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.     

Hemodynamic and neurohumoral responses to intravenous nicorandil in congestive heart failure in humans.

Nicorandil is a vasodilator drug that combines potassium channel opening properties with nitrate effects. The resulting potent and unique vasodilating properties suggest a potential therapeutic role in congestive heart failure. We therefore studied the acute hemodynamic and neurohumoral responses to nicorandil, given as single intravenous bolus doses of 158, 251, 398, or 630 micrograms/kg, to 22 patients with chronic congestive heart failure (ejection fraction less than 40%). Hemodynamic responses occurred within 5 min of dosing and terminated within 240 min. The heart rate was significantly increased only at 5 min after the 158 micrograms/kg dose, and was unchanged after all other doses. The mean arterial pressure was reduced only by the 398 and 630 micrograms/kg doses. The pulmonary capillary wedge pressure and right atrial pressure were significantly reduced by all doses within the initial 30 min; this reduction in pulmonary capillary wedge pressure was better sustained over time by the two larger doses, whereas the reduction in right atrial pressure was sustained only by the 158 micrograms/kg dose. The cardiac index was reduced by the 158 micrograms/kg dose, but increased after 251, 398, and 630 micrograms/kg of nicorandil. Plasma nicorandil concentrations were positively correlated with changes in cardiac index, systemic arterial pressure, pulmonary capillary wedge pressure, heart rate, and systemic vascular resistance. When measured 1 h after dosing, plasma immunoreactive ANF decreased, norepinephrine concentrations did not change, and plasma renin activity increased, but only at the 630 micrograms/kg dose level.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

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。     

Plasma concentration-effect relationship of felodipine intravenously in patients with congestive heart failure

The pharmacodynamics of felodipine were analyzed in patients with congestive heart failure in a randomized, double-blind, placebo-controlled study. Felodipine at a dose of 1 mg (n = 11) or placebo (n = 12) was given intravenously during a 60-min period. Hemodynamic measurements and plasma samples were obtained every 15 min during a 2-hour period. An increase in heart rate (HR, +8%, p less than 0.01) and cardiac output (CO, +36%, p less than 0.001), and a decrease in mean arterial pressure (MAP, -24%, p less than 0.001) and systemic vascular resistance (SVR, -46%, p less than 0.001), were found. Pulmonary artery, right atrial, wedge pressure, and stroke-work index did not change. Linear regression analysis showed a significant correlation between felodipine plasma levels and changes in HR (r = 0.71, p less than 0.05), MAP (r = 0.94, p less than 0.01), CO (r = 0.73, p less than 0.05), and SVR (r = 0.88, p less than 0.01). A strong hyperbolic correlation was demonstrated between individual plasma levels and changes in MAP (r = 0.97, p less than 0.001). Hysteresis analysis showed that plasma levels are directly related to the concentration at the receptor site. A clockwise hysteresis was found in HR, CO, and SVR, but not in MAP. It is concluded that changes in flow and resistance are based on a physiological adjustment, a baroreflex-mediated response to vasodilation induced by felodipine, resulting in MAPs that remain closely related to felodipine plasma levels over a wide range.     

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.     

Acute haemodynamic and neurohumoral effects of intravenous nisoldipine in patients with severe congestive heart failure

Summary Twenty patients (5 females, 15 males) with severe heart failure (NYHA IV), due to coronary artery disease in 14, and congestive cardiomyopathy in 6, received an intravenous bolus of the calcium blocker nisoldipine 0.2 mg followed by a continous infusion of 0.2 g · kg^–1 · min^–1. Haemodynamic measurements were performed at baseline and after 30 min.The mean arterial pressure fell from 91 to 73 mm Hg, pulmonary capillary wedge pressure from 31 to 26 mm Hg and systemic vascular resistance from 1695 to 1040 dyn · s · cm^–5.The cardiac index (2.2 to 2.71 · min^–1 · m^–2, and stroke volume index (25 to 33 ml · m^–2) were markedly increased. There was no reflex tachycardia as the heart rate dropped from 92 to 85 beats · min^–1. Plasma renin activity and norepinephrine concentration did not change significantly.The findings indicate that nisoldipine acts as a strong vasodilator and that it has a beneficial acute haemodynamic effect in patients with severe left heart failure irrespective of its aetiology.     

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.     

Sympathetic responses to atrial natriuretic peptide in patients with congestive heart failure

Previous studies have shown that atrial natriuretic peptide (ANP) has relative sympathoinhibitory effects that are of potential benefit in patients with congestive heart failure (CHF). In this study, cardiac and systemic sympathetic responses to ANP were evaluated and compared with responses to sodium nitroprusside (SNP) in patients with CHF. Right- and left-heart hemodynamics were obtained simultaneously with cardiac (CANESP) and total body (TBNESP) norepinephrine spillover; these were measured by using the radiotracer technique. Reductions in arterial blood pressure and cardiac filling pressures were similar with both drugs. ANP and SNP caused a significant and similar increase in TBNESP. Mean values for CANESP did not change in either group, but the response of individual patients was dependent on the effect on diastolic blood pressure (r = -0.71, p<0.01). These results do not provide evidence for a sympathoinhibitory effect of ANP, but suggest that in patients with CHF, cardiac sympathoexcitatory response to arterial baroreceptor unloading may be countered by a potential sympathoinhibitory effect caused by a reduction in cardiac filling pressures. In the setting of CHF, vasodilator therapy may decrease cardiac sympathetic activity if systemic hypotension is avoided.     

Short-term hemodynamic effects of intravenous methyldopa in patients with congestive heart failure

The acute hemodynamic effects of intravenous methyldopa were studied in six patients with chronic congestive heart failure (New York Heart Association class IV) at 4-6 hours after a 750-mg bolus (period A) and 6-12 hours after a maintenance infusion of 1-2 mg/minute (period B). For period A, the most consistent and striking finding was a significant (48%) fall in pulmonary wedge pressure (33 +/- 6 to 17 +/- 2 mm Hg; p less than 0.05). Stroke volume increased 39% (23 +/- 3 to 32 +/- 4 ml/m2; p less than 0.05), while peripheral vascular resistance decreased 15% (3331 +/- 363 to 2841 +/- 241 dynes.s.cm-5; p less than 0.05). Heart rate fell from 97 +/- 7 to 76 +/- 3 beats/minute (p less than 0.05) with a nonsignificant decline in mean right atrial pressure (18 +/- 4 to 9 +/- 1 mm Hg). These hemodynamic changes were either sustained or enhanced during period B. Concomitant clinical improvement was also noted. As an agent with potent vasodilatory and antiadrenergic properties, methyldopa permitted a rise in stroke volume by virtue of unloading and possible inhibition of sympathetic activity that led to increased density of beta-adrenergic receptors of the heart (up-regulation). Significant reduction of ventricular filling pressure was attributed to venodilation and probable improved diastolic function. In selected patients with severe congestive heart failure, particularly underscored by excessive sympathetic tone, methyldopa may be considered as an alternative agent to improve cardiac performance and clinical symptomatology.     

The hemodynamic effects of ibopamine, a dopamine congener, in patients with congestive heart failure

Ten patients with congestive heart failure underwent noninvasive and invasive hemodynamic testing before and sequentially after the administration of ibopamine to determine the cardiovascular effects of this oral dopamine congener. Single doses of 200, 400 and 600 mg were administered to all patients and 5 repeated doses of 200 or 400 mg were studied in 8. Hemodynamic effects occurred as early as 30 minutes and lasted up to 4 hours after dosing. In general, ibopamine elicited statistically significant dose-related increases in cardiac output and reductions in the derived resistance of the systemic and pulmonary circulations. A biphasic response in central and peripheral pressures was observed; up to 1 hour after administration, ibopamine elevated mean right and left atrial pressures and pulmonary and systemic arterial pressures with a significant reduction of these measurements beyond 1 hour. It did not alter heart rate. Repeated doses qualitatively affected hemodynamics similar to the initial dose and did not appear to be accompanied by short-term tolerance. While oral ibopamine elicits some favorable hemodynamic effects in humans with cardiac failure, the biphasic hemodynamic response is generally undesirable in the majority of these patients.     

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.     

Acute hemodynamic effects of nilvadipine, a new calcium channel blocker, in patients with congestive heart failure.

The acute hemodynamic effects of nilvadipine, a newly synthesized calcium channel blocker, were studied in 12 patients with congestive heart failure. Hemodynamic measurements were made before and 15, 30, and 60 min after oral administration of 6 mg nilvadipine. Substantial reductions in systemic vascular resistance (-28.8 +/- 6.3%, p less than 0.01) and forearm vascular resistance (-52.0 +/- 6.2%, p less than 0.01) after nilvadipine administration were associated with increases in cardiac index (31.1 +/- 8.3%, p less than 0.01) and forearm blood flow (105.2 +/- 27.4%, p less than 0.01). Mean arterial and pulmonary arterial pressures were decreased by 12.2 +/- 3.0% (p less than 0.01) and 14.7 +/- 5.0% (p less than 0.05), respectively, after nilvadipine administration; however, heart rate remained unchanged. Decreases in mean arterial pressure correlated with the baseline arterial pressure (y = 0.58x - 41.6, r = 0.75, p less than 0.01). Pulmonary capillary wedge pressure decreased by 33.1 +/- 9.1% (p less than 0.01) after nilvadipine administration. However, right atrial pressure and the venous stiffness constant remained unchanged, and the venous pressure-volume curve was not shifted significantly. Therefore, the decrease in pulmonary capillary wedge pressure was attributed primarily to afterload reduction. Nilvadipine holds promise as a vasodilator for the therapy of congestive heart failure.     

Long-term therapy with benazepril in patients with congestive heart failure: effects on clinical status and exercise tolerance

Benazepril hydrochloride (CGS 14824A) is an orally active, nonsulfhydryl compound that is transformed in vivo to a long-acting inhibitor of angiotensin-converting enzyme (ACE). Previous studies have shown benazepril to lower blood pressure in hypertensive patients and to confer acute hemodynamic benefits in patients with congestive heart failure (CHF). In the current multicenter investigation, 16 patients with chronic CHF due to left ventricular systolic dysfunction (ejection fraction less than 0.40 at rest) whose symptoms corresponded to New York Heart Association classes II to IV were given open-label benazepril once daily in ascending doses of 2 to 20 mg and followed biweekly for 12 weeks. Evaluation of the 15 subjects who completed the trial showed a progressive increase in treadmill exercise duration (from 7.65 +/- 3.64 [SD] minutes at baseline to 9.74 +/- 3.66 minutes at 12 weeks, P less than .001); augmentation of the mean left ventricular ejection fraction (from 0.266 +/- 0.133 at baseline to 0.292 +/- 0.136 at 12 weeks, P less than .025); relief of exertional dyspnea in 7 of the 15 patients (P less than .02); and improvement in global symptomatic status in 10 of the patients (P less than .01). These responses were accompanied by a reduction in serum ACE activity of 75% (from 27.2 +/- 10.5 IU/L at baseline to 6.7 +/- 1.9 IU/L at 12 weeks, P less than .001), which was independent of dose and duration of treatment. The magnitude of ACE inhibition did not correlate with changes in the efficacy variables. Aside from two instances of symptomatic hypotension (one of which was complicated by volume depletion), the drug was well tolerated.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

曲美他嗪治疗慢性收缩性心力衰竭的临床研究

目的观察曲美他嗪治疗慢性收缩性心力衰竭的临床疗效及安全性。方法采用随机数字表法将120例确诊为慢性收缩性心力衰竭的患者分为两组：对照组（60例）给予常规抗心力衰竭药物治疗;曲美他嗪组（60例）在常规药物治疗的基础上加用曲美他嗪（20mg、3次／d）治疗。治疗前后观察记录患者的一0力衰竭症状和体征,记录NYHA分级,检测患者B型脑钠肽（BNP）浓度,6min步行试验（6rainWT）,超声心动图测定左心室舒张末内径（LVEDD）、LVEF,并记录不良反应及临床事件。结果曲美他嗪组显效率及总有效率均高于对照组,差异均有统计学意义（P〈0．05）。与治疗前比较,两组患者治疗后LVEDD、LVEF均有明显改善,6min聊距离明显延长,BNP水平明显下降,差异均有统计学意义（P〈0．05）。曲美他嗪组治疗后LVEDD、LVEF较对照组明显改善,6minWT距离明显延长,BNP下降更显著,差异均有统计学意义（p〈0．05）。随访期间曲美他嗪组再入院率（5．0％）与对照组再人院率（18．3％）比较,差异有统计学意义（P=0．043）。治疗期间两组均未观察到严重不良反应。结论在慢性心力衰竭常规治疗的基础上加用曲美他嗪能进一步改善心功能、提高患者的运动耐量及改善心室重构。     

Systemic and regional hemodynamic effects of perindopril in congestive heart failure.

The acute systemic and regional hemodynamic responses to a single oral dose (4 mg) of the angiotensin converting enzyme inhibitor perindopril were investigated in 10 patients with severe congestive heart failure. Perindopril produced significant and long-lasting decreases in systemic vascular resistance (-18%), right atrial pressure (-60%), and mean pulmonary capillary wedge pressure (-28%), whereas it significantly increased cardiac index (+ 12%). Brachial (+ 130%, pulsed Doppler technique) and renal (+ 34%) blood flows were also significantly increased whereas hepatic blood flow remained unchanged. Brachial flow/cardiac output and renal flow/cardiac output ratios increased significantly from 0.8 to 1.6 and from 13.2 to 16.5, respectively. The maximal decreases in forearm and renal (but not in systemic) vascular resistances were correlated with the basal plasma norepinephrine concentrations but not plasma epinephrine concentrations or plasma renin activity. We conclude that in severe heart failure (a) perindopril considerably improves systemic hemodynamics and exerts an inhomogeneous vasodilating effect, resulting in a redistribution of flows toward the forearm and renal territories, (b) norepinephrine is a major determinant of the arteriolar tone in these two vascular beds, and (c) the pulsed Doppler is a particularly suitable method to non-invasively detect and assess hemodynamic improvements in heart failure patients.     

高血压所致慢性充血性心力衰竭患者血清sFas水平及临床意义

目的：观察高血压所致慢性充血性心力衰竭（CHF）患者血清sFas浓度的变化并探讨其临床意义。方法：选取高血压所致慢性充血性心力衰竭患者22例,单纯高血压患者19例,正常对照组21例。采用ELISA法测定血清sFas浓度。结果：①与正常对照组相比,高血压CHF组血清sFas水平显著升高（P〈0．01）,高血压无CHF组和对照组之间血清sFas的水平变化无统计学意义（P〉0．05）。②sFas水平随心功能不全的加重而明显升高,心功能Ⅳ级组患者高于心功能Ⅱ、Ⅲ级组患者（P〈0．05）。结论：由高血压所致慢性充血性心力衰竭患者血清凋亡相关因子sFas水平明显升高,细胞凋亡在此类心衰的发病机制中起了重要作用。     

卡维地洛对慢性充血性心力衰竭患者血浆炎性细胞因子及临床疗效的影响

目的 探讨卡维地洛对慢性充血性心力衰竭(CHF)患者血浆炎性细胞因子及临床疗效的影响.方法 选择住院治疗CHF患者72例,采用随机数字表将患者分为观察组与对照组.两组患者入院后予以强心、利尿和扩张血管等常规治疗.观察组患者在此基础上加用卡维地洛治疗,初始剂量3.125 ag,2次/d,逐渐递增加量,直至维持量25mg,2次/d,连用12周.观察比较两组治疗前后血浆肿瘤坏死因子-α(TNF-α)、白细胞介素-1(IL-1)和白细胞介素-6(IL-6)水平变化及临床治疗效果.结果 治疗12周后,两组血浆TNF-α、IL-1和IL-6均较前明显下降(t=3.02、3.17、2.97、2.26、2.25、2.21,均P＜0.05),且观察组下降幅度较对照组更显著(t =2.32、2.35、2.29,均P＜0.05);同时观察组的临床总有效率(94.44％)明显高于对照组(77.78％)(x2 =4.18,P＜0.05),两组患者治疗期间未见明显的药物不良反应.治疗后随访1年,观察组再次住院率(61.11％)明显低于对照组(36.11％)(x2=4.50,P＜0.05),但两组病死率差异无统计学意义(x2=0.26,P＞0.05).结论 卡维地洛治疗CHF安全有效,能降低血浆细胞因子TNF-α、IL-1和IL-6水平,减少患者的再次住院率,改善患者的预后.