title: Gas exchange response to a PAF receptor antagonist, SR 27417A, in acute asthma: a pilot study.
abstract: The pathogenic role of platelet-activating factor (PAF) in asthma has been questioned due to the limited or negative efficacy of PAF antagonists; however, in acute asthma (AA), where the endogenous release of PAF may be enhanced, the effects of PAF antagonist receptors have not been investigated. It was postulated that inhaled PAF provokes gas exchange defects in mild asthma likely to be related to airway vascular leakage. The response to a potent, selective PAF receptor antagonist, SR 27471A, on pulmonary gas exchange was studied, more specifically ventilation-perfusion (VA'/Q') distributions, in patients with AA within 48 h of hospitalization. A randomized, double-blind, placebo-controlled, parallel group (n=6, each) design was used. After baseline measurements, either placebo or SR 27417A (20 mg, orally) was administered and measurements were repeated 3 h later. Conventional anti-asthma medication was not interrupted. Despite a near-complete inhibition of the in vitro, platelet aggregation tests by 40 nM PAF (mean+/-SEM from 72+/-9 to 6+/-2%) and 80 nM PAF (from 81+/-7 to 6+/-3% both p<0.01) by SR 27471A indicating a good bioactivity of the compound, no significant changes in baseline forced expiratory volume in one second, (40+/-6%), respiratory system resistance (6.2+/-0.7 cmH2O x L(-1) x s), alveolar-arterial pressure difference for oxygen (5.2+/-0.4 kPa), arterial oxygen tension (9.0+/-0.5 kPa) or VA'/Q' distributions, as expressed by the dispersion of pulmonary blood flow (LogSD Q, 1.07+/-0.09; normal values <0.60), were observed. It is concluded that SR 27417A has limited value when added to the conventional treatment of acute asthma. These findings minimize the potential pathogenic role of endogenous platelet-activating factor as a relevant mediator of airway inflammation during acute asthma.
authors.affiliation: Dept de Medicina, Institut d'Investigacions Biomédiques August Pi i Sunyer, Hospital Clinic, Universitat de Barcelona, Spain.
authors.forename: F P
authors.initials: FP
authors.lastname: Gómez
authors.forename: R M
authors.initials: RM
authors.lastname: Marrades
authors.forename: R
authors.initials: R
authors.lastname: Iglesia
authors.forename: J
authors.initials: J
authors.lastname: Roca
authors.forename: J A
authors.initials: JA
authors.lastname: Barberà
authors.forename: K F
authors.initials: KF
authors.lastname: Chung
authors.forename: R M
authors.initials: RM
authors.lastname: Rodriguez-Roisin
mesh_terms: D000208:Acute Disease; D000328:Adult; D000403:Airway Resistance; D001249:Asthma / Q000097:blood / Q000188:drug therapy / Q000503:physiopathology*; D001783:Blood Flow Velocity; D001784:Blood Gas Analysis; D004311:Double-Blind Method; D005260:Female; D005541:Forced Expiratory Volume; D006801:Humans; D008297:Male; D010865:Pilot Projects; D010972:Platelet Activating Factor / Q000378:metabolism*; D010974:Platelet Aggregation / Q000187:drug effects; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D011652:Pulmonary Circulation; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D013844:Thiazoles / Q000494:pharmacology*; D014692:Ventilation-Perfusion Ratio / Q000187:drug effects*
chemical_list: D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D013844:Thiazoles; C039351:platelet activating factor receptor; C071317:Foropafant