RESUMEN

BACKGROUND: Activation of neurohormonal systems contributes to the progression of heart failure (HF). The mechanism(s) whereby these systems become activated is(are) not fully explained. We determined whether vagal cardiopulmonary baroreflex control of renal sympathetic nerve activity is abnormal in dogs with left ventricular (LV) dysfunction in the absence of clinical HF, and the relationship of abnormalities in baroreflexes to the development of the neurohumoral excitatory state. METHODS: LV end-systolic and end-diastolic dimensions (echocardiography), arterial baroreflex sensitivity (slope of ΔRR/Δsystolic BP during phenylephrine or nitroglycerin bolus), and neurohumoral profiles (plasma norepinephrine, renin activity, and arginine vasopressin) were measured serially in conscious dogs (n=24) with progressive LV dysfunction due to rapid ventricular pacing. LV dimensions were used to define groups with mild, moderate, and marked LV dilatation (LVD; increase in LV end-diastolic volume <15%, 15-30%, and >30% of control, respectively). Changes in renal nerve activity (RNA) were recorded in response to increases in pulmonary capillary wedge pressure (PCWP) induced by volume infusion in anesthetized, sinoaortic-denervated dogs. RESULTS: Cardiopulmonary baroreflex sensitivity (slope of %ΔRNA/ΔPCWP) for mild LVD (-17.8%/mmHg) was the same as controls (-17.7%/mmHg). However, the slopes of moderate (-5.8%/mmHg) and severe LVD (-1.9%/mmHg) were decreased significantly compared with controls (P < .05). Arterial baroreflex sensitivity was preserved at all stages of LVD. Plasma norepinephrine, renin activity, and arginine vasopressin remained unchanged after 4, 7, and 11 days of pacing. CONCLUSIONS: Vagal cardiopulmonary baroreflex control of renal sympathetic nerve activity is blunted early in the development of LVD. These abnormalities precede neurohumoral excitation and abnormal arterial baroreflexes and become apparent when LV end-diastolic volume starts to increase.

Asunto(s)

Barorreflejo/fisiología , Insuficiencia Cardíaca , Riñón/inervación , Sistema Nervioso Parasimpático/fisiopatología , Sistema Nervioso Simpático/fisiopatología , Animales , Presión Sanguínea/fisiología , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Perros , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/fisiopatología , Frecuencia Cardíaca/fisiología , Mecanorreceptores/fisiología , Transmisión Sináptica/fisiología

RESUMEN

BACKGROUND: Recommendations differ regarding how blood pressure targets should vary with age. Crucial to this controversy is whether treatment benefit varies with age. METHODS: Systematic searches were conducted for trials randomizing treatment in intensive arms to the recommended SBP targets: 120-140 mmHg. Head-to-head meta-analyses and meta-regression were conducted. RESULTS: Sixteen trials met criteria. Relative to higher targets, lower targets reduced cardiovascular events, but treatment benefit differed significantly among trials due to patient age. Treatment significantly benefited older patients (mean age 77, SD = 72-81), relative risk (RR) = 0.77 (0.61,0.97), P = 0.025, but not younger patients (mean age 61, SD = 53-70), RR = 0.90 (0.78,1.03), P = 0.121, even though the latter had much greater statistical power. The (RR in 80 year olds)/(RR in 55 year olds) = 0.68 (0.47,0.97), P = 0.036. Though statistically nonsignificant, corresponding trends for more specific outcomes favored older patients: Coronary artery disease 0.80, stroke 0.85, heart failure 0.54, and total mortality 0.76. For adverse effects this trend was 0.86 (0.33,2.26). The number needed to treat to lower targets to prevent one cardiovascular event over 10 years in eight populations declined with age by 94%+. CONCLUSION: In these novel results, for both RR and absolute risk, treating to SBPs of 120-140 mmHg versus higher targets benefited older patients more than younger patients without an age-related increase in the RR for adverse effects. Nonetheless, because all clinical trials excluded the most frail older patients, clinicians must consider individual patient characteristics such as frailty, autonomy, and cognitive ability when choosing blood pressure targets.

Asunto(s)

Antihipertensivos , Presión Sanguínea/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Antihipertensivos/efectos adversos , Antihipertensivos/farmacología , Antihipertensivos/uso terapéutico , Humanos , Persona de Mediana Edad , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del Tratamiento

Asunto(s)

Determinación de la Presión Sanguínea/instrumentación , Calibración , Humanos , Reproducibilidad de los Resultados , Estados Unidos , United States Food and Drug Administration

RESUMEN

Left ventricular hypertrophy develops in 36%-41% of hypertensive patients and independently predicts cardiovascular events and total mortality. Moreover, drug-induced reduction in left ventricular mass (LVM) correlates with improved prognosis. The optimal thiazide-type diuretic for reducing LVM is unknown. Evidence regarding potency, cardiovascular events, sodium, and potassium suggested the hypothesis that "CHIP" diuretics (CHlorthalidone, Indapamide, and Potassium-sparing diuretic/hydrochlorothiazide [PSD/HCTZ]) would reduce LVM more than HCTZ. Systematic searches of five databases were conducted. Among the 38 randomized trials, a 1% reduction in systolic blood pressure (SBP) predicted a 1% reduction in LVM, P = 0.00001. CHIP-HCTZ differences in reducing LVM differed across trials (ie, heterogeneity), making interpretation uncertain. However, among the 28 double-blind trials, heterogeneity was undetectable, and HCTZ reduced LVM (percent reduction [95% CI]) by -7.3 (-10.4, -4.2), P < 0.0001. CHIP diuretics surpassed HCTZ in reducing LVM: chlorthalidone -8.2 (-14.7, -1.6), P = 0.015; indapamide -7.5 (-12.7, -2.3), P = 0.005; and all CHIP diuretics combined -7.7 (-12.2, -3.1), P < 0.001. The comparison of PSD/HCTZ with HCTZ had low statistical power but favored PSD/HCTZ: -6.0 (-14.1, +2.1), P = 0.149. Thus, compared to HCTZ, CHIP diuretics had twice the effect on LVM. CHIP diuretics did not surpass HCTZ in reducing systolic or diastolic blood pressure: -0.3 (-5.0, +4.3) and -1.6 (-5.6, +2.4), respectively. The strength of evidence that CHIP diuretics surpass HCTZ for reducing LVM was high (GRADE criteria). In conclusion, these novel results have demonstrated that CHIP diuretics reduce LVM 2-fold more than HCTZ among hypertensive patients. Although generally related to LVM, blood pressure fails to explain the superiority of CHIP diuretics for reducing LVM.

Asunto(s)

Clortalidona/farmacología , Diuréticos Conservadores de Potasio/farmacología , Hidroclorotiazida/farmacología , Hipertensión/tratamiento farmacológico , Hipertrofia Ventricular Izquierda/tratamiento farmacológico , Indapamida/farmacología , Antihipertensivos/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Clortalidona/administración & dosificación , Clortalidona/uso terapéutico , Diuréticos Conservadores de Potasio/administración & dosificación , Diuréticos Conservadores de Potasio/uso terapéutico , Quimioterapia Combinada/métodos , Femenino , Humanos , Hidroclorotiazida/administración & dosificación , Hidroclorotiazida/uso terapéutico , Hipertensión/complicaciones , Hipertensión/fisiopatología , Hipertrofia Ventricular Izquierda/epidemiología , Hipertrofia Ventricular Izquierda/fisiopatología , Hipertrofia Ventricular Izquierda/prevención & control , Indapamida/administración & dosificación , Indapamida/uso terapéutico , Masculino , Persona de Mediana Edad , Ensayos Clínicos Controlados Aleatorios como Asunto , Inhibidores de los Simportadores del Cloruro de Sodio/farmacología , Tiazidas/farmacología , Tiazidas/uso terapéutico

RESUMEN

Parenteral diuretics form the cornerstone of decongestion in heart failure. However, parenteral therapy routinely requires emergency room or inpatient care. A novel buffered furosemide formulation with neutral pH was developed to offer "hospital-strength" diuresis for outpatient use, including self-administration at home. Subcutaneous infusion using a biphasic delivery profile resulted in complete bioavailability (99.65%) and equivalent diuresis when compared with intravenous administration. Subcutaneous administration of buffered furosemide was well tolerated with no evidence of any drug-induced skin reactions. Subcutaneous infusion of buffered furosemide in the outpatient setting or home may help to reduce the burden of heart failure.

Asunto(s)

Antihipertensivos/uso terapéutico , Insuficiencia de la Válvula Aórtica/cirugía , Presión Sanguínea/fisiología , Puente de Arteria Coronaria , Implantación de Prótesis de Válvulas Cardíacas , Hipertensión/etiología , Insuficiencia de la Válvula Mitral/cirugía , Anciano , Válvula Aórtica/cirugía , Insuficiencia de la Válvula Aórtica/complicaciones , Frecuencia Cardíaca/fisiología , Humanos , Hipertensión/tratamiento farmacológico , Hipertensión/fisiopatología , Masculino , Válvula Mitral/cirugía , Insuficiencia de la Válvula Mitral/complicaciones , Periodo Posoperatorio , Función Ventricular Izquierda/fisiología

RESUMEN

BACKGROUND: Found in 36-41% of hypertension, elevated left ventricular mass (LVM) independently predicts cardiovascular events and total mortality. Conversely, drug-induced regression of LVM predicts improved outcomes. Previous studies have favored renin-angiotensin system inhibitors (RASIs) over other antihypertensives for reducing LVM but ignored differences among thiazide-type diuretics. From evidence regarding potency, cardiovascular events, and electrolytes, we hypothesized a priori that 'CHIP' diuretics [CHlorthalidone, Indapamide and Potassium-sparing Diuretic/hydrochlorothiazide (PSD/HCTZ)] would rival RASIs for reducing LVM. METHOD AND RESULTS: Systematic review yielded 12 relevant double-blind randomized trials. CHIPs were more closely associated with reduced LVM than HCTZ (P = 0.004), indicating that RASIs must be compared with each diuretic separately. Publication bias favoring RASIs was corrected by cumulative analysis. For reducing LVM, HCTZ tended to be less effective than RASIs. However, the following surpassed RASIs: chlorthalidone Hedge's G: -0.37 (95% CI -0.72 to -0.02), P = 0.036; indapamide -0.20 (-0.39 to -0.01), P = 0.035; all CHIPs combined (with 61% of patients in one trial) -0.25 (-0.41to -0.09), P = 0.002. Statistical significance (P < 0.05) did not depend on any one trial. CHIPs reduction in LVM was 37% greater than that from RASIs. CHIPs superiority tended to increase with trial duration, from a negligible effect at 0.5 year to a maximal effect at 0.9-1.0 years: -0.26 (-0.43 to -0.09), P = 0.003. Fifty-eight percent of patients had information on echocardiographic components of LVM: relative to RASIs, CHIPs significantly reduced end-diastolic LV internal dimension (EDLVID): -0.18 (-0.36 to -0.00), P = 0.046. Strength of evidence favoring CHIPs over RASIs was at least moderate. CONCLUSION: In these novel results in patients with hypertension, CHIPs surpassed RASIs for reducing LVM and EDLVID.

Asunto(s)

Diuréticos/uso terapéutico , Hidroclorotiazida/uso terapéutico , Hipertrofia Ventricular Izquierda/tratamiento farmacológico , Sistema Renina-Angiotensina/efectos de los fármacos , Anciano , Antihipertensivos/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Clortalidona/uso terapéutico , Diuréticos Conservadores de Potasio/uso terapéutico , Método Doble Ciego , Electrólitos , Femenino , Humanos , Hipertensión/fisiopatología , Indapamida/uso terapéutico , Masculino , Persona de Mediana Edad , Ensayos Clínicos Controlados Aleatorios como Asunto , Análisis de Regresión , Inhibidores de los Simportadores del Cloruro de Sodio/uso terapéutico , Resultado del Tratamiento

RESUMEN

BACKGROUND: Azilsartan medoxomil (AZL-M), an angiotensin II receptor blocker, has been developed in fixed-dose combinations (FDCs) with chlorthalidone (CTD). OBJECTIVE/METHODS: We compared FDCs of AZL-M/CTD 20/12.5 mg once daily titrated to 40/25 mg if needed or AZL-M/CTD 40/12.5 mg once daily titrated to 80/25 mg if needed with an olmesartan medoxomil (OLM)-hydrochlorothiazide (HCTZ) 20/12.5 mg FDC once daily titrated to 40/25 mg if needed in a randomized, double-blind, 8-week study of 1085 participants with clinic SBP 160-190 mmHg and DBP 119 mmHg or less. Titration to higher doses occurred at week 4 if BP was at least 140/90 mmHg (≥130/80 mmHg if diabetes or chronic kidney disease). The primary endpoint was change from baseline in clinic SBP; 24-h ambulatory BP monitoring was also measured. RESULTS: Greater reductions in clinic SBP from a baseline of 165 mmHg were observed (P < 0.001) in both AZL-M/CTD arms (-37.6 and -38.2 mmHg) versus OLM/HCTZ (-31.5 mmHg), despite greater dose titration in the OLM/HCTZ group. At 8 weeks, both AZL-M/CTD FDCs reduced 24-h SBP more than OLM/HCTZ (-26.4 and -27.9 versus -20.7 mmHg; both P < 0.001), and higher proportions in both AZL-M/CTD groups achieved target BP compared with the OLM/HCTZ group (69.4 and 68.9 versus 54.7%, both P < 0.001). Adverse events leading to drug discontinuation occurred in 6.2, 9.5, and 3.1% with the AZL-M/CTD lower and higher doses, and OLM/HCTZ, respectively. CONCLUSION: This large, titration-to-target BP study demonstrated AZL-M/CTD FDCs to have superior antihypertensive efficacy compared with the maximum approved dose of OLM/HCTZ.

Asunto(s)

Antihipertensivos/administración & dosificación , Bencimidazoles/administración & dosificación , Clortalidona/administración & dosificación , Diuréticos/administración & dosificación , Hidroclorotiazida/administración & dosificación , Hipertensión/tratamiento farmacológico , Imidazoles/administración & dosificación , Oxadiazoles/administración & dosificación , Tetrazoles/administración & dosificación , Anciano , Presión Sanguínea/efectos de los fármacos , Método Doble Ciego , Combinación de Medicamentos , Femenino , Humanos , Hipertensión/fisiopatología , Masculino , Persona de Mediana Edad

RESUMEN

Diuretics are the most commonly prescribed class of drugs in patients with heart failure, and in the short term they remain the most effective treatment for relief from fluid congestion. This article reviews the mode of action of the various diuretic classes and the physiologic adaptations that follow and sets up the basis for their use in the treatment of volume-retaining states, particularly as applies to the elderly. In addition, the article reviews the common side effects related to diuretics.

Asunto(s)

Diuréticos/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Factores de Edad , Anciano , Humanos

RESUMEN

The efficacy and safety of azilsartan medoxomil (AZL-M) were evaluated in African-American patients with hypertension in a 6-week, double-blind, randomized, placebo-controlled trial, for which the primary end point was change from baseline in 24-hour mean systolic blood pressure (BP). There were 413 patients, with a mean age of 52 years, 57% women, and baseline 24-hour BP of 146/91 mm Hg. Treatment differences in 24-hour systolic BP between AZL-M 40 mg and placebo (-5.0 mm Hg; 95% confidence interval, -8.0 to -2.0) and AZL-M 80 mg and placebo (-7.8 mm Hg; 95% confidence interval, -10.7 to -4.9) were significant (P≤.001 vs placebo for both comparisons). Changes in the clinic BPs were similar to the ambulatory BP results. Incidence rates of adverse events were comparable among the treatment groups, including those of a serious nature. In African-American patients with hypertension, AZL-M significantly reduced ambulatory and clinic BPs in a dose-dependent manner and was well tolerated.

Asunto(s)

Antagonistas de Receptores de Angiotensina/farmacología , Monitoreo Ambulatorio de la Presión Arterial/métodos , Presión Sanguínea/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Adulto , Negro o Afroamericano , Antagonistas de Receptores de Angiotensina/administración & dosificación , Antagonistas de Receptores de Angiotensina/efectos adversos , Antihipertensivos/uso terapéutico , Bencimidazoles/administración & dosificación , Bencimidazoles/efectos adversos , Bencimidazoles/farmacología , Monitoreo Ambulatorio de la Presión Arterial/estadística & datos numéricos , Método Doble Ciego , Femenino , Humanos , Hipertensión/clasificación , Hipertensión/etnología , Masculino , Persona de Mediana Edad , Oxadiazoles/administración & dosificación , Oxadiazoles/efectos adversos , Oxadiazoles/farmacología , Resultado del Tratamiento , Estados Unidos/etnología

RESUMEN

OBJECTIVE: This double-blind, placebo-controlled, interventional trial was conducted to investigate the effects of rotigotine patch on periodic limb movement (PLM)-associated nocturnal systolic blood pressure (SBP) elevations. METHODS: Patients with moderate to severe restless legs syndrome (RLS) were randomized to rotigotine (optimal dose [1-3 mg/24 h]) or placebo. Continuous beat-to-beat blood pressure (BP) assessments were performed during polysomnography at baseline and at the end of 4-week maintenance. Primary outcome was change in number of PLM-associated SBP elevations (defined as slope of linear regression ≥2.5 mm Hg/beat-to-beat interval over 5 consecutive heartbeats [≥10 mm Hg]). Additional outcomes were total SBP elevations, PLM-associated and total diastolic BP (DBP) elevations, periodic limb movements index (PLMI), and PLM in sleep arousal index (PLMSAI). RESULTS: Of 81 randomized patients, 66 (37 rotigotine, 29 placebo) were included in efficacy assessments. PLM-associated SBP elevations were significantly reduced with rotigotine vs placebo (least squares mean treatment difference [95% confidence interval (CI)] -160.34 [-213.23 to -107.45]; p < 0.0001). Rotigotine-treated patients also had greater reduction vs placebo in total SBP elevations (-161.13 [-264.47 to -57.79]; p = 0.0028), PLM-associated elevations (-88.45 [-126.12 to -50.78]; p < 0.0001), and total DBP elevations (-93.81 [-168.45 to -19.16]; p = 0.0146), PLMI (-32.77 [-44.73 to -20.80]; p < 0.0001), and PLMSAI (-7.10 [-11.93 to -2.26]; p = 0.0047). Adverse events included nausea (rotigotine 23%; placebo 8%), headache (18% each), nasopharyngitis (18%; 8%), and fatigue (13%; 15%). CONCLUSIONS: Further investigation is required to determine whether reductions in nocturnal BP elevations observed with rotigotine might modify cardiovascular risk. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with moderate to severe RLS, rotigotine at optimal dose (1-3 mg/24 h) reduced PLM-associated nocturnal SBP elevations.

Asunto(s)

Presión Sanguínea/efectos de los fármacos , Agonistas de Dopamina/administración & dosificación , Síndrome de Mioclonía Nocturna/tratamiento farmacológico , Síndrome de las Piernas Inquietas/fisiopatología , Tetrahidronaftalenos/administración & dosificación , Tiofenos/administración & dosificación , Adolescente , Adulto , Anciano , Presión Sanguínea/fisiología , Determinación de la Presión Sanguínea , Agonistas de Dopamina/efectos adversos , Método Doble Ciego , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Análisis de los Mínimos Cuadrados , Persona de Mediana Edad , Síndrome de Mioclonía Nocturna/complicaciones , Síndrome de Mioclonía Nocturna/fisiopatología , Fotoperiodo , Polisomnografía , Síndrome de las Piernas Inquietas/complicaciones , Síndrome de las Piernas Inquietas/tratamiento farmacológico , Índice de Severidad de la Enfermedad , Tetrahidronaftalenos/efectos adversos , Tiofenos/efectos adversos , Parche Transdérmico/efectos adversos , Resultado del Tratamiento , Adulto Joven

Asunto(s)

Hipertensión , Investigación Biomédica Traslacional , Presión Sanguínea , Humanos

RESUMEN

This review and update focuses on the clinical features of hydrochlorothiazide (HCTZ), the thiazide-like agents chlorthalidone (CTDN) and indapamide (INDAP), potassium-sparing ENaC inhibitors and aldosterone receptor antagonists, and loop diuretics. Diuretics are the second most commonly prescribed class of antihypertensive medication, and thiazide-related diuretics have increased at a rate greater than that of antihypertensive medications as a whole. The latest hypertension guidelines have underscored the importance of diuretics for all patients, but particularly for those with salt-sensitive and resistant hypertension. HCTZ is 4.2-6.2 systolic mm Hg less potent than CTDN, angiotensin-converting enzyme inhibitors, beta blockers, and calcium channel blockers by 24-hour measurements and 5.1mm Hg systolic less potent than INDAP by office measurements. For reducing cardiovascular events (CVEs), HCTZ is less effective than enalapril and amlodipine in randomized trials, and, in network analysis of trials, it is less effective than CTDN and HCTZ-amiloride. Combined with thiazide-type diuretics, potassium-sparing agents decrease ventricular ectopy and reduce the risk for sudden cardiac death relative to thiazide-type diuretics used alone. A recent synthesis of 44 trials has shown that the relative potencies in milligrams among spironolactone (SPIR), amiloride, and eplerenone (EPLER) are approximately from 25 to 10 to 100, respectively, which may be important when SPIR is poorly tolerated. SPIR reduces proteinuria beyond that provided by other renin angiotensin aldosterone inhibitors. EPLER also reduces proteinuria and has beneficial effects on endothelial function. While guidelines often do not differentiate among specific diuretics, this review demonstrates that these distinctions are important for managing hypertension.

Asunto(s)

Diuréticos/uso terapéutico , Hipertensión/tratamiento farmacológico , Humanos

RESUMEN

BACKGROUND: Potassium-sparing diuretics (PSDs) are valuable antihypertensives with additional benefits unrelated to control of systolic blood pressure (SBP). However, their key parameters affecting SBP and serum potassium are poorly defined, fostering underutilization. METHOD: Consequently, we conducted systematic reviews and meta-analyses, yielding 3668 articles and ultimately 84 randomized comparisons. RESULTS: For office SBP, overall placebo-adjusted changes were triamterene -1.9 (low dose only), amiloride -9.9, spironolactone -13.2, and eplerenone -9.2. Differences in antihypertensive effect were due to potency rather than efficacy. Doubling amiloride, eplerenone, and spironolactone doses reduced SBP (95% confidence limits) on average by -2.3 (-3.1, -1.5). Relative antihypertensive potencies were spironolactone>amiloride>eplerenone. Spironolactone had significantly greater antihypertensive potency than amiloride, -4.0 (-7.4, -0.6), and eplerenone, -5.5 (-7.4, -3.6). Dose equivalencies were eplerenone-spironolactone 4.5-to-1 (e.g., eplerenone 125∼spironolactone 25), amiloride-spironolactone 3.3-to-1, and eplerenone-amiloride 1.4-to-1. Increases in serum potassium from amiloride and spironolactone at commonly used doses averaged 0.14-0.29 mEq/l; the dose doubling effect was 0.16 (0.10, 0.22). Spironolactone caused greater hyperkalemia than amiloride across their dose ranges: 0.14, P = 0.043. Seven features make important bias unlikely: a comprehensive literature search, adjustment for covariates, all models explaining 95-100% of the between-study variability, similar dose doubling effects among PSDs, two different methods giving the same potency sequence, similar results from double blind comparisons, and similar results for eplerenone versus spironolactone from analysing direct comparison data (i.e., no meta-regression) for office and 24-h SBP. CONCLUSION: This synthesis accomplishes for PSDs what has already been achieved for thiazide-type diuretics and other antihypertensives and can guide the application of these underutilized medicines.

Asunto(s)

Antihipertensivos/administración & dosificación , Presión Sanguínea/efectos de los fármacos , Potasio/sangre , Amilorida/administración & dosificación , Antihipertensivos/farmacocinética , Antihipertensivos/uso terapéutico , Relación Dosis-Respuesta a Droga , Eplerenona , Humanos , Hiperpotasemia/inducido químicamente , Inhibidores de los Simportadores del Cloruro de Sodio/farmacocinética , Inhibidores de los Simportadores del Cloruro de Sodio/uso terapéutico , Espironolactona/administración & dosificación , Espironolactona/análogos & derivados , Espironolactona/farmacocinética , Equivalencia Terapéutica , Triantereno/administración & dosificación , Triantereno/farmacocinética

Asunto(s)

Comités Consultivos/normas , American Heart Association , Atletas , Cardiología/normas , Anomalías Cardiovasculares/diagnóstico , Hipertensión/diagnóstico , Presión Sanguínea/fisiología , Cardiología/métodos , Anomalías Cardiovasculares/epidemiología , Ejercicio Físico/fisiología , Humanos , Hipertensión/epidemiología , Guías de Práctica Clínica como Asunto/normas , Estados Unidos/epidemiología

RESUMEN

A high fat meal, frequently known as western diet (WD), exacerbates atherosclerosis and diabetes. Both these diseases are frequently associated with renal failure. Recent studies have shown that lipopolysaccharide (LPS) leaks into the circulation from the intestine in the setting of renal failure and after WD. However, it is not clear how renal function and associated disorders are affected by LPS. This study demonstrates that circulatory LPS exacerbates renal insufficiency, atherosclerosis and glucose intolerance. Renal insufficiency was induced by 2/3 nephrectomy in LDL receptor knockout mice. Nx animals were given normal diet (Nx) or WD (Nx+WD). The controls were sham operated animals on normal diet (control) and WD (WD). To verify if LPS plays a role in exaggerating renal insufficiency, polymyxin (PM), a known LPS antagonist, and curcumin (CU), a compound known to ameliorate chronic kidney disease (CKD), was given to Nx animals on western diet (Nx+WD+PM and Nx+WD+CU, respectively). Compared to control, all other groups displayed increased circulatory LPS. The Nx+WD cohort had the highest levels of LPS. Nx group had significant renal insufficiency and glucose intolerance but not atherosclerosis. WD had intense atherosclerosis and glucose intolerance but it did not show signs of renal insufficiency. Compared to other groups, Nx+WD had significantly higher cytokine expression, macrophage infiltration in the kidney, renal insufficiency, glucose intolerance and atherosclerosis. PM treatment blunted the expression of cytokines, deterioration of renal function and associated disorders, albeit not to the levels of Nx, and was significantly inferior to CU. PM is a non-absorbable antibiotic with LPS binding properties, hence its beneficial effect can only be due to its effect within the GI tract. We conclude that LPS may not cause renal insufficiency but can exaggerate kidney failure and associated disorders following renal insufficiency.

Asunto(s)

Aterosclerosis/etiología , Dieta Alta en Grasa/efectos adversos , Dieta Occidental/efectos adversos , Intolerancia a la Glucosa/etiología , Hiperglucemia/etiología , Lipopolisacáridos/metabolismo , Insuficiencia Renal/etiología , Animales , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/metabolismo , Aterosclerosis/patología , Colesterol/efectos adversos , Curcumina/farmacología , Grasas de la Dieta/efectos adversos , Modelos Animales de Enfermedad , Expresión Génica , Intolerancia a la Glucosa/tratamiento farmacológico , Intolerancia a la Glucosa/metabolismo , Intolerancia a la Glucosa/patología , Hiperglucemia/tratamiento farmacológico , Hiperglucemia/metabolismo , Hiperglucemia/patología , Mucosa Intestinal/metabolismo , Intestinos/efectos de los fármacos , Intestinos/patología , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Macrófagos/patología , Ratones , Ratones Noqueados , Nefrectomía/efectos adversos , Polimixinas/farmacología , Receptores de LDL/deficiencia , Receptores de LDL/genética , Insuficiencia Renal/metabolismo , Insuficiencia Renal/patología , Insuficiencia Renal/prevención & control

Asunto(s)

Comités Consultivos , American Heart Association , Atletas , Cardiología/normas , Anomalías Cardiovasculares/terapia , Hipertensión/prevención & control , Adolescente , Adulto , Anomalías Cardiovasculares/diagnóstico , Anomalías Cardiovasculares/epidemiología , Niño , Femenino , Humanos , Hipertensión/diagnóstico , Hipertensión/epidemiología , Masculino , Guías de Práctica Clínica como Asunto/normas , Conducta de Reducción del Riesgo , Estados Unidos/epidemiología , Adulto Joven

RESUMEN

This scientific statement provides a summary of presentations and discussions at a cardiovascular Think Tank co-sponsored by the American Society of Hypertension (ASH), the United States Food and Drug Administration (FDA), and the National Heart, Lung, and Blood Institute (NHLBI) held in North Bethesda, Maryland, on June 26, 2014. Studies of device therapies for the treatment of hypertension are requested by regulators to evaluate their safety and efficacy during their development programs. Think Tank participants thought that important considerations in undertaking such studies were: (1) Preclinical assessment: how likely it is that both efficacy and safety data indicating benefit in humans will be obtained, and/or whether a plausible mechanism of action for efficacy can be identified; (2) Early human trial(s): the ability to determine that the device has an acceptable benefit-to-risk balance for its use in the intended patient population and without the influence of drug therapy during a short-term follow-up period; and (3) Pivotal Phase III trial(s): the ability to prove the effectiveness of the device in a broad population in which the trial can be made as non-confounded as possible while still allowing for the determination for benefits when added to antihypertensive therapies.

Asunto(s)

Desnervación/métodos , Hipertensión/cirugía , Riñón/inervación , Animales , Antihipertensivos/uso terapéutico , Biomarcadores/análisis , Ensayos Clínicos como Asunto , Humanos , Hipertensión/tratamiento farmacológico , Hipertensión/fisiopatología

RESUMEN

Accounting for 15 % of deaths worldwide, hypertension is often treated with hydrochlorothiazide (HCTZ) (50 million prescriptions annually). HCTZ has a <24-h duration of action, is less potent than chlorthalidone and all major antihypertensive drug classes, and is inferior to four antihypertensive drugs for cardiovascular event (CVE) reduction. If there were alternative diuretics, why prescribe HCTZ? Chlorthalidone is often offered as an alternative to HCTZ, but has limited pharmaceutical formulations. However, there are seven evidence-based, single-tablet, alternative diuretics. For reducing CVE, the following are superior to their comparators: chlorthalidone versus four antihypertensives in multiple hypertensive populations; indapamide versus placebo in elderly Chinese (and versus enalapril for left ventricular hypertrophy), triamterene-HCTZ versus placebo in elderly Europeans, amiloride-HCTZ versus three antihypertensives, and indapamide-perindopril versus placebo in three populations. Additionally, chlorthalidone-azilsartan and spironolactone-HCTZ are potent combinations The aldosterone antagonist component of the latter combination has been shown to reduce total mortality by 30 % in heart failure. Five of these seven have multiple dose formulations. Six cost $4-$77 monthly. In conclusion, based on both scientific and practical grounds, new prescriptions for HCTZ are rarely justified.

Asunto(s)

Clortalidona/uso terapéutico , Hipertensión/tratamiento farmacológico , Animales , Presión Sanguínea/efectos de los fármacos , Clortalidona/economía , Práctica Clínica Basada en la Evidencia , Insuficiencia Cardíaca/tratamiento farmacológico , Humanos , Hipertrofia Ventricular Izquierda/tratamiento farmacológico , Comprimidos

RESUMEN

Hydrochlorothiazide (HCTZ) has often been contrasted with chlorthalidone, but relatively little is known about HCTZ versus indapamide (INDAP). This systematic review retrieved 9765 publications, and from these, it identified 14 randomized trials with 883 patients comparing HCTZ with INDAP and chlorthalidone on antihypertensive potency or metabolic effects. To make fair comparisons, the dose of the diuretic in each arm was assigned 1 of 3 dose levels. In random effects meta-analysis, INDAP and chlorthalidone lowered systolic blood pressure more than HCTZ: -5.1 mm Hg (95% confidence interval, -8.7 to -1.6); P=0.004 and -3.6 mm Hg (95% confidence interval, -7.3 to 0.0); P=0.052, respectively. For both comparisons, there was minimal heterogeneity in effect across trials and no evidence for publication bias. The HCTZ-INDAP contrast was biased in favor of greater HCTZ potency because of a much greater contribution to the overall effect from trials in which the HCTZ arm had a higher dose level than the INDAP arm. For the HCTZ-INDAP comparison, no single trial was responsible for the overall result nor was it possible to detect significant modifications of this comparison by duration of follow-up, high- versus low-bias trials, or the presence or absence of background medications. There were no detectable differences between HCTZ and INDAP in metabolic adverse effects, including effects on serum potassium. In conclusion, these head-to-head comparisons demonstrate that, like chlorthalidone, INDAP is more potent than HCTZ at commonly prescribed doses without evidence for greater adverse metabolic effects.

Asunto(s)

Presión Sanguínea/efectos de los fármacos , Clortalidona/uso terapéutico , Hidroclorotiazida/uso terapéutico , Hipertensión/tratamiento farmacológico , Indapamida/uso terapéutico , Potasio/sangre , Diuréticos/uso terapéutico , Humanos , Hipertensión/sangre , Hipopotasemia/sangre , Hipopotasemia/inducido químicamente , Hipopotasemia/prevención & control , Resultado del Tratamiento