[Bizerine: new anticholinesterase drug with selective gastrointestinal action].

Bizerine-oxalate of hexamethylene-bic-[N-methylcarbamic acid-3-(2-dimethylaminomethyl)pyridyl ether] exhibits the properties of acetylcholine esterase (AChE) inhibitor, being comparable in this respect in in vitro tests to aminostigmine. Bizerine is 2.5 and 6.7 times less active in these tests than proserine and distigmine, respectively, but it forms more stable complex with the enzyme. Bizerine is 10-80 times less toxic for laboratory mammals as compared to prozerine; it is 3-60 times more active on the isolated urinary bladder of rats, but it is 100-500 times less effective on the spinal muscle of leeches and skeletal muscles of mice and rats. Bizerine actively inhibits intestinal cholinesterase (ChE) of guinea pigs. In systematic use, it does not inhibit brain ChE of mice. Bizerine is a prolonged peripheral muscarinic potentiating inhibitor of ChE and activator of intestinal peristalsis.

[Finding cholinesterase in endotheliocytes: cholinesterase inhibition by organophosphorus compounds leads to endotheliocyte deformation].

Toxic action of some organophosphorus cholinesterase inhibitors (including phosphacol) on the state of microvessels was studied in rats. Cholinesterase was found in endotheliocytes and it was established that phosphacol inhibited this enzyme. This was one of the factors responsible for deformation of the luminal relief of the vessels and for violation of the blood microcirculation. The expression of these effects was different for various organophosphorus compounds.

[Histamine blockers increase efficacy of specific antidote prophylaxis of intoxication by cholinesterase inhibitors in mice]. / Gistaminoblokatory povyshaiut éffektivnost' spetsificheskoi antidotnoi profilaktiki otravlenii myshei inhibitorami kholinésterazy.

Dimedrol and pipolphen, but not loratadine, increase efficacy of the atropine and dipiroxime treatment of mice--an antidote prophylaxis against their intoxication with phosphacol and aminostigmine. The results of experiments confirm a hypothesis that histamine participates in the formation of secondary toxicity reactions in the case of heavy poisoning with anticholinesterase agents.

[Participation of a distant cholinergic mechanism in the response of the vascular bed to intoxication by organophosphorus inhibitors of cholinesterase]. / Uchastie distantnogo kholinergicheskogo mekhanizma v reaktsii sosudistogo rusla na intoksikatsiiu fosfororganicheskimi ingibitorami kholinésterazy.

Poisoning with phosphacol causes dose--dependent decrease of blood flow speed in small vessels of mesoappendix. Administration of LD50 of phosphacole results in blood stagnation, simultaneous blood pressure fall, which leads to death of part of the animals. Electron microscopic study revealed the presence of acetyl and buthyryl cholinesterase in endotheliocytes of mesoappendicular capillaries, the activity of which was completely suppressed by administration of LD50 of phosphacol. 0,0-dimethyl-0 (2,2-dichlorvinyl) phosphate LD10 caused the damage of endotheliocyte surface. It was suggested that endothelial cholino-receptors that are activated through the rise of redundant acetyl-choline level in blood on the background of cholinesterase inhibition participate in the mechanism of pathological reactions described. Such variant of toxic effect was characterized as distant.

[The distant effects of acetylcholine--links in the pathogenesis of poisoning by cholinesterase inhibitors]. / Distantnye éffekty atsetilkholina--zven'ia v patogeneze intoksikatsii ingibitorami kholinésterazy.

Scanning electron microscopy showed that the capillary endothelial cells of rats poisoned by O,O-dimethyl-O(2,2-dichlorvinyl) phosphate swell and become wrinkled, while some of the cells acquire fenestrae. In 24 h. these changes become weaker. Mass deformity of erythrocytes was seen at the same time and lasted less than 24 h. Since the capillary endothelium and the erythrocytes are devoid of cholinergic innervation but possess cholinoreceptors, the occurring effects may be explained by the distant action of acetylcholine accumulating in the blood in poisoning by cholinestarase inhibitors.

[Protection of mice by carbamates cholinesterase inhibitors against poisoning by armin and its dependence on certain physico-chemical indicators]. / Zashchita myshei ingibitorami kholinésterazy iz klassa karbamatov ot otravleniia arminom i zavisimost' ot nekotorykh fiziko-khimicheskikh pokazatelei.

A series of aminostigmin derivatives with various substituents at nitrogen in the second position of the pyridine ring, has been tested. The efficacy of preventing the death of mice poisoned by armine in five of the seven substances correlates with the constant of the rate of carbamylation of acetylcholinesterase in the in vitro experiments and with the hydrophobic nature. It is suggested that the phenomenon of protection of animals against the toxic effect of organophosphorous compounds involves the "leaving portion" of the molecule of carbamates.

[New data on the pharmacokinetics of aminostigmine]. / Novye dannye o farmakokinetike aminostigmina.

The results of studying the pharmacokinetics of aminostigmine, a new reversible cholinesterase inhibitor produced in Russia, are discussed. Tissue radioactivity after intragastric administration of a toxic dose of aminostigmine was quite quickly absorbed from the intestinal lumen. The half-life period of aminostigmine exceeded considerably that of earlier studied carbamates and correlated with the clinical manifestations of the drug effects. This confirms that the use of aminostigmine in the treatment of neurologic and somatic diseases is preferable.

[Erythrocyte structural changes as a possible reason for the low effectiveness of specific therapy for carbophos poisoning]. / Strukturnye izmeneniia éritrotsitov kak vozmozhnaia prichina nizkoi éffektivnosti spetsificheskoi terapii otravlenii karbofosom.

By method of scanning electron microscopy erythrocyte structure was studied in rats in carbophos poisoning. Following up to 76% acetylcholinesterase inhibition with distinct symptoms of intoxication nearly 30% of erythrocytes were deformed and tended to aggregate. Observation of blood circulation in vessels of pia mater revealed formation of erythrocyte conglomerations in vascular bed. Erythrocytes get stuck in small vessels, disturbing blood microcirculation. Supposedly, obstruction of the smallest vessels with conglomerations is one of the reasons of exotoxic shock development and low efficiency of treatment of carbophos poisoning by means of specific antidotal cholinolytic drugs and cholinesterase reactivators.

[Biochemical characteristics of aminostigmine--a new anticholinesterase agent]. / Biokhimicheskaia kharakteristika aminostigmina--novogo lekarstvennogo antikholinésteraznogo sredstva.

The properties of aminostigmine in comparison with those of other carbamate inhibitors of cholinesterases have been studied in vitro using potentiometric titration and Ellman methods. The bimolecular constants of the inhibition rate of acetyl-, butyryl- and propionylcholinesterase were found to be equal to (8.0-14.0).10(5) (3.8-7.7).10(5) and 11.0.10(5) M-1.min-1, respectively. In terms of inhibitory activity, aminostrigmine is comparable to neostigmine methylsulphate, being inferior to physostigmine and superior to pyridistigmine. The rate of decarbamylation of acetylcholinesterase inhibited by aminostigmine measured by the dilution method, by creating excessive acetylcholine and by dialysis is characterized by k2c constants equal to (1.1-1.6).10(-2), (2.5-2.8).10(-2) and 0.025.10(-2) min-1, respectively. On the whole, aminostigmine belongs to slowly reversible inhibitors. Being carbamylated by aminostigmine, the enzyme is resistant to reactivation by TMB-4 and HI-6. At (4-6).10(-7) M aminostigmine prevents by 50% the irreversible binding of cholinesterase by certain organophosphate inhibitors of cholinesterase when the latter are used at concentrations needed to inhibit the enzymatic activity by 85-90%.

[The comparative clinico-experimental characteristics of aminostigmine and galanthamine used for treating poisonings by choline-blocking substances]. / Sravnitel'naia kliniko-éksperimental'naia kharakteristika aminostigmina i galantamina, ispol'zuemykh dlia lecheniia otravlenii kholinoblokiruiushchimi veshchestvami.

The results of application of cholinesterase inhibitors, aminostigmin and galantamin, for treatment of acute poisoning with cyclodol, dimedrol, and solutan of moderately grave condition are presented. Aminostigmin was shown to exhibit the more pronounced stable and universal effect. The experiments in animals showed that aminostigmine affected peripheral and central M-cholinoreactive structures and conjugated with them more actively than galantamin. Aminostigmin, but not galantamin increases the rate of dopamine circulation and content of cyclic guanozinemonophosphate in frontal brain of rats, and this effect is exhibited even under the conditions of N-cholinoreceptor blockade with amizyl.

[The toxicological characteristics of the interaction of cholinolytics with aminostigmine--a new reversible cholinesterase inhibitor]. / Toksikologicheskaia kharakteristika vzaimovliianiia kholinolitikov s aminostigminom--novym obratimym ingibitorom kholinesterazy.

This investigation has been carried out on albino mice. In the first series of experiments, we determined the dependence of LD50 of aminostigmine on different doses of 10 cholinolytics, and conversely, the dependence of LD50 of cholinolytics on aminostigmine administration. The initial slopes of the dose-effect curves were calculated. This data form the basis for evaluation of the character and degree of interactions. We established that benactyzine, spasmolytin, ftoracizin, arpenal, atropine, ganglerone, and methacin at low doses exhibit antagonism (with decreasing activity), whereas at high doses they exhibit synergism to the toxic effect of aminostigmine. In the interaction with aminostigmine, pirenzepine and amitriptyline (M1--cholinolytics) reveal a slightly pronounced antagonism, whereas aetyrophene, a selective central N-cholinolytic, displays mutual synergism. In the second series of experiments we showed that a combination of M1-, M2-cholinolytic atropine with M1- cholinolytics does not change the efficacy of the prophylaxis of aminostigmine and physostigmine poisoning, whereas a combination with N-cholinolytic increases it.

[Aminostigmine as a cholinesterase inhibitor and as an agent for treating poisonings by cholinergic blockers]. / Aminostigmin kak ingibitor kholinésterazy i kak sredstvo dlia lecheniia otravlenii kholinoblokatorami.

Experiments on non-inbred albino mice have demonstrated that aminostigmine is an active reversible centrally active cholinesterase inhibitor close to the properties of physostigmine, but greatly superior to it in its action duration. Clinical examinations of healthy volunteers and patients have shown that aminostigmine-induced inhibition of cholinesterase activity persists 6 hours. The agent have been found to be more highly effective in treating cholin blocker-induced intoxications than galanthamine, which manifests itself in its greater stability of the therapeutical effect achieved and in its higher ability to prevent cardiovascular events occurring in intoxication.

[The selection of the indices of antidote efficacy]. / Vybor pokazatelei éffektivnosti protivoiadiia.

The application of the following new indices of the efficacy of antidotes has been substantiated and discussed: the "antidotal potency" as a ratio of LD50 of a poison when an antidote used to LD99 in control intact animals, and the "index of solid protection" as a ratio of LD10 in the experiments to LD90 in controls. The two indices are true for changing the lethality curve slope, which makes it impossible to use the currently accepted "protection index" as a ratio of LD50 in experiments to LD50 in controls.

[Morphologic changes of erythrocytes in mice and rats exposed to organophosphate cholinesterase inhibitors]. / Morfologicheskie izmeneniia éritrotsitov myshei i krys pri vozdeistvii fosfororganicheskimi inhibitorami kholinésteraz.

Initial stages of animal poisoning with phosphacole and carbophos are accompanied by growth of erythrocytes in size and considerable changes of their surface shape, which disappear in 15 min--4 hrs regardless of the remaining cholinesterase activity inhibition. The phenomenon of erythrocytes' deformation is reproducible in in vitro experiments under the conditions of simultaneous inhibition of cholinesterase activity and exposure to acetylcholine with concentration of 1 x 10(-8) M and higher.

[The pharmacological characteristics of the new anticholinesterase drug aminostigmine]. / Farmakologicheskaia kharakteristika novogo antikholinésteraznogo lekarstvennogo sredstva aminostigmina.

The pharmacological properties of a new drug approved in the USSR for the treatment of cholinolytics poisonings are described. The drug is as active as physostigmine. However, its action is longer. Aminostigmine exhibits marked central effects, which forms the basis for its use for elimination of brain dysfunctions caused by choline blockers.

[Acceleration of the restoration of conditioned reflexes following anesthesia using aminostigmine]. / Uskorenie vosstanovleniia uslovnykh refleksov posle narkoza ketaminom s pomoshch'iu aminostigmina.

The effect of anesthesia with ketamine (80 mg/kg, intraperitoneally) combined with phenazepam (0.5 mg/kg, subcutaneously) on the reproduction of an elaborated active avoidance reflex in automated reflexometer has been studied on random bred white rats. In has been shown that during 3 hours after the animal is taken out of the lateral position the degree of its learning is significantly lowered and does not return to baseline even a day later. Intramuscular administration of a new cholinesterase inhibitor aminostigmine right after the end of anesthesia restores the disrupted reflex in 3 hours. The optimal antistigmine dose is 0.015 mg/kg, which corresponds to a therapeutic human dose.

[Geometrical method for assessing the interaction of the antidote and the poison in a model experiment]. / Geometricheskii sposob ostenki vzaimodeistviia protivoiadiia i iada v model'nom éksperimente.

A method of construction of isobologram and its approximation is proposed for a quantitative assessment of the relationship between a change in LD50 of one substance (poison) and increasing doses of other (antidote). It is recommended to determine the coefficient of the action of the substances on each other. Its value in cases of antagonism is in the range of from 0 to - infinity and in cases of synergism from 0 to + infinity. A formula for the calculation of the coefficient and a geometrical method for the determination of its value are given. The method assumes the identification of a mean error of the coefficient and its confidence limits.