RESUMO
BACKGROUND: Chronic constipation affects 14%-17% of the population. Elobixibat, a novel, ileal bile acid transporter (IBAT) inhibitor, has been approved as a new chronic constipation drug in Japan in January 2018. The present study aimed to examine the pharmacological effects of elobixibat on colonic motility in conscious dogs using a telemetry system. METHODS: Six male beagle dogs were surgically implanted with strain gauge force transducers for gastrointestinal (GI) motility recording. The motility index was calculated from GI motility at each recording site in conscious and nonrestraint dogs. The fasted dogs were orally administered elobixibat (3, 10, or 30 mg kg-1 ) or 30 mg kg-1 of sennoside as positive control or vehicle using a crossover design and washout period of more than 6 days. One hour after drug administration, the dogs were fed chow, and GI motility and defecation were observed for 10 hours; GI motility was quantified to calculate giant migrating contractions (GMCs). Fecal bile acids (BAs) were determined as well. KEY RESULTS: Elobixibat and sennoside significantly increased the number of defecations, fecal wet weight, and water content within 10 hours after administration. Elobixibat dose-dependently decreased the time to first bowel movement, increased the amount of total fecal BAs, and rapidly induced mild GMCs during defecation; however, higher strength of GMCs was observed with sennoside. CONCLUSIONS & INFERENCE: Elobixibat induces bowel movements faster than sennoside through a different mechanism. Elobixibat locally inhibits IBAT in the ileal lumen, leading to elevated fecal BAs in the colon and induced mild GMCs during defecation.
Assuntos
Defecação/efeitos dos fármacos , Dipeptídeos/farmacologia , Fármacos Gastrointestinais/farmacologia , Complexo Mioelétrico Migratório/efeitos dos fármacos , Tiazepinas/farmacologia , Animais , Estado de Consciência , Cães , Íleo/efeitos dos fármacos , Masculino , Transportadores de Ânions Orgânicos Dependentes de Sódio/antagonistas & inibidores , Simportadores/antagonistas & inibidoresRESUMO
Extended term, continuous measurement and observation of drug responses were performed to examine the feasibility of a custom-made whole-body plethysmograph for measuring respiratory function in unanesthetized, unrestrained monkeys. Using this apparatus, respiratory function (respiration rate, tidal volume, and minute volume) was observed for 23 hr in unanesthetized, unrestrained cynomolgus monkeys (Macaca fascicularis). The respiration rate, tidal volume, and minute volume in the light period (7:00 to 19:00) reached approximately 30% to 50% higher values than in the dark period (19:00 to 7:00), thus clearly exhibiting circadian variation in the cynomolgus monkey respiratory functions. Administration of morphine (10 mg/kg, s.c.) resulted in sustained reduction in tidal volume and minute volume, and ketamine (30 mg/kg [sub-anesthetic dose], i.m.) also produced sustained reduction in respiration rate, tidal volume, and minute volume. With dimorpholamine (1 mg/kg, i.v.) or caffeine (10 mg/kg, s.c.), respiration rate, tidal volume, and minute volume increased. Physiological saline (1 ml/kg, s.c. and 0.1 ml/kg, i.v.) and chlorpromazine (10 mg/kg, s.c.) produced no clear-cut changes in respiration rate, tidal volume, or minute volume. From the above results, we conclude that our custom-made whole-body plethysmograph is useful for measuring respiratory function in unanesthetized and unrestrained monkeys.
Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Pletismografia Total/métodos , Respiração/efeitos dos fármacos , Animais , Ritmo Circadiano , Avaliação Pré-Clínica de Medicamentos/instrumentação , Desenho de Equipamento , Estudos de Viabilidade , Macaca fascicularis , Masculino , Preparações Farmacêuticas/administração & dosagem , Pletismografia Total/instrumentação , Taxa Respiratória/efeitos dos fármacos , Volume de Ventilação Pulmonar/efeitos dos fármacosRESUMO
In safety pharmacology studies, the effects on the QT interval of electrocardiograms are routinely assessed using a telemetry system in cynomolgus monkeys. However, there is a lack of integrated databases concerning in vivo QT assays in conscious monkeys. As part of QT Interval Prolongation: Project for Database Construction (QT PRODACT), the present study examined 10 positive compounds with the potential to prolong the QT interval and 6 negative compounds considered to have no such effect on humans. The experiments were conducted at 7 facilities in accordance with a standard protocol established by QT PRODACT. The vehicle or 3 doses of each test compound were administered orally to male cynomolgus monkeys (n=3-4), and telemetry signals were recorded for 24 h. None of the negative compounds prolonged the corrected QT using Bazett's formula (QTcB) interval. On the other hand, almost all of the positive compounds prolonged the QTcB interval, but haloperidol, terfenadine, and thioridazine did not. The failure to detect the QTcB interval prolongation appeared to be attributable for the differences in metabolism between species and/or disagreement with Bazett's formula for tachycardia. In the cynomolgus monkeys, astemizole induced Torsade de Pointes and cisapride caused tachyarrhythmia at lower plasma concentrations than those observed in humans and dogs. These results suggest that in vivo QT assays in conscious monkeys represent a useful model for assessing the risks of drug-induced QT interval prolongation.
Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Síndrome do QT Longo/induzido quimicamente , Modelos Animais , Animais , Arritmias Cardíacas/induzido quimicamente , Ritmo Circadiano , Bases de Dados Factuais , Eletrocardiografia , Macaca fascicularis , Masculino , Preparações Farmacêuticas/sangue , Farmacocinética , TelemetriaRESUMO
The general pharmacological effects of the hexapeptide KP-102 (D-alanyl-3-(2-naphthyl)-D-alanyl-L-alanyl-L-tryptophyl-D-phenylalanyl-L-lysinamide dihydrochloride, growth hormone-releasing peptide-2, GHRP-2, pralmorelin, CAS 158861-67-7), which potently promotes growth hormone (GH) release by acting at both hypothalamic and pituitary sites, were evaluated in various animal experimental models. The administration of KP-102 showed no obvious effect at a pharmacological dose on the central nervous system. KP-102 had no significant effect on the autonomic nervous system and smooth muscle except a slight and transient increase in spontaneous motility of isolated rabbit ileum and contraction of isolated guinea pig ileum at high doses. There was negligible effect on the respiratory and cardiovascular systems, digestive system, renal function and blood system after KP-102 treatment. These results suggest that KP-102 has no serious general pharmacological effects at dose levels showing GH-releasing activity in the experimental animals. Therefore, it is concluded that KP-102 will be a useful drug for the diagnosis of serious GH deficiency and for treatment of short stature.