[Antileukotrienes. Their use in pediatrics]

[Article in Spanish]

Garde Noguera J.

Hospital General Universitario de Elche, Servicio de Pediatria, Unidad de Alergia Infantil, Elche, Alicante, Valencia, Espana.

The leukotriene antagonists have represented the first novelty in the treatment of asthma over the last 20 years. Their easy oral administration that favours a suitable completion of the treatment, especially on children, together with the proven efficiency and their apparent safety, gave rise to the fact in 1999 the asthma committee of the Spanish Society of Clinical Immunology and Paediatric Allergology (SSCIPA) in the bronchial asthma treatment guide that was presented a year ago during the XXIII National Congress of our Society, considered the antileukotrienes, together with the chromones, as important medicines for stage 2 asthma (frequent episodes) and as useful medicines to reduce the need to take corticoides in cases of persistent asthma. A year later, in our study we proposed to value too suitability or non suitability of this positioning, in the light of the new investigations published and from our own experience. We believe that the bibliography available to date shows that the agonist cysteinyl-leukotrienes are anti-inflammatory medicines, that have an efficiency similar to that of low doses of inhaled corticoids, equally efficient in controlling bronchospasm-induced exercise and they have a good safety profile. We present two studies that are the result of our own experience, one carried out on children with persistent asthma and the other on children with frequent episodic asthma, from which we can apparently deduce that both nedocromil (2 inhalations every 8 hours) and montelukast (5 mg every 24 hours) are medicines that have similar efficacy in the control of asthma. We conclude that the antileukotrienes, together with the chromones, should be seen as important medicines when treating infant asthma.

Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10867384&dopt=Abstract montelukast, Singulair




Role of leukotriene receptor antagonists in pediatric asthma.

Kemp JP.

Division of Immunology and Allergy, Department of Pediatrics, University of California School of Medicine, San Diego, California, USA. jpk aol.com

During the past decade, the inflammatory mechanisms that result in the clinical syndrome we call asthma have been emphasized in research, publications, and the various asthma management guidelines. This information clearly emphasizes the treatment of asthma with maintenance controller therapies early after the onset of symptoms in all but the very mildest of patients. Until the advent of the leukotriene receptor antagonists, nearly all of these maintenance therapies needed to be administered by inhalation through a variety of devices and spacers. Inhalation of medication was necessary to either increase the amount of drug reaching the airways or to increase the therapeutic index of drugs such as corticosteroids. Even under the best circumstances, this route of administration is difficult and expensive for many parents whose children have asthma. Now that oral controller therapies (leukotriene receptor antagonists) are available for children, their role in clinical practice needs to be examined. The latest asthma management guidelines classify asthma into four groups of severity, and base treatment recommendations on the intensity of symptoms, need for rescue medications, and pulmonary function as measured by peak expiratory flow and forced expiratory volume in 1 sec (FEV(1)). The categories of mild intermittent, mild persistent, moderate persistent, and severe asthma in children will be addressed in this presentation by reviewing the available data on the use of the leukotriene receptor antagonist montelukast in children. Mild intermittent asthma can be typified by exercise-induced asthma, a common pediatric condition. In this often troublesome condition, montelukast demonstrated effectiveness at the end of a once a day dose by blocking the effects of this naturally occurring challenge. Drug regulatory approval of a new drug also includes patients with more regular symptoms who are usually classified as having persistent or moderate asthma. In these montelukast pediatric studies, approximately 40% of patients were already taking inhaled corticosteroids. Patients had improvements in FEV(1), symptoms, and rescue medication use, clearly showing an effect with once a day dosing. Pediatric data in severe asthma patients are more limited, but in such patients a therapeutic trial of montelukast would seem preferable to using systemic corticosteroids or increasing inhaled steroids to a level where adverse effects have an increasing potential of occurring. Montelukast has been available in the United States since March 1998 and has received excellent acceptance by physicians, parents, and patients. The 5-mg chewable tablet administered once a day in the evening in children aged 6-14 years apparently fills a previously unmet need in the treatment of pediatric asthma. Copyright 2000 Wiley-Liss, Inc.

Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10922143&dopt=Abstract montelukast, Singulair




A novel hepatointestinal leukotriene B4 receptor. Cloning and functional characterization.

Laz T.

Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA. suke.wang spcorp.com

Leukotriene B(4) (LTB(4)) is a product of eicosanoid metabolism and acts as an extremely potent chemotactic mediator for inflammation. LTB(4) exerts positive effects on the immigration and activation of leukocytes. These effects suggest an involvement of LTB(4) in several diseases: inflammatory bowel disease, psoriasis, arthritis, and asthma. LTB(4) elicits actions through interaction with one or more cell surface receptors that lead to chemotaxis and inflammation. One leukotriene B(4) receptor has been recently identified (LTB(4)-R1). In this report we describe cloning of a cDNA encoding a novel 358-amino acid receptor (LTB(4)-R2) that possesses seven membrane-spanning domains and is homologous (42%) and genetically linked to LTB(4)-R1. Expression of LTB(4)-R2 is broad but highest in liver, intestine, spleen, and kidney. In radioligand binding assays, membranes prepared from COS-7 cells transfected with LTB(4)-R2 cDNA displayed high affinity (K(d) = 0.17 nm) for [(3)H]LTB(4). Radioligand competition assays revealed high affinities of the receptor for LTB(4) and LTB(5), and 20-hydroxy-LTB(4), and intermediate affinities for 15(S)-HETE and 12-oxo-ETE. Three LTB(4) receptor antagonists, 14,15-dehydro-LTB(4), LTB(4)-3-aminopropylamide, and U-75302, had high affinity for LTB(4)-R1 but not for LTB(4)-R2. No apparent affinity binding for the receptors was detected for the CysLT1-selective antagonists montelukast and zafirlukast. LTB(4) functionally mobilized intracellular calcium and inhibited forskolin-stimulated cAMP production in 293 cells. The discovery of this new receptor should aid in further understanding the roles of LTB(4) in pathologies in these tissues and may provide a tool in identification of specific antagonists/agonists for potential therapeutic treatments.

Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11006272&dopt=Abstract montelukast, Singulair




Inhaled porcine pancreatic elastase causes bronchoconstriction via a bradykinin-mediated mechanism.

Abraham WM.

Division of Pulmonary Disease and Critical Care Medicine, University of Miami at Mount Sinai Medical Center, Miami Beach, Florida 33140, USA.

Neutrophil elastase has been linked to inflammatory lung diseases such as chronic obstructive pulmonary disease, adult respiratory distress syndrome, emphysema, and cystic fibrosis. In guinea pigs, aerosol challenge with human neutrophil elastase causes bronchoconstriction, but the mechanism by which this occurs is not completely understood. Our laboratory previously showed that human neutrophil elastase releases tissue kallikrein (TK) from cultured tracheal gland cells. TK has been identified as the major kininogenase of the airway and cleaves both high- and low-molecular weight kininogen to yield lysyl-bradykinin. Because inhaled bradykinin causes bronchoconstriction and airway hyperresponsiveness in asthmatic patients and allergic sheep, we hypothesized that elastase-induced bronchoconstriction could be mediated by bradykinin. To test this hypothesis, we measured lung resistance (RL) in sheep before and after inhalation of porcine pancreatic elastase (PPE) alone and after pretreatment with a bradykinin B(2) antagonist (NPC-567), the specific human elastase inhibitor ICI 200,355, the histamine H(1)-antagonist diphenhydramine hydrochloride, the cysteinyl leukotriene 1 receptor antagonist montelukast, or the cyclooxygenase inhibitor indomethacin. Inhaled PPE (125-1,000 microg) caused a dose-dependent increase in RL. Aerosol challenge with a single 500 microg dose of PPE increased RL by 132 +/- 8% over baseline. This response was blocked by pretreatment with NPC-567 and ICI-200,355 (n = 6; P < 0.001), whereas treatment with diphenhydramine hydrochloride, montelukast, or indomethacin failed to block the PPE-induced bronchoconstriction. Consistent with pharmacological data, TK activity in bronchial lavage fluid increased 134 +/- 57% over baseline (n = 5; P < 0.02). We conclude that, in sheep, PPE-induced bronchoconstriction is in part mediated by the generation of bradykinin. Our findings suggest that elastase-kinin interactions may contribute to changes in bronchial tone during inflammatory diseases of the airways.

Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11007574&dopt=Abstract montelukast, Singulair




Montelukast in childhood asthma.

Mehta PN.

Mehta Hospital, Opposite Putli, Sagrampura, Surat - 395 002, India.

Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11086302&dopt=Abstract montelukast, Singulair