Abstract
1. The effect of a novel series of orally-active acetohydroxamic acid inhibitors of arachidonate 5-lipoxygenase on 'leukotriene-dependent' anaphylactic bronchoconstriction has been investigated in anaesthetized, pump-ventilated guinea-pigs actively sensitized to ovalbumin (OA). In a complementary series of experiments, the pharmacokinetics of these compounds in the plasma compartment following oral administration to guinea-pigs has also been investigated. 2. In animals pretreated with mepyramine (2 mg kg-1, i.v.) and indomethacin (10 mg kg-1, i.v.) and challenged with antigen aerosol (OA 10 mg ml-1; 5 s) compounds BW A4C, BW A137C and BW A797C (10-200 mg kg-1, p.o., 1 h pre-challenge) markedly reduced that component of anaphylactic bronchoconstriction shown to be 'leukotriene-dependent'. 3. The maximum degree of inhibition (up to 75%) of 'leukotriene-dependent' anaphylactic bronchoconstriction by these three compounds was equivalent to that seen with the leukotriene antagonist FPL 55712 (10 mg kg-1, i.v.). 4. The peak levels of unchanged acetohydroxamic acids in the plasma compartment occurred 0.5 h after their oral administration and were as follows: BW A4C: 11.3 +/- 3.9; BW A137C: 7.6 +/- 2.4; BW A797C: 3.9 +/- 1.3 micrograms ml-1 plasma. 5. The inhibition by BW A4C and BW A137C (50 mg kg-1, p.o.) of 'leukotriene-dependent' anaphylactic bronchospasm persisted for up to 3 and 4 h respectively but did not extend to 6 h. The decline in inhibitory activity paralleled the fall in the concentration of unchanged drug in the plasma compartment over this time period.(ABSTRACT TRUNCATED AT 250 WORDS)
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- Daffonchio L., Lees I. W., Payne A. N., Whittle B. J. Pharmacological modulation of bronchial anaphylaxis induced by aerosol challenge in anaesthetized guinea-pigs. Br J Pharmacol. 1987 Jul;91(3):701–708. doi: 10.1111/j.1476-5381.1987.tb11265.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Darius H., Lefer D. J., Smith J. B., Lefer A. M. Role of platelet-activating factor-acether in mediating guinea pig anaphylaxis. Science. 1986 Apr 4;232(4746):58–60. doi: 10.1126/science.3082008. [DOI] [PubMed] [Google Scholar]
- Fitzgerald M. F., Moncada S., Parente L. The anaphylactic release of platelet-activating factor from perfused guinea-pig lungs. Br J Pharmacol. 1986 May;88(1):149–153. doi: 10.1111/j.1476-5381.1986.tb09481.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Higgs G. A., Follenfant R. L., Garland L. G. Selective inhibition of arachidonate 5-lipoxygenase by novel acetohydroxamic acids: effects on acute inflammatory responses. Br J Pharmacol. 1988 Jun;94(2):547–551. doi: 10.1111/j.1476-5381.1988.tb11559.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Higgs G. A., Moncada S. Leukotrienes in disease. Implications for drug development. Drugs. 1985 Jul;30(1):1–5. doi: 10.2165/00003495-198530010-00001. [DOI] [PubMed] [Google Scholar]
- Jackson W. P., Islip P. J., Kneen G., Pugh A., Wates P. J. Acetohydroxamic acids as potent, selective, orally active 5-lipoxygenase inhibitors. J Med Chem. 1988 Mar;31(3):499–500. doi: 10.1021/jm00398a001. [DOI] [PubMed] [Google Scholar]
- Lewis R. A. A presumptive role for leukotrienes in obstructive airways diseases. Chest. 1985 Aug;88(2 Suppl):98S–102S. doi: 10.1378/chest.88.2_supplement.98s. [DOI] [PubMed] [Google Scholar]
- O'Byrne P. M., Leikauf G. D., Aizawa H., Bethel R. A., Ueki I. F., Holtzman M. J., Nadel J. A. Leukotriene B4 induces airway hyperresponsiveness in dogs. J Appl Physiol (1985) 1985 Dec;59(6):1941–1946. doi: 10.1152/jappl.1985.59.6.1941. [DOI] [PubMed] [Google Scholar]
- Payne A. N., de Nucci G. Anaphylaxis in guinea pigs induced by ovalbumin aerosol in vivo and in vitro methods. J Pharmacol Methods. 1987 Mar;17(1):83–90. doi: 10.1016/0160-5402(87)90040-4. [DOI] [PubMed] [Google Scholar]
- Tateson J. E., Randall R. W., Reynolds C. H., Jackson W. P., Bhattacherjee P., Salmon J. A., Garland L. G. Selective inhibition of arachidonate 5-lipoxygenase by novel acetohydroxamic acids: biochemical assessment in vitro and ex vivo. Br J Pharmacol. 1988 Jun;94(2):528–539. doi: 10.1111/j.1476-5381.1988.tb11557.x. [DOI] [PMC free article] [PubMed] [Google Scholar]