1). The previous studies leading to the current reporting period, include 1). We were able to show the benefit of the ethyl acetate extract of the Chinese herbal medicine, Tripterygium wilfordii hook F (TwHF), to the patients with rheumatoid arthritis by a double blind trial; 2). Established the techniques to produce and identify the EA extract of TwHF for clinical trials 3). Delineated the mechanism of the anti-inflammatory and immunossupressive action of the extract of TwHF and its active components that is related to inhibition of transcriptional activation of NFkB, AP-1 and NFAT ; 4). Obtained and identified the usefulness of large quantity of the TwHF materials for further clinical trials. 2). The objectives of the current work are to support a phaseII/III clinical trial on RA. 3). a). We have examined the new EA extract of TwHF made by Phytomedics based on the protocol we provided. The examinations include : TLC and HPLC pattern matching to previous batches of the EA extracts; quantitative measurement of the content of the active components by HPLC; in vivo acute toxicity in mice; in vitro bioactivities. The dose of the EA extract has been determined for clinical trials based upon reproducible results obtained from multiple time measurements and comparable to the EA extracts of previous batches that have been successfully used in RA patients. The therapeutic effect and the safety of the new EA extract have currently been evaluated by a multiple center clinical trial on RA patients. b).We has completed the pharmacokinetic study on the new EA extract and its active component, triptolide, in rats. We have known from the studies that the bioavailability of the EA extract is about 60%. The absorbed triptolide is eliminated up to 90% through urinary tract within 24 hours after administration. Most of the administered triptolide was eliminated as a single metabolite that exhibits similar HPLS pattern and bioactivities to another active ditepenoid of TwHF, tripdiolide. The presence of other components in the EA extract does not significantly interfere with the pharmacokinetic pattern of triptolide. These data provide a theoretical basis for employing triptolide in the treatment of patients with autoimmune diseases. c). By further examination of the inhibitory effect of triptolide on cell activation pathways, we have found that triptolide significantly block DNA binding of AP-1, NFkB, NFAT as well as Oct-1 suggesting triptolide inhibits transcription activation of AP-1, NFkB and NFAT before these transcription factors bind to DNA. These natures of triptolide are very similar to dexamethasone, an agonist of glucocorticoid. However, triptolide has no effect on phosphorylation of mitogen-activated protein kinases including JNK, ErK and p38 however that is different from dexamethasone. These data in conjunction with previous findings that the extract of TwHF did not inhibit early signal transduction suggest that triptolide shares similar mechanism with glucocorticoids for the anti-inflammatory and immunosuppressive effect through blocking multiple transcription factor binding to DNA. The molecular mechanism for the adverse effect of glucocorticoids may be related to the earlier steps of signal transduction and cell activation processes that triptolide has no influence. 4). In summary, an EA extract has been evaluated pre-clinically and currently tested by clinical trials. Basic research on absorption, elimination and metabolism of triptolide and on the molecular mechanism for triptolide-mediated immunosuppressive and anti-inflammatory effect has provided some basis for the clinical application of triptolide. 5). Future studies will be focused on the efficacy of the EA extract or triptolide on other autoimmune diseases including SLE and psoriasis. The pre-clinical studies will include identification of triptolide metabolites in the urine and determination of the efficacy of the EA extract or triptolide or its metabolite on animal models of human SLE, the NZB/WF1 mice.
| Tao, Xuelian; Fan, Fred; Hoffmann, Victoria et al. (2006) Therapeutic impact of the ethyl acetate extract of Tripterygium wilfordii Hook F on nephritis in NZB/W F1 mice. Arthritis Res Ther 8:R24 |
| Tao, Xuelian; Younger, Jean; Fan, Fred Z et al. (2002) Benefit of an extract of Tripterygium Wilfordii Hook F in patients with rheumatoid arthritis: a double-blind, placebo-controlled study. Arthritis Rheum 46:1735-43 |
