粗壮女贞的耐缺氧功能研究

目的 研究粗壮女贞的耐缺氧功能.方法 40只昆明种小鼠被随机分成正常对照组、粗壮女贞低剂量组(1.0 g/kg)、中剂量组(2.0 g/kg)、高剂量组(4.0 g/kg),连续灌胃30 d.观察小鼠的缺氧存活时间及整体耗氧量的变化.结果 与正常对照组相比,粗壮女贞能明显延长小鼠常压缺氧存活时间,降低小鼠的耗氧量.结论 粗壮女贞能提高小鼠的耐缺氧能力.     

夜来香多糖镇静催眠作用的研究

目的 探讨夜来香多糖对小鼠镇静催眠作用的影响.方法 将小鼠随机分为生理盐水组(戊巴比妥钠组)、1.0 mg/kg夜来香多糖组、2.0 mg/kg夜来香多糖组、4.0 mg/kg夜来香多糖组.观察夜来香多糖对小鼠自发活动的影响、对阈上剂量戊巴比妥钠小鼠睡眠时间的影响、对阈下剂量戊巴比妥钠小鼠睡眠时间的影响.结果 与生理盐水组比较,2.0、4.0 mg/kg的夜来香多糖能显著抑制小鼠自发活动(P＜0.05,P＜0.01);与戊巴比妥钠组比较,2.0、4.0 mg/kg的夜来香多糖能显著加速阈上剂量戊巴比妥钠的入睡时间和延长戊巴比妥钠的睡眠时间(P＜0.05,P＜0.01);与戊巴比妥钠组比较,1.0、2.0、4.0 mg/kg的夜来香多糖能显著加速阈下剂量戊巴比妥钠的入睡时间和延长戊巴比妥钠的睡眠时间(P＜0.05,P＜0.01,P＜0.01).结论 夜来香多糖具有明显的镇静催眠作用.     

抗焦胶囊抗焦虑作用的实验研究

目的观察抗焦胶囊的抗焦虑作用。方法采用戊四唑诱发小鼠惊厥模型,观察抗焦胶囊对小鼠惊厥及死亡潜伏期的影响;采用小鼠期待性焦虑实验,观察抗焦胶囊对焦虑小鼠体温的影响;采用戊巴比妥钠的小鼠睡眠模型,观察抗焦胶囊对小鼠入睡的影响。结果抗焦胶囊2.0g、1.0g、0.5g生药/kg组给药30min可显著延长惊厥潜伏期,2.0g生药/kg组给药60、90、120min能显著延长死亡潜伏期;抗焦胶囊2.0g生药/kg组对焦虑小鼠体温升高有明显抑制作用;抗焦胶囊2.0g生药/kg组能显著增加注射阈剂量戊巴比妥钠小鼠的入睡比率。结论抗焦胶囊对焦虑症有一定缓解作用。     

红芪提取物对小鼠免疫功能的影响

目的 探讨红芪提取物对正常小鼠及环磷酰胺(CP)致免疫抑制小鼠免疫功能的影响.方法 实验设8个剂量组,Ⅰ组为阴性对照组、Ⅱ组红芪提取物低剂量组(1.0g/kg·bw)、Ⅲ组为红芪提取物中剂量组(2.0g/kg·bw)、Ⅳ组为红芪提取物高剂量组(4.0 g/kg·bw)、V组为红芪提取物低剂量组(1.0 g/kg·bw)...     

益可颗粒对正常及糖尿病模型小鼠的降糖作用研究

目的:观察益可颗粒对正常和实验性高血糖小鼠血糖水平的影响。方法:正常小鼠连续灌胃给药15d后,利用血糖试纸检测不同剂量益可颗粒对正常小鼠血糖影响;腹腔注射四氧嘧啶制备糖尿病小鼠模型,实验随机分为7组,每组10只小鼠,即正常对照组、模型对照组,阳性对照组、联合用药组、益可颗粒高剂量组(6.0g/kg)、益可颗粒中剂量组(3.0g/kg)及益可颗粒低剂量组(1.0g/kg),连续灌胃30d后,以血搪试纸测定小鼠空腹血糖。结果:三个剂量的益可颗粒连续灌胃给药15天,均不影响正常小鼠的血糖和体重;6.0g/kg益可颗粒组连续灌胃给药30d,可明显降低四氧嘧啶诱发的高血糖小鼠血搪。结论:益可颗粒不降低正常小鼠血糖,可降低实验性糖尿病小鼠的血糖。     

醒脑抗栓灵对脑中风治疗作用的研究

观察醒脑抗栓灵对实验动物的镇静，抗血栓，减少脑梗塞面积作用。结果表明，静滴醒脑抗栓灵2.0g生药/kg，使小鼠自主活动数减少，同剂量对给予阈下剂量戊巴比妥钠的小鼠有明显的协同作用；2.0g生药／kg的醒脑抗栓灵和牛黄清心丸均使小鼠凝血时间明显延长，并能抑制大鼠体外,体内血栓的形成，尤对体内血栓抑制更为明显；静滴1.0g生药／kg醒脑抗栓灵，能减轻局部脑缺血大鼠的行为障碍和一定程度的减少脑梗塞面积的作用。     

复方金降脂胶囊急性毒性实验研究

目的 观察用金降脂给小鼠一次性灌胃引起的快速而剧烈的中毒反应。方法 50只小鼠等分5组。正常组：用蒸馏水0.8ml灌胃。纤维素组：用1%羧甲基纤维素钠（CMC-Na）0.8ml灌胃。低剂量组：按0.4ml/10g浓度为150mg/ml(6g/kg）金降脂灌胃。中剂量组：按0.4ml/10g浓度为200mg/ml(8g/kg）金降脂灌胃。高剂量组：按0.4ml/10g浓度为250mg/ml（10g/kg）金降脂灌胃。灌胃后连续观察一周。结果 一周实验期间各组均无异常、无死亡；体重增长速度正常，各组无明显差异。结论 金降脂灌胃小鼠，给予最大容积0.8ml/20g，最大剂量10g/kg（相当成人用量800倍）；无异常反应，无一死亡，足以说明金降脂是一种安全、无毒治疗剂量范围大的可靠新药。     

长白山哈士蟆油抗小鼠疲劳作用试验研究

1材料和方法1.1 样品 浑江牌长白山哈士蟆油软胶囊,膏状软胶囊装,由白山市北亚药业有限责任公司提供。1.2 实验动物 选用卫生部长春生物制品研究所动物室提供的昆明种雄性小鼠(批准号医动字第:10-5101),体重18～22g。1.3剂量选择 厂家推荐成人(体重以60 kg计)摄入定型产品最低量为6.0 g/d,以厂家最低日推荐成人摄入量的10、20、30倍设置小鼠灌胃剂量,即1.0、2.0、3.0 g/(kg·d),各剂量组以豆油稀释。蒸馏水作空白对照,豆油作溶剂对照。各剂量组小鼠灌胃量0.2 ml/(10g·d),连续灌胃30天。     

心力丸的毒性试验研究

目的 观察心力丸对小鼠的最大耐受量(Maximal tolerance dose,MTD)和大鼠的长期毒性作用,为临床安全用药提供参考依据.方法 (1)最大耐受量的测定采用心力丸以最大剂量单次灌胃,观察给药后小鼠所产生的急性毒性反应和死亡情况.(2)长期毒性试验观察3个剂量组(0.4、0.2、0.1 g·kg-1·d-1)每天灌胃1次,每周给药6 d,连续给药3个月对大鼠产生的毒性反应.结果 (1)按40 ml/kg灌胃16%的心力丸混悬液,未见异常情况.(2)连续给药3个月各组动物一般状况无明显异常.结论 (1)心力丸的最大耐受量大于6.4 g/kg,是临床日用量的1600倍.(2)心力丸在0.4 g·kg-1·d-1,相当于临床最大日用量的100倍以下剂量是安全的.     

天山雪莲培养物对小鼠运动后血乳酸和肝糖原含量的影响

目的研究雪莲培养物的小鼠抗疲劳作用。方法采用灌胃法,治疗组每天给小鼠灌胃不同剂量的雪莲培养物胶囊(0.5g/kg、1.0g/kg、1.5g/kg),对照组给予等量蒸馏水。连续30d后,测定小鼠负重游泳时间、肝糖原等指标。结果显示雪莲培养物能够延长小鼠负重游泳时间;降低血乳酸量;提高肝糖原含量。结论表明雪莲培养物对机体具有抗疲劳作用中、高剂量效果较佳。     

An evaluation of the locomotor stimulating action of ethanol in rats and mice

The locomotor activity of groups of three CD-1 female mice was increased by 1.0 and 2.0 g/kg ethanol, IP, was decreased during the first hour and increased during the second hour by 3.0 and 4.0 g/kg, and was decreased by 5.0 g/kg. The dose (2.0 g/kg) that caused the greatest increase in locomotor activity did not impair motor coordination, measured by the height of aerial righting in mice. Tests after oral administration of ethanol showed that the increase in locomotor activity of mice was not due to peritoneal irritation. The same dose (2.0 g/kg) did not increase the locomotor activity of C57BL/6J mice. Ethanol (0.1 to 3.0 g/kg) had no effect or decreased the locomotor activity of individual male Sprague-Dawley rats. These findings suggest that biological differences in strains and species of laboratory rodents contribute to the apparent variability of locomotor stimulation caused by ethanol. The presence or absence of an ethanol-induced increase in locomotor activity was not dependent on the sex or number of mice or rats tested. Intertrial-interval crossing by rats acquiring or performing an active avoidance task in a shuttle box was increased by ethanol. This action was dependent on the presentation of electric foot shock. Apomorphine (0.25 and 2.5 mg/kg) and fenmetozole (7.5 and 15.0 mg/kg) failed to inhibit the ethanolinduced increase in intertrial-interval crossing by rats, although these drugs have been shown previously to antagonize the ethanol-induced increase in the activity of mice ethanol treatment. The ethanol-induced increases in the spontaneous locomotor activity of CD-1 mice in photocell activity monitors and in intertrial-interval crosses in rats in a shuttle box task thus do not appear to share a common mechanism.     

Toxicology and carcinogenesis studies of kava kava extract (CAS No. 9000-38-8) in F344/N rats and B6C3F1 mice (Gavage Studies)

Kava beverages, made from dried roots of the shrub Piper methysticum, have been used ceremonially and socially in the South Pacific and in Europe since the 1700s. The drink is reported to have pleasant mild psychoactive effects, similar to alcoholic beverages. In the United States, kava kava is an herbal product used extensively as an alternative to anti-anxiety drugs such as Xanax and Valium. It has also been reported as being used to help children with hyperactivity and as a skin-conditioning agent in cosmetics. Kava kava was nominated by the National Cancer Institute for study because of its increasing use as a dietary supplement in the mainstream United States market and reports of liver toxicity among humans. Male and female F344/N rats and B6C3F1 mice received kava kava extract in corn oil by gavage for 2 weeks, 3 months, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Escherichia coli, and mouse peripheral blood erythrocytes. 2-WEEK STUDY IN RATS: Groups of five male and five female rats were administered kava kava extract in corn oil by gavage at doses of 0, 0.125, 0.25, 0.5, 1.0, or 2.0 g/kg body weight, 5 days per week for 16 days. One female rat administered 2.0 g/kg kava kava extract died on day 3 of the study. Mean body weights of all dosed groups of rats were similar to those of the vehicle controls. Clinical findings included abnormal breathing, ataxia, and lethargy in the 2.0 g/kg groups of males and females and ataxia and lethargy in the 1.0 g/kg group of females. Liver weights were significantly increased in 1.0 and 2.0 g/kg males and in 0.5 g/kg or greater females compared to the vehicle controls. Minimal hepatocellular hypertrophy occurred in all 2.0 g/kg males and in all females administered 0.25 g/kg or greater. 2-WEEK STUDY IN MICE: Groups of five male and five female mice were administered kava kava extract in corn oil by gavage at doses of 0, 0.125, 0.25, 0.5, 1.0, or 2.0 g/kg body weight, 5 days per week for 17 days. In the 2.0 g/kg group of males, one died on day 2 and one died on day 3. Mean body weights of all dosed groups of mice were similar to those of the vehicle controls. Clinical findings included abnormal breathing, ataxia, and lethargy in males and females in the 1.0 and 2.0 g/kg groups. Liver weights of 2.0 g/kg males and females were significantly increased. The incidence of hepatocellular hypertrophy in 2.0 g/kg female mice was significantly greater than that in the vehicle control group. 3-MONTH STUDY IN RATS: Groups of 10 male and 10 female rats were administered kava kava extract in corn oil by gavage at doses of 0, 0.125, 0.25, 0.5, 1.0, or 2.0 g/kg, 5 days per week for 14 weeks. Deaths attributed to kava kava extract administration included three males and four females in the 2.0 g/kg groups and one female in the 1.0 g/kg group. One 0.25 g/kg male and one vehicle control female also died before the end of the study. The mean body weights of males in the 1.0 and 2.0 g/kg groups and females in the 2.0 g/kg group were significantly less than those of the vehicle controls. Ataxia and lethargy were observed in males and females in the 1.0 g/kg groups during week 1 and in the 2.0 g/kg groups throughout the study. Increased -glutamyltransferase activity in 1.0 g/kg females and 2.0 g/kg males and females may represent enzyme induction. However, the hepatocellular hypertrophy observed in the 2.0 g/kg females may have contributed to the increased -glutamyltransferase activity. The liver weights of 0.25 g/kg or greater males and 0.5 g/kg or greater females were significantly increased compared to the vehicle controls. The kidney weights of 0.5 g/kg or greater males and females were significantly increased compared to the vehicle controls. The incidence of hepatocellular hypertrophy in 2.0 g/kg females was significantly greater than that in the vehicle controls. 3-MONTH STUDY IN MICE: Groups of 10 male and 10 female mice were administered kava kava extract in corn oil by gavage at doses of 0, 0.125, 0.25, 0.5, 1.0, or 2.0 g/kg, 5 days per week for 14 weeks. Four male and three female 2.0 g/kg mice died during week 1; these deaths were attributed to kava kava extract administration. One additional 2.0 g/kg female died during week 6 due to a gavage accident. The mean body weights of dosed males and females were similar to those of the vehicle controls. Ataxia and lethargy occurred in males and females in the 1.0 and 2.0 g/kg groups during week 1. The liver weights of 2.0 g/kg males and 1.0 and 2.0 g/kg females were significantly increased compared to those of the vehicle control groups. The incidences of centrilobular hypertrophy in the liver of 0.5 g/kg or greater males and 1.0 and 2.0 g/kg females were significantly greater than those in the vehicle controls. 2-YEAR STUDY IN RATS: Groups of 49 or 50 male and 50 female rats were administered kava kava extract in corn oil by gavage at doses of 0, 0.1, 0.3, or 1.0 g/kg, 5 days per week for 104 (males) or 105 (females) weeks. Survival of dosed groups of males and females was similar to that of the vehicle controls. Mean body weights of males administered 1.0 g/kg were less than those of the vehicle controls after week 65, and those of the 1.0 g/kg females were less than those of the vehicle controls after week 41. Clinical findings included ataxia and lethargy that occurred in 21 males and 14 females in the 1.0 g/kg groups during the first 4 weeks of the study. After week 5, ataxia and lethargy were noted in 10 males and eight females in the 1.0 g/kg groups and these findings were observed randomly and intermittently throughout the study. At approximately 1 year into the study, twitching and seizures were observed in males and females in all dosed groups but mainly in the 1.0 g/kg groups. There was a dose-related increase in the incidences of interstitial cell adenoma in the testis with increased incidences of bilateral neoplasms. The incidences of hepatocellular hypertrophy in 1.0 g/kg males and females were significantly greater than those in the vehicle controls. Increased -glutamyltransferase activity and/or bile salt concentrations in males and females may represent a cholestatic event related to the hepatocellular hypertrophy observed in rats. Enzyme induction may have played a role in the increased -glutamyltransferase activity. Significantly increased incidences of centrilobular fatty change occurred in 0.1 and 1.0 g/kg males. The incidences of inflammation, ulcer, and epithelial hyperplasia in the forestomach were significantly increased in 1.0 g/kg males and females. The severity of nephropathy was increased in 1.0 g/kg male rats, and the incidence of nephropathy was significantly increased in 1.0 g/kg females. Incidences of transitional epithelial hyperplasia of the pelvis of the kidney were significantly increased in 1.0 g/kg males and 0.3 and 1.0 g/kg females. The incidences of retinal degeneration in the eye were significantly increased in 1.0 g/kg males and females. The incidences of metaplasia of pancreatic acinar cells to a hepatocytic morphology increased in 1.0 g/kg males and females, and the increase in males was significant. Significantly decreased incidences of pars distalis adenoma in the pituitary gland occurred in 1.0 g/kg males and in 0.1 and 1.0 g/kg females. The incidence of fibroadenoma of the mammary gland in 1.0 g/kg females was significantly less than that in the vehicle control group. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice received kava kava extract in corn oil by gavage at doses of 0, 0.25, 0.5, or 1.0 g/kg, 5 days per week for 105 weeks. Survival of dosed groups of males and females was similar to that of the vehicle controls. Mean body weights of males administered 1.0 g/kg were generally similar to those of the vehicle controls until the end of the study; however, those of 1.0 g/kg females were less than those of the vehicle controls after week 21. Clinical findings included ataxia and lethargy that occurred in 13 males and 31 females in the 1.0 g/kg groups during the first week of the study. Decreasing numbers of animals exhibited ataxia or lethargy during the remainder of the study, but these findings were observed in 1.0 g/kg females as late as week 101. The incidences of hepatoblastoma in 0.5 and 1.0 g/kg males were significantly increased compared to the vehicle controls. The incidences of hepatocellular carcinoma or hepatoblastoma (combined) were significantly increased in 0.5 g/kg males. Incidences of hepatocellular carcinoma were increased in all dosed groups of females, and the increase was significant in the 0.25 g/kg group. The incidences of hepatocellular adenoma or carcinoma (combined) were significantly increased in 0.25 and 0.5 g/kg females. In the liver, the incidences of centrilobular hypertrophy in all dosed groups of males and females were significantly greater than those in the vehicle control groups. Significantly increased incidences of eosinophilic foci occurred in 0.5 g/kg males and in 1.0 g/kg males and females, and the incidence of angiectasis was significantly increased in the 1.0 g/kg males. The incidences of hepatocellular necrosis were significantly increased in 0.25 and 1.0 g/kg males. In the forestomach, the incidences of chronic inflammation, epithelial hyperplasia, and erosion were significantly increased in 0.5 and 1.0 g/kg females, and the incidence of ulceration was significantly increased in 1.0 g/kg females. GENETIC TOXICOLOGY: Kava kava extract was tested for bacterial mutagenicity over a broad range of concentrations in two independent assays using several strains of bacteria (S. typhimurium tester strains TA97, TA98, TA100, and TA1535 and E. coli strain WP2 uvrA/pKM101), with and without exogenous metabolic activation. No increase in mutant colonies was seen in any of the tester strains, under any activation condition. (ABSTRACT TRUNCATED)     

Teratogenic effects of benomyl in the Wistar rat and CD-1 mouse,with emphasis on the route of administration

Benomyl, a systemic fungicide whose molecular basis of action is inhibition of tubulin polymerization, was administered during organogenesis via the dietary and gavage routes to pregnant Wistar rats, and via the gavage route to pregnant CD-1 mice. Benomyl was fetotoxic and teratogenic in both species via the po route of administration, producing a broad spectrum of malformations at a dose of 62.5 mg/kg/day in the rat and 100 mg/kg/day in the mouse. Via the dietary route of administration, benomyl produced fetotoxicity, but no teratogenic effects. The fetotoxic potential of benomyl from dietary exposure was approximately an order of magnitude less effective than from gavage exposure. Benomyl did not affect postnatal growth, viability, or locomotor activity at subteratogenic doses. The most sensitive indicator of perinatal exposure to benomyl via the po route of administration was a permanent reduction in testes and accessory sex gland weight noted in male offspring of dams receiving 31.2 mg/kg/day benomyl during gestation and lactation. No effects on any parameters were evident in rats receiving 15.6 mg/kg/day by po gavage. The relevance of the two routes of administration for risk extrapolation is discussed.     

Toxicity and carcinogenicity studies of nalidixic acid in rodents

Toxicity and carcinogenicity studies of nalidixic acid, an antimicrobial agent used to treat bacterial infections of the urinary tract, were conducted in F344/N rats and B6C3F1 mice of each sex for 13 weeks or 2 years. In the 13-week studies, nalidixic acid was administered at dietary concentrations ranging from 1,000 to 16,000 ppm. Body weights of both rats and mice were reduced in the groups receiving diet containing 8,000 and 16,000 ppm, and feed consumption of rats in the highest treatment groups was approximately two-thirds that of controls. Degeneration of the germinal epithelium in the seminiferous tubules of the testis was observed in male rats that received 16,000 ppm; no other compound-related histopathologic effects were observed in either species. Two-year studies were conducted by feeding diets containing 0, 2,000, or 4,000 ppm nalidixic acid to groups of 50 rats and mice/sex/group. The average daily feed consumption was slightly reduced compared to control groups and resulted in approximate daily doses of 82 or 175 mg nalidixic acid/kg for low dose and high dose rats, and 220 or 475 mg/kg for low dose and high dose mice. Mean body weights of dosed rats and mice were lower than those of controls, except for groups of low dose female rats and male mice. The incidences of preputial gland neoplasms in dosed male rats and of clitoral gland neoplasms in dosed female rats were significantly increased compared to those in controls; responses in low dose groups were similar to those in high dose groups. There were decreased incidences of leukemia and mammary gland neoplasms in dosed female rats and of pituitary gland neoplasms in dosed male rats. Subcutaneous tissue fibrosarcomas were marginally increased in dosed male mice. There were no increased incidences of neoplasms in dosed female mice. Under the conditions of these studies, the dietary administration of nalidixic acid was carcinogenic for rats, causing preputial gland or clitoral gland neoplasms in males and females, respectively. The association of subcutaneous neoplasms with administration of nalidixic acid to male mice was equivocal.     

Toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in C57B1/6 mice

Three-month-old male $\text{C57B1}\text{6}$ mice were given single oral doses of 0, 100, 150, or 200 μg of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)/kg. The LD50 was 114 μ/kgg. In mice that died, depletion of the thymus and spleen were consistently found and edema and terminal hemorrhages occurred frequently. In a second experiment, 4-month-old male mice were dosed po with 0, 0.2, 1.0, 5.0 or 25 μg/kg, once a week for 2 or 6 weeks. Some deaths and growth retardation occurred in the 25 μg/kg dose group. Significantly increased liver and decreased thymus weights were found in the 1, 5 and 25 μg/kg dose groups. Total neutrophils were increased significantly, whereas hemoglobin values and mean corpuscular hemoglobin concentrations were decreased significantly after 6 doses of 25 μg/kg. Total serum protein and α-, β-, and γ-globulins were significantly decreased. TCDD was porphyrogenic. The hepatic porphyria was probably associated with liver damage. Degenerative and necrotic changes in the liver were essentially centrilobular and were accompanied by cellular infiltrates and ceroid pigment deposition. Proliferation of bile duct and bile duct epithelial cells occurred. Lipid accumulation was centrilobulary localized in the mice receiving 0.2 μg/kg, was more pronounced in the mice of the intermediate dose levels, and involved hepatocytes throughout the lobule in the 25 μg/kg dose group.     

Toxicity and Carcinogenicity Studies of Nalidixic Acid in Rodents

ABSTRACT

Toxicity and carcinogenicity studies of nalidixic acid, an antimicrobial agent used to treat bacterial infections of the urinary tract, were conducted in F344/N rats and B6C3F mice of each sex for 13 weeks or 2 years. In the 13–week studies, nalidixlc acid was administered at dietary concentrations ranging from 1,000 to 16,000 pp. Body weights of both rats and mice were reduced in the groups receiving diet containing 8,000 and 16,000 ppm, and feed consumption of rats in the highest treatment groups was approximately tw-thirds that of controls. Degeneration of the germinal epithelium in the seminiferous tubules of the testis was observed in male rats that received 16,000 ppm; no other compound-related histopathologic effects were observed in either species. TWo-year studies were conducted by feeding diets containing 0, 2,000, or 4,000 ppm nalidixic acid to groups of 50 rats and mice/sex/group. The average daily feed consumption was slightly reduced compared to control groups and resulted in approximate daily doses of 82 or 175 mg nalidixic acidfig for low dose and high dose rats, and 220 or 475 mg/kg for low dose and high dose mice. Mean body weights of dosed rats and mice were lower than those of controls, except for groups of low dose female rats and male mice. The incidences of preputial gland neoplasms in dosed male rats and of clitoral gland neoplasms in dosed female rats were significantly increased compared to those in controls; responses in low dose groups were similar to those in high dose groups. There were decreased incidences of leukemia and mammary gland neoplasms in dosed female rats and of pituitary gland neoplasms in dosed male rats. Subcutaneous tissue fibrosarcomas were marginally increased in dosed male mice. There were no increased incidences of neoplasms in dosed female mice. under the conditions of these studies, the dietary administration of nalidixic acid was carcinogenic for rats, causing preputial gland or clitoral gland neoplasms in males and females, respectively. The association of subcutaneous neoplasms with administration of nalidixic acid to male mice was equivocal.     

The effects of sulindac and its metabolites on acute stress-induced gastric ulcers in rats

Rats were given a single intragastric administration of the prodrug sulindac (4.0 mg/kg) or its sulfide (1.0, 2.0, 4.0, or 8.0 mg/kg) or sulfone (1.0, 2.0, 4.0, or 8.0 mg/kg) metabolites and were then subjected to acute stress in the form of immobilization for 3 hr in a cold environment. Control rats received an equal volume of propylene glycol vehicle or nothing po. Other rats received 200 mg/kg acetylsalicylic acid (ASA) with or without stress, to compare the gastrointestinal effects of sulindac metabolites with those of a known non-steroidal anti-inflammatory agent. The sulfide metabolite exacerbated stress-induced gastric glandular ulcer incidence and severity in a dose-related manner relative to all groups except the ASA-stress group, which exhibited the greatest amount of gastric damage. The sulfone metabolite did not potentiate ulcer incidence or severity beyond control (stress only) levels at lower doses. However, at 4.0 and 8.0 mg/kg, the observed ulceration was greater than that seen in stressed but otherwise untreated animals. Sulindac, vehicle, and otherwise untreated rats exhibited a similar degree of stress-induced gastric damage. It appears that the prodrug does not significantly enhance stress-related gut disease, but that the active sulfide metabolite does. Although the clinical literature suggests that the sulfone metabolite is inactive, the present results suggest otherwise. While this metabolite did not, by itself, induce gastric damage at higher doses, sulfone did exacerbate stress ulcer formation. This is the only report of which we are aware, indicating a possible toxic effect of the sulfone metabolite.     

Place conditioning with dopamine D1 and D2 agonists injected peripherally or into nucleus accumbens

The conditioned place preference technique was used to assess the affective properties of the direct dopamine D1 agonist, SKF38393, and the direct D2 agonist, LY171555 (quinpirole). A three compartment apparatus was used: the animals' pre-experimental preference for the two choice compartments was equal and, within each experimental group, half the rats received drug pairings in each choice compartment. Intraperitoneal injections of SKF38393 produced conditioned place aversions at all doses tested (1.0–4.0 mg/kg); LY171555 produced weak conditioned place preferences at 1.0 and 2.0 mg/kg, but no reliable effect at 4.0 mg/kg. Bilateral intra-accumbens microinjections of SKF38393 produced strong preferences at all doses tested (0.5–2.0 µg/side); LY171555 produced strong preferences at two doses (0.5 and 1.0 µg/side) and no effect at a third dose (2.0 µg/side). These results suggest that activation of either D1 or D2 receptors in the nucleus accumbens can produce reward, and that D1 receptors (and possibly also D2 receptors) located elsewhere in the brain or in the periphery may mediate aversive effects.     

Discriminative stimulus properties of phencyclidine.

Rats were trained to discriminate intraperitoneal injections of phencyclidine (4.0 mg/kg) from saline in a two-lever drug discrimination task. After reliable discrimination was established and a dose-response curve was obtained, two doses of each of a variety of agents were tested to determine whether they evoked responding on the phencyclidine-appropriate lever. All doses of the indirect dopamine agonist d-amphetamine (0.5 and 1.0 mg/kg) and the direct dopamine agonist apomorphine (0.5 and 1.0 mg/kg), the direct serotonin agonists LSD (0.08 and 0.16 mg/kg) and quipazine (1.0 and 2.0 mg/kg), and the anticholinergic drugs atropine (0.5 and 1.0 mg/kg) and ditran (3.0 and 6.0 mg/kg) failed to produce phencyclidine-like discriminative effects, as did diazepam (8.0 and 16.0 mg/kg) and a 7.5 mg/kg dose of ketamine. A 15.0 mg/kg dose of ketamine, a compound structurally and pharmacologically similar to phencyclidine, did produce phencyclidine-like discriminative effects.The dopamine blocker haloperidol (0.1 and 0.2 mg/kg), the serotonin blocker cyproheptadine (0.5 and 1.0 mg/kg), the cholinesterase inhibitor physostigmine (1.0 and 2.0 mg/kg), and the nicotinic blocking agent mecamylamine (1.0 and 2.0 mg/kg) when given prior to the 4.0 mg/kg dose of phencyclidine failed to affect discrimination significantly. These compounds also failed to produce phencyclidine-like discriminative effects when given alone. Overall, these results parallel previous findings with other procedures in suggesting that the effects of phencyclidine are unique, and may reflect the wide variety of neurochemical actions produced by the drug.     

5-Hydroxytryptamine M-receptor antagonism to prevent cisplatin-induced emesis

The administration to the ferret of cisplatin, 10mg/kg (i.v.), caused an intense emetic response that was prevented by ICS 205-930 (0.1 and 1.0 mg/kg i.v.) and metoclopramide (4.0 mg/kg i.v.). Smaller doses of ICS 205-930 (0.01 mg/kg i.v.) and metoclopramide (2.0 mg/kg i.v.) attenuated the emetic response to cisplatin. It is concluded that the potent action of ICS 205-930 against cisplatin-induced emesis is the consequence of a 5-hydroxytryptamine M-receptor antagonism which may also contribute to the antiemetic action of metoclopramide.