Radix Rehmanniae, Fructus Schisandrae, Radix Bupleuri, and Fructus Gardeniae are often used alongside with clozapine (CLZ) for schizophrenia patients in order to reduce side effects and enhance therapeutic efficacy. However, worse outcomes were observed raising concern about a critical issue, herb-drug interactions, which were rarely reported when antipsychotics were included. This study aims to determine whether the concomitant use of these herbal medicines affects the pharmacokinetic characteristics of CLZ in rat models. Rats were given a single or multiple intraperitoneal injections of 10 mg/kg CLZ, either alone or with individual herbal water extracts administered orally. CLZ and its two inactive metabolites, norclozapine and clozapine N-oxide, were determined by high-performance liquid chromatography/tandem mass spectrometry. In the acute treatment, the formation of both metabolites was reduced, while no significant change was observed in the CLZ pharmacokinetics for any of the herbal extracts. In the chronic treatment, none of the four herbal extracts significantly influenced the pharmacokinetic parameters of CLZ and its metabolites. Renal and liver functions stayed normal after the 11-day combined use of herbal medicines. Overall, the four herbs had limited interaction effect on CLZ pharmacokinetics in the acute and chronic treatment. Herb-drug interaction includes both pharmacokinetic and pharmacodynamic mechanisms. This result gives us a hint that pharmacodynamic herb-drug interaction, instead of pharmacokinetic types, may exist and need further confirmation. Full article

Herbal supplements are increasingly used in psychiatric practice. Our epidemiological study has identified several herbal preparations associated with adverse outcomes of antipsychotic therapy. In this study, we evaluated the in vitro effects of four herbal preparations—Radix Rehmanniae (RR), Fructus Schisandrae (FS), Radix Bupleuri (RB) and Fructus Gardeniae (FG)—on cytochrome P450s (CYPs) involved in the metabolism of clozapine in human liver microsomes (HLMs) and recombinant human cytochrome P450 enzymes (rCYPs). N-desmethylclozapine and clozapine N-oxide, two major metabolites of clozapine, were measured using high-performance liquid chromatography (HPLC). FG, RR and RB showed negligible inhibitory effects in both in vitro systems, with estimated half-maximal inhibitory concentrations (IC₅₀) and apparent inhibitory constant values (K_i) greater than 1 mg/mL (raw material), suggesting that minimal metabolic interaction occurs when these preparations are used concomitantly with clozapine. The FS extract affected CYP activity with varying potency; its effect on CYP 3A4-catalyzed clozapine oxidation was relatively strong (K_i: 0.11 mg/mL). Overall, the weak-to-moderate inhibitory effect of FS on in vitro clozapine metabolism indicated its potential role in herb-drug interaction in practice. Full article

A complex antioxidant system has been developed in mammals to relieve oxidative stress. However, excessive reactive species derived from oxygen and nitrogen may still lead to oxidative damage to tissue and organs. Oxidative stress has been considered as a conjoint pathological mechanism, and it contributes to initiation and progression of liver injury. A lot of risk factors, including alcohol, drugs, environmental pollutants and irradiation, may induce oxidative stress in liver, which in turn results in severe liver diseases, such as alcoholic liver disease and non-alcoholic steatohepatitis. Application of antioxidants signifies a rational curative strategy to prevent and cure liver diseases involving oxidative stress. Although conclusions drawn from clinical studies remain uncertain, animal studies have revealed the promising in vivo therapeutic effect of antioxidants on liver diseases. Natural antioxidants contained in edible or medicinal plants often possess strong antioxidant and free radical scavenging abilities as well as anti-inflammatory action, which are also supposed to be the basis of other bioactivities and health benefits. In this review, PubMed was extensively searched for literature research. The keywords for searching oxidative stress were free radicals, reactive oxygen, nitrogen species, anti-oxidative therapy, Chinese medicines, natural products, antioxidants and liver diseases. The literature, including ours, with studies on oxidative stress and anti-oxidative therapy in liver diseases were the focus. Various factors that cause oxidative stress in liver and effects of antioxidants in the prevention and treatment of liver diseases were summarized, questioned, and discussed. Full article