[Therapeutic effects of benactyzine, thiospasmin, hydroxythiospasmin and combinations of benactyzine, with PAM and atropine in experimental parathion poisoning].
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Atropine↗
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The muscarinic antagonists aprophen and benactyzine are noncompetitive inhibitors of the nicotinic acetylcholine receptor.
Certain muscarinic antagonists (e.g., atropine, aprophen, and benactyzine) are used as antidotes for the treatment of organophosphate poisoning. We have studied the interaction of aprophen and benactyzine, both aromatic esters of diethylaminoethanol, with nicotinic acetylcholine receptor (AChR) in BC3H-1 intact muscle cells and with receptor-enriched membranes of Torpedo californica. Aprophen and benactyzine diminish the maximal carbamylcholine-elicited sodium influx into muscle cells without shifting Kact (carbamylcholine concentration eliciting 50% of the maximal 22Na+ influx). The concentration dependence for the inhibition of the initial rate of 22Na+ influx by aprophen and benactyzine occurs at lower concentrations (Kant = 3 and 50 microM, respectively) than those needed to inhibit the initial rate of [125I]-alpha-bungarotoxin binding to the agonist/antagonist sites of the AChR (Kp = 83 and 800 microM, respectively). The effective concentration for atropine inhibition of AChR response (Kant = 150 microM in BC3H-1 cells) is significantly higher than those obtained for aprophen and benactyzine. Both aprophen and benactyzine interact with the AChR in its desensitized state in BC3H-1 cells without further enhancing agonist affinity. Furthermore, these ligands do not alter the value of Kdes (equilibrium concentration of agonist which diminishes 50% of the maximal receptor response) in BC3H-1 muscle cells. The affinity of aprophen and benactyzine for the allosterically coupled noncompetitive inhibitor site of the AChR in Torpedo was determined using [3H]phencyclidine as a probe. Both compounds were found to preferentially associate with the high affinity (desensitized) state rather than the resting state of Torpedo AChR. There is a 14- to 23-fold increase in the affinity of aprophen and benactyzine for the AChR (KD = 0.7 and 28.0 microM in the desensitized state compared to 16.4 and 384 microM in the resting state, respectively). These data indicate that aprophen and benactyzine binding are allosterically regulated by the agonist sites of Torpedo AChR. Thus, aprophen and benactyzine are effective noncompetitive inhibitors of the AChR at concentrations of 1-50 microM, in either Torpedo or mammalian AChR. These concentrations correspond very well with the blood level of these drugs found in vivo to produce a therapeutic response against organophosphate poisoning.
Animals↗
Benactyzine increases alarm call rates in the squirrel monkey.
The effects of benactyzine (0.01-3.0 mg/kg) were examined on the frequency of alarm calls of squirrel monkeys in a laboratory setting. Under baseline conditions, few calls occurred, and neither saline nor a low dose (0.01 mg/kg) of benactyzine increased calling. Higher doses (0.03-3.0 mg/kg) of benactyzine significantly increased call rate (to 1-2 calls per s) in a dose-dependent manner. The rate-increasing effect of benactyzine on alarm calls appears to be related to a central antimuscarinic effect, as it could be partially blocked by 0.01 mg/kg physostigmine, completely blocked by 0.1 mg/kg physostigmine, but was not blocked at all by 0.1 mg/kg neostigmine. Neither of these cholinomimetics increased call rates when given alone. These findings show that benactyzine can increase alarm call rates in squirrel monkeys under defined laboratory conditions, and may serve as a useful pharmacological probe to study neurochemical mechanisms mediating the production of this type of vocalization. In the squirrel monkey, one such mechanism apparently involves a cholinergic substrate.
Animals↗
Influence of trimedoxime bromide on degradation of benactyzine in acidic injectable solutions.
The stability of benactyzine in a multicomponent injectable antidote formulation in deuterium oxide was studied in the presence of various concentrations of trimedoxime bromide. Benactyzine was found to be more stable in the absence of trimedoxime bromide and its degradation rate accelerated linearly with increasing concentrations of trimedoxime bromide. The main reasons for the accelerated decomposition rate of benactyzine were found to be the nucleophilic effect of the bromide ion and the oxime moiety. For each trimedoxime concentration studied, t90 for benactyzine at 25 degrees C was calculated and was found to be 5.3-1.5 years within the concentrations range of 0-120 mg/ml. Rate constants and activation energies for benactyzine degradation were determined for each of the concentrations studied.
Benactyzine↗
Inhibition effects of benactyzine and drofenine on human serum butyrylcholinesterase.
Benactyzine and drofenine are widely used anticholinergic drugs. Benactyzine is used to treat organophosphate poisoning and drofenine acts on smooth muscle to stop muscle spasms. Both of these drugs are esters. After they enter the bloodstream, they will interact with butyrylcholinesterase (BChE; acylcholine acyl hydrolase: EC 3.1.1.8), which has an ability to hydrolyze a wide variety of esters. Therefore, the kinetic analysis of their inhibitory effects on human serum BChE was examined using butyrylthiocholine as substrate. Both drugs were competitive inhibitors of BChE and the Ki values of benactyzine and drofenine were calculated to be 0.010 +/- 0.001 and 0.003 +/- 0.000 mM, respectively, using the Systat (version 5.03, 1991) nonlinear regression analysis software package. According to these parameters, drofenine is a more potent competitive inhibitor of BChE than benactyzine.
Benactyzine↗
Visual and spatial trials paired in a new behavioral procedure: effects of benactyzine.
A paired discrimination (PD) task in which visual and spatial discrimination trials were combined is offered as a method for the evaluation of drug effects on various behavioral parameters. Acquisition of the PD task is characterized by six different parameters simultaneously recorded each session. Analysis of memory requirements suggest that intact reference memory is involved in the performance of both types of trials while working memory is involved only in the performance of the spatial trial. Benactyzine (1-4 mg/kg), an anticholinergic drug, was tested for its effects on visual and spatial tasks presented either separately or in the PD combination. Benactyzine-induced mydriasis was also determined for its possible role in photophobic-induced errors. Benactyzine was found to differentially increase the number of errors performed during the spatial but not during the visual trials. The data are in accord with earlier finding of specific cholinergic involvement in working memory processes. Thus, low doses of benactyzine, and the PD task, can prove useful in the cognitive analysis of cholinergic hypofunction and its reversal by memory-enhancing drugs.
Animals↗
Molecular modification of anticholinergics as probes for muscarinic receptors. 3. Conformationally restricted analogues of benactyzine.
The synthesis and pharmacological evaluation of conformationally restricted analogues of certain anticholinergic agents is a powerful method for probing the topography of the muscarinic receptor. In the present study, clues as to the binding conformation of structurally flexible anticholinergics are provided by approximating certain conformations of benactyzine by synthetic analogues 1-6, which are structurally locked into desired conformations. The pharmacological activity of each analogue is an indication of how well particular conformational models are accommodated by the receptor. The conformation of benactyzine in which an intramolecular hydrogen bond may exist between the hydroxyl group and the carbonyl oxygen of the ester group (conformation I) is approximated by the synthetic analogue 2,2-diphenyl-3-tetrahydrofuranyl (diethylamino)ethyl ether (1) and related analogues. Pharmacological evaluation using dose-response experiments on isolated rat ileum tissue demonstrated that these compounds noncompetitively inhibited acetylcholine-induced ileum contractions. Restriction of the conformational freedom of the amino side chain of 1 by synthesis of the hexahydro[3,4-b]furan derivative 3 provided a weak but competitive inhibitor at low concentration. The conformation of benactyzine in which an intramolecular hydrogen bond may exist between the hydroxyl group and the ether oxygen of the ester group (conformation II) is approximated by 2,2-diphenyl-4-[2-(diethylamino)ethyl]-3-tetrahydrofuranone (4). Pharmacological studies showed that this compound competitively inhibited acetylcholine-induced ileum contractions. These experiments provide evidence that receptor-bound conformation II for benactyzine is preferred over conformation I in providing competitive binding with the muscarinic receptor.
Acetylcholine↗
Mechanism of relaxant action of papaverine. III. Comparison of sodium ion dependencies on the relaxant effects of papaverine, Aspaminol and benactyzine in guinea-pig taenia coli.
The role of sodium ion on the relaxant action of papaverine in guinea-pig taenia coli contracted by hypertonic 40 mM KCl were studied by manipulating the external sodium ion concentration and compared with those of its allied antispasmodics, Aspaminol and benactyzine. Whereas all of the three antispasmodics relaxed the taenia in all media used herein, their relaxant activities were declined by eliminating sodium ion from the bathing media. The declined relaxant activities were restored by re-introducing sodium ion to the solution depending on the amount of sodium ion but sodium ion dependencies of the restoration were not equal for each. In a solution containing 20 mM sodium ion, almost complete restoration was encountered with papaverine, while displayed only a slight restoration with Aspaminol and benactyzine. When a small amount of sodium ion was applied to the taenia before or after the treatment with the antispasmodics, the relaxation in response to papaverine was augmented, but those in response to Aspaminol and benactyzine were not affected. All of the three antispasmodics inhibited the cellular 45Ca-uptake in all media. While, their inhibitory activities were reduced by eliminating sodium ion from the media and were not restored so markedly by re-introducing 20 mM sodium ion to the solution. From these findings, it is suggested that papaverine may induce the smooth muscle relaxation not only by inhibiting the Ca-influx independently of the presence of sodium ion but also by other mechanisms sensitive to sodium ion, by contrast, Aspaminol and benactyzine may evoke the relaxation through mechanisms less sensitive to the presence of sodium ion, which include the inhibition of Ca-influx.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
[Histamine-induced contraction of the guinea pig taenia coli and its inhibition by D-600, papaverine, and benactyzine].
The histamine-induced contractions and effects of some smooth muscle relaxants on their contractions were examined in the guinea-pig taenia coli. Application of Ca to the Ca-free physiological solution caused a contraction of the taenia coli (Ca contraction), and histamine accelerated and increased the Ca contraction (H . Ca contraction). Histamine also contracted the taenia coli in the Ca-free solution (Ca(-) . H contraction). D-600 which preferentially reduces the Ca influx into muscle cells, more effectively depressed the H . Ca contraction and more feebly the Ca(-) . H contraction than histamine-induced contraction in the normal physiological solution. Papaverine inhibited the H . Ca contraction and the Ca(-) . H contraction more than the histamine-induced contraction. Benactyzine was a specific agent against the Ca(-) . H contraction. When the Ca contraction reached the peak, application of histamine induced a further contraction. D-600 effectively inhibited the Ca contraction and the further contraction induced by histamine. Although papaverine blocked the Ca contraction similarly to D-600, the application of histamine produced a large contraction. Benactyzine induced only a feeble inhibition on the Ca contraction, but it was effective against the following contraction caused by histamine. Histamine probably mobilizes the extracellular and cellular Ca and contracts the smooth muscle. Papaverine seems to inhibit smooth muscle contractions by diverse actions. Benactyzine may exert the main inhibition on the mobilization of the cellular Ca through the competition with Ca.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Effects of benactyzine hydrochloride on dynamic vision functions.
We have investigated the effects of an anticholinergic drug, benactyzine HCl on vision and vision function. Our experiments assess the time course and severity of benactyzine effects on visual acuity for static and moving targets, amplitude and dynamics of accommodation, pupil response to light and the spatial contrast sensitivity function. A single dose of the drug (4.14 mg/70 kg body weight, which is within the therapeutic range) and placebo were administered intramuscularly to 12 subjects. Large and significant decrements in visual function were demonstrated after the administration of benactyzine, particularly for those functions performed at near focus. The drug effect was rapid in onset, beginning 7-10 min after injection, peaked at approximately 30-40 min, and declined to baseline values over the next 2 h. The drug increased pulse rate and blood pressure, and induced an intoxicated state involving loss of concentration, attention, and short-term memory.
Accommodation, Ocular↗
Effects of an anticholinergic drug, benactyzine hyrochloride, on vision and vision performance.
Benactyzine is an anticholinergic agent which has been used in past years in psychiatry, but is little used today. It has central and peripheral anticholinergic effects, and when administered intramuscularly, it has a rapid onset of action. This may make it useful as an antidote for organophosphate poisoning, in spite of side-effects such as deficits of short term memory, concentration, and attention. As an anticholinergic drug it could also be expected to produce vision changes by its action on the intraocular musculature controlling the pupil and lens accommodation. We tested the drug on six volunteer subjects to establish the visual side-effects of intramuscular administration. We found that it reduced static and dynamic visual acuity, increased pupil size, reduced amplitude of accommodation and contrast sensitivity, while having little or no effect on glare recovery, color vision, intraocular pressure, stereoacuity, oculomotor tracking, and distance heterophoria. Benactyzine produced reductions in visual performance for up to 3 h and had the greatest effects on functions which have significant cognitive components. The present results suggest that the drug is unsuitable for treatment for oganophosphate poisoning when continuous performance is required, although a definitive test of ths suggestion would require that performance should be tested when benactyzine and the organophosphate of interest were combined.
Adult↗
The effects of atropine, benactyzine, and physostigmine on a repeated acquisition baseline in monkeys.
A repeated acquisition procedure was used with cynomolgus monkeys to test the effects of one anticholinesterase (physostigmine) and two anticholinergic (atropine and benactyzine) compounds on learning and performance. Learning was defined as the number of response chains (trials) required to meet a criterion of three consecutive chains at 90% accuracy or better. Measures were the number of trials to criterion and the number of errors made. Following learning, behavior was analyzed as performance. Measures were total errors after learning and errors per trial. Time-out minutes (i.e., periods of enforced no responding after errors) were analyzed separately from total session time. Atropine (0.014, 0.044, 0.14, and 0.44 mg/kg) produced large learning disruptions and performance decrements at the highest dose. Learning decrements due to benactyzine (0.057, 0.18, 0.57, and 1.82 mg/kg) were not significant and produced little effect on performance. The effect of physostigmine (0.025, 0.050, and 0.075 mg/kg on learning was not consistent. The anticholinergics increased performance errors per trial, while the anticholinesterase had little effect. Session times showed dose-related increases for all drugs and were significantly increased by the highest doses of each. The session time increases observed after the anticholinergics were interpreted to be due to both an effect on learning and an effect on response rate, whereas the anticholinesterase effect was due primarily to response suppression.
Animals↗
Effects of benactyzine on an equilibrium and multiple response task in rhesus monkeys.
Five Macaca mulatta were tested for performance changes following exposure to benactyzine HCl (intramuscular) at four doses ranging from 0.054 mg/kg to 1.7 mg/kg. Subjects simultaneously operated a primate equilibrium platform and responded to a multiple alternative reaction task. Performance on both the continuous and discrete tasks were progressively degraded as benactyzine dose increased. At the higher doses it appeared that they concentrated their efforts on one of the tasks while neglecting the other. Thus, performance on one task might be normal and at the same time performance on another task would be degraded.
Animals↗
The influence of pharmacological pretreatment on efficacy of HI-6 oxime in combination with benactyzine in soman poisoning in rats.
1. The influence of pharmacological pretreatment (pyridostigmine, benactyzine and trihexyphenidyle), designated PANPAL, on soman-induced cholinergic and stressogenic effects as well as on the efficacy of antidotal treatment (HI-6 plus obidoxime) in rats was studied. 2. PANPAL prophylaxis significantly decreased soman-induced cholinesterase inhibition in blood, brain and diaphragm as well as stressogenic effects of soman (an increase in plasma corticosterone level and liver tyrosine aminotransferase activity). 3. PANPAL pretreatment did not improve the efficacy of HI-6 in combination with benactyzine on soman-induced anticholinesterase and stressogenic effects. 4. These findings confirm that PANPAL prophylaxis can improve prognosis of soman poisoning especially by protection of cholinesterases.
Animals↗
Effect of Panpal pretreatment and antidotal treatment (HI-6 plus benactyzine) on respiratory and circulatory function in soman-poisoned rats.
1 The effect of pharmacological pretreatment (pyridostigmine, benactyzine and trihexyphenidyle), designated Panpal, and antidotal treatment (the oxime HI-6 plus benactyzine) in soman poisoning was investigated in a rat model with on-line monitoring of respiratory and circulatory parameters. 2 Soman poisoning caused a high decrease in respiratory rate as well as minute respiratory volume and an increase in mean arterial pressure from 30-120 min following soman challenge. Soman at sublethal dose also significantly inhibited acetylcholinesterase activity in diaphragm and various brain parts. 3 Panpal pretreatment as well as antidotal treatment were effective in improving the respiratory and circulatory function disturbed by soman without the ability to increase significantly soman-inhibited acetylcholinesterase activity in all brain parts studied. 4 The efficacy of combined Panpal pretreatment and antidotal treatment against sublethal soman poisoning was not different from the efficacy of Panpal pretreatment or antidotal treatment alone. 5 The results of this investigation suggest that Panpal pretreatment as well as antidotal treatment are able to restore respiratory and circulatory function in soman-poisoned rats without significant reactivation of brain acetylcholinesterase.
Acetylcholinesterase↗
[Ba-induced contraction of the guinea pig ileal longitudinal muscle and its inhibition by D-600, benactyzine, and papaverine].
In the guinea-pig ileal longitudinal smooth muscle, Ba caused an initial phasic contraction, followed by a gradual decrease of the contraction (tonic contraction). In the Ca-free and the Ca-free, K-rich physiological solution, Ba could also contract the longitudinal muscle, but 30 min- and 60 min-immersion of the tissue in the Ca-free solution decreased lower than 20% of control of the Ba contraction. Although the K-induced depolarization intensified the Ba contraction after the 30 min-immersion, within 10 min after the immersion in the two solutions there is no difference in the height of Ba contractions. In the normal physiological solution, Ba seems to serve the contractile protein with free Ca ions rather than itself for the Ba contraction. D-600 induced an equal inhibition on the Ba contractions in the normal physiological solution and in the Ca-free solution, and it inhibited the tonic contraction more than the phasic one. The phasic component may be due to the cellular Ca mobilized by Ba which passes through D-600-sensitive pathway, and at least part of the tonic component may utilize the extracellular Ca. Benactyzine perferentially inhibited the Ba contraction in the Ca-free solution, and it depressed the phasic component more than the tonic one. Treatment with papaverine induced an equal inhibition on the phasic and tonic components of Ba contractions and the Ba contraction in the Ca-free solution. Benactyzine may exert the main influence on the mobilization of the cellular Ca through the competition with Ca. Papaverine seems to inhibit the Ba contractions by diverse actions.
Animals↗
Effect of chlorpromazine, reserpine, benactyzine and phenobarbitone on the release of corticotrophin in the rat.
A single injection into the rat of chlorpromazine, reserpine, benactyzine or phenobarbitone stimulates the release of corticotrophin. This effect is not seen after the drugs have been injected daily for 5 days, nor when the rats are hypophysectomized or pretreated with hydrocortisone. The stimulant effect of ether on corticotrophin release is not modified by pretreatment with a single injection, nor to any great extent after 5 daily injections of these drugs.
Adrenocorticotropic Hormone↗
Therapeutic effects of HS-3, HS-6, benactyzine, and atropine in soman poisoning of dogs.
Investigations into the therapeutic properties of various combinations of the bispyridinium salts HS-3 and HS-6 and the cholinolytics atropine and benactyzine against soman poisoning in unanesthetized male beagles were performed. In our investigations we observed that: 1. The most effective protection against soman poisoning was attained if both oximes were applied early i.m. 6 min after intoxication together with the cholinolytics. 2. On the basis of clinical symptoms HS-6 proved to have a more intensive therapeutic effect than HS-3 upon early application. 3. If HS-3 was applied early after s.c. intoxication with low concentrations of soman (up to 3 LD50), a significant protection or reactivation effect on serium cholinesterase was measured. 4. When HS-3 was applied at the beginning of convulsions--generally 28 min after s.c. intoxication--it also raised the rate of surviving animals. 5. The maximal blood levels for HS-3 and HS-6 were measured 20-30 min after i.m. injection; the half-life values of HS-3 and HS-6 in plasma were 45-60 min.
Animals↗