A herbal-drug interaction study of keishi-bukuryo-gan, a traditional herbal preparation used for menopausal symptoms, in healthy female volunteers.

OBJECTIVES: Many patients use herbal medicines to relieve menopausal symptoms. Keishi-bukuryo-gan contains five herbal components, and has been used for treating hypermenorrhoea, dysmenorrhoea and menopausal symptoms in Asian countries. In this study, we investigated the potential herb-drug interactions of keishi-bukuryo-gan in healthy female subjects. METHODS: Thirty-one healthy females (20-27 years) were studied to evaluate their baseline activity of cytochrome P450 (CYP) 1A2, CYP2D6, CYP3A, xanthine oxidase (XO) and N-acetyltransferase 2 (NAT2) based on the urinary metabolic indices of an 8-h urine sample collected after a 150-mg dose of caffeine and a 30-mg dose of dextromethorphan, and also the urinary excretion ratio of 6ß-hydroxycortisol to cortisol. Thereafter, the subjects received 3.75g of keishi-bukuryo-gan twice daily for seven days, and underwent the same tests on post-dose day 7. KEY FINDINGS: The geometric mean phenotypic index for CYP1A2 significantly decreased by 16% on day 7 compared with the baseline (P=0.026). Keishi-bukuryo-gan did not alter the indices for CYP2D6, CYP3A, XO and NAT2. CONCLUSIONS: Keishi-bukuryo-gan may inhibit the activity of CYP1A2, which is predominantly involved in oestrogen metabolism. However, TJ-25 is unlikely to participate in herb-drug interactions involving medications predominantly metabolized by CYP2D6, CYP3A, XO and NAT2. K

Superoxide scavenging activity of pirfenidone-iron complex.

Pirfenidone (PFD) is focused on a new anti-fibrotic drug, which can minimize lung fibrosis etc. We evaluated the superoxide (O2*-) scavenging activities of PFD and the PFD-iron complex by electron spin resonance (ESR) spectroscopy, luminol-dependent chemiluminescence assay, and cytochrome c reduction assay. Firstly, we confirmed that the PFD-iron complex was formed by mixing iron chloride with threefold molar PFD, and the complex was stable in distilled water and ethanol. Secondary, the PFD-iron complex reduced the amount of O2*- produced by xanthine oxidase/hypoxanthine without inhibiting the enzyme activity. Thirdly, it also reduced the amount of O2*- released from phorbor ester-stimulated human neutrophils. PFD alone showed few such effects. These results suggest the possibility that the O2*- scavenging effect of the PFD-iron complex contributes to the anti-fibrotic action of PFD used for treating idiopathic pulmonary fibrosis.

Applicability of new spin trap agent, 2-diphenylphosphinoyl-2-methyl-3,4-dihydro-2H-pyrrole N-oxide, in biological system.

Electron spin resonance using spin-trapping is a useful technique for detecting direct reactive oxygen species, such as superoxide (O2.-). However, the widely used spin trap 2,2-dimethyl-3,4-dihydro-2H-pyrrole N-oxide (DMPO) has several fundamental limitations in terms of half-life and stability. Recently, the new spin trap 2-diphenylphosphinoyl-2-methyl-3,4-dihydro-2H-pyrrole N-oxide (DPhPMPO) was developed by us. We evaluated the biological applicability of DPhPMPO to analyze O2.- in both cell-free and cellular systems. DPhPMPO had a larger rate constant for O2.- and formed more stable spin adducts for O2.- than DMPO in the xanthine/xanthine oxidase (X/XO) system. In the phorbol myristate acetate-activated neutrophil system, the detection potential of DPhPMPO for O2.- was significantly higher than that of DMPO (k(DMPO)=13.95M(-1)s(-1), k(DPhPMPO)=42.4M(-1)s(-1)). These results indicated that DPhPMPO is a potentially good candidate for trapping O2.- in a biological system.