Inhibitors Of Hydroxymethylglutaryl Coenzyme Research Articles

A Study Comparative of Some Haematological Parameters after Treatment by Extracted Octacosanol and Atorvastatin in Female Rats

Hematological and serum parameters are a prerequisite to understand the normal functioning of the system and to confirm the nontoxic nature of the administered crude drug. Hematological parameters such as mean platelet volume (MPV) and RBCs count are associated with the increased risk for cardio vascular diseases CVD. Octacosanol is the major effective component of policosanol forming about (62.9%), it has antioxidative, lipid lowering, antithrombotic (antiplatelet) effects and provides protection against free radical associated diseases. Statins are the inhibitors of hydroxymethyl glutaryl coenzyme A (HMG CoA) reductase. They are mostly used to treat hyperlipidaemia. Statins such as atorvastatin and some of medical plants have shown their beneficial effect on the cardiovascular disease (CVD) by virtue of their lipid lowering, antioxidant and cardioprotective effects. The present study was designed to compare some of hematological parameters after treatment of extracted octacosanol and atorvastatin in female Norwegian rats. Thirty two females rat with (10-12) weeks old-and weighting (200-250 gm) were used in the current study. Policosanol was extracted from sugarcane that obtained from Mesan province. Octacosanol is determined in this extraction by gas chromatography – mass spectrometry (GC/MS). Animals were divided into 4 equal groups: G.1 (n=8) (Control) : only 0.5 ml/ animal of Dimethyl Sulphoxide (DMSO). G.2 (n=8) animals treated with (0.02 mg/ animal) of standard octacosanol . G.3 (n=8) animals treated with (0.02mg/ animal) of octacocosanol extraction, G. 4 (n=8) treated with only (0.02mg/ animal) of atorvastatine. The treatment continued for 30 days. All animals were then sacrificed and blood samples were collected in EDTA tubes for measuring of hematological parameters. Results: all hematological parameters (RBCs, Hb, MCV, MCH and MCHC) in group treated with extracted octacosanol were nearby the control group except platelet count and MPV level were lower than those of control group, while platelet count and MPV were higher in extracted group than those in the Atorvastatin group (all P≤0.05). In conclusion: The antiplatelet activity of the extracted octacosanol is more than atorvastatin and without side effects. So the extracted octacosanol successfully used in prevention of platelet aggregation and thrombosis in patients with CVD.

Statins and Pregnancy

Cardiovascular diseases are the leading cause of mortality in industrialized countries. Treatment with statins is effective in primary prevention in patients at high cardiovascular risk. Statins are inhibitors of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase and are classed as lipid-lowering drugs. In 2010, atorvastatin was the biggest-selling drug in the world ($US10.73 billion). Increases in the average age of pregnant women and in the prevalence of morbid obesity have inevitably led to exposure to statins in certain women during the first trimester of pregnancy. The teratogenic risk attendant upon use of statins is unclear because the available data are contradictory, but statins remain contraindicated in pregnant women. The benefits of statins in prevention of cardiovascular risk may not be solely due to their cholesterol-lowering effects: the so-called pleiotropic effects of vascular protection lead some experts to posit a potential benefit in the management of preeclampsia. In this review we evaluate the theoretical benefits and supposed risks of statins in pregnant women. After a brief overview of the pharmacodynamic properties of statins, we address the question of the teratogenic risk of statins, and then detail the rationale for the therapeutic potential of statins in preeclampsia.

Recognition and Management of Dyslipidemia in Children and Adolescents

Cardiovascular disease (CVD) remains the number one cause of death in the United States. The origins of atherosclerosis and CVD begin in childhood. Dyslipidemia and obesity are endemic in American youth and require urgent action. A detailed literature search from 1985-2008 was performed using PubMed and subsequent reference searches of retrieved articles. Selection of included articles was based on rigor of scientific design, adequate sample size, quality of the data, statistical analysis, and hypothesis testing. CVD risk factors in children predict pathological lesions of atherosclerosis in young adults, and their clinical manifestations, as judged by carotid intima medial thickness, coronary artery calcium, or brachial flow-mediated dilatation. About half the offspring of a parent with premature CVD have a primary dyslipidemia. However, use of family history to identify such youth will miss the majority of children with dyslipidemia. Treatment of dyslipidemia starts with a low-fat diet supplemented with water-soluble fiber, plant stanols, and plant sterols, weight control, and exercise. Drug therapy with inhibitors of hydroxymethylglutaryl coenzyme A reductase, bile acid sequestrants (BAS), and cholesterol absorption inhibitors can be considered in adolescents with a positive family history of premature CVD and a low-density lipoprotein cholesterol of more than 160 mg/dL. Such dietary and drug therapy appears safe and efficacious and is likely to retard atherosclerosis. Early identification and treatment of youth at risk for early atherosclerosis will require an integrated assessment of predisposing CVD risk factors and a comprehensive universal screening and treatment program.

Effects of various statins on cytokine‐dependent growth and IgE‐dependent release of histamine in human mast cells

Statins are inhibitors of hydroxymethylglutaryl coenzyme A (HMG CoA) reductase, a key enzyme in mevalonic acid (MVA)-dependent signaling. Recent data suggest that statins exhibit profound inhibitory effects on growth and function of various immune cells. In the present study, we examined the in vitro effects of five different statins on primary human mast cells (MCs), MC progenitors, and the human MC line HMC-1. Histamine release experiments were conducted on isolated MCs using statins and an anti-immunoglobulin E (IgE) antibody. Culture experiments were performed with stem cell factor (SCF) and interleukin (IL)-6, and cord blood-derived progenitors. Preincubation of primary lung MCs with cerivastatin or atorvastatin (1-50 microM) for 24 h resulted in inhibition of anti-IgE-induced release of histamine. The effects of both statins were dose-dependent. Moreover, both statins, and to a lesser degree lovastatin, were found to inhibit the SCF-induced differentiation of MCs from their progenitors. The other statins tested (simvastatin, pravastatin) did not affect mediator release or growth of MCs. Cerivastatin and atorvastatin act as inhibitors of growth and function of human MCs.

Adverse Effects of Statins

A key role in the pathogenesis of atherosclerotic lesions is represented by cholesterol deposition in the arterial vessel wall, and a large body of international, randomised, controlled clinical trials have shown that the clinical use of drugs that are active in lowering serum cholesterol concentrations, such as competitive inhibitors of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase (collectively defined as 'statins'), produces significant reductions of cardiovascular mortality and morbidity through different and sometimes not fully elucidated mechanisms. However, it is important to consider that the patients who get the largest benefit from taking statins (frequently at high doses) are at the same time those with the highest risk of presenting adverse effects related to the use of these drugs. These patients are usually elderly, hypertensive and diabetic, often have renal function impairment or other associated clinical conditions and are usually receiving multiple therapies. Consequently, these patients may be exposed to adverse effects caused by pharmacological interactions of other drug classes with statins. Because of this, cardiologists need to be properly aware of the beneficial potential of these compounds but also of the potential limits and risks associated with the use of statins in the population at large.This article is aimed at examining the safety profile linked to the clinical use of statins and suggesting an adequate management to prevent the potential adverse effects while taking advantage of the outstanding cardiovascular benefits of statins.

Inhibitors of Hydroxymethylglutaryl-Coenzyme A Reductase and Risk of Fracture Among Older Women

Agents that inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, known as statins, promote new bone formation in rodents and cultured human cells. Increased bone mineral density at the femoral neck has been documented with statin treatment in a small-scale study. The present case-control study compared the risk of fracture in 928 women aged 60 years and older who had an incident diagnosis of fracture of the humerus, wrist, hip, distal tibia, or vertebra and 2747 control women of similar age. Women with pathologic fractures and those treated for osteoporosis were excluded. Both groups had an average age of 76 years. Women prescribed a statin 13 times or more during the past 2 years were less likely to have a fracture. The odds ratio, adjusted for age, hospital admissions, chronic disease score, and use of nonstatin lipid-lowering drugs, was 0.48. The fracture risk was not significantly associated with a lower level of statin use. These findings imply that statins protect elderly women against nonpathologic fractures, probably by increasing bone mineral density. If this is in fact the case, the statins would be a promising means of treating osteoporosis. Lancet 2000;355:2185–2188

Inhibitors of hydroxymethylglutaryl-coenzyme A reductase and risk of fracture among older women

Inhibitors of hydroxymethylglutaryl-coenzyme A reductase (statins) increase new bone formation in rodents and in human cells in vitro. Statin use is associated with increased bone mineral density of the femoral neck. We undertook a population-based case-control study at six health-maintenance organisations in the USA to investigate further the relation between statin use and fracture risk among older women. We investigated women aged 60 years or older. Exposure, outcome, and confounder information was obtained from automated claims and pharmacy data from October, 1994, to September, 1997. Cases had an incident diagnosis of non-pathological fracture of the hip, humerus, distal tibia, wrist, or vertebrae between October, 1996, and September, 1997. Controls had no fracture during this period. We excluded women with records of dispensing of drugs to treat osteoporosis. There were 928 cases and 2747 controls. Compared with women who had no record of statin dispensing during the previous 2 years, women with 13 or more statin dispensings during this period had a decreased risk of non-pathological fracture (odds ratio 0.48 [95% CI 0.27-0.83]) after adjustment for age, number of hospital admissions during the previous year, chronic disease score, and use of non-statin lipid-lowering drugs. No association was found between fracture risk and fewer than 13 dispensings of statins or between fracture risk and use of non-statin lipid-lowering drugs. Statins seem to be protective against non-pathological fracture among older women. These findings are compatible with the hypothesis that statins increase bone mineral density in human beings and thereby decrease the risk of osteoporotic fractures.

A Randomized Multicenter Trial Comparing and Efficacy of Simvastatin and Fluvastatin.

BACKGROUND: Inhibitors of hydroxymethylglutaryl co-enzyme A reductase are widely used for the treatment of hypercholesterolemia. Physicians and third-party payers need an accurate measure of their relative potency and hypolipidemic efficacy. We have therefore compared simvastatin against fluvastatin, the newest member of this class. METHODS AND RESULTS: One hundred fifty-eight hypercholesterolemic patients in seven United States lipid clinics participated in this balanced double-blind incomplete block study. After a placebo-diet run-in period, patients received treatment with active drug for three consecutive 5-week periods, with measurement of lipids in a NHLBI-CDC standardized central laboratory at the end of each period. Each patient was randomly assigned to three of the following five treatments: simvastatin 5 mg, 10 mg, and 20 mg and fluvastatin 20 mg and 40 mg. The mean percent reductions in low density lipoprotein cholesterol from baseline were 21, 27, 32, 16, and 23 respectively. The simvastatin/fluvastatin milligram potency ratio was 6.8 (95% CI, 5.3-9.3). At the same 20 mg dose, simvastatin produced an effect on LDL cholesterol approximately double that of fluvastatin and resulted in 46% of patients achieving their National Cholesterol Education Program low density lipoprotein cholesterol target levels, compared to 12% for fluvastatin. CONCLUSIONS: Fluvastatin at its maximal dose of 40 mg daily is approximately equivalent to simvastatin 5 mg daily. Higher doses of simvastatin are considerably more effective in the treatment of primary hypercholesterolemia.

Lovastatin 5-year safety and efficacy study. Lovastatin Study Groups I through IV

Inhibitors of hydroxymethylglutaryl co-enzyme A reductase are widely used to treat hypercholesterolemia. They have a good short- to medium-term safety profile, but long-term safety data are limited. Seven hundred forty-five patients with severe hypercholesterolemia (mean baseline plasma cholesterol level on diet, 9.3 mmol/L [360 mg/dL]) were treated with lovastatin for a median duration of 5.2 years. Their mean age at baseline was 50 years, 68% were male, 60% had familial hypercholesterolemia, and 42% had a history of coronary heart disease. Seventy-seven percent of patients had titrations of lovastatin to 80 mg/d, and 58% took other lipid-lowering agents, usually bile acid sequestrants, concomitantly. The mean changes at 5 years in total, low-density lipoprotein, and high-density lipoprotein cholesterol were -35%, -44%, and +14%, respectively. Eighty percent of patients completed the study, 13% were unavailable for follow-up, 4% were discontinued due to adverse events unlikely to be related to lovastatin, and 3% (21) were discontinued because of drug-attributable adverse events: marked but asymptomatic increase in aminotransferase values (10 patients), gastrointestinal disturbance (three patients), rash (two patients), myalgia (one patient), myopathy (two patients), arthralgia (one patient), insomnia (one patient), and weight gain (one patient). Sixteen patients died during the study, all of coronary disease. Of these, 14 had coronary heart disease at baseline. There were no deaths attributable to trauma, suicide, or homicide, and there were only 14 cases of cancer (vs 21 expected). There was no evidence for an adverse effect on the lens. Lovastatin is a generally well-tolerated and effective drug during long-term use.

Lipid-Lowering Therapy and Macrovascular Disease in Diabetes Mellitus

Patients with diabetes mellitus are at increased risk of morbidity and mortality from macrovascular disease manifesting as coronary heart disease, cerebrovascular accidents, and peripheral vascular disease. Increased frequency of dyslipidemia, hyperglycemia, obesity, hypertension, and associated nephropathy may contribute to accelerated atherogenesis in diabetic patients. Therefore, besides intensive control of hyperglycemia, management of dyslipidemia, hypertension, and obesity should also be emphasized in diabetic patients. Those who smoke should be strongly encouraged to quit smoking. Besides attempts to achieve normal levels of plasma lipoproteins, consideration also should be given to normalization of compositional abnormalities of various lipoproteins in patients with diabetes mellitus. The therapeutic goals for cholesterol reduction should be lower in diabetic patients than nondiabetic subjects. The first step is to achieve good metabolic control of diabetes mellitus by diet, exercise, and weight reduction and, if needed, with sulfonylureas or insulin therapy. Because most of the patients with insulin-dependent diabetes mellitus achieve normal levels of plasma lipoproteins with intensive insulin therapy, lipid-lowering medications are rarely needed. In patients with non-insulin-dependent diabetes mellitus, however, dyslipidemia often persists despite good glycemic control. Lipid-lowering medications should be considered in such patients. Because nicotinic acid can cause marked deterioration in glycemic control, and bile acid-binding resins may accentuate hypertriglyceridemia, these agents are less desirable for use by diabetic patients. Inhibitors of hydroxymethylglutaryl coenzyme A reductase may be preferred in patients with elevated LDL cholesterol and mld hypertriglyceridemia. For diabetic patients with marked hypertriglyceridemia, however, fibric acid derivatives should be the drug of choice.

Inhibitors of hydroxymethylglutaryl coenzyme A reductase for treating hypercholesterolaemia.

Inhibitors of hydroxymethylglutaryl coenzyme A reductase for treating hypercholesterolaemia.

Strategies to reduce risk factors in hypertensive patients who smoke

Hypertensive patients who smoke have a high risk of developing premature cardiovascular disease. In addition to encouraging these patients to stop smoking, effective nondrug therapies include weight reduction, salt restriction, and alcohol limitation. For patients whose hypertension is severe or who have other health problems, antihypertensive drug therapy is also used. In the past, diuretics and beta-blockers have proved popular. However, these drugs have produced biochemical disturbances, such as diuretic-induced hypokalemia and both diuretic- and beta-blocker-induced alterations in blood lipids. The hazard of such drug-induced alterations may be greater in hypertensive patients, who may already suffer from hypercholesterolemia. Other drugs are available that can treat hypertension with no or beneficial influence on blood lipids. For smokers, the selective α 1-receptor inhibitors may be more attractive, since they also act to counteract the vasoconstriction produced by nicotine. In the future, inhibitors of hydroxymethylglutaryl coenzyme A reductase may offer potential for effective control of blood lipids in hypertensive patients who smoke.

An overview of lipid-lowering drugs.

The long term use of lipid-lowering drugs in the treatment of patients with hyperlipoproteinaemia is aimed at reducing plasma concentrations of known atherogenic lipoproteins with a favourable effect on lipid deposition in the arterial wall. A less common aim is to prevent the adverse sequelae of hyperchylomicronaemia in patients with severe hypertriglyceridaemia. The decision to begin drug therapy should be made only after the exclusion of secondary factors and after an adequate trial of diet has failed to produce acceptable concentrations of plasma lipids and lipoproteins. The bile acid sequestrants (cholestyramine and colestipol), nicotinic acid, fenofibrate and inhibitors of hydroxymethylglutaryl coenzyme A (HMG CoA) reductase (e.g. lovastatin or simvastatin) are the most effective drugs for use in patients with primary hypercholesterolaemia; these agents reduce plasma concentrations of total and LDL-cholesterol by 15 to 45%. For those patients with concurrent hypertriglyceridaemia, nicotinic acid, lovastatin or simvastatin, or fenofibrate are the preferred drugs for initial use; bile acid sequestrants frequently exacerbate hypertriglyceridaemia in these patients. Fibric acid derivatives (e.g. clofibrate, gemfibrozil, bezafibrate or fenofibrate) are all effective in the therapy of patients with type III hyperlipoproteinaemia, as is nicotinic acid and I have found lovastatin to be effective also. Gemfibrozil or nicotinic acid are the most effective agents to use in the treatment of patients with severe hypertriglyceridaemia who are at increased risk of abdominal pain and pancreatitis. Combined therapy with drugs which have different mechanisms of action can be effectively used in the treatment of patients with severe hypercholesterolaemia or combined hyperlipidaemia; for the former group, combinations which use bile acid sequestrants, HMG CoA reductase inhibitors and nicotinic acid are the most effective.