DNA重组hGH的生物测定方法的探讨 Ⅰ．去垂体大鼠体重增加法

为用于ＤＮＡ重组ｈＧＨ的生物测定，本文探讨了未成年去垂体大鼠体重增加法。实验表明：牛生长激素ｂＧＨ在０．００４～０．５００ＩＵ／鼠、ｄ，人生长激素ｈＧＮ在０．０１５～０．１３５ＩＵ／鼠、ｄ剂量范围内ｌｏｇ剂量（Ｘ）与反应（Ｙ）呈直线关系。６０～８０ｇ去垂体大鼠，每天给药２次，连续给药４ｄ或６ｄ为最佳实验条件。通过多批进口和国产ＤＮＡ重组ｈＧＨ产品的生物测定，说明用该法检测ｒｈＧＨ是颇为实用的方法之一。     

注射用重组人凝血因子Ⅷ大鼠单次与反复给药毒性研究

目的进行注射用重组人凝血因子Ⅷ的大鼠药物安全性评价,为临床安全用药提供参考信息。方法急性毒性试验对SD大鼠采用最大给药剂量法(66 460 IU/kg·bw),观察给药后大鼠出现的毒性反应。反复给药毒性试验设50、250和1 250 IU/kg·bw 3个给药组(分别相当于临床剂量的1、5和25倍)及溶剂对照组,连续给药30 d,停药后恢复期观察4周。结果急性毒性试验,动物临床观察结果、体重、大体解剖结果,给药组与对照组相比未见任何显著性差异。30 d连续给药试验中,出现与凝血因子Ⅷ抑制物相关的临床症状,如APTT延长、出血和A/G降低等,未发现与给药明确相关的毒性病理改变,未见明显与给药相关的延迟或蓄积毒性。结论 SD大鼠单次静脉注射注射用重组人凝血因子Ⅷ的最大耐受剂量大于66 460 IU/kg·bw;30 d重复给药未见明显毒性反应剂量(NOAEL)为1 250 IU/kg·bw。本试验结果为该品的临床应用提供了参考数据。     

抗生素89—07多次给予Beagle犬的毒性

用４种不同剂量［３、１０、３０和６０ｍｇ／（ｋｇｄ）］的抗生素８９－０７ｉｖ给予Ｂｅａｇｌｅ犬，连续９０ｄ，主要中毒表现是：给药１４ｄ内，６０ｍｇ组动物出现四肢无力；药后６０ｄ大于１０ｍｇ剂量组的动物肌酐及尿素氮升高，红细胞、血红蛋白及血细胞比容降低。病理组织学的变化，主要是肾小管上皮细胞变性和坏死，受损程度随剂量增加而加重。肾脏重量有随剂量加大而增加的趋势。３ｍｇ组动物未见明显异常，功能与病理形态学的改变均证明抗生素８９－０７与其它氨基糖苷类抗生素一样，反复给药的主要毒性靶器官是肾脏。在本试验条件下，Ｂｅａｇｌｅ犬ｉｖ１０ｍｇ可视为基本安全剂量。     

肾移植术后受者环孢素的血药浓度监测

目的 观察环孢素血药浓度与肾移植效果间关系。方法 对９７例接受同种异体肾脏移植术受者术后８周内２０６例次环孢素血药浓度监测结果进行回顾性分析，按照受者术后的临床表现、生化指标将其分为术后正常组、急性排斥组、急性毒性组，采用荧光偏振免疫测定法，以单克隆抗体试剂测定环孢素血药浓度。结果 术后正常组６２例移植肾功能良好，环孢素的给药剂量为５２±１．９ ｍｇ／ｋｇ·ｄ，１７１例次环孢素血药浓度的平均值为３０９．８５±１３１．６９μｇ／Ｌ；术后急性排斥组 ２６例，距发生排斥反应最近一次的环孢素血药浓度平均为１６５．８０±１２３．１３μｇ／Ｌ，环孢素的给药剂量为 ４．８±１．６ｍｇ／ｋｇ·ｄ；术后急性毒性组９例，距发生毒性反应最近一次的环孢素血药浓度平均为５５６．５１±１０２．５０μｇ／Ｌ，环孢素的给药剂量为６．２±１．０ｍｇ／ｋｇ·ｄ。三组之间环孢素的给药剂量无显著性差异（Ｐ＞０．０５），但环孢素血药浓度却相差很大，两两之间有显著性差异（正常组与排斥组 Ｐ＜ ０．０５；正常组与毒性组Ｐ＜ ０．０５；排斥组与毒性组Ｐ＜ ０．０１）。结论 环孢素浓度较低时，出现排斥反应的可能性较大；而环孢素浓度较高时，发生毒性反应的机会较多。     

神经生长因子(NGF)对小鼠的围产期毒理学研究

神经生长因子（ＮＧＦ）分为１６０００ＢＵ／ｋｇ／ｄ、８０００ＢＵ／ｋｇ／ｄ、４０００ＢＵ／ｋｇ／ｄ三个剂量组于皮下给药。给药时间为孕鼠妊娠１５天开始至断乳时止。实验结果表明,各剂量组无明显的生殖毒性作用,其Ｆ１代小鼠对神经行为发育、生殖功能均无明显的影响。但在哺乳期给药期间,随着剂量的增高,不同程度影响母鼠乳汁的分泌而影响仔鼠的生存。     

重组人角质细胞生长因子-2对兔眼的长期毒性作用

目的观察重组人角质细胞生长因子-2(recombination human keratinocyte growth factor-2,rhKGF-2)对兔眼的长期毒性。方法 32只新西兰白兔,随机分为对照组及高(2 000 mg·L-1)、中(500 mg·L-1)、低(125 mg·L-1)剂量组,每组8只,连续滴眼给药重组人角质细胞生长因子-2,每天6次,每2 h给药1次,单眼给药0.1 m L,给药4周,停药后恢复2周。观察一般药物反应及眼部症状,检测动物血液学、血液生化学和组织病理学等指标。结果除了中高剂量组分别有7例和8例眼部有少量类似眼屎的黏性分泌物及高剂量组有3例出现睑结膜充血呈鲜红色外,其他动物眼部未见与给药相关的明显异常变化;体质量、进食量、体温、心电图、尿液、血液学、凝血、血液生化学、骨髓细胞、脏器质量、脏器系数和病理学检查均未见明显与给药相关的异常变化。结论本试验选用3个剂量分别为有效剂量浓度的5、20和80倍,并未对新西兰白兔产生明显毒性,说明该剂量对新西兰白兔眼部用药是安全的。     

依替米星的耳毒性试验 Ⅲ.依替米星与庆大霉素、阿米卡星对前庭功能影响的比较

为比较依替米星与庆大霉素（ＧＭ）、阿米卡星（ＡＭＫ）长期给药对前庭功能的影响，本研究用豚鼠１３６只，分别用３种药物与生理盐水注射。每种药物又分４个剂量，每天肌注一次，共２８ｄ。给药期间，每周及给药完成后均检查一次前庭功能。结果表明：ＧＭ 随药物积累，前庭功能损伤极大，量效关系极显著。ＡＭＫ对前庭功能损伤较小。依替米星对前庭功能损伤更小。依替米星是一种前庭毒性不明显的新药。     

依替米星的耳毒性试验 Ⅲ.依替米星与庆大霉素,阿米卡星对？…

为比较依替米星与庆大霉素（ＧＭ）、阿米卡星（ＡＭＫ）长期给药对前庭功能的影响，本研究用豚鼠１３６只，分别用３种药物与生理盐水注射。每种药物发为４个剂量，每天肌注一次，共２８ｄ。给药期间，每周及给药完成后均检查一次前庭功能。结果表明：ＧＭ随药物积累，前庭功能损伤极大，量效关系极显著。ＡＭＫ对前功能损伤校小。依替米星对前庭功能损伤更小。依替米量是一种前庭毒性不明显的新药。     

重组人胰岛素注射液临床前生物相似性评价研究

目的 通过Beagle犬长期给药毒性试验及免疫原性试验,评价重组人胰岛素注射液(Insulin R)与原研药(Humulin R)的生物相似性。方法 进行Beagle犬scInsulin R 30 d停药14 d长期给药毒性试验,Insulin R剂量为0.5、1.0、1.5 IU/kg,Humulin R剂量为1.5 IU/kg,检测指标包括一般状况、进食量、体温、心电图、血液学、凝血、血清生化、电解质及尿液等,于给药期结束及停药期结束分两次剖杀动物,测定主要脏器的脏器系数并进行常规病理组织学检查;ELISA法检测Beagle犬血清的免疫原性。结果 Beagle犬重复sc Insulin R 30 d毒性试验中,中、高剂量组部分动物出现食欲降低、食量减少,高剂量1只雄性动物出现流涎、站立不稳、心率加速、抽搐等低血糖症状,中、高剂量组动物心率增加;原研药组与InsulinR高剂量组毒性反应相当;Beagle犬给予Insulin R 30 d未检测到抗药抗体。结论 Beagle犬sc Insulin R 30 d时的最大无毒反应剂量为0.5 IU/kg,相当于临床等效剂量的0.5倍,且未产生抗药抗体,与Humulin R具有较好的临床前生物相似性。     

多沙唑嗪对犬的长期毒性实验研究

目的：在动物体内验证多沙唑嗪临床毒副反应及性质。方法：以多沙唑嗪１，４，１６ｍｇ／ｋｇ，给犬连续９０ｄ，ｐｏ，并设对照组，观察用药期间毒性反应及停药２１ｄ期间恢复情况。结果：高剂量组在给药初期动物出现眼睑下垂、结膜及巩膜充血、瞬膜弛缓、眼分泌增多等现象，部分动物活动量减少，当继续用药１０￣２０ｄ后症状逐渐减轻并消失。在用药６３ｄ后，动物体重增长明显减慢（Ｐ〈０．０５），且在６０ｄ及９０ｄＢＵＮ含量     

重组链激酶在急性下肢深静脉血栓形成中的应用

目的 :观察重组链激酶 (r SK )对急性下肢深静脉血栓形成的疗效和安全性。方法 :60例急性下肢深静脉血栓形成病人随机分为 2组。r SK组(30例 )给予r SK 5 0万IU加入 5 %葡萄糖注射液5 0 0mL中 ,静脉滴注 ,d 1,bid ,d 2～ 5 ,qd ,d 5起口服华法林 2 .5mg ,qd(首剂加倍 ) ,连续 3mo。尿激酶 (UK)组 (30例 )给予UK 5 0万IU加入 5 %葡萄糖注射液 5 0 0mL中 ,静脉滴注 ,d 1,bid ,d 2～ 5 ,qd ,口服华法令同r SK组。 1wk和 3mo后根据患肢消肿程度及磁共振或B超检查结果判断疗效。结果 :1wk后r SK组和UK组总有效率分别为90 % ,63% (P <0 .0 5 ) ;3mo后分别为 97% ,77%(P >0 .0 5 )。无严重不良反应。结论 :应用r SK治疗急性下肢深静脉血栓形成是一种安全、疗效好的治疗方法     

国产重组葡激酶对兔股动脉血栓溶栓疗效的对照研究

目的观察同等剂量国产重组葡激酶(r-SAK)、重组链激酶(r-SK)和尿激酶(UK)对兔股动脉血栓的溶栓疗效。方法新西兰兔20只,随机分为对照组、r-SAK组、UK组和r-SK组。用球囊损伤法制作兔右股动脉血栓形成模型。球囊损伤后2h分别经耳缘静脉匀速输注各溶栓药物,持续30min:①对照组:生理盐水10ml;②r-SAK组:r-SAK3.0万U/kg;③UK组:UK3.0万U/kg;④r-SK组:r-SK3.0万U/kg。溶栓后持续监测兔股动脉压力以判断血管开通状况。结果球囊损伤后120min各实验组右股动脉脉压均降为0或低于左侧脉压的10%;对照组输注生理盐水后右股动脉压力无显著变化,r-SAK组溶栓后右股动脉脉压均显著增加至大于左侧脉压的50%,而UK和r-SK组溶栓后右侧股动脉压力较溶栓前均无显著变化;溶栓后5h,r-SAK组所有再通血管的脉压均下降至左侧脉压的50%以下。结论同等剂量的国产r-SAK溶栓疗效优于UK和r-SK。     

链激酶抗体变化与重组链激酶溶栓疗法治疗急性心肌梗死的关系

目的 :观察急性心肌梗死 (AMI)病人链激酶抗体 (SK AB)变化与重组链激酶 (r SK)溶栓疗效的关系。方法 :AMI病人 13例 ,男性 9例 ,女性 4例 ,年龄 56a±s 13a。予r SK 1.5MU于 5%葡萄糖注射液 10 0mL中于 60min内静脉滴注 1次。溶栓前即刻 ,溶栓后 2 ,6,12 ,2 4h ,3d和 7d测定血清SK AB。结果 :溶栓成功者 11例 ,占 85% ;溶栓前平均SK AB滴度为 1∶160 0 ,溶栓后 2h降至 1∶4 0 0 ,并持续至d 3(P <0 .0 1) ,7d明显升高超过 1∶640 0 ;分析溶栓成功者 ,SK AB变化特点相似 ,未发现过敏反应及显著不良反应。结论 :r SK溶栓治疗成功率较高 ,且较安全。SK AB水平高低似与溶栓效果无关。     

Thrombolytic efficacy of native recombinant staphylokinase on femoral artery thrombus of rabbits

AIM: To investigate the thrombolytic efficacy, ideal dosage and administration of native recombinant staphylokinase (r-SAK). METHODS: Forty New Zealand rabbits were randomly assigned into the control, r-SAK low-dose, medial-dose, high dose, single bolus, allied therapy, recombinant streptokinase (r-SK) and urokinase (UK) groups. The right femoral artery thrombosis models were made by balloon injury, and 120 min after the injury, the thrombolytic agents were infused through the rabbits' parallel-ear vein. RESULTS: (1) 2 h after balloon injury, the pulse pressures of the right femoral arteries reduced to 0 or less than 10% of that of left femoral arteries in all groups; (2) after thrombolytic therapy, the pulse pressures in some of the femoral arteries markedly enhanced to more than 50% of that of left femoral arteries; (3) the reopening rates in the r-SAK medial and high dose groups were significantly higher than that of the control. The reopening rate of the same dose native r-SAK was significant higher than that of UK and r-SK; (4) the patency score of the right femoral arteries tended to be better in the r-SAK medial and high-dose groups than that of the low-dose group, and the time to reopening in the allied therapy group tended to be shorter. CONCLUSION: (1) r-SAK has a definite thrombolytic effect on the femoral artery thrombus of rabbits; (2) single bolus is an effective manner of r-SAK therapy, and r-SAK allied therapy with heparin may shorten the time to recanalization; (3) the efficacy of the same dose native r-SAK was superior to that of r-SK and UK.     

基因重组链激酶治疗颅内血肿62例分析

目的：分析重组链激酶(r-SK)加血浆在颅内血肿外科治疗中的局部应用及疗效。方法：入选62例外伤性颅内血肿患者，采用定向钻孔置管，局部应用5mg的重组链激酶加自体血浆2mL灌注，溶解引流血肿。结果：近期疗效优49例(79．03％)，好转9例(14．52％)，4例无效(6．45％)。结论：定向钻孔血浆加r-SK局部应用溶解引流血肿有较好疗效。     

3775株临床分离革兰阴性菌耐药性分析

目的分析我院2006-2007年临床分离革兰阴性菌对抗菌药物的耐药性,为临床合理使用抗菌药物提供依据。方法采用纸片扩散法对3775株临床分离革兰阴性菌进行药敏试验,结果采用美国临床和实验室标准协会2006年版标准判断,数据统计分析采用WHONET5.4软件。结果两年共收集革兰阴性菌3775株,革兰阴性非发酵菌占36.3%。最常见菌种依次为大肠埃希菌、肺炎克雷伯菌、副流感嗜血杆菌、鲍曼不动杆菌、铜绿假单胞菌、嗜麦芽窄食单胞菌。主要引起呼吸道感染。大肠埃希菌、肺炎克雷伯菌ESBLS的检出率分别为62.7%、42.6%。亚胺培南和美罗培南对肠杆菌科细菌具有较高的敏感性（〉94%）。头孢呋辛和头孢曲松对流感嗜血杆菌和副流感嗜血杆菌均具有较高的敏感性（〉89%）。鲍曼不动杆菌对亚胺培南、美罗培南、头孢哌酮/舒巴坦、米诺环素的耐药率在8.8%以下。铜绿假单胞菌对妥布霉素耐药率最低,其次为美罗培南、头孢他啶、阿米卡星、亚胺培南（10.1%～16.1%）。米诺环素对嗜麦芽窄食单胞菌、脑膜炎败血性黄杆菌、产吲哚黄杆菌、洋葱伯克霍尔德菌有较好的抗菌活性（耐药率1.3%～8%）。结论碳青霉烯类对肠杆菌科、鲍曼不动杆菌、铜绿假单胞菌仍保持高活性。根据病原菌的种类及药物敏感性结果合理使用抗菌药物,是有效控制感染和减少耐药菌株产生的重要手段。     

溶栓药物纤维蛋白亲和力的简便测定

建立了一种简便可行的测定溶栓药物与纤维蛋白亲和力的方法，对我院自制的链激酶，尿激酶和对茴香酰纤溶酶原链激酶激活剂复合物进行测定，并作比较，所得结果与国外文献报道一致。     

尿激酶与链激酶治疗急性心肌梗死的比较

目的：探讨国产尿激酶与进口链激酶溶栓治疗急性心肌梗死（ＡＭＩ）的疗效和副作用。方法：ＡＭＩ病人９７例,分为２组。尿激酶组５４例（男性３５例,女性１９例;年龄６２ａ±ｓ８ａ）给尿激酶１．５ＭＵ,链激酶组４３例（男性２８例,女性１５例;年龄６３ａ±９ａ）给链激酶１．５ＭＵ;２药均溶于５％葡萄糖注射液１５０ｍＬ中于３０ｍｉｎ内静脉滴注×１次;２组常规治疗相同。结果：尿激酶组与链激酶组的血管开通率和死亡率比较,依次为６７％（３６／５４）,７０％（３０／４３）和７％（４／５４）,７％（３／４３）,均Ｐ＞０．０５,链激酶组１例出现脑出血。结论：尿激酶治疗ＡＭＩ疗效与链激酶相似。     

Alterations in endocrine responses in male Sprague-Dawley rats following oral administration of methyl tert-butyl ether.

Methyl tert-butyl ether (MTBE) is an oxygenated fuel additive used to decrease carbon monoxide emissions during combustion. MTBE is a nongenotoxic chemical that induces Leydig cell tumors (LCT) in male rats. The mechanism of MTBE-induced LCT is not known; however, LCT induced by other nongenotoxic chemicals have been associated with the disruption of the hypothalamus-pituitary-testicular (HPT) axis. The objective of this study was to determine whether MTBE functions as an endocrine-active compound by affecting levels of specific hormones involved in the maintenance of the HPT axis. Nine-week-old male Sprague-Dawley rats were administered MTBE by gavage at 0, 250, 500, 1000, or 1500 mg MTBE/kg/day for 15 or 28 consecutive days and sacrificed 1 h following the last dose. Relative testis weights were increased only in high-dose animals treated for 28 days, and no testicular lesions were observed at any dose level. Adrenal gland, liver, and kidney weights were also increased. Histologic changes included protein droplet nephropathy of the kidney and centrilobular hypertrophy of the liver. Interstitial fluid and serum testosterone levels as well as serum prolactin levels were decreased only in animals treated with 1500 mg MTBE/kg/day for 15 days. At 28 days, serum triiodothyronine (T3) was significantly decreased at 1000 and 1500 mg MTBE/kg/day compared to control animals, and a decrease in serum luteinizing hormone and dihydrotestosterone was observed at 1500 mg MTBE/kg/day. These results indicate that MTBE causes mild perturbations in T3 and prolactin; however, the changes in testosterone and LH levels did not fit the pattern caused by known Leydig cell tumorigens.     

Prior,repeated exposure to cocaine potentiates locomotor responsivity to central injections of corticotropin-releasing factor (CRF) in rats

Rationale There is considerable evidence that the stress-related neuropeptide, corticotropin-releasing factor (CRF), plays an important role in mediating behavioural changes induced by prior experience with cocaine. From this perspective, it is conceivable that repeated exposure to cocaine induces a form of sensitization in CRF systems that makes animals more responsive to CRF following prolonged drug-free periods.Objectives To study the effects of repeated cocaine exposure on locomotor activity induced by different doses of CRF after drug-free periods ranging from 24 h to 28 days.Methods Male Wistar rats were injected once daily for 7 days with cocaine (15 mg/kg, IP on days 1 and 7 in locomotor chambers; 30 mg/kg, IP, on days 2–6 in home cages) or saline. In experiment 1, starting 10 days after the last injection, animals were tested for their locomotor response to intracerebroventricular (ICV) injections of vehicle and three doses of CRF (0.25, 0.5, and 5 µg). In experiment 2, animals were tested for their locomotor response to ICV injections of 0.5 µg CRF after drug-free periods of 1–2, 10–11 and 28–29 days.Results Compared to saline pre-exposed animals, cocaine pre-exposed animals showed a significantly greater locomotor response to CRF, relative to vehicle, at all doses tested (experiment 1) and after drug-free periods of up to 28 days (experiment 2). The effects were clear and extremely consistent in magnitude between experiments and conditions.Conclusions These results suggest that cocaine pre-exposure induces long-term changes in the responsivity of the central nervous system to CRF.