RESUMO
Proton pump inhibitors, the reference standard in adults with acid-related disorders, are increasingly being used in children despite limited pediatric safety and pharmacokinetic data. This study evaluated these parameters in rats aged 21-60 days, which approximately correlates with children aged 2-11 years. Lansoprazole at doses of 0, 5, 15, 50, or 150 mg/kg per day was administered to Sprague-Dawley rats from weaning through sexual maturity. Safety assessments included clinical, neurobehavioral, ophthalmologic, and gender-specific developmental milestones, clinical pathology including urinalysis, organ weight (at necropsy), and histopathologic evaluation. Blood samples for pharmacokinetics were collected on the first and last days of treatment. After the end of dosing, decreases in body weight gain, serum total protein and albumin (males), and microcytic hypochromic anemia were observed at doses of > or =50mg/kg per day, and hypoglycaemia (females) at 150 mg/kg per day. Selected groups exhibited increases in absolute and relative duodenal and stomach weights (> or =15 mg/kg per day), decreases in absolute and relative thymus weights (> or =50 mg/kg per day), increased relative liver weights (> or =50 mg/kg per day), and chronic adhesions to the spleen (> or =15 mg/kg per day). No other changes were observed. The area under the curve values in 60-day-old rats was less than those observed in 21-day-old rats. Areas under the curve values for lansoprazole were higher in female than male 60-day-old rats. No unexpected signs of toxicity were observed in the current preadolescent rats relative to those observed in adult rats in previous studies. The NOEL in preadolescent rats was similar to adults and gives a safety margin of one- to five-fold relative to the pediatric dose (0.87 mg/kg in 2-11-year-olds). These results provide comparative evidence for the value of studies in rats to support safety in a pediatric population.
Assuntos
Antiulcerosos/farmacocinética , Antiulcerosos/toxicidade , Omeprazol/farmacocinética , Omeprazol/toxicidade , Maturidade Sexual/efeitos dos fármacos , 2-Piridinilmetilsulfinilbenzimidazóis , Administração Oral , Anemia Hipocrômica/induzido quimicamente , Animais , Antiulcerosos/administração & dosagem , Área Sob a Curva , Comportamento Animal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Hipoglicemia/induzido quimicamente , Lansoprazol , Modelos Animais , Nível de Efeito Adverso não Observado , Omeprazol/análogos & derivados , Tamanho do Órgão/efeitos dos fármacos , Ratos , Ratos Wistar , Albumina Sérica/efeitos dos fármacos , Maturidade Sexual/fisiologia , DesmameRESUMO
The toxicity of ionizing radiation is associated with massive apoptosis in radiosensitive organs. Here, we investigate whether a drug that activates a signaling mechanism used by tumor cells to suppress apoptosis can protect healthy cells from the harmful effects of radiation. We studied CBLB502, a polypeptide drug derived from Salmonella flagellin that binds to Toll-like receptor 5 (TLR5) and activates nuclear factor-kappaB signaling. A single injection of CBLB502 before lethal total-body irradiation protected mice from both gastrointestinal and hematopoietic acute radiation syndromes and resulted in improved survival. CBLB502 injected after irradiation also enhanced survival, but at lower radiation doses. It is noteworthy that the drug did not decrease tumor radiosensitivity in mouse models. CBLB502 also showed radioprotective activity in lethally irradiated rhesus monkeys. Thus, TLR5 agonists could potentially improve the therapeutic index of cancer radiotherapy and serve as biological protectants in radiation emergencies.
Assuntos
NF-kappa B/metabolismo , Peptídeos/farmacologia , Lesões Experimentais por Radiação/prevenção & controle , Tolerância a Radiação/efeitos dos fármacos , Protetores contra Radiação/farmacologia , Receptor 5 Toll-Like/agonistas , Sequência de Aminoácidos , Animais , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Quimioterapia Adjuvante , Flagelina/química , Flagelina/farmacologia , Raios gama , Sistema Hematopoético/efeitos dos fármacos , Sistema Hematopoético/efeitos da radiação , Intestino Delgado/citologia , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/efeitos da radiação , Macaca mulatta , Camundongos , Camundongos Endogâmicos ICR , Dados de Sequência Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/radioterapia , Peptídeos/administração & dosagem , Peptídeos/química , Peptídeos/toxicidade , Doses de Radiação , Protetores contra Radiação/administração & dosagem , Protetores contra Radiação/química , Protetores contra Radiação/toxicidade , Salmonella enterica , Transdução de Sinais , Receptor 5 Toll-Like/metabolismo , Irradiação Corporal TotalRESUMO
This study examined the response of the Eker rat to nephrotoxic compounds and to genotoxic nonrenal carcinogens. Groups of male Eker rats received either no treatment; a vehicle treatment; treatment with a noncarcinogenic nephrotoxin (aluminum nitrilotriacetate, 2 mg/kg/day of aluminum, intraperitoneally, 3 days per week or cyclosporine A, 30 mg/kg/day, orally by gavage, 7 days/week); or treatment with a genotoxic nonrenal carcinogen (furan, 8 mg/kg/day, orally by gavage, 5 days/week or 2,4-diaminotoluene, 6.5 mg/kg/day, orally by gavage, 7 days/week or 2-nitropropane, 89 mg/kg/day, orally by gavage, 3 days/week). Duration of treatment was 4 and/or 6 months. Tissues from the Eker rats were evaluated microscopically and numbers of proliferative renal lesions were counted. Administration of nephrotoxic compounds (Al-NTA and cyclosporine) significantly increased the number of preneoplastic and neoplastic renal lesions in the Eker rat compared to concurrent vehicle controls. The genotoxic nonrenal carcinogens had no consistent effect on numbers of preneoplastic or neoplastic renal lesions and did not produce neoplasms in the expected target organ (liver).