BACKGROUND:

Despite recent advances in hepatitis C (HCV) treatment, speci fically the addition of direct acting antivirals (DAAs), pegylated interferon-alpha remains the backbone of HCV therapy. Therefore, the impact of DAAs on the management of co-morbid psychi atric illness and neuropsychiatric sequalae remains an ongoing concern during HCV therapy. This paper provides a review of the neuropsychiatric adverse effects of DAAs and drug-drug interactions (DDIs) between DAAs and psychiatric medications.

METHODS:

We conducted a Pubmed search using relevant search terms and hand searched reference lists of related review articles. In addition, we searched abstracts for major hepatology conferences and contacted respective pharmaceutical companies for additional studies.

RESULTS:

Limited data is available on the neuropsychiatric adverse effects of DAAs; however, data from major clinical trials suggest that DAAs have minimal neuropsychiatric risk. DAAs can potentially interact with a variety of psychotropic agents via cytochrome P450 and p-glycoprotein interactions. Triazolam, oral midazolam, St. John's Wort, carbamazepine and pimozide, are contraindicated with DAAs. DDIs between DAAs and antidepressants, anxiolytics, hypnotics, mood stabilizers, antipsychotics and treatments for opioid dependence are summarized.

CONCLUSIONS:

Although DAAs do not add significant neuropsychiatric risk, the potential for DDIs is high. Consideration of DDIs is paramount to improving medication adherence and mitigating adverse effects during HCV therapy.

Changes in the expression level and activity of cytochrome P450 (CYP) in the liver are caused by various factors and affect the pharmacokinetics of drugs. The purpose of this study was to determine whether the expression of CYP3A is affected by a high-fat diet. In addition, we examined whether the type of diet given to mice could produce changes in the expression level and activity of CYP3A. Mice were fed a purified diet containing 10 kcal% lard (control group) or 60 kcal% lard (HF group) or regular mouse chow containing 13 kcal% of fat (MF group) for 4 weeks. No significant differences were observed in the hepatic CYP3A protein expression level between the HF group and the control group. The CYP3A protein expression in the MF group was significantly higher than that observed in the control group. In the MF group, the area under the curve (AUC) of intraperitoneally administered triazolam was lower. Because lithocholic acid (LCA) is known to increase hepatic CYP3A expression, the levels of Clostridium sordellii and LCA in the feces were measured. In the MF group, the levels of Clostridium sordellii and LCA were higher. It has been demonstrated that a high-fat diet does not cause any changes in hepatic CYP3A expression. In addition, the different diets caused alterations in the enteric environment, which triggered changes in CYP3A expression. Therefore, it is necessary to carefully consider the type of feed while performing animal experiments to evaluate the pharmacokinetics of drugs.

The present studies evaluated the role of α1 and α5 subunit-containing GABAA receptors (α1GABAA and α5GABAA receptors, respectively) in the ability of benzodiazepine (BZ)-type drugs to alter performance in the cognitive domain of executive function. Five adult female rhesus monkeys (ages of 9-17years old) were trained on the object retrieval with detours (ORD) task of executive function. For the ORD task, the monkeys were required to retrieve food items from a clear box with one open end that was rotated to different positions along with varying placements of food. When the non-selective BZ triazolam and the α1GABAA-preferring agonists zolpidem and zaleplon were evaluated in the ORD task, deficits in performance occurred at doses that did not increase the latency of monkeys to initiate responding and/or increase the percentage of reaches that were incorrect (i.e., reaches in which food was not obtained). Cognition-impairing effects of triazolam and zolpidem in ORD were blocked by the α1GABAA-preferring antagonist, βCCT, whereas the α5GABAA-preferring antagonist XLi-093 blocked the effects of triazolam but not zolpidem. While these findings suggest a role for both α1GABAA and α5GABAA receptor mechanisms, α1GABAA receptor mechanisms appear to be sufficient for impairments in executive function induced by BZ-type drugs.

Abstract 1. To search an appropriate evaluation methodology for the intestinal first-pass metabolism of new drug candidates, grapefruit juice (GFJ)- and vehicle (tap water)-pretreated mice or rats were orally administered midazolam (MDZ) or triazolam (TRZ), and blood levels of the parent compounds and their metabolites were measured by liquid chromatography/MS/MS. A significant effect of GFJ to elevate the blood levels was observed only for TRZ in mice. 2. In vitro experiments using mouse, rat and human intestinal and hepatic microsomal fractions demonstrated that GFJ suppressed the intestinal microsomal oxidation of MDZ and especially TRZ. Substrate inhibition by MDZ caused reduction in 1'-hydroxylation but not 4-hydroxylation in both intestinal and hepatic microsomal fractions. The kinetic profiles of MDZ oxidation and the substrate inhibition in mouse intestinal and hepatic microsomal fractions were very similar to those in human microsomes but were different from those in rat microsomes. Furthermore, MDZ caused mechanism-based inactivation of cytochrome P450 3A-dependent TRZ 1'-hydroxylation in mouse, rat and human intestinal microsomes with similar potencies. 3. These results are useful information in the analysis of data obtained in mouse and rat for the evaluation of first-pass effects of drug candidates to be metabolized by CYP3A enzymes.

Syndromes of fear/anxiety are currently ill-defined, with no accepted human biomarkers for anxiety-specific processes. A unique common neural action of different classes of anxiolytic drugs may provide such a biomarker. In rodents, a reduction in low frequency (4-12Hz; "theta") brain rhythmicity is produced by all anxiolytics (even those lacking panicolytic or antidepressant action) and not by any non-anxiolytics. This rhythmicity is a key property of the Behavioural Inhibition System (BIS) postulated to be one neural substrate of anxiety. We sought homologous anxiolytic-sensitive changes in human surface EEG rhythmicity.Thirty-four healthy volunteers in parallel groups were administered double blind single doses of triazolam 0.25mg, buspirone 10mg or placebo 1 hour prior to completing the stop-signal task. Right frontal conflict-specific EEG power (previously shown to correlate with trait anxiety and neuroticism in this task) was extracted as a contrast between trials with balanced approach-avoidance (stop-go) conflict and the average of trials with net approach and net avoidance.Compared with placebo, both triazolam and buspirone decreased right-frontal, 9-10Hz, conflict-specific-power.Only one dose of each of only two classes of anxiolytic and no non-anxiolytics were tested, so additional tests are needed to determine generality.There is a distinct rhythmic system in humans that is sensitive to both classical/GABAergic and novel/serotonergic anxiolytics. This conflict-specific rhythmicity should provide a biomarker, with a strong pre-clinical neuropsychology, for a novel approach to classifying anxiety disorders.

INTRODUCTION:

Eszopiclone is the active S-enantiomer of R,S-zopiclone, and is a cyclopyrrolone hypnotic acting via the GABA-benzodiazepine receptor system. Nearly 6 million prescriptions for eszopiclone are written yearly in the United States. AREAS COVERED: This paper addresses the pharmacokinetic properties of eszopiclone and the extent to which the longer half-life of eszopiclone compared to other commonly used hypnotics (immediate-release zolpidem, modified-release zolpidem, triazolam, zaleplon) may translate into either improved efficacy in enhancing sleep maintenance, or increased probability of residual sedative or performance-impairing effects. EXPERT OPINION: Eszopiclone is metabolized mainly by Cytochrome P450-3A (CYP3A) isoforms. The mean half-life in healthy nonelderly individuals (6.1 h) is prolonged in the elderly, in patients with hepatic insufficiency, and by coadministration of CYP3A inhibitors. In clinical trials, eszopiclone consistently improves sleep maintenance relative to placebo, based on measures of shortened wake time after sleep onset, and prolonged total sleep time. However eszopiclone may also produce residual sedation and impairment of driving performance in the initial morning waking hours. A bitter or metallic taste is a common though non-serious adverse effect of eszopiclone. Overall, eszopiclone provides a therapeutic option for patients with sleep maintenance problems, though with accompanying potential for residual morning sedation, as well as a relatively high dollar cost of treatment.

Human CYP3A is the most abundant P450 isozyme present in the human liver and small intestine, and metabolizes around 50% of medical drugs on the market. The human CYP3A subfamily comprises four members (CYP3A4, CYP3A5, CYP3A7, CYP3A43) encoded on human chromosome 7. However, transgenic mouse lines carrying the entire human CYP3A cluster have not been constructed because of limitations in conventional cloning techniques. Here, we show that the introduction of a human artificial chromosome (HAC) containing the entire genomic human CYP3A locus recapitulates tissue- and stage-specific expression of human CYP3A genes and xenobiotic metabolism in mice. About 700 kb of the entire CYP3A genomic segment was cloned into a HAC (CYP3A-HAC), and trans-chromosomic (Tc) mice carrying a single copy of germline-transmittable CYP3A-HAC were generated via a chromosome-engineering technique. The tissue- and stage-specific expression profiles of CYP3A genes were consistent with those seen in humans. We further generated mice carrying the CYP3A-HAC in the background homozygous for targeted deletion of most endogenous Cyp3a genes. In this mouse strain with 'fully humanized' CYP3A genes, the kinetics of triazolam metabolism, CYP3A-mediated mechanism-based inactivation effects and formation of fetal-specific metabolites of dehydroepiandrosterone observed in humans were well reproduced. Thus, these mice are likely to be valuable in evaluating novel drugs metabolized by CYP3A enzymes and in studying the regulation of human CYP3A gene expression. Furthermore, this system can also be used for generating Tc mice carrying other human metabolic genes.

Several studies have documented impairments in memory processes as a result of ketamine administration; however, few studies have compared the profile of cognitive effects of ketamine to other drugs.The aim of this study was to compare the cognitive effects of ketamine with those of triazolam in healthy volunteers.Doses of ketamine (0.2, 0.4 mg/kg intramuscular (i.m.)), triazolam (0.2, 0.4 mg/70 kg p.o.), and double-dummy placebos were administered to 20 volunteers under repeated measures, counterbalanced, double-blind conditions. Peak physiological, psychomotor, subjective, and cognitive effects were examined.Ketamine impaired balance when balance was assessed early in the task order, whereas triazolam impaired psychomotor coordination and divided attention irrespective of task order. Triazolam also tended to produce greater effects on working memory and episodic memory tasks than ketamine at doses that produced lower subjective effects and higher estimates of performance.Ketamine produces less cognitive impairment than triazolam at doses that produced greater subjective effects. Thus ketamine does not produce the underestimation of cognitive impairment typically seen with triazolam.

Although concerns surrounding high-dose dextromethorphan (DXM) abuse have recently increased, few studies have examined the acute cognitive effects of high doses of DXM. The aim of this study was to compare the cognitive effects of DXM with those of triazolam and placebo.Single, acute, oral doses of DXM (100, 200, 300, 400, 500, 600, 700, 800 mg/70 kg), triazolam (0.25, 0.5mg/70 kg), and placebo were administered p.o. to twelve healthy volunteers with histories of hallucinogen use, under double-blind conditions, using an ascending dose run-up design. Effects on cognitive performance were examined at baseline and after drug administration for up to 6h.Both triazolam and DXM produced acute impairments in attention, working memory, episodic memory, and metacognition. Impairments observed following doses of 100-300 mg/70 kg DXM were generally smaller in magnitude than those observed after 0.5mg/70 kg triazolam. Doses of DXM that impaired performance to the same extent as triazolam were in excess of 10-30 times the therapeutic dose of DXM.The magnitude of the doses required for these effects and the absence of effects on some tasks within the 100-300 mg/70 kg dose range of DXM, speak to the relatively broad therapeutic window of over-the-counter DXM preparations when used appropriately. However, the administration of supratherapeutic doses of DXM resulted in acute cognitive impairments on all tasks that were examined. These findings are likely relevant to cases of high-dose DXM abuse.

The present study evaluated the possibility of drug interactions involving blueberry juice (BBJ) and substrate drugs whose clearance is dependent on cytochromes P4503A (CYP3A) and P4502C9 (CYP2C9).A 50:50 mixture of lowbush and highbush BBJ was evaluated in vitro as an inhibitor of CYP3A activity (hydroxylation of triazolam and dealkylation of buspirone) and of CYP2C9 activity (flurbiprofen hydroxylation) using human liver microsomes. In clinical studies, clearance of oral buspirone and oral flurbiprofen was studied in healthy volunteers with and without co-treatment with BBJ.BBJ inhibited CYP3A and CYP2C9 activity in vitro, with 50% inhibitory concentrations (IC50 ) of less than 2%, but without evidence of mechanism-based (irreversible) inhibition. Grapefruit juice (GFJ) also inhibited CYP3A activity, but inhibitory potency was increased by pre-incubation, consistent with mechanism-based inhibition. In clinical studies, GFJ significantly increased area under the plasma concentration-time curve (AUC) for the CYP3A substrate buspirone. The geometric mean ratio (GMR = AUC with GFJ divided by AUC with water) was 2.12. In contrast, the effect of BBJ (GMR = 1.39) was not significant. In the study of flurbiprofen (CYP2C9 substrate), the positive control inhibitor fluconazole significantly increased flurbiprofen AUC (GMR = 1.71), but BBJ had no significant effect (GMR = 1.03).The increased buspirone AUC associated with BBJ is quantitatively small and could have occurred by chance. BBJ has no effect on flurbiprofen AUC. The studies provide no evidence for concern about clinically important pharmacokinetic drug interactions of BBJ with substrate drugs metabolized by CYP3A or CYP2C9.