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1.
The development of a unifying framework for conceptualizing the commonalities in various forms of substance abuse must encompass the data base focused upon the stimulus functions of drugs. In the first instance, for example, the research on drug self-administration has provided convincing evidence of a remarkable concordance between laboratory animals and human substance abusers in the reinforcing stimulus functions of a range of chemical agents. The recognition of these cross-species and cross-drug generalities has radically changed conceptualizations of substance abuse from a reactive to a more active process and has encouraged the kind of functional analysis of drug-seeking and drug-taking that has proven productive and useful in the study of other behavioral interactions. In this regard as well, recent refinements in the analysis of the discriminative stimulus functions of drugs have provided a more comprehensive basis for characterizing a chemical agent's spectrum of action and evaluating its abuse liability. While the correlation between the discriminative stimulus functions and the reinforcing stimulus functions is remarkably high for some drug classes, there are notable exceptions. Finally, the assessment of abuse liability requires an analysis of the eliciting stimulus functions of drugs as reflected by the physiological and behavioral changes, both acute and chronic, that follow drug administration. The methods used to evaluate both physiological dependence and behavioral toxicity in relationship to sensory and motor effects for a range of abused drugs have depended heavily upon an assessment of the eliciting stimulus functions of such compounds. 相似文献
2.
HELEN J. GILL JAMES L. MAGGS STEPHEN MADDEN MUNIR PIRMOHAMED & B. KEVIN PARK 《British journal of clinical pharmacology》1996,42(3):347-353
1 Cytochrome P450-mediated bioactivation of sulphamethoxazole to a hydroxylamine has been implicated in the hypersensitivity reactions associated with co-trimoxazole administration. Inhibiting the formation of the hydroxylamine may be one method of preventing the high frequency of toxicity which is observed in HIV-infected patients. Therefore, in this study, we have investigated the ability of fluconazole and ketoconazole, known cytochrome P450 inhibitors, to inhibit the formation of sulphamethoxazole hydroxylamine.
2 Ten healthy male volunteers were given co-trimoxazole (800 mg sulphamethoxazole and 160 mg trimethoprim) alone or 1 h after either fluconazole (150 mg) or ketoconazole (200 mg) in a randomized fashion with a washout period of at least 1 week between each phase. Urine was collected for 24 h, and sulphamethoxazole and its metabolites were quantified by electrospray LC-MS.
3 Ketoconazole had no effect on the urinary recovery of sulphamethoxazole or any of its metabolites. In contrast, fluconazole significantly ( P <0.001) inhibited the formation of sulphamethoxazole hydroxylamine by 50.0±15.1%. Fluconazole also inhibited the oxidation of sulphamethoxazole to the 5-methylhydroxy and 5-methylhydroxy acetate metabolites by 69.9±15.8% and 64.0±12.0%, respectively, but had no effect on the amount of sulphamethoxazole, N4 -acetyl sulphamethoxazole, or sulphamethoxazole N1 -glucuronide excreted in urine.
4 The potential clinical benefit of using fluconazole to prevent hypersensitivity to co-trimoxazole in patients with AIDS needs to be assessed in a prospective study using both metabolite formation and the clinical occurrence of adverse reactions as end-points. 相似文献
2 Ten healthy male volunteers were given co-trimoxazole (800 mg sulphamethoxazole and 160 mg trimethoprim) alone or 1 h after either fluconazole (150 mg) or ketoconazole (200 mg) in a randomized fashion with a washout period of at least 1 week between each phase. Urine was collected for 24 h, and sulphamethoxazole and its metabolites were quantified by electrospray LC-MS.
3 Ketoconazole had no effect on the urinary recovery of sulphamethoxazole or any of its metabolites. In contrast, fluconazole significantly ( P <0.001) inhibited the formation of sulphamethoxazole hydroxylamine by 50.0±15.1%. Fluconazole also inhibited the oxidation of sulphamethoxazole to the 5-methylhydroxy and 5-methylhydroxy acetate metabolites by 69.9±15.8% and 64.0±12.0%, respectively, but had no effect on the amount of sulphamethoxazole, N
4 The potential clinical benefit of using fluconazole to prevent hypersensitivity to co-trimoxazole in patients with AIDS needs to be assessed in a prospective study using both metabolite formation and the clinical occurrence of adverse reactions as end-points. 相似文献
3.
测定了马杜霉素渣中铅、砷、镉、铬的含量及对小白鼠的毒性和对鸡的抗球虫性能。试验结果:马杜霉素渣中铅含量1.05mg/kg,砷含量小于1.0mg/kg,镉含量1.2mg/kg,铬含量26mg/kg;马杜霉素渣对小白鼠的LD50为354.65mg/kg,比马杜霉素毒性大。马杜霉素渣的抗球虫指数为173~175.1,属中等强度抗球虫药。以上结果表明,马杜霉素渣可以作为抗球虫药应用,但应用时要防止中毒的发生。 相似文献
4.
Alexandra H. Heussner Evelyn O'Brien Daniel R. Dietrich 《Experimental and toxicologic pathology》2002,54(2):151-159
The mycotoxin ochratoxin A (OTA) is a potent renal carcinogen in rodents and induces renal fibrosis in pigs. Furthermore, OTA has been associated with the development of renal tumors and nephropathies in humans. Large species- and sex-differences are observed in sensitivity toward OTA-mediated toxicity and carcinogenicity, yet neither the mechanism(s) resulting in OTA toxicity nor the reasons for the observed species- and sex-specificities are known. This paper investigated variations in OTA handling viz binding to renal proteins which could possibly explain the observed differences in OTA susceptibility in vivo and in vitro. The results obtained via a modification of a standard receptor-binding assay demonstrated the presence of at least one homogeneous binding component in renal cortical homogenates from pig, mouse, rat and humans. This component was shown to bind OTA in a specific and saturable manner. A range of compounds selected for their affinity for steroid receptors and/or for various known organic anion transporters were employed in a competition assay to answer the question whether this homogenous OTA binding component represents a steroid-like receptor component or one of the known organic anion transporters of the kidney. Although many of the compounds were able to compete with OTA for protein-binding, the competition patterns displayed a distinct species specificity and did not correspond to the competition patterns associated with presently known organic anion transporters of the kidney in the mouse, rat or human. The data thus suggests the presence of a new organic anion transporter or more likely, a cytosolic binding component of unknown function with high affinity and capacity for OTA binding in humans, rats, mice and possibly pigs. 相似文献
5.
Summary: Oral administration of carbamazepine (CBZ)(15, 10, or 5 mg/kg) to mice significantly decreased both humoral and cellular immune responses evaluated by enumeration of direct and indirect plaque-forming spleen cells (PFC) and delayed–type hypersensitivity reaction (DTH) against sheep red blood cells (SRBC) as compared with those observed in normal control animals. Moreover, spleen T cells obtained from CBZ–treated donor mice were capable of decreasing both PFC and DTH responses of normal spleen cells transferred into lethally irradiated recipient animals. The immunodepressor effect of CBZ was observed even though administration of CBZ induced augmentation of spleen cellularity. 相似文献
6.
Nodular hyperplasia surrounding fibrolamellar carcinoma 总被引:2,自引:0,他引:2
We report a case of acetaminophen-induced liver necrosis in a 14-year-old girl. At autopsy, a 9 cm subcapsular nodule was present in the right lobe of the liver which showed distinct zonation: a central greyish white area of fibrolamellar carcinoma with a peripheral fleshy, tan-coloured rim ranging from 1 to 2 cm in thickness. This peripheral zone consisted of nodular, hyperplastic parenchyma resembling the changes seen in focal nodular hyperplasia, and stood out from the adjacent necrotic parenchyma. The sparing of this zone from the deleterious effects of acetaminophen provides indirect evidence of a predominantly arterial rather than portal blood supply to this region. The arterial supply was most probably derived from the tumour vasculature and may explain the parenchymal hyperplasia sometimes reported adjacent to a fibrolamellar carcinoma. Awareness of this phenomenon is essential when evaluating a needle biopsy, as sampling of this region may lead to a false negative diagnosis. 相似文献
7.
S. Ju
wiak T. Raiska T. Dutkiewicz U. Cioch B. Olenderek B. Krasowska L. Rzewicka Z. Juzyszyn J. Wjcicki L. Samochowiec 《Phytotherapy research : PTR》1992,6(3):141-145
Cernitins are preparations obtained from plant pollen which contain numerous compounds of potential biological significance. This work deals with the influence of cernitins upon acute paracetamol toxicity in mice. The survival rate and indices of hepatic injury: aminotransferase and alkaline phosphatase activities, bilirubin level in serum, glutathione and cytochrome P-450 content in liver, liver weight, histopathologic picture of the liver and presence of glycogen and lipids in stained liver sections, under different experimental protocols, were determined. It was found that cernitins are able to increase the survival rate of mice and reduce liver injury in acute paracetamol poisoning. Cernitins are more effective when administered after, rather than before, a dose of paracetamol. The possible mechanism through which cernitins may act is discussed. 相似文献
8.
Acute toxicity of two pyrethroids,permethrin, and cypermethrin in neonatal and adult rats 总被引:2,自引:0,他引:2
Franco Cantalamessa 《Archives of toxicology》1993,67(7):510-513
The present study aims specifically at obtaining a comparison of the acute toxicity of cypermethrin (CY), a type I pyrethroid, and permethrin (PERM), a type II pyrethroid, administered orally as a single dose to neonatal and adult rats, and at assessing the importance of pyrethroid biotransformation in CY and PERM toxicity through use of drug metabolism inhibitors. Our experiments show that CY is more toxic than PERM to adult and neonatal rats. The sensitivity of neonatal rats both to CY and to PERM toxicity is higher, the younger the animals. CY is much more toxic than PERM in the neonatal rat, compared with the adult. In rats aged 8, 16, and 21 days, pretreatment with piperonil butoxide (PB), a monooxygenase inhibitor, or with tri-o-tolyl phosphate (TOTP), an esterase inhibitor, does not produce significant variations in the lethal effects of CY and PERM. Instead, in the adult rats, a significant increase in CY (X2=5.97;p<0.05) and PERM (X2=4.37;p<0.05) mortality occurred in rats pretreated with esterase inhibitors, whereas no increase in CY and PERM toxicity was found in adult animals pretreated with monooxygenase inhibitor. It was concluded that the higher level of sensitivity of the neonate rat to pyrethroid toxicity is probably due to incomplete development of the enzymes which catalyze the metabolism of pyrethroids in the liver of young animals. It is suggested that ester hydrolysis is an important pyrethroids detoxification reaction in the adult rat. 相似文献
9.
几种中草药复配杀虫剂的急性毒性实验研究 总被引:1,自引:1,他引:0
为有效开发植物杀虫剂资源及今后的推广应用提供科学依据。用两种粉剂和两种醇剂的杀虫应用浓度给小白鼠灌,而家兔则行皮肤刺激试验。结果显示,除醒剂Y-13经口有中毒情况发生外,其它3种制剂均无中毒现象,醇剂Y-13的家兔皮肤也无刺激反应发生。作者认为:4种制剂在有杀虫效果的前提下,杀虫应用浓度对人和动物都较安全。有开发和推广应用价值。 相似文献
10.
The influence of a fraction obtained from Galeopsis ladanum L. on the central nervous system of rodents was examined. The results of these investigations show that the fraction impeded CNS activity. It is practically nontoxic and at a dose of 2000 mg/kg i.p. it does not have a soporific influence on mice. It reduces considerably the spontaneous locomotor activity of mice as well as the locomotor activity of mice stimulated by caffeine, but did not influence the locomotor activity induced by amphetamine. The extract did not exhibit a synergetic effect with barbiturates. The results suggest that the pharmacological activity of the extract resembled the activity of drugs which generally depress the CNS, being on the border between ataractic and sedative drugs. 相似文献