Introduction
respiratory infectious diseases, deaths, Forsythiae Fructus
CONTAGIOUS DISEASE, PROLIFERATION, INFLUENZA, COMMON COLD, INFLUENZA
Influenza, a highly contagious disease, is a global health, medical and economic health problem. Worldwide, the annual number of deaths resulting from influenza is approximately 290,000–650,000 [Forsythiae Fructus (FF, Lianqiao in Chinese) is widely used for the clinical treatment of respiratory infectious diseases in China, Japan and Korea [Forsythin has several pharmacological effects, including antiviral, antipyretic, anti-fibrotic [Forsythin is being developed as a novel drug to treat the common cold and influenza. In preclinical studies, forsythin has shown antiviral effects, antipyretic–analgesic and anti-inflammatory effects. The antipyretic–analgesic effect results from sweating, antiviral effects and decreased levels of prostaglandin E2 (PGE2), Interleukin-1β (IL-1β) and cyclic adenosine monophosphate (cAMP) in the brain tissue of model animals. The antiviral effect was related to the inhibition of viral proliferation and reduction of inflammatory cytokines. Forsythin showed dose-dependent antiviral effects in mouse models. Based on preclinical pharmacodynamic results, two metabolites, aglycone M1 and M1 sulphate (M2), were found to be active. The activity of M2 was higher than that of M1 but lower than that of forsythin. The no-observed-adverse-effect level of forsythin was 6.4 g/kg for Sprague Dawley rats and 0.8 g/kg for Beagle dogs. In different animal models, the effective dose was 6.75–27 mg/kg of forsythin. Forsythin showed good antiviral effects at a dose range of 16–26 mg/kg. Therefore, the human equivalent effective dose is 65–260 mg. Preclinical data of forsythin indicated that the maximum tolerable starting dose in initial clinical trials in healthy adult volunteers was 2592 mg, with a 10-fold tolerability factor [The objective of this phase 1a trial was to assess the safety, tolerability and pharmacokinetic (PK) profiles as well as the food effect of forsythin. This study helped select the dosages for the phase 2 study, which is currently conducted in China.