European Journal of Clinical Pharmacology

Gammage, M.; Murray, R.; Littler, W.

doi: 10.1007/BF00615952pmid: 3709607

228 29 29 6 6 M. D. Gammage R. G. Murray W. A. Littler Department of Cardiovascular Medicine University of Birmingham and East Birmingham Hospital, Bordesley Green East Birmingham UK Summary Eleven patients with acute left ventricular failure following acute myocardial infarction (mean pulmonary capillary wedge pressure (PCW)>20 20 mmHg) were entered into an open, haemodynamic study of oral isosorbide-5-mononitrate (ISMN). Left ventricular failure was resistant to intravenous diuretic therapy. No patient received concurrent cardioactive drugs nor further diuretic therapy during the study period. Haemodynamic data were acquired via a flow-directed thermodilution catheter placed in the pulmonary artery. Baseline data were acquired prior to the intravenous administration of an ISMN challenge. Thereafter, oral ISMN (20 mg, 8 hourly) was administered over 48 h. Following intravenous ISMN challenge, mean PCW fell from 26.2 to 17.5 mmHg. Cardiac index fell from 2.4 to 2.3 l/min/m 2 due to a fall in heart rate (103 to 96.8 beats/min) as stroke volume and blood pressure were unchanged. At 8 h following ISMN, two patients were withdrawn due to hypotension (systolic pressure <85 mmHg). In the remainder, PCW remained acceptable throughout 48 h (13.1 mmHg at 48 h), cardiac output, systemic blood pressure and heart rate showed no further significant change. These data suggest that ISMN is effective in the treatment of acute left ventricular failure following acute myocardial infarction.

Plänitz, V.

doi: 10.1007/BF00615953pmid: 3709608

228 29 29 6 6 V. Plänitz Clinical Research Beiersdorf AG Hamburg Federal Republic of Germany Summary Thirty hypertensive outpatients were treated with moxonidine for 4 weeks in an intraindividual comparison study. After a wash-out period of at least 2 weeks the same patients were given prazosin for 4 weeks. The initial daily doses were 0.2 mg moxonidine and 1 mg prazosin. The antihypertensive dose was titrated individually until the diastolic blood pressure (BP) fell below 95 mm Hg. Within 3 days of dose titration, a mean dose of 0.37 mg moxonidine produced a significant decrease in BP from a mean of 184/100 to 155/90 mm Hg, while in prazosin treated patients 5 to 8 days were necessary to reduce the BP from 180/100 to 149/89 mm Hg; the mean prazosin dose was 2.8 mg. In addition to the lower dose of moxonidine compared to prazosin, it was found that in 67% of patients moxonidine was given once daily whilst prazosin was administered three-time daily in 73%. Within the first week of moxonidine treatment 14/30 patients experienced dryness of the mouth, but it was so mild that the patients did not want to discontinue the trial. In contrast, 3/30 patients discontinued therapy with prazosin because of side effects. The most frequent adverse effects of prazosin were orthostatic dysregulation in 6 patients, pain in the chest in 5, giddiness and tachycardia in 4 and nervousness in 3 patients; no patient had these complaints whilst on moxonidine. In intraindividual comparisons with moxonidine, efficacy, tolerance and the well-being of the patients were significantly better than when on prazosin.

Silke, B.; Graham, D.; Verma, S.; Reynolds, G.; Frais, M.; Finlayson, J.; Taylor, S.

doi: 10.1007/BF00615954pmid: 3709609

228 29 29 6 6 B. Silke D. J. M. Graham S. P. Verma G. Reynolds M. A. Frais J. R. Finlayson S. H. Taylor University Department of Cardiovascular Studies The General Infirmary at Leeds Leeds UK Summary Pharmacokinetic, haemodynamic and radionuclide studies explored the acute pharmacokinetic and pharmacodynamic actions of nicardipine in patients with coronary heart disease. Nicardipine infusion resulted in dose-related reductions in systolic and diastolic blood pressure and an increased heart rate. Pharmacodynamic activity was evident between 12 and 24 min following 5 and 10 mg i.v. nicardipine but by 3–6 min following the higher doses of 15 and 20 mg; hypotensive activity persisted for up to 2 h. Post-infusion nicardipine concentrations declined biexponentially; however the limited data precluded formal compartmental analysis. Plasma clearance ranged from 5–12 ml/min/kg, and appeared lower than previously reported volunteer data. The haemodynamic actions of nicardipine (10 mg infusion over 10 min) in 6 patients undergoing diagnostic catheterization were reductions in systolic, diastolic and mean systemic arterial pressure and systemic vascular resistance index. Heart rate and stroke volume index increased, and there was a small but statistically significant increase in pulmonary artery occluded pressure. Radionuclide parameters were measured in 20 patients with stable angina, at rest and during supine bicycle exercise, before and 3–5 min after nicardipine 10 mg intravenously. The left ventricular ejection fraction increased by 4% at rest but not during exercise. The left ventricular rest and exercise ejection and filling rates both increased with a concurrently reduced left ventricular ejection time. There was a highly significant inverse relationship between baseline exercise ejection fraction and the response to nicardipine; ejection fraction increased with low initial values but was either unchanged or fell with higher initial values. These data suggest that the acute effects of nicardipine in stable coronary artery disease probably reflect a reduction in left ventricular afterload and an associated augmentation of cardiac pumping performance. The acute circulatory profile of nicardipine appears sufficiently promising to warrant longer-term studies in ischaemic heart disease.

Silke, B.; Frais, M.; Verma, S.; Reynolds, G.; Taylor, S.

doi: 10.1007/BF00615955pmid: 2872054

228 29 29 6 6 B. Silke M. A. Frais S. P. Verma G. Reynolds S. H. Taylor University Department of Cardiovascular Studies General Infirmary at Leeds Leeds UK Summary Theoretically the increased sympathoadrenal activity following acute myocardial infarction might augment the haemodynamic impact of beta-adrenoceptor blockade. To evaluate this question 32 haemodynamic studies were performed to compare the effects of equivalent beta-blocking doses of propranolol (8 mg i.v.) and pindolol (0.8 mg i.v.) in patients with a recent acute myocardial infarction (A.M.I.) or stable coronary artery disease (and a presumptive low sympathetic state). In stable coronary artery disease there were clear differences between the haemodynamic impact of propranolol and pindolol. Propranolol decreased both heart rate (ΔHR −7 beat/min) and cardiac index (ΔCI −0.4l/min/m 2 ), with an increased pulmonary artery occluded pressure (ΔPAOP +4 mmHg) and systemic vascular resistance index (ΔSVRI +358 dyn · s · cm −5 m 2 ). However an equivalent beta-blocking dose of pindolol increased PAOP (ΔPAOP +3 mmHg) leaving other variables unchanged. These differential actions of propranolol and pindolol have previously been ascribed to the intrinsic synpathomimetic activity (I.S.A.) of pindolol maintaining cardiac pumping function in a low sympathetic state. In contrast following myocardial infarction, both drugs reduced cardiac index to a significantly greater extent compared with stable coronary artery disease (ΔCI propranolol −0.8l/min/m 2 ; pindolol −0.4l/min/m 2 ; p <0.05); propranolol also reduced the systemic arterial blood pressure (Δsystolic −10 mmHg; Δmean −5 mmHg; p <0.05). The haemodynamic relevance of the I.S.A. of pindolol appeared attenuated following A.M.I. These data are compatible with experimental evidence of sympathetic nervous activation following coronary occlusion; the resulting hyperadrenergic state appears to condition an augmented haemodynamic response to beta-blocking drugs irrespective of their ancillary pharmacological properties. The implications of these findings for clinical therapy warrant further examination.

Barrios, L.; Geboers, J.; Piessens, J.; Geest, H.

doi: 10.1007/BF00615956pmid: 2872055

228 29 29 6 6 L. Barrios J. Geboers J. H. Piessens H. de Geest Department of Cardiology, Clinic for Internal Medicine University Hospital Gasthuisberg Leuven Belgium Division of Epidemiology, School of Public Health Catholic University of Leuven Leuven Belgium Summary The effects of xamoterol on exercise capacity have been evaluated in 10 patients with angina pectoris and well-preserved left ventricular function. Compared to placebo a single 200 mg dose of xamoterol produced a slight but insignificant increase in exercise capacity. At maximum work load, ST-T segment depression was reduced (3 mm and 2.19 mm after placebo and xamoterol, respectively; p <0.05). The changes paralleled an insignificant reduction in maximal heart rate and pressure-rate product. At rest, xamoterol increased the heart rate from 80 to 86 beats/min. Thus, at rest, when sympathetic tone is low, xamoterol acts as a beta-receptor agonist but during exercise, when sympathetic tone is high, xamoterol acts as an antagonist and reduces myocardial ischaemia.

Ekelund, L.; Nilsson, E.; Walldius, G.

doi: 10.1007/BF00615957pmid: 3519236

228 29 29 6 6 L. -G. Ekelund E. Nilsson G. Walldius Department of Clinical Physiology Karolinska Hospital Stockholm Sweden Department of Internal Medicine Karolinska Hospital Stockholm Sweden Duke University Medical Center Box 3022 27710 Durham NC USA Summary The efficacy of disopyramide compared to placebo for exercise induced ventricular arrhythmias was tested in a double-blind randomized controlled clinical trial with cross-over design in 14 patients with coronary heart disease. Disopyramide was given as ordinary capsules (q.i.d.) or as a slow release preparation (b.i.d.) in a total dose of 600 mg per day. The placebo preparations were identical looking capsules and tablets. Each treatment period lasted one week. Efficacy was assessed by a standardized exercise test on a bicycle ergometer and a 6-h Holter monitoring at the end of each period. Plasma levels of disopyramide, measured in conjunction with exercise test, fell within therapeutic range, with a mean value of 7.9 and 8.9 µmol/l for capsules and slow release tablets, respectively. Disopyramide gave a marked and significant reduction of ventricular ectopic beats both at rest and during and after exercise. There was also a significant decrease in the number of ectopic beats recorded on tape during treatment periods compared to during placebo periods. There were no differences between the two preparations with respect to antiarrhythmic effect. Only mild side-effects, mainly mild anticholinergic symptoms, similar for both preparations were reported. No significant cardiovascular changes (heart rate and blood pressure response) were observed.

Thomas, M.; Tattersfield, A.

doi: 10.1007/BF00615958pmid: 2872056

228 29 29 6 6 M. S. Thomas A. E. Tattersfield Medicine 1, Southampton General Hospital Tremona Road Southampton UK City Hospital Hucknall Road Nottingham Summary 1. The beta-adrenergic selectivity of diacetolol, the major metabolite of acebutolol, has been compared with that of acebutolol, metoprolol and propranolol in 11 normal subjects. 2. Bronchial and cardiac beta-adrenoceptor blockade were assessed on separate occasions after diacetolol 600 mg, acebutolol 400 mg, metoprolol 200 mg, propranolol 80 mg and placebo. 3. Bronchial beta-adrenoceptor blockade was assessed as the displacement of the bronchodilator dose response curve to inhaled isoprenaline after each beta blocking drug compared to placebo and expressed as the dose ratio. Bronchodilatation was measured as change in specific airway conductance (sGaw) in the body plethysmograph. Cardiac beta-adrenoceptor blockade was assessed as the percentage reduction in exercise heart rate during the 5th minute of exercise at 70% of the subject's maximum work rate. 4. There was a significant reduction in exercise heart rate with all 4 beta-blocking drugs when compared with placebo, 22% for diacetolol, 24% for acebutolol, 25% for propranolol and 28% for metoprolol. The reduction with metoprolol was significantly greater than the reduction with the other three beta-adrenoceptor antagonists. 5. Mean dose ratios for the airway isoprenaline dose response curves after each of the 4 beta-blocking drugs were 2.4 for diacetolol, 2.7 for metoprolol, 8 for acebutolol and 72 for propranolol. The difference between diacetolol and metoprolol was not significant. 6. Thus diacetolol appears to be more cardioselective than acebutolol and both are more cardioselective than propranolol in man. Metoprolol is probably more cardioselective than diacetolol though interpretation of the differences in exercise heart rate is complicated by the fact that diacetolol has some intrinsic sympathomimetic activity.

Burgess, C.; Crane, J.

doi: 10.1007/BF00615959pmid: 3709610

228 29 29 6 6 C. D. Burgess J. Crane Division of Clinical Pharmacology, Department of Medicine, Wellington Clinical School of Medicine University of Otago Wellington New Zealand Summary The effects of the ingestion of food and digoxin on the cardiovascular system alone and in combination have been observed in eight healthy subjects. A positive inotropic response was seen following food (2.5 MJ) and intravenous digoxin (0.01 mg/kg) with significant decreases in QS 2 Index (QS 2 I) pre-ejection period (PEP) and PEP/LVET (LVET — left ventricular ejection time). These responses were potentiated when food and digoxin were combined. Opposing effects of food and digoxin on % diastole (%D) and diastolic time were observed, food decreasing %D and DT while digoxin increased these variables. Both food and digoxin decreased T-wave amplitude, and digoxin alone or in combination with food decreased QT c . The positive inotropic effect of a 2.5 MJ mixed meal and a loading dose of digoxin in healthy subjects are of similar degree, different mechanism, and are potentiated in combination.

Terhaag, B.; Hermann, U.

doi: 10.1007/BF00615960pmid: 3709611

228 29 29 6 6 B. Terhaag U. Hermann Institute of Clinical Pharmacology and Clinic of Surgery Medical Academy Dresden German Democratic Republic Summary The biliary elimination of indomethacin 100 mg p.o. has been investigated in patients with a T-tube drain after cholecystectomy, who had normal or abnormal liver function (Group I n =5, and Group II n =4, respectively). In plasma, the concentration maximum (Group I 9.5±1.4 µmol·1 −1 ; Group II 19.4±3.8 µmol·1 −1 ) and the total clearance (Group I 1.56±0.28 ml·min −1 ·kg −1 , Group II 0.5±0.06 ml·min −1 ·kg −1 ) were significant different in the two groups. The bile:plasma ratio (bpr) in Group I was 1.3±0.33 and 10.1±3.2, respectively, for indomethacin (In) and conjugated In. The conjugated fraction of In was 87.5±1.9% of the total concentration. In Group II the bpr was lower (0.65±0.1). In is eliminated in bile by diffusion and conjugated In by active secretion. In Group I 0.99±0.1 mg In and 6.1±0.7 mg conjugated In and in Group II 2.1±0.3 mg In ( p <0.05) were eliminated in bile. No influence of In on the biliary lipids was observed or on the bile acid-independent fraction of bile flow. It is concluded that the total plasma clearance of In was dependent of liver function. Conjugated In undergoes enterohepatic circulation.

Horber, F.; Guentert, T.; Weidekamm, E.; Heizmann, P.; Descoeudres, C.; Frey, F.

doi: 10.1007/BF00615961pmid: 3709612

228 29 29 6 6 F. F. Horber T. W. Guentert E. Weidekamm P. Heizmann C. Descoeudres F. J. Frey Medizinische Poliklinik, Inselspital Bern Switzerland F.Hoffmann-La Roche & Co. Ltd. Basel Switzerland Summary The pharmacokinetics of tenoxicam after a single oral dose of 20 mg has been studied in 12 patients with various degrees of decreased renal function. Unchanged tenoxicam and its 5′OH-metabolite in plasma and urine were determined by HPLC. The mean areas under the plasma concentration-time curve (138±53 µg/ml·h) and terminal half-lives in patients with impaired renal function did not differ from values previously reported in normal volunteers, nor did the peak concentration of tenoxicam. The half-life of 5′OH-tenoxicam and unchanged tenoxicam where the same. The urinary excretion of 5′OH-tenoxicam fell with decreasing renal function. Thus no dosage adjustment should be necessary and the usual daily dose of tenoxicam may be administered once daily also to patients with renal failure.