018, the only oral factor Xa inhibitor approved by the FDA for use in acutely medically ill patients. Darexaban development was discontinued in September 2011; in a trial for prevention of recurrences of myocardial infarction in addition to dual antiplatelet therapy (DAPT), the drug did not demonstrate effectiveness, and the risk of bleeding was increased by approximately 300%. The development of letaxaban for acute coronary syndrome was discontinued in May 2011 following negative results from a Phase II study.

Direct thrombin inhibitors
Another type of anticoagulant is the direct thrombin inhibitor. Current members of this class include the bivalent drugs hirudin, lepirudin, and bivalirudin and the monovalent drugs argatroban and dabigatran. An oral direct thrombin inhibitor, ximelagatran (Exanta), was denied approval by the Food and Drug Administration (FDA) in September 2004 and was pulled from the market entirely in February 2006 after reports of severe liver damage and heart attacks. In November 2010, dabigatran etexilate was approved by the FDA to prevent thrombosis in atrial fibrillation.

Relevance to dental treatments
As in any invasive procedure, patients on anticoagulation therapy have an increased risk for bleeding, and caution should be used along with local hemostatic methods to minimize bleeding risk during the operation as well as postoperatively. However, with regards to DOACs and invasive dental treatments, there has not been enough clinical evidence and experience to prove any reliable adverse effects, relevance or interaction between these two. Further clinical prospective studies on DOACs are required to investigate the bleeding risk and hemostasis associated with surgical and dental procedures.

Recommendations of modifications to the usage/dosage of DOACs before dental treatments are made based on the balance of the bleeding risk of each procedure and also the individual's own bleeding risks and renal functionality. With low-bleeding-risk dental procedures, it is recommended that DOACs be continued by the patient to avoid any increase in the risk of a thromboembolic event. For dental procedures with a higher risk of bleeding complications (i.e. complex extractions, adjacent extractions leading to a large wound, or more than three extractions), the recommended practice is for the patient to miss or delay a dose of their DOAC before such procedures to minimize the effect on bleeding risk.

Antithrombin protein therapeutics
The antithrombin protein is used as a protein therapeutic that can be purified from human plasma or produced recombinantly (for example, Atryn, produced in the milk of genetically modified goats).

The FDA approves Antithrombin as an anticoagulant for preventing clots before, during, or after surgery or birthing in patients with hereditary antithrombin deficiency.

Other
Many other anticoagulants exist in research and development, diagnostics, or as drug candidates.
 * Batroxobin, a toxin from snake venom, clots platelet-rich plasma without affecting platelet functions (cleaves fibrinogen).
 * Hementin is an anticoagulant protease from the salivary glands of the giant Amazon leech, Haementeria ghilianii.
 * Vitamin E
 * Alcoholic beverage

Reversal agents
With the growing number of patients taking oral anticoagulation therapy, studies into reversal agents are gaining increasing interest due to major bleeding events and the need for urgent anticoagulant reversal therapy. Reversal agents for warfarin are more widely studied, and established guidelines for reversal exist due to a longer history of use of warfarin and the ability to get a more accurate measurement of anticoagulation effect in a patient via measuring the INR (International Normalized Ratio). In general, vitamin K is most commonly used to reverse the effect of warfarin in non-urgent settings. However, in urgent settings or settings with extremely high INR (INR >20), hemostatic reversal agents such as fresh frozen plasma (FFP), recombinant factor VIIa, and prothrombin complex concentrate (PCC) have been utilized with proven efficacy. Specifically with warfarin, four-factor PCC (4F-PCC) has been shown to have superior safety and mortality benefits compared to FPP in lowering INR levels.

Although specific antidotes and reversal agents for DOACs are not as widely studied, idarucizumab (for dabigatran) and andexanet alfa (for factor Xa inhibitor) have been used in clinical settings with varying efficacy. Idarucizumab is a monoclonal antibody, approved by the US FDA in 2015, that reverses the effect of dabigatran by binding to both free and thrombin-bound dabigatran. Andexanet alfa is a recombinant modified human factor Xa decoy that reverses the effect of factor Xa inhibitors by binding at the active sites of factor Xa inhibitor and making it catalytically inactive. Andexanet alfa was approved by the US FDA in 2018. Another drug called ciraparantag, a potential reversal agent for direct factor Xa inhibitors, is still under investigation. Additionally, hemostatic reversal agents have also been used with varying efficacy to reverse the effects of DOACs.

Coagulation inhibitor measurement
A Bethesda unit (BU) is a measure of blood coagulation inhibitor activity. It is the amount of inhibitor that will inactivate half of a coagulant during the incubation period. It is the standard measure used in the United States and is so named because it was adopted as a standard at a conference in Bethesda, Maryland.

Laboratory use
If blood is allowed to clot, laboratory instruments, blood transfusion bags, and medical and surgical equipment will get clogged up and non-operational. In addition, test tubes used for laboratory blood tests will have chemicals added to stop blood clotting. Besides heparin, most of these chemicals bind calcium ions, preventing the coagulation proteins from using them.
 * Ethylenediaminetetraacetic acid (EDTA) strongly and irreversibly chelates (binds) calcium ions, preventing blood from clotting.
 * Citrate is in liquid form in the tube and is used for coagulation tests and blood transfusion bags. It binds calcium but not as strongly as EDTA. The correct proportion of this anticoagulant to blood is crucial because of the dilution, which can be reversed with the addition of calcium. Formulations include plain sodium citrate, acid-citrate-dextrose, and more.
 * Oxalate has a mechanism similar to that of citrate. It is the anticoagulant used in fluoride/oxalate tubes to determine glucose and lactate levels. The fluoride inhibits glycolysis, which can throw off blood sugar measurements. Citrate/fluoride/EDTA tubes work better in this regard.

Dental considerations for long-term users
Dental practitioners play an important role in the early detection of anticoagulant overdose through oral manifestations, as the patient does not show any symptoms. Dental treatment of patients taking anticoagulant or antiplatelet medication raises safety concerns in terms of the potential risk of bleeding complications following invasive dental procedures. Therefore, certain guidelines for the dental care of patients taking these drugs are needed.

Detecting overdose

An overdose of anticoagulants usually occurs in people who have heart problems and need to take anticoagulants in the long term to reduce the risk of stroke from their high blood pressure.

An International Normalised Ratio (INR) test would be recommended to confirm the overdose so that the dosage can be adjusted to an acceptable standard. The INR test measures the time it takes for a clot to form in a blood sample relative to a standard.

An INR value of 1 indicates a level of coagulation equivalent to that of an average patient not taking warfarin, and values greater than 1 indicate a longer clotting time and, thus, a longer bleeding time.

Assessing bleeding risk

There are two main parts to the assessment of bleeding risk:
 * Assessment of the likely risk of bleeding associated with the required dental procedure
 * Assessment of the patient's individual-level bleeding risk

Managing bleeding risk

A patient who is on anticoagulants or antiplatelet medications may undergo dental treatments which are unlikely to cause bleeding, such as local anesthesia injection, basic gum charting, removal of plaque, calculus and stain above the gum level, direct or indirect fillings which are above the gingiva, root canal treatment, taking impression for denture or crown and fitting or adjustment of orthodontic appliances. For all these procedures, it is recommended that the dentist treat the patient following the normal standard procedure and taking care to avoid any bleeding.

For a patient who needs to undergo dental treatments which are more likely to cause bleeding, such as simple tooth extractions (1-3 teeth with small wound size), drainage of swelling inside the mouth, periodontal charting, root planing, direct or indirect filling which extends below the gingiva, complex filling, flap raising procedure, gingival recontouring and biopsies, the dentist needs to take extra precautions apart from the standard procedure. The recommendations are as follows:
 * if the patient has another medical condition or is taking other medication that may increase bleeding risk, consult the patient's general medical practitioner or specialist
 * if the patient is on a short course of anticoagulant or antiplatelet therapy, delay the non-urgent, invasive procedure until the medication has been discontinued
 * plan treatment for early in the day and week, where possible, to allow time for the management of prolonged bleeding or re-bleeding if it occurs
 * perform the procedure as traumatically as possible, use appropriate local measures and only discharge the patient once hemostasis has been confirmed
 * if travel time to emergency care is a concern, place particular emphasis at the time of the initial treatment on the use of measures to avoid complications
 * advise    the patient to take paracetamol, unless contraindicated, for pain relief rather than NSAIDs such as aspirin, ibuprofen, diclofenac or naproxen
 * provide the patient with written post-treatment advice and emergency contact details
 * follow the specific recommendations and advice given for the management of patients taking different anticoagulants or antiplatelet drugs

There is general agreement that in most cases, treatment regimens with older anticoagulants (e.g., warfarin) and antiplatelet agents (e.g., clopidogrel, ticlopidine, prasugrel, ticagrelor, and/or aspirin) should not be altered before dental procedures. The risks of stopping or reducing these medication regimens (i.e., thromboembolism, stroke, myocardial infarction) far outweigh the consequences of prolonged bleeding, which can be controlled with local measures. In patients with other existing medical conditions that can increase the risk of prolonged bleeding after dental treatment or receiving other therapy that can increase bleeding risk, dental practitioners may wish to consult the patient's physician to determine whether care can safely be delivered in a primary care office. Any suggested modification to the medication regimen before dental surgery should be done in consultation and on the advice of the patient's physician.

Based on limited evidence, the consensus appears to be that in most patients who are receiving the newer direct-acting oral anticoagulants (i.e., dabigatran, rivaroxaban, apixaban, or edoxaban) and undergoing dental treatment (in conjunction with usual local measures to control bleeding), no change to the anticoagulant regimen is required. In patients deemed to be at higher risk of bleeding (e.g., patients with other medical conditions or undergoing more extensive procedures associated with higher bleeding risk), consideration may be given, in consultation with and on advice of the patient's physician, to postponing the timing of the daily dose of the anticoagulant until after the procedure; timing the dental intervention as late as possible after last dose of anticoagulant; or temporarily interrupting drug therapy for 24 to 48 hours.

Research
A substantial number of compounds are being investigated for use as anticoagulants. The most promising ones act on the contact activation system (factor XIIa and factor XIa); it is anticipated that this may provide agents that prevent thrombosis without conferring a risk of bleeding.

, the direct factor XIa inhibitor milvexian is in Phase II clinical trials for the prevention of an embolism after surgery.

title: Anticoagulant