戈那瑞林在奶牛体内药物代谢动力学及临床试验研究
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摘要
戈那瑞林为人工合成的GnRH类似物,肌注之后,它通过提高普通的下丘脑-垂体功能,改善总体受精率,从而恢复卵泡的正常生长和成熟。本试验拟研究戈那瑞林在奶牛体内药物代谢动力学、奶牛卵巢囊肿的治疗效果以及其对奶牛生理生化指标的影响,为该药的进一步推广应用提供临床资料。结果如下:
1.戈那瑞林在奶牛体内的药动学研究戈那瑞林(Gonadorelin)为人工合成的促性腺激素释放激素(gonadotropin-releasing hormone,GnRH)类似物。为了分析戈那瑞林在奶牛体内的药物代谢动力学过程,为兽医临床合理用药提供理论依据,对6头奶牛进行摘除卵巢手术,术后30 d单剂量肌内注射用戈那瑞林,16 h内不同时间19次静脉采血,应用酶联免疫吸附法(ELISA)测定血清中促性腺激素释放激素(GnRH)浓度,残数法拟合药时曲线,计算药物动力学参数。结果显示,戈那瑞林在奶牛体内的药物动力学配置符合有吸收因素二室开放模型,其药—时曲线最佳方程为C=68.7632e-7.6743t+9.6987e-0.4437t-78.4619e-16.0215t。主要药物动力学参数:消除相半衰期t1/2β为1.5638±0.0661 h,药-时曲线下面积AUC为25.6411±2.3926 ng·mL-1·h,达峰浓度为24.2902±3.6515 ng·mL-1,达峰时间为0.1033±0.0150 h。结果表明,奶牛肌注戈那瑞林后,吸收快,消除也快。
2.戈那瑞林对奶牛卵泡囊肿的临床治疗试验为了了解戈那瑞林对奶牛卵泡囊肿的治疗效果。利用临床检查、直肠检查和B超诊断仪综合诊断出的40头患卵泡囊肿的奶牛并分为戈那瑞林治疗组和药物对照(黄体酮)治疗组。戈那瑞林组分为高、中(推荐剂量)、低三个试验组,每组试验动物10头,高、中(推荐剂量)、低3个试验组分别于第1天,第2天和第9天各肌注“注射用戈那瑞林”200μg、100μg和50μg,黄体酮对照组,奶牛每次50 mg~150 mg,每天或隔天肌注一次,连用2~7 d。以临床症状是否消失,B超探查患卵泡囊肿的卵巢体积是否恢复至正常以及奶牛是否能恢复正常发情周期并发情配种,判定戈那瑞林对奶牛卵泡囊肿的治疗效果。结果显示,经戈那瑞林治疗后,患卵巢囊肿奶牛临床症状消失或明显改善,B超探查,患卵泡囊肿的卵巢体积恢复至正常,大部分奶牛恢复正常发情周期并发情配种。结果说明,于第一天、第二天和第9天给牛肌肉注射戈那瑞林100μg,可有效治疗奶牛卵泡囊肿。
3.戈那瑞林对奶牛生理生化指标的影响的研究为了了解戈那瑞林对奶牛生理生化指标的影响,给奶牛单剂量注射戈那瑞林100μg后测定奶牛生理生化指标。结果显示,奶牛注射戈那瑞林后,对奶牛体温、呼吸频率、心率及血液学指标进行测定,均未发现异常。结果说明戈那瑞林对于奶牛的生理生化指标没有影响。
Gonadorelin, a synthetic GnRH analogue, can raise the normal hypothalamus-pituitary function and improve the overall fertility rate to recover thereby the normal growth and maturation of follicular after intramuscular injection. In order to provide clinical information for the further application of Gonadorelin, the "Gonadorelin" pharmacokinetics in cows, its treatment dairy ovarian cysts, physiological and biochemical indices of blood in cows , were researched in this study. The detail is as follows:
1. Study on pharmacokinetics of Gonadorelin in cows Gonadorelin is a synthetic GnRH analogues. In order to analyze the pharmacokinetic course of Gonadorelin in cows and provid theoretical basis of rational drug using for clinical veterinary surgeon, six cows were excised ovaries and injected Gonadorelin by single-dose 30 days after the operation.Then blood was collected 19 times in different time of 16 hours after intramuscular injection. The concentration of GnRH in serum was determined by ELISA, and the concentration-time curve and the pharmacokinetic parameters were made by residual method. The results show that the pharmacokinetics allocation of Gonadorelin in cows is in line with the two-compartment open model with the coefficient of absorption.The best medicine-time curve equation is C=68.7632e-7.6743t+9.6987e-0.4437t-78.4619e-16.0215t .The main pharmacokinetic parameters : The half - time of beta phase of it (t1/2β) is 1.5638±0.0661 h, the area under curve (AUC) is 25.6411±2.3926 ng·mL-1·h, the peak concentration is 24.2902±3.6515 ng·mL-1 , the time to peak is 0.1033±0.0150 h. The results show that it absorbs quickly and eliminates quickly too after intramuscular injection of Gonadorelin in cows.
2. Treament of Gonadorelin to dairy ovarian cysts In order to understand the Treament of Gonadorelin to dairy ovarian cysts, according to the comprehensive diagnosis including the clinical examination, rectal examination and examination by B-type ultrasonic diagnostic apparatus, the 40 cows suffered from cystic graafian follicles are divided into Gonadorelin the treatment group and drug control (progesterone) group. Gonadorelin group was divided into three test groups of 10 cows in each group which consist of high dose group, medium dose group (the recommended dose) and low dose group. The three test groups were injected with Gonadorelin for Injection 200μg , 100μg and 50μg on first, second and nineth day. Progesterone control group is injected with progesterone 50 mg~150 mg per cow every day or the next day lasting of 2~7 days. Based on the disappearance of clinical symptoms, ovary back to normal size by B-type ultrasonic diagnostic apparatus as well as the cows returning to normal estrus cycle, the therapeutic effect on cystic graafian follicle in cows by Gonadorelin was determined. The results show that after being treated with Gonadorelin, the clinical symptoms of ovarian cysts in cows were disappeared or markedly improved, ovary is back to normal size, the majority of cows return to normal estrus cycle and estrus service. The results showed that injected gonadorelin 100μg to cows in the first day, second day and 9th day, the cows ovarian cysts can be effectively treated.
3. Effects of Gonadorelin on physiological and biochemical indices of blood in cows
In order to understand the effects of Gonadorelin on physiological and biochemical indices of blood in cows,detected the physiological and biochemical indices of blood after injecting a single dose of 100μg gonadorelin to cows. The results showed that the indicators about cows including temperature, respiration rate, heart rate and blood parameters were all normal afer injecting the cows with Gonadorelin.The results showed that there were no effect to the dariy cows on physiological and biochemical indices of blood.
1.戈那瑞林在奶牛体内的药动学研究戈那瑞林(Gonadorelin)为人工合成的促性腺激素释放激素(gonadotropin-releasing hormone,GnRH)类似物。为了分析戈那瑞林在奶牛体内的药物代谢动力学过程,为兽医临床合理用药提供理论依据,对6头奶牛进行摘除卵巢手术,术后30 d单剂量肌内注射用戈那瑞林,16 h内不同时间19次静脉采血,应用酶联免疫吸附法(ELISA)测定血清中促性腺激素释放激素(GnRH)浓度,残数法拟合药时曲线,计算药物动力学参数。结果显示,戈那瑞林在奶牛体内的药物动力学配置符合有吸收因素二室开放模型,其药—时曲线最佳方程为C=68.7632e-7.6743t+9.6987e-0.4437t-78.4619e-16.0215t。主要药物动力学参数:消除相半衰期t1/2β为1.5638±0.0661 h,药-时曲线下面积AUC为25.6411±2.3926 ng·mL-1·h,达峰浓度为24.2902±3.6515 ng·mL-1,达峰时间为0.1033±0.0150 h。结果表明,奶牛肌注戈那瑞林后,吸收快,消除也快。
2.戈那瑞林对奶牛卵泡囊肿的临床治疗试验为了了解戈那瑞林对奶牛卵泡囊肿的治疗效果。利用临床检查、直肠检查和B超诊断仪综合诊断出的40头患卵泡囊肿的奶牛并分为戈那瑞林治疗组和药物对照(黄体酮)治疗组。戈那瑞林组分为高、中(推荐剂量)、低三个试验组,每组试验动物10头,高、中(推荐剂量)、低3个试验组分别于第1天,第2天和第9天各肌注“注射用戈那瑞林”200μg、100μg和50μg,黄体酮对照组,奶牛每次50 mg~150 mg,每天或隔天肌注一次,连用2~7 d。以临床症状是否消失,B超探查患卵泡囊肿的卵巢体积是否恢复至正常以及奶牛是否能恢复正常发情周期并发情配种,判定戈那瑞林对奶牛卵泡囊肿的治疗效果。结果显示,经戈那瑞林治疗后,患卵巢囊肿奶牛临床症状消失或明显改善,B超探查,患卵泡囊肿的卵巢体积恢复至正常,大部分奶牛恢复正常发情周期并发情配种。结果说明,于第一天、第二天和第9天给牛肌肉注射戈那瑞林100μg,可有效治疗奶牛卵泡囊肿。
3.戈那瑞林对奶牛生理生化指标的影响的研究为了了解戈那瑞林对奶牛生理生化指标的影响,给奶牛单剂量注射戈那瑞林100μg后测定奶牛生理生化指标。结果显示,奶牛注射戈那瑞林后,对奶牛体温、呼吸频率、心率及血液学指标进行测定,均未发现异常。结果说明戈那瑞林对于奶牛的生理生化指标没有影响。
Gonadorelin, a synthetic GnRH analogue, can raise the normal hypothalamus-pituitary function and improve the overall fertility rate to recover thereby the normal growth and maturation of follicular after intramuscular injection. In order to provide clinical information for the further application of Gonadorelin, the "Gonadorelin" pharmacokinetics in cows, its treatment dairy ovarian cysts, physiological and biochemical indices of blood in cows , were researched in this study. The detail is as follows:
1. Study on pharmacokinetics of Gonadorelin in cows Gonadorelin is a synthetic GnRH analogues. In order to analyze the pharmacokinetic course of Gonadorelin in cows and provid theoretical basis of rational drug using for clinical veterinary surgeon, six cows were excised ovaries and injected Gonadorelin by single-dose 30 days after the operation.Then blood was collected 19 times in different time of 16 hours after intramuscular injection. The concentration of GnRH in serum was determined by ELISA, and the concentration-time curve and the pharmacokinetic parameters were made by residual method. The results show that the pharmacokinetics allocation of Gonadorelin in cows is in line with the two-compartment open model with the coefficient of absorption.The best medicine-time curve equation is C=68.7632e-7.6743t+9.6987e-0.4437t-78.4619e-16.0215t .The main pharmacokinetic parameters : The half - time of beta phase of it (t1/2β) is 1.5638±0.0661 h, the area under curve (AUC) is 25.6411±2.3926 ng·mL-1·h, the peak concentration is 24.2902±3.6515 ng·mL-1 , the time to peak is 0.1033±0.0150 h. The results show that it absorbs quickly and eliminates quickly too after intramuscular injection of Gonadorelin in cows.
2. Treament of Gonadorelin to dairy ovarian cysts In order to understand the Treament of Gonadorelin to dairy ovarian cysts, according to the comprehensive diagnosis including the clinical examination, rectal examination and examination by B-type ultrasonic diagnostic apparatus, the 40 cows suffered from cystic graafian follicles are divided into Gonadorelin the treatment group and drug control (progesterone) group. Gonadorelin group was divided into three test groups of 10 cows in each group which consist of high dose group, medium dose group (the recommended dose) and low dose group. The three test groups were injected with Gonadorelin for Injection 200μg , 100μg and 50μg on first, second and nineth day. Progesterone control group is injected with progesterone 50 mg~150 mg per cow every day or the next day lasting of 2~7 days. Based on the disappearance of clinical symptoms, ovary back to normal size by B-type ultrasonic diagnostic apparatus as well as the cows returning to normal estrus cycle, the therapeutic effect on cystic graafian follicle in cows by Gonadorelin was determined. The results show that after being treated with Gonadorelin, the clinical symptoms of ovarian cysts in cows were disappeared or markedly improved, ovary is back to normal size, the majority of cows return to normal estrus cycle and estrus service. The results showed that injected gonadorelin 100μg to cows in the first day, second day and 9th day, the cows ovarian cysts can be effectively treated.
3. Effects of Gonadorelin on physiological and biochemical indices of blood in cows
In order to understand the effects of Gonadorelin on physiological and biochemical indices of blood in cows,detected the physiological and biochemical indices of blood after injecting a single dose of 100μg gonadorelin to cows. The results showed that the indicators about cows including temperature, respiration rate, heart rate and blood parameters were all normal afer injecting the cows with Gonadorelin.The results showed that there were no effect to the dariy cows on physiological and biochemical indices of blood.
引文
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Basil TC,Helen BN. 2003.Gonadotropin-releasing hormone antagonists:impact of IVF practice and potential non-assis-ted reproductive technology applications. Curr Opin Obstet Gynecol.15(3):259.
Bex F J. 1981.LHRH agonist termination of pregnancy in hypophysectomized rats extrapituitary site of action.Endocrinology.108(2): 273~275.
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ElterK, Nelson LR. 2001. Use of third generation gonadotropin releasing hormone antagonists in in vitro fertilization-embryo transfer: a review.ObstetGynecolSurv.56(9): 576-588.
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Garveric H A. 1997. Ovarian follicular cyst s in dairy cows. J Dairy Sci.30 :995~1004.
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Huang WeiQuan , Yao Bing , Sun Lan , Pu RuoLei , Wang Lei , Zhang RongQing. 2001.Immunohistochemical and in situ hybridization studies of GnRH and its receptor. Life Science.68(15): 1727~1734.
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Koray E, Linda R. 2001. Use of third generation gonadotropin-releasing hormone antagonists in in vitro fertilization-embryo transfer: a review.ObstetGynecolSurv.56(9): 576~588.
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朱名胜,宋明华.2007.Dot-ELISA和IEST检测斯氏狸殖吸虫抗体.中国人兽共患病学报.23(3):301.
张浩,单虎,吴延功,张守富,吴晓东,王志亮,刘佩兰,朱绍辉.2008.单抗捕捉ELISA检测猪附红细胞体血清抗体方法的建立.中国兽医杂志.44(9):16~18.
周韧,Hartmut Merz,杨水友.1998.碱性磷酸酶底物的研究.中国组织化学与细胞化学杂志.7(1):51~57.
赵银丽,张改平,邓瑞广,柴书军,滕蔓.2008.恩诺沙星多克隆抗体制备及阻断ELISA检测方法的研究.河南工业大学学报(自然科学版).29(5):63~70.
赵荣飞.2008.奶牛卵泡囊肿的防治方法.畜牧兽医科技信息.12:58.
郑家三,Silvia W J,夏成.2008.应用实时B超诊断奶牛卵巢疾病.动物医学进展.29(8):110~112.
曾衍霖.1980.药物动力学中的第二个计算问题——原始数据的权量与线数字模型房室的确定.药学学报.15(9):574.
中国兽药典委员会.中华人民共和国兽药典兽药使用指南.化学药品卷.2005年版.北京:中国农业出版社:267.
Donald C.Plumb.2005.Plumb`s兽药手册.第5版.沈建忠,冯忠武主译.2009.北京:中国农业大学出版社:520-521. Alejandro D. Montaner, Lucas Mongiat, Victoria A. Lux-Lantos, Carol Warby, Brad Chewpoy, María S. Bianchi, Carlos Libertun, Jean E. Rivier, Nancy M. Sherwood, Gustavo M. Somoza. 2002. Guinea pig gonadotripin-releasing hormone: expression pattern, characterization and biological activity in rodent. Neuroendocrinology.75(5): 326~338.
Basil TC,Helen BN. 2003.Gonadotropin-releasing hormone antagonists:impact of IVF practice and potential non-assis-ted reproductive technology applications. Curr Opin Obstet Gynecol.15(3):259.
Bex F J. 1981.LHRH agonist termination of pregnancy in hypophysectomized rats extrapituitary site of action.Endocrinology.108(2): 273~275.
Calder M D , M anikkam M ,Salfen A E ,Youngquist R S,Lubanhn D B,Lamberson W R,Garverick H A .2001.Dominant bovine ovarian follicular cysts express increased levels of messenger RNAs for luteinizing hormone receptor and 3β-hydroxysteroid dehydrogenase isomerase compared to normal dominant follicles. Bio Reprod.65 (2) :471~476.
Chabbert-BuffetN. 2003. GnRH antagonists. Clin ObstetGyneco.46(2): 254~264.
C. Albano, R.E. Felberbaum, J. Smitz, H. Riethmüller-Winzen, J. Engel, K. Diedrich, P. Devroey,on behalf of the European Cetrorelix Study Group.2000.Ovarian stimulation with HMG: results of a prospective randomized phase III European study comparing the luteinizing hormone releasing hormone (LHRH)-antagonist cetrorelix and the LHRH-agonist buserelin. Hum Reprod.15(3): 526~531.
E. A. Dubois, M. A. Zandbergen, J. Peute, H. J. Goos.2002.Evolutionary development of three GnRH systems in vertebrates. Brain Research Bulletin.57(3~4): 413~418.
ElterK, Nelson LR. 2001. Use of third generation gonadotropin releasing hormone antagonists in in vitro fertilization-embryo transfer: a review.ObstetGynecolSurv.56(9): 576-588.
Farin P W,Youngquist R S ,Parfet J R , Garverick H A. 1992.Diagnosis of luteal and follicular ovarian cysts by palpation per rectum and linear-array ultrasonography in dairy cows . J Am Vet Med Assoc.200 (8) :1085.
Guillenmin R. 1971.Purification amino acid composition and N-terminus of the hypothalamic luteinzing hormone releasing factor (LRF) of ovine origin. Biochem Biophys Res Commun.44(1): 205~210.
Garveric H A. 1997. Ovarian follicular cyst s in dairy cows. J Dairy Sci.30 :995~1004.
Grégoy Y Bédécarrats, Ursula B Kaiser. 2003.Differential regulation of gonadotropin subunit gene promoter activity by pulsatile gonadotropin-releasing hormone (GnRH) in perifused LβT2 cells:role ofGnRHreceptor concentration. Endocrinology.144(5): 1802~1811.
Huang WeiQuan , Yao Bing , Sun Lan , Pu RuoLei , Wang Lei , Zhang RongQing. 2001.Immunohistochemical and in situ hybridization studies of GnRH and its receptor. Life Science.68(15): 1727~1734.
Jimenez linan M,Rubin B. 2001.Examination of guinea pig luteinizing hormone-releasing hormone gene reveals a unique decapeptide and existence of two transcripts in the brain. Endocrinology. 138:4123~4137.
Jan Y N, Jan L Y, Kuffler S W. 1979. A peptide as a possible transmitter in sympathetic ganglia of the frog. Proc Natl Acad Sci USA.76(3): 1501~1505.
John C M, Christine A E, Christopher R M. 2001. Hypothalamic dysfunction. Molecular and Cellular Endocrinology.183(1~2): 29~32.
Jennifer M, Mulvaney. 2000. Divergent signaling pathways requiring discrete calcium signals mediate concurrent activation of two mitogen-activated protein kinases by gonadotropin-releasing hormone. The Journal of Biological Chemistry. 275(19): 14182~14189.
J. M. Dejarnette, M. L. Day, R. B. House, R. A. Wallace , C. E. Marshall. 2001.Effect of GnRH pretreatment on reproductive performance of postpartum suckled beef cows following synchronization of estrus using GnRH and PGF2alpha. Journal of Animal Science. 79(7):1675~1682.
Koray E, Linda R. 2001. Use of third generation gonadotropin-releasing hormone antagonists in in vitro fertilization-embryo transfer: a review.ObstetGynecolSurv.56(9): 576~588.
Lei Wang,Li Ping Xie,Wei Quan Huang,Bing Yao, Ruo Lei Pu, Rong Qing Zhang. 2001.Presence of gonadotropin-releasing hormone (GnRH) and its mRNA in rat pancreas.Molecular and Cellular Endocrinology.172(1~2): 185~191.
Moore J J, Wray S. 2000.Luteinizing hormone-releasing hormone(LHRH) biosynthesis and secretion in embryonic LHRH neurons. Endocrinology. 141(12): 4486~4495.
Naor Z,Shacham S. 1995.Signal transduction of the GnRH recepter: crosstalk of calcium protein kinase C(PKC) and arachidonic acid.Cell MolNeurobiol.15:527~544.
Ribadu A Y,Nakada K,Moriyoshi M , Zhang W C, Tanaka Y , Nakao T .2000.The role of LH pulse frequency in ACTH-induced ovarian follicular cysts in heifers. Anita Reprod Sci. 64 (1~2) :21~31.
Shally A V. 1971.Structure of the porcine LH and FSH releasing hormone confirmation of the proposed structure by conventional sequential analyses. Biochem Biophy Res Commun.44(1): 459~463.
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