Registration of amiloride in South Africa: Cutting the Gordian knot.

Amiloride is an antagonist of the renal tubular epithelial sodium channel (ENaC). As such, it is a diuretic that is both potassium and magnesium sparing. It is used for the treatment of potassium depletion and hypertension, and is the specific therapy for hypertension due to overactivity of the ENaC (Liddle syndrome and several additional genetic causes of the Liddle phenotype - low renin and low aldosterone). It is listed as a World Health Organization essential drug, but has never been registered in South Africa (SA) and can therefore only be prescribed under a Section 21 application to the SA Health Products Regulatory Authority (SAHPRA) on a case-by-case basis. In SA, >50% of patients treated for hypertension are not controlled. In the USA, the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study reported that African Americans are more likely to be diagnosed with hypertension, more likely to be treated, more likely to be treated intensively, and less likely to achieve blood pressure (BP) control. Although the reasons are complex, studies show that 10 - 20% of blacks may carry the Liddle phenotype. Observational data and a controlled clinical trial done in three African countries have shown that these patients respond to amiloride and not to conventional guideline-based antihypertensive treatment. The former is likely to result in a significant reduction in cardiovascular, stroke and kidney morbidity and mortality, because of improved BP control. Amiloride is very unlikely to ever be registered in SA, as it was first developed >50 years ago, and SAHPRA regulations prevent widespread prescription of this essential drug. This is a classic Gordian knot that requires a novel approach from authorities to sever the knot and improve the health of many South Africans.

Pharmacodynamic assessment of diuretic efficacy and braking in a furosemide continuous infusion model.

INTRODUCTION: Diuretic failure is a potential life-ending event but is unpredictable and poorly understood. The objectives of this study were to evaluate pharmacodynamic markers of furosemide-induced diuresis and to investigate mechanisms of diuretic braking in dogs receiving constant rate infusion (CRI) of furosemide. ANIMALS: Six healthy male dogs. METHODS: Raw data and stored samples from one arm of a previously published study were further analyzed to mechanistically investigate causes of diuretic braking in these dogs. Urine volume was recorded hourly during a 5-h furosemide CRI. Urine and blood samples were collected hourly to measure serum and urine electrolytes, urine aldosterone, and plasma and urine furosemide. Serum electrolyte fractional excretion was calculated. Urine sodium concentration was indexed to urine potassium (uNa:uK) and urine furosemide (uNa:uFur) concentrations, plasma furosemide concentration was indexed to urine furosemide concentration (pFur:uFur), and urine aldosterone was indexed to urine creatinine (UAldo:C). Temporal change and the relationship to urine volume were evaluated for these measured and calculated variables. RESULTS: Urine volume was significantly correlated with urine electrolyte amounts and with uNa:uK. The ratio of pFur:uFur decreased during the infusion, whereas furosemide excretion was unchanged. CONCLUSIONS: There was a strong relationship between urine volume and absolute urine electrolyte excretion. Urine volume was strongly correlated to uNa:uK, giving it potential as a spot indicator of urine production during diuresis. The decrease in uNa:uK over time during the infusion is consistent with mineralocorticoid modification of urinary electrolyte excretion, supporting renin-angiotensin-aldosterone activation as a cause of diuretic braking in this model.

Dynamic tissue perfusion assessment reflects associations between antihypertensive treatment and renal cortical perfusion in patients with chronic kidney disease and hypertension.

PURPOSE: Renal cortical perfusion measured in noninvasive, dynamic ultrasonic method is connected with the hemodynamic cardiac properties and renal function. Antihypertensive drugs affect the functioning of the heart and kidneys. The aim of the study was to evaluate the effect of a chronic use of antihypertensive drugs on ultrasound parameters of renal cortical perfusion. METHODS: The study included 56 consecutive patients (49 M + 7 F, age 54.0 ± 13.3) with stable chronic kidney disease and hypertension. Color Doppler dynamic tissue perfusion measurement was used to assess renal cortical perfusion. RESULTS: Patients were treated with a mean of 2.7 ± 1.4 antihypertensive drugs, of which diuretics accounted for 25%, angiotensin-converting enzyme inhibitors (ACE-I) together with angiotensin receptor blockers (ARB) 24%, beta-blockers (BB) 23%, calcium channel blockers 16%, alpha-1 blockers (α1B) 9% and centrally acting drugs 3%. All investigated groups of drugs correlated significantly with parameters of renal perfusion. In multivariable regression analyses adjusted to age, diuretics were connected with the decrease (r = - 0.473) and ACE-I + ARB (r = 0.390) with the improvement of proximal and whole renal cortex perfusion (R2 = 0.28; p < 0.001), whereas BB (r = - 0.372) and α1B (r = - 0.280) independently correlated with worsened perfusion of renal distal cortex (R2 = 0.21, p < 0.01). CONCLUSIONS: The type of antihypertensive therapy had a significant influence on the ultrasound parameters of renal cortical perfusion. Noninvasive, ultrasonic dynamic tissue perfusion measurement method appears to be an adequate tool to assess the impact of drugs on renal cortical perfusion.

Echo and natriuretic peptide guided therapy improves outcome and reduces worsening renal function in systolic heart failure: An observational study of 1137 outpatients.

BACKGROUND: B-type natriuretic peptide (BNP) and echocardiography are potentially useful adjunct to guide management of patients with chronic heart failure (HF).Thus, the aim of this retrospective, multicenter study was to compare outcomes and renal function in outpatients with chronic HF with reduced ejection fraction (HFrEF) who underwent an echo and BNP guided or a clinically driven protocol for follow-up. METHODS AND RESULTS: In 1137 consecutive outpatients, management was guided according to echo-Doppler signs of elevated left ventricular filling pressure and BNP levels conforming to the protocol of the Network Labs Ultrasound (NEBULA) in HF Study Group in 570 (mean EF=30%), while management was clinically driven based on the institutional protocol of the HF Unit of the Cardiovascular and Thoracic Department in 567 (mean EF=33%). Propensity score, matching several confounding baseline variables, was used to match pairs based on treatment strategy. The median follow-up was 37.4months. After propensity matching, a lower incidence of death (HR 0.45, 95%CI: 0.30-0.67, p<0.0001), and death or worsening renal function (HR 0.49, 95%CI 0.36-0.67, p<0.0001) was apparent in echo-BNP-guided group compared to clinically-guided group. Worsening of renal function (≥0.3mg/dl increase in serum creatinine) was observed in 9.8% of echo-BNP-guided group and in 21.4% of clinical assessed group (p<0.0001). The daily dose of loop diuretics did not change in echo-BNP-guided group, while it increased in 65% of patients in clinically-guided group (p<0.0001). CONCLUSIONS: Echo and BNP guided management may improve the outcome and reduce worsening of renal function in outpatients with chronic HFrEF.

Discordance Between Hemoconcentration and Clinical Assessment of Decongestion in Acute Heart Failure.

INTRODUCTION: Hemoconcentration has been proposed as a surrogate for successful decongestion in acute heart failure (AHF). The aim of the present study was to evaluate the relationship between hemoconcentration and clinical measures of congestion. METHODS AND RESULTS: We studied 704 patients with AHF and volume overload. A composite congestion score was calculated at admission and discharge, with a score >1 denoting persistent congestion. Hemoconcentration was defined as any increase in hematocrit and hemoglobin levels between baseline and discharge. Of 276 patient with hemoconcentration, 66 (23.9%) had persistent congestion. Conversely, of 428 patients without hemoconcentration, 304 (71.0%) had no clinical evidence of congestion. Mean hematocrit changes were similar with and without persistent congestion (0.18 ± 3.4% and -0.19 ± 3.6%, respectively; P = .17). There was no correlation between the decline in congestion score and the change in hematocrit (P = .93). Hemoconcentration predicted lower mortality (hazard ratio 0.70, 95% confidence interval 0.54-0.90; P = .006). Persistent congestion was associated with increased mortality independent of hemoconcentration (Ptrend = .0003 for increasing levels of congestion score). CONCLUSIONS: Hemoconcentration is weakly related to congestion as assessed clinically. Persistent congestion at discharge is associated with increased mortality regardless of hemoconcentration. Hemoconcentration is associated with better outcome but cannot substitute for clinically derived estimates of congestion to determine whether decongestion has been achieved.

Diuretic use in black patients with uncontrolled hypertension.

BACKGROUND: Highly publicized recommendations favor the use of diuretics as a first-line or add-on agent in the management of hypertension, particularly among black patients and patients with resistant hypertension. Failure to follow such guidelines might contribute to high rates of uncontrolled hypertension. This study assessed diuretic prescribing patterns in a sample of black patients with uncontrolled hypertension who were identified from a population of home care recipients. METHODS: The study was conducted in an urban home health organization. Participants were black, aged 21 to 80 years, and had a diagnosis of hypertension. Participants with uncontrolled hypertension were identified, and in-home interviewers collected information on prescribed antihypertensive medications. RESULTS: Of 658 participants, 5.5% were not prescribed any antihypertensives, and only 46% were prescribed a diuretic. Participants who were not taking a diuretic were taking fewer antihypertensive medications (1.7 vs. 2.9; P < 0.0001), had a higher mean diastolic blood pressure (89.2 vs. 85.5; P = 0.0005), and were more likely to have a systolic blood pressure ≥160mm Hg (57.6% vs. 49.0%; P = 0.04). The adjusted mean systolic and diastolic blood pressures were 5 and 4mm Hg lower, respectively, in patients who were taking a diuretic. CONCLUSIONS: In this sample of black patients with uncontrolled hypertension, despite wide publicizing of the recommendations for use of diuretics, a majority are still not receiving a diuretic. This important issue merits continued attention.

Hydration assessment using the cardiovascular response to standing.

The cardiovascular response to standing (sit-to-stand change in heart rate; SSΔHR) is commonly employed as a screening tool to detect hypohydration (body water deficit). No study has systematically evaluated SSΔHR cut points using different magnitudes or different types of controlled hypohydration. The objective of this study was to determine the diagnostic accuracy of the often proposed 20 b/min SSΔHR cut point using both hypertonic and isotonic models of hypohydration. Thirteen healthy young adults (8M, 5F) underwent three bouts of controlled hypohydration. The first bout used sweating to elicit large losses of body water (mass) (>3 % sweat). The second two bouts were matched to elicit 3 % body mass losses (3 % diuretic; 3 % sweat). A euhydration control trial (EUH) was paired with each hypohydration trial for a total of six trials. Heart rate was assessed after 3-min sitting and after 1-min standing during all trials. SSΔHR was compared among trials, and receiver operator characteristic curve analysis was used to determine diagnostic accuracy of the 20 b/min SSΔHR cut point. Volunteers lost 4.5 ± 1.1, 3.0 ± 0.6, and 3.2 ± 0.6 % body mass during >3 % sweat, 3 % diuretic, and 3 % sweat trials, respectively. SSΔHR (b/min) was 9 ± 8 (EUH), 20 ± 12 (>3 % sweat; P < 0.05 vs. EUH), 17 ± 7 (3 % diuretic; P < 0.05 vs. EUH), and 13 ± 11 (3 % sweat). The 20 beats/min cut point had high specificity (90 %) but low sensitivity (44 %) and overall diagnostic accuracy of 67 %. SSΔHR increased significantly in response to severe hypertonic hypohydration and moderate isotonic hypohydration, but not moderate hypertonic hypohydration. However, the 20 beats/min cut point afforded only marginal diagnostic accuracy.

Costs of eprosartan versus diuretics for treatment of hypertension in a geriatric population: an observational, open-label, multicentre study.

BACKGROUND: Diuretics are considered to be agents of first choice when treating hypertension in the elderly because of their clinical efficacy and, in particular, their low cost. Indeed, the latter consideration has been used by health resource managers to promote the use of diuretics. However, when considering the costs of treating hypertension in a population it is also necessary to assess the adverse effects that diuretics produce, particularly in elderly people. OBJECTIVE: To compare the overall expenditure associated with the treatment of hypertension (specifically the angiotensin II type 1 receptor antagonist eprosartan vs diuretics) in an elderly population, taking into consideration not only the drug acquisition costs but also the adverse effects of treatment and the costs associated with such adverse effects. METHODS: This was a prospective, observational, nonrandomized, open-label, multicentre study based in eight community health centres and the Hypertension Unit of the University Hospital of Salamanca, Spain. The study included 220 hypertensive geriatric outpatients (males and females aged >or=65 years) referred from general practitioners and the Hypertension Unit, with a mean age of 71.8 years and distributed into two groups: one (n = 90) treated with diuretics and the other (n = 130) treated with eprosartan. Following an initial clinical assessment of patients at the beginning of the study, monitoring of treatment continued for 1 year with follow-up consultations scheduled for 3, 6 and 12 months. Both the costs relating to acquisition of the drugs and the costs derived from secondary adverse effects of drug treatment were included in the analysis. RESULTS: The response to the antihypertensive therapy was similar in both groups. In patients taking diuretics, adverse events resulted in increased use of healthcare resources because of urinary incontinence, purchase of adsorbents, hyponatraemia and the need to admit two patients to hospital. The patient/day cost was euro 1.05 for the group treated with diuretics and euro 0.98 for the group treated with eprosartan (year of costing 2006). CONCLUSION: In the geriatric population, the acquisition cost of the prescribed diuretics is not representative of the actual antihypertensive treatment expenditure. According to the results obtained in our study, the overall costs of eprosartan therapy were no different to those of diuretics, despite the fact that eprosartan had a higher acquisition cost. This is consistent with a more favourable safety profile for eprosartan, which may possibly contribute to improved prescription compliance. This conclusion should be taken into consideration when evaluating economic restrictions on the use of drugs.

Assessment of diuretic effects and changes in plasma aldosterone concentration following oral administration of a single dose of furosemide or azosemide in healthy dogs.

OBJECTIVE: To determine the diuretic effects and changes in plasma aldosterone concentration (PAC) following oral administration of a single dose of furosemide or azosemide in healthy dogs. ANIMALS: 8 mixed-breed dogs. PROCEDURES: A single dose of furosemide (2 mg/kg), azosemide (1, 5, or 10 mg/kg), or placebo (bifidobacterium [1 mg/kg]) was administered orally (in random order at 7-day intervals) to each dog (5 treatments/dog). Urine and blood samples were collected before (2 hours after evacuation of the urinary bladder; baseline) and at intervals for 24 hours after drug treatment to assess urine volume and plasma and urine biochemical variables. RESULTS: Compared with baseline values, treatment with furosemide and azosemide (5 and 10 mg/kg) increased urine output for 1 to 2 hours and 2 to 4 hours, respectively. The 24-hour urine volume and urinary sodium excretion were significantly increased following furosemide and azosemide (5 and 10 mg/kg) treatments, compared with effects of placebo; these increases were dose dependent for azosemide, and increases were similar for furosemide and the 5 mg/kg dose of azosemide. Compared with other treatments, 24-hour urinary potassium excretion was significantly increased with azosemide at 10 mg/kg. Azosemide (5 and 10 mg/kg) significantly increased plasma total protein concentration and decreased plasma potassium concentration, compared with baseline values. Compared with the effect of placebo, PAC was significantly increased by furosemide and the 10 mg/kg dose of azosemide. CONCLUSIONS AND CLINICAL RELEVANCE: In healthy dogs, a moderate dose of azosemide caused sufficient diuretic action and increased PAC to a lesser extent than furosemide.

Should chlorthalidone be the diuretic of choice for antihypertensive therapy?

For decades, diuretic therapy has been a cornerstone in treating hypertension, an approach supported by multiple randomized controlled trials demonstrating reduced morbidity and mortality from cardiovascular events. Yet controversy persists regarding the potential detrimental metabolic effects and side effects of diuretic agents. Within the risk-benefit debates about diuretic therapy is a second dialogue regarding the best thiazide or thiazidelike agent to prescribe. Proponents of chlorthalidone emphasize the demonstrated reductions in cardiovascular events reported from multiple classic trials and its longer half-life, whereas opponents point to its limited availability in low-dose forms and comparable favorable results from hydrochlorothiazide-based therapy to discredit claims of superiority. This review presents the data available on both sides of this issue to help the reader decide which claims are most valid, and offers recommendations for treatment.

Additional small amounts of diuretics improve blood pressure control at low cost without disadvantages in blood sugar metabolism.

We evaluated our present treatment of hypertension and sought a way to improve it. We studied 164 of outpatients we treated in 2002. Mean systolic blood pressure (SBP)+/-SD was 142.0+/-11.3, and 56% of patients had SBP over 140 mmHg. We used more diuretics in patients with good control of SBP (19% vs. 7% of patients; p=0.012). After observing our hypertensive patients, we changed our treatment in a goal-oriented manner. Our goal was blood pressure below 140/90 mmHg. We used, in principle, additional small amounts of diuretics for inadequately treated patients. We followed 147 of the 164 patients from 2002 to 2006. During this period, mean SBP decreased to 134.7+/-9.1 mmHg (p<0.001), and the frequency of patients with SBP>140 mmHg decreased to 14% (p<0.001). We used more diuretics in 2006 than in 2002 (12% to 46% p<0.001). To estimate the risks and benefits of diuretics, in 2006 we analyzed 510 patients who had been followed for at least 2 years. Potassium supplementation was needed in 28% of diuretic-treated patients and 7% of patients without diuretics. We found a correlation between the use of diuretics and good SBP control in the entire patient group as well as in patients with diabetes. In the control of diabetes mellitus, we found no statistical difference between patients treated with diuretics and those not. We found diuretics had no adverse effects with respect to new-onset diabetes mellitus.

Confidence intervals for the amount of heterogeneity in meta-analysis.

Effect size estimates to be combined in a systematic review are often found to be more variable than one would expect based on sampling differences alone. This is usually interpreted as evidence that the effect sizes are heterogeneous. A random-effects model is then often used to account for the heterogeneity in the effect sizes. A novel method for constructing confidence intervals for the amount of heterogeneity in the effect sizes is proposed that guarantees nominal coverage probabilities even in small samples when model assumptions are satisfied. A variety of existing approaches for constructing such confidence intervals are summarized and the various methods are applied to an example to illustrate their use. A simulation study reveals that the newly proposed method yields the most accurate coverage probabilities under conditions more analogous to practice, where assumptions about normally distributed effect size estimates and known sampling variances only hold asymptotically.

Screening for the alpha-adducin Gly460Trp variant in hypertensive patients: a cost-effectiveness analysis.

BACKGROUND: Studies have shown that approximately 80% of hypertensive patients do not take diuretics despite their recommendation as a first-line therapy. A recent study reported that hypertensive patients with the Gly460Trp variant in the alpha-adducin gene are more likely to benefit from diuretic therapy. The objective of this study was to evaluate the potential cost effectiveness of screening for the alpha-adducin Gly460Trp variant among hypertensive patients. METHODS: A decision analytic Markov model was developed to estimate the clinical and economic outcomes comparing screening for the Gly460Trp variant to identify patients for addition of a diuretic compared to no screening and no addition of diuretic (usual care) in a hypothetical cohort of treated hypertensive patients not receiving diuretic therapy. We used a lifetime horizon and payer perspective. Cost, utility and epidemiological data were obtained from the literature. One-way, probabilistic, and scenario sensitivity analyses were conducted to evaluate the uncertainty in the results. RESULTS: The screening strategy increased quality adjusted life years (QALYs) by 0.14 (95% confidence range [CR]: 0.05, 0.36) and saved dollar 1834 (dollar 505, dollar 5174) compared to usual care. The most influential input was the strength of the interaction between the alpha-adducin gene variant and diuretic effect. CONCLUSIONS: Our results suggest that screening for the alpha-adducin gene variant may be a useful mechanism to identify patients most likely to benefit from diuretic therapy and improve compliance with current treatment guidelines.

Application of red laser video-rate scanning confocal microscopy to in vivo assessment of tubular function in the rat: selective action of diuretics on tubular diameter.

This study examined the use of a red laser illuminated, video-rate scanning confocal reflection microscopy (VRSCM) system, with improved structural and functional imaging at high temporal resolution, to visualize physiological changes in the kidney in response to pharmacological stimuli. We applied VRSCM to superficial nephrons in vivo and measured temporal changes in the diameter of proximal and/or distal tubular segments in response to the administration of three major classes of diuretics with known selective actions at specific nephron sites. Mannitol caused measurable increases in both proximal and distal tubular diameter, whereas frusemide and hydrochlorothiazide caused dilation of the distal tubules only. The findings indicate that VRSCM is capable of detecting and quantifying predicted dynamic changes in renal tubular diameter.

Properties of quantal transmission at CA1 synapses.

We have used Monte Carlo simulations to understand the generation of quantal responses at the single active zones of CA1 synapses. We constructed a model of AMPA channel activation that accounts for the responses to controlled glutamate application and a model of glutamate diffusion in the synaptic cleft. With no further adjustments to these models, we simulated the response to the release of glutamate from a single vesicle. The predicted response closely matches the rise time of observed responses, which recent measurements show is much faster (<100 micros) than previously thought. The simulations show that initial channel opening is driven by a brief (<100 micros) glutamate spike near the site of vesicle fusion, producing a hotspot of channel activation (diameter: approximately 250 nm) smaller than many synapses. Quantal size therefore depends more strongly on the density of channels than their number, a finding that has important implications for measuring synaptic strength. Recent measurements allow estimation of AMPA receptor density at CA1 synapses. Using this value, our simulations correctly predicts a quantal amplitude of approximately 10 pA. We have also analyzed the properties of excitatory postsynaptic currents (EPSCs) generated by the multivesicular release that can occur during evoked responses. We find that summation is nearly linear and that the existence of multiple narrow peaks in amplitude histograms can be accounted for. It has been unclear how to reconcile the existence of these narrow peaks, which indicate that the variation of quantal amplitude is small (CV < 0.2) with the highly variable amplitude of miniature EPSCs (mEPSCs; CV approximately 0.6). According to one theory, mEPSC variability arises from variation in vesicle glutamate content. However, both our modeling results and recent experimental results indicate that this view cannot account for the observed rise time/amplitude correlation of mEPSCs. In contrast, this correlation and the high mEPSC variability can be accounted for if some mEPSCs are generated by two or more vesicles released with small temporal jitter. We conclude that a broad range of results can be accounted for by simple principles: quantal amplitude (approximately 10 pA) is stereotyped, some mEPSCs are multivesicular at moderate and large synapses, and evoked responses are generated by quasi-linear summation of multiple quanta.

Electrophysiological assessment of sensations arising from the bladder: are there objective criteria for subjective perceptions?

PURPOSE: Initial bladder filling sensation, first and strong desire to void are subjective perceptions that occur periodically during the urine storage mode of bladder function, representing sensory input from the lower urinary tract. To our knowledge methods for evaluating sensory bladder function are not available. We studied a simple electrophysiological procedure for the objective assessment of bladder sensations using sympathetic skin responses and surface pelvic floor electromyography. MATERIALS AND METHODS: Informed consent was provided by 8 healthy male subjects, who were administered 20 mg. furosemide and 1 l. fluid to drink. Palmar and plantar sympathetic skin responses, and surface pelvic floor electromyogram were continuously recorded during bladder filling, voluntary pelvic floor contraction and voiding. RESULTS: First desire to void evoked simultaneous sympathetic skin responses and pelvic floor contractions. This pattern appeared periodically with the desire to void sensation as well as with strong desire to void at maximum bladder capacity and it correlated well with the subjective sensation of the subjects. Voluntary pelvic floor contraction decreased the subjective intensity of the desire to void sensation as well as sympathetic skin response activity for the same short period. During voiding sympathetic skin responses almost complete absence of sympathetic skin responses was observed. CONCLUSIONS: Sensations arising from the bladder induce combined activation of sympathetic skin responses and pelvic floor activity. This coherence indicates synchronized activation and inactivation of the autonomic and somatic pathways necessary for appropriate urine storage and coordinated voiding. Our observations may introduce a new approach for objectively assessing subjective sensations arising from the urinary tract.

Spironolactone in heart failure--a revived role for an old drug.

Spironolactone is an aldosterone antagonist which has been used as a mild potassium-sparing diuretic and in treatment of ascites in liver failure. Recent studies have shown that it has an additive effect to those of ACE inhibitors in heart failure treatment.