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BACKGROUND: Insulin and its precursors found in increased plasma concentrations in non-insulin-dependent diabetes mellitus (NIDDM) augment synthesis of plasminogen activator inhibitor type 1 (PAI-1) in Hep G2 cells in vitro and in rabbit liver in vivo. Reduced endogenous fibrinolysis secondary to increased PAI-1 activity may exacerbate atherogenesis. Recently, the reduction of the coronary heart disease incidence in the Helsinki Heart Study has implicated favorable modulation of endogenous fibrinolysis by gemfibrozil. METHODS AND RESULTS: In Hep G2 cells, 500 (700) mumol/L gemfibrozil decreased basal secretion of PAI-1 by 26% (43%) (P = .012 and P = .021, respectively) and attenuated insulin-induced (10 nmol/L) augmentation of PAI-1 in conditioned media by 61% (109%) (P = .010) within 24 hours. Inhibition was dependent on the duration of exposure (0 to 48 hours) and on the concentration of gemfibrozil (0 to 700 mumol/L) but not on the concentration of insulin (0.1 to 100 nmol/L). Gemfibrozil attenuated the augmentation of PAI-1 secretion induced by proinsulin (> 100%), by des(31,32)proinsulin (75%), and by des(64,65) proinsulin (77%) as well (10 nmol/L each). The specificity of these effects was confirmed by the unaltered levels of newly synthesized protein (metabolic labeling) and of total protein (both in conditioned media and cell lysates). Secretion of fibrinogen by Hep G2 cells was not affected by gemfibrozil. Changes in PAI-1 protein levels reflected modulation of PAI-1 gene expression as manifested by changes in levels of 3.2-kb PAI-1 mRNA (Northern blots). CONCLUSIONS: Gemfibrozil attenuated the augmentation of synthesis and secretion of PAI-1 induced by insulin and its precursors directly and specifically. Accordingly, gemfibrozil may exert favorable therapeutic effects normalizing impaired fibrinolysis in patients with hyperinsulinemia such as NIDDM.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9024157&dopt=Abstract
JAMA. 1990 Apr 25;263(16):2185-8.
Prescribed use of cholesterol-lowering drugs in the United States, 1978 through 1988.
Wysowski DK, Kennedy DL, Gross TP.
Division of Epidemiology and Surveillance, Food and Drug Administration, Rockville, Md.
Data from two pharmaceutical marketing research databases, the National Prescription Audit and the National Disease and Therapeutic Index, were used to study trends in outpatient use of cholesterol-lowering drugs in the United States from 1978 through 1988. Retail pharmacies dispensed an estimated 4.4 million prescriptions for cholesterol-lowering drugs in 1978. This declined to 2.6 million in 1983 and increased dramatically to nearly 13 million in 1988. This fivefold increase between 1983 and 1988 was accounted for primarily by the introduction and use of two new drugs, gemfibrozil and lovastatin, and, to a lesser extent, by the increasing use of some older drugs. In 1988, after 1 full year of marketing, lovastatin was the leading cholesterol-lowering drug, followed closely by gemfibrozil; both drugs are currently considered second-line agents. Clofibrate and dextrothyroxine, drugs that ranked first and second in 1978, declined to ranks of sixth and eighth out of eight in 1988. Cholestyramine, gemfibrozil, and lovastatin accounted for about 75% of all lipid-lowering prescriptions in 1988. From 1978 through 1988, an average 54% of individuals using cholesterol-lowering drugs were 60 years of age or older. The 13 million prescriptions for cholesterol-lowering drugs in 1988 represent a maximum estimate of 13 million treated individuals. This number compares with the 60 million Americans with high cholesterol levels who are candidates for dietary advice, and, if cholesterol levels do not improve, for combined diet and drug intervention.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2319684&dopt=Abstract
Biol Pharm Bull. 1997 Apr;20(4):315-21.
Effect of gemfibrozil on centrifugal behavior of rat peroxisomes and activities of peroxisomal enzymes involved in lipid metabolism.
Hashimoto F, Hamada S, Hayashi H.
Faculty of Pharmaceutical Sciences, Josai University, Saitama, Japan.
The effect of gemfibrozil, and analogue of clofibric acid, on the centrifugal behavior of peroxisomes and activity of peroxisomal enzymes involved in lipid metabolism was studied. Rats were fed chow containing 0.2% gemfibrozil for 2 weeks. Nycodenz gradient centrifugation of the light mitochondrial fraction revealed that peroxisomes of gemfibrozil-treated rats were concentrated in fractions of higher density compared with control rats. The activity of fatty acyl-CoA oxidase, crotonase, beta-hydroxybutyryl-CoA dehydrogenase, and thiolase (individual enzymes of the peroxisomal fatty acid beta-oxidation system) were enhanced 9.6, 2.3, 3.4 and 9.1 times respectively compared with controls, by treatment. The hydroxymethylglutaryl-CoA (HMG-CoA) reductase (rate-limiting enzyme of cholesterol synthesis) activity of peroxisomes and microsomes was greatly increased by in vivo treatment with gemfibrozil, but was decreased by addition of the agent to the assay mixture of the enzyme. Gemfibrozil directly inhibited the reductase activity and did so at a lower concentration than clofibric acid. Peroxisomal reductase was more resistant to damage by the agent than the microsomal enzyme. The HMG-CoA reductase activity of peroxisomes and microsomes of hyperlipidemic rats was also increased by in vivo treatment with gemfibrozil, whereas the serum cholesterol level was hardly changed. These results indicate that the effect of gemfibrozil differs from that of clofibric acid, the main difference being the effect on HMG-CoA reductase. Gemfibrozil increased reductase activity in vivo, unlike clofibric acid, but inhibited the enzyme in vitro to a greater extent than clofibric acid.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9145201&dopt=Abstract
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