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Purpose: Benzodiazepines (BZDs) and related drugs (Z-drugs) are mainly taken chronically, and older people are much more likely to take them on a chronic basis despite recommendations. Withdrawal symptoms could be an obstacle to stopping BZD/Z-drug administration. The main objective of this study is to estimate the prevalence of withdrawal symptoms in patients aged 65 years and older who have experience a stop of BZD/Z-drug. The secondary objectives are to describe the withdrawal symptoms and identify factors associated. Method: This ancillary study was based on a national observational study in patients with chronic BZD/Z-drug consumption. Patients who made at least one BZD/Z-drug stop experience were selected. Withdrawal symptoms are described, and a logistic regression was carried out to identify the variables most associated with withdrawal symptoms. Results: In total, 697 patients were selected: 78% experienced at least one withdrawal symptom after a stop administering BZDs or Z-drugs; most of the withdrawal symptoms were psychological disorders. Conclusion: Our study identifies a specific population experiencing withdrawal symptoms and who cannot stop administering BZD/Z-drug. We assume that withdrawal symptoms in patients with chronic use play an essential role in the nonstop use of BZD/Z-drugs. [ABSTRACT FROM AUTHOR]

The term 'baboon syndrome' was introduced in 1984 to describe a special form of systemic, contact-type dermatitis that occurs after ingestion or systemic absorption of a contact allergen in individuals previously sensitized by topical exposure to the same allergen in the same areas. Its clinical picture presents as an erythema of the buttocks and upper inner thighs resembling the red bottom of baboons. This reaction was originally observed with mercury, nickel, and ampicillin. In 2004, some authors proposed the acronym SDRIFE standing for 'symmetric drug-related intertriginous and flexural exanthema' specifically for cases elicited by systemically administered drugs. Since 1984, about 100 cases have been reported in the literature; for most of the concerned drugs, previous skin sensitization or possible cross-sensitization has not been shown. We report the first case of SDRIFE due to rivastigmine, with the exception of an erythematous maculopapular eruption due to rivastigmine that was previously reported. Rivastigmine is a reversible and noncompetitive acetyicholinesterase inhibitor used for the treatment of Alzheimer disease. SDRIFE is an important condition to keep in mind in order to avoid a misdiagnosis when dealing with other exanthematous disorders and to prevent re-exposure to the responsible allergen in the future. [ABSTRACT FROM AUTHOR]

Because the elderly are often treated by multiple-drug regimens, their iatrogenic risks are considerably raised. However, despite the serious side-effects that diuretic agents may have in this population, SPCs (summary of product characteristics) do not specify how often serum chemistry should be monitored. This study of long-term diuretic therapy prescription and monitoring in elderly patients was conducted by the Department of Clinical Pharmacology of the Nantes teaching hospital in collaboration with the medical department of the French national health insurance scheme. Data were extracted from the French national health insurance database. Patients were 75 years old or more and had been receiving a diuretic agent for 1 year or longer. The patients were classified into two groups: one group included those patients whose serum chemistry had been monitored at least once (electrolyte levels and/or urea and creatinine blood levels); the other group included the non-monitored patients. Mean patient age was 80 ± 4.6 (SD) years. The non-monitored patients represented 22.8% of the cohort. The at-risk patients were mainly women suffering from no severe disease, treated by a single practitioner (often a general practitioner) and/or always receiving the same type of diuretic agent. Many elderly patients receiving diuretic agents do not benefit from regular serum chemistry monitoring. The prescription of serum chemistry assays is correlated to the presence of various patient-related risk factors. Recommendations should be made to help practitioners to ensure a minimal serum chemistry monitoring in all elderly patients receiving diuretics. [ABSTRACT FROM AUTHOR]

Objective: The influence of nevirapine, efavirenz and tenofovir co-administration on ritonavir-boosted atazanavir pharmacokinetics was investigated in HIV (human immunodeficiency virus)-infected patients. Methods: A population pharmacokinetic analysis was performed in the context of therapeutic drug monitoring (87 patients, 121 samples). Results: A significant increase of atazanavir clearance (Cl/F) was found when either tenofovir (group B), efavirenz (group C), or nevirapine (group D) were co administered with atazanavir/ritonavir in comparison with patients treated with atazanavir/ritonavir and nucleoside reverse transcriptase inhibitors (group A): 6.24±0.36 1 h-1 (group A) versus 7.42±0.25 1 h-1 (group B) versus 9.60±0.27 1 h-1 (group C) versus 17.53±0.57 1 h-1 (group D) (P<0.001). However, the decrease of the mean trough plasma concentration of atazanavir was significant only in group D: 1.02±0.86 mg/l (group A) versus 0.21±013 mg/l (group D) (P<0.001). Conclusion: The increase in atazanavir clearance when it is used in combination with nevirapine, efavirenz and/or tenofovir suggests that therapeutic drug monitoring of atazanavir should be performed in such circumstances. [ABSTRACT FROM AUTHOR]

Objective: The influence of nevirapine (NVP) on lopinavir (LPV) pharmacokinetics was investigated by a population analysis based on a non-linear mixedeffect modelling method. Methods: In this analysis, 95 HIV-1 infected patients were studied [52 treated with LPV/ritonavir (400/100 mg twice a day) plus nucleoside reverse transcriptase inhibitors (group A), 22 patients treated with LPV/ritonavir (533.3/133.3 mg twice a day) plus NVP (group B) and 21 patients treated with LPV/ritonavir (400/ 100 mg twice a day) plus NVP (group C)]. Results: The apparent clearance of LPV [mean±SD: 4.56±3.94 l h-1 (group A) versus 7.14±1.77 l h-1 (group B) versus 7.74±1.45 l h-1 (group C)] was significantly (P <0.001) increased by the presence of NVP in the antiretroviral regimen and the mean trough plasma concentration of LPV was reduced in group C relative to group A [mean±SD: 2.23±1.35 mg/l versus 5.29±2.19 mg/l (P < 0.001)]. Conclusion: These results suggest an induction of LPV metabolism by NVP. [ABSTRACT FROM AUTHOR]

Objective. A prospective population pharmacokinetic study of nevirapine (NVP) was performed to test the relationship between hepatotoxicity and NVP trough plasma concentration and to identify which covariates could influence NVP pharmacokinetics. Methods. All patients [77 HIV-1 (human immunodeficiency virus type 1)-infected patients (128 samples)] were either on first-line antiretroviral therapy or switched from successful therapy containing protease inhibitor. Population pharmacokinetic parameters were estimated by a non-linear mixed-effect modelling method. Hepatotoxicity was evaluated by ASAT (aspartate aminotransferase) plasma level. Results. No correlation was found between high NVP trough plasma concentration and high ASAT level or the increase of ASAT level on NVP therapy. Age and Caucasian race were found to be significant covariates of NVP clearance (Cl/F). Population pharmacokinetic parameters (rate absorption constant=1.04 h-1; Cl/F=3.31 h-1; apparent volume of distribution=92 l) are consistent with previous studies. Conclusion. High NVP trough plasma concentrations are not correlated with hepatotoxicity in our population. NVP clearance is decreased in the elderly patients, suggesting a potential increase of NVP plasma level and the interest of therapeutic drug monitoring for this population. [ABSTRACT FROM AUTHOR]

Abstract Rationale: Strain differences in mice have been reported in response to drugs in the mouse forced swimming test (FST), even if few antidepressants were examined. Objectives: The aim of the present study was to investigate the influence of genetic factors, using five antidepressants (imipramine, desipramine, citalopram, paroxetine and bupropion) in the mouse FST, in outbred strains (Swiss, NMRI) and inbred strains (DBA/2, C57BL/6J Rj). Moreover, whole brain levels of dopamine (DA), noradrenaline (NA), serotonin (5-HT) in vehicle treated animals, which were or were not subjected to the FST, were measured by HPLC analysis in an attempt to explain behavioural differences. Methods: For each antidepressant, a dose range (1-16 mg/kg) was tested in the locomotor apparatus and only non-psychostimulant doses were then tested in the FST in order to detect antidepressant-like activity. Results: No baseline differences among Swiss, NMRI, DBA/2 and C57BL/6J Rj strains were observed in our experiments, allowing the comparison of different antidepressants in each strain. Imipramine (16 mg/kg), desipramine, citalopram (416 mg/kg) and paroxetine (8 and 16 mg/kg) treatment decreased the immobility time in the Swiss strain and the size of the effect reached more than 20% for each of these antidepressants. C57BL/6J Rj was the only strain sensitive to bupropion (2 and 4 mg/kg). In the NMRI strain, only paroxetine treatment decreased the immobility time (16 mg/kg). Conclusion: Our study showed that drug sensitivity is genotype dependent. FST results have shown that Swiss mice are the most sensitive strain to detect 5-HT and/or NA treatment. The use of DBA/2 inbred mice may be limited, as an absence of antidepressant-like response was observed in the FST. The lack of sensitivity to antidepressant treatment in DBA/2 strains could be due to high DA, NA and 5-HT whole brain concentrations. [ABSTRACT FROM AUTHOR]

Abstract Rationale: A recent study suggested that selective serotonin reuptake inhibitors were inactive in 40week-old male mice in the mouse forced swimming test, possibly because of alteration of 5-HT[sub 1] receptors. Objectives: The present study was aimed at investigating the action of various antidepressant drugs in 4- and 40-week-old male mice using the mouse forced swimming test and determining the involvement of 5-HT[sub 1A] and 5HT[sub 1B] receptors mediating the effects. Methods': Different classes of antidepressants [imipramine (tricyclic), maprotiline (noradrenline reuptake inhibitor), venlafaxine (mixed serotonin and noradrenaline reuptake inhibitors), fluvoxamine and sertraline (selective serotonin reuptake inhibitor)] were tested in the same randomised experimental session, alone and in combination with 5-HT[sub 1A] and 5-HT[sub 1B] receptor agonists [buspirone (partial 5-HT[sub 1A] agonist), anpirtoline (5-HT1B agonist)] in the mouse forced swimming test. Results: All antidepressants were found to be active in the mouse forced swimming test in 4-week-old mice and 40-week-old mice, with the exception of fluvoxamine in the 40-week-old mice. The antiimmobility effect after antidepressant administration was higher in 4-week-old male mice than in 40-week-old male mice. Venlafaxine is the most active antidepressant drug in 40-week-old mice. Prior administration of buspitone (0.06 mg/kg, IP) or anpirtoline (1 mg/kg, IP) enhanced the antidepressant-like effects in 4-week-old mice (except in the case of sertraline, 8 mg/kg). In elderly mice, only prior administration of buspirone enhanced the antidepressant-like effects of fluvoxamine. A neurochemical study showed that significantly higher serotonin and... [ABSTRACT FROM AUTHOR]

Purpose. The objective of this work was to assess the influence of binding to plasma proteins and to serum on the brain extraction of four antiinflammatory oxicams. Methods. The brain extraction of isoxicam, tenoxicam, meloxicam and piroxicam was investigated in rats using the carotid injection technique. Blood protein binding parameters were determined by equilibrium dialysis using human serum, human serum albumin (HSA) and alpha-1-acid glycoprotein (AAG) solutions at various concentrations. Results. All oxicams had low values of brain extraction, between 19% and 39% when dissolved in serum, i.e. under physiological conditions. Brain efflux rate constants calculated from the wash-out curves were the same in the absence or presence of serum. Brain efflux was inversely related to the polarity of the oxicams, such that the higher their H-bonding capacity, the lower their brain efflux. The free dialyzable drug fraction was inversely related to protein concentration. However, rat brain extraction was always higher than expected from in vitro measurements of the dialyzable fraction. Conclusions. Except for piroxicam whose brain extraction was partially decreased in the presence of proteins, the serum unbound and initially bound fractions of oxicams both seem available for transfer into the brain. Modest affinities for AAG rule out any related effect. More surprising is the apparent lack of effect on brain transfer of the high-affinity binding to HSA and serum. The enhanced brain uptake of meloxicam in the presence of AAG could be a result of interactions between this globular protein and the endothelial wall. [ABSTRACT FROM AUTHOR]

Purpose. The binding interactions of binedaline, nicardipine and darodipine with lipoproteins (HDL, LDL, VLDL) were examined as a function of pH in order to evaluate the role of lipoprotein components and ligand protonation in the binding process. Methods. Binding studies were performed by equilibrium dialysis with radiolabeled ligands and differential UV-visible spectroscopy. Results. Deprotonated ligands had a markedly higher affinity for lipoproteins than the protonated forms, resulting in a concomitant decrease in the pKa of bound ligands, i.e., a decrease in the basicity of the ligand in the bound state. The UV-visible difference spectra generated upon binding of auramine O to lipoproteins also showed that there was a contribution to the binding arising from the deprotonation of the ligand. Ligand binding was related to the phospholipid and cholesteryl ester content and to a lesser degree to the free cholesterol and protein content of lipoproteins, therefore to the surface monolayer components of lipoproteins. This relationship was even more accurate for the deprotonated, high-affinity, than for the protonated species. Conclusions. It is suggested that among other possible interactions, ligand binding to lipoproteins involves proton exchange between the reactants and that the high affinity ligand species interact more specifically with the phospholipids of the lipoprotein surface monolayer. [ABSTRACT FROM AUTHOR]