RESUMO
BACKGROUND: To evaluate the bioequivalence between test and reference formulations of perindopril tert-butylamine under fasting and fed conditions and to assess their pharmacokinetic (PK) and safety profiles. METHOD: A randomized, open-label, single-dose, crossover trial was conducted in healthy Chinese subjects. Test or reference perindopril tert-butylamine tablets (4 mg) were randomly given to subjects under fasting (2-period crossover, with an administration sequence of test tablet (T), reference tablet (R) or RT) and fed (4-period crossover, with an administration sequence of TRTR or RTRT) conditions, while each single administration was followed by a 14-day washout period. The plasma concentrations and corresponding non-compartmental PK parameters of perindopril and perindoprilat were determined. The two formulations were considered to be bioequivalent if the 90 % confidence intervals (CIs) of the geometric mean (GM) ratio (test/reference) for Cmax, AUC0-t, and AUC0-∞ (perindopril) was both within the range of 80-125 %. Safety assessments including vital signs, physical examination, laboratory examination, 12-lead ECG and reports of treatment emergent adverse events (TEAEs) were carefully documented. RESULTS: A total of 64 subjects (32 in each trial) were randomized and all completed the trials. Regardless of fasting or fed trials, the PK characteristics of perindopril and perindoprilat for the test formulation were similar to those of the reference formulation (all P > 0.05). The 90 % CIs of the geometric mean (GM) ratio for Cmax, AUC0-t, and AUC0-∞, respectively, were 92.86-106.81 %, 98.44-102.88 % and 98.48-103.02 % under the fasting condition and 90.64-110.04 %, 96.95-101.90 % and 96.83-101.78 % under the fed condition, which were both within the pre-specified range of 80-125 %. A total of 10 (31.3 %) fasted subjects and 11 (34.4 %) fed subjects experienced 11 and 24 TEAEs, respectively, all of which were within the severity of grade 1. The incidence of TEAEs and drug-related TEAEs were similar between test and reference formulations (all P > 0.05) and no serious TEAEs or deaths occurred during the trials. CONCLUSIONS: The test and reference formulations of perindopril tert-butylamine tablets (4 mg) were bioequivalent and well tolerated in healthy Chinese subjects under fasting and fed conditions.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacocinética , Anti-Hipertensivos/farmacocinética , Butilaminas/farmacocinética , Medicamentos Genéricos/farmacocinética , Perindopril/análogos & derivados , Perindopril/farmacocinética , Administração Oral , Adulto , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/efeitos adversos , Butilaminas/administração & dosagem , Butilaminas/efeitos adversos , China , Estudos Cross-Over , Composição de Medicamentos , Medicamentos Genéricos/administração & dosagem , Medicamentos Genéricos/efeitos adversos , Jejum/sangue , Feminino , Humanos , Masculino , Perindopril/administração & dosagem , Perindopril/efeitos adversos , Período Pós-Prandial , Comprimidos , Equivalência Terapêutica , Adulto JovemRESUMO
A series of phosphonate analogues related to perindopril and ramipril were prepared and tested to estimate their ability to inhibit angiotensin converting enzyme. These new synthesized compounds were active ACE inhibitors with a promising activity.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/química , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Organofosfonatos/química , Perindopril/análogos & derivados , Perindopril/farmacologia , Ramipril/análogos & derivados , Ramipril/farmacologia , Inibidores da Enzima Conversora de Angiotensina/síntese química , Inibidores da Enzima Conversora de Angiotensina/metabolismo , Sítios de Ligação , Domínio Catalítico , Ativação Enzimática/efeitos dos fármacos , Humanos , Simulação de Acoplamento Molecular , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/metabolismo , Perindopril/síntese química , Perindopril/metabolismo , Ligação Proteica , Ramipril/síntese química , Ramipril/metabolismo , EstereoisomerismoRESUMO
The aim of the study was to estimate the efficiency of combination therapy with Preductal and Prestarium after MI. We investigated 152 patients with acute MI of anterior wall (Q wave) and Heart Failure (II-III class by NYHA). I group included 92 p, which were treated by Preductal (60 mg daily) on the background of the standard therapy. II group (60 p) treated by standard therapy. (ACE inhibitor, diuretic, beta-blocks). We divided the patients in 2 subgroups, with EF>45% and EF<45%. Echo investigation was performed after 1,3,6.12 months from the beginning of MI. We estimated LV EDV and ESV, EF, FS, SV and diastolic function. 12 month after myocardial infarction decreases of average heart failure and angina classes. After 6,12 months was noted decreased EDV and ESV, increased EF, FS,SV in both groups confidence, but spatially in the I gr. Patients, who had EF<45% and were treated with Preductal improved EF with 30,1%(p<0,05) confidence, which was 1,5 times more then in the control gr, also increased FS and SV by 32,7%, 13,6% p<0,05. At the same time was observed diastolic function improvement, particular decreased Ve, Ve/Va, and increased Va specially in the Preductal group more intensive and confidence. The treatment with Preductal during 12 months indicates his positive influence on the LV systolic and diastolic function, which is most significant in the patients with low EF.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/tratamento farmacológico , Perindopril , Trimetazidina , Vasodilatadores/farmacologia , Vasodilatadores/uso terapêutico , Função Ventricular Esquerda/efeitos dos fármacos , Idoso , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Perindopril/análogos & derivados , Perindopril/farmacologia , Perindopril/uso terapêutico , Trimetazidina/análogos & derivados , Trimetazidina/farmacologia , Trimetazidina/uso terapêuticoRESUMO
Transforming growth factor (TGF)-beta is believed to play a key role in the development of many autoimmune and malignant diseases, such as radiation and drug-induced organ disease. The aim of the present study was to determine messenger RNA (mRNA) production of TGF-beta 1 in the lungs of C57Bl6 mice after low-dose whole-body irradiation. Control (irradiated) and irradiated angiotensin-converting enzyme (ACE) inhibitor-treated animals were simultaneously examined. The ACE inhibitor group received butylaminiperindopril for 9 days after irradiation (7 Gy) at a daily dose of 0.1 mg/kg per rectum. On day 9 all mice were sacrificed and the production of mRNA TGF-beta 1 in lung tissue was determined semiquantitatively using reverse transcriptase polymerase chain reaction. In butylaminiperindopril-treated mice, a decrease in transcript of TGF-beta 1 (to 59% in comparison with controls) was observed.