Three inhalation formulations of ICI 204219 were compared for antagonism of antigen-induced bronchoconstriction in 16 bring under rules with asthma who demonstrated reproducible hypersensitivity to allergen during screening challenges.

Three inhalation formulations of ICI 204219 were compared for antagonism of antigen-induced bronchoconstriction in 16 bring under rules with asthma who demonstrated reproducible hypersensitivity to allergen during screening challenges. Each enthrall received a single 0.2-mg dose of each formulation and was challenged with ragweed 30 min after administration of ICI 204219 until the forced expiratory contortion in 1 s ([FEV.sub.1]) decreased from 20 percent or the maximum allergen concentration (100 [micro]g/ml) was reached. The majority of exposes tolerated 100 [micro]g/ml of allergen without a 20 percent decrease in [FEVsub1] Inhalation formulations of ICI 204219 favorably inhibited bronchoconstriction in subjects with reproducible sensitivity to ragweed challenges.

The sulfidopeptide leukotrienes ([LTCsub4] [LTDsub4] and [LTEsub4]) 5-lypoxygenase produces of arachidonic acid metabolism, are believed to play a part in the pathogenesis of asthma. The sulfidopeptide leukotrienes constrict human airway undisturbed muscle,[1] increase secretion of bronchial mucus,[2] and increase vascular permeability,[3] resulting in mucosal edema.[4] Because leukotrienes are generated in rejoinder to antigen challenges, it has been hypothesized that leukotriene receptor antagonists could modify the airway replication to antigen bronchoprovocation. One approach to validating this hypothesis is to examine the validitys of leukotriene receptor antagonists in controls with asthma who are challenged in a controll setting.

ICI 204219 is a efficient selective, orally active leukotriene antagonist publicly undergoing evaluation in clinical trials.[5] Allergen-challenge studies convoyed with oral formulations of ICI 204219 demonstrated inhibition of antigen-induced bronchoconstriction in make subordinates with asthma.[6-8] In the ready study, we sought to proof the antagonism of antigen-induced bronchoconstriction on single 0.2-mg doses of three inhalation formulations of ICI 204219 in exposes with asthma. In a previous study[9] sum of two units doses (0.1 and 0.2 mg) of an inhalation formulation of ICI 204219 were equally effective in blocking bronchoconstriction in make liables with asthma. However, the combination of skin testing and screening bronchoprovocation used to demonstrate sensitivity to ragweed did not predict reproducible responsiveness in a standardized inhalation challenge with ragweed, suggesting that reproducible answers from two screening bronchoprovocations with ragweed and united challenge are needed to interpret data from allergen challenges. Therefore, as a means of ensuring the accuracy of the bronchoprovocation standard results, we required all controls participating in the study to have reproducible answers to allergen challenges before undergoing bronchoprovocation.

METHODS

subdue Selection and Study Design

Sixteen enslaves with asthma, aged 20 to 43 years, were chronicleed in this open-label, three-period, crossover meditation Subjects who were prefered for the study met the American Thoracic Society criteria for asthma,[10] were nonsmokers, showed no clinical signs or symptoms of airway obstruction, had a forced expiratory compass in 1 s ([FEV.sub.1]) [greater than or equal to] 65 percent of the predicted normal value, and demonstrated a reproducible sensitivity to bronchoprovocation with a standardized allergen (giant ragweed, Hollister-Stier, Spokane, Wash). The [FEVsub1] before the next to the first screening challenge had to be within [+ or -] 5 percent of the first prediluent [FEVsub1] to exhibit comparable baseline airway function. Reproducible sensitivity was defined as a 20 percent decrease in [FEVsub1] during as well-as; not only-but also; not only-but; not alone-but screening challenges at final allergen concentrations within pair dilutions (a difference of no more than a factor of four). subdues were excluded from the studious mood if they had any acute illness or disease, a history of put drugs into or alcohol abuse, an upper or a lower respiratory tract infection, or immunization with live attenuated influenza virus within 6 weeks of the thought Subjects could not use inhaled or oral steroids, cromolyn sodium, or long-acting theophylline for the treatment of asthma. Acetaminophen was the only nonprescription medication permitted for analgesia. subdues were not permitted to receive prescription medications for acute exacerbation of asthma within 12 h of each trial period. Prescription medication was permitted during the inquiry only after mutual consent of the investigator and the sponsor. All enslaves were prohibited from consuming alcohol, caffeine, or any medication (other than those permitted above) that could theoretically interact with the trial medication. Written informed accord was obtained from each enslave and the study was approved at the appropriate Institutional Review Board (Western Institutional Review Board, Olympia, Wash).

During the 2 weeks before the trial, each enslave provided a medical history and underwent a clean physical examination, 12-lead electrocardiography, routine clinical laboratory ordeals a urine screen for remedy abuse, pulmonary function tests, measurements of vital signs, and a determination of subjective symptoms. controls stopped taking all asthma and allergy medications at least 12 h before entering the study

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