Effect of a novel potent platelet-activating factor antagonist, modipafant, in clinical asthma.
Platelet-activating factor (PAF), proposed as an important inflammatory mediator in asthma, reproduces several of the features of asthma, such as microvascular leakage, mucus secretion, bronchoconstriction, and possibly increased airway responsiveness. Modipafant (UK-80,067) is the (+)-enantiomer of UK-74,505, a potent and specific PAF antagonist. We have assessed the effect of modipafant over 28 d in adult subjects with moderately severe asthma in a placebo-controlled parallel group study. A total of 218 patients with asthma were enrolled into the single-blind run-in, of whom 120 (93 males and 27 females, mean age 41.0 yr) entered the double-blind treatment phase after demonstrating symptomatic asthma in the final week of the single-blind run-in phase. Patients could take up to 1600 micrograms inhaled corticosteroid and an inhaled beta 2 agonist as rescue medication. A total of 59 patients with asthma took modipafant (one 50 mg capsule twice daily), and 61 took matched placebo. There was no significant difference between placebo and modipafant in diurnal variation in PEF, morning and evening PEF, clinic FEV1, rescue bronchodilator usage, symptom score, or airway responsiveness. We previously showed that the racemate UK-74,505 had no effect on antigen challenge, and this study shows that the active (+)-enantiomer modipafant has no effect in chronic asthma. This suggests that PAF is not an important mediator in asthma.
Kuitert
L M
LM
Department of Thoracic Medicine, London Chest Hospital and National Heart and Lung Institute, United Kingdom.
Angus
R M
RM
Barnes
N C
NC
Barnes
P J
PJ
Bone
M F
MF
Chung
K F
KF
Fairfax
A J
AJ
Higenbotham
T W
TW
O'Connor
B J
BJ
Piotrowska
B
B
D000328:Adult; D000368:Aged; D001249:Asthma / Q000188:drug therapy* / Q000503:physiopathology; D004095:Dihydropyridines / Q000009:adverse effects / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D005541:Forced Expiratory Volume; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D010366:Peak Expiratory Flow Rate; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000502:physiology; D011788:Quality of Life; D016037:Single-Blind Method
D004095:Dihydropyridines; D007093:Imidazoles; D010972:Platelet Activating Factor; C073027:modipafant