Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020473 (hyperlipidemia)
 15,891 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of lovastatin on the hyperlipidemia induced in rats with experimental nephrotic syndrome was investigated; toxicity and the effects on common blood chemistry parameters were also assessed. Hyperlipoproteinemia in this particular model is associated with an increase in hepatic synthesis of lipoproteins, and treatment with lovastatin could be the most suitable, since the drug inhibits cellular cholesterol synthesis. Lovastatin treatment resulted in a considerable reduction in plasma cholesterol and triglyceride levels. The decrease in cholesterol levels with treatment was mainly confined to the low-density lipoproteins (LDL) although there was a reduction in the nephrotic-syndrome-induced incremental level of high-density lipoprotein cholesterol. Other lipoprotein fractions were unaffected by lovastatin. LDL apoprotein B was increased in both groups of rats, but to a lesser degree in the lovastatin-treated group, suggesting a double effect, inhibition of both, cholesterol and apoprotein synthesis. Both groups of rats showed a certain degree of renal impairment as shown by significant elevations in plasma urea and creatinine levels. Hepatic damage was also observed, chemically and microscopically, in both groups of rats, being more pronounced in those rats treated with lovastatin in which a 50% mortality ensued after 2 weeks of treatment. At the dosage used this may have some implications in its therapeutic use in certain conditions.
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PMID:Toxicity of lovastatin in rats with experimentally induced nephrotic syndrome. 207 99

We investigated the metabolism of very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL), and low density lipoprotein (LDL) apolipoprotein B (apoB) in seven patients with combined hyperlipidemia (CHL), using 125I-labeled VLDL and 131I-labeled LDL and compartmental modeling, before and during lovastatin treatment. Lovastatin therapy significantly reduced plasma levels of LDL cholesterol (142 vs 93 mg/dl, P less than 0.0005) and apoB (1328 vs 797 micrograms/ml, P less than 0.001). Before treatment, CHL patients had high production rates (PR) of LDL apoB. Three-fourths of this LDL apoB flux was derived from sources other than circulating VLDL and was, therefore, defined as "cold" LDL apoB flux. Compared to baseline, treatment with lovastatin was associated with a significant reduction in the total rate of entry of apoB-containing lipoproteins into plasma in all seven CHL subjects (40.7 vs. 25.7 mg/kg.day, P less than 0.003). This reduction was associated with a fall in total LDL apoB PR and in "cold" LDL apoB PR in six out of seven CHL subjects. VLDL apoB PR fell in five out of seven CHL subjects. Treatment with lovastatin did not significantly alter VLDL apoB conversion to LDL apoB or LDL apoB fractional catabolic rate (FCR) in CHL patients. In three patients with familial hypercholesterolemia who were studied for comparison, lovastatin treatment increased LDL apoB FCR but did not consistently alter LDL apoB PR. We conclude that lovastatin lowers LDL cholesterol and apoB concentrations in CHL patients by reducing the rate of entry of apoB-containing lipoproteins into plasma, either as VLDL or as directly secreted LDL.
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PMID:Lovastatin therapy reduces low density lipoprotein apoB levels in subjects with combined hyperlipidemia by reducing the production of apoB-containing lipoproteins: implications for the pathophysiology of apoB production. 235 67

Hypercholesterolemia (type II hyperlipidemia) after cardiac transplantation is common and may play a role in the accelerated rate of coronary atherosclerosis seen following the procedure. However, conventional cholesterol-lowering drugs are either ineffective or contraindicated for use in transplant recipients. The presence of type II hyperlipidemia was identified in 11 cardiac transplant recipients during a mean follow-up period of 15 months (range 3 to 41) after transplantation. Lovastatin, at an initial dosage of 20 mg/day, was administered for a period of 1 year. The maximal dosage of lovastatin was 60 mg/day. All patients received maintenance dosages of immunosuppressive agents, including cyclosporine-A, prednisone and, in some instances, azathioprine. Lipid profiles, hepatic transaminases, serum creatinine, creatine kinase and cyclosporine-A serum trough levels were measured quarterly. Total cholesterol decreased by 27% (354 +/- 50 vs 258 +/- 36 mg/dl, p less than 0.01) after 3 months and remained stable thereafter. Similarly, low density lipoprotein cholesterol decreased by 34% (221 +/- 51 vs 146 +/- 40 mg/dl, p less than 0.01) after 3 months and remained constant. Triglycerides, high density lipoprotein, hepatic transaminases, creatinine, creatine kinase and trough cyclosporine-A levels remained stable during the 1-year follow-up period. Lovastatin was uniformly well tolerated in this study group. When given in modest dosages, lovastatin appears to be a safe, effective and well-tolerated therapy for hypercholesterolemia in cardiac transplant recipients.
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PMID:Lovastatin therapy for hypercholesterolemia in cardiac transplant recipients. 267 84

Lovastatin is the first of a new class of cholesterol lowering drugs that competitively inhibit HMG-CoA reductase. This new drug decreases cholesterol synthesis and apolipoprotein B concentrations, and increases LDL receptor activity without adverse effects on other products in the cholesterol pathway. In patients with heterozygous familial or polygenic (non-familial) hypercholesterolaemia, oral lovastatin 20 to 40 mg twice daily reduces plasma total cholesterol and LDL-cholesterol concentrations by 25 to 40% over a period of several weeks. Lovastatin also produces decreases in plasma triglyceride and VLDL-cholesterol concentrations, although to a lesser extent. In addition, small though significant increases in HDL-cholesterol concentrations have been observed. Combined administration of lovastatin with other lipid-lowering drugs results in further reductions in plasma total and LDL-cholesterol concentrations beyond those seen with either drug alone. From findings in short term studies, lovastatin appears to be well tolerated with a low incidence of side effects. However, liver function tests and eye examinations for possible lens opacities are advised, and further long term studies in larger groups of patients are necessary before the side effect profile of lovastatin will be clearly established. As would be expected at this relatively early stage of its clinical 'life,' lovastatin has not yet been studied in a manner that would determine its effect on cardiovascular mortality during long term administration. Nevertheless, if the substantial improvements to patients' lipid and lipoprotein profiles observed in short term studies are maintained during long term administration, then lovastatin will have an important role in the pharmacological management of hyperlipidaemia.
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PMID:Lovastatin. A preliminary review of its pharmacodynamic properties and therapeutic use in hyperlipidaemia. 306 36

Familial dysbetalipoproteinemia is characterized by hyperlipidemia, increases in beta-migrating, very low density lipoproteins (beta-VLDL), and homozygosity for apolipoprotein E2 (apo E2). In this study, 3 patients with familial dysbetalipoproteinemia were treated with lovastatin, and kinetics for apolipoprotein B (apo B) were determined in control and drug treatment periods. Multicompartmental analyses of apo B kinetics in VLDL and in low density lipoproteins (LDL) were carried out. Lovastatin therapy generally lowered plasma concentrations of apo B and cholesterol in VLDL and LDL. The reductions in concentrations were due mainly to a decrease in transport (production) rates for these fractions. Indeed, the fractional clearance rate (FCR) for LDL-apo B was reduced during lovastatin therapy. The decreased transport rate for VLDL-apo B and LDL-apo B could have been due to an inhibition of the synthesis of lipoproteins containing apo B. An alternate explanation is that lovastatin promoted direct removal of a rapidly-catabolized fraction of VLDL-apo B that is a precursor for longer-lived lipoproteins in the circulation; this mechanism could decrease input rates of identifiable lipoprotein species and retard their clearance because of "saturation" of LDL receptors by more rapidly removed lipoproteins. Finally, both mechanisms, i.e., decreased production and increased clearance of lipoproteins, may have contributed to the fall in VLDL-apo B and LDL-apo B concentrations during lovastatin therapy.
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PMID:Lovastatin therapy in familial dysbetalipoproteinemia: effects on kinetics of apolipoprotein B. 316 80

The nephrotic syndrome is characterized by proteinuria, hypoalbuminemia, and hypercholesterolemia. Hypertriglyceridemia often is present as well. In this study, the kinetics of plasma lipoproteins were investigated in four patients with nephrotic hyperlipidemia, and repeat studies were carried out in three of these patients during therapy with lovastatin. Before lovastatin therapy, the patients had an extremely delayed catabolism of very low density lipoproteins (VLDL) without evidence of overproduction of lipoproteins in this fraction. Three of four patients had elevated levels of low density lipoprotein (LDL) that were due mainly to increased production rates for LDL. In the three patients treated with lovastatin, the drug therapy lowered plasma concentrations of total cholesterol, triglycerides, VLDL-cholesterol, and LDL-cholesterol, and raised high density lipoprotein (HDL)-cholesterol. Lovastatin therapy decreased VLDL-triglycerides primarily by enhancing their catabolism, and lowered LDL-cholesterol levels mainly by reducing input rates for LDL. Overall, lovastatin appears to be an effective drug for the treatment of hyperlipidemia in the nephrotic syndrome.
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PMID:Lovastatin therapy in nephrotic hyperlipidemia: effects on lipoprotein metabolism. 316 83

Hyperlipidemia, particularly hypercholesterolemia, occurs in cardiac transplant recipients both as a preexisting condition and as a consequence of immunosuppressive therapy. Lovastatin (Mevacor) has emerged as an agent that may effectively manage this condition. Few serious side effects of this drug have been observed. We describe two cardiac transplant recipients treated with lovastatin in conjunction with their other medications, including cyclosporine, who developed acute renal failure and rhabdomyolysis. Resolution of muscle damage followed discontinuation of cyclosporine and lovastatin therapy. We postulate that hepatic dysfunction secondary to cyclosporine predisposed these patients to lovastatin-induced muscle damage. Use of this drug in cardiac and other organ transplant recipients should be accompanied by close surveillance of creatine kinase, hepatic transaminases, and cyclosporine levels.
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PMID:Rhabdomyolysis and renal injury with lovastatin use. Report of two cases in cardiac transplant recipients. 329 May 20

Cholesteryl ester storage disease (CESD) is characterized by the deficient activity of lysosomal cholesteryl ester (CE) hydrolase, accumulation of LDL-derived CE in lysosomes, and hyperlipidemia. We studied the kinetics of VLDL and LDL apolipoprotein B (apoB), using 125I-VLDL and 131I-LDL, in a 9-yr-old female with CESD and elevated total cholesterol (TC) (271.0 +/- 4.4 mg/dl), triglyceride (TG) (150.0 +/- 7.8 mg/dl), and LDL cholesterol (184.7 +/- 3.4 mg/dl). These studies demonstrated a markedly elevated production rate (PR) of apoB, primarily in LDL, with normal fractional catabolism of apoB in VLDL and LDL. Urine mevalonate levels were elevated, indicative of increased synthesis of endogenous cholesterol. Treatment with lovastatin, a competitive inhibitor of hydroxymethylglutaryl coenzyme A reductase, resulted in significant reductions in TC (196.8 +/- 7.9 mg/dl), TG (100.8 +/- 20.6 mg/dl), and LDL cholesterol (102.0 +/- 10.9 mg/dl). Therapy reduced VLDL apoB PR (5.2 vs. 12.2 mg/kg per d pretreatment) and LDL apoB PR (12.7 vs. 24.2 mg/kg per d pretreatment). Urine mevalonate levels also decreased during therapy. These results indicate that, in CESD, the inability to release free cholesterol from lysosomal CE resulted in elevated synthesis of endogenous cholesterol and increased production of apoB-containing lipoproteins. Lovastatin reduced both the rate of cholesterol synthesis and the secretion of apoB-containing lipoproteins.
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PMID:Suppression of apolipoprotein B production during treatment of cholesteryl ester storage disease with lovastatin. Implications for regulation of apolipoprotein B synthesis. 368 May 22

In the past history of the pharmaceutical industry, secondary metabolites have been screened almost exclusively for antimicrobial activities. This biased and narrow view has severely limited the potential application of microbial metabolites. Fortunately, this situation is changing and we are now entering into a new era in which microbial metabolites are being applied to diseases heretofore only subjected to synthetic compounds. This new approach is the application of microbial secondary metabolites to diseases that are not caused by other bacteria or fungi. For years, major drugs such as hypotensive and anti-inflammatory agents that are used for non-infectious diseases have been strictly synthetic products. Similarly, major therapeutics for parasitic diseases in animals (for example, coccidiostats and anthelminthics) resulted strictly from screens of chemically synthesized compounds followed by molecular modification. However, today fermentation products such as monensin and lasalocid dominate the coccidiostat market. The avermectins, another group of streptomycete products, have high activity against helminths and arthropods. Indeed, their activity appears to be an order of magnitude greater than previously discovered anthelminthic agents, the vast majority of which are synthetic compounds. Umezawa's group in Japan has isolated many microbial products with important pharmacological activities by screening with simple enzymic assays. There is much interest in a natural inhibitor of intestinal glucosidase, which is produced by an actinomycete of the genus Actinoplanes. The aim is to decrease hyperglycaemia and triacylglycerol synthesis in adipose tissue, liver and the intestinal wall of patients with diabetes, obesity and type IV hyperlipidaemia. Another natural compound of interest is mevinolin, a fungal product which acts as a cholesterol-lowering agent in animals. Mevinolin is produced by Aspergillus terreus. In its hydroxyacid form (mevinolinic acid), mevinolin is a potent competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase from liver. It is clear that, although the microbe has contributed greatly to the benefit of mankind, we have merely scratched the surface of the potential of microbial activity.
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PMID:A new era of exploitation of microbial metabolites. 640 Apr 79

The hydroxymethylglutaryl coenzyme A (HMG CoA) reductase inhibitor lovastatin is used to treat hyperlipidaemia. This agent prevents the isoprenylation of some proteins involved in signal transduction processes and inhibits IgE-receptor-linked mediator release from RBL-2H3 cells. In this study the effect of in vivo and in vitro administration of lovastatin on histamine release from rat peritoneal mast cells was examined. Lovastatin (4 mg/kg/day for 2 weeks) inhibited histamine release induced by concanavalin A (con A) from rat peritoneal mast cells of Hooded-Lister rats and both homozygous lean and obese Zucker rats. In contrast, release induced by antirat IgE (anti-IgE) was only significantly inhibited in cells derived from Hooded-Lister rats and that induced by compound 48/80 was not altered. Lovastatin (20 microM, 24 h, in vitro) caused a significant inhibition of the subsequent histamine release to con A, anti-IgE and compound 48/80 but not to the calcium ionophore A 23187. It is important to determine whether such inhibitory effects are also observed after the chronic, clinical administration of lovastatin and other HMG CoA reductase inhibitors.
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PMID:Effect of in vivo and in vitro lovastatin treatment on mast cell activation. 758 Feb 88


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