bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of the autoinduction of ifosfamide metabolism by a population pharmacokinetic approach using NONMEM
Authors: Kerbusch T. , Huitema A. D. R. , Ouwerkerk J. , Keizer H. J. , Mathôt R. A. A. , Schellens J. H. M. , Beijnen J. H.
Published: March 2003

Aims
 This study investigated the population pharmacokinetics of ifosfamide in 15 patients treated for soft tissue sarcoma with 9 or 12 g m−2 ifosfamide by means of a 72 h continuous i.v. infusion.

Methods
 A model was developed using nonlinear mixed effects modelling (NONMEM) to describe the nonlinear pharmacokinetics of ifosfamide by linking the ifosfamide plasma concentrations to the extent of the autoinduction.

Results
 The proposed model revealed the effect of autoinduction on the disposition of ifosfamide. The initial clearance, volume of distribution, rate constant for enzyme degradation, induction half‐life of the enzyme and the ifosfamide concentration at 50% of the maximum inhibition of enzyme degradation were estimated at 2.94 ± 0.27 l h−1, 43.5 ± 2.9 l, 0.0546 ± 0.0078 h−1, 12.7 h and 30.7 ± 4.8 µm, respectively. Interindividual variabilities of initial clearance, volume of distribution, rate constant for enzyme degradation were 24.5, 23.4 and 22.7%, respectively. Proportional and additive variability not explained by the model were 13.6% and 0.0763 µm, respectively.

Conclusions
 The absence of a lag time for the autoinduction of ifosfamide metabolism could be the result of an immediate inhibition of the enzymatic degradation of CYP3A4 by ifosfamide. By application of the autoinduction model individual pharmacokinetic profiles of patients were described with adequate precision. This model may therefore be used in the future development of a model to individualize dose selection in patients.
Single and multiple dose pharmacokinetics of nelfinavir and CYP2C19 activity in human immunodeficiency virus‐infected patients with chronic liver disease
Authors: Khaliq Yasmin , Gallicano Keith , Seguin Isabelle , Fyke Kathryn , Carignan Germain , Bulman Dennis , Badley Andrew , Cameron D. William
Published: March 2003

Aims
To evaluate the single‐dose and multiple‐dose pharmacokinetics of nelfinavir and its active M8 metabolite in eight HIV‐seropositive patients with liver disease, and to examine the relationship between CYP2C19 activity (genotype and plasma M8/nelfinavir metabolic ratio) and the severity of liver disease in these patients.

Methods
Nelfinavir was given as a single dose (500 or 750 mg) to patients beginning therapy and twice (500, 750 or 1000 mg) or three times (250 or 750 mg) daily during chronic therapy. Single‐dose pharmacokinetic values were used to predict multiple‐dose regimens. Peak and total plasma exposures between 2–4 µg ml−1 and 45–75 µg ml−1 h, respectively, and predose levels > 0.7 µg ml−1 were targeted for multidose nelfinavir. Genotype was determined by analysis for CYP2C19*1, CYP2C19*2, and CYP2C19*3. Individuals were grouped according to their genotype, molar M8/nelfinavir AUC ratio (low: < 0.1, intermediate: 0.1–0.3, high > 0.3), and Child‐Pugh classification for severity of liver disease.

Results
Nelfinavir pharmacokinetics were characterized by wide interindividual variability, low clearance (181–496 ml min−1 70 kg−1, n = 7), and prolonged half‐life (5–20 h, n = 7). M8/nelfinavir AUC ratio increased 58% (n = 4) and α1‐acid glycoprotein levels decreased up to 39% (n = 5) from single to multiple dosing. CYP2C19 activity was low (metabolic AUC ratio < 0.1) in four patients with moderate to severe liver disease even though they were genetically extensive CYP2C19 metabolizers (*1/*1 or *1/*2). Three patients required lower daily doses than the standard regimen of 750 mg every 8 h to achieve target concentrations and maintain virologic suppression at < 50 RNA copies ml−1 (up to 20 months).

Conclusions
Acquired CYP2C19 deficiency from moderate or severe liver disease resulted in decreased M8 formation. Long‐term HIV suppression is possible using low nelfinavir doses in patients with liver disease.
Evaluation of dihydropyrimidine dehydrogenase activity in South‐west Asian, Kenyan and Ghanaian populations
Authors: Morsman Janine M. , Sludden Julieann , Ameyaw, Margaret‐Mary , Githang'a Jessie , Indalo Anne , Ofori‐Adjei David , McLeod Howard L.
Published: March 2003

Aims
Dihydropyrimidine dehydrogenase (DPD) reduces endogenous pyrimidines and therapeutic analogues such as the anticancer agent 5‐fluorouracil (5FU). Among Caucasian populations DPD activity is highly variable and subject to polymorphic regulation. To evaluate interethnic influence, DPD activity was assessed in South‐west Asian, Kenyan and Ghanaian populations.

Methods
DPD activity was determined in peripheral mononuclear cells using[14C]‐5‐fluorouracil and h.p.l.c. analysis.

Results
A high degree of variation in DPD activity was observed within each population (range CV = 34–48%). Median DPD activity also varied between these populations. South‐west Asian and Kenyan subjects exhibited almost identical median values (192 and 193.5 pmol min−1 mg−1, respectively), which were similar to Caucasians (median 215 pmol min−1 mg−1). A significantly lower median DPD activity (119 pmol min−1 mg−1) was observed in the Ghanaian population.

Conclusions
The similarity in DPD activity between Caucasian, Kenyan and South‐west Asian populations suggests that the incidence of 5FU‐related toxicity may be comparable in these groups. The pharmacokinetic implications of lower activity amongst Ghanaians needs to be evaluated.
Population pharmacokinetics of doxorubicin, etoposide and ifosfamide in small cell lung cancer patients: results of a multicentre study
Authors: Freyer Gilles , Tranchand Brigitte , Ligneau, Blandine , Ardiet Claude , Souquet, Pierre‐Jean , Court‐Fortune, Isabelle , Riou, Robert , Rebattu, Paul , Boissel Jean‐Pierre , Trillet‐Lenoir Véronique , Girard Pascal
Published: March 2003

Aims
To determine the population pharmacokinetic (PK) parameters of doxorubicin (Dox), etoposide (Eto) and ifosfamide (Ifo) in small cell lung cancer (SCLC) patients, to assess the potential relationship between those parameters and to estimate the impact of individual morphological and biological covariates on patients' PK parameters.

Methods
Twenty‐four patients with either SCLC limited to the thorax or extensive SCLC entered the study. All but one received at least two 3 day courses of the standard AVI (Dox 50 mg m−2 day 1, Eto 120 mg m−2 day 1,2,3, Ifo 2000 mg m−2 day 1,2) regimen. Individual blood samples were collected during each course and data on 47 courses were available. Data were analysed with the NONMEM program. Dox, Eto and Ifo plasma concentrations were studied with multicompartment (3, 2 and 2, respectively) models. Inter‐individual and interoccasion (course‐to‐course) variabilities were estimated. The influence of individual covariates (age, sex, stage of the disease, weight, height, body‐surface area, serum creatinine, total protein, LDH, ASAT, ALAT, alkaline phosphatase, gamma‐GT, bilirubin) on PK parameters was also assessed. Correlations between individual PK parameters of Dox, Eto and Ifo were explored by using Pearson's correlation coefficient.

Results
Multiple data were available for each patient. Dox clearance (CL) and volume of distribution (Vd) were 32.0 l h−1 and 9.3 l (Inter‐individual variability: 17.2% and 19.2%). Eto CL (l h−1) and Vd were, respectively, 3.34–0.0083* serum creatinine (µmol l−1) and 6.38 l (interindividual variability: 15.6% and 18.7%). Ifo CL and Vd at day 1 were 5.6 l h−1 and 26.0 l (interindividual variability: 10.1% and 17.2%, respectively). Estimation of course‐to‐course variability improved the precision of PK models in some cases. No correlation was observed between the respective PK parameters of each drug. Of individual covariates tested, only serum creatinine correlated with Eto CL (r = −0.37, P < 0.001). Self‐induction of the metabolism of Ifo was apparent (mean CL increase from day 1 to day 2 : 42%) and individually correlated with the CL value at day 1 (r = −0.61, P < 0.001).

Conclusions
Assessment of potential relationships between individual systemic exposure of chemotherapy and therapeutic endpoints (tumour response, toxicity and survival) will be required to adjust drugs dosages based on individual PK parameters rather than questionable body‐surface area. However, all three drugs in the AVI regimen should be monitored simultaneously.
Detection and incidence of drug‐induced liver injuries in hospital: a prospective analysis from laboratory signals
Authors: Bagheri H. , Michel F. , Lapeyre‐Mestre M. , Lagier E. , Cambus J. P. , Valdiguié P. , Montastruc J. L.
Published: March 2003

Aims  Liver damage remains the most frequent type of adverse drug reaction (ADRs) that can lead to the withdrawal of a drug from the market. The abnormal laboratory data identified by computerized hospital information systems can be used in order to improve the detection of ADRs. Our objectives were to assess the detection and incidence of drug‐induced liver abnormalities in a university hospital inpatient population and to evaluate the underreporting rate of drug‐induced liver injury.

Methods  We conducted a prospective study performed 1 week per month from June to October 1997. We selected patients by a computerized process using biochemistry laboratory data, based on serum enzyme values, alanine aminotransferase (over 2 fold normal) and alkaline phosphatase (over 1.5 fold normal).

Results  Among 1976 ALT and 1814 AP assays performed during the period of the study, 156 (7.9%) and 159 (8.8%) tests, respectively, fell into the selected criteria. These concerne 147 patients. Among these patients, 13 (8.8%) cases of drug‐induced liver injuries were suspected. Seven cases were asymptomatic. Six cases were classified as serious by these criteria: hospitalization to investigate the cause of health status impairment (4 patients), prolongation of hospitalization (1 patient) and life‐threathening (1 patient). Using the hospitalization database, the incidence of drug‐induced liver injuries was estimated as 6.6 per 1000 inpatients a week. Only 1 case was reported by physicians in the same period.

Conclusions  Computerization of biochemical data would allow the development of systems to improve detection of drug‐induced injury. Moreover, underreporting remains important for such potentially serious ADRs, even in a university hospital.
Pharmacokinetics of SDZ RAD and cyclosporin including their metabolites in seven kidney graft patients after the first dose of SDZ RAD
Authors: Kirchner Gabriele I. , Winkler Michael , Mueller Lueke , Vidal Christian , Jacobsen Wolfgang , Franzke Anke , Wagner Siegfried , Blick Stefan , Manns Michael P. , Sewing Karl‐Friedrich
Published: March 2003

Aims The aim of the study was to investigate the pharmacokinetics and metabolism of the new immunosuppressant SDZ RAD during concomitant therapy with cyclosporin in stable renal transplant patients. Furthermore, we studied the influence of SDZ RAD on the pharmacokinetics of cyclosporin at steady state levels.

Methods SDZ RAD was administered orally in different doses (0.25–15 mg day−1) to seven patients, who were on standard cyclosporin‐based immunosuppression. The blood concentrations of both drugs including their main groups of metabolites were measured simultaneously by LC/electrospray‐mass spectrometry.

Results The mean area under the blood concentration‐time curve to 12 h (AUC(0,12 h)) was 4244 ± 1311 µg l−1h for cyclosporin before SDZ RAD treatment and 4683 ± 1174 µg l−1h (P = 0.106) on the day of SDZ RAD treatment (95% CI for difference ‐126, 1003). On both study daysCmax, andtmaxof cyclosporin were not significantly different. The metabolite pattern of cyclosporin did not change. The pharmacokinetic data of SDZ RAD dose‐normalized to 1 mg SDZ RAD were as follows: AUC(0,24 h): 35.4 ± 13.1 µg l−1h,Cmax: 7.9 ± 2.7 µg l−1andtmax: 1.5 ± 0.9 h. The metabolites of SDZ RAD found in blood were hydroxy‐SDZ RAD, dihydroxy‐SDZ RAD, demethyl‐SDZ RAD, and a ring‐opened form of SDZ RAD.

Conclusions A single dose of SDZ RAD did not influence significantly the pharmacokinetics of cyclosporin. The most important metabolite of SDZ RAD was the hydroxy‐SDZ RAD, its AUC(0,24 h) being nearly half that of the parent compound SDZ RAD.
The influence of the hand circulation on the assessment of venous distensibility of the human forearm with venous occlusion plethysmography
Authors: Burggraaf Jacobus , Kemme Michiel J. B. , Muller Linda M. , Schoemaker Rik C. , Cohen Adam F.
Published: March 2003

Aims  To determine the influence of the hand circulation on the determination of venous distensibility with venous occlusion plethysmography.

Methods  In a randomised study, duplicate measurements of forearm venous distensibility, with and without a wrist cuff, were made over occlusion periods of 3 and 12 min in eight volunteers. Treatments were compared with paired Student's t‐tests and differences are presented as 95% confidence intervals (CI). Intra‐subject variability was assessed with analysis of variance.

Results  Non‐significant differences in increases in forearm volume between the occlusions with and without wrist cuff were found for the 3 min occlusion (CI: −0.4, + 0.2%) and the 12 min occlusion period (CI: −0.7, + 0.2%). However, the coefficient of variation was lower with the use of a wrist cuff; after 3 min occlusion (12% vs 19%) and after 12 min of occlusion (14% vs 24%). Forearm volume after 12 min of venous occlusion was 0.5% (CI: + 0.4, + 0.7) higher than after 3 min.

Conclusions  Although venous distensibility was equal when assessed with and without wrist cuff, exclusion of the hand circulation reduces intraindividual variability. Equilibrium in forearm volume is not reached after 3 min period of venous occlusion, as often assumed. The magnitude of the additional increase after prolonged occlusion stresses the need for well‐controlled studies.
Pharmacodynamic models for the cardiovascular effects of moxonidine in patients with congestive heart failure
Authors: Brynne Lena , McNay John L. , Schaefer Hans G. , Swedberg Karl , Wiltse Curtis G. , Karlsson Mats O.
Published: March 2003

Aims  To assess the pharmacodynamics of moxonidine in patients with functional NYHA Class II‐III congestive heart failure (CHF).

Methods  A parallel population pharmacokinetic/pharmacodynamic (PK/PD) analysis was performed to assess the effect of moxonidine (0.1, 0.2, 0.3 mg twice daily) and placebo treatment on plasma noradrenaline (NA) levels, standing systolic blood pressure (SBP), and heart rate (HR) over 12 weeks in 97 patients with CHF using a parallel group design with dose escalation. A sequential analysis was also developed, where the relative changes in NA concentration were related to both SBP and HR.

Results  In the parallel PD analysis, an effect delay was shown for all three end points (NA, SBP, and HR). An inhibitory Emax model was used to characterize the concentration‐effect relationships. For SBP and HR, the EC50 value increased over time. For NA, there was a positive baseline drift over the 12 weeks; this was interpreted as disease progression. Moxonidine delayed this increase by 9.8 weeks. For SBP, there was a circadian pattern at baseline. In the sequential PD analysis, the relationship between the drug response (NA) and SBP or HR was best described by an inhibitory Emax model. No effect delays between the response and effects were found.

Conclusions  Effects of moxonidine on NA, SBP, and HR could be quantified by an effect compartment model in the presence of disease progression and circadian variations. Disease progression, as judged by increasing NA levels with time, was delayed by moxonidine. A direct relationship was found between NA and SBP/HR.
Mephenytoin as a probe for CYP2C19 phenotyping:effect of sample storage, intra‐individual reproducibility and occurrence of adverse events
Authors: Tamminga Wim J. , Wemer Johan , Oosterhuis Berend , Wieling Jaap , Touw Daan J. , De Zeeuw Rokus A. , De Leij Lou F. M. H. , Jonkman Jan H. G.
Published: March 2003

Aims  To further evaluate mephenytoin as a probe for CYP2C19 phenotyping.

Methods  Healthy subjects (n = 2638) were phenotyped using the urinary (S)‐mephenytoin to (R)‐mephenytoin ratio. This method was evaluated for (a) the stability of the S/R‐ratio following sample storage, (b) the intraindividual reproducibility of the ratio, and (c) the occurrence of adverse events.

Results  After prolonged storage, the S/R‐ratio of samples from extensive metabolisers (EM) increased up to 85%. In 1.5% of the cases (1 out 66), this led to incorrect classification of phenotype. In EMs, but not in poor metabolisers (PMs), the S/R‐ratio increased after acid treatment. The intraindividual reproducibility of the mephenytoin phenotyping procedure was 28%. No major side‐effects were observed and there was no relationship between the incidence of side‐effects and the phenotype of the subject.

Conclusions  After prolonged storage the S/R‐ratio significantly increased in EMs and, although low, the risk of incorrect classification should not be ignored. Our data support the use of mephenytoin as a safe drug for CYP2C19 phenotyping.
Dose requirement and prolactin elevation of antipsychotics in male and female patients with schizophrenia or related psychoses
Authors: Melkersson Kristina I. , Hulting Anna‐Lena , Rane Anders J.
Published: March 2003

Aims  The aim of this study was to investigate the prolactin (PRL) secretion and the growth hormone (GH)‐insulin‐like growth factor I (IGF‐I) axis in relation to gender and side‐effects and dose of antipsychotic drugs during long‐term treatment.

Methods  Forty‐seven patients (21 men and 26 women), diagnosed with schizophrenia or related psychoses according to the Diagnostic and Statistical Manual of Mental Disorders (DSM‐IV) criteria and treated with different classical antipsychotics, were studied. Prolactin, GH and IGF‐I were measured, as well as the serum concentration of the antipsychotics. In addition, body mass index (BMI) was calculated.

Results  The median daily, as well as the median body weight, adjusted daily dose of antipsychotic drugs was twofold higher in male compared with female patients. Antipsychotic‐induced hyperprolactinaemia was more frequent and occurred at a lower daily dose of antipsychotics in women. Irrespective of sex, more than half of the patients had elevated BMI. Two patients had a slight increment in IGF‐I levels, whereas the GH concentration, as assessed on a single occasion, was normal in all patients.

Conclusions  Patients on long‐term antipsychotic therapy, with doses adjusted according to therapeutic efficiency, exhibited hyperprolactinaemia and elevated BMI, but no obvious influence on the GH‐IGF‐I axis. Furthermore, it appeared that the males required twice the dose of antipsychotic compared with females.
Dopamine D2‐like receptors and amino acid‐induced glomerular hyperfiltration in humans
Authors: Luippold Gerd , Schneider Swetlana , Stefanescu Andreea , Benöhr Peter , Mühlbauer Bernd
Published: March 2003

Aims  In rodents, blockade of dopamine D2‐like receptors abolishes both the physiological increase in glomerular filtration rate (GFR) induced by amino acids and the pathological hyperfiltration in experimental diabetes mellitus. This study addressed the contribution of dopamine D2‐like receptors to changes in renal haemodynamics after amino acid infusion in humans.

Methods  Twelve healthy volunteers participated in this double‐blind, randomized, cross‐over study. GFR and renal blood flow (RPF) were assessed by renal clearance of inulin and p‐aminohippuric acid (PAH), respectively. Following infusion of 0.45% saline at baseline, an electrolyte‐balanced solution of mixed amino acids (10%) was infused. Prior to the experiments, the subjects received orally either placebo, or sulpiride (10 mg kg−1), a centrally and peripherally acting D2‐like receptor antagonist, or domperidone (1 mg kg−1) which affects only peripheral D2‐like receptors.

Results  In the placebo series, amino acid infusion significantly increased GFR and RPF by up to 15.8 ± 5.3% and 14.4 ± 6.1%, respectively, while mean blood pressure and heart rate remained unchanged. Pretreatment with domperidone only marginally altered the renal response to amino acids (maximal increase by 13.2 ± 5.6 and 11.9 ± 4.0% in GFR and RPF, respectively), while sulpiride completely abolished the renal haemodynamic changes induced by amino acids. Total and fractional urinary sodium excretion as well as urinary osmolality were similar at baseline and increased in response to amino acids, to the same extent, in all series. No changes in renal dopamine excretion occurred.

Conclusion  The results indicate that in man dopamine D2‐like receptors are involved in the renal haemodynamic response to amino acid infusion. Whether dopamine D2‐like receptor blockade diminishes glomerular hyperfiltration in pathological states requires clinical investigations.
Start of a selective serotonin reuptake inhibitor (SSRI) and increase of antiparkinsonian drug treatment in patients on levodopa
Authors: Van De Vijver D. A. M. C. , Roos R. A. C. , Jansen P. A. F. , Porsius A. J. , De Boer A.
Published: March 2003

Aims  We determined whether the start of selective serotonin reuptake inhibitors (SSRI) in levodopa users was followed by a faster increase of antiparkinsonian drug treatment.

Methods  Selected were all levodopa users of 55 years and older from the PHARMO prescription database. The rate of increase of antiparkinsonian drug treatment was compared using Cox's proportional hazard model for starters of SSRI (n = 15) with starters of tricyclic antidepressants (TCA) (n = 31) and with patients not using antidepressants (n = 304), and was adjusted for age, gender, and duration of levodopa use.

Results  The hazard ratio for the SSRI group compared with the TCA group was 4.2 (95% confidence interval 1.4, 12.6) and compared with the second control group was 2.7 (1.2, 5.2).

Conclusions  The start of SSRI therapy in levodopa users is followed by a faster increase of antiparkinsonian drug treatment.
Omeprazole hydroxylation is inhibited by a single dose of moclobemide in homozygotic EM genotype for CYP2C19
Authors: Cho Joo‐Youn , Yu Kyung‐Sang , Jang In‐Jin , Yang Byung‐Hwan , Shin Sang‐Goo , Yim Dong‐Seok
Published: March 2003

Aims  The pharmacokinetics of omeprazole and its metabolites in healthy subjects were evaluated to determine if a single dose of moclobemide inhibited CYP2C19 activity.

Methods  Sixteen volunteers, of whom eight were extensive metabolizers (EM) and eight were poor metabolizers for CYP2C19, participated in two studies. Venous blood samples were collected for 24 h after oral ingestion of 40 mg omeprazole with or without 300 mg moclobemide coadministration. The pharmacokinetic change of omeprazole, omeprazole sulphone and 5‐hydroxyomeprazole concentrations were assessed to test for an interaction between omeprazole and moclobemide.

Results  The coadministration of moclobemide in EMs approximately doubled the mean AUC (from 1834 to 3760 ng ml−1 h) and Cmax (from 987 to 1649 ng ml−1) of omeprazole, and increased the AUC of omeprazole sulphone without changing AUC ratio of omeprazole to omeprazole sulphone. Moclobemide coadministration more than doubled the AUC ratio of omeprazole to 5‐hydroxyomeprazole (from 2.5 to 5.3) in EMs, too. There was a significant decrease in Cmax and AUC of 5‐hydroxyomeprazole in PMs but no significant changes were seen in the results for omeprazole and omeprazole sulphone AUCs.

Conclusions  A single dose of moclobemide resulted in significant suppression of CYP2C19 activity in EMs. We conclude that physicians prescribing moclobemide should pay attention to its pharmacokinetic interactions even on the first day of coadministration with CYP2C19 substrates.
Population pharmacokinetics model and limited sampling strategy for intravenous vinorelbine derived from phase I clinical trials
Authors: Nguyen Laurent , Tranchand Brigitte , Puozzo Christian , Variol Philippe
Published: March 2003

Aims a) To characterize the pharmacokinetics of intravenous vinorelbine, b) to use a population analysis for the identification of patient covariates that might appreciably influence its disposition and c) to define a limited sampling strategy for further Bayesian estimation of individual pharmacokinetic parameters.

Methods All data were collected from 64 patients (99 courses) entered in three different phase I trials that have been previously reported. All patients received vinorelbine as a 20 min infusion with dose levels ranging from 20–45 mg m−2. The population pharmacokinetic model was built in a sequential manner on a subset of two‐thirds of the data, starting with a covariate‐free model then progressing to a covariate model using the nonlinear‐mixed effect methodology. The remaining one‐third of the data were used to validate several sparse sampling designs.

Results A linear three‐compartment model characterized vinorelbine blood concentrations (n=1228). Two primary pharmacokinetic parameters (total clearance and volume of distribution) were related to various combinations of covariates. The relationship for total clearance (CLtotal(l h−1)=29.2×BSA×(1−0.0090 Plt)+6.7×Wt/Crs) was dependent on the patient's body surface area (BSA), weight (Wt), serum creatinine (Crs) and platelet count before administration (Plt). The optimal limited sampling strategy consisted of a combination of three measured blood concentrations; the first immediately before the end of infusion or 20 min later, the second at either 1 h, 3 h or 6 h and the third at 24 h after drug administration.

Conclusions A population pharmacokinetic model and a limited sampling strategy for intravenous vinorelbine have been developed. This is the first population analysis performed on the basis of a large phase I database that has identified clinical covariates influencing the disposition of i.v. vinorelbine. The model can be used to obtain accurate Bayesian estimates of pharmacokinetic parameters in situations where extensive pharmacokinetic sampling is not feasable.
Lack of effect of single and repeated doses of levocetirizine, a new antihistamine drug, on cognitive and psychomotor functions in healthy volunteers
Authors: Gandon J. M. , Allain H.
Published: March 2003

Aims  Levocetirizine (R‐cetirizine), is the active enantiomer of cetirizine, an antihistamine indicated in the treatment of allergic rhinitis and chronic idiopathic urticaria. The purpose of this trial was to analyse the effects of levocetirizine single and multiple doses on CNS using integrated measures of cognitive and psychometric performance.

Methods  A battery of psychometric tests was used: critical flicker fusion (CFF), choice reaction time (CRT), body sway (BS), learning memory test (LMT) and subjective assessments of alertness compared with placebo. Nineteen (19) healthy male volunteers received either levocetirizine 5 mg (therapeutic dose), diphenhydramine 50 mg or placebo once daily for 5 consecutive days (3‐way cross‐over). Diphenhydramine was used as a positive control. CFF tests were performed on days 1 and 5 at baseline and up to 24 h following drug intake. Subjects used the Bond‐Lader visual analogue scales (VAS) to assess their mood and vigilance.

Results  In contrast to diphenhydramine, when compared with placebo, levocetirizine did not modify the CFF (primary endpoint), regardless of the dosing scheme (−1.62 Hz [−2.61, −0.64] and −0.81 Hz [−1.80, 0.19], respectively, 3 h after dosing on day 1). CRT was decreased with both levocetirizine and placebo up to 5 h after dosing on day 1 and up to 3 h after dosing on day 5. Body sway data were similar with levocetirizine and placebo but increased with diphenhydramine. LMT was similar in all three groups. No relevant difference between placebo and levocetirizine was recorded by the subjects on their assessment of alertness using the VAS, whilst decreased alertness was reported following diphenhydramine 50 mg.

Conclusions  This study showed that levocetirizine does not produce any deleterious effect on cognitive and psychometric functions compared with placebo in healthy male volunteers.
Serotonergic modulating drugs for functional gastrointestinal diseases
Authors: Spiller Robin
Published: March 2003

After many years of basic research we have now begun to learn how to manipulate the serotonergic mechanisms within the gut. This has lead to a number of significant advances including 5HT3 antagonists for the treatment of functional diarrhoea, 5HT4 agonists for the treatment of constipation and 5HT1 agonists for the treatment of impaired fundal relaxation. Initial enthusiasm has been somewhat dented by the withdrawal of alosetron because of ischaemic colitis, but it remains to be seen whether this adverse event will be seen with other 5HT3 antagonists. Finally it should be recognized that, in a substantial proportion of patients attending clinics complaining of functional symptoms, anxiety is a major component. The drugs so far described are by and large devoid of CNS effects. It remains possible therefore that a drug which combines both peripheral and central effects would likely to be beneficial.
Lack of pharmacokinetic interaction between the oral anti‐influenza neuraminidase inhibitor prodrug oseltamivir and antacids
Authors: Snell Paul , Oo Charles , Dorr Al , Barrett Joanne
Published: March 2003

Aims
Oseltamivir is an oral ester prodrug of its active metabolite Ro 64–0802, a potent and selective neuraminidase inhibitor of the influenza virus. The object of this study was to evaluate whether the oral absorption of oseltamivir was reduced in the presence of two main classes of antacid, Maalox® suspension (containing magnesium hydroxide and aluminium hydroxide) and Titralac® tablets (containing calcium carbonate).

Methods
Twelve healthy volunteers completed a randomized, single dose, three‐period crossover study. Each volunteer received in a fasted state, 150 mg oseltamivir alone (Treatment A), 150 mg oseltamivir with a 20 ml Maalox® suspension (Treatment  B),  and  150 mg  oseltamivir  with  four  Titralac® tablets  (Treatment  C),  with 7–10 days washout in between treatments. Plasma and urine concentrations of oseltamivir  and  Ro  64–0802  were  measured  using  a  validated  h.p.l.c./MS/MS assay. Pharmacokinetic parameters were calculated for oseltamivir and Ro 64–0802. Since antacids are locally acting drugs and generally not expected to be absorbed substantially into the systemic system, no plasma or urine concentrations of antacids were measured.

Results
Bioequivalence was achieved for the primary pharmacokinetic parameters Cmax and AUC(0,∞) of Ro 64–0802 following administration of oseltamivir with either Maalox® suspension or Titralac® tablets vs administration of oseltamivir alone. The bioavailability (90% confidence intervals) of Ro 64–0802 following administration of oseltamivir together with Maalox® suspension vs administration of oseltamivir alone, was 90% (83.6, 96.9%) for Cmax and 94.1% (91.4, 96.9%) for AUC(0,∞); similarly, for Titralac® tablets, the equivalent values were 95.1% (88.3, 102%) for Cmax and 94.7% (91.9, 97.5%) for AUC(0,∞).

Conclusions
The coadministration of either Maalox® suspension or Titralac® tablets with oseltamivir has no effect on the pharmacokinetics of either oseltamivir or Ro 64–0802, and conversely, there is no evidence that coadministration with oseltamivir has an effect on the safety and tolerability of either Maalox® suspension or Titralac® tablets. There was no pharmacokinetic interaction between oseltamivir with either antacid, demonstrating that the oral absorption of oseltamivir was not impaired in the presence of antacids containing magnesium, aluminium or calcium.
Population PKPD modelling of the long‐term hypoglycaemic effect of gliclazide given as a once‐a‐day modified release (MR) formulation
Authors: Frey N. , Laveille C. , Paraire M. , Francillard M. , Holford N. H. G. , Jochemsen Roeline
Published: March 2003

Aims To study the relationship between the pharmacokinetics (PK) of gliclazide and its long‐term pharmacodynamic (PD) effect in a large population of Type 2 diabetic patients and to identify factors predicting intersubject variability.

Methods A PKPD database of 634 Type 2 diabetic patients with a total of 5258 fasting plasma glucose (FPG) samples was built up from the data collected during the clinical development of a modified release formulation of gliclazide (gliclazide MR). The PKPD analysis used a nonlinear mixed effect modelling approach. A mixture model was used to identify patients with a FPG response to treatment. In patients identified as responders, the decrease in FPG was related to gliclazide exposure (AUC) by an Emax relationship. An effect compartment was used to describe the link between PK and PD. A linear disease‐progression model was used to assess the glycaemic deterioration observable over several months of treatment. Simulations were performed to evaluate the predictive performance of the PKPD model and to illustrate the time course of the antidiabetic effect of gliclazide MR.

Results Disease state was found to be the main explanatory factor for intersubject variability in response to gliclazide. The percentage of responders to gliclazide, used as monotherapy, increased inversely to the number of classes of antidiabetic agents received prior to entry in the studies. In responders, the initial dose (30 mg) of the gliclazide MR dosing regimen induced half of the maximum hypoglycaemic effect. The equilibration half‐life between the PK and PD steady states was 3 weeks (intersubject variability of 84%). The rate of disease progression was 0.84 mmol l−1 year−1 (intersubject variability 143%). The PKPD model adequately predicted the FPG profiles of 234 patients who received the current formulation of gliclazide. Simulation of a 1‐year parallel dose ranging clinical trial illustrated the influence of dose, time and type of previous antidiabetic treatment on the percentage of patients with clinically significant improvement of blood glucose control.

Conclusions This population PKPD analysis has characterized the relationship between the exposure to gliclazide and its long‐term hypoglycaemic effect, and has established that the intersubject variability in response is mostly related to disease state. These results underline the clinical interest of quickly increasing the dose of gliclazide MR according to the response to treatment in order to achieve effective blood glucose control.
A case of guttate psoriasis following Kawasaki disease
Authors: Han M-H. , Jang K-A. , Sung K-J. , Moon K-C. , Koh J-K. , Choi J-H.
Published: March 2003

We report a case of guttate psoriasis following Kawasaki disease, in a patient with Staphylococcus aureus demonstrated in a throat swab. We suggest that preceding staphylococcal infection can play a key role in the pathogenesis of some cases of guttate psoriasis, possibly by the production of superantigens.
Platelet‐like particle formation in the human megakaryoblastic leukaemia cell lines, MEG‐01 and MEG‐01s
Authors: Takeuchi Kikuko , Satoh Motonobu , Kuno Haruhiko , Yoshida Toho , Kondo Hiroshi , Takeuchi Masao
Published: March 2003

The platelet‐sized particle formation in the human megakaryoblastic leukaemia cell line MEG‐01 and its subline MEG‐01s was examined. MEG‐01 and MEG‐01s cells spontaneously released platelet‐sized particles into the culture medium, in which the cells occasionally extended cytoplasmic processes similar to those of megakaryocyte proplatelets. Scanning electron microscopic images showed cytoplasmic processes elongated from blebs on the MEG‐01 and MEG‐01s cell surface and were constricted between segments of platelet size. Immunofluorescence staining with anti‐tubulin antibody showed that the cytoplasmic processes contained microtubules that were organized into a ring, which is a characteristic of circulating platelets. Some platelet‐sized particles, probably released by ruptures at the sites of the process constriction, were metabolically active in an MTT assay (about 50%). Some particles also expressed the platelet‐specific glycoproteins GPIIb, IIIa and GMP‐140. Rarely, in response to thrombin, particles underwent a shape change from spherical to a shape with irregular membrane protrusions and fine filopodia, and aggregating with one another. The particles also had increased GMP‐140 (P‐selectin) expression with the addition of thrombin. These results show the usefulness of the MEG‐01 and MEG‐01s cell lines for the study of thrombopoiesis.
Repeated treatment with horse antilymphocyte globulin for severe aplastic anaemia
Authors: Tichelli André , Passweg Jakob , Nissen Catherine , Bargetzi Mario , Hoffmann Till , Wodnar‐Filipowicz Aleksandra , Signer Erich , Speck Bruno , Gratwohl Alois
Published: March 2003

In a single‐centre study the feasibility and efficacy of repeated antilymphocyte globulin (ALG) for patients with severe aplastic anaemia (SAA) not responding to an initial ALG treatment or relapsing after initial response to ALG was evaluated. 139 consecutive patients with newly diagnosed SAA were treated with ALG between 1976 and 1995. 89 patients responded to a first course; 50 patients did not become transfusion independent. Of the 89 responders, 66 remained in remission, 23 relapsed. 43 patients received a second or subsequent course of ALG for failure to respond (n = 25) or relapse (n = 18) and were given a total of 53 courses. Acute reactions in the multiply exposed patients occurred during the first ALG treatment in 11 (26%) and during subsequent exposures in 16/53 courses (30%; P > 0.2). Incidence of serum sickness was 63% (27/43) after the initial course compared to 57% (30/53) after subsequent courses (P > 0.2), but clinical signs of serum sickness occurred earlier after repeated (median 6 d) as compared to initial exposure (13 d; P = 0.008). Transfusion‐independent haemopoiesis was achieved in 27/43 (63%) and survival probabilities for the 43 patients receiving multiple courses of ALG was 52 ± 8% at 10 years. The probability of developing a late clonal disorder was 53 ± 10% after multiple, as compared to 34 ± 7% after single exposure (P = 0.15). No difference in results was observed between patients retreated for failure to first ALG or for relapse. ALG of the same species can be repeated without increased risks of side‐effects in patients with SAA. A second or subsequent course of ALG from the same source can be effective when the first course has failed.
False negative factor V Leiden assay following allogeneic stem cell transplant
Authors: Crookston Kendall P. , Henderson Ruth , Chandler Wayne L.
Published: March 2003

We report a case where a phenotypic test (an activity assay for activated protein C resistance) correctly indicated that the patient had an abnormality, whereas the initial genetic test (a PCR‐based DNA assay used to detect the mutation in the FV gene) incorrectly indicated that the patient did not. The apparent false negative result of the DNA‐based test was due to the use of peripheral blood leucocytes for DNA analysis. The patient had undergone a stem cell transplant several months before, and the leucocytes in her blood were derived from the stem cell donor, which lacked the FV defect.
MDR1 gene expression and drug resistance of AML cells
Authors: NØrgaard Jan Maxwell , Bukh Anne , Tyge Langkjer Sven , Clausen Niels , Palshof Torben , Hokland Peter
Published: March 2003

We investigated the cellular drug resistance to aclarubicin (Acla), cytosine arabinoside (Ara‐C), daunorubicin (Dau), doxorubicin (Dox), etoposide (Etop) and mitoxantrone (Mitox) using the MTT assay at time of disease presentation in 93 cases of acute myeloid leukaemia (AML). In 31 cases we concomitantly investigated MDR1 (multiple drug resistance 1 gene) expression (semi‐quantitative competitive RT‐PCR) of the leukaemic cells. Drug resistance towards Dau, Dox and Etop was correlated to the MDR1 expression of the AML cells (P < 0.05) with high MDR1 expression being associated with high drug resistance towards these drugs. Although the data did not allow firm conclusions to be drawn on the correlation between MDR1 expression and drug resistance towards Ara‐C and Mitox, the drug resistance towards Acla clearly was not correlated to, or dependent on, the MDR1 expression level of the AML blast cells. In addition, when examining the cross‐activities among the six drugs distinct patterns emerged. Thus, high to very high degrees of cross‐activity were found to exist between Dau, Dox, Etop and Mitox, whereas Ara‐C had moderate cross‐activity with the other drugs except Acla, which showed absent to moderate cross‐activity with the other drugs. We conclude that MDR1 gene expression is of significance for cellular drug resistance towards specific (MDR1‐related) drugs in AML, whereas it is not of significance regarding drug resistance towards other drugs, which is the case with the anthracycline Acla. We suggest that in the place of other more or less complicated ways to circumvent MDR1‐mediated drug resistance, Acla may be used to replace Dau, Dox and other MDR1‐related drugs if proven as potent as the drug it is to substitute.
Successful use of cyclosporine A in the treatment of refractory thrombotic thrombocytopenic purpura
Authors: Hand  , Lawlor  , Yong  , Davis
Published: March 2003

Thrombotic thrombocytopenic purpura (TTP) is, in most cases, treatable with plasma exchange therapy (PLEX). Rarely, patients do not respond to PLEX or develop refractory disease despite an initial remission. In these cases, treatment options are limited and the response to established alternative therapies is often disappointing. We report the case of a paediatric patient with TTP who developed refractory disease after an initial response to PLEX. She was subsequently treated with cyclosporine A and showed an immediate and sustained response. CSA may be a safe and effective therapy for patients with refractory TTP and should be studied in randomized, prospective clinical trials.
Haemostatic factors and prediction of ischaemic heart disease and stroke in claudicants
Authors: Smith  , Rumley  , Lee  , Leng  , Fowkes  , Lowe
Published: March 2003

Thrombotic risk factors may be important in determining cardiovascular outcome in patients with symptomatic peripheral arterial disease. A cohort study with a 6‐year follow‐up period was established to determine the relationships between haemostatic and rheological factors and incident ischaemic heart disease (IHD) and stroke events in patients with peripheral arterial disease. A consecutive series of 607 patients with intermittent claudication was examined between 1989 and 1990 at the Peripheral Vascular Clinic, Royal Infirmary of Edinburgh. Main outcome measures were combined fatal and non‐fatal stroke, non‐fatal myocardial infarction (MI), coronary death and total coronary events. A total of 210 patients died during follow‐up. 203 patients did not experience a vascular event or deterioration of limb ischaemia. Median levels of fibrinogen, von Willebrand factor (VWF), tissue plasminogen activator (t‐PA) antigen, fibrin D‐dimer and whole blood viscosity were significantly higher in those who experienced an event compared with those who did not. After adjusting for age and sex, fibrin D‐dimer was significantly associated with risk of non‐fatal myocardial infarction (RR 1.50, 95% CI 1.09–2.06, P  0.01). Both fibrinogen and fibrin D‐dimer were associated with risk of total coronary events (P  0.05). The risk of stroke was related to baseline levels of t‐PA antigen (RR 1.87, 95% CI 1.04–3.34, P  0.05) and whole blood viscosity (RR 1.33, 95% CI 1.07–1.65, P  0.01). All the relationships became weaker and statistically non‐significant after further adjustment for cigarette smoking, systolic blood pressure, glucose and baseline IHD. The associations of these factors to IHD and stroke may therefore be partly related to cardiovascular risk factors, but are likely to be important in the pathogenesis of future atherothrombotic events in subjects with peripheral arterial disease.
Loss of HLA molecules in B lymphomas is associated with an aggressive clinical course
Authors: Amiot Laurence , Onno Myriam , Lamy Thierry , Dauriac Charles , LE Prise Pierre‐Yves , Fauchet RenÉE , Drenou Bernard
Published: March 2003

Major histocompatibility complex class I molecule expression is reduced in some malignant tumours permitting escape from immune surveillance and is therefore associated with a poor prognosis. Seven cases of non‐Hodgkin lymphomas out of 300 cases of malignant lymphoproliferative disorders totally lacked expression of class I molecules as determined by flow cytometry. Clinical data confirmed a particular aggressiveness of these cases with frequent extra‐nodal involvement, a poor international prognostic index, a histological high grade and a poor outcome leading to early death in five of the seven cases. A previous diagnosis of follicular lymphoma characterized by bcl‐2 rearrangements was made in four of these cases. HLA‐G (class Ib gene), which is reported to bind killer inhibitory receptors on NK cells, was absent from the cell surface. However, it was detected in three out of four cases at the mRNA level with transcripts encoding soluble forms. Additional analysis revealed other abnormalities: class II was negative in four out of the seven NHL cases and decreased expression of β2 microglobulin was observed in all cases. Peptide transporter proteins (TAP1) were detected in various degrees by immunocytochemistry. These observations showed that total lack of class I or class II molecules is a rare event in NHL and is associated with a poor prognosis. This could support a role for specific autologous T cells in immune surveillance.
Rapid heterozygote detection in Glanzmann's thrombasthenia
Authors: Sharp  , Khanduri  , Christie
Published: March 2003

To assess the potential of using flow cytometric analysis of platelet glycoprotein IIb in the detection of heterozygotes in Glanzmann's thrombasthenia (GT) we compared the fluorescence intensity of anti‐CD41‐labelled platelets of obligatory heterozygotes with that of normal subjects. This study showed that normal subjects had relative fluorescences occasionally overlapping with heterozygotes. Use of an independent factor, the mean platelet volume, as a correction factor for platelet size differences eliminated this overlap. This study indicates that it is possible to confidently and rapidly predict the carrier status of family members of GT sufferers, both type I and type II, by flow cytometric means.
Severe coagulation factor V deficiency caused by a 4 bp deletion in the factor V gene
Authors: Guasch Joan F. , Cannegieter Suzanne , Reitsma Pieter H. , Van 't Veer‐Korthof Elizabeth T. , Bertina Rogier M.
Published: March 2003

Factor V (FV) deficiency (parahaemophilia) is an autosomal recessive bleeding disorder with an incidence of 1:106. We have studied a young girl with very mild bleeding symptoms and undetectable levels of plasma factor V antigen and activity (<0.3% and <1.6% of normal, respectively). Both parents showed plasma levels of factor V activity of about 50% of normal. Sequence analysis of the 5′‐ and 3′‐untranslated, coding and adjacent regions of the factor V gene revealed the presence of a 4 bp deletion in exon 13. Subsequent screening of members of the family for the mutation showed that both parents were heterozygous for the mutation, that one healthy sister carried only normal alleles, and that the patient was homozygous for the mutated allele. The mutation introduced a frameshift and a novel premature stop codon in codon 1303, and would predict the synthesis of a truncated factor V molecule that lacks part of the B domain and the complete light chain. However, no factor V heavy chain could be detected in the plasma of the patient. Furthermore, factor V activity could not be detected in the patients' platelets. This is the first reported mutation in the factor V gene that predicts a type I quantitative factor V deficiency. Surprisingly, the patient, who is homozygous for the mutation, so far has only a very mild bleeding tendency.