Evaluation of voriconazole anti-Acanthamoeba polyphaga in vitro activity, rat cornea penetration and efficacy against experimental rat Acanthamoeba keratitis

International audienceBackground: Acanthamoeba keratitis (AK) is a sight-threatening infectious disease. Its effective and safe medical therapy remains highly debated. Recently, voriconazole, a monotriazole with noted in vitro activity against a large variety of fungi, has been successfully used both topically and systemically to treat human AK cases.Objectives: To measure anti-Acanthamoeba polyphaga in vitro activity, anti-rat AK efficiency and rat cornea penetration of eye-drop and oral voriconazole.Methods: A. polyphaga was maintained in axenic cultures. In vitro, amoebicidal and cysticidal activities of voriconazole were measured using an XTT assay. AK lesions of Sprague Dawley rats were scored from grade 0 to grade 3. For 21 days, from day 7 post-infection, voriconazole (1% solution) eye drops were instilled or voriconazole was administered by gavage (60 mg/kg/day). After killing, superficial corneal epithelium scrapings were cultured and analysed by PCR, and eye-globe histology was performed. Cornea and plasma concentrations were determined using 2D HPLC separation and tandem MS.Results: In vitro, voriconazole inhibited trophozoite proliferation with an IC50 value of 0.02 mg/L and an IC90 value of 2.86 mg/L; no cysticidal effect was found. In AK rats, eye drops reduced clinical worsening from day 7 to day 14 post-infection and oral voriconazole was not effective. Voriconazole cornea concentrations were directly dependent on the frequency of eye-drop instillations, which resulted in lower plasma concentrations, whilst oral voriconazole resulted in lower cornea concentrations.Conclusions: Present data underline the need for high-frequency eye-drop instillation regimens for efficient AK therapy

Beneficial Effects of Remifentanil Against Excitotoxic Brain Damage in Newborn Mice

Background: Remifentanil, a synthetic opioid used for analgesia during cesarean sections, has been shown in ex vivo experiments to exert anti-apoptotic activity on immature mice brains. The present study aimed to characterize the impact of remifentanil on brain lesions using an in vivo model of excitotoxic neonatal brain injury.Methods: Postnatal day 2 (P2) mice received three intraperitoneal injections of remifentanil (500 ng/g over a 10-min period) or saline just before an intracortical injection of ibotenate (10 μg). Cerebral reactive oxygen species (ROS) production, cell death, in situ labeling of cortical caspase activity, astrogliosis, inflammation mediators, and lesion size were determined at various time points after ibotenate injection. Finally, behavioral tests were performed until P18.Results: In the injured neonatal brain, remifentanil significantly decreased ROS production, cortical caspase activity, DNA fragmentation, interleukin-1β levels, and reactive astrogliosis. At P7, the sizes of the ibotenate-induced lesions were significantly reduced by remifentanil treatment. Performance on negative geotaxis (P6-8) and grasping reflex (P10-12) tests was improved in the remifentanil group. At P18, a sex specificity was noticed; remifentanil-treated females spent more time in the open field center than did the controls, suggesting less anxiety in young female mice.Conclusions:In vivo exposure to remifentanil exerts a beneficial effect against excitotoxicity on the developing mouse brain, which is associated with a reduction in the size of ibotenate-induced brain lesion as well as prevention of some behavioral deficits in young mice. The long-term effect of neonatal exposure to remifentanil should be investigated

Étude sur le bon usage et le suivi thérapeutique pharmacologique du voriconazole dans deux établissements de santé de Rouen

L'incidence des infections fongiques invasives a significativement augmenté au cours des vingt dernières années. Le voriconazole est un antifongique à large spectre utilisé dans le fraitement de première intention des aspergilloses invasives et il représente aussi une nouvelle alternative pour les candidoses systémiques. Le but de notre étude était d'évaluer le bon usage et le suivi thérapeutique pharmacologique du voriconazole. Les patients recrutés de juin 2010 à Mai 2012 avaient eu au moins un dosage de voriconazole lors de leur hospitalisation au sein du CHU de Rouen ou du centre anticancéreux H. Becquerel. Les critères retenus étaient la pathologie sous-jacente, le champignon isolé et sa CMI, la voie d'administration, la posologie, la valeur des dosages du voriconazole, la survenue d'effets indésirables et l'existence d'interactions médicamenteuses. Notre étude a porté sur 98 patients. Les indications de traitement par voriconazole étaient conformes à l'AMM dans seulement 35 % des cas. Chez les adultes, les posologies suivaient globalement les iecommandations, au contraire, les enfants recevaient des doses systématiquement inférieures à celles préconisées. Seule la moitié des patients a présenté des concentrations de voriconazole dans l'intervalle thérapeutique lors du premier dosage. Ceci est d'autant plus frappant chez les patients atteints de mucovisidose qui présentaient majoritairement des dosages inférieurs au seuil d'efficacité. Le délai de rendu du dosage de voriconazole était inférieur à 24 heures dans 81 % des cas. Seuls 24 % des patients ont bénéficié d'ajustement de posologies lorsque les dosages étaient en dehors de l'intervalle thérapeutique. Le suivi thérapeutique pharmacologique systématique du voriconazole nous parait indispensable pour optimiser l'efficacité du traitement par voriconazole. Il nous semble donc primordial de définir conjointement des axes d'amélioration de ce traitement, notamment, par l'utilisation de la pharmacogénétique.ROUEN-BU Médecine-Pharmacie (765402102) / SudocSudocFranceF