iloprost and Peritonitis

cis-4-(Piperazin-1-yl)-5,6,7a,8,9,10,11,11a-octahydrobenzofuro[2,3-h]quinazolin-2-amine, 4 (A-987306) is a new histamine H(4) antagonist. The compound is potent in H(4) receptor binding assays (rat H(4), K(i) = 3.4 nM, human H(4) K(i) = 5.8 nM) and demonstrated potent functional antagonism in vitro at human, rat, and mouse H(4) receptors in cell-based FLIPR assays. Compound 4 also demonstrated H(4) antagonism in vivo in mice, blocking H(4)-agonist induced scratch responses, and showed anti-inflammatory activity in mice in a peritonitis model. Most interesting was the high potency and efficacy of this compound in blocking pain responses, where it showed an ED(50) of 42 mumol/kg (ip) in a rat post-carrageenan thermal hyperalgesia model of inflammatory pain.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzofurans; Carrageenan; Disease Models, Animal; Drug Design; Drug Evaluation, Preclinical; Humans; Hyperalgesia; Ligands; Mice; Molecular Structure; Pain; Peritonitis; Quinazolines; Rats; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H4; Stereoisomerism; Structure-Activity Relationship

Tissue oxygenation in the gastrointestinal tract and in the liver was studied in a porcine model where septic shock was induced by fecal peritonitis. The effects of different fluid regimes were compared. In one group (n = 8) a moderate amount of crystalloid fluids was given, in another (n = 7) crystalloids and colloids, and in a third group (n = 6) iloprost, a prostacyclin analogue, was administered intra-arterially (10 ng x kg-1 b.w. x min-1) in combination with the crystalline and colloid fluid regime. Septic shock induced by fecal peritonitis reduced cardiac index and oxygen supply to splanchnic organs. Iloprost improved the hepatic arterial blood flow, and tended to attenuate the reduction in liver oxygen delivery. Oxygen consumption (VO2) in the gastrointestinal tract and the liver was significantly increased in the group given crystalloids. These animals developed a hypovolemic/hypodynamic septic shock. Liver VO2 in these animals became flow dependent reflected by increasing hepatic venous lactate values and inversion of lactate turnover by the liver. In the two other groups gastrointestinal and liver VO2 remained constant during the observation period. Oxygen extraction over the liver increased when oxygen delivery decreased. The increased liver VO2 is suggested to be secondary to impaired microcirculation and accumulation of macrophages and leukocytes in the septic liver.

Topics: Animals; Dextrans; Female; Iloprost; Liver; Male; Microcirculation; Oxygen Consumption; Peritonitis; Shock, Hemorrhagic; Splanchnic Circulation; Swine

1. Oral administration of high doses of paracetamol (600 mg kg-1 or more) resulted in inhibition of the writhing and reduced the levels of prostacyclin (PGI2, measured as 6-keto-PGF1 alpha) induced by intraperitoneal administration of zymosan in mice. The high oral doses of paracetamol required were accompanied by behavioural toxicity which may have contributed to the inhibition of writhing. 2. The number of writhes per mouse and the proportion of mice writhing at least once correlated significantly with the levels of 6-keto-PGF1 alpha. However, inhibition of writhing by paracetamol occurred at higher levels of 6-keto-PGF1 alpha than was previously observed with acidic non-steroidal anti-inflammatory agents. 3. When injected i.p., PGI2, carbacyclin and iloprost (agonists at the PGI2 receptor) induced writhing. Intraperitoneal injection of PGI2 reversed the inhibition of writhing induced by indomethacin (1 mg kg-1, p.o.) but not that induced by oral administration of paracetamol. 4. Paracetamol at 800 mg kg-1, p.o., inhibited carbacyclin-induced writhing but indomethacin at 1 mg kg-1 p.o. did not. Paracetamol administered i.p. at 100 mg kg-1 reduced the peritoneal levels of 6-keto-PGF1 alpha and inhibited zymosan-induced but not carbacyclin-induced writhing and did not produce behavioural toxicity. 5. The in vitro potency of paracetamol as a prostaglandin synthesis inhibitor is known to be reduced by the presence of lipid peroxides. However, no lipid peroxides, measured as thiobarbituric acid reactive material, were detected in the peritoneal lavage fluid of zymosan-injected mice. 6. Intraperitoneal administration of a mixture of superoxide dismutase and catalase reduced detectable superoxide anion by 98% without inhibiting the writhing response to zymosan or the antinociceptive potency of paracetamol. 7. The data are consistent with the suggestion that inhibition of PGI2 synthesis in the peritoneal cavity by paracetamol is responsible for only a part of its antinociceptive activity in this test. However, extremely high oral doses of paracetamol were required which produced behavioural toxicity which clearly contributed to the inhibition of writhing. The low potency of paracetamol in this model cannot be attributed to the generation of lipid peroxides via the oxidative burst.

Topics: 6-Ketoprostaglandin F1 alpha; Acetaminophen; Analgesics; Animals; Dinoprostone; Epoprostenol; Free Radicals; Iloprost; Lipid Peroxides; Luminescent Measurements; Macrophages; Male; Mice; Peritonitis; Platelet Aggregation Inhibitors; Superoxides; Zymosan