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.

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.

RSR-13, an allosteric effector of hemoglobin, increases systemic and iliac vascular resistance in rats.

Tissue O2 delivery in excess of metabolic demand may be a factor in the development of high vascular resistance in experimental models of volume-expanded hypertension. This hypothesis was previously tested in rats with an exchange transfusion of red blood cells treated with inositol hexaphosphate or an intravenous infusion of RSR-4, allosteric effectors of hemoglobin. The binding of these drugs with hemoglobin effect a conformational change in the molecule, such that the affinity for O2 is reduced.

Identification of a putative microvascular oxygen sensor.

The vascular response to changes in oxygen levels in the blood and tissue is a highly adaptive physiological response that functions to match tissue oxygen supply to metabolic demand. Defining the cellular mechanisms that can sense physiologically relevant changes in PO2 and adjust vascular diameter are vital to our understanding of this process. A cytochrome P450 (P450) enzyme of the 4A family of omega-hydroxylases was localized in renal microvessels, renal cortex, and a striated muscle microvascular bed (cremaster) of the rat.