ABSTRACT
The substituted oxazolopyridine 2-[3-(1,1-dimethylethyl)-5-methoxyphenyl]oxazolo[4,5-b]pyridine (OZP) inhibits phorbol myristate acetate-induced increases in vascular permeability and neutrophil accumulation in rat ears with ED50 of 253 and 200 micrograms, respectively. This compound is as potent as indomethacin to inhibit UV-induced erythema in guinea pig skin and is an effective analgesic when applied topically to the rat footpad in the yeast hyperalgesia model. OZP is a cyclooxygenase inhibitor with an IC50 of 0.06 mumol/l and inhibits prostaglandin E2, but not leukotriene C4 synthesis, by mouse peritoneal macrophages. This compound is inactive in the carrageenan paw edema assay at 90 mg/kg when administered orally or intraperitoneally, but is effective when injected into the paw. OZP is not a contact allergen and does not cause gastric irritation in rats at doses up to 180 mg/kg orally. OZP is rapidly metabolized by rat liver microsomes in a concentration and time dependent manner. Furthermore, when administered orally, OZP is cleared rapidly in rats with plasma levels being detected only at 5 and 30 min following a 2 mg/kg dose. There was no drug in the gastrointestinal tract of rats 3 h after an oral dose. Thus, this compound appears to be a new, potent and safe topical antiinflammatory and an analgesic agent lacking systemic effects.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Pyridines/pharmacology , Analgesics , Animals , Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Anti-Inflammatory Agents, Non-Steroidal/metabolism , Capillary Permeability/drug effects , Edema/prevention & control , Erythema/prevention & control , Female , Granuloma/prevention & control , Guinea Pigs , Humans , In Vitro Techniques , Macrophages/drug effects , Male , Mice , Microsomes, Liver/metabolism , Prostaglandins/biosynthesis , Pyridines/metabolism , Rats , Rats, Inbred Strains , Seminal Vesicles/metabolism , Stomach Ulcer/chemically inducedABSTRACT
Two tumors, human sarcoma #1 (HS #1) and human epidermoid carcinoma #3 (HEp #3), were cultured on the chorioallantoic membrane of chick embryos. Under experimental conditions, HS #1 does not metastasize, whereas HEp #3 metastasizes extensively to chick embryo lungs and other organs. The glycosphingolipid profiles of these tumors were studied and HEp #3 wad found to contain about 2.5-fold less lipid-bound sialic acid per 100 mg of total lipid extracted than did HS #1, due mainly to smaller levels of monosialoganglioside (3.7-fold) and disialoganglioside (3.8-fold) in HEp #3. The total amount of neutral glycosphingolipids was approximately the same in both tumors, but their profiles differed. Treatment of these tumors with 6,7,8,9-tetrahydro-1-mercapto-1,2,4-triazolo-[4,3-a]quinazolin-5-ol (2.5 mg/egg/tumor) completely inhibited the formation of metastases in HEp #3 and increased the total content of lipid-bound sialic acid in the tumor by 63% (hematoside, monosialoganglioside, and disialoganglioside by 71, 99, and 67%, respectively). No change was seen in the content of lipid-bound sialic acid in HS #1. Treatment of HEp #3 with a smaller dose of te quinazolinol derivative (1.25 mg/egg) caused an average of 88% inhibition of metastasis, with a 37% increase in lipid-bound sialic acid. Another compound, 2,5-diphenylthiazolo-[5,4-d]thiazole (500 microgram/egg), completely inhibited the formation of metastasis and caused a substantial increase in the amount of lipid-bound sialic acid (77%). The data showed the existence of a correlation between the level of gangliosides in HEp #3 and the ability of these tumors to metastasize.
