ABSTRACT
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
One of prospective methods for immunotherapy of tumors is modulation via immunological checkpoints, specifically, via the PD-1(CD279)/PD-L1(CD274) system. Interactions between tumor cell receptor (CD279) and the ligand on lymphocytes (CD274) leads to lymphocyte inactivation, which allows tumor escape from the immune control. Experiments on C57BL/6 mice with Lewis lung carcinoma demonstrate the possibility of reducing the expression of CD279 and CD274 on the peripheral blood and tumor tissue lymphocytes under the effects of Tussilago farfara L. polysaccharides. This phenomenon can underlie the antitumor and antimetastatic effects of these substances.
Subject(s)
B7-H1 Antigen/metabolism , Carcinoma, Lewis Lung/drug therapy , Carcinoma, Lewis Lung/metabolism , Lung Neoplasms/drug therapy , Lung Neoplasms/metabolism , Polysaccharides/therapeutic use , Programmed Cell Death 1 Receptor/metabolism , Tussilago/chemistry , Animals , Female , Flow Cytometry , Immunotherapy , Mice , Mice, Inbred C57BLABSTRACT
A possibility for correction of damaging effects of polychemotherapy on the intestinal epithelium with Tussilago farfara L. polysaccharides was studied on C57Bl/6 mice with Lewis lung carcinoma. The polysaccharides had protective and/or stimulating effects on the intestinal epithelium during polychemotherapy and promoted reparative regeneration in the intestine.
Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carcinoma, Lewis Lung/drug therapy , Intestinal Mucosa/drug effects , Polysaccharides/pharmacology , Tussilago/chemistry , Animals , Antineoplastic Agents, Phytogenic/isolation & purification , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Carcinoma, Lewis Lung/pathology , Cisplatin/administration & dosage , Cisplatin/adverse effects , Eosine Yellowish-(YS) , Etoposide/administration & dosage , Etoposide/adverse effects , Female , Hematoxylin , Histocytochemistry , Intestinal Mucosa/pathology , Irinotecan/administration & dosage , Irinotecan/adverse effects , Mice , Mice, Inbred C57BL , Paclitaxel/administration & dosage , Paclitaxel/adverse effects , Plant Extracts/chemistry , Polysaccharides/isolation & purificationABSTRACT
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
Using DNA comet assay we found that polysaccharides from Tussilago farfara L. reduced the intensity of polychemotherapy-induced apoptosis and DNA damage in bone marrow cells and small intestinal epithelium of C57Bl/6 mice, which attested to genoprotective properties of these polysaccharides.
Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Antineoplastic Combined Chemotherapy Protocols/antagonists & inhibitors , Bone Marrow Cells/drug effects , DNA/chemistry , Intestinal Mucosa/drug effects , Polysaccharides/pharmacology , Tussilago/chemistry , Animals , Antineoplastic Agents, Phytogenic/isolation & purification , Antineoplastic Combined Chemotherapy Protocols/toxicity , Apoptosis/drug effects , Bone Marrow Cells/cytology , Bone Marrow Cells/metabolism , Cisplatin/antagonists & inhibitors , Cisplatin/toxicity , Comet Assay , DNA/metabolism , Duodenum/cytology , Duodenum/drug effects , Duodenum/metabolism , Female , Injections, Intraperitoneal , Intestinal Mucosa/cytology , Intestinal Mucosa/metabolism , Irinotecan/antagonists & inhibitors , Irinotecan/toxicity , Mice , Mice, Inbred C57BL , Paclitaxel/antagonists & inhibitors , Paclitaxel/toxicity , Plant Extracts/chemistry , Polysaccharides/isolation & purificationABSTRACT
The experiments on C57Bl/6 mice with Lewis lung carcinoma showed that addition of Tussilago farfara L. polysaccharides to conventional cisplatin/paclitaxel polychemotherapy moderated neutropenia caused by antitumor therapy and increased its efficiency. The stimulating effect of polysaccharides on the granulopoietic lineage cells is comparable with that of recombinant CSF Neupogen.
Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Carcinoma, Lewis Lung/drug therapy , Cisplatin/pharmacology , Paclitaxel/pharmacology , Polysaccharides/pharmacology , Tussilago/chemistry , Animals , Antineoplastic Agents, Phytogenic/isolation & purification , Carcinoma, Lewis Lung/immunology , Carcinoma, Lewis Lung/pathology , Female , Filgrastim/pharmacology , Granulocytes/drug effects , Granulocytes/immunology , Granulocytes/pathology , Hematologic Agents/pharmacology , Leukocyte Count , Mice , Mice, Inbred C57BL , Plant Extracts/chemistry , Polysaccharides/isolation & purification , Treatment Outcome , Tumor Burden/drug effectsABSTRACT
Tumor cells can maintain their growth via immunosuppression and escape from host antitumor immunity by controlling the PD-1/PD-L1 system. Expression of PD-L1 (CD274) is an inhibitory signal for T cells, while the increase in CD326 expression in the tumor tissue correlates with metastasis development. The experimental preparation on the basis of α(1,2)-L-rhamno-α(1,4)-D-galactopyranosyluronan from Acorus calamus L. produces an antitumor effect: it reduces tumor node size and the number and area of metastases after transplantation of Lewis lung carcinoma. Using flow cytometry, we demonstrated a decrease in the population of tumor cells expressing surface CD274 (PD-L1) and CD326 antigens after 20-day course of α(1,2)-L-rhamno-α(1,4)-D-galactopyranosyluronan.
Subject(s)
Acorus/chemistry , Antineoplastic Agents, Phytogenic/administration & dosage , B7-H1 Antigen/metabolism , Carcinoma, Lewis Lung/drug therapy , Epithelial Cell Adhesion Molecule/metabolism , Animals , B7-H1 Antigen/genetics , Carcinoma, Lewis Lung/metabolism , Carcinoma, Lewis Lung/pathology , Cell Line, Tumor , Epithelial Cell Adhesion Molecule/genetics , Female , Mice, Inbred C57BL , Plant Extracts/pharmacology , Plant Roots/chemistry , Rats , Tumor Burden , Xenograft Model Antitumor AssaysABSTRACT
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
Polysaccharides from Tussilago farfara L., Acorus calamus L., and Echinacea purpurea (L.) Moench attenuated the toxic effect of fl uorouracil on the small intestinal epithelium of mice with Lewis lung carcinoma. Addition of polysaccharides to chemotherapy protocols stimulated reparative regeneration processes in the small intestine damaged by the cytostatic treatment. No stimulating effects of the polysaccharides on tumor growth and metastasizing were revealed.
Subject(s)
Antimetabolites, Antineoplastic/toxicity , Fluorouracil/toxicity , Intestine, Small/pathology , Plant Extracts/pharmacology , Animals , Antimetabolites, Antineoplastic/therapeutic use , Carcinoma, Lewis Lung/drug therapy , Drug Screening Assays, Antitumor , Female , Fluorouracil/therapeutic use , Intestinal Mucosa/drug effects , Intestinal Mucosa/pathology , Intestine, Small/drug effects , Mice, Inbred C57BL , Neoplasm TransplantationABSTRACT
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
The pharmacological properties of plant polysaccharides are reviewed and original experimental data on the properties of water-soluble polysaccharides isolated from Acorus calamus L. are presented. The possibility of using plant (in particular, Acorus calamus) polysaccharides to increase the effectiveness of anticancer treatment of transferred tumors and to reduce the toxic effects of cytostatic treatment on the normal cells of blood, liver, and epithelium of thin intestine in experimental animals has been demonstrated.
Subject(s)
Acorus/chemistry , Antineoplastic Agents/therapeutic use , Cytotoxins/therapeutic use , Neoplasms/drug therapy , Polysaccharides/therapeutic use , Animals , Antineoplastic Agents/chemistry , Cytotoxins/chemistry , Humans , Polysaccharides/chemistryABSTRACT
The effects of various alginate forms on the development of transplanted tumors in mice and efficiency of cytostatic therapy were studied. High-molecular-weight Ca and Na alginates, acid-soluble hydrolysate, and sodium alginate fraction inhibited the growth of Ehrlich adenocarcinoma. The use of acid-insoluble sodium alginate in chemotherapy protocol improved the treatment efficiency. All alginate forms inhibited metastasizing of Lewis pulmonary carcinoma; in combination with cyclophosphamide they potentiated its antimetastatic effect.
Subject(s)
Alginates/therapeutic use , Animals , Carcinoma, Ehrlich Tumor/drug therapy , Carcinoma, Lewis Lung/drug therapy , Female , Glucuronic Acid/therapeutic use , Hexuronic Acids/therapeutic use , Male , Neoplasm TransplantationABSTRACT
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
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
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
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.
Subject(s)
Anti-Ulcer Agents/therapeutic use , Pectins/therapeutic use , Stomach Ulcer/prevention & control , Animals , Female , Gastric Mucosa/drug effects , Gastric Mucosa/pathology , Male , Mice , Rats , Rats, Wistar , Stomach Ulcer/etiology , Stomach Ulcer/pathologyABSTRACT
Experiments on C57LB/6 mice with transplanted Luis lung carcinoma showed that the officinal Echinacea purpurea preparation did not influence the efficacy of cytostatic therapy. This echinacea preparation did not change the development of metastases and even stimulated the tumor growth. In contrast, a hydrophilic polysaccharide complex isolated from echinacea increased the antitumor and antimetastatic activity of cyclophosphamide.