Comparison of three inhaled non-steroidal anti-inflammatory drugs on the airway response to sodium metabisulphite and adenosine 5'-monophosphate challenge in asthma.
BACKGROUND
Non-steroidal anti-inflammatory drugs (NSAIDs) are used to assess the role of prostaglandins in asthma but their effects on bronchoconstrictor challenges have been inconsistent. The effects of three nebulised nonsteroidal anti-inflammatory drugs on the airway response to inhaled sodium metabisulphite (MBS) and adenosine 5'-monophosphate (AMP) were compared in the same asthmatic subjects to see whether contractile prostaglandins were involved in MBS or AMP induced bronchoconstriction. A possible protective effect of the osmolarity or pH of the inhaled solutions was also assessed.


METHODS
Two double blind placebo controlled studies were carried out. In study 1, 15 non-aspirin sensitive patients with mild asthma attended on four occasions and inhaled 5 ml of lysine aspirin (L-aspirin) 900 mg, indomethacin 50 mg, sodium salicylate 800 mg, or saline 20 minutes before an inhaled MBS challenge. On four further occasions 14 of the patients inhaled the same solutions followed by an inhaled AMP challenge. In study 2, 10 of the patients attended on four additional occasions and inhaled 5 ml of 0.9%, 3%, 10%, or 9.5% saline with indomethacin 50 mg 20 minutes before an inhaled MBS challenge.


RESULTS
In study 1 inhaled lysine aspirin had a similar effect on MBS and AMP induced bronchoconstriction, increasing the provocative dose causing a 20% fall in FEV1 (PD20) by 1.29 (95% CI 0.54 to 2.03) and 1.23 (95% CI 0.53 to 1.93) doubling doses, respectively. Indomethacin increased the MBS PD20 and AMP PD20 by 0.64 (95% CI -0.1 to 1.38) and 0.99 (95% CI 0.29 to 1.69) doubling doses, respectively. Sodium salicylate had no significant effect on either challenge. The two solutions causing most inhibition were the most acidic and the most alkaline. In study 2 inhaled 9.5% saline with indomethacin (osmolarity 3005 mOsm/kg) increased the MBS PD20 by 1.1 doubling doses (95% CI 0.2 to 2.0) compared with only 0.09 (95% CI -0.83 to 1.0) and 0.04 (95% CI -0.88 to 0.95) doubling doses with 3% saline (918 mOsm/kg) and 10% saline (2994 mOsm/ kg), respectively.


CONCLUSIONS
Inhaled L-aspirin and indomethacin have broadly similar protective effects against MBS and AMP induced bronchoconstriction in the doses given, although the effect of indomethacin on MBS was not quite statistically significant. The osmolarity and pH of the solutions did not appear to be important determinants of the response. The effect of L-aspirin and indomethacin is likely to be the result of cyclooxygenase inhibition reducing the production of contractile prostaglandins during MBS and AMP challenge.
Wang
M
M
Respiratory Medicine Unit, City Hospital, Nottingham, UK.
Wisniewski
A
A
Pavord
I
I
Knox
A
A
Tattersfield
A
A
D000249:Adenosine Monophosphate; D000280:Administration, Inhalation; D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage* / Q000494:pharmacology; D001241:Aspirin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D001249:Asthma / Q000188:drug therapy* / Q000503:physiopathology; D016535:Bronchial Hyperreactivity / Q000517:prevention & control*; D001985:Bronchial Provocation Tests; D016085:Bronchoconstrictor Agents; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007213:Indomethacin / Q000008:administration & dosage / Q000494:pharmacology; D008168:Lung / Q000503:physiopathology*; D008239:Lysine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009994:Osmolar Concentration; D012980:Sodium Salicylate / Q000008:administration & dosage / Q000494:pharmacology; D013447:Sulfites
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016085:Bronchoconstrictor Agents; D013447:Sulfites; D000249:Adenosine Monophosphate; C005200:sodium metabisulfite; D008239:Lysine; D001241:Aspirin; D012980:Sodium Salicylate; C010395:acetylsalicylic acid lysinate; D007213:Indomethacin