Acute haemodynamic effects of felodipine in congestive heart failure

Summary The haemodynamic effects of felodipine 0.1 mg/kg p.o., a new arteriolar dilator, were studied in 7 patients with severe congestive heart failure of NYHA Class IV (Group A) and in 3 patients in Class II–III (Group B). In Group A, measurements were made before and 1 and 4 h after felodipine administration. There was a substantial fall in systemic arterial pressure, which was not associated with a compensatory tachycardia. In fact, there was a fall in heart rate from 92 to 82 beats/min 1 h after drug administration. The pulmonary capillary wedge pressure was reduced from 22 to 14 mm Hg and the cardiac index and stroke volume index rose significantly. Consequently, there was a marked reduction in systemic vascular resistance. In Group B measurements were performed at rest and during exercise before and 1 h after felodipine. The pulmonary wedge capillary pressure during exercise was lower than in the control situation. Coronary sinus flow was increased and there was a pronounced fall in coronary vascular resistance. The results would suggest that felodipine, by virtue of its ventricular unloading potency, might be a valuable drug in the treatment of congestive heart failure.     

非洛地平治疗慢性充血性心力衰竭的临床药学分析

目的：探讨非洛地平对慢性充血性心力衰竭（CHF）的治疗作用。方法：选择Ⅱ～Ⅲ级CHF患者100例,随机分为对照组50例,以洋地黄、利尿剂和卡托普利治疗;治疗组50例,在对照组方案的基础上,加用非洛地平每日2．5～5mg,疗程4周。观察血压、心率及心功能变化,通过X线胸片、超声心动图测定治疗前后心胸比率、LVEF及LVDd参教。结果：发现两组治疗后均有收缩压下降、心率减慢、LVEF升高（P〈0．001或P〈0．05）。治疗组心胸比率、LVDd缩小（P〈0．05）而对照组变化不明显（P〉0．05）;治疗组收缩压下降,LVEF升高的幅度比对照组明显（P〈0．001或P〈0．01）。结论：在CHF治疗中短期应用非洛地平可进一步改善心功能,降低血压,逆转扩大的心脏。增加心排量。     

Plasma concentration-effect relationships of intravenous and extended-release oral felodipine in hypertensive patients.

Felodipine, a dihydropyridine calcium antagonist, was given double-blind in a crossover design comparing once-daily doses of 20 mg felodipine extended-release (ER) tablets with placebo in 12 hypertensive patients. A 2-h intravenous infusion was given after a placebo washout. After oral felodipine, blood pressure (BP) was significantly lower than after placebo, both after the first dose and after 2 weeks of treatment. Supine BP 24 h after the first dose of placebo and felodipine was 159/97 and 153/92 mm Hg (p less than 0.01/0.05), respectively. Corresponding BPs at 2 weeks were 158/99 and 144/89 mm Hg (p less than 0.01/0.01). Approximately 75% of the maximal and 60% of the trough effect at steady state were obtained already after the first dose. The plasma concentration (CpF) vs. time curve after felodipine ER was relatively flat. After oral felodipine, a linear correlation was found between BP reduction and logarithmic CpF. After intravenous administration, CpF correlated well with a hyperbolic function. These data indicate that there is an almost linear relation between BP reduction and log CpF in the range from 2-20 nmol/L, and that little additional effect is to be expected above approximately 20 nmol/L. No hysteresis was found for the relationship between CpF and BP reduction. The absolute bioavailability of felodipine ER was 22%.     

Pharmacokinetics of felodipine after intravenous and chronic oral administration in patients with congestive heart failure.

1. In a randomized, parallel, double-blind study felodipine was administered to 11 and placebo to 12 patients with congestive heart failure. The kinetics of felodipine were studied after acute intravenous administration and after chronic oral treatment for 8 weeks. The relationship between cardiac output and pharmacokinetics was analyzed. The pharmacokinetic data were compared with data from young healthy individuals and hypertensive patients. 2. After oral therapy, significant correlations were found between cardiac output and AUC and systemic bioavailability (F). Furthermore, cardiac output before therapy was also significantly correlated with absorption characteristics. No relationship could be demonstrated between cardiac output and i.v. pharmacokinetics. A comparison of patients with heart failure and young healthy individuals revealed that the AUC was three times higher in heart failure patient, while Vss and the ratio of the AUC of the pyridine metabolite to that of felodipine were similar. Oral clearance was reduced by 50% and the terminal half-life was concomitantly increased. Pharmacokinetic data for felodipine are similar in patients with heart failure to published data from elderly hypertensive patients. 3. An increase in liver blood flow during chronic oral therapy, induced by felodipine itself, appears to explain an increase in bioavailability and thus to higher plasma drug concentrations. Thus, it is advisable to start felodipine treatment at a low dosage in patients with congestive heart failure.     

Oral pharmacokinetics of felodipine in patients with congestive heart failure: variable prediction using intravenous data

Peak and trough concentrations after 8 weeks oral therapy with felodipine, a vasodilating calcium antagonist of the dihydropyridine group, were predicted from intravenous pharmacokinetic data before therapy in 11 patients, randomly allocated to felodipine treatment 10 mg b.i.d., during a placebo controlled study in patients with congestive heart failure. Peak concentrations were well predictable, but trough levels varied between a good agreement in some patients to a large underestimation in others. Predictability was significantly correlated with half life, plasma clearance and distribution volume of the intravenous pharmacokinetic study. After 8 weeks chronic oral therapy no significant differences could be detected between the oral pharmacokinetics of predictable (n = 6) and unpredictable (n = 5) patients. This demonstrates that felodipine kinetics change during felodipine treatment. Differences in the distribution of blood flow before therapy combined with an interindividual variability in blood flow response during therapy is probably responsible for the observed impossibility to calculate trough levels, and thus oral dosage schedules, from intravenous pharmacokinetic data in patients with congestive heart failure.     

Central and peripheral haemodynamic responses to felodipine in congestive heart failure

Summary Using non-invasive radionuclide techniques, we studied the arterial and venous effects of 0.1 mg/kg oral felodipine in 12 men with heart failure due to ischaemic heart disease aged 37–72 y. All were in New York Heart Association Class II or III, required frusemide 40–120 mg daily and were clinically stable.Felodipine produced significant falls in blood pressure (–19%) and systemic vascular resistance (–39%) with increases in cardiac index (+34%), heart rate (+12%) and left ventricular ejection fraction (from 0.25 to 0.32). Peripheral venous volume fell by 10.6% after felodipine indicating venoconstriction rather than venodilatation and may be caused by an acute sympathetic reflex associated with the increase in heart rate.Our results confirm that felodipine is an arterial vasodilator. The previously observed changes in cardiac filling pressures may simply represent improved ventricular function as a consequence of reduced afterload, not venodilatation.     

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.     

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。     

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.     

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.     

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.     

非洛地平治疗慢性充血性心力衰竭的临床药学效果分析

目的：观察非洛地平对慢性充血性心力衰竭（CCHF）的患者的临床疗效。方法68例Ⅲ级充血性心力衰竭患者随机分为对照组和治疗组,对照组予常规治疗药物;治疗组在对照组基础上加用非洛地平,分析两组患者的疗效。结果治疗组的总有效率91.43%显著高于对照组66.67%,差异有统计学意义（P〈0.05）,治疗组治疗后相关指标均有改善。结论使用非洛地平治疗CCHF效果良好,值得予以推广。     

Long-term clinical, hemodynamic, angiographic, and neurohumoral responses to vasodilation with felodipine in patients with chronic congestive heart failure.

Twenty patients on conventional therapy for severe congestive heart failure (CHF) were randomly assigned to adjunctive treatment with felodipine (n = 10) or placebo (n = 10) and followed over a 6-month period. Baseline clinical, hemodynamic, angiographic, and neurohumoral estimates of CHF were comparable in the two treatment groups. These estimates remained virtually unchanged at 6 months in patients on placebo therapy, but circulating noradrenaline levels were further augmented. In patients on felodipine therapy, substantial reductions in left ventricular end-systolic pressure, mean arterial pressure, and systemic vascular resistance were observed at 6 months. This afterload reduction led to a preferential increment in the stroke volume (36%) which increased cardiac output (30%), whereas heart rate tended to decrease. The improved hemodynamics during felodipine treatment were paralleled by marked improvements in the angiographic left ventricular ejection fraction and regional segmental wall motion score. The enhanced contractile state of the left ventricle was accompanied by significant reductions in the augmented plasma levels of catecholamines, and the patient clinical status improved. The 6-month mortality rate in the 20 patients was 40% and indicated a closer relation to baseline noradrenaline plasma levels than to hemodynamic or angiographic estimates of CHF. Despite the limited number of patients, the long-term clinical efficacy of felodipine is thus evidenced in patients with CHF and is related to sustained arteriolar dilatation and improved neurohumoral profile by this vasoselective calcium antagonist.     

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.     

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。     

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.     

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.     

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。