The Activity of a New, Novel Inhibitor of Leukotriene Synthesis in Rhesus Monkey Ascaris Reactors

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Abstract
The IgE-mediated hypersensitivity to Ascaris antigen in reactor rhesus primates was used to assess the pharmacologic profile of U-60,257, a pyrrole analog of prostacyclin. Whether the compound was given by aerosol or intravenously, it effectively inhibited the bronchopulmonary effects of antigen challenge. Dose responses by the aerosol route showed a dose-dependent inhibition of resistance (RL) and compliance (Cdyn) changes (100% ± 0 to 10.2% ± 14.5 for RL and 79.9% ± 20 to 0% for Cdyn after 15 breaths of 1.0–0.01 % solutions delivered into the lungs; n = 16). When administered at 1.0% by aerosol the duration of the inhibitory effect was 6 h (n = 3). Dose-dependent inhibition in both RL (93.3% ± 5.6 to 69.4% ± 34.8) and Cdyn (51.4 ± 40.4 to 47.0% ± 28.5) was also seen when the compound was given intravenously (5.0–0.01 mg/kg; n = 16). U-60,257 is a selective inhibitor of leukotriene synthesis in in vitro systems. Therefore, the finding of synergism in the inhibition of response of primates to Ascaris between this compound and the H1 histamine blocker diphenhydramine suggests that the leukotrienes may play an etiologic role in this response.