A Study On Toxicity,pharmacokinetics And Antibacterial Activity Of Amphenmulin

A series of novel pleuromutilin derivatives were synthesized in our lab,and the in vitro antibacterial activities of these derivatives against bacterium were evaluated.The results shown that Amphenmulin has excellent antibacterial activity.In order to evaluate the effectiveness and safety of Amphenmulin,we studieda subsequent pharmacological investigation of Amphenmulin,containingacute toxicity?pharmacokinetic studies and antibacterial activity in vivo in mice.The in vitro minimum inhibitory concentration,bacterial time-killing curves and post-antibiotic effectandof Amphenmulin againstStaphylococcus aureuswere investigated.The results showed that Amphenmulin has a excellent antibacrerial activity against S.aureus,the Minimal inhibitory concentration=0.0156–8?g/m L.The in vitro bacterial time-killing curves were esblished to determine the rate and extent of bacterial killing by Amphenmulin against S.aureus in broth.According to the bacterial killing profile,the antibacterial activity of Amphenmulin against S.aureus is abviously time-dependent.The PAEs of S.aureus exposed to 4MIC Amphenmulin for 1h and 2h were 1.78 h and 2.83h respectively,which indicate that Amphenmulin has a prolonged PAE to S.aureus.We carried out a preliminary study on the acute toxicity of Amphenmulin in vivo.mice were stratified by weight and randomly assigned to six groups:five treatment groups and one vehicle control group,The results showed that when the maximal dose of 5000 mg/kg was given,no death occurred,The results show that the 50%lethal dose(LD₅₀)of Amphenmulin was abouve 5000 mg/kg,This shows that Ampenmulin was anon-toxic profile and has a high security as a new drug.A sensitive,specific,accurate liquid chromatography tandem mass spectrometry?LC-MS?MS?method for the determination of Amphenmulin in mice plasma was developed.The plasma concentration-time data of the Amphenmulin were analyzed with non-compartmental method.After IV administration,the mean values of pharmacokinetic parameters included T_1/2,AUC,MRT were 1.92±0.28 h,12.23±1.35?g·h/mL,2.57±0.19 h respectively.and after IM administration,the mean values of pharmacokinetic parameters afterincluded T_1/2,AUC,MRT were 2.64±0.72 h,2.52±0.81?g·h/mL,3.28±0.42 h respectively,The corresponding values were 2.91±0.81 h,1.67±0.66?g·h/m L,4.01±0.62 h,following P.O administration.In this study,we investigated the antimicrobial activity of Amphenmulin against skintrauma-mediated MRSA infection in mice.The mice was treatment with Amphenmulin or vancomycin.The levels of TNF-?,IL-6 and MCP-1 in the serum of mice were measured by ELISA,and we measured the number of bacteria colonized at the wound aerea.The results showed that Amphenmulin decreased MRSA bacterial counts in the wounded region,enhanced wound closure and promote the healing of wound.Treatment with Amphenmulin decreased serum levels of the proinflammatory cytokines TNF-?,IL-6 and MCP-1.Inconclusion,Amphenmulin may be effective at treating clinical MRSA,and may enhance wound recovery.