Sylvie Saivin

Clinical Pharmacokinetics of Acamprosate

Acamprosate is a new psychotropic drug used in the treatment of alcohol (ethanol)-dependence. Recent studies suggest that acamprosate inhibits neuronal hyperexcitability by antagonising excitatory amino acids. It is available as a 333mg enteric-coated tablet, with a recommended dosage of 1.3 g/day for patients with a bodyweight <60kg and 2 g/day for patients with a bodyweight ≥60kg. Treatment with higher dose strength tablets 2 × 500mg twice daily is bioequivalent to treatment with the 2 × 333mg 3 times daily dosage regimen.Acamprosate is absorbed via the paracellular route in the gastrointestinal tract. Absorption is rapid but limited after oral administration. At steady-state, acamprosate has a moderate distribution volume of about 20L. Acamprosate is not protein bound or metabolised. Half of the elimination of acamprosate occurs as unchanged acetyl-homotaurine in urine, the other half might be eliminated by biliary excretion.The administration of the enteric-coated tablets showed a flip-flop mechanism with a terminal elimination half-life 10-fold higher than the 3-hour half-life reported after intravenous infusion. During repeated oral administration of 666mg 3 times daily, steady-state is reached after 5 to 7 days and leads to plasma concentrations ranging from 370 to 650 μg/L. The pharmacokinetics of acamprosate administered as an enteric-coated tablets are timesand dose-independent, and its accumulation ratio is about 2.4 at steady-state.Acamprosate disposition does not differ between males and females. The pharmacokinetics of acamprosate are not modified in patients with hepatic insufficiency or chronic alcoholism. In contrast, renal insufficiency influences the elimination of acamprosate and it is, therefore, contraindicated under such circumstances.Interaction studies have confirmed that when acamprosate is concomitantly administered with food, the amount absorbed is decreased. When combined with diazepam, disulfiram or alcohol, the pharmacokinetic disposition of acamprosate is not modified. Acamprosate does not influence the kinetics of diazepam, alcohol or imipramine and its metabolite desipramine.

Microdialysis probes calibration: Gradient and tissue dependent changes in No Net Flux and reverse dialysis methods

Probe calibrations are required for accurate estimations of extracellular concentrations in microdialysis experiments. Several methods have been developed and validated for in vivo determination of dialysis membrane recovery such as the perfusion rate method and the No Net Flux method. In this study, the No Net Flux and the reverse dialysis methods were investigated. Both measure the net transport of drug across the dialysis membrane. The recovery was defined as R = (Cin - Cout)/Cin, where Cin and Cout were the concentrations of a compound in the perfusate and in the dialysate, respectively. First, the accuracy of the No Net Flux method to estimate in vivo recovery was compared in two situations: diffusion from the probe into the dialysis medium and diffusion from the outer medium into the probe. The point of no net transport was used to estimate the concentration surrounding the probe. Neither difference between extracellular concentrations (intercept values) nor difference between recoveries were observed. Then the reverse dialysis method was tested to estimate the relative loss of drug from the perfusate when the probe was placed in a drug-free medium. Finally comparisons of the behavior of the drug diffusion across the membrane under increasing gradient conditions have shown an asymptotic profile, specific of the tissue; blood, muscle, and adipose tissue. The faster a drug was removed by microvascular transport (blood > muscle > adipocytes), the higher was the recovery, until the perfusate concentration reached a threshold value where the transport process became gradient limited and no more tissue limited.(ABSTRACT TRUNCATED AT 250 WORDS)

Risk of emergence of Pseudomonas aeruginosa resistance to β-lactam antibiotics in intensive care units

Objective:The emergence of Pseudomonas aeruginosa resistance to antimicrobial drugs is frequent in intensive care units and may be correlated with the use of some specific drugs. The purpose of our study was to identify a relationship between the use of various β-lactam antibiotics and the emergence of resistance and to characterize the mechanism of resistance involved. Design:We conducted an open prospective study over a 3-yr period by including all patients in whom P. aeruginosa had been isolated from one or more specimens: bronchial aspiration, blood cultures, catheters, and urinary cultures. Setting:General intensive care unit. Patients:One hundred and thirty-two intensive care unit patients. Interventions:The antibiotics studied were amoxiclav, piperacillin-tazobactam, cefotaxime, ceftazidime, cefepim, and imipenem. The mechanisms of resistance studied were production of penicillinase or cephalosporinase, nonenzymatic mechanisms, and loss of porin OprD2. Analysis was performed using Cox proportional-hazard regression with time-dependant variables. Measurements and Main Results:Forty-two strains became resistant, 30 to one antibiotic, nine to two, and three to three, leading to the study of 57 resistant strains. Imipenem (hazard ratio 7.8; 95% confidence interval, 3.4–18.1), piperacillin-tazobactam (hazard ratio 3.9; 95% confidence interval, 1.3–11.9), and cefotaxim (hazard ratio 9.3; 95% confidence interval, 2.9–30.2) were strongly linked to the emergence of resistance. The use of imipenem (p < .0001) was associated with the loss of porin OprD2. Thirty-six strains from nine patients, assayed by pulsed-field gel electrophoresis, showed that for any one patient, all the strains were genetically related. Conclusions:Our results show that there is a high risk of the emergence of drug resistance during treatment with cefotaxime, imipenem, and piperacillin-tazobactam. This has to be taken into account in the therapeutic choice and in the patient’s surveillance.

Increased creatinine clearance in polytrauma patients with normal serum creatinine: a retrospective observational study.

IntroductionThe aim of this study, performed in an intensive care unit (ICU) population with a normal serum creatinine, was to estimate urinary creatinine clearance (CLCR) in a population of polytrauma patients (PT) through a comparison with a population of non trauma patients (NPT).MethodsThis was a retrospective, observational study in a medical and surgical ICU in a university hospital. A total of 284 patients were consecutively included. Two different groups were studied: PT (n = 144) and NPT (n = 140). Within the second week after admission to the ICU, renal function was assessed using serum creatinine, 24 h urinary CLCR .ResultsAmong the 106 patients with a CLCR above 120 mL minute-1 1.73 m-2, 79 were PT and 27 NPT (P < 0.0001). Only 63 patients had a CLCR below 60 mL minute-1 1.73 m-2 with 15 PT and 48 NPT (P < 0.0001). Patients with CLCR greater than 120 mL minute-1. 1.73 m -2 were younger, had a lower SAPS II score and a higher male ratio as compared to those having CLCR lower than 120 mL minute-1. 1.73 m -2. Through a logistic regression analysis, age and trauma were the only factors independently correlated to CLCR.ConclusionsIn ICU patients with normal serum creatinine, CLCR, is higher in PT than in NPT. The measure of CLCR should be proposed as routine for PT patients in order to adjust dose regimen, especially for drugs with renal elimination.

Influence of Simulated Weightlessness on the Oral Pharmacokinetics of Acetaminophen as a Gastric Emptying Probe in Man: A Plasma and a Saliva Study

This study evaluated the effect of simulated weightlessness on gastric emptying, using acetaminophen as a probe and −6° 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‐∞, AUC0‐t, and t1/2 were calculated for plasma and saliva. The plasma Cmax showed a significant increase (10.43 μg/mL [day 1] to 14.74 μg/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.

Use of multiple sources and capture–recapture method to estimate the frequency of hospitalizations related to drug abuse

Addictive behaviours are often associated with hidden characteristics that are difficult to detect by usual approaches. This study aimed to estimate the incidence of serious drug‐related complications by using the capture–recapture method in defined geographical area.

Blood Concentrations of Hydroxychloroquine and Its Desethyl Derivative Correlate Negatively with the Percentage of CD45RO+ Cells among CD4+ Lymphocytes in Hydroxychloroquine-Treated Lupus Patients

Abstract:  The objective of the study was to investigate the influence of the blood concentrations of hydroxychloroquine ([HCQ]) and its derivative desethylhydroxychloroquine ([DHCQ]) on lymphocyte activation or differentiation in HCQ‐treated lupus patients. We studied the correlations between [HCQ], [DHCQ], and the frequency of various lymphocyte subsets in 58 HCQ‐treated lupus patients (mean HCQ dose: 4.93 ± 1.58 mg/kg/day; mean duration of the disease: 122 ± 64 months). [HCQ] and [DHCQ] were determined by high‐performance liquid chromatography (HPLC). Lymphocyte markers were studied by flow cytometry using monoclonal anti‐CD3, ‐CD4, ‐CD8, ‐CD25, ‐DR, ‐CD45RA,‐CD45RO, ‐CD19, ‐CD38, and ‐CD86 antibodies. sIL2‐R serum concentrations were measured by enzyme‐linked immunosorbent assay (ELISA). [HCQ] and [DHCQ] were 599.9 ng/mL (median: 529.5; range: 55–1935) and 353.43 (median: 286 ng/mL; range: 118–1090). In a multiple regression analysis, [HCQ] and [DHCQ] were associated with the HCQ prescribed dose in mg/kg/day (P= 0.0002 and P= 0.03) and with compliance to the treatment (P= 0.004 and P= 0.03). We found a negative correlation between [HCQ], [DHCQ], and the CD45RO+ cell frequency among CD3+CD4+ cells (P= 0.03 and P= 0.007, respectively). Other lymphocyte subset markers (LSMs) and sIL2‐R concentrations were not significantly associated with [HCQ] or [DHCQ]. In the multiple regression analysis, CD45RO+ expression was negatively influenced by [HCQ] (P= 0.005), and positively influenced by smoking habits (P= 0.005) and age (P= 0.005). Similar results were found in the multivariate model including [DHCQ]. Disease activity and taking more than 10 mg/day of corticosteroids or an immunosuppressive drug did not influence CD45RO+ expression. Lupus patients had less CD3+CD4+CD45RO+ cells than controls (P= 0.03). In lupus patients, HCQ and DHCQ may alter the generation or the blood circulation of CD4+CD45RO+ lymphocytes in a concentration‐dependent pattern.

The pharmacodynamics of tinzaparin in healthy volunteers

Summary. We report the pharmacodynamic properties of tinzaparin (175 U/kg antifactor Xa) given as a single daily administration for 5 consecutive days to 14 healthy volunteers as a known safe, effective treatment of deep vein thrombosis and pulmonary embolism. The Cmax for antifactor Xa (0·87 ± 0·15 U/ml) was associated with a 2·4 ± 0·5‐fold prolongation of the activated partial thromboplastin time (APTT) and a high antithrombin activity (0·38 ± 0·1 U/ml). The Cmax value of antifactor Xa was 1·5‐ and twofold lower than those generated by similar doses of nadroparin and enoxaparin respectively. The clearance of antifactor Xa activity (1·29 ± 0·2 l/h) was 1·5‐ and twofold greater than those reported for nadroparin and enoxaparin respectively. These results indicated that the antithrombotic and prohaemorrhagic effects of a low molecular weight heparin were independent from the absolute levels of antifactor Xa activities and from the prolongation of the APTT.

Influence of simulated weightlessness on the pharmacokinetics of acetaminophen administered by the oral route: a study in the rat

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 influence of weightlessness on pharmacokinetics.

The primary hostile factor during a spaceflight is the lack of gravity, which can induce space motion sickness and act on bones, muscles and the cardiovascular system. These physiological effects may modify the pharmacokinetics of the drugs administered during the flight producing reduced pharmacological activity or appearance of adverse effects. Given the small number of spaceflights and the difficulties of conducting experiments during missions, pharmacokinetic data obtained in flight are insufficient to determine if drug monitoring is necessary for the drugs present in the onboard medical kit. Therefore, validated earthbound models like tail‐suspension performed with animals and long‐term bedrest performed with human volunteers are used to simulate weightlessness and to study the pharmacokinetic variations of either absorption, distribution, or elimination of drugs. As a result of these studies, it is possible to make some dosing recommendations but more information is necessary to predict with precision all of the pharmacokinetic variations occurring in spaceflight. To collect more pharmacokinetic information, head‐down bedrest studies are still the best solution and as saliva is an appropriate substitution for plasma for some drugs, salivary sampling can be planned during flights.