Design,synthesis and biological evaluation of novel drugs for metabolic syndrome / 国际药学研究杂志

Objective To design and synthesize novel drugs for metabolic syndrome. Methods A kind of drugs treating met?abolic syndrome was designed by linking acipimox with the lipid lowering function group of fibrates. Primary amine intermediates were synthesized from 4-aminophenol,4-(aminomethyl)phenol and 4-(2-aminoethyl)phenol by 3 steps,then target compounds were ob?tained by coupling acipimox with these primary amine intermediates,and their hypolipidaemic activity in Triton WR-1339 induced hy?perlipi daemic mice was evaluated. Results and Conclusion 5 target compounds were synthesized and identified by 1H NMR and ESI MS methods. It showed that all the compounds could decrease blood-lipid,and 4c exhibited anti-hyperlipidemic activities close to the positive control(bezafibrate)in in vivo hypolipidemic activity tests. The results have good value for the discovery of novel drugs for metabolic myndrome.

Design, synthesis and biological evaluation of novel drugs for metabolic syndrome / 国际药学研究杂志

Objective To design and synthesize novel drugs for metabolic syndrome. Methods A kind of drugs treating metabolic syndrome was designed by linking acipimox with the lipid lowering function group of fibrates. Primary amine intermediates were synthesized from 4-aminophenol, 4- (aminomethyl)phenol and 4- (2-aminoethyl)phenol by 3 steps, then target compounds were obtained by coupling acipimox with these primary amine intermediates, and their hypolipidaemic activity in Triton WR-1339 induced hyperlipi daemic mice was evaluated. Results and Conclusion 5 target compounds were synthesized and identified by1H NMR and ESI MS methods. It showed that all the compounds could decrease blood-lipid, and 4c exhibited anti-hyperlipidemic activities close to the positive control(bezafibrate)in in vivo hypolipidemic activity tests. The results have good value for the discovery of novel drugs for metabolic myndrome.

Therapeutic effect and safety of acipimox combined with small-dose atorvastatin on combined hyperlipidemia after renal transplantation / 器官移植

Objective To assess the therapeutic effect and safety of acipimox combined with small-dose atorvastatin on combined hyperlipidemia after renal transplantation. Methods Fifty-six patients complicated with combined hyperlipidemia after renal transplantation were randomized into the combined small-dose group [n =28,acipimox (250 mg,twice a day) +atorvastatin (1 0 mg,once a day)]and normal dose group [n =28,atorvastatin (20-40 mg,once a day)].Total cholesterol (TC),triglyceride (TG),high density lipoprotein cholesterin (HDL-C ), low density lipoprotein cholesterin (LDL-C ), aspartate aminotransaminase (AST),alanine aminotransferase (ALT),serum creatinine (Scr),blood urea nitrogen (BUN),uric acid (UA)and creatine kinase (CK)were observed before treatment and 1 ,2 and 3 months after treatment.Adverse drug reaction was recorded.Results Compared with those before treatment,TC,TG and LDL-C of the normal dose group and the combined small-dose group decreased after treatment,but HDL-C increased,and the difference had statistical significance (all in P <0.01 ).Compared with the normal dose group,TG and LDL-C of the combined small-dose group were lower and HDL-C was higher,and the difference had statistical significance (all in P <0.01 ).At each time point before and after treatment,ALT,AST,Scr, BUN,UA and CK of the normal dose group and the combined small-dose group showed no statistically significant difference (all in P >0.05).There was significant difference in the incidence of adverse reactions in the digestive system,nervous system,musculoskeletal system and skin/vascular of the normal dose group and the combined small-dose group (all in P <0.05 ).Conclusions Acipimox combined with small-dose atorvastatin can treat combined hyperlipidemia after renal transplantation safely and effectively.

Determination of Acipimox in Human Serum by HPLC / 中国药房

OBJECTIVE: To establish HPLC method for the determination of acipimox in human serum. METHODS: The determination was performed on C18 column under room temperature, the mobile phase consisted of methanol -water(15:85) with a flow rate of 0.8ml/ min and detection wavelength of 260nm, the quantitation was conducted by external reference method,the serum was subjected to protein sediment by methanol,the supernate fluid obtained thereafter was undergone sample injection. RESULTS: The linear range of acipimox was 1.0-16.0?g/ml (r = 0.9 987),the minimum detection concentration was 0.5?g/ ml; the average recovery of method was 96.05% . CONCLUSION: This method is simple, fast, sensitive and accurate, and which can be applied for blood concentration monitoring and pharmacokinetic study of acipimox.

What is the Key Step in Muscle Fatty Acid Oxidation after Change of Plasma Free Fatty Acids Level in Rats?

The purpose of this study was to discern the critical point in skeletal muscle fatty acid oxidation by changing plasma free fatty acids (FFA) level in rat. In the study, 3 key steps in lipid oxidation were examined after changing plasma FFA level by acipimox. The rates of both palmitate and palmitoyl- carnitine oxidation were decreased by decrease of plasma FFA level, however, carnitine palmitoyl transferase (CPT) 1 activity was not changed, suggesting CPT1 activity may not be involved in the fatty acid oxidation at the early phase of plasma FFA change. In the fasted rats, beta-hydroxy acyl-CoA dehydrogenase (beta-HAD) activity was depressed to a similar extent as palmitate oxidation by a decrease of plasma FFA level. This suggested that beta-oxidation might be an important process to regulate fatty acid oxidation at the early period of plasma FFA change. Citrate synthase activity was not altered by the change of plasma FFA level. In conclusion, the critical step in fatty acids oxidation of skeletal muscles by the change of plasma FFA level by acipimox in fasting rats might be the beta-oxidation step rather than CPT1 and TCA cycle pathways.

The effects on serum lipoprotein(a) of antihyperlipidemic agents

BACKGROUND: Many studies to reduce serum lipoprotein(a) are done because serum lipoprotein(a) has been known to be an independent risk factor of coronary artery disease along with age, smoking, diabetes, hypertension, and hyperlipidemia. Till now, oral estrogen/androgen therapy, niacin analogue and plasmapheresis are known therapeutic methods. This study examined the relative effects of three antihyperlipidemic agents, acipimox, lovastatin, fenofibrate. METHODS: Among 70 subjects (male-19, female-51) with their serum cholesterol level of more than 240mg/dL, 56 subjects who were completed 2 months antihyperlipidemic treatment (acipimox-20, lovastatin-18, fenofibrate-18) were examined for baseline total cholesterol, HDL cholesterol, triglyceride, and lipoprotein(a) and were followed up 2 months later. RESULTS: Mean values of each group for acipimox, lovastatin, fenofibrate were as follows: total cholesterol (268.1+/-19.03, 287.1+/-36.42, 268.9+/-25.99), HDL cholesterol (43.5+/-10.99, 42.7+/-11.88, 37.9+/-8.20), triglyceride (226.1+/-165.03, 260.4+/-175.98, 234.3+/-124.33), LDL cholesterol (179.3+/-30.40, 192.3+/-41.52, 184.1+/-38.08), lipoprotein(a) (26.2+/-15.32,34.8+/-18.56,29.9+/-12.58). Mean percentile reduction of lipoprotein(a) was acipimox-41.4%(P<0.0001), lovastatin-22.2%(P<0.0001), fenofibrate-16.1%(P<0.05), and p value was less than 0.05 in the comparison of groups. Lipoprotein(a) showed no relations with age, sex, BMI, WHR, smoking, total cholesterol, HDL cholesterol, triglyceride and LDL cholesterol. After 2 months treatment, mean reduction percentages of total cholesterol was acipimox-12.2%(P<0.0001), lovastatin-17.6%(P<0.0001), fenofibrate-8.85%(P<0.05). LDL cholesterol was acipimox-16.12%(P<0.0001), lovastatin-22.89%(P<0.0001), fenofibrate-12.06% (P<0.05). Triglyceride was acipimox-17.24%(P<0.0001), lovastatin-17.39%(P<0.0001), fenofibrate-9,78%(P<0.05). HDL cholesterol was elevated in acipimox-17.24%(P<0.05), lovastatin-16.10%(P<0.05) and fenofibrate-12.06(P<0.05). In total cholesterol(P<0.05) and LDL cholesterol(P<0.05), there were significant differences among 3 groups, but not in HDLcholesterol and triglycerides. CONCLUSION: In two months treatment of acipimox, lovastatin and fenofibrate in hyperlipidemic patients, lipoprotein(a), known for independent risk factor of coronary artery disease, was reduced significantly in the order of acipimox, lovastatin and fenofibrate.

Effect of Antiliyolytic Agents on Glueose Metabolism in Thyrotoxic Patients / 대한내분비학회지

Decreased glucose tolerance is often found in patients with thyrotoxicosis but the pathogenetic mechanisms are poorly understood. Since the concentrations of free fatty acid are usually elevated due to increased lipolysis in thyrotoxicosis, the preferential oxidation of the free fatty acids may explain the decreased glucose tolerance in hyperthyroidism. The aim of this study was to investigate whether lowering plasma free fatty acid(FFA) by acipimox, a long-acting antilipolytic agent, could affect glucose metabolism in thyrotoxicosis. We performed intravenous glucose tolerance test with acipimox or placebo in 6 untreated thyrotoxicmen and 6 age-and body mass index(BMI)-matched controls. The following results were obtained.1) The basal plasma FFA concentration in thyrotoxic patients were significantly higher than those in controls(997.0+-303.4 uEq/L vs. 290.5+-169.1 uEq/L; p<0.01). 2) Plasma FFA concentrations decreased rapidly with acipimox ingestion in both controls and thyrotoxic patients.3) Plasma glucose concentrations were significantly lower with acipimox ingestion than with placebo in thyrotoxic patients from 17min after intravenous glucose load and to the end of the study.4) Plasma insulin concentrations in thyrotoxic patients with acipimox ingestion were higher at 5, 7 min after iv glucose load.5) In thyrotoxic patients, glucose disappearance rate(K_glucose) in acipimox treatment was significantly higher than that in placebo treatment(2.44+-0.84 vs. 1.58+-0.37;p<0.05). 6) K_glucose values were inversely correlated with basal FFA concentrations(r=-0.58, p<0.05). In summary, in thyrotoxic patients with elevated plasma FFA levels, acipimox lowered plasma FFA, which in turn improved glucose tolerance.