AIM To provide toxicokinetics data for toxicity studies of repeated doses of sodium 9-[2-(phosphonomethoxy) ethyl] adenine (PMEA-Na). METHODS The concentrations of PMEA-Na in plasma and urine were determined by HPLC/MS/MS method after single and multiple iv administrations in dogs. Data were executed by the statistical moment method to acquire the toxicokinetics parameters. Serum biochemical tests and histopathological examination were performed. RESULTS The system exposure of PMEA-Na in dogs was dose-dependent over the dose range of 1.0-6.0 mg·kg-1. The areas under the plasma concentration-time curve of PMEA-Na after single and multiple iv administrations at 1.0, 3.0 and 6.0 mg·kg-1 dosage were (2.3±0.5), (8.4±1.6), (17.5±3.7) and (5.0±0.4), (15.9±3.2), (30.3±4.7)mg·L-1·h, respectively. The urinary excretion of PMEA-Na in 72 h after iv administration was (87.0±4.8)% at the dose of 3.0 mg·kg-1. In 6.0 mg·kg-1 dose group, liver enzyme activity of glutamic-pyruvic transaminase and serum levels of total bilirubin, blood urea nitrogen, creatinine and triglycerides were all significantly elevated; glucose level significantly decreased comparing with the control group. Histopathological observation showed distinct pathological changes in liver and kidney tissues of 6.0 mg·kg-1 dose group. CONCLUSION There was evidence of toxicity after repeated-dose (14 d) of PMEA-Na in dogs and the major toxicity target organs were the kidney and liver.

Objective To preliminarily explore the effects and brain protective mechanism of intermittent hypoxia preconditioning ( IHP) on rats with seizures induced by lithium-pilocarpine ( Li-pilo) .Methods A total of 96 8-week old male Sprague Dawley rats ( clean grade ) were randomly divided into control group , seizure group and four IHP-seizure groups.The animal model of epilepsy was established by intraperitoneal injection of Li-pilo in the seizure group and four IHP-seizure groups (Li-pilo was injected at 1, 3, 7, or 14 days after a 5-day regimen of IHP).Subsequent seizure behavior , the latency period and percentage of generalized seizures were quantitatively evaluated for 240 min and the cognitive function was tested by Morris water maze task , and followed by the detection of hippocampus neuron apoptosis and related protein (BCL-2, Bax, and cleaved-caspase-3) by TUNEL labeling and Western blot, respectively.Results The induced seizure peaked on an average between 50-150 min after Li-pilo administration , scored using a modified Racine scale.The average scores of modified Racine scale in the IHP-3d seizure group was significantly lower than that in the other groups.The latency period and percentage of generalized seizures in the IHP-3d seizure group rats were significantly different from the parameters in the seizure group rats (P<0.05).IHP-3d seizure rats showed lower escape latency, neuronal apoptosis counts and higher percentage of time in the probe quadrant compare with the seizure group and the other three IHP-seizure groups ( P <0.05 ) .Compared with the control group , the parameters of water maze and apoptosis detection in the IHP-3d seizure group showed no significant changes (P>0.05).Conclusions The results indicate that IHP treatment may help to decrease the susceptibility to epilepsy by reducing abnormal apoptosis , and has a brain protective effect on the seizure rats .

Objective Study on skin irritation and allergenicity of indomethacin emulsion ,in order to provide theoretical basis for clinical safe medication .Methods New Zealand white rabbits were used to test skin irritation ,given 0 .5g test sub-stance for 14 days .The skin irritation was observed in the two groups with eight rabbits each during the experiment .Six rab-bits in each group were sacrificed 72 hours after the last medication and skin tissues were taken for histopathology examination ;and the skin tissues of remaining two rabbits were taken for histopathology examination in 14th day after the last medication . Guinea pigs were used to test skin allergenicity ,given 0 .5g test substance on day 0 ,7 ,14 for local induction .On day 28 ,the animal subjects were given 0 .4g test substance on non-administration skin of guinea pigs for local excitation .Results Slight ir-ritation of indomethacin emulsion on normal or damaged skin was observed but it is reversible after withdrawal for rabbits .Sen-sitization effect on the skin of guinea pig was not found .Conclusion Indomethacin emulsion is not suitable to long-term use clinically ,and skin irritation need to pay more attention .