【摘要】：雞球蟲主要寄生于雞腸道細(xì)胞內(nèi),引起以腸道病變?yōu)橹饕卣鞯碾u球蟲病,嚴(yán)重危害養(yǎng)雞業(yè)的發(fā)展。目前,由于預(yù)防雞球蟲病的疫苗大部分是活苗,接種活苗可能出現(xiàn)返祖、散毒現(xiàn)象。所以,藥物防治雞球蟲病仍是最主要方式,例如鹽霉素、馬杜霉素、莫能菌素、海南霉素等。但隨著球蟲蟲株抗藥性問題的出現(xiàn),使得臨床防治陷入很大的困境。因此,有必要尋找新的藥物來防治雞球蟲病。近來研究發(fā)現(xiàn)蛋白酶抑制劑藥物能夠抑制原蟲侵入細(xì)胞。3,4-二氯異香豆素(3,4-dichloroisocoumarin,DCI)是一種絲氨酸蛋白酶抑制劑藥物,能夠抑制球蟲子孢子侵入宿主細(xì)胞。吉非替尼、厄洛替尼及克里唑蒂尼是酪氨酸激酶抑制劑藥物,可以抑制弓形蟲入侵宿主細(xì)胞。但DCI、吉非替尼等蛋白酶抑制劑是否具有抗雞球蟲效果尚未見報(bào)道。因此,本試驗(yàn)擬通過DCI、吉非替尼、厄洛替尼和克里唑蒂尼預(yù)防和治療雞球蟲病試驗(yàn),篩選出能夠有效防治雞球蟲病的藥物,并通過臨床觀察和血液生化學(xué)等各項(xiàng)指標(biāo)對(duì)篩選出的藥物進(jìn)行安全性評(píng)價(jià)。為雞球蟲病防治提供新的候選藥物。1、預(yù)防雞球蟲病蛋白酶抑制劑藥物的篩選試驗(yàn)選擇體重相近的健康雛雞380只,按照不同給藥劑量分為19組,20只/組,(陽性對(duì)照組、藥物對(duì)照組、空白對(duì)照組、DCI倍比劑量3個(gè)組,吉非替尼倍比劑量4個(gè)組,克里唑蒂尼倍比劑量4個(gè)組,厄洛替尼倍比劑量5個(gè)組)�？瞻讓�(duì)照組除外,其余組給藥7天后,每只試驗(yàn)雞經(jīng)口服方式接種1.0×104個(gè)E.tenella孢子化卵囊。感染期間觀察雞的精神、食欲狀況。接種球蟲一周后,每組逐只稱重、剖殺計(jì)算存活率、增重率、血便記分、相對(duì)增重率、盲腸病變記分,收集每組糞便,計(jì)算卵囊數(shù)量。結(jié)果表明:DCI綜合評(píng)價(jià)其抗球蟲指數(shù)為117.34-161.04;吉非替尼綜合評(píng)價(jià)其抗球蟲指數(shù)為87.83-110.55;克里唑蒂尼綜合評(píng)價(jià)其抗球蟲指數(shù)為98.94-132.79;厄洛替尼綜合評(píng)價(jià)其抗球蟲指數(shù)為68.54-97.49。表明DCI中劑量組預(yù)防雞球蟲病效果較好,抗球蟲指數(shù)為161.04,即0.005mg/只,飲水給藥,連用7天。2、治療雞球蟲病蛋白酶抑制劑藥物的篩選試驗(yàn)選擇體重相近的健康雛雞380只,按照不同劑量分為19組,20只/組,(陽性對(duì)照組、藥物對(duì)照組、空白對(duì)照組、DCI倍比劑量3個(gè)組,吉非替尼倍比劑量4個(gè)組,克里唑蒂尼倍比劑量4個(gè)組,厄洛替尼倍比劑量5個(gè)組)。除空白對(duì)照組外,其余各組均給雛雞接入球蟲,每只試驗(yàn)雞經(jīng)口服方式接種1.0×104個(gè)E.tenella孢子化卵囊,接種球蟲后即給藥5天。接種球蟲一周后,每組逐只稱重,剖殺計(jì)算存活率、增重率、血便記分、相對(duì)增重率、盲腸病變記分等,收集每組糞便,計(jì)算卵囊數(shù)量。結(jié)果表明:DCI組綜合評(píng)價(jià)其抗球蟲指數(shù)為133.13-178.73;吉非替尼組綜合評(píng)價(jià)其抗球蟲指數(shù)為110.66-135.96;克里唑蒂尼組綜合評(píng)價(jià)其抗球蟲指數(shù)為85.51-125.17;厄洛替尼組綜合評(píng)價(jià)其抗球蟲指數(shù)為89.76-109.47。試驗(yàn)表明DCI中劑量組療效較好,綜合評(píng)價(jià)抗球蟲指數(shù)為178.73,即0.005mg/只,飲水給藥,連用5天。3、DCI對(duì)靶動(dòng)物雞的安全性評(píng)價(jià)將250只8日齡雛雞,分成5組,每組50只,按照不同給藥劑量分組為空白對(duì)照組、1倍劑量組(0.005mg/只)、3倍劑量組(0.015mg/只)、5倍劑量組(0.025mg/只)和10倍劑量組(0.05mg/只)�？瞻讓�(duì)照組飲用自來水,其余各組連續(xù)飲水給藥21天。通過臨床觀察和對(duì)實(shí)驗(yàn)動(dòng)物的血液學(xué)、血液生化學(xué)、組織病理學(xué)及尸體剖檢各項(xiàng)指標(biāo)進(jìn)行藥物的安全性評(píng)價(jià)。結(jié)果表明,與對(duì)照組相比,DCI各劑量組血液學(xué)參數(shù)差異不顯著(P0.05);1倍劑量組用藥血液生化學(xué)與眼觀組織無病理變化,3倍及以上劑量組用藥血液生化檢測(cè)堿性磷酸酶、谷草轉(zhuǎn)氨酶及膽紅素與對(duì)照組相比差異顯著(P0.05),個(gè)別雞只出現(xiàn)肝臟黃染、腸道出血點(diǎn)或出血斑;組織病理學(xué)觀察,鏡下觀察肝臟和腸組織切片,3倍劑量組肝臟有輕度的水腫和脂肪變性現(xiàn)象,腸道無病理變化;5倍劑量組脂肪變性嚴(yán)重,腸絨毛斷裂;10倍劑量組有炎性細(xì)胞造成的網(wǎng)狀病變,引起脂肪變性,腸絨毛斷裂。安全性試驗(yàn)表明,3倍及以上劑量組對(duì)雛雞有危害,主要對(duì)雞的肝臟和腸道有損傷。結(jié)果表明,DCI 0.005mg/只給藥臨床用藥安全。
[Abstract]:The coccidiosis of the chicken is mainly in the intestinal tract of the chicken, which causes the chicken coccidiosis which is the main characteristic of the intestinal pathological changes, and seriously harms the development of the chicken industry. At present, due to the prevention of the chicken coccidiosis, most of the vaccines are live seedlings, and the inoculation live seedlings may have the phenomenon of back-and-back. Therefore, the drug control and control of the chicken coccidiosis is still the most important way, such as, for example, the salinomycin, the maduramicin, the monensin, the hainan, and the like. However, with the emergence of the drug-resistance of the Eimeria strain, the clinical prevention and control are in great difficulty. Therefore, it is necessary to find new drugs to control the coccidiosis of the chicken. Recently, it has been found that the protease inhibitor drug can inhibit the invasion of the protozoa. Gefitinib, erlotinib, and criptinidine are tyrosine kinase inhibitor drugs, which can inhibit the invasion of host cells of Toxoplasma gondii. However, whether a protease inhibitor such as DCI or gefitinib has the effect of anti-coccidiosis has not been reported. Therefore, this test is to prevent and treat the chicken coccidiosis by DCI, gefitinib, erlotinib and Crinopini, and to screen out the drugs which can effectively prevent and control the coccidiosis of the chicken, and to evaluate the safety of the screened drugs through the clinical observation and the blood biochemical indexes. in order to provide a new candidate for the prevention and treatment of chicken coccidiosis, a screening test for preventing the preparation of the protease inhibitor of the chicken coccidiosis selected from the group consisting of 380 healthy chickens with similar body weight,19 groups according to the different administration doses,20/ group, (positive control group, drug control group, blank control group, The DCI-time-specific dose of 3 groups, the gefitinib-fold specific dose of 4 groups, the Kristinian-fold specific dose of 4 groups, and the erlotinib-fold specific dose of 5 groups). Except for the blank control group, after 7 days of administration of the rest of the group, 1.0 to 104 E. tenella sporulated oocysts were administered orally. The spirit and the appetite of the chicken were observed during the infection. After a week of coccidiosis, each group was weighed individually, the survival rate, the weight gain rate, the blood stool score, the relative weight gain rate and the cecum lesion score were calculated, and each group of feces was collected and the number of oocysts was calculated. The results showed that the anti-coccidiosis index was 117.34-161.04, the anti-coccidiosis index of gefitinib was 87.83-110.55, and the anti-coccidiosis index was 98.94-132.79, and the anti-coccidiosis index of erlotinib was 68.54-97.49. The results showed that the anti-coccidiosis effect of the dose group in the DCI is good, the anti-coccidiosis index is 161.04, that is, 0.005 mg/ min, the drinking water is administered for 7 days.2, the screening test for the treatment of the chicken coccidiosis protease inhibitor drug selects 380 healthy chickens with similar body weight, and is divided into 19 groups and 20/ groups according to different doses. (Positive control group, drug control group, blank control group, DCI-time ratio dose of 3 groups, gefitinib-time-ratio 4 groups, Kristitinix dose of 4 groups, erlotinib-times-specific dose of 5 groups). In addition to the blank control group, the other groups were inoculated with coccidiosis in the chicks, and 1.0 to 104 E. tenella sporozoites were inoculated orally, and 5 days after the inoculation of the coccidia. After a week of coccidiosis, each group was weighed individually, the survival rate, the weight gain rate, the blood score, the relative weight gain rate, the cecum lesion score, and the like were calculated, and each group of feces was collected and the number of oocysts was calculated. The results showed that the anti-coccidiosis index was 133.13-178.73 in the DCI group, the anti-coccidiosis index was 110.66-135.96 in the gefitinib group, 85.51-125.17, and the anti-coccidiosis index was 89.76-109.47 in the erlotinib group. The results indicated that the efficacy of the dose group in the DCI group was good, the comprehensive evaluation of the anti-coccidiosis index was 178.73, that is, 0.005 mg/ kg, the drinking water was administered for 5 days. The safety evaluation of the DCI on the target animal was estimated to be 250-day-old chicks, divided into 5 groups, each group of 50 chickens. The dose groups were grouped into the blank control group, the 1-fold dose group (0.005 mg/ day), the 3-fold dose group (0.015 mg/ day), the 5-fold dose group (0.025 mg/ day) and the 10-fold dose group (0.05 mg/ day) according to the different dose groups. The blank control group was treated with tap water and the rest of the other groups were treated with continuous drinking water for 21 days. The safety evaluation of the drug was carried out by clinical observation and the hematology, blood chemistry, histopathology and the body cross-section of the experimental animals. The results showed that there was no significant difference in the hematology parameters in the DCI group compared with the control group (P0.05). The blood biochemical and ocular tissue of the 1-fold dose group did not change the pathological changes, and the blood biochemical test of the alkaline phosphatase was detected in the 3-fold and higher dose group. Compared with the control group, the difference was significant (P0.05). The liver and intestinal tissue sections were observed in individual chickens, and the liver and intestinal tissue sections were observed under the microscope. The liver of the 3-fold dose group had mild edema and fat degeneration. There were no pathological changes in the intestinal tract; the fatty degeneration of the 5-fold group was severe, and the intestinal villi were broken; the reticulopathy caused by the inflammatory cells in the 10-fold group resulted in the degeneration of the fat and the break of the intestinal villi. The safety test shows that the three times and above dose groups are harmful to the chicks, and the liver and the intestinal tract of the chicken are mainly damaged. The results showed that the DCI 0.005 mg/ only was safe for clinical medication.
【學(xué)位授予單位】：吉林大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2016
【分類號(hào)】：S858.31

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