Stabilization of Bioelectrical Activity

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From the earliest studies to the latest, the evidence is consistent that phenytoin (PHT) selectively corrects hyperexcitability as in post-tetanic potentiation and post-tetanic afterdischarge. This normalization of hyperexcitability is achieved without interfering with initial single impulses, and without impairment of normal transmission of nerve impulses. PHT's effects are in direct proportion to the frequency of axonal firing or synaptic transmission: the more the system fires, the greater PUT's effects. Mechanisms by which this selective action may be achieved, including effects on the sodium and calcium channel and glial cell ion homeostasis, are discussed in Sodium, Potassium and Calcium Regulation. See also Neurotransmitter Regulatory Effects of PHT, Muscle, and Cardiovascular Basic Mechanisms sections. The following studies are in chronological order.

Putnam and Merritt, Science (1937),11 Archives of Neurology and Psychiatry (1938),250 and JAMA (1938),557 were the first to discover that PHT was a therapeutically effective substance when they demonstrated that it counteracted electrically-induced hyperexcitability and convulsions in the cat. Others had previously tested PHT and, finding that it was not a sedative, had not investigated its properties further. The authors demonstrated that PHT was much more effective in controlling convulsions than the bromides and phenobarbital. They also observed that PHT, unlike these other substances, did not sedate. The authors applied their laboratory findings to clinical use and with PHT treated a group of 118 patients with chronic grand mal attacks who had not responded to treatment with bromides and phenobarbital. The results were dramatic. Fifty-eight percent of these intractable cases became free of attacks and twenty-seven percent showed marked improvement, without sedation. Although Putnam and Merritt were focusing on epilepsy at the time, they suggested that PHT might be useful for a broad range of dysrhythmias.

11. Putnam, T. J. and Merritt, H. H., Experimental determination of the anticonvulsant properties of some phenyl derivatives, Science, 85: 525-526, 1937.
250. Merritt, H. H. and Putnam, T. J., A new series of anticonvulsant drugs tested by experiments on animals, Arch. Neurol. Psychiat., 39: 1003-1015, 1938.
557. Merritt, H. H. and Putnam, T. J., Sodium diphenylhydantoinate in the treatment of convulsive disorders, JAMA, 111: 1068-1073, 1938.

Toman, Electroencephalography and Clinical Neurophysiology (1949),458 studied the effect of PHT on isolated frog sciatic nerve. The frog sciatic nerve was electrically stimulated and the action potential, with and without PHT, was recorded. PHT was found to have little effect upon the membrane threshold for single shocks. However, PHT increased membrane stability when repetitive shocks were used. The author noted that these findings might explain PHT's effectiveness in preventing abnormal spread of electrical discharge, without affecting normal function. The author stressed the fact that these stabilizing effects were achieved with low concentrations of PHT, without interfering with normal function. He suggested that the protective properties of PHT could have broad applicability when neurons are more sensitive than normal, such as the conditions brought on by injury or ischemia.

458. Toman, J. E. P., The neuropharmacology of antiepileptics, Electroenceph. Clin. Neurophysiol., 1: 33-44, 1949.

Korey, Proceedings of the Society of Experimental Biology and Medicine (1951),472 studied the effect of PHT on the giant axon of squid. The nerve and its ganglion were dissected and kept in a solution of artificial sea water to maintain ionic equilibrium. The nerve was then exposed to other solutions and electrical recordings were made. When PHT was added to the "normal" artificial sea water, no appreciable effect on the electrical activity of the giant axon was observed. When the sea water was changed by reducing calcium and magnesium, but without PHT, a hyperexcitable state of spontaneous firing occurred. When the sea water was brought back to normal by adding calcium and magnesium, it took ten to fifteen minutes to reverse the spontaneous firing. However, when PHT was added to the solution from which calcium and magnesium had been withdrawn, it took only two or three minutes to correct the excessive firing. The author concludes that PHT does not affect normal nerve function. However, in an abnormal condition of hyperexcitability, induced by withdrawal of calcium and magnesium, PHT corrects hyperexcitability.

472. Korey, S. R., Effect of Dilantin and Mesantoin on the giant axon of the squid, Proc. Soc. Exp. Biol. Med., 76: 297-299, 1951.

Esplin, Journal of Pharmacology and Experimental Therapeutics (1957), 90 studied the effect of PHT on post-tetanic potentiation in cat spinal cord, stellate ganglion and vagus nerve C fibers.The author found that PHT reduced or abolished post-tetanic potentiation but only slightly affected single impulses in spinal cord and stellate ganglion.The author states that post-tetanic potentiation may be a significant factor in all functions of the nervous system characterized by repetitive activity.

90. Esplin, D. W., Effects of diphenylhydantoin on synaptic transmission in cat spinal cord and stellate ganglion, J. Pharm. Exp. Ther., 120: 301-323, 1957.

Morrell, Bradley and Ptashne, Neurology (1958),257 examined the effects of PHT on the peripheral nerve in rabbit. Hyperexcitability was induced by both chemical and electrical methods.The authors found that PHT (10-25 mg/kg) raised the resistance of the peripheral nerve to being made hyperexcitable by repetitive electrical stimulation. In a separate experiment they showed that when the nerve was made hyperexcitable by the removal of calcium, PHT corrected this hyperexcitability.

257. Morrell, F., Bradley, W., and Ptashne, M., Effect of diphenylhydantoin on peripheral nerve, Neurology, 8: 140-144, 1958.

Morrell, Bradley and Ptashne, Neurology (1959), 258 found that PHT limited the spread of seizure activity from an epileptogenic focus induced in rabbit visual cortex.

258. Morrell, F., Bradley, W., and Ptashne, M., Effect of drugs on discharge characteristics of chronic epileptogenic lesions, Neurology, 9: 492-498, 1959.

Stille, Nervenarzt (1960), 352 in a study of the basis for the beneficial effect of PHT on pain, found that PHT (20 mg/kg) reduced the cortical response to single or low-frequency electrical stimulation of the reticular formation in rabbits. The author notes that PHT differs from the barbiturates and chlorpromazine in that it does not interfere with the arousal reaction produced by electrical stimulation of the mesencephalic reticular formation, or by sensory stimulation.

352. Stille, G., On the question of the action of diphenylhydantoin in states of pain: a neurophysiological analysis, Nervenarzt, 31: 109-112, 1960.

Aston and Domino, Psychopharmacologia (1961), 6 found, in the rhesus monkey, that the effective elevation of motor cortical thresholds could be accomplished by PHT without markedly altering the reactivity of the reticular core to electrical stimulation and without significant anesthetic effect.

6. Aston, R. and Domino, E. F., Differential effects of phenobarbital, pentobarbital and diphenylhydantoin on motor cortical and reticular thresholds in the rhesus monkey, Psychopharmacologia, 2: 304-317, 1961.

Nakamura and Kurebe, Japanese Journal of Pharmacology (1962), 264 using concentric bipolar stimulating and recording electrodes, demonstrated, in cat, that PHT (5-20 mg/kg) elevated hippocampal seizure threshold and suppressed propagation, with no effect on after discharge pattern. At doses sufficient to prevent hippocampal seizure PHT did not interfere with reticular arousal thresholds.

264. Nakamura, K. and Kurebe, M., Differential effects of antiepileptics on hippocampal and pallidal after discharges in cats, Jap. J. Pharmacol., 12: 180-190, 1962.

Tuttle and Preston, Journal of Pharmacology and Experimental Therapeutics (1963), 365 studied the influence of PHT (10-60 mg/kg) on neural pathways in the cat. They state that, confirming previous studies, PHT was found to have no apparent effect on single-impulse transmission or monosynaptic reflex amplitude, whether initiated by dorsal root stimulation or by peripheral nerve stimulation. However, when post-tetanic potentiation was produced by repetitive electrical stimulation, PHT counteracted the abnormal state.

365. Tuttle, R. S., and Preston, J. B., The effects of diphenylhydantoin (Dilantin) on segmental and suprasegmental facilitation and inhibition of segmental motoneurons in the cat, J. Pharm. Exp. Ther., 141: 84-91, 1963.

Parisi and Raines, Federation Proceedings (1963), 1400 studied the effect of PHT on the soleus nerve of the cat, and on neuromuscular transmission via this nerve. In this study the effect that PHT had on neuromuscular transmission was gauged by its effect on twitch response to repeated nerve volleys and also on the twitch response to single impulses. Repeated nerve volleys caused post-tetanic repetitive discharge of the motor nerve terminals which in turn caused a contractile post-tetanic potentiation in the muscle. Intravenous PHT (20 mg/kg) abolished this abnormal muscle post-tetanic potentiation. When a normal muscle was given a single volley, PHT did not affect the normal twitch. The authors placed emphasis on this selective action of PHT which enables it to counteract post-tetanic repetitive activity without interfering with normal transmission or contraction.

1400. Parisi, A. F. and Raines, A., Diphenylhydantoin suppression of repetitive activity generated in nerve endings, Fed. Proc., Abstract 22: 390, 1963.

Toman, The Pharmacological Basis of Therapeutics (1965), 359 noted that PHT modifies the pattern of maximal tonic-clonic electroshock seizures elicited by supramaximal current. The characteristic tonic phase, representing maximal interneuronal facilitation in the brain, can be abolished completely by PHT.

359. Toman, J. E. P., Drugs effective in convulsive disorders, The Pharmacological Basis of Therapeutics, 3rd Ed., 215-224, Goodman, L. S., Gilman, A., Eds., Macmillan, New York, 1965.

Raines and Standaert, Journal of Pharmacology and Experimental Therapeutics (1966), 289 found that intravenous PHT (10-20 mg/kg) abolished repetitive after discharges originating in the nerve terminals of soleus motor axons of the cat. The suppression of these after discharges markedly reduced post-tetanic potentiation of the soleus muscle.

289. Raines, A. and Standaert, F. G., Pre- and postjunctional effects of diphenylhydantoin at the cat soleus neuromuscular junction, J. Pharm. Exp. Ther., 153: 361-366, 1966.

Brumlik and Moretti, Neurology (1966), 469 found that PHT did not affect normal conduction velocities in human median and ulnar nerve.

469. Brumlik, J. and Moretti, L., The effect of diphenylhydantoin on nerve conduction velocity, Neurology, 16: 1217-1218, 1966.

Raines and Standaert, Journal of Pharmacology and Experimental Therapeutics (1967), 467 showed that PHT abolishes post-tetanic potentiation originating in the central terminals of dorsal root fibers of spinal cats.

467. Raines, A. and Standaert, F. G., An effect of diphenylhydantoin on post-tetanic hyperpolarization of intramedullary nerve terminals, J. Pharm. Exp. Ther., 156: 591-597, 1967.

Rosenberg and Bartels, Journal of Pharmacology and Experimental Therapeutics (1967), 311 studying the effects of PHT on the spontaneous electrical activity of squid giant axon, found that at concentrations of PHT which do not affect the action potential response to stimulation, spontaneous activity is decreased. Resting potential was unaltered.

311. Rosenberg, P. and Bartels, E., Drug effects on the spontaneous electrical activity of the squid giant axon, J. Pharm. Exp. Ther., 155: 532-544, 1967.

Julien and Halpern, Journal of Pharmacology and Experimental Therapeutics (l970), 1197 studied the effect of PHT on the electrical responsiveness of isolated rabbit vagus nerve after repetitive electrical stimulation. PHT did not affect the compound action potential produced by a single electrical stimulation. Conduction velocity of both the myelinated and nonmyelinated fibers was not affected by PHT. The authors noted that the effects of PHT were in contrast to those of barbiturates which depress axonal conduction. In addition, PHT markedly shortened the duration of post-tetanic hypoexcitability of C fibers. PHT enhanced this recovery without depressing conduction velocity or excitability thresholds.

1197. Julien, R. M. and Halpern, L. M., Stabilization of excitable membrane by chronic administration of diphenylhydantoin, J. Pharmacol. Exp. Ther., 175: 206-212, 1970.

Riehl and McIntyre, Electroencephaography and Clinical Neurophysiology (1970), 1467 studied the effect of intravenous PHT on the electroencephalogram analyzed quantitatively by frequency/voltage ratio. In seven previously untreated epileptic patients with unilateral EEG abnormalities, PHT (250 mg) produced a decrease in abnormal EEG activity. The effect was observed within ten to fifteen minutes in the pathologically affected hemisphere. In the normal unaffected hemisphere of these same patients, and in three control normal subjects, no effect of PHT was observed. (See also Ref. 461.)

1467. Riehl, J. L. and McIntyre, H. B., Acute effects of Dilantin on the EEG of epileptic patients: a quantitative study, Electroenceph. Clin. Neurophysiol., 28: 94, 1970.
461. Riehl, J. and McIntyre, H. B., A quantitative study of the acute effects of diphenylhydantoin on the electroencephalogram of epileptic patients: Theoretical considerations for its use in the treatment of status epilepticus, Neurology, 18: 1 107-1112, 1968.

Baker, Okamoto and Riker, Pharmacologist (1971), 789 found that, in a cat soleus nerve-muscle preparation, pretreatment with PHT counteracted abnormal excitability produced by exogenous acetylcholine. The authors note that PHT selectively suppresses the post-tetanic potentiation of motor nerve terminals without impairing single-impulse transmission.

789. Baker, T., Okamoto, M., and Riker, W. F., Diphenylhydantoin (DPH) suppression of motor nerve terminal (MNT) excitation by acetylcholine (ACh), Pharmacologist, 13: 265, 1971.

Rutledge, Sohn and Sardinas, Pharmacologist (1971), 1494 studied the effect of PHT on the hyperexcitability of a cat soleus nerve-muscle preparation. They found that PHT (20-40 mg/kg) counteracted succinylcholine-induced muscle fasciculation and twitch potentiation, but did not impair normal neuromuscular transmission.

1494. Rutledge, R., Sohn, Y. J., and Sardinas, A., Interaction of diphenylhydantoin and succinylcholine at the neuromuscular junction, Pharmacologist, 13: 265, 1971.

Julien and Halpern, Epilepsia (1972), 1199 studied the effect of PHT on cerebellar Purkinje cell discharge rates and cerebral cortical epileptiform activity in cats with penicillin-induced foci in sensorimotor cortex. In control experiments, using extracellular microelectrode recordings, Purkinje cell activity revealed characteristic low-frequency discharge rates during periods of cortical quiescence and discharge rates of 150 Hz occurring concomitant with focal cortical spike activity. Purkinje cell discharges abruptly ceased during development of cortical epileptiform bursts which became generalized and maximal in both cerebral hemispheres. Following intravenous PHT (10 mg/kg), cortical epileptiform burst frequency and duration were markedly reduced, and sustained Purkinje cell discharge rates of 140 Hz were recorded. To establish that PHT's effect on the Purkinje cell was important in inhibition of the cortical epileptiform burst activity, the authors removed the cerebellum. Consistent with their hypothesis, PHT was less effective in reducing cortical bursts after cerebellectomy. (See Refs. 1117, 1198.)

1199. Julien, R. M. and Halpern, L. M., Effects of diphenylhydantoin and other antiepileptic drugs on epileptiform activity and Purkinje cell discharge rates, Epilepsia, 13: 387-400, 1972.
1117. Halpern, L. M. and Julien, R. M., Augmentation of cerebellar Purkinje cell discharge rate after diphenylhydantoin, Epilepsy Abstracts, 5: 236-237, 1972.
1198. Julien, R. M. and Halpern, L. M., Diphenylhydantoin: evidence for a central action, Life Sci., 10: 575-582, 1971.

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