The neuropharmacology of antiepileptics

Toman, James E. P.

doi:10.1016/0013-4694(49)90008-5

Cited by 9 publications

(11 citation statements)

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“…DPH appears to have both a reversible acute toxic effect on the peripheral nerves and a long-term effect after prolonged treatment. The animal experiments of Toman (1949) and Morrell et al (1958) demonstrated a depressant effect of DPH on peripheral nerve. Korey (1951) also demonstrated an inhibitory action of DPH on the giant axon of the squid which was made hyperexcitable by low calcium and magnesium.…”

Section: Discussionmentioning

confidence: 91%

“…There have been recent indications of direct toxic effects of diphenylhydantoin (DPH) on human peripheral nerve (Hopf, 1968;Lovelace and Horwitz, 1968;Birket-Smith and Krogh, 1971;DeCastro et al, 1972;Encinoza, 1974;Eisen et al, 1974), although these have been noted in experimental animal studies in the past (Toman, 1949;Korey, 1951;Morrell et al, 1958). In the report by Hopf (1968) and Lovelace and Horwitz (1968), the conduction velocity study was not correlated with serum DPH levels.…”

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confidence: 99%

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Motor nerve conduction study in patients on diphenylhydantoin therapy.

Chokroverty¹,

Sayeed²

1975

Journal of Neurology, Neurosurgery & Psychiatry

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Section: Discussionmentioning

confidence: 91%

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confidence: 99%

Motor nerve conduction study in patients on diphenylhydantoin therapy.

Chokroverty¹,

Sayeed²

1975

Journal of Neurology, Neurosurgery & Psychiatry

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“…The majority of investigations concerning these drugs have been confined to testing their influence on polysynaptic pathways and evidence has been gained that synaptic transmission is depressed (Goodman and Gilman, 1970). Some findings in experimental animals (Toman, 1949;Korey, 1951;Morrell, Bradley, and Ptashne, 1958), however, as well as clinical observations (Lovelace and Horwitz, 1968), have pointed to the fact that, for example, diphenylhydantoin might induce impairment of the function of lower motor neurones. Corresponding changes have been observed in peripheral nerves exposed to barbiturates (Heinbecker and Bartley, 1940).…”

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confidence: 99%

Anticonvulsant drugs and spike propagation of motor nerves and skeletal muscle

Hopf

1973

Journal of Neurology, Neurosurgery & Psychiatry

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SUMMARY The propagation velocity of evoked muscle spikes was measured and normal values are presented. Carbamazepine, phenobarbitone, diazepam, and bromide-containing drugs were tested for their effect on conduction velocity of motor nerve and skeletal muscle fibres. All these drugs caused a decrease in spike propagation, both of motor nerves and skeletal muscle. After discussion of the probable mode and site of action of these drugs, it was supposed that the underlying eventsperhaps changes in permeability of excitable membranes during excitation-are an essential factor in the anticonvulsant action of these drugs.

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“…Although this drug has been widely used in patient care (3), and voluminously investigated (3,4), no clear-cut ionic mechanism of action for it on any excitable membrane has emerged. In peripheral nerve this compound has, nonspecially, been considered to be a membrane "stabilizer" because it prevented or interrupted repetitive electrical activity induced by various means (5)(6)(7). However, a decrease in the maximum rate of rise of the action potential in isolated rat atrial fibers indirectly suggests that this drug can impair the sodium mechanism involved in the genesis of the action potential (8,9).…”

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Diphenylhydantoin Inhibition of Sodium Conductance in Squid Giant Axon

Lipicky

Gilbert

Stillman

1972

Proc. Natl. Acad. Sci. U.S.A.

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Diphenylhydantoin, in concentrations of Fig. 1. The lower curves show the relation of the maximal sodium current (the peak of the transient, inwardly directed current) to the membrane potentials to which the axon membrane was clamped. The upper curves show the same relation for the potassium current (the delayed, steadystate, positive current).The principal result was a reduction of the transient, sodium currents. The effects with 10 ,M diphenylhydantoin were greater than with 5 I&M (Fig. 1), and 50 p&M drug reduced the peak sodium current by about 75%. The effect was largely reversible, with "recovery" to 65-90% of the initial (control) sodium conductance upon return to control artificial sea water. In no experiment did the drug significantly change the voltage (i.e., less than 5-10 mV, representing the accuracy of the method used) at which the peak transient current occurred. Inconsistent, small (i.e., less than 0.1 msec) increases in the time to reach this peak current (for any given depolarizing step) lead us to tentatively conclude that no significant change in the time-to-peak sodium current occurred.Diphenylhydantoin had little or no effect on the resting membrane potential or on the leakage currents. Its effects are probably not on the "resting elements" of the membrane, but rather upon the ionic channels that are associated with a change from the resting to the active state of the membrane. This permeability change (activated sodium conductance) is best characterized by the empirical formulations of Hodgkin and Huxley (10) as a product of three parameters (i.e., 9Na = gNamlh). The absence of any voltage shift or delay in the time-to-peak sodium currents speak against the drug affecting the process of sodium activation (m), or sodium inactivation (h), or either of their time constants. Occasionally, small changes in the sodium reversal potential (as in Fig. 1) occurred (i.e., the potential where the sodium current is zero was shifted to the left after drug administration). Even when present, this effect was of insufficient magnitude to account for the observed decrease in the sodium current.Thus, it appears that diphenylhydantoin principally alters the sodium conductance, ONa, presumably by directly blocking the activated channels through which the sodium ions normally enter the axon. This effect (decreasing #Na, without appreciably altering m or h) is similar to the effects of saxitoxin (13) and tetrodotoxin (14,17), and is somewhat different from the effects of procaine (15). (Fig. 2). The upper section of Fig. 2 shows the peak sodium 1758

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The neuropharmacology of antiepileptics

Cited by 9 publications

References 0 publications

Motor nerve conduction study in patients on diphenylhydantoin therapy.

Motor nerve conduction study in patients on diphenylhydantoin therapy.

Anticonvulsant drugs and spike propagation of motor nerves and skeletal muscle

Diphenylhydantoin Inhibition of Sodium Conductance in Squid Giant Axon

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