Population pharmacokinetics of tolvaptan in healthy subjects and patients with hyponatremia secondary to congestive heart failure or hepatic cirrhosis

Tolvaptan is a selective V₂‐receptor antagonist used to treat hypervolemic and euvolemic hyponatremia. A population pharmacokinetic (PK) analysis was performed for tolvaptan in NONMEM® based upon data obtained from three trials conducted in 93 healthy subjects and six trials conducted in 628 congestive heart failure (CHF) patients or 24 hepatic cirrhosis patients receiving oral tolvaptan (5 to 240 mg). A two‐compartment model with first‐order absorption and elimination best described tolvaptan PK. Relative oral bioavailability was modeled relative to 100% for a 30 mg dose and ranged from 79.4% to 122%. Body weight and the impact of CHF or hepatic cirrhosis relative to healthy subjects were statistically significant (p < 0.001) predictors of both the apparent oral clearance (CL/F) and apparent central volume of distribution (V_c/F). The CL/F was reduced to 58.2% for New York Heart Association (NYHA) Class 1 or 2 CHF, 45.5% for NYHA Class 3 or 4 CHF, and 58.0% for hepatic cirrhosis relative to healthy subjects. V_c/F was reduced to 59.9% for NYHA Class 1 or 2 CHF and 51.3% for NYHA Class 3 or 4 CHF, and was 64.8% larger for severe hepatic cirrhosis (Child‐Pugh score ≥ 10) relative to healthy subjects. A slight additional decrease in CL/F of 18.3% was also detected for patients with moderate hyponatremia (serum sodium of 115–130 mEq/l) after adjusting for CHF or cirrhosis (p < 0.001). This population PK model enabled assessment of tolvaptan PK with varying degrees of CHF and hepatic cirrhosis with fluid overload and may be used to explore PK‐PD relationships with respect to fluid and electrolyte balance. Copyright © 2013 John Wiley & Sons, Ltd.     

Pharmacokinetics of flosequinan in elderly patients with chronic congestive heart failure

Summary We have investigated the pharmacokinetics of the direct vasodilator flosequinan in elderly patients with congestive heart failure. Eight patients received a single dose of 50 mg, and 8 patients received once-daily treatment with 25 mg for two weeks.In the single dose study, the t_max of flosequinan was 2.5 h, C_max was 1.17 g · ml^–1 and t_1/2 was 5.63 h. The t_max of the metabolite BTS 53554 was 20.3 h, C_max was 1.44 g · ml^–1 and t_1/2 was 62.0 h.BTS 53554 accumulated gradually in the 14-day repeated dose study and steady-state was reached after approximately 2 weeks. Flosequinan was not found to accumulate.Adverse reactions were not observed in either the single or repeated dose study.It is advisable to consider renal function and body weight when flosequinan is to be administered to elderly patients with congestive heart failure. The initial dose should be 25 mg.     

Population pharmacokinetics of levosimendan in patients with congestive heart failure

AIMS: The aim of this study was to characterize the population pharmacokinetics of levosimendan in patients with heart failure (NYHA grades III and IV) and its relationship to demographic factors, disease severity and concomitant use of digoxin and beta-blocking agents. METHODS: Data from two efficacy studies with levosimendan administered by intravenous infusion were combined (190 patients in total). The data were analysed using a nonlinear mixed-effects modelling approach as implemented in the NONMEM program. The model development was done in three sequential steps. First the best structural model was determined (e.g. a one-, two- or three-compartment pharmacokinetic model). This was followed by the identification and incorporation of important covariates into the model. Lastly the stochastic part of the model was refined. RESULTS: A two-compartment model best described levosimendan pharmacokinetics. Clearance and the central volume of distribution were found to increase linearly with bodyweight. No other covariates, including concomitant use of digoxin and beta-blocking agents, influenced the pharmacokinetics. In the final model, a 76-kg patient was estimated to have a clearance +/- s.e. of 13.3 +/- 0.4 l h-1 and a central volume of distribution of 16.8 +/- 0.79 l. The interindividual variability was estimated to be 39% and 60% for clearance and central volume of distribution, respectively. Weight changed clearance by 1.5% [95% confidence interval (CI) 0.9%, 2.1%] and the central volume of distribution by 0.9% (95% CI 0.5%, 1.3%) per kg. CONCLUSIONS: The population pharmacokinetics parameters of levosimendan in this patient group were comparable to those obtained by traditional methods in healthy volunteers and patients with mild heart failure. Bodyweight influenced the clearance and the central volume of distribution, which in practice is accounted for by weight adjusting doses. None of the other covariates, including digoxin and beta-blocking agents, significantly influenced the pharmacokinetics of levosimendan.     

Relationship of changes in felodipine pharmacokinetics to haemodynamics during chronic oral treatment of congestive heart failure patients

In congestive heart failure patients the kinetics of felodipine, a dihydropyridine calcium antagonist, show interpatient differences after acute i.v. administration that disappear after 8 weeks oral treatment with a change in kinetics in the patients with the largest clearances (CL) and the smallest volumes of distribution (V _SS). Pharmacokinetic and haemodynamic data were combined to construct a haemodynamic-pharmacokinetic model. This model shows that the differences between the patients in i.v. pharmacokinetics are consistent with a difference in plasma flow distribution between liver and poorly perfused tissues. In patients in whom kinetics changed, felodipine treatment is supposed to cause a redistribution of flow from liver to peripheral tissues, accompanied by a decreased work load of the heart and a larger increase in VO_2max during therapy than in the other patients, whose workload increased. This suggests a better therapeutic response in the patients whose kinetics changed. As change in kinetics is related to felodipine CL and CL to liver plasma flow, felodipine CL or even indocyanine CL might be predictive for the therapeutic effect of felodipine.     

Comparison of the pharmacokinetics of fosinoprilat with enalaprilat and lisinopril in patients with congestive heart failure and chronic renal insufficiency

AIMS: To compare the serum pharmacokinetics of fosinoprilat with enalaprilat and lisinopril after 1 and 10 days of dosing with fosinopril, enalapril and lisinopril. METHODS: Patients with congestive heart failure (CHF, NYHA Class II-IV) and chronic renal insufficiency (creatinine clearance 相似文献   

Altered prazosin pharmacokinetics in congestive heart failure

Summary The pharmacokinetics of prazosin (Minipress^®) were studied in nine patients with NYHA Class 3 or 4 congestive heart failure and in five healthy controls. After a single 5 mg oral dose, plasma concentrations of prazosin, as reflected in the area under the plasma concentration-time curve (AUC) and prazosin plasma half-life, were approximately double in the patients in comparison to the control group. Reduction in hepatic blood flow, altered gastrointestinal absorption of the drug or diminished intrinsic hepatic metabolic activity in the patient group may have contributed to the observed changes in prazosin disposition. The finding of higher prazosin plasma concentrations in patients with refractory heart failure demonstrates the need for close monitoring of these individuals following administration of the drug in the treatment of chronic congestive heart failure.Sponsored by the National Institute of General Medical Sciences Training Grant GM 07546 and by a grant from Pfizer Corporation     

NT-proBNP在充血性心力衰竭患者中的临床应用价值

目的探讨血清N末端B型钠尿肽(NT-proBNP)在充血性心力衰竭(CHF)患者中的临床应用价值。方法胶体金法检测70例CHF患者的血清NT-proBNP水平,超声心动图测定左心室射血分数(LVEF)≤45%,20例健康人作为正常对照组。结果 CHF患者NYHAⅡ级、Ⅲ级、Ⅳ级组各组间NT-proBNP水平有统计学意义,且均高于对照组[分别为(1 210±45.7),(2 402±44.9),(3 809±67.1)nmol.L-1对(435±54.1)nmol.L-1,P0.01]。血浆NT-proBNP水平与LVEF值呈负相关(r=-0.754,P0.01)。血清NT-proBNP水平对CHF的诊断最适分界点为445 nmol.L-1时,其敏感性为90.5%,特异性为91.8%,阳性预测值为96.2%,阴性预测值为79.8%。结论血清NT-proBNP有助于心衰的诊断及其严重程度的评估,有重要的临床应用价值。     

Metabolism of procainamide in patients with chronic heart failure,chronic respiratory failure and chronic renal failure

Summary Fractional hydrolysis and acetylation of procainamide, acetylation of procainamide-derived p-aminobenzoic acid and plasma hydrolysis of procaine were studied in 20 patients with chronic heart failure (CHF), 20 patients with chronic respiratory insufficiency (CRI) and 20 patients with chronic renal failure (RF). The results were compared with those obtained in a group of 20 normal volunteers. Hydrolysis of procainamide and procaine were reduced in patients with CHF and CRI, but not in patients with RF. Moreover, more marked decreases in procainamide and procaine hydrolysis were seen in subgroups with secondary hepatic dysfunction. The diminution of hydrolysis of procainamide was not paralleled by changes in acetylation of procainamide or p-aminobenzoic acid. It is concluded that in patients with hepatic involvement secondary to advanced CHF or CRI, hepatic and plasmatic hydrolysis activity is decreased to a degree equivalent to primary liver failure.Preliminary results presented at the Seventy-eight Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics, Dallas, Texas 1977.Supported in part by a grant from Centre de Recherche Merrell International.Recipient of a Merck Sharp & Dohme International Fellowship in Clinical Pharmacology.     

Bioavailability and pharmacokinetics of ketanserin in elderly subjects

Summary The bioavailability of ketanserin has been examined in a cross-over experiment in 21 elderly subjects (aged 59–72 years) by administration of tablets (40 mg), solution (40 mg) and injectable solution (10 mg). After two weeks of treatment with 40 mg ketanserin tablets further 18 blood samples for analysis were collected under steady-state conditions. Plasma levels were measured by HPLC. The absolute bioavailability of ketanserin tablets was 52.7%; their relative bioavailability compared to a solution containing an equal quantity of active compound was 85.5%. Therefore, the low absolute bioavailability of ketanserin cannot be attributed to the formulation.The active compound was rapidly liberated from the tablet, reaching a peak of 103.8 ng/ml after 0.97 h. Individual plasma level-time curves were fitted to an open three compartment model and a half-life of 17.7±7.26 h was calculated for the terminal elimination phase. An average terminal elimination half-life of 15.4±4.2 ng/ml was found after administration of the ketanserin solution.Multiple dosing with 40 mg tablets b.d.s. resulted in an AUC over one dosing interval at steady-state of 666±201 ng × h/ml. The AUC extrapolated to infinity was 1200±405 ng × h/ml for the last tablet. This is 1.8-times the AUC in one dosing interval, and 2.3-times the AUC of a single dose. Under steady-state conditions, the mean peak plasma level was 155.1 ng/ml (1.08 h after dosing) and the terminal half-life was 19.1±5.1 h.For the metabolite ketanserinol terminal half-lives of 21.4 h after a single tablet and 31.0 h after discontinuation of multiple dosing were calculated. Compared to the parent compound there was much more marked accumulation of ketanserinol.Despite moderate accumulation and prolongation of the terminal half-life of ketanserin under steady-state conditions, dosage adjustment is not required in elderly people. First-pass metabolism and bioavailability remained in the range found in previous studies of ketanserin in young subjects.     

Digoxin-felodipine interaction in patients with congestive heart failure

Summary A possible interaction between felodipine and digoxin was studied in 23 patients with congestive heart failure before and after 8 weeks treatment with both drugs.A modest, non-significant increase in serum digoxin level 2 h postdose (+15%) was found in the felodipine group (n=11) compared to placebo (n=12), with no change in the trough and 6 h postdose levels.There was a bimodal distribution of the observed changes in serum digoxin level 2 h postdose: a significant increase (p<0.001) was observed only in patients with a high plasma felodipine level, which may have been caused by changes in the absorption rate in those patients. Changes in the elimination of digoxin after felodipine therapy appeared unlikely, since the trough and 6 h post-dose levels were unchanged.Analysis of the clinical characteristics, haemodynamics and laboratory values revealed no significant differences between the subgroups. The observed increase in serum digoxin warrants monitoring the trough and peak levels digoxin in patients with congestive heart failure who are also being treated with felodipine.     

护理干预在减少老年慢性心力衰竭反复发作中的应用

目的 探讨护理干预对老年慢性心力衰竭患者的反复发作的预防效果.方法 选取80例老年慢性心力衰竭衰竭患者为研究对象,随机分为观察组和对照组各40例.对照组采用常规护理模式,观察组对患者服药依从性,睡眠,情绪进行护理干预.随访6个月,比较两组患者睡眠质量,焦虑、抑郁评分及心力衰竭复发情况.结果 观察组PSQI,SAS,SDS评分改善情况显著优于对照组（P＜0.05）.6个月随访期间观察组治疗完全遵从比例高于对照组（P＜0.05）.观察组心衰复发人数显著低于对照组（P＜0.05）.结论 护理干预可改善老年慢性心力衰竭患者的睡眠质量,降低焦虑、抑郁评分,有效提高治疗依从性,降低慢性心力衰竭复发.     

氨力农治疗心力衰竭的疗效

目的：观察氨力农治疗心力衰竭（心衰）的临床疗效。方法：３６例心衰的病人，男性２４例，女性１２例；年龄５４±ｓ１４ａ，分为２组，其中３２例给氨力农０．５～１．０ｍｇ／ｋｇ用０．９％氯化钠注射液稀释至１０～２０ｍＬ，静脉注射，５～１０ｍｉｎ注射完，继以５～１０μｇ／ｋｇ氨力农用０．９％氯化钠注射液稀释至１８０ｍＬ，静脉滴注（静滴）６ｈ，共１０ｄ为治疗组；另１６例为用０．９％氯化钠注射液作为安慰剂对照组（其中１２例为安慰剂治疗无效后改为氨力农组），用药方法同治疗组。结果∶氨力农组治疗后总有效率９１％（２９／３２），对照组全部无效，组间比较Ｐ＜０．０１。氨力农组６例于用药ｄ１０的药前及药后２ｈ测血药浓度，发现有效血药浓度为１．１～３．２１μｇ／ｍＬ。结论：氨力农对慢性难治性心衰有效且安全。     

螺内酯联合依那普利对老年慢性心力衰竭患者血流动力学影响研究

目的：探讨螺内酯联合依那普利对老年慢性心力衰竭患者血流动力学的影响。方法：将210例老年慢性充血性心力衰竭患者按1∶1随机分为治疗组和观察组。对照组给予常规抗心力衰竭治疗,观察组在对照组的基础上加用螺内酯和依那普利治疗。结果：观察组的总有效率高于对照组（P=0.0005）,并且观察组患者的左心射血分数（LVEF）、左心室舒张早期充盈速度（VE）、舒张晚期充盈速度（VA）、VE/VA比值等指标均明显高于对照组（P值均〈0.05）。结论：螺内酯联合依那普利能改善老年慢性充血性心力衰竭患者的心脏功能,且无明显不良反应。     

慢性阻塞性肺疾病合并慢性心力衰竭高龄患者的临床护理干预

目的探讨临床护理干预对慢性阻塞性肺疾病（COPD）合并慢性心力衰竭高龄患者的应用疗效。方法选取本院2009年4月～2011年11月收治的67例慢性阻塞性肺疾病合并慢性心力衰竭高龄患者,将其随机分为两组,其中,33例患者采用常规护理作为对照组,34例患者采用护理干预作为观察组。检测并比较所有患者护理干预治疗后的临床指标。结果护理干预后,观察组患者在体力限制评分、社会限制评分、情绪评分、症状评分等几个方面均明显低于对照组,观察组患者的住院时间明显少于对照组,观察组患者的心率、左室舒张末径、脑利钠肽（BNP）均明显低于对照组,观察组左室射血分数、E/A比值、用力肺活量（FVC）、第一秒用力呼出量占肺活量比值（FEV1.0/FVC）均明显高于对照组,差异均有统计学意义（P〈0.05）。结论有效的护理干预可以明显改善慢性阻塞性肺疾病合并慢性心衰高龄患者的心肺功能,提高生活质量,缩短治疗时间。     

Antisecretory effect and oral pharmacokinetics of omeprazole in patients with chronic renal failure

Summary The inhibitory effect of omeprazole on gastric acid secretion was tested in a group of patients on haemodialysis for chronic renal failure. Single 30 mg doses almost totally inhibited basal acid output on both dialysis and non-dialysis days. Plateau acid output was reduced by a mean of 77% and 90% on non-dialysis and dialysis days respectively. The absorption and pharmacokinetic profile of omeprazole were not affected by dialysis. Omeprazole was not recoverable from dialysis fluid. It is concluded that omeprazole is a potent inhibitor of gastric acid secretion in patients with chronic renal failure, and its effect is not influenced by haemodialysis.     

中西医结合治疗老年慢性心力衰竭的临床效果观察

目的 探讨中西医结合疗法治疗老年慢性心力衰竭的临床效果.方法 选取本院70例慢性心力衰竭患者,按照随机对照原则将患者分为观察组和试验组,各35例.对照组给予常规综合治疗,试验组在常规治疗基础上加用益气复脉注射液治疗.比较两组临床疗效.结果 试验组有效率91.43％,对照组85.71％,差异具有统计学意义(P＜0.05).结论 在常规治疗基础上应用益气复脉注射液治疗慢性心力衰竭临床疗效确切,值得临床进一步推广使用.     

老年慢性心力衰竭患者应用辛伐他汀、曲美他嗪联合治疗的疗效分析

目的 探讨辛伐他汀、曲美他嗪联合治疗老年慢性心力衰竭患者的临床效果.方法 收集我院2013年1月至2015年6月收治的老年慢性心力衰竭患者80例,随机分为对照组和实验组.对照组临床常规治疗,实验组在以上基础上加服辛伐他汀与曲美他嗪,比较两组超声心动图、生化指标变化与心功能分级情况.结果 两组治疗后左室射血分数、左室收缩末期内径、左室舒张末期内径、血胆固醇、低密度脂蛋白胆与高敏C-反应蛋白水平分别与治疗前组内比较,差异有统计学意义(P＜0.01);两组治疗后左室射血分数、左室收缩末期内径、左室舒张末期内径、血胆固醇、低密度脂蛋白胆与高敏C-反应蛋白水平组间比较,差异有统计学意义(P＜0.01);实验组治疗后心功能分级情况显著优于对照组,差异有统计学意义(P＜0.01).结论 辛伐他汀、曲美他嗪联合治疗老年慢性心力衰竭患者临床效果显著,具有借鉴性.     

卡维地洛对慢性心衰合并肾功能不全患者肾功能的影响

目的:评价卡维地洛对慢性心衰(CHF)合并慢性肾功能不全(CRF)患者肾功能的影响。方法:入选27例CHF合并CRF患者,在充分抗心力衰竭治疗的基础上,加用卡维地洛,观察不同阶段左室射血分数(LVEF)和肾功能的变化。结果:卡维地洛治疗后,LVEF在治疗3个月后开始升高,12个月后显著高于基线水平(p<0.01)。治疗后1个月,血肌酐(Scr)升高(p<0.05),3个月时回落到基线水平以下(p<0.05),12个月时仍低于基线水平(p<0.05);治疗后1个月,内生肌酐清除率(Ccr)先轻度下降(p<0.05),3个月时回升高于基线水平(p<0.01),12个月时仍显著高于基线水平(p<0.01)。卡维地洛对尿微量白蛋白和24h尿蛋白定量影响不大(p>0.05)。结论:第三代β-受体阻滞剂卡维地洛,可改善慢性心衰合并慢性肾功能不全患者的心功能,早期引起肾功能的轻度降低,随后肾功能显著改善。     

慢性肾衰患者血液透析时司帕沙星的药物动力学

目的 观察司帕沙星在慢性肾衰患者血液透析时的药物动力学特征.方法 用高效液相色谱法测定透析和非透析住院患者单剂量口服司帕沙星后血清和尿药物浓度,并计算药物动力学参数.结果 经PKNP-N_1药代动力学软件摸拟和计算,司帕沙星的药物动力学符合一级吸收二室开放模型,主要药动学参数:透析时T_(1/2(ka))=(1.25±0.57)h,T_(1/2β)=(11.88±4.13)h,T_(peak)=(4.18±0.78)h,C_(max)=(0.80±0.17)mg·L~(-1),AUC_(0~∞)=(6.90±3.25)mg·h·L~(-1)尿中24h原形药物排除率为(8.98±3.92)%;未透析时T_(1/2(ka))=(1.12±0.42)h,T_(1/2β)=(15．93±5．20)h,T_(peak)=(3.88±0.75)h,C_(max)=(0.69±0.37)mg·L~(-1),AUC_(0~∞)=(10.05±4.13)mg·h·L~(-1),尿中24h原形药物排出率为(10.58±5.64)%.结论 司帕沙星在慢性肾衰患者血液透析时消除加快.