Double-blind Evaluation of Verapamil,Propranolol, and Isosorbide Dinitrate against a Placebo in the Treatment of Angina Pectoris

In the treatment of angina pectoris a double-blind evaluation of verapamil (Cordilox) at two dose levels—namely, 80 mg thrice daily and 120 mg thrice daily—propranolol (Inderal) 100 mg thrice daily, and isosorbide dinitrate (Vascardin) 20 mg thrice daily has been made against a placebo. The assessment was based on relief from daily attacks of angina on effort and the response to a whole-body exercise test. We can find no statistically significant difference between the effects of verapamil (120 mg three times a day) and propranolol (100 mg three times a day) in the treatment of angina of effort. Both of these preparations are more effective than a placebo both in the reduction of daily attacks (P < 0·01) and in the prolongation of exercise test (P < 0·05). Isosorbide dinitrate (20 mg three times a day) appears to be no more effective than a placebo in the treatment of angina on effort, but 14 out of 32 patients experienced headache of such severity that even when the dose was reduced to 10 mg thrice daily this drug therapy had to be withdrawn. Both propranolol (100 mg three times a day) and verapamil (120 mg three times a day) had a significant lowering effect on the diastolic blood pressure as measured with the patient standing (P < 0·01).     

Assessment of dermal glyceryl trinitrate and isosorbide dinitrate for patients with angina pectoris.

Dermal nitrate preparations are claimed to be useful in the treatment of angina, as their slow absorption by-passing the liver leads to a sustained action. Ten patients with angina were exercised on a treadmill after dermal application of 16.64 mg glyceryl trinitrate or 100 mg isosorbide dinitrate or placebo. Exercise duration was significantly increased at one and three hours for both nitrate preparations but not at six hours after application. The calculated workload achieved was significantly increased (p less than 0.01) at one and three hours for both preparations and at six hours (p less than 0.05) for isosorbide dinitrate. Headaches were common with glyceryl trinitrate cream. The dermal nitrate preparations studied had a duration of antianginal action similar to that of oral nitrate tablets. Aside from their value when the oral route cannot be used or absorption may be delayed, dermal nitrate preparations have no advantage over oral preparations for angina pectoris.     

硝酸异山梨酯片联合美托洛尔治疗老年冠心病心绞痛的疗效及对IL-18及hs-CRP水平的影响．

目的：观察硝酸异山梨酯片联合美托洛尔治疗老年冠心病心绞痛的临床效果,观察联合用药对患者血浆白介素．18（Inter．1eukin,IL-18）、超敏C反应蛋白（HighsensitivityCreactiveprotein,hs—CRP）的影响。方法：选择本院收治的老年冠心病心绞痛患者84例,随机分为研究组和对照组,各42例,研究组给予硝酸异山梨酯片20mg,3次／d,口服,美托洛尔12．5mg,1次／d,口服;对照组仅给予硝酸异山梨酯片20mg,3次／d,口服,疗程均为28d。观察两组用药后心绞痛改善情况,并观察两组治疗前后血清IL-8、hs-CRP变化。结果：治疗后,研究组总有效率为90．5％;对照组总有效率为69．0％,研究组总有效率明显高于对照组（P〈0．01）。治疗后两组心率、心绞痛发作频率明显降低,持续时间明显缩短（P〈0．05）;研究组心率、心绞痛发作频率明显低于对照组,持续时间也较对照组短（P〈0．05）。治疗前两组血浆IL-18、hs-CRP水平比较无统计学差异（P〉0．05）;治疗后研究组IL．18、hs．CRP水平明显低于对照组（P〈O．05）。结论：硝酸异山梨酯片联合美托洛尔治疗老年冠心病心绞痛能够进一步减轻患者IL．18、hs．CRP水平,对心绞痛治疗效果较单独应用酸异山梨酯片更佳。     

Trasicor in Angina Pectoris: a Double-blind Trial

Eighteen patients entered a double-blind trial of the beta-adrenergic blocking drug Trasicor in the treatment of angina pectoris. Six patients had to be withdrawn from the trial when substitution of placebo for Trasicor caused severe exacerbation of angina attacks. In these cases the frequency and severity of angina attacks fell to a minimum when Trasicor was re-established. A further 10 patients were significantly improved by Trasicor. Two patients showed no significant improvement. No side-effects were observed in doses ranging up to 400 mg. daily.     

Dependence of a drop in blood pressure in pulmonary circulation and in the right heart on dosage of isosorbide dinitrate]

An effect of isosorbide dinitrate on blood pressure values in the pulmonary circulation and the right heart has been investigated in 25 patients with a history of the first transmural myocardial infarction. Group I including 12 patients has been given 5 mg isosorbide nitrate in a 60-minute intravenous infusion while group II of 13 patients has been given 10 mg of the drug in the same way. Both groups have been matched in clinical data and blood pressure value in the pulmonary circulation which has been normal. Pulmonary blood pressure has been measured with Swan-Ganz catheter prior to the administration of drug, and 15, 30, 45 and 60 minutes following an infusion. Isosorbide dinitrate in a dose of 5 mg did not decrease blood pressure in the pulmonary circulation statistically significantly. The differences in blood pressure falls did exceed 9%. Filling pressure in the right ventricle did not change either while systolic blood pressure decrease by 16.6%. A double dose of isosorbide dinitrate reduced blood pressure in the pulmonary artery by about 1/3 of the baseline value, and blood pressure in the right ventricle (mean right atrial pressure) by 57.2%. Both systolic and diastolic arterial pressures were reduced. Isosorbide dinitrate reduced blood pressure in the pulmonary circulation in patients who underwent myocardial infarction, and hypotensive effect has been dose-related. A reduction in the right ventricular filling pressure has been a one of important mechanisms decreasing pulmonary pressures.     

Increased exercise tolerance with nitrates in beta-blockaded patients with angina.

In 14 beta-blockaded anginal subjects, 10 of whom had poor left ventricular function, sublingual isosorbide dinitrate significantly increased maximal exercise capacity on a standardized multistage treadmill test. This was associated with changes in heart rate and blood pressure suggestive of a fall in left ventricular work. The effect of isosorbide lasts for at least two hours and when taken before exercise may be a useful addition to beta-blockade in patients with angina.     

Clinical Evaluation of Perhexiline Maleate in Patients with Angina Pectoris

This paper reports a double-blind trial of a new antianginal drug, perhexiline. Fifty-five patients suffering from angina pectoris were studied for periods of 12 or 24 weeks in a cross-over comparison against a placebo in four centres in the United Kingdom and Ireland. Perhexiline was effective in most patients as judged by reducing the number of anginal attacks in 84% and the consumption of glyceryl trinitrate tablets in 64%. The major side effect, dizziness, noted in one-third of the patients, may be dose/body-weight related. Perhexiline is a valuable new agent for the treatment of patients with angina, especially those who do not respond to other antianginal agents.     

Rebound of vasospastic angina after cessation of long-term treatment with nifedipine.

The beneficial effect of calcium antagonists in the treatment of vasospastic angina is now well recognized. Although withdrawal symptoms have been reported following abrupt cessation of therapy with some cardiovascular drugs, there is no detailed report on similar complications of the cessation of therapy with calcium antagonists. In a 4-month period eight patients with well documented and well controlled vasospastic angina experienced a marked increase in the frequency and duration of anginal episodes at rest following the involuntary cessation of treatment with nifedipine, 10 to 20 mg four times a day. The increase began within 2 to 5 days after the cessation of treatment. Substitute therapy with isosorbide dinitrate, 30 mg, and verapamil, 80 to 120 mg, each four times a day, was effective in all cases. Although the mechanism responsible for this rebound phenomenon is not known, awareness of its existence is essential considering the widespread use of calcium antagonists.     

Acute coronary syndromes following abrupt cessation of oral propranolol therapy.

Abrupt cessation of oral propranolol therapy was followed by 15 acute coronary events in 14 patients with severe angina who had been receiving propranolol in daily doses of 80 to 400 mg for periods of 7 days to 6 years. Propranolol had been stopped 1 to 14 days before each acute event because of angiographic study (seven patients), increasing symptoms (three), acute coronary insufficiency (one), asymptomatic bradycardia (one), elective surgery (one) and unknown reasons (two). Before abrupt cessation of propranolol treatment anginal symptoms had been stable in six instances but had increased in the other nine. Cessation was followed by rapid progression of symptoms prior to 11 of the 15 acute events. There were six acute transmural myocardial infarctions with three deaths, three intramural myocardial infarctions, one with ventricular fibrillation, and six episodes of acute coronary insufficiency, Unstable angina followed nine of the events and responded to propranolol therapy (160 to 320 mg/d) in eight instances. Three other patients underwent aortocoronary bypass surgery; perioperative acute myocardial infarction occurred in two. These data suggest that in a minority of patients abrupt cessation of propranolol may be hazardous, particularly in severe or unstable disease. Cessation or propranolol therapy in such patients should be gradual and closely observed. Recurrent symptoms respond to reinstitution of propranolol therapy.     

尼可地尔对冠心病合并2型糖尿病不完全血运重建术后的疗效观察

目的:比较尼可地尔与单硝酸异山梨酯对冠心病合并2型糖尿病患者不完全血运重建术后的疗效。方法:入选112例经皮冠状动脉介入治疗(PCI)部分血运重建的冠心病合并2型糖尿病患者。随机分为2组:尼可地尔组(5 mg,3次/d,口服)60例,单硝酸异山梨酯组(50 mg,1次/d,口服)52例,两组患者均给予常规冠心病及糖尿病药物治疗。术后4周末行运动负荷试验,观察总运动时间,从开始运动到出现ST段压低1.0 mv和出现心绞痛的时间(s),以及最大ST段压低幅度,同时记录每周心绞痛发作次数及硝酸甘油用量。结果:4周后两组患者同服药前比较,从开始运动到出现ST段压低1.0 mv的时间延长,总运动时间延长,从开始运动到出现心绞痛的时间延长,最大ST段压低幅度降低(P0.01),但尼可地尔组与单硝酸异山梨酯组比较无明显统计学差异(P0.05);尼可地尔组每周心绞痛发作次数及硝酸甘油用量明显少于单硝酸异山梨酯组(P0.05)。结论:尼可地尔可增加冠心病合并糖尿病患者行不完全血运重建术后患者运动耐量,在减少心绞痛方面作用优于单硝酸异山梨酯。     

Topical treatment of erectile dysfunction: randomised double blind placebo controlled trial of cream containing aminophylline,isosorbide dinitrate,and co-dergocrine mesylate.

OBJECTIVE--To examine the effectiveness in treating impotence to topically applied cream containing three vasodilators--aminophylline, isosorbide dinitrate, and co-dergocrine mesylate--which act by different mechanisms. DESIGN--Randomised double blinded placebo controlled crossover trial over two weeks. SUBJECTS--36 men with erectile dysfunction randomly allocated to two equal groups. INTERVENTIONS--Active cream containing aminophylline 3%, isosorbide dinitrate 0.25%, and co-dergocrine mesylate 0.05% for one week and placebo for another. MAIN OUTCOME MEASURES--Patients'' reported experience of penile responses and side effects of treatment in questionnaires. Penile tumescence and arterial flow in the laboratory. RESULTS--21 patients reported full erection and satisfactory intercourse with the active cream. Three men reported full erection and satisfactory intercourse with either cream. The active cream was more effective in psychogenic than organic impotence (eight out of nine men with psychogenic impotence achieved a full erection upsilon four out of eight with neurogenic impotence and two out of seven with arterial insufficiency). No major side effects were reported. In the laboratory the active cream increased penile arterial flow (0.19 (SD 0.08) m/s upsilon 0.02 (0.15) m/s with placebo) and induced tumescence in 24 patients. CONCLUSIONS--Topical treatment with a cream containing three different vasodilators might be considered before intracavernous injection of vasoactive agents, particularly in psychogenic impotence.     

Objective assessment of antianginal treatment: a double-blind comparison of propranolol,nifedipine, and their combination.

In a double-blind clinical trial the antianginal effects of nifedipine (30 and 60 mg/day) and propranolol 240 and 480 mg/day) and a combination of both drugs were compared with those of placebo in 16 patients with severe exertional angina pectoris. Response to treatment was assessed by the objective criteria of 16-point precordial exercise mapping and 48-hour ambulatory electrocardiographic monitoring and subjectively by analysis of patients'' daily diaries of episodes of angina and consumption of glyceryl trintrate. The incidence of pain and consumption of glyceryl trinitrate were significantly decreased by each drug compared with placebo, and the combination produced a further significant improvement. Objectively the total area and amount of ST depression on the precordial exercise map and the total number of episodes of ST depression detected on ambulatory monitoring confirmed the efficacy of each treatment regimen; the combination was significantly better than either drug alone (p <0.005). The objective methods permitted greater separation of treatment efficacy and showed reliably that the combination of propranolol and nifedipine was significantly better than either drug alone. Thus this combination is a safe and effective form of treatment for angina.     

Prognosis of new and worsening angina pectoris.

The natural history of new and worsening angina pectoris was studied in 251 men aged under 70 years. Most were ambulant and all were referred by selected general practitioners to a special hospital clinic over two and a half years. Heart attacks developed in 39 patients, nine of whom died. Seventy-two per cent of the attacks occurred within six weeks of the onset or worsening of angina. Of the 212 patients who did not suffer myocardial infarction and who were clinically reviewed six months after their first attendance 66 had been pain free for the previous three months and 14 had experienced only infrequent attacks of angina. Of the 128 men aged under 65 years who were previously in employment 81% had returned to full-time work six months after their first attendance. A discriminant function analysis using many variables was made to develop a predictive index that would allow patients with new or worsening angina who were likely to develop serious cardiac complications to be identified. This did not prove possible, and the only predictive factor of significance was an increased cardiothoracic ratio. The syndrome of new and worsening angina has a low risk of early death, and many patients are symptom free six months later. In general, emergency coronary arteriography and surgery is not indicated.     

Effect of isosorbide dinitrate (sorbonit) on the exercise reaction in patients with coronary disease and in healthy individuals

The study aimed at evaluating an effect of a single dose of isosorbide dinitrate (Sorbonit) on the exercise reaction in the patients with coronary disease of various degree and in healthy individuals. The study involved 20 male patients of mean age 54.0 +/- 4.5 years with history of myocardial infarction and 12 healthy males of mean age 45.6 +/- 5.0 years. Ergometric test has been performed twice: prior to and 15 minutes after sublingual administration of isosorbide dinitrate in the dose of 10-15 mg. The first test has been interrupted when horizontal ST load exceeded 1 mm or contractions rate was 60% of the maximum value. Similar loads have been used after the administration of Sorbonit. The following parameters have been evaluated: heart rate (HR), systolic blood pressure (BPS), HR x BPS, lactate level (LA), and cardiac index. The value of the load has been measured with the aid of oxygen consumption (VO2). Significant depression of ST segment (less than 3 mm) in the exercise ECG has been noted in 8 patients following isosorbide dinitrate. Exercise tolerance has increased in these patients - CI increased during exercise following drug administration (VO2 the same as prior to the drug administration), and VO2/CI has became closer - physiological.     

Effect of isosorbide dinitrate,verapamil, and labetalol on portal pressure in cirrhosis.

The effects on portal pressure of the vasodilatory drugs isosorbide dinitrate and verapamil and of an alpha and beta blocking agent, labetalol, were assessed in 21 patients with cirrhosis and portal hypertension. The wedged hepatic venous pressure gradient (wedged minus free hepatic venous pressures) was used as an index of portal pressure and was not significantly changed by treatment with labetalol (n = 5) but was significantly decreased by verapamil (n = 6; p less than 0.05) and isosorbide dinitrate (n = 10; p less than 0.01). Long term administration of isosorbide dinitrate also had a significant effect (p less than 0.01).     

不同剂量氯吡格雷治疗急性ST段抬高心肌梗死的临床研究

目的:观察标准治疗基础上联合不同剂量氯吡格雷治疗急性ST段抬高心肌梗死的疗效及安全性。方法:2004年9月至2008年3月就诊我院的124例12小时以内发病的ST段抬高型心肌梗死患者,随机分为3组,3组均在入院后前3天给予阿司匹林300mg/d,此后给予阿司匹林100mg/d,A组常规不给予氯吡格雷治疗,B组给予氯吡格雷75mg/d,C组入院即刻给予氯吡格雷300mg,继之75 mg/d治疗,随访30天。观察溶栓血管再通率、梗死后心绞痛发作、心力衰竭事件及死亡、再发心肌梗死、或脑卒中的联合终点。结果:与A组相比,B组、C组患者溶栓成功率提高、梗死后心绞痛发作减少。P<0.05:进一步分析发现C组与B组差异无统计学意义,P>0.05。三组均无主要和次要出血事件发生,轻微出血发生率无统计学差异,P<0.05。结论:ST段抬高的急性心肌梗死患者在标准治疗的基础上早期加用氯吡格雷75 mg/d或先予300 mg负荷量,继之75 mg/d口服,均可提高溶栓成功率,降低梗死后心绞痛发生,而氯吡格雷负荷剂量组并不优于普通剂量组,且两组安全耐受性好。     

Ischaemic Heart Disease: A Secondary Prevention Trial Using Clofibrate

A trial is reported of the effects of giving clofibrate to prevent progression of pre-existing ischaemic heart disease. There were two groups randomly distributed between clofibrate (350 patients) and placebo (367 patients) regimens. The trial lasted about six years and was conducted in 19 hospitals in Scotland. The criteria of acceptance into the trial were precise and were monitored by one observer. The standards of diagnosis of events were defined and all protocols and electrocardiograms were read blind by one observer.Three categories of patients were admissible to the trial: (1) patients with one myocardial infarction (W.H.O. E.C.G. criteria) between 8 and 16 weeks before the start of the trial; (2) patients with angina of a duration of 3 to 24 months, provided their E.C.G. showed signs of myocardial ischaemia at rest or after exercise; and (3) patients with one recent myocardial infarction and pre-existing angina as defined above.There were fewer deaths in patients with angina (categories 2 and 3 above) treated with clofibrate than in those on placebo. The mortality in the former group was reduced by 62%, and this is a statistically significant difference. Clofibrate did not have any statistically significant effect in reducing the rate of non-fatal infarction in patients with angina or in those with myocardial infarction and pre-existing angina, though a beneficial trend was evident when both subgroups were combined (a 44% reduction compared with the placebo group). There was a significant reduction in all events (fatal and non-fatal) in patients with angina (“all anginas”) in the clofibrate-treated group; the rate was reduced by 53%.Clofibrate did not alter the overall mortality or morbidity rates in patients admitted to the trial with recent myocardial infarction without preceding angina of more than three months'' duration. In one subgroup there was a statistically significant adverse effect in the clofibrate-treated group. The lack of any overall effect in patients with myocardial infarction might be related to the unexpectedly low mortality rate (2·97%) in the placebo group; it is usually in the region of 4-9% per annum after first myocardial infarction.In patients categorized as “all anginas” there was significant reduction in events whether the initial serum cholesterol level was high (greater than 260 mg/100 ml) or normal. Clofibrate seemed to have a small but not significant beneficial effect in patients with myocardial infarction with initially high serum cholesterol levels, but was of no value in those with initially normal serum cholesterol levels. There was no significant relationship between the response or lack of response of serum cholesterol to clofibrate and the incidence of events either in patients with angina or in those with infarction.The main conclusion of this trial is that clofibrate had a beneficial effect in reducing mortality and, to a lesser extent, morbidity in patients who presented with angina (“all anginas”). This effect was independent of initial serum cholesterol levels or the extent to which serum cholesterol was lowered. The drug had no significant overall effect on prognosis in patients with myocardial infarction alone.     

Prophylactic Treatment of Angina Pectoris. A Double-Blind Cross-Over Comparison of Alprenolol and Pentanitrol

Twenty-one patients with angina pectoris took part in a double-blind cross-over comparison of alprenolol (an adrenergic β-blocker), pentanitrol (pentaerythritol tetranitrate), and placebo. Two-thirds of the patients were clinically improved on alprenolol 100 mg. four times daily, which was found to be significantly better than pentanitrol 30 mg. four times daily and placebo. There was also an indication of reduced severity of anginal attacks during alprenolol therapy. It is concluded that success in at least two-thirds can be expected with alprenolol. No serious complications or side-effects occurred during alprenolol treatment.     

Prenylamine in Angina Pectoris

The therapeutic value of prenylamine in angina pectoris was tested in two ways. Fourteen patients received 270 mg. of prenylamine per day for one month. This was preceded and followed by one month of placebo therapy. Assessment was made, first by twice-monthly treadmill exercise tests, and secondly by daily records of anginal attacks and nitroglycerin usage. The occurrence of pain and electrocardiographic changes during treadmill exercise was apparently uninfluenced by the drug. However, there was a reduced incidence of spontaneous angina and nitroglycerin usage during the month on prenylamine by contrast with either month on placebo (p <0.05).     

Improved method for the rapid determination of isosorbide dinitrate in human plasma and its application in pharmacokinetic studies

A rapid, accurate and highly sensitive method was developed for the determination of isosorbide dinitrate in human plasma. Concentrations in the lower nanogram and subnanogram range are determined by a one-step extraction of 2 ml plasma, containing 4 ng/ml nitroglycerine as internal standard, with 5.5 ml n-pentane. The extract is subjected to gas—liquid chromatography—electron capture detection analysis. The lower limit of quantitation is 200 pg/ml, but concentrations as low as 50 pg/ml are still detectable. The method allows the quantitative determination of isosorbide dinitrate plasma levels in man following a 5 mg sublingual administration up to four hours after application.