Drugs online research references
Metabolism. 1994 Feb;43(2):257-62.
Increase in intracellular triglyceride synthesis induced by gemfibrozil.
Baldo A, Sniderman AD, Cianflone K.
McGill Unit for the Prevention of Cardiovascular Disease, Royal Victoria Hospital, Montreal, Quebec, Canada.
Gemfibrozil is an effective hypotriglyceridemic agent. Its mechanism of action has not been determined with certainty, but it is generally thought to act by virtue of an effect on lipoprotein lipase. However, this study was designed to test the hypothesis that gemfibrozil directly affects intracellular triglyceride synthesis in peripheral cells, and indeed, when added to the medium, gemfibrozil markedly stimulated triglyceride synthesis in cultured human skin fibroblasts. The effect was concentration-dependent, with a maximum effect at a gemfibrozil concentration of 40 micrograms/mL. A marked increase in triglyceride synthesis was observed when either labeled glucose or labeled fatty acid were added to the medium, indicating that the stimulation was substrate-coordinated. The effect was sustained for hours, with an onset of action within minutes. Lineweaver-Burk plots were constructed, and these revealed no apparent change in Km for either oleate or glucose (8.18 +/- 2.97 v 6.40 +/- 2.10 mumol/L for oleate and 0.113 +/- 0.004 v 0.107 +/- 0.051 mmol/L for glucose, control v gemfibrozil, P = NS). By contrast, there was a significant increase in the maximum triglyceride synthetic rate (Vmax) for both oleate and glucose (14.57 +/- 0.01 v 32.66 +/- 1.85 nmol/mg/4 h for oleate and 67.72 +/- 1.22 v 156.77 +/- 17.61 nmol/mg/4 h for glucose, control v gemfibrozil, P < .025). Given the rapid onset in action, these data suggest that gemfibrozil altered the active state of a limiting step in the triglyceride synthetic pathway. The effect of gemfibrozil on triglyceride synthesis was also determined on differentiated human preadipocytes and HepG2 cells.(ABSTRACT TRUNCATED AT 250 WORDS)
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8121311&dopt=Abstract
J Am Coll Cardiol. 1992 May;19(6):1315-21.
Hyperlipidemia after heart transplantation: report of a 6-year experience, with treatment recommendations.
Ballantyne CM, Radovancevic B, Farmer JA, Frazier OH, Chandler L, Payton-Ross C, Cocanougher B, Jones PH, Young JB, Gotto AM Jr.
Department of Medicine, Methodist Hospital, Houston, Texas.
Mean plasma lipid values in 100 patients who survived greater than 3 months after heart transplantation increased significantly at 3 months over pretransplantation values: total cholesterol from 168 +/- 7 to 234 +/- 7 mg/dl, low density lipoprotein (LDL) cholesterol from 111 +/- 6 to 148 +/- 6 mg/dl, high density lipoprotein (HDL) cholesterol from 34 +/- 1 to 47 +/- 1 mg/dl and triglycerides from 107 +/- 6 to 195 +/- 10 mg/dl. There were no significant increases after this time. The LDL cholesterol values reamined greater than or equal to 130 mg/dl in 64% of patients and triglyceride values remained greater than or equal to 200 mg/dl in 41% of patients 6 months after postoperative dietary instructions. Beginning in 1985, select patients whose total cholesterol values remained greater than 300 mg/dl despite 6 months of dietary intervention were treated with lovastatin given alone in a high dose (40 to 80 mg/day) or in combination with another hypolipidemic agent. Four of the five patients so treated developed rhabdomyolysis; two of the four had acute renal failure. Beginning in 1988, a second protocol--lovastatin at 20 mg/day as monotherapy--was used in patients who despite dietary intervention had total cholesterol greater than 240 mg/dl (mean follow-up 13 months). In the 15 patients so treated, mean total cholesterol decreased from 299 +/- 10 mg/dl before treatment with lovastatin to 235 +/- 9 mg/dl during treatment (21% reduction, p less than 0.001) and mean LDL cholesterol was reduced from a baseline value of 190 +/- 10 to 132 +/- 12 mg/dl during treatment (31% reduction, p less than 0.001). In this study, lovastatin at a dose of less than or equal to 20 mg/day as monotherapy was a well tolerated, effective treatment for hyperlipidemia after heart transplantation. It did not result in rhabdomyolysis and required no alteration in immunosuppressive therapy. However, the dose should not exceed 20 mg/day and combination therapy with either gemfibrozil or nicotinic acid should be avoided, even if the target LDL cholesterol value is not reached.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1564233&dopt=Abstract
Nephrol Dial Transplant. 1996 Nov;11(11):2223-8.
The effects of gemfibrozil upon the hypercoagulable state in dyslipidaemic patients with chronic renal failure.
Irish AB, Thompson CH.
Oxford Renal Unit, Churchill Hospital, Headington, Oxford, UK.
BACKGROUND: The dyslipidaemia of chronic renal disease could contribute to a hypercoagulable state by activation of blood coagulation and/or impairment of fibrinolysis, thereby increasing cardiovascular disease (CVD) risk. METHODS: We measured the coagulation activation marker prothrombin fragment F1 + 2 (F1 + 2), fibrinogen, plasminogen activator inhibitor-1 activity (PAI1), interleukin-6 (IL6), insulin, lipids and lipoprotein(a) (Lp(a)), in 12 patients with chronic renal disease before and after gemfibrozil. RESULTS: Gemfibrozil significantly reduced triglycerides by 44% and increased HDL-cholesterol by 31% without significant change in LDL cholesterol. Before treatment, patients had increased F1 + 2, fibrinogen and IL6, but similar PAI1 compared with the controls, consistent with a hypercoagulable and persistent inflammatory state. Following treatment, F1 + 2 decreased to within the normal range and this reduction correlated with the decrease in triglycerides and inversely with the increase in HDL-cholesterol. A non-significant decrease in fibrinogen was inversely correlated with a significant increase in albumin. However, Lp(a) and PAI1 activity significantly increased whilst insulin and IL6 were unchanged. CONCLUSIONS: Gemfibrozil improved the uraemic dyslipidaemia and hypercoagulable state by reduction in activation of blood coagulation, indirectly suggesting a reduction in lipid-dependent extrinsic pathway activity which should contribute to reduced risk of thrombosis and CVD. Reduced fibrinogen and increased albumin are consistent with a reduction in the acute phase response. Increased PAI1 and Lp(a) could impair fibrinolysis and potentially increase CVD risk, although the mechanism for these effects is uncertain but does not appear related to cytokine or insulin mediated mechanisms and requires further study. Large prospective studies are required to determine if gemfibrozil can reduce CVD events in uraemia.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8941582&dopt=Abstract
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