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PubMed1988

Effects of selected muscarinic cholinergic antagonists on [3H]acetylcholine release from rat hippocampal slices.

A number of cholinergic muscarinic (M) agonists and antagonists were studied for their ability to enhance tritiated acetylcholine ([3H]ACh) release from electrically field-stimulated rat hippocampal slices. A Ca++-free medium and carbachol, but not nicotine, inhibited [3H]ACh release. Atropine, methylatropine and dexetimide produced concentration-dependent increases in [3H]ACh release to a maximum of about 50% above control. Aprophen and benactyzine produced a maximal response 25 to 35% above control. The selective M1 antagonist pirenzepine had the least effect on [3H]ACh release. Of the nonspecific M1-M2 antagonists studied, benactyzine produced the least amount of [3H]ACh release. The order of potency of the M antagonists in promoting a 15% increase in [3H]ACh release was aprophen greater than benactyzine greater than methylatropine greater than dexetimide greater than pirenzepine greater than atropine. However, the order of promoting maximal release of [3H]ACh was atropine greater than dexetimide greater than methylatropine greater than aprophen greater than benactyzine greater than pirenzepine.

Acetylcholine↗

PubMed1978

[Effect of amizil and arecoline on 45Ca uptake by rat brain nerve endings].

The effect of benactyzine (amizyl--the central cholinolytic) and arecoline (cholinomimetic) in vitro on the 45Ca uptake by the nerve endings (synaptosomes) of the rat brain was studied. Benactyzine proved to evoke a biphasic change of the isotope uptake, whereas arecoline induced an initial rapid increase of the 45Ca uptake. Benactyzine suppressed the influence of arecoline and of depolarization on the isotope uptake. A conclusion was drawn that an increase of the 45Ca uptake under the action of arecoline was connected with activization of the Na-K canals. On the contrary, benactyzine depressed the permeability of these canals for 45Ca and activated the calcium canals proper.

Animals↗

PubMed1993

Pharmacological modulation of soman-induced seizures.

Anticholinergics, benzodiazepines and N-methyl-D-aspartate (NMDA) antagonists have been shown to modulate the expression of nerve agent-induced seizures. This study examined whether the anticonvulsant actions of these drugs varied depending on the duration of prior seizure activity. Rats implanted with electrodes to record electroencephalographic (EEG) activity were pretreated with the oxime HI-6 (125 mg/kg, IP) to prolong survival, and then challenged with a convulsant dose of the nerve agent soman (180 micrograms/kg, SC); treatment compounds (scopolamine, diazepam, MK-801, atropine, benactyzine, and trihexyphenidyl) were delivered IV at specific times after seizure onset. Both diazepam and MK-801 displayed a similar profile of activity: At both short or long times after seizure initiation the anticonvulsant efficacy of each drug remained the same. Diazepam, and especially MK-801, enhanced the lethal actions of soman by potentiating the respiratory depressant effects of the agent; scopolamine given prior to diazepam or MK-801 protected against the respiratory depression. Scopolamine and atropine showed a dose- and time-dependent effectiveness; the longer the seizure progressed the higher the dose of drug required to terminate the seizure, with eventual loss of anticonvulsant activity if the seizure had progressed for 40 min. In contrast, benactyzine and trihexyphenidyl showed a third profile of activity: There was a smaller increase in drug dosage required for anticonvulsant activity as seizure duration increased, and both drugs could terminate seizures that had progressed for 40 min. The early anticonvulsant action of anticholinergics is interpreted as a specific effect that blocks the primary cholinergic excitatory drive that initiates, and first maintains, nerve agent seizures. If allowed to progress, the seizure activity itself recruits excitatory neurotransmitter systems (i.e., NMDA) that eventually maintain the seizure independent of the initial cholinergic drive. This is indicated by the eventual ineffectiveness of scopolamine and atropine as the duration of the seizure progresses. Diazepam and MK-801 appear to act to moderate nerve agent seizures by enhancing inhibitory activity (diazepam) or dampening the secondarily activated noncholinergic excitatory system (MK-801). Benactyzine and trihexyphenidyl represent compounds that possibly have both anticholinergic and NMDA antagonistic properties.

Animals↗

PubMed2000

The influence of anticholinergic drug selection on the efficacy of antidotal treatment of soman-poisoned rats.

The influence of some anticholinergic drugs (atropine, benactyzine, biperiden, scopolamine) on the efficacy of antidotal treatment to eliminate soman (O-pinacolyl methylphosphonofluoridate)-induced disturbance of respiration and circulation and to protect experimental animals poisoned with supralethal dose of soman (1.5 x LD(50)) was investigated in a rat model with on-line monitoring of respiratory and circulatory parameters. While the oxime HI-6 in combination with atropine prevented soman-induced changes in monitored physiological parameters insufficiently and very shortly, the combination of HI-6 with benactyzine or biperiden is able to prevent soman-induced alteration of respiration and circulation much more longer. Nevertheless, only rats treated with HI-6 in combination with scopolamine were fully protected against the lethal toxic effects of soman within 2 h following soman challenge. Our findings confirm that anticholinergic drugs with the strong central antimuscarinic activity, such as benactyzine, biperiden and especially scopolamine, seem to be more effective adjuncts to HI-6 treatment of severe acute soman-induced poisoning than atropine.

Animals↗

PubMed1997

Importance of cholinolytic drug selection for the efficacy of HI-6 against soman in rats.

The influence of cholinolytic drugs (atropine, benactyzine, biperiden) on the efficacy of the oxime HI-6 (1-[[[(4-aminocarbonyl)pyridinio]methoxy ]methyl]-2-[hydroxyimino)methyl]pyridinium dichloride monohydrate) on soman-induced anticholinesterase and stressogenic effects was studied in rats. Soman-induced acetylcholinesterase inhibition in blood and diaphragm and the stressogenic effects of soman, i.e. an increase in plasma corticosterone level and liver tyrosine aminotransferase activity, were more significantly diminished by HI-6 in combination with benactyzine or biperiden in comparison with HI-6 plus atropine. These findings support a hypothesis that benactyzine as well as biperiden can increase the efficacy of the oxime HI-6 in comparison with atropine. They demonstrate the importance of cholinolytic drug selection in the treatment of soman poisoning in rats. Ltd.

Acetylcholinesterase↗

PubMed1991

Actions and interactions of cholinolytics and cholinesterase reactivators in the treatment of acute organophosphorus toxicity.

Different drug combinations consisting of cholinolytic and a cholinesterase (ChE) reactivator provide greater therapeutic efficacy in acute organophosphorus (OP) poisoning in mice than when used alone. Maximum protection, as determined by a shift of the LD50 for the two OP agents, was observed with the cholinolytic benactyzine. A protection index (P.I.) of 42 was obtained when benactyzine was given along with obidoxime in diisopropylphosphorofluoridate (DFP) intoxication. With the more toxic OP agent soman (o-pinacolylmethylphosphonofluoridate), the same cholinolytic only offered a maximum P.I. of 3.2 when administered with HS-6, another bispyridinium ChE reactivator. This beneficial effect of benactyzine is possibly due to its greater antimuscarinic effect in the central nervous system than atropine or dexetimide.

Acute Disease↗

PubMed1977

[Rat brain Mg2+-ATPase activity and Ca2+ and Mg2+ concentration in the presence of amizil and arecoline].

The effect of benactyzine (the central cholinolytic) in a dose of 40 mg/kg and arecoline (cholinomimetic) in a dose of 2.5 mg/kg on the activity of Mg2+-dependent ATP-ase and the content of Ca2+ and Mg2+ ions in the brain was studied in rats. It was shown that benactyzine and arecoline evoked a biphasic change in the activity of the enzyme and the electrolyte content. A conclusion was drawn that the enzyme inhibition was connected with the accumulation of Ca2+ ions in the brain tissue, whereas its inhibition--with the Mg2+ ion accumulation. It is supposed that throught these effects benactyzine and arecoline influenced the release and retention of the neuromediators in the tissue depot.

Adenosine Triphosphatases↗

PubMedDate not supplied

[Effect of amisyl and spasmolytin on the blood supply and oxygen metabolism of the brain].

The effect of benactyzine and spasmolytin adiphenine on the blood circulation in the oxygen consumption by the brain were investigated in experiments on dogs. The resulting data point to a biphasic action of benacyzine and spasmolytin on the blood supply of the brain (after a short-lived increase of the blood flow a clearcut decline of it is noted). The oxygen intake from the blood varies irregularly. In chlorophos-poisoned dogs the oxygen absorption by the brain changes under the effect of benactyzine and rises after administration of spasmolytin. The cerebral circulation then changes non-uniformly under the effect of benactyzine, while following spasmolytin injections it dicreases in the majority of experiments.

Absorption↗

PubMed1994

[Comparison of the effect of selected anticholinergic agents on cholinergic and noncholinergic effects of GV substances during acute poisoning in rats].

In experiments on male rats, the effect of selected cholinolytic agents (atropine, benactyzine, G 3063) in combination with the reactivator of cholinesterases HI-6 on the cholinergic and non-cholinergic effects of GV substance in the course of acute sublethal intoxication was compared. The cholinergic affects of GV substance were examined by means of the changes in the activity of cholinesterases in whole blood, the CNS, diaphragm and liver, the noncholinergic stressogenic effects by means of the changes in the level of corticosterone in plasma and the activity of tyrosine amino transferase in the liver. It follows from the changes in the activity of cholinesterases that the cholinergic effects of GV substance are least influenced by atropine, whereas benactyzine and G 3063 exert an approximately similar effect. The difference in the effect is evident especially in the 24th hour of intoxication. Similarly stressogenic effects of GV substance are least influenced by an antidotal combination of atropine and HI-6. It means that the centrally acting cholinolytic agents benactyzine and G 3063 are more advantageous for the therapy of GV substance poisonings than the peripherally acting atropine.

Acute Disease↗

PubMed1997

[The effect of parasympatholytics on the therapeutic effectiveness of the oxime HI-6 against organophosphorus compounds (Soman, substance VX, Fosdrin) in mice].

BACKGROUND: Causal antidotal therapy of acute intoxications with organophosphorus compounds involving administration of the parasympatholytic and cholineesterase reactivator (oxime) has not been resolved so far satisfactorily despite knowledge of the basic mechanism of action of these noxious substances. METHODS AND RESULTS: In experiments on mice the therapeutic effect of parasympatholytics atropine, benactyzine and biperidene (Akineton) combined with oxime HI-6 on the toxicity of highly toxic organophosphates soman and substance VX and the organophosphorus insecticide phosdrine was compared as regards their influence on the LD50 of these noxious substances during 24-hour survival of experimental animals. Two levels of antidotes were tested. These findings confirm that the LD50 value of untreated intoxication with all three organophosphorus compounds is most increased by oxime HI-6 combined with benactyzine regardless of the antidote dosage. CONCLUSIONS: Oxime HI-6 is the most effective against highly toxic organophosphates and organophosphorus insecticides when combined with the centrally acting parasympatholytic benactyzine.

Animals↗

PubMed2001

Effects of selected anticholinergics on acoustic startle response in rats.

The present study compared the effects of the anticholinergics aprophen hydrochloride, atropine sulfate, azaprophen hydrochloride, benactyzine hydrochloride, biperiden hydrochloride, diazepam, procyclidine hydrochloride, scopolamine hydrobromide and trihexyphenidyl hydrochloride on acoustic startle response in rats. Peak startle amplitude, latency to peak startle amplitude and prepulse inhibition following 100- and 120-dB tones were recorded 15 min following drug administration in food-restricted rats. Aprophen, atropine, azaprophen, benactyzine, biperiden and scopolamine significantly increased peak startle amplitude and decreased latency to peak startle amplitude following 100-dB pulses. In contrast, only biperiden increased peak startle amplitude following 120-dB pulses, whereas atropine and trihexyphenidyl decreased latency to peak startle amplitude following 120-dB pulses. Benactyzine decreased prepulse inhibition following both 100- and 120-dB pulses, whereas both biperiden and scopolamine decreased prepulse inhibition following 120-dB pulses. Acoustic startle response measures were effective in differentiating the effects of anticholinergic compounds. The comparison of drug effects on the acoustic startle response may be useful in selecting efficacious anticholinergic drug therapies with a minimal range of side-effects. In addition, these data may be useful in down-selecting the number of anticholinergic drugs that need to be tested in comparison studies involving more complex behavioral tests.

Acoustic Stimulation↗

PubMed2006

The influence of oxime and anticholinergic drug selection on the potency of antidotal treatment to counteract acute toxic effects of tabun in mice.

The influence of newly developed oximes, K027 [1-(4-hydroxyiminomethylpyridinium)-3-(4-carbamoylpyridinium) propane dibromide] and K048 [1-(4-hydroxyiminomethylpyridinium)-3-(4-carbamoylpyridinium) butane dibromide], or currently used oximes (pralidoxime, obidoxime, trimedoxime, HI-6) and anticholinergic drugs (atropine, benactyzine) on the ability of antidotal treatment to eliminate tabun-induced acute toxic effects was studied in mice. The therapeutical efficacy of trimedoxime and both newly developed oximes (K027, K048) is significantly higher than the potency of pralidoxime (regardless of the choice of anticholinergic drug), obidoxime (in the case of its combination with atropine) and the oxime HI-6 (in the case of its combination with benactyzine). All studied oximes with the exception of pralidoxime and the oxime HI-6, when combined with benactyzine, appear to be more efficacious in the elimination of toxic effects of the lethal dose of tabun than their combination with atropine. The findings support the hypothesis that the choice of acetylcholinesterase reactivators as well as the anticholinergic drug selection are important for the effectiveness of an antidotal mixture in the case of antidotal treatment of tabun-induced acute poisonings.

Animals↗

PubMed1999

Dose-response curves and time-course effects of selected anticholinergics on locomotor activity in rats.

RATIONALE: In order to facilitate direct comparisons of anticholinergic drug effects on activity, nine drugs were tested in one laboratory using a standardized procedure. OBJECTIVE: The present study compared the effects of aprophen hydrochloride, atropine sulfate, azaprophen hydrochloride, benactyzine hydrochloride, biperiden hydrochloride, diazepam, procyclidine hydrochloride, scopolamine hydrobromide, and trihexyphenidyl hydrochloride on activity levels in rats. METHODS: Both fine motor activity (reflecting smaller movements) and ambulatory activity (reflecting larger movements) were recorded for 23 h following drug administration in food-restricted rats. All drugs were administered during the light period of the photocycle. RESULTS: Atropine, azaprophen, biperiden, scopolamine, and trihexyphenidyl increased both ambulations and fine motor activity significantly during the first hour post-injection, but the increased activity levels returned to vehicle control levels within 2-6 h post-injection. Benactyzine and procyclidine only increased fine motor activity significantly above vehicle control levels and activity levels returned to vehicle control levels within 2-3 h. Finally, aprophen and diazepam generally did not increase measures of activity significantly above vehicle controls at the dose ranges examined. CONCLUSIONS: Based on potencies relative to scopolamine, the potency of the drugs could be ranked as follows: scopolamine > trihexyphenidyl > biperiden > azaprophen > procyclidine > benactyzine > atropine > aprophen. The comparison of drug effects on activity may be useful in selecting anticholinergic drug therapies with a minimal range of side effects. In addition, these data may reduce the number of anticholinergic drugs that need to be tested in comparison studies involving more complex behavioral tests.

Animals↗

PubMed2000

Anticonvulsant treatment of nerve agent seizures: anticholinergics versus diazepam in soman-intoxicated guinea pigs.

A total of eight anticholinergic drugs (aprophen, atropine, azaprophen, benactyzine, biperiden, procyclidine, scopolamine, trihexyphenidyl) were tested in parallel with diazepam for the ability to terminate seizure activity induced by the nerve agent soman. Guinea pigs, implanted with electrodes to record cortical electroencephalographic (EEG) activity, were pretreated with pyridostigmine Br (0.026 mg/kg, i.m.) and 30 min later challenged with 2 x LD50 soman (56 microg/kg, s.c.) followed 1 min later by treatment with atropine SO4 (2 mg/kg, i.m.) and pralidoxime chloride (2-PAM Cl; 25 mg/kg, i.m.). All guinea pigs developed sustained seizure activity following this treatment. Dose-effect curves were determined for the ability of each drug to terminate seizure activity when anticonvulsant treatment was given either 5 or 40 min after seizure onset. Body weight gain and recovery of behavioral performance of a previously trained one-way avoidance task were measured after exposure. With the exception of atropine, all anticholinergic drugs were effective at lower doses than diazepam in terminating seizures when given 5 min after seizure onset; benactyzine, procyclidine and aprophen terminated seizures most rapidly while scopolamine, trihexyphenidyl, biperiden, and diazepam were significantly slower. When given 40 min after seizure onset, diazepam was the most potent compound tested, followed by scopolamine, benactyzine and biperiden; atropine was not effective when tested 40 min after seizure onset. For diazepam, the time to terminate the seizure was the same whether it was given at the 5- or 40-min delay. In contrast, most anticholinergics were significantly slower in terminating seizure activity when

Animals↗

PubMed1976

[The effect of neurotropic substances on the self-stimulation reaction at the thalamic level].

The effect of d-amphetamine, cocaine, caffeine, morphine, imipramine, phenobarbital, LSD-25, benactyzine, meprobamate, diazepam, chloridiazepoxide on the lateral hypothalamic self-stimulation of rats was investigated. D-amphetamine, cocaine, caffeine, morphine, imipramine decreased the threshold of selfstimulation. Meprobamate, diazepam, chlordiazepoxide failed to influence this index, but increase the intensity of self-stimulation during the threshold, the optimum and more than the optimum cirrent intensity. Benactyzine, LSD-25, phenobarbital decreased the threshold and increased the frequency of self-stimulation during all the current intensities. A comparative study of the above results showed the agents of the first group to exert a direct stimulating action on the positive reinforcement system. Tranquillizers activated this system due to their depressive action on the negative reinforcement system. Benactyzine, LSD-25, phenobarbital activated the system and depressed the system of negative reinforcement.

Animals↗

PubMed1987

Comparison of in vitro actions with behavioral effects of antimuscarinic agents.

In vitro potencies of a series of muscarinic antagonists were compared with their effects on operant behavior. Ki values for inhibition of [3H]N-methylscopolamine binding in N4TG1 neuroblastoma cells correlated positively with ED50 values for the inhibition of carbachol-induced alpha-amylase release from pancreatic acini cells and with KB values for inhibition of acetylcholine-induced contractions of guinea pig ileum. The rank order of potency for inhibition of [3H]N-methylscopolamine binding was quinuclidinyl benzilate = quinuclidinyl xanthene-9-carboxylate greater than (methyl atropine = atropine) greater than benactyzine greater than azaprophen greater than (adiphenine = aprophen) greater than pirenzepine greater than ethyl aprophen. The M1 antagonist, pirenzepine, was a weak inhibitor in the guinea pig ileum and alpha-amylase assays relative to its ability to inhibit [3H]N-methylscopolamine binding; azaprophen exhibited the opposite relationship. Lever-press responses of rats were maintained by food delivery under a schedule requiring 10 responses for each food presentation. The high response rates engendered by this schedule were decreased in a dose-dependent manner by all compounds. The order of potency for this behavioral effect (ED50) was atropine = azaprophen greater than aprophen greater than (methyl atropine = benactyzine) greater than pirenzepine greater than adiphenine. Behavioral depressant actions of the antimuscarinics correlated positively with their potencies in inhibiting alpha-amylase secretion. Pirenzepine was unique in being relatively more potent in its behavioral effects than in its actions in vitro. In contrast to the other antimuscarinic agents studied, the benzilates, benactyzine, aprophen and adiphenine, but not azaprophen, increased behavioral response rates.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1964

SOME ACTIONS OF CENTRALLY ACTIVE AND OTHER DRUGS ON THE TRANSMISSION OF SINGLE NERVE IMPULSES THROUGH THE ISOLATED SUPERIOR CERVICAL GANGLION PREPARATION OF THE RABBIT.

The effect of some centrally-active and other drugs on the transmission of single nerve impulses through the isolated superior cervical ganglion preparation of the rabbit has been studied by recording both preganglionic and postganglionic action potentials. Block of conduction in the axon could be distinguished from block of the synaptic mechanism. The drugs did not appear to exert any one characteristic form of blocking action. A continuous spectrum of drug action linked an agent such as meprobamate which acted predominantly on the synapse to benactyzine which acted mainly by blocking axonal conduction. The drugs have been divided into three groups. Group I: hexamethonium, meprobamate, paraldehyde, amylobarbitone, methylpentynol and azacyclonal; these acted relatively selectively at the ganglion. Group II: N714C (the cis-isomer of chlorprothixene), prochlorperazine, methylpentynol carbamate, pipradrol, promethazine, perphenazine and procaine; the action of these drugs on the ganglion could be accounted for entirely in terms of their axonal depressant action. Group III: chlorprothixene, promazine, N720 (dihydrochlorprothixene), chlorpromazine, hydroxyzine and benactyzine; these drugs also blocked axonal conduction but in addition they appeared to exert a "facilitating" action at the ganglionic synapse. The actions of adrenaline, adrenochrome, iproniazid, ergotoxine, mescaline and lysergic acid diethylamide on transmission were also studied. The implications of the modifications of ganglionic transmission produced by these drugs is discussed.

Action Potentials↗

PubMed1982

Kinetics and stability of a multicomponent organophosphate antidote formulation in glass and plastic.

An aqueous solution of trimedoxime bromide, atropine, and benactyzine hydrochloride was formulated to have maximum stability as an antidote in organophosphorus poisoning. The stability of the mixture in glass and plastic cartridges was determined. Glass cartridges were more desirable than plastic; there was less vapor loss, color formation, and anomalous reaction. Trimedoxime was stable, losing 1.4% of its potency after 1 year at 25 degrees and atropine was more stable than trimedoxime. Considerable degradation of benactyzine occurred; 20% of its potency was lost after 1 year at 25 degrees. Equations for predicting the shelf life of each ingredient at selected temperatures are presented.

Antidotes↗