The pharmacological actions of ephedrine alkaloids-free Ephreda Herb extract and preparation for clinical application

Abstract

Ephedra Herb is defined in the 17th edition of the Japanese Pharmacopoeia as the terrestrial stem of Ephedra sinica Stapf., Ephedra intermedia Schrenk et C.A. Meyer, or Ephedra equisetina Bunge (Ephedraceae) which contains more than 0.7% ephedrine alkaloids (ephedrine and pseudoephedrine). The primary effects and adverse effects of Ephedra Herb are traditionally believed to be mediated by ephedrine alkaloids. We recently reported that Ephedra Herb extract (EHE) exhibits antimetastatic and antitumor effects by suppressing the hepatocyte growth factor-c-Met signaling pathway through the inhibition of c-Met tyrosine kinase activity. We confirmed that the non-alkaloidal fraction of EHE had c-Met-inhibitory activity. Moreover, we discovered herbacetin glycosides in EHE and demonstrated that her-bacetin, the aglycone of the glycosides, shows c-Met-inhibitory activity and analgesic action. These findings suggest that some pharmacological actions of EHE may be produced by its non-alkaloidal fraction, which does not cause the adverse effects of ephedrine alkaloids. Therefore, we prepared ephedrine alkaloids-free EHE (EFE) by removing ephedrine alkaloids from EHE using ion-exchange column chromatography. EFE had c-Met-inhibitory action, analgesic effects, and antiinfluenza activity similar to EHE but had no toxicity. Now, we are evaluating the safety of EFE in healthy volunteers and its efficacy in patients to obtain licensing approval for its therapeutic use in the future.