| ObjectiveThallium and its compounds are toxic, acute or chronic exposure to high intake can cause poisoning. Thallium salt has gradually become one of the major toxic poison or terrorist attacks in the category at home and abroad.We have no standard clinical treatment of thallium poisoning.Considering the existed clinical case reports,We select different treatments:Prussian Blue(PB), hemoperfusion( HP) and PB+HP.To determine thallium in whole blood and tissue by atomic absorption detection method, and to investigate the eliminating power of HP for thallium in blood.On the basis,to set up acute thallium poisoning model on Beagle dogs,observe the state of animals after exposure,explore the effect of different treatments for acute thallium poisoning,and provide experimental evidence and theoretical support for the clinical treatment.METHODS1.We built applications of detecting thallium in blood and digestion solution of organization by atomic absorption spectrometer,and complete the method validation;2.Established exposure model in vitro and monitored:9 healthy dogs were used for testing(weight 8~10Kg).The blood of 9 Beagle dogs which had not exposed to thallium before were taken to prepare to different concentration of thallium-containing solution according to the conversion formula based on animal weight and volume of blood. High, middle, and low dose of thallium nitrate( Tl NO3)were prepared with different concentration of thallium in blood, and then HP was performed in the simulated vivo environment. The blood samples were harvested before and after HP for thallium measurement by atomic absorption spectrometer,which was originally set up in this study. Finally, the thallium concentration in blood was analyzed statistically;3.Established exposure model in vivo and monitored:24 healthy Beagle dogs withequal males and females were randomly divided into 4 groups(n=6),and they were poisoned by median lethal dose(LD50=45mg/Kg) of Tl NO3 by gavage.Gave different therapeutic measures to each group,including control(exposed to Tl NO3 and then give normal saline 50 ml gavage,3 times a day for 5 days),PB(4h after exposure then give PB 467mg/Kg/d gavage,3 times a day for 5 days,reference the USA FDA recommended PB treatment amount),HP(4h after exposure then give HP 2h,once a day for 5 days)and PB+ HP(combined PB with HP).Observed changement of exposured animals for 10 day.Collected blood at different times before and after exposure0.5h,1h,2h,3h,4h,6h,8h,12 h,24h,48 h,96h,120 h,144h,168 h,192h,216 h,240h to detect thallium concentration in blood and analyzed the pharmacokinetics;collected blood at different times before and after exposure 12 h,24h,48 h,96h,120 h,144h,168 h,192h,216 h,240h to acquire the difference of biochemical indexes;in the end accessed tissue specimen of brain( cortex,hippocampus,corpus striatum,hypothalamus,cerebellum,brain stem),liver and kidney from dead animals.Measured thallium concentration of these samples by atomic absorption spectrometer.All these data were analyzed statistically.RESULTS1.Results of the test method and its methodological studyThallium had a good linear relationship in the range of 0~200 μg/L in blood and0~100 μg/L in tissue digestion solution( r=0.9996,0.9987); the intra-day precision(RSD)was less than 8.7%,the intra-day recovery rate was 88.2%~117.5%, the inter-day precision( RSD) was less than 9.8%,the inter-day recovery rate was89.58% ~110.0%.2. Results of exposure model in vitroThis part was about investigation the eliminating power of HP for thallium in blood.The concentration of thallium in blood was significantly reduced after four times HP among different groups,87.36% in high dose group,94.84% in medium dose group,and 92.72% in low dose group( F=4.231, P= 0.07).3.Results of exposure model in vivoThis part was about analysis on the relevant indicators and parameters of different treatment models,and the efficacy of different treatment methods.3.1 Changment of thallium in blood:Content of thallium in blood of treatment groups were lower than control, which had significant difference( P<0.001).There was no significant difference among treatment groups( P>0.05).But the PB+HPgroup decreased most significantly, followed by HP group,PB group was the last;We did statistical analysis of each time of blood collected.The onser time of PB+HP( the starting time of statistical significance compared with the control group) was 6h after the treatment( P=0.007),HP was 8h( P=0.025), PB was24h( P=0.008), since the treatment effecting to the end of the observation,the treatment groups had significant difference compared with control group( P < 0.05), there was no significant difference among treatment groups( P < 0.05).3.2 Changment of toxicokinetic parameters:Compared treatment groups with control,there was significant difference of t1/2 in HP and PB+HP,Cmax in PB+HP,AUC0-t in PB,HP and PB+HP,MRT0-t in HP( P=0.029, 0.022, 0.034, 0.049,0.028,0.031, 0.029). There was no significant difference in other regions( P >0.05).There was no significant difference among treatment groups( P > 0.05).3.3 Changment of thallium in organs:The kidney had highest thallium content among detected tissues and organs.The concentration in different brain regions(cortex,hippocampus, corpus striatum, hypothalamus,cerebellum, brain stem),liver and kidney of treatment groups were lower than control group,decreased most significantly in striatum.Compared treatment groups with control,there was no significant difference in hypothalamus and brain stem( P > 0.05).Compared HP group with control,there was no significant difference in hippocampus, cerebellum and cortex( P= 0.084, 0.052,0.057).Compared PB+HP group with control,there was no significant difference incortex( P=0.05).There was significant difference in other regions between treatment groups and control.The comparison among treatment groups, there was significantly decreased trend in hypothalamus, brain stem,liver and kidney by PB+HP compared with PB( P = 0.038, 0.049, 0.012, 0.013). there was no significant difference of these four regions( P >0.05); There was significant difference in hippocampus,corpus stratum and cortex among treatment groups( P <0.05).3.4 Changement of biochemical indicators:The damagement in function of liver and kidney of treatment groups was light than control.There was significant difference of ALT in PB+HP,BUN in PB,HP and PB+HP( P = 0.043, 0.001, 0.002, 0.001).There was no significant difference in other indexes( P > 0.05).There was no significant difference among treatment groups(P > 0.05).3.5 Changement of survival trends:The survival time was prolonged in treatment groups,and PB group was most obviously,but there was no significant differencebetween treatment groups and control or among treatment groups( P > 0.05).CONCLUSIONThe test for measuring thallium of blood and tissue was set up, which show a very sensitive detective capacity for thallium,and it was also stable and simple.HP could effectively get rid of the thallium out of blood. Thallium concentration could reduce by 90% after 4 times of HP. HP was also effective even thallium concentration was not high enough. PB, HP and PB+HP treatment were all effective for acut thallium poisoning, they could remove toxins, accelerate poison release, reduce liver and kidney dysfunction,and lessen the distribution in tissue.Overallconsideration,PB+HP onset rapidly, removed poison mostly, reduced damage of tissue effectively.It might be the most ideal method of the treatment of acute thallium poisoning. |
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