Effect of congestive heart failure on clentiazem pharmacokinetics in a dog model.

Clentiazem, 8-chloro diltiazem, is a calcium channel blocker currently undergoing evaluation for the treatment of stable angina and hypertension. As patients with ischaemic disorders often present some degree of heart failure, the aim of this study was to investigate the effect of congestive heart failure on clentiazem (200 micrograms kg-1, i.v. bolus) pharmacokinetics in a canine model. Congestive heart failure was induced in six dogs by rapid ventricular pacing (240 beats min-1) for 3-5 weeks. Clentiazem pharmacokinetics was studied in each dog under the control condition and after the development of clinical signs of heart failure (ascites, dyspnea, fatigue). Blood samples were collected up to 480 min post-dose. Clentiazem plasma concentrations were determined by high performance liquid chromatography. The area under the plasma concentration versus time curves (AUC0-infinity) was significantly increased in congestive heart failure dogs (8.8 +/- 1.6 vs 21.8 +/- 1.4 micrograms min ml-1) (mean +/- SEM). These changes were related to a reduction of the volume of distribution of the central compartment (0.9 +/- 0.1 vs 0.2 +/- 0.11 kg-1) and total body clearance (1.9 +/- 0.4 vs 0.7 +/- 0.21 h-1 kg-1). It is concluded that, in our model, congestive heart failure significantly modifies clentiazem disposition. These results suggest that caution should be exercised when clentiazem is given to patients with a low ejection fraction and a compromised cardiac function. Reduced loading and maintenance doses might be recommended in patients with severe congestive heart failure.     

Impaired elimination of propranolol due to right heart failure: drug clearance in the isolated liver and its relationship to intrinsic metabolic capacity.

It is unclear if reduced hepatic drug elimination in congestive heart failure is primarily due to impairment of enzyme function as a result of tissue hypoxia, to the direct effects of hepatic congestion, or to changes intrinsic to the liver, such as reductions in enzyme content and activity. We therefore compared propranolol clearance in perfused rat livers from animals with right ventricular failure (RVF) with that from control animals. Despite the fact that both groups were perfused at comparable flow rates, perfusion pressures, and levels of oxygen delivery, hepatic extraction of propranolol was significantly reduced in RVF livers (0.688 +/- 0.122 versus 0.991 +/- 0.006 ml/min/g of liver in controls, P <.001). This effect was reflected in a 97% reduction in propranolol intrinsic clearance in RVF livers (5 +/- 4 versus 172 +/- 82 ml/min/g of liver in controls, P <.01). In RVF livers, total hepatic CYP expression was reduced by 19% compared with controls, whereas cytochrome P450 isoenzymes 1A1/2 and 2D1 were reduced by 41 and 26%, respectively. Despite the 97% reduction in propranolol intrinsic clearance in perfused RVF liver, intrinsic clearance in microsomal preparations from the same livers was reduced by only 48% compared with controls (P <.05). These findings suggest that impaired propranolol clearance in RVF is not primarily accounted for by reduced hepatic oxygen delivery or by changes in hepatic content and activity of drug-metabolizing enzymes.     

卡维地洛对慢性心衰的治疗作用

目的 探讨卡维地洛(CAV)治疗心力衰竭的疗效及机制。方法 对慢性心衰病人76例，随机分为3组：常规治疗组20例(A组)、卡维地洛组30例(B组)、美托洛尔组26例(C组)，治疗前后分别观察心功能变化、测量LVEF、左室质量及血浆脂质过氧化物(LPO)和超氧化物歧化酶(SOD)的水平。结果 (1)B组和C组治疗6个月后患心功能明显好转，且疗效优于A组(P＜0．01)，但B组和C组之间疗效差异无显性(P＞0．05)。(2)B组血浆LPO水平较治疗前下降，红细胞SOD升高(P＜0．01)，而A组和C组治疗前后无明显变化。结论 CAV对慢性心衰有明显治疗作用，可能与其脂质过氧化有关。     

磷酸肌酸钠治疗充血性心力衰竭的疗效研究

目的：探讨磷酸肌酸钠治疗充血性心力衰竭的疗效。方法选取2011年4月—2014年4月信阳市中心医院收治的充血性心力衰竭患者100例,随机分为试验组与对照组,各50例。对照组患者予以常规药物治疗,试验组患者在对照组基础上加用磷酸肌酸钠治疗。观察两组患者临床疗效及治疗前后心功能指标。结果试验组患者总有效率为84%,高于对照组的62%,差异有统计学意义（ P <0.05）;治疗前两组患者左室收缩末期内径（LVESD）、左室舒张末期内径（LVEDD）和左心室射血分数（LVEF）比较,差异无统计学意义（P>0.05）;治疗后试验组患者LVESD和LVEDD短于对照组,LVEF高于对照组,差异有统计学意义（ P<0.05）。结论磷酸肌酸钠治疗充血性心力衰竭的疗效显著,可改善患者心功能指标。     

Effect of congestive heart failure on the pharmacokinetics of cibenzoline

Six patients with chronic congestive heart failure (CHF) (New York Heart Association functional class II or III) and five healthy subjects completed this study designed to determine if CHF alters the pharmacokinetics and absolute bioavailability of cibenzoline when compared with healthy subjects. Each subject or patient was administered a one-hour intravenous infusion of 80 mg of 15N2-cibenzoline and simultaneously received an 80-mg oral dose of cibenzoline that allowed for analytic separation of each route of administration. Resulting plasma concentration-time profiles and urinary excretion rate data were used to determine pharmacokinetic parameters for cibenzoline. There were no statistically significant differences in any pharmacokinetic parameter between patients with CHF and healthy subjects. The absolute bioavailability ranged from 74% to 97% in those with CHF. The volume of distribution following the intravenous dose ranged from 3.4 to 6.1 L/kg, and plasma clearance ranged from 245 to 642 mL/min, with an apparent elimination half-life of approximately ten hours. Approximately 60% of the dose was recovered in the urine. Overall, the pharmacokinetics of cibenzoline in patients with chronic CHF do not differ from those observed in healthy subjects.     

Sudden death in congestive heart failure.

Despite significant advances in recent years in the diagnosis and treatment of congestive heart failure, sudden unexpected cardiac death is still considered a major epidemiologic problem among those patients. This article lists some of the predisposing factors to the development of cardiac arrhythmias and sudden death in patients with congestive heart failure. These include electrolyte or autonomic nervous system inbalance, the use of certain anti-arrhythmic drugs, or intermittent myocardial ischemia. This paper shows that an advanced degree of left ventricular dysfunction and the preference frequent or complex ventricular arrhythmias appear to be major predictors of total and sudden mortality among patients with congestive heart failure. A screening of 24 hours ambulatory Holter monitor recording appears to be useful in identifying patients at risk of sudden cardiac death.     

Diastolic dysfunction in congestive heart failure.

The available literature on the evaluation of diastolic function, the importance of diastolic dysfunction in congestive heart failure (CHF), and the effects of therapeutic agents on diastolic dysfunction are summarized. The normal cardiac cycle consists of two components: systole (contraction; ventricular emptying) and diastole (dilation; ventricular filling). Recent studies have shown that 30-40% of patients with CHF have normal systolic function; the majority of these patients have diastolic dysfunction as the underlying disorder. As a result, the role of diastolic dysfunction in CHF is currently an area of interest for researchers. The two primary causes of diastolic dysfunction are left ventricular hypertrophy and ischemic heart disease. Patients with CHF caused by diastolic dysfunction and patients with CHF caused by systolic dysfunction have nearly identical clinical presentations. Therapy with diuretics, vasodilators, angiotensin-converting-enzyme inhibitors, beta-agonists, the partial beta-agonist xamoterol, phosphodiesterase III inhibitors, or calcium-channel blockers may be beneficial in patients with diastolic dysfunction. Therapy with digitalis glycosides would be of no benefit, and could theoretically be detrimental, in patients with predominant diastolic dysfunction. Available data indicate that beta blockers have neither an important beneficial effect nor an important detrimental effect on diastolic function. Continued studies into diastolic dysfunction and the diastolic properties of agents that are used in the treatment of CHF should enhance the understanding of this clinical syndrome and the drugs used to treat it.     

Effect of phentolamine on peripheral venous distensibility in congestive heart failure

Summary Seven patients with congestive heart failure received an infusion of phentolamine, 5 mg per hour for one hour, and seven others, considered as controls, received an infusion of dextrose. The small dose of phentolamine produced a minimal increase in pulse rate, and no significant change in arterial blood pressure and forearm blood flow. Venous distensibility was measured in the forearm by occlusion plethysmography. It was significantly increased by phentolamine, the rise in venous volume being 20–30% greater than in controls for the same effective venous pressure.     

芦沙坦对老年慢性心力衰竭的血液动力学效应

目的：观察芦沙坦对老年慢性充血性心力衰竭的治疗作用。方法：采用开放、分组对照研究方法对６６例入院老年充血性心力衰竭（ＣＨＦ）患者按区组随机化分组,分别运用Ｌｏｓ和依那普利治疗１２ｗｋ,观察两组的心功能及临床症状的变化,并采用多普勒心超仪监测用药前后的血液动力学。结果：两组每搏量（ＳＶ）、心脏指数（ＣＩ）和左室射血分数（ＥＦ）治疗后均显著提高（Ｐ〈０．０１,Ｐ〈０．００１和Ｐ〈０．０５）;心功能明显     

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     

Bioavailability of quinidine in congestive heart failure.

1 The oral bioavailability of quinidine was evaluated in eight patients with moderate to severe congestive heart failure. Each patient was given a 400 mg dose of quinidine gluconate by intravenous infusion and orally in solution. Serial plasma samples and total urine for drug analysis were collected for 24 and 48 h after drug administration, respectively. 2 When compared to control cardiac patients, the rate of quinidine absorption was slower in the heart failure patients. The mean value for the apparent absorption half-life and time to achieve peak plasma quinidine concentration was 38 +/- 18 min and 2.4 +/- 1.5 h respectively. The corresponding values observed in the control subjects were 18 +/- 6 min and 1.0 +/- 0.6 h. 3 The extent of quinidine absorption when evaluated by the AUC and urinary excretion methods was about 72% of the administered dose in the congestive heart failure patients. This value was similar to the extent of quinidine absorption (approximately 73%) observed in the control subjects. 5 When compared with non-heart failure cardiac patients, the results of this study suggest that patients with congestive heart failure may require smaller oral quinidine dosages to achieve therapeutic drug concentrations in the plasma or serum.     

Elimination of canrenone in congestive heart failure and chronic liver disease

Summary The elimination half-life (T1/2) of canrenone, the principal unconjugated metabolite of spironolactone, was 59 h (range 32–105 h) in 5 patients with chronic liver disease and 37 h (range 19–48 h) in 7 patients with congestive heart failure. In comparison the T1/2 in normal subjects was 13.5–24 h in previous reports and 20.5 h in the present study. However there was no evidence of greater cumulation of canrenone in the plasma of those patients with a prolonged T1/2.     

Bumetanide in congestive heart failure

Summary

Bumetanide, a new diuretic exerting its major effect on the ascending limb of the loop of Henle, was evaluated in 20 patients with congestive heart failure. Dosage ranged from 1 mg to 3 mg daily depending on the patient's condition. The results after 3 and 8 days' treatment showed that bumetanide caused a significant diuresis, an increased excretion of sodium, potassium and chloride, and a comparable fall in the serum levels of these electrolytes. Changes in electrolyte levels were directly related to the dose of the drug. The resultant hypochloraemia was accompanied by a slight metabolic alkalosis.

A comparative crossover study between placebo, bumetanide and frusemide using equipotent doses was performed in 10 patients. Both drugs had a similar effect upon water excretion and the serum and urinary electrolytes.     

beta-Blockers in congestive heart failure

Recent advances in the understanding of the basic mechanisms underlying congestive heart failure (CHF) have focused on the role of neurohormonal activation. Chronic adrenergic overstimulation is directly toxic to myocardial cells, impairs function, causes peripheral vasoconstriction and may induce programmed cell death via apoptosis. beta-Adrenergic blockade can interrupt this pathological process. Accumulating evidence now points to a clear role for beta-blocking agents in the management of heart failure, reducing both the morbidity and mortality associated with CHF. This report will review the recent clinical trials supporting the use of beta-blockers in CHF, briefly highlight some practical considerations in the use of these drugs in patients with CHF and discuss several areas of controversy in which further study is needed.     

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.