(Z)-Butylidenephthalide

Local interstitial delivery of z-butylidenephthalide by polymer wafers against malignant human gliomas.[Pubmed:21565841]

Neuro Oncol. 2011 Jun;13(6):635-48.

We have shown that the natural compound z-butylidenephthalide (Bdph), isolated from the chloroform extract of Angelica sinensis, has antitumor effects. Because of the limitation of the blood-brain barrier, the Bdph dosage required for treatment of glioma is relatively high. To solve this problem, we developed a local-release system with Bdph incorporated into a biodegradable polyanhydride material, p(CPP-SA; Bdph-Wafer), and investigated its antitumor effects. On the basis of in vitro release kinetics, we demonstrated that the Bdph-Wafer released 50% of the available Bdph by the sixth day, and the release reached a plateau phase (90% of Bdph) by the 30th day. To investigate the in situ antitumor effects of the Bdph-Wafer on glioblastoma multiforme (GBM), we used 2 xenograft animal models-F344 rats (for rat GBM) and nude mice (for human GBM)-which were injected with RG2 and DBTRG-05MG cells, respectively, for tumor formation and subsequently treated subcutaneously with Bdph-Wafers. We observed a significant inhibitory effect on tumor growth, with no significant adverse effects on the rodents. Moreover, we demonstrated that the antitumor effect of Bdph on RG2 cells was via the PKC pathway, which upregulated Nurr77 and promoted its translocation from the nucleus to the cytoplasm. Finally, to study the effect of the interstitial administration of Bdph in cranial brain tumor, Bdph-Wafers were surgically placed in FGF-SV40 transgenic mice. Our Bdph-Wafer significantly reduced tumor size in a dose-dependent manner. In summary, our study showed that p(CPP-SA) containing Bdph delivered a sufficient concentration of Bdph to the tumor site and effectively inhibited the tumor growth in the glioma.

Metabolic conversion from co-existing ingredient leading to significant systemic exposure of Z-butylidenephthalide, a minor ingredient in Chuanxiong Rhizoma in rats.[Pubmed:22554277]

Curr Drug Metab. 2012 Jun 1;13(5):524-34.

Pharmacokinetic (PK) study of medicinal herbs is a great challenge, because which component(s) is(are) the bioactive ingredients is largely unknown. Most of the reported PK studies of herbs focused on the major ingredients regardless of their in vivo bioactivities, while PK of components with low content in herbs is often ignored. The present study demonstrates how PK study can reveal potential importance of a low content ingredient to the herbal bioactivities using Z-butylidenephthalide (BuPh), a bioactive phthalide present in a significantly low quantity in medicinal herb Chuanxiong Rhizoma, as an example. PK of BuPh was investigated in rats using Chuanxiong extract, fraction containing BuPh and ligustilide, and pure BuPh, respectively. The results demonstrated that remarkable blood concentrations of BuPh were observed after administration of the herbal extract and its systemic exposure was significantly different between BuPh given in pure and mixed forms. More interestingly, AUC of BuPh via intake of fraction (9.3-fold) and extract (4.5-fold) was significantly greater than that obtained from pure BuPh, which was further evidenced to be mainly due to metabolic conversion from ligustilide, a major component in Chuanxiong. Our findings revealed that although it naturally occurred in low amount, BuPh reached significant systemic concentrations via metabolic conversion from ligustilide. Moreover, our results demonstrated that PK study is one of crucial and inevitable steps for revealing in vivo bioactive ingredients of herbal medicines, and such studies should be more appropriate to focus on in vivo profile of the ingredients co-existing in herbs rather than only studying them individually.

Optimization of pressurized liquid extraction for Z-ligustilide, Z-butylidenephthalide and ferulic acid in Angelica sinensis.[Pubmed:16242882]

J Pharm Biomed Anal. 2006 Mar 18;40(5):1073-9.

Pressurized liquid extraction, one of the most promising and recent sample preparation techniques, offers the advantages of reducing solvent consumption and allowing for automated sample handling. It is being exploited in diverse areas because of its distinct advantages. However, because the extraction is performed at elevated temperatures using PLE, thermal degradation could be a concern. Z-ligustilide, one of the biologically active components in Angelica sinensis, is an unstable compound, which decomposes rapidly at high temperature. In this study, we carried out a comparative study to evaluate PLE as a possible alternative to current extraction methods like Soxhlet and sonication for simultaneous extraction of Z-ligustilide, Z-butylidenephthalide and ferulic acid in A. sinensis. The operating parameters for PLE including extraction solvent, particle size, pressure, temperature, static extraction time, flush volume and numbers of extraction were optimized by using univariate approach coupled with central composite design (CCD) in order to obtain the highest extraction efficiency. Determination of Z-ligustilide, Z-butylidenephthalide and ferulic acid were carried out by means of high performance liquid chromatography with diode-array detector. The results showed that PLE was a simple, high efficient and automated method with lower solvent consumption compared to conventional extraction methods such as Soxhlet and sonication. PLE could be used for simultaneous extraction of Z-ligustilide, Z-butylidenephthalide and ferulic acid in A. sinensis.