【作者】 郭世宁；

【导师】 佟恒敏；

【作者基本信息】 东北农业大学 ， 基础兽医学， 2002， 博士

【摘要】 本文通过连翘、黄芩、益母草、淫羊藿、栀子、当归、苦参、紫草、蛇床子、硼砂、红花等十一种中药、复方Ⅰ（益母草、淫羊藿等）、复方Ⅱ（益母草、当归等）以及西药恩诺沙星对奶牛子宫内膜炎的四种常见致病菌大肠杆菌、金黄色葡萄球菌、链球菌和绿脓杆菌的体外最低抑菌浓度（MIC）的测定，筛选出了抑菌效果好的连翘、黄芩和恩诺沙星等，按照中兽医医药理论的组方原则将筛选所得中药与西药恩诺沙星组成复方制剂宫炎清，并对宫炎清的稳定性、安全性、临床防治效果、对子宫（离体和在体）的影响以及宫炎清中部分主要药物的代谢动力学进行了研究，并探讨了宫炎清在防治奶牛子宫内膜炎的作用、作用机理、剂型、剂量、给药途径、毒副作用等。 试验结果表明： 在温度T 40±2℃，相对湿度为75％的情况下，3个月内，宫炎清的外观性状、pH值、相对密度无明显变化，其黄芩甙含量稳定，这说明宫炎清对热稳定：在2500勒克司（LX）的连续光照15天的情况下，宫炎清的外观性状、pH值、相对密度无明显变化，其黄芩甙含量稳定，这说明宫炎清对光稳定。 临床药效学表明，用宫炎清和思诺沙星对69头奶牛进行子宫内膜炎预防对比试验，其中青年奶牛28头，成年奶牛41头，结果表明宫炎清对青年奶牛的预防效果可以达到100％，对成年奶牛的预防效果为91.30％，均明显优于单用恩诺沙星进行预防（P＜0.05），对成年奶牛产后初次发情时间可以提前9.6天，成年奶牛产后至受孕时间缩短约13天，对成年奶牛用药后第1情期的受孕率有明显提高（P＜0.05），对于青年奶牛用药后第1、2、3情期的受孕率有明显提高，青年奶牛产后至受孕时间缩短约7.9天：对78头患有子宫内膜炎的奶牛用宫炎清和恩诺沙星进行了治疗对比试验，其中青年牛21头，成年牛57头，结果表明宫炎清对青年和成年奶牛均能显著提高用药后3个情期的受孕率（P＜0.05），初次用药至发情时间缩短，成年奶牛提前约13.5天，青年奶牛约17.9天，可以缩短初次用药至受孕的时间，成年奶牛约18.5天，青年奶牛约34.7天，无论预防组还是治疗组均有减少用药次数的情况。 昆明种小白鼠的急性毒性试验表明，小白鼠一次经口口服宫炎清其LD₅₀大于15000mg／kg．b.w，口服最大耐受量倍数为187.5倍；小白鼠腹腔注射宫炎清后，其LD₅₀为364.3343mg／kg．b.w。豚鼠的皮肤致敏试验表明，宫炎清无致敏源性。家兔眼结膜刺激性试验表明，宫炎清只有温和的刺激作用，主要表现为6h时眼结膜血管充血，并有少量分泌物，此作用48h后消失，说明宫炎清可以通过局部给药。 在家兔离体子宫中加入宫炎清5min后，其收缩幅度显著增加（P＜0.05），收缩频率和一子宫活动力显著增强（P＜0刀1），同加入催产素组比较无明显差异，但是宫炎清对子宫活动力的影响以增加频率为主，而催产素是以增加收缩振幅为主；10min后，宫炎清组同smin前收缩振幅、频率和活动力没有明显变化，而催产素组收缩振幅稍有降低，表明宫炎清作用持久。对于家兔在体子宫的影响，前smin类似于离体子宫，只是收缩幅度和频率都高于或大于离体子宫，但是 10min时，宫炎清组的收缩频率明显高于催产素组，可能与中药的慢效应或后效应有关。 以HPLC法做为药物浓度定量手段，应用MCP－KP房室分析程序处理药物浓度时间数据，分析了宫炎清中黄革成、淫羊蕾贰和恩诺沙星在血浆和乳汁中的药代动力学参数，结果表明于宫内灌注宫炎清后，黄苹贰、恩诺沙星以及恩诺沙星的代谢产物环丙沙星的药时数据均符合一级吸收一室开放模型，其中黄＄at在血浆中的药动学参数为 C。0．37pg／ffil，K。1．73h“，K 0．25h’，T；。。。0二sh，T；。。0．70h，TmaxZ．15h，Cm。0二4Pg／ml，AUC．52mg／L·h，T。、0．50h，其一项指数方程为 C－0．52（e”‘“”－e”‘”） 在乳汁中药动学参数为 C。0．76ug／ml，K。0．88h“’，K 0．38h’，TQ。0．79h，T；。。l石Zh，T＿3二7h，C。。0．3lqg／ml，AUC 12，00mg／L七，T；、l石oh，其二项指数方程为C＝0厂0(e’‘“”－e““叮恩诺沙星的药动学参数为C。4石934pg／ml，K。1·453卯”‘，K O．3263n‘，TI。K。O．5662h，TI。KZ．4598h，几。2．0223卜，民。2．62引呛m乙A＊C14·7186mg／’L七，T，叩0．5988h，其二项指数方程为 C一7刀84（e－’“’‘’－e＊‘’‘） 在孪汁中的药动学参数为C。37808pg／ml，K。0．4629h‘，K 0．3579h’，T；；。。。1．5706h，T；。。2二587h，Tm。3．5325h，Cm。1·5054ug／ml，AUC 3．1457mg／L七，T，、0．8205h，二项指数方程是 C＝10二62（e－‘“”’－e“’“”）。恩诺沙星的代谢产物环丙沙星的在血浆中药动学参数为 C。1．6129pg／ffil，K。0．4933h’，K0·4289h“‘，T；。。。1．4477h，T；。。且石657h，Tm。3．3483h，Cm。0．5551Pg／ml，AUC 36．7368mg／L七，T；。。1．1177h其二项指数方程为为 C＝6769（e－“’”－e“’‘”’）；在乳汁中药动学参数为 C。0·9652阶l，K。0．4412h“‘，K 0．3068h”‘，T；；。。。1．5706h，T；。。l．2．2587h，Tm。3．5325h，C＿更多还原

【Abstract】 The MlCs (minimum inhibitory concentrations) of 11 Chinese herbal medicines such asForsythia suspensa (Thunb.), Scutellaria baicalensis Georgi, Carthamus tinctorius L.,, Cnidiummonnieri (L.) Cuss, EPimedium brevicornam Maxim, Angelica sinensis(Oliv). Arnebia euchroma(Royle) Johnst, Gardenia jasminoides Ellis Sophora flavescens Ait. and borax were detected onthe pathogenic bacteria causing endowmetritis in cows in vitro. Enrofloxacin was done the sameas the former. The medicines which had better antibacterial action than the others such asForsythia suspensa (Thunb.), Scutellaria baicalensis Georgi, enrofloxcain etc were selected bythe effect of MICs. According to the Chinese veterinary medicine theories the complexprescreiption gonponqtw was made up of the former medicines. The stabilities, securities, effectsof prevention and treatment cow endometritis at clinic, effects ofgongyanqing on uterus in vitroand in vivo in rabbits and pharmacokinetics ofgongyanqing were studied. The result showed asfoIIowed.Under the condition of 40 f 2 C and 75% of relative humidity the appearantcharacteristcs,PH and the relative condense of gOmpqtw had no notable changes and thecontent of bacicalin was very stable fOr three months, which showed that gongyanqing was notsensitive to the high temperature. On the other hand,when exposed to the 2500LX strong light fOrl5 days,all the characteristics were stable, which showed that the light had no effect ongongyanqlng.The studies of cIinic paramacodynatics showed that when gompqtw and Enrofloxacincombination was applied to treat the endometritis of 69 cows (28 young cows and 41 maturecows), the ratio of cure were l00% for young cows and 9l .30%for mature cows .The effect wasbetter than the enrofloxacin alone (P<0.05). After mature cows were given the combination, thefirst oestrum was 9.6 days ahead and the time between postpartUm and pregnacy was deceded byl 3 days. The ratio of pregnancy in the first oestrum had been increased distinctively (P<0.05). Forthe young cows, the ratio of pregnacy in the first, second and third oestrUm could alI be increaseddistinctively, and the time betWeen postpartUm and pregnacy was deceded by 7.9days.GoMnqing and Enrofloxacin were aPplied respectively to treat the endometritis of 78 cows (21young cows and 57 mature cows). The results showed that goWnqtw could increase the ratio ofpregnacy in the three oestrUm after administration both for young cows and mature cows (P<0.05).The primary administration hed the effects on the oestnJm. The first oestrUm was l3.5 days ahead7Wf*&tez $ff $jhanX#for mature cows and l7.9 days for young cows and the time betWen postPartUIn and l8.5 days formature cows and 34.7 dnys for young cows deceded prmp BOth the prevention and thetreatment groups had the trend to decrease the tAnes of administraion.The results of acute toxic experimeme on mouse were as folIowing: After oral adIninistraion,the LD5, was over l0000mg/kg.b.w and the medmum tolerant dose was l87.5 times. Afterintraperitonea1 injection administraion, the LD5, was 364’3343 ml/kg.b.w The result of skinhypersencitive experiments on caVy showed that gOmpqtw had no hypersencition-Ieadingproperties. The resultS of eyes irrtant experimentS on rabbit showed that gOWqing had thegentle irritant action and this action would disaPpear after fOUrty-eight hours, which showed thatgowtqtw could be given through mucosal administrition.At the fifth minute after giving drug to uterus in vbo of rabbit, the shrinking range was boostup strongly re<0.05) and the shrinking frequency and the activation of uterus were also increased(P<0.0l). The reactions were almost the same as the groups with oxytocin, but gOmpqtw hadmore effectS on the shrinking frequency while the oxytocin had more effects on the shrinkingrange. At the tenth minute, the action ofgOWtw groups had no distinCtive change than thoseat the fifth minute but the oxytocin groups’ effectS on s更多还原