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doi: 10.1007/BF00606546pmid: 9291
228 9 9 5 6 R. I. Ogilvie Division of Clinical Pharmacology, The Montreal General Hospital and Depts. of Medicine, Pharmacology and Therapeutics McGill University Montreal Quebec Canada Summary Five male subjects with essential hypertension received chlorthalidone at each of four dose levels (25, 50, 100, and 200 mg/day) for eight week periods each preceded by an eight week placebo period. Dosage order was randomized and double-blind. During the last week of each active and placebo period an upright bicycle exercise study was carried out at three loads (100, 200, 300 kpm/min) for 6 min each. Oxygen consumption at the maximal workload was 42% of predicted at a heart rate of 170. During placebo therapy, increasing workloads were associated with a progressive increase in blood pressure, heart rate, and pressure-rate index (systolic pressure times heart rate). With increasing doses of chlorthalidone up to 100 mg/day, there was a progressive reduction in blood pressure and pressure-rate index. At 200 mg/day there were paradoxical increases in diastolic pressures, heart rates and pressure-rate indices above values observed at 100 mg/day. With increasing doses of chlorthalidone, there was a progressive increase in arterial blood CO 2 content and pH. Increasing workloads were associated with increased arterial blood lactate and decreased arterial blood pH. The changes in lactate and pH were not different at the different dose levels. The best antihypertensive effect in these exercising subjects was observed at a daily dose of 100 mg of chlorthalidone. The exercise response was useful in the determination of potentially adverse hemodynamic consequences of the larger dose of chlorthalidone.
Wirth, K.; Frölich, J.; Hollifield, J.; Falkner, F.; Sweetman, B.; Oates, J.
doi: 10.1007/BF00606547pmid: 971699
228 9 9 5 6 K. E. Wirth J. C. Frölich J. W. Hollifield F. C. Falkner B. S. Sweetman J. A. Oates Department of Medicine and Pharmacology, Division of Clinical Pharmacology Vanderbilt University Nashville Tennessee USA Pharmakologisches Institut der Univ. Moorenstraße 5 D - 4000 Düsseldorf Federal Republic of Germany Summary The effect of spironolactone on the metabolism of intravenously administered 3 H-digitoxin (80 µCi) was investigated in eight patients. In three of them the labelled glycoside was given on a second occasion after spironolactone treatment had been discontinued for at least 65 days. Of total urinary radioactivity 79 % was unaltered drug and 12 % consisted of water soluble compounds. No digitoxigenin or digoxigenin and only trace amounts (<2 %) of digoxin and the bis- and monoglycosides of digoxigenin were found. After spironolactone total urinary radioactivity was unchanged but the fraction eliminated as unchanged digitoxin fell from 79 to 66 % and the water soluble compounds increased from 12 to 26 % (p<0.05). In addition spironolactone caused a 20 % reduction in the half-life of serum radioactivity (p<0.01) and a 16 % reduction in the volume of distribution (p<0.05). Induction of hepatic enzymes by spironolactone is proposed to explain the alteration in the metabolism of digitoxin in man. Both the altered metabolic pattern and the reduction in the volume of distribution appear to contribute to the reduction in half-life.
O'Malley, K.; Velasco, M.; Wells, J.; McNay, J.
doi: 10.1007/BF00606548pmid: 971700
228 9 9 5 6 K. O'Malley M. Velasco J. Wells J. McNay Clinical Pharmacology Program and Division of Nephrology, Dept. of Medicine Emory University School of Medicine Atlanta Georgia U.S.A. Dept. of Pharmacology and Therapeutics Dundee Univ. Medical School Ninewells Dundee Scotland, U.K. Summary A study, using non-invasive techniques, was carried out in ten patients with essential hypertension to examine the mechanism of the hypotensive effect of propranolol when used in combination with a potent vasodilator antihypertensive — minoxidil. The hypotensive effect of minoxidil, a mean (± SEM) decrease of 42.4±4.3 mm Hg, was accompanied by a marked increase in heart rate, cardiac index and plasma renin activity and a significant decrease in total peripheral resistance, limb vascular resistance and pre-ejection period. Addition of propranolol further reduced mean arterial pressure by an average of 12.9±2.0 mm Hg. Propranolol returned cardiac index to control values and total peripheral resistance index rose but not to control levels. Plasma renin activity was significantly reduced by propranolol. By multiple regression analysis no correlation was found between propranolol-induced decrease in mean arterial pressure and changes in cardiac index, total peripheral resistance index or plasma renin activity. Quantitatively, the reduction in cardiac index observed probably accounted for the hypotensive effect of propranolol. The role of plasma renin activity reduction in the hypotensive effect of propranolol in this situation remains to be clarified. The findings in the present study were consonant with the known actions of vasodilator antihypertensive agents and propranolol and indicate the applicability of non-invasive methodology to the investigation of cardiovascular drugs in man.
Hansson, L.; Westerlund, A.; Åberg, H.; Karlberg, B.
doi: 10.1007/BF00606549pmid: 786662
228 9 9 5 6 L. Hansson A. Westerlund H. Åberg B. E. Karlberg Dept. of Internal Medicine I Sahlgren's Hospital Göteborg Sweden Dept. of Internal Medicine Academic Hospital Uppsala Sweden Dept. of Internal Medicine University Hospital Linköping Sweden Summary Propranolol was given to 30 patients with essential hypertension following randomised, double-blind administration of either placebo or a new cardioselective beta-adrenergic receptor antagonist, atenolol (Tenormin ® , ICI 66 082). Both atenolol and propranolol caused statistically significant reduction of recumbent and erect blood pressure and heart rate. There were no important differences between these variables on comparison of atenolol and propranolol.
Brown, H.; Carruthers, S.; Kelly, J.; McDevitt, D.; Shanks, R.
doi: 10.1007/BF00606550pmid: 971701
228 9 9 5 6 H. C. Brown S. G. Carruthers J. G. Kelly D. G. McDevitt R. G. Shanks Department of Therapeutics and Pharmacology The Queen's University Belfast Northern Ireland Summary The effects of sotalol after oral administration were measured on the tachycardia induced by strenuous exercise in normal subjects. Plasma sotalol levels were also determined. The oral administration of sotalol (50, 100, 200 and 400 mg) to 6 subjects produced a progressive reduction in the tachycardia induced by severe exercise. This was similar to the effects of 25, 50, 100, 200, 400 and 800 mg given to different subjects. Each increase in sotalol dose produced a successively greater reduction in exercise tachycardia. This did not appear to be maximum even with 800 mg. Oral sotalol was rapidly absorbed and produced peak blood levels in 2 – 3 hours. The plasma levels of sotalol measured 2 hours after the oral administration of 25 to 800 mg showed never more than a six-fold variation between different subjects. The half-life of sotalol in plasma was 12.7 ± SE 1.6 hours. There was a significant correlation between the logarithm of the plasma sotalol concentration and the percentage reduction of exercise heart rate. It is concluded that the oral administration of sotalol either once or twice daily (depending on dose level) will provide satisfactory 24-hour blockade of β-adrenoceptors.
Rietbrock, N.; Guggenmos, J.; Kuhlmann, J.; Hess, U.
doi: 10.1007/BF00606551pmid: 971702
228 9 9 5 6 N. Rietbrock J. Guggenmos J. Kuhlmann U. Hess Dept. of Clinical Pharmacology Klinikum Steglitz der Freien Universität Berlin Berlin Federal Republic of Germany Summary To obtain true half lives, glycoside elimination from six healthy subjects was studied for 14 days after multiple intravenous doses or oral administration of a daily maintenance dose of β-methyldigoxin 0.3 mg. After oral or intravenous administration of β-methyldigoxin ceased, the plasma concentrations declined from the 14th to the 16th days with a half life of 1.7 days. From the 16th to the 20th day a change from a shorter to a longer half life of 2.8 and 2.9 days was observed. Similar half lives were found in urine: after the last dose the initial slope from the 14th to the 16th day had a half life of 1.8 days, and the terminal slope had one of 3.2 days. The results indicate release of the glycoside from slowly equilibrating tissues.
Levine, D.; Ramsay, L.; Auty, R.; Branch, R.; Tidd, M.
doi: 10.1007/BF00606552pmid: 786663
228 9 9 5 6 D. Levine L. Ramsay R. Auty R. Branch M. Tidd Dept. of Clinical Pharmacology Bristol Royal Infirmary Bristol England Division of Scientific Affairs G.D. Searle & Co. Ltd. High Wycombe England Summary The pharmacological activity of single oral doses of a new aldosterone antagonist, prorenoate potassium, has been compared with spironolactone and placebo in a balanced double-blind crossover study in six healthy subjects. Endogenous mineralocorticoids were stimulated by administration of frusemide followed by dietary sodium restriction, and the urinary excretion of electrolytes in response to prorenoate potassium, spironolactone and placebo was measured over a 24 hour period. Significant activity of prorenoate potassium and spironolactone was observed between 2 – 24 hours after medication, with peak activity at 6 – 8 hours. The active drugs significantly increased sodium excretion and the sodium: potassium (Na/K) ratio, but changes in potassium excretion were not significant. The total urine Na/K response to prorenoate potassium 45 mg was significantly greater than to spironolactone 100 mg.
doi: 10.1007/BF00606553pmid: 786664
228 9 9 5 6 G. K. Wolf Institut für Medizinische Dokumentation Statistik und Datenverarbeitung der Universität Heidelberg Heidelberg Federal Republic of Germany Summary The effect of Arwin ® on peripheral arterial occlusive disease has been studied in two multicentre trials. In the first, in cases of severe peripheral arterial circulatory disorders of the lower extremities with permanent rest pain (stages III and III + IV according to Fontaine) Arwin ® had a better intravenous therapeutic effect than anticoagulant treatment. A further trial was done to investigate whether subcutaneous administration of Arwin ® would have an effect superior to classical conservative therapy with vasodilator drugs in this type of disease. The results were assessed by sequential analysis. Arwin ® was again shown to be a much better treatment. Problems of medical documentation and statistics are discussed in relation to the value of sequential analysis.
doi: 10.1007/BF00606554pmid: 786665
228 9 9 5 6 C. Grassi G. C. Morandini Dept. of Tuberculosis and Respiratory Diseases Pavia Univ. Pavia Italy Summary In 69 out-patients with chronic bronchitis in 6 centres the effects of acetylcysteine 600 mg daily, 3 days a week for 6 months, and a placebo have been compared in a double-blind controlled trial. Thirty-five patients were treated with the mucolytic and 34 with the dummy preparation. In the former the clinical course of the chronic bronchitis improved to a greater extent and a significantly lower number of exacerbations was observed. The advantages of long-term oral treatment with the mucolytic in chronic bronchitis suggest that it may be useful as an alternative to long-term antibiotic prophylaxis, or to complement brief courses of antibiotics, in addition to the usual physiotherapy.
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