新合成磺酰脲类化合物I_4抗血小板聚集及抗血栓作用

目的研究新合成磺酰脲类化合物I4抗血小板聚集及抗血栓作用。方法测定I4对ADP诱导兔血小板聚集、小鼠凝血时间、大鼠颈动脉旁路血栓、大鼠血栓阻塞时间的作用。结果 I4显著抑制二磷酸腺苷(ADP)诱导的体外兔血小板聚集,延长小鼠凝血时间,降低大鼠颈动脉旁路血栓重量,明显延长电刺激诱导的大鼠颈动脉血栓形成时间。结论 I4具有显著的抗血小板聚集及抗凝血作用。     

银杏总内酯抗血小板聚集与抗血栓作用

目的：探讨银杏总内酯抗血栓形成及抑制血小板聚集的作用.方法：采用大鼠动静脉旁路血栓模型和Chandler氏血栓形成法,利用血小板活化因子（platelet activating factor,PAF）、花生四烯酸（arachidonic acid,AA）和二磷酸腺苷（adenosine diphosphate,ADP）诱导家兔血小板聚集,测定血栓形成抑制率、血小板在不同时间点的聚集率以及最大聚集率.结果：银杏总内酯可不同程度地抑制大鼠动静脉旁路血栓和Chandler氏体外血栓形成,减轻血栓重量,血栓形成抑制率分别达到 41.58%和 59.31%;银杏总内酯可抑制PAF和ADP诱导的家兔血小板在不同时间点的聚集,降低其最大聚集率.结论：银杏总内酯可明显对抗血栓形成,并具有显著的抗PAF和ADP诱导血小板聚集作用.     

清脑胶囊对家兔体内血栓形成的影响

目的研究清脑胶囊在家兔体内对血栓的溶栓作用和对血小板聚集的影响。方法采用家兔颈动脉穿线法形成颈动脉血栓模型,观察清脑胶囊对家兔血栓形成以及胶原诱导的血小板聚集作用的影响。结果清脑胶囊能明显降低家兔颈动脉血栓的湿重,并对血小板聚集有明显的抑制作用。结论清脑胶囊具有显著的抗血栓形成的作用。     

新型磺酰胺类化合物SZ427的抗血小板聚集作用

目的研究新型磺酰胺类化合物4-乙氧基-N,N'-二(4-吡啶乙基)-1,3-苯二磺酰胺(SZ427)的抗血小板聚集作用。方法在体外药效学实验中,采用血小板聚集分析仪观察化合物SZ427对花生四烯酸(arachidonic acid,AA)、二磷酸腺苷(adenonisine disphosphate,ADP)和胶原诱导的家兔血小板聚集的影响。在体内药效学实验中,通过小鼠尾静脉出血时间、大鼠颈总动脉血栓和小鼠急性肺血栓三种模型分别观察化合物SZ427对出血时间、血栓质量和死亡时间的影响。结果在体外药效实验中,化合物SZ427能显著抑制AA、ADP和胶原诱导的家兔血小板的聚集作用;在体内药效学实验中,化合物SZ427能延长小鼠尾静脉出血时间,具有抗血小板聚集作用;能减少大鼠颈总动脉血栓质量,抑制血栓形成;能显著延长急性肺血栓小鼠的死亡时间,明显降低死亡率。结论化合物SZ427能抑制慢性血栓和急性血栓的形成,具有抗血小板聚集的作用。     

蛇床子素抑制血栓形成和血小板聚集的实验研究

目的　观察蛇床子素抑制血栓形成和血小板聚集的作用。方法　利用大鼠动-静脉旁路血栓形成模型和小鼠尾静脉注射胶原-肾上腺素合剂诱导血栓形成模型,分别测定给蛇床子素10、20、40mg·kg-1后血栓湿重和干重, 5min内小鼠死亡数和15min内偏瘫恢复数;分别采用ADP、凝血酶、花生四烯酸钠为诱导剂,测定经不同浓度蛇床子素处理后1、3、5min时血小板聚集率及最大聚集率的改变。结果　蛇床子素可以抑制大鼠动-静脉旁路血栓形成,减轻血栓湿重及干重;抑制胶原-肾上腺素合剂诱导的血栓形成,降低5min内的小鼠死亡率,提高15min内偏瘫小鼠的恢复率;蛇床子素在体外可抑制ADP、凝血酶、花生四烯酸钠诱导的血小板聚集,其IC50分别为0 .44、0 .186、0 .421g·L-1。结论　蛇床子素可明显抑制血栓形成和血小板的聚集。     

补阳还五注射液对大鼠血液流变学及大鼠实验性血栓的影响

目的观察补阳还五注射液对大鼠血液流变学及实验性血栓的影响。方法用冰水浴刺激及肾上腺素应激法建立大鼠急性血瘀模型,观察补阳还五注射液静脉注射给药10、5、2.5 g.kg-1对大鼠血液流变学的影响;用大鼠动静脉旁路法建立实验性血栓模型,观察补阳还五注射液静脉注射给药10、5、2.5 g.kg-1对大鼠实验性动脉血栓的影响;体外法观察补阳还五注射液对腺苷二磷酸(ADP)诱导家兔体外血小板聚集率的影响。结果补阳还五注射液能降低全血黏度和血浆黏度;能对抗大鼠的实验性动脉血栓的形成,抑制ADP诱导家兔血小板聚集作用。结论补阳还五注射液具有较好的降低血液黏度、降低血小板的聚集率及抑制实验性血栓形成的作用。     

竹叶提取物的抗血栓作用

目的从抗血小板聚集,抗凝血,及纤溶3个方面研究竹叶提取物的抗血栓作用。方法采用小鼠肺血栓模型、家兔颈总动脉血栓模型,测定家兔体外血浆凝血酶时间、凝血酶原时间、部分凝血活酶时间、血浆复钙时间和小鼠优球蛋白溶解时间及小鼠全血凝块质量等指标,考察竹叶提取物的抗血栓作用。结果竹叶提取物静脉给药可显著提高胶原蛋白肾上腺素混合诱导剂所致肺血栓小鼠的存活率;明显抑制家兔颈总动脉血栓形成;显著降低小鼠优球蛋白溶解时间,减轻小鼠全血凝块重量;其体外给药能显著延长家兔凝血酶、凝血酶原、部分凝血活酶时间,延长血浆复钙时间。结论竹叶提取物具有明显的抗血栓形成作用。     

奥沙普嗪对血小板聚集和血栓形成的影响

目的:研究奥沙普嗪对家兔和大鼠血小板聚集和血栓形成的影响.方法:麻醉动物颈动脉取血,制备富含血小板血浆(PRP),加入奥沙普嗪,用多功能血小板聚集仪测定二磷腺苷(ADP)诱导的血小板聚集作用.结果:奥沙普嗪能明显抑制ADP诱导动物体内外血小板聚集和降低胶原 肾上腺素静脉注射所致的小鼠死亡率.结论:初步证实奥沙普嗪具有类似阿司匹林抑制血小板聚集作用.     

丰城鸡血藤总黄酮抗血小板聚集及抗血栓作用研究

目的 研究丰城鸡血藤总黄酮对实验性大鼠血小板聚集和血栓形成的影响。方法 以二磷酸腺苷(adenosine diphosphate,ADP)、胶原和凝血酶作诱导剂诱导大鼠血小板聚集,丰城鸡血藤总黄酮按25,50,100 mg·kg^-1的剂量灌胃给药,测定大鼠血小板聚集率,计算聚集抑制率;用血栓法测定大鼠血栓形成重量。结果 丰城鸡血藤总黄酮各剂量均能抑制ADP、胶原和凝血酶诱导的大鼠血小板聚集,并能减少血栓形成的重量。结论 丰城鸡血藤总黄酮具有明显的抗血小板聚集及抗血栓形成的作用。     

醋柳黄酮对家兔血液流变性、血小板及凝血功能的影响

目的:研究醋柳黄酮(TFH)对家兔血液流变性、血小板及凝血功能的影响.方法:测定醋柳黄酮灌胃给药对家兔血黏度、血小板聚集、血栓形成和凝血功能的影响.结果:醋柳黄酮灌胃1.5～10 mg·kg-1可显著降低家兔全血黏度、血浆黏度;抑制ADP诱导的家兔血小板聚集;抑制血栓形成;明显延长活化部分凝血酶原时间(APTT).结论:醋柳黄酮具有改善家兔血液流变性、抑制血栓形成作用.     

Potentiation of apomorphine-induced stereotyped behaviour by acute treatment with dopamine depleting agents: a potential role for an increased stimulation of D1 dopamine receptors

Treatment of mice with reserpine (10 mg/kg, s.c.) and alpha-methylparatyrosine (400 mg/kg) led to the potentiation of stereotyped behaviour, induced by apomorphine (0.37-1.5 mg/kg, s.c.), i.e. to the appearance of licking and gnawing in addition to climbing and sniffing occurring in control mice. Similar results were obtained by combined treatment with SK&F 38393 (30 mg/kg, s.c.) and RU 24926 (15 mg/kg, i.p.). In mice treated with dopamine depleting agents, SCH 23390 (1.25-20 micrograms/kg, s.c.) and metoclopramide (0.62-20 mg/kg, i.p.) antagonized gnawing induced by 0.75 mg/kg (s.c.) apomorphine, at doses significantly larger than those required for the antagonism of climbing and sniffing. The same treatment with reserpine and alpha-methylparatyrosine produced an increased formation of cyclic AMP, induced by SK&F 38393 (10(-8)-10(-4) M), from homogenates of the striatum of the rat. Potentiation of apomorphine-induced stereotyped behaviour and increased SK&F 38393-induced formation of cyclic AMP had similar time-courses with a maximum 18 hr after treatment. These data suggest that the potentiation of apomorphine-induced stereotyped behaviour produced by acute treatment with dopamine depleting agents is at least partly due to an increased activity of the adenylate cyclase linked to D1 dopamine receptors. Finally, a small dose of amisulpride (a discriminant benzamide derivative) potentiated the stereotyped behaviour induced by the combined treatment with SK&F 38393 and RU 24926 in naive mice and, in a more marked manner, in mice treated with dopamine depleting agents; amisulpride did not produce stereotyped behaviour when combined with SK&F 38393 or RU 24926 administered alone.(ABSTRACT TRUNCATED AT 250 WORDS)     

The rise of body temperature induced by the stimulation of dopamine D1 receptors is increased in acutely reserpinized mice

In naive mice, the selective D1 agonist, SK&F 38393 (7.5-30 mg/kg s.c.), induced a significant rise of body temperature (0.5-1 degree C) which was antagonized by SCH 23390 (100 micrograms/kg s.c.) and by flupenthixol (0.4 mg/kg i.p.). In mice treated with reserpine (5 mg/kg s.c.) 18 h before testing, which on its own caused intense hypothermia (10-12 degrees C), SK&F 38393 (1.87-30 mg/kg s.c.) induced a dose-dependent and more marked rise of body temperature (5-7 degrees C). Similarly, SK&F 38393 (30 mg/kg s.c.) partially prevented reserpine-induced hypothermia. The central origin of the SK&F 38393 effects in reserpine-treated mice is indicated by the rise of body temperature induced by the i.c.v. administration of the drug (12.5-50 micrograms per mice). The SK&F 38393-induced rise of body temperature in acutely reserpinized mice was antagonized by SCH 23390 (50-200 micrograms/kg s.c.), clozapine (1.87-30 mg/kg i.p.) or chlorpromazine (2-32 mg/kg i.p.) but not by metoclopramide (25 or 100 mg/kg i.p.) or amisulpride (12.5 or 50 mg/kg). In naive mice, apomorphine (1 mg/kg s.c.) or LY 171555 (0.4 mg/kg s.c.) induced hypothermia which was antagonized by amisulpride (12.5 mg/kg i.p.); a transiently increased body temperature was even measured 30 min after apomorphine injection in amisulpride-treated mice. Apomorphine (1 mg/kg s.c.) induced a rise of body temperature in acutely reserpinized mice which was significantly reduced by SCH 23390 (50 and 200 micrograms/kg s.c.) and significantly increased by amisulpride (12.5 and 50 mg/kg i.p.). These data suggest that pharmacologically different dopamine receptor subtypes mediate different effects on body temperature in mice: D1 dopamine receptors mediate a rise of body temperature which is increased in hypothermic reserpinized animals and dopamine receptors of the D4 subtype mediate the decrease of body temperature in naive mice.     

Toxicology and carcinogenesis studies of bis(2-chloroethoxy)methane (CAS No. 111-91-1) in F344/N rats and B6C3F1 mice (dermal studies)

Bis(2-chloroethoxy)methane is used as a solvent and the starting agent in the production of fungicides and polysulfide polymers. Bis(2-chloroethoxy)methane was nominated for study by the National Institute of Environmental Health Sciences because of its widespread use as a starting material to produce polysulfide elastomers, and because there were no 2-year carcinogenicity studies reported in the literature. Male and female F344/N rats and B6C3F1 mice received dermal applications of bis(2-chloroethoxy)-methane in ethanol (greater than 98% pure) for 2 weeks, 3 months, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and Escherichia coli, rat bone marrow cells, and mouse peripheral blood erythrocytes. 2-WEEK STUDY IN RATS: Groups of five male and five female rats were dermally administered 0, 12.5, 25, 50, 100, or 200 mg bis(2-chloroethoxy)methane/kg body weight in ethanol, 5 days per week for 16 days. All rats survived to the end of the study. Mean body weights of dosed rats were similar to those of the vehicle control groups. There were no histopathologic lesions related to bis(2-chloroethoxy)methane administration. 2-WEEK STUDY IN MICE: Groups of five male and five female mice were dermally administered 0, 12.5, 25, 50, 100, or 200 mg bis(2-chloroethoxy)methane/kg body weight in ethanol, 5 days per week for 17 days. All mice survived to the end of the study. Mean body weights of dosed mice were similar to those of the vehicle control groups. There were no histopathologic lesions related to bis(2-chloroethoxy)methane administration. 3-MONTH STUDY IN RATS: Groups of 10 male and 10 female rats were dermally administered 0, 50, 100, 200, 400, or 600 mg bis(2-chloroethoxy)methane/kg body weight in ethanol, 5 days per week for 14 weeks. Additional clinical pathology groups of 10 male and 10 female rats were administered the same doses for 23 days. All core study 600 mg/kg males and females and two 400 mg/kg females died before the end of the study. The cause of death was considered to be related to the cardiotoxic effect of bis(2-chloroethoxy)methane. There were no significant differences between final mean body weights of dosed rats and those of the vehicle control groups; the mean body weight gain of 400 mg/kg males was significantly less than that of the vehicle controls. Clinical findings included prostration and ataxia in 600 mg/kg rats during the first week of the study and nasal/eye discharge, lethargy, ataxia, and abnormal breathing in 400 and 600 mg/kg females beginning week 5. An enlarged heart was noted in one 100 mg/kg female rat. Relative kidney weights of 100, 200, and 400 mg/kg males were significantly greater than that of the vehicle control group. Increased incidences and severities of myofiber cytoplasmic vacuolization and interstitial mononuclear cell infiltration in the heart occurred in 400 and 600 mg/kg male and female rats and in 200 mg/kg females. Increased incidences and severities of myofiber necrosis occurred in 600 mg/kg males and females; one female each in the 200 and 400 mg/kg groups also had this lesion. Three 600 mg/kg males had atrial thrombosis. 3-MONTH STUDY IN MICE: Groups of 10 male and 10 female mice were dermally administered 0, 50, 100, 200, 400, or 600 mg bis(2-chloroethoxy)methane/kg body weight in ethanol, 5 days per week for 14 weeks. Except for three 600 mg/kg females, all mice survived to the end of the study. Mean body weights of dosed and vehicle control mice were similar. One 600 mg/kg female that died early exhibited lethargy, abnormal breathing, and tremors, and one animal had clonic seizures. One 600 mg/kg female that died early had focal erosion of the glandular stomach and a focus in the duodenum found to consist of acute suppurative inflammation and thrombosis. Absolute and relative kidney weights of 400 and 600 mg/kg males and 600 mg/kg females were significantly greater than those of the vehicle control groups. Absolute liver weights of 400 and 600 mg/kg females were also significantly increased. Significantly increased incidences of myofiber cytoplasmic vacuolization occurred in 400 and 600 mg/kg females. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were dermally administered 0, 75, 150, or 300 mg bis(2-chloroethoxy)methane/kg body weight in ethanol, 5 days per week for 105 weeks. Survival of all dosed groups of rats was generally similar to that of the vehicle controls. Mean body weights of dosed rats were similar to those of the vehicle controls throughout the study. Clinical findings in 300 mg/kg females that died during the first year of the study included abnormal breathing, lethargy, thinness, nasal discharge, and ataxia. Significantly increased incidences of degeneration of the olfactory epithelium in the nose occurred in all dosed groups of males and in 150 and 300 mg/kg females. The incidences of inflammation of the forestomach were significantly increased in 150 and 300 mg/kg males, and the incidence of ulcers was significantly increased in 300 mg/kg males. Increased incidences of cystic degeneration of the liver occurred in 150 and 300 mg/kg male rats; the incidence was significantly increased in the 300 mg/kg group. 2-YEAR STUDY IN MICE: Groups of 50 male mice were dermally administered 0, 150, 300, or 600 mg bis(2-chloroethoxy)methane/kg body weight in ethanol, 5 days per week for 105 weeks. Groups of 50 female mice were dermally administered 0, 100, 200, or 400 mg/kg in ethanol, 5 days per week for 104 weeks. Survival of 600 mg/kg male mice was significantly less than that of the vehicle control group. Mean body weights of dosed mice were generally similar to those of the vehicle controls throughout the study. Clinical findings observed in 600 mg/kg male mice that died during the first year of the study included lethargy and thinness. Myocardial heart changes were recorded according to the characteristic lesions of cardiomyopathy syndrome (necrosis, mononuclear cell infiltration, myocardial cell vacuolization, and interstitial fibrosis) separately, and in addition, where appropriate, they were also categorized as cardiomyopathy. Increased incidences of cardiomyopathy and mononuclear cell infiltration occurred in 600 mg/kg males and 400 mg/kg females; the incidences were significantly increased in 600 mg/kg males compared to the vehicle controls. Significantly increased incidences of cardiomyocyte vacuolization and interstitial fibrosis occurred in 600 mg/kg males. A few early deaths in the 600 mg/kg males were considered to be due, at least in part and probably exclusively, to bis(2-chloroethoxy)methane-induced cardiotoxicity. The incidence of ulceration of the forestomach was significantly increased in 600 mg/kg males. Significantly increased incidences of dermal inflammation and fibrosis and epidermal hyperplasia at the site of application occurred in 600 mg/kg male mice. GENETIC TOXICOLOGY: Bis(2-chloroethoxy)methane was mutagenic in S. typhimurium strains TA100 and TA1535 in the presence of exogenous metabolic activation enzymes (S9) in one study; results from a second bacterial mutagenicity test were judged to be equivocal based on responses observed in TA100 and in E. coli strain WP2 uvrA/pKM101 in the presence of S9. No mutagenicity was observed in other tester strains or in the absence of S9. Bis(2-chloroethoxy)methane did not increase the frequency of micronucleated reticulocytes in bone marrow of male F344/N rats following three daily treatments by gavage or micronucleated erythrocytes in peripheral blood of male or female mice after 3 months of dermal exposure. CONCLUSIONS: Under the conditions of these 2-year dermal studies, there was no evidence of carcinogenic activity of bis(2-chloroethoxy)methane in male or female F344/N rats administered 75, 150, or 300 mg/kg. There was no evidence of carcinogenic activity of bis(2-chloroethoxy)methane in male B6C3F1 mice administered 150, 300, or 600 mg/kg or in female B6C3F1 mice administered 100, 200, or 400 mg/kg. The administration of bis(2-chloroethoxy)methane for 2 years resulted in increased incidences of nonneoplastic lesions in the nose of male and female rats, the forestomach of male rats, the heart of male and female mice, and the forestomach and skin of male mice.     

Further evidence for two directions of D-1:D-2 dopamine receptor interaction revealed concurrently in distinct elements of typical and atypical behaviour: studies with the new enantioselective D-2 agonist LY 163502

The new, extremely potent and enantioselective D-2 agonist LY 163502 failed to induce compulsive stereotyped behaviour. Very low doses (3–6 g/kg) inhibited spontaneous sniffing and locomotion, while higher doses (12–50 g/kg) induced episodes of non-stereotyped sniffing and chewing; these actions showed complete enantioselectivity. Up to 200-fold higher doses modestly induced only locomotion. Responsivity to LY 163502 was enantioselectively blocked by the selective D-2 antagonist R-piquindone. This responsivity was also enantioselectively blocked by the selective D-1 antagonist R-SK&F 83566 but, additionally, episodes of atypical limb/body jerking behaviour were released; thus, LY 163502 induced such jerking only when tonic D-1 activity was suppressed. These data extend our notion that there may be at least two forms of functional interaction between D-1 and D-2 receptor systems: one cooperative, as in the regulation of typical sniffing, and another oppositional, as in the regulation of atypical jerking.     

Toxicology and carcinogenesis studies of isoeugenol (CAS No. 97-54-1) in F344/N rats and B6C3F1 mice (gavage studies)

Isoeugenol is one of several structurally similar phenylpropenoid compounds produced by plants. It has been extracted from calamus, savory, basil, ylang-ylang, clove, tuberose, jonquil, nutmeg, tobacco, sandalwood, dill seed, mace, gardenia, petunia, and other flowers. Isoeugenol can also be produced by isomerization of eugenol, which occurs naturally in clove, pimento, bay leaf, and cinnamon. As a fragrance with a spicy, carnation-like odor, isoeugenol is incorporated into numerous household and personal hygiene products, including perfumes, cream lotions, soaps, and detergents. As a flavoring agent, isoeugenol is added to nonalcoholic drinks, baked foods, and chewing gums. Isoeugenol was nominated by the National Cancer Institute and was selected for carcinogenicity testing because of widespread human exposure through its use as a flavoring and fragrance agent and because of its structural similarity to phenylpropenoids such as safrole, isosafrole, eugenol, methyleugenol, estragole, and anethole, most of which are known rodent carcinogens. Male and female F344/N rats and B6C3F1 mice were administered isoeugenol (99% or greater pure) in corn oil by gavage for 3 months or 2 years. Genetic toxicity tests were conducted in Salmonella typhimurium, Escherichia coli, cultured Chinese hamster ovary cells, and mouse peripheral blood erythrocytes. 3-MONTH STUDY IN RATS: Groups of 10 male and 10 female rats were exposed to isoeugenol in corn oil by gavage at doses of 0, 37.5, 75, 150, 300, or 600 mg/kg, 5 days per week for 14 weeks. All rats survived to the end of the study except one 600 mg/kg male and one 37.5 mg/kg female that were killed in dosing accidents. Mean body weights of all exposed groups of males were significantly less than that of the vehicle control group; however, only the decrease for the 600 mg/kg group exceeded 10% and was considered related to isoeugenol exposure. Liver weights were significantly increased in 300 and 600 mg/kg females. The incidences of minimal atrophy of the olfactory epithelium of the nose were significantly increased in 150 mg/kg or greater males and in 300 or 600 mg/kg females. The incidence of atrophy of olfactory nerve bundles was significantly increased in 600 mg/kg females. Minimal to mild periportal hepatocellular cytoplasmic alteration occurred in all 300 or 600 mg/kg females. 3-MONTH STUDY IN MICE: Groups of 10 male and 10 female mice were exposed to isoeugenol in corn oil by gavage at doses of 0, 37.5, 75, 150, 300, or 600 mg/kg, 5 days per week for 14 weeks. All mice survived to the end of the study. The mean body weight of 600 mg/kg males was significantly less (12%) than that of the vehicle controls. Liver weights of 300 and 600 mg/kg males were significantly greater than those of the vehicle controls. Minimal to moderate atrophy of olfactory epithelial tissue and nerve bundles was observed in 600 mg/kg males and females. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were exposed to isoeugenol in corn oil by gavage at doses of 0, 75, 150, or 300 mg/kg, 5 days per week for 105 weeks. Survival rates of exposed male and female rats were similar to those of vehicle controls. Mean body weights of 300 mg/kg male rats were 9% greater than the vehicle controls at the end of the study. The general lack of toxicity and nonneoplastic lesions indicates that rats might have been able to tolerate higher doses. Two male rats in the 300 mg/kg group had rare benign or malignant thymomas, while two other males in this group had rare mammary gland carcinomas. Low incidences of minimal atrophy and minimal to mild respiratory metaplasia of the olfactory epithelium were increased in 150 mg/kg males and 300 mg/kg males and females. Similar incidences of minimal to mild olfactory epithelial degeneration in 300 mg/kg males were also increased. Incidences of keratoacanthoma of the skin were decreased in 150 and 300 mg/kg males. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were exposed to isoeugenol in corn oil by gavage at doses of 0, 75, 150, or 300 mg/kg, 5 days per week for 104 (females) or 105 (males) weeks. Survival of 300 mg/kg males was significantly decreased compared to the vehicle controls. Mean body weights of 300 mg/kg male and female groups were less than those of vehicle controls at the end of the study, 10% and 15% less, respectively. In all groups of exposed males, the incidences of hepatocellular adenoma, hepatocellular carcinoma, and hepatocellular adenoma or carcinoma (combined) were significantly greater than those in the vehicle control group; incidences of multiple hepatocellular adenoma were also significantly increased. Incidences of clear cell focus were significantly increased in 75 and 150 mg/kg male mice. There was a significant positive trend in the incidences of histiocytic sarcoma in females, and this neoplasm occurred in multiple tissues. Incidences of respiratory metaplasia in olfactory epithelium in all exposed groups and of atrophy and hyaline droplet accumulation in all exposed groups except 75 mg/kg females were significantly greater than those in corresponding vehicle control groups. Incidences of minimal to marked hyperplasia of Bowman's gland were increased significantly in all exposed groups. Incidences of minimal to mild necrosis of renal papilla and mild to moderate necrosis of renal tubules were increased significantly in 300 mg/kg females. Incidences of forestomach squamous hyperplasia, inflammation, and ulceration (males only) increased with exposure and were significant in the 300 mg/kg groups. The incidence of glandular stomach ulcers was low but significantly increased in the 300 mg/kg groups. GENETIC TOXICOLOGY: Isoeugenol was not mutagenic in two independent assays in bacteria (S. typhimurium and E. coli) conducted with and without exogenous metabolic activation (S9 liver enzymes). Neither did it induce chromosomal aberrations in cultured Chinese hamster ovary cells, with or without S9 activation. Frequencies of micronucleated erythrocytes were not increased in peripheral blood of male mice exposed to isoeugenol by gavage for 3 months; however, an increasing trend and a threefold increase in the 600 mg/kg group indicate a positive result for this test in female mice. CONCLUSIONS: Under the conditions of these 2-year gavage studies, there was equivocal evidence of carcinogenic activity of isoeugenol in male F344/N rats based on increased incidences of rarely occurring thymoma and mammary gland carcinoma. There was no evidence of carcinogenic activity of isoeugenol in female F344/N rats administered 75, 150, or 300 mg/kg. There was clear evidence of carcinogenic activity of isoeugenol in male B6C3F1 mice based on increased incidences of hepatocellular adenoma, hepatocellular carcinoma, and hepatocellular adenoma or carcinoma (combined). There was equivocal evidence of carcinogenic activity of isoeugenol in female B6C3F1 mice based on increased incidences of histiocytic sarcoma. Exposure to isoeugenol resulted in nonneoplastic lesions of the nose in male and female rats; of the nose, forestomach, and glandular stomach in male and female mice; and of the kidney in female mice.     

Toxicological evaluation of 4-vinylcyclohexene. I. Prechronic (14-day) and subchronic (13-week) gavage studies in Fischer 344 rats and B6C3F1 mice

4-Vinylcyclohexene (VCH), a dimer of 1,3-butadiene present in the gases discharged during tire curing, was examined for its toxic effects in Fischer 344 (F344) rats and B6C3F1 mice by 14-d prechronic and 13-wk subchronic testing. In the 14-d studies, VCH was administered orally by gavage in corn oil at doses of 0 (vehicle control), 300, 600, 1250, 2500, or 5000 mg/kg body weight to groups of five F344 rats and B6C3F1 mice of each sex, while the doses for the 13-wk studies (10 animals/group; 5 d/wk) were 0 (vehicle control), 50, 100, 200, 400, or 800 mg/kg body weight for rats and 0 (vehicle control), 75, 150, 300, 600, or 1200 mg/kg body weight for mice. All rats and most mice in the 14-d studies died when administered doses greater than or equal to 1250 mg/kg, although no compound-related gross or histopathologic effects were observed. In the 13-wk studies, extensive mortality was observed only in mice dosed at 1200 mg/kg. Final body weights were reduced in the 13-wk studies in male rats receiving doses greater than or equal to 400 mg VCH/kg, in female rats receiving 800 mg/kg, and in female mice receiving 600 mg/kg. Compound-related histopathologic effects in the 13-wk studies included hyaline droplet degeneration of the proximal convoluted tubules of the kidney in dosed male rats, the severity of which was dose-related, and a reduction in the number of primary follicles and mature graafian follicles in the ovaries of female mice receiving 1200 mg VCH/kg. No compound-related gross or histopathologic effects were evident in dosed female rats or male mice in the 13-wk studies.     

Cisplatin-induced conditioned taste aversion: attenuation by dexamethasone but not zacopride or GR38032F.

The 5-HT3 receptor antagonists zacopride and GR38032F are highly effective inhibitors of emesis induced by ionizing radiation and chemotherapeutic drugs such as cisplatin. The present study evaluated zacopride and GR38032F for efficacy in inhibiting the formation of the conditioned taste aversion (CTA) induced by cisplatin or lithium chloride in rats. The glucocorticoid dexamethasone, which has been reported to be effective against both the emetic and CTA-inducing effects of cisplatin, was included as a reference compound. When administered alone by i.p. injection, zacopride (0.1-10 mg/kg), GR38032F (10 mg/kg) and cisplatin (0.32-1.8 mg/kg) induced a CTA to an 0.1% saccharin solution; lower doses of each compound were ineffective. When administered as a pretreatment, neither zacopride (0.001-0.1 mg/kg) nor GR38032F (0.01-10 mg/kg) attenuated the CTA induced by cisplatin (0.32 and 0.56 mg/kg) or lithium chloride (10 mg/kg). In contrast, dexamethasone (0.32 and 1.0 mg/kg) attenuated the CTA induced by 0.32 but not 0.56 mg/kg of cisplatin. In an attempt to evaluate higher doses of zacopride against cisplatin without the potentially confounding factor that these doses by themselves induce a CTA, rats were injected with zacopride on three separate days prior to the aversion conditioning session. This pre-exposure treatment blocked the formation of the zacopride-induced CTA, but did not improve the efficacy of zacopride in attenuating the cisplatin-induced CTA. These results suggest that neither the cisplatin- nor the lithium-induced CTA in rats are due to effects that are sensitive to 5-HT3 receptor blockade.     

Investigations on cell proliferation and enzyme induction in male rat kidney and female mouse liver caused by tetrahydrofuran.

To elucidate possible mechanism(s) of carcinogenic action of tetrahydrofuran (THF) that had been demonstrated in previous inhalation studies, groups of male F344 rats and female B6C3F(1) mice were exposed to dynamic atmospheric concentrations of 0, 600, 1800, or 5400 mg/m(3) for 6 h per day, either for 5 consecutive days or for a period of 4 weeks (5 days per week). The reversibility of treatment-related changes was investigated in rats and mice exposed for 5 days and sacrificed 21 days after the last exposure. Female B6C3F(1) mice exposed to 5400 mg/m(3) showed significantly increased cytochrome P450 content, increased ethoxyresorufin-O-deethylase and pentoxyresorufin-O-depentylase activities, increased cell proliferation (5-bromo-2'-deoxyuridine-method) and an increased mitotic index in liver zones 2 (midzonal region) and 3 (central vein region). The changes were found to be reversible after a 3-week treatment-free period (cell proliferation examined, only). Male F344 rats showed dose-related alpha2u-globulin (alpha2u) accumulation in the renal cortex after 5 or 20 exposures, and there were no signs of reversal after a 3-week treatment-free period. After 20 exposures at 5400 mg/m(3), the alpha2u accumulation was found to be associated with increased cell proliferation in "hot spots" of the renal cortex and increased apoptosis. Increased cell proliferation was also detected after 20 exposures at 1800 mg/m(3). There were no effects at 600 mg/m(3). It is concluded that THF enhances tumor formation in male rat kidney and female mouse liver via induction of cell proliferation. These features present essential elements that should be taken into account for the carcinogenic risk assessment of THF.     

The putative 5-HT1A antagonist BMY 7378 blocks 8-OH-DPAT-induced changes in local cerebral glucose utilization in the conscious rat.

It has previously been shown that the 5-HT1A agonist, 8-OH-DPAT, caused discrete changes in cerebral glucose utilization in the rat, as assessed by quantitative 2-deoxyglucose autoradiography. Here, the effect of the putative 5-HT1A antagonist, BMY 7378, on regional cerebral glucose utilization was examined, when injected alone and in rats treated with 8-OH-DPAT. In control rats, BMY 7378 (5 mg/kg, s.c.) markedly increased glucose utilization in the lateral habenular nucleus and moderately reduced glucose utilization in the hippocampal formation. Pretreatment with BMY 7378 (5 mg/kg) significantly attenuated the reductions in glucose utilization in the hippocampus, entorhinal, piriform and cingulate cortex, induced by 8-OH-DPAT (0.25 mg/kg). The 8-OH-DPAT-induced increase in glucose utilization in the copula pyramis, that is putatively associated with the appearance of the 5-HT behavioural syndrome, was also blocked by BMY 7378, as was the behavioural syndrome. In summary, BMY 7378 produced few of the discrete changes in cerebral glucose utilization that are seen with 8-OH-DPAT. However, many of the changes induced by 8-OH-DPAT were reversed by BMY 7378. These data are consistent with the hypothesis that the effects of 8-OH-DPAT on regional cerebral glucose utilization are mediated by 5-HT1A receptors.     

Dopaminergic behaviour stereospecifically promoted by the D1 agonist R-SK & F 38393 and selectively blocked by the D1 antagonist SCH 23390

The selective D₁ dopamine receptor agonist R-SK & F 38393 (20 mg/kg), but not its S-antipode, stereospecifically promoted episodes of prominent grooming behaviour. Typical stereotyped behaviour, such at that induced by apomorphine, was not seen. Grooming responses to 20 mg/kg R-SK & F 38393 were blocked by 0.1–0.5 mg/kg of the selective D₁ antagonist SCH 23390 but not by 1.0–5.0 mg/kg of the selective D₂ antagonist metoclopramide, while stereotyped behaviour induced by 0.5 mg/kg apomorphine was blocked by both antagonists. These results are consistent with certain individual dopaminergic behaviours such as grooming being mediated by D₁ receptors. Other dopaminergic syndromes may involve complex functional interactions between D₁ and D₂ receptors.