RESUMO
The histamine H1 antagonist astemizole (Hismanal) was tested for carcinogenicity in Swiss mice and Wistar rats. Astemizole was administered with the food to mice for 18 and to rats for 24 consecutive months. The doses given--approximately 5, 20, and 80 mg/kg body weight.day--were equivalent to 25, 100, and 400 times, respectively, the recommended human dose of 10 mg/day. Survival of both mice and rats was comparable between groups. Peto's age-adjusted, dose-related trend analysis for the tumor-bearing rats did not reveal a statistically significant difference for males or females. There was no evidence that astemizole led to an increased incidence of spontaneously or unusually occurring neoplastic lesions in either mice or rats. Special attention was given to the effect of astemizole on the progression of spontaneously occurring mammary gland adenomas and fibroadenomas. Peto's analysis applied to the number of female rats bearing these benign mammary gland tumors disclosed no statistically significant dose-related trend. There was no positive trend for the onset of this tumor type, and the median size of the tumor over time per rat was also not statistically significantly different in a comparison of the control group with each of the dosed groups. The findings from these carcinogenicity studies suggest that astemizole is not tumorigenic and that it does not promote tumor growth.
Assuntos
Astemizol/toxicidade , Antagonistas dos Receptores Histamínicos H1/toxicidade , Envelhecimento/patologia , Animais , Testes de Carcinogenicidade , Relação Dose-Resposta a Droga , Feminino , Hiperplasia/induzido quimicamente , Masculino , Camundongos , Neoplasias Experimentais/induzido quimicamente , Ratos , Fatores de TempoRESUMO
Rats bearing mammary carcinomas induced by N-nitroso-N-methylurea (NMU) were subjected to either no treatment (C), to ovariectomy (O), to continuous ketoconazole dosing at 400 ppm into the diet (K) or to both ovariectomy and ketoconazole dosing (O + K). In both C and K groups survival over the experimental period of 15 weeks was low (12.5% and 15.8%, respectively). In the O group and the O + K group survival markedly improved (52.6%, P less than 0.05 and 68.4%, P less than 0.01, respectively) and partial or complete tumor regression was noted respectively in 2 and 8 rats out of 19. Whereas C and K dosed groups showed an equally high tumor multiplicity and fast tumor growth, both parameters were markedly reduced in the O group and more markedly reduced in the O + K group which showed an overall decrease of the number of tumors. These findings indicate a synergistic effect of ketoconazole dosing and ovariectomy.
Assuntos
Castração , Cetoconazol/uso terapêutico , Neoplasias Mamárias Experimentais/terapia , Animais , Terapia Combinada , Feminino , Neoplasias Mamárias Experimentais/induzido quimicamente , Neoplasias Mamárias Experimentais/tratamento farmacológico , Metilnitrosoureia , Ratos , Ratos Endogâmicos , Fatores de TempoRESUMO
The bovine corneal opacity-permeability assay (BCO-P) was evaluated as an in vitro alternative test model for the Draize eye irritancy test. Fifty pharmaceutical and commercially available compounds were tested in the BCO-P assay. The compounds were selected on the basis of their in vivo irritancy potential as determined in previous Draize tests. Liquids as well as solids were tested. Corneal opacity and permeability were measured to determine ocular irritation potential. When two irritancy classifications (non-irritant and irritant) were considered, 96% of the tested chemicals were classified correctly. A 72% concordance was obtained when four irritancy classifications (non-irritant, mild, moderate and severe irritant) were considered. Furthermore, all compounds that were severe eye irritants in vivo were equally scored in vitro. The results of this study show that the BCO-P assay is a competent in vitro test system for the prediction of ocular irritation of chemicals. This test model can be used as a first screen to avoid in vivo testing of severe ocular irritants.
RESUMO
The hen's egg test-chorioallantoic membrane (HET-CAM) assay, an alternative to the Draize eye irritation test, was developed by Luepke and has been improved on by means of a microscopic examination and the use of a test substance applicator (TSA). The TSA is a double teflon ring in which a perlon mesh is locked, and has several advantages over conventional protocols, reducing subjectivity of the method and avoiding the need for rinsing after treatment. It was confirmed by statistical analysis that the HET-CAM-TSA method can reproduce potentialin vivo irritant effects on the conjunctiva. The classification based on thein vitro results was compared with fourin vivo classifications [MAS (maximal average score) with thresholds of 15.0 and 25.0; the Kay and Calandra method; and EC criteria]. Cooper's parameters (specificity, sensitivity and concordance with the Draize test) were calculated according to these fourin vivo classifications. When the most rigorous classification (MAS threshold of 15.0) was taken into account, a sensitivity of 80%, a specificity of 81.3% and a concordance with the Draize test of 80.4% were obtained for this set of 46 compounds.
RESUMO
The Hen's Egg Test-Chorioallantoic Membrane (HET-CAM) method was modified in our laboratory by means of microscopic evaluation, a clear description of the three in vitro endpoints (haemorrhage, lysis and coagulation) and the use of a test substance applicator (TSA). A previous study on 46 chemicals demonstrated the usage of the HET-CAM-TSA assay as a screening test for eye irritancy. In order to extend our database and to come to a more reliable conclusion concerning the use of the HET-CAM-TSA method, a second set of 60 test substances was tested. The in vitro irritation scores (IS) were compared with the in vivo modified maximum average scores (MMAS) calculated 24 hr after instillation. The MMAS irritancy threshold was set at 15.0. The results were analysed according to the Cooper's parameters (specificity, sensitivity and concordance with the Draize test) and the Pearson's correlation coefficient. It was concluded that the HET-CAM-TSA test was a valuable screening test. To compensate for the misclassifications generated, it was also concluded that the HET-CAM-TSA method should be considered as a part of a test battery, together with the Bovine Corneal Opacity-Permeability (BCOP) assay.
RESUMO
The effect of repeated and exaggerated mebendazole administration was evaluated in dogs with and without experimentally induced altered liver function. Irish Setters and Toy Poodles were dosed at 1, 3, and 5 times the therapeutic dose (22 mg/kg) of mebendazole for 17 days, without any effect on the liver. Mixed breed dogs that received increasing doses of mebendazole at 11 to 110 times the therapeutic dose for 2 months did not show adverse effects and remained in good health throughout the experiment. There was not substantial evidence that carbon tetrachloride-induced liver changes were exacerbated by subsequent repeated treatments with mebendazole at 15 times the therapeutic dose. Additionally, in dogs whose liver function was compromised experimentally by glutathione depletion and microsomal enzyme induction, administration of mebendazole at this same dosage for 30 days did not result in any hepatotoxic effect. When mebendazole was given at 15 times the therapeutic dose prior to an hypoxic episode in dogs pretreated with a barbiturate and high protein diet, there was no evidence of any adverse effect on liver function. These metabolic manipulations, in conjunction with mebendazole administration, failed to reveal any mechanism of hepatic dysfunction associated with mebendazole treatment. Unrecognized factors appear to be involved with the rare cases of hepatic dysfunction that have been reported after mebendazole administration. Only careful documentation of field cases and further laboratory research can identify these factors.
Assuntos
Benzimidazóis/farmacologia , Cães/fisiologia , Fígado/efeitos dos fármacos , Mebendazol/farmacologia , Animais , Doença Hepática Induzida por Substâncias e Drogas , Doenças do Cão/induzido quimicamente , Doenças do Cão/fisiopatologia , Avaliação de Medicamentos/veterinária , Feminino , Fígado/fisiologia , Fígado/fisiopatologia , Hepatopatias/fisiopatologia , Hepatopatias/veterinária , Masculino , Mebendazol/administração & dosagem , Mebendazol/toxicidade , Ratos , Doenças dos Roedores/induzido quimicamenteAssuntos
Carcinógenos Ambientais/química , Ciclodextrinas/química , beta-Ciclodextrinas , 2-Hidroxipropil-beta-Ciclodextrina , Animais , Benzo(a)pireno/química , Benzo(a)pireno/toxicidade , Ácidos e Sais Biliares , Carcinógenos Ambientais/toxicidade , Ciclodextrinas/farmacologia , Sinergismo Farmacológico , Humanos , Lipídeos , Neoplasias Pancreáticas/induzido quimicamente , SolubilidadeRESUMO
The acute, subacute and chronic toxicity studies in laboratory animals showed that closantel is a well tolerated substance. At multiples of the clinical dose, overdosing might result in central nervous system effects and death. Repeated oral dosing was without effects up to 40 mg/kg in rats and dogs except for focal swelling of the epididymis in male rats at 40 mg/kg due to formation of spermatic granulomas. In sheep repeated dosing at 10 and 40 mg/kg orally and at 5 and 20 mg/kg intramuscularly every four weeks during 40 weeks demonstrated an acceptable safety margin in this target species. Reproduction studies including a three-generation study in rats showed that fertility was not affected except slightly in male rats at 40 mg/kg whereas an embryotoxic or teratogenic potential in rats and rabbits was absent. Peri- and postnatal parameters in rats were not affected. In target animals, reproduction was extensively studied in bulls, rams and ewes showing no risk of closantel for reproduction parameters. A mutagenic potential was found to be absent in a Salmonella Ames test, a sex-linked recessive lethal test in Drosophila melanogaster and a dominant lethal test in male and female mice. In 400 mice and 400 rats closantel was shown not to be carcinogenic. Tolerance studies in sheep and cattle demonstrated that oral and parenteral clinical doses were very well tolerated and devoid of serious side-effects.
Assuntos
Salicilamidas/toxicidade , Salicilanilidas/toxicidade , Administração Oral , Animais , Bovinos , Tolerância a Medicamentos , Embrião de Mamíferos/efeitos dos fármacos , Epididimo/efeitos dos fármacos , Feminino , Granuloma/induzido quimicamente , Injeções Intramusculares , Dose Letal Mediana , Masculino , Camundongos , Testes de Mutagenicidade , Ratos , Ratos Endogâmicos , Salicilanilidas/administração & dosagem , Ovinos , Espermatogênese/efeitos dos fármacos , Neoplasias Testiculares/induzido quimicamente , Fatores de TempoRESUMO
Several pharmacologic studies of itraconazole, an orally active antifungal triazole, were conducted in humans and animals. In dogs and rats, no significant toxic effects were seen at doses of up to 40 mg/kg. Endocrinologic studies demonstrated that itraconazole, unlike ketoconazole, does not significantly affect human testicular and adrenal steroidogenesis. Pharmacokinetic studies indicated that itraconazole has a high tissue affinity and a longer half-life than ketoconazole. These pharmacologic observations suggest that itraconazole has a broader spectrum of activity than ketoconazole and a lower potential for producing adverse effects.
Assuntos
Antifúngicos/farmacologia , Cetoconazol/análogos & derivados , Glândulas Suprarrenais/efeitos dos fármacos , Animais , Antifúngicos/metabolismo , Antifúngicos/toxicidade , Cães , Feminino , Cobaias , Humanos , Itraconazol , Cetoconazol/metabolismo , Cetoconazol/farmacologia , Cetoconazol/toxicidade , Cinética , Masculino , Camundongos , Coelhos , Ratos , Testículo/efeitos dos fármacosRESUMO
Hundreds of pharmaceuticals have been reported to give a positive result in the standard "Chronic Bioassay", which consists of an 18 to 24 month daily administration of the test compound in mice and rats. This is in contrast with 20 pharmaceuticals, which are known to be carcinogenic to humans. The high incidence of apparently false-positive results in the Chronic Bioassay may be related to differences in mechanism of pharmacological action between rodents and humans, but also to the very high dose levels that have to be administered to rodents in accordance to regulatory guidelines. Lack of relevance to man therefore often has to be demonstrated by additional mechanistic studies. Based upon the deficiencies of the Chronic Bioassay and on the increased knowledge on cellular and molecular mechanisms involved in carcinogenicity, extensive discussions have recently taken place between regulatory agencies and industry associations at the occasion of International Conferences on Harmonization (ICH). These discussions have resulted in the possibility to use alternative short-to-medium-term carcinogenicity models in combination with a single two-year carcinogenicity study for evaluation of carcinogenicity. A description of these models is provided in this review as well as possible strategies for carcinogenicity testing and evaluation in the future.
Assuntos
Alternativas aos Testes com Animais , Testes de Carcinogenicidade/métodos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Animais , Bioensaio/métodos , Bioensaio/tendências , Testes de Carcinogenicidade/tendências , Guias como Assunto , Humanos , Cooperação Internacional , Camundongos , Testes de Mutagenicidade/métodos , Testes de Mutagenicidade/tendências , Ratos , Medição de RiscoRESUMO
1-[2-(2,4-Dichlorophenyl)-2-(2-propenyloxy)-ethyl]-1H-imidazole (imazalil) base and different salts were tested in vitro on various pathogenic fungi and bacteria; in vivo on guinea-pigs, rats and turkeys experimentally infected with dermatophytes and Candida albicans. In vitro the dermatophytes were the most sensitive. The plant-pathogenic fungi were more sensitive to the base than to the salts. The antibacterial activity was low. The in vivo antifungal activity was high for the dermatophytes and rather low for Candida. The acute, subacute and chronic toxicity studies in rats and dogs showed that imazalil wa a well tolerated substance. Ocular and dermal irritation were not seen at therapeutic doses. Fertility and reproductive capacity were not affected and embryotoxicity and teratogenicity were not seen. No mutagenic or cancerogenic potential was found.
Assuntos
Antifúngicos/farmacologia , Imidazóis/farmacologia , Administração Oral , Administração Tópica , Animais , Antifúngicos/toxicidade , Cães , Feminino , Fungos/efeitos dos fármacos , Fungicidas Industriais , Cobaias , Imidazóis/toxicidade , Masculino , Micoses/tratamento farmacológico , Fenômenos Fisiológicos Vegetais , RatosRESUMO
The mutagenic and leukemogenic potential of haloperidol, a neuroleptic of the butyrophenone class, has been studied in an in vitro Ames Salmonella/microsome test and in an 18-month carcinogenicity study in mice. Three variants of the Salmonella mutation assay were included: the spot test, the standard plate incorporation test and the preincubation test. There was no evidence that haloperidol had any mutagenic activity in any of the Salmonella mutation tests with any of the Salmonella typhimurium tester strains in the presence or absence of Aroclor 1254-induced rat- or mouse-liver S9-mix. In the 18-month study, haloperidol was injected intraperitoneally as a solution (HaldolR) at a dosage of 5 mg/kg daily for 5, 10 and 20 consecutive days in 5-week-old mice. Leucocyte counts at several time points and histopathological tumor evaluation 18 months later did not reveal any leukemogenic or other carcinogenic effect. On the basis of these data, it may be concluded that haloperidol is not mutagenic in Salmonella nor leukemogenic in mice.
Assuntos
Haloperidol/toxicidade , Leucemia Experimental/induzido quimicamente , Mutagênicos , Animais , Injeções Intraperitoneais , Masculino , Camundongos , Camundongos Endogâmicos , Testes de Mutagenicidade/métodosRESUMO
For the development of new systemically acting, oral antifungal azoles, it is of key importance to compare them with ketoconazole, the first available drug in this therapeutic class. Ketoconazole is a major breakthrough although hepatic side-effects as well as interactions with mammalian steroids might rarely occur during prolonged treatment. The prediction of these side-effects is difficult but the potential to interact with mammalian cytochrome P-450 enzymes is considered to be important. Therefore, for the selection of itraconazole a multidisciplinary approach was applied to study this potential. The present paper deals with the toxicological profile of itraconazole and its safety evaluation. In addition, a further comparison with ketoconazole and also with fluconazole is provided, in so far sufficient information is available. For the liver as a potential target organ, the available data indicate that itraconazole is not a predictable hepatotoxic drug in man. The major endocrine targets for overdosing with antifungal azoles are the adrenal cortex and the gonads. Endocrine studies show that itraconazole is not bearing a potential to interfere with steroid hormones in patients, which is a major improvement when compared to ketoconazole. In rats, elevation of serum cholesterol is observed especially after chronic exposure to itraconazole. This species-specific phenomenon leads at toxic dose levels to secondary events, especially in the long-term toxicity studies. In man, including those with existing hypercholesterolemia, serum cholesterol is not adversely affected by itraconazole. In pregnant rats, ketoconazole was shown to be teratogenic at high, toxic doses. The same observation has been made for itraconazole and this also might be true for fluconazole.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Antifúngicos/toxicidade , Fluconazol/toxicidade , Cetoconazol/análogos & derivados , Cetoconazol/toxicidade , Anormalidades Induzidas por Medicamentos , Animais , Glândulas Endócrinas/efeitos dos fármacos , Humanos , Itraconazol , Fígado/efeitos dos fármacosRESUMO
Four main targets have to be considered when evaluating the safety of new systemically acting, oral antifungals: the liver, the endocrine system, serum cholesterol and the developing embryo. The major endocrine targets for high levels of the antifungal azoles are the adrenal cortex and the gonads. Endocrine studies demonstrate that itraconazole has little potential for interfering with steroid hormones in man. Available data also indicate that itraconazole has low predictable hepatotoxicity potential in man. In rats, serum cholesterol levels are raised during treatment with itraconazole, especially after chronic exposure. This is, however, a species-specific phenomenon which leads to secondary events at toxic doses, especially in long-term toxicity studies. In man, including patients with existing hypercholesterolaemia, serum cholesterol levels are not raised. Ketoconazole has been shown to be teratogenic at high, toxic doses in pregnant rats. The same observation has been made for itraconazole, and it may also be true for fluconazole. However, all three azoles show no teratogenicity in the rabbit. Studies with itraconazole in adrenalectomised rats and in rats given exogenous arachidonic acid indicate that adrenal effects occurring at toxic dose levels are important mediators of teratogenicity. Since itraconazole does not affect adrenal function at levels used to treat infections in man, the teratogenic risk is estimated to be low. Itraconazole is therefore a promising new drug, especially with regard to the assessment of its safety in the liver and endocrine system. Moreover, it is more potent and has a broader antifungal spectrum than other azole antifungals, and its development is considered to be an important step forward in chemotherapy.
Assuntos
Antifúngicos/efeitos adversos , Cetoconazol/análogos & derivados , Anormalidades Induzidas por Medicamentos , Administração Oral , Animais , Antifúngicos/administração & dosagem , Glândulas Endócrinas/efeitos dos fármacos , Humanos , Hipercolesterolemia/induzido quimicamente , Itraconazol , Cetoconazol/administração & dosagem , Cetoconazol/efeitos adversos , Fígado/efeitos dos fármacosRESUMO
The approach to chronic toxicity testing over the past decade is reviewed and assessed in the light of developing ICH guidelines. The 1990's have seen a general acceptance that studies with a maximal duration of 6 months in rodents are all that is required for adequate safety assessment of developmental pharmaceutical agents. However, controversy has arisen concerning the most appropriate duration for chronic toxicity testing in non-rodents. Initial suggestions that 6 months duration was sufficient have been countered by findings noted in 12-month studies that were not seen in shorter-term studies. Retrospective analysis of available data eventually lead to a subsequent ICH recommendation that studies of 9 months duration would be now acceptable. However, until recently the FDA position on this recommendation was unclear and an analysis of industry practices since the ICH recommendation was made in 1997 has shown that the 9-month guideline is not widely applied. Recent clarification by the FDA will probably result in a continued but limited use of this alternative. An industry view on the future of chronic toxicology testing in rodents and non-rodents is presented.
Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Indústria Farmacêutica , Toxicologia , Animais , Humanos , Roedores , Estados Unidos , United States Food and Drug AdministrationRESUMO
The antitumoral activity of a novel imidazole derivative, R 75,251, has been studied in the androgen-dependent R3327G Dunning prostate adenocarcinoma grafted subcutaneously in syngeneic rats. Dietary application resulting approximately in dose levels of 80, 120, and 160 mg/kg reduced tumor weight by 66, 81, and 79%, respectively. This effect was not significantly different from that measured after castration (-82%). In intact animals, however, serum testosterone levels were almost not affected by R 75,251 treatment while LH levels rose two- to threefold. In castrated rats a tenfold increase in LH was observed. Moreover, prostate and seminal vesicles weights decreased much less after R 75,251 treatment than after castration. In castrated animals, treatment with R 75,251 induced a slight, non-significant reduction in tumor weight (-36%) compared with castration alone. In castrated animals, tumor growth was restored by exogenous administration of testosterone. In such animals R 75,251 also significantly reduced tumor weight by 57%. Similar results were obtained with Dunning R3327G prostate adenocarcinoma grafted beneath the renal capsule in male syngeneic rats receiving twice daily orally by gavage a dose of 80 mg/kg of R 75,251. These data suggest that R 75,251 exerts an antitumoral effect independent of its inhibition of androgen biosynthesis.