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991.
992.
Pharmacodynamic interaction between the new selective cholesterol absorption inhibitor ezetimibe and simvastatin 总被引:5,自引:0,他引:5 下载免费PDF全文
Kosoglou T Meyer I Veltri EP Statkevich P Yang B Zhu Y Mellars L Maxwell SE Patrick JE Cutler DL Batra VK Affrime MB 《British journal of clinical pharmacology》2002,54(3):309-319
AIMS: The primary aims of these two single-centre, randomized, evaluator-blind, placebo/positive-controlled, parallel-group studies were to evaluate the potential for pharmacodynamic and pharmacokinetic interaction between ezetimibe 0.25, 1, or 10 mg and simvastatin 10 mg (Study 1), and a pharmacodynamic interaction between ezetimibe 10 mg and simvastatin 20 mg (Study 2). Evaluation of the tolerance of the coadministration of ezetimibe and simvastatin was a secondary objective. METHODS: Eighty-two healthy men with low-density lipoprotein cholesterol (LDL-C) >or=130 mg dl-1 received study drug once daily in the morning for 14 days. In Study 1 (n=58), five groups of 11-12 subjects received simvastatin 10 mg alone, or with ezetimibe 0.25, 1, or 10 mg or placebo. In Study 2 (n=24), three groups of eight subjects received simvastatin 20 mg alone, ezetimibe 10 mg alone, or the combination. Blood samples were collected to measure serum lipids in both studies. Steady-state pharmacokinetics of simvastatin and its beta-hydroxy metabolite were evaluated in Study 1 only. RESULTS: In both studies, reported side-effects were generally mild, nonspecific, and similar among treatment groups. In Study 1, there were no indications of pharmacokinetic interactions between simvastatin and ezetimibe. All active treatments caused statistically significant (P<0.01) decreases in LDL-C concentration vs placebo from baseline to day 14. The coadministration of ezetimibe and simvastatin caused a dose-dependent reduction in LDL-C and total cholesterol, with no apparent effect on high-density lipoprotein cholesterol (HDL-C) or triglycerides. The coadministration of ezetimibe 10 mg and simvastatin 10 mg or 20 mg caused a statistically (P<0.01) greater percentage reduction (mean -17%, 95% CI -27.7, -6.2, and -18%, -28.4, -7.4, respectively) in LDL-C than simvastatin alone. CONCLUSIONS: The coadministration of ezetimibe at doses up to 10 mg with simvastatin 10 or 20 mg daily was well tolerated and caused a significant additive reduction in LDL-C compared with simvastatin alone. Additional clinical studies to assess the efficacy and safety of coadministration of ezetimibe and simvastatin are warranted. 相似文献
993.
Draijer R Volger OL Dahlmans VE de Wit EC Havekes LM Princen HM 《Biochemical pharmacology》2002,63(9):1755-1761
Previous rodent studies suggested that the potent hypolipidemic agent 4-amino-2-(4,4-dimethyl-2-oxo-1-imidazolidinyl)pyrimidine-5-N-(trifluoromethyl-phenyl) carboxamide monohydrochloride (HOE 402) is an inducer of the LDL receptor (LDLR). Using wild-type and heterozygous and homozygous LDLR-deficient (LDLR+/0 and LDLR0/0) mice, fed a low or high cholesterol diet, we investigated whether HOE 402 specifically induces the LDLR and whether other pathways are affected. Upon treatment with 0.05% (w/w) HOE 402, the serum cholesterol levels of wild-type, LDLR+/0 and LDLR0/0 mice, were maximally reduced by 53, 56, and 73%, respectively (P<0.05), by reducing levels in very low density-lipoprotein (VLDL), intermediate density-lipoprotein (IDL), and low density-lipoprotein (LDL) cholesterol, whereas high density-lipoprotein (HDL) cholesterol levels were increased. The observations that HOE 402 exhibited no effect on in vivo clearance of 125I-labeled LDL in wild-type mice, and clearly reduced serum cholesterol levels in LDLR0/0 mice, indicate that the LDLR is not the main target for the compound. In wild-type mice, production of VLDL-TG, and cholesterol were reduced by more than 50% by HOE 402 (P<0.05), whereas VLDL apolipoprotein B (ApoB) secretion was unaffected, indicating that HOE 402 treatment changes the size, rather than the number of the secreted VLDL particles. The reduced VLDL production was accompanied by a 22% decreased hepatic cholesterol ester concentration (P<0.05). Additionally, HOE 402 treatment strongly reduced the aortic content of atherosclerotic lesions by 90 and 72% in LDLR+/0 and LDLR0/0 mice, respectively (P<0.01). In conclusion, HOE 402 is a potent cholesterol-lowering compound, which inhibits VLDL production, and consequently attenuates atherosclerosis development. 相似文献
994.
Somatostatin (somatotropin release inhibiting factor, SRIF), exerts its effects via specific G protein coupled receptors of which five subtypes have been cloned (sst1-5). Recently, SRIF receptors have also been cloned from fish tissues. In this study, goldfish sst5 receptors (gfsst5) were expressed and characterised in the Chinese hamster lung fibroblast cell line, that harbours the luciferase reporter gene driven by the serum responsive element (CCL39-SRE-Luci). The agonist radioligands [125I]-LTT-SRIF-28 ([Leu8, DTrp22, 125I-Tyr25]SRIF-28) and [125I][Tyr10]cortistatin-14 labelled similar receptor densities with high affinity and in a saturable manner (pKd: 9.99-9.71; Bmax: 300-350 fmol mg-1). 5'-Guanylyl-imidodiphosphate inhibited radioligand binding to some degree (38.5-57.9%). In competition binding studies, the pharmacological profile of SRIF binding sites defined with [125I]LTT-SRIF-28 and [125I][Tyr10]cortistatin-14 correlated significantly (r2=0.97, n=20). Pharmacological profiles of human and mouse sst5 receptors expressed in CCL39 cells correlated markedly less with those of the gfsst5 profile (r2=0.52-0.78, n > or = b16). Functional expression of the gfsst5 receptor was examined by measurement of agonist-induced luciferase expression and stimulation of [35S]GTPgammaS ([35S]guanosine 5'-O-(3-thiotriphosphate) binding. Profiles were similar to those achieved in radioligand binding studies (r2=0.81-0.93, n=20), although relative potency (pEC50) was reduced compared to pKd values. Relative efficacy profiles of luciferase expression and [35S]GTPgammaS binding, were rather divergent (r2=0.48, n=20) with peptides showing full agonism at one pathway and absence of agonism at the other. BIM 23056 (D-Phe-Phe-Tyr-D-Trp-Lys-Val-Phe-D-Nal-NH2) acted as an antagonist on the effects of SRIF-14 (pKB=6.74 +/- 0.23) on stimulation of [35S]GTPgammaS binding. Pertussis toxin abolished the effect of SRIF-14 on luciferase expression and [35S]GTPgammaS binding suggesting coupling of the receptor to G(i)/G(o) proteins. In summary, the present studies demonstrate that the gfsst5 receptor has a similar pharmacological profile and transductional properties to mammalian sst5 receptors. The difference in efficacy profiles defined using different functional assays suggests numerous, agonist specific, conformational receptor states, and/or ligand-dependent receptor trafficking. 相似文献
995.
Klingel R Mumme C Fassbender T Himmelsbach F Altes U Lotz J Pohlmann T Beyer J Küstner E 《Therapeutic apheresis and dialysis : official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy》2003,7(4):444-455
Rheopheresis is a specific application of membrane differential filtration, synonymous with double filtration plasmapheresis, for extracorporeal hemorheotherapy. Safety and efficacy of Rheopheresis for wound healing and skin oxygenation were investigated in patients with ischemic diabetic foot syndrome. Eight patients with type 2 diabetes mellitus and non-healing foot ulcers caused by severe ischemic diabetic foot syndrome were treated by a series of seven Rheopheresis sessions in a time span of 11 weeks. Wound healing had not been detectable under conditions of standardized wound care during at least 2 months. Wound status was classified by its morphology, severity and location, according to the criteria of Wagner. Transcutaneous oxygen pressure (tcPO2), laser Doppler flowmetry and vital capillary microscopy were repeatedly performed to monitor the effects of the Rheopheresis treatment series on microcirculation and skin blood flow. Laboratory parameters of blood rheology, endothelial function and inflammatory state were measured in addition to safety parameters. In four patients (baseline Wagner stage 2), Rheopheresis accelerated wound healing of foot ulcers and was associated with an improvement of Wagner stage and a pronounced increase in tcPO2. In two patients (baseline Wagner stage 2), wound healing was unchanged but mean tcPO2 increased, allowing successful minor amputation. Values of tcPO2 remained stable and enhanced for the 3 months follow-up period. In two patients (baseline Wagner stage 4 or 5), no improvements in foot lesions were observed within the treatment period. As an adjunct therapeutic option, Rheopheresis may preserve a functional lower extremity, delay amputation or reduce the extent of amputation. 相似文献
996.
This population-based cross-sectional study assessed lipid and lipoprotein parameters in women using progestogen-only contraceptives or medications and in those using no hormones. Unselected women about age 40 to 42 years were invited, and the participation rate was 65.6%. A total of 30,636 women were premenopausal, not pregnant, and used either a progestogen [n = 3000, including 2463 users of a intrauterine device (IUD) with levonorgestrel 20 microg/24 h] or no sex hormones. Those using the hormone-releasing IUD reported better health and a healthier lifestyle than nonusers of hormones, while women using depot medroxyprogesterone acetate had a less healthy lifestyle. Compared with nonusers of hormones, users of a levonorgestrel IUD were more likely to have high density lipoprotein (HDL)-cholesterol concentrations < or =1.1 mmol/L (odds ratio 1.4; 95% CI 1.2-1.5), while users of oral norethisterone or lynestrenol, or depot medroxyprogesterone acetate had a doubled to tripled risk of low HDL-cholesterol concentrations. Use of the IUD with levonorgestrel was also linked with a decreased risk of high serum triglycerides and of high non-HDL-cholesterol concentrations and a total/HDL-cholesterol ratio similar to that of nonusers of hormones. 相似文献
997.
Hypercholesterolaemia is a major risk factor for coronary heart disease (CHD). Therefore, the reduction of low-density lipoprotein (LDL) cholesterol is one of the primary targets of the current recommendations to decrease CHD risk in the population. Whereas, the mechanisms involved in de novo cholesterol synthesis and its uptake by cells via the LDL receptor are well known, we still need better understanding about the mechanisms involved in intestinal cholesterol absorption and excretion. The recent discovery of ABCG5 and ABCG8 transporters will significantly improve our understanding of cholesterol trafficking and it will lead to better and new therapeutic strategies to maintain cholesterol homeostasis. 相似文献
998.
Repo-Tiihonen E Halonen P Tiihonen J Virkkunen M 《European archives of psychiatry and clinical neuroscience》2002,252(1):8-11
Associations between low total serum cholesterol (TC) levels and antisocial personality disorder (ASPD), violent and suicidal
behavior have been found. We investigated the associations between TC levels, violent and suicidal behavior, age of onset
of the conduct disorder (CD) and the age of death among 250 Finnish male criminal offenders with ASPD. The CD had begun before
the age of 10 two times more often in non-violent criminal offenders who had lower than median TC levels. The violent criminal
offenders having lower than median TC levels were seven times more likely to die before the median age of death in the study
material. The violent offenders having lower than median TC levels were eight times more likely to die of unnatural causes.
The mean TC level of these male offenders with ASPD was lower than that of the general Finnish male population. Low TC levels
are associated with childhood onset type of the CD, and premature and unnatural mortality among male offenders with ASPD.
The TC level seems to be a peripheral marker with prognostic value among boys with conduct disorder and antisocial male offenders.
Received: 5 July 2001 / Accepted: 24 October 2001 相似文献
999.
Pedrosa RC Meyre-Silva C Cechinel-Filho V Benassi JC Oliveira LF Zancanaro V Dal Magro J Yunes RA 《Phytotherapy research : PTR》2002,16(8):765-768
The lipid-lowering action of the leaves of the Aleurites moluccana methanol extract was studied in Triton W-1339 and high-fat-diet fed rats. The serum lipids (total cholesterol, LDL- and HDL-cholesterol and triglycerides) and body weight were found to be lowered by A. moluccana (300 mg/kg, b.w.) in rats with Triton-induced hypercholesterolaemia and on a hyperlipaemic diet. The results suggest that the lipid lowering action of this natural product is mediated through inhibition of hepatic cholesterol biosynthesis and reduction of lipid absorption in the intestine. 相似文献
1000.
OBJECTIVE: To assess the relationship between total serum cholesterol and various psychosocial variables in depressed in-patients. METHOD: One hundred and eighty-six patients had their total fasting serum cholesterol assessed following admission; psychiatric diagnoses were obtained with the structured clinical interview for DSM-IV (SCID) interview. Psychopathology was measured with a clinician rated scale [Montgomery and Asberg Depressive Rating Scale (MADRS)] and a self-rating scale [Symptom checklist-90 (SCL-90)]. RESULTS: Univariate analyses showed lower total serum cholesterol levels being correlated with higher scores in several psychopathological areas. Multivariate analyses indicated that male gender, lower age and higher MADRS scores were the most predictive variables for lower cholesterol levels. CONCLUSION: The data suggest, in this depressed population, an association between serum cholesterol and depressive symptoms. What is the cause and what is its effect is not possible to say from this cross-sectional study. 相似文献