[Mechanism of the antidepressive and learning-stimulating effects of thyroliberin and its analogs]. / K mekhanizmu antidepressantnogo i stimuliruiushchego obuchenie éffektov tiroliberina i ego analogov.

To define the role of different fragments of TRF molecule in its neurotropic activity a number of newly synthesized dipeptides of pyroglutamic acid with beta-alanine residue, GABA or GABA ester have been studied. The compounds were compared with TRF in their ability to influence spontaneous or amphetamine-stimulated locomotor activity in mice and to affect the elaboration of passive avoidance reflex in rats. Unlike TRF, the pyroglutamate dipeptides studied were shown to exhibit no activity in amphetamine potentiation test, thus providing additional evidence of the importance ofthe "histidylproline" fragment in TRF antidepressant effect. On the other hand, the above pyroglutamate derivatives caused a pronounced improvement in the learning abilities of under-trained rats. These dipeptides were shown to be more active in this test than TRF. This suggests the important role of pyroglutamyl moiety in the stimulation of the learning processes.

[Pharmacology of troparil]. / Farmakologiia troparila.

The physiological action of the tropan derivative troparil (2-beta-methoxycarbonyl-3-beta-phenyltropan or 2-exo-3-exo-2-carbomethoxy-aryltropan was studied. Troparil was demonstrated to be a highly active stimulant of the nervous activity according to a lot of parameters. The drug appeared more powerful than amphetamine but less toxic.

[Effect of opiate receptor agonists and antagonists on the resistance of animals to hypoxic hypoxia]. / Vliianie agonistov i antagonistov opiatnykh retseptorov na ustoichivost' zhivotnykh k gipoksicheskoi gipoksii.

The effects of morphine, a series of synthetic enkephalin analogs and antagonists of narcotic analgesics on the animals' survival rate under hypoxic hypoxia were studied in experiments on mice, rabbits, and cats. It was shown that the agonists of mu-opiate receptors, morphine, FK 33-824 (Tyr-D-Ala-Gly-MePhe-Met-(O)-ol, Tyr-D-Ala-Gly-Phe-(NO2)-NH2 and Tyr-D-Ala-Gly-MePhe-Gly-ol increase the survival rate in a hermetic chamber and that this effect is arrested by naloxone, nalorphine, and TRH. Tyr-D-Ala-Gly-D-Leu, an agonist of delta-opiate receptors has no antihypoxic properties. The data obtained point to the involvement of opiate receptors (at least of those of the mu-type) in realization of the reactions that increase the resistance to hypoxia. Bicuculline was shown to be able to remove the antihypoxic effect of the agonists of opiate receptors, suggesting the GABAergic modulation of this effect.

[Mediators in the mechanism of the neurotropic action of thyroliberin]. / Mediatroy v mekhanizme neirotropnogo deistviia tiroliberina.

The involvement of acetylcholine (ACH), noradrenaline, gamma-aminobutyric acid (GABA) in the mechanism of neurotropic action of thyrotropin-releasing hormone (TRH) was studied by pharmacological analysis. Spontaneous locomotor activity of mice and antagonism to hexenal according to the awakening effect in mice were used as parameters of the physiologic action of TRH. Agonists and antagonists of appropriate neurotransmitters were employed for pharmacological analysis. TRH appeared to bean antagonist of atropine and physostigmine by locomotor activity and hypnotic effect of hexenal and to be an agonist of phenylephrine, isadrin, amphetamine and an antagonist of phentolamine and propranolol as shown by behavioral tests. According to the same tests TRH was found to be an antagonist of muscimol and an agonist of bicuculline. Thus, it may be assumed that ACH, NA and GABA are involved in TRH mechanism of action.

[Effect of tropane on the cholinoreceptors of the cerebral cortex]. / Vliianie tropana na kholinoretseptory kory golovnogo mozga.

Spontaneous electric activity of single neurons of the sensorimotor cortex was recorded extracellularly in experiments on unanesthetized rabbits. During microiontophoretic application of tropane and acetylcholine to the neurons, the response to both the agents was the same. The cells excitable by acetylcholine are also excitable by tropane, while those inhibited by acetylcholine are also inhibited by tropane. The cells that do not respond to acetylcholine are also irresponsive to tropane. The excitatory response pattern to tropane is similar to that of acetylcholine. Under the same conditions of microiontophoretic application, tropane causes less excitation as compared with acetylcholine. Tropane preliminarily applied to the neuron reduces the excitatory effect of acetylcholine. The possible role of agonist-antagonist relations between tropane and acetylcholine in the mechanism of the pharmacological effects of tropane and its derivatives is discussed.

[Pharmacology of uxepam]. / Farmakologiia uksepama.

A new daytime tranquilizer uxepam--1-methyl-4-carbamoyl-5-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1, 4-benzodiazepine-2-on (RGH-3331) administered to animals removes emotional-behavioral abnormalities under conflict situation, reduces aggressiveness induced by electric and painful stimulation, prevents convulsions induced by corasole and electric shock, prolongs the hypnotic effect of hexenal. When applied in high doses the drug suppresses the avoidance reflex, orienting-research behavior and motor activity, disturbs movement coordination. Within wide dosage range uxepam potentiates the summation activity in the central nervous system. As regards anxiolytic activity, the drug does not yield to diazepam and compares very favourably with chlordiazepoxide. The sedative and myorelaxant effects displayed by uxepam are insignificant. The data obtained make it possible to attribute uxepam to daytime tranquilizers.

[Pharmacology of thyroliberin]. / K farmakologii tiroliberina.

The influence of synthetic thyrotropin-releasing hormone (TRH) on locomotion, on the effects of analgetics, learning and memory, electrical activity of hypothalamic neurons, blood pressure, and cerebral circulation have been studied. TRH increases the spontaneous motility and potentiates the stimulating effect of amphetamine and apomorphine. It also antagonizes the decrease of motility induced by tetrabenazine in all these tests. TRH exhibits the similarity to antidepressants. TRH antagonizes the effects of morphine and Tyr-D-Ala-Gly-Phe-(NO2)-NH2, especially in respect of respiratory depression experiments made on rats and rabbits. TRH facilitates the learning in active avoidance paradigme, diminishes the degree of retrograde amnesia evoked by maximal electroconvulsive shock. The latter effect suggests that TRH can be considered as a substance having some signs of nootropic activity. TRH seems to interact with central M-cholinergic system. This is evidenced by the ability of atropine to diminish the excitatory effect of TRH applied microiontophoretically to single neurons of the lateral hypothalamus. TRH elevates blood pressure and volume velocity of the cerebral circulation in normotensive animals and recovers the hemodynamics during hemorrhagic hypotension. The spectrum and mechanism of TRH pharmacological activity are discussed. The data suggest that TRH may be of interest for clinical trials.

[Anti-arrhythmia properties of pyromecaine]. / Antiaritmicheskie svoistva piromekaina.

Antiarrhythmic activity of the local anesthetic pyromecaine has been studied. The drug has been shown to eliminate flutter of the atria provoked by electrical stimulation of the myocardium, by aconitin, strophanthine and barium chloride. It prevents ventricular fibrillation arising due to calcium chloride poisoning. The drug exhibits marked antiarrhythmic properties. It is similar to lidocaine but less toxic and has a broader therapeutic range. It does not produce any adverse action on myocardial contractility or conduction. Pyromecaine has been demonstrated to exert appreciable antiarrhythmic activity in patients. The Pharmacological Committee of the USSR Ministry of Health approved pyromecaine for use in medical practice as an antiarrhythmic drug.

GABA-opiates interactions in the activity of analgesics.

The influence of compounds which reduce or potentiate GABA-ergic inhibition on the effect of analgesics of various structures was studied. The effect was estimated according to the analgesic activity (experiments in rats) and the suppression of the impulse summation in the central nervous system (experiments in rabbits). It was shown that GABA-negative agents (bicucullin, thiosemicarbazide) markedly decreased the effect of morphine, hydrocodone and the enkephaline analogs: Tyr-D-Ala-Gly-Phe-NH2 and Tyr-D-Ala-Gly-Phe(NO2)NH2. The action of bicuculline was close to that of naloxone, an opiate receptor blocker. GABA-positive agents (muscimol, GABA cetyl ether, valproate) potentiated the activity of the mentioned narcotic analgesics. The effect of GABA-positive agents was blocked not only by GABA-negative compounds, but also by naloxone. The obtained data are interpreted in terms of the assumed mutual complementary of GABA-ergic and opioidergic systems. It was shown that the effects of the analgesics of a different structure: phenylpiperidine derivatives (trimeperidine, fentanyl), diphenylacetic acid derivative (dimenoxadol) and 3-benzazocine tricyclic derivative (pentazocine) were unchanged by the studied GABA-ergic analyzers. The reasons for those dissimilarities between analgesics of different structures are discussed.

[Combined action of caffeine and sydnocarb]. / Kombinirovannoe deistvie kofeina i sidnokarba.

Combined application of two stimulants caffeine and sydnocarb (a sydnonimine derivative) was studied in rabbits, rats and mice using the method of summation of impulses in the central nervous system, the method of conditioned avoidance response, forced swimming and hexobarbital sleep in order to find out the changes in their main and side effects. It was established that the main stimulant effect of the drug combination given in optimal doses appeared to be additive, while side effects on the ECG and blood pressure remained unchanged.

[Tropane ligands of different types of opiate receptors]. / Tropanovye ligandy opiatnykh retseptorov raznogo tipa.

Interaction of tropane derivatives (motropin, atropine, cocaine) with opiates (morphine) and opioids (an enkephalin amide analog) was studied according to varying tests: pain sensitivity, impulse summation in the central nervous system, respiration. It appeared that motropin is a morphine antagonist and enkephalin amide analog from the standpoint of effect on analgetic action and impulse summation, but is not their antagonist as regards the effect on respiration. Atropine is a weak morphine antagonist in terms of the effect on analgesia, impulse summation and respiration as well. Cocaine is a morphine synergist as regards all the tests indicated. Therefore, the effect of tropane derivatives on pain sensitivity, impulse summation and respiration is mediated via different opiate receptors, which does not exclude the involvement of other neurochemical mechanisms in their action.

[Effect of prostaglandins, cyclic nucleotides and ions on the analgesic effect of enkephalin analogs]. / Vliianie prostaglindinov, tsiklicheskikh nukleotidov, ionov na anal'geticheskii éffekt analogov énkefalinov.

The effect of intracellular modulators and ions on the analgetic action of the two tetrapeptide analogs, Tyr-D-Ala-Gly-Phe-NH2 and Tyr-D-Ala-Gly-Phe (NO) NH2, was studied in rat experiments. The threshold of pain reaction to electrical stimulation of the tail, evidenced by vocalization, was measured. PGE1, PGE2, PGE2 alpha, cAMP, and dibutyryl cAMP were shown to diminish the effect of the above-mentioned enkephalin analogs. In contrast to cAMP, cGMP was not active in this respect. Among the ions under study (calcium, lithium, rubidium, and cesium), cesium was shown to be the most active. It prevented the increase of the pain reaction threshold and shortened the duration of analgesia. Lithium had no antagonistic effect as regards the enkephalin-induced analgesia. Comparison of these findings with the previously obtained data on the antagonism of the substances under consideration with morphine suggests similarities in the mechanisms of modulation of the effects of opiates and opioids. At the same time the failure of lithium to antagonize the enkephalin analogs and the presence of morphine antagonism point out that the similarities in the mechanisms of ion regulation of exogenous analgetics and enkephalins cannot be regarded as complete enough.

[Deontological problems in pharmacology]. / Problemy deontologii v farmakologii.

Scientific and technological progress in the XX century had a great impact on the development of pharmacology. Deontological problems are quite urgent in modern pharmacology. The philosophical, moral and ethical, social and economic concepts play a significant role in it. THe drugs in the developed countries are manufactured on a fairly large scale, medical service makes up an important part of the state expenses. The quality of the medical service affects the productive forces of the country. The modern highly active drugs have to be properly and skillfully employed. The drugs should be examined first in experiments on animals on then in clinics in accordance with the scientific and deontological principles.