Effects of combination therapy with montelukast and carbocysteine in allergen-induced airway hyperresponsiveness and airway inflammation.
OBJECTIVE
Montelukast and S-carbocysteine have been used in asthmatic patients as an anti-inflammatory or mucolytic agent respectively. S-carbocysteine also exhibits anti-inflammatory properties.


METHODS
Ovalbumin (OVA) sensitized BALB/c mice were challenged with OVA for 3 days followed by single OVA re-challenge (secondary challenge) 2 weeks later. Forty-eight hours after secondary challenge, mice were assessed for airway hyperresponsiveness (AHR) and cell composition in bronchoalveolar lavage (BAL) fluid. Suboptimal doses of 10 mg.kg(-1) of S-carbocysteine by intraperitoneal injection (ip), 20 mg.kg(-1) of montelukast by gavage, the combination of S-carbocysteine and montelukast or 3 mg.kg(-1) of dexamethasone as a control were administered from 1 day before the secondary challenge to the last experimental day. Isolated lung cells were cultured with OVA and montelukast to determine the effects on cytokine production.


RESULTS
Treatment with S-carbocysteine or montelukast reduced both AHR and the numbers of eosinophils in BAL fluid. Neutralizing IFN-gamma abolished the effects of S-carbocysteine on these airway responses. Combination of the two drugs showed further decreases in both AHR and eosinophils in the BAL fluid. Goblet cell metaplasia and Th2-type cytokines, interleukin (IL)-4, IL-5 and IL-13, in BAL fluid were decreased with montelukast treatment. Conversely, S-carbocysteine increased Th1-type cytokines, IFN-gamma and IL-12 in BAL fluid.


CONCLUSIONS
The combination of two agents, montelukast and S-carbocysteine, demonstrated additive effects on AHR and airway inflammation in a secondary allergen model most likely through independent mechanisms of action.
Takeda
K
K
Department of Pediatrics, National Jewish Health, Denver, CO, USA.
Shiraishi
Y
Y
Matsubara
S
S
Miyahara
N
N
Matsuda
H
H
Okamoto
M
M
Joetham
A
A
Gelfand
E W
EW
D000085:Acetates / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology; D016535:Bronchial Hyperreactivity / Q000188:drug therapy* / Q000276:immunology; D001992:Bronchoalveolar Lavage Fluid; D002233:Carbocysteine / Q000008:administration & dosage / Q000494:pharmacology*; D003521:Cyclopropanes; D003907:Dexamethasone / Q000494:pharmacology; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004804:Eosinophils / Q000378:metabolism; D005260:Female; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology; D007274:Injections, Intraperitoneal; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000276:immunology; D011804:Quinolines / Q000008:administration & dosage / Q000494:pharmacology*; D013440:Sulfides
D000085:Acetates; D018927:Anti-Asthmatic Agents; D000893:Anti-Inflammatory Agents; D003521:Cyclopropanes; D011804:Quinolines; D013440:Sulfides; D002233:Carbocysteine; D003907:Dexamethasone; D010047:Ovalbumin; C093875:montelukast