Methadone, Buprenorphine, and Street Drug Interactions with Antiretroviral Medications

While street drugs appear unlikely to alter the metabolism of antiretroviral (ARV) medications, several ARVs may induce or inhibit metabolism of various street drugs. However, research on these interactions is limited. Case reports have documented life-threatening overdoses of ecstasy and gamma-hydroxybutyrate after starting ritonavir, an ARV that inhibits several metabolic enzymes. For opioid addiction, methadone or buprenorphine are the treatments of choice. Because a number of ARVs decrease or increase methadone levels, patients should be monitored for methadone withdrawal or toxicity when they start or stop ARVs. Most ARVs do not cause buprenorphine withdrawal or toxicity, even if they alter buprenorphine levels, with rare exceptions to date including atazanavir/ritonavir associated with significant increases in buprenorphine and adverse events related to sedation and mental status changes in some cases. There are newer medications yet to be studied with methadone or buprenorphine. Further, there are many frequently used medications in treatment of complications of HIV disease that have not been studied. There is need for continuing research to define these drug interactions and their clinical significance

Genetic Polymorphisms in CYP2E1: Association with Schizophrenia Susceptibility and Risperidone Response in the Chinese Han Population

CYP2E1 is a member of the cytochrome P450 superfamily, which is involved in the metabolism and activation of both endobiotics and xenobiotics. The genetic polymorphisms of CYP2E1 gene (Chromosome 10q26.3, Accession Number NC_000010.10) are reported to be related to the development of several mental diseases and to be involved in the clinical efficacy of some psychiatric medications. We investigated the possible association of CYP2E1 polymorphisms with susceptibility to schizophrenia in the Chinese Han Population as well as the relationship with response to risperidone in schizophrenia patients.In a case-control study, we identified 11 polymorphisms in the 5' flanking region of CYP2E1 in 228 schizophrenia patients and 384 healthy controls of Chinese Han origin. From among the cases, we chose 130 patients who had undergone 8 weeks of risperidone monotherapy to examine the relationship between their response to risperidone and CYP2E1 polymorphisms. Clinical efficacy was assessed using the Brief Psychiatric Rating Scale (BPRS).Statistically significant differences in allele or genotype frequencies were found between cases and controls at rs8192766 (genotype p = 0.0048, permutation p = 0.0483) and rs2070673 (allele: p = 0.0018, permutation p = 0.0199, OR = 1.4528 95%CI = 1.1487-1.8374; genotype: p = 0.0020, permutation p = 0.0225). In addition, a GTCAC haplotype containing 5 SNPs (rs3813867, rs2031920, rs2031921, rs3813870 and rs2031922) was observed to be significantly associated with schizophrenia (p = 7.47E-12, permutation p<0.0001). However, no association was found between CYP2E1 polymorphisms/haplotypes and risperidone response.Our results suggest that CYP2E1 may be a potential risk gene for schizophrenia in the Chinese Han population. However, polymorphisms of the CYP2E1 gene may not contribute significantly to individual differences in the therapeutic efficacy of risperidone. Further studies in larger groups are warranted to confirm our results

Unexpectedly high barriers to M–P rotation in tertiary phobane complexes : PhobPR behavior that is commensurate with tBu2PR

The four isomers of 9-butylphosphabicyclo[3.3.1]nonane, s-PhobPBu, where Bu = n-butyl, sec-butyl, isobutyl, tert-butyl, have been prepared. Seven isomers of 9-butylphosphabicyclo[4.2.1]nonane (a5-PhobPBu, where Bu = n-butyl, sec-butyl, isobutyl, tert-butyl; a7-PhobPBu, where Bu = n-butyl, isobutyl, tert-butyl) have been identified in solution; isomerically pure a5-PhobPBu and a7-PhobPBu, where Bu = n-butyl, isobutyl, have been isolated. The σ-donor properties of the PhobPBu ligands have been compared using the JPSe values for the PhobP(═Se)Bu derivatives. The following complexes have been prepared: trans-[PtCl2(s-PhobPR)2] (R = nBu (1a), iBu (1b), sBu (1c), tBu (1d)); trans-[PtCl2(a5-PhobPR)2] (R = nBu (2a), iBu (2b)); trans-[PtCl2(a7-PhobPR)2] (R = nBu (3a), iBu (3b)); trans-[PdCl2(s-PhobPR)2] (R = nBu (4a), iBu (4b)); trans-[PdCl2(a5-PhobPR)2] (R = nBu (5a), iBu (5b)); trans-[PdCl2(a7-PhobPR)2] (R = nBu (6a), iBu (6b)). The crystal structures of 1a–4a and 1b–6b have been determined, and of the ten structures, eight show an anti conformation with respect to the position of the ligand R groups and two show a syn conformation. Solution variable-temperature 31P NMR studies reveal that all of the Pt and Pd complexes are fluxional on the NMR time scale. In each case, two species are present (assigned to be the syn and anti conformers) which interconvert with kinetic barriers in the range 9 to >19 kcal mol–1. The observed trend is that, the greater the bulk, the higher the barrier. The magnitudes of the barriers to M–P bond rotation for the PhobPR complexes are of the same order as those previously reported for tBu2PR complexes. Rotational profiles have been calculated for the model anionic complexes [PhobPR-PdCl3]− using DFT, and these faithfully reproduce the trends seen in the NMR studies of trans-[MCl2(PhobPR)2]. Rotational profiles have also been calculated for [tBu2PR-PdCl3]−, and these show that the greater the bulk of the R group, the lower the rotational barrier: i.e., the opposite of the trend for [PhobPR-PdCl3]−. Calculated structures for the species at the maxima and minima in the M–P rotation energy curves indicate the origin of the restricted rotation. In the case of the PhobPR complexes, it is the rigidity of the bicycle that enforces unfavorable H···Cl clashes involving the Pd–Cl groups with H atoms on the α- or β-carbon in the R substituent and H atoms in 1,3-axial sites within the phosphabicycle