73-578: 4F2A , 2OBD , 4EWS 1071 n/a ENSG00000087237 n/a P11597 n/a NM_000078 NM_001286085 n/a NP_000069 NP_001273014 n/a Cholesteryl ester transfer protein ( CETP ), also called plasma lipid transfer protein , is a plasma protein that facilitates the transport of cholesteryl esters and triglycerides between the lipoproteins . It collects triglycerides from very-low-density lipoproteins (VLDL) or Chylomicrons and exchanges them for cholesteryl esters from high-density lipoproteins (HDL), and vice versa. Most of
146-443: A centrifuge until the blood cells fall to the bottom of the tube. The blood plasma is then poured or drawn off. For point-of-care testing applications, plasma can be extracted from whole blood via filtration or via agglutination to allow for rapid testing of specific biomarkers. Blood plasma has a density of approximately 1,025 kg/m (1.025 g/ml). Blood serum is blood plasma without clotting factors. Plasmapheresis
219-443: 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%. Atorvastatin undergoes rapid absorption when taken orally, with an approximate time to maximum plasma concentration ( T max ) of 1–2 h. The absolute bioavailability of
292-449: A four-fold increase in both C max and AUC. People with Child Pugh stage B liver disease show a 16-fold increase in C max and an 11-fold increase in AUC. Geriatric people (>65 years old) exhibit altered pharmacokinetics of atorvastatin compared to young adults, with mean AUC and C max values that are 40% and 30% higher, respectively. Additionally, healthy elderly people show
365-672: A greater pharmacodynamic response to atorvastatin at any dose; therefore, this population may have lower effective doses. 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. There are several studies showing genetic variants and variable response to atorvastatin. The polymorphisms that showed genome wide significance in Caucasian population were
438-455: A high cardiovascular disease risk; however, there is limited clinical benefit noted for most cardiovascular outcomes. Statins with shorter half-lives are more effective when taken in the evening, so their peak effect occurs when the body’s natural cholesterol production is at its highest. A recent meta-analysis suggested that statins with longer half-lives, including atorvastatin, may also be more effective at lowering LDL cholesterol if taken in
511-461: 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. The atorvastatin calcium complex involves two atorvastatin ions, one calcium ion and three water molecules. Bruce Roth , who
584-434: A large cohort need to be conducted in different ethnicities to identify more polymorphisms that can affect atorvastatin pharmacokinetics and treatment response. 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
657-587: A month's supply—until other manufacturers began to supply the medication in May 2012. 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
730-406: A result, approximately 12% of blood plasma volume will cross into the extravascular compartment . This plasma shift causes an increase in hematocrit , serum total protein , blood viscosity and, as a result of increased concentration of coagulation factors , it causes orthostatic hypercoagulability . Serum albumins are the most common plasma proteins, and they are responsible for maintaining
803-517: A risk of patient blood loss such as surgical suite facilities. Blood plasma volume may be expanded by or drained to extravascular fluid when there are changes in Starling forces across capillary walls. For example, when blood pressure drops in circulatory shock , Starling forces drive fluid into the interstitium , causing third spacing . Standing still for a prolonged period will cause an increase in transcapillary hydrostatic pressure . As
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#1732773290615876-472: A scientist from Vilanova i la Geltrú, Spain, founded Laboratorios Grifols in 1940. Dr. Grifols pioneered a first-of-its-kind technique called plasmapheresis , where a donor's red blood cells would be returned to the donor's body almost immediately after the separation of the blood plasma. This technique is still in practice today, almost 80 years later. In 1945, Dr. Grifols opened the world's first plasma donation center. The "Blood for Britain" program during
949-651: A substitute for whole blood and for transfusion purposes was proposed in March 1918, in the correspondence columns of the British Medical Journal, by Gordon R. Ward. "Dried plasmas" in powder or strips of material format were developed and first used in World War II . Prior to the United States' involvement in the war, liquid plasma and whole blood were used. Dr. José Antonio Grifols Lucas,
1022-484: A trial of a combination of torcetrapib and atorvastatin , an increase in cardiovascular events and mortality. A compound related to torcetrapib, Dalcetrapib (investigative name JTT-705/R1658), was also studied, but trials have ceased. It increases HDL levels by 30%, as compared to 60% by torcetrapib. Two CETP inhibitors were previously under development. One was Merck's MK-0859 anacetrapib , which in initial studies did not increase blood pressure. In 2017, its development
1095-440: 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 . 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
1168-501: 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
1241-552: Is a medical therapy that involves blood plasma extraction, treatment, and reintegration. Fresh frozen plasma is on the WHO Model List of Essential Medicines , the most important medications needed in a basic health system . It is of critical importance in the treatment of many types of trauma which result in blood loss, and is therefore kept stocked universally in all medical facilities capable of treating trauma (e.g., trauma centers , hospitals, and ambulances) or that pose
1314-403: Is a similar thought process with using high-dose atorvastatin as a form of secondary thrombotic stroke recurrence prevention. 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
1387-449: Is being studied as a method of improving HDL levels. To be specific, in a 2004 study, the small molecular agent torcetrapib was shown to increase HDL levels, alone and with a statin , and lower LDL when co-administered with a statin. Studies into cardiovascular endpoints, however, were largely disappointing. While they confirmed the change in lipid levels, most reported an increase in blood pressure , no change in atherosclerosis, and, in
1460-589: 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
1533-424: 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. Statins (predominantly simvastatin ) have been evaluated in clinical trials in combination with fibrates to manage dyslipidemia in people who also have type 2 diabetes, and
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#17327732906151606-468: Is often considered the "universal donor" for plasma. Special programs exist just to cater to the male AB plasma donor, because of concerns about transfusion related acute lung injury (TRALI) and female donors who may have higher leukocyte antibodies. However, some studies show an increased risk of TRALI despite increased leukocyte antibodies in women who have been pregnant. Following fears of variant Creutzfeldt-Jakob disease ( vCJD ) being spread through
1679-603: 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
1752-467: 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. Atorvastatin calcium tablets are sold under
1825-588: Is released from broken blood cells. Plasma is normally relatively transparent, but sometimes it can be opaque. Opaqueness is typically due to elevated content of lipids like cholesterol and triglycerides . Plasma and serum are both derived from full blood, but serum is obtained by removing blood cells, fibrin clots, and other coagulation factors while plasma is obtained by only removing blood cells . Blood plasma and blood serum are often used in blood tests . Tests can be done on plasma, serum or both. In addition, some tests have to be done with whole blood , such as
1898-620: Is similar to intracellular SMP domains, and originated in bacteria. The crystal structure of CETP has been obtained with bound CETP inhibitors . However, this has not resolved the doubt over whether CETP function as a lipid tube or shuttle. Rare mutations leading to reduced function of CETP have been linked to accelerated atherosclerosis . In contrast, a polymorphism (I405V) of the CETP gene leading to lower serum levels has also been linked to exceptional longevity and to metabolic response to nutritional intervention. However, this mutation also increases
1971-468: Is the most desirable and is considered a "universal donor," since it has neither A nor B antigens and can be safely transfused to most recipients. Type AB+ is the "universal recipient" type for PRBC donations. However, for plasma the situation is somewhat reversed. Blood donation centers will sometimes collect only plasma from AB donors through apheresis , as their plasma does not contain the antibodies that may cross react with recipient antigens. As such, AB
2044-554: The National Research Council , in charge of blood collection for the United States Army and Navy . Drew argued against the armed forces directive that blood/plasma was to be separated by the race of the donor . Drew insisted that there was no racial difference in human blood and that the policy would lead to needless deaths as soldiers and sailors were required to wait for "same race" blood. By
2117-518: 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 . 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 2022, it was the most commonly prescribed medication in
2190-693: The British government sold an 80% stake in PRUK to American hedge fund Bain Capital , in a deal estimated to be worth £200 million. The sale was met with criticism in the UK. In 2009, the U.K. stopped importing plasma from the United States, as it was no longer a viable option due to regulatory and jurisdictional challenges. At present (2024), blood donated in the United Kingdom is used by UK Blood Services for
2263-545: 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. In hepatic insufficiency , plasma concentrations of atorvastatin are significantly affected by concurrent liver disease. People with Child-Pugh Stage A liver disease show
Cholesteryl ester transfer protein - Misplaced Pages Continue
2336-652: 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
2409-556: The United States, with more than 109 million prescriptions filled for over 27 million people. In Australia, it was one of the top 10 most prescribed medications between 2017 and 2023. The primary uses of atorvastatin is for the treatment of dyslipidemia and the prevention of cardiovascular disease : 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 people with acute coronary syndrome . The SATURN trial, which compared
2482-404: The blood supply, the British government began to phase out blood plasma from U.K. donors and by the end of 1999 had imported all blood products made with plasma from the United States. In 2002, the British government purchased Life Resources Incorporated, an American blood supply company, to import plasma. The company became Plasma Resources UK (PRUK) which owned Bio Products Laboratory . In 2013,
2555-434: The body's total blood volume. It is the intravascular part of extracellular fluid (all body fluid outside cells). It is mostly water (up to 95% by volume), and contains important dissolved proteins (6–8%; e.g., serum albumins , globulins , and fibrinogen ), glucose , clotting factors , electrolytes ( Na , Ca , Mg , HCO 3 , Cl , etc.), hormones , carbon dioxide (plasma being
2628-408: The brand name Lipitor. Pfizer also packages the medication in combination with other medications, such as atorvastatin/amlodipine . 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
2701-549: 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 ). Vitamin D supplementation lowers atorvastatin and active metabolite concentrations, yet synergistically reduces LDL and total cholesterol concentrations. Grapefruit juice components are known inhibitors of intestinal CYP3A4. Drinking grapefruit juice with atorvastatin may cause an increase in C max and area under
2774-468: The combined use of statins and the fibrate drug class (such as gemfibrozil , fenofibrate ) may increase the risk of myopathy and rhabdomyolysis , there is insufficient evidence to firmly establish this association with atorvastatin. 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
2847-439: 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
2920-431: The determination of the amount of blood cells in blood via flow cytometry . Plasma was already well known when described by William Harvey in de Motu Cordis in 1628, but knowledge of it probably dates as far back as Vesalius (1514–1564). The discovery of fibrinogen by William Henson, c. 1770 , made it easier to study plasma, as ordinarily, upon coming in contact with a foreign surface – something other than
2993-595: The early 1940s was quite successful (and popular in the United States) based on Charles Drew 's contribution. A large project began in August 1940 to collect blood in New York City hospitals for the export of plasma to Britain. Drew was appointed medical supervisor of the " Plasma for Britain " project. His notable contribution at this time was to transform the test tube methods of many blood researchers into
Cholesteryl ester transfer protein - Misplaced Pages Continue
3066-400: 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. A few cases of myopathy have been reported when atorvastatin is given with colchicine . As with other statins, atorvastatin
3139-594: The effects of high-dose atorvastatin and rosuvastatin , also confirmed these findings. 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 are conflicting for whether statins reduce risk of kidney failure. Statins, including atorvastatin, before heart surgery do not prevent acute kidney injury. Prior to contrast medium (CM) administration, pre-treatment with atorvastatin therapy can reduce
3212-399: 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." In 1996, Warner-Lambert entered into a co-marketing agreement with Pfizer to sell Lipitor, and in 2000, Pfizer acquired Warner-Lambert for $ 90.2 billion. Lipitor
3285-663: The end of the war the American Red Cross had provided enough blood for over six million plasma packages. Most of the surplus plasma was returned to the United States for civilian use. Serum albumin replaced dried plasma for combat use during the Korean War . Plasma as a blood product prepared from blood donations is used in blood transfusions , typically as fresh frozen plasma (FFP) or Plasma Frozen within 24 hours after phlebotomy (PF24). When donating whole blood or packed red blood cell (PRBC) transfusions, O-
3358-457: The evening. However, the only study included in the meta-analysis of atorvastatin in people with heart disease did not specifically investigate if morning or evening dosing was more effective for reducing LDL cholesterol. The trial did confirm that, irrespective of dosing time, atorvastatin is very effective at reducing total cholesterol, LDL cholesterol and triglycerides, and increasing HDL cholesterol levels. Hence, atorvastatin should be taken at
3431-416: The first successful mass production techniques. Nevertheless, the decision was made to develop a dried plasma package for the armed forces as it would reduce breakage and make the transportation, packaging, and storage much simpler. The resulting dried plasma package came in two tin cans containing 400 cc bottles. One bottle contained enough distilled water to reconstitute the dried plasma contained within
3504-418: The helices to produce a cylinder 6 x 2.5 x 2.5 nm. CETP contains two of these domains that interact head-to-head via an interface made of 6 beta-sheets , 3 from each protomer . The same fold is shared by Bacterial Permeability Inducing proteins (examples: BPIFP1 BPIFP2 BPIFA3 and BPIFB4 ), phospholipid transfer protein ( PLTP ), and long-Palate Lung, and Nasal Epithelium protein (L-PLUNC) . The fold
3577-526: 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 . 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
3650-659: The human body with a defense system against invading pathogens and other immune diseases. Fibrinogen proteins make up most of the remaining proteins in the blood. Fibrinogens are responsible for clotting blood to help prevent blood loss. Plasma is normally yellow due to bilirubin , carotenoids , hemoglobin , and transferrin . In abnormal cases, plasma can have varying shades of orange, green, or brown. The green color can be due to ceruloplasmin or sulfhemoglobin . The latter may form due to medicines that are able to form sulfonamides once ingested. A dark brown or reddish color can appear due to hemolysis , in which methemoglobin
3723-540: The immune system and transport hormones and other compounds around the body. There are three main types of globulins. Alpha-1 and Alpha-2 globulins are formed in the liver and play an important role in mineral transport and the inhibition of blood coagulation. An example of beta globulin found in blood plasma includes low-density lipoproteins (LDL) which are responsible for transporting fat to the cells for steroid and membrane synthesis. Gamma globulin, better known as immunoglobulins, are produced by plasma B cells, and provides
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#17327732906153796-404: The main medium for excretory product transportation), and oxygen . It plays a vital role in an intravascular osmotic effect that keeps electrolyte concentration balanced and protects the body from infection and other blood-related disorders. Blood plasma can be separated from whole blood through blood fractionation , by adding an anticoagulant to a tube filled with blood, which is spun in
3869-536: The manufacture of plasma blood components (Fresh Frozen Plasma (FFP) and cryoprecipitate). However, plasma from UK donors is still not used for the commercial manufacture of fractionated plasma medicines. Simulated body fluid (SBF) is a solution having a similar ion concentration to that of human blood plasma. SBF is normally used for the surface modification of metallic implants, and more recently in gene delivery application. Atorvastatin Atorvastatin
3942-481: 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 max (rate of absorption) and a 9% reduction in AUC (extent of absorption), although food does not affect
4015-486: The name Zarator. In the US, Lipitor is marketed by Viatris after Upjohn was spun off from Pfizer. 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
4088-453: The osmotic pressure of the blood. Without albumins , the consistency of blood would be closer to that of water. The increased viscosity of blood prevents fluid from entering the bloodstream from outside the capillaries. Albumins are produced in the liver, assuming the absence of a hepatocellular deficiency. The second most common type of protein in the blood plasma are globulins. Important globulins include immunoglobins which are important for
4161-566: The other bottle. In about three minutes, the plasma would be ready to use and could stay fresh for around four hours. The Blood for Britain program operated successfully for five months, with total collections of almost 15,000 people donating blood, and with over 5,500 vials of blood plasma. Following the Supplying Blood Plasma to England project, Drew was named director of the Red Cross blood bank and assistant director of
4234-440: The plasma LDL-C -lowering efficacy of atorvastatin. Evening dose administration is known to reduce the C max and AUC by 30% each. However, time of administration does not affect the plasma LDL-C-lowering efficacy of atorvastatin. 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 in human breastmilk. Atorvastatin metabolism
4307-461: 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. Antacids can rarely decrease the plasma concentrations of statin medications, but do not affect the LDL-C -lowering efficacy . Niacin also is proved to increase
4380-459: The prevalence of coronary heart disease in patients with hypertriglyceridemia . The D442G mutation, which lowers CETP levels and increases HDL levels also increases coronary heart disease. Elaidic acid , a major component of trans fat , increases CETP activity. As HDL can alleviate atherosclerosis and other cardiovascular diseases , and certain disease states such as the metabolic syndrome feature low HDL, pharmacological inhibition of CETP
4453-477: 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
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#17327732906154526-565: The risk of contrast-induced acute kidney injury (CI-AKI) in people 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
4599-421: The risk of myopathy or rhabdomyolysis. 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
4672-560: The risks for cognition are likely outweighed by the beneficial effects of adherence to statin therapy on cardiovascular and cerebrovascular disease. A 2012 meta-analysis found that statin therapy might reduce the risk of pancreatitis in people with normal or mildly elevated blood triglyceride levels. Statins seem to have a positive effect on erectile dysfunction . Fibrates are a class of drugs that can be used for severe or refractory mixed hyperlipidaemia in combination with statins or as monotherapy. While studies have suggested that
4745-769: The same time each day, at a time that is most convenient for the patient, so it does not compromise compliance. The following have been shown to occur in 1–10% of people taking atorvastatin in clinical trials: Atorvastatin has been associated with a small increase in fasting blood glucose levels over a 2-year period, particularly in patients with Type 2 Diabetes, however evidence is conflicting and clinical significance of this increase has not been determined. Regular blood glucose monitoring may be advised in patients with Type 2 Diabetes. 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
4818-422: The stereochemistry of the first of the two alcohol functional groups via a diastereoselective aldol reaction . 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
4891-472: The time, however, CETP does a heteroexchange, trading a triglyceride for a cholesteryl ester or a cholesteryl ester for a triglyceride. The CETP gene is located on chromosome 16 (16q21). The crystal structure of CETP is that of dimer of two TUbular LIPid (TULIP) binding domains. Each domain consists of a core of 6 elements: 4 beta-sheets forming an extended superhelix; 2 flanking elements that tend to include some alpha helix . The sheets wrap around
4964-416: The vascular endothelium – clotting factors become activated and clotting proceeds rapidly, trapping RBCs etc. in the plasma and preventing separation of plasma from the blood. Adding citrate and other anticoagulants is a relatively recent advance. Upon the formation of a clot, the remaining clear fluid (if any) is blood serum, which is essentially plasma without the clotting factors The use of blood plasma as
5037-475: Was abandoned by Merck . The other was Eli Lilly's evacetrapib, which failed in Phase 3 trials. Click on genes, proteins and metabolites below to link to respective articles. Blood plasma Blood plasma is a light amber -colored liquid component of blood in which blood cells are absent, but which contains proteins and other constituents of whole blood in suspension . It makes up about 55% of
5110-461: 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 –
5183-493: 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. In 1994, the findings of a Merck-funded study were published in The Lancet concluding
5256-566: 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 $ 125 billion in sales over approximately 14.5 years. and $ 13 billion a year at its peak, Lipitor alone "provided up to a quarter of Pfizer Inc.'s annual revenue for years." Pfizer's patent on atorvastatin expired in November 2011. Atorvastatin
5329-545: 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. 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,
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