Lawrence M. Halpern

Effects of Diphenylhydantoin and Other Antiepileptic Drugs on Epileptiform Activity and Purkinje Cell Discharge Rates

The effects of antiepileptic drugs on cerebellar Purkinje cell discharge rates and cerebral cortical epileptiform activity were studied in cats with penicillin foci in sensory‐motor cortex. In control experiments, extracellular microelectrode recordings of P‐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. P‐cell discharges abruptly ceased during development of cortical epileptiform bursts (CEB) which became generalized and maximal in both cerebral hemispheres. Following DPH (10 mg/kg i.v.) CEB frequency and duration were markedly reduced and sustained P‐cell discharge rates of 140 Hz were recorded. Following cerebellectomy in DPH‐treated animals, CEB activity intensified, was more frequent, involved both cerebral hemispheres, and was of much longer duration. Administration of DPH subsequent to cerebellectomy was less effective in reducing CEB activity. After phenobarbital (20 and 40 mg/kg i.v.) reduction of CEB activity was observed as was a consistent increase in P‐cell discharge frequency. Trimethadione (300 mg/kg i.v.) and acetazolamide (35 mg/kg i.v.) did not reduce CEB activity and no increase in P‐cell discharge rate was observed. Thus, after doses of antiepileptic drugs reducing CEB activity, cerebellar P‐cell discharge rates were increased. Conversely, P‐cell discharge rates did not increase following administration of antiepileptic drugs which did not decrease CEB activity.

Flaxedil (Gallamine Triethiodide): Evidence for a Central Action

A central action of gallamine triethiodide has been demonstrated in cats with permanently implanted electrodes that permit direct repetitive stimulation and recording of afterdischarges from cerebral cortex. Systemically administered gallamine produced a consistent and reproducible augmentation of duration of afterdischarge at doses just sufficient to produce skeletal muscle paralysis. Simultaneous examination of expiratory carbon dioxide, blood pressure, body temperature, blood glucose, and direct cortical response to brief single stimuli failed to reveal any consistent peripheral change to which the centrally observed effecte Could be attributed.

Augmentation of cerebellar Purkinje cell discharge rate after diphenylhydantoin.

Extracellular microelectrode recordings were made of cerebellar Purkinje cell (P‐cell) discharge rates before and after systemic administration of antiepileptic compounds. Prior to drug administration, P‐cell discharge rate averaged 24±20 (S.D.) Hz. After diphenylhydantoin (DPH) (10 mg/kg i.v.), P‐cell discharge rate averaged 141±37 Hz. High frequency sustained discharges reached a maximum 1± hr after DPH and persisted for several hours thereafter. Similar high frequency P‐cell discharges averaging 140±79 Hz were observed in animals chronically pretreated with DPH (5 mg/kg i.p. 2 ± daily for 3 days). After phenobarbital (20 and 40 mg/kg i.v.), P‐cell discharge rates of 72±20 and 120±42 Hz were recorded. Following tri‐methadione (300 mg/kg i.v.) or acetazolamide (35 mg/kg i.v.), no increase in P‐cell discharge rates was observed. The possible relation between cerebellar P‐cell activity, antiepileptic drugs, and seizure mechanisms is discussed.

Sulthiame: Evaluation as an Anticonvulsant

A double‐blind crossover study showed that sulthiame as sole anticonvulsant was preferable to diphenylhydantoin in only 4 of 21 patients, and other patients had more seizures or unbearable toxicity on sulthiame. When the concentration of diphenylhydantoin in serum was increased and other anticonvulsants withdrawn, seizures were better controlled and side effects often diminished. Although the few patients benefited by sulthiame alone felt more alert, neuropsychologic tests showed that organic communications and intellectual processing deficits were accentuated. Hyperpnea could be troublesome. Previous favorable reports on sulthiame may have been due to the increase it causes in serum diphenylhydantoin when the two drugs are given together.

Turnover kinetics of dopamine and norepinephrine in the forebrain after kindling in rats

Abstract Turnover rate constants for dopamine (DA) and norepinephrine (NE) were estimated for the forebrain of kindled rats from which overt motor seizures had been elicited by stimulation of basolateral amygdala. Kindled rats had significantly higher rate constants for DA turnover in the hemisphere ipsilateral to electrical stimulation. Turnover rate constant for DA in contralateral hemisphere tended to be greater in kindled rats and was not significantly different from that determined for ipsilateral hemisphere. NE turnover rate constants were not significantly different between hemispheres nor between groups of kindled and control rats.

Microelectrode studies of the afferent connections and efferent projections of neurons in the sensorimotor cortex of the cat

Abstract The functional anatomy of neurons of cat sigmoid gyrus has been studied. Simultaneous recording with four microelectrodes in pre- and postcruciate cortex was carried out. Various inputs were investigated with regard to their ability to evoke the same cortical unit. Stimulation sites included: primary sensory receiving area (S1); ventrolateral nucleus of the thalamus (VL); center median (CM); red nucleus (RN); as well as pyramid and pes pedunculi. Following classification of units as pyramidal tract (Pt) neurons or, as units not identifiable as pyramidal tract (nPt) neurons, they were compared with regard to their response to stimulation at the sites listed above. In addition to Pt neurons, units were antidromically evoked by stimulation of S1, VL, and RN but not by stimulation of CM. The Pt and nPt neurons were observed to project to S1, but no Pt neuron projected to VL. Neurons with output to VL were not evoked by stimuuation of RN. The Pt neurons, orthodromically evoked by VL stimulation, did not respond, but some nPt neurons did respond to input from S1. The Pt neurons orthodromically evoked by single-pulse stimulation of CM were not evoked by stimulation of VL. Some convergence of synaptic input on Pt neurons from S1 and CM was observed. There was convergence of inputs from VL and CM on the majority of nPt neurons studied.

Diphenylhydantoin: Evidence for a central action

Abstract Cerebellar Purkinje cells display random firing rates which vary spontaneously from 5 to 300 Hz under normal circumstances. Diphenylhydantoin, a clinically useful antiepileptic drug, was studied to determine its effect on Purkinje cell discharge patterns. After diphenylhydantoin (10 mg/kg i.v.) the usual pattern of spontaneous random alteration in P-cell firing rate was replaced by sustained high frequency discharge at 140 Hz, which persisted for several hours. Concomitant with the increased Purkinje cell discharge rate, DPH reduced spread of spontaneous cortical epileptiform activity from a penicillin-induced cortical focus. The possible relation between these events is discussed.

CARBAMAZEPINE (TEGRETOL) AS AN ANTICONVULSANT A CONTROLLED DOUBLE‐BLIND COMPARISON WITH DIPHENYLHYDANTOIN (DILANTIN)

A large double blind crossover study of carbamazepine (CBZ) in comparison to diphenylhydantoin (DPH) is underway, and the results are presented for the first 20 patients to complete the protocol. The importance of preparatory steps is outlined – beginning with the gathering of preliminary kinetic data about half‐life and peak‐time in epileptic patients. A detailed pilot study was performed with open administration of the agents and hospitalization during the crossover. Detailed blood level monitoring and dose‐equivalence calculations lead to the design of blind crossover protocol from the pilot study.

Synchronization of hippocampal and cortical electroencephalogram by thyrotropin-releasing hormone

Abstract The septal region has recently been shown to be extremely sensitive to thyrotropin-releasing hormone (TRH)-induced antagonism of pentobarbital narcosis in the rat. As the septohippocampal system is thought to provide a neuroanatomical substrate mediating synchronization of the hippocampal EEG, we hypothesized that TRH would induce hippocampal synchrony. Animals were pretreated with pentobarbital and both hippocampal and cortical EEG monitored. By using spectral analysis of the EEG, it was shown that intracerebroventricular administration of TRH caused a significant increase in both hippocampal (3 to 7 Hz) and cortical (7 to 11 Hz) synchrony. It is postulated that TRH-induced hippocampal synchrony may play a role in TRH antagonism of pentobarbital narcosis.

D--phenylalanine; a putative enkephalinase inhibitor studied in a primate acute pain model

&NA; d‐Phenylalanine, along with morphine, acetylsalicylic acid and zomepirac sodium were evaluated for their antinociceptive actions in monkeys (M. fascicularis) trained to autoregulate nociceptive stimulation using a discrete‐trials, aversive‐threshold paradigm. Morphine sulfate produced dose‐related increases in aversive threshold which were reversible after administration of naloxone (12.5 or 25 &mgr;/kg i.m.). d‐Phenylalanine (500 mg/kg p.o.) produced a small increase in aversive threshold which was not statistically significant and not naloxone reversible. Acetylsalicylic acid (200 mg/kg p.o.) but not zomepirac sodium (200 mg/kg p.o.) in combination with d‐phenylalanine (500 mg/kg) produced a small statistically significant increase in aversive threshold. Our results argue against the hypothesis that d‐phenylalanine is responsible for increasing aversive thresholds via opiate receptor mechanisms involving increased activity of enkephalins at synaptic loci. Previous studies by others in rats and mice showed that d‐phenylalanine and acetylsalicylic acid produced increases in nociceptive thresholds which were naloxone reversible. Our failure to find opiate receptor mediated analgesia in a primate model with demonstrated opiate receptor selectivity and sensitivity is discussed in terms of previous basic and clinical research indicating an analgesic role for d‐phenylalanine. Possible species difference in drug action is discussed in terms of inhibition by d‐phenylalanine of carboxy‐peptidase‐like enkephalin processing enzymes as well as inhibition of carboxypeptidase‐like enkephalin degrading enzymes.