Specificities of Meningitis and Meningo-Encephalitis After Kidney Transplantation: A French Retrospective Cohort Study.

Kidney transplant recipients develop atypical infections in their epidemiology, presentation and outcome. Among these, meningitis and meningoencephalitis require urgent and adapted anti-infectious therapy, but published data is scarce in KTRs. The aim of this study was to describe their epidemiology, presentation and outcome, in order to improve their diagnostic and management. We performed a retrospective, multicentric cohort study in 15 French hospitals that included all 199 cases of M/ME in KTRs between 2007 and 2018 (0.9 case per 1,000 KTRs annually). Epidemiology was different from that in the general population: 20% were due to Cryptococcus neoformans, 13.5% to varicella-zoster virus, 5.5% to Mycobacterium tuberculosis, and 4.5% to Enterobacteria (half of which produced extended spectrum beta-lactamases), and 5% were Post Transplant Lymphoproliferative Disorders. Microorganisms causing M/ME in the general population were infrequent (2%, for Streptococcus pneumoniae) or absent (Neisseria meningitidis). M/ME caused by Enterobacteria, Staphylococci or filamentous fungi were associated with high and early mortality (50%-70% at 1 year). Graft survival was not associated with the etiology of M/ME, nor was impacted by immunosuppression reduction. Based on these results, we suggest international studies to adapt guidelines in order to improve the diagnosis and the probabilistic treatment of M/ME in SOTRs.

Pharmacogenetic allele nomenclature: International workgroup recommendations for test result reporting.

This article provides nomenclature recommendations developed by an international workgroup to increase transparency and standardization of pharmacogenetic (PGx) result reporting. Presently, sequence variants identified by PGx tests are described using different nomenclature systems. In addition, PGx analysis may detect different sets of variants for each gene, which can affect interpretation of results. This practice has caused confusion and may thereby impede the adoption of clinical PGx testing. Standardization is critical to move PGx forward.

Evidence-based guideline: Antiepileptic drug selection for people with HIV/AIDS: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Ad Hoc Task Force of the Commission on Therapeutic Strategies of the International League Against Epilepsy.

OBJECTIVE: To develop guidelines for selection of antiepileptic drugs (AEDs) among people with HIV/AIDS. METHODS: The literature was systematically reviewed to assess the global burden of relevant comorbid entities, to determine the number of patients who potentially utilize AEDs and antiretroviral agents (ARVs), and to address AED-ARV interactions. RESULTS AND RECOMMENDATIONS: AED-ARV administration may be indicated in up to 55% of people taking ARVs. Patients receiving phenytoin may require a lopinavir/ritonavir dosage increase of ~50% to maintain unchanged serum concentrations (Level C). Patients receiving valproic acid may require a zidovudine dosage reduction to maintain unchanged serum zidovudine concentrations (Level C). Coadministration of valproic acid and efavirenz may not require efavirenz dosage adjustment (Level C). Patients receiving ritonavir/atazanavir may require a lamotrigine dosage increase of ∼50% to maintain unchanged lamotrigine serum concentrations (Level C). Coadministration of raltegravir/atazanavir and lamotrigine may not require lamotrigine dosage adjustment (Level C). Coadministration of raltegravir and midazolam may not require midazolam dosage adjustment (Level C). Patients may be counseled that it is unclear whether dosage adjustment is necessary when other AEDs and ARVs are combined (Level U). It may be important to avoid enzyme-inducing AEDs in people on ARV regimens that include protease inhibitors or nonnucleoside reverse transcriptase inhibitors, as pharmacokinetic interactions may result in virologic failure, which has clinical implications for disease progression and development of ARV resistance. If such regimens are required for seizure control, patients may be monitored through pharmacokinetic assessments to ensure efficacy of the ARV regimen (Level C).

Are circulating metabolites important in drug-drug interactions?: Quantitative analysis of risk prediction and inhibitory potency.

The potential of metabolites to contribute to drug-drug interactions (DDIs) is not well defined. The aim of this study was to determine the quantitative role of circulating metabolites in inhibitory DDIs in vivo. The area under the plasma concentration-time curve (AUC) data related to at least one circulating metabolite was available for 71% of the 102 inhibitor drugs identified. Of the 80 metabolites characterized at steady state, 78% had AUCs >10% of that of the parent drug. A comparison of the inhibitor concentration/inhibition constant ([I]/K(i)) ratios of metabolites and the respective parent drugs showed that 17 of the 21 (80%) reversible inhibitors studied had metabolites that were likely to contribute to in vivo DDIs, with some metabolites predicted to have inhibitory effects greater than those of the parent drug. The in vivo drug interaction risks associated with amiodarone, bupropion, and sertraline could be identified from in vitro data only, when data pertaining to metabolites were included in the predictions. In conclusion, cytochrome P450 (CYP) inhibitors often have circulating metabolites that contribute to clinically observed CYP inhibition.

Prediction of maximum exposure in poor metabolizers following inhibition of nonpolymorphic pathways.

Marked increases in exposure of some substrates have been noted in poor metabolizers given inhibitors of nonpolymorphic enzymes. Among the small number of clinical trials conducted to investigate this problem, a wide variation in the degree of maximum exposure ratios (area under the curve in poor metabolizers in the presence of inhibitor/area under the curve in extensive metabolizers) among the different substrates has been reported, with some trials reporting profound increases (> tenfold), and others demonstrating less remarkable changes (< twofold). The conduct of such trials raises safety concerns for the trial participants, in addition to other ethical and logistic concerns; therefore, the possibility was investigated that maximum exposure (area under the curve in poor metabolizers in the presence of an inhibitor) could be predicted, and that substrates susceptible to large increases in exposure could be identified. Existing clinical trials were identified by data mining the literature. A theoretical approach was developed to predict maximum exposure in poor metabolizers from studies in extensive metabolizers treated with an inhibitor of the nonpolymorphic pathway. Maximum exposure was predicted in eleven instances and the mean percentage difference between predicted and observed was 11.9%. Substrates with a fraction of substrate dose metabolized by the polymorphic enzyme (fm(POLY)) higher than 75% are at greater risk of exhibiting maximum exposure ratios of more than tenfold.

Relationship between extent of inhibition and inhibitor dose: literature evaluation based on the metabolism and transport drug interaction database.

A comprehensive search of the literature was undertaken using the Metabolism and Transport Drug Interaction Database (http://depts.washington.edu/didbase/) to evaluate the relationship between extent of inhibition and inhibitor dose. The search included reversible and irreversible inhibitors in studies conducted in the period 1966-2003. Only twelve inhibitors met the criterion of the search: study population exposed to more than one dose of inhibitor within a given study design. Six were reversible inhibitors: ciprofloxacin, enoxacin, felbamate, fluconazole, fluvoxamine and ketoconazole. The other six (cimetidine, diltiazem, disulfiram, paroxetine, verapamil and ritonavir) are considered irreversible inhibitors. Most of the AUC/Clearance data available for both types of inhibitors suggested evidence of dose-dependent inhibition. In the case of reversible inhibitors, the evidence of dose-dependent inhibition is consistent with a number of recent studies suggesting the determination of in vivo inhibition constants based on plasma concentration of inhibitor.

gamma-Glutamyltransferase dependent generation of reactive oxygen species from a glutathione/transferrin system.

In the presence of molecular oxygen and iron or copper ions, a number of antioxidants paradoxically generate reactive oxygen species (ROS) leading to free radical damage of nucleic acids and oxidative modification of lipids and proteins. The present work demonstrates that the combination of three components, which are often considered as part of an antioxidant protection system, can generate ROS. Purified human gamma-glutamyltransferase (GGT) in the presence of 2 mM glutathione (GSH) and 80 microM transferrin, as an iron source, at pH 7.4 generates ROS, as measured by chemiluminescence of luminol. Initiated by the addition of purified GGT, generation of ROS reached a maximal rate in the first 6 min. Intensity of the chemiluminescence was only slightly enhanced by addition of 200 microM hydrogen peroxide. Generation of ROS was also investigated in transfected V79 cells expressing human GGT. In comparison with GGT negative V79 cells, only recombinant cells expressing a high level of GGT on the cell membrane were able to generate ROS. Generation of ROS in these cells reached a maximum within 2 min and was enhanced by 200 microM hydrogen peroxide. We further confirmed the hypothesis that cysteinylglycine (CysGly), a product of GGT/GSH reaction, identified by high-performance liquid chromatography, but not GSH, was responsible for ROS formation initiated by the reductive release of iron from transferrin. These data clearly indicate that under physiological conditions, GGT is directly involved in ROS generation.

gamma-Glutamyltransferase expression during all-trans retinoic acid-induced differentiation of hematopoietic cell lines.

gamma-Glutamyltransferase activity, genes transcripts and differentiation by all-trans retinoic acid have been investigated in cultured HL-60, U937, and K562 cells. Acquisition of morphological and functional characteristics confirmed the terminal differentiation of HL-60 and U937 cells. All-trans retinoic acid increased gamma-glutamyltransferase activity in a cell type- and time dependent manner. Treatments with all-trans retinoic acid isomers and structurally analogs showed that only retinoids with carboxylic acid group were able to induce enzyme activity in terminal differentiated cells. Additionally, the analysis of gamma-glutamyltransferase genes transcription products demonstrated clearly that, both in untreated and in RA treated cells, only mRNA type I transcribed from the gene 6, was expressed.