RESUMO
OBJECTIVE: To examine the efficacy and safety of canagliflozin monotherapy, a sodium/glucose co-transporter 2 inhibitor, in Japanese type 2 diabetes patients. METHODS: In this double-blind, multi-centre Phase III study, patients aged ≥ 20 years with hemoglobin A1c (HbA1c) 7.0-10.0% on diet/exercise therapy alone received placebo or canagliflozin (100 or 200 mg) once daily for 24 weeks. The main outcome measure was the change in HbA1c from baseline to Week 24. RESULTS: The changes in HbA1c (-0.74 and -0.76 vs + 0.29%), fasting plasma glucose (1 mg/dl = 0.0555 mmol/l; -31.6 and -31.9 vs + 3.7 mg/dl), 2-h plasma glucose after 75-g glucose load (-84.9 and -79.0 vs -0.5 mg/dl), body weight (percent change: -3.76 and -4.02 vs -0.76%) and systolic blood pressure (-7.88 and -6.24 vs -2.72 mmHg) were significantly greater with 100 and 200 mg canagliflozin than with placebo (all, p < 0.05). Genital infections in females (6.5, 6.3 and 0%) and asymptomatic hypoglycemia (4.4, 5.6 and 2.2%), but not symptomatic hypoglycemia (2.2, 1.1 and 1.1%), were more frequent in the 100- and 200-mg groups than in the placebo group. CONCLUSION: Canagliflozin significantly improved glycemic control and was well tolerated.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucosídeos/uso terapêutico , Hipoglicemiantes/uso terapêutico , Tiofenos/uso terapêutico , Idoso , Glicemia , Pressão Sanguínea/efeitos dos fármacos , Canagliflozina , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/dietoterapia , Método Duplo-Cego , Terapia por Exercício , Feminino , Glucosídeos/efeitos adversos , Hemoglobinas Glicadas/metabolismo , Humanos , Hipoglicemiantes/efeitos adversos , Japão , Corpos Cetônicos/sangue , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Tiofenos/efeitos adversos , Resultado do Tratamento , Redução de PesoRESUMO
Innate immunity is the first line of defence against infectious micro-organisms, and the basic mechanisms of pathogen recognition and response activation are evolutionarily conserved. In mammals, the innate immune response in combination with antigen-specific recognition is required for the activation of adaptive immunity. Therefore, innate immunity is a pharmaceutical target for the development of immune regulators. Here, for the purpose of pharmaceutical screening, we established an in vitro culture based on the innate immune response of Drosophila. The in vitro system is capable of measuring lipopolysaccharide (LPS)-dependent activation of the immune deficiency (imd) pathway, which is similar to the tumour necrosis factor signalling pathway in mammals. Screening revealed that well-known inhibitors of phospholipase A(2) (PLA(2)), dexamethasone (Dex) and p-bromophenacyl bromide (BPB) inhibit LPS-dependent activation of the imd pathway. The inhibitory effects of Dex and BPB were suppressed by the addition of an excess of three (arachidonic acid, eicosapentaenoic acid and gamma-linolenic acid) of the fatty acids so far tested. Arachidonic acid, however, did not activate the imd pathway when used as the sole agonist. These findings indicate that PLA(2) participates in LPS-dependent activation of the imd pathway via the generation of arachidonic acid and other mediators, but requires additional signalling from LPS stimulation. Moreover, PLA(2) was activated in response to bacterial infection in Sarcophaga. These results suggest a functional link between the PLA(2)-generated fatty acid cascade and the LPS-stimulated imd pathway in insect immunity.