Safety Evaluation Of Children With Multiple Tic Disorder Treated With Jianpi Zhixing Decoction And Establishment Of TS Model Of Spleen Deficiency Syndrome

Tourette syndrome (TS) is a common neuropsychiatric disease in childhood, which characterized by motor tics and (or) vocal tics. With the gradual increase of the incidence and adverse effects to mental development and personality of children, TS has received a great deal of attentioa The commonly used dopamine-receptor antagonist, central alpha agonists and other drugs may appear a series of extrapyramidal reactions after taking, so it is difficult to accept by TS children and their parents. Supported by the project of young teachers in the Beijing University of Chinese medicine, safety of Jian-Pi-Zhi-Dong Decoction and spleen deficiency syndrome TS mice model was researched.Based on the theory ofchildren’s physiological characteristics "insufficient spleen, excess liver" and principle of treatment" reinforce the earth to reduce the wood, balance Yin and Yang", curative effect of Jian-Pi-Zhi-Dong Decoction on spleen deficiency and liver hyperactivity TS children by Professor Wang Sumei is significantly. TS has recurrence and long duration, so clinical medication time is often long. The safety of Jian-Pi-Zhi-Dong Decoction needs to be evaluated. The project studied retrospectively to explore the safety of the decoction in 12 weeks and laid the foundation for the development of new drugs in clinical application.In neural biochemical mechanism of Jian-Pi-Zhi-Dong Decoction researches, TS mice model induced by intraperitoneal injection IDPN were used, aimed at neurotransmitters in cortico-striato-thalamo-cortical (CSTC) loop, including dopamine (DA), serotonin (5-HT), norepinepbrine (NE), y-amino butyric acid (GABA), glutamate (Glu) and receptors. But animal disease model is difficult to reflect the characteristics of syndrome differentiation of Chinese Medicine. Construction of spleen deficiency TS animal model is the inevitable.The first part:Literature Review.Review one:Research Progress in Establishment of Animal Model of Chinese MedicineOverview the current animal model establishment methods of Chinese Medicine, including disease animal model, syndrome animal model and combine model.Review two:Progress in the Study of Western Medicine in Children with Tourette syndromeOverview the latest research progress of TS epidemiology, etiology, and treatment, etc.The second part:Clinical StudySafety Evaluation of Jian-Pi-Zhi-Dong Decoction in Treating Children with Tourette syndromeObjective:To explore the safety of Jian-Pi-Zhi-Dong Decoction for 12 weeks and lay the foundation for further.Methods:91 cases of spleen deficiency and liver hyperactivity TS children were compared in liver function, renal function, ASO before and after the treatment.Results:After 12 weeks, liver function of ALT and AST were elevated in 1 case, renal function of Cr, BUN had no increase after treatment. Cr decreased after treatment was reached in 86 cases, accounted for 94.5%. ASO after treatment than before treatment decreased significantly.Conclusion:Jian-Pi-Zhi-Dong Decoction in treating spleen deficiency and liver hyperactivity of TS for 12 weeks has no obvious damage to liver and kidney function, with good safety, and can control the streptococcal infection.The third part:Experimental StudyExperiment one:Establishment of Tourette syndrome Model of Spleen Deficiency and Preliminary EvaluationObjective:To establish spleen deficiency TS mouse model and research general characteristics of it. Provide the model foundation for further exploration on biological characteristics and Jian-Pi-Zhi-Dong Decoction.Methods:30 male ICR mice were randomly divided into 3 groups,10 rats in control group, model group, and spleen deficiency group respectively. Mice in model group and spleen deficiency group were intraperitoneal injection of IDPN,350 mg·kg-1·d-1 (IDPN stock solution was diluted with physiological saline 50 times,17 ml·kg-1·d-1), control group salineintraperitoneal injection of equal volume.1 times a day, for 8 consecutive days. From the first day, spleen deficiency group mice were gastric lavage in Senna granules solution,20 ml·kg-1·d-1 (Sennagranules in warm water to dissolve,1 g·ml-1),8 consecutive days. Observe the activity, morphology, hair color, diet, defecation and abdomen shape, surface changes. Through the independent activity counts, stereotyped movement score, body weight, food intake, stool grains, thymus and spleen index, gastrin, D-xylose and other indexes of spleen deficiency, TS mice were evaluated.Results:After modeling, the activity distance and average speed in the same time was significantly increased, and stereotyped movement had no significant difference between model group and spleen deficiency group. Compared with control group, no significant difference in body weight in spleen deficiency and model group after making the mold, but the overall weight was lower, especially spleen deficiency group. Intake of spleen deficiency group was lower at the same time compared with the control group and model group, particularly obvious after the first week. Fecal particle number is basically the same after modeling, but with the extension of time, from the fourteenth day, the number of fecal particles increasing higher amplitude in spleen deficiency group in a premise of the death of a mouse. Thymus index, spleen index and gastrin, D-xylose concentration have no significant statistical difference.Conclusion:TS model induced by intraperitoneal injection of IDPN 350 mg·kg-1·d-1 is stable. Surface validity is good, and can maintain a longer period of time (at least 1 month). Combined with the concentration of 1g·ml-1 Sennagranules solution 20 ml·kg-1·d-1 gavage, tic symptom is stable, with some symptoms of spleen deficiency syndrome, and have face validity of spleen deficiency syndrome of TS to a certain extent. But overall, the biological behavior is poor.Experiment two:Comparison of Two Spleen Deficiency Syndrome of Tourette syndrome ModelsObjective:To establish and compare spleen deficiency syndrome TS mouse models by rhubarb and senna.Methods:36 male ICR mice were randomly divided into 3 groups,10 rats in control group, rhubarb group and senna group respectively. All mice were intraperitoneal injection of IDPN,350 mg·kg-1·d-1 (IDPN stock solution was diluted with physiological saline 50 times, 17ml·kg-1·d-1) for 8 consecutive days. From the first day, mice in rhubarb group were given rhubarb granules solution,50ml·kg-1·d-1 (Dahuang granule warm water to dissolve, 1g·ml 1), 8 consecutive days. Senna group mice were given Senna granules solution by gavage,50 ml·kg-1·d-1 (Senna granules in warm water to dissolve, 1g/ml),8 consecutive days. Observe the activity, morphology, hair color, diet, defecation and abdomen shape, surface changes, rigid motion score, thymus and spleen index, gastrin, D-xylose.Results:Mice in rhubarb group and senna group appeared slow weight gain, loss of appetite, a slight contamination of anus, stool and other symptoms of spleen deficiency, besides twitch and rotational behaviors. Compared with the model group, spleen index and D-xylose concentrations were significantly decreased in rhubarb group, while D-xylose decreased only in Senna group.Conclusion:ICR mice by intraperitoneal injection of IDPN 350 mg·kg-1·d-1 with a concentration of 1g·ml-1 rhubarb granules solution 50 ml·kg-1·d-1 have face validity and structure validity of spleen deficiency TS to some extent, and better than the model which is induced by Senna granules solution gastric perfusion 50ml·kg-1·d-1.