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- Leukotriene -
9/6/05 re: Singulair used in Hodgkin's disease I have a patient who has Hodgkin's in remission. Can he get singular? Is there any contraindication in this case to its use?
I am not aware of any evidence that montelukast (Singulair), a blocker of the receptor for cysteinyl leukotrienes, is contra-indicated in those with Hodgkin's disease. I could also find nothing concerning this in a Medline search.
12/18/03 re: Efficacy of leukotriene antagonists Is there literature to support the use of leukotriene antagonists in the elderly asthmatic? In a review of previous studies, Creticos et al noted in 2002 that the leukotriene antagonist zafirlukast conferred only very modest improvement in asthmatics > 50 years old, significantly less than the improvement seen with inhaled steroid (fluticasone) treatment (see enclosed abstract). I am not aware if any published reports concerning comparisons of montelukast and inhaled steroids in older individuals. I could also not find any such reports in a Medline search. Such information may be available through Merck, the manufacturer of Singulair. Dr. Ted Reiss of Merck has been very active in their clinical studies of Singulair. Ann Allergy Asthma Immunol. 2002 Apr;88(4):401-9.
Loss of response to treatment with leukotriene receptor antagonists but not inhaled corticosteroids in patients over 50 years of age.
Creticos P, Knobil K, Edwards LD, Rickard KA, Dorinsky P.
John Hopkins Asthma and Allergy Center, Baltimore, Maryland 21442, USA.
BACKGROUND: There are limited published data describing the relative efficacy of available treatment options in younger versus older patients with persistent asthma. OBJECTIVE: To compare the efficacy of fluticasone propionate (FP) and zafirlukast (Z) in younger (12 to 49 years of age) versus older (50 years and older) patients with asthma. METHODS: A retrospective analysis of five randomized, double-blind, double-dummy studies 4 to 12 weeks in duration of 1,742 patients <50 years of age and 243 patients aged 50 years or older. Interventions were inhaled fluticasone propionate (FP) 88 microg, oral Z 20 mg, or placebo twice daily. RESULTS: Treatment with FP resulted in significantly greater improvements than Z in all efficacy measurements (except for nighttime awakenings) regardless of age. In older patients, treatment with FP significantly increased pulmonary function compared with Z: FEV (FP= +0.19 L; placebo = -0.34 L; Z = -0.06 L); AM peak expiratory flow rate [PEFR] (FP = +25 L/minute; placebo = -18 L/minute; Z = +4 L/minute); PM PEFR (FP = +24 L/minute; placebo = -24 L/minute; Z = +5 L/minute; P < or = 0.023; for all comparisons).
Compared with Z, treatment with FP in older patients also resulted in significantly greater increases in the percentage of symptom-free days (25% vs 13%) and rescue-free days (35% vs 17%); and significantly greater reductions in albuterol use (-1.6 vs -0.3 puffs/day) and the percentage of patients with exacerbations (2.7% vs 14.3%; P < or = 0.031). CONCLUSIONS: Regardless of age, treatment with FP in patients with asthma significantly improved pulmonary function and overall asthma control. In contrast, treatment with Z in older patients with asthma resulted in small improvements in asthma symptoms, whereas lung function improved minimally or not at all, and exacerbations increased. These data suggest that FP effectively controls inflammation in older patients, whereas Z may mask inflammation and may not provide the level of bronchodilatory or anti-inflammatory activity needed for effective asthma control in older or anti-inflammatory activity needed for effective asthma control in older patients.7/22/03 re: Dose of Singulair I am a Registered Nurse and a mother of an asthmatic child. I recently visited our Pediatric Allergist. My son is 10 and weighs 110lbs. He has been on Singular for 3 years at 5mg po qhs. He has done very well and has limited the usage of his inhaler and nembulizer. The doctor said at this visit that he could take 10 mg qod. The pharmacist was concerned about this dosing because it is not in the normal range for those 15 years of age and younger. I thought that maybe the MD did this for dosing purposes via my son's weight, but according to the medication insert, this medicine is not dosed for weight.
I am hesitant because the pharmacist is anxious about it, but when the MD was questioned, he showed no concern. He said to do what I wanted to do. Any thoughts?
As an Internist, I have not participated in the care of young children with asthma for some time. Therefore, I consulted a colleague, Dr. Joel Fiedler, a highly experienced and expert Pediatric Allergist in the Children's Hospital of Philadelphia. His response is enclosed below. I would agree with Dr. Fiedler that dosing with Singulair in depends on how well your child has been doing with regards to the asthma. If the need for inhaled beta agonist is very infrequent, there are no nocturnal flares, vigorous exercise can be carried out without inducing symptoms and the pulmonary function measured by spirometry in the office has been consistently normal or close to it, one might consider a trial of withdrawing the Singulair with close monitoring of inhaled beta agonist use, sequential office spirometry, etc thereafter. On the other hand, if the exercise tolerance and/or pulmonary function is significantly impaired even if the child's asthma appears to be "under control" an increase in the Singulair dose to 10 mg is a reasonable approach in a child whose weight is greater than 45 kg.
____________________________________________Dr. Fiedler's response:
The questioner is correct. The dosing of Singulair is on age, not weight- I am not quite sure why. As a result, there is tremendous variation in terms of Singulair dosing on a mg/kg basis. The recommendation is to use 4mg for children from age 1 yr.( a granule preparation was just released within the past 2 weeks) until age 6 yr. and 5 mg for ages 6-14 yr. It is 10 mg for ages 14 yr. and above. That being said if necessary kids no matter what their age, I will dose at 10 mg , if necessary, once they are more than 45 kg, which this child is. My only disagreement with the physician who recommended increasing the dose is that it sounds like the child is very well controlled on the present regimen, so why increase the dose? We always tell parents that we want to control the children on the least amount of medicine possible, so if someone is doing well, I would not necessarily increase the dosage because of weight or age. As you realize a lot of children when they enter late childhood or early adolescence can go through a quiescent period. Since this child has been on singulair for 3 years and by mother's report has been doing exceptionally well, with very minimal use of beta agonist medication, my question would actually be, could we take the child off medicine completely for a while. I obviously don't know what the PFT's look like or the exact use of the beta agonist (is it less than 2-3 times per month?). Under circumstances described above if asthma symptoms really are very mild intermittent with normal PFT's, my approach would have been to see how child does for a few months off singulair, obviously following PFT's and clincal use of beta agonist medication.3/12/03 re: Literature reference for effects of adding leukotriene antagonist to Advair treatment I am trying to find current literature (journal articles, etc.) that discuss trials conducted in regards to a combined therapy of Advair and Leukotriene antagonists (Singulair or Accolate) in patients. I am finding this particularly difficult. Do you have any suggestions for literature where I may find such studies? First, I will briefly review some background information about the effects of adding treatment with cysteinyl leukotriene antagonists (LA) to inhaled corticosteroids (ICS) in asthma treatment. There has been some debate about whether addition of LA treatment significantly reduces the amount of ICS needed for control of moderate asthma (1,2,3,4,). There has also been conflicting findings in studies of whether addition of LA improved control of asthma not well-controlled by ICS alone (3, 5,6,). In a comparison of adding LA vs adding inhaled long-acting beta agonist therapy (LABA) to ICS, Busse et al (7) reported that added salmeterol provided better asthma control than added zafirlukast. It is well established that added LABA significantly reduces ICS dosage needed for control (8). Perhaps the most convincing evidence that addition of LA yields only modest added benefit to ICS (w/wo inhaled LABA such as salmeterol) comes from the recent meta-analysis referred to above (4, also see enclosed abstract of that report). Also, there is evidence that addition of LA to ICS is less cost-effective than addition of LABA (see enclosed abstract).
I am not aware of a report specifically comparing the effects of adding LA vs adding placebo to Advair in treatment of moderate to severe asthma. However, based on indirect evidence quoted above, I would expect that added LA treatment would not confer an impressive improvement in moderate asthma already being treated with high dose Advair.
REFERENCES
1) N Eng J Med 1999;340:197-206
2) Ann Intern Med 1997;127:472-480
3) Lancet 2001;357:2007-11
4) Cochrane Database Syst Rev 2002:CD003133
5) Am J. Resp Crit Care Med 1999;160:1862-8
6) Am J. Resp Crit Care Med 2000;162:578-85
7) JACI 199; 103:1075-80
8) JAMA 2001;285:2594-2503
_________________________________________________________________Cochrane Database Syst Rev 2002;(1):CD003133
Update of: Cochrane Database Syst Rev. 2001;(3):CD003133.
Addition of anti-leukotriene agents to inhaled corticosteroids for chronic asthma.
Ducharme F, Hicks G, Kakuma R.
Pediatrics and Epidemiology & Biostatistics, McGill University Health Centre, Montreal Chidren's Hospital, 2300 Tupper Street, Room C-538E, Montreal, Quebec, Canada, H3H 1P3.
BACKGROUND: Anti-leukotriene (AL) agents are being considered as "add-on" therapy to inhaled corticosteroids (ICS), in chronic asthma. OBJECTIVES: To examine the safety and efficacy of daily AL plus ICS compared to ICS alone, and determine the corticosteroid-sparing effect of AL when added to ICS in chronic asthma. SEARCH STRATEGY: We searched Medline, Embase, Cinahl (until September 2001), reference lists of review articles and trials, contacted international headquarters of AL manufacturers and ATS meeting abstracts (1998-2000). SELECTION CRITERIA: Randomised placebo-controlled trials of asthmatics aged 2 years and older with at least one month intervention. DATA COLLECTION AND ANALYSIS: Two reviewers assessed quality and extracted data independently. Trials were grouped by asthma control at baseline (symptomatic or well-controlled) and dose of ICS in the control group (same or double). MAIN RESULTS: Of 438 citations, 13 (12 adult and 1 paediatric) trials met inclusion criteria. Seven were published in full-text. In symptomatic patients, addition of licensed doses of anti-leukotrienes to ICS resulted in a non-significant reduction in the risk of exacerbations requiring systemic steroids: Relative Risk (RR) 0.61; 95% Confidence Interval (CI) 0.36,1.05). A modest improvement group difference in PEF was seen (Weighted Mean Difference (WMD) 7.71 L/min; 95%CI 2.98, 12.44 L/min) together with beta2-agonist use (WMD= -0.32 puffs/day; 95%CI -0.0.08, -0.56). No trials that compared the use of licensed doses of anti-leukotrienes with doubling-dose of inhaled glucocorticoids could be pooled.
In ICS-sparing studies in patients who were well controlled at baseline, addition of anti-leukotrienes produced no overall difference in dose of inhaled glucocorticoids (WMD -44.4 mcg/d, 95%CI -147.9, 59.0 mcg/d), but it was associated with fewer withdrawals due to poor asthma control (RR= 0.56, 95%CI 0.35, 0.89). REVIEWER'S CONCLUSIONS: There is insufficient evidence to firmly support the use of licensed doses of anti-leukotrienes as add-on therapy to inhaled glucocorticoids. Addition of anti-leukotrienes to inhaled glucocorticoids may slightly improve asthma control, but the available data do not permit this strategy to be recommended as a substitute for increasing the dose of inhaled glucocorticoids. Addition of anti-leukotrienes may be Associated with superior asthma control after glucocorticoid tapering, but a glucocorticoid-sparing effect cannot be quantified at present.
_____________________________________________________
Chest 2002 Apr;121(4):1028-35
Two-year retrospective economic evaluation of three dual-controller therapies used in the treatment of asthma.
O'Connor RD, O'Donnell JC, Pinto LA, Wiener DJ, Legorreta AP.
Sharp Rees Stealy Medical Center, San Diego, CA, USA.
OBJECTIVE: To compare asthma-related health-care utilization and expenditures for patients prescribed one of three dual-controller therapies: fluticasone plus salmeterol, inhaled corticosteroids (ICS) [excluding fluticasone] plus salmeterol, and ICS plus a leukotriene modifier (LTM). MATERIALS AND METHODS: Asthma-related medical claims from two major health plans were obtained for the 12 months before and after the initiation of dual therapy. A total of 1,325 patients > or = 12 years old with no claims for COPD or respiratory tract cancer were selected from the approximately 3.5 million lives covered. Multivariable regression was used to assess differences in asthma-related expenditures. To compensate for positive skew, all cost variables were log-transformed. RESULTS: Risk-adjusted total asthma-related costs for the fluticasone-plus-salmeterol cohort (n = 121), the ICS-plus-salmeterol cohort (n = 844), and the ICS-plus-LTM cohort (n = 360) [corrected] were $975, $1,089, and $1,268, respectively. Risk-adjusted pharmacy costs were $813, $841, and $996, respectively. Generalized linear modeling, controlling for baseline covariates, indicated that compared to ICS-plus-LTM therapy, fluticasone-plus-salmeterol therapy was associated with a significant reduction in asthma-related total (p = 0.0014) and pharmacy (p = 0.001) costs. Similar results were found when the ICS-plus-salmeterol group and the ICS-plus-LTM group were compared (p = 0.0001).
The number of inpatient, outpatient, and emergency department visits and their corresponding costs were lower for the fluticasone-plus-salmeterol cohort, but were not statistically significant (p > 0.05). CONCLUSION: Results from managed-care practice suggest that treatment with fluticasone plus salmeterol, and more broadly ICS plus salmeterol, yield important cost savings when compared to treatment with ICS plus LTM.1/9/02 re: Safety of leukotriene antagonists in pregnancy A 27 yr. old female with controlled bronchial asthma on inhaled steroids fluticasone 500 micrograms/day, salmeterol and montelukast. Unable to remove montelukast. Now wishes to become pregnant. Please give advice re montelukast in pregnancy. In responding to your question, I consulted Dr. Michael Schatz of the Kaiser Permanente Program in San Diego, CA, one of the world’s leading investigators of the treatment of allergies and asthma in pregnancy. Dr. Schatz kindly responded very promptly to my request for input. His comments are enclosed below. "There are no definitive published human data. Animal studies are reassuring for zafirlukast and montelukast (FDA Category B). Merck has a registry for montelukast. I think the best current recommendation would be to only consider leukotriene antagonists in patients who 1) were well-controlled on one of them prior to pregnancy and who would be expected to have severe recalcitrant asthma without them, or 2) are not controlled during pregnancy on serevent, moderate doses of inhaled steroids, and theophylline (if tolerated). The fact that there is some reassuring registry human data for montelukast (and presumably equivalent efficacy to zafirlukast) probably makes me more comfortable using montelukast than zafirlukast during pregnancy, but I'm not sure this unpublished data is strong enough to make definitive recommendations in that regard."
11/1/01 re: Leukotriene receptor saturation At a recent lunch program, an Allergist stated that leukotriene receptor antagonist would be effective 100% of the time if the leukotriene receptor sites were not saturated. He stated that a course of oral prednisone would free up the receptor site and leukotriene receptor antagonist agents would be effective. Is this correct, effective 100% of the time? How effective? Can it replace inhaled steroids, some MD want to add Singular for all pediatric asthmatic patients and gradually discontinue inhaled steroid. Any studies/information on this treatment? Talk was sponsored by Merck. I am not aware of any evidence concerning the theory that the leukotriene receptors are saturated with effects of corticosteroid therapy on such saturation. I also could not find anything describing these events in a brief Medline search. Therefore, I consulted Dr. Sally Wenzel of the National Jewish Center Medical and Research Center in Denver, an acknowledged expert in the clinical effects of leukotriene antagonists (see enclosed abstract of one of her review articles). Her response is enclosed below. I suggest that you may wish to contact Dr. Jilly Evans of MerckFrost in Canada, as Dr. Wenzel suggests, if you wish to search further in this area of study (see abstract of article in which Dr. Evans is a co-author below). Her address is Department of Pharmacology, Merck Frosst Canada Inc., Pointe Claire-Dorval, QC. Dr. Wenzel's Response
"That is one of the most bizarre stories I have heard! I do not know of ANY data that supports that. If any one would know, it would be Jilly Evans, at MerckFRost in Canada. Even though she works for Merck, she is a pretty straight shooter."
Curr Opin Pediatr 1999 Dec;11(6):540-7
Erratum in:
Curr Opin Pediatr 2000 Feb;12(1):96
Use of leukotriene antagonists in childhood asthma.
Krawiec ME, Wenzel SE.
Department of Pediatrics, National Jewish Medical and Research Center, Denver,
Colorado, USA"Leukotrienes have been shown to cause bronchoconstriction, increased mucus production, and airway inflammation, three critical features in asthma. Antileukotriene drugs were developed to inhibit the effects of these lipid mediators. This class of drugs represents the first new approach to asthma therapy in 25 years. The leukotriene receptor antagonists, montelukast, zafirlukast, and pranlukast, and the 5-lipoxygenase inhibitor, zileuton, are unique in their ability to target specific components of asthmatic inflammation. Although the role of these drugs continues to evolve, the antileukotrienes have demonstrated efficacy against exercise and allergen-induced bronchoconstriction and additive benefit for use in patients with symptomatic, moderate asthma on maintenance-inhaled corticosteroids. Further, they may be considered for primary use in patients with mild, persistent asthma, especially those who are steroid-phobic or who have compliance issues."
J Biol Chem 2000 Sep 29;275(39):30531-6
Characterization of the human cysteinyl leukotriene 2 receptor.
Heise CE, O'Dowd BF, Figueroa DJ, Sawyer N, Nguyen T, Im DS, Stocco R, Bellefeuille JN, Abramovitz M, Cheng R, Williams DL Jr, Zeng Z, Liu Q, Ma L, Clements MK, Coulombe N, Liu Y, Austin CP, George SR, O'Neill GP, Metters KM, Lynch KR, Evans JF.
Department of Pharmacology, University of Virginia, School of Medicine, Charlottesville, Virginia 22908, USA."The contractile and inflammatory actions of the cysteinyl leukotrienes (CysLTs), LTC (4), LTD(4), and LTE(4), are thought to be mediated through at least two distinct but related CysLT G protein-coupled receptors. The human CysLT(1) receptor has been recently cloned and characterized. We describe here the cloning and characterization of the second cysteinyl leukotriene receptor, CysLT(2), a 346-amino acid protein with 38% amino acid identity to the CysLT(1) receptor. The recombinant human CysLT(2) receptor was expressed in Xenopus oocytes and HEK293T cells and shown to couple to elevation of intracellular calcium when activated by LTC(4), LTD(4), or LTE(4). Analyses of radiolabeled LTD (4) binding to the recombinant CysLT(2) receptor demonstrated high affinity binding and a rank order of potency for competition of LTC(4) = LTD(4) LTE(4). In contrast to the dual CysLT(1)/CysLT(2) antagonist, BAY u9773, the CysLT(1) receptor-selective antagonists MK-571, montelukast (Singulair(TM)), zafirlukast (Accolate(TM)), and pranlukast (Onon(TM)) exhibited low potency in competition for LTD(4) binding and as antagonists of CysLT(2) receptor signaling. CysLT(2) receptor mRNA was detected in lung macrophages and airway smooth muscle, cardiac Purkinje cells, adrenal medulla cells, peripheral blood leukocytes, and brain, and the receptor gene was mapped to chromosome 13q14, a region linked to atopic asthma."
3/30/01 re: Throat swelling during montelukast therapy 40 yrs old female with bronchial asthma on inhaled steroids, serevent; was placed on Singulair and about 5 weeks later, reported feeling of swelling in her throat, numbness in her left arm, had no rash and after stopping Singulair, the symptoms have decreased. Please comment. I am not aware of isolated throat swelling as an adverse effect of montelukast (Mon) therapy. I also could find no reference to such an adverse effect in a Medline review. Has the presence of oral mucosal edema been verified by physical exam? Assuming that such angioedema is documented., several questions could be asked:
- Have other causes of oral angioedema been ruled out?- ACE inhibitor-induced?, HAE variant? Oral allergy syndrome?
- Does the patient have aspirin-associated angioedema? There has been a report of aggravation/precipitation of mucosal angioedema by leukotriene-antagonist therapy in such patients.
- Has there been any eosinophilia or other signs of the Churg-Strauss Syndrome (CSS), reported with use of both zafirlukast and Mon? This could explain her neurologic symptoms if she mononeuritis multiplex secondary to the CSS. However, most of the patients reported with such CSS had been on oral steroids for asthma which were the gradually withdrawn when the leukotriene antagonist were added to the treatment program.
From the practical viewpoint, I would not restart the Mon. even in a cautious trial, if asthma control can be maintained on a moderate dose or lower of inhaled steroids.
12/13/00 re: Value of leukotriene antagonist therapy in chronic urticaria What is the current status of accolate in the treatment of urticaria? There have been scattered reports of uncontrolled trials of leukotriene antagonists (LTA) in chronic idiopathic urticaria (CIU). The largest reported experience of which I am aware is the retrospective brief analysis by Bensch and Borish of the National Jewish Medical Center in Denver, CO (Annals Allergy, Asthma and Immunology, 10/99 issue, pg 348). Here they reported a dramatic improvement in 10 of 18 CIU patients formerly unresponsive to antihistamines and often other anti-inflammatory agents who were treated with added montelukast (5 patients), zafirlukast (4 patients) and both zafirlukast and zileuton (1 patient). Onset of clinical improvement was seen within 1 month, often within 1 week. Their brief description of their patient group did nor provide any clue as to predicting which patients would be helped by LTA therapy. Of note, they found that the the beneficial effects of LTA were seen only when these agents were used along with H1-antihistamines. The LTA apparently had no beneficial effect when used alone. For this reason, the authors postulated that one mechanism underlying the beneficial effect of LTA therapy might be a synergistic effect with H1 blockers. They commented that controlled studies were required.
In my discussion with a colleague who treats many CIU patients, he said that he has found impressive benefit of LTA therapy in some, but certainly not all CIU patients.
4/14/00 re: Value of leukotriene antagonists in acute asthma flares Can you please tell me the role of leukotriene inhibitors in ACUTE asthma exacerbations. I know they are not used but why? There is little or no published information about trials of leukotriene receptor (LT) antagonists in acute, severe asthma flares. This apparent lack of interest/enthusiasm for trials of LT antagonists may be related to evidence that these agents induce only modest (about 9%) improvement in FEV-1 within 1-2 hours after oral administration. Although chronic use of LT antagonists may lead to decreased need for beta agonists and decreased frequency of acute flares, these effects may not be prominent or early enough to control acute, severe asthma. I have enclosed my review of a recent review article about leukotrienes in asthma which I wrote for the Current Literature Section of this AADMC web site. You may wish to read the entire review article.
Review of leukotriene antagonists effects in asthma
SUMMARY Barnes of the London Chest Hospital in the UK recently reviewed a large number of studies of the effects of the leukotriene (LT) antagonists zafirlukast and montelukast in asthma. They generally induce an acute improvement of 6-9% in FEV1 starting within one hour of oral administration. When used chronically as monotherapy, there was about 9% improvement in FEV1, 30% decrease in both overall symptoms and rescue beta agonist use and about a 50% decrease in the frequency of acute asthma exacerbations. Although inhaled beclomethasone 400 microgr/day induced , overall, about twice the improvement as did LT antagonists, there was considerable heterogeneity in the response of different patients to both types of treatment. Recent smaller studies have suggested that addition of montelukast or zafirlukast to low dose inhaled steroids led to significant added improvement, sometimes as much as seen by doubling the inhaled steroid dose. However, there has been no strong evidence that LT antagonists have significant steroid-sparing effects.
These agents have been well-tolerated with no evidence of hepatotoxicity but some drug interactions (Coumadin, theophylline) are seen in the case of zafirlukast. It is still uncertain whether the limited number of cases of Churg-Strauss Syndrome (CSS) observed in LT antagonist-treated patients were induced by these drugs or due to unmasking of pre-existent CSS as oral steroid dosage was reduced.
REFERENCE - Am J Respir Crit Care Med 2000;161:S73-S76
EDITOR'S COMMENTS
This is a good, concise, well-balanced review. I agree with the author's conclusions that the exact place of LT antagonists in the anti-asthma therapeutic approach is not fully established. This review is well worth reading by clinicians who wish to use LT antagonists intelligently in asthma2/21/00 re: Use of montelukast in children under 2 years old Looking for latest info on montelukast for children under 2 yrs old Montelukast is currently FDA approved for use in children of 6 years or older. Several recent reviews have suggested efficacy of montelukast in younger children (see enclosed abstracts). I suggest that you contact the office of Dr. Theodore Reiss in Merck to find out if and when Singulair (Montelukast) will be approved for use in younger children. Dr. Reiss has been a leader of Merck¹s research efforts in Singulair. I do not have his telephone number with me but perhaps his office can be contacted through the Professional Services of Merck listed in the PDR. Pediatr Pulmonol 2000 Jan;29(1):46-61
Pharmacotherapy of asthma in children, with special reference to leukotriene receptor antagonists.
Weisberg SC
Department of Medicine, University of Minnesota, Minneapolis, MN, USA.
SCWEISMD@AOL.COM
Asthma in adults is generally recognized as a chronic inflammatory airway disease, although this association is less well established in childhood asthma. Thus, recent asthma guidelines have emphasized that asthma treatment should be directed toward the underlying inflammatory aspects of the disease. The prevalence of asthma and resultant hospitalizations and deaths have increased or remained stable over the past 10 years in the United States. In part, this appears to be caused by shortcomings of available antiasthma therapeutic agents. Because these trends are particularly troublesome in children and young adults, there is a need for effective anti-inflammatory therapies that are safe and tolerable. The leukotrienes are a family of lipid mediators that appear to play an important role in the symptomology and pathogenesis of asthma. The results of clinical trials in adults with asthma demonstrated that antileukotriene drugs such as zafirlukast, montelukast, and zileuton improve pulmonary function, decrease asthma symptoms, and decrease the concomitant use of other antiasthma drugs. Most antileukotriene agents are orally bioavailable and well tolerated, offering the potential for improved patient compliance. Montelukast and zafirlukast have received approval for use in pediatric asthma patients, and approval of zafirlukast in this patient population is pending.Curr Opin Pediatr 1999 Dec;11(6):540-7
Use of leukotriene antagonists in childhood asthma.
Krawiec ME, Wenzel SE
Department of Pediatrics, National Jewish Medical and Research Center, Denver, Colorado, USA.
krawiecm@njc.org
Leukotrienes have been shown to cause bronchoconstriction, increased mucus production, and airway inflammation, three critical features in asthma. Antileukotriene drugs were developed to inhibit the effects of these lipid mediators. This class of drugs represents the first new approach to asthma therapy in 25 years. The leukotriene receptor antagonists, montelukast, zafirlukast, and pranlukast, and the 5-lipoxygenase inhibitor, zileuton, are unique in their ability to target specific components of asthmatic inflammation. Although the role of these drugs continues to evolve, the antileukotrienes have demonstrated efficacy against exercise and allergen-induced bronchoconstriction and additive benefit for use in patients with symptomatic, moderate asthma on maintenance-inhaled corticosteroids. Further, they may be considered for primary use in patients with mild, persistent asthma, especially those who are steroid-phobic or who have compliance issues.3/17/99 re: Lekotr inhibitors My questions is about the role of Lekotr inhibitors (LI) in management of Chronic Asthma. To my knowledge, not all asthmatics respond to LI, and how do we differentiate reponsive vs non-responsive patients and in your opinion which particular patient charateristic will predict responsiveness? Second, are their any studies which looked at efficacy of HIGH Therapetic DOSE inhaled Steroids vs LI? Please also enlighten us with your own experience and success with LI and recomendations about the usage of LI. Any preferences i.e Singular vs Acculate. There have been somewhat varying impressions to date about the role of anti-leukotriene therapy in chronic asthma. I will confine my comments to the leukotriene antagonists (zafirlukast, Accolate and montelukast, Singulair) hereafter abbreviated LA. Although the 5-LO antagonist agent zileuton appears to exert similar efficacy, the need for q6h zileuton dosing and the requirement for monitoring for adverse hepatic effects makes zileuton treatment less attractive. The current recommendation for LA treatment is for mild to moderate asthma, with possibly particular efficacy in those with aspirin-induced asthma. (See responses to previous Ask the Expert Questions). Some investigators report efficacy of LA in more severe asthma but a more general experience is that the efficacy of these agents is about equal or less than low dose inhaled steroids.
My personal preference for LA as monotherapy is in these with mild to moderate persistent asthma (NAEP classification), particularly in individuals like older children and adolescents in whom compliance with chronic inhaled therapy is less reliable. However, airflow measurements must be monitored regularly with addition of inhaled steroid therapy if insufficient improvement is observed after LA monotherapy. In those with more severe asthma, it is worth adding LA therapy in an attempt to reduce the daily dosage of inhaled steroids required for adequate asthma control. Although LA therapy is not officially considered "steroid-sparing", any adjunct therapy that can reduce inhaled steroid dosage is worth considering in face of the current debate about adverse systemic effects of higher dose chronic inhaled steroid treatment.
Insofar as choosing between Singulair and Accolate, I prefer the former only because of its once-daily dosing. Remarkably, the protective effect of Singulair on exercise-induced asthma has been shown to last for at least 18 hours.
4/27/98 re: clinical efficacy of leukotriene receptor antagonists (LTRA) in chronic allergic rhinitis Are leukotriene receptor antagonists showing any benefit in uncontrolled allergic rhinitis? At least two recent studies have shown clinical efficacy of leukotriene receptor antagonists (LTRA) in chronic allergic rhinitis. However, from what I can tell, the patients studied were not those with poor symptomatic control by nasal steroids and antihistamines. Based on what we know about the broader anti-inflammatory action of steroids than LTRA, I would not expect the latter to be impressively efficacious in cases where intranasal steroid treatment had not controlled symptoms. It is possible that the nasal steroid sprays are not reaching the affected mucosal areas in a patient. There are approaches one can use to circumvent this problem. But it is reasonable to try LTRA for a period of several weeks. 9/20/97 re: treatment of mild asthma Which do you think leukotriene inhibitors like Accolate or ß2 antagonists like salmeterol are better for treating mild asthma? Many authorities, particularly in Canada, feel that continuous asthma symptoms, even if relatively mild, warrant anti-inflammatory treatment (e.g., inhaled nedocromil or low-dose inhaled steroids). A minority of investigators feel that excellent control can often be achieved with continued use of salmeterol q12h alone with the understanding that pulmonary air flow is returned to, or close to, normal. Leukotriene antagonists (e.g.) such as Accolate are also used in the treatment of mild asthma, particularly if there is "triad asthma" with nasal polyps and aspirin-induced asthma (where leukotriene release is reportedly much increased). Accolate has had a very reasonable safety profile in early studies. However, the FDA recently sent out an alert about six cases of Churg-Strauss syndrome which had been reported in Accolate-treated patients. It is still too early to say whether this occurrence is a coincidence or not. Almost all patients with the Churg-Strauss syndrome have preceding asthma activity.
7/24/97 re: Churg-Strauss syndrome and Zafirlukast I understand that Zeneca is about to release information regarding reports of an association between Churg-Strauss Syndrome and Zafirlukast. Are there recent independent reports available? I have heard anectodal reports of an apparently increased incidence of Chung-Strauss syndrome in patients receiving Zafinkulast but have not seen results of an independent systematic analysis. A recent FDA alert was sent out about 6 reported cases of apparent Churg-Strauss in Accolate-treated asthmatics. 6/9/97 re: Accolate/Zyflow How does Accolate differ from Zyflo? Accolate is the first released of a group of drugs that block binding of leukotriene D4 (LTD4) to its cell receptor. LTD4 is a potent bronchoconstrictor, increases vascular permeability and may increase mucus secretion. Accolate has been shown to be of value in mild to moderate asthma and particularly in aspirin-induced asthma ("triad asthma"). There is a low incidence of side effects. Zyflow (zileuton) is an inhibitor of the lipoxygenase pathway. This results in reduced production of not only LTC4/LTD4 but also reduced production of leukotriene B4 (LTB4), a potent attractant of neutrophils into inflammatory sites. Zyflow also appears most indicated in mild to moderate asthma. Because reversible hepatotoxicity occurs in a small percentage of treated individuals, particularly in the first months of therapy, regular monitoring of liver function tests is necessary.If you need more assistance, I suggest consulting a certified allergist-immunologist in your region. 800.822.2762
5/14/97 re: urticaria Is there any indication that the new Leukotriene-inhibitors (such as Accolate) may be of therapeutic value in Chronic Urticaria? I know of no impressive improvement following treatment with Accolate of an unselected population of patients with chronic urticaria. Theoretically, one might expect some reduction of Accolate treatment of the urticaria triggered by aspirin ingestion. 1/23/97 re: Accolate use in 5 year old severely asthmatic boy I am a practicing pediatrician in Galesburg, IL and am considering the usage of Accolate in a 5 year old severely asthmatic boy. Do you have any experience in that respect? I checked further into the matter about use of Accolate for asthma in a 5 year old child. Accolate is currently approved for use in children 12 years or older. 1/9/97 re: role of leukotrine inhibitors in the treatment of asthma What is the role of leukotrine inhibitors in the treatment of asthma? In response to your inquiry, recent studies have shown that leukotrienes C4/D4/E4 (identified several years ago as the chemical nature of what had been called "slow reacting substance of Anaphylaxis") play a partial role in asthma. A recently released LTD4 antagonist (Accolate) is listed for the indications of mild-moderate asthma. There is no definitive evidence of steroid -sparing effects. Other LTD4 antagonists and a 5-lipoxugenase inhibitor (blocking the formation of LTC4/LTD4/LTE4) will likely be released fir clinical release soon. These types of drugs may be particularly effective in those with "triad asthma"often characterized by very prominent release of these leukotrienes. If you are not an allergist-immunologist, you may wish to consult such an individual, qualified to help in asthma management.
