Population pharmacokinetics of imipenem in burn patients

The interindividual variability of imipenem pharmacokinetic parameters in burn patients suggest that these parameters have to be estimated with a large number of patients. The aim of this study is (i) to estimate these parameters with a population pharmacokinetic approach, and (ii) to test the influence of factors on pharmacokinetics parameters. Data are provided by therapeutic drug monitoring (n = 47,118 samples) and analysed by a nonlinear mixed effect modelling method. Among the tested covariates (age, gender, body weight, height, size of burn and creatinine plasma level) creatinine plasma level affects imipenem pharmacokinetic parameters substantially. The best fit is obtained with a two-compartment model integrating a linear-inverse relationship between imipenem clearance and creatinine plasma level. The estimates of imipenem clearance (16.37 +/- 0.204 L/h) and of the distribution volume of the central compartment (0.376 +/- 0.039 L/kg) are higher in the population of burn patients than the estimates in healthy subjects. This result is connected with high values of glomerule filtration rate and confirms the interest of therapeutic drug monitoring of imipenem in burn patients and particularly for patients with extreme values of creatinine clearance.     

Effects of creatine on body composition and strength gains after 4 weeks of resistance training in previously nonresistance-trained humans

This study examined the effects of Cr supplementation on muscle strength in conjunction with resistance training in nonresistance-trained males utilizing strategies previously reported in the literature to help optimize muscle CR uptake. Nineteen nonresistance-trained males underwent 4 weeks of resistance training (3 days x week(-1)) while assigned to Cr (20 g x d(-1) Cr + 140 g x d(-1) glucose) for 7 days (loading), followed by 5 g x d(-1) Cr + 35 g x d(-1) glucose for 21 days (maintenance; n = 9) or placebo (160 g x d(-1) glucose [loading] followed by 40 g x d(-1) [maintenance; n = 10]). In subjects classified as "responders" to Cr on the basis of body mass changes (n = 7), the magnitude of change in 180 degrees x s(-1) isokinetic (p = .029) and isometric (p = .036) force was greater compared to the placebo group. A positive correlation was found between changes in body mass and 180 degrees x s(-1) isokinetic (loading: r = 0.68, p = .04; maintenance: r = 0.70, p = .037) and isometric (loading: r = 0.82, p < .01) force. Estimated Cr uptake was also positively correlated with changes in isometric force (r = 0.71, p = .033). These results indicate that Cr supplementation can increase muscle strength (allied with 4 weeks of strength training) but only in subjects whose estimated Cr uptake and body mass are significantly increased; the greater the Cr uptake and associated body mass changes, the greater the performance gains.     

A follow-up study of a population of schizophrenic patients treated with clozapine

1. Clozapine is a dibenzodiazepine neuroleptic which presents the advantage of not having undesirable neurological side-effects. Its efficacy for the treatment of the symptoms of schizophrenia is known, but the use of clozapine is limited to treatment-resistant schizophrenic patients as it induces agranulocytosis with a higher incidence than that of other neuroleptic drugs.

2. The present study was designed in order to evaluate the benefit/risk of chronic treatment. The analysis was performed using the files of schizophrenic patients. These patients were not stabilized by a classical neuroleptic treatment and/or presented individual secondary effects.

3. Clozapine induced neutropenia and 1 case of agranulocytosis in 3 females. Analysis of leukocyte expression highlighted some premonitory symptoms in patients who presented neutropenia. The observation of 2 to 3 early successive peaks in leukocyte expression (between the third and tenth week of treatment) could be predictive of neutropenia in the 3 to 4 months of treatment.

4. The patients who presented a lower leukocyte base-line following a peak had a higher risk, of developing neutropenia. This might explain some late accidents beyond the first six months of treatment.

5. The present study confirmed the advantages of clozapine treatment and demonstrated that the risk of neutropenia may be diminished by the detection of premonitory symptoms and the early monitoring of patients at risk i.e. female patients and subjects with a lower leukocyte base-line.

Evidence of zolpidem abuse and dependence: results of the French Centre for Evaluation and Information on Pharmacodependence (CEIP) network survey

AIM: To show that the nonbenzodiazepine hypnotic zolpidem has a higher abuse potential than previously documented. METHOD: An official enquiry was carried out by the Nantes Centre for Evaluation and Information on Pharmacodependence (CEIP). The authors made a review of literature and analysed French data corresponding to the drug's postmarketing period collected by the CEIP network from 1993 to 2002. RESULTS: The literature review yielded mixed results concerning the behavioural effects of zolpidem. Data from the CEIP and the 53 literature case reports highlight significant dependence and abuse potential of zolpidem. CONCLUSIONS: This study adds to the growing evidence that zolpidem has the potential for abuse and dependence. As a consequence, the French drug monograph has been modified by the French Health Authorities.     

Comparison between a liquid chromatography-tandem mass spectrometry assay and a fluorescent polarization immunoassay to measure whole blood everolimus concentration in heart and renal transplantations

Various methods [fluorescent polarization immunoassay (FPIA) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay] are used for therapeutic drug monitoring of everolimus. The aim of this study is to compare these assays in renal and heart transplantation. The correlation between results was investigated by linear regression in 44 patients (24 heart recipients and 20 renal recipients--137 samples). The comparison between assays was performed by a paired t-test. A highly significant correlation was found between FPIA and LC-MS/MS in heart and renal recipients [FPIA=0.851 x LC-MS/MS+1.773r(2)=0.8738 (P<0.001)]. Paired t-tests did not show a significant difference between everolimus whole blood concentrations in the populations of heart and renal recipients or heart recipients or renal recipients. FPIA and LC-MS/MS assays gave consistent overall results although some significant differences were observed in some samples between these methods indicating that FPIA assay has limitations that deserve further investigations.     

Effect of noradrenergic system on the anxiolytic-like effect of DOI (5-HT2A/2C agonists) in the four-plate test

Rationale Selective serotonin reuptake inhibitors and serotonin and noradrenaline reuptake inhibitors demonstrated an anxiolytic-like effect in the four-plate test (FPT). (+/−)-1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane (DOI; a 5-HT_2A receptor agonist) also possessed strong anxiolytic-like effect in the same test. A 5-HT_2A mechanism seems to be implicated in the mechanism of action of both antidepressants and DOI in this test. On the other hand, the α-adrenergic ligands have also demonstrated an activity in other models of anxiety. A previous study demonstrated that the α₂-adrenoceptor agonists abolished the anxiolytic-like effect of antidepressants. Objectives The aim of the present study was to evaluate the role of noradrenergic system on the regulation of 5-HT₂ receptors implicated in the DOI anxiolytic-like activity in the FPT. Methods First, the effect of noradrenergic and serotonergic lesions on DOI anxiolytic-like activity was studied in the FPT. Second, the effect of co-administration of α-adrenoceptor ligands and DOI was evaluated in the same test. Results The noradrenergic and serotonergic lesions had no effect on DOI (1 mg/kg) anti-punishment activity in the FPT. Adrafinil 0.25 and 4 mg/kg (an α₁-adrenoceptor agonist), prazosin 0.5 and 2 mg/kg (an α₁-adrenoceptor antagonist) and idazoxan 1 and 4 mg/kg (an α₂-adrenoceptor antagonist) did not modify the activity of DOI. Clonidine 0.06 mg/kg, guanabenz 0.125 and 0.5 mg/kg (two α₂-adrenoceptor agonists) and guanfacine 0.06 and 0.125 mg/kg (a specific α_2A-adrenoceptor agonist) completely abolished DOI-induced increase in punished passages. Conclusion These results indicate that the DOI seems to act on the 5-HT₂ receptors post-synaptically located. The effect of DOI is regulated by the α₂-adrenoceptors.     

Level of evidence for therapeutic drug monitoring of voriconazole

Voriconazole is a major antifungal drug with activity against endemic fungi, Candida and Aspergillus species in immunocompromised patients. Voriconazole has a good bioavailability, an high protein binding percentage in plasma and is metabolized in liver via CYP2C19. It presents important neuro- and hepatotoxicities. Some studies determined trough concentrations of voriconazole in plasma using liquid chromatography coupled with UV or tandem mass detection. These studies showed a relationship between trough concentrations of voriconazole and efficacy or toxicity. Indeed, some studies reported a relationship between a lack of clinical response and concentrations below 1 or 2 μg/mL according to the localization of infection, while toxicities are frequently observed at concentrations above 5 μg/mL. Some particular populations will have to be taken into account such as children, patients with hemodialysis-dependent renal deficiency or hepatic insufficiency, cystic fibrosis patients or those treated concomitantly with interfering drugs. According to our survey, therapeutic drug monitoring of voriconazole appears recommended. However, controlled studies are still necessary to validate it prospectively and to evaluate pharmacokinetically-based methods proposed for individual dose adjustment.     

Specificity and efficacy of noradrenaline, serotonin depletion in discrete brain areas of Swiss mice by neurotoxins

The aim of this work is to define neurotoxins doses to have efficient and specific depletion of noradrenaline (NA), serotonin (5-HT) neurotransmission in cortex, striatum, hippocampus and hypothalamus of Swiss mice after intraperitoneal administration of, respectively, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4) and para-chlorophenylalanine methyl ester hydrochloride (PCPA). The neurotransmitters concentrations were determined by high performance liquid chromatography with amperometric detection. The minimal single dose necessary to produce a highly significant decrease of NA levels (p<0.01 in comparison with control group) in hypothalamus (-44%), hippocampus (-91%), striatum (-40%) and cortex (-68%) was 50mg/kg but DA and 5-HT levels were modified, respectively, in hypothalamus and striatum. Three doses of PCPA 300 mg/kg over 3 consecutive days involve a profound depletion of 5-HT transmission in all discrete brain areas but NA and DA levels were also significantly reduced. In conclusion, DSP-4 has a different efficacy in discrete brain areas with a noradrenergic specificity which is not absolute, PCPA has a similar efficacy in all brain areas but is unspecific of 5-HT transmission.