The efficacy and tolerability of enalapril in a formulation with a very low dose of hydrochlorothiazide in hypertensive patients resistent to enalapril monotherapy.

The antihypertensive efficacy and tolerability of formulations of enalapril and low (12.5 mg) and very low (6 mg) doses of hydrochlorothiazide (HCTZ) were compared with enalapril and placebo. Four hundred and two patients with mild to moderate essential hypertension were treated with 20 mg enalapril for 8 weeks. Patients (n = 296) with persistent supine diastolic blood pressure > 95 mm Hg after enalapril monotherapy were randomized to receive enalapril/placebo (group I), 6 mg enalapril/HCTZ (group II), or 12.5 mg enalapril/HCTZ (group III) for another 8 weeks in a double-blind design. The mean reductions in blood pressure were significantly larger in groups II and III compared to group I, 7.3 (95% CI, -9.0; -6.2), 7.7 (-9.2;-6.3), and 4.1 (-5.9;-2.9) mm Hg, respectively P < .01 for groups II and III compared to group I). No difference in side effects was observed between the three groups. A very low dose of 6 mg HCTZ acts synergistically when given together with enalapril, but is devoid of adverse metabolic effects.

Relation between low dose of hydrochlorothiazide, antihypertensive effect and adverse effects.

Thiazide diuretics are widely used in the drug treatment of hypertension but their dose-response curves for the antihypertensive and adverse metabolic effects differ. To characterize the lower end of the dose-response curve a double-blind, parallel group trial was performed as multicentre study in Scandinavia. One hundred and eleven patients with newly diagnosed or previously treated mild to moderate hypertension (untreated diastolic blood pressure of 95-115 mmHg after 4 weeks placebo) were randomly allocated to various doses of hydrochlorothiazide (3, 6, 12.5 or 25 mg) or placebo for 6 weeks. Blood pressure and biochemical variables (plasma renin activity, serum potassium, magnesium, urate, fasting glucose, total cholesterol, HDL-cholesterol, triglycerides and apolipoproteins A1 and B were measured. 12.5 mg hydrochlorothiazide had a borderline effect on blood pressure whilst 25 mg had a definite antihypertensive effect. Biochemical changes were seen in plasma renin activity, serum potassium and urate after the 12.5 and 25 mg dose. Three and 6 mg had no effect on blood pressure or metabolic parameters.

Left ventricular mass, serum electrolyte levels and cardiac arrhythmias in patients with mild hypertension treated with cilazapril or hydrochlorothiazide.

Thirty-five patients with mild hypertension (WHO Class I) participated in a double-blind cross-over study involving two 8-week periods of treatment with cilazapril 2.5-5 mg once daily or hydrochlorothiazide 25-50 mg once daily, in each case preceded by a 4-week placebo period. Thirty-two patients completed the study, the aim of which was to compare the effects of the drugs on serum electrolyte levels, left ventricular mass and cardiac arrhythmias, as assessed by echocardiography and 48-h Holter monitoring. Both drugs significantly reduced systolic (P < 0.01) and diastolic (P < 0.001) blood pressures (comparisons with placebo periods). Cilazapril and hydrochlorothiazide had opposite effects on ventricular ectopic activity. The beneficial effect of cilazapril on ventricular extrasystole counts correlated significantly (P < 0.001) with the reduction of left ventricular mass index. Hydrochlorothiazide had no effects on left ventricular mass or diastolic function. Serum potassium values were significantly (P < 0.001) reduced by hydrochlorothiazide but there was no correlation between changes in potassium levels and changes in ventricular ectopic activity. The results of the study suggest that hydrochlorothiazide and cilazapril were equally effective in reducing blood pressure, but only cilazapril reduced left ventricular hypertrophy and suppressed ventricular ectopic activity.

Transdermal and oral clonidine.

The antihypertensive efficacy and side effects of transdermal clonidine (Catapres-TTS) and oral clonidine in equivalent doses on a weight basis were compared under double blind (double dummy) and cross over conditions in 16 outpatients with mild to moderate hypertension. After four weeks of placebo TTS and placebo tablet treatment, the patients were randomly placed into groups for six weeks of active treatment and, after an intervening week of placebo treatment, a second six week treatment period. Transdermal clonidine reduced supine and standing blood pressures (P less than 0.01) and heart rates (P less than 0.05) compared with the values at the end of the placebo periods, while oral clonidine did so to the extent of supine systolic blood pressure (P less than 0.01) and standing heart rate (P less than 0.05), respectively. There were, however, no differences in the values between transdermal and oral clonidine at the end of these six week periods. The plasma clonidine concentration was lower 12 hours after a dose of oral clonidine than after transdermal clonidine (P less than 0.05). The side effects did not differ. Seven patients said afterwards that they preferred the transdermal treatment, two preferred the oral treatment and four could not state any preference. It is concluded that transdermal clonidine is similar in its effect to oral clonidine in mild to moderate hypertension. Transdermal clonidine once a week may increase patients' compliance with antihypertensive treatment.

Nicardipine in combination with other antihypertensive drugs: calcium antagonist and prazosin have no additive antihypertensive effect?

The combined antihypertensive effects of a new 4-dihydropyridine derivate calcium antagonist, nicardipine, and propranolol, atenolol, labetalol, clonidine, prazosin or captopril were studied in 14 hypertensive outpatients. Nicardipine in combination with atenolol or clonidine most effectively lowered blood pressure. Prazosin combined with nicardipine had no additive antihypertensive effect at the doses used. Clonidine and prazosin in combination with nicardipine were not well tolerated. The antihypertensive effect of the drug combinations seemed to be related to their bradycardic effect.

The effect of potassium and potassium plus magnesium supplementation on ventricular extrasystoles in mild hypertensives treated with hydrochlorothiazide.

Eleven mild hypertensives with base-line ventricular extrasystoles underwent a 24-week period of treatment with hydrochlorothiazide 50 mg daily. After 8 weeks of treatment either potassium as hydrochloride 1 g twice daily, or a combination of potassium hydrochloride 1 g and magnesium hydroxide 500 mg twice daily was added to the diuretic therapy in a randomised, double-blind, cross-over design. Each treatment period lasted 8 weeks. Supplementation with potassium or potassium plus magnesium resulted in a clear trend for suppression of ventricular ectopic activity. There was no difference in ventricular extrasystoles between the two supplementation groups. Supplementation with potassium plus magnesium but not with potassium only, resulted in a significant rise in serum potassium values (P less than 0.01). Our study suggests that potassium should be supplemented in thiazide-treated hypertensives who are prone to develop ventricular extrasystoles. Addition of magnesium to potassium supplementation does not result in further improvement in ventricular ectopic suppression.

Abrupt change from a beta-adrenoceptor blocking drug to enalapril in hypertension.

The haemodynamic and hormonal effects of an elective change of antihypertensive therapy from a beta-adrenoceptor blocking drug to a converting enzyme inhibitor, enalapril, were monitored in 12 hypertensive in-patients (WHO I). Blood pressure and heart rate were determined every 2-4 h using an automatic sphygmomanometer during an abrupt cessation of the previous beta-adrenoceptor blocking drug and commencement of treatment with enalapril 20 mg o.d. 12 h later. Mean blood pressure values at rest and during the hand grip test were lower when on enalapril, but heart rate was significantly higher, and three patients suffered from palpitations during the change. The change resulted in an improvement in cardiac function both at rest and during isometric work, as shown by echocardiography. A rapid decrease in plasma angiotensin converting enzyme (ACE) activity and an increase in renin activity were also seen after the change, while plasma levels of atrial natriuretic peptide (ANP) decreased towards normal values. The results suggest that an abrupt change from a chronic beta-adrenoceptor blocking drug to enalapril is safe, feasible and is likely to produce favourable haemodynamic and hormonal effects in hypertensive patients.

Comparisons of verapamil administration twice and three times daily in hypertension.

The antihypertensive effect of verapamil administered either two or three times daily was compared in a double blind, cross over study in 15 patients with mild to moderate essential hypertension. During the dose titration period with t.i.d. administration, normotension was obtained with daily doses of 240 mg in 7 patients, 360 mg in 7 patients and with 480 mg in one patient. Systolic and diastolic blood pressures (BP) in the supine (13/14 mmHg) and standing (14/14 mmHg) positions were significantly (p less than 0.001) reduced during the dose titration period. There was no statistically significant difference in the BP values between the twice and three times a day regimens. Five to 7-fold individual variations in the serum verapamil concentrations between individuals were observed. No significant correlations were found between serum drug concentrations and the change in mean arterial BP. There was no significant difference in the incidence of side effects between the two treatment regimens. Our results suggest that verapamil administered twice daily is effective in mild to moderate hypertension.

5- and 10-year mortality in a rural middle-aged population at Haapavesi, Northern Finland, with special reference to ischaemic heart disease.

As a part of a larger prospective population study of ischaemic heart disease (IHD) the causes of 5- and 10-year mortality were analysed in 1554 rural inhabitants aged 40 to 59 years (90.0% of the population of this age group) in Northern Finland. The total mortality in 5 years was 2.3% among women and 6.3% among men. The respective 10-year mortality figures were 6.2% and 13.4%. The proportion of IHD as a cause of these deaths among women was 35% and 34% in 5 and 10 years, respectively; among men 46% and 46% of the deaths were due to IHD in 5 and 10 years, respectively. Among women the proportion of strokes was 22% and 19% in 5 and 10 years, respectively; the other causes of death among women amounted to 43% and 47% in 5 and 10 years, respectively. Among men, strokes resulted in the death of 14% and 7% in 5 and 10 years, respectively, the other causes of death amounted to 40% and 47% in 5 and 10 years, respectively. The incidence of IHD as a cause of death among women was higher than previously reported.

Combined action of enalapril or timolol with hydrochlorothiazide plus amiloride in hypertension.

59 mild to moderate hypertensives were treated for four weeks with 50 mg hydrochlorothiazide plus 5 mg of amiloride, then concomitantly with these diuretics with either enalapril (10-20 mg) or timolol (10-20 mg) in two parallel treatment groups for an additional 12 weeks in an open study. Addition of these drugs lowered the blood pressure by 25 +/- 3/16 +/- 2 mm Hg and 15 +/- 3/14 +/- 1 mm Hg, respectively. The difference of the reduction of the systolic blood pressure between enalapril and timolol group at the end of the combined treatment was statistically significant (p less than 0.01). The mean serum potassium was elevated by 0.3 mmol/l after addition of enalapril to the diuretic treatment, but none of the patients developed hyperkalaemia. No adverse effects on other routine laboratory values were observed. Both drug combinations can be considered efficient, well tolerated and safe in the treatment of mild to moderate hypertension.

Intake of alcohol and benzodiazepines and reliability of drug history in patients admitted to hospital.

Withdrawal syndromes of both alcohol and benzodiazepines have been recognized increasingly as modifying symptoms of diseases in acute medicine. In 198 consecutive patients admitted for medical or surgical reasons to Oulu University Hospital blood alcohol and urine metabolites of benzodiazepines were measured in samples taken on admission. Based on these measurements out of 198 patients 48 (24.2%) had taken alcohol and/or benzodiazepines. Only alcohol was detected in 17 (8.6%) and only benzodiazepines in 27 (13.6%) patients. Both benzodiazepines and alcohol were found in four (2.2%) patients. When compared with drug history obtained on admission 70.6% of alcohol and 33.3% of benzodiazepine intakes were recorded. No clear withdrawal symptoms were seen in patients during the observation time which varied from 1 to 7 days (mean 2.5 days). Our results show that many patients neglect their drug intakes from drug history on admission. The physician should keep in mind the possibility of withdrawal symptoms in acute medicine.

Cardiac arrhythmias in hypertensive outpatients on various diuretics. Correlation between incidence and serum potassium and magnesium levels.

Twenty-four hypertensive out-patients (WHO I) underwent an ambulatory 24-hour electrocardiogram-monitoring both before and after 8 weeks treatment with either hydrochlorothiazide (20-50 mg/day, N = 6), indacrinone (50-100 mg/day, N = 6) or indacrinone plus amiloride (50-100 mg and 5-10 mg/day, N = 12) in a double-blind fashion in 3 parallel groups. A 4-weeks placebo run-in period preceded the active treatment. Serum potassium fell significantly in the hydrochlorothiazide group (p less than 0.001) and in the indacrinone group (p less than 0.005). Serum magnesium values remained unchanged. In 4 out of the 24 patients ventricular ectopic activity increased but there was no correlation with changes in serum potassium or magnesium values in these patients. Treatment with different diuretics had a similar influence on the occurrence of ventricular extrasystoles.

Interaction between clonidine and alpha blockers.

This report reviews the available evidence for and against the combined use of clonidine and prazosin in treating hypertension. Clinical studies have resulted in modest or no enhancement of the antihypertensive effects when prazosin has been added to clonidine. This report discusses the possible mechanisms of an interaction of clonidine and prazosin, which may show cause that the antihypertensive effects of these drugs are not additive.

Antihypertensive effects of urapidil and clonidine: a double-blind cross-over study.

The antihypertensive effects of urapidil and clonidine have been studied in a double-blind cross-over trial in 11 hypertensive outpatients with mild to moderate hypertension, at rest and during isometric exercise. Urapidil 30 mg b.i.d. significantly decreased the standing diastolic blood pressure (p less than 0.05) and the systolic blood pressure at the end of isometric exercise (p less than 0.05). Clonidine 0.075-0.15 mg b.i.d. was more effective in decreasing both systolic and diastolic blood pressure in the supine and standing positions as well as during isometric work (p less than 0.05-0.001). Urapidil caused fewer side-effects than clonidine. Overall, in the doses used urapidil had a weaker antihypertensive effect and caused fewer side-effects than clonidine.

Haemodynamic effects of prazosin combinations during dynamic and isometric exercise.

Haemodynamic effects of atenolol 50 mg, clonidine 0.15 mg, and prazosin 5 mg, given twice daily, and of the combinations atenolol + prazosin and clonidine + prazosin were studied in 8 hypertensive outpatients. Measurements were made at rest, during isometric sustained handgrip and submaximal ergometer work in mostly double-blind and cross-over fashion. Given individually atenolol and prazosin lowered resting supine blood pressure. The addition of prazosin increased the antihypertensive effects of atenolol but not of clonidine. At the end of the isometric exercise atenolol and prazosin given alone both lowered diastolic blood pressure as compared to respective pretreatment values. During handgrip prazosin contributed a little, but not much, to the antihypertensive effects of atenolol and clonidine. During dynamic exercise atenolol, clonidine, and prazosin given alone each lowered blood pressure, prazosin decreasing diastolic blood pressure in particular. Prazosin added to the antihypertensive effect of atenolol more than that of clonidine. Echocardiographic measurements revealed no significant differences between treatments at rest. During handgrip the mean velocity of left ventricular circumferential muscle fibre shortening was reduced by atenolol as compared to pretreatment values. We conclude that atenolol + prazosin may help the patients to maintain adequate haemodynamics during daily physical stresses whilst the combination prazosin + clonidine may not offer any particular advantages.

Comparison of cyclothiazide and hydrochlorthiazide in hypertension. Effects of different doses of diuretics.

In a group of 12 hypertensive outpatients, randomized double-blind cross-over comparison of the antihypertensive effect of various doses of cyclothiazide and hydrochlorthiazide revealed that 2.5 mg of cyclothiazide daily or 25 mg of hydrochlorthiazide daily have an equal antihypertensive effect. Increasing the dose of either diuretic did not further reduce the blood pressure.

Disopyramide pharmacokinetics in patients with acute myocardial infarction.

To study the effects of acute myocardial infarction on the pharmacokinetics of disopyramide a single oral dose of disopyramide base (200 mg) was administered to 6 patients with myocardial infarction both in the acute (Study I) and recovery (Study II) phases. An intravenous tracer dose of 14C-disopyramide (2.5 micrograms/0.3 mg) was given simultaneously with the oral dose. On the basis of the intravenous tracer data, the volume of distribution, binding to plasma proteins, total plasma clearance, renal clearance and elimination half-life of disopyramide and mono-N-dealkyl disopyramide were the same in Studies I and II. The peak serum concentrations of disopyramide after oral dosing in Studies I and II were 2.6 +/- 1.2 (SEM) and 6.4 +/- 1.9 microgram/ml, respectively (p less than 0.05), the peak times 3.29 +/- 1.22 and 1.21 +/- 0.39 h (N.S.) and the AUCINF 38.0 +/- 7.7 and 60.7 +/- 9.9 micrograms . h . ml-1 (p less than 0.05). The recovery of disopyramide in urine over 3 days averaged 46% and 47% of dose, and that of mono-N-dealkyl disopyramide 22% and 16% of the dose, respectively. Thus, the gastrointestinal absorption of disopyramide was disturbed, resulting in low plasma concentrations after oral dosing, whereas the elimination of disopyramide was unaltered in the acute phase of myocardial infarction.

Botulism revisited. A case report.

Two cases of food-borne botulism following consumption of commercially canned German-made liver sausage are presented. The more serious case involved respiratory paralysis for 15 days, the milder one only muscle weakness in the area of the cranial nerves. Both of the patients recovered well and returned to their jobs half a year after the onset of the illness.

Survey of acute poisoning cases in North-Finland during 1973-1982.

In a total of 2239 toxicological laboratory screenings requested from health centres and hospitals in North-Finland during 1973-1982, the most commonly found drug groups were benzodiazepines and phenothiazines. Alcohol was found in an average 45% of the patients screened during the years 1979-1982. Females accounted for 45% of all requests. No seasonal variation in the requests could be observed.