RESUMO
Small molecule DGAT2 inhibitors have shown promise for the treatment of metabolic diseases in preclinical models. Herein, we report the first toxicological evaluation of imidazopyridine-based DGAT2 inhibitors and show that the arteriopathy associated with imidazopyridine 1 can be mitigated with small structural modifications, and is thus not mechanism related.
RESUMO
Similarities in the physicochemical properties of caffeine and thiopental would suggest that the apparent volume of distribution of caffeine (aVd) may be comparable to the initial volume of distribution of thiopental. It is the initial volume of distribution of thiopental that is critical in the early minutes of anesthetic induction. A comparison of the aVd of caffeine and thiopental induction dose was made in 21 male New Zealand white rabbits. The aVd of caffeine was determined from serial saliva determinations following intravenous injection of caffeine (7.5 mg/kg). The loss of the pupillary light reflex was used as the end point for induction with thiopental. A statistically significant correlation (r = .722, P less than .0001) was found between the aVd of caffeine and thiopental induction dose. Also, both thiopental induction dose and caffeine aVd decreased significantly with age in these animals. These findings provide a basis for development of an uninvasive test for predicting thiopental dose in humans.
Assuntos
Cafeína/metabolismo , Tiopental/administração & dosagem , Animais , Peso Corporal , Masculino , Coelhos , Saliva/metabolismo , Tiopental/metabolismoRESUMO
The correlation between the apparent volume of distribution (aVd) of caffeine and the induction dose of thiopental was studied in 23 patients. Caffeine, which has an effective partition coefficient that approaches that of thiopental, was used as an indicator substance to estimate the immediate volume of distribution of thiopental. The immediate volume of distribution is critical in determining thiopental induction dose. The aVd of caffeine was determined noninvasively from serial saliva samples after consumption of caffeine, which was given to the patients as coffee. A strong correlation (r = .69; P less than .01) was found between the aVd of caffeine and the anesthetic induction dose of thiopental when the loss of eyelid reflex was used as the end point. The correlation between thiopental induction dose and body weight for the same individuals (r = .188) was not statistically significant.
Assuntos
Cafeína/metabolismo , Tiopental/farmacologia , Adulto , Piscadela/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Humanos , Cinética , Pessoa de Meia-Idade , Esterilização Tubária , Tiopental/administração & dosagemRESUMO
The safety of dirlotapide in dogs was evaluated in two studies with parallel designs. In an acute tolerance study, 24 beagles (six dogs per treatment) were treated orally once daily for 14 days with placebo or dirlotapide at 2.5, 5.0, or 10.0 mg/kg/day. In a margin-of-safety study, 38 overweight, neutered beagles were treated orally once daily for 3 months with dirlotapide at doses up to 0.5 mg/kg/day (six dogs), 1.5 mg/kg/day (12 dogs) and 2.5 mg/kg/day (six dogs). Control dogs received placebo at 0.3 mL/kg/day (10 dogs) and 0.5 mL/kg/day (four dogs). Results were similar for both studies, and no serious adverse events were observed. Dirlotapide was clinically well-tolerated in dogs at dosages up to 10 mg/kg/day for 14 days and 2.5 mg/kg/day for 3 months. Dirlotapide produced the expected decrease in food intake and body weight (up to 20-40%) without ill effects. Clinical, pathologic, and histopathologic findings were reversible and consistent with suppression of food intake and rapid weight loss produced by elevated dirlotapide dosages. In both studies, sporadic emesis and loose stools were observed in both placebo and dirlotapide-treated dogs. Incidence of emesis generally increased with dose and decreased with treatment time. Elevations in hepatic transaminase activity were seen in dogs treated with more than 1.5 mg/kg dirlotapide daily, but were not associated with clinical signs or microscopic evidence of hepatic degeneration or necrosis.
Assuntos
Fármacos Antiobesidade/uso terapêutico , Carbamatos/uso terapêutico , Doenças do Cão/tratamento farmacológico , Indóis/uso terapêutico , Obesidade/veterinária , Administração Oral , Animais , Fármacos Antiobesidade/administração & dosagem , Fármacos Antiobesidade/efeitos adversos , Carbamatos/administração & dosagem , Carbamatos/efeitos adversos , Doenças do Cão/sangue , Cães , Feminino , Indóis/administração & dosagem , Indóis/efeitos adversos , Masculino , Obesidade/tratamento farmacológico , SegurançaRESUMO
Escherichia coli-derived recombinant human interleukin-10 (rhuIL-10) has been evaluated in an extensive series of in vivo and in vitro nonclinical safety studies, including genetic toxicology, single- and repeat-dose systemic toxicity and toxicokinetics, reproductive toxicity, and specialized irritation studies. The primary test species in the toxicology studies were the mouse and monkey based on rhuIL-10 activity in receptor binding and ex vivo cytokine assays. Supported by a detailed preclinical program of therapeutic and prophylactic animal models in autoimmune diseases, the initial clinical development program has focused on investigating the therapeutic potential of rhuIL-10 (Tenovil) in Crohn's disease and rheumatoid arthritis. The results of the subcutaneous toxicity studies, up to 3 months dosing duration in mice and 6 months dosing duration in monkeys, support the development of rhuIL-10 for present and future clinical indications by the subcutaneous route of administration.