Kwang‐Hyeon Liu

OBJECTIVE: Hyperprolactinemia and associated side effects often occur with antipsychotics. The authors investigated the effect of adjunctive treatment with aripiprazole on hyperprolactinemia and psychopathology in patients with schizophrenia maintained with haloperidol. METHOD: Fifty-six patients with hyperprolactinemia taking haloperidol were enrolled. Haloperidol dose was fixed; aripiprazole was dosed at 15 mg/day for the first 4 weeks, then 30 mg/day for the following 4 weeks. Serum prolactin, haloperidol, and aripiprazole levels were measured. Symptoms and side effects were assessed with the Brief Psychiatric Rating Scale (BPRS), Scale for the Assessment of Negative Symptoms, Clinical Global Impression symptom scale, Simpson-Angus Rating Scale, and Barnes Akathisia Rating Scale at weeks 1, 2, 4, 6, and 8. RESULTS: Prolactin levels of patients receiving aripiprazole significantly decreased over time, demonstrating a significant time effect and a time-by-group interaction. In the aripiprazole group, 88.5% of patients at week 8 had prolactin levels normalize compared to 3.6% of patients receiving placebo. Among 11 female patients with menstrual disturbances randomly assigned to aripiprazole, seven patients regained menstruation during the study, whereas none receiving placebo did. Plasma levels of haloperidol were not significantly altered. No significant time effect and time-by-group interactions on BPRS, Scale for the Assessment of Negative Symptoms, and Simpson-Angus Rating Scale scores were noted. CONCLUSIONS: Adjunctive aripiprazole treatment reversed hyperprolactinemia in both sexes, resulting in reinstatement of menstruation in female patients, with no significant effects on psychopathology and extrapyramidal symptoms. Aripiprazole has higher affinity to dopamine D(2) receptors than haloperidol, which is the likely cause of this observation.

The early detection of potential drug-drug interactions is an important issue of drug discovery that has led to the development of high-throughput screening (HTS) methods for potential drug interactions. We developed a HTS method for potential interactions of inhibitory drugs for nine human P450 enzymes using cocktail incubation and tandem mass spectrometry in vitro. This new method involves incubation of two cocktail doses and single cassette analysis. The two cocktail doses in vitro were developed to minimize solvent effects and mutual drug interactions among substrates: cocktail A was composed of phenacetin for CYP1A2, coumarin for CYP2A6, paclitaxel for CYP2C8, S-mephenytoin for CYP2C19, dextromethorphan for CYP2D6, and midazolam for CYP3A4; and cocktail B was composed of three substrates including bupropion for CYP2B6, tolbutamide for CYP2C9, and chlorzoxazone for CYP2E1. In the incubation study of these cocktails, the reaction mixtures were pooled and simultaneously analyzed using liquid chromatography/tandem mass spectrometry employing a fast gradient. The method was validated by comparing the inhibition data obtained from the incubation of each individual probe substrate alone with data from the new method. The IC50 value of each inhibitor in the cocktail agreed well with that of the individual probe drug as well as with values previously reported in the literature. As a HTS method for potential interactions of the inhibition of these nine P450 enzymes, this new method will be useful in the drug discovery process and for the mechanistic understanding of drug interactions.

Liquid chromatography-mass and multivariate analyses were employed to measure the composition of pu-erh teas and to determine the general changes in the compositional patterns of pu-erh teas during postfermentation. Principle component analysis of pu-erh teas indicated two large distinct clusters in the score plot: ripened pu-erh teas and raw pu-erh teas. The raw pu-erh teas contained more antioxidant compounds compared to ripened pu-erh teas. As a result, the raw pu-erh teas showed significantly higher antioxidant activities than the ripened pu-erh teas in the 1,1-diphenyl-2-picrylhydrazyl, Trolox equivalent antioxidant capacity, and ferric reducing antioxidant power assays. In addition, raw pu-erh teas showed significantly higher NO inhibitory and cell protective activities than the ripened pu-erh teas. Significant correlations between compounds and postfermentation year were observed in raw pu-erh teas; epigallocatechin-3-gallate, epigallocatechin, epicatechin-3-gallate, and quinic acid were decreased and gallic acid was increased in a year-dependent manner. The antioxidant activity was shown to decrease as the number of antioxidant compounds in raw pu-erh tea decreased. These findings indicate that a metabolomic approach is a useful tool for analyzing manufacturing type, postfermentation year, and antioxidant activity of pu-erh tea.