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W Gerald M D Smetana - One of the best experts on this subject based on the ideXlab platform.
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triamterene in the treatment of hypertension more than just potassium sparing
Journal of General Internal Medicine, 2016Co-Authors: W Gerald M D SmetanaAbstract:H ypertension is the most commonly encountered chronic medical condition in primary care practice and is a major risk factor for stroke and coronary artery disease. For decades, thiazide Diuretics have been a recommended first line option for antihypertensive therapy. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) recommended thiazides as first line therapy unless a compelling indication existed for another agent. JNC-8 recommends Diuretics as one of four acceptable first line options for non-black patients without chronic kidney disease (other options include angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, or calcium channel blockers), and as one of two acceptable options for African American patients without chronic kidney disease (the other option is calcium channel blockers). Hypokalemia frequently results from the administration of thiazide Diuretics. This effect is more common with chlorthalidone than hydrochlorothiazide (HCTZ) or indapamide, and occurs in a dose dependent fashion. In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), one of the largest trials of antihypertensive therapy (n=33,357), mean potassium levels at 4 years fell 0.2 mEq/L among chlorthalidone treated patients, and potassium fell below 3.5 mEq/L in 8.5% of patients at 4 years (as opposed to 1.9 % of amlodipine treated patients). Hypokalemia, when it occurs, usually appears within the first 2 weeks after initiating diuretic therapy. If hypokalemia occurs, clinicians have the option of beginning potassium chloride replacement therapy (typical doses are 20–40 mEq per day for patients with normal renal function), or beginning a potassium sparing diuretic. Potassium sparing Diuretics include triamterene and amiloride (epithelial sodium channel inhibitors) and spironolactone and eplerenone (mineralocorticoid receptor antagonists). The choice of potassium replacement or a Potassium-Sparing diuretic has been typically left to the discretion of the clinician, as no evidence has suggested that the addition of Potassium-Sparing Diuretics provides additional value in terms of blood pressure lowering or a reduction in cardiovascular events. From the patient perspective, a disadvantage of potassium replacement is the requirement to add either large pills that are often difficult to swallow, or a salty tasting solution to the thiazide. No studies exist of triamterene as monotherapy for the treatment of hypertension. In a recent Cochrane systematic review, authors evaluated the blood pressure lowering effect of Potassium-Sparing Diuretics that block the epithelial sodium channel when given in combination with another antihypertensive agent. Only six trials of 496 patients existed; all six studies were performed in the 1980s. Two trials (n=211) evaluated the incremental benefit of triamterene 50mg per day when added to chlorthalidone at 25 to 50 mg per day. The addition of triamterene provided no incremental reduction in systolic blood pressure (−0.01, 95 % CI −3.63 to 3.61), or diastolic blood pressure (+0.20, 95 % CI −2.01 to 2.41), but total sample sizes were too small to draw any meaningful conclusions. In this issue of JGIM, Tu and colleagues queried a large network electronic medical record system to determine the incremental blood pressure lowering effect of triamterene. They identified 17,291 patients with a diagnosis of hypertension over an 8-year period and divided these patients into those with and without a pharmacy claim for triamterene. Patients who received triamterene were more likely to be female or African American, and less likely to have diabetes, coronary artery disease, congestive heart failure, a history of stroke, or chronic obstructive pulmonary disease. A direct comparison of the blood pressure values in these two groups would be confounded by substantial selection bias due to the nonrandom assignment between the groups. Tu et al. used a novel approach to attempt to correct for limitations inherent in these observational data. They used propensity score matching to estimate the probability that a patient would receive a particular treatment, based on logistic regression that adjusted for 14 clinical characteristics. They then stratified patients into quartiles of estimated propensity and compared the recorded blood pressures for those who had or had not received triamterene. They evaluated separately the impact of adding triamterene to HCTZ or to combinations of drugs that included HCTZ. They present no data on chlorthalidone use; in their network, triamterene was most commonly prescribed as a fixed combination pill with HCTZ (initial dose was HCTZ 25 mg daily and triamterene 37.5 mg daily). Published online September 18, 2015
Nancy J Brown - One of the best experts on this subject based on the ideXlab platform.
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differing effects of mineralocorticoid receptor dependent and independent potassium sparing Diuretics on fibrinolytic balance
Hypertension, 2005Co-Authors: Francisco Albornoz, Daniel W Byrne, Douglas E Vaughan, Nancy J BrownAbstract:This study tests the hypothesis that spironolactone influences plasminogen activator inhibitor-1 (PAI-1) concentrations through mineralocorticoid receptor antagonism rather than through changes in potassium. Effects of spironolactone (50 mg per day) and triamterene (50 mg per day) on fibrinolytic balance were compared in 18 normotensive and 20 hypertensive subjects pretreated with hydrochlorothiazide (HCTZ; 12.5 mg per day). Blood pressure and serum potassium were similar in spironolactone and triamterene treatment groups. The effect of the 2 drugs on the renin-angiotensin-aldosterone system was also similar. In contrast, spironolactone and triamterene exerted opposing effects on PAI-1 antigen ( P =0.006 for drug effect). In normotensive subjects, triamterene (from 10.1±7.8 to 16.9±9.9 ng/mL at 9 am, P =0.019; from 7.6±5.4 to 11.5±7.3 ng/mL at 11 am, P =0.027; from 9.3±7.7 to 13.7±8.5 ng/mL for average of all time points, P =0.054) but not spironolactone significantly increased PAI-1 antigen. In hypertensive subjects, spironolactone significantly decreased PAI-1 antigen (from 22.0±23.4 to 16.7±19.0 ng/mL at 10 am, P =0.041; from 17.5±21.7 to 12.7±16.8 ng/mL at 11 am, P =0.043; from 20.3±22.6 to 16.6±19.7 ng/mL for average of all time points, P =0.014), whereas there was no effect of triamterene. Only spironolactone significantly decreased the molar ratio of PAI-1 to tissue-type plasminogen activator (t-PA) in hypertensive subjects. By regression analysis, predictors of mean PAI-1 response were spironolactone versus triamterene ( P =0.014), hypertension ( P =0.002), and PAI-1 response to HCTZ ( P =0.019), with a trend for aldosterone ( P =0.061). Mineralocorticoid receptor antagonism prevents the effect of activation of the renin-angiotensin-aldosterone system on PAI-1 antigen in normotensive subjects and improves fibrinolytic balance in hypertensive subjects through a potassium-independent mechanism.
Ali Ahmed - One of the best experts on this subject based on the ideXlab platform.
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a propensity matched study of the effects of chronic diuretic therapy on mortality and hospitalization in older adults with heart failure
International Journal of Cardiology, 2008Co-Authors: Ali Ahmed, Thomas E Love, James B Young, Raynald Levesque, Bertram PittAbstract:Abstract Background Non-Potassium-Sparing Diuretics may increase mortality and hospitalizations in heart failure patients. Most heart failure patients are older adults, yet the effect of Diuretics on cause-specific mortality and hospitalizations in older adults with heart failure is unknown. The objective of this propensity-matched study was to determine the effect of Diuretics on mortality and hospitalizations in heart failure patients ≥65 years. Methods Of the 7788 Digitalis Investigation Group participants, 4036 were ≥65 years and 3271 (81%) were receiving Diuretics. Propensity scores for diuretic use for each of the 4036 patients were calculated using a non-parsimonious multivariable logistic regression model incorporating all measured baseline covariates, and were used to match 651 (85%) patients not receiving Diuretics with 651 patients receiving Diuretics. Effects of Diuretics on mortality and hospitalization at 37 months of median follow-up were assessed using matched Cox regression models. Results All-cause mortality occurred in 173 patients not receiving Diuretics and 208 patients receiving Diuretics respectively during 2056 and 1943 person-years of follow-up (hazard ratio {HR}=1.36; 95% confidence interval {CI}=1.08–1.71; p =0.009). All-cause hospitalizations occurred in 413 patients not receiving and 438 patients receiving Diuretics respectively during 1255 and 1144 person-years of follow-up (HR=1.18; 95% CI=0.99–1.39; p =0.063). Diuretic use was associated with significant increased risk of cardiovascular mortality (HR=1.50; 95% CI=1.15–1.96; p =0.003).and heart failure hospitalization (HR=1.48; 95% CI=1.13–1.94; p =0.005). Conclusions Chronic diuretic use was associated with significant increased mortality and hospitalization in ambulatory older adults with heart failure receiving angiotensin converting enzyme inhibitor and Diuretics.
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heart failure chronic diuretic use and increase in mortality and hospitalization an observational study using propensity score methods
European Heart Journal, 2006Co-Authors: Ali Ahmed, Ahsan Husain, Thomas E Love, Giovanni Gambassi, Louis J Dellitalia, Gary S Francis, Mihai Gheorghiade, Richard M Allman, Sreelatha Meleth, Robert C BourgeAbstract:Aims Non-Potassium-Sparing Diuretics are commonly used in heart failure (HF). They activate the neurohormonal system, and are potentially harmful. Yet, the long-term effects of chronic diuretic use in HF are largely unknown. We retrospectively analysed the Digitalis Investigation Group (DIG) data to determine the effects of Diuretics on HF outcomes. Methods and results Propensity scores for diuretic use were calculated for each of the 7788 DIG participants using a non-parsimonious multivariable logistic regression model, and were used to match 1391 (81%) no-diuretic patients with 1391 diuretic patients. Effects of Diuretics on mortality and hospitalization at 40 months of median follow-up were assessed using matched Cox regression models. All-cause mortality was 21% for no-diuretic patients and 29% for diuretic patients [hazard ratio (HR) 1.31; 95% confidence interval (CI) 1.11–1.55; P ¼ 0.002]. HF hospitalizations occurred in 18% of no-diuretic patients and 23% of diuretic patients (HR 1.37; 95% CI 1.13–1.65; P ¼ 0.001). Conclusion Chronic diuretic use was associated with increased long-term mortality and hospitalizations in a wide spectrum of ambulatory chronic systolic and diastolic HF patients. The findings of the current study challenge the wisdom of routine chronic use of Diuretics in HF patients who are asymptomatic or minimally symptomatic without fluid retention, and are on complete neurohormonal blockade. These findings, based on a non-randomized design, need to be further studied in randomized trials.
Bertram Pitt - One of the best experts on this subject based on the ideXlab platform.
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a propensity matched study of the effects of chronic diuretic therapy on mortality and hospitalization in older adults with heart failure
International Journal of Cardiology, 2008Co-Authors: Ali Ahmed, Thomas E Love, James B Young, Raynald Levesque, Bertram PittAbstract:Abstract Background Non-Potassium-Sparing Diuretics may increase mortality and hospitalizations in heart failure patients. Most heart failure patients are older adults, yet the effect of Diuretics on cause-specific mortality and hospitalizations in older adults with heart failure is unknown. The objective of this propensity-matched study was to determine the effect of Diuretics on mortality and hospitalizations in heart failure patients ≥65 years. Methods Of the 7788 Digitalis Investigation Group participants, 4036 were ≥65 years and 3271 (81%) were receiving Diuretics. Propensity scores for diuretic use for each of the 4036 patients were calculated using a non-parsimonious multivariable logistic regression model incorporating all measured baseline covariates, and were used to match 651 (85%) patients not receiving Diuretics with 651 patients receiving Diuretics. Effects of Diuretics on mortality and hospitalization at 37 months of median follow-up were assessed using matched Cox regression models. Results All-cause mortality occurred in 173 patients not receiving Diuretics and 208 patients receiving Diuretics respectively during 2056 and 1943 person-years of follow-up (hazard ratio {HR}=1.36; 95% confidence interval {CI}=1.08–1.71; p =0.009). All-cause hospitalizations occurred in 413 patients not receiving and 438 patients receiving Diuretics respectively during 1255 and 1144 person-years of follow-up (HR=1.18; 95% CI=0.99–1.39; p =0.063). Diuretic use was associated with significant increased risk of cardiovascular mortality (HR=1.50; 95% CI=1.15–1.96; p =0.003).and heart failure hospitalization (HR=1.48; 95% CI=1.13–1.94; p =0.005). Conclusions Chronic diuretic use was associated with significant increased mortality and hospitalization in ambulatory older adults with heart failure receiving angiotensin converting enzyme inhibitor and Diuretics.
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diuretic use progressive heart failure and death in patients in the studies of left ventricular dysfunction solvd
Journal of the American College of Cardiology, 2003Co-Authors: Michael J Domanski, Bertram Pitt, James E Norman, Mark C Haigney, Stephen U Hanlon, Eliot PeysterAbstract:Abstract Objectives We sought to determine whether non–Potassium-Sparing Diuretics (PSDs) in the absence of a PSD may result in progressive heart failure (HF). Background Angiotensin-converting enzyme (ACE) inhibitors incompletely suppress ACE activity in HF patients. Furthermore, non-PSDs are activators of aldosterone secretion. We reasoned that non-PSDs, in the absence of a PSD, might result in progressive HF. Methods In the 6,797 patients in the Studies Of Left Ventricular Dysfunction (SOLVD), we compared the risk of hospitalization for, or death from, HF between those taking a PSD and those who were not, adjusting for known covariates. Results The risk of hospitalization from worsening HF in those taking a PSD relative to those taking only a non-PSD was 0.74 (95% confidence interval [CI] 0.55 to 0.99; p = 0.047). The relative risk for cardiovascular death was 0.74 (95% CI 0.59 to 0.93; p = 0.011), for death from all causes 0.73 (95% CI 0.59 to 0.90; p = 0.004), and for hospitalization for, or death from, HF 0.75 (95% CI 0.58 to 0.97; p = 0.030). Compared with patients not taking any diuretic, the risk of hospitalization or death due to worsening HF in patients taking non-PSDs alone was significantly increased (risk ratio [RR] = 1.31, 95% CI 1.09 to 1.57; p = 0.0004); this was not observed in patients taking PSDs with or without a non-PSD (RR = 0.99, 95% CI 0.76 to 1.30; p = 0.95). Conclusions The use of PSDs in HF patients is associated with a reduced risk of death from, or hospitalization for, progressive HF or all-cause or cardiovascular death, compared with patients taking only a non-PSD.
Delbert G Gillespie - One of the best experts on this subject based on the ideXlab platform.
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8 aminoguanosine and 8 aminoguanine exert diuretic natriuretic glucosuric and antihypertensive activity
Journal of Pharmacology and Experimental Therapeutics, 2016Co-Authors: Edwin K Jackson, Delbert G GillespieAbstract:In vivo, guanine moieties in DNA, RNA, guanine nucleotides, or guanosine or guanine per se can undergo nitration (for example, by peroxynitrite) or hydroxylation (for example, by superoxide anion) on position 8 of the purine ring. Subsequent catabolism of these modified biomolecules leads to the production of a diverse group of 8-nitro, 8-amino, and 8-hydroxy guanosine and guanine compounds. Indeed, studies suggest the in vivo existence of 8-nitroguanosine, 8-nitroguanine, 8-aminoguanosine, 8-aminoguanine, 8-hydroxyguanosine, 8-hydroxy-2′-deoxyguanosine, and 8-hydroxyguanine. Since a multitude of these compounds exist in vivo, and since the renal effects of 8-substituted guanosine and guanine compounds are entirely unknown, we examined the effects of guanosine, guanine, 8-nitroguanosine, 8-nitroguanine, 8-hydroxyguanosine, 8-hydroxyguanine, 8-hydroxy-2′-deoxyguanosine, 8-aminoguanosine, and 8-aminoguanine (33.5 µmol/kg; intravenous bolus) on excretion of sodium, potassium, and glucose in rats. Guanosine, 8-nitroguanosine, and 8-hydroxy-2′-deoxyguanosine had minimal natriuretic activity. Guanine, 8-nitroguanine, 8-hydroxyguanosine, and 8-hydroxyguanine had moderate natriuretic activity (increased sodium excretion by 9.4-, 7.8-, 7.1-, and 8.6-fold, respectively). In comparison with all other compounds, 8-aminoguanosine and 8-aminoguanine were highly efficacious and increased sodium excretion by 26.6- and 17.2-fold, respectively, exceeding that of a matched dose of amiloride (13.6-fold increase). 8-Aminoguanosine and 8-aminoguanine also increased glucose excretion by 12.1- and 12.2-fold, respectively, and decreased potassium excretion by 69.1 and 71.0%, respectively. Long-term radiotelemetry studies demonstrated that oral 8-aminoguanosine and 8-aminoguanine (5 mg/kg/day) suppressed deoxycorticosterone/salt-induced hypertension. These experiments demonstrate that some naturally occurring 8-substitued guanosine and guanine compounds, particularly 8-aminoguanosine and 8-aminoguanine, are potent and efficacious Potassium-Sparing Diuretics/natriuretics that may represent a novel class of antihypertensive Diuretics.
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abstract 070 discovery of a novel class of endogenous small molecule potent efficacious and potassium sparing Diuretics natriuretics with antihypertensive and glucosuric activity
Hypertension, 2016Co-Authors: Edwin K Jackson, Delbert G Gillespie, Zaichuan MiAbstract:In vivo, guanine moieties in DNA, RNA, guanine nucleotides or guanosine can undergo nitration (e.g., by peroxynitrite) or hydroxylation (e.g., by superoxide anion) on position 8 of the purine ring. Catabolism of these biomolecules leads to the in vivo production of a diverse group of 8-nitro, 8-amino and 8-hydroxy guanosine and guanine compounds. Since the renal effects of these compounds are entirely unknown, we examined in rats the effects of guanosine, guanine, 8-nitroguanosine, 8-nitroguanine, 8-hydroxyguanosine, 8-hydroxyguanine, 8-hydroxy-2-deoxyguanosine, 8-aminoguanosine and 8-aminoguanine (33 μmoles/kg/min; intravenous infusion for 115 minutes) on excretion of Na + , K + and glucose. Guanosine, 8-nitroguanosine and 8-hydroxy-2-deoxyguanosine had minimal activity. Guanine, 8-nitroguanine, 8-hydroxyguanosine and 8-hydroxyguanine had moderate natriuretic activity (increased sodium excretion by 9.4-fold, 7.8-fold, 7.1-fold and 8.6-fold, respectively). In contrast, 8-aminoguanosine (n=6) and 8-aminoguanine (n=6) were highly efficacious and increased Na + excretion by 26.6-fold (from 5.13 ± 2.16 to 136.44 ± 20.14 μmoles/30 min) and 17.2-fold (from 4.38 ± 2.00 to 75.28 ± 23.37 μmoles/30 min), respectively. 8-Aminoguanosine and 8-aminoguanine also increased glucose excretion by 12.1-fold (from 36.68 ± 11.22 to 445.11 ± 63.78 μg/30 min) and 12.2-fold (from 31.40 ± 16.70 to 382.68 ± 97.81 μg/30 min), respectively, and decreased K + excretion by 69.1% (from 51.11 ± 11.37 to 15.78 ± 2.74 μmoles/30 min) and 71.0% (from 28.57 ± 6.62 to 8.28 ± 2.14 μmoles/30 min), respectively. Radiotelemetry studies demonstrated that 8-aminoguanosine (n=3) and 8-aminoguanine (n=3) in drinking water (5 mg/kg/day) suppressed deoxycorticosterone/salt-induced (DOCA/salt) hypertension. For example, in untreated DOCA/salt rats, MABP increased from 103 ± 4 to 184 ± 9 mm Hg after 65 days of DOCA/salt; whereas in 8-aminoguanosine-treated DOCA/salt rats, MABP increased from 98 ± 2 to 148 ± 9 mm Hg during the same time period. We conclude that 8-aminoguanosine and 8-aminoguanine are endogenous, potent and efficacious K + -sparing Diuretics/natriuretics that may regulate renal function and blood pressure and may represent a new class of antihypertensive drugs.