Allosteric modification of oxygen delivery by hemoglobin

Hemoglobin affinity for oxygen is altered by pH, temperature, and high alti tude, making oxygen more readily available to the tissues. RSR13 (Allos The rapeutics, Denver, CO), an analog of the drugs clofibrate and bezofibrate, causes a dose-dependent, rightward shift of the oxygen dissociation curve i n animals and humans. We tested the safety, pharmacodynamic, and pharmacoki netics of RSR13, an allosteric modifier of hemoglobin, in patients having g eneral surgery in a prospective, randomized, double-blinded, placebo-contro lled, dose-escalation clinical trial. After the induction of general anesth esia with endotracheal intubation, 26 patients who consented were randomly assigned to receive an infusion of RSR13 or placebo (2:1) in an ascending d ose scheme. Doses studied were 10, 20, 30, 40, 50, 60, 75, and 100 mg/kg in fused for 30-60 minutes. Samples were taken for determination of RSR13 conc entration in plasma, red blood cells, and urine, as well as for determinati on of the p50 in blood by using three-point tonometry at frequent intervals after the infusion of the study drug. The RSR13 administration resulted in a dose-dependent rightward shift of the oxygen dissociation curve, with th e target p50 shift of 10 mm Hg achieved at the 75- and 100-mg/kg doses. No differences were seen between RSR13 and placebo groups in laboratory or hem odynamic findings, with the exception of a transient, limited increase in s erum creatinine in 3 patients who received RSR13. These increases peaked at 48 h (2.2, 3.5, and 4.5 mg/dL respectively), were not associated with olig uria, did not require treatment, and did not prolong hospitalization in any patient. The reasons for the unexplained increases in serum creatinine wer e not evident, but potentially included surgery itself (nephrectomy), patie nt condition, or the concomitant administration of renally cleared medicati ons or drugs that affect renal blood flow.