The pharmacological profile of 2-(8-methyl-10,11-dihydro-11-oxodibenz[b,f]oxepin-2-yl)propionic acid (AD-1590), a new non-steroidal anti-inflammatory agent with potent antipyretic activity. 1983

H Nakamura, and Y Yokoyama, and S Motoyoshi, and K Ishii, and C Imazu, and Y Seto, and T Kadokawa, and M Shimizu

Anti-inflammatory, analgesic, antipyretic and gastrointestinal ulcerogenic activities of 2-(8-methyl-10,11-dihydro-11-oxodibenz(b,f]oxepin-2-yl)propionic acid (AD-1590), a new non-steroidal anti-inflammatory drug, were compared with indomethacin (INN: indomethacin) and other non-steroidal anti-inflammatory drugs (NSAID) in experimental animals. AD-1590 showed the potent inhibitory activity on acute and subacute inflammation such as carrageenin hind paw edema (oral ED50 = 1.35 mg/kg), acetic acid-induced increased vascular permeability (0.205 mg/kg), UV-erythema (0.295 mg/kg) and felt pellet-induced granuloma formation (1.7 mg/kg), and its potency was on the whole 2 to 3 times that of indomethacin. Oral analgesic ED50-values of AD-1590 were 0.245, 8.32 and 13.9 mg/kg in the writhing tests, and 2.45 mg/kg in the silver nitrate-induced arthritic pain test. Analgesic potency of AD-1590 was on the whole comparable to that of indomethacin. Against the pyrexia caused by two kinds of pyrogens (yeast and adjuvant), AD-1590 exerted a strong antipyretic action at oral doses as low as 0.02 to 0.1 mg/kg, and its potency (ED50 equal 0.0210 and 0.0406 mg/kg) was 8.7 to 11 times that of indomethacin. , AD-1590 displayed the antipyretic activity at low doses which were widely different from its anti-inflammatory and analgesic effective dose. The body temperature was not affected by 20 mg/kg p.o. of AD-1590 in the afebrile animals. AD-1590 was the strongest antipyretic drug among 10 NSAID tested. In rats, AD-1590 produced gastrointestinal ulcer similar to indomethacin, and its gastric ulcerogenicity (SUD50 equal 13.8 mg/kg p.o.) was about one-half that of indomethacin. The activity of AD-1590 in the fecal occult bleeding test in beagle dogs was weaker than that of indomethacin. The potency of AD-1590 (IC50 equal 0.78 mumol/l) as a prostaglandin synthetase inhibitor was about 2.7 times that of indomethacin in the in vitro test. The safety index (SUD50/ED50) of AD-1590 was larger than that of indomethacin, extremely large (the index equal 657 and 340) in the antipyretic activity. Besides, acute lethal toxicity of AD-1590 (oral LD50 equal 147 mg/kg in rats, 500 mg/kg in mice) was about 1/8 and 1/24 that of indomethacin. From these results, it was suggested that AD-1590 had extraordinarily potent antipyretic activity, potent anti-inflammatory activity superior to indomethacin, analgesic activity equivalent to indomethacin, and a wide safety margin.

UI MeSH Term Description Entries
D007249 Inflammation A pathological process characterized by injury or destruction of tissues caused by a variety of cytologic and chemical reactions. It is usually manifested by typical signs of pain, heat, redness, swelling, and loss of function. Innate Inflammatory Response,Inflammations,Inflammatory Response, Innate,Innate Inflammatory Responses
D008297 Male Males
D010146 Pain An unpleasant sensation induced by noxious stimuli which are detected by NERVE ENDINGS of NOCICEPTIVE NEURONS. Suffering, Physical,Ache,Pain, Burning,Pain, Crushing,Pain, Migratory,Pain, Radiating,Pain, Splitting,Aches,Burning Pain,Burning Pains,Crushing Pain,Crushing Pains,Migratory Pain,Migratory Pains,Pains, Burning,Pains, Crushing,Pains, Migratory,Pains, Radiating,Pains, Splitting,Physical Suffering,Physical Sufferings,Radiating Pain,Radiating Pains,Splitting Pain,Splitting Pains,Sufferings, Physical
D010437 Peptic Ulcer Ulcer that occurs in the regions of the GASTROINTESTINAL TRACT which come into contact with GASTRIC JUICE containing PEPSIN and GASTRIC ACID. It occurs when there are defects in the MUCOSA barrier. The common forms of peptic ulcers are associated with HELICOBACTER PYLORI and the consumption of nonsteroidal anti-inflammatory drugs (NSAIDS). Gastroduodenal Ulcer,Marginal Ulcer,Gastroduodenal Ulcers,Marginal Ulcers,Peptic Ulcers,Ulcer, Gastroduodenal,Ulcer, Marginal,Ulcer, Peptic,Ulcers, Gastroduodenal,Ulcers, Marginal,Ulcers, Peptic
D010998 Pleurisy INFLAMMATION of PLEURA, the lining of the LUNG. When PARIETAL PLEURA is involved, there is pleuritic CHEST PAIN. Pleuritis,Pleurisies,Pleuritides
D011453 Prostaglandins A group of compounds derived from unsaturated 20-carbon fatty acids, primarily arachidonic acid, via the cyclooxygenase pathway. They are extremely potent mediators of a diverse group of physiological processes. Prostaglandin,Prostanoid,Prostanoids
D011919 Rats, Inbred Strains Genetically identical individuals developed from brother and sister matings which have been carried out for twenty or more generations or by parent x offspring matings carried out with certain restrictions. This also includes animals with a long history of closed colony breeding. August Rats,Inbred Rat Strains,Inbred Strain of Rat,Inbred Strain of Rats,Inbred Strains of Rats,Rat, Inbred Strain,August Rat,Inbred Rat Strain,Inbred Strain Rat,Inbred Strain Rats,Inbred Strains Rat,Inbred Strains Rats,Rat Inbred Strain,Rat Inbred Strains,Rat Strain, Inbred,Rat Strains, Inbred,Rat, August,Rat, Inbred Strains,Rats Inbred Strain,Rats Inbred Strains,Rats, August,Rats, Inbred Strain,Strain Rat, Inbred,Strain Rats, Inbred,Strain, Inbred Rat,Strains, Inbred Rat
D002199 Capillary Permeability The property of blood capillary ENDOTHELIUM that allows for the selective exchange of substances between the blood and surrounding tissues and through membranous barriers such as the BLOOD-AIR BARRIER; BLOOD-AQUEOUS BARRIER; BLOOD-BRAIN BARRIER; BLOOD-NERVE BARRIER; BLOOD-RETINAL BARRIER; and BLOOD-TESTIS BARRIER. Small lipid-soluble molecules such as carbon dioxide and oxygen move freely by diffusion. Water and water-soluble molecules cannot pass through the endothelial walls and are dependent on microscopic pores. These pores show narrow areas (TIGHT JUNCTIONS) which may limit large molecule movement. Microvascular Permeability,Permeability, Capillary,Permeability, Microvascular,Vascular Permeability,Capillary Permeabilities,Microvascular Permeabilities,Permeabilities, Capillary,Permeabilities, Microvascular,Permeabilities, Vascular,Permeability, Vascular,Vascular Permeabilities
D003990 Dibenzoxepins
D004890 Erythema Redness of the skin produced by congestion of the capillaries. This condition may result from a variety of disease processes. Erythemas

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