piriprost and Asthma

Topics: Acetophenones; Asthma; Chromones; Epoprostenol; Humans; Hydroxyquinolines; Keto Acids; Leukotriene B4; Phenylbutyrates; Quinolines; SRS-A; Sulfones; Tetrazoles

Human dispersed lung cells containing 5-10% mast cells synthesised and released large quantities of prostaglandin D2 (PGD2) and thromboxane B2 (TXB2), with either IgE-dependent activation or ionophore A23187 challenge. The generation of these prostanoids and the release of histamine was related to the strength of activation stimulus. After activation the release of histamine and PGD2 proceeded in parallel, and the significant correlation between the release of these mediators suggests a common mast cell origin. This hypothesis is supported by cell enrichment experiments using Percoll density gradients. Prostaglandin D2 and histamine release was always associated with those fractions containing mast cells, whereas the generation of TXB2 was mainly associated with cells of the monocyte-macrophage series. The putative 5-lipoxygenase inhibitor 6,9-deepoxy-6, 9-(phenylimino)- 6,8-prostaglandin I1 (U-60,257, Piriprost) had complex inhibitory and potentiating effects on immunoreactive leukotriene C4 generation from ionophore activated human lung cells. The drug also had a surprising potentiating action on PGD2 release, while simultaneously inhibiting the generation of TXB2. The release of prostanoids from human lung cells is discussed in relation to the putative role of prostaglandins in asthma, with particular emphasis on the pharmacological actions of PGD2 on human airway function in vivo.

Topics: Airway Resistance; Asthma; Bronchi; Eicosanoic Acids; Epoprostenol; Humans; Lung; Prostaglandins

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.

Topics: Administration, Inhalation; Adult; Airway Resistance; Asthma; Asthma, Exercise-Induced; Clinical Trials as Topic; Double-Blind Method; Epoprostenol; Female; Humans; Male; Peak Expiratory Flow Rate

Topics: Aspirin; Asthma; Epoprostenol; Forced Expiratory Volume; Humans; SRS-A

Topics: Animals; Asthma; Disease Models, Animal; Dogs; Epoprostenol; Guinea Pigs; Haplorhini; Humans; Neutrophils; SRS-A

Piriprost (U-60,257), a selective inhibitor of the 5-lipoxygenase, inhibited bronchoconstriction in a modification of the Konzett-Rossler procedure in which bronchoconstriction in sensitized guinea pigs may reflect leukotriene production. The duration of action of this compound and also the possible development of tachyphylaxis to its action upon repeated dosing were studied using a newly developed procedure for dosing conscious animals via the aerosol route. Duration of action with the lowest concentration which afforded maximum protection (180 s exposure to a 0.01% solution) was approximately 1.5 h. No decrease in drug potency was observed after 7 daily drug treatments.

Topics: Administration, Oral; Allergens; Animals; Asthma; Bronchial Spasm; Bronchodilator Agents; Disease Models, Animal; Drug Administration Schedule; Epoprostenol; Guinea Pigs; Lipoxygenase Inhibitors; SRS-A; Time Factors

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Asthma; Epoprostenol; Humans; Leukotriene B4; Leukotriene E4; Lipoxygenase Inhibitors; SRS-A