RESUMO
PURPOSE: This study aimed to evaluate the efficacy and tolerability of irbesartan (IRB) and amlodipine (AML) combination therapy in patients with essential hypertension whose blood pressure (BP) was not controlled by IRB monotherapy. METHODS: Two multicenter, randomized, double-blind, placebo-controlled, phase III studies were conducted in Korea (the I-DUO 301 study and the I-DUO 302 study). After a 4-week run-in period with either 150 mg IRB (I-DUO 301 study) or 300 mg IRB (I-DUO 302 study), patients with uncontrolled BP (ie, mean sitting systolic BP [MSSBP] ≥140 mmHg to <180 mmHg and mean sitting diastolic BP <110 mmHg) were randomized to the placebo, AML 5 mg, or AML 10 mg group. A total of 428 participants were enrolled in the 2 I-DUO studies. In the I-DUO 301 study, 271 participants were randomized in a 1:1:1 ratio to receive either IRB/AML 150/5 mg, IRB/AML 150/10 mg, or IRB 150 mg/placebo. In the I-DUO 302 study, 157 participants were randomized in a 1:1 ratio to receive IRB/AML 300/5 mg or IRB 300 mg/placebo. The primary endpoint was the change in MSSBP from baseline to week 8. Tolerability was assessed according to the development of treatment-emergent adverse events (TEAEs) and clinically significant changes in physical examination, laboratory tests, pulse, and 12-lead electrocardiography. FINDINGS: In I-DUO 301, the mean (SD) changes of MSSBP at week 8 from baseline were -14.78 (12.35) mmHg, -21.47 (12.78) mmHg, and -8.61 (12.19) mmHg in the IRB/AML 150/5 mg, IRB/AML 150/10 mg, and IRB 150 mg/placebo groups, respectively. In I-DUO 302, the mean (SD) changes of MSSBP at week 8 from baseline were -13.30 (12.47) mmHg and -7.19 (15.37) mmHg in the IRB/AML 300/5 mg and IRB 300 mg/placebo groups, respectively. In both studies, all combination groups showed a significantly higher reduction in MSSBP than the IRB monotherapy groups (P < 0.001 for both). TEAEs occurred in 10.00%, 10.99%, and 12.22% of participants in the IRB/AML 150/5 mg, IRB/AML 150/10 mg, and IRB 150 mg/placebo groups, respectively, in I-DUO 301 and in 6.33% and 10.67% of participants in the IRB/AML 300/5 mg and IRB 300 mg/placebo groups, respectively, in I-DUO 302, with no significant between-group differences. Overall, there was one serious adverse event throughout I-DUO study. IMPLICATIONS: The combination of IRB and AML has superior antihypertensive effects compared with IRB alone over an 8-week treatment period, with placebo-like tolerability. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT05476354 (I-DUO 301), NCT05475665 (I-DUO 302).
Assuntos
Anlodipino , Anti-Hipertensivos , Pressão Sanguínea , Quimioterapia Combinada , Hipertensão Essencial , Irbesartana , Humanos , Anlodipino/efeitos adversos , Anlodipino/administração & dosagem , Anlodipino/uso terapêutico , Irbesartana/administração & dosagem , Irbesartana/efeitos adversos , Irbesartana/uso terapêutico , Feminino , Masculino , Pessoa de Meia-Idade , Método Duplo-Cego , Hipertensão Essencial/tratamento farmacológico , Anti-Hipertensivos/efeitos adversos , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Idoso , Resultado do Tratamento , Adulto , República da Coreia , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologiaRESUMO
AIM: To evaluate the long-term safety and efficacy of enavogliflozin 0.3 mg/day added to metformin in patients with type 2 diabetes mellitus. MATERIALS AND METHODS: After 24 weeks of a randomized, double-blind treatment period with enavogliflozin 0.3 mg/day (n = 101) or dapagliflozin 10 mg/day (n = 99) added to metformin, all patients received enavogliflozin 0.3 mg/day plus metformin for an additional 28 weeks during the open-label extension period. RESULTS: Eighty-two patients continued enavogliflozin (maintenance group), and 77 were switched from dapagliflozin to enavogliflozin (switch group). All adverse drug reactions (ADR) were mild in severity. In the maintenance group, ADRs (cystitis and vaginal infection) were reported in two patients (2.44%) during 52 weeks. In the switch group, ADR (hypoglycaemia) was reported in one patient (1.30%) during a 28-week open-label extension period. At week 52, glycated haemoglobin and fasting plasma glucose were significantly lower than at the baseline, by 0.85% and 29.08 mg/dl, respectively, in the maintenance group (p < .0001 for both), and by 0.81% and 32.77 mg/dl, respectively, in the switch group (p < .0001 for both). At week 52, 68.92% of patients from the maintenance group and 64.29% from the switch group achieved glycated haemoglobin <7%. A significant increase in the urine glucose-creatinine ratio was observed at week 52, by 58.81 g/g and 63.77 g/g in the maintenance and switch groups, respectively (p < .0001). CONCLUSIONS: Enavogliflozin added to metformin was tolerated well for up to 52 weeks and provided continual glycaemic control in type 2 diabetes mellitus, along with a significant increase in the urine glucose-creatinine ratio.
Assuntos
Compostos Benzidrílicos , Diabetes Mellitus Tipo 2 , Glucosídeos , Hipoglicemiantes , Metformina , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Compostos Benzidrílicos/efeitos adversos , Compostos Benzidrílicos/uso terapêutico , Benzofuranos , Glicemia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Método Duplo-Cego , Quimioterapia Combinada , Glucosídeos/efeitos adversos , Glucosídeos/uso terapêutico , Glucosídeos/administração & dosagem , Hemoglobinas Glicadas/análise , Hipoglicemia/induzido quimicamente , Hipoglicemia/epidemiologia , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/uso terapêutico , Hipoglicemiantes/administração & dosagem , Metformina/efeitos adversos , Metformina/uso terapêutico , Metformina/administração & dosagem , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/administração & dosagem , Resultado do TratamentoRESUMO
Parkinson's disease (PD) is characterized by slow, progressive degeneration of dopaminergic neurons in the substantia nigra. The cause of neuronal death in PD is largely unknown, but several genetic loci, including leucine-rich repeat kinase 2 (LRRK2), have been identified. LRRK2 has guanosine triphosphatase (GTPase) and kinase activities, and mutations in LRRK2 are the major cause of autosomal-dominant familial PD. Histone deacetylases (HDACs) remove acetyl groups from lysine residues on histone tails, promoting transcriptional repression via condensation of chromatin. Here, we demonstrate that LRRK2 binds to and directly phosphorylates HDAC3 at Ser-424, thereby stimulating HDAC activity. Specifically, LRRK2 promoted the deacetylation of Lys-5 and Lys-12 on histone H4, causing repression of gene transcription. Moreover, LRRK2 stimulated nuclear translocation of HDAC3 via the phoshorylation of karyopherin subunit α2 and α6. HDAC3 phosphorylation and its nuclear translocation were increased in response to 6-hydroxydopamine (6-OHDA) treatment. LRRK2 also inhibited myocyte-specific enhancer factor 2D activity, which is required for neuronal survival. LRRK2 ultimately promoted 6-OHDA-induced cell death via positive modulation of HDAC3. These findings suggest that LRRK2 affects epigenetic histone modification and neuronal survival by facilitating HDAC3 activity and regulating its localization.
Assuntos
Encéfalo/patologia , Neurônios Dopaminérgicos/patologia , Histona Desacetilases/metabolismo , Histonas/metabolismo , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/metabolismo , Neuritos/patologia , Neuroblastoma/patologia , Acetilação , Animais , Encéfalo/metabolismo , Sobrevivência Celular , Células Cultivadas , Neurônios Dopaminérgicos/metabolismo , Embrião de Mamíferos/metabolismo , Embrião de Mamíferos/patologia , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Células HEK293 , Histona Desacetilases/genética , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Neuritos/metabolismo , Neuroblastoma/metabolismo , Fosforilação , RatosRESUMO
Mutations in the parkin gene underlie a familial form of Parkinson's disease known as autosomal recessive juvenile Parkinsonism (AR-JP). Dysfunction of parkin, a ubiquitin E3 ligase, has been implicated in the accumulation of ubiquitin proteasome system-destined substrates and eventually leads to cell death. However, regulation of parkin enzymatic activity is incompletely understood. Here we investigated whether the ubiquitin E3 ligase activity of parkin could be regulated by neddylation. We found that parkin could be a target of covalent modification with NEDD8, a ubiquitin-like posttranslational modifier. In addition, NEDD8 attachment caused an increase of parkin activity through the increased binding affinity for ubiquitin-conjugating E2 enzyme as well as the enhanced formation of the complex containing parkin and substrates. These findings point to the functional importance of NEDD8 and suggest that neddylation is one to the diverse modes of parkin regulation, potentially linking it to the pathogenesis of AR-JP.
Assuntos
Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinas/metabolismo , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacologia , Animais , Células Cultivadas , Cicloeximida/farmacologia , Embrião de Mamíferos , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Hipocampo/citologia , Humanos , Imunoprecipitação , Leupeptinas/farmacologia , Mutação/genética , Proteína NEDD8 , Neuroblastoma/patologia , Neurotoxinas/farmacologia , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/genética , Inibidores da Síntese de Proteínas/farmacologia , RNA Interferente Pequeno/farmacologia , Ratos , Sincalida/metabolismo , Células-Tronco , Frações Subcelulares/efeitos dos fármacos , Frações Subcelulares/metabolismo , Fatores de Tempo , Transfecção , Ubiquitina-Proteína Ligases/genética , Ubiquitinação/efeitos dos fármacos , Ubiquitinação/fisiologia , Ubiquitinas/genéticaRESUMO
A sequential injection analysis (SIA) system was developed to monitor the concentration of l-cysteine in biological processes on-line. It is based on the redox reaction of l-cysteine with iron(III) in the presence of 1,10-phenanthroline (phen) and the detection of the red-iron(II)-phen complex with a spectrophotometry. The system was fully automated using software written in the LabVIEWtrade mark development environment. A number of system variables such as the flow rate of the carrier buffer solution, the volume ratio of the sample to the reagents, and the reaction coil length, etc., were evaluated to increase the sensitivity and performance of the SIA system. Under partially optimized operating conditions the performance of the SIA system was linear up to a concentration of l-cysteine of 1mM (R(2)=0.998) with a detection limit of 0.005mM and a sample frequency of 15hr(-1). The SIA system was employed to monitor the concentration of l-cysteine on-line in a continuously stirred reactor and a fermentation process of Saccharomyces cerevisiae. The on-line monitored data were in good agreement with the off-line data measured by a HPLC with a fluorescence detector (n=15, R(2)=09899).