Antianginal effect of conventional and controlled release diltiazem in stable angina pectoris

Two preparations of diltiazem, controlled release (CR) given twice a day (b.i.d.) and plain given 4 times a day (q.i.d.), were compared in a multicentre, double-blind, crossover study in 41 patients with stable angina pectoris. Therapeutic efficacy was assessed with maximal exercise tests, patient recordings on nitroglycerine consumption and angina attacks. No significant differences between the CR and plain tablets were seen in any of the efficacy variables. Maximal workload significantly increased from 127 W on placebo to 146 W on CR tablets and to 147 W on plain tablets. Anginal attacks/week significantly decreased from 11.7 on placebo to 4.9 on CR tablets and to 5.0 on plain tablets. Consumption of nitroglycerine tablets/week significantly decreased from 6.3 on placebo to 2.6 and to 3.4 on CR and plain-tablets, respectively. The number or the seriousness of the adverse events did not differ between the groups. The results imply that diltiazem CR b.i.d. is equally potent and safe as conventional diltiazem q.i.d. in the control of stable angina pectoris.     

An 8-week double-blind study of amlodipine and diltiazem in patients with stable exertional angina pectoris

A multicenter, double-blind study was performed to compare the antianginal efficacy and safety of the new dihydropyridine calcium antagonist amlodipine with the benzothiazepine calcium antagonist diltiazem in patients with stable exertional angina pectoris. Following a 2-week placebo run-in period, 39 patients were randomized to receive amlodipine (2.5-10 mg once daily) and 41 patients to receive diltiazem (60-120 mg three times daily) in an 8-week double-blind treatment phase. The study used standardized bicycle exercise testing as a primary efficacy assessment. Patients also recorded angina frequency and nitroglycerin (NTG) tablet consumption/ week. Treatment with amlodipine and diltiazem resulted in an improvement in total exercise time, time to angina and total work, mean ST-segment deviation at maximum common load, median number of angina attacks/week, and NTG tablet consumption/week. The incidence and severity of possibly treatment-related side effects and laboratory test abnormalities were comparable for both drugs. The most frequently reported side effects were dizziness, headache, peripheral edema, and nausea. Two patients withdrew from diltiazem treatment due to pruritus in one case and severe headache and moderate dyspnea in the other. No amlodipine-treated patients withdrew due to side effects. In conclusion, this study demonstrated that the antianginal efficacy and tolerability of amlodipine is equivalent to diltiazem, but amlodipine has the advantage of once-daily dosing.     

Antihypertensive efficacy of twice daily controlled release diltiazem using 24 hour intra-arterial blood pressure monitoring

The aim of the study was to examine the efficacy of a new controlled release formulation of diltiazem administered in a twice-daily dose in patients with essential hypertension using 24 hour intra-arterial ambulatory blood pressure monitoring.Sixteen patients (2 female) of mean age 53 years with mild to moderate essential hypertension, defined as a supine resting diastolic cuff blood pressure 95 mm Hg, were recruited to a sequential dose ranging study of controlled release (CR) diltiazem. After a six week run-in period without any anti-hypertensive medication, intra-arterial blood pressure monitoring with 60° tilt, isometric handgrip and bicycle exercise testing were performed. Patients were then treated for one week with CR diltiazem 120 mg b.i.d. If supine resting diastolic cuff blood pressure fell by <10 mm Hg compared to the last run-in value and remained >90 mm Hg, the dose was increased to 240 mg b.i.d. for a week, and if necessary to 360 mg b.i.d. for a week. Patients continued for further one month on the dose of CR diltiazem at which they achieved target blood pressure reduction. At the end of this maintenance treatment, 24 hour intra-arterial blood pressure monitoring was repeated.Twelve patients were satisfactorily controlled on 120 mg b.i.d. CR diltiazem, three on 240 mg twice daily and one on 360 mg twice daily. During rest and exercise, blood pressure and heart rate were significantly lower after treatment with CR diltiazem than before treatment. The hypotensive effect of diltiazem was maintained throughout the 12 hour dosing interval and the early morning blood pressure response was blunted. No adverse effects or ECG abnormalities were reported.It was concluded that CR diltiazem 120 mg, administered twice daily to a total daily dose of between 240 mg and 720 mg, is effective and well tolerated in the treatment of mild to moderate essential hypertension.     

Efficacy and safety of the 200–300 mg sustained release formulation of diltiazem administered once daily in patients with stable angina

The aim of this multicentre randomised double blind study was to compare the efficacy and safety of the 200–300 mg sustained release diltiazem formulation administered once daily (200–300 SR) with standard diltiazem (D) given three or four times daily to patients with stable angina. Patients aged 59 years, with a reproducible exercise test on placebo, were randomised to 4 weeks of treatment with 200–300 SR (n=70) or D (n=74). The initial dosage was 200 mg in the 200–300 SR group and 60 mg t.i.d. in the D group, increased to 300 mg once daily or 60 mg q.i.d., respectively, if ergometric parameters, which were always measured at the end of the dosing period, had not improved after two weeks. After 4 weeks of treatment, the antianginal efficacy at rest was comparable in the 200–300 SR and the D group; there was a prolongation of the total duration of exertion of 14% and 18% respectively (P<0.01 vs placebo for both groups with no intergroup difference). A dose-effect relation was found with both formulations.The 200–300 SR formulation gave full 24 hour anti-ischaemic protection when administered once daily. Its efficacy and safety were comparable to those of standard diltiazem t.i.d. or q.i.d. in patients with stable angina. The once daily administration should improve treatment compliance.     

美托洛尔与地尔硫卓治疗不稳定性心绞痛的疗效分析

目的：比较美托洛尔与地尔硫卓治疗不稳定性心绞痛病人的疗效。方法：44例不稳定性心绞痛患者随机分成两组,一组给予美托洛尔6．25mg．口服,2次／天,另一组给地尔硫卓30mg,口服,3次／天．疗程均为1个月。结果：美托洛尔组的疼痛症状缓解,疼痛再发和心肌梗死的发生率减少均显著优于地尔硫卓组（P〈0．05）。结论：小刺量美托洛尔选择性阻断岛受体,降低心肌的耗氧量。有对抗儿茶酚胺的心脏毒性作用,在预防心肌梗死及改善心绞痛症状上优于地尔硫卓,其长期效果仍需继续观察。     

Efficacy and Tolerability of Nisoldipine Coat-Core vs Diltiazem Retard in Combination with a Beta-Blocker in Patients with Stable Exertional Angina Pectoris

A randomised, double-blind, placebo-controlled, parallel-group trial with forced titration study to investigate possible equivalence of efficacy and tolerability between nisoldipine coat-core (CC) 40mg once daily, and diltiazem retard 120mg twice daily, was carried out in 176 patients with stable angina pectoris who were already receiving beta-blocker therapy. A total of 164 patients were included in the tolerability analysis and 135 patients were evaluable for efficacy (nisoldipine CC, n = 69; diltiazem retard, n = 66). During bicycle exercise tolerance tests, time to 1mm ST-segment depression, total exercise time, and time to angina were assessed at baseline and at the end of the treatment period. The number of angina attacks and of consumed nitroglycerin tablets were recorded in weekly diaries. Time to onset of 1mm ST-segment depression increased by 69.4 +/- 100.0 seconds with nisoldipine CC and by 65.9 +/- 87.6 seconds with diltiazem retard. The two treatment regimens were equally effective in time to onset of 1mm ST-segment depression, time to angina pectoris, and in exercise duration. A beneficial effect on angina attacks and nitroglycerin consumption was achieved with both treatments. Patient compliance, as assessed by the number of returned tablets, was high, at over 80%. Six patients withdrew from the treatment because of adverse events. Mild and transient adverse events were reported by 24 patients during treatment. One patient experienced a severe circulatory shock on the combination of diltiazem retard and atenolol. Peripheral oedema and headache were more common on nisoldipine CC. We concluded that the two treatments were equally efficacious and tolerated in patients with stable angina pectoris.     

Antianginal Response to Once-Daily Diltiazem CD in Patients Receiving Concomitant β-Blockers,Long-Acting Nitrates,or Both

Study Objective . To determine the safety and efficacy of diltiazem CD 180 mg administered once/day in patients with chronic stable angina inadequately controlled with β-blockers, long-acting nitrates, or both. Design . Multicenter, randomized, double-blind, placebo-controlled, parallel-group trial. Setting . Medical clinics in the private and academic sectors. Patients . Of 172 patients, 170 completed the 2-week double-blind treatment period. Interventions . Patients received either diltiazem CD 180 mg or placebo once/day in combination with existing antianginal therapy. Measurements and Main Results . The time to termination of exercise tolerance testing, 24 hours after the dose increased significantly in the diltiazem CD group (37.2 sec) compared with the placebo group (21.3 sec, p=0.0438). Time to onset of angina during exercise testing also increased (57.6 vs 35.0 sec, respectively, p=0.0324), as did time to moderate angina (37.5 vs 20.6 sec, respectively, p=0.0354). The rates of total angina attacks and of angina attacks on exertion were significantly reduced in the diltiazem CD group versus placebo (p<0.05). Significant reductions in systolic and diastolic blood pressures and heart rate-blood pressure product measured at rest, submaximum exercise, and exercise termination were observed in diltiazem CD-treated patients compared with placebo (p<0.05). The frequency of treatment-related adverse events was identical in the two groups, 15.1%. Conclusion . Diltiazem CD 180 mg once/day is an effective, safe, and beneficial initial dosage when added to existing antianginal therapy.     

Open comparative study to assess the efficacy and safety of two calcium antagonists: amlodipine and diltiazem in the treatment of symptomatic myocardial ischemia

The efficacy and safety of amlodipine (5-10 mg once daily) and diltiazem (30-60 mg three times daily) were compared in 40 patients with symptomatic myocardial ischemia. A 2-week placebo run-in period was followed by 10 weeks of open treatment with amlodipine (n = 20) or diltiazem (n = 20). Concomitant treatment with other antianginal drugs (except other calcium antagonists) was permitted throughout the study. The baseline blood pressures were 166/93 and 160/91 mm Hg for the amlodipine group and diltiazem groups, respectively. Amlodipine (mean final daily dose of 9.25 mg) reduced blood pressure by - 27/-11 mm Hg compared with a reduction of - 17/-8 mm Hg for diltiazem (mean final daily dose of 180 mg), with no significant effects on heart rate. A significantly greater reduction in the mean rate-pressure product was observed after amlodipine (-20.8%) when compared with diltiazem (-13.1%) (p < 0.05). Amlodipine reduced the mean weekly angina attacks to zero after 6 weeks of treatment (baseline of 3.4 attacks/week) compared with a reduction from 3.3 to 0.35 attacks/week after 10 weeks of treatment with diltiazem. The amlodipine group had a reduction in mean nitroglycerin consumption from baseline of 1.1 mg/week to zero by week 6, whereas the diltiazem group had reduced mean weekly intake from 0.9 to 0.1 mg at the end of the study. The overall assessment of clinical efficacy was excellent for 100% of amlodipine patients compared with 40% of diltiazem patients. The high-density lipoprotein cholesterol/total cholesterol ratio increased by 15.8% with amlodipine compared to diltiazem, which produced a 4.5% decrease. Amlodipine decreased triglycerides by 7.1% compared to 4.5% with diltiazem. The incidence and severity of side effects was comparable for both treatments. Amlodipine once daily was effective and well tolerated in the treatment of patients with symptomatic myocardial ischemia and was comparable with diltiazem three times daily.     

A comparative study of the steady-state pharmacokinetics of immediate-release and controlled-release diltiazem tablets

We have studied the controlled-release properties and relative systemic availabilities of two dosages of the same controlled-release (CR) diltiazem tablet formulation by comparing them at steady state with those of an immediate-release formulation. We measured 24-hour plasma concentration profiles during 4-day treatments with diltiazem 90 mg CR tablet bd diltiazem 120 mg CR tablet bd, and conventional diltiazem 60 mg immediate-release (IR) tablet tid. The study had a randomized, three-way crossover design. Twelve healthy men (38–52 y) participated.Trough plasma concentrations were determined on days 3 and 4. The 24-h plasma concentration-time profiles were assessed after the last morning dose on day 4 of each period. The following steady-state pharmacokinetic values were calculated: the minimum plasma concentration (C_min), the maximum plasma concentration (C_max), the time interval during which the plasma concentration exceeded 75% of C_max (t₇₅), the area under the plasma concentration-time curve (AUC_72–96), the peak-to-trough fluctuation (PTF), and the area-under-the-curve fluctuation (AUCF).Steady state was achieved on day 3. The pharmacokinetics were comparable. For diltiazem CR 90 mg and diltiazem CR 120 mg, AUC_84–96 (night) was approximately 75% of AUC_72–84 (daytime). The diltiazem plasma concentration increased slowly from about 6 h after the evening dose of both CR tablets, resulting in relatively high plasma concentrations in the early morning hours. Only during treatment with diltiazem CR 120 mg were the plasma concentrations of diltiazem maintained above the minimum therapeutic plasma concentration of 50 g·1^–1 throughout the full 24 h.In conclusion, twice-daily treatment with diltiazem CR tablets can replace thrice-daily treatment with the conventional diltiazem IR tablet. The early morning rise of the diltiazem plasma concentration, which might lead to a lower incidence of ischaemic events, may be an important clinical advantage of both CR tablets. Because of the minimum therapeutic plasma concentration of 50 g·1^–1, twice-daily administration of the 120 mg CR tablet may be preferred from a therapeutic point of view.Diltiazem, a benzothiazepine, is a calcium antagonist used in the treatment of angina pectoris and hypertension. The anti-ischaemic mechanism of diltiazem seems to result from an increase of myocardial oxygen supply and a reduction in myocardial oxygen demand, respectively by coronary artery dilatation and/or direct and indirect haemodynamic effects, such as afterload reduction and heart rate decrease (Braunwald 1982). Its therapeutic effect is evident at daily dosages between 180 and 360 mg (Low et al. 1981). After oral administration it is almost completely absorbed from the gastrointestinal tract, but owing to extensive first-pass metabolism, its systemic availability is approximately 40–50% (Echizen and Eichelbaum 1986). The time to maximum plasma concentrations after oral administration of immediate-release formulations is approximately 3 to 4 h. The elimination half-life of diltiazem is 3.5–7 h, implying that frequent dosing is required to maintain effective plasma concentrations. Therefore, a controlled-release formulation of diltiazem, designed to be taken twice daily, has been developed.The aim of this crossover study was to compare the systemic availability and steady-state pharmacokinetics of a controlled-release diltiazem tablet formulation (90 and 120 mg) with those of a conventional diltiazem immediate-release tablet in healthy volunteers.     

Effects of a new metabolic modulator, ranolazine, on exercise tolerance in angina pectoris patients treated with beta-blocker or diltiazem.

Ranolazine (RS 43285) is a new piperazine derivative with anti-ischemic properties attributed to a modulation of myocardial metabolism. Its antianginal action was assessed in 104 patients recruited in a double-blind, crossover, randomized study comparing placebo with a single dose of ranolazine (10, 60, 120, and 240 mg). All patients had chronic stable angina pectoris and remained symptomatic (at least 0.1 mV ST-segment depression and angina during prestudy exercise testing) despite treatment with a beta-blocker or with diltiazem. No significant effects of ranolazine on exercise duration or time to angina were observed after the dose of 10, 60, and 120 mg. After the 240 mg dose, however, significant improvement in exercise duration (+13.1% in the combined group, two-tailed p = 0.002; +14.3% in the beta-blocker group, p = 0.009; +11.9% in the diltiazem group, p = 0.06), in time to angina (+56.8 s, p = 0.008), and in time to 1 mm ST-segment depression was observed. The cumulative proportion of patients who improved their time to angina by at least 30 s above placebo were 25, 42, 50, and 72% with the doses of 10, 60, 120, and 240 mg, respectively. Sixty-seven percent of the patients with ranolazine plasma levels above 500 ng/ml improved their time to angina against 40% at plasma levels below 500 ng/ml and summed ST-segment depression during exercise and recovery was also significantly reduced at these plasma concentrations. Both heart rate and arterial pressure at rest and at peak exercise were unchanged after ranolazine, 240 mg.(ABSTRACT TRUNCATED AT 250 WORDS)     

An open multicenter efficacy and safety evaluation of amlodipine in the treatment of symptomatic myocardial ischemia

The efficacy and safety of amlodipine (5-10 mg) once daily were studied in an open study in patients with symptomatic myocardial ischemia. The study is ongoing and this report is based on an interim analysis of data from 78 patients. A 2-week baseline period in which patients maintained their current antianginal therapy was followed by a 10-week treatment period with 5-10 mg of amlodipine/day. Both the median number of angina attacks per week and the median number of nitroglycerin (NTG) tablets consumed/week were significantly reduced after amlodipine (mean daily dose of 8.6 mg) when compared with baseline (p < 0.05). A total of 98.4% of patients (63/64) experienced a reduction in the frequency of angina attacks/week and 91% of patients (58/64) had angina attacks reduced to < or = 2/week. In self-assessments, 95% of patients (55/58) reported improved angina control and 91% (53/58) felt their ability to perform usual activities had improved. Twenty-seven patients experienced adverse events reported as drug related. The most common adverse event noted was edema. Amlodipine once daily significantly reduced the incidence of angina attacks and the concomitant need of nitroglycerin for relief of symptoms and thus improved the patients' ability to perform daily activities. Most adverse events reported were mild or moderate and the incidence is as would be expected in this patient population.     

A randomized, double-blind comparison of the efficacy and tolerability of once-daily modified-release diltiazem capsules with once-daily amlodipine tablets in patients with stable angina

A randomized, double-blind, parallel-group study comparing the efficacy and tolerability of once-daily diltiazem capsules with amlodipine tablets in patients with stable angina. After a run-in period of 1 to 3 weeks, 34 patients received once-daily diltiazem and 33 patients received amlodipine. Patients received either diltiazem, 240 mg/day, or amlodipine, 5 mg/day, for 2 weeks followed by diltiazem, 360 mg/day, or amlodipine, 10 mg/day, for 2 weeks. Standard treadmill exercise testing was the primary efficacy assessment. Patients also recorded incidence of angina attacks and use of glyceryl trinitrate spray. Both treatments gave significant improvement in time to onset of angina and time to maximal exercise. With the exception of amlodipine, 5 mg/day, both treatments gave significant increases in time to 1-mm ST segment depression. Diltiazem, 360 mg/day, gave a significant decrease in rate pressure product. There were no significant treatment differences in any of the exercise test parameters. Both treatments reduced incidence of angina attacks and use of glyceryl trinitrate spray. The incidence of edema was significantly less in patients receiving diltiazem. In conclusion, both treatments were effective in controlling patients' angina, but diltiazem was better tolerated, with a lower incidence of edema.     

Comparison of the antianginal efficacy of four calcium antagonists and propranolol in stable angina pectoris

Summary The antianginal effects of propranolol 160 mg/day, diltiazem 240 mg/day, nicardipine 80 mg/day, nifedipine 40 to 80 mg/day and verapamil 320 mg/day were compared in 12 patients with chronic stable angina pectoris using a symptom-limited exercise test.Compared to placebo propranolol and calcium antagonists similarly reduced (p<0.001) the frequency of antianginal attacks and nitroglycerin consumption, and increased exercise tolerance and time to 1 mm S-T segment depression. After propranolol the pressure-rate product at submaximal and maximal exercise was significantly decreased. The calcium antagonists produced a significant reduction in the submaximal pressure-rate product, but no significant change in the peak pressure-rate product. Maximum ST depression was significantly lower after propranolol and was unchanged after the calcium antagonists. None of the drugs caused significant adverse effects.The results indicate that in patients with stable effort angina pectoris, diltiazem, nicardipine, nifedipine and verapamil were as effective as propranolol in improving exercise tolerance and time to ischaemia, and they did not alter the peak pressurerate product. Different antianginal mechanisms may be operative for the various calcium antagonists.     

Treatment of Stable Angina Pectoris with Trimetazidine Modified Release in Indian Primary-Care Practice

INTRODUCTION: In primary-care practice, trimetazidine is frequently used in combination with other antianginal drugs to enhance antianginal efficacy because of its metabolic mode of action. This study investigates whether a new twice-daily trimetazidine modified release formulation with improved pharmacokinetic properties is more effective and acceptable than the older thrice-daily immediate-release formulation. METHODS: In a multicenter prospective study, patients with uncontrolled stable angina pectoris receiving combination antianginal treatment that included the thrice-daily trimetazidine were identified. The immediate-release trimetazidine formulation was substituted with twice-daily trimetazidine modified release (Flavedon) MR), with no other changes in the treatment regimen. Follow-up was for 3 months. The primary outcomes were entirely clinical: frequency of anginal attacks and nitroglycerin (glyceryl trinitrate) consumption. RESULTS: In 279 patients, substitution of thrice-daily trimetazidine with twice-daily trimetazidine modified release reduced mean frequency of angina by four attacks per week (95% CI 3.1, 4.9; p < 0.01) and nitroglycerin consumption by 3.6 tablets per week (95% CI 2.9, 4.3; p < 0.01). The magnitude of these benefits was directly proportional to the number of antianginal drugs used in combination with trimetazidine. There were no withdrawals due to adverse effects, and daily compliance was 98%. CONCLUSION: The twice-daily trimetazidine modified release is more effective and acceptable than the thrice-daily formulation for the combination treatment of stable angina in primary-care practice.     

美托洛尔片对原发性高血压合并2型糖尿病患者的疗效观察

目的：观察美托洛尔片对原发性高血压患者血糖代谢的影响。方法：选取收治的血糖控制较好的轻中度原发性高血压患者120例,以随机抽样法分成对照组（服用卡托普利片）及观察组（服用美托洛尔片）各60例。对照组给予卡托普利片25～50 mg,3次/d;观察组给予美托洛尔片25～50 mg,2次/d。初始剂量均为半量,治疗12周后,观察2组患者血压、血糖、心率的变化。结果：治疗后2组患者空腹血糖（FPG）、餐后2 h血糖（2hPG）、糖化血红蛋白（HbA1c）、血胰岛素水平及血压指标均无显著差异（P〉0.05）。结论：美托洛尔片对合并2型糖尿病的原发性高血压疗效确切,对血糖代谢无不良影响。     

Pharmacokinetics of diltiazem and its metabolites after single and multiple dosing in healthy volunteers

The pharmacokinetics of diltiazem in healthy middle-aged volunteers have been investigated after single and multiple doses. Twenty men or women were recruited and were given one single dose and one steady-state treatment in a crossover fashion. Ten were given 60-mg single dose and 60-mg t.i.d. during 14 days and 10 received 120 mg as a single dose and as 120-mg t.i.d. The single dose and the last dose in steady state were pulsed with 1.85 MBq [14C]diltiazem. The absorption was rapid and did not differ between treatments. The disposition could be described using a two-compartment model with terminal half-lives of 6.27 +/- 3.23 h (mean +/- SD) after a single dose of 60 mg diltiazem, 6.05 +/- 1.59 h after 60-mg diltiazem t.i.d., 5.85 +/- 1.04 h after 120-mg diltiazem and 5.90 +/- 0.69 h after 120-mg diltiazem t.i.d. The half-life of the metabolite N-demethyldiltiazem was similar to that of diltiazem whereas the half-lives of the metabolites deacetyldiltiazem and N-demethyldeacetyldiltiazem were longer. The area under the curve of diltiazem in a dosing interval at steady state increased significantly compared with the single dose, indicating an increased bioavailability after repeated dosing, probably because of decreased presystemic elimination. The cumulative excretions of radioactivity in urine within 120 h were 72 +/- 5%, 71 +/- 8%, 71 +/- 6%, and 73 +/- 4%, respectively. The remaining amounts were excreted in feces.     

曲美他嗪联合地尔硫卓治疗心绞痛的疗效

目的观察曲美他嗪联合地尔硫卓治疗心绞痛的疗效。方法选取笔者所在医院心绞痛患者50例,随机分为治疗组和对照组。对照组给予休息、吸氧、镇静、抗凝和抗血小板聚集等常规抗心绞痛处理,治疗组在此基础上,给予口服曲美他嗪片和地尔硫卓片,治疗2周后观察疗效和心电图情况。结果治疗组总有效率88%,对照组总有效率64%,治疗组疗效明显高于对照组,差异有统计学意义(P<0.01)。两组心电图改变情况比较,治疗组总有效率72%,对照组总有效率52%,治疗组心电图改变情况明显优于对照组,差异有统计学意义(P<0.01)。治疗后,治疗组使用硝酸甘油情况明显较对照组少,差异有统计学意义(P<0.01)。两组均未发现皮疹等过敏反应,也未发现肝肾功能损害。结论在常规治疗心绞痛的基础上,使用曲美他嗪联合地尔硫卓片治疗心绞痛,能够取得满意效果,值得临床推广。     

Discrepancy between bioavailability as estimated from urinary recovery of frusemide and total diuretic effect.

1. Frusemide was given at a dose of 60 mg as two oral controlled release (CR) formulations and as plain tablets in a randomised, balanced, three way cross over design to 26 healthy volunteers. Urinary volume, and contents of frusemide, sodium, chloride and potassium were measured in samples taken over 24 h. 2. There was a marked difference between the CR formulations on one hand and the plain tablets on the other, in excretion of frusemide and diuresis vs time. The total diuretic/saluretic effect was only marginally lower (19 and 28% respectively, P less than 0.05) after CR compared with plain tablets although the fraction absorbed was markedly decreased (39 and 51% lower, respectively, P less than 0.05), estimated as urinary recovery of frusemide. The total diuresis of the two CR formulations did not differ although the urinary recovery was significantly different (P less than 0.05). 3. The diuretic effect vs frusemide excretion rate showed minimal counter-clockwise hysteresis after plain tablets while the CR formulations produced clockwise hysteresis indicating tolerance. 4. In agreement with the concept of efficiency, the higher diuretic/saluretic effect per amount of excreted frusemide may be a consequence of the slower output of frusemide in urine with the CR formulations compared with plain tablets. The major part of the pharmacological effect was produced with a higher efficiency after CR compared with plain tablets. It should be noted that the pharmacokinetics of a drug and its pharmacodynamic potency independently determine the total response.(ABSTRACT TRUNCATED AT 250 WORDS)     

参松养心胶囊治疗心绞痛伴窦性心动过速的疗效研究

目的探讨参松养心胶囊治疗心绞痛伴窦性心动过速的疗效与安全性。方法将60例心绞痛及窦性心动过速患者随机分为实验组(n=30例)和对照组(n=30例)。实验组用参松养心胶囊(4粒/次,3次/d)+美托洛尔片(12.5mg/次,2次/d)+单硝酸异山梨酯胶囊(20mg/次,2次/d);对照组口服美托洛尔片(12.5mg/次,2次/d)+单硝酸异山梨酯胶囊(20mg/次,2次/d),均治疗4周。观察患者治疗前后24h动态心电图平均心率、每周平均心绞痛发作次数、平均持续时间、疗效判定,注意检测肝肾功能并观察不良反应。结果实验组与对照组的总有效率分别为96.6%和73.3%,差异有统计学意义(P<0.05);对照组、实验组治疗后平均心率、心绞痛发作次数、平均持续时间、疗效与治疗前比较,差异均有统计学意义(P<0.05);实验组治疗后平均心率、心绞痛发作次数、平均持续时间、疗效与对照组治疗后比较,差异均有统计学意义(P<0.05);对照组与实验组在治疗过程中各有3例(10%)出现轻微恶心、腹胀、头痛。结论在基础治疗上加用参松养心胶囊对治疗心绞痛及窦性心动过速疗效好、安全性高,有一定的临床应用及预防价值。