Beneficial effects of TCV-309, a novel potent and selective platelet activating factor antagonist in endotoxin and anaphylactic shock in rodents. 1992

Z Terashita, and M Kawamura, and M Takatani, and S Tsushima, and Y Imura, and K Nishikawa
Biology Research Laboratory, Takeda Chemical Industries, Ltd, Osaka, Japan.

Pharmacological profiles of a novel specific platelet activating factor (PAF) antagonist, TCV-309 (3-bromo-5-[N-phenyl-N-[2-[2- (1,2,3,4-tetrahydro-2-isoquinolycarbonyloxy)ethyl] carbamoyl]ethyl] carbamoyl]-1-propylpyridinium nitrate] and its beneficial effects in shock were examined. TCV-309 specifically inhibited PAF-induced aggregation of rabbit and human platelets, and [3H]PAF binding to rabbit platelet microsomes with IC50 values of 33, 58 and 27 nM, respectively. It was as potent as WEB 2086 and more potent than CV-6209 and CV-3988. TCV-309 did not cause hemolysis in human or rat blood due to a detergent-like action. In rats, TCV-309 selectively inhibited the PAF-induced hypotension, hemoconcentration and death with ED50 values of 2.7, 6.4 and 1.7 micrograms/kg (i.v.), respectively. TCV-309 most potently protected mice from death induced by PAF and due to anaphylactic shock with ED50 values of 2.1 and 2.6 micrograms/kg (i.v.), respectively, when compared with CV-3988, CV-6209, WEB 2086 (i.v.) and L-652731 (p.o.). TCV-309 also reversed PAF-induced hypotension and endotoxin-induced hypotension in rats with ED50 values of 3.3 and 1.2 micrograms/kg (i.v.), respectively. There was a significant linear relationship between the ability (ED50 value) of these PAF antagonists to prevent death induced by PAF and death due to anaphylactic shock in mice, and between their reversing ability (ED50 value) for the hypotension induced by PAF and endotoxin in rats. TCV-309 (100 micrograms/kg i.v.) protected rats from death induced by endotoxin. Thus, PAF may be a lethal mediator in anaphylactic shock and a hypotensive mediator in endotoxin shock in rodents.

UI MeSH Term Description Entries
D007022 Hypotension Abnormally low BLOOD PRESSURE that can result in inadequate blood flow to the brain and other vital organs. Common symptom is DIZZINESS but greater negative impacts on the body occur when there is prolonged depravation of oxygen and nutrients. Blood Pressure, Low,Hypotension, Vascular,Low Blood Pressure,Vascular Hypotension
D007546 Isoquinolines A group of compounds with the heterocyclic ring structure of benzo(c)pyridine. The ring structure is characteristic of the group of opium alkaloids such as papaverine. (From Stedman, 25th ed)
D008297 Male Males
D008861 Microsomes Artifactual vesicles formed from the endoplasmic reticulum when cells are disrupted. They are isolated by differential centrifugation and are composed of three structural features: rough vesicles, smooth vesicles, and ribosomes. Numerous enzyme activities are associated with the microsomal fraction. (Glick, Glossary of Biochemistry and Molecular Biology, 1990; from Rieger et al., Glossary of Genetics: Classical and Molecular, 5th ed) Microsome
D010742 Phospholipid Ethers Phospholipids which have an alcohol moiety in ethereal linkage with a saturated or unsaturated aliphatic alcohol. They are usually derivatives of phosphoglycerols or phosphatidates. The other two alcohol groups of the glycerol backbone are usually in ester linkage. These compounds are widely distributed in animal tissues. Ether Phosphatidates,Ether Phospholipids,Glycerol Phosphate Ethers,Glycerophosphate Ethers,1-Alkyl-2-Acylphosphatidates,1 Alkyl 2 Acylphosphatidates,Ethers, Glycerol Phosphate,Ethers, Glycerophosphate,Ethers, Phospholipid,Phosphate Ethers, Glycerol,Phosphatidates, Ether,Phospholipids, Ether
D010972 Platelet Activating Factor A phospholipid derivative formed by PLATELETS; BASOPHILS; NEUTROPHILS; MONOCYTES; and MACROPHAGES. It is a potent platelet aggregating agent and inducer of systemic anaphylactic symptoms, including HYPOTENSION; THROMBOCYTOPENIA; NEUTROPENIA; and BRONCHOCONSTRICTION. AGEPC,Acetyl Glyceryl Ether Phosphorylcholine,PAF-Acether,Phosphorylcholine, Acetyl Glyceryl Ether,1-Alkyl-2-acetyl-sn-glycerophosphocholine,Platelet Aggregating Factor,Platelet Aggregation Enhancing Factor,Platelet-Activating Substance,Thrombocyte Aggregating Activity,1 Alkyl 2 acetyl sn glycerophosphocholine,Aggregating Factor, Platelet,Factor, Platelet Activating,PAF Acether,Platelet Activating Substance
D010974 Platelet Aggregation The attachment of PLATELETS to one another. This clumping together can be induced by a number of agents (e.g., THROMBIN; COLLAGEN) and is part of the mechanism leading to the formation of a THROMBUS. Aggregation, Platelet
D010975 Platelet Aggregation Inhibitors Drugs or agents which antagonize or impair any mechanism leading to blood platelet aggregation, whether during the phases of activation and shape change or following the dense-granule release reaction and stimulation of the prostaglandin-thromboxane system. Antiaggregants, Platelet,Antiplatelet Agent,Antiplatelet Agents,Antiplatelet Drug,Blood Platelet Aggregation Inhibitor,Blood Platelet Antagonist,Blood Platelet Antiaggregant,PAR-1 Antagonists,Platelet Aggregation Inhibitor,Platelet Antagonist,Platelet Antagonists,Platelet Antiaggregant,Platelet Antiaggregants,Platelet Inhibitor,Protease-Activated Receptor-1 Antagonists,Antiplatelet Drugs,Blood Platelet Aggregation Inhibitors,Blood Platelet Antagonists,Blood Platelet Antiaggregants,Platelet Inhibitors,Agent, Antiplatelet,Aggregation Inhibitor, Platelet,Antagonist, Blood Platelet,Antagonist, Platelet,Antiaggregant, Blood Platelet,Antiaggregant, Platelet,Drug, Antiplatelet,Inhibitor, Platelet,Inhibitor, Platelet Aggregation,PAR 1 Antagonists,Platelet Antagonist, Blood,Platelet Antiaggregant, Blood,Protease Activated Receptor 1 Antagonists
D011726 Pyridinium Compounds Derivatives of PYRIDINE containing a cation C5H5NH or radical C5H6N. Compounds, Pyridinium
D011817 Rabbits A burrowing plant-eating mammal with hind limbs that are longer than its fore limbs. It belongs to the family Leporidae of the order Lagomorpha, and in contrast to hares, possesses 22 instead of 24 pairs of chromosomes. Belgian Hare,New Zealand Rabbit,New Zealand Rabbits,New Zealand White Rabbit,Rabbit,Rabbit, Domestic,Chinchilla Rabbits,NZW Rabbits,New Zealand White Rabbits,Oryctolagus cuniculus,Chinchilla Rabbit,Domestic Rabbit,Domestic Rabbits,Hare, Belgian,NZW Rabbit,Rabbit, Chinchilla,Rabbit, NZW,Rabbit, New Zealand,Rabbits, Chinchilla,Rabbits, Domestic,Rabbits, NZW,Rabbits, New Zealand,Zealand Rabbit, New,Zealand Rabbits, New,cuniculus, Oryctolagus

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