[Preclinical safety investigation of GB-115 dipeptide].

Preclinical safety investigations of newly synthesized dipeptide compound GB-115 (amide N-phenylhexanoyl-glycyl-L-tryptophan), an antagonist of cholecystokinin receptors, were performed. No animals were lost after GB-115 acute oral administration at a maximum dose of 6000 mg/kg in mice and at 3500 mg/kg in rats. GB-115 administered per os during 6 months in rabbits and rats (both males and females) at the doses of 0.1 and 10 mg/kg induced no irreversible pathological changes in organs and systems studied. The tested dipeptide exhibited no allergenic, immunotoxic and mutagenic activity, and did not affect generative function and the antenatal and postnatal development of progeny. GB-115 at a dose of 10 mg/kg produced suppression of the inflammatory reaction to concanavalin A.

[The effect of hemantane on the generative function and gonad morphology in rats]. / Vliianie Gimantana na generativnuiu funktsiiu i morfologiiu gonad.

Effect of the new potential antiparkinsonian drug hemantane (N-(adamant-2-yl)hexamethyleneimine hydrochloride) on the generative function and gonad morphology was studied in a group of male and female mongrel rats. The generative function was studied after peroral drug administration in a dose of 10 mg/kg (ED50) and 50 mg/kg (5 ED50): males were treated over a 60-day period of spermatogenesis, while females received the drug in the same doses over 15 days (three estrous cycles). The gonad morphology was studied after a 6-month treatment of experimental animals with hemantane in the same doses. It was established that the administration hemantane in indicated doses did not influence the generative function and gonad morphology in male and female rats.

[Effect of himantane on the rat embryo development]. / Vliianie gimantana na émbrional'noe razvitie krys.

Himantane introduced via a gastric tube to pregnant rats in a dose of 10, 30, 50, and 100 mg/kg produced a dose-dependent embryotoxic and teratogenic action. An analysis of the experimental results and published data suggests that the embryotoxicity of himantane can be related to its general toxic action upon the organism of pregnant female rats.

[Preclinical study of noopept toxicity]. / Doklinicheskoe izuchenie toksichnisti noopepta.

Within the framework of a preclinical investigation, the new nootrope drug noopept (N-phenyl-acetyl-L-propyl-glycine ethylate) was tested for chronic toxicity upon peroral administration in a dose of 10 or 100 mg/kg over 6 months in both male and female rabbits. The results of observations showed that noopept administered in this dose range induced no irreversible pathologic changes in the organs and systems studied and exhibited no allergenic, immunotoxic, and mutagen activity. The drug affected neither the generative function nor the antenatal or postnatal progeny development. Noopept produced a dose-dependent suppression of inflammation reaction to concanavalin A and stimulated the cellular and humoral immune response in mice.

[The effect of lithium oxybutyrate on the development of the fetus and progeny in alcoholic intoxication of male rats]. / Vliianie litiia oksibutirata na razvitie ploda i potomstva v usloviiakh alkogol'noi intoksikatsii samtsov krys.

The effect of lithium hydroxybutyrate on the development of the fetus and offsprings was studied on a model of alcohol intoxication of male rats. Under such conditions lithium hydroxybutyrate relieved completely the negative action of alcohol on the reproductive function, according to all parameters. The learning ability of the offsprings and their behavioral disorders in a stress situation caused by alcohol were normalized. Two-week administration of 100 mg/kg lithium hydroxybutyrate had no negative effect on the embryonal and postnatal development of the offsprings.

[The significance of perinatal alcoholization and its withdrawal in the development of late cognitive disorders in rats]. / Zanchenie perinatal'noi alkogolizatsii i ee otmeny v razvitii otdalennykh kognitivnykh narushenii u krys.

To study the effect of perinatal alcoholization and its withdrawal on cognitive functions of rats, 25% ethanol solution was administered intragastrically: (1) over the whole period of the rat pregnancy in a dose of 5 g/kg/day; (2) from the Ist day of pregnancy to the 7th day after genera in a dose of 5 g/kg/day; (3) from the Ist day of pregnancy to the 2nd day after genera in a dose of 5 g/kg/day; and then in daily decreased doses (by 1g/kg) to the 7th day. A less pronounced increase in the rat mass and disturbances in maternal behavior (eating up the descendants) was observed for all alcoholization regimes. Alcoholization inhibited the eye opening, but did not affect the body mass increase and elementary inborn reflexes of descendants during the first three weeks of life, whereas in adult male descendants alcoholization deteriorated the ability to training and memory on the "open field" model and bilateral avoidance response. The cognitive disorders in descendants were more pronounced after abrupt withdrawal of ethanol directly after the birth and were minimal after gradual withdrawal of alcohol.

[The correction with nooglutil and L-pyroglutamyl-D-alanine amide of cognitive disorders in rats due to intrauterine hypoxia]. / Korrekstiia noogliutilom i amidom L-piroglutamil-D-alanina kognitivnykh narushenii u krys, vyzvannykh vnutriutrobnoi gipoksiei.

Novel nootropic compounds, nooglutyl (N-5-hydroxy(nicotinoyl)-L-glutamine acid, 25 mg/kg/day) and L-pyroglutamyl-D-alanine amide (1 mg/kg/day) administered intracutaneously from the 8th to 20th day of life prevent from movement hyperactivity in "open field", disturbances in ability to training and in memory in an alternate test and in tests of passive and active avoidance and normalize behavior of the adult mail rats (subjected to two-hour hypobaric hypoxia in on the 15-day of intrauterine life, vacuum corresponded to the height 8500 m) in-extrapolation avoidance test. Additionally, nooglutyl recovered the normal growth of rats in the first month of their life, prevented from deceleration of investigating behavior of adults animals and disturbances of the mink reflex in them.

[Sodium oxybutyrate normalizes the central nervous system functions in the progeny of rats subjected to hypobaric hypoxia during pregnancy]. / Natriia oksibutirat mormalizuet funktsii tsentral'noi nervnoi sistemy u potomstva krys, podvergshikhsia gipobaricheskoi gipoksii vo vremia beremennosti.

Two-hour hypobaric hypoxia of rats on day 15 of their pregnancy led to a reduction in weight gain of pups within 20 days after birth, disturbed memory in active and passive paradigms, changed adaptive behavior in the extrapolatory water avoidance test, and impaired sleep in adult animals. Postnatal treatment with sodium hydroxybutyrate given in a dose of 50 mg/kg/day on days 8 to 20 of life normalized mnestic functions of the brain, the process of falling asleep, and physical development which had been impaired by intrauterine hypoxia.

[The effect of fenazepam and phenobarbital on the course of pregnancy in rats and on the early postnatal development of their progeny]. / Vliianie fenazepama i fenobarbitala na techenie beremennosti krys i rannee postnatal'noe razvitie ikh potomstva.

Examining the effects of phenazepam and phenobarbital on the course of pregnancy and the development of offsprings has revealed that phenobarbital that has an embryotoxic effect reduced the number of rat offsprings and diminished their weight, but failed to affect the behavioral responses of newborn rats. On the contrary, phenazepam had no embryotoxic effect, but on entering the newborn rats' organism with milk it inhibited some behavioral reactions in the early postnatal period.

[Behavior disorders in rats exposed to intrauterine hypoxia, and their correction by postnatal treatment with piracetam]. / Narusheniia povedeniia krys, podvergshikhsia vnutriutrobnoi gipoksii, i ikh korrektsiia postnatal'nym vozdeistviem piratsetama.

Hypobaric hypoxia of the pregnant rats was followed by the reduction of weight gain of the newborn pups, delayed impairment of memory (passive and active tasks) and changes of extrapolative water escape. Piracetam (200 mg/kg/day) administered at early postnatal period (from 8th to 20th day of life) corrected behavioral disturbances and physical development in rats. Postnatal therapy by nootropics didn't influence in adaptive behavior damaged by prenatal hypoxia.

[The nooglutil correction of functional disorders of the central nervous system caused by prenatal alcoholization in rats]. / Korrektsiia noogliutilom narushenii funktsii tsentral'noi nervnoi sistemy, vyzvannykh prenatal'noi alkogolizatsiei u krys.

Administration of ethanol (5 g/kg/day, per os) to the pregnant rats evoked delayed impairments of the learning and memory in the offspring. Prenatal alcoholization of the animals attenuated the habituation of the exploration behavior in open field, impaired acquisition and retention of active avoidance in a shuttle box, increased slow activity of the EEG spectrum power, disturbed the function of the serotoninergic system in the brain cortex and of the dopaminergic system in the hippocamp. The new nootropic drug nooglutyl (N-5/hydroxynicotinoyl/-L-glutamic acid) administered in a dose of 25 mg/kg/day from the 8th to the 20th day of life prevented the above-mentioned delayed disturbances of higher integrative functions and biochemical processes in rat brain.

[The lithium oxybutyrate correction of disorders in higher nervous activity in the progeny of alcoholized male rats]. / Korrektsiia litiia oksibutiratom narushenii vysshei nervnoi deiatel'nosti potomstva alkogolizirovannykh krys-samtsov.

In experiments on rats it was shown that alcohol administered intragastrically in a dose of 8 g/kg for 4 weeks produced long-term disturbances of CNS function in the offspring similar to those observed under clinical conditions. Early postnatal administration of lithium oxybutyrate (from the 8th through the 14th day of life) was found to prevent the development of the disturbances.

[A behavioral and biochemical analysis of the therapeutic effect of sodium oxybutyrate in alcoholic encephalopathy in progeny]. / Povedencheskii i biokhimicheskii analiz terapevticheskogo éffekta natriia oksibutirata pri alkogol'noi éntsefalopatii u potomstva.

The alcoholization of pregnant female rats (5 g/kg) results in a decrease of endogenous ethanol level in their offspring and distant disturbances of the conditioned reflex activities of the young rats deteriorating the formation and preservation of the skill with an emotional positive reinforcement. Sodium gamma-gydroxybutyrate administered in a dose of 50 mg/kg from the 8th to the 20th day of life prevents the above-mentioned disturbances of learning and memory, restores the level of endogenous ethanol, corrects the parameters of lipid and mediator metabolism in the brain and blood changed by prenatal alcoholization.

[L-pyroglutamyl-D-alanine amide normalizes the function of the developing brain damaged by antenatal alcoholization in rats]. / Normalizatsiia amido L-piroglutamil-D-alanina funktsii razvivaiushchegosia mozga, narushennykh antenatal'noi alkogolizatsiei krys.

The effects of the synthetic dipeptide, L-pyroglutamyl-D-alaninamide (LPDA) were studied in the experiments on offspring of alcoholized during the pregnancy (5 g/kg/day) females. This dipeptide, which revealed the nootropic activity in previous experiments, was injected to the pups in dose of 1 mg/kg from 8 to 19 days of life. LPDA was shown to prevent the delayed disturbances of learning in passive avoidance test, of extrapolatory behaviour in escape test, to attenuate the emotional hyperreactivity. LPDA normalized EEG power spectrum, decreased interhemispheric asymmetry. This substance attenuated the disbalance evoked by prenatal alcoholization.

[Sodium oxybutyrate correction of the disorders in higher nervous activity in the progeny of alcoholized animals]. / Korrektsiia natriia oksibutiratom narushenii vysshei nervnoi deiatel'nosti potomstva alkogolizirovannykh zhivotnykh.

Alcoholization of female rats before pregnancy (8 g/kg) or during pregnancy (4 g/kg) leads to disturbances in the development of the offspring higher nervous activity manifested by impaired learning abilities, disordered emotional reactivity, reduced capacity to overcome stress-situation, deficit of GABAergic inhibitory processes in the cerebral cortex. An early postnatal administration of sodium hydroxybutyrate in a dose of 50 mg/kg prevents the development of the above mentioned disturbances of the higher nervous activity and neurophysiological alterations.

[Effect of piracetam on the postnatal development of rats]. / Vliianie piratsetama na postnatal'noe razvitie krys.

Administration of piracetam (2 g/kg) to rats during the whole pregnancy caused a decrease of motor activity in young rats at an early age and an increase of the activity of adult male rats. The antenatal use of piracetam improved learning abilities and tolerance of stress situations in the offspring.

[A preclinical study on the safety of a new antialcoholic drug inmecarb]. / Doklinicheskoe issledovanie bezopasnosti novogo protivoalkogol'nogo preparata inmekarba.

A preclinical study on safety of a new antialcoholic drug inmecarb was carried out on three species of experimental animals (rats, guinea pigs, dogs) receiving the drug at different doses including a subtoxic one (1/5 of LD50) for 6 months. The authors concluded that on the basis of a relatively low toxicity and the absence of specific toxicity and long-term side effects the drug may be recommended for clinical use as an antialcoholic agent.

[Effect of teturam on the development of the offspring of alcoholized animals]. / Vliianie teturama na razvitie potomstva alkogolizirovannykh zhivotnykh.

During experiments on rats it was found that in alcoholized animals teturam on the whole did not potentiate and in some cases even attenuated the toxic effect of alcohol on the offspring development. The data confirm the idea about necessity of studying toxicity of drugs under the conditions corresponding to their clinical use.

[Normalizing effect of GABA derivatives on late behavioral disorders occurring in rats with early postnatal suppression of protein synthesis]. / Normalizuiushchee vliianie proizvodnykh GAMK na otdalennye narusheniia povedeniia, voznikaiushchie u krys pri rannem postnatalnom ugnetenii belkovogo sinteza.

Changes in the central nervous system activity caused by an early postnatal (7th day of life) injection of cycloheximide (CHX) were studied during experiments on adult rats. Disturbances in the process of learning in the experiments on conditioned reflexes of active and passive avoidance, difficulties in solving the extrapolatory task, weakening of habituation, motor hyperactivity, disorder of movement coordination were noted. Electrophysiological analysis by means of evoked potential recovery cycles revealed deficiency of GABAergic inhibition in the cerebral cortex. Hydroxybutyric salts of sodium and lithium as well as piracetam injected after CHX (from 8th through 14th days of life) normalized general behavior and learning capability of adult rats. Phenibut (beta-phenyl-GABA) was inferior by its efficacy, GABA exhibited no distinct effect.