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Abstract: Ethnopharmacological relevance: Xiang–Fu–Si–Wu Decoction (XFSWD) has been widely used to treat primary dysmenorrhea in clinical practice for hundreds of years and shown great efficacy. One fraction of XFSWD, which was an elution product by macroporous adsorption resin from aqueous extract solution with 60% ethanol (XFSWE), showed great analgesic effect. The present study was conducted to investigate the possible pharmacokinetic and tissue distribution profiles of four major bioactive constituents (berberine, protopine, tetrahydrocoptisine and tetrahydropalmatine) after oral administration of XFSWE in dysmenorrheal symptom rats, and to compare the difference between normal and dysmenorrheal symptom rats. Materials and methods: Estradiol benzoate and oxytocin were used to produce dysmenorrheal symptom rat model. The experimental period was seven days. At the final day of experimental period, both normal and dysmenorrheal symptom rats were orally administrated with XFSWE, and then the blood and tissues samples were collected at different time points. Berberine, protopine, tetrahydrocoptisine and tetrahydropalmatine in blood and tissue samples were determined by LC–MS/MS. Pharmacokinetic parameters were calculated from the plasma concentration–time data using non-compartmental methods. The differences of pharmacokinetic parameters among groups were tested by one-way analysis of variance (ANOVA). Results: There were statistically significant differences (P<0.05) in C max, T max, AUC 0−t , AUC 0−∞ , MRT 0−t , MRT 0−∞ and CL/F between normal and dysmenorrheal symptom rats that orally administered with same dosage of XFSWE. In tissue distribution study, the results showed that the overall trend was C Spleen>C Liver>C Kidney>C Uterus>C Heart>C Lung>C Ovary>C Brain>C Thymus, C M-60min>C M-120min>C M-30min>C C-60min>C C-120 min>C C-30 min. The contents of protopine in liver, spleen and uterus were more than that in other tissues of dysmenorrheal symptom rats. Compared to normal rats, partial contents of the compounds in dysmenorrheal symptom rats׳ tissues at different time points had significant difference (P<0.05). Conclusions: This study was the first report about pharmacokinetic and tissue distribution investigation in dysmenorrheal symptom animals. The results indicated that berberine, protopine, tetrahydrocoptisine and tetrahydropalmatine have higher uptake and slower elimination in the rats with dysmenorrheal syndrome, which suggests that the rate and extent of drug metabolism were altered in dysmenorrheal syndrome rats. And the results also demonstrated that berberine, protopine and tetrahydropalmatine in normal and dysmenorrheal symptom rats had obvious differences in some organs and time points, suggesting that the blood flow and perfusion rate of the organ were altered in dysmenorrheal symptom animals. [Copyright &y& Elsevier]

Abstract: Aim of the study: This present study was carried out to evaluate the anti-inflammatory and analgesic effects of 85% ethanol extract (EE) of Commiphora myrrha and its different fractions partitioned with petroleum ether extract (EPE), ethyl acetate extract (EEA), n-butanol extract (EBu), and the water extract (ECY). Moreover, the chemical constituents in EPE were analyzed and identified by UPLC–QTOF/MS/MS. Materials and methods: The anti-inflammatory activities were investigated by utilizing the paw edema mice induced by formalin. In addition, we determined the levels of PGE2 in the edema paw. While the analgesic activity was examined against thermally and chemically induced nociceptive pain in mice, using the acetic acid and hot-plate test methods. The effects of the administration of dolantin or indomethacin were also studied for references. The components in EPE were analyzed by the ultra-performance liquid chromatography coupled with mass spectrum. Results: In the anti-inflammatory test, EE inhibited the development of paw swelling induced by formalin significantly. The pharmacological activities of the petroleum ether fraction (EPE) were stronger than the EE extract and other fractions at the dose of 100mg/kg, and furthermore significantly decreased the levels of inflammatory factor PGE2 in the edema paw tissue at the fourth hour after formalin injection. It has been also shown that the ethanol extract (EE) significantly reduced acetic acid-induced writhing response in mice at the dose of 200mg/kg, and 100mg/kg. The petroleum ether fraction (EPE) showed significant analgesic activity in the model at the dose of 100mg/kg (p <0.01), and the ethyl acetate fraction (EEA) exhibited less analgesic activity (p <0.05). All test samples showed no significant analgesic activity on the hot plate pain threshold in mice. The UPLC–MS/MS chromatogram analysis of EPE stated that EPE contains the ingredients of sesquiterpenes, diterpenes, and diterpenic acids. Moreover, seven main compounds were identified. Conclusion: These data demonstrated that the EE and EPE posses analgesic and anti-inflammatory activities and may support the fact the traditional application of this herb in treating various diseases associated with inflammatory pain. [Copyright &y& Elsevier]