Modulation of the transport of valproic acid through the blood-brain barrier in rats by the Gastrodia elata extracts.

HEADINGS ETHNOPHARMACOLOGICAL RELEVANCE: Valproic acid (VPA) is primarily used as a medicine for the treatment of seizures. Gastrodia elata (G. elata) extract has been used as an alternative medicine for epilepsy patients. Cotreatment with VPA and G. elata extract is commonly prescribed in Taiwan and mainland China. Nevertheless, the mechanism of the blood-brain barrier (BBB) transportation effect of G. elata extract on VPA has not been characterized. AIM OF STUDY: Our hypothesis is that G. elata extract modulates the BBB penetration of VPA through specific transporter transfer. MATERIALS AND METHODS: A validated liquid chromatography-tandem mass spectrometry and multiple microdialysis method was developed to simultaneously monitor VPA in the blood and brain of rats. To investigate the mechanism of BBB modulation by the G. elata extract on VPA in the brain, cyclosporin A, a P-glycoprotein (P-gp) inhibitor and organic anion transporting polypeptide (OATP) inhibitor, was coadministered with the G. elata extract and VPA. RESULTS: The pharmacokinetic results demonstrated that the VPA penetration ratio of the BBB, determined by the area under the concentration curve (AUC) ratio of VPA (AUCbrain/AUCblood), was approximately 0.36. After treatment with the G. elata extract (1 and 3 g/kg, p.o. for 5 consecutive days), the VPA penetration ratios were significantly enhanced to 1.47 and 1.02, respectively. However, in the experimental group coadministered cyclosporin A, the G. elata extract was unable to enhance the BBB transportation of VPA. Instead, the VPA penetration ratio in the brain was suppressed back to 0.38. CONCLUSIONS: The present study reveals that the enhancement effect of the transporter mechanism of G. elata extract on VPA transport into the brain occurs through the OATP transporter but not the P-gp transporter.

Preclinical Pharmacokinetic Interaction and Histopathological Analyses of Hedyotis diffusa on Sorafenib in Rats.

Sorafenib is one of the most effective target therapeutic agents for patients with late-stage hepatocellular carcinoma. To seek possible alternative adjuvant agents to enhance the efficacy and improve the side effect of sorafenib, Hedyotis diffusa, one of the most prescribed phytomedicines for treating liver cancer patients in Taiwan, was evaluated in this work. We hypothesized that H. diffusa extract is a safety herb combination on the pharmacokinetic and pharmacodynamic effects of sorafenib. We designed treatments of sorafenib in combination with or without H. diffusa extract to examine its pharmacokinetic properties and effects on liver inflammation. The HPLC-photodiode-array method was designed for monitoring the plasma level and pharmacokinetic parameter of sorafenib in rat plasma. The pharmacokinetic results demonstrated that the area under the curve of sorafenib (10 mg/kg, p.o.) in combination with various doses of H. diffusa formulation (1, 3, and 10 g/kg, p.o.) for 5 consecutive days were 5560 ± 1392, 7965 ± 2055, 7271 ± 1371, and 8821 ± 1705 min µg/mL, respectively, no significant difference when compared with sorafenib treatment alone. Furthermore, the hepatic activity in rats administered with sorafenib with/without H. diffusa extract was quantitatively scored by modified hepatic activity index grading. H. diffusa extract in the range of 1 to 10 g/kg per day did not elicit significant herb-induced hepatotoxicity in rats, based on the histopathological study. Consequently, our findings provided positive safety outcomes for the administration of sorafenib in combination with the phytomedicine H. diffusa.

Herb-Drug Interaction between the Traditional Hepatoprotective Formulation and Sorafenib on Hepatotoxicity, Histopathology and Pharmacokinetics in Rats.

Sorafenib has been used as a standard therapy for advanced hepatocellular carcinoma (HCC). In Asia, patients with HCC are potentially treated with the combination of sorafenib and Chinese herbal medicines to improve the efficiency and reduce the side effects of sorafenib. However, limited information about the herb-drug interactions is available. We hypothesize that the Chinese herbal medicine may exert hepatoprotective effects on the sorafenib-treated group. The aim of this study is to investigate the pharmacokinetic mechanism of drug-drug interactions of sorafenib including interacting with hepatoprotective formulation, Long-Dan-Xie-Gan-Tang formulation (LDXGT) and with two cytochrome P450 3A4 (CYP3A4) inhibitors, grapefruit juice and ketoconazole. Liver enzyme levels and histopathology of liver slices were used to evaluate sorafenib-induced hepatotoxicity and the potential hepatoprotective effects of the LDXGT formulation on subjects treated with the combination of sorafenib and the herbal medicine. In this study, a validated HPLC-photodiode array analytical system was developed for the pharmacokinetic study of sorafenib in rats. As the result of the pharmacokinetic data, pretreatment with the LDXGT formulation did not significantly interact with sorafenib compared with sorafenib oral administration alone. Furthermore, grapefruit juice and ketoconazole did not significantly affect sorafenib metabolism. Furthermore, pretreatment with variable, single or repeat doses of the LDXGT formulation did not suppress or exacerbate the sorafenib-induced hepatotoxicity and histopathological alterations. According to these results, the LDXGT formulation is safe, but has no beneficial effects on sorafenib-induced hepatotoxicity. A detailed clinical trial should be performed to further evaluate the efficacy or adverse effects of the LDXGT formulation in combination with sorafenib in humans.

Prescription frequency and patterns of Chinese herbal medicine for liver cancer patients in Taiwan: a cross-sectional analysis of the National Health Insurance Research Database.

BACKGROUND: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. Chinese herbal medicine (CHM) is frequently provided to HCC patients. The aim of this study was to understand the prescription frequency and patterns of CHM for HCC patients by analyzing the claims data from the National Health Insurance (NHI) in Taiwan. METHODS: We identified 73918 newly diagnosed HCC subjects from the database of Registry for Catastrophic Illness during 2002 to 2009 and to analyze the frequency and pattern of corresponding CHM prescriptions for HCC patients. RESULTS: There were a total of 685,079 single Chinese herbal prescriptions and 553,952 Chinese herbal formula prescriptions used for 17,373 HCC subjects before 2 years of HCC diagnosis. Among the 13,093 HCC subjects who used CHMs after HCC diagnosis, there were 462,786 single Chinese herbal prescriptions and 300,153 Chinese herbal formula prescriptions were counted. By adjusting with person-year and ratio of standardized incidence rate, the top ten prescribed single herbal drugs and Chinese herbal formulas for HCC patients were described in our study. Among them, we concluded that, Oldenlandia diffusa (Chinese herbal name: Bai-Hua-She-She-Cao), Radix et Rhizoma Rhei (Da Huang) and the herbal preparation of Xiao-Chai-Hu-Tang and Gan-Lu-Yin, were the most obviously increased and important CHMs been used for HCC patients. CONCLUSION: We established an accurate and validated method for the actual frequency and patterns of CHM use in treating HCC in Taiwan. We propose that these breakthrough findings may have important implications for HCC therapy, clinical trials and modernization of CHM.

Preventive and therapeutic role of traditional Chinese herbal medicine in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies worldwide. The clinical management of HCC remains a substantial challenge. Although surgical resection of tumor tissues seems promising, a high recurrence and/or metastasis rate accounting for disease-related death has led to an urgent need for improved postsurgical preventive/therapeutic clinical intervention. Developing advanced target-therapy agents such as sorafenib appears to be the only effective clinical intervention for patients with HCC to date, but only limited trials have been conducted in this regard. Because of their enhanced preventive/therapeutic effects, traditional Chinese herbal medicine (CHM)-derived compounds are considered suitable agents for HCC treatment. The CHM-derived compounds also possess multilevel, multitarget, and coordinated intervention effects, making them ideal candidates for inhibition of tumor progression and HCC metastasis. This article reviews the anticancer activity of various CHMs with the hope of providing a better understanding of how to best use CHM for HCC treatment.