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611.
Local drug interaction of metformin with carvedilol increases drug accumulation in the liver and kidney of rats 下载免费PDF全文
Drug transporters determine plasma and tissue exposure of a broad variety of drugs and play a critical role in drug-drug interaction (DDI). In the present study, we aimed to investigate the effects of carvedilol on pharmacokinetics of metformin as well as the mechanism of their interaction. Results showed that plasma concentration of metformin was not significantly altered after single or 7-day co-administration of carvedilol, and the urinary excretion of metformin was also not influenced by carvedilol.However, the concentration of metformin in the liver and kidney was markedly elevated. Similarly, carvedilol did not affect the renal elimination of metformin, but increased renal concentration in isolated kidney perfusion. On the other hand, carvedilol treatment did not affect the expressions of rOCTs and rMATE1 in the liver and kidney of rats. After long-term co-administration, there were no differences in lactic acid (LCA), uric acid (URIC) and creatinine (CREA) levels between two groups. These results indicated that carvedilol increased hepatic and renal distribution of metformin, resulting in local drug interaction. 相似文献
612.
Pauschinger M Rutschow S Chandrasekharan K Westermann D Weitz A Peter Schwimmbeck L Zeichhardt H Poller W Noutsias M Li J Schultheiss HP Tschope C 《European journal of heart failure》2005,7(4):444-452
BACKGROUND: Proinflammatory cytokines induce the expression of matrix metalloproteinases that play a crucial role in myocardial remodeling. Beta-adrenergic receptor stimulation influences the production of cytokines heralding the possibility of modulating cytokine production by beta-adrenergic blockers. METHODS AND RESULTS: In a coxsackievirus B3 murine myocarditis model (BALB/c), effects of carvedilol and metoprolol on myocardial cytokine expression, inflammatory cell infiltration and MMP/TIMP profiles were investigated. In carvedilol-treated mice, a significant improvement in left ventricular function was documented 10 days post infection. In infected mice (n=10), IL-1beta, TNF-alpha, TGF-beta(1) and IL-10 myocardial mRNA abundance were increased significantly (240%, 200%, 161%, and 230%) compared to controls (n=10), while IL-15 mRNA was markedly reduced (70%). Infected mice showed significantly increased infiltrations with CD3-, CD4- and CD8-T-lymphocytes (730%, 1110%, 380%). In the infected mice, myocardial MMP/TIMP profiles presented a significant upregulation of membrane type-1 MMP, MMP-9, MMP-8 and MMP-3 (150%, 160%, 340%, and 270%) and a significant decrease in TIMP-4 levels (75%). Carvedilol attenuated over-expression of myocardial TGF-beta(1), IL-1beta and MMP-8 mRNA expression significantly and induced a relevant IL-10 mRNA expression in the infected mice (n=10). By an unchanged infiltration with CD3-T-lymphocytes, carvedilol showed a representative reduction in CD4-T-lymphocytes. CONCLUSION: Carvedilol treatment in experimental myocarditis leads to reduced expression of proinflammatory cytokines and MMPs, which contributes to reduced matrix degradation and ultimately to improved structural integrity of the heart. Besides the antiadrenergic potential, carvedilol is beneficial due to a wide range of biological activities (antiinflammatory, antifibrotic, antioxidative and immunomodulatory). 相似文献
613.
目的:观察卡维地洛的抗氧化应激作用及对心肌梗死后心脏的保护机制?方法:兔22只随机分为4组:对照组(5只)?未干预心梗组(5只)?维生素E组(6只)?卡维地洛组(6只)?除对照组外,余均行冠脉结扎术,建立心肌梗死动物模型?后两组分别给以卡维地洛或维生素E行干预性治疗,60~70 d后,测其血流动力学和氧化应激状态指标:左室舒张末期压力(LVEDP)?左室收缩期峰压(LVPSP)?动脉收缩压(ASP)和动脉舒张压(ADP)?血浆中的脂质过氧化物丙二醛(MDA)?超氧化物歧化酶(SOD)?谷胱甘肽过氧化物酶(GSH-PX)及心钠素(ANP)的水平?结果:①未干预心梗组与对照组及药物干预的两组相比,氧自由基堆积,表现为前者血浆中MDA升高,而SOD?GSH-PX明显下降(P<0.05)?对照组与卡维地洛组?维生素E组相比,氧化应激状态各指标差异无统计学意义(P>0.05)?②各组心功能表现为对照组?卡维地洛组心功能明显好于未干预心梗组,未干预心梗组血浆ANP水平明显高于其他三组,ASP明显低于其他3组(P<0.05);未干预心梗组LVEDP高于对照组(P<0.05),LVPSP低于对照组和卡维地洛组(P<0.05)?结论:卡维地洛具有氧自由基清除活性,可阻断心肌梗死后的氧化应激状态,对心肌梗死后的心脏发挥保护作用? 相似文献
614.
B. M. W. Schmidt C. P. Janson M. Wehling 《European journal of clinical pharmacology》1998,54(4):281-285
Objective: Carvedilol, a β-adrenoceptor blocking agent with additional α1-adrenoceptor blocking properties, has been shown to improve left ventricular function in chronic heart failure (CHF). However,
its effect on mortality has recently been the subject of controversial discussion. The aim of this meta-analysis is to review
the data on mortality from two large study programs (the US Carvedilol Heart Failure Study and the study by the Australia/New
Zealand Heart Failure Research Collaborative Group) on additional carvedilol treatment in CHF standard therapy and to analyse
the design and limitations of the individual studies.
Methods and Results: For determination of overall, mortality, all patients who died and all patients who were withdrawn for other reasons during
the open run-in phase of the studies were assigned to the carvedilol group to create a “worst-case analysis.” Meta-analysis
of mortality data using the random effects model shows a significantly reduced relative risk of 0.55 × 95%-confidence interval
0.325–0.924; p < 0.05 of death in patients treated with carvedilol compared with patient on standard treatment only.
Conclusion: Treatment of CHF using carvedilol significantly reduces mortality in patients with CHF, even if the “worst case” is assumed
by assigning all deaths in the open run-in phase to carvedilol.
Received: 6 October 1997 / Accepted in revised form: 18 February 1998 相似文献
615.
Baris N Kalkan S Güneri S Bozdemir V Guven H 《European journal of clinical pharmacology》2006,62(7):535-538
Objective The activity of the human cytochrome P450 and P-glycoprotein (P-gp) changes according to gender. The present study evaluated the effect of gender on the influence of carvedilol on serum digoxin levels in patients with heart failure.Methods Twenty-four patients (12 female and 12 male) with New York Heart Association class II-III heart failure were included in the study. Patients were taking oral digoxin (0.0625–0.25 mg, once a day) and were administered oral carvedilol (6.25 mg, two times daily) for 7 days.Results In the male group, carvedilol led to statistically significant increases in the area under the concentration time curve to 16 h (AUC0–16h) and the peak concentration (Cmax) for digoxin, with no change in time to peak (tmax)(AUC0–16h= 24.1±9.2 ng.h/ml vs. 15.4±5.8 ng.h/ml, p<0.001, Cmax=2.2±1.0 ng/ml vs. 1.6±0.6 ng/ml, p<0.01, tmax=2.4±2.2 h vs. 2.1±1.0 h, p>0.05). In the female group, carvedilol administration did not cause statistically significant change in the AUC0–16h, Cmax, or tmax for digoxin (p>0.05). In the male group, carvedilol resulted in a significant increase in the AUC0–16h and Cmax for digoxin compared with the female group (AUC0–16h=24.1± 9.2ng.h/ml vs. 17.0±6.8 ng.h/ml, Cmax=2.2±1.0 ng/ml vs. 1.5±0.6 ng/ml, p<0.05, respectively).Conclusion Men seem to have a higher activity relative to women for the drug efflux transporter P-gp. Our results suggest that carvedilol will cause drug interaction with digoxin following the inhibition of P-gp-mediated transcellular transport of digoxin in males.The first two authors contributed equally. 相似文献
616.
Skeletal muscle myofibrillar protein oxidation in heart failure and the protective effect of Carvedilol 总被引:5,自引:0,他引:5
Dalla Libera L Ravara B Gobbo V Danieli Betto D Germinario E Angelini A Vescovo G 《Journal of molecular and cellular cardiology》2005,38(5):803-807
Heart failure is characterized by limited exercise tolerance and by a skeletal muscle myopathy with atrophy and shift toward fast fibres. An inflammatory status with elevated pro-inflammatory cytokines and exaggerated free radicals production, can worsen muscle damage. In a well established model of heart failure, the monocrotaline treated rat, we show that CHF is accompanied by oxidation of the skeletal muscle actin, tropomyosin and myosin, which further depresses muscle function and exercise capacity. We have also tested the efficacy of Carvedilol, a non-selective beta(1)-beta(2)-blocker, which has been widely used in clinical trials to improve exercise tolerance and reduce mortality in moderate and severe CHF, in preventing contractile protein oxidation in CHF rats. As comparison we used Bisoprolol a beta(1) selective agent, without known anti-oxidative properties. Carvedilol at the dose of 2 mg/kg per day was able to prevent the myofibrillar protein oxidation, while Bisoprolol (0.1 mg/kg) did it only partially, as demonstrated by the oxyblot analysis. While Carvedilol improved force production on isolated muscles, Bisoprolol did not. After the COMET trial, the anti-oxidative capacity of Carvedilol has been invoked as one of the mechanism that makes this drug superior to other selective beta-blockers in the treatment of CHF. One of the reason of Carvedilol superiority could be the effect on skeletal muscle with reduction of contractile protein peroxidation, amelioration of muscle function and improvement of exercise tolerance. Inhibition of reactive oxygen species (ROS) production, and of pro-inflammatory cytokines may also lead to a decreased muscle wastage, another factor contributing to worsening of exercise tolerance. 相似文献
617.
2-(2-甲氧苯氧)乙胺的合成 总被引:1,自引:0,他引:1
2-(2-甲氧苯氧)乙胺是合成某些β-受体阻断剂的重要中间体。我们探讨了几种不同的制备途径,发现将愈创木酚与1,2-二氯乙烷(或1,2-二溴乙烷)反应的单取代卤代物转化为叠氮化物,通过催化氢化,可以获得产率高,纯度好的伯胺。目标物也可以通过Gabriel反应或通过相应睛的还原制得,但是叠氮化合物途径是一条经济而安全的路线。 相似文献
618.
T. O. Klemsdal H. H. Mundal K. Gjesdal 《European journal of clinical pharmacology》1996,50(6):483-489
Objective: In a double-blind, parallell study, the effects of 25 mg carvedilol and 50 mg atenolol on peripheral finger circulation
and arterial pulse curve configuration were compared.
Methods:
Healthy volunteers (n = 17) were examined at baseline and for 15 min after 60 s of hand cooling in ice-water. Finger temperature and digital plethysmography
were recorded each minute from the cooled and the control hands. Measurements were also made before and 2 h after drug administration.
Results:
Blood pressure declined from 120/86 to 108/74 mm Hg after atenolol (n = 9), and from 122/88 to 108/73 mm Hg after carvedilol (n = 8). In both groups, baseline finger temperature increased slightly after drug, and a more rapid rise in finger temperature
was observed after cooling. There was no group difference in the drug effect on finger temperature, except in the first few
minutes after cooling, when temperature recovery was greater after carvedilol. Carvedilol reduced the vasoconstrictor response
to local cooling (digital plethysmography), compared both to the value before drug and after atenolol. At rest, carvedilol
changed the pulse curves (control hand) towards vasodilatation and high compliance, expressed as a mean change in the relative
height of the dicrotic notch of −10.3% versus 0.0% after atenolol.
Conclusion:
Future studies should clarify whether the vasoactive profile of carvedilol may translate into reduced occurrence of cold hands
and feet amongst patients treated for hypertension.
Received: 2 September 1995/Accepted in revised form: 2 January 1996 相似文献
619.
目的评价卡维地洛治疗糖尿病伴心肌梗死患者心功能不全的疗效和安全性。方法将66例糖尿病心肌梗死合并心力衰竭的患者,随机分为卡维地洛组和对照组,在同对照组一样控制血糖,治疗心肌梗死合并心功能不全,卡维地洛组在治疗组的标准用药基础上从小剂量开始用卡维地洛,逐步增加至目标剂量进行治疗,测定两组治疗前、后临床心功能分级、血压、心率、左心室功能及肾功能和血糖、血脂水平。结果两组治疗后左室舒张末期内径(LVEDd)、左室收缩末期内径(LVEDs)均减小(P〈0.05),左心室射血分数(LVEF)及心输出量(CO),短轴缩短率(FS)均有提高(P〈0.05或P〈0.01),但舒张功能均无改善(P〉0.05)。结论卡维地洛治疗糖尿病伴心肌梗死患者心功能不全安全、有效,同时能改善糖代谢和肾功能。 相似文献
620.
目的观察卡维地洛对伴发2型糖尿病的冠心病心力衰竭患者的心功能及血脂、血糖、胰岛素抵抗的影响。方法选择伴2型糖尿病的冠心病心力衰竭患者108例,随机分为两组:常规治疗组52例,卡维地洛组56例,在常规治疗基础上加用卡维地洛。药物治疗前及后3、6、12个月分别行超声心动图检查,计算校正的舒张末期容积指数(LVEDVI)、收缩末期容积指数(LVESVI)和左室射血分数(LVEF),采集空腹静脉血,测定血脂水平和空腹血糖(FPG)、胰岛素(FINS)及胰岛素抵抗指数(HOMA—IR)。结果①治疗6、12个月后卡维地洛组LVEF较对照组显著升高,LVESVI显著下降;②治疗6、12个月后卡维地洛组FINS较对照组显著升高,HOMA—IR较对照组显著降低。结论卡维地洛能明显逆转2型糖尿病并发冠心病心力衰竭患者的心室重塑、改善心功能,同时改善其血糖代谢。 相似文献