Valeria V. Eremina

Objective. To study anticonvulsant activity of thiowurtzine in seizure models induced by pentylenetetrazol and thiosemicarbazide. Material and methods. Experiments were conducted on male CD-1 mice. Thiowurtzine was administered intragastrically at doses of 50, 100 and 200 mg/kg. Carbamazepine (100 mg/kg) was used as a reference drug. Anticonvulsant activity was investigated in antagonism tests with pentylenetetrazol (PTZ 140 mg/kg subcutaneously) and thiosemicarbazide (TSC 30 mg/kg subcutaneously). Anticonvulsant activity was assessed considering latency of various seizure stages, their frequency, and animal survival. Results. In PTZ test, thiowurtzine 100 mg/kg significantly prolonged latent period of myoclonic seizures by 92% and clonic seizures by 95%, as well as survival time by 73% compared to the control group. All changes were significant. Survival reached 41.7% that was comparable to the effect of carbamazepine. At 200 mg/kg, efficacy decreased that indicated a narrow therapeutic window. In TSC model, thiowurtzine did not significantly affect survival. However, dose 100 mg/kg reduced the number of the most severe tonic seizures by 31%. Conclusion. Thiowurtzine possesses anticonvulsant activity, most pronounced in GABA-dependent pentylenetetrazol model. These data indicate membrane-stabilizing effect and expand potentials for this compound in comorbid conditions.

Objective. To assess analgesic action of the newly patented compound from the class of hexaazaisowurzitanes as compared to tramadol in a battery of behavioral tests with various nociceptive systems. Material and methods. The experiments were performed in male mice of CD1 stock. A newly patented 4-(2-ethoxyacetyl)-2.6,8.10.12-pentaacetyl2.4,6.8,10.12hexaazatetracyclo [5.5,0.03.11.05.9]dodecane (M1) was administered daily through a probe at a dose 25—200 mg/kg. Tramadol was administered in a single dose 10 mg /kg for 1-3 days. The last injection was an hour before experimental manipulations. Analgesic effect was evaluated in a three-day administration on a model of chemical irritation of the peritoneum, in a single administration (test of central pain genesis “hot plate”) and mechanical paw compression (Randall-Selitto method). Results. Analysis of specific pharmacological activity in models of somatogenic pain (thermal, visceral pain, mechanical compression) revealed high analgesic activity of the newly synthesized compound 4-(2-ethoxyacetyl)-2.6,8.10.12-pentaacetyl 2.4,6.8,10.12 hexaazatetracyclo[5.5,0.03.11.05.9]dodecane (substance M1). The last one is comparable or exceeds the effect of tramadol. Analgesic effect of the new compound is realized at different levels of conduction and modulation of pain sensitivity. Conclusion. The results of experimental tests with different nociception systems indicate advisability of further preclinical studies of the newly synthesized molecule with high analgesic therapeutic potential.

Aim. To assess the anti-inflammatory and gastroprotective effects of ethowurtzine compared to the reference drug diclofenac in a rat model of chronic inflammation; to evaluate the influence of ethowurtzine on nitric oxide production as a possible mechanism of its anti-inflammatory effects.Materials and methods. The object of the study was a new patented ethowurtzine from the class of hexaazaizowurtzitane derivatives with an acceptable safety profile.The gastroprotective and anti-inflammatory effects of ethowurtzine compared to diclofenac were studied in a model of chronic inflammation using 69 female SD rats. The compound (12.5–100 mg / kg) and a non-selective COX inhibitor diclofenac (5 mg / kg) were administered intragastrically for 7 days, 1 hour before subcutaneous implantation of a cotton swab. On day 8, the proliferative response (%), the exudative response (%), and the ulcerogenic effect of the compounds were assessed.Nitric oxide (NO) synthesis by macrophages obtained from peritoneal cavity of 25 C57Bl/6 mice (in vitro inflammation model) was evaluated by the concentration of nitrites in the cell supernatant after incubating cells in the presence of ethowurtzine and / or lipopolysaccharide (LPS) for 48 hours. The classical MTT test (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT, Sigma, USA)) was used to assess the effects of ethowurtzine on macrophage proliferation.Results. A comparative study of ethowurtzine and diclofenac in a rat model of chronic inflammation revealed the predominant anti-exudative effect of the new substance and a suppressive effect on granulation tissue proliferation comparable to that of NSAID.The macroscopic examination of the gastric mucosa in rats receiving ethowurtzine did not reveal any ulcer damage. On the contrary, in 30% of the rats receiving diclofenac, the severity score of ulcer was 2. In the in vitro inflammation model, the addition of LPS to the macrophage culture resulted in a significant increase in NO synthesis. The introduction of ethowurtzine at different concentrations together with LPS dose-dependently reduced the NO production. A statistically significant decrease in the NO synthesis was noted at high doses of the test substance compared to the group of isolated LPS use. However, the introduction of ethowurtzine at different concentrations together with LPS did not cause statistically significant changes in the proliferation of macrophages compared to the group with the isolated LPS use.Conclusion. The newly synthesized ethowurtzine had a pronounced anti-inflammatory effect and caused a significant decrease in granulomatous infiltration and exudative edema in the chronic inflammation model. Suppression of the NO synthesis is one of the possible mechanisms in the anti-inflammatory effect of ethowurtzine. The obtained data allow to suggest possible administration of the new patented analgetic ethowurtzine in chronic pain treatment associated with inflammation.

Описан способ получения перспективного ненаркотического анальгетического средства вещества с выраженной противовоспалительной активностью из класса гексаазаизовюрцитанов. Рассмотрены способы снижения стоимости получения целевого вещества и приведены его полные физико-химические характеристики. Эффективность и безопасность полученного средства показана на нескольких животных моделях.