Disease activated drugs: A new concept for the treatment of asthma

Disease activated drugs (DAD) are pro-drugs of one active principle or comb inations of two drugs. which have a proven efficacy for the treatment of th e target disease. In opposition to pro-drugs, DAD are activated in inflamed but not normal tissues. Due to the disease specific activation, the amount of locally released drug(s) should be related directly to the severity of the inflammation. To test this concept in asthma a PDE4 inhibitor, an isoqu inoline derivative, was chemically derivatized into prodrugs or combined wi th corticosteroids. These new compounds were more readily cleaved into acti ve PDE4 inhibitor, in bronchoalveolar lavage fluid (BALF) from Brown-Norway rats with lung inflammation than in BALF from rats without airway inflamma tion. The DAD concept (local selective release and improved therapeutic win dow) was validated in vivo using the inhibition of methacholine induced bro nchoconstriction in guinea pigs with or without ozone induced lung inflamma tion. An example of DAD hydrolysis (isoquinoline-dexamethasone) was also ex amined in BALF from asthmatics and healthy volunteers. (C) 2001 Elsevier Sc ience Ltd. All rights reserved.