Antileukotrienes

Leff AR (2001) Discovery of leukotrienes and development of antileukotriene agents. Ann Allergy Immunol 86 (Suppl) 864-86 8... 

Riccioni G, Bucciarelli T, Mancini B, Di Ilio C, D Orazio N. Antileukotriene drugs clinical application, effectiveness and safety. Curr Med Chem 2007 14(18) 1966-77. 

LTC4 and LTD4 are potent bronchoconstrictors and are recognized as the primary components of the slow-reacting substance of anaphylaxis (SRS-A) that is secreted in asthma and anaphylaxis. There are four current approaches to antileukotriene drug development 5-LOX enzyme inhibitors, leukotriene-receptor antagonists, inhibitors of FLAP, and phospholipase A2 inhibitors. 

In case of an obstruction of the nasal airways, the swelling should first be reduced and then the patient should apply the anti-inflammatory medication to ensure its necessary distribution over the complete mucosa. Antihistamines in addition to oral therapy may also be applied locally, intranasally or conjunctivally. The combination of all three substance groups (H, antihistamines, topic glucocorticoids and antileukotrienes) as a pretreatment as well as a symptomatic treatment during immunotherapy increases the chances of success of hyposensitization in our experience [unpubl. data]. 

As reflected in another chapter of this volume, especially anti-inflammatory treatment by antihistamines, antileukotrienes or corticoids might influence the success of immunotherapies, because it normalizes and standardizes the immunological base of treatment [13]. In severe cases a reduction of IgE levels by anti-IgE antibodies or even a slight general immunosuppressive treatment may also be considerable [14],... 

Incidence and prevalence of allergies are an increasing phenomenon worldwide. The most efficient therapy is the avoidance of the allergen. This, unfortunately, is not practicable in most cases. Antihistamines provide a very well-acting and well-accepted symptomatic treatment, which in its recent form is liberated from most side effects and which can be easily applied locally or sys-temically over a long period. At present new promising and interesting methods of symptomatic treatment are available, such as antileukotrienes or anti-IgE. 

The Cochrane Library is a relatively new and growing electronic library that provides more than 850 summaries of published literature about pharmaceutical and other interventions to improve health. The Library adds new titles four times a year to its cumulative online and CD versions (the latter, available by subscription, offers more databases). The Library s 2000 Issue 3 contains evidence on dozens of clinical dilemmas, such as antibiotic treatment for traveler s diarrhea, antileukotriene agents compared to inhaled corticosteroids in the management of recurrent and/or chronic asthma, opioid antagonists for alcohol dependence, and bromocriptine versus levodopa in early Parkinson s disease. The Cochrane Library also updates earlier reviews when important new evidence becomes available. Among the newest updates are tacrine for Alzheimer s disease, tricyclic and related drugs for nocturnal enuresis in children, and nicotine replacement therapy for smoking cessation. 

The roles of muscarinic receptor blockers (theophylline, cromolyn, and nedocromil), adrenal steroids, and antileukotrienes in the treatment of asthma are discussed. Their modes of action are illustrated in Figure VI-1-4. 

Even though various antileukotriene drugs have been synthesized, none has reached clinical acceptability. Inhibition of histamine release by an apparent mast cell stabilizing mechanism (in lung tissue, but probably not elsewhere) is achieved with the carboxy-chromone derivative cromolyn sodium. The mechanism is believed to involve inhibition of histamine release from pulmonary mast cells by blocking Ca2+ movement through membrane channels. 

Arachidonic acid can also be converted into a leukotriene. Because they induce contraction of the muscle that lines the airways to the lungs, leukotrienes are implicated in allergic reactions, inflammatory reactions, and heart attacks. Leukotrienes also bring on the symptoms of asthma and are implicated in anaphylactic shock, a potentially fatal allergic reaction. There are several antileukotriene agents available for the treatment of asthma. 

Brouns I, Pintelon I, De Proost I, Alewaters R, Timmermans JP, Adriaensen D (2006) Neurochemical characterisation of sensory receptors in airway smooth muscle comparison with pulmonary neuroepithelial bodies. Histochem CeU Biol 125(4) 351-67 Brozmanova M, Plevkova J, Bartos V, Plank L, Tatar M (2005) Antileukotriene treatment and allergic rhinitis-related cough in guinea pigs. J Physiol Pharmacol 56 (Suppl 4) 21-30 Burki NK, Dale WJ, Lee LY (2005) Intravenous adenosine and dyspnea in humans. J Appl Physiol 98(1) 180-5... 

Wenzel S. Antileukotriene drugs in the management of asthma. JAMA 1998 280 38-39. 

Many specific mediator receptors are involved in asthma but they are so abundant that specific antagonists for these receptors have little effect, with an exception for cysteinyl leukotriene-1 (cys-LTj) receptors which are distributed predominantly on airway smooth muscle and (to a lesser extent) on macrophages. Their numbers are small, however, and this may explain why antileukotrienes like montelukast and zafirlukast, which prevent predominantly leukotriene-induced bronchoconstriction, are less effective than P2-agonists. 

There is evidence that oral antileukotrienes agents provide benefit for the treatment of allergic rhinitis. Further study is needed before treatment recommendations can be provided (85,86). Rupatadine is a novel orally active dual antagonist of histamine and PAF. This agent is under investigation for the treatment of seasonal and perennial allergic rhinitis (87). 

Over the last 30 years, significant scientific advances have elucidated the biochemical processes that result in acute and chronic allergic inflammatory rhinitis. The basic laboratory work on IgE has translated into the cUnical application of anti-IgE MAb as a therapeutic agent for allergic rhinitis. Similar progress has been made with respect to antileukotrienes, PAF inhibitors, a thromboxane-prostanoid receptor antagonist, and inhibitors of important cytokines such as IL4 and IL-5. These advances are expected in the near future to reduce the considerable morbidity that allergic rhinitis patients presently withstand in daily life. 

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