HM30181A,a potent P-glycoprotein inhibitor,potentiates the absorption and in vivo antitumor efficacy of paclitaxel in an orthotopic brain tumor model

Objective:Delivery of chemotherapeutic drugs to the brain has remained a major obstacle in the treatment of glioma,owing to the presence of the blood-brain barrier and the activity of P-gp,which pumps its substrate back into the systemic circulation.The aim of the present study was to develop an intravenous formulation of HM30181 A(HM)to inhibit P-gp in the brain to effectively deliver paclitaxel(PTX)for the treatment of malignant glioma.Methods:Two formulations of solubilized HM were designed on the basis of different solid dispersion strategies:i)spray-drying[polyvinlypyrrolidone(PVP)-HM]and ii)solvent evaporation[HP-β-cyclodextrin(cyclodextrin)-HM].The P-gp inhibition of these 2 formulations was assessed on the basis of rhodamine 123 uptake in cancer cells.Blood and brain pharmacokinetic parameters were also determined,and the antitumor effect of cyclodextrin-HM with PTX was evaluated in an orthotopic glioma xenograft mouse model.Results:Although both PVP-HM and cyclodextrin-HM formulations showed promising P-gp inhibition activity in vitro,cyclodextrin-HM had a higher maximum tolerated dose in mice than did PVP-HM.Pharmacokinetic study of cyclodextrin-HM revealed a plasma concentration plateau at 20 mg/kg,and the mice began to lose weight at doses above this level.Cyclodextrin-HM(10 mg/kg)administered with PTX at 10 mg/kg showed optimal antitumor activity in a mouse model,according to both tumor volume measurement and survival time(P<0.05).Conclusions:In a mouse orthotopic brain tumor model,the intravenous co-administration of cyclodextrin-HM with PTX showed potent antitumor effects and therefore may have potential for glioma therapy in humans.

Effect of Rorrico, extracted from group of Chinese medicines, on influenza A and H1N1 infections

OBJECTIVE: To investigate the therapeutic and preventive effects of Rorrico on influenza, especially influenza A viral infection, including swine flu(H1N1)in humans.METHODS: Eighty-nine subjects were recruited in Hong Kong and Macao, and divided into treatment group(TG) and prevention group(PG) based on their influenza A and swine flu symptoms. All subjects were prescribed Rorrico or placebo, and monitored by a Chinese medicine practitioner. Blood samples were collected before and after 7-day Rorrico or placebo treatment for laboratory investigations.RESULTS: After treatment, there were some full recoveries and obvious relief of onset symptoms in the TG. Blood test results showed that Rorrico produced(a) no adverse effects on subjects' renal andliver functions, muscle enzyme and hematological status,(b) no up-regulation of pro-inflammatory cytokines tumour necrosis factor-a and interleukin-18 in both TG and PG,(c) mild yet statistically significant elevation of plasma mannose-binding lectin(MBL) in PG.CONCLUSION: Rorrico has no up-regulating effect on the participants' immune response, or, equally likely, the immuno-modulatory effects of Rorrico do not non-specifically or unnecessarily promote inflammation when not required. It is possible that oral administration of Rorrico can promote hepatic synthesis of MBL in healthy PG subjects, thereby conferring increased protection against infection.