Продолжительное использование препаратов бензодиазепинового ряда нередко приводит к формированию лекарственной зависимости. В данной работе изучено влияние афобазола на показатели поведения в тесте приподнятый крестообразный лабиринт (ПКЛ) и содержание биогенных аминов в структурах мозга при моделировании синдрома отмены диазепама (4 мг/кг/день, внутрибрюшинно, 30 сут) у крыс. Через 48 ч после последней инъекции диазепама афобазол в дозе 5,0 мг/кг препятствовал развитию тревожной реакции, восстанавливая поведенческий паттерн в ПКЛ до уровня животных из контрольной группы. Афобазол повышал сниженное в условиях отмены диазепама содержание дофамина (+ 23,8 %, p < 0,05) в стриатуме. Полученные данные дают основания полагать, что афобазол может быть эффективен при купировании индуцированного отменой диазепама анксиогенеза за счет модуляции функциональной активности дофаминергической системы.

The study examined the antinociceptive potency of dipeptide compound GB-115 (amide N-6-phenylhexanoyl-glycyl-L-tryptophan) during thermal and chemical noxious stimulation of mice. Peroral administration of GB-115 (0.1-20 mg/kg) decreased the incidence of abdominal contractions induced with intraperitoneal acetic acid (0.75%). This effect was comparable to that of sodium diclofenac (20 mg/kg); it was only partially antagonized with naloxone indicating the presence of significant non-opioid component in analgesic effect of GB-115. Ability of this dipeptide to moderate the nociceptive response in tail flick test under a non-selective blockade of the opioid receptors with naloxone and the absence of similar analgesic potency assessed in the hot plate test attest to predominant effect of GB-115 on spinal opioid receptors.

The effects of GB-115 dipeptide, a retroanalog of endogenous CCK-4, on the behavioral indices in "elevated plus maze" (EPM) test and on the content of biogenic amines in the brain structures after discontinuation of a chronic administration of benzodiazepine (BZ) derivatives phenazepam (2.0 mg/kg, i.p.) and diazepam (4.0 mg/kg, i.p.) have been studied in outbred and inbred MR/MNRA rats. It is established that, in 24-48 h following BZ withdrawal, GB-115 dipeptide administered in doses of 0.1 and 0.5 mg/kg, i.p., produced an anxiolytic effect in all animals, which was manifested by increasing the stay time and number of entries in EPM. In the striatum of outbred rats, GB-115 increased DOPAC (+25%) and DA (+31.6%) levels that were decreased during diazepam withdrawal syndrome. The obtained results showed the GB-115 efficiency in attenuating the anxiety caused by BZ withdrawal.

The DNA comet assay was used to evaluate the severity of genotoxic changes in embryonic tissues and placenta of rats daily exposed to tobacco smoke per se or in combination with an anxiolytic agent afobazole. The exposure to tobacco smoke (4 cigarettes containing 13 mg tar and 1 mg nicotine per 72 dm(3)) for 20 min on days 1-13 of pregnancy increased the degree of DNA damage and elevation of apoptotic DNA comets in cells of the placenta and embryo from pregnant rats. Afobazole (1 and 10 mg/kg orally) reduced the genotoxic effect of tobacco smoke and decreased the amount of apoptotic DNA comets in placental tissue and embryonic tissue from rats.

The effects of afobazole (1.0 and 10.0 mg/kg, i.p.) on the antinociceptive properties of morphine (3.0 mg/kg, i.p.) were studied in mice. It is shown that afobazole attenuates the analgesic action of morphine in the "hot plate" and "tail flick" tests. This effect was prevented by sigma 1 receptor antagonist haloperidol (2.0 mg/kg, i.p.). Data obtained suggested that a decrease in the morphine antinociceptive action by afobazole is related to its agonistic interaction with sigma 1 receptors at supraspinal and spinal levels.

Experiments on outbred mice showed that compound GB-115, a retropeptide analogue of the tetrapeptide cholecystokinin, produced a naloxone-dependent potentiating effect on morphine-induced analgesia in the hot-plate test, but did not modulate animal behavior in the tail-flick test in outbred mice. This potentiation of antinociceptive activity of morphine was probably related to the interaction of GB-115 with supraspinal opioidergic mechanisms.

The antinociceptive and anxiolytic properties of the new drug GB-115 (0.0125-4 mg/kg, i.p.), which is a short peptide antagonist of CCK2-receptors, have been studied in rats and mice using thermal models of nociception and the standard "elevated plus-maze" (EPM) test for measuring anxiety. It s established that GB-115 (4 mg/kg) significantly increases the response latency in naloxone-independent manner in the "hot plate" test in mice and produced a moderate naloxone-reversible analgesic effect in the "tail flick" test in mice. The blocking of opioid receptors by naloxone does not influence the anxiolytic effects of GB-115 (0.025 and 4 mg/kg) in the EPM test on rats. It has been suggested that GB-115 produced anxiolytic acting on CCK2-receptors, and its role in the control of pain perception is manifested through the interaction with opioidergic mechanisms on a spinal level rather than with non-opioid mechanisms on a supraspinal level.

We studied expression of Flt-1 and Flk-1 receptors on tumor cells obtained from 83 patients with locally advanced breast cancer after neoadjuvant chemotherapy. The mean period of observations was 32.3 months. The median recurrence-free survival periods for Flt-(1+) and Flt-(1-) patients were 55 and 32 months, respectively (p=0.0064). The overall survival periods for Flt-(1-) and Flt-(1+) patients were 45 and 67.6 months, respectively (P=0.014). The mean recurrence-free survival periods for Flk-(1+) and Flk-(1-) patients were 40.8 and 60.9 months, respectively (p=0.035). Expression of VEGF had no prognostic value. Our results show that overexpression of Flk-1 on breast cancer cells in patients receiving neoadjuvant chemotherapy is associated with a poor prognosis. By contrast, overexpression of Flt-1 improves survival.

Administration of morphine to outbred female rats is shown to result in increased anxiety in the conflict test and reduced pain sensitivity in the tail flick test in 2.5-monthold offspring. In prenatally morphinized offspring the analgetic effect of morphine was enhanced, while the anxiolytic effect of buspirone was lower than in intact animals, which suggests rearrangements in the opioid and serotoninergic systems of the brain.