European Journal of Clinical Pharmacology

Schaik, B.; Geyskes, G.; Boer, P.; Dorhout Mees, E.

doi: 10.1007/BF00613510pmid: 3028815

228 31 31 4 4 B. A. M. van Schaik G. G. Geyskes P. Boer E. J. Dorhout Mees Department of Nephrology and Hypertension University Hospital Utrecht The Netherlands Summary In 12 patients with essential hypertension who remained hypertensive despite chronic chlorthalidone treatment, the effect of 2 weeks of additional therapy with the converting enzyme inhibitor (CEI) enalapril on blood pressure and body fluid volumes has been evaluated. The objective was to examine the influence of a diuretic-stimulated renin-angiotensin-aldosterone system (RAAS) on haemodynamics and body fluid volume. Mean arterial pressure (MAP −21%), total peripheral resistance index (TPRI −22%) and plasma aldosterone concentration (PAC −39%) were decreased, and plasma renin activity (PRA 660%) was increased. The average heart rate (HR), cardiac index (CI), plasma volume (PV), blood volume (BV), extracellular fluid volume (ECFV) and body weight (BW) remained unchanged. A negative correlation was found between the per cent changes in ECFV and PAC. Thus, body fluid volumes during chronic diuretic treatment are well preserved even when the RAAS with its sodium retaining properties is suppressed by CEI. Possible mechanisms are a volume (not angiotensin II) — dependent stimulation of aldosterone and a fall in blood pressure.

Gjørup, T.; Hartling, O.; Kelbæk, H.; Nielsen, S.

doi: 10.1007/BF00613511pmid: 3816916

228 31 31 4 4 T. Gjørup O. J. Hartling H. Kelbæk S. L. Nielsen Department of Clinical Physiology and Nuclear Medicine, Herlev Hospital University of Copenhagen Copenhagen Denmark Summary In a controlled double blind trial the symptomatic effect of the calcium channel blocker nisoldipine was assessed in 19 patients with idiopathic Raynaud's phenomenon. Nisoldipine significantly reduced the frequency of attacks ( p <0.05), whilst having a non-significant tendency ( p <0.10) to reduce the severity of attacks. Side-effects were uncommon. It is concluded that nisoldipine is a promising agent for the symptomatic treatment of idiopathic Raynaud's phenomenon.

Kirch, W.; Logemann, C.; Heidemann, H.; Santos, S.; Ohnhaus, E.

doi: 10.1007/BF00613512pmid: 3816917

228 31 31 4 4 W. Kirch C. Logemann H. Heidemann S. R. Santos E. E. Ohnhaus I. Medical Hospital Christian Albrechts University Kiel Germany Medizinische Klinik and Poliklinik Universitätsklinikum Hufelandstraße 55 D-4300 Essen Germany Summary The effect of two different doses of nitrendipine on plasma digoxin levels, urinary recovery and systolic time intervals was investigated in 8 healthy volunteers. Following a loading dose, digoxin 0.25 mg b.d. p.o. was given alone for 2 weeks. Then 0.25 mg digoxin b.d. was administered for two 1-week periods combined with nitrendipine 10 mg or 20 mg once daily. The study was completed with another digoxin monotherapy phase lasting 7 days. Nitrendipine 20 mg daily led to a significant increase in plasma digoxin levels and in its area under the plasma concentration-time curve AUC (0–12) compared to digoxin monotherapy. The AUC (0–12) was 9.7 ng ml −1 h when digoxin alone was given and 11.2 ng ml −1 h on co-administration of the calcium antagonist. Urinary recovery and renal clearance of digoxin were slightly but not significantly increased by nitrendipine. Nitrendipine 10 mg once daily caused a small, insignificant tendency to elevate the plasma digoxin level. Nitrendipine co-administration (10 and 20 mg once daily) did not significantly alter systolic time intervals, as non-invasively measured haemodynamic parameters, compared to digoxin treatment alone. Thus, nitrendipine 20 mg daily caused a significant increase in plasma digoxin concentrations and in its AUC, which would rarely be of clinical relevance.

Hinderling, P.; Eckert, M.; Gasic, S.; Eichler, H.; Pötzi, R.; Heizmann, P.

doi: 10.1007/BF00613513pmid: 3816918

228 31 31 4 4 P. H. Hinderling M. Eckert S. Gasic H. G. Eichler R. Pötzi P. Heizmann Departments of Clinical and Biopharmaceutical Research F. Hoffmann-La Roche & CO. LTD. Basle Switzerland Pharma Switzerland F. Hoffmann-La Roche & CO. LTD. Basle Switzerland Department of Clinical Pharmacology I. Medical University Hospital Vienna Austria University Hospital for Gastroenterology and Hepatology Vienna Austria Summary Tiapamil 70 mg was administered i.v. to 8 healthy male volunteers and 8 patients (7 males, 1 female) with biopsy proven hepatic cirrhosis. Two of the patients also received 600 mg p.o. Serial plasma and urine samples were collected and the parent drug in plasma and urine and desmethyl-tiapamil in urine were assayed by a specific HPLC method. The plasma and urine data for the parent drug after i.v. and p.o. dosing were simultaneously fitted to linear p.o. and i.v. two compartment models with exit from and input into the central compartment. Absorption was assumed to be a first order process. In the volunteers the mean pharmacokinetic parameters were: 101 l for the steady-state volume of distribution, 750 ml·min −1 for nonrenal clearance, 195 ml·min −1 for renal clearance and 1.7 h for the half-life of the terminal disposition phase. The urinary recoveries of the parent drug and desmethyltiapamil averaged 21.4 and 0.8% of the dose, respectively. In the patients the steady-state volume of distribution, the amount of unchanged drug in urine and the half-life of the terminal disposition phase were significantly increased (171 l, 29.0% of the dose, 3.5 h, respectively). Decreased plasma protein binding in the patients accounted for the larger steady-state volume of distribution. The nonrenal clearance of 519 ml·min −1 , tended to be smaller in the patients than in the volunteers. Together with the increased urinary recovery of tiapamil in the patients this indicates a moderately impaired elimination capacity in the cirrhotics. The renal clearance was similar in the patients (213 ml·min −1 ) and the volunteers. The absolute oral bioavailability of tiapamil was 55 and 49% in 2 patients. No effects of tiapamil on heart rate or supine blood pressure were detected, either in volunteers or in patients. Negative dromotropic effects were found in 2 volunteers and 2 patients after i.v. dosing.

Schulz, V.; Fischer, W.; Hanselle, U.; Huhmann, W.; Zietsch, V.

doi: 10.1007/BF00613514pmid: 3816919

228 31 31 4 4 V. Schulz W. Fischer U. Hanselle W. Huhmann V. Zietsch Medical Clinic I of Cologne University Cologne Germany A. Nattermann & Co. GmbH Cologne Germany Summary Single doses of motapizone 1 to 10 mg were given to 12 healthy subjects. Before and up to 8 h after each dose the blood pressure and heart rate were measured, as well as thrombocyte aggregation “ex vivo” with collagen, ADP and adrenaline. Motapizone produced a dose-dependent reduction in diastolic blood pressure and an increase in heart rate. These effects were demonstrated with individual variations after 1 to 3 mg and as a rule they were very marked after more than 6 mg. With the highest dose (mean 7.7±2.3 mg) the diastolic pressure fell by an average of 23% 1 h after medication as compared to with the baseline values. At the same time there was marked inhibition of thrombocyte aggregation, which also became apparent after about 3 mg and increased in proportion to the dose. The inhibition of aggregation peaked after 2 h and had disappeared within 8 h. The inhibition of ADP-induced aggregation was particularly marked.

Schulz, V.; Fischer, W.; Hanselle, U.; Huhmann, W.; Zietsch, V.

doi: 10.1007/BF00613515pmid: 3816920

228 31 31 4 4 V. Schulz W. Fischer U. Hanselle W. Huhmann V. Zietsch Medical Clinic I of Cologne University Cologne Germany A. Nattermann & Co. GmbH Cologne Germany Summary Ten healthy subjects took single oral doses of placebo, 8.8±1.8 mg motapizone, 40±13 mg captopril, 25 mg dihydralazine, 20 mg nifedipine and 4.5±1.1 mg prazosin in random order, and, as the last preparation 500 mg acetylsalicylic acid. Thrombocyte aggregation induced “ex-vivo” with collagen, ADP and adrenaline was measured before and after 60 min. Immediately before each dose, the “threshold concentration” of each agent was determined in each subject, i.e. the concentration producing about 90% of maximal aggregation. After the preparation had been taken, aggregation was induced with 1-, 2- and 4-times the threshold concentration. Both motapizone and also acetylsalicylic acid caused marked inhibition of aggregation at up to 4-times the threshold concentration; the dose ratio was about 1:50. Motapizone produced greater inhibition of the aggregation induced by ADP and acetylsalicylic acid than of that due to collagen. The inhibitory actions after captopril, dihydralazine, nifedipine and prazosin were weak and did not significantly differ from placebo.

Gretzer, I.; Alván, G.; Dunér, H.; Garle, M.; Sjöqvist, F.

doi: 10.1007/BF00613516pmid: 2880722

228 31 31 4 4 I. Gretzer G. Alván H. Dunér M. Garle F. Sjöqvist Department of Internal Medicine Sabbatsbergs Hospital Stockholm Sweden Department of Clinical Pharmacology, Karolinska Institute Huddinge Hospital Huddinge Sweden Summary The pharmacokinetics and beta-blocking effect of pindolol has been compared in 20 patients with essential hypertension (WHO Stage I), 10 below 25 years of age and 10 older than 60 years. Each patient received pindolol 10 mg p.o. once a day for 5 days. The area under the curve (AUC) of pindolol was larger in the old than in the young patients both on the first ( p <0.05) and the fifth ( p <0.01) days. The AUC of pindolol was 14% higher on the fifth day compared to the first day in the elderly group, indicating minor accumulation at steady-state. There was no change in AUC in the young patients. Endogenous creatinine clearance was lower in the old (80±9 ml/min) than in the young patients (150±45 ml/min). The beta-blocking effect did not differ between the groups at 2h after administration of pindolol on Days 1 or 5. However, 24 h after the first and fifth doses approximately 60% of the beta-blockade persisted in the old group whereas 17 and 19% of the beta-blockade, respectively, persisted in the young group; the difference between the groups was statistically significant ( p <0.01). The most probable explanation for the more sustained beta-blocking effect in the elderly is the physiologically decrease in renal function, which results in a more sustained plasma level of pindolol in those patients.

Wellstein, A.; Küppers, H.; Pitschner, H.; Palm, D.

doi: 10.1007/BF00613517pmid: 3028816

228 31 31 4 4 A. Wellstein H. Küppers H. F. Pitschner D. Palm Zentrum der Pharmakologie Klinikum der J. W. Goethe-Universität Frankfurt Germany Schwarz GmbH Monheim Germany Summary Bupranolol is a non-selective beta-adrenoceptor antagonist with a K i -value of 6–15 nmol/l (equivalent to 1.5–4 ng/ml in plasma) at beta 1 - (rat salivary gland) and beta 2 -adrenoceptors (rat reticulocytes) in receptor binding studies with 3 H-CGP 12177 in the presence of human plasma. After oral administration of 200 mg bupranolol to healthy volunteers, the maximal plasma concentration was observed within 1.2 h but it only reached a level close to the K i -value. Elimination from plasma was rapid (t 1/2 =2.0 h). Administration of 30 mg bupranolol in a transdermal delivery system (TTS) every 24 h to 6 healthy volunteers for 72 h yielded steady state plasma concentrations 4- to 5-times above the K i -value as shown by in vitro inhibition of beta-adrenoceptor binding by plasma samples. The pharmacodynamic effect, measured as the reduction in exercise tachycardia, showed a stable inhibitory effect; antagonism of a bolus injection of isoprenaline indicated a 10- to 15-fold right shift of the dose-response curve during the observation period of 72 h. It is concluded that steady-state plasma concentrations and effect of the elsewise rapidly eliminated beta-blocker bupranolol can be achieved by a transdermal delivery system applied each day.

Gordin, A.; Pohto, P.; Sundberg, S.; Nykänen, S.; Haataja, H.; Männistö, P.

doi: 10.1007/BF00613518pmid: 3816921

228 31 31 4 4 A. Gordin P. Pohto S. Sundberg S. Nykänen H. Haataja P. Männistö Research Centre Orion Pharmaceutica Espoo Finland Summary The pharmacokinetics and effect of a slow-release and a conventional diltiazem tablet on atrioventricular conduction were compared in a randomized cross-over study after a single dose and at steady state in 12 healthy volunteers. The time to peak concentration was significantly delayed after the slow-release as compared to the conventional tablet, both after a single dose (2.7 vs. 0.9 h) and at steady-state (1.9 vs. 0.9 h). The peak concentration was also significantly reduced. There was no marked loss in bioavailability with the slow-release formulation. The maximal fluctuations in serum diltiazem at steady-state for the slow-release tablet were markedly less than after the conventional tablet (62 vs 87%). The PQ-interval was longer after the conventional tablet as compared to the slow-release tablet (both in doses of 120 mg) after a single dose (187 vs 163 ms) and at steady-state (197 vs 174 ms). The maximal prolongation was seen 1 h after intake of the drug. Heart rate was decreased only by 6–9 beats/min, irrespective of the dose. Slow-release diltiazem appears to have many advantages over a conventional tablet.

Lichey, J.; Hoffmann, M.; Huckauf, H.; Kammradt, G.; Friedrich, T.

doi: 10.1007/BF00613519pmid: 3816922

228 31 31 4 4 J. Lichey M. Hoffmann H. Huckauf G. Kammradt T. Friedrich Department of Internal Medicine, Cardio-Pulmonary Division Free University of Berlin Berlin Germany Department of Medicine Boehringer Ingelheim KG Ingelheim Germany Summary Alinidine is a new bradycardic agent which has been shown to be beneficial in the treatment of coronary heart disease. Patients with both coronary heart disease and obstructive lung disease are difficult to treat, because the use of beta-blockers in them is greatly limited by their potential to provoke bronchospasm. Alinidine has no beta-blocking, muscarinic or quinidine-like properties. In a randomized double-blind cross-over study the heart rate reducing effect and safety of alinidine 40 mg p.o. has been examined in 12 symptom-free asthmatics. Alinidine significantly reduced mean heart rate from 81±10.5 beats/min to 65±9.7 beats/min two hours after administration. Forced expiratory volume in one second (FEV 1 ), vital capacity (CV), airway resistance (R aw ), functional residual capacity (FRC), and specific airway conductance (SG aw ) were not affected. It is concluded that alinidine did not influence respiratory function in patients with bronchial hypersensitivity.