Peter U. Feig

Next-generation biomarkers for detecting kidney toxicity

There is a paucity of biomarkers that reliably detect nephrotoxicity. The Predictive Safety Testing Consortium (PSTC) faced several challenges in identifying novel safety biomarkers in the renal setting.

Efficacy and safety of the selective 11β-HSD-1 inhibitors MK-0736 and MK-0916 in overweight and obese patients with hypertension.

11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) may be involved in several abnormalities associated with the metabolic syndrome. This study evaluated the antihypertensive efficacy and safety of two 11β-HSD1 inhibitors, MK-0736 and MK-0916, in overweight-to-obese hypertensive patients. Patients aged 18-75 years with sitting diastolic blood pressure (SiDBP) 90-104 mm Hg, systolic BP <160 mm Hg (after washout of prior antihypertensive medications), and BMI ≥27 to <41 kg/m(2) were randomized to receive 2 or 7 mg/d MK-0736, 6 mg/d MK-0916, or placebo for 12 weeks (n = 51-54/group). Patients with BMI ≥20 to <27 kg/m(2) received 6 mg/d MK-0916 or placebo for 24 weeks (n = 19/group). The primary endpoint was placebo-adjusted change from baseline in trough SiDBP in patients treated for 12 weeks with 7 mg/d MK-0736. The primary endpoint was not met (placebo-adjusted reduction = 2.2 mm Hg; P = .157). With 7 mg/d MK-0736, placebo-adjusted LDL-C decreased by 12.3%, high-density lipoprotein cholesterol by 6.3%, and body weight by 1.4 kg. Both 11β-HSD1 inhibitors were generally well tolerated. In overweight-to-obese patients with hypertension, reduction in SiDBP with MK-0736 was not statistically significant. Nonetheless, MK-0736 was well tolerated and did appear to modestly improve other BP endpoints, LDL-C, and body weight.

Antihypertensive drug development: current challenges and future opportunities.

The growing rate of obesity and diabetes, and an aging population has led to increased demand for new antihypertensive compounds. This review highlights the challenges and opportunities associated with each phase of drug discovery and development of novel antihypertensive agents. Discovery and development starts with identification of a protein hypothesized to be linked to hypertension. Using the information gathered during this early stage, several potential candidates are often synthesized and moved on through preclinical evaluations, eventually leading to selection of one or more compounds for testing in humans. The compounds then enter preclinical safety studies in laboratory animal species and subsequently are tested in tiered clinical studies. As the compounds enter clinical testing, there is an exponential increase in the investment of resources to demonstrate that a new compound is a viable and worthy therapeutic agent for hypertension. The review provides some forecasting of issues that are likely to impact drug development of novel antihypertensives in the future.

Clinical Use of Pulse Wave Analysis: Proceedings From a Symposium Sponsored by North American Artery

The use of pulse wave analysis may guide the provider in making choices about blood pressure treatment in prehypertensive or hypertensive patients. However, there is little clinical guidance on how to interpret and use pulse wave analysis data in the management of these patients. A panel of clinical researchers and clinicians who study and clinically use pulse wave analysis was assembled to discuss strategies for using pulse wave analysis in the clinical encounter. This manuscript presents an approach to the clinical application of pulse waveform analysis, how to interpret central pressure waveforms, and how to use existing knowledge about the pharmacodynamic effect of antihypertensive drug classes in combination with brachial and central pressure profiles in clinical practice. The discussion was supplemented by case‐based examples provided by panel members, which the authors hope will provoke discussion on how to understand and incorporate pulse wave analysis into clinical practice.

Effects of the renin inhibitor MK-8141 (ACT-077825) in patients with hypertension.

The renin inhibitor MK-8141 (ACT-077825) demonstrates substantial immunoreactive active renin (ir-AR) increase (sevenfold) without a persistent plasma renin activity (PRA) decrease. The present study assessed the antihypertensive efficacy of MK-8141 in hypertensive patients. In this double-blind, placebo- and active comparator-controlled study, 195 patients with hypertension (trough sitting diastolic blood pressure ≥92 to <105 mm Hg, trough sitting systolic blood pressure <170 mm Hg, and 24-hour mean diastolic blood pressure [DBP] ≥80 mm Hg) were randomized to one of four treatments (stratified by race, black versus others): MK-8141 250 mg, MK-8141 500 mg, enalapril 20 mg, or placebo. Blood pressure was measured at trough and as 24-hour ambulatory blood pressure monitoring. The primary end point was change from baseline in 24-hour mean ambulatory DBP measured after 4 weeks. At week 4, the change from baseline in 24-hour mean (95% CI) ambulatory DBP compared with placebo was -1.6 mm Hg (-4.2, 1.1), -1.1 mm Hg (-3.9, 1.6), and -4.9 (-7.5, -2.2) for MK-8141 250 mg, MK-8141 500 mg, and enalapril 20 mg, respectively. Only mean ambulatory DBP-lowering with enalapril 20 mg was statistically significant. Enalapril, but not MK-8141, also significantly lowered 24-hour mean ambulatory systolic blood pressure (SBP) compared with placebo (-6.7 mm Hg [-10.5, -2.8]). Neither enalapril nor MK-8141 significantly lowered trough DBP and SBP compared with placebo. MK-8141 was generally well tolerated. In patients with hypertension, MK-8141 (ACT-077825) did not produce significant blood pressure-lowering efficacy despite a demonstrated effect of the drug on ir-AR, in the absence of durable PRA suppression.

Single-dose effects of isosorbide mononitrate alone or in combination with losartan on central blood pressure.

Antihypertensive drugs can have different effects on central and brachial blood pressures, which may affect outcomes. Nitric oxide donors have acute effects on central blood pressure but have not been assessed with renin-angiotensin system blockade. Thirteen patients with prehypertensive/Stage 1 hypertension were randomized to five single-dose treatments separated by ≤4 days using a double-blind, crossover study design: angiotensin receptor blocker (ARB) losartan 100 mg, isosorbide mononitrate (ISMN) 60 mg, losartan 100 mg + ISMN 15 mg, losartan 100 mg + ISMN 60 mg, and placebo. Central and brachial blood pressures were measured throughout 10 hours. Mean placebo-subtracted decrease from baseline in augmentation index (AIx) approximately 1% for losartan 100 mg, 26% for ISMN 60 mg, 19% for losartan 100 mg + ISMN 15 mg, and 24% for losartan 100 mg + ISMN 60 mg. Administered with losartan 100 mg or alone, ISMN lowered AIx, demonstrating that acute effects of a nitrate donor are much larger than those of an ARB even when administered with an ARB. Differences from placebo were statistically significant except for losartan 100 mg. AIx is a good biomarker of acute hemodynamic effects of nitric oxide in prehypertensive/Stage 1 hypertension.

Central blood pressure measurements—an opportunity for efficacy and safety in drug development?

Over a century of experience with brachial blood pressure has produced a substantial amount of information on the role of blood pressure as a factor in heart disease, stroke and kidney failure. Successful interventions lowering blood pressure and reducing damage to vital organs testify further to the importance of this vital sign. In recent years attempts to probe deeper into the value of knowledge of blood pressure levels closer to the heart (central blood pressures) suggest that noninvasive measurement of central aortic blood pressure may improve further efforts directed at both understanding drug benefit and uncovering potential drug safety issues. This commentary is a summary of a one-day meeting with the FDA in which the role of central blood pressure measurements as an adjunct to drug efficacy and safety were addressed.

Sodium and Fluid Excretion With Torsemide in Healthy Subjects is Limited by the Short Duration of Diuretic Action

Background Loop diuretics are highly natriuretic but their short duration of action permits postdiuretic sodium retention, which limits salt loss unless dietary salt is severely restricted. We tested the hypothesis that a more prolonged duration of action would enhance salt loss. Methods and Results Ten healthy participants were crossed over between 20 mg of oral immediate‐release or extended‐release (ER) torsemide while consuming a fixed diet with 300 mmol·d−1 of Na+. Compared with immediate‐release, plasma torsemide after ER was 59% lower at 1 to 3 hours but 97% higher at 8 to 10 hours as a result of a >3‐fold prolongation of time to maximal plasma concentrations. The relationship of natriuresis to log torsemide excretion showed marked hysteresis, but participants spent twice as long with effective concentrations of torsemide after ER, thereby enhancing diuretic efficiency. Compared with immediate‐release, ER torsemide did not reduce creatinine clearance and increased fluid (1634±385 versus 728±445 mL, P<0.02) and Na+ output (98±15 versus 42±17 mmol, P<0.05) despite an 18% reduction in exposure. Neither formulation increased K+ excretion. Conclusions Torsemide ER prolongs urine drug levels, thereby increasing the time spent with effective drug concentrations, reduces postdiuretic Na+ retention, and moderates a fall in glomerular filtration rate. It caused significant Na+ loss even during very high salt intake. Thus, a short duration of action limits salt loss with loop diuretics. These conclusions warrant testing in subjects with edema and heart failure.