Antinociceptive Effect of Ethowurtzine, a New Compound from the Class of Hexaazaizowurzitane.

Analysis of specific pharmacological activity evaluated high antinociceptive efficacy of the first synthesized compound 10-di(ethoxyacetyl)-2,6,8,12-tetraacetyl-2,4,6,8,10,12-hexaazatetracyclo[5,5,0,03,11,05,9]dodecane (ethowurtzine) in models of somatogenic pain of different genesis (thermal, visceral pain, mechanical compression of paw).The new molecule from the class of hexaazaisowurtzitane effectively blocks nociceptive reactions at the supraspinal and peripheral levels of pain sensitivity organization. The effect of ethowurtzine was comparable or exceeded the effect of tramadol. The obtained results prove the possibility of creating new pharmacologically active molecules based on the high-energy substance hexaazaisowurtzitane.

Evaluation of the Gastroprotective Effect of the Flavonoid Complex from Lychnis chalcedonica L. on the Models of Experimental Ulcerogenesis.

Using rat and mouse models of neurogenic, ethanol-induced, and indometacin-induced damage to the gastric mucosa we demonstrated that course preventive treatment with flavonoid complex from aerial parts of Lychnis chalcedonica L. increased the resistance of gastric mucosa to ulcerogenic factors of different etiology. The gastroprotective effect of the phytocomplex in a dose range of 16-1600 µg/kg was comparable with that of the reference drug plantaglucide and was superior to that of the reference drugs eleutherococcus extract and methyluracil in the therapeutic doses. The antiulcerogenic activity of Lychnis chalcedonica flavonoid complex considerably exceeded activity of Lychnis chalcedonica L. extract demonstrated in our previous experiments.

Some Aspects of Investigation of the Central Mechanism of Antinociceptive Effect of a New Analgetic from the Hexaazaisowurtzitane Group.

Possible involvement of µ1- and κ-opioid receptors and cannabinoid type 1 receptors (CB1) into the mechanism of analgesic activity of the experimental drug product "Thiowurtzine, (capsule 120 mg)" synthesized on the basis of active pharmaceutical substance 4-(3,4-dibromthiophencarbonyl)-2,6,8,12-tetraacethyl-2,4,6,8,10,12hexaazatetracyclo [5,5,0,03,11,05,9]dodecane was studied in vivo using the hot plate test and acetic acid writhing test. The involvement of κ-opioid receptors and noninvolvement of µ1-receptors and CB1 receptors in the mechanism of thiowurtzine analgesia were demonstrated. The mechanism of interaction of the test analgesic with opioid receptors differs from that of the reference drug tramadol. The interaction of thiowurtzine with serotonergic, GABAergic, and muscarinic cholinergic neurotransmitter systems was studied in vivo using pharmacological analyzers. The absence of muscarinic cholinolytic effect of thiowurtzine was demonstrated in the model of arecoline-induced tremor. The central serotonin-blocking activity of the analgesic was revealed in the model of 5-hydroxytryptophan hyperkinesis in mice. Anticonvulsant activity was demonstrated in the corazol convulsions test, which attested to the presence of a GABAergic component. The mechanism of central analgesia caused by the drug product "Thiowurtzine, capsule 120 mg" appeared to be polymodal. The antinociceptive activity of the analgesic was comparable to that of tramadol.

Pharmacokinetics of a New Analgesic on the Basis of Hexaazaisowurtzitane Derivative.

We studied pharmacokinetics of a new analgesic based on a hexaazaisowurtzitane derivative (thiowurtzine, TWZ). A method for measuring TWZ in organs and tissues by HPLC/MS/MS was developed and validated. The sensitivity of the method under conditions of intragastric administration of TWZ to rats in a dose of 100 mg/kg is 0.5 ng/ml (calibration curve 0.5-400 ng/ml). The concentrations of the substance (Cmax) in the plasma, organs, and tissues of animals were 20-100 ng/ml, the time to reach the maximum concentration after a single dose (Tmax) was 2 h. The mean retention time of the substance in the body ranged from 5.67 to 17.15 h after administration. The highest concentrations were found in excretory organs (liver and kidneys), the substance also actively penetrated into muscle tissue. The medium concentrations were found in the brain and adipose tissue. The tropism to the heart tissues was minimal.

Effect of Tussilago farfara L. Polysaccharides on the Content of Hematopoietic Stem Cells (CD117+34+) in the Bone Marrow of Mice Treated with Cyclophosphamide.

Myelotoxicity is a serious side effect of anticancer drugs. The search for drugs that can reduce the hematological complications of chemotherapy through modulation of hematopoietic stem cells is an urgent task of oncopharmacology. In the present study we showed that administration of Tussilago farfara L. polysaccharides to C57BL/6 mice treated with cyclophosphamide can increase the number of hematopoietic stem cells (CD117+34+) in the bone marrow.

Analgesic Activity of Hexaazaisowurtzitane Derivatives.

Pronounced analgesic activity of the innovative compound 4-(3,4-dibromthiophencarbonyl)-2,6,8,12-tetraacethyl-2,4,6,8,10,12hexaazatetracyclo[5,5,0,03, 11,05, 9] dodecane (thiowurtzine) was observed in the thermal nociceptive hot plate test and in the acute visceral and somatic deep pain model (acetic acid writhing test). In these experimental models, naloxone-sensitive thiowurtzine-induced analgesia was revealed. The absence of tropism to peripheral opioid receptors in the acetic acid writhing test was demonstrated using naloxone methiodide. Course administration of low-toxic thiowurtzine in effective doses was not associated with ulcerogenic damage to the gastric mucosa in experimental animals.

Anti-Inflammatory and Analgesic Activities of the Complex of Flavonoids from Lychnis chalcedonica L.

Anti-inflammatory and analgesic activities of the complex of flavonoids from Lychnis chalcedonica L. were studied in the models of acute aseptic inflammation induced by carrageenan, histamine, and serotonin and acetic acid-induced painful chemical stimulation. It is demonstrated that course treatment with flavonoids derived from Lychnis chalcedonica L. produced a stable pharmacological effect comparable with that of the reference anti-inflammatory drug diclofenac.

Effects of Cichorium Intybus L. Root Extract on Secretory Activity of the Stomach in Health and Ulcer Disease.

Gastroprotective effect of Cichorium intybus L. root extract is demonstrated on H. Shay's model of experimental ulcer in rats. The effect is attributed to the antisecretory activity of the plant and stimulation of defense barrier function of the gastric mucosa. The regulatory effect of the phytocomplex on seasonal characteristics of the gastric secretory and defense functions in dogs with Basov's fistula is detected.

Antiulcer activity of extracts of ecdysteroid-containing plants of genera Lychnis and Silene of the Caryophyllaceae family.

We studied antiulcer activity of the extracts of ecdysteroid-containing plants of the Caryophyllaceae family: Lychnis chalcedonica L., Silene viridiflora L.Sp.Pl., and Silene frivaldszkyana Hampe. Experiments on the model of neurogenic and aspirin-induced ulcerogenesis showed unidirectional and pronounced gastroprotective effects of S. viridiflora and L. chalcedonica extracts comparable to the efficacy of famotidine. In these models, a course of intragastric treatment with the extracts reduced ulcerative lesions of all types.

Study of antitumor activity of antibodies to TNF-α on Walker carcinosarcoma model.

The effect of release-active antibodies to TNF-α (Artrofoon) on the development of Walker carcinosarcoma 256 was studied in Wistar rats. Intragastric dose of this drug significantly inhibited the growth of tumor node (55% inhibition of tumor growth), but less effectively than the reference drug cyclophosphamide (80%). The studied drug significantly prolonged animal' lifespan (+97%) and its efficiency in this respect was comparable to that of cyclophosphamide (+96%).

Effects of nonstarch polysaccharides with different molecular weights on the development of Lewis lung carcinoma in mice and efficiency of cytostatic therapy.

The effects of nonstarch polysaccharides with different molecular weights on the development of Lewis' lung carcinoma and efficiency of cyclophosphamide therapy in mice were studied. Treatment with these substances with low molecular weights (<30 kDa) caused no changes in the primary tumor growth, but inhibited its metastasizing, while nonstarch polysaccharides with high molecular weights (>400 kDa) inhibited the growth of Lewis' lung carcinoma node. Antimetastatic effects of cyclophosphamide were stimulated by low and high molecular weight polysaccharides.

Effect of non-starch polysaccharide calcium pectate on the growth and colonization of normal and pathogenic microflora in vitro.

In vitro experiments showed that calcium pectate added to the culture medium produces a dose-dependent prebiotic effect on lacto-and bifidobacteria cultures and on non-pathogenic strain of Escherichia coli. Calcium pectate produced a pronounced bacteriostatic effect on Candida albicans strain; the effects was more pronounced in a concentration of 4%.

[Effect of ginsenoside Rh2 on the development of transferred tumors and chemotherapy efficiency].

Experiments on C57B1/6 mice showed that ginsenoside Rh2 inhibited the growth and metastasis process of Lewis lung tumor and increased the antitumor and antimetastatic effects of cyclophosphamide. On the model of transferred melanoma B-16, ginsenoside Rh2 showed a tendency to increase the antiblastome effect of the cytostatic drug.

[Experimental investigation of antiinflammatory and anesthetic properties of calcium pectate].

Antiinflammatory (antiexudative, antiproliferative) activity of calcium pectate was revealed by tests on the mice leg carrageenan-induced edema and cotton-ball granuloma models. It was also established that this polysaccharide produced an anesthetic effect comparable with that of indomethacin on the model of acetate-induced convulsions in mice.

[Anti-ulcerative effect of non-starch polysaccharides].

Standard models of experimental ulceration (of neurogenic origin, H. Shay ulcer, indomethacine-, ethanol-, prednisolone-, histamine- and acetate-induced ulcers) were used to demonstrate protective effect of non-starch polysaccharides (potassium alginate, potassium pectate, low-esterified pectin). Potassium pectate proved to be the most efficacious protector. Mechanism of its anti-ulcerative action is attributable to antacidic, cytoprotective, and reparative activity. It appeals to optimally stimulate the motor-evacuation function and, besides, exhibits marked anti-inflammatory activity.

[Antiulcer effect of calcium pectate on model of chronic gastric ulcer in rats].

Calcium pectate has been found to exhibit an antiulcer activity in rats with model of chronic ulcers. Course treatment of the experimental animals with calcium pectate (i) accelerated the repair of experimental damage due to better integrity and higher secretory activity of epithelium and (ii) decreased hemodynamic disorders in surrounding mucous and epithelial membranes. The maximum effect, which was achieved with calcium pectate in a dose of 50 mg/kg, exceeded the action of the reference drug maalox on both 14th and 21st days of experiment.

Effect of ultralow doses of antibodies to histamine on the development of chronic ulcerative process in the stomach of experimental animals.

Antiulcer activity of ultralow doses of antibodies to histamine was demonstrated on the model of chronic acetate-induced gastric ulcer in rats. Course therapy with the preparation accelerated healing of chronic experimental ulcer by correcting hemodynamic disturbances and stimulating mucus formation in the gastric wall.

Gastroprotective effect of nonstarch polysaccharide calcium pectate under experimental conditions.

Course prophylactic administration and single therapeutic treatment with calcium pectate improved resistance of rat gastroduodenal mucosa to ethanol-induced ulcers, prednisolone-induced ulcers, and H. Shay ulceration of the gastric mucosa.

Licorice preparations improve efficiency of chemotherapy and surgical treatment of transplanted tumors.

Experiments on animals with Lewis lung carcinoma and Ehrlich tumor showed that licorice (glycyrrhiza) extract and glyciram prepared from this plant improved the antitumor effect of cyclophosphamide. Glyciram reduced the toxic effect of the cytostatic on peripheral blood leukocytes. Licorice extract inhibited the growth of Ehrlich tumor and development of metastases in mice with Lewis lung carcinoma. Glyciram administered to mice after removal of Lewis lung carcinoma produced an antimetastatic effect and prevented relapses.

[Experimental evaluation of the antiulcer activity of calcium pectate].

Both chronic (prophylactic) and single administration of standardized calcium pectate considerably increased the resistance of rat stomach mucous membrane with respect to ulcerogenic factors of various etiology, including immobilized stress, indomethacin, ethanol, prednizolone, and histamine, according to H. Shay's model. The gastroprotective effect of this polysaccharide was comparable with or exceeded the action of famotidine, sea buckthorn oil, and maalox.