Synthetic Allosteric Modifier Of Hemoglobin Research Articles

Reduction in Hemoglobin–Oxygen Affinity Results in the Improvement of Exercise Capacity in Mice With Chronic Heart Failure

This study examined whether a reduction in hemoglobin-oxygen affinity improves exercise capacity in mice with heart failure. Exercise intolerance is a major determinant of quality of life in patients with chronic heart failure. One of the major goals of the treatment for chronic heart failure is to improve quality of life. Four weeks after left coronary ligation, we transplanted bone marrow cells isolated from the transgenic mice expressing a hemoglobin variant with low oxygen affinity, Presbyterian, into the lethally irradiated mice with heart failure or administered a synthetic allosteric modifier of hemoglobin. The mice were then exercised on a treadmill. Four weeks after the left coronary artery ligation, mice showed cardiac dysfunction and chamber dilation, which were characteristics of heart failure. The transplantation led to a reduction in hemoglobin-oxygen affinity and an increase in oxygen supply for skeletal muscle without changes in muscle properties. The transplanted mice showed improved running performance on a treadmill despite impaired cardiac contractility. Furthermore, administration of the synthetic allosteric modifier of hemoglobin showed a similar effect. Allosteric modification of hemoglobin represents a therapeutic option for improving exercise capacity in patients with chronic heart failure. One mechanism of improvement in exercise capacity is enhanced oxygen delivery in the skeletal muscle.

The influence of efaproxiral on breast cancer xenograft hypoxia and HIF-1-alpha expression

10102 Background: Efaproxiral (E), a synthetic allosteric modifier of hemoglobin, has demonstrated clinical safety and efficacy as a radiosensitizer in patients with brain metastases from breast cancer. Although shown to enhance oxygenation in a murine mammary tumor, efaproxiral has not previously been tested in a human breast cancer xenograft. We studied changes in tumor oxygenation in a human xenograft and evaluated whether efaproxiral induces cell signaling events of potential therapeutic value. Methods: MDA-MB-468 breast cancer cells in matrigel were injected into the flank of nude mice. After tumors grew to 1–1.5 cm, animals were subjected to 1 of 3 treatments: ip saline +room air breathing (RA), ip saline + 50% oxygen breathing (O2), or ip efaproxiral (300 mg/kg) + 50% oxygen breathing (E+O2). Twenty minutes later the hypoxia marker, pimonidazole (pimo), was given, and 70 minutes later tumors were harvested for immunohistochemical study of hypoxia and hypoxia-inducible factor 1-alpha (HIF1-α) and RNA extraction to identify early changes in gene expression. Image analysis software was used to quantify observations. Results: Tumor hypoxia and HIF1-α staining were significantly decreased by efaproxiral (Table). HIF1-α staining did not entirely colocalize with pimo, implying different oxygen tension levels for HIF1-α ubiquitination and pimo reduction. Gene arrays indicated that after E+O2, expression of the hypoxia-induced DR1 transcription repressor was reduced compared with O2. Conclusions: The combination of E+O2 reduced hypoxia and HIF1-α expression in MDA-MB-468 human breast tumors in vivo, and an early effect on gene expression was reduced DR1. The results demonstrate an efaproxiral-mediated enhanced oxygenation of human hypoxic breast cancer. Furthermore, the efaproxiral-mediated down-regulation of HIF1-α suggests possible new opportunities in the clinical application of efaproxiral, notably as an adjuvant to systemic agents for which HIF1-α-mediated resistance limits efficacy. [Table: see text] [Table: see text]

Efaproxiral: A Radiation Enhancer Used in Brain Metastases from Breast Cancer

To review the mechanism of action and clinical data of efaproxiral use in brain metastases of breast cancer. Articles were identified through MEDLINE (1966-June 2005) and EMBASE (1980-May 2005) searches using the key words efaproxiral and RSR13. Published abstracts over the previous 10 years from various scientific meetings, including American Society of Clinical Oncology and San Antonio Breast Cancer Symposium, were also searched for investigations of efaproxiral. Data on efaproxiral were also provided by Allos Therapeutics. All published clinical data in humans regarding efaproxiral use in brain metastases from breast cancer were selected for this review. In addition, published studies in humans that discussed the pharmacokinetics, pharmacodynamics, and safety of efaproxiral were evaluated. Efaproxiral is a synthetic allosteric modifier of hemoglobin that results in a shift of the hemoglobin oxygen dissociation curve to the right. Therefore, oxygen is more readily released from hemoglobin into tissues. Efaproxiral demonstrated a significant survival benefit when used as a radiation enhancer in patients with brain metastases originating from breast cancer. The safety profile of efaproxiral and improved survival rates make this agent advantageous over radiation alone. Further investigation and results from the ongoing clinical trials will help to define the role of efaproxiral in clinical practice. Efaproxiral is the first synthetic allosteric modifier to demonstrate significant improvement in survival in patients undergoing radiation therapy for brain metastases of breast cancer. Validation of this effect in ongoing clinical trials will be important in determining the role of efaproxiral in brain metastases from breast cancer.

Population pharmacokinetic-pharmacodynamic modeling of efaproxiral in cancer patients receiving radiation therapy

Aims Efaproxiral (EFP), a synthetic allosteric modifier of hemoglobin (Hb), reduces O2-binding affinity in blood (p50) and is investigated as a radiation therapy sensitizer. The goal of this work was to describe the pharmacokinetics (PK) and pharmacodynamics (PD) of EFP in cancer (CA) patients. Methods Pooled data from 6 phase I -III trials included: 451 patients, 2582 plasma and 2881 RBC concentrations, and 2483 p50 values. Covariates were age, weight, height, sex, concomitant medications, CA type, Hb, albumin, creatinine clearance, body surface area (BSA) and dose. Data were analyzed using NONMEM. Results A linear, 2-compartment model with RBC:plasma proportionality constant and a linear RBC-p50 model described the PK-PD relationship. Parameters were consistent with previously reported values (%SE): CL=1.88 L/hr (8%), V1=10.5 L (2%), Q=2.58 L/hr (12%), V2=18.1 L (10%), SLPRBC=0.982 (1%), INTp50=26.9 mmHg (~0%), SLPp50=0.0193 mmHg/(μg/mL) (5%). The inclusion of covariates resulted in improvements in goodness of fit and decreases in the estimated inter-individual variances. The final model adequately described the central tendency and population variability for the observed data. Conclusions Differences in PK-PD response due to CA type were small, may have been study-related and were probably not clinically relevant. EFP exposure increased with age, but the clinical relevance of this effect was unknown. BSA was the most important predictor of EFP disposition. Clinical Pharmacology & Therapeutics (2005) 77, P89–P89; doi: 10.1016/j.clpt.2004.12.233

Detection in urine of efaproxiral (RSR13), a potential doping agent, by a routine screening procedure based on methylation followed by gas chromatography/mass spectrometry

Efaproxiral (also known as RSR13) is a synthetic allosteric modifier of hemoglobin. The ability to increase maximal muscle oxygen uptake makes RSR13 a potential performance-enhancing agent for athletes and, therefore, a new agent to be taken into account by the antidoping control laboratories. In this work, a new method for the detection of efaproxiral in urine by gas chromatography/mass spectrometry is described.

RSR13 modulates tumor hypoxia and HIF-1-alpha expression in H226 xenografts in vivo

Purpose/Objective: Interstitial tumor oxygen measurements and radiosensitivity assays have established that RSR13 (efaproxiral), a synthetic allosteric modifier of hemoglobin that decreases hemoglobin-oxygen binding affinity, improves radiosensitivity in vivo by reducing the hypoxic fraction in solid tumors. To characterize the micro-regional distribution of RSR13-mediated oxygenation and evaluate its effect upon hypoxia-induced gene expression, a xenograft model was analyzed for the geographic pattern of changes in hypoxia and the resulting impact upon hypoxia-inducible factor 1-alpha (HIF1-α) expression.

The effect of RSR13, a synthetic allosteric modifier of hemoglobin, on brain tissue pO2 (measured by EPR oximetry) following severe hemorrhagic shock in rats.

RSR13 is a synthetic allosteric modifier of hemoglobin that decreases the oxygen binding affinity of hemoglobin, potentially increasing oxygen availability to hypoxic tissues. Using in vivo EPR to directly measure cortical pO2, we examined whether RSR13 would improve brain tissue pO2 following severe hemorrhagic shock in rats. Hemorrhagic shock was induced by withdrawing blood (2.7-2.8 mL/100 g/15 min). Following a 30 min shock period, resuscitation was performed by infusion with Ringer lactate plus RSR13 (150 mg/kg) or saline (control). Following hemorrhage, brain pO2 decreased by about 14 mm Hg in both groups. Following crystalloid resuscitation brain pO2 remained depressed in the control group but returned to the pre-hemorrhage values in the rats that received RSR13. RSR13 immediately increased and maintained the paO2 while controls had a very gradual increase towards pre-hemorrhage values. There was no difference in the blood pressure or heart rate between groups. RSR13 may have useful applications to decrease the effects of acute hemorrhagic hypoxemia by increasing brain oxygenation.

The dose-dependent effect of RSR13, a synthetic allosteric modifier of hemoglobin, on physiological parameters and brain tissue oxygenation in rats.

RSR13 is a synthetic allosteric modifier of hemoglobin that decreases the oxygen-binding affinity of hemoglobin, increasing the P50. As a result, tissue oxygen tension is expected to increase. Using the capabilities of in vivo EPR, we directly examined the effect of RSR13 on brain pO2 in rats and the relationship between any change in brain oxygenation and changes in physiological parameters, including blood gases. The brain pO2 and arterial blood paO2 were increased significantly (p < 0.005) following RSR13 administration. The peak increase of brain tissue pO2 was 8.8 +/- 1.2 mm Hg in the animals receiving 150 mg/kg RSR13 and 13 +/- 3 mm Hg in the animals receiving 300 mg/kg RSR13. There was no difference among groups in MBP, heart rate, paCO2, pH, or HCO3. These data indicate that in anesthetized rats, RSR13 dose-dependently increases brain pO2 without affecting other physiologic parameters. This capability is likely to be very useful in circumstances where the pO2 of the brain is compromised.

Pharmacological correction of hypothermic P(50) shift does not alter outcome from focal cerebral ischemia in rats.

Hypothermia decreases the arterial PO(2) at which hemoglobin is 50% saturated (P(50)), increasing hemoglobin O(2)-binding affinity. We used RSR13, a synthetic allosteric modifier of hemoglobin that increases P(50), to study the role of altered hemoglobin O(2)-binding affinity in mild hypothermic neuroprotection. RSR13 (150 mg/kg iv) restored P(50) to normothermic values. Rats underwent 70 min of middle cerebral artery occlusion (MCAO) at 30.0, 34.0, or 37.5 degrees C with hemoglobin saturation held at 98-100%. The 34.0 degrees C group received RSR13 or vehicle before ischemia. After 7 days of recovery, infarct volumes were reduced in all hypothermic groups, without evidence of a detrimental effect on infarct size or neurological score as a result of P(50) correction. To examine for a beneficial effect of P(50) correction, ischemia duration was increased to 120 min in rats maintained at 34.0 degrees C. Correction of P(50) by RSR13 did not alter cerebral infarct sizes or neurological scores. The decrease in P(50), caused by mild hypothermia, could not be associated with infarct size or neurological deficit resulting from ischemic brain hypoxia in rats.

RSR13, a potential athletic performance enhancement agent: detection in urine by gas chromatography/mass spectrometry

RSR13 (2-[4-[[(3,5-dimethylanilino)carbonyl]methyl]phenoxyl]-2-methylpropionic acid) is a synthetic allosteric modifier of hemoglobin that is currently in a phase III clinical trial as a radio-enhancing agent. RSR13 has been shown to increase maximum oxygen uptake (VO(2max)) in a canine skeletal model, which makes it a potential performance-enhancing agent for endurance athletes, since VO(2max) is an index of aerobic capacity. In this study we present a method for the detection of RSR13-bis-TMS in human urine by gas chromatography/electron impact ionization mass spectrometry (GC/EI-MS) suitable for doping control laboratories. The presence of RSR13 is detected by monitoring the ions m/z 485 ([M](+.)) and 470 ([M - CH3](+)). The limit of detection (LOD) is less than 2 ng/mL in urine. Urine samples collected from clinical trial subjects immediately prior to receiving an infusion of RSR13 showed no evidence of RSR13, whereas post-infusion urine samples contained up to 1181 microg/mL. A urine sample collected 36 h after administration of a small dose (10 mg/kg) and diluted 100-fold showed a signal 80 times higher than the LOD. Urine samples obtained from 100 randomly selected athletes in our routine testing program did not show any traces of RSR13. Sport authorities may wish to add RSR13 to the list of prohibited substances.

RSR13, a Synthetic Allosteric Modifier of Hemoglobin, Improves Myocardial Recovery Following Hypothermic Cardiopulmonary Bypass

Background —During hypothermic blood cardioplegia, oxygen delivery to myocytes is minimal with ineffective anaerobic metabolism predominating. RSR13, 2-[4-[[(3,5-dimethylanilino) carbonyl]methyl]phenoxy]-2-methylpropionic acid, a synthetic allosteric modifier of hemoglobin (Hb), increases release of oxygen from Hb, increasing oxygen availability to hypoxic tissues, and reverses the hypothermia-dependent increase in Hb oxygen affinity. We studied recovery of myocardial mechanical and metabolic function and examined myocardial morphology after cardioplegia, comparing RSR13 (1.75 mmol/L)-supplemented blood (RSR13-BC) to standard blood cardioplegia (BC). Methods and Results —Twelve dogs underwent 15 minutes of 37°C global ischemia on cardiopulmonary bypass, followed by 75 minutes of hypothermic cardioplegia (13°C) with either BC (n=6) or RSR13-BC (n=6). There were no differences in baseline function between groups. Cardiac function was assessed after 30 minutes of 37°C reperfusion (BC versus RSR13-BC, respectively) by measuring: % return to normal sinus rhythm (0/100%), % of baseline+dP/dt (33.7±1.7/76.3±1.9), % of baseline−dP/dt (26.6±2.0/81.1±1.6), stroke volume (3.5±0.5/7.1±0.9 mL), cardiac output (340±20/880±40.3 mL/min), and LVEDP (11.3±2.2/0.3±2.9 mm Hg). Postischemic oxidative and metabolic parameters including myocardial lactate, pyruvate, ATP content, and percent water content also were determined. Histological analysis demonstrated preservation of endothelial and myocyte morphology in hearts receiving RSR13-BC compared with BC. Conclusions —These results indicate that in the setting of hypothermic cardiopulmonary bypass, RSR13 improves recovery of myocardial mechanical and metabolic function compared with standard hypothermic BC. Findings from this study suggest that RSR13-BC, by decreasing hemoglobin oxygen affinity, improves oxidative metabolism and preserves cellular morphology, resulting in significantly improved contractile recovery on reperfusion.

RSR13, a synthetic allosteric modifier of hemoglobin, improves myocardial recovery following hypothermic cardiopulmonary bypass.

During hypothermic blood cardioplegia, oxygen delivery to myocytes is minimal with ineffective anaerobic metabolism predominating. RSR13, 2-[4-[[(3,5-dimethylanilino) carbonyl]methyl]phenoxy]-2-methylpropionic acid, a synthetic allosteric modifier of hemoglobin (Hb), increases release of oxygen from Hb, increasing oxygen availability to hypoxic tissues, and reverses the hypothermia-dependent increase in Hb oxygen affinity. We studied recovery of myocardial mechanical and metabolic function and examined myocardial morphology after cardioplegia, comparing RSR13 (1.75 mmol/L)-supplemented blood (RSR13-BC) to standard blood cardioplegia (BC). Twelve dogs underwent 15 minutes of 37 degrees C global ischemia on cardiopulmonary bypass, followed by 75 minutes of hypothermic cardioplegia (13 degrees C) with either BC (n=6) or RSR13-BC (n=6). There were no differences in baseline function between groups. Cardiac function was assessed after 30 minutes of 37 degrees C reperfusion (BC versus RSR13-BC, respectively) by measuring: % return to normal sinus rhythm (0/100%), % of baseline+dP/dt (33.7+/-1.7/76.3+/-1.9), % of baseline-dP/dt (26.6+/-2.0/81.1+/-1.6), stroke volume (3.5+/-0.5/7.1+/-0.9 mL), cardiac output (340+/-20/880+/-40.3 mL/min), and LVEDP (11.3+/-2.2/0. 3+/-2.9 mm Hg). Postischemic oxidative and metabolic parameters including myocardial lactate, pyruvate, ATP content, and percent water content also were determined. Histological analysis demonstrated preservation of endothelial and myocyte morphology in hearts receiving RSR13-BC compared with BC. These results indicate that in the setting of hypothermic cardiopulmonary bypass, RSR13 improves recovery of myocardial mechanical and metabolic function compared with standard hypothermic BC. Findings from this study suggest that RSR13-BC, by decreasing hemoglobin oxygen affinity, improves oxidative metabolism and preserves cellular morphology, resulting in significantly improved contractile recovery on reperfusion.

Effects of RSR13, a synthetic allosteric modifier of hemoglobin, alone and in combination with dizocilpine, on outcome from transient focal cerebral ischemia in the rat

This study examined the effect of a pharmacologically induced rightward shift in the partial pressure of oxygen at which 50% of hemoglobin is saturated ( P 50) on outcome from transient focal cerebral ischemia in the rat. Halothane anesthetized rats ( n=20 per group) were given saline or a single 15-min infusion of 150 mg/kg RSR13 (2-[4-[[3,5-dimethylanilino) carbonyl]methyl]phenoxy]-2-methylproprionic acid) intravenously before or 30 min after onset of 75 min of middle cerebral artery filament occlusion (MCAO). Seven days later, severity of hemiparesis and cerebral infarct size were examined. RSR13 alone did not significantly improve outcome. Conscious normothermic rats ( n=12 per group) were also given RSR13 (150 mg/kg) or 0.9% NaCl intravenously and subjected to 75 min of MCAO with 7 days of recovery. Again, RSR13 alone did not significantly reduce infarct size or improve neurologic score. A dose–response curve for dizocilpine (MK-801) was then constructed in conscious normothermic rats subjected to 75 min of MCAO. Dizocilpine (0.5 mg/kg i.v.) caused a 90% reduction in mean infarct size while 0.25 mg/kg reduced infarct size by 48%. Other rats were then subjected to 75 min of MCAO after being given dizocilpine (0.25 mg/kg i.v.; n=18) or RSR13 (150 mg/kg i.v.)+dizocilpine (0.25 mg/kg i.v.; n=15). RSR13+dizocilpine resulted in smaller cortical infarct volume (8±14 mm 3 vs. 34±37 mm 3, p<0.02) and total cerebral infarct volume (46±28 mm 3 vs. 81±60 mm 3, p<0.05) compared to dizocilpine alone, respectively. We conclude that a pre-ischemic peak increase in P 50 of ∼25 mmHg alone is insufficient to reduce focal ischemic injury, but may be advantageous when used in conjunction with other neuroprotective agents.

Right-shifting the oxyhemoglobin dissociation curve with RSR13: effects on high-energy phosphates and myocardial recovery after low-flow ischemia.

RSR13[2-(4[[(3,5-Dimethylanilino)carbonyl] methyl] phenoxy)-2-methyl propionic acid], a synthetic allosteric modifier of hemoglobin, increases O2 release from hemoglobin at low oxygen tension. The isolated blood-perfused rat heart was examined during potassium-arrest to determine the effects of RSR13 on the concentration of phosphocreatine (PCr) and adenosine triphosphate (ATP) by using 31P nuclear magnetic resonance (NMR) spectroscopy throughout an episode of low-flow ischemia. All hearts were perfused at constant flow during control (2.0 ml/min) and low-flow (0.2 ml/min) conditions. In normoxic hearts, RSR13 had no effect on either the 31P NMR spectrum or the rate-pressure product. In hearts subjected to 30 min of reduced flow, treatment with RSR13 improved mechanical function on reperfusion (p = 0.026 after 20 min; p = 0.032 after 25 min; and p = 0.045 after 30 min) at 2.0 ml/min with normokalemic blood perfusate. In potassium-arrested hearts, the rate of decrease of [ATP] was reduced in hearts exposed to RSR13 (p < or = 0.05 between 10 and 35.8 min of ischemia except at 28.4 min) during low flow. These results indicate a protective effect of RSR13 on high-energy phosphates during low-flow ischemia and mechanical recovery after reperfusion.

RSR13, a synthetic allosteric modifier of hemoglobin, as an adjunct to radiotherapy: preliminary studies with EMT6 cells and tumors and normal tissues in mice.

RSR13, 2[4-[[(3,5dimethylanilino)carbonyl]methyl]phenoxy]-2-methylpropion ic acid, a synthetic allosteric modifier of hemoglobin, reduces the affinity of hemoglobin for oxygen. The experiments reported here examined the effect of treatment with RSR13, combined with oxygen breathing, on the radiation response of EMT6 mammary tumors in BALB/c mice and of two normal tissues. RSR13 plus oxygen breathing increased the response of EMT6 tumors to irradiation. RSR13 had no discernible effects on tumors rendered maximally hypoxic by nitrogen asphyxiation, no discernible cytotoxic effects in EMT6 tumors, and no effect on the viability or radiation response of EMT6 cells in vitro under either aerobic or hypoxic conditions. The effects of RSR13 therefore reflect changes in tumor oxygenation, rather than a direct cytotoxic or radiosensitizing effect of the drug. RSR13 plus oxygen reduced the hypoxic fraction to 9% from the value of 24% found in both air-breathing and oxygen-breathing mice. Treatment with RSR13 plus oxygen did not alter the radiation response of the bone marrow progenitor cells (CFU-S) or acute radiation reactions in the skin. The improvement in tumor radiation response produced by treatment with RSR13 plus oxygen, combined with the absence of enhanced radiation reactions in the normal tissues, support further testing of RSR13 as an adjunct to radiotherapy.

RSR13, a synthetic allosteric modifier of hemoglobin, as an adjunct to radiotherapy: Preliminary studies with EMT6 cells and tumors and normal tissues in mice

RSR13, 2[4-[[(3,5Dimethylanilino)carbonyl]methyl]phenoxy]-2-methylpropionic acid, a synthetic allosteric modifier of hemoglobin, reduces the affinity of hemoglobin for oxygen. The experiments reported here examined the effect of treatment with RSR13, combined with oxygen breathing, on the radiation response of EMT6 mammary tumors in BALB/c mice and of two normal tissues. RSR13 plus oxygen breathing increased the response of EMT6 tumors to irradiation. RSR13 had no discernible effects on tumors rendered maximally hypoxic by nitrogen asphyxiation, no discernible cytotoxic effects in EMT6 tumors, and no effect on the viability or radiation response of EMT6 cells in vitro under either aerobic or hypoxic conditions. The effects of RSR13 therefore reflect changes in tumor oxygenation, rather than a direct cytotoxic or radiosensitizing effect of the drug. RSR13 plus oxygen reduced the hypoxic fraction to 9% from the value of 24% found in both air-breathing and oxygen-breathing mice. Treatment with RSR13 plus oxygen did not alter the radiation response of the bone marrow progenitor cells (CFU-S) or acute radiation reactions in the skin. The improvement in tumor radiation response produced by treatment with RSR13 plus oxygen, combined with the absence of enhanced radiation reactions in the normal tissues, support further testing of RSR13 as an adjunct to radiotherapy. Radiat. Oncol. Invest. 6:199–208, 1998. © 1998 Wiley-Liss, Inc.

Effect of RSR13 on temperature-dependent changes in hemoglobin oxygen affinity of human whole blood.

RSR13, 2-[4-[[(3,5-Dimethylanilino)carbonyl]methyl]phenoxy]-2-methylpropionic acid sodium salt (MW 363), is a synthetic allosteric modifier of hemoglobin (Figure 1). RSR13 is a small molecule that noncovalently binds in the central water cavity of the hemoglobin tetramer, reduces hemoglobin-oxygen (Hb-O2) affinity1 and enhances the diffusion of oxygen from the blood to the tissues.2,3,4 RSR13 emulates the function of natural allosteric modifiers such as hydrogen ions, carbon dioxide, and 2,3-diphosphoglycerate. This therapeutic strategy of “turbocharging” oxygen unloading from hemoglobin to tissue emulates and amplifies physiological tissue oxygenation. This approach has potential application in clinical conditions characterized by tissue hypoxia due to: 1) inadequate blood flow (regional or global), 2) insufficient oxygen carrying capacity (e.g., hemorrhage or dilutional anemia), 3) increased tissue oxygen demand unmatched by supply, and/or 4) insufficient oxygen loading/unloading capacity of hemoglobin (e.g., hypothermia).

RSR13, a synthetic allosteric modifier of hemoglobin, enhances recovery of stunned myocardium in dogs.

RSR132-[4-[[(3,5-dimethylanilino)carbonyl]methyl]phenoxyl]-2-methylproprionic acid sodium salt; (Figure 1) is a compound that mimics the natural physiological effects of 2,3-diphosphoglycerate by allosterically modifying hemoglobin (Hb) saturation. RSR13 binds to and stabilizes deoxyHb in vitro (1). These actions cause a rightward shift of the oxygen (O2)-Hb dissociation curve and increase tissue O2 delivery in vivo (2). RSR13 maintains pH and preserves high-energy phosphates during myocardial ischemia by improving O2 delivery (3). Thus, allosteric modification of Hb affinity for O2 with drugs that stabilize the deoxyHb may be an important new approach to the treatment of myocardial hypoxemia due to ischemic heart disease. We tested the hypothesis that RSR13 enhances the recovery of contractile function of postischemic, reperfused myocardium generated by repetitive, brief episodes of ischemia and reperfusion in barbiturate-anesthetized, acutely instrumented dogs.KeywordsLeft Anterior DescendMyocardial Blood FlowAllosteric ModifierStun MyocardiumRightward ShiftThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

2179 A phase Ib study to evaluate repeated daily intravenous doses of RSR 13 administered to cancer patients receiving concurrent radiation therapy

Purpose: In animal models RSR13, a synthetic allosteric modifier of hemoglobin (I-Ib), oxygenates and thus radiosensitizes hypoxic solid tumors by decreasing the oxygen (Or) affinity of Hb. A phase Ib open label, multi-center dose-frequency escalation study was conducted to evaluate the safety, tolerance, pharmacokinetics, and pharmacodynamics of repeated daily intravenous (IV) infusions of RSRl3 administered to cancer patients receiving palliative radiation therapy (RT).