Peptide-leukotriene antagonists

The peptide leukotrienes 99,100, and 101 cause contraction of the bronchial smooth muscle and probably play an important role as mediators in allergic reactions (e.g. asthma) and inflammations. Antagonistic blockade of the leukotriene action of 99,100, and 101, by analogy with histamine Hj-reccptor antagonists, would therefore be an important principle in the treatment of allergic symptoms. A number of selective peptide leukotriene antagonists have in fact been synthesized by Smith Kline ... 

Inhalation of peptide leukotrienes has been shovm to induce a reproducible, robust, well-tolerated bronchoconstriction in humans. Because of this, most clinical studies of CysLTl antagonists have begun with an assessment of their in vivo potency through measurement of their ability to inhibit LT-induced bronchoconstriction. Because these studies can be done over a broad time range, they can also be used to determine human pharmacodynamic values. The most frequent measure was the shift in the LT-induced dose-response curve that is produced by a specified dose of a drug at a particular pretreatment time. Friedman (238) has reviewed the pulmonary-oriented clinical results obtained with most of the earlv peptide leukotriene antagonists and lipoxygenase inhibitors. 

Many research groups have prepared leukotriene analogs incorporating modifications to the peptide portion, as tools to better understand structure-activity relationships and to aid in the search for effective antagonists and inhibitors. 

The theory behind the inclusion of histamine Hi antagonists in the premedication is obvious but the mode of action of corticosteroids is not completely understood so some beheve its inclusion cannot be explained and justified. Corticosteroids ultimately inhibit kaUikrem, a peptide that lowers blood pressure and liberates bradykinin. Corticosteroids also act in the arachidonic acid cascade to inhibit the production of prostaglandins and leukotrienes, so there does seem to be some rationale for their use. There are some indications that premedication prevents the recurrence of many minor reactions. Some, or even many, of these reactions may not be immune mediated, proceeding instead via a nonspecific and low-level histamine release. In the case of severe inunediate reactions, IgE antibody-mediated explosive histamine release from mast cells may overwhelm the potential effectiveness of premedication. 

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