Decreased vancomycin clearance in patients with congestive heart failure

Purpose

Congestive heart failure (CHF) alters the pharmacokinetics of various drugs, including cardiovascular agents, due to decreased cardiac output and decreased renal blood flow. The purpose of this study was to evaluate the influence of CHF on the clearance of vancomycin, a glycopeptide antibacterial agent.

Methods

After reviewing more than 1,500 clinical charts of patients who received vancomycin therapy and whose serum vancomycin level was monitored, we identified 101 patients who also had the left ventricular ejection fraction (LVEF) assessed at that time. The fluorescence polarization immunoassay method was used to measure vancomycin serum concentrations in these patients 1 h after the end of vancomycin infusion and just before the next administration. Using these two measurements, we calculated the pharmacokinetic parameters using the Bayesian estimator.

Results

Patients with an LVEF of?<40 % (16 patients) or those with an LVEF of ≥ 40 %? and <60 % (40 %?≤?LVEF?<?60 % ; 32 patients) had a significantly lower vancomycin clearance than patients with LVEF of?≥60 % (53 patients) (2.29?±?0.95 or 2.79?±?0.99 vs. 3.50?±?1.04 L/h; p?<?0.001 or p?<?0.01, respectively). Vancomycin clearance was strongly correlated not only with estimated creatinine clearance (CLcr) in patients with an LVEF of?<40 % (r?=?0.828) and 40 %?≤?LVEF?<?60 % (r?=?0.773), but also with an LVEF in patients with a CLcr of?<60 mL/min (r?=?0.646). Consistent with these findings, multiple regression analysis revealed that CLcr, LVEF and body weight were important independent variables for vancomycin clearance (r ²?=?0.649).

Conclusions

Vancomycin clearance decreased with decreasing cardiac function (LVEF) and decreasing CLcr. This finding suggests that vancomycin clearance is affected by cardiac function and would be predicted not only CLcr but also by LVEF.     

Effect of itraconazole on digoxin clearance in patients with congestive heart failure

We showed a digoxin-itraconazole interaction in three patients in whom digoxin serum concentrations were increased. Their electrocardiograms revealed arrhythmias such as ventricular premature contraction, atrioventricular block, and ST depression. The elimination half-life of digoxin in case 3 patient who continued itraconazole therapy was 8.4 days, which was estimated by nonlinear least squares method from the serum concentrations of digoxin versus time curve. In order to evaluate the influence of itraconazole on pharmacokinetic parameters of digoxin, we estimated digoxin clearance by the Bayesian method using the population pharmacokinetic parameters in Japanese patients. During the concomitant use of itraconazole and digoxin, the digoxin clearance in all patients decreased to 50.5 +/- 8.8% (mean +/- S.D.) of the clearance without itraconazole. When digoxin and itraconazole are used concomitantly, careful monitoring of digoxin serum concentrations is necessary. Based on our results of digoxin clearance evaluation, the dose of digoxin should be reduced to 50% of original dose after itraconazole is started, and digoxin serum concentration might be controlled at the same level before the concomitant use.     

Increased risk of congestive heart failure in patients with acetaminophen poisoning: A nationwide cohort study

Acetaminophen poisoning increases cytochrome P450 2E1 expression and reactive oxygen species production, which may lead to maladaptive myocardial remodeling and congestive heart failure (CHF). We conducted a nationwide cohort study to investigate the incidence and risk of CHF in patients with acetaminophen poisoning. We identified a cohort of adult patients with newly diagnosed acetaminophen poisoning in the inpatient claims of the Taiwan National Health Insurance Research Database for the 1998–2011 period. A comparison cohort was frequency matched at a 4:1 ratio for sex, age and index year. All patients were followed up until the occurrence of CHF, withdrawal from the National Health Insurance program, or December 31, 2011. Cox proportional hazards models were employed to calculate the risk of CHF in the acetaminophen poisoning cohort compared with the comparison cohort, and the hazard ratios with 95% confidence intervals are presented. A total of 3546 and 14 184 patients with and without acetaminophen poisoning were followed up for a total of 25 856 and 102 119 person‐years, respectively. The overall incidence of CHF was higher in the acetaminophen poisoning cohort than in the comparison cohort (8.12 vs. 5.19 per 10 000 person‐years). After adjustment for covariates, the acetaminophen poisoning cohort exhibited a 1.59‐fold higher risk of CHF (adjusted hazard ratio = 1.59; 95% confidence interval = 1.43–1.75) than did the comparison cohort. Patients with acetaminophen poisoning exhibited a significantly higher risk of CHF compared with the comparison cohort. Clinicians should follow up heart function in patients with acetaminophen poisoning.     

Decreased renal clearance of digoxin in chronic congestive heart failure

Summary Renal digoxin clearance was compared in patients suffering from atrial fibrillation with well preserved cardiac function (n=9; salt intake ±170 mmol daily) and patients with chronic congestive heart failure (n=10; salt intake 50 mmol daily and maintenance treatment with diuretics). There was no difference between the groups concering digoxin dosage, creatinine clearance, diuresis or sodium excretion in the urine. Digoxin clearance in chronic heart failure proved to be significantly lower than in atrial fibrillation (48±21 vs 71±36 ml·min^–1, p<0.05), and Cdig/Ccreat was similarly reduced at 0.73±0.15 compared to 1.09±0.27 (p<0.005). Steady state serum digoxin concentration was significantly higher in patients with congestive heart failure (1.44±0.47 vs 0.87±0.33 µg·l^–1, p<0.01). Chronic congestive heart failure is a state with reduced digoxin clearance by the kidney, which could lead to digoxin intoxication not explicable by overdose, reduced renal function or the effect of interacting drugs.     

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.     

Oxaprozin pharmacokinetics in patients with congestive heart failure

12 patients aged 26-71 years with stable, compensated congestive heart failure (CHF) and 12 healthy controls matched for age, sex, height, weight, and serum albumin, received a 1200-mg oral dose of the nonsteroidal antiinflammatory agent 4,5-diphenyl-2-oxazolepropionic acid (oxaprozin). Serum oxaprozin levels were measured by high pressure liquid chromatography during the next 14 days. Oxaprozin elimination half-life was not different between controls and CHF patients (63 vs 69 h), but peak serum levels were lower (79 vs 63 micrograms/ml, p less than 0.01), apparent volume of distribution was larger (0.22 vs 0.29 l/kg, p less than 0.05) and clearance tended to be higher, although not significantly so, (0.042 vs 0.053 ml/min/kg) in CHF patients. These differences might have been due to reduced serum protein binding (increased free fraction) in CHF patients (0.25 vs 0.44% unbound, p less than 0.1). After correction for individual values of free fraction, groups did not differ in peak free oxaprozin serum levels (0.20 vs 0.26 micrograms/ml), unbound volume of distribution (92 vs 83 l/kg), or unbound clearance (17.5 vs 15.0 ml/min/kg). Thus protein binding of oxaprozin in the present study was reduced in CHF due either to the underlying disease or to the concurrent medications. This in turn caused reciprocal reduction in total (free plus bound) oxaprozin levels and elevated estimates of volume of distribution and clearance. Although protein binding is altered, CHF causes no significant alteration in distribution of free oxaprozin nor free clearance of oxaprozin, which is accomplished by a combination of oxidation and conjugation.     

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。     

冠心病患者中无心功能不全与合并心功能不全的脂联素水平观察

目的血清脂联素（adiponectin,APN）,一种脂肪组织来源的胶原样血浆蛋白,具有抗动脉粥样硬化、抗炎及改善胰岛素敏感性等作用,本文旨在探讨冠心病无合并心功能不全组与冠心病合并心功能不全组血清脂联素水平及其与NTproBNP的关系,及探讨脂联素在冠心病合并慢性心功能不全发病机制中的作用。方法收集连续入院的冠心病合并NYHAⅡ-Ⅳ级患者60例和冠心病无心功能不全患者60例的血清和临床资料,选取性别与年龄与病例组相匹配对照组25例,测定空腹血清脂联素水平、N末端前脑钠肽（N-terminal portion of proBNP,NTproBNP）、hsCRP（high sensitivity C-Reactive Protein）及生化指标,比较各组间脂联素水平及与NTproBNP、hsCRP及生化指标的关系。结果冠心病患者中无心功能不全组血清脂联素显著低于对照组,而冠心病合并心功能不全组显著高于冠心病无心功能不全组及对照组,且冠心病合并心功能不全组随着心功能不全分级的增加,脂联素水平是升高的。Spearson偏相关分析显示经年龄、性别及BMI校正后冠心病组脂联素水平与NT-proBNP、hs-CRP呈正相关,与LVEF、TC、TG呈负相关,多元逐步回归分析显示NTproBNP、HDL-C、TC是影响血浆APN的独立因素。结论本文研究发现冠心病无心功能不全患者血清脂联素水平明显低于对照组,而在冠心病合并心功能不全组血清脂联素是明显高于其他二组,且随着心功能不全分级的增加而明显递增,同时冠心病患者血清脂联素与NTproBNP及hsCRP呈正相关,提示脂联素可能参与冠心病及心功能不全的发病机制,其确凿的作用机制还有待进一步的深入研究证明,血清脂联素的变化趋势对于心功能不全的进展及转归可能有一定的指导意义。     

Oral enoximone pharmacokinetics in patients with congestive heart failure

The pharmacokinetics of enoximone and its sulfoxide metabolite were determined following administration of a single oral dose of 1 or 2 mg/kg in seven patients with congestive heart failure, and in two normal volunteers following a single 75-mg capsule, and were compared to those published previously. Plasma concentrations of the metabolite were higher than enoximone, and their terminal slopes were parallel. Enoximone and enoximone sulfoxide plasma concentration-time data were fitted to a simple model that included a lag time. Absorption half-lives in patinets and normal volunteers averaged 17 minutes; the elimination half-life of enoximone in patients averaged 2.9 hours, and was slightly prolonged as compared with normal volunteers. The elimination half-life of enoximone sulfoxide averaged 17 minutes in patients and normal volunteers, and was considerably shorter than that reported in other studies. The oral clearance of enoximone in patients averaged 99 L/hr, and was lower than that observed in normal volunteers. The ratio of the area under the plasma concentration time curve of enoximone sulfoxide to enoximone averaged 4.7 in patients, and was similar to that observed in normal subjects. Enoximone oral clearance and the ratio of metabolite to parent were related to liver blood flow (determined by indocyanine green). Enoximone is 65% bound to albumin, which accounts for most of the drug bound to human plasma protein.     

GM-CSF与P-选择素在充血性心力衰竭中的研究

目的检测充血性心力衰竭(CHF)患者血清粒细胞-巨噬细胞集落刺激因子(GMCSF)及P-选择素(P-sd)的水平,并探讨它们在CHF中的关系.方法CHF患者59例和年龄、性别相匹配的健康对照组19例,根据NYHA分级将CHF患者分成心功能Ⅱ、Ⅲ、Ⅳ级3组,测定血清GM-CSF及血浆P-sel水平.GM-CSF采用放射免疫法检测,P-sel用ELISA法检测.结果CHF组血清GM-CSF及血浆P-sel水平与对照组比较差异有显著意义(P＜0.01),CHF患者在心功能Ⅱ、Ⅲ、Ⅳ级各组GM-CSF、P-sel较对照组升高差异有显著意义(P＜0.01),且Ⅲ、Ⅳ级组与Ⅱ级组比较显著升高(P＜0.01),其中GM-CSF在心功能Ⅳ级组较Ⅲ级组升高有统计学意义(P＜0.05).不同病因的CHF患者之间差异无显著意义(P＞0.05).CHF患者血清GM-CSF与血浆P-sel呈显著正相关(r=0.7035,P＜0.01).结论(1)CHF患者外周血GM-CSF、、P--sel水平增高,提示它们可能参与了CHF的病理生理过程;(2)GM-CSF可能与CHF时血小板活化有关.     

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.     

厄贝沙坦联合美托洛尔治疗充血性心力衰竭疗效观察

目的观察充血性心力衰竭（cry）应用厄贝沙坦联合美托洛尔治疗的临床疗效。方法选择江苏省无锡市第九人民医院2011年2月至2013年1月收治的CHF患者44例设为对照组,洋地黄、血管扩张剂、利尿剂等综合方法治疗,另选择同期收治的CHF患者46例设为观察组,在对照组治疗的基础上应用厄贝沙坦和美托洛尔治疗。观察治疗前后心功能、左室射血分数（IVEF）、左室舒张末内径（LVEDd）、左室收缩末内径（LVESd）、心率及血压等指标的变化。结果观察组总有效率为91.30％,对照组患者总有效率为81．82％,差异有统计学意义（P〈n05）。治疗后LVEDd、LVESd数值两组均显著缩小,LVEF数值增加,心功能得到改善,观察组改善情况优于对照组义（P〈n05）。结论厄贝沙坦联合美托洛尔治疗充血性心力衰竭患者疗效显著,心功能改善明显,不良反应小。     

Pharmacodynamics and pharmacokinetics of nifedipine in patients with congestive heart failure

Twenty-seven cases of congestive heart failure (CHF) were treated with nifedipine (Nif) 20 mg po. Significant improvements in resting hemodynamics were found in 22 cases. The higher the basal systemic vascular resistance (SVR) and pulmonary artery end diastolic pressure (PAEDP) were, the greater the magnitudes of reduction found (r = 0.84 and 0.77, P less than 0.01, respectively). Exercise hemodynamic investigation showed that Nif led to a lowering of SVR, PAEDP and pulmonary vascular resistance (PVR), with increases in SV and concentration of 5-10 ng/ml, with a maximum being observed at the concentration of 20 ng/ml. No further vasodilation was found when the plasma concentration exceeded 20 ng/ml. No remarkable deviations from the normal ranges of Nif pharmacokinetics were found in CHF patients. The plasma norepinephrine level decreased markedly 2 and 7 h after Nif. Thus, it is concluded that oral Nif is beneficial in severe CHF patients having low cardiac output and high SVR.     

Pharmacokinetics of hydrochlorothiazide in patients with congestive heart failure.

1. Hydrochlorothiazide (HCT, 50-75 mg) was administered orally to seven patients with cardiac failure. 2. Plasma levels and urinary concentration of HCT were determined by GLC. 3. The gastrointestinal uptake of the diuretic in three patients was reduced to approximately half that seen in healthy controls. 4. Plasma halflife of HCT was correlated with endogenous creatinine clearance. 5. Pharmacokinetics of HCT are considerably changed in cardiac failure.     

充血性心力衰竭患者心率变异研究

目的:探讨充血性心力衰竭患者心率变异性变化规律。方法:对54例心力衰竭患者进行24小时Holter监测,然后进行24小时心率变异性分析,将54例心力衰竭患者根据NYHA标准分为心功能Ⅰ~Ⅱ级组27例与心功能Ⅲ~Ⅳ级组27例,比较两组间心率变异性指标变化。结果:心力衰竭组SDNN、SDANN、PNN50均比健康对照组减低,心功能Ⅰ~Ⅱ级组比心功能Ⅲ~Ⅳ级组SDNN、SDANN、PNN50减低。结论:心力衰竭患者心率变异性减低。心功能越差,心率变异性减低越明显。     

Selective aldosterone blockade with eplerenone in patients with congestive heart failure

In the Eplerenone Postacute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) the effects of selective aldosterone blockade with eplerenone on cardiovascular mortality and morbidity were studied in patients with reduced left ventricular function postacute myocardial infarction. Data from this landmark study suggest that eplerenone can be an effective addition to the therapy of patients with congestive heart failure and is associated with fewer side effects than spironolactone. Further research is warranted concerning the possible benefits of this new agent in disease states other than congestive heart failure in which an activated renin-angiotensin-aldosterone system system has been implicated.     

培哚普利对充血性心力衰竭患者校正后QT离散度的影响

目的：观察培哚普利对充血性心力衰竭患者校正后ＱＴ离散度的影响。方法：造反确诊的充血性心力衰竭者４２例,随机分为治疗组和对照组。对照组使用强心剂、利尿剂及对症治疗;治疗组在此基础上加用培哚普利４～８ｍｇ;疗程均为３～４周。于治疗前及治疗后进行ＱＴ离散度的测定。结果：治疗组治疗后ＱＴｃｄ明显低于治疗前,而对照组治疗前后ＱＴｃｄ无明显变化。结论：培哚普利能有效地缩短心肌复极化的离散程度,有利于患者心肌电     

A review of quality-of-life evaluations in patients with congestive heart failure

The factors that may lead to an impaired quality of life in congestive heart failure (CHF) are physical symptoms, psychological problems, treatment adverse effects and social limitation. There are now several general and disease-specific quality-of-life (QOL) questionnaires which have been used to measure treatment effects in clinical trials in CHF. We review the design and validation of both generic and disease-specific QOL questionnaires which have been used in clinical trials in CHF. We then evaluate the performance of these QOL questionnaires in recent clinical trials in CHF in relation to other outcome measures. We conclude that there are important differences between these QOL questionnaires. The choice of a QOL questionnaire is relevant to both patient compliance and clinical outcomes in CHF trials. The 36-Item Short Form (SF-36) Health Survey, a generic QOL questionnaire, and the Minnesota Living with Heart Failure questionnaire, a disease-specific QOL questionnaire, have returned informative data in most trials in which they have been used. QOL questionnaires require further development if this important outcome is to be reliably measured in future clinical trials in CHF.     

Pharmacokinetics and pharmacodynamics of enalapril in patients with congestive heart failure and patients with hypertension

The clinical pharmacokinetics and pharmacodynamics of enalapril and its de-esterified active metabolite, MK 422, were determined in eight patients with congestive cardiomyopathy and five patients with hypertension. After administration of single doses of 2.5, 5, and 10 mg enalapril in the congestive heart failure patients and 20 or 40 mg in the hypertensive patients, serum levels and urine elimination of enalapril and MK 422 were determined. Standing and supine heart rate and blood pressure were measured as was ejection fraction in the congestive heart failure group and renin activity, aldosterone levels, and converting enzyme activity in the hypertensive group. Apparent oral clearance after administration of 5 and 10 mg enalapril was lower in the congestive heart failure patients (0.6 +/- 0.2 and 0.7 +/- 0.4 L/min) than after 20 and 40 mg given to hypertensive patients (2.5 +/- 1.3 and 2.7 +/- 2.7 L/min). The elimination of MK 422 was also slower in the congestive heart failure patients (7.8 +/- 5.0 and 6.8 +/- 2.5 h after 5 and 10 mg enalapril, respectively, vs. 4.6 +/- 2.0 and 5.3 +/- 1.1 h after 20 and 40 mg, respectively, in the hypertension group). The enalapril area under the concentration-time curve increased disproportionately to dose increments in both groups, but was more pronounced in congestive heart failure. Twenty and 40 mg enalapril lowered the blood pressure by 2 h after dosing in the hypertension group, and peak effects were seen 4-5 h after dosing. Peak effects correlated with peak serum MK 422 concentrations but not with enalapril (MK 421) levels. Supine heart rates were unchanged after 20 mg, but increased after 40 mg; standing heart rates were transiently increased after 20 and 40 mg enalapril. Blood pressure was not significantly changed in the congestive heart failure group, and cardiac ejection fraction was unchanged. In the hypertension group, renin stimulation and converting enzyme activity inhibition were seen at 4 h and persisted for at least 24 h after administration of 40 mg enalapril. In summary, the clearance of enalapril and elimination of MK 422 was slower in congestive heart failure patients versus hypertensive patients. Therefore, slower onset and longer duration of drug effect might be anticipated in patients with congestive heart failure versus patients with hypertension during enalapril administration.     

Cardiovascular drug therapy in patients with hepatic diseases and patients with congestive heart failure

Hepatic impairment can alter the pharmacokinetic profiles of cardiovascular drugs, which can lead to unwanted toxicity. In the presence of cirrhosis, portosystemic shunting occurs and cytochrome P450 activity is reduced. Impaired oxygen uptake caused by changes in the liver's sinusoids, as proposed by the oxygen limitation theory, may also explain the alteration of drug metabolism seen in cirrhosis. With congestive heart failure, sinusoidal congestion and hypoperfusion of the liver are seen. Similar to cirrhosis, the common pathway for hepatic damage in congestive heart failure seems to be liver hypoxia, which may explain the disease's effect on drug metabolism. Since routine hepatic function tests do not always relate to the liver's ability to eliminate drugs, existing guidelines for dosing cardiovascular drugs in patients with hepatic impairment are limited. This article provides guidance for dosing cardiovascular drugs in cirrhotic and heart failure patients based on available research data. Altered drug metabolism, especially in congestive heart failure, tends to be overlooked or not realized in clinical practice. Therefore, further research is needed in congestive heart failure to better elucidate safe prescribing patterns.