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1.
Food Chem Toxicol ; 36(3): 209-31, 1998 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-9609394

RESUMO

The third phase in a series of investigations of the relationship between low volume eye test (LVET) data, Draize eye irritation test data, and comparable data from in vitro assay protocols is presented. These investigations utilize Draize eye test and in vitro endpoint data generated previously as part of the CTFA Evaluation of Alternatives Program. LVET data were generated de novo using the same 25 representative surfactant-based personal-care formulations. In general, these formulations were minimally to moderately irritating. The linear correlation between maximum average score as determined by the Draize test (MAS) and the LVET (LVET-MAS) was 0.87; LVET-MAS values were typically about 30% lower then corresponding MAS values. Comparison of in vitro assay performance with that of the LVET was determined by statistical analysis of the relationship between LVET-MAS and in vitro endpoint. Regression modelling was the primary means of enabling such a comparison, the objective being to predict LVET-MAS for a given test material (and to place upper and lower prediction bounds on the range in which the LVET-MAS is anticipated to fall with high probability) based on observation of an in vitro score for that material. The degree of 95% confidence in prediction is quantified in terms of the relative widths of prediction intervals constructed about the fitted regression curves. Twenty in vitro endpoints were shown to have the greatest agreement with the LVET (these endpoints included those with low discordance rates relative to the Draize test) and were therefore selected for regression modelling. Although prediction interval widths tended to be narrower when predicting LVET-MAS compared with predicting MAS, the confidence with which the selected in vitro endpoints predicted both LVET-MAS and MAS for surfactant-based formulations was greatest when values were close to the lower or upper limits of the observed irritation range (i.e. 95% prediction interval widths were most narrow in these areas). Overall precision of LVET-MAS prediction for surfactant-based formulations was similar to that previously reported for hydroalcoholic formulations and considerably better than was reported for oil/water emulsions.


Assuntos
Alternativas aos Testes com Animais , Cosméticos/toxicidade , Olho/efeitos dos fármacos , Irritantes/toxicidade , Soluções Oftálmicas/toxicidade , Tensoativos/toxicidade , Testes de Toxicidade/métodos , Álcoois , Animais , Química Farmacêutica , Cosméticos/normas , Emulsões , Técnicas In Vitro , Óleos , Soluções Oftálmicas/normas , Coelhos , Análise de Regressão , Tensoativos/normas , Água
2.
Food Chem Toxicol ; 36(1): 47-59, 1998 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-9487363

RESUMO

The second phase in a series of investigations of the relationship between low volume eye test (LVET) data, Draize eye irritation test data, and comparable data from in vitro eye irritation test protocols is presented. These investigations utilize Draize eye test and in vitro endpoint data generated previously as part of the CTFA Evaluation of Alternatives Program. LVET data were generated de novo using the same 18 representative oil/water based personal-care formulations. In general, these formulations were minimally to mildly irritating; only three were classified as moderate eye irritants. The linear correlation between maximum average score as determined by the Draize test (MAS) and the LVET (LVET-MAS) was 0.85; LVET-MAS values were typically about half the corresponding MAS values. Comparison of in vitro assay performance with that of the LVET was determined by statistical analysis of the relationship between LVET-MAS and each in vitro endpoint. Regression modelling was the primary means of enabling such a comparison, the objective being to predict LVET-MAS for a given test material (and to place upper and lower 95% prediction bounds on the range in which the LVET-MAS is anticipated to fall with high probability) based on observation of an in vitro score for that material. The degree of confidence in prediction is quantified in terms of the relative widths of prediction intervals constructed about the fitted regression curves. Sixteen endpoints were shown to have the greatest agreement with the LVET (all but two were selected for modelling when compared with the Draize procedure). While the lower maximum average scores values (compared with the Draize test) in the LVET led to lower variability in LVET-MAS compared to MAS, the upper and lower bounds on predicted LVET-MAS values conditional on observed in vitro scores were still wide. Because there was overlap in the range of scores determined by the prediction bounds for many formulations, each of the selected endpoints was frequently unable to distinguish between test formulations in terms of statistically different predicted LVET-MAS values. In summary, none of the in vitro endpoints evaluated were able to reliably predict values of LVET-MAS among the set of oil/water emulsions considered here.


Assuntos
Alternativas aos Testes com Animais/métodos , Olho/efeitos dos fármacos , Irritantes/farmacologia , Soluções Oftálmicas/farmacologia , Testes de Toxicidade/métodos , Animais , Emulsões , Estudos de Avaliação como Assunto , Óleos , Coelhos , Água
3.
Food Chem Toxicol ; 34(8): 737-49, 1996 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-8883476

RESUMO

The first phase in a series of investigations of the relationship between low-volume eye test (LVET) data, Draize eye irritation test data, and comparable data from 25 in vitro assay protocols is presented. These investigations utilize Draize eye test and in vitro assay data generated previously as part of the Cosmetic, Toiletry and Fragrance Association (CTFA) Evaluation of Alternatives Program. LVET data were generated de novo using the same 10 representative hydroalcoholic personal-care formulations. The linear correlation between maximum average score (MAS) as determined by the Draize test and the LVET (LVET-MAS) was 0.93. Comparison of in vitro assay performance with that of the LVET was determined by statistical analysis of the relationship between LVET-MAS and in vitro endpoint. As in the CTFA program, regression modelling is the primary means of enabling such a comparison. The objective is to predict LVET-MAS for a given test material (and to place upper and lower prediction interval bounds in the range in which the LVET-MAS is anticipated to fall with high probability) conditional on observing an in vitro assay score for that material. The degree of confidence in prediction is quantified in terms of the relative widths of prediction intervals constructed about the fitted regression curves. Four assays [EYTEX MPA (membrane partition assay), HET-CAM (hen's egg test-chorioallantoic membrane HET-CAM) I, neutral red release and HET-CAM II] were shown to have the greatest agreement with the LVET. These assays were also among those with low discordance rates relative to the Draize test. Prediction of LVET-MAS values from experimentally determined in vitro scores was more accurate for hydroalcoholic formulations with lower rather than higher irritancy potential.


Assuntos
Alternativas aos Testes com Animais , Olho/efeitos dos fármacos , Soluções Oftálmicas/toxicidade , Animais , Etanol/análise , Etanol/toxicidade , Feminino , Humanos , Técnicas In Vitro , Irritantes/toxicidade , Masculino , Soluções Oftálmicas/normas , Vigilância de Produtos Comercializados , Controle de Qualidade , Coelhos , Análise de Regressão
4.
Food Chem Toxicol ; 34(1): 79-117, 1996 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-8603801

RESUMO

The CTFA Evaluation of Alternatives Program is an evaluation of the relationship between data from the Draize primary eye irritation test and comparable data from a selection of promising in vitro eye irritation tests. In Phase III, data from the Draize test and 41 in vitro endpoints on 25 representative surfactant-based personal care formulations were compared. As in Phase I and Phase II, regression modelling of the relationship between maximum average Draize score (MAS) and in vitro endpoint was the primary approach adopted for evaluating in vitro assay performance. The degree of confidence in prediction of MAS for a given in vitro endpoint is quantified in terms of the relative widths of prediction intervals constructed about the fitted regression curve. Prediction intervals reflect not only the error attributed to the model but also the material-specific components of variation in both the Draize and the in vitro assays. Among the in vitro assays selected for regression modeling in Phase III, the relationship between MAS and in vitro score was relatively well defined. The prediction bounds on MAS were most narrow for materials at the lower or upper end of the effective irritation range (MAS = 0-45), where variability in MAS was smallest. This, the confidence with which the MAS of surfactant-based formulations is predicted is greatest when MAS approaches zero or when MAS approaches 45 (no comment is made on prediction of MAS > 45 since extrapolation beyond the range of observed data is not possible). No single in vitro endpoint was found to exhibit relative superiority with regard to prediction of MAS. Variability associated with Draize test outcome (e.g. in MAS values) must be considered in any future comparisons of in vivo and in vitro test results if the purpose is to predict in vivo response using in vitro data.


Assuntos
Alternativas aos Testes com Animais , Cosméticos/toxicidade , Preparações para Cabelo/toxicidade , Sabões/toxicidade , Tensoativos/toxicidade , Animais , Linhagem Celular , Células Cultivadas , Embrião de Galinha , Estudos de Avaliação como Assunto , Olho/efeitos dos fármacos , Feminino , Hemólise , Humanos , Masculino , Valor Preditivo dos Testes , Coelhos , Distribuição Aleatória , Análise de Regressão , Reprodutibilidade dos Testes , Pele/citologia , Pele/efeitos dos fármacos
5.
Clin Pharmacol Ther ; 27(3): 297-300, 1980 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-7357788

RESUMO

The protein binding of phenytoin, propranolol, salicylic acid, warfarin, and bilirubin was determined in heparinized plasma and serum obtained from the same healthy adult subjects. There were no significant differences in the free fraction values of these compounds in plasma and serum. Addition of heparin to serum had no significant effect on protein binding. Contact with Vacutainer stoppers increased the free fraction of the weak base propranolol in serum and plasma but no significant effect on the protein binding of the other, weakly acidic compounds tested. The lack of differences in the protein binding of phenytoin, salicylic acid, warfarin, and bilirubin in human plasma and serum is in contrast with the pronounced differences observed previously in rat serum and plasma.


Assuntos
Bilirrubina/sangue , Fenitoína/sangue , Plastificantes/farmacologia , Propranolol/sangue , Salicilatos/sangue , Varfarina/sangue , Adulto , Feminino , Heparina/farmacologia , Humanos , Ponto Isoelétrico , Masculino , Ligação Proteica/efeitos dos fármacos
7.
Experientia ; 33(11): 1495-7, 1977 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-923723

RESUMO

Hypophysectomized rats given cyproheptadine (40 mg/kg) for 10 days exhibited a loss of pancreatic immunoreactive insulin and ultrastructural changes in the cytoplasm of beta-cells. Sham-operated animals given cyproheptadine showed identical changes in pancreatic beta-cells except that cytoplasmic involvement progressed to the formation of large vacuoles. The pituitary is not directly involved with the cyproheptadine-induced depletion of pancreatic insulin but plays a role in the formation of large cytoplasmic vacuoles.


Assuntos
Ciproeptadina/toxicidade , Pâncreas/efeitos dos fármacos , Hipófise/fisiologia , Animais , Hipofisectomia , Insulina/metabolismo , Masculino , Pâncreas/citologia , Pâncreas/ultraestrutura , Ratos
9.
Toxicology ; 7(2): 133-40, 1977 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-324024

RESUMO

The relationship between chemical structure and the pancreotoxic potential of positional isomers of diphenylmethylpiperidine was investigated in rats. The chemical synthesis of these compounds and their N-methylated analogs is reported. Oral administration of 4-diphenylmethylpiperidine and its N-methylated derivative (130 and 260 micronmoles/kg) to rats for 14 days resulted in hyperglycemia, reduced pancreatic insulin content and the formation of large vacuoles in the cytoplasm of pancreatic islet cells. No effect on beta cell morphology or insulin content was observed after administration of 2- and 3-diphenylmethylpiperidine and their N-methylated analogs.


Assuntos
Ilhotas Pancreáticas/efeitos dos fármacos , Piperidinas/toxicidade , Animais , Compostos Benzidrílicos , Glicemia/análise , Relação Dose-Resposta a Droga , Insulina/sangue , Ilhotas Pancreáticas/citologia , Isomerismo , Masculino , Ratos , Relação Estrutura-Atividade , Vacúolos
10.
J Toxicol Environ Health ; 1(4): 587-605, 1976 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-1263279

RESUMO

Studies were conducted to elucidate the processes involved in the biological disposition of diethylstilbestrol (DES). The apparent biological half-life of [14C] DES decreased with increasing age in immature rats. The half-life of DES in adult rats (14 min) was reached between the 15th and 25th day after birth. Comparison of the intestinal absorption of [14C] DES and [14C]DES monoglucuronide showed the unconjugated drug to be absorbed much more rapidly. Hydrolysis of the conjugate took place in the lower intestine, and this permitted the drug to undergo enterohepatic cycling.


Assuntos
Dietilestilbestrol/metabolismo , Fatores Etários , Animais , Interações Medicamentosas , Feminino , Glucuronatos/metabolismo , Humanos , Absorção Intestinal , Troca Materno-Fetal , Fenobarbital/farmacologia , Gravidez , Ratos , Fatores de Tempo , Útero/efeitos dos fármacos
11.
Drug Metab Dispos ; 3(1): 1-9, 1975.
Artigo em Inglês | MEDLINE | ID: mdl-234828

RESUMO

Radioactivity was excreted in the urine and feces of rats, mice, and humans after a dose of 14C-cyproheptadine. The major metabolite in rat urine was unconjugated, but the majority of radioactive materials in mouse and human urine were conjugated with glucuronic acid. Identification of the rat urinary metabolite of cyproheptadine as an epoxide was accomplished with mass spectrometry and other methods. The rat metabolite was 10.11 -epoxydesmethylcyproheptadine and accounted for about 25% of a 45-mg dose of cyproheptadine per kg. Only a small amount of this epoxide was found in mouse urine, and none was apparent in the urine of two humans who received 5 mg of the drug. Dihydrodiols, which could arise by epoxide hydrase hydrolysis of possible 10.11-epoxy metabolites, were not found in the urine of any of the species studied. The spoxide found in rat urine appears to be unusually stable to in vivo hydrolysis. Possible implications of these results in the species-selective pancreotoxicity of cyproheptadine in the rat are presented.


Assuntos
Ciproeptadina/metabolismo , Adulto , Animais , Radioisótopos de Carbono , Cromatografia em Camada Fina , Distribuição Contracorrente , Ciproeptadina/sangue , Ciproeptadina/urina , Compostos de Epóxi/sangue , Compostos de Epóxi/metabolismo , Compostos de Epóxi/urina , Fezes/análise , Humanos , Masculino , Espectrometria de Massas , Camundongos , Ratos , Especificidade da Espécie , Fatores de Tempo
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