The haemodynamic effects of long term felodipine therapy in previously untreated essential hypertension

Summary Sixteen patients with previously untreated mild/moderate hypertension (WHO Stage I) were studied: 7 women and 9 men, mean age 56.2 y. Haemodynamics, central and pulmonary blood volumes were measured by radionuclide techniques and repeated after 8 weeks felodipine therapy. To achieve a target diastolic blood pressure of < 95 mm Hg 12 patients required 5 mg bid, 2 10 mg bid and 1 2.5 mg bid; 1 withdrew after 2 weeks.Mean (SD) arterial blood pressure (mm Hg) was 189/106 before, and 182/103 after 2 weeks placebo treatment and fell to 148/84 after 8 weeks felodipine therapy. Relative systemic vascular resistance fell by 19% from 2146 to 1734 dyn.s.cm^–5. There were no significant changes in heart rate, cardiac index, total blood volume, pulmonary blood volume or left ventricular ejection fraction. Plasma renin activity did not rise significantly. Short lived vasodilator side effects occurred in 7/16 patients during initial treatment and mild ankle oedema persisted in 4/16 patients.In contrast to the haemodynamic changes seen acutely with felodipine, the only sustained changes after 8 weeks therapy are reductions in systemic vascular resistance and blood pressure.     

Attenuation of renal ischaemic injury by felodipine

Summary Felodipine is a vasodilating calcium channel blocker of the dihydropyridine type. The effects of felodipine on post-ischaemic renal function were evaluated in rats subjected to bilateral renal artery occlusion for 30 or 60 min.In a first set of experiments the recovery of renal function after 30 or 60 min of renal artery occlusion was followed intermittently for 16 days by endogenous creatinine clearance. Renal function was better preserved in rats given felodipine (45 nmol/kg i.v.) during the occlusion period than in vehicle-treated control rats. The survival rate after 60-min occlusion was 11% in controls but 70% in the felodipine-treated rats. After occlusion for 30 min the survival rate was similar in the two groups, but renal function recovered faster in the felodipine group than in the controls.In a second series, acute renal damage was evaluated by the extent of erythrocytes trapped in the kidney after 30-min reperfusion following 60-min renal artery occlusion. Felodipine administration (45 nmol/kg) during the occlusion reduced renal damage compared with vehicle controls. Kidney weight and systemic haematocrit were also better maintained in the felodipine-treated rats. Furthermore, renal damage was reduced by the t-butyl analogue or felodipine, H 186/86, which is devoid of vasodilatory effects. The results demonstrate that treatment with the vasodilator calcium channel blocker felodipine protects the kidney from ischaemic/reperfusion injuries. The tissue protection is not related to the haemodynamic effects alone, since the haemodynamically inactive dihydropyridine H 186/86 also reduced the extent of renal damage. An additional antiperoxidant or scavanger-like effect inherent in the dihydropyridine molecule is suggested. Send offprint requests to M. Nordlander at the above address     

The acute haemodynamic and renal effects of oral felodipine and ramipril in healthy subjects

Summary The aim of the present investigation was to compare the acute haemodynamic and renal effects of the calcium antagonist felodipine with the ACE inhibitor ramipril and with placebo.Single oral doses of felodipine 5 and 20 mg, ramipril 2.5 and 10 mg, and placebo were given to ten healthy subjects in a double-blind cross-over study. Blood pressure, heart rate, forearm blood flow (FBF), forearm vascular resistance (FVR), renal blood flow (RBF), renal vascular resistance (RVR), glomerular filtration rate (GFR), filtration fraction (FF), diuresis, and sodium excretion were recorded for 4.75 h after administration.Felodipine 20 mg caused a significant fall in diastolic blood pressure, maximal 12 % compared with placebo, while there were no significant effects of felodipine 5 mg or the two doses of ramipril. Heart rate increased significantly after both doses of felodipine, maximal 28% after the 20 mg dose. There was also a small but significant increase in heart rate of 12% after ramipril 2.5 mg. FVR fell significantly after both doses of felodipine, maximal 38 % after the 20 mg dose. There were no significant changes in FVR after any of the ramipril doses. Both doses of felodipine and both doses of ramipril caused significant reductions in RVR. Maximal reduction, 33 %, was found after felodipine 20 mg. There were no significant changes in GFR or FF with either drug. Felodipine caused a significant increase in natriuresis, maximal 129% while ramipril did not.     

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.     

Effect of menthol on the pharmacokinetics and pharmacodynamics of felodipine in healthy subjects

Objectives The present study was undertaken to determine whether menthol affects the metabolism of and pharmacological responses to the calcium channel antagonist felodipine in people.Methods Eleven healthy subjects (ten female, one male) participated in a randomized, double-blind, two-way crossover study, comparing the kinetics and effects of a single oral dose of felodipine ER tablet (Plendil, 10 mg) with menthol (test) or placebo (reference) capsules. Ten subjects completed the study. At the beginning of the study, a 10-mg felodipine ER tablet and a 100-mg menthol or placebo capsule were given. During the 2^nd, 5^th and 7^th hours of the study, 50, 25 and 25 mg menthol or placebo capsules were given, respectively. Blood samples and cardiovascular measurements were obtained at frequent intervals. Serum felodipine and dehydrofelodipine concentrations were determined by means of gas chromatography/mass spectrometry.Results Pharmacokinetic parameters of felodipine and dehydrofelodipine (AUC_0–24, C _max, t _max, dehydrofelodipine/felodipine AUC_0–24 ratio) were not markedly changed with menthol coadministration. Only eight female subjects cardiovascular data were included in the analysis because of technical problems during the measurements. There were no statistically significant differences in blood pressures and heart rates between the two treatments.Conclusions We conclude that the pharmacokinetics and pharmacodynamics of felodipine were essentially unaltered by menthol.     

非洛地平与缬沙坦对原发性高血压肾脏保护作用的对比研究

目的探讨非洛地平与缬沙坦对原发性高血压患者肾脏的保护作用。方法将我院2011年2月至2012年3月收治的56例原发性高血压伴蛋白尿患者随机分为A组、B组,每组28例。A组给予非洛地平,B组给予缬沙坦,疗程为3个月,比较两组药物的治疗效果。结果两组患者治疗后血压与治疗前相比,差异均有统计学意义(P<0.01);但治疗后两组血压相比差异无统计学意义(P>0.05);两组患者治疗后24 h蛋白尿与治疗前相比,差异均有统计学意义(P<0.01);但治疗后两组24 h蛋白尿比较差异无统计学意义(P>0.05)。结论非洛地平和缬沙坦均具有显著的降压作用,可保护原发性高血压患者肾脏功能,但非洛地平价格明显低于缬沙坦,有望成为广大基层医院原发性高血压的首选肾脏保护药物。     

Single-dose pharmacokinetics of nefazodone in healthy young and elderly subjects and in subjects with renal or hepatic impairment

The single-dose pharmacokinetics of nefazodone (NEF) and its metabolites hydroxynefazodone (HO-NEF) and m-chlorophenylpiperazine (mCPP) were examined in 12 healthy younger subjects 55 years of age (YNG), 12 elderly subjects 65 years of age (ELD), 12 patients with biopsy proven hepatic cirrhosis (HEP) and 12 patients with moderate renal impairment (REN), Cl_CR 20–60 ml·min^–1. The study was of parallel group design, with each of the four subject groups receiving escalating single oral doses of 50, 100 and 200 mg of nefazodone at 1 week intervals. Serial blood samples for pharmacokinetic analysis were collected for 48 h following each dose and plasma samples were assayed for NEF, HO-NEF and mCPP by a validated HPLC method.Single oral doses up to 200 mg of nefazodone were well tolerated by all subjects. Maximum plasma levels of NEF and HO-NEF were generally attained within 1 h after administration of nefazodone. HO-NEF and mCPP plasma levels were about 1/3 and <1/10 those of NEF, respectively. There were no apparent gender-related pharmacokinetic differences in any group of subjects. NEF and HO-NEF pharmacokinetics were dose dependent in all four subject groups; a superproportional increase in AUC and an increase in t_1/2 with increasing dose was obtained, indicative of nonlinear pharmacokinetics. Relative to normal subjects, elderly and cirrhotic subjects exhibited increased systemic exposure to NEF and HO-NEF, as reflected by AUC, at all doses of nefazodone; subjects with moderate renal impairment did not.Elderly and cirrhotic patients may require lower doses of NEF to achieve and maintain therapeutic effectiveness.     

尼卡地平与非洛地平治疗老年原发性高血压的比较

目的以非洛地平作对照,观察尼卡地平的降压疗效。方法选择老年高血压病患者42例,经停用所有降压药1周后,随机分成A组（21例）：口服尼卡地平每天10mg;B组（21例）：口服非洛地平每天5mg,连续治疗4周,观察血压、心率、肝肾功能、不良反应等指标。结果尼卡地平与非洛地平降压作用明显（P〈0.05）,对偶测血压、脉压有下降作用（P〈0.05）,2组之间降压疗效差异无统计学意义（P〉0.05）;用药前后心率均差异无统计学意义（P〉0.05）;2组生化指标治疗前后差异无统计学意义（P〉0.05）,患者耐受性好,不良反应较少。结论尼卡地平是治疗老年原发性高血压的有效而安全的药物。     

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。     

Pharmacokinetics and blood pressure effects of felodipine in elderly hypertensive patients. A comparison with young healthy subjects

The pharmacokinetics and antihypertensive effects of felodipine, a new dihydropyridine calcium channel blocker, were studied in elderly hypertensive patients, 67 to 79 years of age and in young healthy subjects, 20 to 34 years of age following oral administration of 5 mg twice daily to steady-state. A single intravenous dose of 3H-felodipine (0.04mg) was given together with the oral dose on the study day. Cmax (17 nmol/L), Cmin (5 nmol/L) and AUC (82 nmol/L.h) were 3 times higher in the elderly than in the young subjects. Systemic availability was about 15% in both groups. Plasma clearance (CL) was reduced from 56.1 L/h in the young to 25.4 L/h in the elderly. There was no effect of age on the volume of distribution at steady-state (Vss). Reduced hepatic blood flow and enzyme activity or increased gut wall metabolism are possible reasons for the altered pharmacokinetics in the elderly. Blood pressure was reduced in the elderly from 190/99 to 177/91 mm Hg 12 hours after 5mg felodipine during twice daily dosage. The effect on blood pressure correlated with plasma concentrations of felodipine.     

Restoration of renal and mesenteric hemodynamics by felodipine in a canine model of hemorrhagic shock

Summary The effects of felodipine, a dihydropyridine vasodilator, were investigated in a canine model of hemorrhagic shock. Mongrel dogs were anesthetized with sodium pentobarbital and subjected to hemorrhagic shock by allowing the animals to bleed into a reservoir. After maintaining the hypotensive state (mean blood pressure: 40–60 mmHg) for a period of 150 min, the blood was reinfused and the recovery of the various parameters were monitored for an additional 120 min. These studies were conducted in three different groups of dogs: (A) controls, (B) felodipine, 0.01 mol/kg i.v., was administered before reinfusion of the blood and (C) felodipine, 0.01 mol/kg i.v., was administered prior to hemorrhage. In all the three groups, arterial blood pressure returned essentially to pre-hemorrhage levels following reinfusion; in the groups A and B, there was about 80% recovery of the cardiac output, whereas in the group C cardiac output returned completely to the basal values. During the hemorrhagic hypotension, renal and mesenteric blood flows fell to 10–40% of the basal values in all the three groups. In the control group A, there was only 40 to 45% recovery in the renal and mesenteric flows after reinfusion indicating sustained vasoconstriction in these vascular beds. Felodipine administration before reinfusion (group B), resulted in 70% to 90% recovery in the renal and mesenteric flows after reinfusion. In the group C (felodipine before hemorrhage) there was 85% recovery in the renal flow and 100% in the mesenteric blood flow after reinfusion. The observations made in this study suggest that felodipine, an arteriolar dilator, may be clinically useful in restoring organ blood flows which are seriously compromised during the hemorrhagic shock. Send offprint requests to B. S. Jandhyala     

非洛地平对慢性充血性心力衰竭的治疗作用

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40例,随机分为对照组20例,以洋地黄、利尿剂和卡托普利治疗;治疗组20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参数.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.     

Haemodynamic effects of ajmaline in man

Summary The haemodynamic effects of ajmaline have been studied in eleven patients during diagnostic cardiac catheterisation. Single doses of 50 mg were injected intravenously during two minute periods and brachial and pulmonary artery pressures, cardiac output, stroke volume, heart rate, peripheral vascular resistance and the E. C. G. were recorded continuously. Serum concentrations of ajmaline were also determined. No significant haemodynamic effects were observed, except a reduction in systolic arterial pressure during the first five minutes and a slight increase in heart rate. QRS-complexes became wider in all subjects and bundle branch block occurred in three of them who had been digitalized. It was concluded that ajmaline had no marked unfavourable haemodynamic effects in the dose used. However, until further experience has been gained, ajmaline should be used with caution in digitalized patients and in those with impaired intra-cardiac conduction.     

Stereoselective pharmacokinetics of oral felodipine and nitrendipine in healthy subjects: correlation with nifedipine pharmacokinetics

Summary The pharmacokinetics of racemic (rac) felodipine, rac-nitrendipine and nifedipine (all given as an oral dose of 20 mg in solution) have been investigated in a randomised cross-over study in 12 healthy male subjects using stereoselective assays. Both felodipine and nitrendipine exhibited stereoselective pharmacokinetics. On average, the AUCs of the active (S)-enantiomers of felodipine and nitrendipine were 139% and 104% higher than those of their optical antipodes, but the elimination half-lives of the enantiomers of each racemate were not different. The AUCs of nifedipine, rac-felodipine, rac-nitrendipine and of their enantiomers were highly correlated (all r>0.83), suggesting closely related rate limiting steps in the in vivo first-pass metabolism of these high-clearance drugs. Stereoselectivity was only a minor contributor to inter-individual variability in the oral pharmacokinetics of these compounds in healthy subjects.Haemodynamic data and pharmacokinetic-pharmacodynamic relationships obtained in this study are reported in the accompanying paper     

Comparative effects of felodipine,nitrendipine and nifedipine in healthy subjects: concentration-effect relationships of racemic drugs and enantiomers

Summary The effects of racemic (rac) felodipine, rac-nitrendipine and nifedipine (all 20 mg solution p.o.) on non-invasively measured blood pressure and heart rate were investigated in a randomised, double-blind, cross-over study in 12 normotensive, young, healthy males. Compared to baseline values, heart rate increased more after rac-felodipine treatment (+47% at maximum) than rac-nitrendipine (+40%) and nifedipine (+38%); only small and variable changes in blood pressure were observed with any of the drugs. The baseline-corrected area under the heart rate-time curve up to 4 h after the administration of rac-felodipine was 197% and 180% larger than after nifedipine and rac-nitrendipine treatment, respectively. The effects on heart rate could be fitted individually to a sigmoidal E_max-model without hysteresis for all drugs under investigation. The relative potencies of the unbound drugs for their indirect effects on heart rate were 1:7:43 for nifedipine, rac-nitrendipine and rac-felodipine, respectively. The active (S)-enantiomers of felodipine and nitrendipine appeared to be 9-and 60-times as potent as nifedipine in this respect, assuming no (inter)activity of the (R)-enantiomers. Individual and mean changes in blood pressure were small, they were not related to plasma concentrations, and did not differ between treatments.Pharmacokinetic data obtained in this study are reported in the accompanying paper     

心房肽Ⅲ对麻醉大鼠血流动力学的影响

给麻醉大鼠一次或恒速静脉注射APⅢ(40μg/kg或4μg/kg·min)可显著降低LVSP,SAP,DAP和MAP。但不明显改变麻醉大鼠的(dP/dt)/P,±(dP/dt)_(max),LVEDP及HR等。恒速静脉输注APⅢ(4μg/kg·min)20min大鼠的尿量平均增加5.2倍。然而侧脑室内给予APⅢ(5和15μg/kg)对麻醉大鼠血流动力学各指标以及尿量均无影响,可见APⅢ对心血管系统及肾脏等靶器官的作用可能没有中枢机制参与。     

Haemodynamic effects of short-term treatment with bopindolol in essential hypertension

Summary Ten patients (mean age 53 years) with essential hypertension have been studied at rest and during exercise following oral treatment for 6 weeks with a new beta-adrenoceptor blocking agent, bopindolol.The treatment caused a significant decrease in systolic and diastolic arterial blood pressure and heart rate, both at rest and during exercise. Stroke volume fell, too, and therefore so did cardiac output, whereas the systemic vascular resistance was increased. Left ventricular filling pressure was elevated both at rest and during exercise following bopindolol therapy.However, a different haemodynamic pattern was noted in patients with elevated total peripheral resistance prior to therapy (Group 1) compared to patients with normal or subnormal peripheral resistance (Group 2). A decrease in systemic vascular resistance seemed to be the cause of the fall in blood pressure in Group 1, as the expected increase in vascular resistance did not occur, whereas a reduction in cardiac output was of greater importance in Group 2. During exercise the lowering of arterial blood pressure in both groups was mediated by a reduction in cardiac output.     

Pharmacokinetic and pharmacodynamic studies of felodipine in healthy subjects after various single, oral and intravenous doses

The objective of this single-dose study was to evaluate the pharmacokinetics and haemodynamic changes in healthy male subjects following the administration of three oral (5, 15, and 40 mg) and two intravenous (1 and 3 mg) doses of felodipine, a new calcium antagonist with a selective effect on the peripheral resistance vessels. Felodipine was rapidly absorbed within 1 h when administered as an oral solution, but underwent extensive presystemic elimination. The systemic availability varied between 10 and 23 per cent. The disposition was adequately described by a two-compartment model: the disposition was essentially dose-independent up to 40 mg orally and 3 mg intravenously. Felodipine produced significant dose-dependent reduction of diastolic blood pressure and a significant reflexogenic increase in heart rate, without having any major effect on systolic blood pressure. These changes indicate that felodipine acts predominantly as an arteriodilator. The decrease in diastolic blood pressure and increase in heart rate were closely correlated with the plasma concentrations of unchanged felodipine, being maximal at 0.5 h and lasting for at least 4 h after the highest dose.