RESUMO
AIM: The main treatment strategy in type 1 cardiorenal syndrome (CRS1) is vascular decongestion. It is probable that sequential blockage of the renal tubule with combined diuretics (CD) will obtain similar benefits compared with stepped-dose furosemide (SF). METHODS: In a pilot double-blind randomized controlled trial of CRS1 patients were allocated in a 1:1 fashion to SF or CD. The SF group received a continuous infusion of furosemide 100 mg during the first day, with daily incremental doses to 200 mg, 300 mg and 400 mg. The CD group received a combination of diuretics, including 4 consecutive days of oral chlorthalidone 50 mg, spironolactone 50 mg and infusion of furosemide 100 mg. The objectives were to assess renal function recovery and variables associated with vascular decongestion. RESULTS: From July 2017 to February 2020, 80 patients were randomized, 40 to the SF and 40 to the CD group. Groups were similar at baseline and had several very high-risk features. Their mean age was 59 ± 14.5 years, there were 37 men (46.2%). The primary endpoint occurred in 20% of the SF group and 15.2% of the DC group (p = 0.49). All secondary and exploratory endpoints were similar between groups. Adverse events occurred frequently (85%) with no differences between groups (p = 0.53). CONCLUSION: In patients with CRS1 and a high risk of resistance to diuretics, the use of CD compared to SF offers the same results in renal recovery, diuresis, vascular decongestion and adverse events, and it can be considered an alternative treatment. ClinicalTrials.gov with number NCT04393493 on 19/05/2020 retrospectively registered.
Assuntos
Síndrome Cardiorrenal/tratamento farmacológico , Síndrome Cardiorrenal/fisiopatologia , Diuréticos/administração & dosagem , Adulto , Clortalidona/administração & dosagem , Clortalidona/efeitos adversos , Diuréticos/efeitos adversos , Método Duplo-Cego , Esquema de Medicação , Feminino , Furosemida/administração & dosagem , Furosemida/efeitos adversos , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos Prospectivos , Espironolactona/administração & dosagem , Espironolactona/efeitos adversos , Resultado do TratamentoRESUMO
AIMS: To compare the blood pressure (BP)-lowering efficacy of a chlorthalidone/amiloride combination pill with losartan, during initial management of JNC 7 Stage I hypertension in patients with type 2 diabetes mellitus. METHODS: In an a priori subgroup analysis of a randomized, double-blind, controlled trial, volunteers aged 30-70 years, with stage I hypertension and diabetes mellitus, were randomized to 12.5/2.5 mg of chlorthalidone/amiloride (N = 47) or 50 mg of losartan (N = 50), and followed for 18 months in 21 clinical centers. If BP remained uncontrolled after three months, study medication dose was doubled, and if uncontrolled after six months, amlodipine (5 and 10 mg) and propranolol (40 and 80 mg BID) were added as open label drugs in a progressive fashion. RESULTS: Systolic BP decreased to a greater extent in participants allocated to diuretics compared to losartan (P < 0.001). After 18 months of follow-up, systolic BP was 128.4 ± 10.3 mmHg in the diuretic group versus 133.5 ± 8.0 in the losartan group (P < 0.01). In the diuretic group, 36 out of 43 participants (83.7%) had a JNC 7 normal BP, compared to 31/47 (66%) in the losartan group (P = 0.089). Serum cholesterol was higher in the diuretic arm at the end of the trial. Other biochemical parameters and reports of adverse events did not differ by treatment. CONCLUSIONS: Treatment of hypertension based on a combination of chlorthalidone and amiloride is more effective for BP lowering compared to losartan in patients with diabetes mellitus and hypertension. TRIAL REGISTRATION: Clinical trials registration number: NCT00971165.
Assuntos
Amilorida/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Clortalidona/administração & dosagem , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipertensão/tratamento farmacológico , Losartan/administração & dosagem , Adulto , Idoso , Amilorida/efeitos adversos , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/efeitos adversos , Brasil , Clortalidona/efeitos adversos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/fisiopatologia , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Hipertensão/complicações , Hipertensão/patologia , Losartan/efeitos adversos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
BACKGROUND: Thiazide diuretics have demonstrated favorable blood pressure lowering efficacy, but the equivalent doses of their more common agents, chlorthalidone and hydrochlorothiazide, are still unclear. Further, concerns exist regarding adverse metabolic effects, which may be attenuated with the concomitant administration of a potassium-sparing diuretic, such as amiloride. This trial aims to investigate the efficacy of chlorthalidone and hydrochlorothiazide, in combination with amiloride at different doses, for initial management of patients with primary hypertension. METHODS/DESIGN: This is a factorial (2 × 2) randomized double-blinded clinical trial comparing the association of a thiazide diuretic (chlorthalidone 25 mg/day or hydrochlorothiazide 50 mg/day) with a potassium-sparing diuretic (amiloride 10 mg/day or amiloride 20 mg/day) in patients with primary hypertension. The primary outcome will be the mean change from baseline in 24-h systolic and diastolic blood pressure measured by ambulatory blood pressure monitoring. The secondary outcomes will be the mean change from baseline in daytime and nighttime systolic and diastolic blood pressure measured by ambulatory blood pressure monitoring, mean change from baseline in systolic and diastolic blood pressure measured by office blood pressure, incidence of adverse events, variation of laboratory parameters, and proportion of patients who achieved blood pressure control. The follow-up will last 12 weeks. For a P alpha of 0.05, power of 80%, standard deviation of 9 mmHg, and absolute difference of 6 mmHg on systolic blood pressure on 24-h ambulatory blood pressure monitoring, it will be necessary to study a total of 76 patients. The sample size will be increased by 10% to compensate for losses, resulting in 84 patients being randomized. DISCUSSION: Diuretics are pivotal drugs for the treatment of hypertension. Chlorthalidone and hydrochlorothiazide, in combination with amiloride in multiple doses, will be tested in terms of blood pressure lowering efficacy and safety. Since the intensity of blood pressure reduction is the major determinant of reduction in cardiovascular risk in hypertensive patients, this study will help to determine which combination of diuretics represents the most appropriate treatment for this population. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03928145. Registered on 25 April 2019. Last update on 29 April 2019.
Assuntos
Amilorida/administração & dosagem , Anti-Hipertensivos/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Clortalidona/administração & dosagem , Hidroclorotiazida/administração & dosagem , Hipertensão/tratamento farmacológico , Inibidores de Simportadores de Cloreto de Sódio/administração & dosagem , Amilorida/efeitos adversos , Anti-Hipertensivos/efeitos adversos , Brasil , Clortalidona/efeitos adversos , Método Duplo-Cego , Combinação de Medicamentos , Humanos , Hidroclorotiazida/efeitos adversos , Hipertensão/diagnóstico , Hipertensão/fisiopatologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Inibidores de Simportadores de Cloreto de Sódio/efeitos adversos , Fatores de Tempo , Resultado do TratamentoRESUMO
Supersaturating drug delivery systems (SDDS), as solid dispersions (SDs), stand out among strategies to enhance bioavailability of poorly soluble drugs. After oral administration, their dissolution in gastrointestinal fluids often leads to supersaturation, which drives to a rapid and sustained absorption. Polymers and surfactants play important roles in SDs through inhibiting precipitation caused by transitions from amorphous into crystalline form, in supersaturated solutions, and also through improving SDs physical stability. Novel chlorthalidone SDs, a BCS IV drug, were developed using polymeric and non-polymeric carriers, specially a polymer-surfactant complex. SDs drug releases were evaluated using sink and non-sink conditions in water and biorelevant medium. Their physical stability was also monitored under different storage conditions. Polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (SOL), sodium lauryl sulfate (SLS) and a combination of both showed promising results in apparent solubility studies, and therefore they were selected to compose the spray dried SDs. Dissolution studies demonstrated the SOL-SLS complex potential for providing chlorthalidone fast release (>80% in 15min), producing and maintaining in vitro supersaturation. This formulation comprising high drug loading (75%) reached a high supersaturation degree under non-sink condition (up to 6-fold the equilibrium solubility) once maintained for 6h in biorelevant medium. In addition, this SD presented better physical stability when compared to the chlorthalidone neat amorphous. The SOL-SLS complex impacts positively on chlorthalidone release and physical stability, highlighting its potential as carrier in SDDS of a poorly soluble drug.
Assuntos
Anti-Hipertensivos/administração & dosagem , Clortalidona/administração & dosagem , Portadores de Fármacos/química , Polietilenoglicóis/química , Polivinil/química , Dodecilsulfato de Sódio/química , Tensoativos/química , Composição de Medicamentos , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , SolubilidadeRESUMO
BACKGROUND: Prehypertension is associated with higher cardiovascular risk, target organ damage, and incidence of hypertension. The Prevention of Hypertension in Patients with PreHypertension (PREVER-Prevention) trial aimed to evaluate the efficacy and safety of a low-dose diuretic for the prevention of hypertension and end-organ damage. METHODS AND RESULTS: This randomized, parallel, double-blind, placebo-controlled trial was conducted in 21 Brazilian academic medical centers. Participants with prehypertension who were aged 30 to 70 years and who did not reach optimal blood pressure after 3 months of lifestyle intervention were randomized to a chlorthalidone/amiloride combination pill or placebo and were evaluated every 3 months during 18 months of treatment. The primary outcome was incidence of hypertension. Development or worsening of microalbuminuria, new-onset diabetes mellitus, and reduction of left ventricular mass were secondary outcomes. Participant characteristics were evenly distributed by trial arms. The incidence of hypertension was significantly lower in 372 study participants allocated to diuretics compared with 358 allocated to placebo (hazard ratio 0.56, 95% CI 0.38-0.82), resulting in a cumulative incidence of 11.7% in the diuretic arm versus 19.5% in the placebo arm (P=0.004). Adverse events; levels of blood glucose, glycosylated hemoglobin, creatinine, and microalbuminuria; and incidence of diabetes mellitus were no different between the 2 arms. Left ventricular mass assessed through Sokolow-Lyon voltage and voltage-duration product decreased to a greater extent in participants allocated to diuretic therapy compared with placebo (P=0.02). CONCLUSIONS: A combination of low-dose chlorthalidone and amiloride effectively reduces the risk of incident hypertension and beneficially affects left ventricular mass in patients with prehypertension. CLINICAL TRIAL REGISTRATION: URL: http://www.ClinicalTrials.gov, www.ensaiosclinicos.gov. Unique identifiers: NCT00970931, RBR-74rr6s.
Assuntos
Amilorida/administração & dosagem , Anti-Hipertensivos/administração & dosagem , Clortalidona/administração & dosagem , Diuréticos/administração & dosagem , Hipertensão/prevenção & controle , Adulto , Idoso , Pressão Sanguínea/efeitos dos fármacos , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Seguimentos , Humanos , Hipertensão/fisiopatologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Hipertrofia Ventricular Esquerda/prevenção & controle , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoAssuntos
Humanos , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Hipertensão/reabilitação , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Clortalidona/administração & dosagem , Espironolactona/administração & dosagem , Hidroclorotiazida/administração & dosagem , Potássio na Dieta/administração & dosagemRESUMO
Resolution of binary mixtures of atenolol (ATE) and chlorthalidone (CTD) with minimum sample pre-treatment and without analyte separation has been successfully achieved, using a new and rapid method based on partial least squares (PLS1) analysis of UV spectral data. The simultaneous determination of both analytes was possible by PLS1 processing of sample absorbances between 255 and 300 nm for ATE and evaluation of absorbances in the 253-268 nm region for CTD. The mean recoveries for synthetic samples were 100.3 +/- 1.0% and 100.7 +/- 0.7% for ATE and CTD, respectively. Application of the proposed method to two commercial tablet preparations in the content uniformity test showed them to contain 103.5 +/- 0.8% and 104.9 +/- 1.8% ATE respectively, as well as 103.4 +/- 1.2% and 104.5 +/- 2.2% CTD. Use of this method also allowed the elaboration of dissolution profiles of the drugs in two commercial combined formulation products, through the simultaneous determination of both drugs during the dissolution test. At the dissolution time of 45 min specified by USP XXIV, both pharmaceutical formulations complied with the test.
Assuntos
Anti-Hipertensivos/análise , Atenolol/análise , Clortalidona/análise , Espectrofotometria Ultravioleta , Algoritmos , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/química , Atenolol/administração & dosagem , Atenolol/química , Calibragem , Clortalidona/administração & dosagem , Clortalidona/química , Combinação de Medicamentos , Reprodutibilidade dos Testes , Espectrofotometria Ultravioleta/normas , ComprimidosRESUMO
The optimal first-line treatment of hypertension has been a contentious issue. Despite the probable advantage of diuretics, which was demonstrated in early clinical trials, concern about their metabolic effects meant that therapy was often commenced with drugs of other types. The results of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), which compared agents of three groups of new antihypertensive drugs with a diuretic, demonstrated the equivalence between these drugs and chlorthalidone (Tenoretic AstraZeneca) in the prevention of incident fatal coronary heart disease and nonfatal myocardial infarction. The diuretic was superior to other drugs in preventing some major secondary end-points, such as cerebrovascular disease and heart failure. These findings, together with other very practical reasons, such as easy administration, few side effects and low cost, demonstrate that diuretics are the first option for drug management of hypertension.
Assuntos
Anti-Hipertensivos/administração & dosagem , Diuréticos/administração & dosagem , Hipertensão/tratamento farmacológico , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Clortalidona/administração & dosagem , Quimioterapia Combinada , Humanos , Hipolipemiantes/administração & dosagem , Lisinopril/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
PURPOSE: To evaluate the hemodynamic effects of low doses of chlorthalidone (CHT) in patients with systemic arterial hypertension (SAH). METHODS: Eight patients with mild SAH, mean age of 52 +/- 8.9 years, 7 men, were studied. Clinical evaluation, systolic (SBP) and diastolic (DBP) blood pressure and heart rate (HR), in supine and standing positions, were obtained before and every two weeks, first two in placebo, during 12 weeks. Laboratory data, hemogram, sodium, potassium, urea, creatinine, glucose, hepatic aminotransferases and urinalysis, were done and at end of study. Hemodynamic monitorization was performed by Swan-Ganz catheter in pulmonary artery to obtain RAP and PAWP, in mmHg. Cardiac output (CO) was obtained by thermodilution method. Systemic vascular resistance (SVR) arose from variables above. Hemodynamic variables were measured at 2nd and 12th weeks during treatment with 50mg of chlorthalidone each 48 h. RESULTS: A significant reduction of SBP (p = 0.005 and p = 0.003), DBP (p < 0.0001 and p < 0.0001), respectively in supine and standing positions. HR did not show statistical difference. At hemodynamic monitoring was observed a significative reduction of SVR (p < 0.02), but not with CO. CONCLUSION: Chlorthalidone in low dosis was effective to treat mild SAH, basically by lowering SVR.
Assuntos
Clortalidona/administração & dosagem , Hemodinâmica/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Adulto , Pressão Sanguínea/efeitos dos fármacos , Débito Cardíaco/efeitos dos fármacos , Clortalidona/uso terapêutico , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resistência Vascular/efeitos dos fármacosRESUMO
Objetivo - Avaliar os efeitos hemodinâmicos de baixas doses de clortalidona em pacientes com hipertensäo arterial sistêmica leve. Métodos - Oito pacientes com hipertensäo arterial sistêmica (HAS) leve, com idade de 52 ñ 8.9 anos, sendo 7 do sexo masculino. Avaliaçäo clínica, medidas da pressäo arterial sistólica (PAS), diastólica (PAD) e da freqüência cardíaca, em posiçöes supina e ortostática, foram obtidas no início e, posteriormente, a cada 2 semanas, durante 12 semanas, sendo as 2 primeiras em uso de placebo. Os exames laboratoriais hemograma, sódio, potássio, uréia, creatinina, glicemia, transaminases hepáticas e urina I, foram realizados no início e no final do estudo. A monitorizaçäo hemodinâmica foi realizada com cateter de Swan-Ganz em artéria pulmonar obtendo-se as pressöes médias de átrio direito, artéria pulmonar e capilar pulmonar, em mmHg. O débito cardíaco (DC) foi obtido pela técnica da termodiluiçäo. Como parâmetro derivado obteve-se a resistência vascular sistêmica (RVS). As medidas foram realizadas nas 2ª (pré) e 12ª (pós) semanas de tratamento com 50mg de clortalidona em dias alternados. Resultados - Observou-se reduçäo significante, nas posiçöes supina e ortostática, da PAS (p = 0,005 e p = 0,003) e PAD (p < 0,001 em ambas as posiçöes). A FC manteve-se inalterada. A monitorizaçäo hemodinâmica observou-se reduçäo estatisticamente significativa da RVS (p < 0,02) e o DC manteve-se inalterado. Conclusäo - A clortalidona em baixas doses mostrou-se eficaz no tratamento da HAS e o mecanismo básico deve-se a reduçäo da RVS
Purpose - To evaluate the hemodynamic effects of low dosis of chlortalidone (CHT) in patients with systemic arterial hypertension (SAH). Methods - Eight patients with mild SAH, mean age of 52± 8.9 years, 7 men, were studied. Clinical evaluation, systolic (SBP) and diastolic (DBP) blood pressure and heart rate (HR), in supine and standing positions, were obtuined before and every two weeks, first two in placebo, during 12 weeks. Laboratory data, hemogram, sodium, potassium, urea, creatinine, glucose, hepatic aminotransferases and urinalysis, were done and at end of study. Hemodynamic monitorization was periormed by Swan-Gans catheter in pulmonary artery to obtain RAP and PAWP, in mmHg. Cardiac output (CO) was obtained by thermodilution method. Systemic vascular resistence (SVR) arised from variables above. Hemodynamic variables were measured at 2nd and 12th weeks during treatment with 50mg of chlorthalidone each 48 h. Results - A significant reduction of SBP (p = 0.005 and p = 0.003), DBP (p < 0.0001 and p < 0.0001), respectively in supine and standing positions. HR did not show statistical diference. At hemodynamic monitoring was observed a signifcative reduction of SVR (p < 0.02), but not with CO. Conclusion - Chlorthalidone in low dosis was effective to treat mild SAH, basically by lowering SVR
Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Clortalidona/administração & dosagem , Hemodinâmica , Hipertensão/tratamento farmacológico , Resistência Vascular/efeitos dos fármacos , Clortalidona/uso terapêutico , Débito Cardíaco , Pressão Arterial , Relação Dose-Resposta a DrogaAssuntos
Clortalidona/administração & dosagem , Hipertensão/tratamento farmacológico , Adulto , Pressão Sanguínea/efeitos dos fármacos , Clortalidona/uso terapêutico , Ensaios Clínicos como Assunto , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Hipopotassemia/induzido quimicamente , Masculino , Pessoa de Meia-IdadeRESUMO
En 20 pacientes con hipertensión arterial esencial leve a moderada se valoró en forma comparativa el efecto antihipertensivo y metabólico de una combinación de 50 mg de hidroclorotiacida con 5 mg de amilorida con el obtenido tras la administración de clorotalidona sola y agregado sales de potasio por vía oral. Cada grupo se formó de 10 enfermos que recibieron indistintamente uno de los medicamentos durante tres meses. Al final del estudio se observó una disminución similar en la tensión arterial media en ambos grupos, con promedio de 25 mm Hg. Sin embargo, los pacientes que recibieron clorotalidona desarrollaron alcalosis y disminución sérica (4.6 + 0.1 a 3.5 + 0.1 mEg/L, p 0.01) e intraglobular de potasio (98 + 1 a 86 + 1.1 mEq/L, p 0.001). La administración oral de sales de potasio sólo originó incremento en la eliminación renal del electrólito, sin modificación del potasio en el suero o en el eritrocito. Los pacientes que recibieron hidroclorotiacida más amilorida no mostraron alteración electrolítica, lo que pone de manifiesto la eficiencia de la amilorida para prevenir esos efectos indeseables de los diuréticos tiacídicos