Gupta, Unal, Bashour and Webb, Diseases of the Chest (1967),496 were the first to demonstrate that PHT (20 mg/kg, intravenously) increases coronary blood flow in dogs.

496. Gupta, D. N., Unal, M. O., Bashour, F. A., and Webb, W. R., Effects of diphenylhydantoin (Dilantin) on peripheral and coronary circulation and myocardial contractility in the experimental animal, Dis. Chest, 51: 248-255, 1967.

Nayler, McInnes, Swann, Race, Carson and Lowe, American Heart Journal (1968),402 demonstrated, in dogs, that PHT (3.5 mg/kg) increases coronary blood flow and reduces myocardial oxygen consumption, without altering the work capacity of the left ventricle.

402. Nayler, W. G., McInnes, I., Swann, J. B., Race, D., Carson, V., and Lowe, T. E., Some effects of diphenylhydantoin and propranolol on the cardiovascular system, Amer. Heart J., 75: 8396,1968.

Zeft, Rembert, Curry and Greenfield, Cardiovascular Research (1973),1711 in a study examining coronary blood flow, found that in intact conscious dogs, with the heart rate uncontrolled, PHT (5 mg/kg) produced a mean increase of 61% in coronary blood flow. With the heart rate controlled by ventricular pacing, a similar dose of PHT produced a mean increase in coronary blood flow of 57%. There was no significant change in either aortic blood flow or peripheral vascular resistance.

1711. Zeft, H. J., Rembert, J. C., Curry, C. L., and Greenfield, C., Effects of diphenylhydantoin on coronary and systemic haemodynamics in awake dogs, Cardiovasc. Res., 7: 331-335, 1973.

Zeft, Whalen, Ratliff, Davenport and McIntosh, The Journal of Pharmacology and Experimental Therapeutics (1968),392 conducted a study to evaluate the hypothesis that PHT, 20 mg/kg initially, followed by 5 mg/kg every eight hours for seventy-two hours, would be effective in preventing death from ventricular arrhythmias resulting from experimental myocardial infarction. The left anterior descending coronary artery of forty farm pigs was gradually occluded. The farm pig was chosen because its coronary artery pattern is relatively constant and similar to that of man. Almost twice as many control animals (eleven of twenty) expired as PHT-treated animals (six of twenty). Although the sample was not large enough to be conclusive, the authors state that there is an indication that PHT, used prophylactically, increases the chance of survival in experimental myocardial infarction in pigs. As a result of this experiment the authors suggest that consideration should be given to the use of PHT on a regular basis to prevent fatalities originating from coronary artery disorders.

392. Zeft, H. J., Whalen, R. E., Ratliff, N. B., Jr., Davenport, R. D., Jr., and McIntosh, H. D., Diphenylhydantoin therapy in experimental myocardial infarction, J. Pharm. Exp. Ther., 162: 80-84, 1968.

Raines and Niner, Neuropharmacology (1975),2032 studied the response to bilateral carotid occlusion in cats before and after administration of PHT. Occlusion produced the expected increases in diastolic blood pressure, heart rate and occasional cardiac arrhythmias. PHT (5 mg/kg) reduced the reflex-induced tachycardia. Higher doses (10 mg/kg) reduced the hypertensive responses as well as the tachycardia.

2032. Raines, A. and Niner, J. M., Blockade of a sympathetic nervous system reflex by diphenylhydantoin, Neuropharmacology, 14: 61-66,1975.

Aldrete and Cubillos, Sixth European Congress of Anaesthesiology (1982),2279 compared the protective effects of PHT and thiopentone to placebo in rabbits subjected to anoxia under anesthesia. Intravenous PHT (15 mg/kg) significantly delayed the onset of change in heart rate and ventricular fibrillation, compared to thiopentone and placebo. Beneficial blood pressure changes were also observed in the PHT-treated animals.

2279. Aldrete, J. A., Cubillos, P., Protection against anoxia by phenytoin and thiopentone in rabbits, Sixth Eur. Congress of Anaesthesiology, 248, Sept. 8-15, 1982.

Pulsinelli, Mann, Welch, Zivin, Maisel, Rubin, Verro, Graham, Pierce, Kugler, Mohberg, Knapp and Poole, Neurology (1999),3590 investigated the clinical efficacy of fosphenytoin sodium in the treatment of acute ischemic stroke. A double-blind, randomized study with a total of 600 patients with acute ischemic stroke was conducted in the U.S and Canada. Double-blind treatment consisted of a loading dose (LD) of fosphenytoin 20 mgPE/kg or placebo, followed by 4 maintenance doses (MD) of fosphenytoin 5 mgPE/kg/day or placebo, administered every 12 hours starting 24 hours after LD. Four forms of outcome assessments were used at months 1 and 3 including the Modified Rankin Scale (MRS), Barthel's Index (BI), Glagow Outcome Scale (GOS), and NIH Stroke Scale (NIHSS). An independent data review revealed a lack of efficiency with fosphenytoin as assessed by all four outcome measures. Lack of efficiency was attributed to the therapeutic window for fosphenytoin being less than 4 hours, blood pressure decrease with fosphenytoin administration and failure of MCAO animal model to predict an effect in human stroke. Fosphenytoin was concluded to be ineffective in the treatment of patients with acute ischemic stroke when administered within four hours of stroke onset.

3590. Pulsinelli, W.A., Mann, M.E., Welch, M.A., Zivin, J.A., Biller, J., Maisel, J., Rubin, J.J., Verro, P., Graham, G.D., Pierce, M., et al., Fosphenytoin in acute ischemic stroke: efficacy results, Neurology, 52(2): A384, 1999.