Enhanced effectiveness of combined sustained-release forms of isosorbide dinitrate and diltiazem for stable angina pectoris

In 14 patients with documented coronary artery disease, the extent and duration of acute anti-ischemic, antianginal and hemodynamic effects of monotherapies with 120 mg of sustained-release isosorbide dinitrate and diltiazem were compared; their combined therapy administered once daily in the morning with diltiazem given again in the evening were also compared according to a randomized, double-blind, crossover, placebo-controlled protocol including exercise testing for assessment of ST-segment depression (ST decreases) at an identical work load, exercise capacity and determination of plasma concentrations of both substances. Comparison of individual substances revealed more marked and sustained effects of isosorbide dinitrate (ST decreases at 2 hours, -66%; at 6 hours, -50%; p less than or equal to 0.05 for both), remaining statistically significant up to 12 hours (-24%) than of diltiazem (2 hours, -30%; 6 hours, -16%; p less than 0.05). Combined therapy resulted in increased effects (ST decreases at 2 hours, -80%; 6 hours, -76%; 12 hours, -30%; p less than or equal to 0.05) as opposed to individual substances for a period of up to 12 hours. However, therapeutic coverage over 24 hours could not be demonstrated, even with renewed administration of sustained-release diltiazem in the evening. Plasma concentrations of isosorbide-5-mononitrate were greater than 250 ng/ml for 12 hours on days when isosorbide dinitrate was given, decreasing to less than 100 ng/ml at 24 hours. On days when diltiazem was given, plasma levels greater than 50 ng/ml were detected only at 2 and at 6 hours, and at 24 hours only after a second tablet was given.     

Isosorbide mononitrate 30% immediate-release 70% sustained-release formulation: a review. DUMQOL (DUtch Mononitrate Quality of Life) Study Group

Since the first publication of isosorbide mononitrate 30% immediate-release 70% sustained-release (IR-SR) formulation in 1985, a considerable body of literature concerning its clinical efficacy and safety has become available. Theoretically, the formulation has the advantage over conventional isosorbide mononitrate or dinitrate (ISMN/ISDN) that it has a simpler and more predictable pharmacokinetic profile. The objectives of this paper are to review published data so far and to see whether the theoretical advantages translate into better clinical effectiveness. 1. After oral administration, isosorbide mononitrate IR-SR has a rapid onset of action (30 minutes), and effects are evident for up to 17 hours. 2. The antianginal effects of once-daily isosorbide mononitrate IR-SR increased with increasing dosages, were generally larger than those of either placebo or equipotent doses of conventional ISMN/ISDN, and were somewhat larger than those of the beta blocker bupranolol. The effects were generally similar to those of sustained release nifedipine. 3. Patients showed significantly greater improvement in some quality-of-life indices with once-daily isosorbide mononitrate IR-SR than with twice or three times daily regimens of conventional ISMN/ISDN. This was particularly so with mobility, psychological distress, and life satisfaction indices. 4. Tolerance did not develop after 13 months of once daily isosorbide dinitrate IR-SR. No rebound increase in incidence of ischemic episodes was observed after discontinuation of treatment. 5. Long-term efficacy data both of isosorbide mononitrate IR-SR and of conventional ISMN/ISDN are limited so far. Large studies in patients with angina pectoris and patients with heart failure addressing long-term effects are ongoing, and some of the data will be completed within the next months. Isosorbide mononitrate IR-SR has a rapid onset of action and has been shown to be clinically efficient and, in addition, to be more so than conventional ISMN / ISDN. Nitrate tolerance with continued use of the formulation has not yet been reported. Long-term effects on morbidity and mortality are currently being assessed.     

单硝酸异山梨酯缓释胶囊治疗心绞痛的疗效分析

目的：探讨单硝酸异山梨酯缓释胶囊治疗心绞痛的疗效。方法选取2012年10月至2013年6月我院收治的100例心绞痛患者,将其随机分成两组,每组50例,观察组采用单硝酸异山梨酯缓释胶囊配合心绞痛常规治疗,对照组采用心绞痛常规治疗,观察两组的治疗效果。结果经治疗,观察组的心电图改善情况明显优于对照组（94.0％ vs 70.0％）,临床疗效也明显高于对照组（96.0％ vs 78.0％）,P〈0.05,具有统计学意义。结论单硝酸异山梨酯缓释胶囊治疗心绞痛的疗效显著,相对安全,有助于缓解心绞痛患者的症状,值得临床推广应用。     

Development of tolerance with regard to the anti-ischemic effect of isosorbide dinitrate in regular multiple daily administration

In previous studies it had been shown that during longterm treatment of coronary artery disease with isosorbide dinitrate (ISDN) in sustained-release form, there was no reduction in exercise-induced ST-segment depression, no decrease in the rate of anginal attacks or nitrate consumption and no changes in blood pressure or heart rate [1, 4]. To determine to what extent tolerance development is a fundamental property of longterm administration of ISDN, this study, carried out according to a randomized, double-blind, cross-over, placebo-controlled protocol (Figure 1), was undertaken. The anti-ischemic effects of 40 mg ISDN were analyzed after acute administration and during longterm treatment with 40 mg four times daily in eleven patients with stable angina pectoris and reproducible ST-segment depression. Additionally, the influence of this therapy on the anti-ischemic effects of 0.8 mg sublingually-administered nitroglycerin (GTN) was assessed in ten of the eleven patients. On acute administration, 40 mg ISDN led to a reduction in ST-segment depression at one hour from 2.05 to 0.18 mm (p less than 0.01), and at six hours from 2.35 to 1.20 mm (p less than 0.01) (Figure 2, Table 1). During chronic treatment, statistically significant changes were no longer detectable. In eight of the eleven patients there was a complete loss of effects; in the remaining three, a marked attenuation was observed (Figure 3). Acute administration of 40 mg ISDN resulted in plasma concentrations of 221 ng/ml 5-ISMN, 53 ng/ml 2-ISMN and 23 ng/ml ISDN (Figure 6, Table 2).(ABSTRACT TRUNCATED AT 250 WORDS)     

尼可地尔治疗稳定型心绞痛有效性和安全性的临床研究

目的：探讨尼可地尔治疗冠心病稳定型心绞痛（SAP）的疗效和安全性。方法：收集我院2010年4月至2012年4月门诊及住院的60例SAP患者,随机分为尼可地尔组（28例,口服：尼可地尔5mg,3次/d）,单硝酸异山梨酯组（32例,口服：单硝酸异山梨酯缓释片30mg/d）,两组均同时服用美托洛尔25mg,2次/d、阿托伐他汀20mg,1次/d、阿司匹林100mg,1次/d。4周治疗后分别观察两组心绞痛、心电图、运动耐量和不良事件情况。结果：与单硝酸异山梨酯组比较,尼可地尔组治疗心绞痛有效率（71.9%比96.4%）、改善运动耐量率（68.8%比92.9%）均显著提高（P均〈0.05）;尼可地尔组轻微头痛（25%比10.7%）显著减少（P〈0.05）。结论：尼可地尔能在不增加患者不良事件的基础上,明显提高对稳定型心绞痛患者的疗效。     

Pharmacokinetics of isosorbide mononitrate.

Pharmacokinetic studies show that isosorbide mononitrate is rapidly absorbed after oral administration, reaches peak concentrations within an hour, undergoes no significant first-pass metabolism, and is virtually 100% bioavailable. The half-life is approximately 5 hours, the volume of distribution is 0.62 liter/kg, and the systemic clearance is 115 mL/min. Only 1-2% of an orally administered dose is excreted unchanged in the urine, with the remainder being eliminated as inactive metabolites. Isosorbide mononitrate follows dose-linear kinetics after single and multiple doses. Its pharmacokinetic profile is consistent and highly reproducible and is unchanged in the elderly and in patients with coronary artery disease, renal failure, or liver cirrhosis. An asymmetrical dosage regimen of isosorbide mononitrate has been shown to provide antianginal efficacy for at least 12 hours. Because asymmetrical dosing creates irregular, sawtooth-like changes in plasma concentrations and a fall below a critical threshold level during the night, tolerance does not develop.     

Induction and circumvention of nitrate tolerance applying different dosage intervals

There is increasing evidence that constant nitrate plasma levels, as induced by at least three-times-daily ingestions of isosorbide dinitrate in sustained-release form, lead to an attenuation or even complete loss of the anti-ischemic effects (nitrate tolerance). Therefore, the dependence of tolerance development on dosage intervals according to once-daily and twice-daily ingestions was assessed. Tablets of isosorbide dinitrate (80 mg) in sustained-release form were administered once-daily at 8 A.M. (dosage interval 24 hours) or twice-daily at 8 A.M. and 8 P.M. (dosage interval 12 hours), as well as at 8 A.M. and 2 P.M., respectively (maximal dosage interval 18 hours). A total of 34 patients with angiographically proven coronary artery disease, a history of stable, exercise-dependent angina pectoris, and a reproducible, exercise-induced ST-segment depression of at least 0.15 mV (1.5 mm), who initially showed a response to 80 mg of isosorbide dinitrate, were enrolled. The anti-ischemic effects of isosorbide dinitrate on exercise-induced ischemia were objectively determined by the measurement of exercise-induced ST-segment depression before as well as two, six, and 12 hours after the ingestion at the first and the 15th day of the studies. Since the dosage interval of 12 hours resulted in constant plasma levels, the initially beneficial anti-ischemic effects of isosorbide dinitrate were considerably attenuated after two weeks of treatment. In contrast, the once-daily regimen with its intermittent peaks and valleys of nitrate plasma levels showed identical anti-ischemic effects at the 15th day as compared with the first day. Ingestions at 8 A.M. and 2 P.M. also circumvented the development of nitrate tolerance, however, combined with an even more pronounced anti-ischemic effect after 12 hours as compared with the once-daily regimen. Thus, the circumvention of nitrate tolerance requires a daily "nitrate-poor" interval. The best compromise between a maximal possible anti-ischemic effect and the circumvention of tolerance development was found for the "eccentric" dosage regimen in which the tablets were ingested in the morning and early afternoon.     

Selection of therapy with nitrates in patients with stable effort angina: results of comparative study of common isosorbide dinitrate and long acting preparation of isosorbide-5-mononitrate

AIM: To assess efficacy and tolerability of a novel drug form of isosorbide-5-mononitrate in patients with ischemic heart disease and stable effort angina as compared with common isosorbide dinitrate pills. MATERIAL AND METHODS: Patients with stable class II-III effort angina (n=30) were included into a randomized crossover study in which they received isosorbide dinitrate (nitrosorbide, 10-20 mg t.i.d.) and long acting isosorbide-5-mononitrate (ephox-long, 50-100 mg o.d.) for 3 weeks each. Efficacy of treatment was assessed by clinical data and treadmill exercise tests. Questionnaires were used for registration of frequency and intensity of attacks of headache. RESULTS: The use of both isosorbide dinitrate and 5-mononitrate was associated with significant improvements of exercise tolerance however effect of mononitrate lasted longer. Nitroglycerine requirement diminished during first week of use of both drugs and remained on this level by the end of 3-rd week of treatment with mononitrate but substantially rose by the end of treatment with dinitrate. Number of attacks of headache increased during first week of treatment with both drugs, became even higher by the end of use of dinitrate and decreased by the end of use of mononitrate. CONCLUSION: Long acting form of isosorbide-5-mononitrate ephox-long taken once daily provides sufficient antianginal effect throughout a day and is better tolerated than nitrosorbide preparation of isosorbide dinitrate with moderately prolonged activity.     

国产5-单硝酸异山梨醇酯缓释片治疗心绞痛的临床疗效

目的 :观察国产 5 单硝酸异山梨醇酯缓释片治疗冠心病心绞痛疗效安全性。方法 :所选冠心病心绞痛患者共 117例 ,分两组进行治疗。治疗组 :80例 ,口服国产 5 单硝酸异山梨醇酯缓释片 6 0mg ,每日 1次 ,每次1片。对照组 :37例 ,口服长效异乐定 5 0mg ,每日 1次 ,每次 1片。两组均服药 30d为 1个疗程。结果 :治疗组治疗心绞痛的总有效率为 91.2 5 % ,对照组为 91.89%。治疗组治疗后 ,硝酸甘油消耗量明显减少甚至完全停用 ,缺血性ST T变化明显改善 ,心电图疗效达 6 1.6 % ,与对照组相比 ,差异无显著性意义。两组均无明显不良反应。结论 :5 单硝酸异山梨醇酯缓释片疗效确切、安全 ,无明显毒副反应 ,有利于冠心病心绞痛的长期治疗     

Duration of effects and tolerance of slow-release isosorbide-5-mononitrate for angina pectoris

Isosorbide-5-mononitrate (IS-5MN) is an active metabolite of isosorbide dinitrate, but unlike its parent compound, is nearly 100% bioavailable after oral administration. Once-a-day therapy with a slow-release formulation of IS-5MN is used widely in Europe for 24-hour prophylaxis of angina pectoris. In a randomized, crossover, double-blind, placebo-controlled study, the duration of effects of 50 and 100 mg of slow-release IS-5MN were evaluated after the first dose and after once-a-day therapy for 1 week in 9 patients with stable angina pectoris. Compared with placebo values, standing blood pressure decreased (p less than 0.001) and exercise time to the onset of angina and total exercise duration increased (p less than 0.008 and p less than 0.003) at 4 hours, but not at 20 or 24 hours after first dose of 50 and 100 mg of slow-release IS-5MN. After once-a-day therapy for 1 week, no improvement in exercise duration or reduction in ST-segment depression was seen after 50 or 100 mg of slow-release IS-5MN at 4, 20 or 24 hours despite high plasma IS-5MN concentrations. Thus, despite therapeutic plasma concentrations, 50 and 100 mg of slow-release IS-5MN did not exert antianginal or anti-ischemic effects at 20 and 24 hours after the first dose and at 4, 20 and 24 hours after sustained once-a-day therapy for 1 week.     

Ethacizin: a new efficacious Soviet antiarrhythmic drug of the phenothiazine group

Ethacizin, a new Soviet antiarrhythmic agent of the phenothiazine group, was tested on 82 patients with ventricular rhythm disturbances. Antiarrhythmic effects of the drug were assessed by means of ambulatory ECG monitoring. The investigation protocol included acute drug testing with 50 mg, 100 mg, and 150 mg, and short-term maintenance therapy with 150 to 300 mg/24 hours of ethacizin (mean 183 +/- 46 mg/24 hours) for 3 to 14 days (mean 7 +/- 3 days). Ethacizin reduced the total number of ventricular premature beats (VPBs) from 17,263/24 hours (on placebo) to 3458/24 hours (p less than 0.001) and suppressed couplets and ventricular tachycardia (VT) runs by 90% in 94% and 96% of patients, respectively. Maximum blood plasma concentration of ethacizin was observed in 110 to 120 minutes and accounted for 300 to 447 ng/ml (mean 354 +/- 77 ng/ml), with a minimum therapeutic drug plasma concentration ranging from 29 to 101 ng/ml (mean 73 +/- 27 ng/ml). There was a significant increase in PQ and QRS intervals with ethacizin. Ethacizin was well tolerated. Thus ethacizin had high antiarrhythmic efficacy in patients with VPBs and no significant side effects.     

Coronary artery disease observed in general hospitals: ETTIC study. Comparison between trimetazidine and mononitrate isosorbide for patients receiving betablockers

The extended use of interventional surgery of revascularisation has modified the prognosis and the evolution of ischaemic heart diseases. However, both coronary artery bypass graft and percutaneous transluminal coronary angioplasty failed to make the symptomatic or subclinical ischaemic manifestations of chronic coronary insufficiency disappear. The interest of using betablockers as a first-line therapy was widely demonstrated. However, their combination with another efficient molecule is often necessary. The aim of this trial has been to appreciate the efficiency of the association of a betablocker with either trimetazidine or with isosorbide monoitrate. Hundred and eighty five patients retaining a positive effort test despite 100 mg of atenolol, received in addition, either 60 mg of trimetazidine (93 cases) of 60 mg of isosorbide mononitrate (92 cases) for a two-month period and are then re-evaluated at the end of this period. The ischaemic threshold is delayed in a significant way in both groups (p < 0.0001; trimetazidine +7%, isosorbide mononitrate +10.7%). Twenty-three percent of the exercise tests under trimetzidine and 19% under isosorbide mononitrate become negative after two months of the therapeutic combination. The clinical improvement is even clearer with the disappearance of the angina crisis during the week before the second exercise test in 63% of the cases under trimetazidine and 54% of the cases under isosorbide mononitrate, among the patients who had kept it under atenolol at the inclusion. In conclusion, the combination of a second efficient molecule, trimetazidine or isosorbide mononitrate, brings a functional and objective improvement to patients with insufficient chronic coronary disease not totally controlled using a betablocker, even with high dosage. One should notice two important advantages in favour of the trimetazidine: one is practical due to a better tolerance (lack of cephalalgia), the other is conceptual (use of the complementary metabolic approach of cellular oxygenation rather than the haemodynamic approach of nitrate compounds which are already in concurrency with all other anti-ischaemic molecules).     

Clinical and pharmacokinetic comparison of 2 oral preparations of nifedipine: 10 mg capsules and 20 mg delayed-release tablets

The effects and pharmacokinetic parameters of two oral formulations of nifedipine, 10 mg capsule (Adaltat) and 20 mg slow release tablet (Adalat a.p.). With the 10 mg capsule nifedipine was rapidly absorbed, reaching a maximum concentration of 120 +/- 39 ng/ml in 0.52 +/- 0.07 h, and also rapidly eliminated with an apparent halflife of 5.51 +/- 0.64 h. A fall in blood pressure and a raise in heart rate, that significantly correlated with plasma levels, were observed. 83% of the subjects reported headache, that was probably due to the sudden increase in plasma levels. With the 20 mg slow release tablet nifedipine absorption was slower, reaching a maximum concentration of 39 +/- 7 ng/ml in 1.82 +/- 0.43 h, and the apparent half-life (16.89 +/- 3.14 h) was longer than with the capsule. A fall in blood pressure was observed that significantly correlated with plasma levels; however, there was no significant correlation between these and changes in heart rate. Only 17% of the subjects reported headache. Pharmacokinetic data indicate that, in most subjects, nifedipine therapeutics plasma levels (over 15 ng/ml) can be maintained with the administration of a 20 mg slow release tablet every 12 hours. This, joined to the reduction in side effects, suggest that this formulation is the adequate alternative in chronic treatments with nifedipine, such as arterial hypertension.     

Resistance to isosorbide dinitrate in patients with severe chronic heart failure: incidence and attempt at hemodynamic prediction

Oral isosorbide dinitrate has been widely used to lower elevated left ventricular filling pressure in patients with chronic heart failure. Although the recommended dose of this drug is 40 mg every 6 h, failure to respond to this dose has been observed in many patients with heart failure. In the present study the incidence of resistance to isosorbide dinitrate was evaluated and an attempt was made to identify baseline hemodynamic predictors for this phenomenon in 50 patients with severe chronic heart failure due to left ventricular systolic dysfunction (mean left ventricular ejection fraction 0.23 +/- 0.08). Twenty-seven (54%) of the 50 patients responded to 40 mg of isosorbide dinitrate (greater than 20% decrease in mean pulmonary artery wedge pressure sustained greater than or equal to 1 h) and 23 patients (46%) failed to respond. Nonresponders to 40 mg of isosorbide dinitrate had a significantly higher baseline right atrial pressure than did responders (14 +/- 5 versus 10 +/- 6 mm Hg, p less than 0.02). In addition, all 7 patients with a baseline right atrial pressure of less than 7 mm Hg and 12 of 14 patients with a baseline right atrial pressure less than 10 mm Hg responded to 40 mg. No significant differences were noted between responders and nonresponders in any other baseline hemodynamic or clinical variables, or in peak isosorbide dinitrate serum levels (32 +/- 19 ng/ml in nonresponders versus 44 +/- 36 ng/ml in responders). Of the 23 nonresponders to 40 mg, 22 received a higher dose (80 to 120 mg).(ABSTRACT TRUNCATED AT 250 WORDS)     

A double-blind, parallel-group study of amlodipine versus long-acting nitrate in the management of elderly patients with stable angina.

Ninety-seven elderly patients with stable angina were included in a 28-week, randomized, double-blind, parallel-group comparison of amlodipine 5-10 mg and isosorbide mononitrate 25-50 mg once daily. The total exercise time, as limited by angina, was recorded together with the median incidence per week of angina attacks and glyceryl trinitrate consumption. Safety was assessed by adverse event frequency, measurement of vital signs and laboratory parameters, and quality of life. At the final visit, the total exercise time was significantly greater relative to baseline with amlodipine than isosorbide mononitrate (final/baseline difference: 112.2 vs. 32.2, p = 0.016). There were no statistically significant differences between the groups in relation to the incidence of adverse events. Once daily amlodipine provides significantly better control of stable angina than isosorbide mononitrate in this elderly population.     

Pharmacokinetics and bioavailability of digoxin capsules,solution and tablets after single and multiple doses

The bioavailability of single doses of digoxin capsules (0.4 mg), digoxin solution (0.4 mg) and reference tablets (0.5 mg) was compared with that of single intravenous doses (0.4 mg) of digoxin using measurement of 24 hour urinary excretion and area under the plasma concentration curve. The absolute systemic availability of all three oral preparations was significantly less than 100 percent. The bioavailability of capsules and solution was nearly identical (79 percent and 76 percent, respectively, as assessed with values for area under the concentration curve and 65 percent and 62 percent as assessed with urinary excretion values); both forms had greater systemic availability than the tablet, which had bioavailability values of 50 percent using area under the curve and 41 percent using urinary excretion. Capsules and solution also were similar in peak plasma digoxin levels achieved (3.7 and 3.1 ng/ml), time of peak concentration (0.8 and 0.6 hour after dosage) and apparent first order absorption half-life (11.3 and 10.2 minutes); both capsules and solution differed significantly from tablets (peak level 1.6 ng/ml, time of peak concentration 1.2 hours and absorption half-life 27.1 minutes). Single dose findings were substantiated when steady state plasma levels and 24 hour urinary excretion values were measured from days 11 through 16 of the period of once daily ingestion. Mean plasma levels (0.70 ng/ml) and urinary excretion values (45.1 percent of dose) for capsules were nearly identical to those for solution (0.69 ng/ml and 42.5 percent of the dose), and values for both capsules and solution were significantly greater than those for tablets. Within- and between-subject variation in bioavailability was similar for the three oral preparations. Thus the single dose bioavailability study was predictive of the steady state findings. The bioavailability of digoxin capsules is equivalent to that of a solution and significantly greater than that of a reference tablet formulation.     

Arterial flow in the lower leg correlated with plasma levels of two formulations of papaverine hydrochloride

In patients with severe peripheral vascular disease (mean arterial flow of 40 ml/min), a suspension of papaverine in a soft gelatin capsule produced plasma levels almost three times higher than those following treatment with a sustained-release tablet formulation. The higher plasma levels resulted in significantly greater vasodilation with increased distal arterial flow. The onset of peak pulsatile flow with the soft gelatin form came sooner than with the sustained-release form. However the durations of vasodilation were similar with both papaverine preparations. The vasodilatory activity of papaverine appeared to be greater in the sympathectomized leg. The soft gelatin formulation of papter reconstruction of a large artery, and may be effective in sustaining a longer vasodilatory effect in patients with small vessel disease, when surgical procedures may not be applicable.     

Effect duration and dose-response relation of molsidomine in patients with coronary heart disease

The dose-effect relation and duration of action of 2 mg, 4 mg and 6 mg molsidomine on ischemic ST-segment depression in the exercise-ECG were determined in a randomized and double-blind acute study of 12 patients with confirmed coronary artery disease. With 2 mg molsidomine a significant reduction in the amount of ischemic ST-depression from 18.0 mm to 8.1 mm, 45% of the baseline-figure, resulted. With 6 mg molsidomine a diminuation of the ST-segment depression from 16.2 mm to 6 mm, approximately 40%, was noted. The significant antianginal effect of 2 mg molsidomine lasted at least 3 hours. After 5 hours an effect was seen only in some patients. 4 mg and 6 mg molsidomine still showed a significant reduction of ST-segment depression after 5 hours. A sufficient antianginal efect over 24 hours is only achieved with a 2-mg dose administered 5-6 times or with a 4-6 mg dose applied 4-5 times daily. The most marked fall in blood pressure was noticed after 6 mg molsidomine. On average, the systolic blood pressure fell 41 mm Hg (22%). Orthostatic reactions were not seen. The maximal dose-dependent plasma levels were 15.8 ng/ml, 30.1 ng/ml and 50.0 ng/ml. A definite, reliable clinical effect was seen in some cases from plasma levels above 2 ng/ml.     

Medical treatment of patients with severe exertional and rest angina: double blind comparison of beta blocker, calcium antagonist, and nitrate

The role of medical treatment of patients who had resting nocturnal angina as well as exertional angina was investigate. The effects of atenolol 100 mg a day, nifedipine 20 mg three times a day, and isosorbide mononitrate 40 mg twice a day were investigated in a double blind, triple dummy randomised study. Nine patients with coronary artery disease, early positive exercise tests, and transient daytime and nocturnal ambulatory ST segment changes were initially assessed off all antianginal medication. They were then treated with each drug for three five day periods. Angina diaries were reviewed and maximal treadmill exercise tests and 48 hour ambulatory ST segment monitoring were performed at the end of each treatment period. Resting and exercise heart rate and blood pressure were significantly lower on atenolol than on either isosorbide mononitrate or nifedipine. The duration of exercise to 1 mm ST segment depression was significantly greater on atenolol than on isosorbide mononitrate. Only one patient had an improvement in exercise tolerance on nifedipine that was greater than the improvement on atenolol; this patient had single vessel disease. The total number and duration of episodes of ST segment change during ambulatory monitoring were significantly lower with atenolol than on either isosorbide mononitrate or nifedipine. Nocturnal ST segment changes were abolished in six patients on atenolol, in six patients on nifedipine, and in five patients on isosorbide mononitrate. When nocturnal ST segment changes occurred, their frequency was reduced with all three drugs. Pain was abolished in four patients on atenolol and pain relief was significantly better on atenolol than on isosorbide mononitrate. There was no significant difference in pain relief between isosorbide mononitrate and nifedipine. Thus beta receptor blockade with atenolol was the most effective means of reducing myocardial ischaemia both during exercise and at rest at night without causing deterioration in any patient. Nocturnal myocardial ischaemia in patients with severe coronary artery disease can be effectively treated with beta receptor antagonists and vasodilators.     

Medical treatment of patients with severe exertional and rest angina: double blind comparison of beta blocker, calcium antagonist, and nitrate.

The role of medical treatment of patients who had resting nocturnal angina as well as exertional angina was investigate. The effects of atenolol 100 mg a day, nifedipine 20 mg three times a day, and isosorbide mononitrate 40 mg twice a day were investigated in a double blind, triple dummy randomised study. Nine patients with coronary artery disease, early positive exercise tests, and transient daytime and nocturnal ambulatory ST segment changes were initially assessed off all antianginal medication. They were then treated with each drug for three five day periods. Angina diaries were reviewed and maximal treadmill exercise tests and 48 hour ambulatory ST segment monitoring were performed at the end of each treatment period. Resting and exercise heart rate and blood pressure were significantly lower on atenolol than on either isosorbide mononitrate or nifedipine. The duration of exercise to 1 mm ST segment depression was significantly greater on atenolol than on isosorbide mononitrate. Only one patient had an improvement in exercise tolerance on nifedipine that was greater than the improvement on atenolol; this patient had single vessel disease. The total number and duration of episodes of ST segment change during ambulatory monitoring were significantly lower with atenolol than on either isosorbide mononitrate or nifedipine. Nocturnal ST segment changes were abolished in six patients on atenolol, in six patients on nifedipine, and in five patients on isosorbide mononitrate. When nocturnal ST segment changes occurred, their frequency was reduced with all three drugs. Pain was abolished in four patients on atenolol and pain relief was significantly better on atenolol than on isosorbide mononitrate. There was no significant difference in pain relief between isosorbide mononitrate and nifedipine. Thus beta receptor blockade with atenolol was the most effective means of reducing myocardial ischaemia both during exercise and at rest at night without causing deterioration in any patient. Nocturnal myocardial ischaemia in patients with severe coronary artery disease can be effectively treated with beta receptor antagonists and vasodilators.