title: Vitamin C

text: Simple tests are available to measure the levels of vitamin C in urine and serum. These better reflect recent dietary intake rather than total body content. It has been observed that while serum concentrations follow a circadian rhythm or reflect short-term dietary influence, content within cells or tissues is more stable and can give a better view of the availability of ascorbate within the entire organism. However, very few hospital laboratories are adequately equipped and trained to carry out such detailed analyses.


title: Vitamin C

text: Most animals and plants are able to synthesize vitamin C through a sequence of enzyme-driven steps, which convert monosaccharides to vitamin C. Yeasts do not make -ascorbic acid but rather its stereoisomer, erythorbic acid. In plants, synthesis is accomplished through the conversion of mannose or galactose to ascorbic acid. In animals, the starting material is glucose. In some species that synthesize ascorbate in the liver (including mammals and perching birds), the glucose is extracted from glycogen; ascorbate synthesis is a glycogenolysis-dependent process. In humans and in animals that cannot synthesize vitamin C, the enzyme -gulonolactone oxidase (GULO), which catalyses the last step in the biosynthesis, is highly mutated and non-functional.


title: Vitamin C

text: There is some information on serum vitamin C concentrations maintained in animal species that are able to synthesize vitamin C. One study of several breeds of dogs reported an average of 35.9 μmol/L. A report on goats, sheep and cattle reported ranges of 100–110, 265-270 and 160-350 μmol/L, respectively.


title: Vitamin C

text: The biosynthesis of ascorbic acid in vertebrates starts with the formation of UDP-glucuronic acid. UDP-glucuronic acid is formed when UDP-glucose undergoes two oxidations catalyzed by the enzyme UDP-glucose 6-dehydrogenase. UDP-glucose 6-dehydrogenase uses the co-factor NAD as the electron acceptor. The transferase UDP-glucuronate pyrophosphorylase removes a UMP and glucuronokinase, with the cofactor ADP, removes the final phosphate leading to -glucuronic acid. The aldehyde group of this compound is reduced to a primary alcohol using the enzyme glucuronate reductase and the cofactor NADPH, yielding -gulonic acid. This is followed by lactone formationutilizing the hydrolase gluconolactonasebetween the carbonyl on C1 and hydroxyl group on C4. -Gulonolactone then reacts with oxygen, catalyzed by the enzyme L-gulonolactone oxidase (which is nonfunctional in humans and other Haplorrhini primates; see Unitary pseudogenes) and the cofactor FAD+. This reaction produces 2-oxogulonolactone (2-keto-gulonolactone), which spontaneously undergoes enolization to form ascorbic acid.


title: Vitamin C

text: Some mammals have lost the ability to synthesize vitamin C, including simians and tarsiers, which together make up one of two major primate suborders, Haplorrhini. This group includes humans. The other more primitive primates (Strepsirrhini) have the ability to make vitamin C. Synthesis does not occur in most bats nor in species in the rodent family Caviidae, which includes guinea pigs and capybaras, but does occur in other rodents, including rats and mice.


title: Vitamin C

text: Reptiles and older orders of birds make ascorbic acid in their kidneys. Recent orders of birds and most mammals make ascorbic acid in their liver. A number of species of passerine birds also do not synthesize, but not all of them, and those that do not are not clearly related; there is a theory that the ability was lost separately a number of times in birds. In particular, the ability to synthesize vitamin C is presumed to have been lost and then later re-acquired in at least two cases. The ability to synthesize vitaminC has also been lost in about 96% of fish (the teleosts).


title: Vitamin C

text: Most tested families of bats (order Chiroptera), including major insect and fruit-eating bat families, cannot synthesize vitamin C. A trace of gulonolactone oxidase was detected in only 1 of 34 bat species tested, across the range of 6 families of bats tested. There are at least two species of bats, frugivorous bat ("Rousettus leschenaultii") and insectivorous bat ("Hipposideros armiger"), that retain (or regained) their ability of vitamin C production.


title: Vitamin C

text: Some of these species (including humans) are able to make do with the lower amounts available from their diets by recycling oxidised vitamin C.


title: Vitamin C

text: On a milligram consumed per kilogram of body weight basis, most simian species consume the vitamin in amounts 10 to 20 times higher than what is recommended by governments for humans. This discrepancy constitutes much of the basis of the controversy on current recommended dietary allowances. It is countered by arguments that humans are very good at conserving dietary vitamin C, and are able to maintain blood levels of vitamin C comparable with simians on a far smaller dietary intake, perhaps by recycling oxidized vitamin C.


title: Vitamin C

text: Ascorbic acid is a common enzymatic cofactor in mammals used in the synthesis of collagen, as well as a powerful reducing agent capable of rapidly scavenging a number of reactive oxygen species (ROS). Given that ascorbate has these important functions, it is surprising that the ability to synthesize this molecule has not always been conserved. In fact, anthropoid primates, "Cavia porcellus" (guinea pigs), teleost fishes, most bats, and some passerine birds have all independently lost the ability to internally synthesize vitamin C in either the kidney or the liver. In all of the cases where genomic analysis was done on an ascorbic acid auxotroph, the origin of the change was found to be a result of loss-of-function mutations in the gene that encodes -gulono-γ-lactone oxidase, the enzyme that catalyzes the last step of the ascorbic acid pathway outlined above. One explanation for the repeated loss of the ability to synthesize vitamin C is that it was the result of genetic drift; assuming that the diet was rich in vitaminC, natural selection would not act to preserve it.


title: Vitamin C

text: In the case of the simians, it is thought that the loss of the ability to make vitamin C may have occurred much farther back in evolutionary history than the emergence of humans or even apes, since it evidently occurred soon after the appearance of the first primates, yet sometime after the split of early primates into the two major suborders Haplorrhini (which cannot make vitamin C) and its sister suborder of non-tarsier prosimians, the Strepsirrhini ("wet-nosed" primates), which retained the ability to make vitamin C. According to molecular clock dating, these two suborder primate branches parted ways about 63 to 60 million years ago. Approximately three to five million years later (58 million years ago), only a short time afterward from an evolutionary perspective, the infraorder Tarsiiformes, whose only remaining family is that of the tarsier (Tarsiidae), branched off from the other haplorrhines. Since tarsiers also cannot make vitamin C, this implies the mutation had already occurred, and thus must have occurred between these two marker points (63 to 58 million years ago).


title: Vitamin C

text: It has also been noted that the loss of the ability to synthesize ascorbate strikingly parallels the inability to break down uric acid, also a characteristic of primates. Uric acid and ascorbate are both strong reducing agents. This has led to the suggestion that, in higher primates, uric acid has taken over some of the functions of ascorbate.


title: Vitamin C

text: There are many different biosynthesis pathways for ascorbic acid in plants. Most of these pathways are derived from products found in glycolysis and other pathways. For example, one pathway goes through the plant cell wall polymers. The plant ascorbic acid biosynthesis pathway most principal seems to be -galactose. -Galactose reacts with the enzyme -galactose dehydrogenase, whereby the lactone ring opens and forms again but with lactone between the carbonyl on C1 and hydroxyl group on C4, resulting in -galactonolactone. -Galactonolactone then reacts with the mitochondrial flavoenzyme -galactonolactone dehydrogenase. to produce ascorbic acid. -Ascorbic acid has a negative feedback on -galactose dehydrogenase in spinach.


title: Vitamin C

text: Ascorbic acid efflux by embryo of dicots plants is a well-established mechanism of iron reduction, and a step obligatory for iron uptake.


title: Vitamin C

text: All plants synthesize ascorbic acid. Ascorbic acid functions as a cofactor for enzymes involved in photosynthesis, synthesis of plant hormones, as an antioxidant and also regenerator of other antioxidants. Plants use multiple pathways to synthesize vitamin C. The major pathway starts with glucose, fructose or mannose (all simple sugars) and proceeds to L-galactose, L-galactonolactone and ascorbic acid. There is feedback regulation in place, in that the presence of ascorbic acid inhibits enzymes in the synthesis pathway. This process follows a diurnal rhythm, so that enzyme expression peaks in the morning to support biosynthesis later on when mid-day sunlight intensity demands high ascorbic acid concentrations. Minor pathways may be specific to certain parts of plants; these can be either identical to the vertebrate pathway (including the GLO enzyme), or start with inositol and get to ascorbic acid via L-galactonic acid to L-galactonolactone.


title: Vitamin C

text: Vitamin C is produced from glucose by two main routes. The Reichstein process, developed in the 1930s, uses a single pre-fermentation followed by a purely chemical route. The modern two-step fermentation process, originally developed in China in the 1960s, uses additional fermentation to replace part of the later chemical stages. The Reichstein process and the modern two-step fermentation processes use sorbitol as the starting material and convert it to sorbose using fermentation. The modern two-step fermentation process then converts sorbose to 2-keto-l-gulonic acid (KGA) through another fermentation step, avoiding an extra intermediate.


title: Vitamin C

text: In 2017, China produced about 95% of the world supply of ascorbic acid (vitamin C), which is China's most exported vitamin, having total revenue of US$880 million in 2017. Due to pressure on Chinese industry to discontinue burning coal normally used for vitamin C manufacturing, the price of vitamin C rose three-fold in 2016 alone to US$12 per kg.


title: Vitamin C

text: In the 1497 expedition of Vasco da Gama, the curative effects of citrus fruit were known. Later, the Portuguese planted fruit trees and vegetables in Saint Helena, a stopping point for homebound voyages from Asia, which sustained passing ships.


title: Vitamin C

text: Authorities occasionally recommended plant food to prevent scurvy during long sea voyages. John Woodall, the first surgeon to the British East India Company, recommended the preventive and curative use of lemon juice in his 1617 book, "The Surgeon's Mate". In 1734, the Dutch writer Johann Bachstrom gave the firm opinion, "scurvy is solely owing to a total abstinence from fresh vegetable food, and greens."


title: Vitamin C

text: Scurvy had long been a principal killer of sailors during the long sea voyages. According to Jonathan Lamb, "In 1499, Vasco da Gama lost 116 of his crew of 170; In 1520, Magellan lost 208 out of 230;...all mainly to scurvy."


title: Vitamin C

text: The first attempt to give scientific basis for the cause of this disease was by a ship's surgeon in the Royal Navy, James Lind. While at sea in May 1747, Lind provided some crew members with two oranges and one lemon per day, in addition to normal rations, while others continued on cider, vinegar, sulfuric acid or seawater, along with their normal rations, in one of the world's first controlled experiments. The results showed that citrus fruits prevented the disease. Lind published his work in 1753 in his "Treatise on the Scurvy".


title: Vitamin C

text: Fresh fruit was expensive to keep on board, whereas boiling it down to juice allowed easy storage but destroyed the vitamin (especially if boiled in copper kettles). It was 1796 before the British navy adopted lemon juice as standard issue at sea. In 1845, ships in the West Indies were provided with lime juice instead, and in 1860 lime juice was used throughout the Royal Navy, giving rise to the American use of the nickname "limey" for the British. Captain James Cook had previously demonstrated the advantages of carrying "Sour krout" on board, by taking his crews to the Hawaiian Islands without losing any of his men to scurvy. For this, the British Admiralty awarded him a medal.


title: Vitamin C

text: The name "antiscorbutic" was used in the eighteenth and nineteenth centuries for foods known to prevent scurvy. These foods included lemons, limes, oranges, sauerkraut, cabbage, malt, and portable soup. In 1928, the Canadian Arctic anthropologist Vilhjalmur Stefansson showed that the Inuit avoid scurvy on a diet of largely raw meat. Later studies on traditional food diets of the Yukon First Nations, Dene, Inuit, and Métis of Northern Canada showed that their daily intake of vitamin C averaged between 52 and 62 mg/day, comparable with the Estimated Average Requirement.


title: Vitamin C

text: Vitamin C was discovered in 1912, isolated in 1928 and synthesized in 1933, making it the first vitamin to be synthesized. Shortly thereafter Tadeus Reichstein succeeded in synthesizing the vitamin in bulk by what is now called the Reichstein process. This made possible the inexpensive mass-production of vitamin C. In 1934 Hoffmann–La Roche trademarked synthetic vitamin C under the brand name Redoxon and began to market it as a dietary supplement.


title: Vitamin C

text: In 1907 a laboratory animal model which would help to identify the antiscorbutic factor was discovered by the Norwegian physicians Axel Holst and Theodor Frølich, who when studying shipboard beriberi, fed guinea pigs their test diet of grains and flour and were surprised when scurvy resulted instead of beriberi. By luck, this species did not make its own vitamin C, whereas mice and rats do. In 1912, the Polish biochemist Casimir Funk developed the concept of vitamins. One of these was thought to be the anti-scorbutic factor. In 1928, this was referred to as "water-soluble C", although its chemical structure had not been determined.


title: Vitamin C

text: From 1928 to 1932, Albert Szent-Györgyi and Joseph L. Svirbely's Hungarian team, and Charles Glen King's American team, identified the anti-scorbutic factor. Szent-Györgyi isolated hexuronic acid from animal adrenal glands, and suspected it to be the antiscorbutic factor. In late 1931, Szent-Györgyi gave Svirbely the last of his adrenal-derived hexuronic acid with the suggestion that it might be the anti-scorbutic factor. By the spring of 1932, King's laboratory had proven this, but published the result without giving Szent-Györgyi credit for it. This led to a bitter dispute over priority. In 1933, Walter Norman Haworth chemically identified the vitamin as -hexuronic acid, proving this by synthesis in 1933. Haworth and Szent-Györgyi proposed that L-hexuronic acid be named a-scorbic acid, and chemically -ascorbic acid, in honor of its activity against scurvy. The term's etymology is from Latin, "a-" meaning away, or off from, while -scorbic is from Medieval Latin "scorbuticus" (pertaining to scurvy), cognate with Old Norse "skyrbjugr", French "scorbut", Dutch "scheurbuik" and Low German "scharbock". Partly for this discovery, Szent-Györgyi was awarded the 1937 Nobel Prize in Medicine, and Haworth shared that year's Nobel Prize in Chemistry.


title: Vitamin C

text: In 1957, J. J. Burns showed that some mammals are susceptible to scurvy as their liver does not produce the enzyme -gulonolactone oxidase, the last of the chain of four enzymes that synthesize vitamin C. American biochemist Irwin Stone was the first to exploit vitamin C for its food preservative properties. He later developed the theory that humans possess a mutated form of the -gulonolactone oxidase coding gene.


title: Vitamin C

text: In 2008, researchers at the University of Montpellier discovered that in humans and other primates the red blood cells have evolved a mechanism to more efficiently utilize the vitamin C present in the body by recycling oxidized -dehydroascorbic acid (DHA) back into ascorbic acid for reuse by the body. The mechanism was not found to be present in mammals that synthesize their own vitamin C.


title: Vitamin C

text: Vitamin C megadosage is a term describing the consumption or injection of vitamin C in doses comparable to or higher than the amounts produced by the livers of mammals which are able to synthesize vitamin C. The theory behind this, although not the actual term, was described in 1970 in an article by Linus Pauling. Briefly, his position was that for optimal health, humans should be consuming at least 2,300 mg/day to compensate for the inability to synthesize vitamin C. The recommendation also fell into the consumption range for gorillas - a non-synthesizing near-relative to humans. A second argument for high intake is that serum ascorbic acid concentrations increase as intake increases until it plateaus at about 190 to 200 micromoles per liter (µmol/L) once consumption exceeds 1,250 milligrams. As noted, government recommendations are a range of 40 to 110 mg/day and normal plasma is approximately 50 µmol/L, so 'normal' is about 25% of what can be achieved when oral consumption is in the proposed megadose range.


title: Vitamin C

text: Pauling popularized the concept of high dose vitamin C as prevention and treatment of the common cold in 1970. A few years later he proposed that vitamin C would prevent cardiovascular disease, and that 10 grams/day, initially (10 days) administered intravenously and thereafter orally, would cure late-stage cancer. Mega-dosing with ascorbic acid has other champions, among them chemist Irwin Stone and the controversial Matthias Rath and Patrick Holford, who both have been accused of making unsubstantiated treatment claims for treating cancer and HIV infection.


title: Vitamin C

text: The mega-dosing theory is to a large degree discredited. Modest benefits are demonstrated for the common cold. Benefits are not superior when supplement intakes of more than 1,000 mg/day are compared to intakes between 200 and 1,000 mg/day, and so not limited to the mega-dose range. The theory that large amounts of intravenous ascorbic acid can be used to treat late-stage cancer is - some forty years after Pauling's seminal paper - still considered unproven and still in need of high quality research. However, a lack of evidence has not stopped individual physicians from prescribing intravenous ascorbic acid to thousands of people with cancer.


title: Vitamin C

text: In February 2011, the Swiss Post issued a postage stamp bearing a depiction of a model of a molecule of vitamin C to mark the International Year of Chemistry.


title: Vitamin C

text: Vitamin C is sold around the world as a stand-alone product at amounts up to 1,000 mg and as part of fixed-dose combination products, under many brand names.


title: Atorvastatin

text: Atorvastatin is a statin medication used to prevent cardiovascular disease in those at high risk and to treat abnormal lipid levels. For the prevention of cardiovascular disease, statins are a first-line treatment. It is taken by mouth.


title: Atorvastatin

text: Common side effects include joint pain, diarrhea, heartburn, nausea, and muscle pains. Serious side effects may include rhabdomyolysis, liver problems, and diabetes. Use during pregnancy may harm the fetus. Like all statins, atorvastatin works by inhibiting HMG-CoA reductase, an enzyme found in the liver that plays a role in producing cholesterol.


title: Atorvastatin

text: Atorvastatin was patented in 1986, and approved for medical use in the United States in 1996. It is on the World Health Organization's List of Essential Medicines. It is available as a generic medication. In 2020, it was the most commonly prescribed medication in the United States, with more than 114million prescriptions.


title: Atorvastatin

text: The primary uses of atorvastatin is for the treatment of dyslipidemia and the prevention of cardiovascular disease:


title: Atorvastatin

text: A 2014 meta-analysis showed high-dose statin therapy was significantly superior compared to moderate or low-intensity statin therapy in reducing plaque volume in patients with acute coronary syndrome. The SATURN trial which compared the effects of high-dose atorvastatin and rosuvastatin also confirmed these findings. Despite the high dosage, the 40 mg pravastatin study arm in the REVERSAL trial failed to halt plaque progression, which suggests other factors such as which statin is used, duration and location of the plaque may also affect plaque volume reduction and thereby plaque-stabilization. Overall, plaque reduction should be considered as a surrogate endpoint and should not be directly used to determine clinical benefit of therapy. Increased risk of adverse events should also be taken into account when considering high-dose statin therapy.


title: Atorvastatin

text: There is evidence from systematic review and meta-analyses that statins, particularly atorvastatin, reduce both decline in kidney function (eGFR) and the severity of protein excretion in urine, with higher doses having greater effect. Data is conflicting for whether statins reduce risk of kidney failure. Statins, including atorvastatin, before heart surgery do not prevent acute kidney injury.


title: Atorvastatin

text: Prior to contrast medium (CM) administration, pre-treatment with atorvastatin therapy can reduce the risk of contrast-induced acute kidney injury (CI-AKI) in patients with pre-existing chronic kidney disease (CKD) (eGFR < 60mL/min/1.73m2) who undergo interventional procedures such as cardiac catheterisation, coronary angiography (CAG) or percutaneous coronary intervention (PCI). A meta-analysis of 21 RCTs confirmed that high dose (80 mg) atorvastatin therapy is more effective than regular dose or low dose statin therapy at preventing CI-AKI. Atorvastatin therapy can also help to prevent in-hospital dialysis post CM administration, however there is no evidence that it reduces all-cause mortality associated with CI-AKI. Overall, the evidence concludes that statin therapy, irrespective of the dose, is still more effective than no treatment or placebo at reducing the risk of CI-AKI.


title: Atorvastatin

text: Statins (predominantly simvastatin) have been trialled in combination with fibrates to manage dyslipidemia in patients who also have type 2 diabetes, and a high cardiovascular disease risk, however, there is limited clinical benefit noted for most cardiovascular outcomes


title: Atorvastatin

text: While many statin medications should be administered at bedtime for optimal effect, atorvastatin can be dosed at any time of day, as long as it is continually dosed once daily at the same time.


title: Atorvastatin

text: There have been rare reports of reversible memory loss and confusion with all statins, including atorvastatin; however, there has not been enough evidence to associate statin use with cognitive impairment, and the risks for cognition are likely outweighed by the beneficial effects of adherence to statin therapy on cardiovascular and cerebrovascular disease.


title: Atorvastatin

text: There is some evidence that atorvastatin use may increase the risk of acute pancreatitis, in people who are already at a higher risk. However, there is also evidence that atorvastatin use decreases the risk of acute pancreatitis in people with mild to moderate hypertriglyceridemia, by lowering triglyceride levels.


title: Atorvastatin

text: Fibrates are a class of drugs that can be used for severe or refractory mixed hyperlipidaemia in combination with statins or as monotherapy. Concomitant therapy of atorvastatin with drugs from the fibrate drug class (such as gemfibrozil, fenofibrate) can increase the risk of myopathy and rhabdomyolysis.


title: Atorvastatin

text: Co-administration of atorvastatin with one of CYP3A4 inhibitors such as itraconazole, telithromycin, and voriconazole, may increase serum concentrations of atorvastatin, which may lead to adverse reactions. This is less likely to happen with other CYP3A4 inhibitors such as diltiazem, erythromycin, fluconazole, ketoconazole, clarithromycin, cyclosporine, protease inhibitors, or verapamil, and only rarely with other CYP3A4 inhibitors, such as amiodarone and aprepitant. Often, bosentan, fosphenytoin, and phenytoin, which are CYP3A4 inducers, can decrease the plasma concentrations of atorvastatin. Only rarely, though, barbiturates, carbamazepine, efavirenz, nevirapine, oxcarbazepine, rifampin, and rifamycin, which are also CYP3A4 inducers, can decrease the plasma concentrations of atorvastatin. Oral contraceptives increased AUC values for norethisterone and ethinylestradiol; these increases should be considered when selecting an oral contraceptive for a woman taking atorvastatin.


title: Atorvastatin

text: Antacids can rarely decrease the plasma concentrations of statin medications, but do not affect the LDL-C-lowering efficacy.


title: Atorvastatin

text: Some statins may also alter the concentrations of other medications, such as warfarin or digoxin, leading to alterations in effect or a requirement for clinical monitoring. The increase in digoxin levels due to atorvastatin is a 1.2 fold elevation in the area under the curve (AUC), resulting in a minor drug-drug interaction. The American Heart Association states that the combination of digoxin and atorvastatin is reasonable. In contrast to some other statins, atorvastatin does not interact with warfarin concentrations in a clinically meaningful way (similar to pitavastatin).


title: Atorvastatin

text: Vitamin D supplementation lowers atorvastatin and active metabolite concentrations, yet synergistically reduces LDL and total cholesterol concentrations.


title: Atorvastatin

text: Grapefruit juice components are known inhibitors of intestinal CYP3A4. Drinking grapefruit juice with atorvastatin may cause an increase in C and area under the curve (AUC). This finding initially gave rise to concerns of toxicity, and in 2000, it was recommended that people taking atorvastatin should not consume grapefruit juice "in an unsupervised manner." Small studies (using mostly young participants) examining the effects of grapefruit juice consumption on mainly lower doses of atorvastatin have shown that grapefruit juice increases blood levels of atorvastatin, which could increase the risk of adverse effects. No studies assessing the impact of grapefruit juice consumption have included participants taking the highest dose of atorvastatin (80 mg daily), which is often prescribed for people with a history of cardiovascular disease (such as heart attack or ischaemic stroke) or in people at high risk of cardiovascular disease. People taking atorvastatin should consult with their doctor or pharmacist before consuming grapefruit juice, as the effects of grapefruit juice consumption on atorvastatin will vary according to factors such as the amount and frequency of juice consumption in addition to differences in juice components, quality and method of juice preparation between different batches or brands.


title: Atorvastatin

text: As with other statins, atorvastatin is a competitive inhibitor of HMG-CoA reductase. Unlike most others, however, it is a completely synthetic compound. HMG-CoA reductase catalyzes the reduction of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) to mevalonate, which is the rate-limiting step in hepatic cholesterol biosynthesis. Inhibition of the enzyme decreases "de novo" cholesterol synthesis, increasing expression of low-density lipoprotein receptors (LDL receptors) on hepatocytes. This increases LDL uptake by the hepatocytes, decreasing the amount of LDL-cholesterol in the blood. Like other statins, atorvastatin also reduces blood levels of triglycerides and slightly increases levels of HDL-cholesterol.


title: Atorvastatin

text: In people with acute coronary syndrome, high-dose atorvastatin treatment may play a plaque-stabilizing role. At high doses, statins have anti-inflammatory effects, incite reduction of the necrotic plaque core, and improve endothelial function, leading to plaque stabilization and, sometimes, plaque regression. There is a similar thought process with using high-dose atorvastatin as a form of secondary thrombotic stroke recurrence prevention.


title: Atorvastatin

text: The liver is the primary site of action of atorvastatin, as this is the principal site of both cholesterol synthesis and LDL clearance. It is the dosage of atorvastatin, rather than systemic medication concentration, which correlates with extent of LDL-C reduction. In a Cochrane systematic review the dose-related magnitude of atorvastatin on blood lipids was determined. Over the dose range of 10 to 80 mg/day total cholesterol was reduced by 27.0% to 37.9%, LDL cholesterol by 37.1% to 51.7% and triglycerides by 18.0% to 28.3%.


title: Atorvastatin

text: Atorvastatin undergoes rapid absorption when taken orally, with an approximate time to maximum plasma concentration (T) of 1–2 h. The absolute bioavailability of the medication is about 14%, but the systemic availability for HMG-CoA reductase activity is approximately 30%. Atorvastatin undergoes high intestinal clearance and first-pass metabolism, which is the main cause for the low systemic availability. Administration of atorvastatin with food produces a 25% reduction in C (rate of absorption) and a 9% reduction in AUC (extent of absorption), although food does not affect the plasma LDL-C-lowering efficacy of atorvastatin. Evening dose administration is known to reduce the C and AUC by 30% each. However, time of administration does not affect the plasma LDL-C-lowering efficacy of atorvastatin.


title: Atorvastatin

text: The mean volume of distribution of atorvastatin is approximately 381 L. It is highly protein bound (≥98%), and studies have shown it is likely secreted into human breastmilk.


title: Atorvastatin

text: Atorvastatin metabolism is primarily through cytochrome P450 3A4 hydroxylation to form active ortho- and parahydroxylated metabolites, as well as various beta-oxidation metabolites. The ortho- and parahydroxylated metabolites are responsible for 70% of systemic HMG-CoA reductase activity. The ortho-hydroxy metabolite undergoes further metabolism via glucuronidation. As a substrate for the CYP3A4 isozyme, it has shown susceptibility to inhibitors and inducers of CYP3A4 to produce increased or decreased plasma concentrations, respectively. This interaction was tested "in vitro" with concurrent administration of erythromycin, a known CYP3A4 isozyme inhibitor, which resulted in increased plasma concentrations of atorvastatin. It is also an inhibitor of cytochrome 3A4.


title: Atorvastatin

text: Atorvastatin is primarily eliminated via hepatic biliary excretion, with less than 2% recovered in the urine. Bile elimination follows hepatic and/or extrahepatic metabolism. There does not appear to be any entero-hepatic recirculation. Atorvastatin has an approximate elimination half-life of 14 hours. Noteworthy, the HMG-CoA reductase inhibitory activity appears to have a half-life of 20–30 hours, which is thought to be due to the active metabolites. Atorvastatin is also a substrate of the intestinal P-glycoprotein efflux transporter, which pumps the medication back into the intestinal lumen during medication absorption.


title: Atorvastatin

text: In hepatic insufficiency, plasma concentrations of atorvastatin are significantly affected by concurrent liver disease. People with Child-Pugh Stage A liver disease show a four-fold increase in both C and AUC. People with Child Pugh stage B liver disease show a 16-fold increase in C and an 11-fold increase in AUC.


title: Atorvastatin

text: Geriatric people (>65years old) exhibit altered pharmacokinetics of atorvastatin compared to young adults, with mean AUC and C values that are 40% and 30% higher, respectively. Additionally, healthy elderly people show a greater pharmacodynamic response to atorvastatin at any dose; therefore, this population may have lower effective doses.


title: Atorvastatin

text: Several genetic polymorphisms may be linked to an increase in statin-related side effects with single nucleotide polymorphisms (SNPs) in the SLCO1B1 gene showing a 45 fold higher incidence of statin related myopathy than people without the polymorphism.


title: Atorvastatin

text: There are several studies showing genetic variants and variable response to atorvastatin. The polymorphisms that showed genome wide significance in Caucasian population were the SNPs in the apoE region; rs445925, rs7412, rs429358 and rs4420638 which showed variable LDL-c response depending on the genotype when treated with atorvastatin. Another genetic variant that showed genome wide significance in Caucasians was the SNP rs10455872 in the LPA gene that lead to higher Lp(a) levels which cause an apparent lower LDL-c response to atorvastatin. These studies were in Caucasian population, more research with a large cohort need to be conducted in different ethnicities to identify more polymorphisms that can affect atorvastatin pharmacokinetics and treatment response.


title: Atorvastatin

text: The first synthesis of atorvastatin at Parke-Davis that occurred during drug discovery was racemic followed by chiral chromatographic separation of the enantiomers. An early enantioselective route to atorvastatin made use of an ester chiral auxiliary to set the stereochemistry of the first of the two alcohol functional groups via a diastereoselective aldol reaction.


title: Atorvastatin

text: Once the compound entered pre-clinical development, process chemistry developed a cost-effective and scalable synthesis. In atorvastatin's case, a key element of the overall synthesis was ensuring stereochemical purity in the final drug substance, and hence establishing the first stereocenter became a key aspect of the overall design. The final commercial production of atorvastatin relied on a chiral pool approach, where the stereochemistry of the first alcohol functional group was carried into the synthesis—through the choice of isoascorbic acid, an inexpensive and easily sourced plant-derived natural product.


title: Atorvastatin

text: The "atorvastatin calcium" complex involves two atorvastatin ions, one calcium ion and three water molecules.


title: Atorvastatin

text: Bruce Roth, who was hired by Warner-Lambert as a chemist in 1982, had synthesized an "experimental compound" codenamed CI 981 – later called atorvastatin. It was first made in August 1985. Warner-Lambert management was concerned that atorvastatin was a me-too version of rival Merck & Co.'s orphan drug lovastatin (brand name Mevacor). Mevacor, which was first marketed in 1987, was the industry's first statin and Merck's synthetic version – simvastatin – was in the advanced stages of development. Nevertheless, Bruce Roth and his bosses, Roger Newton and Ronald Cresswell, in 1985, convinced company executives to move the compound into expensive clinical trials. Early results comparing atorvastatin to simvastatin demonstrated that atorvastatin appeared more potent and with fewer side effects.


title: Atorvastatin

text: In 1994, the findings of a Merck-funded study were published in "The Lancet" concluding the efficacy of statins in lowering cholesterol proving for the first time not only that a "statin reduced 'bad' LDL cholesterol but also that it led to a sharp drop in fatal heart attacks among people with heart disease."


title: Atorvastatin

text: In 1996, Warner-Lambert entered into a co-marketing agreement with Pfizer to sell Lipitor, and in 2000, Pfizer acquired Warner-Lambert for $90.2billion. Lipitor was on the market by 1996. By 2003, Lipitor had become the best selling pharmaceutical in the United States. From 1996 to 2012, under the trade name Lipitor, atorvastatin became the world's best-selling medication of all time, with more than $125billion in sales over approximately 14.5years. and $13 billion a year at its peak, Lipitor alone "provided up to a quarter of Pfizer Inc.'s annual revenue for years."


title: Atorvastatin

text: Atorvastatin is relatively inexpensive. Under provisions of the Patient Protection and Affordable Care Act (PPACA) in the United States, health plans may cover the costs of atorvastatin 10 mg and 20 mg for adults aged 40–75 years based on United States Preventive Services Task Force (USPSTF) recommendations. Some plans only cover other statins.


title: Atorvastatin

text: Atorvastatin calcium tablets are sold under the brand name Lipitor. Pfizer also packages the medication in combination with other medications, such as atorvastatin/amlodipine.


title: Atorvastatin

text: Pfizer's U.S. patent on Lipitor expired on 30 November 2011. Initially, generic atorvastatin was manufactured only by Watson Pharmaceuticals and India's Ranbaxy Laboratories. Prices for the generic version did not drop to the level of other generics—$10 or less for a month's supply—until other manufacturers began to supply the medication in May 2012.


title: Atorvastatin

text: In other countries, atorvastatin calcium is made in tablet form by generic medication makers under various brand names including Atoris, Atorlip, Atorva, Atorvastatin Teva, Atorvastatina Parke-Davis, Avas, Cardyl, Liprimar, Litorva, Mactor, Orbeos, Prevencor, Sortis, Stator, Tahor, Torid, Torvacard, Torvast, Totalip, Tulip, Xarator, and Zarator. Pfizer also makes its own generic version under the name Zarator.


title: Atorvastatin

text: On 9 November 2012, Indian drugmaker Ranbaxy Laboratories Ltd. voluntarily recalled 10-, 20- and 40-mg doses of its generic version of atorvastatin in the United States. The lots of atorvastatin, packaged in bottles of 90 and 500 tablets, were recalled due to possible contamination with very small glass particles similar to the size of a grain of sand (less than 1mm in size). The FDA received no reports of injury from the contamination. Ranbaxy also issued recalls of bottles of 10-milligram tablets in August 2012 and March 2014, due to concerns that the bottles might contain larger, 20-milligram tablets and thus cause potential dosing errors.


title: Third World

text: The term "Third World" arose during the Cold War to define countries that remained non-aligned with either NATO or the Warsaw Pact. The United States, Canada, Japan, South Korea, Western European nations and their allies represented the "First World", while the Soviet Union, China, Cuba, North Korea, Vietnam and their allies represented the "Second World". This terminology provided a way of broadly categorizing the nations of the Earth into three groups based on political divisions. Strictly speaking, "Third World" was a political, rather than an economic, grouping. Since the dissolution of the Soviet Union and the end of the Cold War, the term "Third World" has decreased in use. It is being replaced with terms such as developing countries, least developed countries or the Global South. The concept itself has become outdated as it no longer represents the current political or economic state of the world and as historically poor countries have transited different income stages.


title: Third World

text: The Third World was normally seen to include many countries with colonial pasts in Africa, Latin America, Eastern Europe, Oceania, and Asia. It was also sometimes taken as synonymous with countries in the Non-Aligned Movement. In the dependency theory of thinkers like Raúl Prebisch, Walter Rodney, Theotônio dos Santos, and Andre Gunder Frank, the Third World has also been connected to the world-systemic economic division as "periphery" countries dominated by the countries comprising the economic "core".


title: Third World

text: Due to the complex history of evolving meanings and contexts, there is no clear or agreed-upon definition of the Third World. Some countries in the Eastern Bloc, such as Cuba, were often regarded as "Third World". Because many Third World countries were economically poor and non-industrialized, it became a stereotype to refer to developing countries as "third world countries", yet the "Third World" term is also often taken to include newly industrialized countries like Brazil, China and India now more commonly referred to as part of BRIC. In the Cold War, some European democracies (Austria, Finland, Republic of Ireland, Sweden, and Switzerland) were neutral in the sense of not joining NATO, but were prosperous, never joined the Non-Aligned Movement, and seldom self-identified as part of the Third World.


title: Third World

text: French demographer, anthropologist, and historian Alfred Sauvy, in an article published in the French magazine "", August 14, 1952, coined the term "third world" (), referring to countries that were playing little role on the international scene. His usage was a reference to the Third Estate (), the commoners of France who, before and during the French Revolution, opposed the clergy and nobles, who composed the First Estate and Second Estate, respectively (hence the use of the older form "tiers" rather than the modern for "third"). Sauvy wrote, "This third world ignored, exploited, despised like the third estate also wants to be something." In the context of the Cold War, he conveyed the concept of political non-alignment with either the capitalist or communist bloc. Simplistic interpretations quickly led to the term merely designating these unaligned countries.


title: Third World

text: The "Three Worlds Theory" developed by Mao Zedong is different from the Western theory of the Three Worlds or Third World. For example, in the Western theory, China and India belong respectively to the second and third worlds, but in Mao's theory both China and India are part of the Third World which he defined as consisting of exploited nations.


title: Third World

text: Third Worldism is a political movement that argues for the unity of third-world nations against first-world influence and the principle of non-interference in other countries' domestic affairs. Groups most notable for expressing and exercising this idea are the Non-Aligned Movement (NAM) and the Group of 77 which provide a base for relations and diplomacy between not just the third-world countries, but between the third-world and the first and second worlds. The notion has been criticized as providing a fig leaf for human rights violations and political repression by dictatorships.


title: Third World

text: Since 1990, this term has been redefined to make it more correct politically. Initially, the term “third world” meant that a nation is “under-developed”. However, today it is replaced by the term “developing".


title: Third World

text: Many times there is a clear distinction between First and Third Worlds. When talking about the Global North and the Global South, the majority of the time the two go hand in hand. People refer to the two as "Third World/South" and "First World/North" because the Global North is more affluent and developed, whereas the Global South is less developed and often poorer.


title: Third World

text: To counter this mode of thought, some scholars began proposing the idea of a change in world dynamics that began in the late 1980s, and termed it the Great Convergence. As Jack A. Goldstone and his colleagues put it, "in the twentieth century, the Great Divergence peaked before the First World War and continued until the early 1970s, then, after two decades of indeterminate fluctuations, in the late 1980s, it was replaced by the Great Convergence as the majority of Third World countries reached economic growth rates significantly higher than those in most First World countries".


title: Third World

text: Others have observed a return to Cold War-era alignments (MacKinnon, 2007; Lucas, 2008), this time with substantial changes between 1990–2015 in geography, the world economy and relationship dynamics between current and emerging world powers; not necessarily redefining the classic meaning of "First", "Second", and "Third World" terms, but rather which countries belong to them by way of association to which world power or coalition of countries — such as G7, the European Union, OECD; G20, OPEC, N-11, BRICS, ASEAN; the African Union, and the Eurasian Union.


title: Third World

text: Most Third World countries are former colonies. Having gained independence, many of these countries, especially smaller ones, were faced with the challenges of nation- and institution-building on their own for the first time. Due to this common background, many of these nations were "developing" in economic terms for most of the 20th century, and many still are. This term, used today, generally denotes countries that have not developed to the same levels as OECD countries, and are thus in the process of "developing".


title: Third World

text: In the 1980s, economist Peter Bauer offered a competing definition for the term "Third World". He claimed that the attachment of Third World status to a particular country was not based on any stable economic or political criteria, and was a mostly arbitrary process. The large diversity of countries considered part of the Third World — from Indonesia to Afghanistan — ranged widely from economically primitive to economically advanced and from politically non-aligned to Soviet- or Western-leaning. An argument could also be made for how parts of the U.S. are more like the Third World.


title: Third World

text: The only characteristic that Bauer found common in all Third World countries was that their governments "demand and receive Western aid," the giving of which he strongly opposed. Thus, the aggregate term "Third World" was challenged as misleading even during the Cold War period, because it had no consistent or collective identity among the countries it supposedly encompassed.


title: Third World

text: During the Cold War, unaligned countries of the Third World were seen as potential allies by both the First and Second World. Therefore, the United States and the Soviet Union went to great lengths to establish connections in these countries by offering economic and military support to gain strategically located alliances (e.g., the United States in Vietnam or the Soviet Union in Cuba). By the end of the Cold War, many Third World countries had adopted capitalist or communist economic models and continued to receive support from the side they had chosen. Throughout the Cold War and beyond, the countries of the Third World have been the priority recipients of Western foreign aid and the focus of economic development through mainstream theories such as modernization theory and dependency theory.


title: Third World

text: By the end of the 1960s, the idea of the Third World came to represent countries in Africa, Asia, and Latin America that were considered underdeveloped by the West based on a variety of characteristics (low economic development, low life expectancy, high rates of poverty and disease, etc.). These countries became the targets for aid and support from governments, NGOs and individuals from wealthier nations. One popular model, known as Rostow's stages of growth, argued that development took place in 5 stages (Traditional Society; Pre-conditions for Take-off; Take-off; Drive to Maturity; Age of High Mass Consumption). W. W. Rostow argued that "Take-off" was the critical stage that the Third World was missing or struggling with. Thus, foreign aid was needed to help kick-start industrialization and economic growth in these countries.


title: Third World

text: Since 1990 the term "Third World" has been redefined in many evolving dictionaries in several languages to refer to countries considered to be underdeveloped economically and/or socially. From a "political correctness" standpoint the term "Third World" may be considered outdated, which its concept is mostly a historical term and cannot fully address what means by developing and less-developed countries today. Around the early 1960s, the term "underdeveloped countries" occurred and the Third World serves to be its synonym, but after it has been officially used by politicians, 'underdeveloped countries' is soon been replaced by 'developing' and 'less-developed countries,' because the prior one shows hostility and disrespect, in which the Third World is often characterized with stereotypes. The whole 'Four Worlds' system of classification has also been described as derogatory because the standard mainly focused on each nations' Gross National Product.


title: Third World

text: The general definition of the Third World can be traced back to the history that nations positioned as neutral and independent during the Cold War were considered as Third World Countries, and normally these countries are defined by high poverty rates, lack of resources, and unstable financial standing. However, based on the rapid development of modernization and globalization, countries that were used to be considered as Third World countries achieve big economic growth, such as Brazil, India, and Indonesia, which can no longer be defined by poor economic status or low GNP today. The differences among nations of the Third World are continually growing throughout time, and it will be hard to use the Third World to define and organize groups of nations based on their common political arrangements since most countries live under diverse creeds in this era, such as Mexico, El Salvador, and Singapore, which they all have their own political system. The Third World categorization becomes anachronistic since its political classification and economic system are distinct to be applied in today's society. Based on the Third World standards, any region of the world can be categorized into any of the four types of relationships among state and society, and will eventually end in four outcomes: praetorianism, multi-authority, quasi-democratic and viable democracy. However, political culture is never going to be limited by the rule and the concept of the Third World can be circumscribed.


title: Doordarshan

text: Doordarshan (abbreviated as DD; Hindi: , ) is an Indian public service broadcaster founded by the Government of India, owned by the Ministry of Information and Broadcasting and one of Prasar Bharati's two divisions. One of India's largest broadcasting organisations in studio and transmitter infrastructure, it was established on 15 September 1959. Doordarshan, which also broadcasts on digital terrestrial transmitters, provides television, radio, online and mobile service throughout metropolitan and regional India and overseas.


title: Doordarshan

text: The channel began modestly as an experimental broadcaster in Delhi on 15 September 1959, with a small transmitter and a makeshift studio. Regular daily transmission started in 1965 as part of All India Radio, with a five-minute news bulletin read by Pratima Puri. Salma Sultan joined Doordarshan in 1967, and became a news anchor.


title: Doordarshan

text: "Krishi Darshan" debuted on Doordarshan on 26 January 1967, and is Indian television's longest running program.


title: Doordarshan

text: Television service was extended to Bombay (now Mumbai) and Amritsar in 1972. Until 1975 only seven Indian cities had television service, and Doordarshan was the country's sole television provider.


title: Doordarshan

text: Television service was separated from radio on 1 April 1976. The All India Radio and Doordarshan were placed under the management of separate directors-general in New Delhi. In 1982, Doordarshan became a national broadcaster.


title: Doordarshan

text: National telecasts (DD National) was introduced in 1982. Colour television began in India with the live telecast of the Independence Day speech by Prime Minister Indira Gandhi on 15 August of that year, followed by the colour telecast of the 1982 Asian Games in Delhi. Two years later, Doordarshan as a TV network finally took shape: the then sole TV channel was split into the nationally aired DD-1 and city channel DD-2, later rebranded in 1993 as "DD National" and "DD Metro".


title: Doordarshan

text: Live telecasts of the opening and closing ceremonies of the 2012 Summer Olympics were broadcast on its national channel, and DD Sports provided round-the-clock coverage.


title: Doordarshan

text: On 17 November 2014, Doordarshan director-general Vijayalaxmi Chhabra introduced a pink-and-purple colour scheme and a new slogan: "Desh Ka Apna Channel" ("The country's own channel"). Doordarshan transmitted over a network of nearly 1,400 terrestrial transmitters in 2017, with 46 studios producing TV programmes. After the introduction of private channels Doordarshan is struggling to keep its position in the television space. Currently Doordarshan is trying to improve its studios and programmes while its primary aim is to serve the country.


title: Doordarshan

text: Doordarshan operates 46 studios and 21 television channels: two all-India channels (DD National and DD News), 17 regional satellite channels, 11 state networks, an international channel (DD India), a sports channel (DD Sports), DD Bharati, DD Retro, DD Urdu and an agricultural channel, DD Kisan. On DD National (formerly DD-1), regional and local programs are carried on a time-sharing basis for terrestrial broadcasting only. DD News, launched on 3 November 2003 replacing DD Metro (formerly known as the DD-2 entertainment channel), provides 24-hour news. These channels are relayed by all terrestrial transmitters in India. The regional-language satellite channels have two components: a regional service for a particular state (relayed by all terrestrial transmitters in the state), and additional programs in the regional language available through cable operators and DTH operators. DD Sports broadcasts sporting events of national and international importance. It is the only sports channel which telecasts rural sports such as kho-kho and kabbadi.


title: Doordarshan

text: A new regional channel, DD Arunprabha (a 24/7 satellite television channel focusing on the North Eastern region) was scheduled to begin on 15 February 2018; however, its launch was placed on hold. DD Arunprabha was launched on 9 February 2019.


title: Doordarshan

text: On 9 March 2019, Prasar Bharati brought 11 more State DD Channels on the Satellite footprint of India through DD Free Dish. This includes five channels for Northeastern states. This will go a long way in strengthening regional cultures and fulfilling people's aspirations. These are – DD Bangla, DD Chhattisgarh, DD Goa, DD Haryana, DD Himachal Pradesh, DD Jharkhand, DD Manipur, DD Meghalaya, DD Mizoram, DD Nagaland, DD Tripura and DD Uttarakhand. DD Bangla launched on 9 August 1975, the network's programming consists of soap operas, infotainment series, news and current affairs, social programs and films in Bengali language.


title: Doordarshan

text: On 13 April 2020, DD Retro was launched by Prasar Bharati which showed old classic Hindi serials of Doordarshan.


title: Doordarshan

text: The DD India satellite channel has been broadcast in 146 countries. In United Kingdom, it was available through the Eurobird satellite on the Sky system's channel 833; its logo was Rayat TV. Transmission via Sky Digital ended in June 2008, and via DirecTV in the United States the following month.


title: Doordarshan

text: Ramayan on DD National created a world record by becoming highest viewed entertainment programme globally. The 9 PM show on 16 April 2020 was watched by a mammoth 7.7 crore (77 million) viewers. The show managed to reach more than 28.5 crore (285 million) viewers through the length of the broadcast. As a broadcasting response to nation-wide lockdown, apart from Ramayan, many other nostalgia shows were broadcast on DD network. These included Mahabharat, Chanakya, Shri Krishna, Byomkesh Bakshi and Shaktimaan.


title: Doordarshan

text: In light of increasing public demand for such retro content, Prasar Bharati launched ‘DD Retro’ as a full-time channel dedicated for the same. The channel started garnering viewership of almost 5 crore (50 million) within five weeks of its launch.


title: Doordarshan

text: Delivering on its mandate of public messaging, DD network, through COVID-focused awareness messages and shows, reached more than 40 crore (400 million) viewers during first wave of the pandemic in 2020.


title: Doordarshan

text: Prasar Bharati is Doordarshan's parent body, and its board members are appointed by the Government of India through the Information and Broadcasting Ministry.


title: Doordarshan

text: Doordarshan has been used, especially during the Emergency, to disseminate government propaganda. During Operation Blue Star in 1984, only government sources were used to report the story. Doordarshan was complicit in the production of a video claiming acts of violence which, when investigated by independent journalists, were found to be false.


title: Doordarshan

text: In 2004, it censored a controversial documentary on Jayaprakash Narayan, an opposition leader during the Emergency.


title: Doordarshan

text: In 2014, When Doordarshan broadcast a 70-minute Vijayadashami speech by Rashtriya Swayamsevak Sangh (RSS) leader Mohan Bhagwat, the Narendra Modi administration and the BJP were criticised for "misusing" the public broadcaster. According to DD director-general Archana Datta, the "speech was like any other news event; therefore, we covered it."


title: Doordarshan

text: Since private television channels were authorised in 1991, Doordarshan has experienced a steep decline in viewership. Although it earns significant advertising revenue—due to its compulsory feed—from the highest bidder for national events (including cricket matches), there has been a proposal to fund it by imposing a licence fee to own a television in India.


title: Terracotta Army

text: The Terracotta Army is a collection of terracotta sculptures depicting the armies of Qin Shi Huang, the first emperor of China. It is a form of funerary art buried with the emperor in 210–209 BCE with the purpose of protecting the emperor in his afterlife.


title: Terracotta Army

text: The figures, dating from approximately the late third century BCE, were discovered in 1974 by local farmers in Lintong County, outside Xi'an, Shaanxi, China. The figures vary in height according to their roles, the tallest being the generals. The figures include warriors, chariots and horses. Estimates from 2007 were that the three pits containing the Terracotta Army held more than 8,000 soldiers, 130 chariots with 520 horses, and 150 cavalry horses, the majority of which remained buried in the pits near Qin Shi Huang's mausoleum. Other terracotta non-military figures were found in other pits, including officials, acrobats, strongmen, and musicians.


title: Terracotta Army

text: The construction of the tomb was described by historian Sima Qian (14590 BCE) in "Records of the Grand Historian", the first of China's 24 dynastic histories, which was written a century after the mausoleum's completion. Work on the mausoleum began in 246 BCE soon after Emperor Qin (then aged 13) ascended the throne, and the project eventually involved 700,000 conscripted workers. Geographer Li Daoyuan, writing six centuries after the first emperor's death, recorded in "Shui Jing Zhu" that Mount Li was a favoured location due to its auspicious geology: "famed for its jade mines, its northern side was rich in gold, and its southern side rich in beautiful jade; the first emperor, covetous of its fine reputation, therefore chose to be buried there". Sima Qian wrote that the first emperor was buried with palaces, towers, officials, valuable artifacts and wondrous objects. According to this account, 100 flowing rivers were simulated using mercury, and above them the ceiling was decorated with heavenly bodies, below which were the features of the land. Some translations of this passage refer to "models" or "imitations"; however, those words were not used in the original text, which makes no mention of the terracotta army. High levels of mercury were found in the soil of the tomb mound, giving credence to Sima Qian's account. Later historical accounts suggested that the complex and tomb itself had been looted by Xiang Yu, a contender for the throne after the death of the first emperor. However, there are indications that the tomb itself may not have been plundered.


title: Terracotta Army

text: was discovered on 29 March 1974 by a group of farmers—Yang Zhifa, his five brothers, and neighbour Wang Puzhi—who were digging a well approximately east of the Qin Emperor's tomb mound at Mount Li (Lishan), a region riddled with underground springs and watercourses. For centuries, occasional reports mentioned pieces of terracotta figures and fragments of the Qin necropolis – roofing tiles, bricks and chunks of masonry. This discovery prompted Chinese archaeologists, including Zhao Kangmin, to investigate, revealing the largest pottery figurine group ever found. A museum complex has since been constructed over the area, the largest pit being enclosed by a roofed structure.


title: Terracotta Army

text: The Terracotta Army is part of a much larger necropolis. Ground-penetrating radar and core sampling have measured the area to be approximately 98 square kilometers (38 square miles).


title: Terracotta Army

text: The necropolis was constructed as a microcosm of the emperor's imperial palace or compound, and covers a large area around the tomb mound of the first emperor. The earthen tomb mound is located at the foot of Mount Li and built in a pyramidal shape, and is surrounded by two solidly built rammed earth walls with gateway entrances. The necropolis consists of several offices, halls, stables, other structures as well as an imperial park placed around the tomb mound.


title: Terracotta Army

text: The warriors stand guard to the east of the tomb. Up to of reddish, sandy soil had accumulated over the site in the two millennia following its construction, but archaeologists found evidence of earlier disturbances at the site. During the excavations near the Mount Li burial mound, archaeologists found several graves dating from the 18th and 19th centuries, where diggers had apparently struck terracotta fragments. These were discarded as worthless and used along with soil to backfill the excavations.


title: Terracotta Army

text: The tomb appears to be a hermetically sealed space roughly the size of a football pitch (c. 100 × 75 m). The tomb remains unopened, possibly due to concerns over preservation of its artifacts. For example, after the excavation of the Terracotta Army, the painted surface present on some terracotta figures began to flake and fade. The lacquer covering the paint can curl in fifteen seconds once exposed to Xi'an's dry air and can flake off in just four minutes.


title: Terracotta Army

text: Four main pits approximately deep have been excavated. These are located approximately east of the burial mound. The soldiers within were laid out as if to protect the tomb from the east, where the Qin Emperor's conquered states lay.


title: Terracotta Army

text: Pit 1, which is long and wide, contains the main army of more than 6,000 figures. Pit 1 has eleven corridors, most more than wide and paved with small bricks with a wooden ceiling supported by large beams and posts. This design was also used for the tombs of nobles and would have resembled palace hallways when built. The wooden ceilings were covered with reed mats and layers of clay for waterproofing, and then mounded with more soil raising them about above the surrounding ground level when completed.


title: Terracotta Army

text: Pit 2 has cavalry and infantry units as well as war chariots and is thought to represent a military guard. Pit 3 is the command post, with high-ranking officers and a war chariot. Pit 4 is empty, perhaps left unfinished by its builders.


title: Terracotta Army

text: Some of the figures in Pits 1 and 2 show fire damage, while remains of burnt ceiling rafters have also been found. These, together with the missing weapons, have been taken as evidence of the reported looting by Xiang Yu and the subsequent burning of the site, which is thought to have caused the roof to collapse and crush the army figures below. The terracotta figures currently on display have been restored from the fragments.


title: Terracotta Army

text: Other pits that formed the necropolis have also been excavated. These pits lie within and outside the walls surrounding the tomb mound. They variously contain bronze carriages, terracotta figures of entertainers such as acrobats and strongmen, officials, stone armour suits, burial sites of horses, rare animals and labourers, as well as bronze cranes and ducks set in an underground park.


title: Terracotta Army

text: The terracotta figures are life-sized, typically ranging from to about (the officers are typically taller). They vary in height, uniform, and hairstyle in accordance with rank. Their faces appear to be different for each individual figure; scholars, however, have identified 10 basic face shapes. The figures are of these general types: armored infantry; unarmored infantry; cavalrymen who wear a pillbox hat; helmeted drivers of chariots with more armor protection; spear-carrying charioteers; kneeling crossbowmen or archers who are armored; standing archers who are not; as well as generals and other lower-ranking officers. There are, however, many variations in the uniforms within the ranks: for example, some may wear shin pads while others not; they may wear either long or short trousers, some of which may be padded; and their body armors vary depending on rank, function, and position in formation. There are also terracotta horses placed among the warrior figures.


title: Terracotta Army

text: Originally, the figures were painted with: ground precious stones, intensely fired bones (white), pigments of iron oxide (dark red), cinnabar (red), malachite (green), azurite (blue), charcoal (black), cinnabar barium copper silicate mix (Chinese purple or Han purple), tree sap from a nearby source, (more than likely from the Chinese lacquer tree) (brown). Other colors including pink, lilac, red, white, and one unidentified color. The colored lacquer finish and individual facial features would have given the figures a realistic feel, with eyebrows and facial hair in black and the faces done in pink.


title: Terracotta Army

text: However, in Xi'an's dry climate, much of the color coating would flake off in less than four minutes after removing the mud surrounding the army.


title: Terracotta Army

text: Some scholars have speculated a possible Hellenistic link to these sculptures, because of the lack of life-sized and realistic sculptures before the Qin dynasty. They argued that potential Greek influence is particularly evident in some terracotta figures such as those of acrobats, combined with rare bronze artifacts made with a lost wax technique known in Greece and Egypt. However, this idea is disputed by scholars who claim that there is "no substantial evidence at all" for contact between ancient Greeks and Chinese builders of the tomb, and the bases of such speculation are often imprecise or false interpretation of source materials or far-fetched conjectures. They argue that such speculations rest on flawed and old "Eurocentric" ideas that assumed other civilizations were incapable of sophisticated artistry and thus foreign artistry must be seen through Western traditions.


title: Terracotta Army

text: The terracotta army figures were manufactured in workshops by government laborers and local craftsmen using local materials. Heads, arms, legs, and torsos were created separately and then assembled by luting the pieces together. When completed, the terracotta figures were placed in the pits in precise military formation according to rank and duty.


title: Terracotta Army

text: The faces were created using molds, and at least ten face molds may have been used. Clay was then added after assembly to provide individual facial features to make each figure appear different. It is believed that the warriors' legs were made in much the same way that terracotta drainage pipes were manufactured at the time. This would classify the process as assembly line production, with specific parts manufactured and assembled after being fired, as opposed to crafting a figure as one solid piece and subsequently firing it. In those times of tight imperial control, each workshop was required to inscribe its name on items produced to ensure quality control. This has aided modern historians in verifying which workshops were commandeered to make tiles and other mundane items for the terracotta army.


title: Terracotta Army

text: Most of the figures originally held real weapons, which would have increased their realism. The majority of these weapons were looted shortly after the creation of the army or have rotted away. Despite this, over 40,000 bronze items of weaponry have been recovered, including swords, daggers, spears, lances, battle-axes, scimitars, shields, crossbows, and crossbow triggers. Most of the recovered items are arrowheads, which are usually found in bundles of 100 units. Studies of these arrowheads suggests that they were produced by self-sufficient, autonomous workshops using a process referred to as "cellular production" or "Toyotism". Some weapons were coated with a 10–15 micrometer layer of chromium dioxide before burial that was believed to have protected them from any form of decay for the last 2200 years. However, research in 2019 indicated that the chromium was merely contamination from nearby lacquer, not a means of protecting the weapons. The slightly alkaline pH and small particle size of the burial soil most likely preserved the weapons.


title: Terracotta Army

text: The swords contain an alloy of copper, tin, and other elements including nickel, magnesium, and cobalt. Some carry inscriptions that date their manufacture to between 245 and 228 BCE, indicating that they were used before burial.


title: Terracotta Army

text: In 2007, scientists at Stanford University and the Advanced Light Source facility in Berkeley, California, reported that powder diffraction experiments combined with energy-dispersive X-ray spectroscopy and micro-X-ray fluorescence analysis showed that the process of producing terracotta figures colored with Chinese purple dye consisting of barium copper silicate was derived from the knowledge gained by Taoist alchemists in their attempts to synthesize jade ornaments.


title: Terracotta Army

text: Since 2006, an international team of researchers at the UCL Institute of Archaeology have been using analytical chemistry techniques to uncover more details about the production techniques employed in the creation of the Terracotta Army. Using X-ray fluorescence spectrometry of 40,000 bronze arrowheads bundled in groups of 100, the researchers reported that the arrowheads within a single bundle formed a relatively tight cluster that was different from other bundles. In addition, the presence or absence of metal impurities was consistent within bundles. Based on the arrows’ chemical compositions, the researchers concluded that a cellular manufacturing system similar to the one used in a modern Toyota factory, as opposed to a continuous assembly line in the early days of the automobile industry, was employed.


title: Terracotta Army

text: Grinding and polishing marks visible under a scanning electron microscope provide evidence for the earliest industrial use of lathes for polishing.


title: Terracotta Army

text: The first exhibition of the figures outside of China was held at National Gallery of Victoria (NGV) in Melbourne in 1982.


title: Terracotta Army

text: A collection of 120 objects from the mausoleum and 12 terracotta warriors were displayed at the British Museum in London as its special exhibition "The First Emperor: China's Terracotta Army" from 13 September 2007 to April 2008. This exhibition made 2008 the British Museum's most successful year and made the British Museum the United Kingdom's top cultural attraction between 2007 and 2008. The exhibition brought the most visitors to the museum since the King Tutankhamun exhibition in 1972. It was reported that the 400,000 advance tickets sold out so fast that the museum extended its opening hours until midnight. According to "The Times", many people had to be turned away, despite the extended hours. During the day of events to mark the Chinese New Year, the crush was so intense that the gates to the museum had to be shut. The Terracotta Army has been described as the only other set of historic artifacts (along with the remnants of wreck of the RMS "Titanic") that can draw a crowd by the name alone.


title: Terracotta Army

text: Warriors and other artifacts were exhibited to the public at the Forum de Barcelona in Barcelona between 9 May and 26 September 2004. It was their most successful exhibition ever. The same exhibition was presented at the Fundación Canal de Isabel II in Madrid between October 2004 and January 2005, their most successful ever. From December 2009 to May 2010, the exhibition was shown in the Centro Cultural La Moneda in Santiago de Chile.


title: Terracotta Army

text: The exhibition traveled to North America and visited museums such as the Asian Art Museum of San Francisco, Bowers Museum in Santa Ana, California, Houston Museum of Natural Science, High Museum of Art in Atlanta, National Geographic Society Museum in Washington, D.C. and the Royal Ontario Museum in Toronto. Subsequently, the exhibition traveled to Sweden and was hosted in the Museum of Far Eastern Antiquities between 28 August 2010 and 20 January 2011. An exhibition entitled 'The First Emperor – China's Entombed Warriors', presenting 120 artifacts was hosted at the Art Gallery of New South Wales, between 2 December 2010 and 13 March 2011. An exhibition entitled "L'Empereur guerrier de Chine et son armée de terre cuite" ("The Warrior-Emperor of China and his terracotta army"), featuring artifacts including statues from the mausoleum, was hosted by the Montreal Museum of Fine Arts from 11 February 2011 to 26 June 2011. In Italy, from July 2008 to 16 November 2008, five of the warriors of the terracotta army were displayed in Turin at the Museum of Antiquities, and from 16 April 2010 to 5 September 2010 were exposed nine warriors in Milan, at the Royal Palace, at the exhibition entitled "The Two Empires". The group consisted of a horse, a counselor, an archer and six lancers. The "Treasures of Ancient China" exhibition, showcasing two terracotta soldiers and other artifacts, including the Longmen Grottoes Buddhist statues, was held between 19 February 2011 and 7 November 2011 in four locations in India: National Museum of New Delhi, Prince of Wales Museum in Mumbai, Salar Jung Museum in Hyderabad and National Library of India in Kolkata.


title: Terracotta Army

text: Soldiers and related items were on display from 15 March 2013 to 17 November 2013, at the Historical Museum of Bern.


title: Terracotta Army

text: Several Terracotta Army figures were on display, along with many other objects, in an exhibit entitled "Age of Empires: Chinese Art of the Qin and Han Dynasties" at The Metropolitan Museum of Art in New York City from 3 April 2017, to 16 July 2017. An exhibition featuring ten Terracotta Army figures and other artifacts, "Terracotta Warriors of the First Emperor," was on display at the Pacific Science Center in Seattle, Washington, from 8 April 2017 to 4 September 2017 before traveling to The Franklin Institute in Philadelphia, Pennsylvania, to be exhibited from 30 September 2017 to 4 March 2018 with the addition of augmented reality.


title: Terracotta Army

text: An exhibition entitled "China's First Emperor and the Terracotta Warriors" was at the World Museum in Liverpool from 9 February 2018 to 28 October 2018. This was the first time in more than 10 years that the warriors travelled to the UK.


title: Terracotta Army

text: An exhibition tour of 120 real-size replicas of Terracotta statues was displayed in the German cities of Frankfurt am Main, Munich, Oberhof, Berlin (at the Palace of the Republic) and Nuremberg between 2003 and 2004.


title: The Voyeurs

text: The Voyeurs is a 2021 American erotic thriller film written and directed by Michael Mohan. Shot and set in Montreal, Quebec, Canada, it stars Sydney Sweeney and Justice Smith as a young couple who spy on and become obsessed by the lives of their neighbors across the street (Ben Hardy and Natasha Liu Bordizzo). Greg Gilreath and Adam Hendricks serve as producers under their Divide/Conquer banner.


title: The Voyeurs

text: It was released on September 10, 2021, by Amazon Studios, on the Amazon Prime Video streaming service. Despite receiving mixed reviews from critics, this film's streaming performance had exceeded Amazon Studios' expectations.


title: The Voyeurs

text: A young couple, Pippa and Thomas, move into their first apartment together in Montreal. They soon realize that their windows look directly into the apartment across the street, where a man with a professional studio is taking photographs of a woman. Pippa and Thomas watch as the couple have sex. Thomas continues to watch at first, but stops at Pippa's insistence. They jokingly give their neighbors pseudo names, Margot and Brent.


title: The Voyeurs

text: Pippa, who works as a trainee optometrist at L'Optique, receives a bird feeder from her boss as a housewarming gift. Pippa buys a pair of binoculars so she and Thomas can watch the couple. They often see "Brent" having sex with several models while "Margot" is out.


title: The Voyeurs

text: Pippa expresses interest in knowing what the neighbors are saying, eventually learning that Thomas knows a way to listen in on another room using a laser pointer; the process requires a reflective surface to send the laser beam back to them. When "Brent" and "Margot" throw a Halloween costume party in their apartment, Pippa and Thomas sneak in by posing as guests. Pippa plants a mirror in the apartment, later allowing her and Thomas to listen in on their conversations. They are unsettled to hear "Margot" confront "Brent" about his adultery; "Brent" assaults "Margot" and convinces her that her suspicions are unfounded.


title: The Voyeurs

text: The next day, "Margot", whose real name is Julia, visits L'Optique where she receives an eye exam from Pippa and orders a new set of stylish glasses recommended by her. Julia invites Pippa to hang out. Pippa wants to warn Julia about "Brent's" adultery, but Thomas insists that she stop spying on the neighbors. Later, Pippa and Julia meet at a spa; Julia reveals that her husband is named Sebastian, or Seb, and is a well-known photographer.


title: The Voyeurs

text: Pippa observes Seb having a threesome and throwing a condom away afterwards. She later discovers how to access Julia and Seb's wireless printer, which she uses to anonymously expose Seb's infidelities to Julia, mentioning the condom as proof. Thomas angrily confronts Pippa about being so invested in Julia and Seb's lives. The next morning, Pippa apologizes to Thomas and promises to stop watching the neighbors. However, they then see Seb discover Julia's body in the bathroom, after she seemingly slit her own throat. Thomas blames Pippa for Julia's death, breaks up with her, and leaves.


title: The Voyeurs

text: Although heartbroken, Pippa continues to watch Seb and one evening decides to follow him to a nearby pub. Seb sits by Pippa and they talk. He asks her to let him photograph her at his apartment, which she accepts. Seb convinces Pippa to pose nude for him, and they eventually have sex. Upon returning home, Thomas consumes a drink Pippa left in the refrigerator and pours it into her bird feeder. He notices Pippa having sex with Seb across the street. The next morning, a horrified Pippa finds Thomas dead in their apartment, having apparently hanged himself.


title: The Voyeurs

text: Pippa and her friend Ari go to Seb's exhibition, which turns out to be a collaboration with Julia, who is alive. Pippa and Thomas are revealed to be the subjects of the exhibition. Seb and Julia divulge that they own the apartment rented by Pippa and Thomas (whose lease included a clause stating that they consented to be photographed), and they knew they were being watched. Distressed, Pippa storms off. She decides to move out of the apartment, and notices dead birds on a grate just below her bird feeder.


title: The Voyeurs

text: Following an interview promoting their exhibition, Seb and Julia return home to find a congratulatory bottle of wine by their door. As they drink the wine, Pippa sends a message to their printer saying she knows they killed Thomas. After leading Seb and Julia into L'Optique, Pippa deduces that while she was having sex with Seb, Julia poisoned Thomas's drink and staged his suicide. Pippa also reveals that she spiked their wine, causing Julia and Seb to faint. Pippa places the two under a LASIK machine, using it to burn their corneas.


title: The Voyeurs

text: A new couple have moved into Pippa and Thomas's former apartment. They observe Seb and Julia in their apartment, both of whom are now blind. Pippa watches Seb and Julia from the rooftop, before leaving her binoculars behind.


title: The Voyeurs

text: In September 2019, it was announced Michael Mohan would direct the film from a screenplay he wrote, with Greg Gilreath and Adam Hendricks serving as producers under their Divide/Conquer banner, and Amazon Studios distributing. In November 2019, Sydney Sweeney, Justice Smith, Natasha Liu Bordizzo and Ben Hardy joined the cast of the film.


title: The Voyeurs

text: "The Voyeurs" was released on September 10, 2021, on the Amazon Prime Video streaming service. This film's streaming performance had exceeded Amazon Studios' expectations.


title: The Voyeurs

text: The film received mixed reviews from critics, who compared it unfavorably to its forebears in the voyeuristic thriller genre, such as "Rear Window" (1954) and "Body Double" (1984). On Rotten Tomatoes, "The Voyeurs" holds a 43% approval rating based on 35 reviews, with an average rating of 5.8/10. On Metacritic, the film has a weighted average score of 54 out of 100, based on 9 critics, indicating "mixed or average reviews".


title: The Voyeurs

text: In a negative review for the "Chicago Sun-Times", Richard Roeper described "The Voyeurs" as a "salacious and wildly implausible story that holds our interest for a while before flying off the cliff and into an abyss of creepy, ludicrous and ultimately ridiculous twists and turns". Nick Schager of "Variety" was also critical of the film, which he found "plays like rehashed leftovers cooked up for young viewers who've never seen any of its superior inspirations", such as Hitchcock's "Rear Window" (1954). In the "San Francisco Chronicle", G. Allen Johnson felt Michael Mohan's script was "pedestrian" and unfavorably compared his direction to that of David Lynch and Brian De Palma. "One suspects they would have a bit more fun and taken us further down the moral rabbit hole," Johnson explained, "And the sex would have been better too."


title: The Voyeurs

text: On the other hand, Charles Bramesco was more appreciative of "The Voyeurs". In a four-out-of-five star review for "The Guardian", he found the film to be "the real deal, an ideal cocktail of funny, diabolical and perverted," and a timely update of "Rear Window". "At last, a homage that dares to ask," Bramesco quipped, "what if Grace Kelly had been able to give the wheelchair-bound Jimmy Stewart a hand job the first time they both looked in on his neighbors across the way?"


title: Sonoya Mizuno

text: She notably starred in the miniseries "Maniac" and the "Game of Thrones" prequel series "House of the Dragon", and appeared in all the works directed by Alex Garland, such as the films "Ex Machina", "Annihilation", and "Men", and his miniseries "Devs". Other roles include minor appearances in "La La Land", "Beauty and the Beast", and "Crazy Rich Asians".


title: Sonoya Mizuno

text: Born in Tokyo, Mizuno was raised in Somerset, England. Her mother is of half English and half Argentine descent and her father is Japanese. She graduated from the Royal Ballet School before dancing with several ballet companies, including Semperoper Ballet in Dresden, Ballet Ireland, New English Ballet Theatre and Scottish Ballet.


title: Sonoya Mizuno

text: Mizuno took up professional modelling at age 20 with Profile Models in London and has modelled for Chanel, Alexander McQueen, Saint Laurent and Louis Vuitton. During 2014, she appeared in Arthur Pita's work of dance theatre "The World's Greatest Show" at Greenwich Dance and the Royal Opera House.


title: Sonoya Mizuno

text: She made her film debut in Alex Garland's science-fiction thriller "Ex Machina" in 2014. Mizuno appeared in the dance film "High Strung", directed by Michael Damian and released in 2016. Also in 2016, she was the feature dancer in the music video for "Wide Open" by The Chemical Brothers and Beck, and appeared in the music video for Frank Ocean's song "Nikes". Later in 2016, she was in "La La Land", playing the role of Caitlin, one of the three roommates of Mia, played by Emma Stone.


title: Sonoya Mizuno

text: In 2017, Mizuno appeared in a small role as the debutante in Disney's live-action adaptation of "Beauty and the Beast", and in 2018, she acted in the Warner Bros. film "Crazy Rich Asians."


title: Sonoya Mizuno

text: She has appeared in television/ streaming roles including Cary Joji Fukunaga's "Maniac" on Netflix. In 2018, she took the lead role of Lily Chan in Alex Garland's miniseries for FX, "Devs".


title: Sonoya Mizuno

text: Mizuno starred in the 2016 Dom & Nic video for The Chemical Brothers' "Wide Open", featuring Beck, where she played a dancer gradually transformed into a 3-D lattice.


title: David Leitch

text: David Leitch (born November 16, 1975) is an American filmmaker, actor, stunt performer and stunt coordinator who made his directorial debut on the 2014 action film "John Wick" with Chad Stahelski, though only Stahelski was credited. Leitch then directed the 2017 thriller film "Atomic Blonde", starring Charlize Theron, 2018's "Deadpool 2", the sequel to the 2016 film. In 2019, he directed "Hobbs & Shaw", a spin-off of the "Fast & Furious" franchise, and in 2022 directed "Bullet Train", starring Brad Pitt.


title: David Leitch

text: Leitch was a stunt double for Brad Pitt five times and two times for Jean-Claude Van Damme. Leitch and his crew won two awards for "The Bourne Ultimatum" at the Screen Actors Guild Awards. He also shared a 2008 Taurus World Stunt Award with fellow stunt-person Kai Martin for high work.


title: David Leitch

text: He wrote and starred in "Confessions of an Action Star", a parody of action films and the action film industry released in 2009.


title: David Leitch

text: Leitch and Chad Stahelski opened an action design production company called 87Eleven in 1997. In 2009, Stahelski and Leitch were second-unit directors and stunt co-ordinators on "Ninja Assassin." The two co-directed the 2014 film "John Wick", although Leitch himself was not credited as co-director. Leitch executive produced the two "John Wick" sequels, which Stahelski solo directed.


title: David Leitch

text: He moved on to direct films such as "Atomic Blonde", "Deadpool 2" and "Fast & Furious Presents: Hobbs & Shaw" with his wife and creative partner Kelly McCormick serving as a producer. In 2022, he also directed Brad Pitt in the action-thriller "Bullet Train".


title: David Leitch

text: In January 2019, Leitch signed on to direct "Undying Love", based on the limited comic book series by Tomm Coker and Daniel Freedman, for Studio 8. In September 2020, Leitch signed on to direct and produce stuntman drama "The Fall Guy" for Universal Pictures, with Drew Pearce writing the screenplay and Ryan Gosling and Emily Blunt starring; the film, based on the 1980s television series of the same name, is scheduled for release on March 1, 2024. In November 2022, Leitch became attached to direct spy thriller "Red Shirt", based on a pitch by Simon Kinberg and with Channing Tatum set to star; by the end of the month, the project was picked up by Amazon Studios.


title: David Leitch

text: Leitch was set to direct action thriller "Fast & Loose" for Netflix and STXfilms, with Will Smith set to star, but by March 2022, he had departed the project to focus instead on "The Fall Guy".


title: Jon Cryer

text: Jonathan Niven Cryer (born April 16, 1965) is an American actor, writer, director and producer. Born into a show business family, he made his motion picture debut as a teenage photographer in the 1984 romantic comedy "No Small Affair"; his breakout role came in 1986, in the John Hughes-written film "Pretty in Pink". In 1998, he wrote and produced the independent film "Went to Coney Island on a Mission from God... Be Back by Five".


title: Jon Cryer

text: Although he gained fame with his early film roles, it took several years to find success on television as none of his star vehicles, including "The Famous Teddy Z", "Partners", and "The Trouble with Normal", lasted more than 22 episodes. In 2003, he was cast in a co-leading role as Alan Harper on the CBS sitcom "Two and a Half Men", a major hit for twelve seasons for which he won two Primetime Emmy Awards (in 2009 and 2012). He received a star on the Hollywood Walk of Fame for Television in 2011.


title: Jon Cryer

text: Cryer's other film appearances include "" (1987), "Hiding Out" (1987), "Hot Shots!" (1991), "Holy Man" (1998), "Tortured" (2008), "Shorts" (2009), and "Hit by Lightning" (2014). He also has appeared in the recurring role of Lex Luthor in the CW series "Supergirl", "Arrow", and "Batwoman". After appearing on the podcast "Crime Writers On..." it was announced that he would join the "Undisclosed" podcast for their second season.


title: Jon Cryer

text: Cryer was born in New York City. His mother, Gretchen Kiger, is a playwright, songwriter, actress and singer. His father, Donald David Cryer, is an actor and singer who originally studied to be a minister. His paternal grandfather, the Rev. Donald W. Cryer, was a prominent Methodist minister. He has two sisters, Robin and Shelly.


title: Jon Cryer

text: When Cryer was twelve years old, he decided he wanted to become an actor. When his mother heard this, she thought he should have a backup plan, and joked, "Plumbing is a pretty good career." Cryer attended Stagedoor Manor Performing Arts Training Center for several summers as a teenager, and is a 1983 graduate of the Bronx High School of Science. He was classmates with screenwriter and film director Boaz Yakin. To his mother's "great disappointment," he skipped college and went to the Royal Academy of Dramatic Art in London, England, for a summer short course in Shakespeare.


title: Jon Cryer

text: Cryer's first professional acting effort was as David in the Broadway play "Torch Song Trilogy", replacing Matthew Broderick, whom he "closely resembled." He reprised the role in San Francisco and Los Angeles. He was later a standby and replacement for Broderick as Eugene Jerome in the original Broadway production of Neil Simon's "Brighton Beach Memoirs" in 1984.


title: Jon Cryer

text: At age 19, Cryer appeared in the 1984 romantic comedy film "No Small Affair", in the lead role as Charles Cummings, after the original production with Matthew Broderick was shut down when director Martin Ritt suffered a heart attack. He went on to appear in small roles in films and television movies.


title: Jon Cryer

text: Cryer made his film breakthrough as Philip F. "Duckie" Dale in the John Hughes-scripted film "Pretty in Pink". In an interview with the "Daily News", Cryer's mother Gretchen said that after "Pretty in Pink", she started getting calls from teenage girls from all over the world, who would leave hysterical, giggling messages on her answering machine.


title: Jon Cryer

text: Cryer then starred in the 1987 film "Hiding Out" as a stockbroker on the run from a Mafia hit man. His mother Gretchen played his aunt. The film broke even, but Cryer's performance as a character who was much older than him was critically acclaimed. In 1989, he got the lead role in the TV comedy series "The Famous Teddy Z". His performance gained poor reviews and the show was canceled after the first season.


title: Jon Cryer

text: In 1990 Cryer appeared as Sandy in an Off-Broadway adaptation of "Carnal Knowledge". That same year he appeared alongside future "Two and a Half Men" costar Charlie Sheen in the Jim Abrahams comedy "Hot Shots!", which was received very positively. Cryer is frequently linked to the Brat Pack. In a March 2009 interview on Anytime with Bob Kushell, Cryer stated that he had auditioned for "St. Elmo's Fire" but was not cast in a role. In 1993, he was asked to audition for the role of Chandler Bing on "Friends", while doing a play in London. His reading was videotaped by a British casting agent but the tape failed to arrive in the U.S. before the network had made its final decision.


title: Jon Cryer

text: In 1995, he was cast as Bob in the sitcom "Partners", which, like his prior show "The Famous Teddy Z", was canceled after its first season. In an interview with "Time Out New York" he stated, "Hey, every show I'm in goes down. Think about this: George Clooney was in 28 pilots, or something. It means nothing." After guest starring on shows such as "Dharma & Greg" and "The Outer Limits", he wrote, produced and co-starred in the film "Went to Coney Island on a Mission from God... Be Back by Five". It debuted in 1998 at the Los Angeles Film Festival and gained positive reviews from critics. Leonard Maltin from "Playboy Magazine" called it "a breath of fresh air." That same year, Cryer landed in another TV series, the Fox sitcom "Getting Personal", alongside Vivica A. Fox and Duane Martin. Although the show was picked up for a second season after its abbreviated spring run, it was canceled that fall, after airing 17 episodes in total.


title: Jon Cryer

text: In 1999, Cryer appeared as Neal in Jeffrey Sweet's play "Bluff" at the Victory Gardens Theater. In 2000, he was cast as the lead in a comedy series called "The Trouble With Normal". For the third time, Cryer starred in a show which was canceled after its first season.


title: Jon Cryer

text: Cryer's long run of unsuccessful TV projects finally ended in 2003. Against the wishes of CBS executives (who were aware of his past failures) and due to a friendship with Charlie Sheen, he was cast as Alan Harper on the hit comedy series "Two and a Half Men". (He had auditioned for the role of Gaius Baltar on the Sci-Fi Channel's reimagined "Battlestar Galactica" at around the same time, but the role went to James Callis.) Cryer earned seven Primetime Emmy Award nominations and two wins for his acting work on the show. In a comment on the show's high ratings, he said: "When you’re on a show that's fighting for survival every week, you stop trusting your instincts, because you think, ‘My instincts haven't worked so far.’ But when people clearly like the show and are watching it in great numbers, it takes a huge amount of pressure off you. It allows you to trust your instincts and go with what has worked for you before." After Sheen's departure from the series, Cryer's character became the show's main protagonist (with Ashton Kutcher being cast as the co-lead) during the final four seasons. Cryer is the only actor to have appeared in every episode of the series; Sheen was fired in March 2011 and Cryer's on-screen son Angus T. Jones left the series at the end of season 10, after describing the show as "filth" and calling himself a "paid hypocrite." (Jones did return for the series finale.)


title: Jon Cryer

text: In 2008, Cryer appeared with Laurence Fishburne and James Cromwell in the film "Tortured", and in 2009 co-starred with James Spader in the film "Shorts".


title: Jon Cryer

text: In 2011, Cryer played the role of David in a concert staging of Stephen Sondheim's musical "Company" with the New York Philharmonic at Lincoln Center. The all-star cast was headed by Neil Patrick Harris and Patti LuPone. The concert subsequently aired on PBS's Great Performances.


title: Jon Cryer

text: Cryer made a guest appearance on the sitcom series "Husbands" in its second season. He was initially cast to voice the lead character in DisneyToon Studios' animated film "Planes", a spin-off of Pixar's "Cars" franchise, but later dropped out and was replaced by Dane Cook. Cryer did however receive a credit on the film for "additional story material."


title: Jon Cryer

text: In 2015, Cryer released a book titled "So That Happened", a breezy, often comic tale chronicling Cryer's 30-year career on stage, film and television.


title: Jon Cryer

text: Cryer currently appears in the highly popular CBS drama series "NCIS", where he currently plays Navy Dr. Cyril Taft who treats NCIS Special Agent Leroy Jethro Gibbs (Mark Harmon). Cryer had expressed a desire to appear in "NCIS" since it premiered in 2003.


title: Jon Cryer

text: Pursuing a passion for criminal justice, Cryer joined the team of the popular podcast "Undisclosed" where he will be voicing the weekly addendum episode for the second season.


title: Jon Cryer

text: On May 21, 2018, Cryer was featured in the premier of Episode 1, Season 9 of genealogy program "Who Do You Think You Are?" Cryer uncovered the dramatic tale of his ancestor James Adams, a Scottish Covenanter soldier who was captured during the Battle of Dunbar in 1650, and endured horrific conditions as a prisoner. He was then transported to America an indentured servant to work at the Saugus Iron Works at Lynn, Massachusetts. As part of his research for the episode, Cryer visited the site of the Battle of Dunbar, Durham Cathedral in Durham, North East England – where surviving Scottish prisoners were held until they were indentured – and the Saugus Iron Works national historic site. Cryer said: "Seeing the resilience of my family over centuries, you can see the legacy he left. I can't help but feel lucky...clearly, the resilience of my family, that spine of steel, was not something that came from nowhere. Moving forward, I'm going to take James Adams' strength as my inspiration and know that when you go through very, very difficult times, if you can turn around and help the people around you who had it even worse, that's real strength. And I aspire to be one of those people."