Current treatment of asthma--focus on leukotrienes.

Since their identification in 1979, the cysteinyl leukotrienes (cysLTs) have been shown to be prominent in many inflammatory conditions, including asthma, allergic rhinitis, rheumatoid arthritis, psoriasis, cystic fibrosis and inflammatory bowel disease. They are potent pro-inflammatory agents, as well as causing bronchoconstriction, and undoubtedly have a role in asthma. The cysLTs are products of arachidonic acid metabolism and have been shown to have effects via a cysteinyl leukotriene receptor (CysLTR1) on vascular permeability, mucus production, chemotaxis and bronchial smooth muscle. Their detection in certain body fluids in allergic, aspirin-sensitive and exercise-induced asthma is well documented and potential roles in pathogenesis, proposed. The development of agents affecting production or action offers an exciting new approach to the treatment of asthma. Two approaches to antileukotriene therapy have been developed: blocking their production by inhibiting the action of 5-lipoxygenase enzyme or blocking the CysLTR1. Both approaches have been tried in studies in asthma and overall the results are encouraging, with a decrease in both daytime and nocturnal symptoms, a decrease in additional beta 2 agonist usage and improvement in lung function. The changes, however, are small in some studies. This may be a reflection of disease severity in the study subjects, but of note is a heterogeneity of response to these treatments that may be genetically determined. Antileukotriene therapy has been shown to have an effect in specific types of asthma where the role of cysLTs seems well established--aspirin-sensitive/intolerant asthma and exercise-induced asthma. Longer term studies are needed in other areas such as severe asthma and chronic persistent asthma in both children and adults to provide evidence for the appropriate placement of antileukotriene treatment in current asthma guidelines, in comparison with other established treatments.

Selective airway responsiveness in asthma.

Hyperresponsiveness of airway smooth muscle accounts for the susceptibility of asthmatic subjects to diverse bronchoconstrictor agents. It is widely presumed that hyperresponsiveness is not spasmogen selective. Hence, inhalation of methacholine is used routinely for clinical assessment of asthma and for evaluation of anti-asthma drugs. Comparative studies employing multiple spasmogens have revealed hyperresponsiveness to be markedly spasmogen selective. Because of this pronounced heterogeneity of hyperresponsiveness, sensitivity to methacholine cannot provide a reliable index of responsiveness. Development of exceptional hyperresponsiveness to bradykinin and to peptidoleukotrienes during allergic and other reactions could warrant the development of specific antagonists for asthma therapy. These issues are discussed here by Brian O'Connor, Simon Crowther, John Costello and John Morley.

Sympathomimetic enantiomers and asthma.

Airways of asthma patients can become hyperresponsive to airway spasmogens following regular use of isoprenaline or beta 2-selective sympathomimetics. Hyper-reactivity that results from acute exposure of animals to these drugs is pre-empted by vagal section (a procedure which does not influence spasmolytic efficacy of sympathomimetics), is not diminished by antagonism of beta 2-adrenoceptors and is not associated with loss of responsivity of beta 2-adrenoceptors in the airways. Since activation, modulation, or blockade of beta 2-adrenoceptors does not determine this form of hyperreactivity, the possibility that distomers may induce hyperreactivity must be considered. Ocular and vascular responses to distomers of sympathomimetics have long been recognised and, more recently, comparable observations have been made for the airways. Thus, reactivity of guinea-pig airways to spasmogens was increased following exposure to S-isoprenaline, S-salbutamol, or S-terbutaline and exposure to S-isoprenaline or S-salbutamol can intensify symptoms in asthmatics. Regular exposure to the racemate, especially during or following an allergic reaction, predisposes to expression of hyper-reactivity, which is nullified, acutely, by the eutomer. These observations imply that biological effects of sympathomimetic distomers may contribute to morbidity and mortality in asthma patients.