pyrimidinones and chinoin-127

According earlier, investigations nitrogen bridgehead compounds make a representative group of non-prostaglandin type gastroprotective agents. One member of this group is CHINOIN-127 (1,6-dimethyl-4-oxo-1, 6, 7, 8, 9, 9a-hexahydro-4H-pyrido-(1, 2a)-pyrimidine-3-carbox-amide). CHINOIN-127 is a potent non-narcotic analgesic and antiinflammatory agent and has a remarkable protective effect on indomethacin induced ulcer (ED50 = 25 mg/kg p.o.) and on acidified ethanol induced ulcer (ED50 = 26 mg/kg p.o.). In this study we examined the mechanism of action of cytoprotective effect of this drug and we made a comparison between the cytoprotective effect of 20% ethanol and 25 mg/kg CHINOIN-127. In the gastric mucosa of control rats we observed a balance between TxA2 and PGI2 (PGI2/TxA2 = 3.8) and between the cytoprotective prostaglandins (PGI2 and PGE2) and ulcerogen eicosanoids (TxA2 and leukotrienes) (PGI2 + PGE2/TxA2 + LTs = 3.9). 100% ethanol treatment causes disintegration of this balance, shifting the synthesis towards the ulcerogen eicosanoids production. CHINOIN-127 and 20% ethanol pretreatment improves the deranged balance between cytoprotective prostaglandins and ulcerogen eicosanoids. Our results demonstrate that CHINOIN-127 and 20% ethanol have a similar mechanism of cytoprotective action on ethanol induced ulcer in rats.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Anti-Inflammatory Agents, Non-Steroidal; Anti-Ulcer Agents; Epoprostenol; Ethanol; Gastric Mucosa; Pyrimidinones; Rats; Rats, Wistar; Stomach Ulcer; Thromboxane B2

Topics: Animals; Anti-Ulcer Agents; Epoprostenol; Indomethacin; Prostaglandin-Endoperoxide Synthases; Pyrimidinones; Rats; Stomach Ulcer; Thromboxane-A Synthase

The production of prostacyclin (PGI2) and thromboxane A2 (TXA2) was studied in an indometacin-induced ulcer model in rats. The specific activities of prostacyclin synthetase and thromboxane synthetase as well as the tissue content of these prostaglandins were determined. The anti-ulcer effect of cimetidine and a novel agent, i.e. 1,6-dimethyl-4-oxo-1,6,7,8,9,9a-hexahydro-4H-pyrido(1,1-a)-pyrimidine-3- carboxamide (Chinoin-127) was compared in this respect. The indometacin treatment shifted the balance of TXA2/PGI2 to the formation of TXA2, and the anti-ulcer agents repaired it. The role of this balance in cytoprotection is discussed.

Topics: Animals; Anti-Ulcer Agents; Cimetidine; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Epoprostenol; Gastric Mucosa; Indomethacin; Intramolecular Oxidoreductases; Isomerases; Male; Pyrimidinones; Rats; Rats, Inbred Strains; Thromboxane A2; Thromboxane-A Synthase

1,6-Dimethyl-4-oxo-1,6,7,8,9,9a-hexahydro-4H-pyrido 1,2-a pyrimidine-3-carboxamide (Ch-127) significantly inhibited the intestinal ulceration induced by a single dose of indomethacin (15 mg/kg p.o.). Moreover, indomethacin produced 75% lethality in the dose of 3.5 mg/kg p.o. administered daily for 2 weeks. The concurrent daily administration of Ch-127 (50 mg/kg p.o. +25 mg/kg s.c.) with indomethacin prevented the gastrointestinal mucosa from histologically detectable changes, and none of the animals died. The 80% lethality following the daily administration of naproxen (60 mg/kg p.o.) for two weeks was also significantly decreased by combining it with Ch-127 (50 mg/kg p.o.).

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Drug Combinations; Indomethacin; Intestinal Diseases; Male; Naproxen; Pyrimidinones; Rats; Rats, Inbred Strains; Ulcer

The effect of three non-steroidal anti-inflammatory agents (NSAIs) and of two new pyrido-pyrimidine derivatives, CHINOIN 127 (1-6-dimethyl-4-oxo-1,6,7,8,9)a-hexahydro-4H-pyrido (1,2-2)pyrimidine-3-carboxamide) and CHINOIN 105 (1-6-dimethyl-4-oxo-1,6,7,8-tetrahydro-4H pyrido (1,2-a) pyrimidine-3-carboxamide) was compared in immune tests using human cells in vitro including T and B lymphocyte proliferation induced with mitogens, spontaneous motility of polymorphonuclear leukocytes, lymphokine (LIF) production, antibody-dependent cell-mediated cytotoxicity (ADCC) and natural killer cell (NK) activity. Indomethacin (INDO) at therapeutic concentrations enhanced the proliferation of lymphocytes stimulated by both Con A and PWM. Acetylsalicylic acid (ASA) increased proliferation of lymphocytes stimulated by Con A and at high concentration inhibited DNA synthesis induced by PWM. Phenylbutazone (PhB) increased DNA synthesis induced by PWM but not by Con A. CHINOIN 127 and CHINOIN 105 inhibited the proliferation of T lymphocytes but failed to influence DNA synthesis of B cells. Indomethacin, ASA and PhB inhibited the spontaneous motility (migration) of polymorphonuclear leukocytes. LIF production of lymphocytes was inhibited by INDO, ASA, PhB, CHINOIN 127 and CHINOIN 105. Phenylbutazone and ASA inhibit ADCC and NK. INDO, Chinoin 127 and Chinoin 105 failed to influence the effector cells of ADC and NK cytotoxicity.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antibody-Dependent Cell Cytotoxicity; Humans; In Vitro Techniques; Killer Cells, Natural; Leukocyte Migration-Inhibitory Factors; Lymphocytes; Prohibitins; Pyrimidinones

Topics: Anti-Inflammatory Agents, Non-Steroidal; Chemical Phenomena; Chemistry; Drug Stability; Pyrimidinones