A Double‐Blind, Randomized, Crossover Comparative Study for Evaluating the Clinical Safety of Ephedrine Alkaloids‐Free Ephedra Herb Extract (EFE)

Abstract

Ephedra Herb is an important crude drug; it is used in various Traditional Japanese Medicine (Kampo) formulations. Its significant pharmacological effects have been believed to be attributed to ephedrine and pseudoephedrine, which sometimes induce adverse effects. On the other hand, it has been reported that some of these pharmacological effects are not dependent on ephedrine or pseudoephedrine. Ephedrine alkaloids-free Ephedra Herb extract has been newly developed. It has been reported to have analgesic, anti-influenza, and antimetastatic effects. This clinical trial was aimed at verifying the noninferiority of EFE's safety compared to that of Ephedra Herb extract (EHE) in humans. This was a single-institution, double-blinded, randomized, two-drug, two-stage, crossover comparative study. Twelve healthy male subjects were equally and randomly allocated into two groups: prior administration of EFE (EFE-P) and prior administration of EHE (EHE-P). In Stage 1, EFE and EHE were orally administered to the EFE-P and EHE-P groups, respectively, for six days. After a 4-week washout period, Stage 2 was initiated wherein the subjects were given a study drug different from Stage 1 study drug for six days. Eleven adverse events with a causal relationship to the study drugs (EHE: 8; EFE: 3) were noted; all events were mild in severity. With regard to the incidence of adverse events, EHE and EFE administration, respectively, accounted for 4 cases (out of 12 subjects, similarly below) and 1 case of increased pulse rate (p=0.32) and 3 cases and 1 case of insomnia (p=0.59). Further, there was one case of hot flashes (p=1.00) due to EFE administration and one case of dysuria (p=1.00) due to EHE administration. There were no significant differences in the incidences of adverse events between EHE administration and EFE administration. Therefore, we concluded that EFE is not inferior to EHE in terms of safety.

Effect of Ephedra Herb on Erlotinib Resistance in c‐Met‐Overexpressing Non‐Small‐Cell Lung Cancer Cell Line, H1993, through Promotion of Endocytosis and Degradation of c‐Met

“…EFE may be better suited for clinical treatment than EHE, because ephedrine alkaloids may cause side-effects. Recently, we reported that EFE treatment has none of the adverse sideeffects, such as excitation, insomnia, and arrhythmia, observed with ephedrine alkaloids [20], and we revealed the clinical safety of EFE in a double-blind, randomized, crossover comparative study [21]. In the future, we hope to obtain licensing approval for the therapeutic use of EFE.…”

Antiviral Effect of Ephedrine Alkaloids-Free Ephedra Herb Extract against SARS-CoV-2 In Vitro

“…EFE has been shown to reduce the side effects of Ephedra Herb such as excitation, insomnia, and arrhythmias [ 6 ], and to have a high safety profile for humans [ 7 ]. Thus, it is expected to have a wide range of applications for the treatment of COVID-19.…”

“…EFE retained the same level of anti-influenza, analgesic, and anticancer effects as the Ephedra Herb [ 5 ]. We have previously reported that alkaloid-derived side effects are reduced [ 6 ], and that EFE is safer than the Ephedra Herb in humans [ 7 ].…”

Regulatory science of natural products

“…In 2016, Dr. Odaguchi (OMRC-Kitasato) and our cooperative team performed a double-blind, randomized, crossover comparative study to evaluate the clinical safety of EFE (UMIN000022061) [ 142 ]. The results suggested that EFE was not inferior to EHE in terms of safety.…”