CRTX Critical Therapeutics S-1
Message 19934524
Some background
Leukotriene modifiers
Cysteinyl leukotrienes (cys LT), generated from the enzyme 5-lipoxygenase (5-LO), are potent bronchoconstrictors as well as inducers of plasma exudation and promoters of eosinophilic inflammation. 5-LO inhibitors (zileuton) and cys-LT receptor antagonists (pranlukast, zafirlukast, montelukast) have been developed for the treatment of asthma to obtain successful results (7). However, zileuton has some limitations for clinical use due to its short plasma half life, requiring four times daily medication, and its frequent side effects on liver functions. Several new 5-LO inhibitors with longer plasma half life were then developed, only to obtain clinically unsuccessful results, mainly due to their side effects on liver function.
Contrastingly, thus far cys-LT receptor antagonists (LTRAs) have no serious class-specific side effects. A major advantage of these agents is that they are orally active, and they are now positioned as the alternative treatment to ICS in GINA 2002 (1). LTRAs are effective in 60-70% of patients with mild-to-moderate asthma, according to the results of clinical trials performed in Japan, to produce increased peak expiratory flow (Fig. 1). It seems that asthmatic subjects can be divided into responders and nonresponders to antileukotrienes, which may be partly explained by genetic polymorphisms in the 5-LO pathways (8), or cys-LT receptors. LTRAs are also possible to use as add-on therapy to ICS. For example, it was recently shown by 12-week double-blinded trials that a combination of montelukast (10 mg) and budesonide 800 mg was at least as effective as doubling the budesonide dose to 1600 mg with a lower incidence of respiratory adverse events than high-dose budesonide (the COMPACT study) (9). It should be added that clinical trials of new LTRAs are currently under way in Japan, based on the accumulated efficacy of these drugs in asthma.
prous.com |
