Efficacy comparison of the novel water-soluble propofol prodrug HX0969w and fospropofol in mice and rats.

BACKGROUND HX0969w is a novel water-soluble prodrug designed to release propofol and gamma-hydroxybutyrate (GHB) and has a sedative-hypnotic effect. This study was performed to compare the efficacy of HX0969w with fospropofol in mice and rats. METHODS We performed hydrolysis studies in the plasma from mice and rats. The half-maximal effective doses (ED50) and half-maximal lethal doses (LD50) of fospropofol and HX0969w were determined. A pharmacodynamics comparison of these two compounds was also performed. Time to loss of righting reflex, time to return of righting reflex, recovery time, and adverse effects were recorded. RESULTS The hydrolysis studies demonstrated that HX0969w released propofol as expected. HX0969w ED50 values in mice and rats were 133.03 and 53.79 mg kg(-1), respectively, and LD50 values were 607.11 and 283.79 mg kg(-1), respectively. The calculated therapeutic index (TI), safety index (SI), and certain safety factor (CSF) of HX0969w were 4.56, 3.33, and 2.92 for mice, and 5.28, 3.94, and 3.49 for rats, respectively. The pharmacodynamic comparison studies suggest that HX0969w has a longer onset time and shorter duration than fospropofol. CONCLUSIONS Similar to fospropofol, HX0969w is an effective, water-soluble prodrug that is capable of inducing a sedative-hypnotic effect in mice and rats. Unlike fospropofol, HX0969w releases GHB instead of formaldehyde. Further studies regarding the efficacy and safety of HX0969w are necessary.