Voriconazole Therapeutic Drug Monitoring in Patients with Invasive Mycoses Improves Efficacy and Safety Outcomes

Background. Voriconazole is the therapy of choice for aspergillosis and a new treatment option for candidiasis. Liver disease, age, genetic polymorphism of the cytochrome CYP2C19, and comedications influence voriconazole metabolism. Large variations in voriconazole pharmacokinetics may be associated with decreased efficacy or with toxicity. Methods. This study was conducted to assess the utility of measuring voriconazole blood levels with individualized dose adjustments. Results. A total of 181 measurements with high-pressure liquid chromatography were performed during 2388 treatment days in 52 patients. A large variability in voriconazole trough blood levels was observed, ranging from ⩽1 mg/L (the minimum inhibitory concentration at which, for most fungal pathogens, 90% of isolates are susceptible) in 25% of cases to >5.5 mg/L (a level possibly associated with toxicity) in 31% of cases. Lack of response to therapy was more frequent in patients with voriconazole levels ⩽1 mg/L (6 [46%] of 13 patients, including 5 patients with aspergillosis, 4 of whom were treated orally with a median dosage of 6 mg/kg per day) than in those with voriconazole levels >1 mg/L (15 [12%] of 39 patients; P=.02). Blood levels >1 mg/L were reached after increasing the voriconazole dosage, with complete resolution of infection in all 6 cases. Among 16 patients with voriconazole trough blood levels >5.5 mg/L, 5 patients (31%) presented with an encephalopathy, including 4 patients who were treated intravenously with a median voriconazole dosage of 8 mg/kg per day, whereas none of the patients with levels ⩽5.5 mg/L presented with neurological toxicity (P=.002). Comedication with omeprazole possibly contributed to voriconazole accumulation in 4 patients. In all cases, discontinuation of therapy resulted in prompt and complete neurological recovery. Conclusions. Voriconazole therapeutic drug monitoring improves the efficacy and safety of therapy in severely ill patients with invasive mycose

Challenging Recommended Oral and Intravenous Voriconazole Doses for Improved Efficacy and Safety: Population Pharmacokinetics-Based Analysis of Adult Patients With Invasive Fungal Infections

This population-pharmacokinetics analysis involving adult patients with invasive fungal infections challenges recommended voriconazole dosing regimens. Higher oral than intravenous doses, followed by individualized adjustments based on therapeutic drug monitoring, are needed to improve achievement of the therapeutic target for maximizing response by minimizing neurotoxicit

NPY Y1 receptor is not involved in the hemodynamic response to an acute cold pressor test in mice

The vasoconstrictor neuropeptide Y (NPY) has been shown to down-regulate tyrosine hydroxylase expression in cultured adrenal chromaffin cells, which probably accounts for the higher plasma resting norepinephrine (NE) and epinephrine (E) concentrations observed in Y1 knock-out mice (Y1-/-) than in wild-type mice (Y1+/+). The aim of this work was to study the hemodynamic response of Y1-/- mice to an acute stimulation of the sympathetic nervous system (cold pressor test, CPT). Plasma catecholamine concentrations were higher in Y1-/- mice than in wild-type animals at the end of the CPT. The CPT-induced increase in mean arterial blood pressure (MAP) and heart rate (HR) was similar in both genotypes. Independently of the genotype, females had significantly slower HR than males throughout the 15 min duration of the CPT. There was no difference in the sensitivity of the baroreceptor reflex, as reflected by the change in HR divided by the concurrent change in MBP between Y1-/- and Y1+/+ mice. In conclusion, mice lacking the Y1 receptor can maintain normal hemodynamic response to an acute activation of the sympathetic system, albeit at the expense of increased catecholamine discharge.http://www.sciencedirect.com/science/article/B6T0M-4MT54Y4-3/1/f346666c9ec021eeffb80529f17474d

Cascaded PID controller for anaesthesia delivery

The technologies for continuous measurement of the anaesthetic agents circulating in body fluids are not mature yet, though some preliminary prototypes exist already. We present a control algorithm that based on the real measurement of propofol plasma concentration may adjust the delivery rate. This opens a possibility for a safer anesthesia when the technologies for online measurement of drug concentration will be mature enough to be combined with our model

Additifs alimentaires et troubles de l’attention/hyperactivité chez l’enfant

La conservation des aliments a toujours été une préoccupation capitale des sociétés humaines (et même animales!). Le sel ou le sucre en hautes concentrations, la fumée, le chauffage, la réfrigération, la congélation illustrent quelques unes des techniques utilisées dans l’histoire. Au XIXème siècle, l’industrialisation de l’alimentation, les progrès de la chimie et les nouvelles connaissances en microbiologie conduisent progressivement à l’utilisation d’additifs alimentaires chimiquement identifiés, destinés notamment à prévenir les dégradations microbiologiques des aliments, mais aussi à en moduler de nombreux aspects, la couleur en particulier. Une opposition critique à l’usage de ces additifs, notamment les colorants et les agents conservateurs, s’est d’emblée manifestée, mais n’a pas empêché la généralisation de leur usage au cours du siècle passé. Cependant, des études récentes ont remis en cause l’innocuité de certains de ces additifs, en relation notamment avec le syndrome de troubles déficitaires de l’attention/hyperactivité (TDA/H). Ces nouvelles données font l’objet d’une brève revue dans les paragraphes qui suivent

Hospitalisations pour effet indésirable médicamenteux: recensement prospectif dans un Service d'urgences médicales.

[Table des matières] I. Mise en perspective et méthodologie. II. Données démographiques : intoxications volontaires: descriptif succinct. III. Effets indésirables, descriptifs. 1. Médicaments. 2. Effets indésirables. 3. Imputabilité. 4. Gravité. 5. Evitabilité. 6. Responsabilité de l'évitabilité. 7. Destination des patients à la sortie de l'hôpital. 8. Caractéristiques des patients. 9. Durée de séjour et coûts. 10. Durée d'hospitalisation. 11. Jours d'hospitalisation imputables et évitables. 12. Coût des hospitalisations. IV. Associations. 1. Effets indésirables et médicaments incriminés. 2. Nombre de médicaments consommés. 3. Profil clinique des patients. V. Validation

The bioavailability of bromazepam, omeprazole and paracetamol given by nasogastric feeding tube

Aims: To characterize and compare the pharmacokinetic profiles of bromazepam, omeprazole and paracetamol when administered by the oral and nasogastric routes to the same healthy cohort of volunteers. Methods: In a prospective, monocentric, randomized crossover study, eight healthy volunteers received the three drugs by the oral (OR) and nasogastric routes (NT). Sequential plasma samples were analyzed by high-performance liquid chromatography-UV, pharmacokinetic parameters (Cmax, $${\text{AUC}}_{0 - \infty }$$ , t½, ke, tmax) were compared statistically, and Cmax, $${\text{AUC}}_{0 - \infty }$$ and tmax were analyzed for bioequivalence. Results: A statistically significant difference was seen in the $${\text{AUC}}_{0 - \infty }$$ of bromazepam, with nasogastric administration decreasing availability by about 25%: AUCOR = 2501 ng mL−1 h; AUCNT = 1855ng mL−1 h (p  0.05); ratio (geometric mean) = 1.01 (90% CI 0.64-1.61). An extended study with a larger number of subjects may possibly provide clearer answers. The narrow 90% confidence limits of paracetamol indicate bioequivalence: AUCOR = 37μg mL−1 h; AUCNT = 41μg mL−1 h(p > 0.05); ratio (geometric mean) = 1.12 (90% CI 0.98-1.28). Conclusion: The results of this study show that the nasogastric route of administration does not appear to cause marked, clinically unsuitable alterations in the bioavailability of the tested drug