Antileukotriene Drugs Research Articles

A risk-benefit assessment of antileukotrienes in asthma.

The antileukotriene drugs are the first new therapeutic agents approved for the treatment of asthma in more than 20 years. The currently available compounds are orally active and either prevent the cysteinyl leukotrienes from binding to and activating the cysLT-1 receptor in the lung (leukotriene receptor antagonists) or inhibit leukotriene synthesis (leukotriene synthesis inhibitors). Studies performed in individuals without asthma and patients with asthma reveal that antileukotrienes prevent the bronchoconstriction produced by exercise, cold-air, allergen, aspirin (acetylsalicylic acid) and sulphur dioxide. Except for the setting of aspirin sensitivity where the antileukotrienes are nearly uniformly effective, individual responses to them are variable with complete protection in some, no protection in others and a modest degree of protection in the majority. The antileukotrienes bronchodilate the airways of patients with baseline bronchoconstriction, although usually not as well as beta-agonists. When given for weeks to months they rapidly improve pulmonary function and symptoms in patients with mild-to-moderate asthma, and probably in patients with more severe asthma as well, and these improvements persist for the duration of treatment. Here too, their beneficial effects are variable and not predictable based on clinical criteria. Recent studies suggest they can reduce asthma-induced airway inflammation and are equal or more effective than sodium cromoglycate, but equal or less effective than low-to-moderate dosages of inhaled corticosteroids. Initial experience with the antileukotrienes reveals limited toxicity and what appears to be a favourable therapeutic-to-toxic ratio. However, exposure of more patients with differing characteristics for longer periods of time is needed to substantiate this initial impression. The exact role of the antileukotrienes in the treatment of asthma remains to be determined, as does the relative potency of the various agents.

Childhood asthma and allergic rhinitis: the role of leukotrienes

Research in the past two decades has shown that patients with asthma and rhinitis have inflammation of the involved tissues. This perception has been reflected in recent treatment guidelines, which stress the decreased use of symptom-based therapy and increased use of antiinflammatory therapies to control underlying inflammation. Corticosteroids are the most effective drugs currently in use; however, their use may be limited by potential problems with safety and patient/family adherence, which includes the "fear factor." In addition, the use of high doses of topical corticosteroids (especially when used in both the nose and airways) may have adverse effects when used continuously for long periods. The inflammatory response is complex, involving numerous inflammatory mediators and cells that interact in complicated and interrelated pathways. This provides researchers with numerous interactions at which molecular intervention may result in the attenuation of inflammation, and thus clinical disease. The leukotrienes, a group of important inflammatory mediators, cause vascular leakage and tissue edema; they also promote mucus secretion and a potent bronchoconstriction in patients with asthma. Currently a number of antileukotriene drugs have been developed and preliminary research indicates that they may provide clinicians with a non-steroidal antiinflammatory therapy that may provide steroid-sparing effects. This review examines the leukotrienes and the effects of antileukotriene agents in patients with asthma and allergic rhinitis.

Will the Advent of Antileukotriene Therapy Lead to Changes in Asthma Treatment Guidelines?

Leukotrienes are bronchoconstrictor and pro-inflammatory mediators implicated in asthma. Drugs that block leukotriene synthesis or activity are set to become the first major breakthrough in asthma therapy for 25 years. Antileukotriene drugs block bronchoconstriction after challenge with allergen, aspirin or exercise, and in clinical trials in patients with asthma they improve baseline lung function, reduce night-time awakenings, improve daytime symptom scores and halve the number of acute exacerbations. They are likely to be used as oral prophylactic therapy to reduce the dosage of corticosteroids right across the spectrum of asthma severity. Further studies on possible long term anti-inflammatory effects are currently in progress.

Leukotrienes in asthma. The potential therapeutic role of antileukotriene agents.

Recent advances in research have led to the identification of an inflammatory component to asthma. Although many endogenous mediators are involved in inflammation, leukotrienes appear to play an especially important role in asthma. The leukotrienes produce tissue edema, mucus secretion, and smooth-muscle proliferation, along with a powerful bronchoconstriction. In addition, antileukotriene drugs have emerged as potential therapeutic agents for asthma. This study was designed to review the current information on these new agents. In this review, full-length articles of antileukotriene agents are examined. These articles were found through MEDLINE under the following medical headings: asthma, inflammation, leukotriene, leukotriene-receptor antagonist, and leukotriene-synthesis inhibitor. Most clinical studies cited are placebo-controlled trials involving healthy individuals and patients with asthma. These studies indicate that antileukotriene agents improve lung function and reduce the symptoms of asthma and the need for additional medication. Drugs that inhibit leukotriene-receptor binding and leukotriene synthesis hold promise as new additions to the armamentarium of clinicians who treat asthma. Furthermore, these drugs have already helped to elucidate some details of the pathophysiological features of asthma.

Pharmacology of leukotriene antagonists and other anti-leukotriene drugs

The cysteinyl leukotrienes (cys-LTs), i.e. LTC4, LTD4 and LTE4, trigger contractile and inflammatory processes through the specific interaction with cell surface receptors belonging to the purine receptor cluster of the rhodopsin family of the G protein-coupled receptor (GPCR) genes. Cys-LTs have a clear role in pathophysiological conditions such as asthma, allergic rhinitis and other nasal allergies, and have been implicated in a number of inflammatory conditions including cardiovascular and gastrointestinal diseases. Pharmacological studies have identified two classes of cys-LT receptors (CysLT1 and CysLT2) based on their sensitivity to CysLT1 selective antagonists, albeit there is evidence for additional subtypes. Molecular cloning of the human CysLT1 and CysLT2 receptors has confirmed both their structure as putative seven transmembrane domain G protein-coupled receptors and most of the previous pharmacological characterization. The rank order of potency of agonist activation for the CysLT1 receptor is LTD4>LTC4>LTE4 and for the CysLT2 receptor is LTC4=LTD4>LTE4. The CysLT1 receptor is most highly expressed in spleen, peripheral blood leukocytes, interstitial lung macrophages and in airway smooth muscle. The CysLT2 receptor is mostly expressed in heart, adrenals, placenta, spleen, peripheral blood leukocytes and less strongly in the brain. Gene cloning of CysLT1 and CysLT2 receptors has renewed the attention on the cys-LTs field and will, hopefully, encourage future studies on the regulation of CysLT receptors expression and the dissection of their signalling pathways. Furthermore, the peculiar pattern of expression of the two receptor subtypes will promote the discovery of new functions for cys-LTs in physiological and pathological conditions. Only CysLT1 selective receptor antagonists have been described to date and are currently available for the treatment of asthma. Molecular cloning of different CysLT receptor subtypes will certainly foster the development of new selective antagonists based on molecular modelling studies.

Leukotriene Receptor Antagonists and Biosynthesis Inhibitors in Asthma

The 5-lipoxygenase metabolites of arachidonic acid, leukotrienes B4, C4, D4 and E4, are potent pro-inflammatory mediators that are implicated in the pathophysiology of asthma. Therefore, many antileukotriene compounds have been developed. Two major categories of these drugs are presently under investigation in patients with asthma: (a) leukotriene D4 receptor antagonists, which block the effects of cysteinyl leukotrienes at the receptor site; (b) leukotriene biosynthesis inhibitors, which prevent the formation of both cysteinyl leukotrienes and leukotriene B4. Both categories provide clinically relevant protection against bronchoconstrictor stimuli, such as exercise, cold dry air, and aspirin (acetylsalicylic acid). Unexpectedly, in allergen inhalation studies, leukotriene receptor antagonists have been shown to be more effective than the biosynthesis inhibitors. Consequently, owing to their favourable pharmacokinetic profile, potent antileukotriene drugs represent a potential first-line treatment in the management of certain types of asthma such as exercise and aspirin-induced asthma. However, the definite place in therapy of both categories of drugs will depend on the results of long term treatment in the various subgroups of asthmatic patients in comparison with and in addition to present antiasthma medication.

Increased urinary leukotriene excretion in patients with cardiac ischemia. In vivo evidence for 5-lipoxygenase activation.

Experimental cardiac ischemia in some animal models results in the activation of the enzyme 5-lipoxygenase and the subsequent production of leukotrienes, potent proinflammatory lipid mediators, by the affected myocardium. Furthermore, prototype antileukotriene drugs can show some beneficial effects on infarct size and cardiac function in these models. Accordingly, urinary excretion of leukotriene E4 (LTE4), the major urinary metabolite of peptide leukotrienes in humans, was measured in patients admitted to the hospital with evidence of acute myocardial ischemia to assess in vivo release of 5-lipoxygenase products during and after the ischemic episode. Urinary leukotriene excretion was measured by reversed-phase high-performance liquid chromatography and specific radioimmunoassay on admission with acute chest pain and again on day 3 in the following patient groups: acute myocardial infarction (AMI), AMI and clinical evidence of early reperfusion after treatment with recombinant tissue-type plasminogen activator (rt-PA), diagnosis of unstable angina (UA) based on clinical history and coronary arteriography, controls with nonischemic chest pain who underwent coronary arteriography, and age-matched controls and normal hospital employees. In 16 patients with diagnosis of AMI, LTE4 excretion on admission (331 +/- 99 pg/mg creatinine sulfate; mean +/- SEM) was considerably higher than that measured on day 3 (195 +/- 59 pg/mg creatinine sulfate). In a subgroup of seven subjects treated with rt-PA resulting in early reperfusion, day 1 excretion was similar (215 +/- 50 pg/mg) but had significantly declined by day 3 (65 +/- 16 pg/mg; p less than 0.01). Urinary LTE4 excretion at admission for chest pain was also elevated in 14 patients having unstable angina (UA; 370 +/- 125 pg LTE4/mg creatinine sulfate). This had declined significantly (p less than 0.05) by day 3 (at which time chest pain had resolved) to 94 +/- 31 pg/mg creatinine sulfate, an excretion rate comparable with that measured in eight similarly aged subjects (64 +/- 12 pg/mg creatinine). This study suggests that peptide leukotrienes are released during episodes of myocardial ischemia and provides clinical evidence for involvement of their biosynthetic enzyme, 5-lipoxygenase, during and after acute myocardial infarction and unstable angina attacks. Thus, potent and specific orally active leukotriene biosynthesis inhibitors may have therapeutic potential in limiting myocardial damage and functional abnormalities after acute ischemia.