Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 3 de 3
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Oligonucleotides ; 14(4): 299-310, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15665597

RESUMO

The effects of renal injury on the urinary excretion and tissue distribution of a 20-mer phosphorothioate oligonucleotide were investigated in male Sprague-Dawley rats. Renal injury was produced by treating the rats with either 5.0 mg/kg cisplatin or 2.5 mg/kg of a monoclonal antibody (mAb) directed toward Thy1.1. Controls received saline. Three days after cisplatin treatment or 2 days after anti- Thy1.1 treatment, the rats received 10 mg/kg ISIS 3521. Blood was collected at various times to assess the plasma concentrations of ISIS 3521, and rats were killed at various times from 6 to 48 hours after intravenous (i.v.) infusion of oligonucleotide to assess tissue concentrations by capillary gel electrophoresis (CGE). Cisplatin and anti-Thy1.1 antibody produced histologic and biochemical changes consistent with proximal tubular damage and glomerular damage, respectively. Urinary excretion of oligonucleotides was increased 2- to 4-fold of control; however, this amount accounted for only 1% to 2% of dose compared to 0.5% in controls. Proximal tubular damage reduced renal accumulations of ISIS 3521 and other oligonucleotide metabolites, but there were no obvious compensatory increases in concentrations in other organs except for a slight increase in spleen levels of total oligonucleotide. Glomerular damage was not associated with any change in oligonucleotide disposition. Immunohistochemical studies showed no evidence of alterations in the pattern of distribution within the injured kidney. The data suggest that acute renal dysfunction, either renal tubular or glomerular, does not markedly alter the urinary elimination and tissue deposition of a phosphorothioate oligonucleotide.


Assuntos
Glomérulos Renais/efeitos dos fármacos , Túbulos Renais/efeitos dos fármacos , Oligodesoxirribonucleotídeos Antissenso/farmacocinética , Tionucleotídeos/farmacocinética , Animais , Imuno-Histoquímica , Glomérulos Renais/lesões , Glomérulos Renais/patologia , Túbulos Renais/lesões , Túbulos Renais/patologia , Masculino , Oligodesoxirribonucleotídeos Antissenso/sangue , Oligodesoxirribonucleotídeos Antissenso/farmacologia , Oligodesoxirribonucleotídeos Antissenso/urina , Especificidade de Órgãos , Ratos , Ratos Sprague-Dawley , Tionucleotídeos/sangue , Tionucleotídeos/farmacologia , Tionucleotídeos/urina , Fatores de Tempo
2.
Regul Toxicol Pharmacol ; 38(3): 291-303, 2003 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-14623480

RESUMO

The potential for nelfinavir mesylate (VIRACEPT) to induce maternal and embryo-fetal toxicity was evaluated in rats and rabbits following oral administration. The drug was administered by gavage to rats at doses of 200, 500, or 1000mg/kg/day on days 6-17 of gestation and to rabbits at doses of 200, 400, or 1000mg/kg/day on days 7-20 of gestation. Dams and does were euthanized on GD20 and 29, respectively, and the offspring were weighed and examined for external, visceral, and skeletal alterations. Maximum plasma nelfinavir concentrations (C(max)) in rats were comparable to C(max) values in humans and were 3- to 6-fold higher than the reported human trough levels, while plasma nelfinavir levels in rabbits were approximately 0.13-0.17x the human C(max) and 0.25-0.5x the human trough. In rats, no treatment-related maternal or embryo-fetal toxicity was observed at any dose level and the NOAEL for both maternal and fetal toxicity was considered to be 1000mg/kg/day. Two rabbits in the 400mg/kg/day group died prior to scheduled termination. Because no deaths occurred in the high dose group and there were no other treatment-related signs of clinical toxicity in any dose group, these deaths were considered unrelated to nelfinavir. Group mean body weight loss in rabbits was observed at 1000mg/kg/day on gestation days 7-10. Food consumption was also reduced in this treatment group throughout the dosing period. There were no treatment-related findings in other maternal or fetal parameters. Thus, the no-observed-adverse-effect-level (NOAEL) for maternal toxicity in the rabbit was considered to be 400mg/kg/day (based on maternal body weight loss in the high dose group), while the NOAEL for embryo-fetal toxicity in the rabbit was considered to be 1000mg/kg/day. Thus, under the conditions of this study, nelfinavir was not considered to be toxic to the rat or rabbit conceptus.


Assuntos
Desenvolvimento Embrionário e Fetal/efeitos dos fármacos , Desenvolvimento Embrionário e Fetal/fisiologia , Nelfinavir/administração & dosagem , Nelfinavir/toxicidade , Administração Oral , Animais , Animais Recém-Nascidos/anatomia & histologia , Animais Recém-Nascidos/fisiologia , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Feto/anormalidades , Feto/efeitos dos fármacos , Troca Materno-Fetal/efeitos dos fármacos , Troca Materno-Fetal/fisiologia , Nelfinavir/farmacocinética , Gravidez , Prenhez/efeitos dos fármacos , Prenhez/fisiologia , Coelhos , Ratos
3.
Regul Toxicol Pharmacol ; 38(3): 304-16, 2003 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-14623481

RESUMO

The potential for nelfinavir mesylate (VIRACEPT) to produce reproductive toxicity was evaluated in rats administered oral doses of 200, 500, or 1000mg/kg/day. In the fertility and early embryonic development to implantation study, male rats were treated beginning 28 days prior to mating until necropsy and females for 2 weeks prior to mating and through gestation day (GD) 7. In the pre- and postnatal development study, pregnant rats were treated from GD 6 through lactation day (LD) 20. Selected F(1) pups from this study were evaluated in sensory and behavioral tests and were subsequently mated. Pregnant F(1) females were euthanized on GD 20 and their F(2) fetuses were examined. F(1) animals were not directly dosed with the drug. No treatment-related effects were observed on any male reproductive parameters. Administration of nelfinavir did not produce adverse effects on fertility, pregnancy, embryo-fetal development, parturition, or lactation in the F(0) generation. Similarly, no adverse effects of nelfinavir treatment were observed on pre- and postnatal growth, development, reproductive performance and embryo-fetal development in the F(1) offspring. Based on the results of this study, the no-observed-adverse-effect-level (NOAEL) for developmental and reproductive toxicity in rats was considered to be 1000mg/kg/day, the highest dose tested.


Assuntos
Desenvolvimento Embrionário e Fetal/efeitos dos fármacos , Nelfinavir/administração & dosagem , Nelfinavir/toxicidade , Reprodução/efeitos dos fármacos , Administração Oral , Animais , Animais Recém-Nascidos/crescimento & desenvolvimento , Animais Recém-Nascidos/fisiologia , Avaliação Pré-Clínica de Medicamentos/métodos , Desenvolvimento Embrionário e Fetal/fisiologia , Feminino , Fertilidade/efeitos dos fármacos , Fertilidade/fisiologia , Feto/efeitos dos fármacos , Lactação/efeitos dos fármacos , Masculino , Troca Materno-Fetal , Micrognatismo , Gravidez , Ratos , Ratos Sprague-Dawley , Reprodução/fisiologia , Fatores de Tempo , Língua/anormalidades
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...