| Objective: This study was designed to observe the adverseeffects of selective cyclooxygenase-2(COX-2) inhibitor celecoxib combi-ning with anti-epileptic drugs(AEDs) carbamazepine for the treatment ofrefractory epilepsy rats, which included the change of antral mucosa,kidneys, coagulation and cTnT. The study of target organ toxicity was toprovide animal experimental basis for clinical medication safety. Method:1. experimental groups: the experiment was divided into seven groups:sham-operated group, the kainic acid surgery group, saline control group,carbamazepine therapy group, celecoxib therapy group, carbamazepinecombining with conventional dose celecoxib therapy group (combinationtherapy group), carbamazepine combining with high dose celecoxibtherapy(high-dose combination therapy group).2. the establishment ofrefractory epilepsy model: A, model of epilepsy: the model of epilepsywas established by kainic acid-induced hippocampal kinding. First, kainicacid(KA)1.5μg (1μg/μl) was injected to exactly right hippocampus CA3region of male Wistar rats, with hippocampal CA3region and the frontalsinus area mounted electrodes. Second, part of the post-operative ratswere classified to kainic acid surgery group, the rest were to epilepsymodel group when they experienced stage Ⅳ level seizures or more in0.5-6hours according to Racine classification and abnormal EEG. B, model of refractory epilepsy: the epilepsy model screened were given125mg/kg carbamazepine gavage treatment daily for28days. After28days, the epilepsy rats still having repeated seizures and abnormal EEGwere finally to refractory epilepsy model. C, sham-operated group:1.5μlsaline was injected into the rat right hippocampal CA3region, withhippocampal CA3region and the frontal sinus area mounted electrodes.3.the criteria of refractory epileptic model: A, seizures behavior after28days’ carbamazepine screening according to the Racine classification:stage0: normal; stage I: seizure was characterized by behavioral arrest,eye closure, facial clonus and ‘wet dog shakes’; stage II: head noddingassociated with more severe facial clonus; stage Ⅲ: clonus of oneforelimb; stage Ⅳ: bilateral clonus accompanied by rearing; stage Ⅴ:rearing and falling accompanied by generalized clonic seizures. Stage Ilevel seizures behavior or more were considered as abnormal behavior. B,EEG after28days,carbamazepine screening: normal rat EEG was5~12Hz wave and20~80μV volatility. Abnormal rat EEG such as highsharp amplitude was the diagnosis of epileptic seizures. C, abnormalbehavior and EEG indicate successful refractory epilepsy model.4. drugtreatment: seven experiment groups were given corresponding drugtreatment for28days.5, detection of indicators: rats were executed after28days’ treatment to detect rats histopathology of gastric antrum andkidney, coagulation and myocardial injury markers cTnT through cardiacblood. Results:1. The antral mucosal lesion rate of celecoxib therapy group, carbamazepine therapy group and combination therapy group werealways0, so there was no significant difference; There was no significantdifference between high-dose combination therapy group and salinegroup to the rats antral mucosal lesion rate(p=0.485, p>0.05). The resultssuggest that both carbamazepine combining with conventional dosecelecoxib and carbamazepine combining with high-dose celecoxib had noadverse effects on the rats gastric antrum in treating refractory epilepsy.2.The kidney tissue lesion rate of carbamazepine therapy group and salinegroup group were both0, so there was no significant difference. Therewas no significant difference between celecoxib therapy group and salinegroup to the kidney tissue lesion rate (p=1.00，p>0.05), so as to thedifference between combination therapy group and the saline group;There was no significant difference between high-dose combinationtherapy group and saline group to the kidney tissue lesion rate (p=0.485，p>0.05). The results showed that both carbamazepine combining withconventional dose celecoxib and high-doses celecoxib had no effects onthe rats kidney tissue in treating refractory epilepsy.3. Compared thecombination therapy group to saline group, there was no significantdifference on the INR value(p=0.179, p>0.05). There was also nosignificant difference between the high-dose combination therapy groupand saline group (p=0.212, p>0.05). It showed that neither carbamazepinecombining with conventional dose celecoxib, nor carbamazepine combi-ning with hgh-doses celecoxib had adverse effect on the rats coagulation in treating refractory epilepsy.4. The cTnT value of kainate surgery groupwas significantly increased by the value of sham group(p=0.00, p<0.01),the difference was statistically significant, which suggested that injectionof kainic acid in the hippocampus to get the epilepsy models, in conditionof not giving a rat anti-epileptic drug therapy, increased myocardial injuryin rats; both the cTnT values of combination therapy group and high-dosecombination therapy group were lower than the saline group(p=0.000, p<0.05), the difference was statistically significant; the cTnT value ofhigh-dose combination therapy group was significantly lower than combi-nation therapy group(p=0.000, p<0.05), and the difference was statistical-ly significant; carbamazepine combined with celecoxib or high-dosecelecoxib having reduced cardiac injury markers cTnT value suggestedthat there was no further side effects on myocardial cells in treatingrefractory epilepsy. Conclusion: Selective COX-2inhibitor celecoxibcombined with antiepileptic drugs carbamazepine had no adverse effectson rats antral, kidney tissue, coagulation, myocardium in treatingrefractory epileptic model rats. |
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