ABSTRACT
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.
Subject(s)
Pain , Tramadol , Humans , Pain Measurement/methods , Pain/drug therapy , Tramadol/pharmacology , Tramadol/therapeutic use , Pain Threshold , Analgesics/pharmacology , Analgesics/therapeutic use , Analgesics, Opioid/pharmacologyABSTRACT
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.
Subject(s)
Anti-Ulcer Agents/therapeutic use , Plant Extracts/therapeutic use , Stomach Ulcer/drug therapy , Animals , Animals, Outbred Strains , Anti-Ulcer Agents/isolation & purification , Anti-Ulcer Agents/pharmacology , Cytoprotection/drug effects , Disease Models, Animal , Ethanol , Flavonoids/isolation & purification , Flavonoids/pharmacology , Flavonoids/therapeutic use , Gastric Mucosa/drug effects , Gastric Mucosa/pathology , Indomethacin , Lychnis/chemistry , Male , Mice , Neurogenic Inflammation/drug therapy , Neurogenic Inflammation/pathology , Phytotherapy , Plant Extracts/pharmacology , Rats , Rats, Wistar , Silene , Stomach Ulcer/chemically induced , Stomach Ulcer/pathologyABSTRACT
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.
Subject(s)
Neurotransmitter Agents/metabolism , Receptors, Opioid/metabolism , Analgesics , Animals , Central Nervous System/metabolism , Disease Models, Animal , Male , Mice , Pain Measurement , Receptor, Cannabinoid, CB1/metabolism , Receptors, Opioid, kappa/metabolismABSTRACT
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.
Subject(s)
Analgesics/chemistry , Chromatography, High Pressure Liquid , Mass Spectrometry , Molecular Structure , Tandem Mass SpectrometryABSTRACT
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.
Subject(s)
Antineoplastic Agents, Alkylating/toxicity , Bone Marrow Cells/drug effects , Bone Marrow/drug effects , Cyclophosphamide/antagonists & inhibitors , Hematopoietic Stem Cells/drug effects , Polysaccharides/pharmacology , Tussilago/chemistry , Animals , Antigens, CD34/genetics , Antigens, CD34/immunology , Biomarkers/metabolism , Bone Marrow/immunology , Bone Marrow Cells/cytology , Bone Marrow Cells/immunology , Cell Count , Cyclophosphamide/toxicity , Female , Gene Expression , Hematopoietic Stem Cells/cytology , Hematopoietic Stem Cells/immunology , Immunophenotyping , Injections, Intraperitoneal , Mice , Mice, Inbred C57BL , Plant Extracts/chemistry , Polysaccharides/isolation & purification , Proto-Oncogene Proteins c-kit/genetics , Proto-Oncogene Proteins c-kit/immunologyABSTRACT
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.
Subject(s)
Analgesics/therapeutic use , Pain/drug therapy , Animals , Disease Models, Animal , Gastric Mucosa/drug effects , Male , Mice , Naloxone/therapeutic use , Pain/physiopathology , Pain Measurement/methodsABSTRACT
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.
Subject(s)
Analgesics/therapeutic use , Anti-Inflammatory Agents/therapeutic use , Carrageenan/toxicity , Flavonoids/therapeutic use , Inflammation/drug therapy , Lychnis/chemistry , Acetic Acid/toxicity , Animals , Diclofenac/therapeutic use , Female , Histamine/toxicity , Inflammation/chemically induced , Male , Mice , Serotonin/toxicityABSTRACT
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.
Subject(s)
Anti-Ulcer Agents/pharmacology , Cichorium intybus/chemistry , Gastric Mucosa/drug effects , Phytotherapy , Plant Extracts/pharmacology , Stomach Ulcer/drug therapy , Animals , Anti-Ulcer Agents/isolation & purification , Carbachol/pharmacology , Dogs , Famotidine/pharmacology , Female , Gastric Fistula , Gastric Juice/chemistry , Gastric Juice/drug effects , Gastric Juice/metabolism , Gastric Mucosa/metabolism , Gastric Mucosa/pathology , Male , Plant Extracts/isolation & purification , Plant Roots/chemistry , Rats , Rats, Sprague-Dawley , Seasons , Stomach/drug effects , Stomach/pathology , Stomach Ulcer/pathologyABSTRACT
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.
Subject(s)
Anti-Ulcer Agents/pharmacology , Ecdysteroids/analysis , Lychnis/chemistry , Plant Extracts/pharmacology , Silene/chemistry , Stomach Ulcer/prevention & control , Animals , Ethanol , Female , Mice , Spectrophotometry, Ultraviolet , Statistics, NonparametricABSTRACT
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%).
Subject(s)
Antibodies/pharmacology , Antineoplastic Agents/pharmacology , Carcinoma 256, Walker/drug therapy , Lymph Nodes/drug effects , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Administration, Mucosal , Animals , Carcinoma 256, Walker/immunology , Carcinoma 256, Walker/pathology , Cyclophosphamide/pharmacology , Female , Gastric Mucosa/drug effects , Gastric Mucosa/immunology , Longevity/drug effects , Lymph Nodes/immunology , Lymph Nodes/pathology , Rats , Rats, Wistar , Tumor Burden/drug effectsABSTRACT
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.
Subject(s)
Carcinoma, Lewis Lung/drug therapy , Cyclophosphamide/therapeutic use , Polysaccharides/therapeutic use , Animals , Carcinoma, Lewis Lung/pathology , Drug Synergism , Female , Mice , Mice, Inbred C57BL , Molecular WeightABSTRACT
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%.
Subject(s)
Pectins/pharmacology , Polysaccharides/pharmacology , Anti-Infective Agents/pharmacology , Bifidobacterium/drug effects , Candida albicans/drug effects , Escherichia coli/drug effectsABSTRACT
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.
Subject(s)
Antineoplastic Agents/pharmacology , Carcinoma, Lewis Lung/drug therapy , Cytostatic Agents/pharmacology , Ginsenosides/pharmacology , Animals , Drug Screening Assays, Antitumor , Female , Melanoma/drug therapy , MiceABSTRACT
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.
Subject(s)
Anesthetics/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Edema/drug therapy , Granuloma/drug therapy , Pectins/pharmacology , Animals , Carrageenan/toxicity , Edema/chemically induced , Female , Granuloma/chemically induced , Indomethacin/pharmacology , Mice , Rats , Rats, WistarABSTRACT
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.
Subject(s)
Alginates/therapeutic use , Biocompatible Materials/therapeutic use , Gastric Emptying/drug effects , Pectins/therapeutic use , Polysaccharides/therapeutic use , Stomach Ulcer/drug therapy , Administration, Oral , Alginates/administration & dosage , Animals , Antidiarrheals/administration & dosage , Antidiarrheals/therapeutic use , Biocompatible Materials/administration & dosage , Disease Models, Animal , Drug Carriers , Female , Glucuronic Acid/administration & dosage , Glucuronic Acid/therapeutic use , Hexuronic Acids/administration & dosage , Hexuronic Acids/therapeutic use , Male , Mice , Pectins/administration & dosage , Polysaccharides/administration & dosage , Rats , Rats, Wistar , Stomach Ulcer/physiopathology , Treatment OutcomeABSTRACT
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.
Subject(s)
Anti-Ulcer Agents/therapeutic use , Gastric Mucosa/drug effects , Pectins/therapeutic use , Stomach Ulcer/drug therapy , Acetates , Aluminum Hydroxide/therapeutic use , Animals , Chronic Disease , Disease Models, Animal , Drug Combinations , Gastric Mucosa/pathology , Magnesium Hydroxide/therapeutic use , Male , Rats , Rats, Wistar , Stomach Ulcer/chemically induced , Stomach Ulcer/pathologyABSTRACT
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.
Subject(s)
Anti-Ulcer Agents/immunology , Anti-Ulcer Agents/therapeutic use , Antibodies/immunology , Antibodies/therapeutic use , Histamine/immunology , Stomach Ulcer/drug therapy , Animals , Male , RatsABSTRACT
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.
Subject(s)
Gastric Mucosa/drug effects , Pectins/pharmacology , Peptic Ulcer/drug therapy , Animals , Anti-Ulcer Agents/pharmacology , Anti-Ulcer Agents/therapeutic use , Ethanol , Female , Gastric Mucosa/pathology , Intestinal Mucosa/drug effects , Intestinal Mucosa/pathology , Male , Pectins/therapeutic use , Peptic Ulcer/chemically induced , Rats , Treatment OutcomeABSTRACT
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.
Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Ehrlich Tumor/drug therapy , Carcinoma, Ehrlich Tumor/surgery , Carcinoma, Lewis Lung/drug therapy , Carcinoma, Lewis Lung/surgery , Glycyrrhiza/chemistry , Neoplasm Transplantation , Animals , Carcinoma, Ehrlich Tumor/pathology , Carcinoma, Lewis Lung/pathology , Female , Glycyrrhetinic Acid/therapeutic use , Mice , Mice, Inbred C57BL , Mice, Inbred CBA , Neoplasm Metastasis/drug therapy , Plant Extracts/therapeutic useABSTRACT
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.