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Biomedical subjects

W M Burnham

Publications and source records attributed to W M Burnham.

At least 73 records · Page 4Linked to original sources
PubMed1983

Effects of phenytoin, carbamazepine, and clonazepam on cortex- and amygdala-evoked potentials.

Multiple doses of phenytoin, carbamazepine, and clonazepam were tested against single- and double-pulse evoked potentials. Evoked responses were triggered from either the amygdala or the cortex and were recorded in both monosynaptic sites and the mesencephalic reticular formation (MRF). In accordance with previous studies of spinal potentials, it was expected that all three drugs would display a depressant action. Contrary to expectation, only clonazepam had any significant effect, and this drug was effective only against potentials triggered in the amygdala and recorded in the MRF. These data appear inconsistent with the traditional belief that anticonvulsants block seizure spread by antagonizing transmission in neural pathways.

Amygdala↗
PubMed1982

alpha 2-adrenergic antagonists suppress epileptiform EEG activity in a petit mal seizure model.

Experiments were performed to determine the effects of yohimbine, piperoxan, and mianserin on the flash-evoked afterdischarge (FEAD) in rat. All three drugs are alpha-adrenergic antagonists, which block the inhibition of norepinephrine-release mediated by presynaptic (alpha 2) receptors. It was predicted that these drugs would exert dose-dependent biphasic effects on FEAD: at low doses, which act presynaptically, the FEAD would be suppressed; while at higher doses, which also block postsynaptic (alpha 1) receptors, the FEAD would be disinhibited. The dose response curves for yohimbine and piperoxan were, in fact, biphasic with low doses decreasing the amount of FEAD, while higher doses returned the amount of FEAD to baseline. No biphasic effect was seen with mianserin. These observations are consistent with the fact that yohimbine and piperoxan are more potent antagonists at alpha 2- than at alpha 1-receptors, whereas the affinities of mianserin for the two receptor types is comparable. The results of these experiments support the hypothesis that norepinephrine modulates FEAD.

Adrenergic beta-Antagonists↗
PubMed1982

The effect of anticonvulsant drugs on convulsions triggered by direct stimulation of the brainstem.

Brainstem-triggered convulsions are generalized convulsive seizures produced by direct electrical stimulation of the mesencephalic reticular formation. Four anticonvulsant drugs, phenobarbital, phenytoin, trimethadione, and ethosuximide, were tested against brainstem-triggered convulsions in the rat using a standard pharmacological dose-response paradigm. All four drugs proved to be active in small, subtoxic doses, producing a response profile similar to that previously reported for maximal pentylenetetrazol seizures. These results appear consistent with the hypotheses that: (1) the brainstem plays an important role in the production of generalized convulsions; and (2) that anticonvulsant drugs exert major therapeutic effects at the brainstem level.

Animals↗
PubMed1982

Pharmacological investigation of gamma-aminobutyric acid (GABA) and fully-developed generalized seizures in the amygdala-kindled rat.

The effects of GABA-modulating drugs were assessed in a pharmacological study of amygdala-kindled seizures in the rat. Fully-kindled subjects were tested with a randomized dose regimen, including drug vehicle, for each of seven drugs. Afterdischarge duration, motor seizure latency, motor seizure duration and motor seizure stage were scored. The GABA synthesis inhibitor, 3-mercaptopropionic acid, the GABA antagonist, bicuculline, and the chloride ionophore blocker, picrotoxin, all decreased motor seizure latency, but did not otherwise alter the kindled seizure duration or seizure stage. The inhibitor of GABA metabolism, gamma-vinyl-GABA, and pentobarbital, which competes for the picrotoxin binding site, both antagonized kindled seizures. Gamma-vinyl-GABA, however, did not appear to antagonize kindled seizures by a specific effect on GABA neurotransmission. The GABA agonists, imidazole acetic acid and [alpha-(chloro-4'phenyl)fluoro-5-hydroxy-2-benzylidene-amino]-4-butyramide (SL 76-002), did not alter the kindled seizures. The results of these experiments are not consistent with the hypothesis that kindled seizures result from a loss of GABA-mediated inhibition; however, GABA may have a role in the modulation of kindled seizure activity.

Amygdala↗
PubMed1982

The effect of cinromide on "kindled" seizures in the rat.

Cinromide, an experimental anticonvulsant (Burroughs Wellcome Co.) was tested against focal cortical (simple partial analog), focal amygdala (complex partial analog), and generalized convulsive (tonic-clonic analog) seizures in the "kindled" rat. The toxicity in the CNS was measured by the ataxia scale devised by Desmedt, Niemegeers, Lewi and Janssen (Arzneimittel-Forsch, 26: 1592-1602, 1976). Cinromide was found to suppress generalized convulsions in small, subtoxic doses, whereas larger, sometimes toxic doses were required to suppress focal seizure activity. The general pattern of response resembles that of the standard clinical anticonvulsants which the present authors have previously investigated. Cinromide, however, was relatively more potent against focal amygdala (complex partial analog) seizures than any drug previously tested, except carbamazepine. These data suggest that cinromide should be clinically effective, not only against tonic-clonic seizures, but also, toxicity permitting, against complex partial attacks as well.

Animals↗
PubMed1981

Power spectral analysis of EEG drug response in the kindled rat brain.

The specificity of procaine as a limbic epileptic focus activator was investigated in rats kindled in the amygdala. Power spectral analysis of spontaneous EEG was employed to assess the effects of two doses of procaine HCl (60 and 100 mg/kg) on the kindled and unkindled amygdala. Analysis revealed a dose-dependent increase in power in the 1--15 c/sec frequency band of the EEG. Power increases were greater in the kindled than in the unkindled amygdala of the same rat, and exceeded power changes induced in unkindled controls. The effects of procaine on the EEG persisted past the day of injection, but returned to baseline by the fifth day. Changes in power over days following an injection of procaine differed in the kindled and unkindled amygdala amygdala of the same rat. The kindled amygdala showed an increase on the day of injection, followed by a steady decline to baseline. The unkindled amygdala showed a delayed rise in power on day 2 and then a decline to baseline levels over days. Comparison of spectral changes induced by drug and by electrically triggered seizures suggested that procaine induces EEG patterns which are seizure-like in the absence of seizures. The data are consistent with the view that procaine may be a useful focus specific activator in the detection of limbic epilepsy.

Amygdala↗
PubMed1981

Saturable binding of [3H]phenytoin to rat brain membrane fraction.

Preliminary studies indicate that [3H]phenytoin binds in a saturable and reversible fashion to at least two distinct sites in the membrane fraction of whole rat brain. One of these displays a high affinity (Kd = 6 nM) and a low maximal capacity (Bmax = 10 pmol/g protein). The other has a low affinity (Kd = 4.8 microM) and is estimated to have a very high maximal capacity. Phenytoin binding is reduced if the membrane fraction is preincubated with proteolytic enzymes and subcellular fractionation studies indicate that P2 fraction has the largest number of binding sites. Competition experiments fail to reveal significant binding interactions with putative neurotransmitters or with other drugs except the hydantoins and anticonvulsant barbiturates. Although it is premature to speculate on the clinical significance of these findings, it is encouraging to note that the low affinity site has a Kd very similar to the therapeutic levels of phenytoin found in cerebrospinal fluid and that there seems to be some relationship between binding potency and anticonvulsant potency within the hydantoin series.

Animals↗
PubMed1980

Effects of d-amphetamine and apomorphine in a new animal model of petit mal epilepsy.

d-Amphetamine is effective in controlling seizures in petit mal epilepsy. The flash-evoked afterdis-charge (FEAD) in rats has been proposed as a model of the peit mal seizure. The experiments reported here investigated the dose response relationship for the suppression of FEAD by d-amphetamine, and compared its effects with those of the dopamine-mimetic, apomorphine. Significant suppression of FEAD was observed at doses of d-amphetamine greater than 0.2 mg/kg. A maximum decrease of 60% occurred at 1.2 mg/kg. Higher doses did not result in any further suppression. In contrast, apomorphine and no effect on the FEAD even at doses that induced intense stereotypic behavior. In other experiments, administration of either the dopamine antagonist pimozide or the alpha-adrenergic antagonist phenoxybenzamine exacerbated FEAD and also prevented the suppression of FEAD by d-amphetamine. The results of these experiments support the hypothesis that the FEAD is a valid model of the petit mal seizure. Furthermore, they provide evidence that norepinephrine is necessary for the seizure-suppressant action of d-amphetamine.

Animals↗
PubMed1980

Flash-evoked afterdischarge in rat as a model of the absence seizure: dose-response studies with therapeutic drugs.

The flash-evoked afterdischarge (FEAD) is a self-sustained burst of wave-and-spike complexes recorded from occipital cortex in the rat and other animals in response to a single light flash. On the basis of behavioral experiments and studies employing single doses of antiepileptic drugs, FEAD has been proposed as a model of the absence seizure. In order to test the validity of FEAD as an absence seizure model, the present experiments determined dose-response relationships for the suppression of FEAD by six antiepileptic drugs with established clinical profiles. It was found that phenobarbital, ethosuximide, and trimethadione suppressed FEAD in a dose-related manner, and that ethosuximide was approximately three times as potent as trimethadione. Mephenytoin produced a maximal reduction of FEAD of only 30 to 40%, which was not dose-related. Neither phenytoin nor acetazolamide suppressed FEAD. The results obtained with ethosuximide, trimethadione, and phenytoin are qualitatively similar to their therapeutic effects in absence epilepsy. The FEAD model failed, however, to unequivocally predict the therapeutic efficacy of mephenytoin or acetazolamide. In this respect, it is similar to the metrazol seizure model. It is concluded that FEAD is a valid absence seizure model with a pharmacological predictive value that is at least as good as the metrazol model.

Acetazolamide↗
PubMed1980

Development of a new pharmacological seizure model: effects of anticonvulsants on cortical- and amygdala-kindled seizures in the rat.

The potency of eight standard anticonvulsants was tested in dose-response studies on kindled rats. Animals with either amygdala- or cortical-generalized seizures were used, and the effects of drugs were assessed on: (1) amygdala focal activity; (2) cortical focal activity; and (3) the generalized convulsion triggered from either focus. Ethosuximide, which is used against absence attacks, was not effective at subtoxic levels against any type of kindled seizure. The seven other drugs, all of which are effective against tonic-clonic seizures, were found to be: (a) most potent against generalized convulsive seizures; (b) slightly less potent against cortical focal activity; and (c) only partially effective against amygdala focal activity even at high (toxic) doses. The effect of these drugs on kindled seizures closely parallels their known clinical effects against (respectively) tonic-clonic, simple partial, and complex partial attacks. It is concluded that the kindling preparation could provide new pharmacological models for several different types of clinical seizure. Its most important use, however, is likely to be as a model for complex partial seizures, since there is at present no satisfactory pharmacological model for these common and drug-resistant attacks.

Amygdala↗
PubMed1979

The effect of procaine hydrochloride and diazepam, separately or in combination, on cortico-generalized kindled seizures.

The effects of cortically kindled seizure responses of procaine hydrochloride, diazepam and combinations of these two drugs were tested in this study. The cortex was stimulated until seizure responses developed past the focal stage (accompanied primarily by brief tonic convulsions) to the cortico-generalized stage (accompanied, typically, by an early brief tonus followed by a longer clonic seizure that is characteristic of subcortically triggered seizures). Diazepam was found to block the generalized component of the cortico-generalized electrographic and motor seizure leaving the tonus only slightly suppressed. Procaine blocked the tonus leaving the clonic seizure and discharge that is characteristic of the generalized response relatively intact. Combinations of half doses of the two drugs completely blocked all electrographic and motor seizure responses in about half the animals. The remaining animals had a very brief discharge with no convulsive responses.

Animals↗
PubMed1979

The effects of atropine and reserpine on cortical kindling in the rat.

The effects on cortical kindling of atropine (a muscarinic, cholinergic blocking agent) and reserpine (a depleter of catecholamines and 5 hydroxytryptamine) were tested in this study. Atropine, which had previously been found to retard amygdaloid kindling, had similar but somewhat weaker effects on cortical kindling. Reserpine also had similar effects on cortical kindling compared to subcortical kindling in that it potentiated seizure responses.

Animals↗
PubMed1978

The effect of taurine on kindled seizures in the rat.

Recently, it has been reported that taurine, an amino acid with anticonvulsant properties, does not suppress experimental seizures generated by the "kindling" technique. This finding seems somewhat paradoxical since taurine antagonizes other sorts of experimental convulsion and since kindled seizures are easily suppressed by other anticonvulsant drugs. Further tests were therefore conducted during which taurine's anticonvulsant effects were assessed: (1) when kindling stimulation was dropped to near-threshold levels; (2) when cortical as well as limbic kindled foci were stimulated; (3) when developing as well as fully kindled seizures were involved; and (4) when taurine was introduced directly into the ventricles of the brain. Even in these tests which were specifically designed to favour the appearance of anticonvulsant effects, no taurine antagonism of kindled seizures was found.

Amygdala↗