Stimulation of B-Lymphopoiesis by Administration of a Trimecaine-Based Ionic Compound in Cyclophosphamide-Induced Hematopoietic-Depressive Model.

According to the WHO, the secondary form of hematopoietic-depressive status increases the risk of death in people with oncological, infectious, and hormonal diseases. The choice of drugs that stimulate the hematopoietic activity of B-lymphopoiesis is limited. The current leucopoiesis drugs have a number of side effects: thymic preparations stimulate the production of PGE2, which causes chronic inflammation and various autoimmune diseases through the differentiation of T helper 1 (Th1) cells, the proliferation of Th17 cells, and the production of IL-22 from Th22 cells through EP2 and EP4 receptors; cytokine preparations can cause uncontrolled immune reactions and impaired contractility of smooth and cardiac muscles; drugs based on nucleic acids can stimulate the division of all cells, including bacterial and cancerous ones. The use of oligonucleotides such as ribozymes and antisense oligodeoxynucleotides (AS-ODNs) shows promise as therapeutic moieties, but faces a number of challenges such as nuclease sensitivity, off-target effects, and efficient delivery. The search for substances that stimulate B-lymphopoiesis among ionic compounds was motivated by the discovery of the unique properties of lidocaine docusate, one of the first ionic liquid forms of the known drugs. The lidocaine docusate (protonated form of lidocaine (2-(diethylamino)-N-(2,6-dimethylphenyl) acetamide + docusate-anion (dioctylsulfosuccinate))) suppresses the division of pheochromocytoma cells and activates immunity in rats. The trimecaine-based ionic compound (TIC) demonstrates high B-lymphopoiesis-stimulating activity. The TIC compound stimulates an increase in the volume of transitional B cells, which play an important role for further differentiation and formation of a sufficient number of mature B1 cells and mature B2 cells, where mature B2 cells make up the bulk of the functional population of B lymphocytes. The TIC compound most strongly stimulated the restoration of the number of marginal zone B cells, follicular B cells, and activated germinal center B cells after the cytotoxic emptying of the follicular centers of the spleen induced cyclophosphamide. It significantly exceeds the activity of the comparison drug methyluracil. The TIC compound does not affect the level of pro-B, pre-B-I, or pre-B-II bone marrow cells, which prevents the risk of the formation of immature functionally defective cells.

Activation of Leukopoiesis in Rat Blood with Trimecaine-Based Ionic Compounds.

A study of myelostimulating activity of ionic compounds-trimecaine alkyl iodide derivatives under the cipher BIV (BIV-117, BIV-118, and BIV-119) was conducted on a model of doxorubicin pancytopenia in white laboratory rats. It was established that the compounds BIV-117 and BIV-119 had a pronounced leukopoiesis-stimulating activity, exceeding the activity of the methyluracil as a comparison drug. Compounds BIV-117 and BIV-119 had erythropoiesis- and thrombocytopoiesis-stimulating activity at the level of methyluracil.

Convergence of nasal and tracheal neural pathways in modulating the cough response in guinea pigs.

In the present study we investigated the possibility of central convergence of neural pathways coming from distant anatomical regions in modulating the cough response. We addressed this issue by inducing cough from the tracheo-bronchial region on the background of capsaicin-stimulated and mesocain-blocked nasal mucosa in 14 anesthetized guinea pigs. The control group consisted of 6 guinea pigs in which the active agents, capsaicin and mesocain, were substituted for by inert physiological saline. All animals were tracheostomized, and the larynx was disconnected from the proximal part of the trachea with preserved innervations, and all were subjected to the same protocol. Cough, induced by mechanical irritation of the tracheo-bronchial mucosa, was elicited three times: in the control condition, after intranasal capsaicin challenge, and after another capsaicin challenge preceded by intranasal instillation of a local anesthetic, mesocain. The main finding of the study was that the number of cough efforts per bout, assessed from positive deflections on the intrapleural pressure recordings, was significantly enhanced by intranasal capsaicin challenge and this effect was reversed by intranasal pretreatment with the anesthetic mesocain [2.1 +/-0.2 (control) vs. 3.5 +/-0.4 (capsaicin) vs. 2.2 +/-0.2 (capsaicin after mesocain) (P<0.01)], with no appreciable changes in the magnitude of cough efforts. The cough response in the control group remained unchanged. We conclude that tracheo-bronchial cough may be modified by neural sensory input to the brain coming from nasal mucosa. Therefore, cough reflex is subject to central convergence of peripheral neural pathways originating at distant anatomical locations.

Membrane mechanisms of antiarrhythmic effect of quaternidine.

Complex electrophysiological study of the effects of quaternidine carried out on intact hearts from cats, myocardial fragments from rats, and single ionic channels of large edible snail showed that quaternidine demonstrates properties of class 1B antiarrhythmic drug according to Vaughan-Williams nomenclature. This agent did not suppress nomotopic pacemaker automaticity, did not change conduction in ventricles, atria, and atrioventricular junction in hearts with preserved sinus rhythm, did not prolong refractoriness of the atria and atrioventricular junction, but prolonged efficient refractory period of heart ventricles. Quaternidine decelerated rapid depolarization of the action potential, but had no effect on its duration. It did not affect potassium conductance.

[The antiarrhythmic activity of the trimecain ammonium derivative in myocardial ischemia]. / Protivoaritmicheskaia aktivnost' ammonievogo proizvodnogo trimekaina na fone ishemicheskogo povrezhdeniia serdtsa.

The results of experiments on cats and dogs showed that quaternidine, a quaternary ammonium derivative of trimecaine, exceeds the structural precursors (trimecaine and lidocaine), as well as the reference drugs quinidine and propranolol, in intensity of the antiarrhythmic action upon single administration on the occlusive and reperfusive arrhythmia models. The therapeutic effect of quaternidine in animals with acute myocardial ischemia lasts for about 8 h, which more than 20 times longer as compared to the duration of action of both lidocaine and trimecaine.

[Mechanism of local anesthesia: long-range orientation effects]. / Mekhanizm mestnoi anestezii: orientatsionnye éffekty na dal'nikh rasstoianiiakh.

The orientation interaction of a molecule of a local anesthetic with a biomembrane and cell-like liquid was studied, based on the model of adsorption of the anesthetic from a cell-like solution on the surface of a biomembrane for compounds of the trimecaine series. A statistically significant correlation equation was obtained, which relates the minimum blocking concentration to the projection of the dipole moment of the anesthetic on the plane X(1)0X2 of the principal axes of inertia. A model is prosed according to which the "anesthetic-biomembrane" interaction is most effective the molecule of the anesthetic rotates around the axis of the maximum moment of inertia.

[The effect of CO2 on conduction blocking in nerve fibers by trimecaine and anestezin]. / Vliianie CO2 na blokirovanie provodimosti v nervnykh voloknakh trimekainom i anestezinom.

It was shown in experiments on the sciatic nerve of the Rana ridibunda frog that CO2 promotes blocking of stimulation conduction in the nerve fibers by the tertiary amine trimecaine but does not change the rate of blocking by the neutral anesthetic anesthesin. The increased rate of trimecaine blockade development is explained by decrease of cytoplasmic pH under the effect of CO2, which leads to increase in the number of charged molecules of the anesthetic entering the sodium canal and blocking it.

[The effect of quaternization on local anesthetic effects of trimecaine]. / Vplyv kvarternizácie na lokálnoanestetický úcinok trimekaínu.

Effects of the local anaesthetic trimecaine and its quaternary derivative on the isolated rat sciatic nerves were examined. Trimecaine inhibited action potential propagation in the isolated nerve in vitro at four-times lower concentrations than its quaternary derivative. Despite extracellular application, the quaternary derivative inhibited action potential propagation in the sciatic nerve but with a longer half-life in comparison with trimecaine. With increasing external pH, the blocking effect of trimecaine was profound. The blocking potency of the quaternary compound was not consistently changed with the changes in external medium pH.

[The effect of CO2 on the blocking of excitation conduction by local anesthetics in feline A-delta and C fibers]. / Vliianie CO2 na blokirovanie provedeniia vozbuzhdeniia mestnymi anestetikami v A-del'ta- i C-voloknakh koshek.

The data obtained showed that the CO2 potentiated the conduction blockade of the saphenous nerve with tertiary amine trimecaine in anesthetised cats. The data suggests that acidification of cytoplasm with increased CO2 increases the concentration of active cationic protonated forms of a local anesthetic agent.

[The local anesthetic activity of inclusion compounds of pirbentan and trimecaine with beta-cyclodextrin]. / Issledovanie mestnoanesteziruiushchei aktivnosti soedinenii vkliucheniia porbentana i trimekaina s beta-tsiklodekstrinom.

Whether the prolonged action of the topical anesthetics trimecaine and pirbentan can be achieved by using inclusion compounds was studied. beta-Cyclodextrin was used as an agent containing topical anesthetics in its molecule. In in vitro and in vivo experiments, the inclusion compounds trimecaine and pirbentan with beta-cyclodextrin produced a more prolonged action in terminal anesthesia than the compounds used alone.

A simple method of determination of partition coefficient for biologically active molecules.

A simple method is presented for the determination of partition coefficient of an effector between water environment and biological material, based on concentration-dependent effects. The method allows the determination of partition coefficients for biological objects such as algae, bacteria and other microorganisms.

Mechanism of inhibitory action of the local anaesthetic trimecaine on the growth of algae (Chlorella vulgaris).

Using the model compound trimecaine, it was found that algicidal effects exhibited by the local anaesthetics of the acetanilide type were caused by two different mechanisms. The first inhibitory mechanism occurring at low concentrations of the anaesthetic is connected with the uncoupling of the photophosphorylations in algal chloroplasts and is accompanied by the enhancement of the oxygen evolving rate in algal photosynthesis. The second mechanism of inhibition of the photosynthesis in algae, taking place at higher concentrations of the anaesthetic, is connected with the damaging of the manganese containing protein on the donor side of photosystem 2 and is accompanied by a decrease of the oxygen evolving rate in algal photosynthesis.

Dogs at high or low risk of ventricular fibrillation. An experimental study of acute myocardial ischaemia.

In the last 15 years, measurement of the ventricular fibrillation threshold (VFT) after ligation of the coronary artery in anaesthetised dogs has become our standard method for the evaluation of the stabilizing effect of antifibrillation drugs. Analysis of a group of 143 dogs revealed that in 75 animals the VFT 8 minutes after the ligation of the coronary artery dropped to less than 1 mA (high risk group), while in the remaining 68 dogs the decrease was smaller and not below 1 mA (low risk animals). The difference between the groups could be seen already before the ligation of the coronary artery. The high risk animals had a lower VFT and a higher heart rate. The groups also differed in the response to drugs administered 15 minutes after the ligation of the coronary artery. Metipranolol, a liposoluble beta blocker of the beta 1 and 2 cardiac receptors (Trimepranol Spofa 0.3 mg.kg-1 b.w.), increased greatly the VFT in both groups already 8 minutes after the injection of the drug and eliminated the difference between the groups. Flunitrazepam (Rohypnol Hoffmann-La Roche 0.25 mg.kg-1 b.w.) increased the VFT less than metipranolol and the difference between the groups disappeared only 30 minutes after its injection. Celiprolol (Selectol Linz Chemie 3.0 mg.kg-1 b.w.) blocking beta 1 and stimulating beta 2 receptors as well as trimecaine (sodium channel blocker, Mesocain Spofa 3.0 mg.kg-1 b.w.) led only to a small insignificant increase in the VFT and the difference between the groups of dogs remained.(ABSTRACT TRUNCATED AT 250 WORDS)

[The effect of a combination of N-propylajmaline bromide and trimecaine on heart arrhythmias of different origins and on the electrophysiological parameters of the myocardium]. / Vliianie kombinatsii N-propilaimalinbromida i trimekaina na aritmii serdtsa raznogo geneza i élektrofiziologicheskie parametry miokarda.

In experiments on dogs and cats with disorders of the atrial and ventricular rhythms of various genesis the combination of N-propylaymalinebromide and trimecaine (the antiarrhythmic drugs of classes IA and IB) was found to potentiate the antiarrhythmic action. This effect was studied in electrophysiological experiments by using the microelectrode technique or on the dog and rat myocardium tissue. The combination of the antiarrhythmic drugs was shown to exert a more significant effect on some electrophysiological parameters determining the arrhythmic readiness of the myocardium.

[Combined action of anti-arrhythmia agents]. / Sochetannoe kombinirovannoe deistvie antiaritmicheskikh sredstv.

A significant potentiation of antiarrhythmic effect was observed in 121 dogs with arrhythmias 24 and 48 hours after the coronary artery ligation when the following drugs were combined: N-propylajmaline bromide (1A class) and trimecaine (1B class), quinidine (1A class) and trimecaine, N-propylajmaline bromide and anaprilin (2 class). The potentiation is attributed to the different molecular mechanisms of action of the drugs.

[Effects of N-propylajmaline bromide and trimecaine combination on normal and abnormal automatism of Purkinje fibers in dogs and arrhythmias at the late stage of experimental myocardial infarct]. / Deistvie kombinatsii N-propilaimalinbromida i trimekaina na normal'nuiu i anomal'nuiu avtomatiiu volokon Purkin'e sobaki i aritmii na pozdnei stadii éksperimental'nogo infarkta miokarda.

Prajmalium bromide in combination with trimecaine was tested for effects on arrhythmias in the late period of canine experimental myocardial infarction. The combination given in subthreshold doses was found to restore sinus rhythm in 8 of 11 cases. It also decreased the maximum repolarization rate in rat papillary muscles to a greater extent than either drug given alone. The rate of spontaneous firing of Purkinje fibers from the ischemic zone was decreased by the combination of the drugs.

Ultrastructural changes in receptor terminals on prolonged action by local anesthetics.

We have studied ultrastructural changes in the terminal plates of the bushy receptors in the frog urinary bladder after exposure for two hours to 0.05% novocaine solution and for one hour to 0.05 dicaine and trimecaine solution. During these periods a steady blockage of the receptor impulse activity develops. The local anesthetics essentially change the ultramicroscopical structure of the terminals. The reaction to the anesthetics investigated shows some common features and certain peculiarities. For each effect three types of change can be determined characterized by various degrees of rearrangement in the neurolemma, neuroplasma, and organelles. Each type of change is assumed to reflect a certain phase of the plate reactive response. Specific features of the reaction to novocaine include slight changes in mitochondria, accumulation of glycogen granules, and deformation and decrease in numbers of vesicles. Under the action of dicaine the mitochondria do not change and the number of vesicles increases without change in their shape, while under the action of trimecaine marked changes can be observed in mitochondria. Changes observed in the terminal plates are regarded as adaptive. The action of the local anesthetics on the receptors is not limited to the blockage of the sodium channels of the afferent fibers, while the biochemical processes occurring in the cytosol of the terminals also change. Their morphological manifestations reflect the ultrastructural changes observed.

Local anesthetics-induced inhibition of chloroplast electron transport.

The effects of local anesthetics on photosynthetic activity of pea chloroplasts were investigated in order to elucidate the role of Ca2+ in photosynthetic electron transport. Dibucaine, benzocaine and tetracaine were found to inhibit the O2-evolving activity. The inhibitory effect decreases in the order dibucaine greater than benzocaine greater than tetracaine greater than trimecaine similarly as does the potency to inhibit propagation of excitation in nerve fibre. As demonstrated in experiments with artificial donors and acceptors, the site of inhibition is the water-splitting site of PSII. The inhibitory power of the anesthetics grows with increasing ionic strength of the incubating mixture (by adding NaCl or MgCl2) and with pH; this is explained by occurrence of the neutral form of amine. At low concentrations the charged anesthetic acts as a protonofore; however, the inactivation of water splitting is not due to the protonophoric effect. The incubation is followed by the disappearance of ESR signal IIs. The role of Ca2+ and Ca2+-binding protein in PSII electron transport and its localization are discussed.