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Increased atherosclerosis risk in hyperlipidemic patients may be a result of the enhanced oxidizability of their plasma lipoproteins. We have previously shown that hypocholesterolemic drug therapy, including the 3-hydroxy-3-methyl-glutaryl CoenzymeA (HMG-CoA) reductase inhibitors, and the hypotriglyceridemic drug bezafibrate, significantly reduced the enhanced susceptibility to oxidation of low density lipoprotein (LDL) isolated from hyperlipidemic patients. Although this antioxidative effect could not be obtained in vitro with all of these drugs, the active drug metabolites, which are formed in vivo, could affect lipoprotein oxidizability. We thus sought to analyze the effect of atorvastatin and gemfibrozil, as well as specific hydroxylated metabolites, on the susceptibility of LDL, very low density lipoprotein (VLDL), and high density lipoprotein (HDL) to oxidation. LDL oxidation induced by either copper ions (10 microM CuSO4), by the free radical generator system 2'-2'-azobis 2-amidino propane hydrochloride (5 mM AAPH), or by the J-774A.1 macrophage-like cell line, was not inhibited by the parent forms of atorvastatin or gemfibrozil, but was substantially inhibited (57-97%), in a concentration-dependent manner, by pharmacological concentrations of the o-hydroxy and the p-hydroxy metabolites of atorvastatin, as well as by the p-hydroxy metabolite (metabolite I) of gemfibrozil. On using the atorvastatin o-hydroxy metabolite and gemfibrozil metabolite I in combination an additive inhibitory effect on LDL oxidizability was found. Similar inhibitory effects (37-96%) of the above metabolites were obtained for the susceptibility of VLDL and HDL to oxidation in the oxidation systems outlined above. The inhibitory effects of these metabolites on LDL, VLDL, and HDL oxidation could be related to their free radical scavenging activity, as well as (mainly for the gemfibrozil metabolite I) to their metal ion chelation capacities. In addition, inhibition of HDL oxidation was associated with the preservation of HDL-associated paraoxonase activity. We conclude that atorvastatin hydroxy metabolites, and gemfibrozil metabolite I possess potent antioxidative potential, and as a result protect LDL, VLDL, and HDL from oxidation. We hypothesize that in addition to their beneficial lipid regulating activity, specific metabolites of both drugs may also reduce the atherogenic potential of lipoproteins through their antioxidant properties.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9690910&dopt=Abstract
J Clin Pharm Ther. 1998 Feb;23(1):49-56.
Evaluation of drug usage and expenditure in a hospital diabetes clinic.
Wu SY, Lung BC, Chang S, Lee SC, Critchley JA, Chan JC.
Department of Pharmacy, The Chinese University of Hong Kong, Shatin, New Territories.
BACKGROUND: Diabetes mellitus is a major public health problem and often coexists with hypertension and dyslipidaemia. A prescription-based survey was conducted to examine the use of antidiabetic, antihypertensive and lipid lowering drugs in a hospital diabetes clinic. The expenditure incurred was also evaluated. METHOD: Prescriptions issued from the diabetes clinic were collected for 4 consecutive weeks. Drugs were categorized into three main classes--antidiabetic, antihypertensive and lipid-lowering drugs. The unit cost of each drug and the total amount prescribed were used to estimate the total drug costs. RESULTS: During the 4-week study period, 534 prescriptions were collected, of which 520 contained antidiabetic drugs. Oral hypoglycaemic agents were prescribed in 379 patients (72.9%). Sulphonylurea was used as a single agent in 119 (22.9%) patients, in combination with metformin in 219 (42%) patients and with insulin in 17 patients (3.3%). Among patients treated with sulphonylureas (n=342), glibenclamide (47.7%) and gliclazide (30.7%) were the main drugs prescribed. Metformin monotherapy was prescribed in only 31 patients (6%). Insulin treatment was prescribed in 141 (27%) patients and in combination with oral drugs in 23 patients (4.5%). Of the 534 prescriptions, 225 (42%) contained antihypertensive drugs. Calcium channel blocking agents and angiotensin converting enzyme inhibitors were the most commonly prescribed drugs in both monotherapy (n=155) and combination therapy (n=70). The antidiabetic and antihypertensive drugs accounted for 45% and 39% of the total drug expenditure, respectively. Lipid-lowering drugs were prescribed in 8% of the diabetic patients. Simvastatin and gemfibrozil were the most common drugs prescribed and accounted for 12% of the total drug expenditure. CONCLUSION: The use of antidiabetic drugs represents a major burden on the health care system. The high proportions of patients requiring antihypertensive drugs and lipid lowering drugs further increase drug expenditure. Most of these treatments have been shown to improve clinical outcomes and quality of life, if used appropriately. The impacts of these long-term medications on health care financing require careful evaluation to assess their cost-effectiveness.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9756112&dopt=Abstract
Comp Biochem Physiol B Biochem Mol Biol. 1998 Jul;120(3):579-86.
Gemfibrozil reduces non-high-density lipoprotein cholesterol in exogenously hypercholesterolemic (ExHC) rats fed a high-cholesterol diet.
Nagao K, Yoshida S, Nakagiri H, Sakono M, Sato M, Imaizumi K.
Department of Food Science and Technology, Faculty of Agriculture, Kyushu University, Fukuoka, Japan.
Gemfibrozil is a widely used drug prescribed to elevate serum high-density lipoprotein (HDL) cholesterol levels and lower triacylglycerols. The present study was done to determine if the drug would alleviate hypercholesterolemia in exogenously hypercholesterolemic (ExHC) rats. In the drug-treated ExHC rats, the serum non-HDL cholesterol levels were lowered and the ratio of the non HDL cholesterol to serum triacylglycerols was decreased to the extent seen in the drug-treated SD rats. Liver cholesterol and triacylglycerols were lowered in the drug-treated rats. There was also an increase in fecal excretion of neutral sterols and bile acids, particularly chenodeoxycholic and beta-muricholic acids. The drug elevated cholesterol 7 alpha-hydroxylase activity and mRNA abundance and acyl-CoA cholesterol acyltransferase activity in the liver, but did not influence low-density lipoprotein receptor mRNA level in the liver. Thus, gemfibrozil is effective in alleviating hypercholesterolemia in exogenously hypercholesterolemic rats, by partitioning hepatic cholesterol into biliary excretion.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9787818&dopt=Abstract
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