Ambrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2.

BACKGROUND: Ambrisentan is a propanoic acid-based, A-selective endothelin receptor antagonist for the once-daily treatment of pulmonary arterial hypertension. METHODS AND RESULTS: Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy Study 1 and 2 (ARIES-1 and ARIES-2) were concurrent, double-blind, placebo-controlled studies that randomized 202 and 192 patients with pulmonary arterial hypertension, respectively, to placebo or ambrisentan (ARIES-1, 5 or 10 mg; ARIES-2, 2.5 or 5 mg) orally once daily for 12 weeks. The primary end point for each study was change in 6-minute walk distance from baseline to week 12. Clinical worsening, World Health Organization functional class, Short Form-36 Health Survey score, Borg dyspnea score, and B-type natriuretic peptide plasma concentrations also were assessed. In addition, a long-term extension study was performed. The 6-minute walk distance increased in all ambrisentan groups; mean placebo-corrected treatment effects were 31 m (P=0.008) and 51 m (P<0.001) in ARIES-1 for 5 and 10 mg ambrisentan, respectively, and 32 m (P=0.022) and 59 m (P<0.001) in ARIES-2 for 2.5 and 5 mg ambrisentan, respectively. Improvements in time to clinical worsening (ARIES-2), World Health Organization functional class (ARIES-1), Short Form-36 score (ARIES-2), Borg dyspnea score (both studies), and B-type natriuretic peptide (both studies) were observed. No patient treated with ambrisentan developed aminotransferase concentrations >3 times the upper limit of normal. In 280 patients completing 48 weeks of treatment with ambrisentan monotherapy, the improvement from baseline in 6-minute walk at 48 weeks was 39 m. CONCLUSIONS: Ambrisentan improves exercise capacity in patients with pulmonary arterial hypertension. Improvements were observed for several secondary end points in each of the studies, although statistical significance was more variable. Ambrisentan is well tolerated and is associated with a low risk of aminotransferase abnormalities.

Low-dose oral enoximone enhances the ability to wean patients with ultra-advanced heart failure from intravenous inotropic support: results of the oral enoximone in intravenous inotrope-dependent subjects trial.

BACKGROUND: We determined whether low-dose oral enoximone could wean patients with ultra-advanced heart failure (UA-HF) from intravenous (i.v.) inotropic support. Chronic parenteral inotropic therapy in UA-HF is costly and requires an indwelling catheter. An effective and safe oral inotrope would have value. METHODS: In this placebo-controlled study, 201 subjects with UA-HF requiring i.v. inotropic therapy were randomized to enoximone or placebo. Subjects receiving intermittent i.v. inotropes were administered study medication of 25 or 50 mg 3 times a day (tid). Subjects receiving continuous i.v. inotropes were administered 50 or 75 mg tid for 1 week, which was reduced to 25 or 50 mg tid. The ability of subjects to remain alive and free of inotropic therapy was assessed for up to 182 days. RESULTS: Thirty days after weaning, 51 (51%) subjects on placebo and 62 (61.4%) subjects in the enoximone group were alive and free of i.v. inotropic therapy (unadjusted primary end point P = 0.14, adjusted for etiology P = .17). At 60 days, the wean rate was 30% in the placebo group and 46.5% in the enoximone group (unadjusted P = .016) Kaplan-Meier curves demonstrated a trend toward a decrease in the time to death or reinitiation of i.v. inotropic therapy over the 182-day study period (hazard ratio 0.76 [95% CI 0.55-1.04]) and a reduction at 60 days (0.62 [95% CI 0.43-0.89], P = .009) and 90 days (0.69 [95% CI 0.49-0.97], P = .031) after weaning in the enoximone group. CONCLUSIONS: Although there was no benefit over placebo in weaning patients from i.v. inotropes from 0 to 30 days, the EMOTE data suggest that low-dose oral enoximone can be used to wean a modest percentage of subjects from i.v. inotropic support for up to 90 days after initiation of therapy.

Efficacy and safety of darusentan in patients with resistant hypertension: results from a randomized, double-blind, placebo-controlled dose-ranging study.

In this phase 2, randomized, double-blind, placebo-controlled forced dose-titration study, 115 patients with resistant hypertension, receiving background therapy with >/=3 antihypertensive medications including a diuretic at full doses, were randomized 2:1 to increasing doses of darusentan (10, 50, 100, 150, and 300 mg), a selective endothelin receptor antagonist, or matching placebo once daily for 10 weeks. Darusentan treatment decreased mean systolic and diastolic blood pressure levels in a dose-dependent fashion compared with placebo; the largest reductions were observed at week 10 (300-mg dose) (systolic, -11.5+/-3.1 mm Hg [P=.015;] diastolic, -6.3+/-2.0 mm Hg [P=.002]). Darusentan (300 mg) also decreased mean 24-hour, daytime, and nighttime ambulatory blood pressures from baseline to week 10. Darusentan was generally well tolerated; mild to moderate edema and headache were the most common adverse events. This study demonstrates a clinical benefit from a new class of antihypertensive agent in patients classified as resistant by the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure guidelines.

Allosteric modification of hemoglobin by RSR13 as a therapeutic strategy.

RSR13 binds to hemoglobin (Hb), reduces oxygen (O2) binding affinity, and enhances O2 unloading from Hb to hypoxic tissue. Tissue hypoxia is common to cancer, surgery, myocardial ischemia, and stroke. RSR13 increases tumor pO2, reduces tumor hypoxic fraction and because O2 is necessary to maximize the effectiveness of radiation therapy, RSR13 enhances the efficacy of radiation therapy. Patients with brain metastases or glioblastoma multiforme receiving RSR13 and radiation therapy have improved median survival, compared to matched historical controls. Myocardial and cerebral hypoxia can be complications to cardiopulmonary bypass (CPB) surgery. RSR13 improves myocardial oxidative metabolism and contractile function in models of myocardial ischemia, including CPB. In CPB patients, RSR13 improved cardiac contractile function and reduced blood product use. In animals, RSR13 increased brain pO2 and reduced neuronal cell death following cerebral ischemia, alone or in combination with excitotoxic neurotransmitter inhibition. Allosteric modification of Hb by RSR13 represents a unique therapeutic strategy.

Ambrisentan therapy in patients with pulmonary arterial hypertension who discontinued bosentan or sitaxsentan due to liver function test abnormalities.

BACKGROUND: Some endothelin receptor antagonists (ERAs) are associated with liver function test (LFT) result abnormalities. However, ambrisentan has an incidence of serum aminotransferase levels more than three times the upper limit of normal (ULN), similar to that observed in PAH patients who are not receiving ERAs. Because ambrisentan may provide benefits in PAH patients who have discontinued ERA therapy due to LFT abnormalities, we evaluated the safety and efficacy of ambrisentan in this patient population. METHODS: Patients who previously discontinued bosentan and/or sitaxsentan due to LFT abnormalities received ambrisentan, 2.5 mg qd, for 4 weeks followed by 5 mg/d for 8 weeks. The primary end point was the incidence of aminotransferase levels more than three times ULN considered by the investigator to be related to ambrisentan and resulting in drug discontinuation. Secondary end points included aminotransferase levels more than five times ULN requiring drug discontinuation and more than three times ULN requiring dose reduction, as well as changes in 6-min walk distance (6MWD), Borg dyspnea index, World Health Organization functional class, and Short Form-36 health survey score. Patients continued treatment beyond the 12-week end point with monthly monitoring of LFTs. RESULTS: Thirty-six patients who previously discontinued bosentan (n = 31), sitaxsentan (n = 2), or both (n = 3) were enrolled. At baseline, 69.4% of patients were receiving prostanoid and/or sildenafil therapy. No patient had an aminotransferase level more than three times ULN that required ambrisentan discontinuation. One patient had a transient aminotransferase level more than three times ULN that resolved following a temporary dose reduction. No additional aminotransferase levels more than three times ULN were observed with long-term treatment (median exposure, 102 weeks), despite dose increases to 10 mg qd in more than half of the patients. Significant improvements in 6MWD and other efficacy assessments were observed. CONCLUSIONS: Ambrisentan treatment may be an option for patients who have discontinued bosentan and/or sitaxsentan therapy due to LFT result abnormalities. TRIAL REGISTRATION: Clinicaltrials.gov Identifier NCT00423592.

Controlling dimensions of polymerized micelles: micelle template versus reaction conditions.

The polymerization of elongated micellar structures offers a novel approach to the production of high aspect ratio, water-soluble amphiphilic nanoparticles. Three different surfactants were synthesized consisting of a cationic surfactant of the form (C(X)H(2X+1))trimethylammonium (where X = 14, 16, or 18) and a vinyl-containing counterion, 4-vinylbenzoate. The resulting polymer-surfactant aggregates have been polymerized to produce high aspect ratio nanoparticles which are insensitive to changes in solution conditions. The radius of the initial template is maintained on polymerization, whereas the template length is not. The aggregate radius is varied by changing the length of the surfactant tail, in this case producing aggregates with radii of 1.7, 2.0, or 2.4 nm. Variation of the initiator decomposition half-life, by means of using different initiators and varying temperature, is used to control the aggregate length between 80 and 500 nm. Through the process discussed here, both the radius and length of the aggregates are controlled independently.

Ambrisentan for pulmonary arterial hypertension.

Endothelin receptor antagonists (ERAs) are an important class of agents used for the treatment of pulmonary arterial hypertension (PAH). Ambrisentan is an oral, once-daily, endothelin type-A receptor (ETA)-selective, propanoic acid class ERA under clinical investigation for the treatment of PAH. In a Phase II study, ambrisentan improved 6-minute walk distance, Borg dyspnea index, World Health Organization Functional Class, and hemodynamics. Ambrisentan was well tolerated and adverse events were not dose related, including a low incidence and severity of liver function test abnormalities. There are no relevant interactions between ambrisentan and cytochrome P450 isoenzymes (metabolism, induction or inhibition) that might alter the activity of P450-metabolized drugs. Potential benefits of ambrisentan include oral, once-daily dosing, ET(A)-receptor selectivity, and the decreased risks of liver toxicity and adverse drug-drug interactions compared with other ERAs.

Rationale and design of the enoximone clinical trials program.

BACKGROUND: Chronic heart failure is a disease syndrome characterized in its advanced stages by a poor quality of life, frequent hospitalizations, and a high risk of mortality. In advanced and ultra-advanced chronic heart failure, many treatment options, such as cardiac transplantation and mechanical devices, are severely limited by availability and cost. Short-term Phase II clinical trials suggest that low-dose oral inotropic therapy with enoximone may improve hemodynamics and exercise capacity, without adversely affecting mortality, in selected subjects with advanced chronic heart failure. Based on these data, the ability of enoximone to deliver safe and efficacious palliative treatment of advanced/ultra-advanced chronic heart failure is being evaluated in Phase III clinical trials. METHODS AND RESULTS: The Enoximone Clinical Trials Program is a series of 4 clinical trials designed to evaluate the safety and efficacy of oral enoximone in advanced chronic heart failure. ESSENTIAL I and II (The Studies of Oral Enoximone Therapy in Advanced Heart Failure) will investigate the effects of oral enoximone on all-cause mortality and cardiovascular hospitalization, submaximal exercise capacity, and quality of life in subjects with New York Heart Association Class III/IV chronic heart failure. EMOTE (Oral Enoximone in Intravenous Inotrope-Dependent Subjects) will evaluate the potential of oral enoximone to wean subjects with ultra-advanced chronic heart failure from chronic intravenous inotropic therapy to which they have been shown to be dependent. EMPOWER (Enoximone Plus Extended-Release Metoprolol Succinate in Subjects with Advanced Chronic Heart Failure) will explore the potential of enoximone to increase the tolerability of continuous release metoprolol in subjects shown previously to be hemodynamically intolerant to beta-blocker treatment. CONCLUSION: These studies are Phase III, multicenter, randomized, double-blinded, placebo-controlled trials designed to test the general hypothesis that chronic oral administration of low doses of enoximone can produce beneficial effects in subjects with advanced or ultra-advanced chronic heart failure.

Characterization of rodlike aggregates generated from a cationic surfactant and a polymerizable counterion.

The polymerization of elongated micellar structures offers a novel approach to the production of high-aspect-ratio, water-soluble amphiphilic nanorods. A cationic surfactant with a vinyl-containing counterion, cetyltrimethylammonium 4-vinylbenzoate, has been synthesized and polymerized to produce high-aspect-ratio nanoparticles which are insensitive to changes in solution conditions. Aggregates are polymerized over a range of initiator concentrations allowing for control of the product length. Small-angle neutron scattering and light scattering are used to characterize the dimensions of the polymerized aggregates, showing them to have a fixed radius of 2 nm and contour lengths varying from 96 to 340 nm. Proton NMR verifies the chemical structure and provides insight into the mobility of the aggregate components. Finally, gel permeation chromatography of the polymer extracted from the aggregates indicates that the polymerization reaction controls the aggregate dimensions.