Inhibition of allergen-induced bronchoconstriction in hyperreactive rats as a model for testing 5-lipoxygenase inhibitors and leukotriene D4 receptor antagonists

Abstract

Sensitized inbred hyperreactive rats showed reproducible episodes of dyspnea when exposed to aerosols of antigen. Following inhibition of the serotonin component of the response by pretreatment with methysergide, the model was shown to be useful for studying the oral activity of compounds that affect the production or action of leukotrienes. This was shown through inhibition of the duration of dyspnea by two selective 5-lipoxygenase inhibitors, L-651,392 and L-615,919, and two selective leukotriene D4 receptor antagonists, L-647,438 and L-649,923. Selectivity of the compounds could be demonstrated by reducing inhibition of the antigen response in the absence of methysergide and failure to inhibit serotonin-induced dyspnea. It is concluded that the model provides a reproducible method for screening large numbers of leukotriene inhibitors and antagonists and gives a measurement of their duration of biological activity.

Effects of a 5-lipoxygenase inhibitior (L-651,392) on primary and late pulmonary responses to ascaris antigen in the squirrel monkey

“…Unpublished results indicate that the compound has no effect on ,,mediator release" in general as exemplified by failure to inhibit histamine release from antigen-challenged smooth muscle preparations and enzyme release from challenged polymorphonuclear leukocytes. Oral activity has been demonstrated in hyperreactive rats where inhibition of antigen-induced dyspnea was observed [5]. The immediate response observed following administration of an aerosol of Ascaris to conscious squirrel monkeys in similar to that observed with an aerosol of leukotriene D4 [6] and is thought in primates to be related to the release of mast cell derived mediators such as histamine and lenkotrienes [7, 81. Evidence in support of a role of leukotrienes in this response has been obtained in the present work using a specific 5-lipoxygenase inhibitor as well with studies with a leukotriene D4 receptor antagonist [9].…”

Substituted (Pyridylmethoxy)naphthalenes as Potent and Orally Active 5-Lipoxygenase Inhibitors: Synthesis, Biological Profile, and Pharmacokinetics of L-739,010

“…Compound 3g was evaluated against antigen-induced dyspnea in hyperreactive rats. 14 When 3g was administered orally at 0.5 mg/kg 4 h before ovalbumin challenge, it produced a 60% (p < 0.01) inhibition of dyspnea. This result is comparable to the activity observed with MK-0591 (56% inhibition) under the same conditions.…”

“…Antigen-Induced Dyspnea in Hyperreactive Rat. The inhibition of ovalbumin-induced dyspnea in hyperreactive rats was assayed as previously described by Piechuta et al …”

“…Respiratory Functional Models. Compound 3g was evaluated against antigen-induced dyspnea in hyperreactive rats . When 3g was administered orally at 0.5 mg/kg 4 h before ovalbumin challenge, it produced a 60% ( p < 0.01) inhibition of dyspnea.…”

Effect of the 5‐lipoxygenase inhibitor, fenleuton, on antigen‐induced neutrophil accumulation and lung function changes in horses with chronic obstructive pulmonary disease

“…This has led to the development of novel therapeutic agents such as the 5‐lipoxygenase inhibitors, which reduce the formation of both LTB 4 and the sulphidopeptides LTC 4 , LTD 4 and LTE 4 . These compounds have proved effective in animal models of human allergic airway disease, inhibiting antigen‐induced bronchoconstriction in a range of experimental animals (McFarlane et al ., 1987; Piechuta et al ., 1987; Johnson & Stout, 1988; Payne et al ., 1988; Abraham et al ., 1992). Moreover, those drugs such as Zileuton, MK‐0591 and Bay X1005, which have reached the stage of clinical trial evaluation in patients with moderately severe asthma, improve airflow and reduce the need for inhaled steroids (Chapman et al ., 1994; Lichey et al ., 1995; Virchow et al ., 1995; Israel et al ., 1996).…”