Conventional and controlled release diltiazem

Diltiazem CR tablets 120 mg b.i.d. for 1 week were compared with plain tablets 60 mg q.i.d. in 13 healthy male volunteers in a study of pharmcokinetic variables. Their antianginal efficacy was also compared in 23 patients with stable angina pectoris who were already on metoprolol. Both studies were of randomised, cross over design, and the clinical study was double blind.The pharmacokinetic variables of the two formulations were very similar except for the longer t_max of 4.4 h for diltiazem CR in comparison to 2.9 h for the plain tablets. The mean relative bioavailability of diltiazem CR in comparison with plain tablets was 1.14.The clinical study showed that after four weeks on diltiazem CR 120 mg b.i.d. or diltiazem plain tablets 60 mg q.i.d. in addition to metoprolol, there were significant decreases in weekly anginal attacks from 11 to 5 attacks/week, the number of nitroglycerin tablets consumed from 6 to 3 tablets/week, and an increase in the maximum workload from 116 to 126 and 123 W for diltiazem CR and plain diltiazem tablets, respectively, as compared to placebo. Five of the patients were angina free during diltiazem treatment. No difference in antianginal efficacy between the two preparations was seen. It was concluded that CR 120 mg b.i.d. appears bioequivalent to plain diltiazem tablets 60 mg q.i.d.     

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.     

Comparison of the new beta-adrenoceptor antagonist, nadolol, and propranolol in the treatment of angina pectoris.

A randomized, double-blind study was carried out in 24 patients with stable angina pectoris to compare the efficacy of nadolol, a new beta-adrenoceptor antagonist, and propranolol. After a period on placebo, 14 patients received nadolol once daily and 10 patients propranolol 4-times daily over a 10-week dose-ranging period followed by a maintenance period of 4 weeks. Optimal daily dosage for nadolol was 100 mg, and 112 mg for propranolol. Parameters used for evaluation of therapeutic effects included the number of anginal attacks, number of nitroglycerine tablets needed, time before onset of chest pain during exercise test, exercise time, and overall clinical impression of response. The results indicated that nadolol given once daily was equally as effective as propranolol 4-times daily in treating 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.     

Comparison of the new beta-adrenoceptor antagonist,nadolol, and propranolol in the treatment of angina pectoris

Summary

A randomized, double-blind study was carried out in 24 patients with stable angina pectoris to compare the efficacy of nadolol, a new beta-adrenoceptor antagonist, and propranolol. After a period on placebo, 14 patients received nadolol once daily and 10 patients propranolol 4-times daily over a 10-week dose-ranging period followed by a maintenance period of 4 weeks. Optimal daily dosage for nadolol was 100?mg, and 112?mg for propranolol. Parameters used for evaluation of therapeutic effects included the number of anginal attacks, number of nitroglycerine tablets needed, time before onset of chest pain during exercise test, exercise time, and overall clinical impression of response. The results indicated that nadolol given once daily was equally as effective as propranolol 4-times daily in treating angina pectoris.     

A clinical trial of a new long-acting nitroglycerine preparation (‘Nitrocontin’) in angina pectoris

Summary

In a double-blind crossover study of 15 patients with angina pectoris, a long-acting nitroglycerine preparation (‘Nitrocontin’) was compared against placebo. Patients received 2 tablets per day of either placebo or ‘Nitrocontin’ (6.4?mg. glvceryl trinitrate per tablet) for 4 weeks and were then crossed to the alternative preparation for a further 4 weeks. The results, as assessed by the number of attacks, consumption of glyceryl trinitrate sublingual tablets and patients' impression of improvement, showed that the active drug produced a significant reduction (p < 0.001) in the frequency of attacks. In a bicycle ergometric study, the long-acting preparation showed a signiJicant improvement (p < 0.001) in exercise performance against placebo.     

地尔硫、单硝酸异山梨酯和阿司匹林联合治疗不稳定型心绞痛

目的 :观察静脉维持滴注地尔硫、口服单硝酸异山梨酯和小剂量阿司匹林治疗不稳定型心绞痛的疗效及安全性。方法 :30例不稳定型心绞痛经6～ 12h常规单硝酸异山梨酯和小剂量阿司匹林联合治疗无效者 ,在原治疗基础上加用地尔硫 2 0 0mg·d- 1,维持静脉滴注 2 4h ,连续 2d。结果 :心绞痛缓解有效率 87% ,其中 1,6,2 4h内缓解分别为18例 (60 % ) ,6例 (2 0 % )和 2例 (7% ) ,无效为 4例 (13% )。结论 :口服单硝酸异山梨酯、小剂量阿司匹林和静脉滴注 2 4h地尔硫治疗不稳定型心绞痛有效、安全。     

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.     

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.     

Effects of nifedipine and diltiazem on myocardial ischemia in patients with severe stable angina pectoris treated with nitrates and beta-blockers.

In a randomized, cross-over, double-blind study, the effects of nifedipine were compared with those of diltiazem in 20 patients with severe stable angina pectoris and multivessel coronary artery disease treated with nitrates and beta-blockers. The comparison was performed by bicycle ergometry, clinical evaluation, and ambulatory 24-h ECG monitoring for 7-8 weeks. As compared with placebo, both nifedipine and diltiazem significantly reduced the daily number of anginal attacks and nitroglycerin consumption; prolonged exercise duration, time to 1-mm ST segment depression, and to onset of angina; and reduced the sum of ST segment depressions at maximal identical load in ergometry. In ambulatory ECG monitoring, only nifedipine significantly diminished the duration of asymptomatic ST segment depression as compared with placebo. Antianginal and antiischemic effects of nifedipine and diltiazem were similar. Both nifedipine and diltiazem significantly increased the effects of treatment with nitrates and beta-blockers. Administration of nifedipine was safer because at night diltiazem caused significant bradycardia despite careful titration of optimum doses of the drug. Although the maximum well-tolerated doses of conventional medication suppressed anginal symptoms in some patients, they did not abolish ischemia either at ergometry or in daily life.     

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.     

Lidoflazine: Double-blind trial of a new coronary vasodilator in angina pectoris

Summary Lidoflazine, a new coronary vasodilator, has been tested in 31 cases of angina pectoris in a double-blind cross-over study. It diminished significantly the frequency of attacks and nitroglycerine consumption of the more severe cases, but its effects were less marked in milder cases. The results are discussed in relation to other anti-anginal drugs. The necessity for a preliminary run-in period in studies of angina pectoris is emphasized and the occurrence of carry-over effects between lidoflazine and the placebo is discussed.     

地尔硫缓释片治疗稳定性心绞痛的临床疗效

目的 :观察地尔硫缓释片治疗稳定性心绞痛的疗效和安全性。方法 :72例稳定性心绞痛病人随机分为 2组 ,地尔硫组 37例 ,男性 2 0例 ,女性 17例 ,年龄 5 6a±s13a ,病程 6a± 4a ,给予地尔硫缓释片 90mg ,po ,qd ;氨氯地平组 35例 ,男性19例 ,女性 16例 ,年龄 5 5a± 13a ,病程 6a± 4a ,给予氨氯地平 5mg ,poqd。 2组服药 2wk后如不能控制心绞痛发作可剂量加倍 ,疗程均 6wk。结果 :对心绞痛症状的疗效地尔硫组显效 5 1% ,有效4 1% ,无效 8% ,总有效率 92 % ;氨氯地平组显效5 1% ,有效 4 0 % ,无效 9% ,总有效率 91% (P >0 .0 5 )。对心电图的疗效地尔硫组显效 2 7% ,改善 2 4 % ,无改变 4 9% ,总有效率 5 1% ;氨氯地平组显效 2 6% ,改善 2 6% ,无改变 4 8% ,总有效率5 2 % (P >0 .0 5 )。未发生严重不良反应。结论 :地尔硫缓释片治疗稳定性心绞痛是安全、有效的。     

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.     

Clinical utility of nifedipine and diltiazem plasma levels in patients with angina pectoris receiving monotherapy and combination treatment

The clinical utility of nifedipine and diltiazem blood levels in patients with angina pectoris receiving monotherapy (N = 14) and combination treatment (N = 9) were assessed in a placebo run-in, double blind, randomized, crossover study. Compared to placebo, diltiazem (mean daily dose 360 mg), nifedipine (mean daily dose 90 mg) and combination diltiazem-nifedipine therapy (mean daily dose 55 mg of nifedipine, 360 mg of diltiazem) were associated with reductions in weekly angina attacks and nitroglycerin consumption. Although both drugs used as monotherapy and in combination were also associated with significant increments in exercise tolerance and other improved angina parameters, these changes were not related to the plasma levels of either drug. Nifedipine plasma levels were measured by gas chromatography and diltiazem plasma levels measured by reverse high-pressure liquid chromatography from specimens obtained 2-5 hours after the last previous dose, after 1, 2 and 3 weeks of treatment, and during baseline placebo and placebo washout periods. With combination therapy, there was no effect on the diltiazem plasma level compared to monotherapy. The significant decrease in the nifedipine dose in patients on combination therapy did not significantly change nifedipine plasma levels. Determinations of plasma levels of diltiazem and nifedipine in the management of patients is of no value in the management of patients with angina pectoris except for monitoring treatment compliance and overdosage.     

曲美他嗪联合地尔硫卓治疗心绞痛的疗效研究

目的研究曲美他嗪联合地尔硫卓治疗心绞痛的效果。方法 80例心绞痛患者,随机分为观察组与对照组,每组40例。两组患者均接受常规治疗,对照组采取曲美他嗪治疗,观察组采取曲美他嗪联合地尔硫卓治疗。比较两组治疗效果,心绞痛发作次数、发作时间,不良反应发生情况。结果观察组的总有效率95.00%高于对照组的77.50%,差异具有统计学意义(P<0.05)。观察组心绞痛发作次数显著少于对照组,心绞痛发作时间短于对照组,差异具有统计学意义(P<0.05)。观察组的不良反应发生率5.00%显著低于对照组的25.00%,差异具有统计学意义(P<0.05)。结论对于心绞痛患者运用曲美他嗪联合地尔硫卓治疗,可以有效控制病情,疗效显著,安全可靠。     

地尔硫与低分子肝素联合应用治疗不稳定型心绞痛的临床疗效观察

目的观察静脉滴注地尔硫与皮下注射低分子肝素联合应用治疗不稳定型心绞痛(UA)的临床疗效及其对心率、血压、心电图、心功能的影响。方法46例UA患者起始给予地尔硫剂量为5μg·kg-1·min-1静脉微泵滴注,若心绞痛控制效果不佳可逐步将剂量递增至6~15μg·kg-1·min-1静脉微泵滴注,直至达到最佳疗效后维持48h;再以其相同剂量每日静脉微泵滴注1次,共3d;随后改为地尔硫缓释片90mg口服,每日1次,持续半个月。同时给予低分子肝素(LMWH)5000U皮下注射,每12h1次,共1周。分别在用药前、后对血压(BP)、心率(HR)、心电图(ECG)ST-T及心功能的左心室心输出量(CO)和左心室射血分数(EF)进行监测。结果患者心绞痛能得到及时有效的控制,心率、血压在48h内与治疗前比较差异有统计学意义(P<0.05);大部分患者的心电图ST-T缺血性改变得到了纠正或明显改善;左心室心输出量与治疗前比较差异有统计学意义(P<0.05)。在治疗过程中无心血管事件的发生。结论地尔硫与低分子肝素合用治疗UA疗效确切、肯定。     

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.     

Trimetazidine for stable angina pectoris

Stable angina pectoris, a symptom of coronary heart disease (CHD), manifests as stress-induced ischaemic episodes resulting in severe chest pain. Therapeutic aims are to improve quality of life by decreasing anginal attacks and to prevent myocardial infarction (MI) and death. Current anginal medications include β-blockers and calcium antagonists, which decrease ischaemic severity by reducing cardiac workload, and nitrates, which increase coronary blood flow. A new therapeutic approach is the use of metabolic agents, such as trimetazidine, which are cytoprotective during ischaemia. Results of several clinical trials demonstrated that trimetazidine, at the standard dose of 20 mg t.i.d., increased exercise capacity, decreased anginal incidence and decreased left-ventricular (LV) dysfunction compared to placebo. Trimetazidine was also as effective as propranolol (120 - 160 mg/day) and nifedipine (40 mg/day) in decreasing anginal episodes and improving exercise parameters. Trimetazidine improved anginal frequency and symptoms in patients in which treatment with diltiazem, nifedipine, propranolol, pindolol, oxprenolol or long-acting nitrates had failed. Trimetazidine was also more effective than isosorbide dinitrate (30 mg/day) as an adjunct to propranolol. Despite efficacy being equivalent to that of β-blockers and calcium antagonists, trimetazidine does not depress cardiac function and, correspondingly, is not contraindicated in any condition. Adverse effects of trimetazidine are mild and infrequent. In summary, clinical data indicate that trimetazidine is a safe, effective treatment for the symptoms of stable angina pectoris when used either as a monotherapy or an adjunctive therapy. Longer-term trials are necessary to determine whether trimetazidine will be effective in reducing rates of mortality and MI.     

Trimetazidine for stable angina pectoris

Stable angina pectoris, a symptom of coronary heart disease (CHD), manifests as stress-induced ischaemic episodes resulting in severe chest pain. Therapeutic aims are to improve quality of life by decreasing anginal attacks and to prevent myocardial infarction (MI) and death. Current anginal medications include beta-blockers and calcium antagonists, which decrease ischaemic severity by reducing cardiac workload, and nitrates, which increase coronary blood flow. A new therapeutic approach is the use of metabolic agents, such as trimetazidine, which are cytoprotective during ischaemia. Results of several clinical trials demonstrated that trimetazidine, at the standard dose of 20 mg t.i.d., increased exercise capacity, decreased anginal incidence and decreased left-ventricular (LV) dysfunction compared to placebo. Trimetazidine was also as effective as propranolol (120 - 160 mg/day) and nifedipine (40 mg/day) in decreasing anginal episodes and improving exercise parameters. Trimetazidine improved anginal frequency and symptoms in patients in which treatment with diltiazem, nifedipine, propranolol, pindolol, oxprenolol or long-acting nitrates had failed. Trimetazidine was also more effective than isosorbide dinitrate (30 mg/day) as an adjunct to propranolol. Despite efficacy being equivalent to that of beta-blockers and calcium antagonists, trimetazidine does not depress cardiac function and, correspondingly, is not contraindicated in any condition. Adverse effects of trimetazidine are mild and infrequent. In summary, clinical data indicate that trimetazidine is a safe, effective treatment for the symptoms of stable angina pectoris when used either as a monotherapy or an adjunctive therapy. Longer-term trials are necessary to determine whether trimetazidine will be effective in reducing rates of mortality and MI.