Skeletal Muscle

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. 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. The authors found that 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 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. 

Jurna and Lanzer, Naunyn-Schmiedebergs Archives of Pharmacology (1969),2636 reported the inhibitory effects of intravenous PHT on reserpine-induced rigidity, as evidenced by increased alpha and decreased gamma motor activity. PHT (50 mg/ kg) consistently normalized alpha and gamma reflex activity. The authors suggest that PHT's effects result from its inhibition of facilitatory processes that follow repetitive activation.

See also Refs. 182, 183.

182. Jurna, I., Depression by antiparkinson drugs of reserpine rigidity, Naunyn-Schmiedeberg Arch. Pharm., 260: 80-88, 1968.
183. Jurna, I. and Regélhy, B., The antagonism between reserpine and some antiparkinson drugs in electroseizure, Naunyn-Schmiedeberg Arch. Pharm., 259: 442-459, 1968.
2636. Juma, I., Lanzer, G., Inhibition of the effect of reserpine on motor control by drugs which influence reserpine rigidity, Naunyn-Schmiedebergs Arch Pharmakcol., 262: 309-24,1969.

Kuhn, Douwes and Kern, Klinische Wochenschrift (1969),2216 found that PHT abolished the myotonia induced with 2, 4-dichlorophenoxyacetate in rat diaphragm.

2216. Kuhn, E., Douwes, 0. and Kern R., The action of hydantoin derivatives on the experimental myotonia induced in the isolated rat diaphragm by 2,4-dichlorophenoxyacetate, Klin. Wschr., 47: 278-80,1969.

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 hyperexcitability in a cat soleus nerve-muscle preparation. PHT (20-40 mg/ kg) counteracted succinyleholine-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.

Gruener and Stern, Nature, New Biology (1972),1103 studied the effects of PHT on muscle fibers from steroid-treated mice. Myopathy was induced in twelve adult mice by the daily intraperitoneal injection of dexamethasone over eight to twelve weeks. Six of these mice then received injections of PHT (25 mg/kg) at 48, 24, 4 and 2 hours prior to measurement of the electro-physiological properties of the extensor digitorum longus muscle. Six mice were untreated. In PHT-treated animals with steroid-induced myopathy, the abnormally low resting potentials, threshold potentials, and excitability were restored to normal levels. PHT was also given to six of twelve normal mice (not treated with steroids), using the same schedule of administration. PHT had no effect on the normal muscle properties in these animals.The authors conclude that PHT reverses the membrane effects produced by chronic administration of corticosteroids in mice by correcting the abnormal ion distribution or permeabilities.

1103. Gruener, R. P. and Stern, L. Z., Diphenylhydantoin reverses membrane effects in steroid myopathy, Nature New Bio., 235: 54-55, 1972.

Su and Feldman, Archives of Neurology (1973),1602 in a microelectrode study of in vivo rat neuromuscular transmission, found that intravenous PHT (10-40 mg/kg) had no effect on normal muscle resting potential or miniature endplate potential (mepp) frequency or amplitude. However, when the neuromuscular junction was abnormally stimulated by depolarization with high potassium (35 mM), PHT increased the resting potential of the muscle membrane by 15% and decreased mepp frequency by 60%. The onset of PHT's effect was rapid, occurring within ten minutes. The authors conclude that PHT stabilizes both the motor-nerve ending and the muscle membrane. They suggest that this stabilizing effect could be a factor in the success of PHT in the treatment of generalized rnyokymia and myotonia.

1602. Su, P. C. and Feldman, D. S., Motor nerve terminal and muscle membrane stabilization by diphenylhydantoin administration, Arch. Neurol., 28: 376-379, 1973.
2057. Roses, A. D., Butterfield, D. A., Appel, S. H. and Chestnut, D. B., Phenytoin and membrane fluidity in myotonic dystrophy, Arch. Neurot., 32 (8): 535-38, 1975.

Herzberg, Challberg, Hess and Howland, Biochemical and Biophysical Research Communications (1975),1897 observed that when dystrophic mice are treated with both PHT and lithium chloride, the abnormally elevated potassium efflux, characteristic of dystrophic diaphragm, returns to within normal limits. The authors note that treatment of normal animals with PHT and lithium chloride does not produce significant inhibition of efflux of potassium, so that the effect appears to be specific for the dystrophic state.

1897. Herzberg, G. R., Challberg, M. D., Hess, B. C. and Howland, J. L., Elevated potassium efflux from dystrophic diaphragm: influence of diphenylhydantoin and lithium, Biochem. Biophys. Res. Commun., 63(4): 858-63, 1975.

Yaari, Rahamimoff and Pincus, Israel Journal of Medical Science (1976), 2130, 2131 demonstrated that PHT (100-200 µM) either increases or decreases the evoked endplate potential at frog neuromuscular junction, depending on whether the calcium in the medium was high or low.

2130. Yaari, Y., Pincus, J. H., Argov, Z., Phenytoin and transmitter release at the neuromuscular junction of the frog, Brain Res., 160: 479-87,1979.
2131. Yaari, Y., Rahamimoff, H. and Pincus, J. H., Action of diphenylhydantoin at the frog neuromuscular junction, Israel J. Med. Sci., 12(2): 171-2, 1976.

Anderson and  Raines, Neurology (1976),1722, 2031 demonstrated that a combination of PHT and chlorpromazine markedly reduced decerebrate rigidity in cats. Since this treatment did not impair neuromuscular transmission or motor coordination, the authors suggest it may be of value for treating the muscle rigidity in some upper motor neuron lesions.

1722. Anderson, R. J. and Raines, A., Suppression of decerebrate rigidity by phenytoin and chlorpromazine, Neurol., 26: 858-62,1976.
2031. Raines, A., Cohan, S. L., Panagakos, J. and Armitage, P., Utility of chlorpromazine (CPZ) and phenytoin (PH) in spasticity, Pharmacologist, 21(3): 183, 1979.

Hulce, Society for Neuroscience Abstracts (1977),1903 examining the basis for the beneficial effect of PHT and chlorpromazine in reducing decerebrate rigidity, demonstrated separate effects of the two agents. PHT (40 mg/kg) reduces the total time of extensor rigidity seen after vestibular stimulation, while chlorpromazine reduces the peak force.

1903. Hulce, V. D., The action of chlorpromazine and phenytoin on muscle rigidity due to cerebellar lesions, Society for Neuroscience, III: 372, 7th Annual Meeting, Nov. 7-10, 1977.

Entrikin, Swanson, Weidoff, Patterson and Wilson, Science (1977),1824 found that PHT (20 mg/kg) injected daily for forty days after hatching markedly improved the righting ability of dystrophic chicks. The characteristically high activity of acetylcholinesterase in dystrophic posterior latissimus dorsi muscles was simultaneously reduced to normal levels. (See also Refs. 2164, 2165.)

1824. Entrikin, R. K., Swanson, K. L., Weidoff, P. M., Patterson, G. T. and Wilson, B. W., Avian muscular dystrophy: functional and biochemical improvement with diphenythydantoin. Science, 195: 873-5, 1977.
2164. Cisson, C. M., Entrikin, R. K. and Wilson, B. W., Actions of phenytoin on AChE synthesis in cultured chick embryo muscle treated with paraoxon, Soc. Neurosci. Abstr., 310: 986, 1977.
2165. Cisson, C. M., Entrikin, R. K. and Wilson, B.W., Effects of phenytoin on acetylcholinesterase activity and cell protein in cultured chick embryonic skeletal muscle, Can. J. Physiol. Pharmacol., 56(2): 287-93,1978.

Entrikin and Bryant, Epilepsy Abstracts (1978),2178, 2179 in studying the mechanism by which the righting ability of dystrophic chickens was improved by PHT, examined posterior latissimus dorsi muscles in vitro by microelectrode stimulation and recording. The authors conclude that PHT effects an improvement by decreasing the abnormal tendency for the muscle to fire repetitively.

2178. Entrikin, R. K. and Bryant, S. H., Membrane electrical effects of phenytoin on skeletal muscle of dystrophic chickens, Epilepsy Abstracts, 11(7): 277, 1978.
2179. Entrikin, R. K. and Bryant, S. H., Suppression of myotonia in dystrophic chicken muscle by phenytoin, Am. J. Physiol., 237(3): C13-6,1979.

Hershkowitz, Mahany, Baizer and Raines, Neuroscience Abstracts (1978), 2591studied the effects of PHT on extensor muscle tone and gamma motoneuron activity in decerebrate cats. PHT reduced extensor tone by 25% at 10 mg/kg and by 50% at 20 mg/kg. The authors state that these effects pro-vide a rationale for the use of PHT in the treatment of abnormally increased muscle tone.

2591. Herschkowitz, N., Mahany, T. M., Baizer, L., Raines, A., Phenytoin reduction of extensor tone and gamma motorneuron activity in the decerebrate cat, Neurosci. Abstr., 4: 297, 1978.

Kwiecinski, Neurology (1978), 2682 studied the effects of PHT, procainamide, ajmaline, isoptin, hydrocortisone and glucose on clofibrate-induced myotonia in rats and in isolated denervated muscle. PHT was the only drug tested that significantly reduced the intensity of the myotonic discharges. PHT also lessened the decline of the myotonic muscle response during continued direct stimulation.

2682. Kwiecinski, H., Myotonia induced with clofibrate in rats, J. Neurol., 219: 107-16, 1978.

Silverman, Atwood and Bloom, Experimental Neurology (1978),2081 found that PHT improved motor control of hind limbs in dystrophic mice. Electromyographic assay demonstrated PHT's ability to reduce the dystrophic myotonic activity within fifteen minutes of a single injection.

2081. Silverman, H., Atwood, H. L. and Bloom, J. W., Phenytoin application in murine muscular dystrophy; behavioral improvement with no change in the abnormal intracellular Na : K ratio in skeletal muscles, Exp. Neurol., 62: 618-27, 1978.

Furman and Barchi, Annals of Neurology (1978),1842 demonstrated that PHT, in concentrations clinically effective in controlling hereditary myotonia in humans, inhibited the myotonia induced by aromatic monocarboxylic acids in rats.

1842. Furman, R. E. and Barchi, R. L., The pathophysiology of myotonia produced by aromatic carboxylic acids, Ann. Neurol., 4(4): 357-65, 1978.

Ozawa, Komatsu and Sato, Journal of the Pharmaceutical Society of Japan (1978),2010 demonstrated that PHT (25 mg/ kg), administered intraperitoneally for nine to eleven days to dystrophic mice, restored the resting membrane potential of skeletal muscle. Comparable studies in normal mice demonstrated that PHT did not affect normal skeletal muscle.

2010. Ozawa, H., Komatsu, K. and Sato, M., Reversal by phenytoin (diphenylhydantoin) of the resting membrane potential of skeletal muscle from genetically dystrophic mice, J. Pharm. Soc. Japan, 98(3): 386-9, 1978.

Gage, Lonergan and Torda, British Journal of Pharmacology (1980),1843 reported that PHT (10 µg/ml) has both pre- and postsynaptic effects at the mouse sternomastoid and diaphragm neuromuscular junction. PHT reduced the amplitude of the muscle endplate potentials by decreasing the average number of quanta of acetylcholine released in response to an action potential and by decreasing the amplitude of the voltage response to each quantum of acetylcholine. Reduction in spontaneous miniature endplate potential amplitude was due to a decrease in the time constant of decay of the miniature endplate currents (i.e., decreased average open time of end-plate channels).

1843. Gage, P. W., Lonergan, M. and Torda, T. A., Presynaptic and postsynaptic depressant effects of phenytoin sodium at the neuromuscular junction, Br. J. Pharmac., 69: 119-21, 1980.

Ionasescu, Ionasescu, Witte, Feld, Cancilla, Kaeding, Kraus and Stern, Journal of the Neurological Sciences (1980), 1905 studied altered protein synthesis in breast muscle cell cultures from dystrophic chick embryos. PHT (20 µg/ml) significantly increased total protein and myosin synthesis and creatine kinase in cells, while decreasing creatine kinase in the medium. The effects were specific since neither turnover for total protein and myosin nor noncollagen protein content were changed.

1905. Ionasescu, V., Ionasescu, R., Witte, D., Feld, R., Cancilla, P., Kaeding, L., Kraus, L. and Stern, L., Altered protein synthesis and creatine kinase in breast muscle cell cultures from dystrophic chick embryos, J. Neurol. Sci., 46: 157-68, 1980. 

Pincus, Yaari and Argov, Antiepileptic Drugs: Mechanisms of Action (1980), 2023 evaluating the effects of PHT on calcium flux at the frog neuromuscular junction, found that PHT (200 µM), in normal calcium medium, reduced quantal content and endplate potential amplitude. In low calcium medium, however, PHT increased quantal content and endplate potential amplitude. PHT increased miniature endplate potential frequency irrespective of calcium concentration. The authors also found that PHT had a frequency-dependent effect on synaptic transmission: the higher the frequency of stimulation, the greater PHT's inhibitory effect.

2023. Pincus, J. H., Yaari, Y. and Argov, Z., Phenytoin: electrophysiological effects at the neuromuscular junction, Antiepileptic Drugs: Mechanism of Action, 363-76, Glaser, G. H., Penry, J. K. and Woodbury, D. M., Eds., Raven Press, New York, 1980.

Entrikin, Patterson and Wilson, Experimental Neurology (1981), 2180 in a blind study including twenty-five, thirty and ninety-day trials, found that PHT (in gradually increasing doses of 10-60 mg/kg, intraperitoneally, twice a day) improved righting ability in dystrophic chickens as early as the tenth day of treatment. Improvement, compared to the untreated chickens, was still present at ninety days, although the disease had progressed in all animals. PHT also reduced plasma creatine kinase and plasma and fast-twitch muscle acetylcholinesterase activity.

2180. Entrikin, R. K., Patterson, G. T. and Wilson, B. W., Phenytoin, methysergide, and penicillamine in hereditary muscular dystrophy of the chicken, Exper. Neurol., 72: 82-90,1981.

Hudecki, Pollina, Heffner and Bhargava, Experimental Neurology (1981), 2207 found that PHT (40 mg/kg, daily) significantly improved the righting ability of dystrophic chickens during a ninety-day trial.

2207, Hudecki, M. S., Pollina, C. M., Heffner, R. R. and Bhargava, A. K., Enhanced functional ability in drug-treated dystrophic chickens: trial results with indomethacin, diphenylhydantoin and prednisolone, Exp. Neurol., 73: 173-85, 1981.

Kwiecinski, European Journal of Clinical Investigation (1984), 2683 showed that PHT (30 µg/ml) inhibited experimentally induced myotonia and completely suppressed the self-sustaining repetitive activity in human myotonic intercostal muscle fibers. Latencies at rheobase were decreased and the number of spikes during a current pulse was markedly diminished. During tetanic isometric contraction, the abnormal myotonic relaxation and the electromyographic after-activity were completely abolished by PHT. The author suggests that PHT inhibits myotonic activity by decreasing voltage-dependent sodium conductance.

2683. Kwiecinski, H., The antimyotonic effect of diphenylhydantoin, Eur. J. Clin. Invest., 14: 37, 1984.

Aichele, Paik and Heller, Experimental Neurology (1985), 2278 studied the efficacy of PHT, procainamide and tocainide in murine genetic myotonia. All three drugs were initially effective against myotonia; however, the duration of the effect was longest for PHT, 89% of its maximum effect still present three hours after injection, compared with 25% for tocainide, and no effect for procainamide. The authors note that the effectiveness of the drugs correlated with their potency in blocking isolated sodium currents.

2278. Aichele, R., Paik, H., Heller, A. H., Efficacy of phenytoin, procainamide, and tocainide in murine genetic myotonia, Exp. Neurol., 87: 377-81, 1985.

Selzer, David and Yaari, Brain Research (1984), 2944 found that PHT (100-300 µM) strongly suppressed the tetanic and post-tetanic potentiation of muscle endplate potentials induced by stimulation (30 Hz), but had only slight effects at low frequencies (0.5 Hz). The authors suggest that PHT's frequency-dependent suppression of excitatory synaptic transmission may also be important in its regulation of hyperexcitability in the CNS.

2944. Selzer, M. E., David, G., Yaari, Y., Phenytoin reduces frequency potentiation of synaptic potentials at the frog neuromuscular junction, Brain Res., 304(1): 149-53, 1984.

David, Selzer and Yaari, Brain Research (1985), 2429 demonstrated that PHT (100-300 µM) suppressed aminopyridine-induced presynaptic afterdischarges and repetitive muscle-fiber activation in a frog nerve-muscle preparation. At the presynaptic terminal, PHT suppressed abnormal afterdischarges, while the primary action potential was never abolished. The authors note that PHT's actions on afterdischarge generation are compatible with its known stabilization of hyperexcitable membranes. 

2429. David, G., Selzer, M. E., Yaari, Y., Suppression by phenytoin of convulsant-induced after-discharges at presynaptic nerve terminals, Brain Res., 330(1): 57-66,1985.

McKinney, Neuroscience Letters (1985), 2781 using intracellular recording techniques, found that PHT (100 µM) reversed veratridine-induced membrane depolarization in frog skeletal muscle by approximately one-third. PHT also inhibited veratridine-induced sodium influx in a dose-dependent manner. The author notes that these findings are consistent with PHT's effects in neurons.

2781. McKinney, L. C., Diphenylhydantoin reduces veratridine-induced sodium permeability in frog skeletal muscle, Neurosci. Lett., 55(2): 173-8, 1985.

Raines, Mahany, Baizer, Swope and Hershkowitz, Journal of Pharmacology and Experimental Therapeutics (1985), 2889 evaluated PHT's ability to reduce motor manifestations of decerebrate rigidity in cats. PHT diminished the force necessary to collapse hyperextended limbs, reduced gamma motoneuron discharges, and markedly depressed mechanical and electromyographic responses evoked by stretch from both forelimb and hindlimb extensor muscles. The authors conclude that PHT has both central and peripheral muscle relaxing effects, consistent with its usefulness in the treatment of spasticity.

2889. Raines, A., Mahany, T. M., Baizer, L., Swope, S., Hershkowitz, N., Description and analysis of the myotonolytic effects of phenytoin in the decerebrate cat: implications for potential utility of phenytoin in spastic disorders, J. Pharmacol. Exp. Ther., 232(1): 283-94, 1985.

Yaari, Selzer and David, Brain Research (1985),3092 studied the effects of PHT (100-300 µM) in frog nerve-muscle preparations using intracellular recordings from muscle endplates and extracellular recordings from motor nerve terminals and their parent axons. With PHT, the number of impulses transmitted across the synapse decreased in a dose-dependent manner. Fewer impulses were transmitted at higher rates of stimulation (100-200 Hz). However, even at lower stimulation frequencies (30-50 Hz), PHT markedly inhibited the buildup of endplate potential amplitude after repetitive nerve stimulation (tetanic potentiation).

3092. Yaari, Y., Selzer, M. E., David, G., Frequency-dependent effects of phenytoin on frog junctional transmission, Brain Res., 345(1): 102-110, 1985.

Hartman, Fiamengo and Riker, Anesthesiology (1986), 2576 found that pretreatment with intravenous PHT (30 mg/kg) suppressed succinylcholine-induced motor nerve terminal repetitive firing and post-tetanic potentiation, as well as muscle fasciculations, in an in situ cat soleus neuromuscular preparation. PHT was found to be more effective than d-tubocurarine in suppressing the fasciculations. In addition, PHT enhanced succinylcholine's desired blocking effect, while d-tubocurarine reduced it. The authors comment that succinylcholine, a depolarizing neuromuscular blocker used in anesthesia, has a number of undesirable side effects which can be reduced by suppressing fasciculations. They suggest that PHT may be clinically useful as a preventative when succinylcholine is used.

2576. Hartman, G. S., Flamengo, S. A., Riker, W. F., Succinylcholine: mechanism of fasciculations and their prevention by d-tubocurarine or diphenylhydantoin, Anesthesiology, 65(4): 405-13, 1986.

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