leukotriene-a4 and Dermatitis

Prostaglandins appear to play an important role as mediators of inflammation since they fulfill the major criteria. They possess powerful proinflammatory properties; they are present in increased concentrations in a wide range of proinflammatory lesions, and anti-inflammatory drugs inhibit their formation. The role of leukotrienes and other hydroxy fatty acid products is far less clear although their participation in cellular events seems probable. Steroid and nonsteroid anti-inflammatory drugs owe their activity at least in part to inhibition of biosynthesis of prostaglandins, although these two drug classes appear to act at different points in the pathways. It becomes increasingly clear that the oxygenation of arachidonic acid leads to the formation of a multiplicity of pharmacologically active fatty acids of which only a few have so far been identified.

Topics: Animals; Anti-Inflammatory Agents; Arachidonic Acid; Arachidonic Acids; Dermatitis; Drug Interactions; Humans; Indomethacin; Leukotriene A4; Leukotriene B4; Prostaglandins; Skin; SRS-A

Leukotriene (LT) A(4) hydrolase is a dual function enzyme that is essential for the conversion of LTA(4) to LTB(4) and also possesses an aminopeptidase activity. SC-57461A (3-[methyl[3-[4-phenylmethyl)phenoxy]propyl]amino]propanoic acid HCl) is a potent inhibitor of human recombinant LTA(4) hydrolase (epoxide hydrolase and aminopeptidase activities, K(i) values = 23 and 27 nM, respectively) as well as calcium ionophore-induced LTB(4) production in human whole blood (IC(50) = 49 nM). In the present study, we investigated its action in several animal models. Oral activity was evident from the ability of the compound to inhibit mouse ex vivo calcium ionophore-stimulated blood LTB(4) production with ED(50) values at 1.0 and 3.0 h of 0.2 and 0.8 mg/kg, respectively. A single oral dose of 10 mg/kg SC-57461A blocked mouse ex vivo LTB(4) production 67% at 18 h and 44% at 24 h, suggesting a long pharmacodynamic half-life. In a rat model of ionophore-induced peritoneal eicosanoid production, SC-57461 inhibited LTB(4) production in a dose-dependent manner (ED(50) = 0.3-1 mg/kg) without affecting LTC(4) or 6-keto-prostaglandin F(1alpha) production. Oral pretreatment with SC-57461 in a rat reversed passive dermal Arthus model blocked LTB(4) production with an ED(90) value of 3 to 10 mg/kg, demonstrating good penetration of drug into skin. Plasma level of intact SC-57461 (3 h after oral gavage dosing with 3 mg/kg) was 0.4 microg/ml, which corresponds to >80% inhibition of dermal LTB(4) production. Oral or topical pretreatment with SC-57461A 1 h before challenge with arachidonic acid blocked ear edema in the mouse. SC-57461A is a competitive, selective, and orally active inhibitor of LTA(4) hydrolase in vivo, making it useful to explore the contribution of LTB(4) to a number of inflammatory diseases.

Topics: Administration, Oral; Administration, Topical; Animals; Arthus Reaction; beta-Alanine; Dermatitis; Edema; Eicosanoids; Enzyme Inhibitors; Epoxide Hydrolases; Hydroxyurea; In Vitro Techniques; Leukotriene A4; Leukotriene Antagonists; Lipoxygenase Inhibitors; Mice; Peritoneum; Rats; Skin