European Journal of Clinical Pharmacology

Frei, F.; Imhof, P.; Dubach, U.

doi: 10.1007/BF00614383pmid: 4152857

228 7 7 1 1 F. Frei P. Imhof U. C. Dubach Research Department, Pharmaceuticals Division CIBa-GEIGY Limited Basle the Department of Internal Medicine University Medical Policlinic, Cantonal Hospital of Basle Switzerland Summary The effects of single oral doses of oxprenolol (20 and 80 mg), phentolamine (20 and 40 mg), and combinations of oxprenolol and phentolamine (80:20 and 20:40 mg, respectively) on blood pressure, heart rate and the systolic time intervals (Q—S 2c , PEP c , LVET c and PEP/LVET) have been studied under double-blind conditions in seven healthy volunteers during recumbency and passive tilting. Heart rate was slowed by oxprenolol and slightly increased by phentolamine, but was not affected by either of the combinations. There were only minimal non-significant changes in blood pressure in the subjects, all of whom were normotensive. Of the systolic time intervals, PEP c was most affected: it was prolonged by oxprenolol because of reduction in myocardial contractility, and shortened by phentolamine as a result of the cardiostimulant effect of this compound. When the two drugs were administered in combination, the negative inotropic effects of the β-blocker always predominated. The changes induced by the drugs were more pronounced during upright titling than in the recumbent position. Measurement of PEP c provides a suitable means of assessing the influence of cardiovascular drugs on left ventricular function in pharmacological studies in man.

Villani, F.; Perret, C.; Jéquier, E.; Schelling, J.

doi: 10.1007/BF00614384pmid: 4851683

228 7 7 1 1 F. Villani C. Perret E. Jéquier J. L. Schelling Division de Pharmacologie clinique, Département de Médecine Hôpital cantonal universitaire Lausanne Switzerland Summary Seven patients with congestive heart failure received an infusion of phentolamine, 5 mg per hour for one hour, and seven others, considered as controls, received an infusion of dextrose. The small dose of phentolamine produced a minimal increase in pulse rate, and no significant change in arterial blood pressure and forearm blood flow. Venous distensibility was measured in the forearm by occlusion plethysmography. It was significantly increased by phentolamine, the rise in venous volume being 20–30% greater than in controls for the same ‘effective venous pressure’.

Gugler, R.; Herold, W.; Dengler, H.

doi: 10.1007/BF00614385pmid: 4853602

228 7 7 1 1 R. Gugler W. Herold H. J. Dengler Medizinische Universitätsklinik 5300 Bonn Federal Republic of Germany Clinical Pharmacology-Toxicology Center University of Kansas Medical Center 66103 Kansas City Kansas USA Summary The kinetics of absorption, distribution and excretion of pindolol have been investigated in 17 volunteers after an oral dose or intravenous infusion of 5 mg. The calculated absorption was 92%. The time course of the plasma levels appeared to follow first order kinetics with an apparent half life of 3.6 (oral) and 3.1 (i.v.) hours. The cumulative urinary excretion at t =∞ was 36.1% and 39.2% of the dose administered, respectively, indicating extensive metabolism of the drug. The distribution volume was 136 l. Peak plasma levels were found 80 min after oral administration and they showed up to 4-fold variation after identical doses. Renal clearance was 216 ml×min −1 and total clearance was 483 ml×min −1 . In plasma 57% of pindolol was bound to protein.

Ohnhaus, E.; Nüesch, E.; Meier, J.; Kalberer, F.

doi: 10.1007/BF00614386pmid: 4853607

228 7 7 1 1 E. E. Ohnhaus E. Nüesch J. Meier F. Kalberer Experimental Therapeutics Department, Biological and Medical Research Division and Biopharmaceutical Section Sandoz Ltd. Basel Switzerland Inselspital Med. Universitätsklinik 3000 Bern Switzerland Summary The elimination of pindolol in 25 patients with various degrees of renal failure has been studied after an intravenous dose of 3 mg. A linear correlation was not found between the elimination rate of pindolol and the endogenous creatinine clearance, and the half-life of the unchanged drug was independent of the severity of the renal failure. This implies greater metabolism of pindolol in anuric patients and the extrarenal elimination rate constant k m was increased. Three patients with severe renal failure were given 3 mg 14 C-pindolol. They showed almost constant plasma levels of radio-activity for 6 h and then slow excretion with a half-life of 48 h, because of accumulation of metabolites in the blood. Up to 90% of the metabolites are glucuronides and sulphates which have no beta-blocking or other clinical activity. Thus, to produce beta-adrenergic blockade the same dose of indolol is required in healthy patients as in those with uraemia.

Odar-Cederlöf, I.; Borgå, O.

doi: 10.1007/BF00614387pmid: 4852619

228 7 7 1 1 I. Odar-Cederlöf O. Borgå Department of Medicine Karolinska Hospital Stockholm Department of Clinical Pharmacology Huddinge University Hospital, Karolinska Institute Stockholm Summary Diphenylhydantoin (2 mg/kg) was infused intravenously in four uraemic patients and four healthy volunteers and its plasma concentration measured during and after the infusion. The plasma concentrations were considerably lower in the uraemic subjects and the apparent volume of distribution was higher. These observations could be explained by the lower plasma protein binding of diphenylhydantoin in the uraemics. The overall elimination rate constant β was greater (shorter half-life) in the uraemic patients. This difference could not be explained by reduced plasma protein binding, but it might be due to induction of diphenylhydantoin metabolism in the uraemic state. it is concluded that monitoring of the plasma levels of drugs in uraemic patients should be combined with determination of the extent to which the compounds are bound to plasma proteins.

Schwartz, D.; Jordan, J.; Ziegler, W.

doi: 10.1007/BF00614388pmid: 4853605

228 7 7 1 1 D. E. Schwartz J. C. Jordan W. H. Ziegler Departments of Experimental Medicine and Clinical Research F. Hoffmann-La Roche & Co. Ltd. Basle Switzerland Summary 14 C-labelled benserazide was administered to six patients with parkinsonism and total radioactivity was measured in the plasma, urine and faeces. Three patients received benserazide both orally and intravenously, while three other patients received benserazide orally alone and together with L-DOPA (= MADOPAR ® ). Plasma levels did not follow first-order kinetics, but indicated rapid absorption of an oral dose. Following intravenous and oral administration, excretion of radioactivity was 88.7 and 57.7% respectively in the urine, 10.1 and 30.7% respectively in the faeces. L-DOPA slightly increased the absorption of benserazide. Following the administration of an oral dose to rats benserazide related radioactivity was distributed almost entirely outside the brain. The drug therefore appears to be suitable for blocking extracerebral decarboxylase whilst leaving the intra-cerebral enzyme almost unaffected.

Monro, A.; Welling, P.

doi: 10.1007/BF00614389pmid: 4854667

228 7 7 1 1 A. M. Monro P. G. Welling Department of Drug Metabolism, Pfizer Central Research Pfizer Ltd. Sandwich Kent England The School of Pharmacy University of Wisconsin Madison Wisconsin U.S.A. Summary A specific TLC assay procedure has been used to compare the bioavailability of three brands of chlorpropamide, Diabetasi, Diabinese, and Prodiaben. Serum concentrations of drug were determined at various times after administration of single oral doses to normal volunteers in a crossover study. Prodiaben gave significantly lower serum levels than the other two brands during the first 24 h after dosing.

Boman, G.; Malmborg, A.

doi: 10.1007/BF00614390pmid: 4212324

228 7 7 1 1 G. Boman A. -S. Malmborg Departments of Thoracic Medicine and Clinical Microbiology Karolinska Hospital Stockholm Sweden Department of Clinical Pharmacology Huddinge Hospital Stockholm Sweden Summary Single oral doses of rifampicin (RMP) were given to 31 patients with pleural effusions of various aetiologies. The concentrations of RMP and its active metabolites in pleural fluid and plasma were determined by an agar diffusion method using paper discs as diffusion centres. The plasma concentrations reached a peak within 3 h and then declined monoexponentially; in pleural fluid, RMP concentration rose slowly to reach a plateau that lasted for several hours. There were marked differences between subjects in the observed concentrations of RMP. During the first 12 h the plasma levels exceeded those in pleural fluid, but after 24 h the concentration of RMP in pleural fluid was higher than in plasma. If multiple oral doses of RMP 10 mg/kg b. w. are given every 24 h, as is common in the treatment of tuberculosis, therapeutic concentrations may be expected in pleural fluid for the major part of each day.

Ohnhaus, E.; Nüesch, E.

doi: 10.1007/BF00614391pmid: 4852635

228 7 7 1 1 E. E. Ohnhaus E. Nüesch Experimental Therapeutics Department, Biological and Medical Research Division Sandoz Ltd. Basel Switzerland Inselspital Med. Universitätsklinik 3000 Bern Switzerland Summary Pizotifen (BC 105) has an orexigenic effect in patients with pulmonary tuberculosis. As these cases are often treated with isonicotinylhydrazine (INH), any effect of one of these drugs on the absorption of the other has been examined in a cross-over study in 8 healthy male volunteers. No difference was found between the absorption of INH given alone or together with pizotifen. It should be safe, therefore, to employ the combination of the orexigenic drug and INH in the treatment of tuberculosis as there will be no change in the concentration of therapeutic drug achieved.

Ringqvist, T.

doi: 10.1007/BF00614392pmid: 4851712

228 7 7 1 1 T. Ringqvist Department of Clinical Physiology Vänersborg-Trollhättan Central County Hospital Vänersborg Sweden Summary Lung resistance and the ECG were studied before and after i.v. injection of verapamil in six healthy subjects and in nine patients with obstructive airways disease. No systematic effect on lung resistance was found in any of the groups. There was prolongation of atrio-ventricular conduction time in those healthy subjects who received a larger dose of verapamil. Inhalation of isoprenaline caused a significant decrease of lung resistance in patients with obstructive airways disease. It is concluded that verapamil is not contraindicated in the latter disease. The results support the hypothesis that verapamil causes quantitatively different effects on the same type of tissue at different sites.