Experiments with rats showed that new nicotinamide derivatives LKhT 8-22 and LKhT 12-22 at a dose of 50 mg/kg have a distinct vestibuloprotective effect demonstrated by an increased food intake after rotation in 2.4 and 1.8 times, respectively. Efficiency of these substances exceeded the reference medicine mexicor (ethylmethylhydroxypyridine succinate) in equal dose in 1.7 and 1.3 times, respectively. More effective LKhT 8-22 exceeded LKhT 12-22 in 1.3 times.

Experiments on hippocampal slices in rats showed that novel heterocyclic compounds LKhT 1-22 and LKhT 4-22 (nicotinic acid derivatives) at the concentration of 5 mM inhibited orthodromic population responses in СА1 by 65  3 and 86  1 %, respectively. Comparison preparation mexicor (ethylmethylhydroxypyridine succinate) in the equal concentration also inhibited the responses by 54  3 %. Effects of LKhT 1-22 and LKhT 4-22 exceeded that of mexicor in 1.2 and 1.6 times, respectively. Besides, LKhT 4-22 was more effective than LKhT 1-22 in 1.3 times. Competitive AMPA receptor antagonist CNQX (1 µM) weakened the depressing effect of LKhT 4-22 in 1.2 times were markedly than LKhT 1-22, i.e. 73  1 % and 61  2 %, respectively. Also, in the presence of L-glutamate (0.75 М) LKhT 1-22 (5 µM) inhibited the evoked neuronal responses by 58  3 %, and LKhT 4-22 (5 µM) by 81  2 %. In its turn, CNQX weakened inhibition of the LKhT 4-22 evoked response in 1.1 times more markedly than LKhT 1-22, i.e. by 76  1 % and 67  2 %, respectively. It follows that LKhT 1-22 and LKhT 4-22 inhibit the synaptic transmission within the Schaffer collateral - СА1 pyramidal neurons. Moreover, LKhT 4-22 demonstrates a largely L-glutamatergic nature which is much less evident in LKhT 1-22. Involvement of AMPA glutamate receptors is highly important for effect of LKhT 4-22 and a bit less for LKhT 1-22. We can conclude that the hippocampus is crucial for the central effect of these novel compounds.

Experiments with rats showed that new heterocyclic compounds – derivatives of nicotinic acid LKhT 1-22 and LKhT 4-22 at a dose of 50 mg/kg – had a pronounced anti-motion sickness effect, as they increased food intake by animals following rotation in 1.8 and 2.1 times, respectively. The vestibuloprotective effect of these compounds excelled that of mexicor (ethylmethylhydroxypyridine succinate) in 1.3 and 1.5 times, respectively.

Experiments on hippocampal slices in rats demonstrated that new nicotinic acid derivative LKHT 20-19 and heterocyclic compound LKhT 3-21 at the concentrations of 5 mM inhibited orthodromic population responses in field СА1 by 78  2 % and 96  3 %, respectively; comparison preparation mexicor (ethylmethylhydroxypyridine succinate) in the similar concentration inhibited these responses by 52  4 %. Effectiveness of LKHT 20-19 and LKHT 3-21 exceeded that of mexicor in 1.5 and 1.8 times, respectively; LKHT 3-21 exceeded LKHT 20-19 in 1.2 times. Competitive AMPA receptor antagonist CNQX at 1 µM counteracted the depressing effect of LKHT 20-19 in 1.1 times more distinctly than of LKHT 3-21: by 91  1 % and 85  1 %, respectively. Also, in the presence of L-glutamate (0.75 М), LKHT 20-19 (5 mМ) inhibited the evoked responses of neurons by 83  1 % and LKHT 3-21 (5 mМ) by 92  1 %. In its turn, CNQX mitigated inhibition of the LKHT 20-19 evoked responses in 1.1 times more distinctly than LKHT 3-21, i.e. by 94  1 % and 84  1 %, respectively. Therefore, LKHT 20-19 and LKHT 3-21 inhibit the synaptic transmission between the Schaffer colaterals and СА1 pyramidal neurons. Both compounds have the L-glutamate origin that shows itself almost entirely in LKHT 3-21 and less, though predominantly, in LKHT 20-19. Effects of these new compounds are achieved owing the main (LKHT 20-19) or predominant (LKHT 3-21) involvement of the AMPA glutamate receptors. It can be concluded that the hippocampus has a significant role in realization of the central effect of these new compounds.

Experiments on hippocampal slices in rats showed that new nicotine acid derivatives LKhT 8-20 and LKhT 9-20 at a concentration of 5 mM inhibited orthrodromic population responses in field СА1 by 89  1 % and 84  2 %, respectively; in comparison, mexicor (reference preparation) in equal concentration inhibited these responses by 52  4 %. Effectiveness of LKhT 8-20 and LKhT 9-20 exceeded that of mexicor in 1.7 and 1.6 times, respectively; LKhT 8-20 exceeded LKhT 9-20 in 1.1 times. Also, in the presence of L-glutamate (0.75 М) LKhT 8-20 (5 mМ) inhibited the evoked neuron responses by 95  2 % and LKhT 9-20 (5 mМ) by 86  1 %. Therefore, LKhT 8-20 and LKhT 9-20 inhibit synaptic transmission between Schaffer collaterals and pyramidal neurons in rat's hippocampal field СА1. Both compounds are L-glutamergic by nature which reveals itself by almost complete in LKhT 8-20 and to a less degree (primarily) in LKhT 9-20. It may be deduced that hippocampus has an important role in the central effect of these new compounds.

Experiments with rats demonstrated the apparent vestibuloprotective properties of new nicotinic acid derivative LKhT 20-19 and heterocyclic compound LKhT 3-21 at a dose of 50 mg/kg. In comparison to the control, they increased food intake following rotation in 1.9 and 2.5 times, respectively. LKhT 20-19 and LKhT 3-21 outperformed reference medicine mexicor (ethylmethylhydroxipyridine succinate) at the equal dose in 1.4 and 1.8 times, respectively. LKhT 3-21 outperformed LKhT 20-19 in 1.3 times.

Aim. To study the effect of a new complex compound LHT-2-20 (2-ethyl-6-methyl-3-hydroxypyridine-2-(3benzoyl phenyl)-propanoate) on free radical oxidation in experimental periodontitis.Materials and methods. The experimental study was performed on 195 white mongrel mice weighing 19–23 g and 137 white mongrel rats weighing 180–220 g. The effect of a new complex compound LHT-2-20 (2-ethyl-6methyl-3-hydroxypyridine-2-(3-benzoyl phenyl)-propanoate) on the intensity of free radical oxidation and the local state of periodontal tissues during a course of intragastric administration was studied on the experimental model of periodontitis. Statistical processing of the results was carried out using the SPSS Statistics 20.0 software package with the analysis of variance (ANOVA) and the parametric Tukey’s test.Results. The LHT-2-20 compound reduced elevated levels of primary and secondary lipoperoxidation products (conjugated dienes, malondialdehyde in plasma and in erythrocytes during spontaneous and iron-induced oxidation) already at the early stages of the experiment, bringing the studied parameters closer to the reference values by the end of the course of treatment. The use of the compound LHT-2-20 contributed to an increase in the activity of the main antioxidant enzymes (catalase and superoxide dismutase), normalizing them to baseline values by the end of the experiment. With the correction of free radical processes, the use of LHT-2-20 limited the local inflammatory response in periodontal tissues, which was confirmed by a decrease in gingival edema and hyperemia, bleeding, depth of periodontal pockets, and tooth mobility.Conclusion. The results of this study confirm the anti-inflammatory potential of the compound and the multiplicity of its effects due to the impact on the mechanisms of oxidative stress. The expediency of further study of the drug is justified by the prospect of creating a new drug and its subsequent wide clinical application as part of the complex therapy of periodontal inflammation.

Experiments with rats demonstrated that 2 new nicotinic acid derivatives LKhT 8-20 and LKhT 9-20 at a dose of 50 mg/kg have equally a distinct anti-motion sickness activity increasing by 2 times, when compared to the control, food consumption following rotation. The vestibuloprotective effect was higher in comparison with mexicor (ethylmethylhydroxypyridine succinate) at similar dose in 1.5 and 1.4 times, respectively.

Experiments on hippocampal slices in rats showed that new nicotinic acid derivatives LKhT 6-20 and LKhT 7-20 at 5 mM inhibited the СА1 orthodromic population responses by 43  4 and 69  5%, respectively, whereas preparation of comparison mexicor in equal concentration inhibited the responses by 52  4 %. Action of LKhT 7-20 exceeded LKhT6–20 in 1.6 times and mexicor, in 1.3 times. The refore, LKhT 6-20 and LKhT 7-20 inhibit synaptic transmission between Schaffer collaterals and pyramidal СА1 neurons. It can be inferred that hippocampus has a significant role in the central action of these new substances.

In experiments with mice under various models of acute hypoxia a new synthesized compound LKhT 3-21 (50 mg/kg) showed a distinct antihypoxic activity. In comparison to mexicor (50 mg/kg), this compound increased lifespan in a hermetic chamber, under hemic hypoxia and histotoxic hypoxia by 107 %, 47 %, and 70 %, respectively. LKhT 3-21 exceeded mexicor in the effect against acute normobaric hypoxia with hypercapnia (in 1.9 times), acute hemic hypoxia (in 1.4 times) and acute histotoxic hypoxia (in 1.6 times).

ВЛИЯНИЕ НОВОГО ПОЛИКОМПОНЕНТНОГО СОЕДИНЕНИЯ ЛХТ-2-20 НА ИНТЕНСИВНОСТЬ ДЕСТРУКТИВНЫХ ПРОЦЕССОВ ПАРОДОНТА ПРИ ЭКСПЕРИМЕНТАЛЬНОМ ПАРОДОНТИТЕХайдар Д.А

Experiments with rats showed that two new nicotinic acid derivatives LKhT 6-20 and LKhT 7-20 at a dose of 50 mg/kg produce a vestibuloprotective effect involving an increased food intake after rotation in 1.3 and 1.9 times respectively, when compared to the control group. Effectiveness of LKhT 7-20 exceeded reference drug mexicor (ethylmethylhydroxypyridine succinate, equal dose) in 1.4 times, and previously tested LKhT 6-20 in 1.5 times.

The literary review encompasses the experimental and clinical evidence of the potency of Russian medicaments nicotinoyl gamma-aminobutyric acid (picamilon), hydroxyzine nicotinoyl glutamate calcium (ampasse), and combineddrug cytoflavin containing nicotinic acid and its derivatives in extreme conditions. Analysis shows that these medicaments and nicotinic acid derivatives protect tangibly from acute and chronic hypoxia of varying genesis, hypo- and hyperthermia, hypokinesia etc. To increase potency and safety of medical care after exposure to extreme factors the search for other nicotinic acid derivatives should be furthered.

Experiments on hippocampal slices in rats showed that, in contrast to piracetam (100 µM to 10 mM), two new tripeptides, i.e. H-asparagil-glutamyl-proline-OH and H-asparagil-glutamyl-arginin-OH (concentrations 500 µM, 1 and 2.5 mM respectively), strengthened the orthodrome population responses in field СА1. In all three concentrations the effect of H-asparagil-glutamyl-proline-OH was stronger than of the other tripeptide. That is both tripeptides facilitate synaptic transmission within the Schaffer collaterals-pyramidal neurons system in hippocumpal field CA1. Similarly to piracetam (100 µM, within 15 minutes) these tripeptides supported short-term potentiation of the hippocampal synaptic transfer by N-methyl-D-aspartate (NMDA). Specific NMDA-receptors antagonist D-AP5 cancelled the NMDA effect fully which infers that the observed effect is achieved through activation of NMDA-receptors. Effect from H-asparagil-glutamyl-proline-OH excelled equally piracetam and H-asparagil-glutamyl-arginin-OH; H-asparagil-glutamyl-arginin-OH excelled piracetam only.

Experiments with cats showed that new 3-hydroxypyridine derivative IBKhF-27, mexidol and melatonin, and combination of IBKhF-27 with melatonin and mexidol affected directly 84.8; 67.8; 77.4; 97.9 and 88.1 % neurons of the 1st vestibular zone of the cerebral cortex, respectively. Inhibition by IBKhF-27 was observed 1.4 times more often than by mexidol. Combinations of IBKhF-27 with melatonin and mexidol produced the inhibitive effects on neurons oftener than each component separately; the direct effect of IBKhF-27 with melatonin occurred oftener than each of these two components separately. Also, the inhibitive effect of IBKhF-27 with melatonin was seen more often than of melatonin combined with mexidol. In the presence of MK-801, specific noncompetitive antagonist of the NMDA-receptor complex and luzindol, specific antagonist of melatonin MT1- and MT2-receptors (before pneumomicroinjection dosages), the direct effect of IBKhF-27 with melatonin or mexidol on the spontaneous activity of neurons was prevented fully or attenuated materially in 95.3 and 88.2 % neurons, respectively. Consequently, 1st vestibular zone of the cerebral cortex has a great role in the central action of these combinations executed fully or partly through the NMDA-receptor complex and melatonin MT1-, MT2-receptors.

Pharmacophoric analysis of the structure of valprazolamide, a 1,3,4-thiadiazolylamide derivative of valproic acid, was carried out. It was shown that the new valproate contains a substituted amide group, hydrophobic and electron-donor domеns – pharmacophores, determining its antiepileptic activity. Valproic acid has only a hydrophobic moiety. Modification of valproic acid by introducing an additional pharmacophore, 1,3,4-thiadiazole, into its structure leads to a decrease in toxicity and an increase in antiepileptic activity.

Two of the five new nicotinic acid derivatives proved to have the antihypoxic properties in tests with mice exposed to acute normobaric hypoxic hypoxia with hypercapnia. Specifically, LKhT 4–19 (100 mg/kg) extended lifetime of the animals by 11 %; LKhT 6-19 doses of 50 and 100 mg/kg extended lifetime by 23 and 34 %, respectively. The antihypoxic effect of LKhT 6–19 (50 mg/kg) outperformed in 1.2 times mexidol (substance of comparison) at the similar dose and was highly competitive at the dose of 100 mg/kg. For reference, mexidol is a 3-hydroxypyridine derivative (ethylmethylhydroxypyridine succinate incorporating, similar to the substances in question, the pyrydine heterocycle). Besides, LKhT 6–19 (100 mg/kg) outperformed mexidol at the similar dose in 1.1 times.