bluuebunny/crossref_metadata_2025_split huggingface dataset:
Paracetamol, alcohol and the liver
Authors: Prescott Laurie F. 
Published: March 2003

It is claimed that chronic alcoholics are at increased risk of paracetamol (acetaminophen) hepatotoxicity not only following overdosage but also with its therapeutic use. Increased susceptibility is supposed to be due to induction of liver microsomal enzymes by ethanol with increased formation of the toxic metabolite of paracetamol. However, the clinical evidence in support of these claims is anecdotal and the same liver damage after overdosage occurs in patients who are not chronic alcoholics. Many alcoholic patients reported to have liver damage after taking paracetamol with ‘therapeutic intent’ had clearly taken substantial overdoses. No proper clinical studies have been carried out to investigate the alleged paracetamol–alcohol interaction and acute liver damage has never been produced by therapeutic doses of paracetamol given as a challenge to a chronic alcoholic.The paracetamol–alcohol interaction is complex; acute and chronic ethanol have opposite effects. In animals, chronic ethanol causes induction of hepatic microsomal enzymes and increases paracetamol hepatotoxicity as expected (ethanol primarily induces CYP2E1 and this isoform is important in the oxidative metabolism of paracetamol). However, in man, chronic alcohol ingestion causes only modest (about twofold) and short‐lived induction of CYP2E1, and there is no corresponding increase (as claimed) in the toxic metabolic activation of paracetamol. The paracetamol–ethanol interaction is not specific for any one isoform of cytochrome P450, and it seems that isoenzymes other than CYP2E1 are primarily responsible for the oxidative metabolism of paracetamol in man. Acute ethanol inhibits the microsomal oxidation of paracetamol both in animals and man. This protects against liver damage in animals and there is evidence that it also does so in man. The protective effect disappears when ethanol is eliminated and the relative timing of ethanol and paracetamol intake is critical.In many of the reports where it is alleged that paracetamol hepatotoxicity was enhanced in chronic alcoholics, the reverse should have been the case because alcohol was actually taken at the same time as the paracetamol. Chronic alcoholics are likely to be most vulnerable to the toxic effects of paracetamol during the first few days of withdrawal but maximum therapeutic doses given at this time have no adverse effect on liver function tests. Although the possibility remains that chronic consumption of alcohol does increase the risk of paracetamol hepatotoxicity in man (perhaps by impairing glutathione synthesis), there is insufficient evidence to support the alleged major toxic interaction. It is astonishing that clinicians and others have unquestion‐ingly accepted this supposed interaction in man for so long with such scant regard for scientific objectivity.
In vitro sensitivity of Plasmodium falciparum and clinical response to lumefantrine (benflumetol) and artemether
Authors: Tanariya Peerapan , Tippawangkoso Pongsri , Karbwang Juntra , Na‐bangchang Kesara , Wernsdorfer Walther H. 
Published: March 2003

Aims  To assess the sensitivity of 103 Plasmodium falciparum isolates to a combination of lumefantrine (benflumetol) and artemether (CGP 56697), with the objective of determining a correlation between in vitro drug sensitivity and therapeutic outcome.Methods  Patients suffered from uncomplicated falciparum malaria and came from areas of Thailand affected by multidrug resistance. CGP 56697 was given in the form of tablets containing 20 mg artemether and 120 mg lumefantrine. The standard dose regimen, 4 doses of 4 tablets over 48 h, was compared with two lower dose regimens (4 × 2 tablets and 3 × 4 tablets).Results  The parasites showed high resistance to chloroquine, fairly advanced resistance to mefloquine and compromised sensitivity to quinine. Sensitivity to artemisinin and lumefantrine prior to treatment was similar in all treatment groups. The 4 × 4 tablet regimen was more effective than the other regimens in coping with infections with relatively low sensitivity to artemisinin and/or lumefantrine. The EC90 for artemisinin is an important determinant of treatment success. Parasite density at the start of treatment was identified as another critical predictor of treatment outcome.Conclusions  The results indicate that parasite exposure to the drugs may have been inadequate and/or too short in the cases of treatment failure, particularly marked in the lower dose regimens. This could probably be remedied by expanding the dose regimen in areas affected by multidrug resistance and in the case of relatively high parasitaemia.
Influence of hydroxychloroquine on the bioavailability of oral metoprolol
Authors: Somer Mika , Kallio Jaana , Pesonen Ullamari , Pyykkö Kaija , Huupponen Risto , Scheinin Mika 
Published: March 2003

Aims
Hydroxychloroquine (HCQ) is used widely in the treatment of chronic inflammatory diseases such as rheumatoid arthritis. Since there is great interindividual variability in the pharmacokinetics of HCQ and chloroquine is a potent inhibitor of CYP2D6‐catalysed pathways in vitro, we wished to study the interaction of HCQ with CYP2D6‐mediated metabolism of other drugs in vivo.
Methods
Metoprolol and dextromethorphan (DM) were selected as probe drugs because they are well‐studied and widely used test substrates of CYP2D6. In this randomized, double‐blind crossover study, seven healthy volunteers with extensive metabolizer phenotype for CYP2D6 ingested either 400 mg hydroxychloroquine or placebo daily for 8 days after which single oral dose pharmacokinetics of metoprolol were investigated. Dextromethorphan metabolic ratio (DM‐MR) was also determined at baseline and after the ingestion of HCQ or placebo.
Results
Concomitant administration of HCQ increased the bioavailability of metoprolol, as indicated by significant increases in the area under the plasma concentration‐time curve (65 ± 4.6%) and maximal plasma concentrations (72 ± 6.9%) of metoprolol. While the DM‐MR values were not significantly changed, the phenotypic classification of one individual, who was heterozygous for a mutant CYP2D6 allele, was converted to a poor metabolizer by HCQ administration.
Conclusions
HCQ inhibits metoprolol metabolism most probably by inhibiting its biotransformation by CYP2D6. The inhibitory effect of HCQ on dextromethorphan metabolism was not apparent when DM‐MR was used as an indicator, except in an individual with limited CYP2D6 capacity.
Frequencies of CYP2D6 mutant alleles in a normal Japanese population and metabolic activity of dextromethorphan O‐demethylation in different CYP2D6 genotypes
Authors: Kubota T. , Yamaura Y. , Ohkawa N. , Hara H. , Chiba K. 
Published: March 2003

Aims
To determine the frequencies of 11 CYP2D6 mutant alleles (CYP2D6*2,*3,*4,*5,*8,*10,*11,*12,*14,*17 and *18), and their relation to the metabolic capacity of CYP2D6 in Japanese subjects.Methods One hundred and sixty‐two unrelated healthy Japanese subjects were genotyped with the polymerase chain reaction amplification method and 35 subjects were phenotyped with dextromethorphan.
Results
The frequencies of CYP2D6*2,*5, *10 and *14 were 12.9, 6.2, 38.6 and 2.2% in our Japanese subjects, respectively. CYP2D6*3, *4, *8, *11, *12, *17 and *18 were not detected. The mean log metabolic ratio of dextromethorphan in subjects with genotypes predicting intermediate metabolizers was significantly greater than that of heterozygotes for functional and defective alleles.Conclusions CYP2D6*5 and CYP2D6*14 are the major defective alleles found in Japanese subjects. In addition, CYP2D6*10 may play a more important role than previously thought for the treatment of Japanese patients with drugs metabolized by CYP2D6.
The link between sunshine and phototoxicity of sparfloxacin
Authors: Pierfitte Corinne , Royer René Jean , Moore Nicholas , Bégaud Bernard 
Published: March 2003

Aims
To test the association between reporting rates for sparfloxacin‐induced phototoxicity and sunlight u.v. exposure, and the effects of regulatory action.
Methods
The reporting rates for phototoxicity with sparfloxacin to the French Pharmacovigilance System or to the Drug Manufacturer were compared with concurrent national mean u.v. exposure obtained from Météo‐France, before and after the regulatory restrictions and warnings.
Results
There were 371 severe phototoxic reaction reports during the first 9 months of marketing (reporting rate of 0.4 per thousand treated patients), approximately four to 25 times that reported for other fluoroquinolones. The reporting rate correlated highly (r = 0.873, P < 0.001) with the mean monthly u.v. exposure from sunlight (from Météo‐France). Regulatory action including warnings for physicians, and restricted indications dramatically decreased the number of reports, but not the reporting rate.
Conclusions
This is the first demonstration of a strong association between sunlight exposure in a population and drug‐induced phototoxicity. Regulatory action had no effect on the reporting rate (individual exposed patient risk), though it solved the public health issue.
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.