European Journal of Clinical Pharmacology

Jansson, J.; Johansson, B.; Boman, K.; Nilsson, T.

doi: 10.1007/BF00265838pmid: 1828764

228 40 40 4 4 J. -H. Jansson B. Johansson K. Boman T. K. Nilsson Department of Internal Medicine Skellefteå Hospital Skellefteå Sweden Community Health Organisation Skellefteå Sweden Department of Clinical Chemistry Umeå Hospital Sweden Summary Disturbances in the fibrinolytic system have been associated with cardiovascular disease and its risk factors. In the present study the effects of an alpha 1 -adrenoceptor inhibitor (doxazosin) and a selective beta-adrenoceptor blocker (atenolol) on the fibrinolytic system have been evaluated. Eighty four subjects with previously untreated mild to moderate hypertension and elevated serum cholesterol were randomized to receive atenolol or doxazosin in a double-blind study over 6 months. Tissue plasminogen activator(tPA) and plasminogen activator inhibitor (PAI-1) were measured in citrated plasma samples before and after venous occlusion before and at the end of the study period. tPA activity after venous occlusion and tPA capacity were significantly increased after doxazosin as compared to pretreatment values. The fibrinolytic variables did not change in the atenolol group. Thus, doxazosin but not atenolol, improved the activity of the fibrinolytic system in patients with hypertension and an elevated serum cholesterol level. This effect of doxazosin warrants consideration when selecting a first-line antihypertensive drug.

Franks, P.; Hartley, K.; Bulpitt, P.; Bulpitt, C.

doi: 10.1007/BF00265839pmid: 2050166

228 40 40 4 4 P. J. Franks K. Hartley P. F. Bulpitt C. J. Bulpitt Division of Geriatric Medicine Department of Medicine, Postgraduate Medical School Hammersmith Hospital W12 OHS London UK Department of Clinical Pharmacology, Royal Postgraduate Medical School Hammersmith Hospita W12 OHS London UK Department of Surgery Charing Cross Hospital Fulham Palace Road W6 8RF London UK Summary The medical records of patients presenting to the Hammersmith Hospital hypertension clinic between 1971 and 1981 were examined to determine presenting clinical data, treatment regimes, and both cardiovascular and non cardiovascular mortality and morbidity. When compared with 1004 patients receiving treatment other than hydralazine 310 patients on hydralazine had a significantly higher risk of developing renal disease (RR=2.71) in men, and severe weight loss in women (RR = 3.06). Renal disease risk also tended to be high in women on hydralazine (RR = 1.95) compared with all other treatments, but this was not statistically significant and could be explained by poorer renal function and significantly higher untreated blood pressure in the hydralazine treated group at presentation. The 422 patients who were treated with methyldopa but not hydralazine had similar risk factors for cardiovascular disease compared with a group of 167 who received hydralazine but not methyldopa. Comparisons of event rates failed to find significant differences in morbidity or mortality between these two groups. The age adjusted male mortality was 14/1000 patient years on hydralazine and 12/1000 on methyldopa and 13/1000 and 6/1000 years for women respectively. There was no evidence of an increased risk of either renal disease (RR=0.3 in men, RR=0.3 in women) on hydralazine or weight loss (RR=0.7 in men, RR=1.6 in women), with similar presenting data. Systemic lupus erythematosus was a rare complication (2 of 314) of treatment with hydralazine.

Prandota, J.; Smith, I.; Hilman, B.; Wilson, J.

doi: 10.1007/BF00265840pmid: 2050167

228 40 40 4 4 J. Prandota I. J. Smith B. C. Hilman J. T. Wilson J. Korczak Memorial Children's Hospital Wrocław Poland Section on Clinical Pharmacology, Departments of Pharmacology and Therapeutics, and Pediatrics Louisiana State University Medical Center USA Shreveport LA Summary The pharmacodynamics and kinetics of single oral and intravenous doses of furosemide were studied in 9 patients (mean age 18.5 y) with cystic fibrosis. The diuretic effect of furosemide lasted for 6 h after oral administration and 2 h following intravenous injection of the drug. The patients with cystic fibrosis had a more pronounced diuretic response both to the oral and intravenous treatments than that reported in normals. Furosemide caused a marked decrease in urine pH for 5 h following the oral dose and between the 2nd and 3rd h after i.v. injection. The baseline nocturnal urine flow rate in 7 of the 9 patients given furosemide orally was increased by 30.6% compared to that reported in healthy subjects. The bioavailability of furosemide, its mean absorption rate and the mean plasma and urinary elimination half-lives both of the oral and the intravenous drug were similar to those reported in normal subjects. The patients with cystic fibrosis showed, however, about double normal mean total clearance after both the oral and i.v. treatments, and its renal clearance was almost half the plasma clearance. Nonrenal clearance was markedly increased in the patients, which agreed with a considerable decrease in the renal excretion of the drug. The mean apparent volume of distribution was also markedly increased compared to data in the literature. Oral furosemide resulted in a moderate increase in haematocrit and haemoglobin levels in 7 of 9 patients with cystic fibrosis and marked hypokalemia developed in 6 of the 9 patients 6 h after dosing. Pulmonary function tests performed at that time were changed in an inconsistent manner. The sweat test was significantly perturbed in those subjects, although the concentration of chloride in sweat did not fall below 60 mEq/l in any of the sweat samples tested.

Skovlund, E.; Fyllingen, G.; Landre, H.; Nesheim, B.

doi: 10.1007/BF00265841pmid: 2050168

228 40 40 4 4 E. Skovlund G. Fyllingen H. Landre B. -I. Nesheim Department of Informatics University of Oslo Oslo Norway Apothekernes Laboratorium AS Oslo Norway Akershus Central Hospital Oslo Norway Summary A new sequential test has been used to compare the effect of paracetamol and placebo on uterine cramping. Paracetamol was significantly superior to placebo at the 5% level. 75 patients were included in the trial, whereas in a fixed sample study 90 patients would have been required to obtain the same significance level and power. The magnitude of the difference in treatment effect was estimated following the sequential test. In addition to the effect on uterine pain, which was the primary variable, the effect on episiotomy pain was also estimated. Paracetamol was also superior to placebo against the episiotomy pain.

Strömberg, C.; Suokas, A.; Seppälä, T.; Kupari, M.

doi: 10.1007/BF00265842pmid: 2050169

228 40 40 4 4 C. Strömberg A. Suokas T. Seppälä M. Kupari Department of Pharmacology and Toxicology University of Helsinki Helsinki Finland Research Unit of Alcohol Diseases Helsinki University Central Hospital Helsinki Finland National Public Health Institute Helsinki Finland First Department of Medicine Helsinki University Central Hospital Helsinki Finland Section on Pharmacology Laboratory of Clinical Sciences Room 2D-45 Building 10 National Institute of Mental Health 9000 Rockville Pike 20892 Bethesda MD USA Summary The echocardiographic and psychometric effects of amitriptyline or imipramine combined with alcohol have been studied in a double-blind cross-over trial in 7 healthy volunteers. Amitriptyline or imipramine 25 mg b.d. were given for three days and then the dose was doubled. On Days 1 and 10–13 echocardiographic measurements were done, and on Day 15 psychomotor tests were performed. Ethanol 1 g/kg in each session was administered 1 h after drug intake. Alcohol alone increased heart rate and decreased the systolic blood pressure and ejection fraction. It also impaired most of the psychomotor measures, horizontal nystagmus being the most sensitive test. On Day 1, the first dose of imipramine decreased the heart rate and increased diastolic blood pressure. These effects were partly counteracted by alcohol. Imipramine + alcohol decreased the WSTR. Amitriptyline alone did not affect the echocardiographic findings on Day 1. In combination with alcohol it reduced cardiac output and prolonged PEP, and increased the PEP/LVET ratio. During subacute treatment (Days 10–13) WSTR was increased by both antidepressants, but only amitriptyline increased the heart rate. Unlike imipramine + alcohol, amitriptyline + alcohol decreased WSTR and MCSR. Digit symbol substitution was the only psychometric test in which the alcohol effect was clearly enhanced by both amitriptyline and imipramine.

Allen, D.; Curran, H.; Lader, M.

doi: 10.1007/BF00265843pmid: 2050170

228 40 40 4 4 D. Allen H. V. Curran M. Lader Department of Psychiatry Institute of Psychiatry De Crespigny Park, Denmark Hill SE5 8AF London UK Summary The effects of a 10 day administration of clomipramine (25–50 mg t.i.d.), alprazolam (0.25–0.75 mg t.i.d.) and placebo were assessed in normal volunteers in a double-blind cross-over study. A battery of physiological, psychomotor and cognitive tests was administered both before and 3 h after drug on days 1, 5 and 10. The effects of alprazolam on EEG and evoked potentials were characteristic of benzodiazepines; clomipramine had little effect. In contrast, reaction speed was markedly slowed by clomipramine but little affected by alprazolam. Neither drug produced any accumulation of effect on a verbal recall task but neither did tolerance develop to the acute impairments produced by active treatments. Alprazolam produced an increase in levels of forgetting, especially on day 5. Subjective ratings for mood and bodily symptoms were adversely affected by clomipramine but little altered by alprazolam. It is suggested that some of the differences between drug treatments may be due to differences in the speed of onset of tolerance.

Sallerin-Caute, B.; Lazorthes, Y.; Monsarrat, B.; Cros, J.; Bastide, R.

doi: 10.1007/BF00265844pmid: 2050171

228 40 40 4 4 B. Sallerin-Caute Y. Lazorthes B. Monsarrat J. Cros R. Bastide Laboratoire de Pharmacie Galénique Faculté des Sciences Pharmaceutiques France Laboratoire de Neurochirurgie et Neurobiologie Appliquée Clinique Universitaire de Neurochirurgie, CHU Toulouse Rangueil, Université Paul Sabatier France Laboratoire de Pharmacologie et de Toxicologie Fondamentales du CNRS Toulouse France Summary The pharmacokinetic parameters in the CSF of baclofen given to 4 patients as an intrathecal bolus are reported. Considerable inter-individual variability in the parameters was observed. The elimination half-life ranged from 0.9 to 5 h and the clearance from 0.013 to 0.08 l·h −1 . In order to optimize treatment, it is suggested that CSF baclofen levels be matched to changes in Hoffman's monosynaptic reflex (H reflex).

Stricker, B.; Groot, R.; Wilson, J.

doi: 10.1007/BF00265845pmid: 1675606

228 40 40 4 4 Dr. B. H.Ch. Stricker R. R. M. de Groot J. H. P. Wilson Department of Internal Medicine II University Hospital Dijkzigt Rotterdam Dutch Centre for Health Care Information Utrecht Netherlands Centre for Monitoring of Adverse Reactions to Drugs Rijswijk The Netherlands Summary In 1981 generalized anaphylaxis was registered on 166 occasions in Dutch general and academic hospitals. Clinical details of 120 of those patients revealed that in 107 anaphylaxis was either probable (n=90) or possible (n=17), whereas in 13 cases some other reaction than anaphylaxis had occurred. The series of confirmed cases contained 46 men and 61 women, with mean ages of 47 y and 48 y, respectively. There was a complete recovery in 102 patients and two patients died. Hypotension was present in 79 cases (74%), dyspnoea in 34 cases (32%) and a skin reaction, mainly urticaria, erythema or angioedema, was mentioned in 62 cases (58%). Most cases of anaphylaxis were drug-induced (76%), the main causes being the analgesic glafenine and contrast media. Glafenine was mentioned as the cause in 36% of all admissions for drug-induced anaphylaxis. Only 3.7% of cases had been reported to the voluntary reporting scheme of the Netherlands Centre for Monitoring of Adverse Reactions to Drugs. On the basis of reimbursement data, the risk of developing severe anaphylaxis to glafenine was estimated at 11.7–19.3-fold relative to indomethacin, and 13.4–20.2-fold relative to oral penicillins.

Mey, C.; Enterling, D.; Hanft, G.

doi: 10.1007/BF00265846pmid: 2050172

228 40 40 4 4 C. de Mey D. Enterling G. Hanft SK & F Institute for Applied Clinical Pharmacology Göttingen FRG Summary The effects of a single dose of 2 mg/kg amrinone (60 min constant rate IV infusion) have been assessed in a double-blind, placebo-controlled, within-subject cross-over study in six healthy volunteers. Combined impedance cardiography, phonocardiography and electrocardiography revealed a protracted drop in mean ventricular ejection time and electromechanical systole together, with a protracted rise in the “contractility” indices dZ/dt max and the Heather index HI. The profile is compatible with combined venous vasodilation and positive inotropic action. In spite of the methodological constraints, endpoints were reached that were both detectable and relevant. The profiling permitted a better distinction to be made between the possible levels of action than systolic time intervals alone could have done. Therefore, these methods may be of value in the early development of “inodilator” drugs.

Mulder, H.; Schopman, W.; Lely, A.

doi: 10.1007/BF00265847pmid: 1904820

228 40 40 4 4 H. Mulder W. Schopman Sr. A. J. van der Lely Department of Internal Medicine Eudokia Hospital Netherlands Department of Endocrinological Biochemistry Municipal Hospital Netherlands Department of Internal Medicine University Hospital Dijkzigt Rotterdam Netherlands Summary In eight patients with uncomplicated non insulin dependent diabetes mellitus, serum insulin levels, serum C-peptide levels and blood glucose levels were measured before and after oral administration of glibenclamide 0.1 mg/kg body weight and a test meal, or after a test meal alone. The rise in serum insulin levels persisted longer after glibenclamide. The initial rise in serum insulin was of the same magnitude in both situations, as was the rise in serum C-peptide levels during the entire 5 h study. It is concluded that glibenclamide is able to maintain a more protonged increase in serum insulin levels by inhibiting the degradation of insulin in the vascular endothelial cells of the liver. The inhibition contributes to the blood glucose lowering effect of glibenclamide.