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[EEG activation with bemegride in epilepsy diagnosis. 1: Literature review].

In patients with suspected epilepsy, an EEG "activation" with bemegride can be performed as last link of the diagnostic chain. The administration of bemegride intends the activation of epileptiform discharges in the EEG of patients with a disposition for epilepsy. This activation is not supposed to occur in healthy subjects at the same dosage. The occurrence of generalized and focal epileptiform discharges during the intravenous administration of bemegride is regarded as a positive test result by most investigators. Changes like a slowing of the background activity, dysrhythmias, parenrhythmias, and focal changes are not reliable. The provocation of seizures should be avoided. Dosage and injection rate must be chosen in such a way that false negative results are more probable than false positive. The result of the bemegride test is influenced by sex, type of seizures, age and alcohol intake. Slight side effects of the intravenous administration of bemegride are relatively common, severe side effects rather uncommon when the test is carefully performed. According to the literature and personal experience, the activation of typical epileptiform discharges in the EEG by bemegride in adults with doubtful episodes of unconsciousness indicates the possible presence of epilepsy (epileptic seizures respectively), but does not confirm this. In our opinion, the bemegride test is contraindicated in patients with established epilepsy (epileptic seizures respectively) or in cases in whom the occurrence of epileptic seizures is probable.

Adolescent↗

[The influence of bemegride on frog spinal cord root potentials].

The effect of the convulsant bemegride (beta-ethyl-beta-methyl-glutharimide) on the electronic potentials in the frog spinal roots was investigated in situ. Intravenous injection of the bemegride subconvulsant doses (6.8 +/- 2.7 mg/kg) depressed rapidly the electrotonic dorsal root potentials (DRP) evoked by a stimulation of the adjacent dorsal root (DR) or the ventral root (VR). They were reduced by 55--67% 3-6 min after the bemegride injection. The effect of bemegride was reversible and the DRP amplitude restored its initial value within an hour. Ventral root potentials after bemegride injection revealed only greater amplitude fluctuations. A conclusion is made that bemegride is a selective and potent depressor of the primary afferent depolarization in the frog spinal cord.

Animals↗

Discriminative stimulus properties of pentylenetetrazol and bemegride: some generalization and antagonism tests.

In an operant procedure of lever pressing on a FR 10 schedule of food reinforcement, male hooded rats were trained to respond with a lever on one side of a food cup following a drug injection, and to respond with a lever on the alternate side following a 1 ml/kg saline injection. All of 14 subjects learned to discriminate reliably between the effects of 20 mg/kg pentylenetetrazol (PTZ) and saline. Seven of eight rats learned to discriminate between the effects of bemegride (5 mg/kg) and saline. None of 14 rats learned to discriminate between 5mg/kg PTZ and saline. The bemegride discriminative stimulus generalized to PTZ (20mg/kg) and was antagonized by chlordiazepoxide (10 mg/kg). Chlordiazepoxide, diazepam, flurazepam, clobazam, and meprobamate were all effective antagonist of PTZ in a dose-dependent manner. Bemegride and cocaine generalized to the PTZ discriminative stimulus in a dose-dependent manner, but d-amphetamine, methylphenidate, and nicotine did not. Since bemegride and PTZ are convulsants at higher doses, the discriminative stimulus properties of these drugs might be based on a subtle convulsive brain state. The anxiolytic properties of benzodiazepines and meprobamate suggest that the discriminative stimulus produced by these convulsants is related to an "anxiety-inducing" action.

Animals↗

Distribution of [14C] bemegride in tissues after intravenous injection.

The distribution and excretion of bemegride labelled at the alpha carbon atoms with (14)C were studied in mice, rats, and guinea-pigs. These studies were supplemented by others made by colorimetric and absorptiometric methods on unlabelled bemegride in the body fluids of rabbits and dogs. Bemegride passed rapidly from plasma to all tissues, including brain, muscle, and fat. In addition it passed readily into the cerebrospinal fluid and the aqueous humour and to the foetus. It persisted in the tissues for longer than 24 hr., to some extent preferentially in the central nervous system. Approximately two-thirds of the dose was excreted in the bile, faeces, and urine within 24 hr. The glutarimide ring of bemegride was not completely degraded biologically.

Animals↗

Effects of bemegride on the sensory responses of neurons in the hippocampus and brain stem reticular formation.

Administration of subconvulsant doses of bemegride results in extensive enhancement of sensory responsiveness to auditory, visual, somatosensory and vibrissa stimulation of neurons in the medullary and mesencephalic reticular formation (RF). This effect is not altered by cord transection. Most neurons in the dorsal hippocampus do not show enhanced sensory responsiveness. In the minority of hippocampal neurons which do show enhancement the effect is much less extensive than that seen in the RF despite larger doses of bemegride. The enhancement of RF neuronal response may involve the reversal of repetition induced response attenuation ('habituation') and reductions in response threshold. During EEG seizures the firing of neurons in RF and hippocampus are temporally correlated with the spikes in the cortical EEG. The effects of bemegride on RF neurons are similar to those previously reported for strychnine and pentylenetetrazol and preliminary studies with physostigmine and bicuculline. These findings further extend the concept that a relatively selective enhancement of the sensory responses of brain stem reticular formation neurons may be indicative of a general neuronal effect of convulsants which may play an important role in the initiation of sensory-induced seizures.

Animals↗

[Changes in somatosensory evoked potentials during EEG activation by bemegride in man].

The use of evoked potentials for the evaluation of neuronal mechanisms by which convulsant drugs activate epilepsy and produce seizure has been reported by many authors. Electrophysiological effects of bemegride with augmented responsivity of brain structure to sensory stimulation is well known, especially in experiments performed with implanted electrodes in animals. After recording evoked activity from parietal scalp following median nerve stimulation before and during 12 human EEG activations by bemegride, the authors find an increase in amplitude of cortical somatosensory evoked potentials. Changes in amplitude after diazepam administration are analysed, as well as morphological changes preceding and following grand mal seizures induced by bemegride administration. This variation in amplitude of evoked responses is compared with those recorded in animals with several convulsant drugs and in man affected with progressive myoclonic encephalopathies. A common action of these agents, beyond their effects on specific neurotransmitters (perhaps mediated by a blockade of neurotransmitter-induced chloride conductance increases), is discussed.

Adolescent↗

Methaqualone discrimination in gerbils: interactions with bemegride and imidazoline (DH-524).

Gerbils were trained in a T-maze to discriminate methaqualone (MTQ), either 16 mg/kg, 12 mg/kg, 8 mg/kg, or 4 mg/kg, from the no drug condition. Discrimination was proportional to dose, MTQ 16 mg/kg vs. no drug being the most rapidly discriminable condition. Challenge of MTQ discrimination with bemegride and imidazoline showed that bemegride, but not imidazoline reversed the MTQ discrimination. The median effective dose of bemegride was related to the amount of MTQ used (16-8 mg/kg).

Animals↗

[Visualization of epileptic lesions using single photon emission computed tomography (SPECT) with N-isopropyl-p-(123I) iodoamphetamine after intravenous loading of bemegride--report of a case].

Single photon emission computed tomography (SPECT) was performed 30 minutes and 4 hours after injection of 111 MBq (3 mCi) N-isopropyl-p-(123I) iodoamphetamine (IMP) which was injected 5 minutes after the completion of intravenous bemegride loading. A 31-year-old female with simple partial seizures evolving to complex partial seizures evolving to generalized tonic-clonic convulsive seizures with a history of hospitalization, suffering from low-grade fever, generalized convulsive seizures, and impaired consciousness at the age of 27 years was studied. Angiographic examinations, X-CT, MRI, CSF examinations, and interictal neurological examinations were normal. She suffered from clonic convulsions in her right shoulder and arm, and hallucinations and dysmnesia which were characteristic of temporal lobe epilepsy. More recently she suffered from impaired consciousness once or twice a month. While the controlled IMP-SPECT study was normal, the IMP-SPECT study examined after the activation by intravenous bemegride loading showed the pattern of a regional increased uptake of IMP in the epileptic lesions corresponding with the epileptic symptoms, and a surrounding border of decreased uptake which might be the inhibition of surrounding neuronal activity and metabolism. In conclusion, the bemegride loading IMP-SPECT study could be a potential diagnostic method in patients with seizures whose epileptic lesions were not determined by the conventional methods or in whom the surgical interventions were considered, by reason of its capability to demonstrate positively the epileptic lesions.

Adult↗

[EEG activation using bemegride in the diagnosis of epilepsy. 2. Catamnestic studies].

43 patients were evaluated catamnestically 5-10 years after a bemegride test in order to proof its relevance. The bemegride test was considered as diagnostically helpful in 37 cases (86%) based on observations of the course. It had been false negative in four cases (9,3%), and false positive in two cases (4,7%). The occurrence of epileptic attacks is indicated by the activation of regular and irregular spike-wave complexes as well as other specific epileptic discharges. These could be activated by an average threshold of 68,5 mg or 1,09 mg/kg body weight in 86,2% of all patients with epileptic attacks. The threshold dose was lower in cases of primary generalized attacks than in complex focal attacks. The indication for the bemegride test is restricted.

Adult↗

Diazepam as a discriminative cue: its antagonism by bemegride.

Gerbils trained to respond differentially to the presence or absence of diazepam (8.0 mg/kg) in a T-maze showed a dose-related antagonism when challenged with bemegride (5.0-40.0 mg/kg). Gerbils trained with a mixture of diazepam (8.0 mg/kg) and bemegride (20.0 mg/kg) evidenced response control more slowly than the group trained solely with diazepam.

Animals↗

Reversed-phase high-performance liquid chromatography method for the determination of bemegride in serum and brain tissue: pharmacokinetics and brain distribution of an intraperitoneal subconvulsive dose in rats.

A simple and rapid HPLC method has been developed for the quantification of bemegride in serum and brain tissue, using p-methylphenobarbital as an internal standard. Serum and brain tissue homogenate samples were extracted with ethyl acetate and the evaporated and redissolved extracts injected into a reversed-phase column. The compounds were eluted with an acetonitrile-phosphate buffer mixture and monitored at 200 nm. A linear response was obtained in the range 1-40 micrograms ml-1 for serum and 1-40 micrograms g-1 for brain tissue. Within-day and between-day precisions were less than 5% and the analytical recovery greater than 76.4%. This method has been used to investigate the kinetic profiles of the drug in serum and discrete areas of rat brain after intraperitoneal administration of a subconvulsive dose of bemegride (10 mg kg-1). Peak concentrations occurred in the brain and serum at the same time (30 min), followed by a biphasic decay. The results also indicated the accumulation of the drug in the brain, with no significant differences (p greater than 0.05) in the impregnation of the different brain areas investigated.

Animals↗

Paradoxical enhancement of hypoperfusion single photon emission CT images in epileptic focus with bemegride activation. Observation from subtraction of 99mTc hexamethyl-propyleneamine oxime brain single photon emission CT images.

Changes of brain images in single photon emission CTs (SPECTs) before and after intravenous injection of bemegride were examined with simultaneous EEG recording in a patient with occipital lobe epilepsy and in a hysteric patient, using a new method, i.e. subtraction of the SPECT images with 99mTc hexamethyl-propyleneamine oxime. The bemegride injection in the epileptic patient paradoxically intensified the hypoperfusion images as epileptic foci in SPECTs, associated with enhanced interictal epileptic discharges, whereas the hysteric showed no such effects. These findings suggest that the hypoperfusion images closely correlate to the severity of epileptic activity, reflecting a functional rather than a morphological deficit.

Adult↗

[Phytopharmacological study on proadiphene, amiphenazole and bemegride in association with phenobarbitone (author's transl)].

The capacity of 2-diethylaminoethyl-alpha, alpha-diphenylvalerate (proadiphene), 2,4-diamino-5-phenyl-thiazole (amiphenazole) and 2,6-dioxo-4-methyl-4-ethyl-piperidine (bemegride) of stimulating or stopping the growth of seedlings of Lepidium sativum L. was tested. Only bemegride shows a weak stimulating effect between 10(-3) and 10(-2) moles/l. In combination with phenobarbital these compounds counteract the stimulating effect and increase the inhibiting one of this barbiturate on the growth of the seedlings.

Bemegride↗

Actions of steroids and bemegride on the GABAA receptor of mouse spinal neurones in culture.

The effects of a synthetic and an endogenous steroid were studied on the GABAA receptors of isolated mouse spinal neurones, maintained in culture. Low doses of alphaxalone reversibly increased GABA-evoked whole-cell currents. Alphaxalone at higher doses (10-50 microM), when pressure ejected onto spinal neurones, also directly evoked a membrane chloride current. Such currents were reversibly suppressed by bicuculline (a GABAA antagonist) and enhanced by phenobarbitone. 5 beta-Pregnan-3 alpha-ol-20-one, a progesterone metabolite, dose-dependently potentiated the amplitude of GABA-evoked whole-cell currents. The mechanism of potentiation was examined at the single-channel level using outside-out patches from spinal neurones. The main action of the steroid on the GABAA receptor appears to be similar to that found for barbiturates, in that they prolonged GABA-activated bursts of channel openings. Bemegride had an antagonistic action on the GABAA receptor, suppressing both GABA- and pentobarbitone-evoked whole-cell currents to similar extents.

Animals↗

[Changes in energy metabolism in the brain of bemegride-kindled rabbits].

Changes in the energetic metabolism in the cortex were examined in bemegride-kindled rabbits. A reliable decrease in the ATP and an increase in the AMP contents in the cortical tissues as well as low ATP/AMP and energetic charge coefficients have been found after kindling the rabbits for 14 and 30-days as compared to the control groups of animals. Considerable disorders in the oxidative phosphorilation in the mitochondria of the cortical tissues have been determined after the succinate and glutamate oxidation: a decrease in the oxygen utilization rate at V3 active metabolic state, lowering the respiratory control coefficient and the disscciation between phosphorilation and oxidation. Those disorders were more expressed after glutamate oxidation as compared to a succinate one. In addition, it has been determined that oxygen utilization at V2 state was reliably decreased; both coefficient of energetic production and ATP-ase reserve activity lowered.

Adenosine Monophosphate↗

The guinea-pig isolated atrium as a model system for the central actions of selected CNS stimulant and depressant drugs. Part 2. Mechanisms involved in the actions and interactions of the convulsant bemegride and its hypnotic homologue 3-methyl-3-n-butylglutarimide.

The present study explores pharmacologically on the model spontaneously beating 3H-noradrenaline pretreated guinea-pig atrial preparation the mechanism(s) by which the representative central nervous system (CNS) stimulant drug 3-methyl-3-ethylglutarimide (bemegride, MEG) and its representative CNS depressant homologue 3-methyl-3-n-butylglutarimide (MBG) affect transmitter release and the force and rate of atrial contraction and contracture, as well as the relevance of these atrial mechanism(s) to those involved in the production of drug-evoked convulsions and hypnosis in the mammalian CNS. The process(es) involved in the interaction of MEG and MBG on the atrial preparation have also been studied to provide insight into possible CNS mechanism(s) that may be involved in the related central phenomena of drug-induced analepsis and anticonvulsant action. It would appear that the actions and interactions of MEG and MBG on the atrium and in the mouse both depend critically on glutarimide-evoked enhancement (MEG) or inhibition (MBG) of Ca2+ flux through potential-operated Ca2+ channels located primarily on the responsive atrial sarcolemmal and neuronal synaptic membranes, respectively. In addition, it seems likely that the reciprocal antagonism shown by these substances on the atrium and in the CNS is predominantly functional in nature. The pharmacological and clinical implications of these findings are discussed, with particular reference to the possible benefit of selective calcium antagonists and related drugs in the management of drug dependence and withdrawal.

Animals↗

Pentobarbital, diazepam and bemegride: their effects on open-field behavior in the gerbil (Meriones unguiculatus).

Open-field activity was measured in female mongolian gerbils treated with pentobarbital, P-barb. (15 and 20 mg/kg) or diazepam, DZP (2,4 and 8 mb/kg), either when given singly or in combination with the analeptic bemegride, BMG (20 and 40 mg/kg). The results indicated that the addition of BMG normalized certain behaviors of the gerbils treated with P-barb. and DZP. The median effective doses of BMG in inducing convulsion and death respectively were 12.0 mg/kg and 22.5 mg/kg. A mutual antagonism is apparent since no animal died after treatment with the drug combinations and seizure activity was also very much reduced.

Animals↗

Alcohol-discrimination in gerbils: interactions with bemegride, DH-524, Amphetamine, and delta9-THC.

Male gerbils were trained to discriminate the effects of an injection of alcohol (1.0, 1.5, and 2.0 g/kg) from the nondrug condition in a T-shaped maze. The formation of the discrimination was related to the training dose used, the high dose (2 g/kg) being the most rapidly discriminable condition. After having reached a criterion of performing 8 correct first-trial choices out of 10 consecutive training sessions the animals were tested for possible generalization or antagonism with bemegride, DH-524, d-amphetamine or delta9-THC. The results suggested that neither of these drugs substituted for alcohol, nor did the drugs reverse or antagonize the alcohol-discrimination, i.e. the gerbils choose the nondrug associated position of the T-maze after single injections of the test-drugs whereas combinations of alcohol and the test-drugs resulted in responding appropriate for the alcohol-(training)-condition.

Animals↗