European Journal of Clinical Pharmacology

Yamazaki, J.; Ohsawa, H.; Uchi, T.; Iida, M.; Nakano, H.; Hosoi, H.; Morishita, T.; Yabe, Y.; Koyama, N.; Komatsu, H.

doi: 10.1007/BF00271360pmid: 8491233

228 44 44 3 3 J. Yamazaki H. Ohsawa T. Uchi M. Iida H. Nakano H. Hosoi T. Morishita Y. Yabe N. Koyama H. Komatsu First Department of Internal Medicine Toho University School of Medicine Tokyo Japan Cardiovascular Diagnostic Laboratory Center Toho University School of Medicine Tokyo Japan Department Thoracic Cardiovascular Surgery Toho University School of Medicine Tokyo Japan Summary The effect of nicorandil on myocardial perfusion in ischaemic heart disease has been studied using exercise-load Tl-201 myocardial SPECT (Ex-SPECT). Ex-SPECT was carried out in 12 patients with previous myocardial infarction (OMI) and 9 with angina pectoris (AP) before and after administration of nicorandil 15 mg/day, for three or more weeks; % Tl uptake and the washout rate in infarcted or ischaemic areas were calculated from short axial images using the Bull's eye method. In the OMI group, % Tl uptake and washout rates in the infarction areas improved significantly from 52.4% and 0.25 before nicorandil to 60.4% and 0.38 after it. In the AP group, too, % Tl uptake and washout rates showed a significant improvement from 56.9% and 0.10 before to 69.1% and 0.33 after administration. Six subjects who had not received the drug, and who showed negative washout rates, had high improvement rates when nicorandil was administered, suggesting that the drug could increase myocardial perfusion during exercise loading as well as suppressing coronary spasm. Ex-SPECT was done in 4 subjects before and after nicorandil and after subsequent surgical treatment (PTCA or CABG) and the effects of the two therapies were compared. The washout rate was improved from 0.01 to 0.34 by administration of nicorandil, and a notable increase in coronary artery blood flow was achieved compared to the level after surgical treatment, i.e. 0.50. It was concluded that, normal dosages of nicorandil have a powerful direct effect of dilating the coronary arteries without any influence on preload or afterload.

Pfeiffer, A.; Schmidt, T.; Höller, T.; Herrmann, H.; Pehl, C.; Wendl, B.; Kaess, H.

doi: 10.1007/BF00271361pmid: 8491234

228 44 44 3 3 A. Pfeiffer T. Schmidt T. Höller H. Herrmann C. Pehl B. Wendl H. Kaess II. Medical Department Hospital München-Bogenhausen Munich Germany Summary The aim of this double-blind, placebo-controlled, cross-over study was to investigate the effect of trospium chloride on gall bladder contraction, gastric emptying of a liquid meal, gastrooesophageal reflux, and orocaecal transit time in healthy subjects. Gall bladder contraction was examined by ultrasonography before and after stimulation with two raw eggs. Gastric emptying was evaluated by an intubation technique and by sonography. To determine gastrooesophageal reflux and orocaecal transit time, 24-hour pH metry and a hydrogen breath test were used. The gall bladder ejection fractions were significantly lower after oral treatment with both 4×10 mg and 4×20 mg trospium compared to placebo, but no difference was seen between the two doses of drug. Gastric emptying of a liquid meal was significantly delayed after intake of 4×15 mg trospium, whilst the time course of the intragastric volume determined by ultrasound did not differ from that after placebo, suggesting an antisecretory effect of trospium on gastric secretion. The fractional time of oesophageal pH<4 as a percentage of the entire 24-hour investigation period was significantly increased by treatment with trospium 3×15 mg per day. The orocaecal transit time of 10 g lactulose was significantly prolonged. Provided that the observed effects on gall bladder contraction, gastric emptying, and orocaecal transit time are reproduced in disease states, trospium should be regarded as a potentially useful antispasmodic agent.

Houezec, J.; Jacob, P.; Benowitz, N.

doi: 10.1007/BF00271362pmid: 8491235

228 44 44 3 3 J. Le Houezec P. Jacob III N. L. Benowitz From the Division of Clinical Pharmacology and Experimental Therapeutics San Francisco General Hospital Medical Center San Francisco California USA Department of Medicine University of California San Francisco California USA CNRS URA 654, Hôpital de la Salpêtrière 47 Bd de l'Hôpital F-75651 Paris Cedex 13 France Summary The stable isotope-labeled compound 3',-3'-dideuteronicotine (nicotine-d 2 ) was used to investigate the disposition kinetics and effects of nicotine administered subcutaneously to 6 smokers. Plasma nicotine-d 2 concentrations were measured for 8 h after subcutaneous injection of 4 doses (0.4, 0.8, 1.2, and 2.4 mg). Peak plasma nicotine concentration correlated well with the dose, averaging 2.8 to 14.8 ng/ml, 19 to 25 min after injection of the 0.4 mg and 2.4 mg doses, respectively. The plasma clearance over bioavailability ratio (CL/f) averaged 12 to 13 ml · min −1 · kg −1 , similar to the clearance reported previously for intravenously administered nicotine. Thus, bioavailability appears to be approximately 100%. The heart rate response was more sensitive to the nicotine dose than the blood pressure response. Subjective effects showed large interindividual variability. The results reported herein may be useful in planning future studies. Administration of nicotine by the subcutaneous route appears to be a practical and safe method for studying the human pharmacology of nicotine.

Miller, R.; Ludden, T.

doi: 10.1007/BF00271363pmid: 8491236

228 44 44 3 3 R. Miller T. M. Ludden Department of Pharmacology University of Durban-Westville Durban Republic of South Africa Department of Pharmacology University of Texas Health Science Center San Antonio Texas USA Summary The absorption properties of a conventional tablet of carbamazepine (T) and a controlled release form of carbamazepine (TCR) have been compared using a nonlinear mixed effect model (NONMEM). Plasma carbamazepine concentration data were obtained from an open, steady-state, crossover bioavailability study in which 494 measurements were obtained from 13 patients, with an equal number of samples per patient for each dosage form. The pharmacokinetic model used was a one-compartment open model with first-order absorption and elimination. The objective function was used as a measure of the goodness of fit of the model to the data. Body weight was an important determinant of carbamazepine clearance (CL) but not volume of distribution (V). Accounting for the interindividual variability in volume of distribution did not significantly influence the objective function. Including different rates of absorption (ka) for the two dosage forms resulted in a significant improvement in the objective function, as well as reducing the interindividual variability in the rate of absorption. Adding a parameter for relative bioavailability (f) of TCR improved the objective function statistically, but an unrealistic value for V was obtained, and the absorption and elimination rates appeared to be transposed in the classical “flip-flop” manner. Fixing V to the value obtained before introducing f did not change the objective function and permitted estimation of f without the confounding influence of excessive parameters. The final population parameter estimates (standard error of estimate) were: CL, 0.0522 (0.0019) l·h −1 ·kg −1 ; V, 63.7 (FIXED)l; kaT, 0.312 (0.064) h −1 ; kaTCR, 0.149 (0.016) h −1 ; f, 1.01 (0.0326); variance (additive) in CL, 0.291 (0.083) (l·h −1 ·kg −1 ) 2 ; residual intrasubject error variance (additive), 0.572 (0.082) (mg·l −1 ) 2 . The 95% confidence interval of the extent of absorption (f) of 93.6%–107.4% was well within the generally accepted range of ±20%, while the rate of absorption of Tegretol CR was significantly slower than that of Tegretol, as expected for a controlled release product.

Oosterhuis, B.; Storm, G.; Cornelissen, P.; Su, C.; Sollie, F.; Jonkman, J.

doi: 10.1007/BF00271364pmid: 8491237

228 44 44 3 3 B. Oosterhuis G. Storm P. J. G. Cornelissen C. A. P. F. Su F. A. E. Sollie J. H. G. Jonkman Pharma Bio-Research International B. V. Zuidlaren The Netherlands Boehringer Ingelheim B. V. Alkmaar The Netherlands Boehringer Ingelheim Deutschland GmbH Biberach Germany Summary Ambroxol is known to promote bronchial secretion and is used as an expectorant. Previous studies had suggested that high doses of ambroxol could reduce the plasma uric acid concentration. The present study was undertaken to confirm this finding, to determine its dose-response relationship and to identify the underlying mechanism of action. Using a placebo-controlled, double-blind parallel group design, 48 healthy male volunteers were randomly allocated to receive placebo b.d. and ambroxol 125 mg b.d., 250 mg b.d. or 500 mg b.d. (12 subjects per group). The subjects were hospitalised during a dietary run-in period of 3 days (Days -3 to -1) and a treatment period of 5 days (Days 1 to 5). On Day -1 (baseline) and Days 1 to 5, all urine was collected and blood samples were taken for the analysis of uric acid, creatinine, xanthine and ambroxol. The measurements were repeated four days after treatment had closed. Steady state plasma concentrations of ambroxol (trough levels) were reached after 2 or 3 days and were linearly related to dose. Ambroxol induced a significant, dose-dependent, reduction in plasma uric acid (250 mg b.d. about 20%; and at 500 mg b.d. about 30%). The diurnally fluctuating uric acid clearance was dose dependently increased and there was no notable effect on creatinine clearance. Plasma hypoxanthine levels were not affected by ambroxol. No severe adverse events were reported and no drug induced changes in the clinical laboratory values were observed. It is concluded that ambroxol has an uricosuric action following oral administration of higher doses (250 mg-500 mg b.d.) and it is well tolerated.

Högstedt, S.; Rane, A.

doi: 10.1007/BF00271365pmid: 8491238

228 44 44 3 3 S. Högstedt A. Rane Department of Obstetrics and Gynaecology Central Hospital Väster»s Sweden Department of Clinical Pharmacology Akademiska Hospital Uppsala Sweden Summary The plasma drug concentration-effect relationship after an oral dose of 100 mg metoprolol has been studied in 8 women in the third trimester of a pregnancy complicated by hypertension. The study was repeated 3–5 months after parturition when all but 2 women were normotensive. Systolic and diastolic blood pressures (SBP and DBP) were measured in the sitting position followed by the change in heart rate on exercise. The average peak plasma concentration of metoprolol was almost 4-times higher in the non-pregnant state. Despite this difference, the reduction in exercise tachycardia and resting SBP was only slightly more pronounced after delivery than during pregnancy. In relation to the plasma drug concentration, metoprolol had four-times and twice the effect on heart rate and SBP during pregnancy as compared to the post partum period. The altered chronotropic response to metoprolol during pregnancy may be due to increased sensitivity or altered function of the β-adrenergic system.

Wangboonskul, J.; White, N.; Nosten, F.; Kuile, F.; Moody, R.; Taylor, R.

doi: 10.1007/BF00271366pmid: 8491239

228 44 44 3 3 J. Wangboonskul N. J. White F. Nosten F. ter Kuile R. R. Moody R. B. Taylor School of Pharmacy Robert Gordon's Institute of Technology Schoolhill Aberdeen UK Faculty of Tropical Medicine Mahidol University Bangkok Thailand Nuffield Department of Clinical Medicine John Radcliffe Hospital Headingtin Oxford UK Unit of Infectious Diseases and Tropical Medicine Academic Medical Center University of Amsterdam The Netherlands Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences Khon Kaen University Khon Kaen Thailand Summary Plasma and whole blood concentrations of proguanil, its active metabolite cycloguanil, and the inactive metabolite 4-chlorophenyl-biguanide, were measured by HPLC in 10 healthy Karen women in the last trimester of pregnancy, following a 200 mg single oral dose of proguanil. Four of these women were restudied 2 months after delivery. The pharmacokinetic properties of proguanil were similar during and after pregnancy. Median peak plasma concentrations of proguanil during pregnancy and following delivery were 212 and 215 ng·ml −1 , and occurred at 4.5 and 5 h, respectively. Mean plasma AUC values for proguanil during and following pregnancy were 94 and 98 ng·h·ml −1 ·kg −1 , respectively. Corresponding whole blood AUC values were 361 and 396 ng·h·ml −1 ·kg −1 . The mean elimination half lives and mean residence times of proguanil in plasma and whole blood were 12.3 and 19.6 h and 13.8 and 20.7 h respectively during pregnancy. Following pregnancy these values were 17.1 and 19.7 h for plasma and 19.7 h and 20.2 h for whole blood respectively. Mean peak plasma and whole blood concentrations of cycloguanil following pregnancy were 25 and 22 ng·ml −1 respectively. During pregnancy peak cycloguanil concentrations in both plasma and whole blood were markedly lower, 13 and 12 ng ml −1 , respectively. Two pregnant women (neither of whom were restudied) were probably poor metabolisers of proguanil. The mean ratio of proguanil to cycloguanil plasma AUC was 16.7 in the third trimester of pregnancy and 7.8 following pregnancy, compared with less than 5 in previously reported studies. The concentrations of 4-chlorophenylbiguanide in both plasma and whole blood in pregnant subjects were also lower than those after pregnancy. These data show that blood concentrations of the active antimalarial metabolite cycloguanil are reduced in late pregnancy and that the currently recommended dose of proguanil could be inadequate for antimalarial prophylaxis in pregnant women.

Sidhu, J.; Charles, B.; Triggs, E.; Tudehope, D.; Gray, P.; Steer, P.

doi: 10.1007/BF00271367pmid: 8491240

228 44 44 3 3 J. S. Sidhu B. G. Charles E. J. Triggs D. I. Tudehope P. H. Gray P. A. Steer Department of Pharmacy The University of Queensland Queensland Australia Department of Neonatology Mater Mothers' Hospital Queensland Australia Summary The use of bioelectrical impedance (BI) analysis as a non-invasive approach for individualising gentamicin therapy in newborn infants has been investigated in a two phase study. In Phase I, 1/impedance and length 2 were identified as statistically significant predictors of the distribution volume of gentamicin (Adj R 2 =0.78, CV=12.42%), and length 2 /impedance and post-conceptual age were predictors of total systemic clearance (Adj R 2 =0.83, CV=14.5%), following the administration of 2.5 mg·kg −1 gentamicin to 17 neonates (gestational age (GA) 27 to 36 weeks). In a prospective validation of these relationships in an independent (Phase II) group of 27 infants (GA 26 to 41 weeks), predicted serum gentamicin concentrations were close to those achieved. Several instances of high prediction errors (predicted minus achieved levels) were observed in infants with known or suspected renal impairment and they caused significant ( P <0.05) perturbation in the bias and accuracy of the models. Daily BI measures over a four to five day period were able to detect individual changes in the fat-free body compartments, which were translated into alterations in gentamicin regimens. This simple, non-invasive and relatively inexpensive bedside technique provides a potentially valuable means to individualise gentamicin therapy without relying on the measurement of serum gentamicin concentration.

Pacifici, G.; Kubrich, M.; Giuliani, L.; Vries, M.; Rane, A.

doi: 10.1007/BF00271368pmid: 8491241

228 44 44 3 3 G. M. Pacifici Associate Professor in Pharmacology M. Kubrich L. Giuliani M. de Vries A. Rane Department of Biomedicine, Medical School University of Pisa Italy Department of Surgery, Medical School University of Pisa Italy Solvay Duphar B. V. Weesp The Netherlands Department of Clinical Pharmacology Uppsala University Hospital Sweden Summary Ritodrine is a β 2 -adrenoceptor agonist used for the management of preterm labour. It is inactivated by conjugation with sulphate and glucuronic acid. There is more ritodrine sulphate than ritodrine glucuronide in urine from the newborn whereas equal amounts of ritodrine glucoronide and sulphate are excreted in maternal urine (Clin. Pharmacol. Ther 44, 634–641, 1988). We show that, in the mid-gestational human fetal liver, ritodrine sulphotransferase is well expressed, whereas the glucuronidation of ritodrine is little developed compared to the adult liver. The average sulphotransferase activity was 308 pmol·min −1 per mg protein in fetal (N=48) and 145 pmol·min −1 per mg protein in adult (N=32) liver. The rates of ritodrine sulphation in fetal gut, lung and kidney were higher than in the corresponding adult tissues. The development and tissue distribution patterns of ritodrine sulphotransferase are consistent with those of dopamine sulphotransferase. Ritodrine and dopamine are sulphated by thermolabile enzymes. The activity of glucuronyl transferase was measurable in only 5 of the 48 foetal livers assayed, and in those in which could be assayed, the average activity was 44.6 pmol·min −1 per mg protein, one-tenth of that in adult livers (524 pmol·min −1 per mg protein).

Ohlman, S.; Lindholm, A.; Hägglund, H.; Säwe, J.; Kahan, B.

doi: 10.1007/BF00271369pmid: 8491242

228 44 44 3 3 S. Ohlman A. Lindholm H. Hägglund J. Säwe B. D. Kahan Department of Transplantation Surgery Karolinska Institute at Huddinge Hospital Huddinge Sweden Department of Clinical Pharmacology Karolinska Institute at Huddinge Hospital Huddinge Sweden Division of Immunology and Organ Transplantation, Department of Surgery The University of Texas Medical School Houston Texas USA Summary The intraindividual variability and circadian variation of oral cyclosporine (CsA) pharmacokinetics were studied over 24 h in 18 renal transplant recipients at steady state, and in 10 of the patients during a second 24 h period. The absolute percentage intraindividual difference in daytime AUC (0–12 h) ranged from 2% to 54% (mean 30%), and the corresponding variability in nighttime AUC (0–12 h) ranged from 5% to 80% (mean 34%). The pharmacokinetic variables t 1/2 , t max and C max were more variable than the AUC (0–12 h) both during the day and at night. The evening trough level was significantly lower than the morning trough level; 185 ng · ml −1 versus 223 ng · ml −1 . This, together with a significantly longer t 1/2 in the night than the day, suggested circadian variability in the pharmacokinetics of CsA. In a separate retrospective study in 162 renal transplant recipients given CsA by constant intravenous infusion, repeated CsA blood concentration measurements at steady state showed lower concentrations during the day than the night, suggesting higher CsA clearance during daytime. It is concluded that CsA pharmacokinetics in renal transplant recipients, besides the well-known interindividual variability, also displays large intraindividual variability as well as circadian variation. Our findings further emphasize the necessity and difficulty of pharmacological monitoring in the clinical use of CsA in organ transplantation.