Effect of selective phosphodiesterase 3 inhibition on the early and late asthmatic responses to inhaled allergen.
OBJECTIVE
Phosphodiesterase isoenzymes may play an important role in the regulation of airway calibre and bronchial smooth muscle function. Immunomodulatory actions may also be important in allergic airway inflammation. We have examined the effect of a phosphodiesterase (PDE) 3 inhibitor (MKS492) on the early and late responses to inhaled allergen in 18 atopic asthmatic subjects.


METHODS
On three separate occasions, 2-4 weeks apart, patients were administered either placebo, 20 mg or 40 mg of oral MKS492 as a single dose. After 90 min they inhaled a dose of allergen (grass pollen or D. pteronyssinus) that had been demonstrated to produce a 20% decrease in FEV1. Measurements of FEV1 were repeated at 30 min intervals over the subsequent 7.5 h.


RESULTS
After placebo, allergen inhalation produced bronchoconstriction with a maximum mean minimum FEV1 of 75.9% (12.7) (mean [s.d.]) of post-saline baseline values and a late response developed in 13 subjects (decrease in FEV1 > or = 15%). MKS492 (40 mg) increased the mean minimum % post-saline FEV1 at 30 min from 81.6% (14.0) for placebo to 93.1% (13.8), difference 11.5, 95% CI (2.6, 20.4). The mean minimum % post-saline FEV1 in the early response (0-2 h) was also increased by the 40 mg dose to 86.5% (11.8) vs 77.9% (13.8) for placebo, but not by the 20 mg dose. Significant bronchodilatation was noted 90 min after dosing (pre-allergen) in the MKS492 40 mg group. Late phase responses as assessed by 4 h % post-saline FEV1 was significantly improved by MKS 492 40 mg to 90.0% (6.3) vs 83.0% (12.4) for placebo-difference 7.0, 95% CI (0.1, 13.9), but again not by the 20 mg dose. Analysis of the area under the FEV1 response-time course curves showed non-significant reduction in the late response after the 40 mg dose (placebo 159.0, 134.8) vs 128.1, [81.5] for 40 mg).


CONCLUSIONS
A novel PDE 3 inhibitor significantly decreases the early bronchoconstrictor response in asthma and attenuates the late response; effects that may be more marked at higher doses.
Bardin
P G
PG
Immunopharmacology Group, University Medicine, Southampton General Hospital, UK.
Dorward
M A
MA
Lampe
F C
FC
Franke
B
B
Holgate
S T
ST
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000293:Adolescent; D000328:Adult; D000485:Allergens / Q000008:administration & dosage*; D001249:Asthma / Q000188:drug therapy*; D001993:Bronchodilator Agents / Q000627:therapeutic use*; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D005260:Female; D005541:Forced Expiratory Volume; D006801:Humans; D019570:Inhalation Exposure; D008297:Male; D008875:Middle Aged; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use*; D010919:Placebos; D011688:Purinones / Q000627:therapeutic use*
D000485:Allergens; D001993:Bronchodilator Agents; D010726:Phosphodiesterase Inhibitors; D010919:Placebos; D011688:Purinones; C073029:SDZ MKS 492; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3