RESUMO
BACKGROUND: In China, the prevalence of hypertension is high and the use of combination antihypertensive therapy is low, which contributes to inadequate blood pressure (BP) control. The availability of simplified treatments combining complementary BP-lowering agents may help more patients achieve their goals. METHODS: This Phase III, multicenter, randomized, double-blind, noninferiority study included Chinese adults with mild-to-moderate hypertension. Following a 1-month run-in on perindopril/indapamide bi-therapy, patients with uncontrolled systolic/diastolic BP (≥140/90âmmHg) were randomized to perindopril 5âmg/indapamide 1.25 mg/amlodipine 5âmg (Per/Ind/Aml) single-pill combination (SPC) or perindopril 4âmg/indapamide 1.25 mg plus amlodipine 5âmg (Per/Ind + Aml) for 6âmonths. Uptitration was permitted from month 2 onwards. The primary efficacy objective was the noninferiority of Per/Ind/Aml in lowering office systolic BP at 2âmonths. The secondary objectives included the effectiveness of SPC on diastolic BP, uptitration efficacy, and office BP control (systolic/diastolic <140/90âmmHg). A subgroup of patients participated in 24-h ambulatory BP monitoring (ABPM). RESULTS: A total of 532 patients were randomized: Per/Ind/Aml ( n â=â262) and Per/Ind + Aml ( n â=â269). Overall, the mean (±SD) age was 55.7â±â8.8âyears, 60.7% were male, and the mean office systolic/diastolic BP at baseline on Per/Ind was 150.4/97.2âmmHg. Systolic BP decreased in both groups at 2âmonths from baseline: -14.99â±â14.46âmmHg Per/Ind/Aml versus -14.49â±â12.87âmmHg Per/Ind +Aml. A predefined noninferiority margin of 4âmmHg was observed ( P â<â0.001). The effectiveness of the Per/Ind/Aml SPC was also demonstrated for all secondary endpoints. ABPM demonstrated sustained BP control over 24âh. Both treatments were well tolerated. CONCLUSIONS: Per/Ind/Aml is an effective substitute for Per/Ind + Aml, providing at least equivalent BP control over 24âh in a single pill, with comparable safety.
Assuntos
Anlodipino , Anti-Hipertensivos , Hipertensão , Indapamida , Perindopril , Humanos , Anlodipino/administração & dosagem , Anlodipino/efeitos adversos , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Indapamida/administração & dosagem , Indapamida/uso terapêutico , Masculino , Pessoa de Meia-Idade , Método Duplo-Cego , Perindopril/administração & dosagem , Perindopril/uso terapêutico , Feminino , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/uso terapêutico , Anti-Hipertensivos/efeitos adversos , Idoso , Resultado do Tratamento , Pressão Sanguínea/efeitos dos fármacos , China , Adulto , Combinação de Medicamentos , Quimioterapia Combinada , População do Leste AsiáticoRESUMO
Previous studies showed that postmenopausal women are more likely to have poorly controlled hypertension than men of the same age. Whether this is caused by inadequate treatment or poor response to antihypertensive agents remains unknown. The aim of this study is to analyze treatment response to the most potent renin angiotensin aldosterone system (RAAS) inhibitor perindopril in different age categories in women and men. Individual patient data were used from the combined European Trial on Reduction of Cardiac Events With Perindopril (EUROPA), Perindopril Protection Against Recurrent Stroke Study (PROGRESS), and Action in Diabetes and Vascular disease: Preterax and Diamicron-MR Controlled Evaluation (ADVANCE) trials, which include patients with vascular disease (n = 29,463). We studied the relative and absolute changes in systolic blood pressure (SBP) and diastolic blood pressure (DBP) during a 4-week run-in phase in which all patients were treated with the perindopril-based treatment in different age categories. In total, 8366 women and 21,097 men were included in the analysis. Women greater than 65 years of age showed a significantly smaller blood pressure reduction after perindopril treatment (2.8 mmHg [95% confidence interval {CI} = 0.1-5.5] less reduction compared to women ≤45 years, p = 0.039). In men, the SBP reduction after perindopril in patients greater than 55-65 and greater than 65 years was lower compared to the age category less than or equal to 45 years (adjusted mean difference >55-65: 2.8 mmHg [95% CI = 1.8-3.7], p < 0.001, >65: 3.7 mmHg [95% CI = 2.7-4.7], p < 0.001). A trend of less blood pressure reduction was seen with ageing in both men and women (p < 0.001). To conclude, we observed that in both women and men the perindopril leads to less SBP reduction with increasing age, whereas the DBP reduction increases with age. More research is needed to determine whether it would be beneficial to use age-adjusted perindopril dosages.
Assuntos
Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Perindopril/administração & dosagem , Perindopril/farmacologia , Adulto , Fatores Etários , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de SaúdeRESUMO
Lots of studies showed the combination therapy of perindopril, indapamide and amlodipine could increase BP lowering efficacy and the benefits of high-risk patients. To evaluate potential pharmacokinetic interaction, a simultaneous UPLC-MS/MS quantification method of perindopril, perindoprilat and indapamide in human plasma was developed and validated. The plasma samples were prepared by solid phase extraction, and then separated on an X-terra MS C18 (2.1 mm × 150 mm, 3.5 µm) with isocratic elution. The ion transitions at m/z 369.165 â 172.000 (perindopril), m/z 341.146 â 170.112 (perindoprilat), m/z 366.010 â 132.100 (indapamide), m/z 389.120 â 206.200 (S10211-1, IS1) and m/z 394.080 â 160.200 (S1641, IS2) were monitored under the positive ion mode of electrospray ionization with multiple reaction monitoring. This method exhibited great sensitivity, linearity, accuracy, and precision for the determination of perindopril, perindoprilat and indapamide over the range of 0.250-50.0 ng/mL. The average extraction recovery of perindopril, perindoprilat and indapamide samples at low, medium, and high concentration levels were between 85.9% and 93.6%, respectively. The stability of analytes over different storage and processing conditions in the whole study was also validated. The method is fast, accurate, sensitive and reproducible, which is suitable for the detection of the concentration of perindopril, perindoprilat and indapamide in human plasma.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Indapamida/sangue , Indóis/sangue , Perindopril/sangue , Espectrometria de Massas em Tandem/métodos , Estudos Cross-Over , Combinação de Medicamentos , Humanos , Indapamida/administração & dosagem , Indapamida/química , Indapamida/farmacocinética , Indóis/química , Indóis/farmacocinética , Modelos Lineares , Masculino , Perindopril/administração & dosagem , Perindopril/química , Perindopril/farmacocinética , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Extração em Fase SólidaRESUMO
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
AIMS: Coronary microvascular dysfunction (CMD) represents a powerful independent predictor of adverse outcome in hypertrophic cardiomyopathy (HCM). No treatment for CMD exists. The angiotensin-converting enzyme (ACE)-inhibitor perindopril improves myocardial blood flow (MBF) in animal models of cardiac hypertrophy and in hypertensive patients. Whether HCM patients with CMD may benefit is unknown. METHODS: Fourteen HCM patients aged 18-60 years with CMD [MBF post 0.56âmg/kg dipyridamole (Dip) infusion <2.1âml/min∗g] were included. Presence of left ventricular outflow obstruction, hypertension and coronary artery disease were exclusion criteria. Perindopril was administered after the initial Dip 13N-NH3 PET study at 10âmg for 6 months. After wash-out, a second PET was performed. MBF before and after treatment was compared. RESULTS: No relevant associations were found between baseline MBF values and sex, genetics, history of angina, type of HCM (apical/classic), maximum left ventricular thickness and left ventricular mass. No significant improvement in Dip-MBF was observed with treatment (1.79â±â0.30 vs.1.76â±â0.26âml/min∗g at baseline; Pâ=â0.59). A limited but significant improvement in Dip-MBF was seen only in the subset without evidence of fibrosis at cardiac MRI (nâ=â4; 28%; 2.03â±â0.13 vs.1.77â±â0.26âml/min∗g at baseline; Pâ=â0.014). The drug was generally well tolerated: only one patient temporarily stopped the drug, because of cough. CONCLUSION: A 6-month perindopril treatment course in HCM patients with CMD was not associated with significant improvement in Dip-MBF. A limited but significant improvement was observed only in the subset of patients without myocardial fibrosis, suggesting potential utility in early disease stages.
Assuntos
Cardiomiopatia Hipertrófica , Circulação Coronária/efeitos dos fármacos , Oclusão Coronária/tratamento farmacológico , Microcirculação/efeitos dos fármacos , Perindopril , Tomografia por Emissão de Pósitrons/métodos , Adulto , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/farmacocinética , Cardiomiopatia Hipertrófica/complicações , Cardiomiopatia Hipertrófica/fisiopatologia , Oclusão Coronária/diagnóstico , Oclusão Coronária/etiologia , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Masculino , Perindopril/administração & dosagem , Perindopril/farmacocinética , Resultado do TratamentoRESUMO
In the care of a cardiovascular risk patient there is certainly a more frequent situation in which we try to influence several risk factors at the same time. Treatment of a single self-occurring risk factor is rather an exception. In most cases, we need to intervene with more risk factors, often involving combination therapy, which can achieve the desired goals more quickly and reliably. However, with the number of tablets taken by the patient, the patients willingness to take long-term and correct use decreases, which has a significant impact on the effectiveness of therapy and the development of individual cardiovascular risk. In an effort to control all risk factors for cardiovascular disease, there is a growing need to extend the availability of fixed drug formulations to suit the patients ease of use and suitably formulated with varying dose grades to meet the needs of our attending physicians. With regard to the fact that early intervention of risk factors brings greater benefits than deferred, we are looking for appropriate ways to manage it. The current intervention of arterial hypertension and dyslipidemia with safe and proven drugs seems to be one of the ways to further improve the results of the prevention of cardiovascular diseases. The new fixed combination of atorvastatin with perindopril, which is entering the Czech market right now, appears to be in many ways an ideal “tablet for cardiovascular prevention”.
Assuntos
Anti-Hipertensivos , Doenças Cardiovasculares , Hipertensão , Anlodipino , Anti-Hipertensivos/administração & dosagem , Atorvastatina/administração & dosagem , Pressão Sanguínea , Doenças Cardiovasculares/prevenção & controle , Combinação de Medicamentos , Humanos , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Perindopril/administração & dosagemAssuntos
Anti-Hipertensivos/administração & dosagem , População Negra , Hipertensão/tratamento farmacológico , Hipertensão/etnologia , Anlodipino/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Bloqueadores dos Canais de Cálcio/administração & dosagem , Pesquisa Comparativa da Efetividade , Ensaios Clínicos Controlados como Assunto , Quimioterapia Combinada , Humanos , Hidroclorotiazida/administração & dosagem , Perindopril/administração & dosagemRESUMO
Poor blood pressure (BP) control contributes to complications in sub-Saharan African (SSA) type 2 diabetic individuals. Experts have advocated the use of combination therapies for effective BP control in these patients. The suggested combinations should include a RAAS antagonist and either a CCB or a thiazide diuretic; however, their efficacy is yet to be established in SSA. We investigated the short-term effects of two combination therapies on BP control in SSA type 2 diabetic individuals. This was a double-blinded randomized controlled trial conducted at the Yaoundé Central Hospital (Cameroon) from October 2016 to May 2017. We included type 2 diabetic patients, newly diagnosed for hypertension. After baseline assessment and 24-hour ABPM, participants were allocated to receive either a fixed combination of perindopril + amlodipine or perindopril + indapamide for 42 days. Data analyses followed the intention-to-treat principle. We included fifteen participants (8 being females) in each group. Both combinations provided good circadian BP control after 6 weeks with similar efficacy. Twenty-four-hour SBP dropped from 144 to 145 mm Hg vs 128 to 126 mm Hg with perindopril-amlodipine and perindopril-indapamide, respectively (P = 0.003 for both groups). Twenty-four-hour DBP dropped from 85 to 78 mm Hg (P = 0.013) vs 89 to 79 mm Hg (P = 0.006) in the same respective groups. No significant adverse effect was reported. A fixed initial combination of perindopril-amlodipine or perindopril-indapamide achieved similar effective BP control after 6 weeks in SSA type 2 diabetic individuals with newly diagnosed hypertension. Therefore, these combinations can be used interchangeably in this indication.
Assuntos
Anlodipino , Diabetes Mellitus Tipo 2 , Hipertensão , Indapamida , Perindopril , África Subsaariana/epidemiologia , Anlodipino/administração & dosagem , Anlodipino/efeitos adversos , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/efeitos adversos , Pressão Sanguínea/efeitos dos fármacos , Monitorização Ambulatorial da Pressão Arterial/métodos , Comorbidade , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Método Duplo-Cego , Combinação de Medicamentos , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Hipertensão/diagnóstico , Hipertensão/tratamento farmacológico , Hipertensão/epidemiologia , Indapamida/administração & dosagem , Indapamida/efeitos adversos , Masculino , Pessoa de Meia-Idade , Perindopril/administração & dosagem , Perindopril/efeitos adversos , Resultado do TratamentoRESUMO
Purpose: Endoglin is a transmembrane glycoprotein which plays an important role in maintaining cardiovascular homeostasis. One of its forms, soluble endoglin (sEng), a molecule with antiangiogenic properties, has been found overexpressed in patients suffering from hypercholesterolemia, diabetes mellitus and hypertension, and is proposed as a marker of endothelial damage. Accordingly, we aimed to quantify the efficacy of various antihypertensive regimens on sEng levels, in hypertensive patients with endothelial dysfunction. Patients and methods: 323 patients were enrolled, and there were 99 patients with normal blood pressure values, 106 hypertensive patients under chronic treatment with different types of antihypertensive molecules (beta blockers, calcium channel blockers, and diuretics) in monotherapy, and 118 hypertensive patients under chronic treatment with perindopril. sEng plasma levels were quantified and were correlated with classical methods of assessing the endothelial damage. Results: Patients under chronic treatment with perindopril had lower sEng plasma levels compared with the other group of hypertensive patients under different regimens of antihypertensive treatment (sEng: 4.73±1.39 versus 5.63±2.33, p<0.01). Conclusion: Decreased sEng plasma levels were found in patients under chronic treatment with perindopril, when compared with other antihypertensive regimens of treatment (beta blockers, calcium channel blockers, and/or diuretics).
Assuntos
Anti-Hipertensivos/farmacologia , Endoglina/antagonistas & inibidores , Endotélio Vascular/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Perindopril/farmacologia , Anti-Hipertensivos/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Estudos Transversais , Endoglina/sangue , Endotélio Vascular/metabolismo , Feminino , Humanos , Hipertensão/metabolismo , Masculino , Pessoa de Meia-Idade , Perindopril/administração & dosagem , SolubilidadeRESUMO
AIMS: To evaluate 1,5-anhydroglucitol (1,5-AG) according to clinical outcomes and assess the effects of glucose- and blood pressure-lowering interventions on change in 1,5-AG levels in people with type 2 diabetes. METHODS: We measured 1,5-AG in 6826 stored samples at baseline and in a random subsample of 684 participants at the 1-year follow-up visit in the ADVANCE trial. We examined baseline 1,5-AG [< 39.7, 39.7-66.2, ≥ 66.2 µmol/L (<6, 6-10, ≥10 µg/mL)] and microvascular and macrovascular events and mortality using Cox regression models during 5 years of follow-up. Using an intention-to-treat approach, we examined 1-year change in 1,5-AG (mean and percent) in response to the glucose- and blood pressure-lowering interventions in the subsample. RESULTS: Low 1,5-AG level [<39.7 µmol/L vs ≥ 66.2 µmol/L (<6 µg/mL vs ≥10 µg/mL)] was associated with microvascular events (hazard ratio 1.28, 95% confidence interval 1.03-1.60) after adjustment for risk factors and baseline glycated haemoglobin (HbA1c); however, the associations for macrovascular events and mortality were not independent of HbA1c. The glucose-lowering intervention was associated with a significant 1-year increase in 1,5-AG (vs standard control) of 6.69 µmol/L (SE 2.52) [1.01 µg/mL (SE 0.38)], corresponding to an 8.26% (SE 0.10%) increase from baseline. We also observed an increase in 1,5-AG of similar magnitude in response to the blood pressure intervention independent of the glucose-lowering effect. CONCLUSIONS: Our results suggest that 1,5-AG is a marker of risk in adults with type 2 diabetes, but only for microvascular events independently of HbA1c. We found that 1,5-AG was improved (increased) in response to an intensive glucose-lowering intervention, although the independent effect of the blood pressure-lowering intervention on 1,5-AG suggests potential non-glycaemic influences.
Assuntos
Anti-Hipertensivos/administração & dosagem , Desoxiglucose/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipertensão/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Idoso , Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/complicações , Quimioterapia Combinada , Feminino , Gliclazida/administração & dosagem , Hemoglobinas Glicadas/efeitos dos fármacos , Humanos , Hipertensão/complicações , Indapamida/administração & dosagem , Análise de Intenção de Tratamento , Masculino , Microvasos/efeitos dos fármacos , Pessoa de Meia-Idade , Perindopril/administração & dosagem , Modelos de Riscos Proporcionais , Fatores de Risco , Resultado do TratamentoRESUMO
The optimal blood pressure (BP) goal in patients with diabetes mellitus remains controversial. We examined whether benefits and risks of intensified antihypertensive therapy in diabetes mellitus are influenced by either baseline BP or cardiovascular disease (CVD) risk. We studied 10 948 people with diabetes mellitus, at moderate-to-high risk, in the ADVANCE trial (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation). Cox models were used to determine whether baseline BP category or CVD risk modified the outcomes of combination perindopril-indapamide treatment, compared with placebo. During 4.3 years of follow-up, treatment with perindopril-indapamide versus placebo reduced mortality and major vascular (macrovascular or microvascular) events. There was no evidence of differences in these effects, regardless of baseline systolic BP (evaluated down to <120 mm Hg; P for heterogeneity, 0.85), diastolic BP (evaluated down to <70 mm Hg; P=0.49), or whether 10-year CVD risk was ≥20% or <20% ( P=0.08). The effects of randomized treatment on discontinuation of treatment because of cough or hypotension/dizziness were also statistically consistent across subgroups defined by baseline BP and CVD risk (all P ≥0.08). Adults with diabetes mellitus appear to benefit from more intensive BP treatment even at levels of BP and CVD risk that some guidelines do not currently recommend for intervention. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT00751972.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Doenças Cardiovasculares/etiologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Indapamida/administração & dosagem , Perindopril/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Anti-Hipertensivos/administração & dosagem , Pressão Sanguínea/fisiologia , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/fisiopatologia , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Feminino , Seguimentos , Saúde Global , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Taxa de Sobrevida/tendências , Resultado do TratamentoRESUMO
BACKGROUND: Angiotensin-converting enzyme inhibitors and calcium channel blockers in combination are widely recommended in hypertension guidelines. The advantages of single-pill combinations (SPCs) are increasingly recognized, so a dosage-adapted combination of perindopril and amlodipine was developed for the initial management of hypertension. OBJECTIVE: This randomized trial evaluated the blood pressure (BP)-lowering efficacy of four incremental doses of perindopril/amlodipine SPC in adults with mild-to-severe hypertension. METHODS: Eligible patients (N = 1617) were randomized to SPC perindopril 3.5 mg/amlodipine 2.5 mg (i.e., 3.5/2.5 mg) daily, uptitrating as required on a monthly basis up to 14/10 mg until BP < 140/90 mmHg (< 130/80 mmHg in patients with diabetes). The primary endpoint (proportion with controlled BP at each uptitrated dose) was evaluated at 6 months, and safety was evaluated at 9 months; 24-h ambulatory BP measurement and BP variability were also investigated. Control-arm participants (n = 1653) were randomized to irbesartan 150 mg daily, uptitrating over 3 months to irbesartan/hydrochlorothiazide 300/25 mg. RESULTS: Significant increases in BP control were observed with each dosage increment of perindopril/amlodipine, which was well tolerated, rising from 21% (3.5/2.5 mg) to 30% (7/5 mg), 37% (14/5 mg), and 42% (14/10 mg) after 1, 2, 3, and 6 months, respectively. Reductions in mean systolic and diastolic BP occurred with each incremental dose of perindopril/amlodipine. After 6 months, mean BP had fallen by 24.8/10.8 mmHg. Irbesartan-based therapy reduced clinic and 24-h BP similarly to perindopril/amlodipine, but perindopril/amlodipine reduced BP variability more in comparison. CONCLUSIONS: Incremental uptitration with dosage-adapted perindopril/amlodipine SPC is a safe and effective strategy for managing hypertension. TRIAL REGISTRATION: EudraCT (No. 2006-005799-42).
Assuntos
Anlodipino/administração & dosagem , Anti-Hipertensivos/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Perindopril/administração & dosagem , Idoso , Anlodipino/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Anti-Hipertensivos/efeitos adversos , Bloqueadores dos Canais de Cálcio/administração & dosagem , Bloqueadores dos Canais de Cálcio/efeitos adversos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Humanos , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Perindopril/efeitos adversos , Índice de Gravidade de DoençaRESUMO
BACKGROUND: The prevalence of hypertension among black African patients is high, and these patients usually need two or more medications for blood-pressure control. However, the most effective two-drug combination that is currently available for blood-pressure control in these patients has not been established. METHODS: In this randomized, single-blind, three-group trial conducted in six countries in sub-Saharan Africa, we randomly assigned 728 black patients with uncontrolled hypertension (≥140/90 mm Hg while the patient was not being treated or was taking only one antihypertensive drug) to receive a daily regimen of 5 mg of amlodipine plus 12.5 mg of hydrochlorothiazide, 5 mg of amlodipine plus 4 mg of perindopril, or 4 mg of perindopril plus 12.5 mg of hydrochlorothiazide for 2 months. Doses were then doubled (10 and 25 mg, 10 and 8 mg, and 8 and 25 mg, respectively) for an additional 4 months. The primary end point was the change in the 24-hour ambulatory systolic blood pressure between baseline and 6 months. RESULTS: The mean age of the patients was 51 years, and 63% were women. Among the 621 patients who underwent 24-hour blood-pressure monitoring at baseline and at 6 months, those receiving amlodipine plus hydrochlorothiazide and those receiving amlodipine plus perindopril had a lower 24-hour ambulatory systolic blood pressure than those receiving perindopril plus hydrochlorothiazide (between-group difference in the change from baseline, -3.14 mm Hg; 95% confidence interval [CI], -5.90 to -0.38; P = 0.03; and -3.00 mm Hg; 95% CI, -5.8 to -0.20; P = 0.04, respectively). The difference between the group receiving amlodipine plus hydrochlorothiazide and the group receiving amlodipine plus perindopril was -0.14 mm Hg (95% CI, -2.90 to 2.61; P=0.92). Similar differential effects on office and ambulatory diastolic blood pressures, along with blood-pressure control and response rates, were apparent among the three groups. CONCLUSIONS: These findings suggest that in black patients in sub-Saharan Africa, amlodipine plus either hydrochlorothiazide or perindopril was more effective than perindopril plus hydrochlorothiazide at lowering blood pressure at 6 months. (Funded by GlaxoSmithKline Africa Noncommunicable Disease Open Lab; CREOLE ClinicalTrials.gov number, NCT02742467.).
Assuntos
Anlodipino/administração & dosagem , Anti-Hipertensivos/administração & dosagem , Hidroclorotiazida/administração & dosagem , Hipertensão/tratamento farmacológico , Perindopril/administração & dosagem , Adulto , África Subsaariana , Idoso , Anlodipino/efeitos adversos , Anti-Hipertensivos/efeitos adversos , População Negra , Pressão Sanguínea/efeitos dos fármacos , Combinação de Medicamentos , Quimioterapia Combinada , Feminino , Humanos , Hidroclorotiazida/efeitos adversos , Hipertensão/etnologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Perindopril/efeitos adversos , Método Simples-CegoRESUMO
BACKGROUND: Despite the overwhelming evidence and the established benefits of antihypertensive treatment, adherence to treatment remains low. OBJECTIVE: To assess the adherence to treatment with a perindopril/indapamide/amlodipine single-pill combination (SPC), its effectiveness on blood pressure (BP) reduction, as well as the safety and tolerability of this SPC over a 4-month treatment period. METHODS: This multicenter, non-interventional study prospectively included 2285 hypertensive patients on perindopril/indapamide/amlodipine SPC. The data were recorded at baseline, 1 month, and 4 months. RESULTS: Of the 2285 hypertensive patients included in the study, 50.5% were at "high/very high risk". Mean systolic (SBP)/diastolic (DBP) decreased from 162.3 ± 13.3/93.1 ± 9.3 mmHg at baseline to 129.7 ± 8.3/78.6 ± 7.1 mmHg at 4 months (p < 0.001). Patients with higher baseline BP levels showed greater BP reduction. Patients with hypertension stages 1, 2, and 3 showed mean SBP/DBP reductions of 21.5/10.4 mmHg, 34.2/14.7 mmHg, and 51.2/22.5 mmHg, respectively, at study end (p < 0.001). Only 26 patients (1.1%) prematurely discontinued treatment (0.58% due to an adverse reaction or event). CONCLUSIONS: Perindopril/indapamide/amlodipine SPC decreased BP levels rapidly and significantly. The degree of BP reduction was associated with the severity of hypertension and/or with total cardiovascular risk at baseline. Simplifying the drug regimen by using this SPC improved adherence and showed excellent tolerability.
Assuntos
Anlodipino/administração & dosagem , Anti-Hipertensivos/administração & dosagem , Hipertensão/tratamento farmacológico , Indapamida/administração & dosagem , Adesão à Medicação , Perindopril/administração & dosagem , Adulto , Idoso , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Combinação de Medicamentos , Feminino , Grécia/epidemiologia , Humanos , Hipertensão/diagnóstico , Hipertensão/epidemiologia , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
Current research work was conducted to synthesize Thiol modified arabinoxylan and its application in fabrication of hydrogel. Thioglycolic acid was esterified with arabinoxylan to prepare Thiolatedarabinoxylan. Appearance of peak at 2533.34 cm-1 in FTIR and thiol content showed successful thiolation. The pH-dependent Thiolatedarabinoxylan/acrylic acid (TAX/AA) hydrogels of perindopril erbumine were prepared via free-radical co-polymerization. Perindopril erbumine (PE) was employed as model drug. Different batches with different feed ratio of TAX, AA, and MBA were prepared and their influence on swelling, solvent penetration, and consequent drug release was investigated. Swelling coefficients increased with increase in pH. TAX/AA hydrogels were characterized by Fourier-transform infrared spectroscopy (FT-IR), Thermal Analysis (TA), X-Ray diffraction (XRD), and scanning electron microscope (SEM). Dissolution studies were performed at pH 1.2 and 7.4 in which drug release showed direct correlation with TAX and AA ratio. In vivo studies showed that Cmax of TAX-co-AA based hydrogel was 81.57 ± 0.35 ng/ml which was maintained for a longer time after its administration. All the results of in vivo studies were significant and TAX-co-AA based hydrogel enhances the bioavailability of perindopril erbumine.
Assuntos
Acrilatos/química , Portadores de Fármacos/química , Perindopril/farmacocinética , Xilanos/química , Animais , Disponibilidade Biológica , Liberação Controlada de Fármacos , Hidrogéis/química , Concentração de Íons de Hidrogênio , Perindopril/administração & dosagem , Plantago/química , Coelhos , Tioglicolatos/química , Xilanos/isolamento & purificaçãoRESUMO
Discontinuation of angiotensin-converting enzyme (ACE) inhibitor is recommended if patients experience ≥30% acute increase in serum creatinine after starting this therapy. However, the long-term effects of its continuation or discontinuation on major clinical outcomes after increases in serum creatinine are unclear. In the ADVANCE trial (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation), 11 140 diabetes mellitus patients were randomly assigned to perindopril-indapamide or placebo after a 6-week active run-in period. The current study included 11 066 participants with 2 serum creatinine measurements recorded before and during the active run-in period (3 weeks apart). Acute increase in creatinine was determined using these 2 measurements and classified into 4 groups: increases in serum creatinine of <10%, 10% to 19%, 20% to 29%, and ≥30%. The primary study outcome was the composite of major macrovascular events, new or worsening nephropathy, and all-cause mortality. An acute increase in serum creatinine was associated with an elevated risk of the primary outcome ( P for trend <0.001). The hazard ratios were 1.11 (95% CI, 0.97-1.28) for those with an increase of 10% to 19%, 1.34 (1.07-1.66) for 20% to 29%, and 1.44 (1.15-1.81) for ≥30%, compared with <10%. However, there was no evidence of heterogeneity in the benefit of randomized treatment effects on the outcome across subgroups defined by acute serum creatinine increase ( P for heterogeneity=0.94). Acute increases in serum creatinine after starting perindopril-indapamide were associated with greater risks of subsequent major clinical outcomes. However, the continuation of angiotensin-converting enzyme inhibitor-based therapy reduced the long-term risk of major clinical outcomes, irrespective of acute increase in creatinine. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT00145925.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Doenças Cardiovasculares/prevenção & controle , Creatinina/sangue , Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas/prevenção & controle , Indapamida , Perindopril , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/mortalidade , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/diagnóstico , Combinação de Medicamentos , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Indapamida/administração & dosagem , Indapamida/efeitos adversos , Masculino , Conduta do Tratamento Medicamentoso , Pessoa de Meia-Idade , Perindopril/administração & dosagem , Perindopril/efeitos adversos , Medição de Risco , Resultado do Tratamento , Suspensão de TratamentoRESUMO
Although anticancer systemic therapy agents clearly lead to improved survival in patients with cancer, these can come at the cost of serious complications including cardiotoxicity. Two types of targeted systemic therapies currently in use for colorectal cancer (CRC) and renal cell cancer (RCC), respectively, include the vascular endothelial growth factor inhibitor bevacizumab (BVZ) and the tyrosine kinase inhibitor sunitinib (SNT). Despite the beneficial effects of BVZ and SNT in improving clinical outcomes in the settings of CRC and RCC, there is an increased risk of cardiac dysfunction. The aim of the present study was to determine whether prophylactic administration of renin-angiotensin system (RAS) inhibitors would attenuate the cardiotoxic side effects of BVZ or SNT in a chronic in vivo murine model. A total of 194 wild-type C57Bl/6 male mice received: 1) 0.9% saline, 2) BVZ (10 mg·kg-1·wk-1), or 3) SNT (40 mg·kg-1·day-1) for 4 wk. Within each arm, mice received daily prophylactic treatment with hydralazine (0.05 mg/ml), aliskiren (50 mg/kg), perindopril (4 mg/kg), or valsartan (2 mg/kg). Although hydralazine effectively lowered blood pressure in BVZ- or SNT-treated mice, it did not prevent left ventricular systolic dysfunction. Prophylactic administration of aliskiren, perindopril, or valsartan prevented adverse cardiovascular remodeling in mice treated with either BVZ or SNT. The addition of RAS antagonists also downregulated expression of phosphorylated p38 and Bcl-2-like 19-kDa interacting protein 3 in SNT-treated mice. In our chronic in vivo murine model, RAS antagonists partially attenuated the development of BVZ- or SNT-mediated cardiac dysfunction. Future clinical studies are warranted to investigate the cardioprotective effects of prophylactic treatment with RAS inhibitors in the settings of CRC and RCC. NEW & NOTEWORTHY In the evolving field of cardio-oncology, bevacizumab and sunitinib improve clinical outcomes in the settings of metastatic colorectal cancer and renal cell cancer, respectively. These anticancer drugs, however, are associated with an increased risk of cardiotoxicity. The prophylactic administration of renin-angiotensin system antagonists is partially cardioprotective against bevacizumab- and sunitinib-mediated cardiac dysfunction.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Antineoplásicos/toxicidade , Sistema Renina-Angiotensina , Disfunção Ventricular/prevenção & controle , Amidas/administração & dosagem , Amidas/uso terapêutico , Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Animais , Anti-Hipertensivos/administração & dosagem , Bevacizumab/toxicidade , Cardiotoxicidade , Fumaratos/administração & dosagem , Fumaratos/uso terapêutico , Hidralazina/administração & dosagem , Hidralazina/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Perindopril/administração & dosagem , Perindopril/uso terapêutico , Sunitinibe/toxicidade , Valsartana/administração & dosagem , Valsartana/uso terapêutico , Disfunção Ventricular/tratamento farmacológico , Disfunção Ventricular/etiologiaRESUMO
PURPOSE: Regorafenib is an oral multi-kinase inhibitor that offers an OS benefit to patients with mCRC refractory to standard therapy (Grothey et al., in Lancet 381:303-312, 2013), but comes with potential significant toxicities including grade 3 hand-foot skin reaction (HFSR). The pathogenesis of regorafenib-induced HFSR is not well established, but may be related to alterations in the capillary endothelium. We hypothesized that perindopril, an angiotensin-converting enzyme (ACE) inhibitor, indicated for the treatment of hypertension (Ceconi et al., in Cardiovasc Res 73:237-246, 2007), and which plays a role in preventing endothelial dysfunction, may help to prevent or reduce the severity of regorafenib-induced HFSR. PATIENTS AND METHODS: In this single-center phase II open-label trial, patients with refractory mCRC were treated with both regorafenib (160 mg/day) and perindopril (4 mg/day) for 21 days per 28-day cycle. The primary end point was to assess the proportion of patients with any grade HFSR toxicity. Secondary end points included time to development of worst (grade 3) HFSR, reduction of all grades of hypertension and all grade toxicities, as well as progression-free survival. All toxicities were evaluated using CTCAE v4.03. RESULTS: A planned interim analysis was performed after ten evaluable patients had completed their first cycle of study treatment. As 50% (5/10) experienced grade 3 HFSR, enrolment was stopped as the addition of perindopril did not lead to a reduced level of HFSR compared with regorafenib alone. Other grade 3 toxicities included hypertension (16.7%) and increased AST (16.7%). CONCLUSION: The addition of an ACE inhibitor perindopril to regorafenib did not reduce HFSR incidence or severity in patients with refractory mCRC.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Síndrome Mão-Pé/prevenção & controle , Perindopril/administração & dosagem , Compostos de Fenilureia/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Idoso , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Resistencia a Medicamentos Antineoplásicos , Feminino , Síndrome Mão-Pé/epidemiologia , Síndrome Mão-Pé/etiologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Compostos de Fenilureia/uso terapêutico , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêutico , Índice de Gravidade de DoençaRESUMO
BACKGROUND AND OBJECTIVES: Management of hypertension and dyslipidemia is important when considering cardiovascular disease risk; however, achievement of optimal lipid and blood pressure (BP) targets in clinical practice remains inadequate. This analysis sought to estimate the frequency, effectiveness, and safety of co-administrated atorvastatin and perindopril in routine care. METHODS: We conducted a post hoc analysis of four Canadian, prospective, multi-center, observational studies assessing real-life effectiveness and safety of perindopril + atorvastatin in mild-to-moderate hypertensive patients with concomitant dyslipidemia over 16 weeks. The safety population comprised patients receiving one or more doses of free combination perindopril + atorvastatin; the full analysis set (FAS) received perindopril + atorvastatin at baseline, with one or more post-baseline systolic BP measurements while on treatment. RESULTS: A total of 3541 and 3172 patients were included in the safety population and FAS, respectively. At the last observation carried forward, significant reductions in mean systolic BP (- 18.0 mmHg; p < 0.001) and diastolic BP (- 8.9 mmHg; p < 0.001) were observed; target BP was achieved by 73.1% of patients. Emergent adverse events (AEs) were reported in 8.0% of patients, the most common being cough (4.5% of patients), headache (0.9%), and dizziness (0.8%). Four serious AEs were reported among three (0.1%) patients. No differences were observed in effectiveness or safety between studies. CONCLUSIONS: Concomitant perindopril + atorvastatin therapy demonstrated similar efficacy across all studies, with significant reductions in BP and achievement of target BP levels observed in a real-world setting. Results align with known safety profiles of atorvastatin and perindopril, with no unexpected AEs observed when compared with data from treatment with the individual drugs.
Assuntos
Anti-Hipertensivos/farmacologia , Atorvastatina/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Perindopril/farmacologia , Administração Oral , Idoso , Anti-Hipertensivos/administração & dosagem , Atorvastatina/administração & dosagem , Canadá , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Perindopril/administração & dosagem , Estudos Prospectivos , Resultado do TratamentoRESUMO
BACKGROUND AND PURPOSE: The endocannabinoid (EC) system has been implicated in the pathogenesis of diabetic nephropathy (DN). We investigated the effects of peripheral blockade of the cannabinoid CB1 receptor as an add-on treatment to ACE-inhibition in type 1 diabetic mice (DM) with established albuminuria. EXPERIMENTAL APPROACH: Renal functional parameters (albumin excretion rate, creatinine clearance), tubular injury, renal structure, both EC and CB receptor levels and markers of podocyte dysfunction, fibrosis and inflammation were studied in streptozotocin-induced DM treated for 14 weeks with vehicle, the ACE-inhibitor perindopril (2 mg·kg-1 ·day-1 ), peripherally-restricted CB1 receptor antagonist AM6545 (10 mg·kg-1 ·day-1 ) or both. Treatments began at 8 weeks after diabetes onset, when early DN is established. KEY RESULTS: CB1 receptors were overexpressed in DM and neither perindopril nor AM6545 altered this effect, while both drugs abolished diabetes-induced overexpression of angiotensin AT1 receptors. Single treatment with either AM6545 or perindopril significantly reduced progression of albuminuria, down-regulation of nephrin and podocin, inflammation and expression of markers of fibrosis. However, reversal of albuminuria was only observed in mice administered both treatments. The ability of the combination therapy to completely abolish slit diaphragm protein loss, monocyte infiltration, overexpression of inflammatory markers and favour macrophage polarization towards an M2 phenotype may explain this greater efficacy. In vitro experiments confirmed that CB1 receptor activation directly inhibits retinoic acid-induced nephrin expression in podocytes and IL-4-induced M2 polarization in macrophages. CONCLUSION AND IMPLICATIONS: Peripheral CB1 receptor blockade used as add-on treatment to ACE-inhibition reverses albuminuria, nephrin loss and inflammation in DM.