银杏内酯B注射液对Beagle犬的长期毒性研究

目的:研究银杏内酯B注射液的长期毒性,为临床试验提供安全性依据。方法:将Beagle犬分为空白对照及银杏内酯B注射液高、中、低剂量(80、20、5mg·kg-1)组,每组6只,♀♂各半,每天静脉滴注给药,每周连续给药6d,共90d,实验时检查各剂量组犬的体重、食量、体温、心电图、血液学、血液生化学、眼科、骨髓、尿常规、病理组织学等,并进行恢复性观察。结果:给药期间,银杏内酯B注射液高剂量组有1只犬出现1次呕吐症状,高、中剂量组犬凝血时间显著延长;恢复期高剂量组有1只犬出现尿蛋白强阳性;各指标显示未见与药物有关的显著毒性反应。结论:银杏内酯B注射液对Beagle犬的无毒反应剂量为20mg·kg-1。     

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。     

前药dl-PHPB在Beagle犬中反复给药毒性及伴随毒代动力学研究

目的评价I类抗脑缺血新药2-(α-羟基戊基)苯甲酸钾(dl-PHPB)在Beagle犬中反复给药30d的毒性及伴随毒代动力学。方法 Beagle犬反复给药30d,给药剂量分别为6、18、54mg/kg(分别相当于临床人体用量的3.6、10.8和32.4倍)并设溶剂对照组,停药后恢复期观察3周。同时采用HPLC-UV方法测定不同剂量下首次和末次给药的血清药物浓度。结果 54mg/kg剂量组的主要毒性反应为部分动物给药过程中出现头部颤抖,给药结束时可见血尿素氮(BUN)、肌酐(Cr)和尿pH值有所增加,相关脏器病理组织学检查未见异常;恢复期结束时上述指标均恢复正常。在6、18、54mg/kg剂量下,药后1h内dl-PHPB即完全转化为丁基苯酞(dl-NBP)。首次给药后,其活性代谢物dl-NBP的AUC0-∞分别为2.8、7.2、32.5μg.h-1.ml-1,末次给药dl-NBP的AUC0-∞分别为2.9、8.1、38.7μg.h-1.ml-1。其转化为dl-NBP的暴露比(AUC30th/AUC1st)分别为1.02、1.12和1.17。结论 Beagle犬静脉滴注dl-PHPB30d连续给药非毒性反应剂量为18mg/kg。伴随毒代动力学研究显示dl-PHPB的毒性反应与其快速转化为dl-NBP密切相关。     

注射用雷贝拉唑钠Beagle犬的长期毒性

目的注射用雷贝拉唑钠属于抑制分泌的药物,通过抑制H /K -ATP酶来抑制胃酸的分泌,主要用于治疗消化道溃疡。本试验通过观察重复静脉注射注射用雷贝拉唑钠后犬出现的毒性反应、毒性效应关系、主要靶器官、毒性反应性质、严重程度及可逆程度;找出无毒反应剂量、毒性反应剂量;进一步了解毒性反应产生时间、持续时间及可能反复产生毒性反应时间,以及蓄积毒性、迟发毒性等。为临床设计人用剂量和主要观察指标等提供必要的参考依据。方法取健康Beagle犬24只,按体重随机分为空白组(Veh)、低[L,2mg/(kg.d)]、中[M,9mg/(kg.d)]、高[H,40mg/(kg.d)]4组,每组6只,雌雄各半。每周给药7d,连续给药1个月(5周)。停药后留取1/3动物继续观察2周。按照要求进行相关检查。结果Veh和L、M组动物未见明显异常,H组动物给药时即普遍流涎、自主活动降低甚至丧失、对外界刺激反应降低,腹卧或蹲位,头部节律性震颤,偶尔出现呕吐,药后1h动物状态可恢复正常。与Veh组比较,各剂量组动物眼科检查、体温、心电图检查、尿常规检查血清生化检查及体重均未见明显异常。给药结束血液学检查可见M组MCV、H组RBC、Hb和MCV降低,与Veh比较差异有统计学意义,其他指标与Veh比较未见明显差异。组织病理学检查M组3/4只、H组4/4只犬甲状腺滤泡内胶质减少或吸收空泡形成,部分滤泡腔内含有细胞碎屑;滤泡上皮增生,由扁平变为立方状或高柱状,部分有乳头形成,恢复期以上病变可恢复。结论注射用雷贝拉唑钠Beagle犬长毒研究2mg/(kg.d)为无毒反应剂量,为临床用药剂量6倍,9~40mg/(kg.d)给药可引起犬甲状腺损伤,此病变是可逆的,停药后可以恢复正常。一般毒性观察可见其对犬神经系统产生一过性影响,建议临床注意神经系统的症状监测。     

曼陀罗子提取物对Beagle犬长期毒性实验研究

目的 观察Beagle犬连续口服曼陀罗子提取物(MTL)的长期毒性反应. 方法Beagle犬24只,随机分为空白对照组及低、中、高剂量药物组,每组6只. 低、中、高剂量药物组分别给予MTL 40,80,160 mg.kg^-1.d^-1,po,qd,连续3个月,空白对照组给予羧甲基纤维素钠. 末次给药24 h每组处死4只犬,停药后恢复2周每组再处死2只犬,分别检测血液学、血液生化学等指标,测定脏器系数,进行系统尸检、脏器组织病理学检查. 结果 中、高剂量药物组犬给药后出现活动先增多后减少、扩瞳、口干、呕吐等症状;与空白对照组比较,中、高剂量药物组犬体质量明显降低,血小板计数、淋巴细胞数目、肌酸磷酸激酶明显升高,粒细胞数目明显降低;组织病理学检查无明显变化. 结论 MTL连续口服给予Beagle犬 3个月,对犬中枢神经系统、消化系统、血液系统、心脏有一定毒性. MTL对Beagle犬安全剂量不高于40 mg•kg^-1•d^-1(相当于生药388 mg.kg^-1.d^-1).     

叶下珠提取物对Beagle犬长期毒性实验研究

目的 研究连续口服给予叶下珠提取物对Beagle犬产生的毒性反应.方法 叶下珠提取物125、250、500mg·kg-1(低、中、高剂量)连续灌胃给药26wk,于给药26wk及停药6wk时取部分犬进行血液学指标、血液生化学指标、尿液指标、病理组织学检查.结果 高剂量组Beagle犬出现食量减少、间歇性呕吐等症状.与空白对照组比较,中、高剂量在给药结束时导致Beagle犬ALT、AST、ALP、T-Bil、BUN、γ-GT等血液生化学指标明显升高(P＜0.05或P＜0.01),停药6wk后,以上指标均恢复正常.给药结束时,高剂量组Beagle犬尿液出现蛋白质和胆红素阳性.病理检查显示,中、高剂量均可导致Beagle犬肝脏和肾脏实质脏器出现可逆性组织病理学改变.结论 长期大剂量口服给予叶下珠提取物,可导致Beagle犬出现肝脏和肾脏功能以及病理组织学可逆性改变.     

左旋和右旋奥硝唑对犬神经毒性的比较研究

目的 本实验进行了Beagle犬静脉输注奥硝唑及其光学对映体神经毒性的比较研究.方法 Beagle犬连续静脉给药2周,观察动物的一般状况和体重变化.给药结束时进行大体解剖,血液学和血液生化学,器官重量和组织病理学检查.结果 左旋奥硝唑组(200mg/kg,iv)Beagle犬仅在给药后1～3h内出现流涎、呕吐、不自主排便、排尿等症状;动物体重增长受到轻度抑制,进食量轻微减少,但与溶媒对照组无明显差异.右旋奥硝唑组(200mg/kg,iv)动物出现流涎、呕吐、四肢无力、不能站立,抽搐等毒性反应,随给药次数增加,毒性反应表现更加明显,且恢复时间延长,对动物体重及进食量有明显抑制.消旋奥硝唑组的毒性反应介于两者之间.各组的血液学和血液生化学检查结果以及器官重量无明显差异.组织学检查结果显示右旋体组犬小脑的蒲肯野细胞数目较溶媒对照组和左旋体组明显减少,细胞呈轻度变性.结论 在本试验条件下,左旋体组Beagle犬给药后的毒性反应比右旋体组轻.右旋体组犬小脑出现可见的蒲肯野细胞变性.结果提示,奥硝唑左旋体较右旋体毒性小,临床用药应更加安全.     

精蛋白重组人胰岛素注射液生物类似药非临床安全性评价

目的 通过小鼠单次给药毒性试验、Beagle犬重复毒性及免疫原性试验和豚鼠全身主动过敏试验,考察精蛋白重组人胰岛素注射液（Insulin NPH）的毒副反应、毒性靶器官或靶组织,为开展临床试验提供依据。方法 ①小鼠单次给药毒性试验：采用最大给药量法分别sc生理盐水、溶媒和Insulin NPH（2092~2488 IU/kg）,监测给药后小鼠一般状态、体质量、脏器异常。②Beagle犬重复毒性试验：sc溶媒、原研对照药（Humulin NPH,1.5 IU/kg）,低、中和高剂量（0.5、1.0和1.5IU/kg）的Insulin NPH,每天1次,连续30 d,停药恢复14 d;在给药期和恢复期内观察动物的一般体征和注射部位的局部刺激性,进行体质量、肛温、血糖及心电图检查,测定血液学、血清生化、尿液常规等指标,并进行脏器质量及组织病理学检查;免疫原性试验采用间接ELISA法检测不同给药期Beagle犬血清中抗药结合抗体。③豚鼠主动全身过敏试验：分别sc低和高剂量（4和12 IU/kg）的Insulin NPH、生理盐水和溶媒,另设卵清白蛋白为阳性对照,使用以上剂量进行5次致敏试验后,iv 3倍致敏剂量进行激发试验,观察豚鼠过敏症状。结果 小鼠sc 165倍临床常用剂量的Insulin NPH后,未见明显毒性反应;Beagle犬重复毒性试验中1.0 IU/kg是Insulin NPH的无毒反应剂量（NOAEL）,该剂量相当于临床拟用剂量的2倍,免疫原性试验各剂量组均未发现抗药结合抗体;豚鼠主动全身过敏试验中未见明显过敏症状。结论 在本试验条件下未观察到Insulin NPH明显毒性反应。     

注射用灯盏花素在比格犬与食蟹猴的体内毒性比较

目的:比较注射用灯盏花素对比格(Beagle)犬和食蟹猴的体内毒性。方法:普通级Beagle犬32只,雌雄各半,设生理氯化钠溶液(NS)对照和注射用灯盏花素40,80,120 mg·kg~(-1)剂量组。食蟹猴4只,设NS对照和注射用灯盏花素200 mg·kg~(-1)组。2种动物均静脉滴注给药13周,停药恢复4周,观察体内毒性。结果:Beagle犬80和120 mg·kg~(-1)组出现呕吐、腹泻、流涎等不良反应。120 mg·kg~(-1)组有1只动物给药11d皮肤出现斑疹、荨麻疹;给药第11周有1只动物出现呕血、便血后死亡。食蟹猴200 mg·kg~(-1)组仅发现1只动物出现间断性流涎。Bea- gle犬和食蟹猴各剂量组体重增长,进食量正常,血液、生化等其他各项检测指标未见明显异常。结论:食蟹猴和Beagle犬对注射用灯盏花素的耐受性、敏感性和毒性反应均存在种属差异。     

聚乙二醇化重组人粒细胞集落刺激因子大鼠和Beagle犬的免疫原性

目的：在进行聚乙二醇化重组人粒细胞集落刺激因子（PEG30-rhG-CSF）大鼠和Beagle犬重复给药毒性试验时,观察给药后动物血清中抗PEG30-rhG-CSF抗体的产生和抗体的中和活性,为非临床安全性评价的确切性以及临床给药周期提供依据。方法：大鼠分为赋形剂对照组、PEG30-rhG-CSF0.75、3.0、12mg/kg组,sc给药,隔日1次,连续2周;Beagle犬分为赋形剂对照组、PEG30-rhG-CSF0.25、1.0和4.0mg/kg,sc,每周1次,连续4周。采用ELISA法检测动物血清中抗PEG30-rhG-CSF的抗体,采用NFS-60细胞/MTT比色法检测抗体的中和活性。结果：大鼠在给药期和恢复期各剂量组动物血清中均未检测到抗PEG30-rhG-CSF的结合抗体。Beagle犬在给药的第1周和第2周,未检测到结合抗体,但在第4周时,低、中和高3个剂量组各有5只（5/6）的动物血清中检测到结合抗体,而抗体滴度与剂量无明显相关性。恢复4周后,仅高剂量组1只（1/2）动物出现抗体,且抗体滴度呈下降趋势。另外,在给药期和恢复期,血清中所产生的抗体均无中和PEG30-rhG-CSF的活性。结论：大鼠重复给予PEG30-rhG-CSF的毒性试验中,所有动物血清中均未检测到结合抗体和中和抗体;Beagle犬用药组的绝大部分动物血清中出现抗PEG30-rhG-CSF的抗体,但所产生抗体无中和活性。     

Beagle犬灌胃厄多司坦盐酸氨溴索混合物的急性和亚慢性毒性研究

目的 观察Beagle犬给予厄多司坦盐酸氨溴索混合物后出现的急性和亚慢性毒性反应,为临床安全用药剂量的设计和毒副反应监测提供参考.方法 选用Beagle犬进行急性和13周亚慢性毒性试验.急性试验中,设置厄多司坦盐酸氨溴索混合物剂量组(5.04 g/kg)、厄多司坦组(4.80 g/kg)、盐酸氨溴索组(0.24 g/k...     

Toxicological studies on pepleomycin sulfate (NK631). III. Subacute toxicity of pepleomycin in dogs (author's transl)]

Subacute toxicity and its recovery of pepleomycin sulfate was studied in both sexes of beagle dogs. At dose levels of 2.4, 1.2 and 0.6 mg/kg, pepleomycin was administered intramuscularly to dogs for 30 successive days. Two dogs of the 1.2 mg/kg dose group were used for recovery test for 35 days. As general symptoms, the decrease of food intake, the loss of body weight, ulceration of foot pad, nail root necrosis and onychoptosic, ulcer of tongue and labia, and alopecia, dermatitis and necrosis at friction sites were observed the more severely in high dose groups, as those in bleomycin were. The death occurred in the 2.4 mg/kg dose group of both sexes. The lesions of liver and kidney were recognized in the 2.4 and 1.2 mg/kg dose groups of both sexes on biochemical, histopathological or urinary findings. Additionally slight fibrous change of lung was observed in all dose groups. Generally subacute toxicity of pepleomycin was revealed approximately in the same as or in a little stronger degree than that of bleomycin, and its recovery was hardly recognized during its period. The maximum safety dose in this studies is estimated to be between 0.3 and 0.6 mg/kg in dogs.     

Absolute bioavailability study in the dog with Visacor, a new cardioselective beta blocking drug with intrinsic sympathomimetic activity

The cardioselective beta-adrenergic blocking drug Visacor (ICI 141,292) was dosed to six beagle dogs in a randomized cross-over manner. Five formulations were examined i.e. a 15 mg/kg intravenous solution, a 50 mg/kg oral solution, and 50, 100 and 200 mg/kg oral powder formulations. Whole blood and urine samples were collected at various times after each dose and analysed for parent drug concentration by a high pressure liquid chromatography procedure. The urine samples were also analysed for parent drug content after hydrolysis with beta-glucuronidase. The normalised intravenous blood levels of ICI 141,292 were found to decay tri-exponentially with a final phase elimination half-life of about 10 h. The computer fitted data showed the drug to possess a high volume of distribution for both the central compartment (54% body weight) and whole body (1384% body weight) indicating the possibility of a high degree of metabolism. The drug clearance following i.v. administration was 196 ml/min and the urinary recovery rate of parent drug was 24% (unhydrolysed) and 40% following hydrolysis with beta-glucuronidase. Following oral dosing at 50 mg/kg (as both powder (C) and solution (B], 100 (D) and 200 (E) mg/kg (as powder) the systemic blood profiles were found to increase with dose. The mean peak blood level attained was 6 +/- 1, 5 +/- 1, 8 +/- 1 and 14 +/- 1 micrograms/ml for formulations, B, C, D and E respectively. The systemic bioavailability of ICI 141,292 was only about 40%. The areas under the curves increased linearly with dose and the elimination phase half-life was unchanged with dose. The calculated half-life (7 h) was apparently shorter after oral administration than after intravenous administration (10 h) but this is probably an artefact dependent on the limit of detection of the assay procedure. At 50 mg/kg there were no significant differences in blood profiles or in the urinary excretion of drug between the solution and powder formulations. However the overall systemic bioavailability was marginally higher with the powder. These observations are consistent for a drug which is cleared by both renal and hepatic elimination processes, which undergoes "first-pass" metabolism on oral dosing and, over the oral dose range studied, obeys linear pharmacokinetics. The significant increase in recovery of parent drug, after hydrolysis of the urine with beta-glucuronidase, indicates that the ICI 141,292 glucuronide conjugate is present to a significant extent. The results also demonstrate that absorption of parent drug from the gastrointestinal tract may not be complete.     

栀子西红花甙对Beagle犬静脉给药的长期毒性研究

目的 :观察栀子西红花甙对Beagle犬的各种毒性反应 ,以评价栀子西红花甙的安全性。方法 :栀子西红花甙以 0、5 0、112、2 5 0mg/kg每天静脉注射给药一次 ,每周 6d ,连续给药 13周。 结果 :静脉注射栀子西红花甙后 ,犬主要表现为皮肤搔痒 ,皮肤、粘膜、巩膜等染成黄色 ,尿液、粪便颜色加深 ,且总胆红素和白细胞显著升高 ,而红细胞计数、血红蛋白及红细胞压积明显降低 ,活动减少等。对犬的血清生化、尿、粪常规、体重增长、心电图等均未发现明显的与药物作用有关的异常变化。组织切片检查表明 ,在所有受检脏器中 ,均未见明显的病理改变。结论 :在此试验条件下 ,栀子西红花甙静脉注射给药 13周对犬的无毒剂量为 5 0mg/kg。     

Hepato- and thyreotoxicity of tifemoxone.

The oral toxicity of Tifemoxone, phenoxymethyl-6 tetrahydroxazine-1, 3 thione-2, a new potential antidepressant was studied during 6 months in rats at 30, 85 and 230 mg/kg/d and in beagle dogs at 10, 55 and 300 mg/kg/d. Thyroid hyperplasia and hypoactivity were observed in the rats and dogs plasma triiodothyronine, determined in dogs, was modified. A dose dependent hepatotoxic effect was observed in the rats and dogs. In dogs at low dose, one animal died after B.S.P. test. Water consumption and urinary volume increased, weight loss and anemia appeared at high doses in both rats and dogs. Hair loss was observed in rats and convulsions in dogs. In conclusion, Tifemoxone like tetrahydroxazine thione and some derivatives caused thyreotoxicity, hairlessness and increased in water comsumption and diuresis and in addition it had strong hepatotoxic effect especially in the dog.     

Toxicity study of cefmatilen hydrochloride hydrate (S-1090) (7)--Three-month repeated oral dose toxicity study in juvenile dogs

To evaluate the repeated oral dose toxicity of Cefmatilen hydrochloride hydrate (S-1090) in juvenile dogs, S-1090 was administered to juvenile beagle dogs at dose levels of 50, 100, 200 and 400 mg potency/kg/day for 3 months. No deaths occurred. Urinalysis in the 400 mg potency/kg group revealed positive reactions of occult blood and protein, and erythrocytes in sediments. Cystitis was observed in the 200 and 400 mg potency/kg groups. In the thyroids, an increased weight in some animals in the groups dosed at 100 mg potency/kg or more and an increased follicular colloid in the 400 mg potency/kg group were observed. However, no related changes were noted in other examination items. Red to dark-red feces (due to chelated products of S-1090 or its decomposition products with Fe3+ in the diet) were observed in all treated groups. Plasma S-1090 concentrations increased in a manner less than dose-proportional. The lesions of urinary bladder were judged as S-1090-induced toxic changes and the NOAEL of S-1090 in this study was assessed to be 100 mg potency/kg/day.     

HR0905安全药理学研究

目的观察HR0905对小鼠神经系统、犬心血管系统及呼吸系统的影响。方法实验均分HR0905高、中、低剂量组及溶媒对照共4个组,小鼠实验给药组分别单次灌胃（ig）HR0905 30,100和300 mg/kg,观察药物对小鼠自发活动和爬杆能力的影响;犬实验给药组分别单次igHR0905 2、6、20 mg/kg,观察药物对犬血压、ECG、呼吸频率及节律的影响。结果与溶媒对照组相比,HR0905单次ig后高剂量组爬杆能力显著下降;给药后1.5 h开始动物自发活动有下降趋势,且3.5 h下降最多;HR0905单次ig后犬心率明显减慢。给药后2.0 h中剂量组及高剂量组Beagle犬收缩压、舒张压及平均动脉压有下降趋势,且4.0 h下降幅度最大。HR0905对Beagle犬ECG之P波电压、T波电压、QRS时间、PR间期、QT间期、ST段无明显影响;HR0905对呼吸频率、幅度和节律无明显影响。结论 HR0905对心血管和神经系统有一定的影响,可使犬心率减慢,犬收缩压、舒张压及平均动脉压有下降趋势,小鼠爬杆能力显著下降,自发活动有下降趋势。     

iv盐酸左氧氟沙星注射液Beagle犬毒动学及毒性研究

z目的 评价盐酸左氧氟沙星注射液在Beagle犬体内的暴露情况及其对动物的长期毒性研究。方法 建立Beagle犬血浆样品中左氧氟沙星的高效液相色谱（HPLC）检测方法;Beagle犬按分层随机法分为对照组和盐酸左氧氟沙星注射液低、高剂量（20、40 mg/kg,分别为人临床拟用剂量的2.33、4.67倍）组,每组8只。iv给药,对照组iv生理盐水,1次/d,给药期4周,恢复期4周。对Beagle犬首、末次给药后血浆样品进行分析测定,采用Winnolin 6.2.1采用非房室模型法（NCA）判定盐酸左氧氟沙星注射液对受试动物体内毒动学的影响。观察动物一般状态;采用生物机能实验系统,以II导联记录Beagle犬给药前、给药期结束、恢复期结束Beagle犬在清醒状态下的心电图。结果 首次给药后,雄性Beagle犬低、高剂量组C_max、AUC_0-t比值分别为1：1.86和1：2.19,MRT比值为1：1.16,CL_F比值为1：0.77,t_1/2比值为1：1.44;末次给药后,低、高剂量组C_max、AUC_0-t比值分别为1：3.73和1：2.24,MRT比值为1：0.87,CL_F比值为1：0.92,t_1/2比值为1：0.94。首次给药后,雌性Beagle犬低、高剂量组C_max、AUC_0-t比值分别为1：2.10和1：2.12,MRT比值为1：1.02,CL_F比值为1：0.63,t_1/2比值为1：1.05;末次给药后,低、高剂量组C_max、AUC_0-t比值分别为1：1.88和1：1.53,MRT比值为1：0.67,CL_F比值为1：1.47,t_1/2比值为1：0.66。盐酸左氧氟沙星注射液低剂量组动物给药第1周内出现困倦（2/8）,皮肤水肿、发红（2/8）,上睑松弛（1/8）,唾液分泌过多（1/8）,呕吐（1/8）;给药第2~4周出现皮肤水肿（1/8）、发红（1/8）;恢复期症状消失;高剂量组动物给药第1、2天出现上睑松弛（1/8）,部分动物出现短期或长期的皮肤水肿（4/8）、困倦（5/8）、呕吐或干呕（6/8）、唾液分泌过多（7/8）、鼻有分泌物（2/8）、皮肤发红（2/8）;给药第2、3周开始出现肌张力降低（2/8）,偶尔出现大小便失禁（4/8）;恢复期症状消失。给药前各组心电指标无明显差异。给药结束盐酸左氧氟沙星注射液低、高剂量组心率显著高于对照组（P<0.05、0.01）,低、高剂量组PR间期显著低于对照组（P<0.05、0.01）;高剂量组QT间期显著低于对照组（P<0.05）;恢复期结束高剂量组心率显著高于对照组（P<0.05）,且作用均呈剂量相关性。结论 不同剂量的盐酸左氧氟沙星注射液在Beagle犬体内存在暴露和蓄积差异;高剂量组雌性Beagle犬药物代谢加快,可能诱导了肝药酶活性,致使药物在体内的暴露减少;供试品高于临床等效剂量给药在给药期间可能发生过敏反应、消化系统损害、全身性损害、神经系统毒性和心血管系统损害,恢复期症状消失。     

Pharmacokinetics of fostedil, a new calcium antagonist, in beagle dogs following oral and intravenous administration

Twelve adult beagle dogs received both an oral and intravenous dose (12 mg/kg) of fostedil in a cross-over design. The plasma levels and urinary excretion of intact fostedil were measured, and the pharmacokinetic parameters of the drug were defined. The results indicate that fostedil was at least 68% bioavailable after an oral dose given as a suspension or solution. The terminal half-life was about 7-8 h. The in vitro protein binding, at concentrations of 0.1-100 micrograms/mL, ranged from 95 to 97%. The binding was not concentration dependent, and saturation of the binding sites was not apparent at concentrations up to 100 micrograms/mL. Excretion of unchanged drug from the kidneys accounted for only a small percentage of drug clearance.