Allosteric modification of oxygen delivery by hemoglobin

Area of Science:

• Pharmacology
• Anesthesiology
• Nephrology

Background:

• Hemoglobin's oxygen affinity is influenced by physiological factors, affecting tissue oxygen delivery.
• RSR13 is an analog of clofibrate and bezofibrate, designed to modify hemoglobin's oxygen binding properties.

Purpose of the Study:

• To evaluate the safety, pharmacodynamics, and pharmacokinetics of RSR13 in patients undergoing general surgery.
• To assess the dose-dependent effects of RSR13 on the oxygen dissociation curve and its tolerability.

Main Methods:

• A prospective, randomized, double-blind, placebo-controlled, dose-escalation trial involving 26 general surgery patients.
• Patients received ascending doses of RSR13 (10-100 mg/kg) or placebo, with frequent blood sampling for drug concentration and p50 determination.
• Hemodynamic and laboratory parameters were monitored throughout the study.

Main Results:

• RSR13 demonstrated a dose-dependent, rightward shift in the oxygen dissociation curve, achieving a target p50 shift of 10 mm Hg at 75- and 100-mg/kg doses.
• No significant differences in laboratory or hemodynamic findings were observed between RSR13 and placebo groups.
• Three patients receiving RSR13 experienced transient, mild increases in serum creatinine, which resolved without treatment or prolonged hospitalization.

Conclusions:

• RSR13 was well-tolerated in general surgery patients, effectively increasing oxygen availability.
• Transient elevations in serum creatinine were observed in a subset of patients but were not clinically significant and resolved spontaneously.