Investigational agents for the treatment of asthma

Abstract

The approach to the treatment of asthma has changed considerably over the years. Initial treatments for asthma were designed to relieve symptoms and included epinephrine, atropine-like drugs, and inhalers such as albuterol. Subsequently, as the inflammatory processes involved in asthma were better understood, agents were developed to decrease these processes. These agents include corticosteroids, theophylline, and cromones. The precise mechanism of action of these drugs has remained unclear. Recently, however, important studies have revealed information regarding causes of asthma including the interrelationships among specific immune cells, cytokines, and other immune mediators. This knowledge has led to tailored treatment approaches and improved application of nonspecific anti-inflammatory drugs in the treatment of asthma. In addition, more specifically targeted agents have been and continue to be developed. Combinations of nonspecific and specific agents may further improve the treatment of asthma. Newer agents that can be categorized as nonspecific controllers of cellular inflammation include some of the newly developed inhaled corticosteroids and noncorticosteroid anti-inflammatory agents. Inhaled corticosteroids reduce mucosal edema and inflammation because of modulation of eosinophils, mast cells, and lymphocytes.1Djukanovic R Wilson JW Bitten KM Wilson SJ Walls AF Roche WR et al.Effect of an inhaled corticosteroid on airway inflammation and symptoms in asthma.Am Rev Respir Dis. 1992; 145: 669-674Crossref PubMed Scopus (572) Google Scholar, 2Robinson D Hasid Q Ying S Bentley A Assoufi B Durham S et al.Prednisolone treatment in asthma is associated with modulation of bronchoalveolar lavage cell interleukin-4, interleukin-5, and interferon-gamma cytokine gene expression.Am Rev Respir Dis. 1993; 148: 401-406Crossref PubMed Scopus (277) Google Scholar, 3Bentley AM Hamid Q Robinson DS Schotman E Meng Q Assoufi B et al.Prednisolone treatment in asthma. Reduction in the numbers of eosinophils, T cells, tryptase-only positive mast cells, and modulation of IL-4, IL-5, and interferon-gamma cytokine gene expression within the bronchial mucosa.Am J Respir Crit Care Med. 1996; 153: 551-556Crossref PubMed Scopus (235) Google Scholar The precise mechanisms involved in this process remain unclear. It is possible that activation of glucocorticoid receptors may directly or indirectly inhibit cytokine production through effects on the glucocorticoid response elements in the genome.4Sousa AR Poston RN Lane SJ Nakhosteen JA Lee TH. Detection of GM-CSF in asthmatic bronchial epithelium and decrease by inhaled corticosteroids.Am Rev Respir Dis. 1993; 147: 1557-1561Crossref PubMed Google Scholar Alternatively, corticosteroids may interfere with transcription factors, such as NF-κB and AP-1, which are involved in the regulation of gene activation.5Mukaida N Morita M Ishikawa Y Rice N Okamoto S Kasahara T et al.Novel mechanism of glucocorticoid-mediated gene repression: nuclear factor-kappa B is target for glucocorticoid-mediated interleukin 8 gene repression.J Biol Chem. 1994; 269: 13289-13295Abstract Full Text PDF PubMed Google Scholar Regardless of the mechanism of action, inhaled corticosteroids are effective in the treatment of asthma. Newer, potentially improved inhaled corticosteroids have been developed to increase potency and the local to systemic ratio to concentrate the drug in the lungs. Compliance has been an issue with the use of inhaled corticosteroids because of their multiple daily dosing. However, a study reported by Pincus et al.6Pincus DJ Szefler SJ Ackerson LM Martin RJ. Chronotherapy of asthma with inhaled steroids: the effect of dosage timing on drug efficacy.J Allergy Clin Immunol. 1995; 95: 1172-1178Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar demonstrated that single daily administration of an inhaled corticosteroid produced similar results to four-times-daily dosing. Noncorticosteroid, nonspecific anti-inflammatory agents (also called steroid-sparing agents) include methotrexate, cyclosporine, and gold salts, among others. These agents are used in patients who are currently receiving oral corticosteroids. Clinical trials of methotrexate have not demonstrated a profound impact on patients with asthma.7Erzurum SC Leff JA Cochran JE Ackerson LM Szefler SJ Martin RJ et al.Lack of benefit of methotrexate in severe, steroid-dependent asthma.Ann Intern Med. 1991; 114: 353-360Crossref PubMed Scopus (118) Google Scholar, 8Hedman J Seideman P Albertioni F Stenius-Aarniala B Controlled trial of methotrexate in patients with severe chronic asthma.Eur J Clin Pharmacol. 1996; 49: 347-349Crossref PubMed Scopus (27) Google Scholar Common side effects include nausea, vomiting, and abdominal pain, and methotrexate therapy should only be used in patients with very severe asthma in controlled settings. Two double-blind clinical trials have demonstrated the effectiveness of cyclosporine compared with placebo in reducing corticosteroid intake, but, the side effects of this therapy are considerable and the mechanism of action remains uncertain, (though likely through effects on lymphocytes).9Alexander AG Barnes NC Kay AB. Trial of cyclosporin in corticosteroid-dependent chronic severe asthma.Lancet. 1992; 339: 324-328Abstract PubMed Scopus (307) Google Scholar, 10Lock SH Kay AB Barnes NC Double-blind, placebo-controlled study of cyclosporin A as a corticosteroid-sparing agent in corticosteroid-dependent asthma.Am J Respir Crit Care Med. 1996; 153: 509-514Crossref PubMed Scopus (195) Google Scholar As with methotrexate, cyclosporine should be reserved for patients with very severe asthma that warrants the use of this treatment. The oral gold compound, auranofin, has been studied in patients with corticosteroid-dependent asthma.11Nierop G Gijzel WP Bel EH Zwinderman AH Dijkman JH. Auranofin in the treatment of steroid-dependent asthma: a double-blind study.Thorax. 1992; 47: 349-354Crossref PubMed Scopus (58) Google Scholar, 12Bernstein IL Bernstein DI Dubb JW Faiferman I Wallin B. A placebo-controlled multicenter study of auranofin in the treatment of patients with corticosteroid-dependent asthma. Auranofin Multicenter Drug Trial.J Allergy Clin Immunol. 1996; 98: 317-324Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar Though its mechanism is unknown, two clinical trials have shown that auranofin may be a useful steroid-sparing agent in the treatment of chronic, corticosteroid-dependent asthma. Other steroid-sparing agents currently undergoing investigation for the treatment of asthma include intravenous gamma globulin, dapsone, and colchicine. Recent studies have provided critical information regarding the inflammatory processes of asthma. This expanding information can be used to develop therapeutic agents that target specific areas of the inflammatory cascade. Agents undergoing investigation, with mixed success, include leukotriene modulators, anti–immunoglobulin E antibodies, anticytokine and anti–adhesion molecule antibodies, bronchoprotective prostanoids (e.g., prostaglandin E2), surfactant, antineuropeptide antibodies, and phosphodiesterase inhibitors.13Kung TT Stelts DM Zurcher JA Adams GK Egan RW Kreutner W et al.Involvement of IL-5 in a murine model of allergic pulmonary inflammation: prophylactic and therapeutic effect of an anti-IL-5 antibody.Am J Respir Cell Mol Biol. 1995; 13: 360-365Crossref PubMed Scopus (198) Google Scholar, 14Mauser PJ Pitman AM Fernandez X Foran SK Adams GK Kreutner W et al.Effects of an antibody to interleukin-5 in a monkey model of asthma.Am J Respir Crit Care Med. 1995; 152: 467-472Crossref PubMed Scopus (325) Google Scholar, 15Pavord ID Wong CS Williams J Tattersfield AE. Effect of inhaled prostaglandin E2 on allergen-induced asthma.Am Rev Respir Dis. 1993; 148: 87-90Crossref PubMed Scopus (175) Google Scholar, 16Holgate ST Bradding P Sampson AP. Leukotriene antagonists and synthesis inhibitors: new directions in asthma therapy.J Allergy Clin Immunol. 1996; 98: 1-13Abstract Full Text Full Text PDF PubMed Google Scholar, 17Wenzel SE Kamada AK. Zileuton: the first 5-lipoxygenase inhibitor for the treatment of asthma.Ann Pharmacother. 1996; 30: 858-864Crossref PubMed Scopus (83) Google Scholar In addition, to target more than one aspect of the inflammatory process, combinations of agents are now beginning to be studied. The eicosanoids, such as the cysteinyl leukotrienes (i.e., LTC4, LTD4, LTE4), thromboxane A2, and prostaglandin D2, are mediators of the inflammatory process and are produced during the metabolism of arachidonic acid (Fig. 1). When studied in vitro and in vivo, the cysteinyl leukotrienes have induced some of the important features of asthma, such as bronchospasm and increased bronchial responsiveness.18Thien FC Walters EH. Eicosanoids and asthma: an update.Prostaglandins Leukot Essent Fatty Acids. 1995; 52: 271-288Abstract Full Text PDF PubMed Scopus (62) Google Scholar To combat the actions of the products of arachidonic acid metabolism, two types of leukotriene modulators have been developed: leukotriene D4 receptor antagonists and 5-lipoxygenase inhibitors. While the leukotriene receptor antagonists block the receptor for the cysteinyl leukotrienes LTC4, LTD4, and LTE4, the 5-lipoxygenase inhibitors block the enzyme 5-lipoxygenase, thus preventing leukotriene synthesis (i.e., cysteinyl leukotrienes, LTB4). The leukotriene D4 receptor antagonists inhibit the activity of the cysteinyl leukotrienes. Several leukotriene D4 receptor antagonists have been studied, including zafirlukast, pranlukast, montelukast, and others (i.e., pobilukast, tomelukast, verlukast).16Holgate ST Bradding P Sampson AP. Leukotriene antagonists and synthesis inhibitors: new directions in asthma therapy.J Allergy Clin Immunol. 1996; 98: 1-13Abstract Full Text Full Text PDF PubMed Google Scholar, 19Spector SL Smith LJ Glass M Effects of 6 weeks of therapy with oral doses of ICI 204, 219, a leukotriene D4 receptor antagonist, in subjects with bronchial asthma.Am J Respir Crit Care Med. 1994; 150: 618-623Crossref PubMed Scopus (343) Google Scholar, 20Gaddy JN Margolskee DJ Bush RK Williams VC Busse WW. Bronchodilation with a potent and selective leukotriene D4 (LTD4) receptor antagonist (MK-571) in patients with asthma.Am Rev Respir Dis. 1992; 146: 358-363Crossref PubMed Scopus (119) Google Scholar In laboratory asthma (as opposed to asthma observed in clinical practice or "day-to-day" asthma), leukotriene D4 receptor antagonists have been shown to attenuate allergen, exercise, and aspirin challenges. In randomized, double-blind clinical trials involving more than 1300 patients with mild to moderate asthma, zafirlukast was shown to improve daytime asthma symptoms (Fig. 2),21Suissa S Dennis R Ernst P Sheehy O Wood-Dauphinee S. Effectiveness of the leukotriene receptor antagonist zafirlukast for mild-to-moderate asthma: a randomized, double-blind, placebo-controlled trial.Ann Intern Med. 1997; 126: 177-183Crossref PubMed Scopus (197) Google Scholar nighttime awakenings, mornings with asthma symptoms, rescue β2-agonist use, forced expiratory volume in 1 second, and peak expiratory flow rate. 21Suissa S Dennis R Ernst P Sheehy O Wood-Dauphinee S. Effectiveness of the leukotriene receptor antagonist zafirlukast for mild-to-moderate asthma: a randomized, double-blind, placebo-controlled trial.Ann Intern Med. 1997; 126: 177-183Crossref PubMed Scopus (197) Google Scholar Zafirlukast is generally well tolerated; the most common side effect was headache, which occurred in about 13% of zafirlukast patients compared with about 12% of placebo patients. To date, there are no data regarding the long-term effects of these agents. In laboratory asthma, 5-lipoxygenase inhibitors have demonstrated efficacy in cold air, exercise, aspirin, and nocturnal asthma. These agents reduce bronchoalveolar lavage, urinary leukotriene, and peripheral eosinophil levels. Zileuton is a 5-lipoxygenase inhibitor that can attenuate induced bronchospasm, produce some degree of bronchodilation, and provide anti-inflammatory or steroid-sparing effects with both single doses and chronic treatment.17Wenzel SE Kamada AK. Zileuton: the first 5-lipoxygenase inhibitor for the treatment of asthma.Ann Pharmacother. 1996; 30: 858-864Crossref PubMed Scopus (83) Google Scholar Importantly, after aspirin challenge in aspirin-sensitive asthmatics, zileuton improved forced expiratory volume in 1 second compared with placebo (Fig. 3).22Israel E Fischer AR Rosenberg MA Lilly CM Callery JC Shapiro J et al.The pivotal role of 5-lipoxygenase products in the reaction of aspirin-sensitive asthmatics to aspirin.Am Rev Respir Dis. 1993; 148: 1447-1451Crossref PubMed Google Scholar In "day-to-day" asthma, zileuton has demonstrated 15% to 18% improvement in forced expiratory volume in 1 second with decreases in symptom scores, β-agonist use, and need for oral steroids. 23Liu MC Dube LM Lancaster J. Acute and chronic effects of a 5-lipoxygenase inhibitor in asthma: a 6-month randomized multicenter trial.J Allergy Clin Immunol. 1996; 98: 859-871Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar In addition, when zileuton was added to “usual care” (i.e., inhaled corticosteroids, theophylline, cromones), it significantly reduced the rates for hospitalization and emergency room visits.24Lazarus SC Lee TM Wright S Sarocco P Rosenstein L Bialek S et al.Secondary outcomes analysis of zileuton plus usual care vs. usual care alone in the treatment of patients with asthma.Ann Allergy Asthma Immunol. 1997; 78 ([abstract]): 94Google Scholar Zileuton was approved in December 1996 by the US Food and Drug Administration. About 3% of patients have developed elevations in alanine aminotransferase. There was one case of jaundice reported. The Food and Drug Administration has recommended monitoring alanine aminotransferase levels every month for the first 3 months, quarterly for the rest of the first year, and then periodically thereafter. In addition, gastrointestinal complaints have been reported in greater numbers of patients treated with zileuton compared with placebo. Several components of the inflammatory process can be targeted when agents with different mechanisms of action are combined. These combinations could include two nonspecific agents, a nonspecific plus a specific agent, or two specific agents. The combination of a specific agent (zileuton) and a nonspecific agent (beclomethasone) has been studied.25O'Connor BJ Godard P Dube LM Swanson LJ Maki R the European Zileuton Study Group The comparative effect of zileuton, a 5-lipoxygenase inhibitor, plus low dose inhaled beclomethasone vs higher dose beclomethasone for asthma.J Allergy Clin Immunol. 1996; 97 ([abstract]): 250Google Scholar The addition of zileuton to beclomethasone resulted in improved peak expiratory flow from baseline to a greater extent than did the improvement observed in response to a doubling of the beclomethasone dosage. The treatment of asthma is improving rapidly and reflects an enhanced understanding of the inflammatory process. Nonspecific controllers of cellular inflammation, such as the newer, inhaled corticosteroids and noncorticosteroid anti-inflammatory agents, have resulted in better asthma control. More specifically targeted agents, including leukotriene-modulating drugs and others that are still in the early stages of development, offer novel approaches to the treatment of this disorder. The promise of the future for asthma treatment may lie with various combinations of these innovative therapies.