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31.
P. Richard Grimm Debra L. Irsik Deann C. Settles J. David Holtzclaw Steven. C. Sansom 《Proceedings of the National Academy of Sciences of the United States of America》2009,106(28):11800-11805
Mice lacking the β1-subunit (gene, Kcnmb1; protein, BK-β1) of the large Ca-activated K channel (BK) are hypertensive. This phenotype is thought to result from diminished BK currents in vascular smooth muscle where BK-β1 is an ancillary subunit. However, the β1-subunit is also expressed in the renal connecting tubule (CNT), a segment of the aldosterone-sensitive distal nephron, where it associates with BK and facilitates K secretion. Because of the correlation between certain forms of hypertension and renal defects, particularly in the distal nephron, it was determined whether the hypertension of Kcnmb1−/− has a renal origin. We found that Kcnmb1−/− are hypertensive, volume expanded, and have reduced urinary K and Na clearances. These conditions are exacerbated when the animals are fed a high K diet (5% K; HK). Supplementing HK-fed Kcnmb1−/− with eplerenone (mineralocorticoid receptor antagonist) corrected the fluid imbalance and more than 70% of the hypertension. Finally, plasma [aldo] was elevated in Kcnmb1−/− under basal conditions (control diet, 0.6% K) and increased significantly more than wild type when fed the HK diet. We conclude that the majority of the hypertension of Kcnmb1−/− is due to aldosteronism, resulting from renal potassium retention and hyperkalemia. 相似文献
32.
Szucs TD Holm MV Schwenkglenks M Zhang Z Weintraub WS Burnier M Erne P 《Cardiovascular drugs and therapy / sponsored by the International Society of Cardiovascular Pharmacotherapy》2006,20(3):193-204
Objective The EPHESUS study demonstrated that aldosterone blockade with eplerenone decreased mortality in patients with left ventricular
systolic dysfunction (LVSD) and heart failure after acute myocardial infarction (AMI). The EPHESUS pharmacoeconomic analysis
was performed to evaluate the cost-effectiveness of eplerenone in the Swiss setting.
Materials and methods A total of 6,632 patients with LVSD and heart failure after AMI were randomized to eplerenone or placebo and followed for
a mean of 16 months. The co-primary endpoints were all-cause death and the composite of cardiovascular death/cardiovascular
hospitalization. The evaluation of resource use included hospitalizations, outpatient services, and medications. Survival
beyond the trial period was estimated using data from the Framingham Heart Study, the Saskatchewan Health database, and the
Worcester Heart Attack Registry. The incremental cost-effectiveness of eplerenone in cost per life-year and quality-adjusted
life-year gained was estimated. The perspective of the Swiss third party payers was used. Daily treatment costs of eplerenone
were set at CHF 3.88. All other resources were valued on the basis of official tariffs. Discounting of the results was performed
at a rate of 3%.
Results The number of life-years gained with eplerenone was 0.1083 based on Framingham, 0.0661 with Saskatchewan and 0.1518 with Worcester
survival estimates. Total costs were CHF 1,028 higher over the trial period in the eplerenone arm, due to drug cost. The incremental
cost-effectiveness ratio was CHF 10,145 per life-year gained with Framingham, CHF 16,178 with Saskatchewan, and CHF 7,693
with Worcester survival estimates. The corresponding costs per QALY were CHF 15,219, CHF 23,965 and CHF 11,337, respectively.
Conclusion Eplerenone is effective in reducing mortality and, in Switzerland, is also cost-effective in increasing years of life for
patients with LVSD after AMI. 相似文献
33.
Purpose. The present study was conducted to characterize the pharmacokinetics of eplerenone (EP), a selective aldosterone receptor antagonist, and its open lactone ring form in the dog.
Methods. Pharmacokinetic studies of EP were conducted in dogs following i.v., oral, and rectal dosing (15 mg/kg) and following intragastric, intraduodenal, intrajejunal, and intracolonic dosing (7.5 mg/kg).
Results. After oral administration, the systemic availability of EP was 79.2%. Systemic availabilities following administration via other routes were similar to that following oral administration. The half-life and plasma clearance of EP were 2.21 hr and 0.329 l/kg/hr, respectively. Plasma concentrations of the open lactone ring form were lower than EP concentrations regardless of the route of administration. The C-14 AUC in red blood cells was approximately 64% and 68% of the plasma AUC for i.v. and oral doses. Percentages of the dose excreted as total radioactivity in urine and feces were 54.2% and 40.6%, respectively, after i.v. administration, and 40.7% and 52.3%, respectively, after oral administration. The percentages of the dose excreted in urine and feces as EP were 13.7% and 2.5%, respectively, after i.v. administration, and 2.1% and 4.6% after oral administration, respectively. Approximately 11% and 15% of the doses were excreted as the open form following i.v. and oral doses.
Conclusions. EP was rapidly and efficiently absorbed throughout the gastrointestinal tract, resulting in a good systemic availability. The drug did not preferentially accumulate in red blood cells. EP was extensively metabolized; however, first-pass metabolism after oral and rectal administration was minimal. EP and its metabolites appear to be highly excreted in the bile. 相似文献
34.
依普利酮治疗原发性高血压量效关系的系统评价 总被引:1,自引:0,他引:1
目的:评价依普利酮治疗原发性高血压的量效关系。方法:按纳入标准,电子检索Cochrane图书馆最近一期(2005年第1期)出版的Cochrane对照试验注册数据库,PubMed,Medline,Embase,Ovid,Medscape,TRIP,CBM,NRR;手工检索发表或未发表的文献,包括心血管系统、高血压病的杂志和会议摘要。文献资料用统一的表格,由两名评价者独立提取,对文献质量进行内部真实性评价,并用Revman4.2.7软件对数据进行Meta分析。结果:共检索到随机对照试验(RCT)9篇,经排查符合纳入标准并进入系统评价的文献共3篇,均为高质量RCT。Meta分析结果显示,依普利酮100mg/d与安慰剂比较,诊室收缩压变化的加权均数差(WMD)=-9.17,95%可信区间为(-10.62,-7.72),P<0.01;诊室舒张压变化的WMD=-3.94,95%可信区间为(-4.67,-3.20),P<0.01。结论:依普利酮100mg/d降压是有效的,由于测量指标是终点替代指标(血压变化),故依普利酮的长期疗效仍需进行更多高质量的RCT才能得出肯定性结论。 相似文献
35.
36.
Murray Epstein 《Nephrology, dialysis, transplantation》2003,18(10):1984-1992
37.
Improved understanding of the adverse pharmacological properties of aldosterone has prompted investigation of the clinical benefits of blocking aldosterone at the receptor level. This article reviews the pharmacology, clinical efficacy, and tolerability of the two available blocking agents, spironolactone and eplerenone. A Medline search identified clinical studies assessing spironolactone and eplerenone. Priority was given to large, well-controlled, clinical trials and comparative studies. Pharmacological differences between spironolactone and eplerenone include lower affinity of eplerenone for progesterone, androgen, and glucocorticoid receptors; more consistently demonstrated nongenomic properties for eplerenone; and the presence of long-acting metabolites for spironolactone. Both agents effectively treat hypertension and heart failure but comparisons are complicated by the deficiency of head-to-head trials and differences between patient populations. There are differences in the tolerability profiles; spironolactone is associated with dose-dependent sexual side effects. Both agents produce dose-dependent increases in potassium concentrations, although the effect with spironolactone appears to be greater when both agents are administered at recommended doses. Choice of a specific agent should be based on individual patient issues, such as the nature of heart failure and patient concerns about adverse events. 相似文献
38.
目的研究依普利酮片单次及多次给药后的人体药动学。方法 30名健康志愿者分为三组,分别服用依普利酮片50、100、200 mg,其中100 mg组为多次给药组,连续给药7 d;采集24 h内动态血标本,高效液相色谱-串联质谱法测定血浆中依普利酮的浓度,并采用DAS 3.2.4软件对试验数据进行处理,计算药动学参数。结果单次口服50、100和200 mg依普利酮片的主要药动学参数ρ_(max)分别为(723.20±203.59)、(1 212.47±249.52)、(2 053.32±394.06)μg·L(-1),t_(max)分别为(1.8±0.7)、(2.1±0.9)、(1.9±0.4)h,t_(1/2)分别为(2.6±0.4)、(3.0±0.7)、(3.4±1.3)h,AUC_(0-24h)分别为(3 621.29±1 1 17.37)、(7 492.68±2 031.58)、(13 796.25±4 594.37)μg·h·L(-1),t_(max)分别为(1.8±0.7)、(2.1±0.9)、(1.9±0.4)h,t_(1/2)分别为(2.6±0.4)、(3.0±0.7)、(3.4±1.3)h,AUC_(0-24h)分别为(3 621.29±1 1 17.37)、(7 492.68±2 031.58)、(13 796.25±4 594.37)μg·h·L(-1),AUC_(0-∞)分别为(3 710.53±1 144.47)、(7 592.98±2 082.12)、(14 074.54±4 870.39)μg·h·L(-1),AUC_(0-∞)分别为(3 710.53±1 144.47)、(7 592.98±2 082.12)、(14 074.54±4 870.39)μg·h·L(-1)。多次给药100 mg后的药动学参数ρ_(max)为(1 231.83±209.99)μg·L(-1)。多次给药100 mg后的药动学参数ρ_(max)为(1 231.83±209.99)μg·L(-1),t_(max)为(1.7±0.9)h,t_(1/2)为(3.0±0.8)h,AUC_(0-24h)为(7 043.78±1 818.54)μg·h·L(-1),t_(max)为(1.7±0.9)h,t_(1/2)为(3.0±0.8)h,AUC_(0-24h)为(7 043.78±1 818.54)μg·h·L(-1),AUC_(0-∞)为(7 131.65±1 840.84)μg·h·L(-1),AUC_(0-∞)为(7 131.65±1 840.84)μg·h·L(-1)。结论在50(-1)。结论在50200 mg给药剂量范围内,依普利酮片在体内呈线性动力学特征。 相似文献
39.
Shigehiro Karashima Takashi Yoneda Mitsuhiro Kometani Masashi Ohe Shunsuke Mori Toshitaka Sawamura 《Clinical and experimental hypertension (New York, N.Y. : 1993)》2016,38(7):565-570
Experimental models recently suggested an interaction between aldosterone and adipose tissue, but clinical investigation has been limited. We studied the effects of eplerenone compared to hydrochlorothiazide (HCTZ) on blood pressure (BP), glucose, and lipid levels in 50 patients with essential hypertension (EHT) and type 2 diabetes mellitus whose BP failed to reach target levels with 8 mg of candesartan alone. BP improved similarly in both groups over the 12-month study period, but BMI, waist circumference, and LDL-cholesterol were decreased in the eplerenone group, while glycohemoglobin was elevated in the HCTZ group. 相似文献
40.