bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacokinetics and pharmacodynamics of Ro 44–3888 after single ascending oral doses of sibrafiban, an oral platelet aggregation inhibitor, in healthy male volunteers
Authors: Wittke Bärbel , Mackie Ian J. , Machin Samuel J. , Timm Uwe , Zell Manfred , Goggin Timothy
Published: March 2003

Aims This study constituted the first administration of the oral platelet inhibitor, sibrafiban, to humans. The aim was to investigate the pharmacokinetics and pharmacodynamics of Ro 44–3888, the active principle of sibrafiban, after single ascending oral doses of sibrafiban. Particular emphasis was placed on intersubject variability of the pharmacokinetic and pharmacodynamic parameters of Ro 44–3888.

Methods The study consisted of three parts. Part I was an open ascending‐dose study to determine target effect ranges of sibrafiban. Part II, a double‐blind, placebo‐controlled, parallel‐group study, addressed the intersubject variability of pharmacokinetic and pharmacodynamic parameters of the active principle at a sibrafiban dose achieving an intermediate effect. Part III was a double‐blind, placebo‐controlled, ascending‐dose design covering the complete plasma concentration vs pharmacodynamic response curve of sibrafiban.

Results At sibrafiban doses between 5 mg and 12 mg, the pharmacokinetics of free Ro 44–3888 in plasma were linear whereas those of total Ro 44–3888 were non‐linear because of the saturable binding to the glycoprotein IIb‐IIIa receptor. Saturation of the GP IIb–IIIa receptor was reached at plasma concentrations of 15.9 ng ml−1. At sibrafiban doses up to 2 mg, ADP‐induced platelet aggregation was inhibited by 50%, whereas the inhibition of TRAP‐induced platelet aggregation was about 20–30%. At the higher doses, ADP‐induced platelet aggregation was almost completely inhibited while a clear dose‐response could be observed with TRAP‐induced inhibition of platelet aggregation at sibrafiban doses of 5 to 12 mg. Ivy bleeding time increased very steeply with dose with a significant prolongation observed at doses of 5 to 7 mg of sibrafiban (5–7 min, >30 min in one case). At a sibrafiban dose of 12 mg, the stopping criterion for dose escalation (prolongation of the Ivy bleeding time >30 min in three out of four subjects per dose group) was reached. The interindividual coefficients of variation of the integrated pharmacokinetic and pharmacodynamic parameters (AUC and AUE) were below 20%, thus lying well within the pre‐set level of acceptance.

Conclusions With a low intersubject variability of its pharmacokinetic and pharmacodynamic parameters, linear pharmacokinetics and pharmacodynamic effects closely related to its plasma concentrations, Ro 44–3888 has good pharmacological prerequisites for a well controllable therapy of secondary prevention of arterial thrombosis in patients with acute coronary syndrome.
Population pharmacokinetics of methadone in opiate users: characterization of time‐dependent changes
Authors: Rostami‐Hodjegan Amin , Wolff Kim , Hay Alastair W. M. , Raistrick Duncan , Calvert Robert , Tucker Geoffrey T.
Published: March 2003

Aims Although methadone is widely used to treat opiate dependence, guidelines for its dosage are poorly defined. There is increasing evidence to suggest that a strategy based on plasma drug monitoring may be useful to detect non‐compliance. Therefore, we have developed a population‐based pharmacokinetic (POP‐PK) model that characterises adaptive changes in methadone kinetics.

Methods Sparse plasma rac‐methadone concentrations measured in 35 opiate‐users were assessed using the P‐Pharm software. The final structural model comprised a biexponential function with first‐order input and allowance for time‐dependent change in both clearance (CL) and initial volume of distribution (V  ). Values of these parameters were allowed to increase or decrease exponentially to an asymptotic value.

Results Increase in individual values of CL and increase or decrease in individual values of V with time was observed in applying the model to the experimental data.

Conclusions A time‐dependent increase in the clearance of methadone is consistent with auto‐induction of CYP3A4, the enzyme responsible for much of the metabolism of the drug. The changes in V  with time might reflect both up‐ and down‐regulation of α1‐acid glycoprotein, the major plasma binding site for methadone. By accounting for adaptive kinetic changes, the POP‐PK model provides an improved basis for forecasting plasma methadone concentrations to predict and adjust dosage of the drug and to monitor compliance in opiate‐users on maintenance treatment.
Birth outcome following maternal use of metoclopramide
Authors: Sørensen Henrik Toft , Nielsen Gunnar Lauge , Christensen Kaare , Tage‐jensen Ulrik , Ekbom Ers , Baron John , Group The Euromap study
Published: March 2003

Aims
 Metoclopramide is an antiemetic drug used widely during pregnancy for nausea and vomiting. Because of its frequent use any adverse effects on infant health would have major public health implications. We therefore examined the safety of metoclopramide during pregnancy.

Methods
 Using the Pharmaco‐Epidemiological Prescription Database of North Jutland County, we identified 309 women with singleton pregnancies who had prescriptions for metoclopramide fom 1 January 1991 to 31 December 1996. Information on malformations, birth weight, preterm deliveries and stillbirth were compared with 13 327 references who did not receive prescriptions of any kind during pregnancy.

Results
 Mean birth weight among exposed women was 3480 g compared with 3470 g among nonexposed. Based on logistic regression models no major differences in the risk were found concerning malformations (OR= 1.11; 95% confidence interval (CI): 0.6–2.1); low birth weight (OR= 1.79; 95% CI: 0.8–3.9) or preterm delivery (OR= 1.02; 95 CI: 0.6–1.7).

Conclusions 
We could not document any association between the use of metoclopramide during pregnancy and adverse pregnancy outcome. Because of the limited power of our study further research is required.
Single dose methodology to assess the influence of an α1‐adrenoceptor antagonist on uroflowmetric parameters in patients with benign prostatic hyperplasia
Authors: Curtis S. P. , Eardley I. , Boyce M. , Larson P. , Haesen R. , Gottesdiener K. , Gertz B. J.
Published: March 2003

Aims 
To establish methodology which rapidly and reliably assesses the effect of an α1‐adrenoceptor antagonist on peak urine flow rates in men with benign prostatic hyperplasia (BPH). This methodology could then be applied to screening new drugs to treat BPH.

Methods 
Twenty‐five patients with BPH enrolled in a double‐blind, placebo‐controlled, two‐period crossover study. Patients were either withdrawn from their current α1‐adrenoceptor antagonist therapy (n = 22) or were untreated prestudy (n = 3) and all met prespecified uroflowmetric criteria including: (1) a peak urine flow rate (Qmax) < 12 ml s−1 off therapy (or  < 10 ml s−1 if untreated prestudy) and (2) a decrease in peak urine flow rate (Qmax) of > 2 ml s−1 after withdrawal from therapy. Study treatment consisted of tamsulosin 0.4 mg (or matching placebo) once daily for 8 days in a two‐period crossover. Uroflowmetry was performed predose and once postdose (4.5–5.5 h postdose) on day 1, and once postdose (4.5–5.5 h postdose) on day 8 of each treatment period.

Results 
After a single dose of tamsulosin, the least‐square mean difference between tamsulosin and placebo in the change from baseline Qmax was 2.8 ml s−1 (P = 0.017 vs placebo). After 8 days dosing of tamsulosin, the least‐square mean difference between tamsulosin and placebo in the change from baseline Qmax was also 2.8 ml s−1 (P = 0.044 vs placebo). Additionally, there was no significant difference observed between the single and multiple dose results (P > 0.200 for between group difference).

Conclusions 
Both single and multiple doses of tamsulosin 0.4 mg increased Qmax in men with BPH. A single dose produced a comparable response to multiple dose administration. The magnitude of the effect was greater than the effect generally seen in longer term clinical trials, but this difference may be explained by the patient population in this study which was preselected for ‘responsiveness’ to an α1‐adrenoceptor antagonist. These results support the utility of single dose uroflowmetric measurements in rapidly providing preliminary data on new investigational agents, specifically agents which act to increase urine flow in men with BPH. However, clinical efficacy would still need to be confirmed with longer term clinical trials.
Pharmacokinetics and pharmacodynamic effects of ABT‐627, an oral ETA selective endothelin antagonist, in humans
Authors: Verhaar Marianne C. , Grahn Amy Y. , Van Weerdt Anton W. M. , Honing Marina L. H. , Morrison Paul J. , Yang Yonghong P. , Padley Robert J. , Rabelink Ton J.
Published: March 2003

Aims  Endothelins (ETs) may play a role in the pathogenesis of a variety of cardiovascular diseases. The present study was designed to investigate the pharmacokinetic and pharmacodynamic effects of the orally active ETA selective receptor antagonist ABT‐627 in healthy humans.

Methods  Healthy volunteers were included in two studies with cross‐over design. Subjects received single or multiple dose (an 8 day period) administration of oralABT‐627 or matched placebo, in a dose range of 0.2–40 mg. The pharmacokinetics of ABT‐627 were described and its effects on systemic haemodynamics under resting conditions and on forearm vasoconstriction in response to ET‐1 were assessed.

Results  ABT‐627 was generally well tolerated in both studies, with transient headache being the most reported adverse event (in 62%vs 4% during placebo, P < 0.05, for Study 1 and in 42%vs 60%, P = 0.2, for Study 2). ABT‐627 was rapidly absorbed, reaching maximum plasma levels at ≈ 1 h post dose. Single dose ABT‐627, at a dose of 20 and 40 mg, inhibited ET‐1 induced forearm vasoconstriction at 8 h post dose. Eight days ABT‐627 treatment, at a dose level of 5 mg and above, also effectively blocked forearm vasoconstriction to ET‐1. ABT‐627 caused a significant reduction in peripheral resistance as compared with placebo (16 ± 1 vs 19 ± 1, 18 ± 2 vs 23 ± 3, 15 ± 1 vs 17 ± 1 AU at 1, 5, 20 mg in Study 2) with only a mild decrease in blood pressure (79 ± 2 vs 84 ± 3, 80 ± 4 vs 90 ± 5, 75 ± 3 vs 79 ± 1 at 1, 5, 20 mg in Study 2). ABT‐627 caused a moderate dose‐dependent increase in circulating immunoreactive ET levels (a maximal increase of 50% over baseline at the 20 mg dose level).

Conclusions  The oral ETA receptor blocker ABT‐627 is well tolerated, rapidly absorbed, effectively blocks ET‐1 induced vasoconstriction and causes a decrease in total peripheral resistance and mean arterial pressure. Our data suggest that ABT‐627 may be a valuable tool in treatment of cardiovascular disease.
In vitroinhibition of the cytochrome P450 (CYP450) system by the antiplatelet drug ticlopidine: potent effect on CYP2C19 and CYP2D6
Authors: Ko, Jae Wook , Desta, Zeruesenay , Soukhova, Nadia V , Tracy Timothy , Flockhart David A
Published: March 2003

Aims To examine the potency of ticlopidine (TCL) as an inhibitor of cytochrome P450s (CYP450s)in vitrousing human liver microsomes (HLMs) and recombinant human CYP450s.

Methods Isoform‐specific substrate probes of CYP1A2, 2C19, 2C9, 2D6, 2E1 and 3A4 were incubated in HLMs or recombinant CYPs with or without TCL. Preliminary data were generated to simulate an appropriate range of substrate and inhibitor concentrations to construct Dixon plots. In order to estimate accurately inhibition constants (Kivalues) of TCL and determine the type of inhibition, data from experiments with three different HLMs for each isoform were fitted to relevant nonlinear regression enzyme inhibition models by WinNonlin.

Results TCL was a potent, competitive inhibitor of CYP2C19 (Ki = 1.2 ± 0.5 µm) and of CYP2D6 (Ki = 3.4 ± 0.3 µm). TheseKivalues fell within the therapeutic steady‐state plasma concentrations of TCL (1–3 µm). TCL was also a moderate inhibitor of CYP1A2 (Ki = 49 ± 19 µm) and a weak inhibitor of CYP2C9 (Ki > 75 µm), but its effect on the activities of CYP2E1 (Ki = 584 ± 48 µm) and CYP3A (> 1000 µm) was marginal.

Conclusions TCL appears to be a broad‐spectrum inhibitor of the CYP isoforms, but clinically significant adverse drug interactions are most likely with drugs that are substrates of CYP2C19 or CYP2D6.
Diurnal variation in the quantitative EEG in healthy adult volunteers
Authors: Cummings L. , Dane A. , Rhodes J. , Lynch P. , Hughes A. M.
Published: March 2003

Aims
To define the change in power in standard waveband frequencies of quantitative cortical electroencephalogram (EEG) data over a 24 h period, in a drug free representative healthy volunteer population.

Methods
This was an open, non randomised study in which 18 volunteers (9 male and 9 female) were studied on 1 study day, over a 24 h period. Volunteers had a cortical EEG recording taken at 0, 2, 4, 6, 8, 10, 12, 16 and 24 h. Each recording lasted for 6 min (3 min eyes open, 3 min eyes closed). All EEG recordings were taken in a quietened ward environment with the curtains drawn round the bed and the volunteer supine. During the 3 min eyes open, volunteers were asked to look at a red circle on a screen at the foot of the bed, and refrain from talking.

Results
Plots produced of geometric mean power by time of the standard wave band frequencies gave some indication of a circadian rhythm over the 24 h period for θ (4.75–6.75 Hz), α1 (7.0–9.5 Hz) and β1 (12.75–18.50 Hz) wavebands. Mixed models were fitted to both the eyes open and eyes closed data which confirmed a change in mean waveband power with time with statistical significance at the conventional 5% level (P < 0.05).

Conclusions
These data indicate the presence of a diurnal variation in the cortical quantitative EEG. They support the use of a placebo control group when designing clinical trials which utilize quantitative EEG to screen for central nervous system (CNS) activity of pharmaceutical agents, to control for the confounding variable of time of day at which the EEG recordings were made.
Effects of potassium channel opener KRN4884 on human conduit arteries used as coronary bypass grafts
Authors: Ren Zhen , Floten Storm , Furnary Anthony , Liu Minghui , Gately Hugh , Swanson Jeffrey , Ahmad Aftab , Yim Anthony P. C. , He Guo‐Wei
Published: March 2003

Aims
The effects of a new potassium channel opener KRN4884 on human arteries have not been studied. This study was designed to investigate the effects of KRN4884 on the human internal mammary artery (IMA) in order to provide information on possible clinical applications of KRN4884 for preventing and relieving vasospasm of arterial grafts in coronary artery bypass grafting.

Methods
IMA segments (n = 140) taken from patients undergoing coronary surgery were studied in the organ chamber. Concentration‐relaxation curves for KRN4884 were established in the IMA precontracted with noradrenaline (NA), 5‐hydroxytryptamine (5‐HT), angiotensin II (ANG II), and endothelin‐1 (ET‐1). The effect of glibenclamide (GBC) on the KRN4884‐induced relaxation was also examined in NA or 5‐HT‐precontracted IMA. Concentration‐contraction curves for the four vasoconstrictors were constructed without/with pretreatment of KNR4884 (1 or 30 µm) for 15 min.

Results
KRN4884 induced less relaxation (P < 0.05) in the precontraction induced by ET‐1 (72.9 ± 5.5%) than by ANG II (94.2 ± 3.2%) or NA (93.7 ± 4.1%) with lower EC50 (P < 0.05) for ANG II (−8.54 ± 0.54 log m) than that for NA (−6.14 ± 0.15 log M) or ET‐1 (−6.69 ± 0.34 log m). The relaxation in the IMA pretreated with GBC was less than that in control (P < 0.05). KRN4884‐pretreatment significantly reduced the contraction (P < 0.05) induced by NA (151.3 ± 18.4% vs 82.7 ± 8.7%), 5‐HT (82.7 ± 12.2% vs 30.1 ± 7.3%), and ANG II (24.3 ± 6.3% vs 5.4 ± 1.6%), but did not significantly reduce the contraction induced by ET‐1 (P > 0.05).

Conclusion
KRN4884 has marked vasorelaxant effects on the human IMA contracted by a variety of vasoconstrictors and the effect is vasoconstrictor‐selective.
Evaluation of the pharmacokinetics and electrocardiographic pharmacodynamics of loratadine with concomitant administration of ketoconazole or cimetidine
Authors: Kosoglou T. , Salfi M. , Lim J. M. , Batra V. K. , Cayen M. N. , Affrime M. B.
Published: March 2003

Aims  To evaluate whether ketoconazole or cimetidine alter the pharmacokinetics of loratadine, or its major metabolite, desloratadine (DCL), or alter the effects of loratadine or DCL on electrocardiographic repolarization in healthy adult volunteers.

Methods  Two randomized, evaluator‐blind, multiple‐dose, three‐way crossover drug interaction studies were performed. In each study, subjects received three 10 day treatments in random sequence, separated by a 14 day washout period. The treatments were loratadine alone, cimetidine or ketoconazole alone, or loratadine plus cimetidine or ketoconazole. The primary study endpoint was the difference in mean QTc intervals from baseline to day 10. In addition, plasma concentrations of loratadine, DCL, and ketoconazole or cimetidine were obtained on day 10.

Results Concomitant administration of loratadine and ketoconazole significantly increased the loratadine plasma concentrations (307%; 90% CI 205‐428%) and DCL concentrations (73%; 62‐85%) compared with administration of loratadine alone. Concomitant administration of loratadine and cimetidine significantly increased the loratadine plasma concentrations (103% increase; 70‐142%) but not DCL concentrations (6% increase; 1‐11%) compared with administration of loratadine alone. Cimetidine or ketoconazole plasma concentrations were unaffected by coadministration with loratadine. Despite increased concentrations of loratadine and DCL, there were no statistically significant differences for the primary electrocardiographic repolarization parameter (QTc) among any of the treatment groups. No other clinically relevant changes in the safety profile of loratadine were observed as assessed by electrocardiographic parameters (mean (90% CI) QTc changes: loratadine vs loratadine + ketoconazole = 3.6 ms (‐2.2, 9.4); loratadine vs loratadine + cimetidine = 3.2 ms (‐1.6, 7.9)), clinical laboratory tests, vital signs, and adverse events.

Conclusions  Loratadine 10 mg daily was devoid of any effects on electrocardiographic parameters when coadministered for 10 days with therapeutic doses of ketoconazole or cimetidine in healthy volunteers. It is concluded that, although there was a significant pharmacokinetic drug interaction between ketoconazole or cimetidine and loratadine, this effect was not accompanied by a change in the QTc interval in healthy adult volunteers.
Effects of cilnidipine, a novel dihydropyridine calcium antagonist, on autonomic function, ambulatory blood pressure and heart rate in patients with essential hypertension
Authors: Minami Junichi , Kawano Yuhei , Makino Yuriko , Matsuoka Hiroaki , Takishita Shuichi
Published: March 2003

Aims  The aim of the present study was to evaluate the effects of cilnidipine, a novel dihydropyridine calcium antagonist, on autonomic function, ambulatory blood pressure and heart rate in patients with essential hypertension.

Methods  Ten inpatients with mild to moderate essential hypertension (four men and six women; age: 44–64 years) underwent a drug‐free period for 7 days and a treatment period with cilnidipine 10 mg orally for another 7 days, in a randomized crossover study. On the sixth day of each period, they underwent autonomic function tests including a mental arithmetic test, a cold pressor test and a Valsalva manoeuvre. After these tests, 24 h ambulatory blood pressure, heart rate, and the electrocardiogram R‐R intervals were monitored every 30 min. A power spectral analysis of R‐R intervals was performed to obtain the low‐and high‐frequency components.

Results  Cilnidipine significantly decreased the 24 h blood pressure by 6.5 ± 1.7 mm Hg systolic (mean ± s.e.mean; P < 0.01) and 5.0 ± 1.1 mmHg diastolic (P < 0.01), whereas cilnidipine did not change heart rate or any indices of power spectral components. During the cold pressor test, the maximum change in systolic blood pressure and percentage changes in both systolic and diastolic blood pressures were significantly lower during the treatment period with cilnidipine than during the drug‐free period. The baroreflex sensitivity measured from the overshoot phase of the Valsalva manoeuvre did not differ significantly between the two periods.

Conclusions  Cilnidipine is effective as a once‐daily antihypertensive agent and causes little influence on heart rate and the autonomic nervous system in patients with mild to moderate essential hypertension. Moreover, it is suggested that cilnidipine has an additional clinical benefit in the inhibition of the pressor response induced by acute cold stress.
The intracellular activation of lamivudine (3TC) and determination of 2′‐deoxycytidine‐5′‐triphosphate (dCTP) pools in the presence and absence of various drugs in HepG2 cells
Authors: Kewn, Stephen , Hoggard, Patrick G. ,   Sean, Sales, D. ,   Mark, Johnson A. , Back David J.
Published: March 2003

Aims
Lamivudine (3TC, 2′‐deoxy‐3′‐thiacytidine) requires intracellular metabolism to its active 5′‐triphosphate, 3TC‐5′‐triphosphate (3TCTP), to inhibit the replication of hepatitis B virus (HBV). We have investigated the activation of 3TC, in the presence and absence of a range of compounds, in HepG2 cells. The intracellular levels of the endogenous competitor of 3TCTP, 2′‐deoxycytidine‐5′‐triphosphate (dCTP), were also determined and 3TCTP/dCTP ratios calculated.

Methods
The effects of a number of compounds on 3TC (3H; 1 µm) phosphorylation were investigated by radiometric h.p.l.c. dCTP levels were determined using a template primer extension assay. 3TCTP/dCTP ratios were calculated from these results.

Results
The phosphorylation of 3TC was significantly increased in the presence of either hydroxyurea (HU), methotrexate (MTX), or fludarabine (FLU). For example, at 100 µm HU, control 3TCTP levels were increased to 361% of control, whereas at 100 µm FLU, control 3TCTP levels were increased to 155%. dCTP pools were significantly reduced in the presence of HU and FLU, at 100 µm concentrations only. However, for all the above three compounds investigated, the ratio of 3TCTP/dCTP was favourably enhanced (e.g. at 1 µm MTX, 255% of control). Neither ganciclovir (GCV), lobucavir (LCV), penciclovir (PCV), adefovir dipivoxil (ADV), nor foscarnet (FOS) had any significant effects on 3TC phosphorylation or dCTP pools.

Conclusions
These results suggest that the activity of 3TC may be potentiated when combined with one of the modulators studied. The lack of an interaction between 3TC and the other anti‐HBV agents is reassuring. These in vitro studies can be used as an initial screen to examine potential interactions at the phosphorylation level.
Pharmacokinetics and pharmacodynamics of sibrafiban alone or in combination with ticlopidine and aspirin
Authors: Wittke, Bärbel , Ensor, Hilary , Chung, Jain , Birnböck, Herbert , Lausecker, Berthold , Ertel, Sylvie I. , Mackie Ian J. , Machin Samuel J.
Published: March 2003

Aims 
The purpose of this clinical study was to evaluate the effects of a ticlopidine/aspirin combination on the pharmacokinetics and pharmacodynamics of sibrafiban and the tolerability of the combination therapy

Methods
 Thirty‐eight healthy male volunteers were randomized to receive one of the following treatments for 7 days: sibrafiban (n = 12), ticlopidine/aspirin (n = 12), or the combination treatment sibrafiban/ticlopidine/aspirin (n = 14). Concentrations of the active metabolite of sibrafiban, Ro 44–3888, in plasma and urine were determined by column‐switching liquid chromatography combined with tandem mass spectrometry. The pharmacodynamics of sibrafiban and ticlopidine/aspirin were examined by measuring the inhibition of ADP‐ or collagen‐induced platelet aggregation.

Results
 The addition of ticlopidine/aspirin to sibrafiban did not significantly alter the pharmacokinetic parameters of Ro 44–3888. the geometric mean ratio for AUC(0,12h) was 110 (95% CI 0.82, 1.22). Separately, sibrafiban and ticlopidine/aspirin inhibited ADP‐and collagen‐induced platelet aggregation and the effects of the two treatments were additive. For example, the average inhibition of ADP‐induced platelet aggregation over 12 h was 42% in the sibrafiban treated group, 55% in the ticlopidine/aspirin group and 69% in the sibrafiban/ticlopidine group. The bleeding time was prolonged in the treatments with ticlopidine/aspirin (8.1 min) and sibrafiban/ticlopidine/aspirin (8.6 min) compared with sibrafiban alone (3.5 min).

Conclusions
 This study shows a significant pharmacodynamic interaction between sibrafiban and ticlopidine/aspirin. Consequently, the simultaneous administration of sibrafiban and ticlopidine/aspirin should be carefully monitored to ensure the patient’s coverage with an antiplatelet drug without exposure to an excessive bleeding risk.
Potent inhibition of CYP2D6 by haloperidol metabolites: stereoselective inhibition by reduced haloperidol
Authors: Shin Jae‐Gook , Kane Khadidjatou , Flockhart David A.
Published: March 2003

Aims   We evaluated the inhibitory effect of haloperidol and its metabolites on CYP2D6 activity in order to better understand the potential role of these metabolites in drug interactions involving haloperidol.

Methods   The inhibitory effects of haloperidol and five of its metabolites on dextrorphan formation from dextromethorphan, a marker probe of CYP2D6 activity, were measured in human liver microsomal preparations. Apparent kinetic parameters for enzyme inhibition were determined by nonlinear regression analysis of the data.

Results  Racemic reduced haloperidol and its metabolite, RHPTP competitively inhibited dextromethorphan O‐demethylation with estimated Ki values (0.24 µm and 0.09 µm, respectively) that were substantially lower than that of haloperidol (0.89 µm). The inhibitory effect of S(–)‐reduced haloperidol was more potent than the R(+)‐enantiomer, with estimated Ki values of 0.11 µm and 1.1 µm, respectively. The pyridinium metabolite of haloperidol, HPP+ inhibited the enzyme activity noncompetitively with a Ki value of 0.79 µm. The N‐dealkylated metabolites of haloperidol (FBPA and CPHP) had a diminished inhibitory potency. While FBPA showed no notable inhibitory effect on dextrorphan formation, CPHP showed moderate competitive inhibition with a Ki value of 20.9 µm.

Conclusions  The principal metabolites of haloperidol inhibit CYP2D6, suggesting that they might contribute to the inhibitory effects of the drug. Reduced haloperidol seems to inhibit CYP2D6 activity in an enantioselective manner with the physiologically occurring S(–) enantiomer being more potent.
Pharmacokinetics of intravenous busulfan in children prior to stem cell transplantation
Authors: Cremers Serge , Schoemaker Rik , Bredius Robbert , Den Hartigh Jan , Ball Lynne , Twiss Irene , Vermeij Pieter , Vossen Jaak
Published: March 2003

Aims  Intravenous formulations of busulfan have recently become available. Although busulfan is used frequently in children as part of a myeloablative regimen prior to bone marrow transplantation, pharmacokinetic data on intravenous busulfan in children are scarce. The aim was to investigate intravenous busulfan pharmacokinetics in children and to suggest a limited sampling strategy in order to determine busulfan systemic exposure with the minimum of inconvenience and risk for the patient.

Methods  Plasma pharmacokinetics after the first administration was investigated in six children using nonlinear mixed effect modelling.

Results  Pharmacokinetics showed little variability and were described adequately with a one‐compartment model (population estimates CL,av=0.29 l h−1 kg−1; V,av=0.84 l kg−1; t1/2=1.7–2.8 h). Combined with limited sampling and a Bayesian fitting procedure, the model can adequately estimate the systemic exposure to intravenous busulfan, which in children appears to be at the lower end of the adult range.

Conclusions  Busulfan systemic exposure in children during intravenous administration can be estimated adequately with limited sampling and a Bayesian fitting procedure from a one‐compartment model. Intravenous busulfan pharmacokinetics in children should be the subject of more research.
Allele and genotype frequencies of polymorphic cytochromes P450 (CYP2C9, CYP2C19, CYP2E1) and dihydropyrimidine dehydrogenase (DPYD) in the Egyptian population
Authors: Hamdy Samar Ismail , Hiratsuka Masahiro , Narahara Kaori , El‐Enany Mervat , Moursi Nadia , Ahmed Mohammed Salah‐Eldin , Mizugaki Michinao
Published: March 2003

Aims  The goal of this study was to determine the frequencies of important allelic variants of CYP2C9, CYP2C19, CYP2E1 and DPYD in the Egyptian population and compare them with the frequencies in other ethnic populations.

Methods  Genotyping of CYP2C9 (*2 and *3), CYP2C19 (*2 and *3), c2 variant of CYP2E1 and DPYD alleles (*2 A‐*6 ) was carried out in a total of 247 unrelated Egyptian subjects. An allele‐specific fluorogenic 5′ nuclease chain reaction assay was applied for detection of CYP2C9 and CYP2C19 variants. Other variants of the CYP2E1 and DPYD genes were determined using polymerase chain reaction (PCR)‐restriction fragment length polymorphism and allele‐specific PCR based assays.

Results  CYP2C9 allele frequencies in 247 Egyptian subjects were 0.820 for CYP2C9*1, 0.120 for CYP2C9*2 and 0.060 for CYP2C9*3. For CYP2C19, the frequencies of the wild type (CYP2C19*1) and the nonfunctional (*2 and *3) alleles were 0.888, 0.110 and 0.002, respectively. CYP2C19*3, which is considered an Asian mutation, was detected in one subject (0.40%) who was heterozygous (*1/*3). Two subjects (0.80%) were homozygous for *2/*2, while no compound heterozygotes (*2/*3) or homozygotes for *3 were detected. For CYP2E1, only four subjects (1.70%) had the rare c2 variant, expressed heterozygously, giving an allele frequency of 0.009. Five variants of DPYD were analysed, with no splice sites (*2 A) or ΔC1897 (*3) found in this population. The frequencies of other variants were 0.028, 0.115 and 0.090 for *4, *5 and *6, respectively.

Conclusions  Comparing our data with that obtained in several Caucasian, African‐American and Asian populations, we found that Egyptians resemble Caucasians with regard to allelic frequencies of the tested variants of CYP2C9, CYP2C19, CYP2E1 and DPYD. Our results may help in better understanding the molecular basis underlying ethnic differences in drug response, and contribute to improved individualization of drug therapy in the Egyptian population.
A clinical audit of the prescribing of celecoxib and rofecoxib in Australian rural general practice
Authors: Cutts Christopher , LaCaze Adam , Tett Susan
Published: March 2003

Aims  The new cyclooxygenase‐2 (COX‐2) selective inhibitors, celecoxib (Celebrex®) and rofecoxib (Vioxx®), have been widely prescribed since their launch. No reviews currently appear in the literature of prescribing patterns in Australia. This paper describes a self‐audit of the clinical use of selective COX‐2 inhibitor therapy undertaken with rural general practitioners (GPs) in Australia.

Methods  A structured audit form was developed and distributed to interested GPs. The form was self‐administered and focused on issues about COX‐2 inhibitors and the types of patients who were receiving them, e.g. indications, patient demographics, risk factors and drug interactions.

Results  A total of 627 patients were recruited (569 celecoxib and 58 rofecoxib). A range of doses was prescribed. Osteoarthritis was the most common indication (68.1%). Risk factors known for the nonselective nonsteroidal anti‐inflammatory drugs were identified in 65.1% of patients, with the most common being advanced age, hypertension and previous peptic ulcer disease. Potential drug interactions were common. A variety of reasons for initiation of therapy was identified; these included perceived increased efficacy, safety and failure of other treatment.

Conclusions  These results show that COX‐2 inhibitors are being prescribed for patients with multiple risk factors that may place the patient at increased risk of adverse drug reactions to a COX‐2 inhibitor. The perception of improved safety and efficacy was common and is of concern. Limitations of the study include the reliance on self‐reporting.
Perception of the risk of adverse drug reactions: differences between health professionals and non health professionals
Authors: Bongard V. , Ménard‐Taché S. , Bagheri H. , Kabiri K. , Lapeyre‐Mestre M. , Montastruc J. L.
Published: March 2003

Aims
To investigate how risk of adverse drug reactions (ADRs) of several drug classes is perceived by health vs non health professionals.

Methods
Four hundred health professionals (i.e. 278 general practitioners, 76 pharmacists and 46 pharmacovigilance professionals) and 153 non health professionals were interviewed. Visual analogue scales were used to define a score of perceived risk of ADRs associated with each drug class (ranking from 0 to 10).

Results
Anticoagulants were ranked as the most dangerous drugs by general practitioners [median score (25th‐75th centiles): 7.9 (6.7–9.0)], pharmacists [8.7 (7.8–9.7)] and pharmacovigilance professionals [8.1 (7.2–9.0)]. For non health professionals, the class ranked first was sleeping pills [8.7 (7.2–9.4)] followed by tranquillisers [8.2 (6.4–9.2)] and antidepressants [8.0 (5.9–9.1)]. Aspirin was listed in the last position by non health professionals [3.4 (1.5–5.4)].

Conclusions
There are major differences in the perception of risk of ADRs between health professionals and non health professionals.
Pharmacodynamic effects and pharmacokinetics of a new HMG‐CoA reductase inhibitor, rosuvastatin, after morning or evening administration in healthy volunteers
Authors: Martin Paul D. , Mitchell Patrick D. , Schneck Dennis W.
Published: March 2003

Aims  To compare the lipid‐regulating effects and steady‐state pharmacokinetics of rosuvastatin, a new synthetic hydroxy methylglutaryl‐coenzyme A (HMG‐CoA) reductase inhibitor, following repeated morning and evening administration in volunteers with fasting serum low‐density lipoprotein cholesterol (LDL‐C) concentrations < 4.14 mmol l−1.

Methods  In this open‐label two‐way crossover trial 24 healthy adult volunteers were randomized to receive rosuvastatin 10 mg orally each morning (07.00 h) or evening (18.00 h) for 14 days. After a 4 week washout period, volunteers received the alternative regimen for 14 days. Rosuvastatin was administered in the absence of food.

Results  Reductions from baseline in serum concentrations of LDL‐C (−41.3%[morning]vs−44.2%[evening]), total cholesterol (−30.9%vs−31.8%), triglycerides (−17.1%vs−22.7%), and apolipoprotein B (−32.4%vs−35.3%) were similar following morning and evening administration. AUC(0,24 h) for plasma mevalonic acid (MVA), an in vivo marker of HMG‐CoA reductase activity, decreased by −29.9% (morning) vs−32.6% (evening). Urinary excretion of MVA declined by −33.6% (morning) vs−29.2% (evening). The steady‐state pharmacokinetics of rosuvastatin were very similar following the morning and evening dosing regimens. The Cmax values were 4.58 vs 4.54 ng ml−1, and AUC(0,24 h) values were 40.1 vs 42.7 ng ml−1 h, following morning and evening administration, respectively. There were no serious adverse events during the trial, and rosuvastatin was well tolerated after morning and evening administration.

Conclusions  The pharmacodynamic effects and pharmacokinetics of rosuvastatin are not dependent on time of dosing. Morning or evening administration is equally effective in lowering LDL‐C.
Paracetamol‐related deaths in Scotland, 1994–2000
Authors: Sheen Christopher L. , Dillon John F. , Bateman D. Nicholas , Simpson Kenneth J. , MacDonald Thomas M.
Published: March 2003

Aims
To investigate the death rate due to paracetamol poisoning in Scotland and what effect the reduction in over‐the‐counter paracetamol pack sizes in 1998 had on the death rate.

Methods
Records from 1994 to 2000 were examined to identify the number and annual incidence of paracetamol‐related deaths. Numbers of deaths before and after the pack size reduction were compared.

Results
No significant differences were shown due to the pack size reduction. The Scottish paracetamol‐related death rate was twice as high as in England and Wales.

Conclusions
Further measures to reduce paracetamol‐related morbidity and mortality in Scotland should be considered.
No effect on central or peripheral blood pressure of systemic urotensin II infusion in humans
Authors: Affolter Jonathan T. , Newby David E. , Wilkinson Ian B. , Winter Matthew J. , Balment Richard J. , Webb David J.
Published: March 2003

Aims In rodent and primate studies, urotensin II is an extremely potent vasoconstrictor peptide with effects in the central aortic and arterial vasculature as well as on cardiac function. The aim of the present study was to assess systemic haemodynamic responses to intravenous urotensin II infusion in humans.

Methods In 10 healthy male volunteers, intravenous urotensin II (3, 30 and 300 pmol min−1) and saline placebo were given on separate occasions in a single‐blind randomized manner. Systemic haemodynamics and arterial stiffness were assessed by sphygmomanometry, transthoracic bioimpedance, and pulse wave analysis. Plasma urotensin II immuno‐reactivity was measured by radio‐immunoassay.

Results Intravenous urotensin II infusions were well tolerated with no adverse clinical effects and no electrocardiographic changes. Circulating plasma urotensin II immuno‐reactivity increased from baseline of 16 ± 1 to 1460 ± 82 pmol l−1 (mean ± s.e. mean) during infusion of urotensin II at 300 pmol min−1 (P < 0.001). However, there were no significant placebo adjusted changes in heart rate (95% confidence intervals: −3.6, + 4.4 min−1), mean arterial pressure (−5.8, + 1.7 mmHg) or cardiac index (−0.1, + 0.4 l min−1 m−2). There were also no changes in augmentation index (−4.1, + 5.2%) or pulse wave velocity (−1.3, + 0.3 m s−1).

Conclusions Intravenous urotensin II infusion did not affect systemic haemodynamics or arterial stiffness, despite achieving an ∼100‐fold increase in plasma immuno‐reactivity. We conclude that urotensin II is unlikely to have a physiological role in the short term regulation of vascular tone or blood pressure in man. Further confirmatory studies with urotensin II receptor antagonists are required.
The effect of ketoconazole on the in vivo intestinal permeability of fexofenadine using a regional perfusion technique
Authors: Tannergren Christer , Knutson Tina , Knutson Lars , Lennernäs Hans
Published: March 2003

Aims To investigate whether the drug–drug interaction between fexofenadine and ketoconazole is localized to efflux transport proteins of the small intestine, and to determine and classify the effective jejunal permeability (Peff) of fexofenadine according to the Biopharmaceutics Classification System (BCS).

Methods Two separate jejunal perfusion experiments were performed using the Loc‐I‐Gut® technique in eight healthy volunteers. During treatment 1 (T1), we investigated the acute effect of ketoconazole on the Peff and plasma pharmacokinetics of fexofenadine. In treatment 2 (T2) we examined the effect of oral pretreatment with ketoconazole (200 mg daily for 5 days) on the same absorption parameters. Each experiment was divided into two periods of 100 min and the jejunal segment was perfused with 93 µm fexofenadine during both periods. In period 2 of each treatment, fexofenadine was coadministered with 94 µm ketoconazole. The concentrations of fexofenadine in intestinal perfusate and plasma were measured by liquid chromatography with mass detection.

Results During T1, the mean (± s.d.) Peff of fexofenadine was low according to the BCS (0.11 ± 0.11 and 0.04 ± 0.13·10−4 cm s−1 in periods 1 and 2, respectively), and the coadministration of ketoconazole in period 2 had no significant acute effect on Peff (95% confidence interval (CI) on the difference −0.37, 0.51). After pretreatment with ketoconazole (T2), the jejunal Peff of fexofenadine increased to 0.29 ± 0.47 and 0.22 ± 0.31·10−4 cm s−1 in both periods 1 and 2, respectively, but the change was not statistically significant when compared with T1 (95% CI on the difference −0.62, 0.27 for T1 0–100 min vs T2 0–100 min; −0.54, 0.34 for T1 0–100 min vs T2 100–200 min). Fexofenadine plasma AUC from 0–100 mg showed no significant difference after pretreatment with ketoconazole (55 ± 101 and 51 ± 33 µg ml−1 min−1 respectively; 95% CI on the difference −108, 115). Total plasma AUC (0–720 min) was 318 ± 426 and 426 ± 232 ng ml−1 min in T1 and T2, respectively (95% CI on the difference −622, 405).

Conclusions No significant effect of acute coadministration or pretreatment with ketoconazole on the in vivo intestinal absorption of fexofenadine was detected in this study.
Lipodystrophy associated with protease inhibitors
Authors: Panse I. , Vasseur E. , Raffin-Sanson M.L. , Staroz F. , Rouveix E. , Saiag P.
Published: March 2003

Lipodystrophies, characterized by reduction of subcutaneous fat over part or all of the body surface, are uncommon. Their causes are unknown. Recently, lipodystrophy has been reported in human immunodeficiency virus (HIV)-infected patients taking protease inhibitors, which have been recommended since 1996 as standard therapy for HIV disease in combination with nucleoside analogues. In these cases, lipodystrophy consists of an association of peripheral lipoatrophy with central adiposity. We report four HIV-infected men on protease inhibitors who developed a disfiguring lipodystrophy. In three of them, the protease inhibitor was administered for a mean duration of 21·5 months (range 19–23) with good immunological and virological responses. Patient 4 had been treated for 2 years with successive combinations of protease inhibitors with nucleoside analogues without success. The four patients progressively developed an increase in abdominal girth associated with fat wasting of the face and legs. Two of them had recurrent paronychia of the great toes. Triglyceride levels were moderately increased in all patients, and one had a slightly increased cholesterol level. One patient had elevated glucose and insulin plasma levels during a glucose tolerance test. In two patients, a deep biopsy taken from the thigh showed thinning of the subcutaneous fat without other morphological changes. Computed tomographic scans of the face and abdomen confirmed the loss of almost all subcutaneous fat of the cheek and temporal regions, and abdominal perivisceral fat accumulation. For patients 1–3, the protease inhibitor was replaced by a non-nucleoside reverse transcriptase inhibitor. Nine months later, dysmorphic changes had not regressed, but lipid abnormalities had returned to normal and the paronychia had disappeared.
N-acetyltransferase 1 and 2 polymorphisms inpara-substituted arylamine-induced contact allergy
Authors: Westphal G.A. , Reich K. , Schulz T.G. , Neumann C. , Hallier E. , Schnuch A.
Published: March 2003

Sensitization to arylamines such as p-phenylenediamine is frequently diagnosed in patients with allergic contact dermatitis. Reactive metabolites of p-phenylenediamine might be produced in the skin by O-acetylation of N-hydroxylamines catalysed by local N-acetyltransferases (NATs). In this study, we tested whether genetic polymorphisms of NATs, which are known to affect enzyme activity, may influence the susceptibility to para-substituted arylamine-induced contact eczema. Using polymerase chain reaction and restriction enzyme analysis, the distribution of polymorphisms of NAT1 and NAT2 was investigated in 88 patients sensitized to para-substituted aryl compounds and 123 healthy controls. NAT2 rapid acetylators, i.e. carriers of the NAT2*4 wild-type allele, were more common in the contact allergy (44%) than in the healthy control group [30%; P = 0·042, odds ratio 1·9 (95% confidence interval, CI 1·05–3·27)]. Slow acetylators carrying the NAT2*5b/2*6a genotype were significantly less frequent among patients [13% vs. 38% in controls; P = 0·009, odds ratio 0·39 (95% CI 0·19–0·78)]. The carriage rate of the NAT1*10 allele, which is supposed to encode for a rapid NAT1 phenotype, was not significantly different between patients and controls [43% vs. 36%; odds ratio 1·5 (95% CI 0·88–2·68)]. Interactions between NAT2*4 and NAT1*10 were suggested by the increased frequency of the NAT2*4/NAT1*10 haplotype in patients (27%) compared with controls [15%; P = 0·039, odds ratio 2·1 (95% CI 1·04–4·04)]. As the NAT1 and NAT2 encoding genes are located in close proximity on chromosome 8p22, the latter finding could at least partly be due to genetic linkage. In fact, a linkage disequilibrium between NAT2*4 and NAT1*10 was observed in the contact allergy (P = 0·0025) and in the control group (P = 0·042). Our data indicate an association between the NAT2*4/NAT1*10 haplotype and contact sensitization to para-substituted aryl compounds. Therefore, acetylation may either enhance contact sensitization or NAT2*4 and NAT1*10 might be linked to an unknown susceptibility factor.
Elevated levels of biologically active soluble CD40 ligand in the serum of patients with chronic lymphocytic leukaemia
Authors: Younes Anas , Snell Virginia , Consoli Ugo , Clodi Katharina , Zhao Shourong , Palmer J. Lynn , Thomas Elaine K. , Armitage Richard J. , Andreeff Michael
Published: March 2003

Chronic lymphocytic leukaemia (CLL) is an indolent lymphoproliferative disorder manifested by low growth fraction and prolonged survival of the malignant cells. The mechanisms that enable CLL cells to live longer and to resist apoptosis remain unclear. Because the malignant CLL cells express CD40 and Fas receptors, which can transduce cell‐survival and cell‐death signals, we examined the role of CD40 in the growth regulation of CLL cells and its interaction with Fas‐mediated and fludarabine‐induced apoptosis in vitro. Primary CLL cells underwent spontaneous apoptosis in culture, which was enhanced by exogenous human Fas ligand (FasL) or fludarabine. Exogenous CD40L rescued CLL cells from spontaneous apoptosis in a dose‐dependent manner, and caused CLL cells to resist apoptosis induced by FasL or fludarabine. Patients' autologous plasma rescued CLL cells from spontaneous apoptosis, an effect that could be reversed with anti‐CD40 ligand (CD40L) antibodies. The levels of soluble CD40 ligand in the sera of 51 CLL patients and 55 healthy donors were determined by enzyme‐linked immunosorbent assay. The mean soluble CD40L level in normal donors was 0.29 ng/ml compared to a mean value of 0.80 ng/ml in CLL patients (P < 0.001). CD40L up‐regulated bcl‐XL mRNA but not bcl‐2 in CLL cells within 3–6 h in culture. Our results demonstrated that serum of patients with CLL contained elevated levels of biologically active soluble CD40L, and that CD40L can prolong survival of CLL cells and mediate their resistance to FasL and fludarabine in vitro.