RESUMO
Drug-drug interactions between canagliflozin, a sodium glucose co-transporter 2 inhibitor, and glyburide, metformin, and simvastatin were evaluated in three phase-1 studies in healthy participants. In these open-label, fixed sequence studies, participants received: Study 1-glyburide 1.25 mg/day (Day 1), canagliflozin 200 mg/day (Days 4-8), canagliflozin with glyburide (Day 9); Study 2-metformin 2,000 mg/day (Day 1), canagliflozin 300 mg/day (Days 4-7), metformin with canagliflozin (Day 8); Study 3-simvastatin 40 mg/day (Day 1), canagliflozin 300 mg/day (Days 2-6), simvastatin with canagliflozin (Day 7). Pharmacokinetic parameters were assessed at prespecified intervals. Co-administration of canagliflozin and glyburide did not affect the overall exposure (maximum plasma concentration [Cmax ] and area under the plasma concentration-time curve [AUC]) of glyburide and its metabolites (4-trans-hydroxy-glyburide and 3-cis-hydroxy-glyburide). Canagliflozin did not affect the peak concentration of metformin; however, AUC increased by 20%. Though Cmax and AUC were slightly increased for simvastatin (9% and 12%) and simvastatin acid (26% and 18%) following coadministration with canagliflozin, compared with simvastatin administration alone; however, no effect on active 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitory activity was observed. There were no serious adverse events or hypoglycemic episodes. No drug-drug interactions were observed between canagliflozin and glyburide, metformin, or simvastatin. All treatments were well-tolerated in healthy participants.
Assuntos
Canagliflozina/administração & dosagem , Glibureto/farmacocinética , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/farmacocinética , Metformina/farmacocinética , Sinvastatina/farmacocinética , Administração Oral , Adolescente , Adulto , Área Sob a Curva , Argentina , Disponibilidade Biológica , Biotransformação , Canagliflozina/efeitos adversos , Esquema de Medicação , Interações Medicamentosas , Feminino , Glibureto/administração & dosagem , Glibureto/efeitos adversos , Glibureto/sangue , Meia-Vida , Voluntários Saudáveis , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Inibidores de Hidroximetilglutaril-CoA Redutases/sangue , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/sangue , Masculino , Taxa de Depuração Metabólica , Metformina/administração & dosagem , Metformina/efeitos adversos , Metformina/sangue , Pessoa de Meia-Idade , Modelos Biológicos , Sinvastatina/administração & dosagem , Sinvastatina/efeitos adversos , Sinvastatina/sangue , Estados Unidos , Adulto JovemRESUMO
BACKGROUND: Maternal risks with pregnancies after an index diagnosis of peripartum cardiomyopathy (PPCM) are inadequately understood. OBJECTIVE: To describe the clinical outcomes of subsequent pregnancy in Haitian women with PPCM. DESIGN: Prospectively identified cases from a defined population base, 2000-2005. SETTING: Hôpital Albert Schweitzer, Deschapelles, Haiti. PATIENTS: 15 patients with PPCM and subsequent pregnancies among 99 prospectively identified patients with PPCM. MEASUREMENTS: Clinical and echocardiographic parameters. RESULTS: Fifteen women with PPCM had 16 subsequent pregnancies after the index pregnancies. Eight of these patients experienced worsening heart failure; of these, 1 died and 1 regained normal left ventricular systolic function. Seven patients tolerated pregnancy without worsening heart failure, and ventricular function recovered in these patients within 30 months after the subsequent pregnancy. LIMITATIONS: The results may not apply to non-Haitian women, and power was insufficient to identify factors that might predict recovery (n = 15). CONCLUSIONS: Half of the women with subsequent pregnancy after PPCM experienced worsening heart failure and long-term systolic dysfunction, while the other half experienced no deterioration and regained normal left ventricular systolic function.
Assuntos
Cardiomiopatias/complicações , Complicações Cardiovasculares na Gravidez , Resultado da Gravidez , Transtornos Puerperais , Adulto , Cardiomiopatias/diagnóstico por imagem , Cardiomiopatias/fisiopatologia , Feminino , Haiti , Humanos , Gravidez , Complicações Cardiovasculares na Gravidez/diagnóstico por imagem , Complicações Cardiovasculares na Gravidez/fisiopatologia , Estudos Prospectivos , Transtornos Puerperais/diagnóstico por imagem , Transtornos Puerperais/fisiopatologia , Fatores de Risco , Ultrassonografia , Disfunção Ventricular Esquerda/fisiopatologiaRESUMO
OBJECTIVE: To determine the incidence and prognosis of peripartum cardiomyopathy (PPCM) in rural Haiti. PATIENTS AND METHODS: Prospectively identified patients with PPCM treated at the Hospital Albert Schweitzer (HAS), Deschapelles, Haiti, were included in this study. Patients who presented to HAS from February 1, 2000, to January 31, 2005, were identified through a search of the HAS PPCM Registry. Clinical and serial echocardiographic data were collected on these patients. RESULTS: The 5-year experience confirms the high incidence of PPCM in this area, approximately 1 case per 300 live births, which is severalfold the estimated incidence in the United States (estimated 1 case per 3000 to 4000 live births). In this population, the ratio of PPCM deaths for the 5-year period was 47.1 per 100,000 births compared with the US ratio of 0.62 per 100,000 births. The mortality rate was 15.3% (15 deaths of 98 patients), and the mean follow-up was 2.2 years (range, 1 month to 5 years). Five years after the initiation of the HAS PPCM Registry search, 26 (28%) of 92 patients with PPCM observed for at least 6 months had regained normal left ventricular function. The difference in left ventricular echocardiographic features at diagnosis between deceased patients and survivors was not statistically significant: mean end-diastolic dimension (6.2 vs 5.8 cm; P=.08), ejection fraction (22% vs 25%; P=.12), and fractional shortening (16% vs 15%; P=.46). Left ventricular echocardiographic features at diagnosis were unable to predict individually who would eventually recover, although a statistically significant difference occurred at diagnosis between the recovered group and nonrecovered group for mean ejection fraction (28% vs 23%; P<.001) and fractional shortening (17% vs 14%; P=.004). CONCLUSION: Peripartum cardiomyopathy occurs significantly more commonly in rural Haiti on a per capita basis than in the United States. Patients with PPCM have a higher mortality rate and a poorer return of normal ventricular function.