thromboxane-a2 and zileuton

Leukotrienes, generated from arachidonic acid via the lipoxygenase pathway, play an important role in the pathophysiology of asthma. Therefore, leukotriene inhibitors, such as Zileuton, are used in the treatment of asthma. However, thromboxanes, generated from arachidonic acid via the cyclooxygenase pathway, play an important role in platelet aggregation and thrombosis. Therefore, we studied whether Zileuton, by shifting arachidonic acid to the cyclooxygenase pathway, enhances thromboxane production and, hence, platelet aggregation. Blood samples were collected from 10 asthmatic patients before and 2 weeks after standard Zileuton treatment. Spontaneous platelet aggregation was measured in platelet-rich plasma. Platelet-rich plasma was also used to determine thromboxane B(2), a stable metabolite of thromboxane A(2), as the indirect measure of thromboxane A(2) because thromboxane A(2) is too unstable for assay. Baseline thromboxane B(2) and platelet aggregation values in the 10 asthmatic patients were normal. Treatment with Zileuton for 2 weeks significantly increased thromboxane B(2) levels from baseline levels of 267 +/- 54 microg/l to 389 +/- 62 microg/l after 2 weeks of treatment (P < 0.0002). Spontaneous platelet aggregation also increased significantly from baseline values of 4.2 +/- 2.4% to 6.8 +/- 2.8% after 2 weeks of treatment (P < 0.0001). These results establish that Zileuton, an effective drug for asthma, adversely affects in vitro platelet function. The findings suggest that this drug, and perhaps related agents also, may pose a thrombotic risk; clinical attention will be needed to address this possibility.

Topics: Adult; Aged; Asthma; Female; Humans; Hydroxyurea; Lipoxygenase Inhibitors; Male; Middle Aged; Platelet Aggregation; Thromboxane A2; Thromboxane B2

The i.v. administration of leukotriene (LT)D4 to anesthetized guinea pigs produced dose-dependent increases in pulmonary microvascular permeability, as measured by extravasation of Evans blue dye into the trachea, main bronchi, and small airways, with an ED50 of approximately 0.05 microgram/kg. When LTD4 was administered at 0.3 microgram/kg, the resulting plasma extravasation into all three airway sections was markedly reduced by pretreatment with a cyclooxygenase inhibitor, meclofenamic acid (2.5 mg/kg, i.v.), a thromboxane (TX) receptor antagonist, SQ 29,548 (0.1 or 1 mg/kg, i.v.), or a peptidoleukotriene receptor antagonist, pranlukast (SB 205312) (0.1 or 1 mg/kg, i.v.), but not by the H1 histamine receptor antagonist, pyrilamine. When LTD4 was administered at 1.0 microgram/kg, meclofenamate (2.5 or 5 mg/kg, i.v.) or SQ 29,548 slightly attenuated plasma extravasation only in the small airway, whereas pranlukast was effective in all three airway segments. Administration of the 5-lipoxygenase inhibitor, zileuton (10 mg/kg, i.v.), or the PAF antagonist, L-659,989 (5 mg/kg, i.v.), did not affect the microvascular leakage response to 1.0 microgram/kg LTD4. In addition, i.v.-administered LTD4 (0.3 or 1.0 microgram/kg) or the prostaglandin (PG)/TXA2 receptor agonist, U-46619 (3.0 micrograms/kg), produced significant bronchoconstriction as measured by increases in pulmonary insufflation pressure. The bronchoconstrictor responses to LTD4 were markedly attenuated by the same inhibitors, namely meclofenamic acid, SQ 29,548, and pranlukast, that reduced the 0.3 microgram/kg LTD4-induced plasma extravasation throughout the airways and the 1.0 microgram/kg LTD4-induced extravasation into the small airways. U-46619-induced bronchoconstriction was blocked only by SQ 29,548.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Bridged Bicyclo Compounds, Heterocyclic; Bronchi; Bronchoconstriction; Capillary Permeability; Chromones; Fatty Acids, Unsaturated; Furans; Guinea Pigs; Hydrazines; Hydroxyurea; Leukotriene D4; Lipoxygenase Inhibitors; Lung; Male; Meclofenamic Acid; Plasma; Prostaglandin Endoperoxides, Synthetic; Pyrilamine; Receptors, Thromboxane; SRS-A; Thromboxane A2; Trachea; Vasoconstrictor Agents