Duration of action of beta blockers.

Three randomized, placebo-controlled, crossover experimental designs were used to define a suitable interdose interval and to study the adequacy of once-daily administration for applications in preventive trials on manifest or latent ischemic patients. Suppression of exercise tachycardia was used as the major effect variable. All measurements were made at different intervals after the last dose when the healthy subjects had been treated for at least 1 wk. Reductions of exercise tachycardia were found 24 hr after the last dose for atenolol, metoprolol, penbutolol, pindolol, propranolol, sotalol, and timolol. Penbutolol and propranolol induced equal reduction of exercise tachycardia at the end of the dose interval regardless of whether the total daily dose was given once daily or divided in 2 daily doses. Atenolol and sotalol, both with long half-lifes (t1/2s), were not superior to other beta blockers. Neither were slow-release preparations of metoprolol and propranolol markedly more effective 24 hr after the preparation than after ordinary tablets. Plasma concentration-time patterns after slow-release preparations may be important in patients with adverse experiences during peak plasma levels after conventional tablets.

Selection of patients for beta-blocking treatment after myocardial infarction.

Based on published studies of patients the following conclusions may be made: a) Long-term mortality and reinfarction rate can be reduced; b) No practically effective or meaningful restricted selection of patients for treatment with beta blockers is possible; c) Treatment starting when patients have stabilized in hospital usually after 5-7 days is well documented; d) Treatment should be maintained 2-3 years and the individual indications should then be re-evaluated; e) beta Blockers other than timolol, propranolol, metoprolol and alprenolol have yet to be documented.

Maximal work performance test in middle-aged women: results from a population study.

Based on sampling from official census lists a sample of middle-aged women was obtained in five different age strata; 38, 46, 50, 54 and 60 years. Based on date of birth a sub-set was sampled for maximal exercise testing. The participation rate was 81% and 194 women underwent the test. In sixteen women the test was interrupted due to poor cooperation or clinical contra-indications against continued loading. 54% of the women considered the maximal load to be at least very straining according to a standardized scale for perceived exertion. The average maximal load decreased from 113 to 98 W with advancing age. In the highest age group only 16% exceeded 130 W compared to 43% in the youngest group. Maximum heart rate decreased with age but maximum respiratory frequency and perceived exertion did not. Systolic blood pressure 2 min after maximal work increased with age. Minnesota Code items 4:1-3 and 5:1-3 were demonstrated in 30% of the women, mainly in the older age strata. Other ECG-abnormalities were uncommon. Despite the widely differing incidence of myocardial infarction these ischaemic ECG-abnormalities were as common in women as in a comparative sample of men. This observation questions the traditional interpretation of the exercise induced ECG response in women.

Pharmacokinetics of intravenous timolol in patients with acute myocardial infarction and in healthy volunteers.

Disappearance pharmacokinetics, pharmacodynamics and general tolerance of i.v. timolol were compared in 12 healthy volunteers and 10 patients with a definite or proven acute myocardial infarction. The drug was administered to the patients immediately on arrival at the hospital after a median delay time of 4 h. Tolerance to the injections was good in both volunteers and patients. The study revealed disappearance pharmacokinetics that were similar in volunteers and patients.

Work capacity in women in relation to age as judged from a maximal work performance test.

Work performance test could be carried out on a population sample of women aged 38-60 years without complications. The work capacity decreased with increasing age and at the same time the maximal heart rate during work decreased with increasing age. Blood pressure increased with age and these differences between the various ages were about the same as at rest. Respiratory frequency and perceived exertion on maximal work were similar in the ages studied. ECG changes were common and were found to be as common as in men who had been studied with the same technique and in the same ages. As ECG changes were very common and as myocardial infraction is very seldom in women of these ages, ECG changes during and after work did not seem to be a good discriminator of women subjected to myocardial infraction.

Pharmacodynamic and pharmacokinetic study of oral and intravenous penbutolol.

The present study was done to establish the dose-response relationships for effects on heart rate and systolic and diastolic blood pressure, tolerance and plasma disappearance kinetics after large intravenous and oral doses of penbutolol. Twelve healthy volunteers were randomly allocated to receive penbutolol (n = 8) or placebo (n = 4) in this single blind, placebo-controlled investigation. The degree of beta-blockade was measured by standarized exercise tests at work loads selected to produce a heart rate of 150/min without treatment. Penbutolol was given as single i.v. doses of 3, 6 and 12 mg and as 40, 80 and 120 mg once daily for one week, measurements being made 2 and 24 h after the last dose. Penbutolol i.v. did not influence the resting heart rate but it did reduce resting systolic blood pressure in a non-dose dependent manner. Exercise heart rate and systolic pressure were lowered by all the intravenous doses. All oral doses of penbutolol lowered exercise heart rate and systolic blood pressure to the same extent. The reductions in exercise tachycardia was still present after 24 h. After i.v. administration t1/2 was approximately 1.2 h and the volume of distribution was 32-421. All doses were well tolerated.

Hypertension and myocardial infarction.

In a representative series of male patients (n = 504) surviving the hospital stay of a first myocardial infarction the prevalence of hypertension and the influence of hypertension on the prognosis during 2 yr follow-up were studied. According to the definitions used hypertension had been detected before or was detected after myocardial infarction in 36% of the patients. Two thirds had a history of hypertension known before infarction. The systolic and diastolic blood pressures measured at 3 months and 1 yr after infarction increased with age. There was no difference between patients with and without hypertension with respect to a number of different variables recorded during the hospital period, nor in multiple risk according to a logistic function. There was no difference in death rate between the two groups. However, the rate of non-fatal reinfarction was significantly higher among the hypertensive patients. Hypertension remained as a risk factor for after myocardial infarction when the possible confounding influences of serum lipid levels and tobacco smoking were analysed.

Angina pectoris and myocardial infarction.

Angina pectoris was studied in a representative series of male patients (n = 504) with a first myocardial infarction (MI) surviving the hospital stay. The prevalence of questionnaire angina before MI was 28% and of effort-induced chest pain alone 40%. Of the patients with effort-induced chest pain, 72% retained symptoms also after MI. No correlation with age was found. Three months after and one year after infarction the prevalence of effort-induced chest pain was 55% and 45%, respectively. The patients with effort-induced chest pain before MI had a somewhat more severe clinical course and a significantly higher death rate (15% versus 6%) than those without chest pain.

Prognosis of women with exercise-induced ECG changes--results from a longitudinal population study.

A comprehensive population study of women aged 38-60 was carried out in Göteborg, Sweden in 1968-1969. A subsample comprising 194 women were submitted to a maximal work performance test using a bicycle ergometer. Exercise-induced ECG changes were common and as common in women as in men in Göteborg who had been studied in the same way. ST depressions (Minnesota Code items 4:1-2) were observed 4 min after maximal exercise in 30 women. All these women were still alive when a follow-up was made 6 years later, none had had myocardial infarction, and only 2 of them reported symptoms of angina pectoris. 1 woman later on had a fatal myocardial infarction as was found in a 12-year-follow-up study. It is concluded that exercise-induced ECG changes are of limited value for predicting myocardial infarction or death from ischaemic heart disease in women.

Smoking and myocardial infarction.

In a representative series of male patients with primary myocardial infarction the prevalence of smokers prior to infarction was higher than in representative population samples. The difference decreased with increasing age, Those patients generally had a somewhat more severe clinical course than those who continued to smoke. Nevertheless, those who stopped had only half the rate of non-fatal recurrences (P smaller than 0.01) and half the cardiovascular mortality-rate (P smaller than 0.05) of those who continued to smoke.

Comparative study of metoprolol and alpha-methyldopa in untreated essential hypertension.

The hypotensive actions of metoprolol and alpha-methyldopa have been compared in 37 men with previously untreated essential hypertension; 36 belonged to stage 1 and 1 to stage 2 of the WHO classification. After four weeks of placebo treatment the patients were randomly allocated to treatment with either of the two drugs. Treatment was started with metoprolol 75 mg daily or alpha-methyldopa 375 mg and was doubled after eight weeks. Satisfactory blood pressure control was defined as systolic blood pressure below 160 mm Hg and diastolic below 95 mm Hg. The patients were examined every four weeks and in those with unsatisfactory control the dose was gradually increased up to a maximum daily dose of metoprolol 450 mg or alpha-methyldopa 2250 mg. The trial lasted for 24 weeks after randomization. Five patients dropped out of the study. After six months, satisfactory blood pressure control was recorded in 16 out of 17 patients and 14 out of 15 patients treated with metoprolol and alpha-methyldopa, respectively. The average reduction in blood pressure produced by the two drugs was comparable. One patient in the alpha-methyldopa group developed drug exanthema and two patients a positive Coombs' test. Other side effects were few and did not differ between the two compounds.

A postmyocardial infarction clinic in Göteborg, Sweden. A follow-up of MI patients in a specialized out-patient clinic.

The registration of all myocardial infarctions (MI) in the city of Göteborg started on Jan. 1st 1968, when a special clinic was set up for ambulatory posthospital care of infarction patients. In 1970 this clinic was expanded to cover all patients below 67 years of age with MI in the city of Göteborg, the aim being to standardize and unify patient care and therapeutic regimens to provide opportunities for the study of patient characteristics, natural history, risk factors and effects of preventive measures. Results from such studies have been published, but so far no unified description of this special out-patient unit, nor of any similar unit elsewhere. Patient recruitment, considerations concerning personnel, patient education procedures and return visit routines are covered, together with investigative methods and criteria for the treatment of complications, symptoms and risk factors. The cumulative drop-out rate up to and including 2 years follow-up was only 3%. A brief bibliography of studies originating at the Postmyocardial Infarction Clinic is included.

A double-blind comparison of a novel indanone diuretic (MK-196) with hydrochlorothiazide in the treatment of essential hypertension.

1 The antihypertensive effect and tolerability of MK-196 (10 mg and 15 mg daily) was compared to hydrochlorothiazide (HCT; 50 mg daily) in a 4-week multiclinic, double-blind study involving 42 patients with mild to moderate, essential hypertension. 2 Both doses of MK-196 were as effective and sometimes more effective than HCT in lowering standing and supine systolic and diastolic blood pressures. 3 HCT consistently brought about significant increases in serum uric acid and significant decreases in serum potassium; both doses of MK-196 produced similar but less frequent and smaller changes in both of these parameters. 4 Both doses of MK-196 brought about significant decreases in body weight at Weeks 3 and 4 of drug treatment. 5 Patients taking MK-196 reported fewer adverse clinical reactions (10 mg = 15%; 15 mg = 13% than those taking HCT (21%). 6 MK-196 may offer a therapeutic advantage over HCT as an antihypertensive agent for use in the treatment of mild to moderate, essential hypertension.