Hypokalemia, cardiac failure, and reporting NXY-059 safety for acute stroke

NXY-059, an alpha-phenyl-N-tert-butyl nitrone derivative, is a free radical-trapping agent presently in late clinical trials as a potential neuroprotectant limiting reperfusion injury following acute stroke. Two recent trials suggest that NXY-059 causes hypokalemia and associated cardiac disturbances. With regard to the mechanism of such association, most investigators agree that potent trapping of free radicals leads to the 11 beta-hydroxysteroid dehydrogenase blockade in kidneys, diminishing renal hydrocortisone oxidation and increasing K⁺ ion urine excretion. Importantly, potassium deficiency represents the major avoidable cause of the array of serious cardiac adverse reactions: QT-prolongation, Torsades de pointes and other life-threatening arrhythmias, and higher risks for perioperative cardiopulmonary resuscitation and cardiac death. Because a prime target for NXY-059 use will likely be acute strokes in the emergency room environment, the potential combination of the drug with intensive therapy including fluid infusions, particularly with diuretics, might be especially harmful because of the synergic depletion of potassium, which might also jeopardize the fate of the novel nitrone neuroprotectant.