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Antibiotic (ATB) prescription in an intensive care unit (ICU) requires continuous monitoring of serum dosages due to the patient's pathophysiological condition. Dosing adjustment is necessary to achieve effective targeted concentrations. Since ICUs routinely use a large number of ATBs, global monitoring needs to be developed. In the present study, we developed a global analytical method for extracting, separating and quantifying the most widely used ATBs in ICUs: amoxicillin, piperacillin, cefazolin, cefepime, cefotaxime, ceftazidime, ceftolozane, ceftriaxone, ertapenem, meropenem, ciprofloxacin, moxifloxacin, levofloxacin, daptomycin, dalbavancin, linezolid and a beta-lactamase inhibitor: tazobactam. To guarantee the robustness of the quantification, we differentiated the 16 ATBs and the beta lactamase inhibitor into 4 pools (ATB1 to ATB4), taking into account prescription frequency in the ICU, the physicochemical properties and the calibration ranges of the ATBs selected. The whole ATB was then separated with two LC columns in reversed phase: Kinetex Polar-C18 100 Å and Polar-RP-80 synergy, in less than 6.5 min. Detection was carried out by electrospray in positive ion mode, by tandem mass spectrometry (LC-MS/MS. The four quantification methods were validated according to the European guidelines on bioanalytical method validation (EMEA guide), after determining the extraction yields, matrix effects, recovery, precision, accuracy, within-run precision and between-run precision. For all analyses, bias is 15% and is comparable to the literature and LOQs vary from 0.05 mg.L

Highlights • Hydroxychloroquine pharmacokinetic behavior in COVID-19 patients cannot be predicted using the systemic lupus erythematosus population or by rheumatoid arthritis patients. • Bronchoalveolar lavage fluid could be considered a much more instructive “quality control” matrix than plasma on the degree of hydroxychloroquine exposure in the lung. • Low plasma concentrations should not induce an increase of the drug dosage because the lung exposure should be high., Different dosage regimens of hydroxychloroquine were used to manage COVID-19 patients, with no information on the lungs’ exposure in this population. The aim of our study was to evaluate hydroxychloroquine concentrations in the lung epithelial lining fluid (ELF) in patients infected with COVID-19. This study is a retrospective, observational, multicenter, pharmacokinetics study of hydroxychloroquine in critically ill patients. No additional interventions or additional samples compared to standard care of these patients were conducted in our teaching hospital. We included all intubated COVID-19 patients treated with crushed hydroxychloroquine tablets, regardless of the dosage administered by the nasogastric tube. Blood and bronchoalveolar lavage (BAL) samples (n= 28) were collected from 22 COVID-19 patients and the total hydroxychloroquine concentrations in epithelial lining fluid were estimated. Median hydroxychloroquine plasma concentrations were of 0.09 [0.06; 0.14] mg/l and 0.07 [0.05; 0.08] mg/l for 400 mg x 1/day and 200 mg x 3/day, respectively. Median hydroxychloroquine ELF concentrations were of 3.74 [1.10; 7.26] mg/l and 1.81 [1.20; 7.25] for 400 mg x 1/day and 200 mg x 3/day, respectively. The median ratio of ELF/plasma concentrations was of 40.0 [7.3; 162.7] and 21.2 [18.4; 109.5] for 400 mg x 1/day and 200 mg x 3/day, respectively. Exposure in the ELF is likely to be underestimated due to the concentrations of plasma hydroxychloroquine. In clinical practice, low plasma concentrations should not induce an increase in drug dosage because the lung exposure may already be high.

International audience; Background and objectives: The incorporation of drugs in the hair of young children differs from that of adults and the metabolism of cannabis cannot be the same. Our primary objective was to analyze the distribution of the different cannabinoids in children's hair samples. The secondary objective was to correlate the intensity of toxic environmental exposure to cannabinoid metabolite levels.Methods: This was a prospective, single-center, observational pilot study of a pediatric cohort. Included subjects were all children less than 6 years of age admitted to a tertiary pediatric emergency unit for proven cannabis intoxication during the reference period. A hair strand was sampled within 12 h of emergency admission.Results: Forty-one pediatric patients were consecutively enrolled. Hair analysis showed that 34 children were positive for D9-THC (range 0.06-284.4 ng/mg); 41 % of them were also positive for THC-COOH (range 0.26-2.76 pg/mg). Depending on the D9-THC concentration (>1 ng/mg), 39 % of the children could be considered exposed to an intensely toxic environment. The rate of THC-COOH detection steadily increased from 2015 to 2018 (18 %, 40 %, 50 %, 58 % for each consecutive year). Children intensely exposed weighed less on admission (p = 0.02), had more comatose presentations (p = 0.02), and more previous social issues (75 % versus 12 %, OR 22.0, p = 0.0002).Conclusion: Hair testing in this context indirectly shows the intensity of children's toxic environmental exposure by the cannabinoid metabolite threshold. This was very helpful during the collegial examination of the toddlers' environment and led to a full investigation and to appropriate decisions concerning social measures. (C) 2020 Elsevier B.V. All rights reserved.

International audience; There is no therapeutic agent approved in cutaneous mastocytosis and mast cell activation syndrome. We report the efficacy of hydroxychloroquine in four patients with cutaneous mastocytosis (n = 2) and mast cell activation syndrome (n = 2). We show that this molecule reduces the long-term survival of primary human mast cells, interferes with lysosome function and leads to the accumulation of non-functional tryptase in the mast cell granules. Furthermore, hydroxychloroquine decreases the production of pro-inflammatory mediators.

Resume Objectif Plusieurs etudes recentes ont etabli une correlation entre le polymorphisme de N-acetyltransferase 2 (NAT2) et l’hepatotoxicite induite par l’isoniazide. L’objectif de ce travail a ete d’evaluer la place du dosage de l’isoniazide, marqueur du phenotype d’acetylation, dans la pratique clinique, au niveau du departement de la Haute-Garonne. Methodes Les donnees issues des declarations obligatoires de tuberculose et les resultats des dosages d’isoniazide effectues au laboratoire de pharmacocinetique et toxicologie clinique ont ete exploites durant la periode de 2009 a 2012. Resultats La pratique actuelle du dosage est loin d’etre systematique : seulement 3,9 % des patients ayant developpe une tuberculose ont beneficie d’un dosage d’isoniazide. La posologie initiale en isoniazide etait adaptee aux capacites d’acetylation pour seulement 33,3 % des patients. Conclusion Un arbre decisionnel a ete realise et permet d’identifier les populations (acetyleurs lents) susceptibles de beneficier d’un dosage d’isoniazide.

Background In the field of addiction, assessment of psychoactive substance use is a key element. Nevertheless, self-reports and clinical examination underestimate the use of psychoactive substances. The implementation of urine drug screening tests (UDS) should improve this assessment. While the diagnostic value of UDS is well demonstrated, the consequences of carrying out UDS on medical management have not been established. Our aim was to summarize the evidence pertaining to the efficacy of UDS for medical management. Methods A systematic review of clinical trials, quasi-randomized and observational studies was performed using PubMed, Cochrane database of systematic review, Cochrane central register of controlled trials, PsycINFO, National Institute on Drug Abuse, ISI Web of Science. The methodological quality was assessed with the score developed by Starrels et al.; the report quality using the CONSORT and the STROBE checklists. The main outcome was medical management or consequences of management for patients in terms of psychoactive substance consumption and its complications, be they medical, social or professional. Results Eight studies met the inclusion criteria: one randomized clinical trial, two quasi-randomized studies, one cohort, and four cross-sectional studies. The methodological quality was judged to be poor, with the exception of the randomized clinical trial (fair quality). The value of UDS in managing patients was not clearly indicated in these studies. Conclusions Few studies, with poor quality, have assessed the value of UDS in managing patients using psychoactive substances; though with insufficiency to demonstrate the interest of carrying out UDS. Therefore, pragmatic intervention studies are necessary.

A simple and sensitive HPLC method has been developed to measure trimebutine (CAS 39133-31-8, maleate: CAS 34140-59-5) and its main metabolite desmethyl-trimebutine in human plasma. The method was validated according to the Washington Consensus Conference on the Validation of Analytical Methods. It involved extraction of the plasma with n-hexane containing 2-pentanol, followed by reversed-phase HPLC using a Partisil(R) ODS2 10 mu m column and UV detection at 265 nm. The retention times of the interval standard (procaine), desmethyl-trimebutine and trimebutine were 2.4, 4.3 and 6.5 min, respectively The standard curves were linear from 20 ng . ml(-1) (limit of quantitation) to 5000 ng . ml(-1) for both compounds. The coefficient of variation for all the criteria of validation were less than 15 %. The extraction recoveries obtained for trimebutine and desmethyl-trimebutine were about 90 %. Both compounds were very stable upon storage in plasma. The method was tested by measuring the plasma concentrations following oral administration to humans during a bioequivalence study and was shown suitable for pharmacokinetic studies.

Objectifs : Le mycophenolate mofetil (MMF) est une prodrogue de l’acide mycophenolique (AMP). Ce dernier est un immunosuppresseur dont le suivi therapeutique pharmacologique (STP) est devenu pratique courante apres des greffes renales, hepatiques et cardiaques. L’objectif de cette etude a ete de comparer deux methodes de dosage de l’AMP (Enzyme Multiplied Immunoassay Technique : EMIT vs la chromatographie liquide couplee a un detecteur UV : CL-UV) en fonction du traitement immunosuppresseur co-administre. Methode : Cent vingt-trois echantillons issus de 58 patients adultes transplantes renaux ont ete analyses selon les deux methodes. Dix-huit patients ont recu du MMF associe a la ciclosporine tandis que 40 ont recu du MMF associe au belatacept. Resultats : Independamment du traitement immunosuppresseur co-administre, les concentrations d’AMP ont ete sous-estimees par la methode EMIT par rapport a la methode CL-UV avec un biais de –0,829 mg/mL soit une sous-estimation de 8,86 %. Une sous-estimation des concentrations d’AMP a ete retrouvee dans le groupe traite par belatacept avec un biais de –1,06 % correspondant a une sous-estimation de 9,9 %, contrairement au groupe traite par ciclosporine. Conclusion : La methode EMIT n’est pas un outil suffisamment specifique pour le suivi therapeutique pharmacologique de l’acide mycophenolique dont le faible index therapeutique ne tolere pas cette limite analytique. On lui preferera une methode chromatographique (CL-UV ou mieux la chromatographie liquide couplee a la spectrometrie de masse CL-SM/SM).

Cas clinique : Un homme de 44 ans a ete admis aux urgences suite a une perte de connaissance avec arret cardio-respiratoire recupere sous adrenaline. Devant le tableau clinico-biologique (defaillance cardiovasculaire, œdeme cerebral, acidose lactique avec lactates a 17,54 mmol/L) et les antecedents du patient (diabete traite par metformine, antecedents psychiatriques), l'origine toxicologique a ete exploree : dosage de l'ethylene glycol et de la metformine. Materiel et methodes : Deux techniques ont ete mises a profit pour doser l'ethylene glycol : la premiere, par colorimetrie, reservee a l'urgence et la deuxieme, technique de confirmation, par chromatographie gazeuse couplee a la spectrometrie de masse (GC-MS) qui permet le dosage de 6 autres glycols. La metformine a ete dosee par chromatographie liquide haute performance. Resultats : La concentration plasmatique de l'ethylene glycol mesuree par colorimetrie a ete de 84 mg/L sur le premier prelevement (realise a l'arrivee aux urgences) pour un seuil de quantification a 50 mg/L. Sur un deuxieme prelevement (2 jour d'hospitalisation), la concentration est passee en dessous du seuil de quantification. Le dosage par GC-MS sur ces memes prelevements n'a pas retrouve de traces d'ethylene glycol. Les concentrations plasmatiques de metformine mesurees aux 1er et 2 jours d'hospitalisation ont ete respectivement de 14,46 mg/L et 0,70 mg/L (concentration therapeutique Les resultats discordants entre la technique GC-MS et la technique colorimetrique (peu specifique) ont permis de reveler une interference analytique entre l'ethylene glycol et les lactates plasmatiques pour une lactatemie > 6,25 mmol/L. Pour tout dosage colorimetrique de l'ethylene glycol, un dosage des lactates doit etre realise pour evaluer le risque d'interference analytique.

International audience

Quinine monitoring should be based on unbound concentration due to variable unbound fraction in malaria patients.

Resume Le tacrolimus (FK506) est un immunosuppresseur presentant un faible index therapeutique, utilise dans la prevention des rejets de greffes. Chez les patients greffes renaux, une correlation significative a ete mise en evidence entre efficacite/effets indesirables et concentrations sanguines residuelles en tacrolimus. Cette correlation, utilisee dans le cadre de l'adaptation de posologie du tacrolimus chez le greffe renal, repose sur une methode analytique sensible, specifique, exacte, precise et particulierement rapide. L'objectif de notre travail a consiste a valider une nouvelle methode de dosage du tacrolimus (antibody conjugated magnetic immunoassay, ACMIA) sur automate RXL Dimension (Dade-Behring) selon les criteres standard de validation et par rapport a la methode habituellement utilisee dans les laboratoires d'analyses medicales (enzyme multiplied immunoassay, EMIT). Nos resultats indiquent que l'inexactitude et la precision de la repetabilite et de la reproductibilite de la methode ACMIA sont inferieures a 15 %. Une forte correlation (y = 0,9373 x - 1,4429 r = 0,9533) a ete mise en evidence entre les resultats obtenus sur automates Cobas-Mira et RXL Dimension lors de l'analyse d'echantillons sanguins de patients. Cette nouvelle methode analytique represente une alternative a EMIT Iors des analyses effectuees en routine, dans le cadre de l'adaptation de posologie du tacrolimus chez le patient greffe renal, compte tenu du gain significatif de temps.

What is already known about this subject • There is only one published study of the population pharmacokinetics of ceftazidime in burn patients. Only one covariate (plasma creatinine concentration) was found to contribute to the interindividual variability in the disposition of the drug. What this study adds • Three other covariables (creatinine clearance, mechanical ventilation and gender) have been added to a two compartment pharmacokinetic model incorporating multiplicative error, and these are able to explain much of the interindividual variability in ceftazidime disposition in burn patients. Aims The aim of this study was to evaluate the disposition of ceftazidime in burn patients using a population pharmacokinetic approach, and to identify the clinical and biological parameters influencing its pharmacokinetics. Methods The development of the pharmacokinetic model was based on 237 serum ceftazidime concentrations from 50 burn patients. The determination of the pharmacokinetic parameters and the selection of covariates were performed using a nonlinear mixed-effect modelling method. Results A two-compartment model with first order elimination incorporating a proportional error model best fitted the data. Ceftazidime clearance (CL, l h−1) was significantly correlated with creatinine clearance (CLCR), and the distribution volume of the peripheral compartment (V2, l) was correlated with gender, mechanical ventilation and the CLCR. The final model was defined by the following equations: Ceftazidime clearance was 6.1 and 5.7 l h−1 for mechanically ventilated males and females, respectively, and 7.2 and 6.6 l h−1 for nonventilated patients. The total volume of distribution was 31.6 and 49.4 l for mechanically ventilated males and females, respectively, and 22.8 and 28.1 l h −1for nonventilated patients. Conclusions We have shown that gender, mechanical ventilation and CLCR significantly influence the disposition of ceftazidime in burn patients. Interindividual variability in the pharmacokinetics of ceftazidime was significant and emphasizes the need for therapeutic monitoring.

Background Salbutamol abuse detection by athletes is based on a urinary upper threshold defined by the World Anti-Doping Agency (WADA). However, this threshold was determined in healthy, untrained individuals and after a dose of salbutamol inhaled that might not really mirror the condition of asthmatic athletes and the experts’s guidelines for asthma management. We aimed to revise this threshold in accordance with recommended clinical practice (that appear to be different from the actual WADA recommendation) and in exercise conditions. Methods For the present open-label design study, we included 12 trained male cyclists (20 to 40 y/o) with asthma. Differently from the previous pharmacokinetic study supporting the actual salbutamol urinary upper threshold, we decided to administer a close to recommended clinical practice daily dose of 3x200 μg.d−1 inhaled salbutamol (instead of 1600 μg.d−1 as authorized by the anti-doping policy). Urine salbutamol concentration was quantified by liquid chromatography-tandem ion trap mass spectrometry and corrected for urine density, at rest and after a 90-min cycling effort at 70-80 % of the maximal aerobic power. Results The maximum urine salbutamol concentration value peaked after the cycling effort and was 510 ng.mL−1. That is twice lower than the actual WADA threshold to sanction salbutamol abuse, this “legal” threshold being based on pharmacokinetic data after a daily dose that is 8 fold the total dose sequentially administrated in our study. Considering its 95 % confidence interval, this threshold value could be more stringent. Conclusion By using conditions in accordance with the experts’ clinical and safety guidelines for asthma management in athletes undergoing an intense exercise bout, our study suggests that the urine salbutamol concentration threshold could be lowered to redefine the rule supporting the decision to sanction an athlete for salbutamol abuse.

To assess intracellular and plasma efavirenz concentrations in HIV-infected patients who switched to efavirenz-based highly active antiretroviral therapy (HAART) from successful protease inhibitor-based HAART.A total of 49 patients were included in this observational cohort study. At inclusion, all patients had plasma HIV-RNA levels50 copies/mL and switched to efavirenz combined with two nucleoside reverse transcriptase inhibitors. Intracellular and plasma concentrations were measured 12 h post-dose, 1 month (M1) and 6 months (M6) after starting efavirenz. Virological success (VS) was defined as plasma HIV-RNA level50 copies/mL within the first 12 months and remaining undetectable at the end of the follow-up.VS was documented in 48 patients for at least 12 months (range 12-78 months). High inter-patient variabilities of intracellular and plasma efavirenz concentrations were observed (coefficients of variation40%). At M1 and M6, respectively, median [Q1; Q3] intracellular efavirenz concentrations were 5300 [2830; 11 530] and 6790 [3870; 8790] ng/mL, median plasma efavirenz concentrations were 2050 [1600; 3100] and 2100 [1410; 2500] ng/mL. No correlation was found between intracellular and plasma concentrations. Plasma efavirenz levels exceeded the proposed threshold of 1000 ng/mL in 96% of patients from M1.For moderately pre-treated HIV-infected patients with few mutations who switched to efavirenz from previous successful HAART, the proposed plasma efficacy-threshold was reached without any dosage adaptation. VS was maintained beyond 12 months, despite high inter-patient and intra-patient variabilities of intracellular and plasma efavirenz concentrations.

Introduction L’objectif de cette etude etait de determiner la part des hospitalisations de patients presentant un usage problematique de codeine et tramadol [abus (y compris intoxication volontaire avec intention de suicide), mesusage ou usage detourne] au sein d’une population de patients avec dosage positif a ces substances opioides. Etant donne l’existence de medicaments a base de l’association de codeine et tramadol avec le paracetamol, les donnees ont ete comparees a celles obtenues pour le paracetamol seul. Methode Cette etude descriptive etait basee sur l’analyse des dossiers des patients du CHU de Toulouse presentant des resultats positifs de dosage de la codeine ou du tramadol. Elle a ete conduite de maniere retrospective sur les mois de janvier a mai de 2012 a 2015. Dix-huit patients ont ete inclus pour la codeine et 40 pour le tramadol. Pour le paracetamol, un echantillon de 100 dosages positifs sur la meme periode a ete tire au sort. Resultats Les demandes de dosage provenaient en majorite de services d’urgence. Parmi les 87 cas de dosage positif au paracetamol exploitables, 18 concernaient une prise concomitante de codeine et/ou de tramadol. La proportion de cas d’« usage problematique » etait tres elevee dans les groupes codeine (17/18) et tramadol (32/40) et tres significativement superieure a celle observee pour le paracetamol seul (31/69) (p Discussion Le dosage du paracetamol etant recommande lors de la prise en charge clinique des patients en cas de suspicion de surdosage, son dosage peut etre demande seul, meme en cas de prise concomitante de codeine ou de tramadol, ce qui conduit a sous-estimer la part de l’« usages problematiques » de ces derniers. Les resultats de ce travail soulignent l’interet du recours aux bases de donnees hospitalieres de dosages de substances pour l’etude de l’evolution des hospitalisations liees a un « usage problematique » de codeine et de tramadol associes ou non au paracetamol, notamment dans le cadre de l’addictovigilance.

This study evaluated the effect of simulated weightlessness on gastric emptying, using acetaminophen as a probe and -6 degrees head-down bed rest to simulate zero gravity. Eighteen volunteers were given 1 g of acetaminophen orally before the bed rest and at days 1, 18, and 80. Cmax, tmax, AUC0- infinity, AUC0-t, and t1/2 were calculated for plasma and saliva. The plasma Cmax showed a significant increase (10.43 microg/mL [day 1] to 14.74 microg/mL [day 80]), while tmax significantly decreased (1.41 h [day 1] to 0.91 h [day 80]). Similar results were obtained with saliva, and there were significant increases in the AUCs. The good correlation between the plasma and saliva data suggests that saliva sampling can be valid for acetaminophen pharmacokinetics. The changes in Cmax and tmax indicated more rapid drug absorption, which could have been as a result of faster gastric emptying or an increased blood flow to the intestine.

Several recent studies have established a correlation between NAT2 polymorphism and hepatotoxicity induced by isoniazid. The objective of this work was to assess the place of isoniazid dosage, marker of acetylation phenotype, in clinical practice in the department of Haute-Garonne.Data from reportable disease of tuberculosis and the results of isoniazid dosage performed at the pharmacokinetics and clinical toxicology laboratory were used during the period 2009-2012.The current practice of dosage is far from being systematical: only 3.9% of patients who developed tuberculosis have benefited from isoniazid dosage. The isoniazid initial posology was adapted to the acetylation capacity for only 33.3% of patients.A decision tree was realized and used to identify populations (low metabolism) liable to benefit from isoniazid dosage.

Resume Des differences significatives en terme de concentration peuvent apparaitre avant l'analyse. Elles definissent la variabilite pre-analytique qui constitue un element de la variabilite globale affectant un resultat biologique. Les principales sources de variabilite doivent etre identifiees et des mesures preventives apportees pour en limiter les consequences cliniques. Certains facteurs agissent in vivo avant et pendant le prelevement ; d'autres in vitro concernent la manipulation et la conservation de l'echantillon.

We assessed whether conversion from tacrolimus (TAC) to cyclosporine (CsA) was associated with a reduction in hepatitis C virus (HCV) viral load among HCV-positive liver transplant (OLT) patients. Patients and Methods Nine OLT patients with recurrent HCV have TAC and prednisone immunosuppression. None received any HCV antiviral therapy. After the last intake of TAC, the patients underwent a 12-hour area under the curve (AUC 12 ) measurement of both TAC and HCV viral loads. The next morning (D 0 ) patients were given CsA (4 mg/kg bid). At the first intake of CsA and at 1 month (M 1 ) later, the patients underwent AUC 12 for CsA and HCV viral loads. Biological data, including aspartate (AST) and alanine (ALT) aminotransferase, gamma-glutamyl transpeptidase (GGT), alkaline phosphatase (AP), and bilirubin levels, were collected during AUC 12 , and at M 1 and M 3 . Results With respect to liver enzymes (AST, ALT, GGT), there was no significant difference between D 0 , M 1 , and M 3 . Conversely, there was a significant decrease in AP between D 0 and M 3 ( P = .02), and a significant increase in total bilirubin between D 0 and M 1 ( P = .04), and between D 0 and M 3 ( P = .01). HCV viral load significantly increased by M 3 ( P = .01). At no time (D 0 , M 1 ) was there any correlation between the AUC 12 of TAC or CsA, and between AUC 12 HCV viral load. Conclusion This pilot study found no acute or chronic anti-HCV effects from CsA that were evident within 12 hours after CsA administrations or beyond 1 month of CsA therapy, respectively.

Resume La mesure des concentrations seriques des digitaliques, obtenues et interpretees dans leur juste contexte pharmacocinetique et clinique, constitue une etape importante dans la determination d'une posologie adaptee a chaque patient. Le suivi therapeutique de cette classe de medicaments necessite la prise en compte de multiples facteurs intrinseques ou extrinseques qui peuvent influencer les concentrations seriques et les effets des digitaliques. Il impose, en outre, une demarche rationnelle tant au niveau de la prescription et du prelevement qu'au niveau de la prise de decision.

Resume Le meprobamate, chef de file de la famille des carbamates primaires, reste encore tres utilise comme anxiolytique en France. Il est implique dans environ 5 % des surdosages par les psychotropes. Les intoxications sont graves et parfois fatales par insuffisance circulatoire aigue. Ainsi, tout laboratoire specialise dans la toxicologie d'urgence doit proposer des methodes fiables d'identification et de dosage de ce medicament dans les milieux biologiques. La chromatographie en phase gazeuse avec detection FID est aujourd'hui consideree comme la technique de reference.

Summary Tacrolimus-based immunosuppression is the most frequently prescribed immunosuppression for kidney-transplant (KT) patients. Because tacrolimus has a narrow therapeutic window, drug monitoring is mandatory. Of the many methods used to assess whole-blood trough levels, antibody-conjugated magnetic immunoassay (ACMIA) is popular because, compared with microparticle enzyme-linked immunoassays (MEIA), there is no need to pretreat samples, thus reducing time taken by the laboratory technician. Herein, we report on a KT tacrolimus-treated patient who experienced falsely elevated whole-blood tacrolimus concentrations after using the ACMIA method. ACMIA gave trough levels of 24 ng/ml, whereas the actual trough level, when measured by enzyme-multiplied immunoassay technique (EMIT) and high-performance liquid chromatography coupled with mass spectrometry (LC-MS/MS), was nil. After a workup we only found one factor that might have caused the elevated concentration: positive anti-double stranded DNA autoantibodies. We conclude that, when ACMIA produces surprisingly high tacrolimus concentrations in organ-transplant patients, these should be reassessed immediately using either LC-MS/MS or another immunoassay in order to eliminate falsely elevated results.

Polyomavirus-associated nephropathy (PVAN) affects 1-10% of kidney-transplant (KT) patients, with graft failure/loss in approximately 90% of cases. Reducing immunosuppression is the key treatment option, but addition of leflunomide may improve BK Virus (BKV) clearance and graft survival. In a prospective open-labeled study, 12 KT patients with biopsy-proven PVAN were treated with reduced immunosuppression and leflunomide. BKV viremia and graft function were followed. PVAN was diagnosed at 6 months (3-192) post-transplant; median serum creatinine concentration (sCC) was 189 micromol/l (92-265). After 16 months (8-30) of follow-up, the sCC was 150 micromol/l (90-378, NS). Renal function improved in six cases (50%), remained stable in two (16.6%) and deteriorated in four (33.4%), with graft loss in two (17%). Clearance of BKV viremia was observed in five (42%) cases. Side effects included anemia in six cases leading to leflunomide withdrawal in two patients, and mild thrombocytopenia. In KT patients diagnosed with PVAN, leflunomide plus reduced immunosuppression improved graft function in 66.6%, cleared BKV viremia in 42%, and resulted in side effects in 17%. This limited efficacy contrasts with other reports and falls short of expectation. We conclude that active screening, earlier diagnosis and intervention remain the cornerstones of treatment.

Chondroitin sulfate (CAS 24967-93-9, CS) is a natural polymer of a disaccharide consisting of glucuronic acid and N-acetyl glucosamine which is sulfated either in the 4 or 6 position. It is administered orally as a slow acting drug to treat osteoarthritis, though there is much debate about its effectiveness and its mode of action, given that macromolecules are not normally absorbed in the gastrointestinal (GI) tract. Initially using a spectro-photometric assay, the stability of CS was tested in the presence of both tissues and lumenal contents of stomach, small intestine, cecum and colon. There was no degradation by the contents of the stomach or small intestine or in any of the tissues. Degradation only took place in the contents of the colon and particularly the cecum. Using 14C-radiolabelled CS it was shown that the cecum contents degraded CS down to the component disac-charides. The 14C-radiolabelled CS was also used to investigate the transport of CS across the different parts of the GI tract in vitro. The CS was transported across the small intestine in low amounts in the intact form, probably by the mechanism of endocytosis. In the colon and the cecum, higher amounts of radioactivity were transported, but most of the radioactivity was in the form of the degradation products, the disacchar-ides. This study shows that small amounts of CS may cross the upper intestine intact, but in the distal GI tract the molecule is effectively degraded, presumably by the enzymes in the intestinal flora.

During space flights, the human body is submitted to weightlessness which induces physiological variations that could modify drug disposition during space missions. Since space experiments are infrequent and difficult to perform, in order to evaluate pharmacokinetic modifications, simulation experiments of weightlessness have to be carried out on earth, using animal-models such as the Morey-Holton model. In this model, rats are suspended by the tail with their front paws on the ground. We studied the effects of simulated weightlessness on drug absorption and on gastric emptying, using acetaminophen as a probe. Three periods of suspension (1, 2 and 5 days) were compared with two control groups (free and attached rats). The attached group was used to evaluate a possible 'stress effect' caused by the suspension device. Each group was composed of 36 rats (12 sampling times and three rats per time). An oral dose of acetaminophen (100 mg/kg) was administered and blood samples were collected before and up to 12 h after administration. Plasma assays were performed using an high-performance liquid chromatography method with UV detection. The calculated population pharmacokinetic parameters were Ka, Kel (first order absorption and elimination constants) and Vd/F (apparent volume of distribution). The statistical interpretation of the population pharmacokinetic parameters indicated that 2 days of suspension significantly decreased the Vd/F by 83% and the Ka by 125%. The increase in the Ka was probably because of an increased acceleration of the gastric emptying and/or to a decrease in the total peripheral resistance which increased intestinal blood flow.

The objective of this study was to attempt to identify patient co-variables which could influence interpatient variability in 5-fluorouracil (5-FU) clearance during a 5-day continuous venous infusion (CVI, cisplatin 100 mg/m2 day 1 then 5-FU 1 g/m2/day days 2-6). The analysis was performed using a NONMEM program according to a linear one-compartment model. A total of 186 cycles (2 samples per day, 8 a.m. and 5 p.m.) were analysed from 104 patients with various cancers (the majority of head and neck and oesophagus). The study co-variables were age, sex, body surface area, hepatic metastases, peripheral mononuclear cell dihydropyrimidine dehydrogenase activity (PMNC-DPD), liver enzymes, clock-time (8 a.m. versus 5 p.m.), elapsed time during CVI. The data showed that 5-FU clearance was significantly reduced by increased age, low PMNC-DPD, high serum alkaline phosphatase and elapsed time during infusion. These data may be useful for improving knowledge of predictive factors which can influence 5-FU exposure and thus predispose to toxic manifestations.

Objectives In pediatric patients, administration of carboplatin according to body surface area results in a large variation in the area under the plasma ultrafilterable carboplatin concentration versus time curve. A population pharmacokinetic study using the NONMEM program was undertaken to determine the effects of a variety of covariates on the clearance of ultrafilterable carboplatin. Patients Plasma carboplatin pharmacokinetics were determined in 57 children (2 months to 18 years old, with serum creatinine levels ranging from 27 to 268 μmol/L) treated for various tumor types. Results The best fit corresponded to the formula: clearance (ml/min) = 2.85 · weight · (1 − 0.00357 · serum creatinine) · (1 − 0.372 · Np) + 8.7 (with serum creatinine in micromoles per liter, weight in kilograms, and Np = 1 or 0 for unilateral nephrectomy or not, respectively). The interindividual variability in clearance, as expressed by the coefficient of variation, decreased from 74% (no covariates) to 49% by taking account of weight, and to 29% under the final regression formula. Conclusion The ability of this formula to predict carboplatin clearance in children should be evaluated prospectively and compared to a method based on the determination of the glomerular filtrationrate. Clinical Pharmacology & Therapeutics (1996) 59, 436–443; doi