[The influence of bemegrid, noradrenalin and artificial respiration on thiopental anesthesia in dogs].
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Analgesia↗
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[Comparative studies on the convulsive action of bemegrid, pentetrazol and picrotoxin].
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Central Nervous System Stimulants↗
Antagonism of pentobarbital induced discrimination in the gerbil.
Previous work has shown that gerbils that could discriminate the effects of an injections of pentobarbital and the effect of saline, as shown by the animals' differential responding (left or right turn) in a T-shaped maze (state-dependent behavior), choose the saline associated position of the maze when challenged with bemegride in conjunction with the barbiturate. The present study examined whether differential responding in a T-maze would appear when gerbils were required to differentiate a pentobarbital (15 mg/kg)-bemegride (20 mg/kg) mixture from a saline condition (group 2) from the start of the discriminative training. The acquisition rate for this group was compared with that of another group which was required to discriminate the barbiturate, when given alone, from the no drug condition (group 1). Complete discrimination had occurred after 20 training sessions in group 1 whereas none was noted for group 2. Hereafter the bemegride was withdrawn and group 2 continued the regular training with pentobarbital solely vis-a-vis saline. Complete discrimination appeared within the next 10 sessions. After session 20 group 1 were given challenge trials which were interposed in the regular training with bemegride, metrazol, and cocaine. Bemegride (20 mg/kg), metrazol (40 mg/kg), but not cocaine (40 mg/kg), antagonized the pentobarbital (15 mg/kg) produced discrimination.
Animals↗
Drug antagonism and audiogenic seizures in mice.
The occurrence of audiogenic seizures in mice has been used as the basis of a method for measuring the antagonism between sodium thiopentone and bemegride or leptazol. Thiopentone in doses of 8 and 16 mg./kg. protected all the mice against the occurrence of audiogenic seizures. Bemegride and leptazol were administered in doses having molecular concentrations which bore a simple relationship to the doses of thiopentone. Bemegride was four times as powerful as leptazol in antagonizing the protective effect of thiopentone, and comparison of their regression lines showed that both analeptics acted in the same way. The antagonistic effect of bemegride occurred with doses less than its normal convulsant dose, but the doses of leptazol needed to antagonize thiopentone were within the convulsant range, and it increased the severity of any audiogenic seizures.
Animals↗
Brain level of pentobarbital is the primary determinant for the development of hypnotic of hypnotic tolerance in mice.
Controlling the duration of hypnotic effect of pentobarbital by simultaneously administered bemegride, the relationship between the duration of hypnosis and the degree of developed tolerance after acute or chronic treatment was investigated in mice. Bemegride attenuated the hypnotic effect of pentobarbital, but neither the brain level of pentobarbital nor the development of tolerance was modified by bemegride, indicating that the brain level of pentobarbital is the primary determinant for the production of tolerance and full duration of hypnosis is not essential in this mechanism.
Animals↗
[Comparative evaluation of the antitoxic activity of central nervous system analeptics and their combinations in barbamyl poisoning].
Tests conducted on rats poisoned with increasingly lethal doses of sodium amytal demonstrated the antitoxic activity of an analeptic mixture to be superior to that of picrotoxin, strichnine, corasol and caffeine entering into its composition and also to the activity of bemegride. As to the degree of antitoxic activity in poisoning of mice with sodium amytal (one LD50) the CNS analeptics are arranged in the following descending oder of their action: analeptic mixture, picrotoxin, bemegride, corasol, strychnine. In poisoning with higher doses of sodium amytal (LD84) corasol, strychnine and caffeine are ineffective, the most productive being analeptic mixture and picrotoxin. Bemegride proves effective only in a single dose of 2.8 LD50 for intact animals.
Amobarbital↗
Interactions between alcohol and other drugs on open-field and temperature measurements in gerbils.
Open-field activity and rectal temperature were measured in mongolian gerbils treated with alcholol (1 and 2 g/kg) only and when alcohol was combined with bemegride (20 and 40 mg/kg), DH-524 (20 mg/kg), or d-amphetamine (8 mg/kg). None of the purported antagonists normalized the alcholol-produced changes in the open-field test, nor did they reverse the alcohol-induced hypothermia. However, alcohol offered protection against bemegride-induced convulsion and death. When compared with pervious data (1) it is suggested that alcohol is differentiated from pentobarbital and diazepam on the basis of their interactional effects with bemegride.
Animals↗
Interaction of the discriminative stimulus properties of diazepam and ethanol in pigeons.
One group of pigeons (n = 5) was trained to discriminate between the effects induced by 5.6 mg/kg of diazepam (DZP) and the vehicle whereas other pigeons (n = 5) had to discriminate between 3.0 g/kg of ethanol (ETOH) and the vehicle, administered intragastrically (IG) 10 and 40 min prior to the training sessions respectively. Once trained, the pigeons were tested with either diazepam or ethanol alone and in combination. The birds trained to discriminate between DZP and the vehicle mostly performed non-drug associated responses when tested with ETOH (0.56 to 3.0 g/kg). Tests with other doses of DZP (0.3 to 3.0 mg/kg) in the diazepam-trained birds resulted in an ED50 value of 1.4 mg/kg. The birds trained to discriminate between ETOH and the vehicle generalized DZP to ETOH, the ED50 value for diazepam being 3.0 mg/kg. Tests with other doses of ETOH (0.56 to 2.0 g/kg) in this latter group resulted in an ED50 value of 1.3 g/kg. Tests with combinations of DZP and ETOH produced a shift of the dose-response curves to the left indicating drug additivity. The discrimination of 5.6 mg/kg of IG administered DZP but not that of ETOH (3.0 g/kg) was attenuated by injections of the analeptic bemegride (ED50 = 5.5 mg/kg), thus suggesting a difference in the cueing processes of the two drugs. When tested singly, bemegride induced non-drug responding or complete suppression of responding in the birds at the doses of 3.0 and 10.0 mg/kg respectively. In conclusion, the discriminable effects of DZP and ETOH are additive or even supra-additive, but the stimulus properties of the two drugs are not identical.
Animals↗
Dipropylacetic acid (Depakine) in experimental epilepsy in the alert cat.
The effect od dipropylacetic acid (DPA; Depakine) on the bemegride-induced convulsive threshold was investigated in alert cats. Forty-five min after DPA 200 mg/kg, s.c., no significant effect was obtained; 5 min after the same dose iv., protection from bemegride-induced seizures was pronounced. DPA did not decrease focal discharges in sensorimotor cortex produced by topical cobalt, although spread of epileptogenic activity from the focus was inhibited. DPA antiepileptic protection tested by the same procedure was about the same as that given by phenobarbital and less than that given by diazepam.
Animals↗
[The effect of hormonal systems on the activity of convulsant agents].
The dynamics of convulsive action exerted by Bemegride, 15 mg/kg, and Corasol (Pentamethylenetetrasol, 50 mg/kg, was examined in rat experiments during extirpation of endocrine glands (pituitary, thyroid, adrenals and gonads). Their effects were found to be unequal in various series of experiments: thyroidectomy intensified the nature of convulsive reactions while gonadectomy attenuated them; sex-specific differences in the effects of the agents were insignificant. It has been suggested that the hormone-mediator interaction is essential in the mechanisms of convulsive action of Bemegride and Corasol.
Adrenal Cortex Hormones↗
[Effector modelling of the action of ligands of the GABA-receptor complex, cooperativity of the processes and the type of modification of the complex by convulsants and their reversible agonists].
The expression of cooperativity of pharmacological effects of convulsants--exogenic ligands of supramolecular GABA-receptor-channel ensemble (GABA-RC)--bicuculline, picrotoxin, pentylenetetrazole, bemegride at intravenous infusion to intact animals and against a background of administration of barbital-Na and phenazepam is determined. The supposed mechanism of bemegride effect is discussed. Analysis of principles of GABA-RC functioning in vivo on the base of pharmacological data (cooperativity coefficients and types of modulation of GABA-RC functions at the interaction of convulsants and their reverse agonists) suggests the formation of biosystem response at modification of structures adequate to one of four subunits of "quartet" (tetrameric) model of GABA-RC.
Animals↗
[Action of analeptics in acute alcoholic intoxication].
Tests conducted on rabbits in a state of acute ethanol poisoning (2.5 g/kg per os) of a medium degree demonstrated that caffein (10 mg/kg) and bemegride (5 mg/kg) introduced one time intravenously at the height of alcoholic intoxication raise the activity of aerobic oxidative processes, but fail to eliminate metabolic acidosis and do not accelerate the excretion of ethanol. Unlike caffein, bemegride shows a tendency toward respiratory compensation of metabolic acidosis and lowers the activity of the alcohol-dehydrogenase.
Acid-Base Equilibrium↗
[State of the antioxidant system during induction in rats of primary generalized epileptic activity].
Antioxidation system in the brain and blood of rats with generalized bemegride-induced epileptic activity was studied. Antioxidation enzyme activity (superoxide dismutase, glutathione peroxidase and glutathione reductase) and alpha-tocopherol content were determined at an early convulsive stage, immediately after generalized seizures and 10-15 min after seizure. Antioxidation enzyme activity and alpha-tocopherol level in the brain homogenate and blood remained unchanged at any stages of investigation. It is suggested that the increased level of lipid peroxidation products in the brain and blood of rats upon the development of bemegride-induced epileptic activity is not related to the decrease in antioxidation system activity. The effect is mediated by the activation of the reaction initiating free radical brain lipid transformations.
Animals↗
[Increase in the peroxidation of neuron membrane lipids, one of the pathogenetic mechanisms of epileptic activity].
It was found that the development of the epileptic activity focus induced in rats by application of penicillin to the sensomotor cortex surface was accompanied by an activation of lipid peroxidation in the focus area. An analogous effect was also observed in the development of general convulsive seizures induced in rats by injection of bemegride. Preliminary administration of antioxidants (alpha-tocopherol and ionol) to the animals prevented the effect of lipid peroxidation activation and sharply lowered the penicillin-induced epileptic activity. This manifested itself in a diminution of the number and frequency of the seizures and a prolongation of the latent period of their development. The protective action of alpha-tocopherol also manifested itself in a considerable reduction of the animals' mortality on administration of lethal doses of bemegride. It is supposed that lipid peroxidation in the neuronal membranes takes part in the mechanisms of epileptic activity development.
Animals↗
Effects of anticonvulsants and glutamate antagonists on the convulsive action of kainic acid.
In its pattern of sensitivity to anticonvulsants, kainic acid (KA) showed little resemblance to pentylenetetrazol (PTZ), 3-mercaptopropionic acid (3-MP), bicuculline, picrotoxin or bemegride. That KA may have an action on the gamma-aminobutyrate system is suggested by the following: it is strongly antagonized by aminooxyacetic acid; ethosuximide is ineffective against KA as it is against 3-MP; and a subconvulsive dose of KA potentiated 3-MP but not PTZ. However, KA is to some extent comparable to PTZ in that it is antagonized by trimethadione, phenobarbital and chlordiazepoxide more effectively than is 3-MP. The convulsive action of KA is potentiated by the glutamate antagonists l-glutamate diethyl ester (GDEE) and l-nuciferine. GDEE also slightly potentiated bicuculline, but not other convulsants tested; it slightly antagonized PTZ. Nuciferine potentiated all except PTZ and bemegride. The failure of these agents to antagonize KA-induced seizures is consistent with the view that KA and glutamate act at separate excitatory receptor sites. The potentiation might possibly be due to a blocking of glutamergic activation of neurons that are inhibitory.
3-Mercaptopropionic Acid↗
[Central effects of clonazepam].
The effects of oral administration of clonazepam, a new benzodiazepine derivative (F. Hoffmann-La Roche), on the central nervous system were compared with those of diazepam and several anticonvulsants in mice and rats. 1) Clonazepam exhibited a moderate inhibitory effect on the locomotor activity observed with open-field situation in mice and no effect in rats, while it inhibited markedly the rearing behavior in both animals, the duration of action being approximately six hours. 2) Clonazepam potentiated the methamphetamine-induced hyper-locomotor activity in mice whereas trimethadione had no effect. 3) Clonazepam inhibited with a moderate potency the conditioned avoidance response and response to a fixed-ratio (FR 20) schedule of food reinforcement in rats, the potency being a little weaker than that of diazepam. 4) The muscle relaxant effect of clonazepam determined by the traction test was slightly more potent as compared with that of diazepam. Thiopental hypnosis was markedly potentiated after clonazepam. 5) The clonic (CL), tonic-flexor (TF) and extensor convulsions (TE) induced by pentetrazol were strongly inhibited after clonazepam in mice, anticonvulsant potency against CL and TE of clonazepam being approximately 23 and 21 times stronger than that of diazepam, 3333 and 3846 times that of trimethadione, and over 3047 and 178 times that of phenytoin, respectively. Clonazepam reduced markedly CL and TE elicited by bemegride with about 12 to 14 times stronger potency than diazepam. On the contrary, the anticonvulsant effect of clonazepam against TE of maximal electroshock seizure evoked by supramaximal current was weak, the potency being 0.71 times weaker than that of phenacemide, 0.14 times than phenytoin and 0.24 times than phenobarbital. By the combined administration of clonazepam with other anticonvulsants such as trimethadione and phenytoin against pentetrazol convulsion, and phenacemide, phenytoin and phenobarbital against maximal electroshock seizure, the antagonistic effect of these anticonvulsants was potentiated by 4 to 5 times. 6) The acute toxicity (LD50) of clonazepam was weak but that of phenacemide or phenytoin was potentiated to a certain degree by combined administration with clonazepam. The results suggest that clonazepam has a psychopharmacological profile similar to that of benzodiazepines with a particularly potent anticonvulsant effect on pentetrazol and bemegride convulsions, and the anticonvulsant effect is synergic with that of other anticonvulsants.
Animals↗
Comparative study of tiapride and neuroleptics with anti-dopamine activity on convulsive seizure in mice.
The effects of tiapride on the convulsive seizures induced by pentylenetetrazole, strychnine, picrotoxin and bemegride, and on electric seizure are reported and compared with those of sulpiride, chlorpromazine, haloperidol and reserpine. The number of deaths and intensity of convulsion increased dose-dependently and also with the increase in amplitude of electric shock. Tiapride and a similar compound, sulpiride, did not affect these seizures, whereas chlorpromazine potentiated strychnine-induced and electric seizure. Haloperidol and reserpine potentiated electric seizure, and chlorpromazine and reserpine tended to potentiate bemegride-induced seizure. Reserpine also tended to potentiate pentylenetetrazole-induced seizure. These results suggest that tiapride would be clinically safer than other drugs with anti-dopamine activity, except for sulpiride.
Animals↗
Drug discrimination under a concurrent schedule.
Three pigeons were trained to discriminate a 5.0 mg/kg dose of pentobarbital from saline under a two-key concurrent schedule with responding on the key associated with the presession injection, under both stimulus conditions, producing four times as many reinforcers as responding on the other key. This concurrent schedule resulted in approximately 70% responding to the higher reinforcement key under the pentobarbital stimulus and approximately 30% responding to that key under the saline stimulus. During testing, then, the pigeons were able to dose-dependently emit higher (>70%) or lower (<30%) values than were established under the control conditions. Dose-response curves were determined for pentobarbital (twice), methamphetamine, phencyclidine, chlordiazepoxide, and the combination of pentobarbital and the barbiturate antagonist bemegride. The results obtained with pentobarbital and chlordiazepoxide showed that, as the dose increased, pentobarbital-appropriate responding also increased. Methamphetamine produced relatively flat dose--response curves, whereas phencyclidine administration produced inconsistent effects on responding. The combination of the training dose of pentobarbital with increasing doses of bemegride produced a decrease in pentobarbital-appropriate responding. The results also showed that the dose-response curves for pentobarbital and chlordiazepoxide, instead of being all or none, were graded functions of the drug dose.
Animals↗