European Journal of Clinical Pharmacology

Markus, H.; Cowley, A.

doi: 10.1007/BF00279964pmid: 1884731

228 40 40 6 6 H. Markus A. J. Cowley Department of Medicine University Hospital Nottingham UK Summary The acute central haemodynamic and neuroendocrine effects of intravenous flosequinan were studied in a group of 10 patients with severe heart failure. Flosequinan improved cardiac output by a maximum of 1.59 l·min −1 , it reduced pulmonary capillary wedge pressure by 11.9 mm Hg and it also caused a reduction in right atrial pressure by a maximum of 7.2 mm Hg. It tended to cause a fall in plasma adrenaline levels but not in plasma noradrenaline. There was little fall in blood pressure in response to flosequinan and no patient developed an adverse event. Intravenous flosequinan may be a useful candidate drug for controlled clinical studies in patients with severe heart failure.

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

doi: 10.1007/BF00279965pmid: 1884732

228 40 40 6 6 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 The efficacy of naproxen and paracetamol in relieving uterine cramps has been compared in a sequential trial. The treatments did not differ significantly in a two-sided test in 56 patients. A corresponding fixed sample test would have required 140 patients to obtain the same significance level and power. In addition to uterine pain, the effect on episiotomy pain was also estimated at the termination of the trial. Again, there seemed to be no difference between naproxen and paracetamol.

Garcća-Alonso, F.

doi: 10.1007/BF00279966pmid: 1884733

228 40 40 6 6 Collaborative Group of the Spanish Society of Clinical Pharmacology Dr. F. Garcća-Alonso Ministerio de Sanidad y Consumo (D-921) Paseo del Prado 18-20 E-28071 Madrid Spain Summary A randomized, double-blind, multicentre clinical trial was designed to compared the analgesic efficacy of i.m. dipyrone 1 and 2 g, i.m. diclofenac sodium and i.m. pethidine in acute renal colic. The study was carried out in 451 patients in 13 Spanish hospitals. Ureteric colic was diagnosed by the clinical features, urinalysis, or when the presence of a ureteric calculus was confirmed. The severity of pain was assessed by the physicians and by patients using visual analogue scales. The main parameter of drug efficacy was the need for rescue treatment-pethidine 100 mg i.m. 30 min after the experimental treatment. Rescue treatment was required in 93 patients: they represented 24.1% of the group given dipyrone 1 g; 22.3% of those on dipyrone 2 g; 16.4% of those given diclofenac sodium; and 19.5% of those on pethidine. The differences between the groups were not significant. In the remaining 358 patients, no difference between treatments was observed. The results suggest that in acute renal colic the use of dipyrone 2 g is unjustified as dipyrone 1 g is equally effective. Diclofenac sodium is a valid alternative, which shows similar analgesic efficacy.

Veronese, M.; McLean, S.

doi: 10.1007/BF00279967pmid: 1884734

228 40 40 6 6 M. E. Veronese S. McLean School of Pharmacy University of Tasmania Hobart Tasmania Australia Department of Clinical Pharmacology School of Medicine Flinders University of South Australia Bedford Park 5042 South Australia Australia Summary The metabolism of paracetamol and phenacetin has been studied in subjects previously phenotyped as either extensive or poor metabolisers of debrisoquine (EM and PM, respectively), in order to examine the relationship between phenacetin and paracetamol activation and debrisoquine oxidation status. In separate experiments, paracetamol and phenacetin were administered orally to groups of 5 EM and 5 PM subjects, and the excretion of metabolites measured for 24 h. There were no differences between EM and PM subjects in the excretion of metabolites. After phenacetin, 0.82 of the dose was recovered in urine, mostly as paracetamol glucuronide (51%) and sulphate (30%), with smaller amounts of free paracetamol (4%) and the mercapturate (5%) and cysteine conjugates (5%), 2-hydroxyphenetidine (5%) and N-hydroxyphenacetin (0.5%). Following paracetamol, 0.87 of the dose was recovered, with similar proportions of paracetamol-derived metabolites. It is concluded that the debrisoquine oxidation phenotype is unrelated to either the metabolic activation of phenacetin and paracetamol, or to their overall metabolic clearance.

Johansson, I.; Yue, Q.; Dahl, M.-L.; Heim, M.; Säwe, J.; Bertilsson, L.; Meyer, U.; Sjöqvist, F.; Ingelman-Sundberg, M.

doi: 10.1007/BF00279968pmid: 1679392

228 40 40 6 6 I. Johansson Q. Y. Yue M.-L. Dahl M. Heim J. Säwe L. Bertilsson U. A. Meyer F. Sjöqvist M. Ingelman-Sundberg Department of Physiological Chemistry Karolinska Institute Stockholm Sweden Department of Pharmacology Biozentrum Basel Switzerland Department of Clinical Pharmacology, Karolinska Institute Huddinge University Hospital Huddinge Sweden Summary The Far Eastern and Caucasian populations are strikingly different with respect to the debrisoquine/sparteine hydroxylation polymorphism. The number of poor metabolizers, as defined for Caucasians, is very low among Chinese and Japanese. We investigated the molecular basis for this difference by analysis of the CYP2D6 gene in 115 Chinese subjects, combined with phenotypic classification of codeine and debrisoquine metabolism. A correlation between the rates of metabolism of these two drugs and genotype, as analyzed by RFLP using XbaI, was observed among the Chinese. A high frequency (37%) of alleles indicative of gene insertions (reflected by Xba I 44kb fragments) was recorded in the Chinese, but was not associated with the poor metabolizer phenotype, as it is in Caucasians. PCR amplification of part of the CYP2D6 gene with mutation specific primers for CYP2D6A (29A) and CYP2D6B (29B) allelic variants revealed that the XbaI 44kb fragment in Chinese apparently contains a functional CYP2D6 gene, in contrast to the situation among Caucasians. The results provide a molecular explanation of the interethnic difference in the metabolism of drugs affected by the debrisoquine hydroxylation polymorphism.

Lind, T.; Cederberg, C.; Olausson, M.; Olbe, L.

doi: 10.1007/BF00279969pmid: 1884735

228 40 40 6 6 T. Lind C. Cederberg M. Olausson L. Olbe Department of Surgery Sahlgren's Hospital Gothenburg Sweden Medical Department AB Hässle Mölndal Sweden Summary The effect of omeprazole on acid secretion and gastrin levels has been investigated in 10 elderly duodenal ulcer patients in remission. Doses of 5, 10, 20 and 40 mg omeprazole were given once daily for 7 consecutive days and the basal (BAO) and peak (PAO) acid output and fasting plasma gastrin concentration were measured 24 h after the seventh dose. Omeprazole suppressed PAO significantly and dose-dependently after doses of 10, 20 and 40 mg, the suppression being 42%, 75% and 85%, respectively. No patient showed complete inhibition of PAO and at least 20 mg had to be given to obtain a marked inhibitory effect in all patients. Increasing the dose to 40 mg had only a slight additional effect compared to 20 mg. There was a relationship between degree of acid inhibition and the increase in fasting plasma gastrin. PAO had to be suppressed by more than 80% before a moderate increase in fasting plasma gastrin was observed. The optimal once-daily oral dose of omeprazole for inhibition of acid secretion in elderly patients appears to be 20 mg. Omeprazole 20–40 mg may cause a moderate increase in fasting plasma gastrin.

Harder, S.; Thürmann, P.; Huber, Th.; Rietbrock, N.

doi: 10.1007/BF00279970pmid: 1884736

228 40 40 6 6 S. Harder P. Thürmann Th. Huber N. Rietbrock Department of Clinical Pharmacology University Hospital Frankfurt Frankfurt/Main FRG Summary The pharmaceutical market in the FRG offers about 11,000 different preparations and formulations. A restricted list (pharmacopoeia) containing approximately 1,000 drugs has been proved to cover the routine requirements of a university clinic and most of the additional drugs demanded by the physicians as ‘exceptis excipiendis’. Restrictive control of requests for drugs not included in the internal pharmacopoeia by clinical pharmacologists has reduced the absolute number of requests by half, and about 60% of the remaining requests could be replaced by drugs listed in the pharmacopoeia. The majority of the special requests arose from the continuation of drugs presented to out-patients by the resident physicians after admission of the patient to the hospital. The supervision may lead to more critical revision of out-patient medication, but a substantial reduction of drug expenditure was not attained, as the drugs requested amounted only to a minor fraction of the overall drug expenditure by the hospital.

Bleck, J.; Schlitt, H.; Christians, U.; Schottmann, R.; Thiesemann, C.; Strohmeyer, S.; Kohlhaw, K.; Wonigeit, K.; Pichlmayr, R.; Sewing, K.-F.

doi: 10.1007/BF00279971pmid: 1679393

Lindholm, A.

doi: 10.1007/BF00279972pmid: 1884737

228 40 40 6 6 A. Lindholm Department of Clinical Pharmacology Huddinge Hospital Huddinge Sweden Department of Transplantation Surgery Huddinge Hospital Huddinge Sweden Summary The free fraction of cyclosporine A (CsA) and its total plasma concentration as determined by HPLC(CsA T ) were prospectively monitored in 66 recipients of renal transplants. The free CsA levels (CsA u ) were calculated. The variability in free CsA levels was no less than for total CsA T levels. The correlation between CsA u and CsA T was high ( r =0.90). Both CsA T and CsA u covaried with serum triglycerides and apolipoprotein A1. Fourty-four of the 66 patients suffered acute rejection episodes on 69 occasions. CsA T and CSA u both decreased and to a similar extent at the occurrence of acute rejection (42% and 59% decrease, respectively; significant vs baseline. Notsignificant difference in decrease in CsA T vsCsA u ). Acute nephrotoxicity occurred on 11 occasions in 10 patients. Both CsA T and CSA u were approximately twice as high at the time of acute nephrotoxicity as compared to one week previously. Both CsA T and CsA u were higher during the first month after transplantation in patients with than in patients without systemic infection. Thus, plasma CsA u gave no additional clinical information or guidance compared to CsA T in renal transplant recipients. Due to the complexity of its assay, which requires two consecutive analyses, there does not appear to be any need for routine monitoring of CsA u in renal transplant recipients.

Schultz, E.; Tarpila, S.; Bäckström, A.-C.; Gordin, A.; Nissinen, E.; Pohto, P.

doi: 10.1007/BF00279973pmid: 1884738

228 40 40 6 6 E. Schultz S. Tarpila A.-C. Bäckström A. Gordin E. Nissinen P. Pohto Research Centre, Orion Pharmaceutica Finland Helsinki Deaconess Hospital Helsinki Finland Summary The effect of increasing single oral doses of the novel catechol-O-methyltransferase (COMT) inhibitor, nitecapone, on enzyme activity in red cells (RBC) and gastroduodenal COMT activity has been studied in healthy male volunteers. A dose-dependent decrease in RBC COMT activity was seen in all cases after 1 to 150 mg of the drug. The highest dose of 300 mg did not produce much more inhibition of COMT than 150 mg. The inhibition was not complete; at the highest doses the COMT activity was reduced by 50–60%. The effect and the duration of the inhibition in RBC COMT was strongly correlated with plasma nitecapone concentrations in the dose range up to 150 mg. RBC COMT activity recovered fully in 4 h after medication. Gastric mucosal COMT activity was several-fold higher than that in RBCs. It was also dose-dependently inhibited at the two doses (25 and 100 mg) studied. The inhibition of gastric and duodenal COMT was greater than that in RBCs. This also indicates that nitecapone is locally active in the gastroduodenal tract. The results confirm nitecapone as a potent COMT inhibitor in human tissues. New COMT inhibitors may provide a valuable approach to the treatment of Parkinson's disease in combination with L-dopa and dopa decarboxylase inhibitor therapy.