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. 1986 Oct;41(10):746–752. doi: 10.1136/thx.41.10.746

Effect of inhaled piriprost (U-60, 257) a novel leukotriene inhibitor, on allergen and exercise induced bronchoconstriction in asthma.

J S Mann, C Robinson, A Q Sheridan, P Clement, M K Bach, S T Holgate
PMCID: PMC460468  PMID: 3538476

Abstract

The leukotrienes, a group of oxidative metabolites of arachidonic acid, have potent pharmacological actions on human airways. We have investigated the effects of a leukotriene synthesis inhibitor, piriprost (U-60, 257) administered by inhalation on allergen and exercise induced bronchoconstriction in 12 subjects with allergic asthma. Subjects underwent diagnostic challenges with allergen and treadmill exercise to define the strengths of the stimuli required to reduce the FEV1 to about 25% of baseline (PS25). On separate study days subjects inhaled either piriprost 1 mg or vehicle placebo, followed 15 minutes later by the PS25 allergen or exercise. The FEV1 was measured at regular intervals before and after challenge up to 60 minutes. After allergen challenge in six subjects peak expiratory flow (PEF) was measured for the following 20 hours. When compared with placebo, inhalation of piriprost had no significant protective effect on the fall in FEV1 at any time point within 60 minutes of allergen or exercise challenge. In the four subjects with a documented late asthmatic reaction 2-12 hours after allergen challenge piriprost had no protective effect when compared with placebo. In the subjects who recorded PEF over 20 hours after allergen challenge there was no significant difference between piriprost and placebo. Piriprost was appreciably more irritant to the respiratory tract than was placebo. On the assumption that inhaled piriprost was bioavailable in the airways, this study casts doubt on any theory of a pivotal role for leukotrienes in the pathogenesis of acute exercise and allergen induced airway bronchoconstriction in asthma.

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Selected References

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  1. Abraham W. M., Delehunt J. C., Yerger L., Marchette B. Characterization of a late phase pulmonary response after antigen challenge in allergic sheep. Am Rev Respir Dis. 1983 Nov;128(5):839–844. doi: 10.1164/arrd.1983.128.5.839. [DOI] [PubMed] [Google Scholar]
  2. Adams G. K., 3rd, Lichtenstein L. In vitro studies of antigen-induced bronchospasm: effect of antihistamine and SRS-A antagonist on response of sensitized guinea pig and human airways to antigen. J Immunol. 1979 Feb;122(2):555–562. [PubMed] [Google Scholar]
  3. Bach M. K., Brashler J. R., Smith H. W., Fitzpatrick F. A., Sun F. F., McGuire J. C. 6,9-deepoxy-6,9,-(phenylimino)-delta 6,8-prostaglandin I1, (U-60,257), a new inhibitor of leukotriene C and D synthesis: in vitro studies. Prostaglandins. 1982 May;23(5):759–771. [PubMed] [Google Scholar]
  4. Bach M. K., Griffin R. L., Richards I. M. Inhibition of the presumably leukotriene-dependent component of antigen-induced bronchoconstriction in the guinea pig by piriprost (U-60,257). Int Arch Allergy Appl Immunol. 1985;77(1-2):264–266. doi: 10.1159/000233806. [DOI] [PubMed] [Google Scholar]
  5. Bach M. K. Prospects for the inhibition of leukotriene synthesis. Biochem Pharmacol. 1984 Feb 15;33(4):515–521. doi: 10.1016/0006-2952(84)90300-9. [DOI] [PubMed] [Google Scholar]
  6. Bisgaard H., Groth S., Madsen F. Bronchial hyperreactivity to leucotriene D4 and histamine in exogenous asthma. Br Med J (Clin Res Ed) 1985 May 18;290(6480):1468–1471. doi: 10.1136/bmj.290.6480.1468. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Burka J. F. Pharmacological modulation of responses of guinea-pig airways contracted with antigen and calcium ionophore A23187. Br J Pharmacol. 1985 Jun;85(2):411–420. doi: 10.1111/j.1476-5381.1985.tb08876.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Cartier A., Thomson N. C., Frith P. A., Roberts R., Hargreave F. E. Allergen-induced increase in bronchial responsiveness to histamine: relationship to the late asthmatic response and change in airway caliber. J Allergy Clin Immunol. 1982 Sep;70(3):170–177. doi: 10.1016/0091-6749(82)90038-0. [DOI] [PubMed] [Google Scholar]
  9. Chai H., Farr R. S., Froehlich L. A., Mathison D. A., McLean J. A., Rosenthal R. R., Sheffer A. L., Spector S. L., Townley R. G. Standardization of bronchial inhalation challenge procedures. J Allergy Clin Immunol. 1975 Oct;56(4):323–327. doi: 10.1016/0091-6749(75)90107-4. [DOI] [PubMed] [Google Scholar]
  10. Dahlén S. E., Hansson G., Hedqvist P., Björck T., Granström E., Dahlén B. Allergen challenge of lung tissue from asthmatics elicits bronchial contraction that correlates with the release of leukotrienes C4, D4, and E4. Proc Natl Acad Sci U S A. 1983 Mar;80(6):1712–1716. doi: 10.1073/pnas.80.6.1712. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Dahlén S. E., Hedqvist P., Hammarström S., Samuelsson B. Leukotrienes are potent constrictors of human bronchi. Nature. 1980 Dec 4;288(5790):484–486. doi: 10.1038/288484a0. [DOI] [PubMed] [Google Scholar]
  12. Dahlén S. E. Pulmonary effects of leukotrienes. Acta Physiol Scand Suppl. 1983;512:1–51. [PubMed] [Google Scholar]
  13. De Monchy J. G., Kauffman H. F., Venge P., Koëter G. H., Jansen H. M., Sluiter H. J., De Vries K. Bronchoalveolar eosinophilia during allergen-induced late asthmatic reactions. Am Rev Respir Dis. 1985 Mar;131(3):373–376. doi: 10.1164/arrd.1985.131.3.373. [DOI] [PubMed] [Google Scholar]
  14. Ford-Hutchinson A. W., Bray M. A., Doig M. V., Shipley M. E., Smith M. J. Leukotriene B, a potent chemokinetic and aggregating substance released from polymorphonuclear leukocytes. Nature. 1980 Jul 17;286(5770):264–265. doi: 10.1038/286264a0. [DOI] [PubMed] [Google Scholar]
  15. Goetzl E. J. Oxygenation products of arachidonic acid as mediators of hypersensitivity and inflammation. Med Clin North Am. 1981 Jul;65(4):809–828. doi: 10.1016/s0025-7125(16)31499-7. [DOI] [PubMed] [Google Scholar]
  16. Hardy C. C., Robinson C., Tattersfield A. E., Holgate S. T. The bronchoconstrictor effect of inhaled prostaglandin D2 in normal and asthmatic men. N Engl J Med. 1984 Jul 26;311(4):209–213. doi: 10.1056/NEJM198407263110401. [DOI] [PubMed] [Google Scholar]
  17. Hardy C., Robinson C., Lewis R. A., Tattersfield A. E., Holgate S. T. Airway and cardiovascular responses to inhaled prostacyclin in normal and asthmatic subjects. Am Rev Respir Dis. 1985 Jan;131(1):18–21. doi: 10.1164/arrd.1985.131.1.18. [DOI] [PubMed] [Google Scholar]
  18. Harvey J., Holgate S. T., Peters B. J., Robinson C., Walker J. R. Oxidative transformations of arachidonic acid in human dispersed lung cells: disparity between the utilization of endogenous and exogenous substrate. Br J Pharmacol. 1985 Oct;86(2):417–426. doi: 10.1111/j.1476-5381.1985.tb08911.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Howarth P. H., Pao G. J., Church M. K., Holgate S. T. Exercise and isocapnic hyperventilation-induced bronchoconstriction in asthma: relevance of circulating basophils to measurements of plasma histamine. J Allergy Clin Immunol. 1984 Mar;73(3):391–399. doi: 10.1016/0091-6749(84)90414-7. [DOI] [PubMed] [Google Scholar]
  20. Johnson H. G., McNee M. L., Bach M. K., Smith H. W. The activity of a new, novel inhibitor of leukotriene synthesis in rhesus monkey Ascaris reactors. Int Arch Allergy Appl Immunol. 1983;70(2):169–173. doi: 10.1159/000233317. [DOI] [PubMed] [Google Scholar]
  21. Lewis R. Nebulisers for lung aerosol therapy. Lancet. 1983 Oct 8;2(8354):849–849. doi: 10.1016/s0140-6736(83)90762-6. [DOI] [PubMed] [Google Scholar]
  22. Lim S. P., Muir T. C. Mechanisms underlying the electrical and mechanical responses of the guinea-pig internal anal sphincter to field stimulation and to drugs. Br J Pharmacol. 1985 Oct;86(2):427–437. doi: 10.1111/j.1476-5381.1985.tb08912.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. MacGlashan D. W., Jr, Schleimer R. P., Peters S. P., Schulman E. S., Adams G. K., 3rd, Newball H. H., Lichtenstein L. M. Generation of leukotrienes by purified human lung mast cells. J Clin Invest. 1982 Oct;70(4):747–751. doi: 10.1172/JCI110670. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Piper P. J. Pharmacology of leukotrienes. Br Med Bull. 1983 Jul;39(3):255–259. doi: 10.1093/oxfordjournals.bmb.a071829. [DOI] [PubMed] [Google Scholar]
  25. Ritchie D. M., Sierchio J. N., Capetola R. J., Rosenthale M. E. SRS-A mediated bronchospasm by pharmacologic modification of lung anaphylaxis in vivo. Agents Actions. 1981 Jul;11(4):396–401. doi: 10.1007/BF01982477. [DOI] [PubMed] [Google Scholar]
  26. Robinson C., Holgate S. T. Ionophore-dependent generation of eicosanoids in human dispersed lung cells. Modulation by 6,9-deepoxy-6,9-(phenylimino)-delta 6,8-prostaglandin I1 (U-60,257). Biochem Pharmacol. 1986 Jun 1;35(11):1903–1908. doi: 10.1016/0006-2952(86)90310-2. [DOI] [PubMed] [Google Scholar]
  27. Ryan G., Latimer K. M., Dolovich J., Hargreave F. E. Bronchial responsiveness to histamine: relationship to diurnal variation of peak flow rate, improvement after bronchodilator, and airway calibre. Thorax. 1982 Jun;37(6):423–429. doi: 10.1136/thx.37.6.423. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Schleimer R. P., MacGlashan D. W., Jr, Peters S. P., Naclerio R., Proud D., Adkinson N. F., Jr, Lichtenstein L. M. Inflammatory mediators and mechanisms of release from purified human basophils and mast cells. J Allergy Clin Immunol. 1984 Oct;74(4 Pt 1):473–481. doi: 10.1016/0091-6749(84)90381-6. [DOI] [PubMed] [Google Scholar]
  29. Smith L. J., Greenberger P. A., Patterson R., Krell R. D., Bernstein P. R. The effect of inhaled leukotriene D4 in humans. Am Rev Respir Dis. 1985 Mar;131(3):368–372. doi: 10.1164/arrd.1985.131.3.368. [DOI] [PubMed] [Google Scholar]
  30. Smith R. J., Sun F. F., Bowman B. J., Iden S. S., Smith H. W., McGuire J. C. Effect of 6,9-deepoxy-6,9-(phenylimino)-delta 6,8-prostaglandin 1(1) (U-60,257), an inhibitor of leukotriene synthesis, on human neutrophil function. Biochem Biophys Res Commun. 1982 Dec 15;109(3):943–949. doi: 10.1016/0006-291x(82)92031-9. [DOI] [PubMed] [Google Scholar]

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