Tolerability of leukotriene modifiers in asthma - A review of clinical experience

The so called leukotriene antagonists or, more accurately, the leukotriene modifiers are a rather heterogeneous set of drugs that work by several mech anisms. Such mechanisms include: (i) 5-lipoxygenase enzyme inhibition (e.g. zileuton); (ii) 5-lipoxygenase-activating-protein inhibition (e.g. quiflap on, BAYx 1005); (iii) LTD4-receptor antagonism (e.g. zafirlukast, monteluka st, MK-571,pranlukast). The first leukotriene modifiers tested (L-649,923 and tomelukast) had adver se,gastrointestinal effects. Since then, several leukotriene modifiers have been marketed, including zafirlukast, zileuton and montelukast. Zafirlukas t has been associated with 8 cases of Churg-Strauss syndrome, although thes e were probably not caused by zafirlukast. It is more likely that this synd rome is related to the underlying illness, which was masked by corticostero ids, and revealed after zafirlukast-mediated asthma treatment allowed stero id withdrawal and unmask-ing of underlying vasculitis. The main adverse eff ects of zileuton include liver function test abnormalities, while monteluka st, the most recently marketed, has so far shown minimal adverse effects. Zafirlukast causes a decrease in warfarin clearance and a clinically signif icant; increase in prothrombin time, probably by cytochrome P450 isoenzyme interactions. Moreover, terfenadine decreases zafirlukast maximum serum con centrations, Calcium antagonists, cyclosporin, cisapride and astemizole are metabolised via the cytochrome P450 system, and interactions with leukotri ene modifiers can be expected.