Anti-leukotrienes: the promise for asthma?

Birkhauser Verlag, 1999. sFr 228 (hardback) (xii + 347 pages)ISBN 3 7643 5884 XAnti-leukotrienes belong to the first new class of anti-asthma drugs to be introduced for over 30 years and have therefore attracted enormous interest among the clinical community. Asthma is a global disease problem and has become the most common chronic disease in industrialized countries. Anti-leukotrienes are drugs that block the effects of cysteinyl leukotrienes, either by blocking their synthesis [e.g. 5′-lipoxygenase (5-LO) inhibitors] or their receptors (leukotriene receptor antagonists). One 5-LO inhibitor and three cysteinyl leukotriene receptor (CysLT1) antagonists are already on the market and several others are in clinical development. The development of anti-leukotrienes was a logical step in the search for a treatment of asthma because cysteinyl leukotrienes are produced by inflammatory cells (predominantly mast cells and eosinophils) in asthma, are potent bronchoconstrictors and induce plasma exudation and mucus secretion, and increase eosinophilic inflammation. Novel Inhibitors of Leukotrienes brings together some of the basic research that laid the foundation for the search and discovery of anti-leukotrienes along with preclinical studies using these drugs, and then discusses results from clinical trials of this new class of drug.Slow-reacting substance of anaphylaxis was shown to be a potent bronchoconstrictor substance 60 years ago, but it was not until 40 years later that its structure was elucidated as a mixture of cysteinyl leukotrienes (LTC4, LTD4 and LTE4) by Bengt Samuelsson and Bob Murphy, two of the co-editors of this book. This volume is one of a series of books on aspects of inflammation research with contributions from many leaders in this field of research, as well as contributions from pharmaceutical companies that have pioneered the discovery of anti-leukotrienes drugs. The book provides an extensive resource for researchers; there are excellent reviews of leukotriene receptors and the enzymes involved in leukotriene synthesis and metabolism. However, the CysLT1 receptor was cloned after the chapters were submitted and it is clear that this discovery will have important implications for the study of anti-leukotrienes in the future. Development of anti-leukotrienes has provided important insights into asthma mechanisms. We know that over 100 mediators are involved in the pathophysiology of asthma, so it seems unlikely that blocking a single mediator would have a useful clinical effect. Indeed, many mediator antagonists, such as antihistamines, thromboxane antagonists and bradykinin antagonists, have been found to have no clinical value, yet anti-leukotrienes have a useful clinical effect, at least in some patients. The role of leukotrienes in aspirin-sensitive asthma, nocturnal exacerbations of asthma and allergic asthma are discussed in good review chapters. The history of anti-leukotrienes is described; it is somewhat surprising to realise that the first CysLT1 antagonist FPL55712 was discovered as long ago as 1973. Now, a wide range of receptor antagonists and 5-LO inhibitor compounds has been discovered. Many of these drugs are discussed in some detail, including the only 5-LO inhibitor currently on the market, zileuton, and the anti-leukotrienes zafirlukast and pranlukast. Curiously, the most widely used anti-leukotriene in the world today, montelukast, is not discussed at all! LTB4 antagonists, which might be useful in neutrophil inflammatory diseases such as chronic obstructive pulmonary disease and inflammatory bowel disease are also discussed, although there are no drugs on the market yet.Although this book was probably up to date at the time it was written (the latest references are 1997), development of anti-leukotrienes is a very rapidly moving field. Results from the large number of clinical studies with these drugs are only just being published and it is still not clear how these drugs should be used clinically. These drugs are clearly less effective than inhaled corticosteroids as asthma controllers, but they are orally active and do not appear to possess major side-effects. Indeed, the whole controversy about whether anti-leukotrienes cause the rare Churg–Strauss syndrome or eosinophil vasculitis or whether the disease is unmasked by a reduction in steroid dose is not discussed. The issue of variability in the patient response to anti-leukotrienes is one of the striking clinical impressions associated with these drugs and is discussed in an excellent chapter on gene polymorphisms of 5-LO; it is likely that genetic polymorphisms of other enzymes and receptors in the leukotriene pathways will also be important in determining why some patients appear to respond better to treatment than others.In a way, this book has been published too early because it has missed most of the clinical data on these drugs and it does not provide any clinical guidance as to how the drugs should be used. However, it does provide a useful review of the discovery and development of anti-leukotrienes and is a useful source of reference.