Nitric oxide synthase inhibitor (MTR-105) during open-heart surgery. A pilot double-blind placebo-controlled study of hemodynamic effects and safety.
OBJECTIVE
Hypotension is common immediately following cardiopulmonary bypass. Experimentally, MTR-105 (S-ethylisothiuronium diethylphosphate), a fast-acting synthetic nitric oxide synthase inhibitor, rapidly increases blood pressure. The purpose of the current study was to assess the influence of MTR-105 on hemodynamics early after cardiopulmonary bypass in patients undergoing open-heart surgery.


METHODS
Thirty-six patients with an ejection fraction >50% undergoing open-heart surgery were randomly assigned to either 50 microg kg(-1) min(-1) MTR-105 (M50, n = 12), 10 microg kg(-1) min(-1) MTR-105 (M10, n = 12) or buffered phosphate solution (placebo control, n = 12). Half suffered from atrial fibrillation and 75% had severe tricuspid regurgitation. Patients received the drug for 6 h after cross-clamp removal. Hemodynamic variables were measured before drug administration until 24 h after operation. Adverse events were recorded from study drug initiation through 30 days after the operation.


RESULTS
Compared with control, both MTR-105 doses were associated with an immediate increase in systemic blood pressure (16%) and systemic vascular resistance and a decrease in cardiac index. Half-life time of MTR-105 was calculated to be 4.1 +/- 0.8 h (M10) and 4.45 +/- 0.92 h (M50). Three patients died during hospitalization, unrelated to the study medication.


CONCLUSIONS
At the doses employed, MTR-105 appears hemodynamically active in increasing both blood pressures.
Sasson
Lior
L
Angela and Sami Shamoon Cardiothoracic Surgery Department, Edith Wolfson Medical Center, Holon, affiliated with the Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
Ureche
Andrei
A
Manolache
Gheorghe
G
Ciubotaru
Anatol
A
Borer
Jeffrey S
JS
Schachner
Arie
A
D000328:Adult; D000368:Aged; D001794:Blood Pressure / Q000187:drug effects*; D006348:Cardiac Surgical Procedures / Q000379:methods*; D002318:Cardiovascular Diseases / Q000601:surgery; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics; D005260:Female; D006207:Half-Life; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007022:Hypotension / Q000188:drug therapy / Q000517:prevention & control*; D007550:Isothiuronium / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D010865:Pilot Projects; D010919:Placebos; D014655:Vascular Resistance / Q000187:drug effects
D004791:Enzyme Inhibitors; D010919:Placebos; D007550:Isothiuronium; C007687:etiron; D019001:Nitric Oxide Synthase