RESUMEN
AIM: To evaluate the efficacy and safety of gemigliptin and dapagliflozin dual add-on therapy (GEMI + DAPA) to metformin in type 2 diabetes (T2D) patients who had inadequate glycaemic control on metformin alone, compared with a single add-on of either gemigliptin (GEMI) or dapagliflozin (DAPA) to metformin. MATERIALS AND METHODS: In this randomized, double-blind, double-dummy, active-controlled, parallel-group, phase 3 study, 469 T2D patients treated with a stable dose of metformin for 8 weeks or longer were randomized to receive GEMI + DAPA (n = 157) and either GEMI (n = 156) or DAPA (n = 156). The primary endpoint was change in HbA1c levels from baseline at week 24. RESULTS: Baseline characteristics including body mass index and T2D duration were similar among groups. At week 24, the least square mean changes in HbA1c from baseline were -1.34% with GEMI + DAPA, -0.90% with GEMI (difference between GEMI + DAPA vs. GEMI -0.44% [95% confidence interval {CI}: -0.58% to -0.31%], P < .01) and -0.78% with DAPA (difference between GEMI + DAPA vs. DAPA -0.56% [95% CI: -0.69% to -0.42%], P < .01). Both upper CIs were less than 0, demonstrating the superiority of GEMI + DAPA for lowering HbA1c. The rates of responders achieving HbA1c less than 7% and less than 6.5% were greater with GEMI + DAPA (84.9%, 56.6%) than with GEMI (55.3%, 32.2%) and DAPA (49.3%, 15.3%). The incidence rate of adverse events was similar across groups, with low incidence rates of hypoglycaemia, urinary tract infection and genital infection. CONCLUSIONS: These results suggest that the addition of GEMI + DAPA to metformin as triple combination therapy was effective, safe and well-tolerated, especially for T2D patients who experienced poor glycaemic control on metformin alone.
Asunto(s)
Compuestos de Bencidrilo , Diabetes Mellitus Tipo 2 , Quimioterapia Combinada , Glucósidos , Hemoglobina Glucada , Hipoglucemiantes , Metformina , Piperidonas , Pirimidinas , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/sangre , Glucósidos/uso terapéutico , Glucósidos/administración & dosificación , Glucósidos/efectos adversos , Metformina/uso terapéutico , Metformina/administración & dosificación , Compuestos de Bencidrilo/uso terapéutico , Femenino , Masculino , Persona de Mediana Edad , Método Doble Ciego , Hemoglobina Glucada/análisis , Hemoglobina Glucada/efectos de los fármacos , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/efectos adversos , Anciano , Piperidonas/uso terapéutico , Piperidonas/administración & dosificación , Piperidonas/efectos adversos , Pirimidinas/uso terapéutico , Pirimidinas/administración & dosificación , Pirimidinas/efectos adversos , Glucemia/efectos de los fármacos , Glucemia/análisis , Glucemia/metabolismo , Control Glucémico/métodos , Adulto , Resultado del Tratamiento , Hipoglucemia/inducido químicamente , Hipoglucemia/epidemiología , Hipoglucemia/prevención & control , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéuticoRESUMEN
AIMS: To evaluate the effect of dapagliflozin on body composition such as total body fat (BF) mass, abdominal visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT) areas compared with glimepiride in Korean patients with type 2 diabetes. MATERIALS AND METHODS: This was a 52-week, multicentre, randomized, parallel-group, open-label, Phase IV (NCT02564926) study. Patients with inadequate glycaemic control (glycated haemoglobin ≥7.0% and <10.0%) on metformin monotherapy (≥1000 mg/day) were randomized 1:1 to receive dapagliflozin 10 mg/day or glimepiride 1-2 mg/day for 12 months as an add-on to metformin. Baseline and end of study body composition evaluations included dual-energy X-ray absorptiometry and abdominal computed tomography scans. RESULTS: Of 124 enrolled patients from 14 centres, 121 received study treatment (dapagliflozin: 60; glimepiride: 61) and 106 (85.5%) completed the study. Over 52 weeks, the dapagliflozin group showed the following differences versus the glimepiride group: -2.59 kg BF mass, -1.94% BF%, -17.55 cm2 VAT area, -18.39 cm2 SAT area, -0.46% glycated haemoglobin, -18.25 mg/dl fasting blood glucose, -3.7 kg weight, -2.21 cm waist circumference, -1.37 kg/m2 body mass index, -6.81 mmHg systolic blood pressure and +657.71 ng/ml in adiponectin; all were statistically significant. Both groups had similar incidences of adverse events; however, hypoglycaemic events were mainly (12 of 15) reported in the glimepiride group. CONCLUSION: Dapagliflozin reduced total BF mass, abdominal VAT and SAT areas, and showed better glycaemic control than glimepiride. Being safe and well-tolerated, dapagliflozin appears to be a more favourable alternative to sulphonylureas as add-on therapy after metformin monotherapy failure in Korean patients with type 2 diabetes.
Asunto(s)
Diabetes Mellitus Tipo 2 , Metformina , Humanos , Metformina/uso terapéutico , Hemoglobina Glucada , Glucemia , Hipoglucemiantes/efectos adversos , Compuestos de Bencidrilo/efectos adversos , Composición Corporal , Quimioterapia Combinada , Método Doble Ciego , Resultado del TratamientoRESUMEN
AIM: To evaluate the safety and effectiveness of uterine fibroid embolization (UFE) in patients with a scarred uterus caused by a previous myomectomy or cesarean section. METHODS: A total of 140 patients who underwent embolization for symptomatic fibroids were included in this retrospective study. The patients were divided into two groups, those with a history of myomectomy and/or cesarean section (scarred uterus group, n = 56), and those without surgical history involving the uterus (no-scar group, n = 84). Demographics, embolization details, outcomes, and complications were analyzed. RESULTS: The overall clinical success rate was 89.28% in the scarred uterus group and 95.24% in the no-scar group. There was no statistical difference in infarction rate or change in fibroid volume in follow-up magnetic resonance imaging between the groups. There was one major complication in the no-scar group, but there was no statistical difference in complications between the groups. The mean follow-up period was 25.9 months. The mean symptom-free time was 27.2 months in the scarred uterus group and 21.9 months in the no-scar group without a significant difference. There were no statistically significant differences in symptom changes, recurrence, and complication rates between the groups. Recurrence seen on imaging or regrowth was more common in the group with myomectomy history. However, there was no significant difference in symptom recurrence rates. CONCLUSION: No statistically significant difference in technical and clinical outcomes was observed between the two groups. There was no significant increase in complication rates of UFE in scarred uterus group.
Asunto(s)
Embolización Terapéutica , Leiomioma , Miomectomía Uterina , Neoplasias Uterinas , Humanos , Femenino , Embarazo , Neoplasias Uterinas/cirugía , Estudios Retrospectivos , Cesárea , Útero/patología , Leiomioma/cirugía , Miomectomía Uterina/efectos adversos , Miomectomía Uterina/métodos , Resultado del TratamientoRESUMEN
Background and Objectives: Type 2 diabetes (T2D) is an independent risk factor for the development of atrial fibrillation (AF). Sodium-glucose cotransporter-2 inhibitors (SGLT-2i) have recently been shown to decrease the incidence of AF through several mechanisms, including the reduction of atrial dilatation via diuresis and the lowering of body weight. In observational studies of diabetic patients, the use of thiazolidinedione (TZD) was found to have a protective effect on new-onset AF. In this study, we aimed to compare the effect of SGLT-2i and TZD on the risk of AF in patients with T2D. Methods: We enrolled 69,122 patients newly prescribed SGLT-2i and 94,262 patients prescribed TZD from January 2014 to December 2018, using the Korean National Health Insurance Service database. We compared new-onset AF events (hospitalizations and outpatient events) in SGLT-2i and TZD groups after having taken medication for greater than 90 days. Results: During a mean follow-up of 1.8 years, 397 (0.72%) new-onset AF events occurred in the SGLT-2i group and 432 (0.79%) events in the TZD group following propensity score matching (each group n = 54,993). The hazard ratio (HR) of AF was 0.918 (95% confidence interval: 0.783-1.076, p = 0.29) in SGLT-2i-treated patients compared with TZD-treated patients. Conclusions: In this study, the risk of new-onset AF is comparable in patients treated with SGLT-2i and TZD in T2D. Either SGLT-2i or TZD would be a reasonable choice for T2D patients who are at risk for AF.
RESUMEN
BACKGROUND: Malignant transformation of endometriosis in extraovarian sites remains rare. Furthermore, the process is not definitely understood. CASE PRESENTATION: Herein, we report the case of a 40-year-old premenopausal nulligravida woman who presented with vaginal bleeding and who was finally diagnosed with a vaginal cancer originating from endometriosis and with a synchronous endometrial cancer. A gynecologic examination revealed a multiple polypoid mass on the posterior vaginal fornix. Magnetic Resonance Imaging of the pelvis showed two masses abutting respectively on the anterior uterine wall, and in the rectovaginal septum. The patient underwent a total laparoscopic excision of the rectovaginal mass, radical hysterectomy and low anterior resection of the rectum. The lesions were diagnosed as endometriosis, endometriosis-associated complex hyperplasia and endometrioid cancer. Furthermore, a synchronous endometrioid endometrial cancer was reported. CONCLUSIONS: This case revealed the multistep process of malignant transformation of deep infiltrating endometriosis. The progression was individualized between implantation sites and in the same organ.
Asunto(s)
Neoplasias Endometriales , Endometriosis , Laparoscopía , Neoplasias Vaginales , Adulto , Neoplasias Endometriales/cirugía , Endometriosis/complicaciones , Endometriosis/cirugía , Femenino , Humanos , Histerectomía , Neoplasias Vaginales/cirugíaRESUMEN
BACKGROUND: Sodium-glucose cotransporter 2 inhibitor (SGLT2i) should be considered for patients with type 2 diabetes (T2D) and chronic kidney disease (CKD) having estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m2 and urine albumin-to-creatinine ratio (UACR) > 30 mg/g. However, SGLT2i is currently underprescribed among eligible, at-risk patients for CKD progression. We analyzed prescription patterns and barriers to initiating SGLT2i in patients with T2D and CKD in real practice. METHODS: A total of 3,703 consecutive outpatients with T2D from four teaching hospitals during six months (2019 ~ 2020) were reviewed. Five eGFR categories (G1, ≥ 90; G2, 60-89; G3ab, 30-59; G4-5, < 30 mL/min/1.73 m2) and three UACR categories (A1, < 30; A2, 30-300; A3, > 300 mg/g) were used to define CKD status. RESULTS: Overall, 25.8 % patients received SGLT2i in the following eGFR and albuminuria categories: G1 (A1, 31 %; A2, 48 %; A3, 45 %); G2 (A1, 18 %; A2, 24 %; A3, 30%); and G3 (A1, 9 %; A2, 7 %; A3, 13 %). Total prevalence estimate of CKD was 33.8 % (n = 1,253), of whom 25.6 % patients received SGLT2i. We defined eGFR ≥ 45 mL/min/1.73 m2 and UACR ≥ 30 mg/g as high-risk CKD group eligible for SGLT2i (n = 905), of whom 32.9 % patients were treated with an SGLT2i. In this high-risk group, SGLT2i initiation showed negative correlations with age ≥ 65 years and recent hospitalization. Conversely, HbA1c level, body mass index (BMI), presence of diabetic retinopathy, and previous heart failure events were positively correlated with SGLT2i initiation. CONCLUSIONS: Only 32.9 % of T2D with CKD eligible for SGLT2i is currently treated with SGLT2i in real-world clinical practice. The older patient group and clinical inertia are the main barriers to initiate SGLT2i for eligible patients. Clinicians should change the glucocentric approach and focus on reducing renal events in T2D.
Asunto(s)
Nefropatías Diabéticas/tratamiento farmacológico , Insuficiencia Renal Crónica/tratamiento farmacológico , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Factores de Edad , Anciano , Diabetes Mellitus Tipo 2/complicaciones , Femenino , Tasa de Filtración Glomerular , Humanos , Masculino , Persona de Mediana EdadRESUMEN
WHAT IS KNOWN AND OBJECTIVE: Age and gender have been reported to play a crucial role in modulating the disposition of pharmacological agents, and to influence the activities of cytochrome P450 (CYP) 2D6, a drug-metabolizing enzyme involved in the disposition of clinically used drugs. In the present study, the effects of age and gender on the CYP2D6 activity were evaluated using dextromethorphan as a probe drug in humans. METHODS: Healthy young (20 < age < 30 years, n = 60) and old age (age >60 years, n = 60) subjects were enrolled and were given 15 mg dextromethorphan orally. Blood samples were collected before and 3 h after medication. Dextromethorphan and its metabolite dextrorphan were measured using HPLC-fluorescence, and dextromethorphan metabolic ratio (MR, log [dextromethorphan/dextrorphan]) was used to evaluate the CYP2D6 activity. RESULTS AND DISCUSSION: Mean (±SD) dextromethorphan MR was -2.42 ± 0.46 for the young male group, -2.28 ± 0.56 for the young female group, -2.46 ± 0.55 for the older male group and -2.34 ± 0.65 for the old female group. Based on our findings, the effects of age and gender on CYP2D6 activity were not statistically significant. WHAT IS NEW AND CONCLUSION: The results of the present study indicate that age and gender play a minor role in the modulation of CYP2D6 activity in the Korean population.
Asunto(s)
Citocromo P-450 CYP2D6/metabolismo , Dextrometorfano/farmacocinética , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Pueblo Asiatico , Dextrometorfano/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , República de Corea , Factores Sexuales , Adulto JovenRESUMEN
Although body composition is related to lung function, few studies have reported the effects of sarcopenic obesity on lung function. Thus, the aim of this study was to investigate the associations between lung function and sarcopenia in the presence and in the absence of obesity. We analyzed nationally representative data of 3044 adults aged > 60 years as collated by the 'Korean National Health and Nutrition Examination Survey 2014-2016. Subjects were classified into four groups: non-sarcopenic non-obese (S-O-), non-sarcopenic obese (S-O+), sarcopenic non-obese (S+O-), and sarcopenic obese (S+O+) according to handgrip strength (GS) and body mass index (BMI). GS was found to be positively associated with forced volume vital capacity (FVC). The S+O+ group had significantly lower FVC values than the S-O- group. Subjects in the S+O+ group were more likely to have restrictive lung disease than those in the S-O- group (odds ratios [ORs] 2.81, 95% confidence interval [CI] 1.72-4.59), and the ORs of restrictive lung disease in S+O+ group were higher than in the S-O+ or S+O- groups. These results were consistent after stratifying by sex and age (61-70 and 71-80). FEV1/FVC ratios (a marker for obstructive lung disease) were not significantly different between S+O+ and S-O- groups. Sarcopenic obesity is associated with a higher risk of restrictive lung disease in Korean elderly.
Asunto(s)
Envejecimiento/fisiología , Pulmón/fisiopatología , Obesidad/fisiopatología , Sarcopenia/fisiopatología , Anciano , Anciano de 80 o más Años , Índice de Masa Corporal , Femenino , Fuerza de la Mano/fisiología , Humanos , Masculino , Persona de Mediana Edad , Músculo Esquelético/fisiopatología , Encuestas Nutricionales , Obesidad/complicaciones , Obesidad/epidemiología , Prevalencia , República de Corea/epidemiología , Pruebas de Función Respiratoria , Sarcopenia/complicaciones , Sarcopenia/epidemiologíaRESUMEN
BACKGROUND AND OBJECTIVE: Varenicline is an effective drug for smoking cessation. The aim of the present study was to compare the pharmacokinetics and safety profiles of two different varenicline formulations (varenicline tartrate (reference) and varenicline oxalate (test)), each containing 1 mg varenicline base in humans. MATERIALS AND METHODS: A randomized, open-label, two-sequence, two-period, single-dose crossover study with a 2-week washout period was conducted with 30 healthy male participants. Blood samples for the pharmacokinetic analysis of varenicline were collected up to 96 hours following the administration of each drug. Pharmacokinetic parameters were also calculated, including the peak plasma concentration (Cmax), area under the plasma concentration-time curve (AUC) from time zero to the time of the last measurable concentration (AUClast) as well as AUC from time zero to infinity (AUCinf). ANOVA for pharmacokinetic equivalence was assessed using log-transformed Cmax and AUC values, and the geometric mean ratios (GMRs) and their 90% confidence intervals (CIs) were assessed as well. The safety profiles were also assessed. RESULTS: 27 participants completed the study. No significant differences were found for any pharmacokinetic parameters of varenicline between the two formulations. The observed average values of Cmax, AUClast, and AUCinf were 4.46 ng/mL, 97.68 ng×h/mL, and 101.60 ng×h/mL for reference and 4.54 ng/mL, 97.10 ng×h/mL, and 100.97 ng×h/mL for test, respectively. The GMRs and 90% CIs for Cmax, AUClast, and AUCinf were 1.0106 (0.9626 - 1.0610), 0.9904 (0.9540 - 1.0282), and 0.9885 (0.9517 - 1.0268), respectively. No clinically relevant changes were observed in the physical, biochemical, hematologic, electrocardiographic, or urinalysis findings during the study, and no serious adverse events were found. CONCLUSION: The results of the present study reveal that varenicline oxalate and varenicline tartrate have similar pharmacokinetic characteristics as varenicline, and that these two formulations exhibit pharmacokinetic equivalence to meet the regulatory criteria. Both varenicline formulations were generally well tolerated.
Asunto(s)
Oxalatos/farmacocinética , Vareniclina/farmacocinética , Área Bajo la Curva , Disponibilidad Biológica , Estudios Cruzados , Humanos , Masculino , Comprimidos , Equivalencia TerapéuticaRESUMEN
Teneligliptin is a recently developed dipeptidyl peptidase-4 (DPP-4) inhibitor for the treatment of type 2 diabetes mellitus. To study simultaneous pharmacokinetics of teneligliptin and its major active metabolite, teneligliptin sulfoxide in human plasma, we developed and validated a LC-MS/MS method. The analytes were detected in the positive mode using multiple reaction monitoring (teneligliptin: m/z 427.2â243.1; teneligliptin-d8 : m/z 435.2â251.3; teneligliptin sulfoxide: m/z 443.2â68.2). The method demonstrated accuracy, precision, and linearity over the concentration range of 5 to 1000 ng/mL for teneligliptin and 2.5 to 500 ng/mL for teneligliptin sulfoxide. The developed method is the first fully validated method capable of simultaneous determination of teneligliptin and its active metabolite, teneligliptin sulfoxide in plasma. The suitability of the method was successfully demonstrated in terms of quantification of teneligliptin and teneligliptin sulfoxide pharmacokinetics in plasma samples collected from healthy volunteers. The measurement of plasma metabolite/parent ratio of teneligliptin was feasible by this method.
Asunto(s)
Cromatografía Liquida/métodos , Pirazoles/sangre , Espectrometría de Masas en Tándem/métodos , Tiazolidinas/sangre , Estabilidad de Medicamentos , Humanos , Límite de Detección , Modelos Lineales , Pirazoles/química , Pirazoles/metabolismo , Pirazoles/farmacocinética , Reproducibilidad de los Resultados , Sulfóxidos/sangre , Sulfóxidos/química , Sulfóxidos/metabolismo , Sulfóxidos/farmacocinética , Tiazolidinas/química , Tiazolidinas/metabolismo , Tiazolidinas/farmacocinéticaRESUMEN
AIM: To evaluate the efficacy and safety of a fixed-dose combination (FDC) of gemigliptin and rosuvastatin in patients with type 2 diabetes and dyslipidaemia. RESEARCH DESIGN AND METHODS: A total of 33 hospitals in Korea participated in this randomized, double-blind trial of diabetic patients with dyslipidaemia. A total of 290 participants were randomly assigned at a 1:1:1 ratio to receive an FDC of gemigliptin (50 mg) and rosuvastatin (20 mg) (GEMI/ROSU FDC group), gemigliptin (50 mg) (GEMI group) or rosuvastatin (20 mg) (ROSU group). Rosuvastatin was up-titrated from 5 to 20 mg/d throughout the study period. Primary efficacy measures were changes in HbA1c and LDL-C from baseline to Week 24 between the GEMI/ROSU FDC and ROSU groups and between the GEMI/ROSU FDC and GEMI groups, respectively. Secondary efficacy measures were changes in HbA1c and LDL-C between the GEMI/ROSU FDC and GEMI groups and between the GEMI/ROSU FDC and ROSU groups, respectively. RESULTS: After 24 weeks of treatment, a significant reduction in HbA1c from baseline was noted in the GEMI/ROSU FDC group (-0.81% of LS mean; P < 0.0001 vs ROSU group), in addition to a significant reduction in LDL-C concentration (-51.9% of LS mean percentage changes, P < 0.0001 vs GEMI group). HbA1c was significantly reduced from baseline in both the GEMI/ROSU FDC and GEMI groups, but the reduction in HbA1c was significantly greater in the GEMI group than in the GEMI/ROSU FDC group, despite receiving the same dose of gemigliptin. The decrease in LDL-C over time was similar between the GEMI/ROSU FDC and ROSU groups. There were no significant differences in adverse events among the groups. CONCLUSION: The FDC of gemigliptin and rosuvastatin is safe and is effective in reducing both blood glucose and LDL-C levels; thus, it could be a good therapeutic choice for type 2 diabetic patients with dyslipidaemia.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Inhibidores de la Dipeptidil-Peptidasa IV , Dislipidemias/tratamiento farmacológico , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Piperidonas , Pirimidinas , Rosuvastatina Cálcica , Anciano , Diabetes Mellitus Tipo 2/complicaciones , Inhibidores de la Dipeptidil-Peptidasa IV/efectos adversos , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Método Doble Ciego , Dislipidemias/complicaciones , Femenino , Hemoglobina Glucada/análisis , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Masculino , Persona de Mediana Edad , Piperidonas/efectos adversos , Piperidonas/uso terapéutico , Pirimidinas/efectos adversos , Pirimidinas/uso terapéutico , Rosuvastatina Cálcica/efectos adversos , Rosuvastatina Cálcica/uso terapéuticoRESUMEN
WHAT IS KNOWN AND OBJECTIVE: Teneligliptin is a DPP-4 inhibitor used for the treatment of type 2 diabetes mellitus, commonly prescribed in combination with glimepiride. Teneligliptin is metabolized by CYP3A4, and glimepiride might be partly metabolized by CYP3A4. The aim of the study was to investigate the possible effect of glimepiride on the pharmacokinetics of teneligliptin in healthy subjects. METHODS: A repeated dose, open-label, fixed-sequence study was conducted in 26 healthy subjects. All participants were administered 20 mg teneligliptin daily for 6 days. On day 7, 4 mg glimepiride was administered together with 20 mg teneligliptin. Plasma teneligliptin concentrations were measured at a steady state, and its pharmacokinetic characteristics were compared without and with glimepiride. RESULTS AND DISCUSSION: No statistically significant difference was found in the effect of glimepiride on teneligliptin pharmacokinetics. The steady-state Cmax,ss values of teneligliptin without and with glimepiride were 207.01 ng/mL and 202.15 ng/mL, respectively. Its AUCτ values at steady-state without and with glimepiride were 1527.8 ng · h/mL and 1578.6 ng · h/mL, respectively. The point estimation of geometric mean ratios (GMR) and the 90% confidence interval for both Cmax,ss and AUCτ were within the equivalence range of 0.8-1.25. The results of the present study revealed that glimepiride did not cause pharmacokinetic interaction with teneligliptin in humans. WHAT IS NEW AND CONCLUSION: Glimepiride did not affect the pharmacokinetic characteristics of teneligliptin in healthy subjects.
Asunto(s)
Interacciones Farmacológicas/fisiología , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/uso terapéutico , Pirazoles/farmacocinética , Compuestos de Sulfonilurea/efectos adversos , Compuestos de Sulfonilurea/uso terapéutico , Tiazolidinas/farmacocinética , Adulto , Diabetes Mellitus Tipo 2/metabolismo , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , República de Corea , Adulto JovenRESUMEN
The aggregation and accumulation of amyloid beta (Aß) peptide is believed to be the primary cause of Alzheimer's disease (AD) pathogenesis. Vitamin D-binding protein (DBP) can attenuate Aß aggregation and accumulation. A biocompatible polymer poly (D,L-lactic acid-co-glycolic acid) (PLGA) can be loaded with therapeutic agents and control the rate of their release. In the present study, a PLGA-based drug delivery system was used to examine the therapeutic effects of DBP-PLGA nanoparticles in Aß-overexpressing (5XFAD) mice. DBP was loaded into PLGA nanoparticles and the characteristics of the DBP-PLGA nanoparticles were analyzed. Using a thioflavin-T assay, we observed that DBP-PLGA nanoparticles significantly inhibited Aß aggregation in vitro. In addition, we found that intravenous injection of DBP-PLGA nanoparticles significantly attenuated the Aß accumulation, neuroinflammation, neuronal loss and cognitive dysfunction in the 5XFAD mice. Collectively, our results suggest that DBP-PLGA nanoparticles could be a promising therapeutic candidate for the treatment of AD.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Portadores de Fármacos/química , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Proteína de Unión a Vitamina D/administración & dosificación , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Animales , Masculino , Ratones , Ratones Transgénicos , Nanopartículas/química , Agregación Patológica de Proteínas/tratamiento farmacológico , Agregación Patológica de Proteínas/metabolismo , Agregación Patológica de Proteínas/patología , Proteína de Unión a Vitamina D/uso terapéuticoRESUMEN
PURPOSE: Tamsulosin is one of the most potent drugs currently available to treat benign prostatic hyperplasia. Cytochrome P450 (CYP) 2D6 and CYP3A are the two major enzymes responsible for tamsulosin metabolism. The purpose of this study was to evaluate the effects of CYP2D6 and CYP3A5 genetic polymorphisms on the pharmacokinetics and hemodynamic effects of tamsulosin in humans. METHODS: Twenty-nine male subjects were enrolled and their CYP2D6 (*2,*4,*5,*10,*14,*21,*41, and *xN) and CYP3A5 (*5) genotypes were screened. Tamsulosin was administered daily for 6 days to assess its steady-state pharmacokinetics and hemodynamic effects according to CYP2D6 and CYP3A5 genotypes. RESULTS: CYP2D6 group 3 (with genotype *10/*10 or *5/*10) exhibited higher plasma levels than CYP2D6 group 1 (with genotype *1/*1,*1/*2,*1/*2xN, or *2/*10xN) or CYP2D6 group 2 (with genotype *1/*10,*1/*41, or *2/*5) (trough concentrations for groups 1, 2, and 3: 1.3, 1.8, and 3.8 ng/mL, respectively [P < 0.001]; peak concentrations for groups 1, 2, 3: 8.3, 10.0, and 13.8 ng/mL, respectively [P < 0.005]). Similarly, CYP2D6 genotypes influenced the hemodynamic effects of tamsulosin based on systolic and diastolic blood pressures. However, the CYP3A5*3 polymorphism did not affect tamsulosin plasma levels and its hemodynamic effects. CONCLUSION: The CYP2D6 but not the CYP3A5 genetic polymorphisms affected the pharmacokinetics and the hemodynamic effects of tamsulosin.
Asunto(s)
Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP3A/genética , Hemodinámica/efectos de los fármacos , Hiperplasia Prostática/tratamiento farmacológico , Tamsulosina , Antagonistas de Receptores Adrenérgicos alfa 1/administración & dosificación , Antagonistas de Receptores Adrenérgicos alfa 1/sangre , Antagonistas de Receptores Adrenérgicos alfa 1/farmacocinética , Adulto , Disponibilidad Biológica , Presión Sanguínea/efectos de los fármacos , Humanos , Masculino , Farmacogenética , Polimorfismo Genético , Hiperplasia Prostática/genética , Tamsulosina/administración & dosificación , Tamsulosina/sangre , Tamsulosina/farmacocinéticaRESUMEN
BACKGROUND/AIM: In research and development of biliary plastic stents (PS), continuous efforts have been made to overcome short patency time and high rate of migration. The aim of this study was to evaluate the patency and migration rate of different PS shapes for a given period of time. METHODS: Using an in vitro bile phantom model, we compared the patency among different shapes of PS (three straight PS, four double-pigtail PS, and a new screw-shaped PS). We performed an analysis of the degree of luminal narrowing by light microscopic examination. Using an in vivo swine model, we compared the patency and migration rate among the three different types of PS. RESULTS: Eight weeks after the bile exposure in the bile flow phantom model, 80 PS were retrieved and analyzed. The straight PS showed less biofilm formation and luminal narrowing than other types of PS (p < 0.05). Forty-nine PS were inserted into the dilated bile ducts of 10 swine models, and 39 PS were successfully retrieved 8 weeks later. The stent migration occurred less frequently in the double-pigtail PS and the screw-shaped PS than it did in the straight PS (11.1, 10, and 27.3%, respectively). However, there was no statistical difference in stent patency among the different shapes. CONCLUSIONS: Stent patency may not be significantly different depending on the shape of PS for 8 weeks. The screw-shaped PS showed similar patency and migration rate to the double-pigtail PS. These results may help guiding future PS development and clinical decisions.
Asunto(s)
Conductos Biliares/cirugía , Dilatación/instrumentación , Diseño de Equipo , Plásticos , Stents , Animales , Dilatación/métodos , Modelos Animales , Fantasmas de Imagen , PorcinosRESUMEN
More than half of all sexual assault victims report experiencing sexual victimization more than once. The aim of this paper was to determine the role post-traumatic cognition plays in the relationship between a history of sexual abuse and post-traumatic stress symptoms in sexual assault victims. The relationship between a history of sexual assault and the severity of post-traumatic stress symptoms was investigated retrospectively using data from a sexual assault crisis center in Korea. Data on psychological symptoms were collected in person at the initial assessment and by telephone 1 month later using the Post-traumatic Cognitions Inventory and the Post-traumatic Stress Disorder Symptoms Scale: Self-report Version. Of 105 women included in the analysis, 10 (9.5%) reported prior sexual abuse and were classified as sexually revictimized. Revictimized women had more post-traumatic negative cognition at initial assessment (t = -2.98; P = 0.004) and more post-traumatic symptoms at 1 month follow-up (t = -2.39; P = 0.019) than singly victimized women. At 1 month follow-up, the severity of post-traumatic stress symptoms had increased in revictimized women but had decreased slightly in singly victimized women. Negative post-traumatic cognition fully mediated the association between a history of sexual abuse and the severity of post-traumatic stress symptoms. Early detection of sexually revictimized women and tailored service and treatment intervention is needed to better serve this group of victims. Interventions targeted at preventing revictimization or post crime victimization may also help victims recover from the trauma and prevent future abuse.
Asunto(s)
Abuso Sexual Infantil/psicología , Cognición/fisiología , Víctimas de Crimen/psicología , Trastornos por Estrés Postraumático/psicología , Adolescente , Adulto , Niño , Bases de Datos Factuales , Femenino , Humanos , Entrevistas como Asunto , Estudios Retrospectivos , Autoinforme , Índice de Severidad de la Enfermedad , Trastornos por Estrés Postraumático/patología , Encuestas y Cuestionarios , Adulto JovenRESUMEN
PURPOSE: To evaluate the effects of increasing the flip angle during the hepatocyte phase of gadobenate dimeglumine-enhanced magnetic resonance imaging (MRI) in cirrhotic patients with hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Sixty-three patients with liver cirrhosis underwent gadobenate dimeglumine-enhanced 1.5T MRI with 90-minute delayed hepatocyte phase with flip angles of 10°, 20°, 30°, consecutively. Relative enhancement and signal-to-noise ratio (SNR) of liver parenchyma at hepatocyte phase according to flip angle were calculated. The liver-to-lesion (low signal intensity HCCs, n = 63; ≥1 cm) and contrast-to-noise ratio (CNR) at the hepatocyte phase according to flip angle were calculated. Two radiologists independently assessed the presence of HCCs using a 5-point scale, and detection sensitivity of HCCs was calculated according to flip angle. RESULTS: The relative enhancement of hepatic parenchyma differed significantly according to flip angle (10°, mean relative enhancement = 0.69 ± 0.46; 20°, mean relative enhancement = 0.63 ± 0.47; 30°, mean relative enhancement = 0.49 ± 0.45; P = 0.043). The SNR of hepatic parenchyma was significantly different according to flip angle (10°, mean SNR = 26.2 ± 5.6; 20°, mean SNR = 25.3 ± 5.7; 30°, mean SNR = 22.8 ± 6.1; P = 0.004). The CNR of lesion was not significantly different according to flip angle (10°, mean CNR = 7.5 ± 6.6; 20°, mean CNR = 10.2 ± 6.9; 30°, mean CNR = 10.1 ± 7.1; P = 0.051). The sensitivities with 10° and 20° for HCCs were significantly higher than those with 30° for one reader (P < 0.05). CONCLUSION: In patients with cirrhosis, hepatocyte phase gadobenate dimeglumine-enhanced 1.5T MRI with 20° flip angle should be recommended rather than 10° and 30° flip angle.
Asunto(s)
Carcinoma Hepatocelular/diagnóstico por imagen , Hepatocitos/citología , Cirrosis Hepática/diagnóstico por imagen , Neoplasias Hepáticas/diagnóstico por imagen , Imagen por Resonancia Magnética , Meglumina/análogos & derivados , Compuestos Organometálicos/química , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Hepatocelular/complicaciones , Carcinoma Hepatocelular/patología , Medios de Contraste/química , Femenino , Humanos , Aumento de la Imagen/métodos , Cirrosis Hepática/complicaciones , Cirrosis Hepática/patología , Neoplasias Hepáticas/complicaciones , Neoplasias Hepáticas/patología , Masculino , Meglumina/química , Persona de Mediana Edad , Radiología , Estudios Retrospectivos , Relación Señal-RuidoRESUMEN
OBJECTIVE: Febuxostat is a selective inhibitor of xanthine oxidase, which is used to manage hyperuricemia in patients with gout. The objective of the study was to compare the pharmacokinetics of two different strength of febuxostat formulations (80 mg and 40 mg). METHODS: A randomized, single-dose, open-label, two-period, two-sequence crossover study with a 7-day washout period was conducted in 30 healthy male subjects. Participants received either reference (1 80 mg) or test (2 40 mg) formulations during the first period and the alternative formulation during the second period. Plasma samples for the drug analysis were collected up to 24 hours after treatment. RESULTS: All pharmacokinetic parameters were comparable between the two formulations The observed mean Cmax, AUC(last), and AUC(∞) values for the reference formulation were 3,670 ng/mL, 12,086 ng x h/mL, and 12,880 ng x h/mL, respectively. Corresponding values for the test formulation were 4,108 ng/mL, 12,689 ng x h/mL, and 13,278 ng x h/mL, respectively. The geometric mean ratios (90% CI) between the two formulations were 1.1273 (1.0286 - 1.2355) for Cmax, 1.054 (1.0115 - 1.0980) for AUC(last), and 1.0395 (0.9959 - 1.0851) for AUC(∞). The changes of serum uric acid at 24 hours after reference and test formations were comparable (-1.36 mg/dL for reference and -1.37 mg/dL for test; p = 0.892). CONCLUSION: The results of the present study indicated that the reference and test formulations have comparable pharmacokinetics and that these two formulations meet the regulatory criteria for bioequivalence. In addition, the reduction of serum UA levels in the reference formulation was similar to that of the test formulation after a single dose.
Asunto(s)
Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/farmacocinética , Supresores de la Gota/administración & dosificación , Supresores de la Gota/farmacocinética , Tiazoles/administración & dosificación , Tiazoles/farmacocinética , Ácido Úrico/sangre , Adulto , Área Bajo la Curva , Biomarcadores/sangre , Estudios Cruzados , Regulación hacia Abajo , Inhibidores Enzimáticos/efectos adversos , Inhibidores Enzimáticos/sangre , Febuxostat , Supresores de la Gota/efectos adversos , Supresores de la Gota/sangre , Semivida , Voluntarios Sanos , Humanos , Modelos Lineales , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Modelos Biológicos , República de Corea , Equivalencia Terapéutica , Tiazoles/efectos adversos , Tiazoles/sangre , Resultado del Tratamiento , Xantina Oxidasa/antagonistas & inhibidores , Xantina Oxidasa/metabolismo , Adulto JovenRESUMEN
BACKGROUND AND OBJECTIVES: Quetiapine is an atypical antipsychotic drug used to treat schizophrenia and acute episodes of mania. Quetiapine is metabolized by CYP3A enzymes including CYP3A5 and is a substrate of P-glycoprotein, an efflux drug transporter encoded by the ABCB1 gene. We assessed the effects of ABCB1 [c.1236C>T (rs1128503), c.2677G>T/A (rs2032582), c.3435C>T (rs1045642)] and CYP3A5*3 (6986A>G) (rs776746) polymorphisms on the pharmacokinetics of quetiapine in humans. MATERIALS AND METHODS: Forty healthy male individuals were enrolled, and their ABCB1 and CYP3A5 polymorphisms were assessed. After a single dose of 100 mg quetiapine was administered, plasma concentrations of quetiapine were measured for 24 h and pharmacokinetic analysis was carried out. RESULTS: The ABCB1 polymorphisms including c.1236C>T, c.2677G>T/A, and c.3435C>>T did not affect plasma levels of quetiapine, and its pharmacokinetic parameters did not differ among ABCB1 genotype groups. However, the CYP3A5*3 polymorphism significantly affected the plasma level of quetiapine and its pharmacokinetics. The peak plasma concentration of quetiapine was 208.39 ng/ml for CYP3A5*1/*1, 243.46 ng/ml for CYP3A5*1/*3, and 332.94 ng/ml for CYP3A5*3/*3 (P=0.0118). The mean AUC(inf) (area under the time vs. concentration curve from 0 to infinity) value was 627.3, 712.77, and 1045.29 ng h/ml, respectively (P=0.0017). CONCLUSION: The results indicated that the genetic polymorphism of CYP3A5*3 but not ABCB1 significantly influences the plasma level of quetiapine and its pharmacokinetics. These findings suggest that the CYP3A5 genetic polymorphism affects the disposition of quetiapine and provide a plausible explanation for interindividual variation in the disposition of this drug.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Antipsicóticos/farmacocinética , Citocromo P-450 CYP3A/genética , Dibenzotiazepinas/farmacocinética , Subfamilia B de Transportador de Casetes de Unión a ATP , Administración Oral , Adulto , Antipsicóticos/sangre , Dibenzotiazepinas/sangre , Frecuencia de los Genes , Genotipo , Voluntarios Sanos , Humanos , Masculino , Polimorfismo de Nucleótido Simple , Fumarato de Quetiapina , Adulto JovenRESUMEN
Type 1 diabetes is a prototypic, organ-specific autoimmune disease. Diverse antigen-specific immunotherapy using insulin or glutamic acid decarboxylase peptides and other immunotherapies, such as antibodies, fusion proteins, cytokines, regulatory T cells, small-molecule inhibitors, nonspecific immune modulators, or dietary modifications, have been attempted in human type 1 diabetes. Some of these immunotherapies delay the onset of diabetes or reduce insulin requirements or blood glucose level in patients with established type 1 diabetes. However, most of these immunotherapies failed to induce complete remission of established type 1 diabetes, which could be due to 1) technical difficulties in the achievement of immune tolerance to diabetic autoantigens or in the inhibition of autoimmune responses to those antigens that can be applied to human patients without significant adverse effects, and 2) markedly reduced ß-cell mass at the time of disease onset that should be replenished. This review focuses on the immunological aspects of the disease and its treatment, and data from previous or ongoing human clinical trials using immune-logical measures, and recent results from immunological studies employing animal models are discussed.