Leukotriene and antileukotriene part 2

Anchalee Senavonge MD.
Allergy and Immunology department
Chulalongkorn University

Basic
• Leukotriene
• Anti-leukotriene drugs
Clinical use of anti-leukotriene therapy
• Preschool wheezing
• Asthma
– Add-on therapy or step down in asthma
– AR co-morbid
– Small airway disease asthma
– Aspirin exacerbated respiratory disease
– Exercise-induced bronchospasm
– Passive smoking
– Obesity
– Elderly
• Other diseases

Add-on or Stepdown
treatment in asthma

GINA guideline 2017
Adults, adolescents, children >6 years

Children > 6 yr, adolescents, adults
STEP 2:
• Other options: LTRA are less effective than ICS (Evidence A).
• They may be appropriate for some patients who are unable or unwilling
to use ICS; experience intolerable side-effects from ICS; or concomitant
AR (Evidence B).
STEP 3: Other options
• Other less efficacious options are low dose ICS plus either LTRA
(Evidence A) or low dose, sustained-release theophylline (Evidence B)
STEP 4:
• Other options that can be added to a medium- or high-dose ICS but that
are less efficacious than adding LABA, include LTRA (Evidence A)
GINA guideline 2017

Children 5 years or younger
GINA guideline 2017

Children 5 years and younger
Step 2: other options
• In young children with persistent asthma, regular treatment with a LTRA
modestly reduces symptoms and need for oral corticosteroids
compared with placebo.
• For recurrent viral-induced wheezing, a recent Cochrane review
concluded that neither regular nor intermittent LTRA reduces oral
corticosteroid-requiring exacerbations (Evidence A)
Step 3: other options
• Addition of a LTRA to low dose ICS may be considered, based on data
from older children (Evidence D).
Step 4: options to consider
• Add a LTRA, theophylline, or a low dose of oral corticosteroid (for a few
weeks only) until asthma control improves (Evidence D)
GINA guideline 2017

Randomized, double-blind, placebo-controlled, parallel-group, multicenter
Method:
• 689 patients aged 2 to 5 years with mild to moderate persistent asthma
• Compare montelukast 4-mg tablet with placebo once daily for 12 week
Objective:
• Primary: to determine the safety profile of montelukast, in preschool children
with persistent asthma
• Secondary: effect of montelukast on exploratory measures of asthma control
Knorr B, et al. Pediatrics 2001;108(3).

P=0.003 P=0.042
P=0.007
P<0.001

• Montelukast is effective therapy and superior to
placebo on following outcome measures
• No significant difference in exacerbations rate,
caregiver’s global evaluation, quality of life
• Benefits observed from first day
• Generally well tolerated without clinically important
adverse effects.
Conclusion

• Multicenter, double-blind, parallel-group study
Method
• Children aged 2 to 5 years, intermittent asthma symptoms
• Compare: montelukast 4 or 5 mg (depending on age) (n=278) or placebo (n=271)
once per day for 12 months
Outcomes
• Primary: number of asthma exacerbation episodes
• Secondary: number of oral/inhaled corticosteroids treatment course, duration of
exacerbation episodes
Bisgaard H, et al. AM J Respir Crit Care Med.2005;171:315-22.
PREVIA

▪ Montelukast also delayed the median time
to first exacerbation by approximately 2
months (p= 0.024), and the rate of inhaled
corticosteroid courses (p = 0.027)
compared with placebo.
▪ Montelukast effectively reduced asthma
exacerbations in 2- to 5-year-old patients
with intermittent asthma over 12 months of
treatment and generally well tolerated.
Bisgaard H, et al. AM J Respir Crit Care Med.2005;171:315-22.
PREVIA

GINA 2017; Options for stepping down treatment once
asthma is well controlled

We included studies of individuals
with stable asthma who stopped ICS
and substituted LTRA (versus
continuing ICS) and who reduced
ICS while starting LTRA (versus
placebo)
Allergy Asthma Proc 36:200–205, 2015

• 4 studies met criteria
• 1 article: increased risk of treatment failure of 30.3% vs
20% for continuing ICS
• 3 articles:,modestly decreased risk ratio that favored
LTRA 0.57 (95% CI, 0.36–0.90)

• Leukotriene are continuously present in the
airways in asthma and play an important role
in maintaining baseline bronchoconstriction
• LTRA and β-agonist
– work through different bronchodilator
pathway
– concomitant treatment with β-agonist
induces additive effect on the
bronchodilation
Wanzel SE. Middleton’s Allergy, 8th edition

• Alternatives to ICS in the treatment of mild
persistent asthma, primarily in those patients who do
not response or who choose not to take ICS.
• Alternative add-on therapy to ICS in patients still
symptomatic while taking single-controller therapy.
• Aspirin-sensitive asthmatic patients
• Mild intermittent asthma, where exercise is a
significant trigger.

Patient with nocturnal asthma
• Increase in airway eosinophils at 4 AM
• Increase urinary LTE4 at night
• Increase in both LTB4 and cysLTs in BAL fluid
at night
Zileuton
• Decreased BAL eosinophils, urinary and BAL
leukotriene levels
• Improved pulmonary function and symptoms

• Pranlukast hydrate and montelukast
• LTRA are used concomitantly with an ICS in patients with asthma that
cannot be completely controlled with medium dose of an ICS
• Additional administration of LTRAs is as effective as a double-dose of an
ICS
• Compared with LABAs, LTRAs are less effective in improving asthma
symptoms and respiratory function and in preventing exacerbation
• LTRAs are useful for asthma complicated by allergic rhinitis, exercise-
induced asthma, and aspirin-exacerbated respiratory disease
Allergology International 2017

• 80 patients treated with an beclomethasone dipropionate 800– 1200
mg/day and bronchodilators for > 3 months, but symptoms persisted
• One group add pranlukast hydrate (225 mg bid), other group without
changes for 4 weeks
K Wada et al. Allergology International (2000) 49: 63–68
LTRA, pranlukast hydrate, is a useful agent for symptomatic asthma who treated with
moderate to high doses of ICS

Allergology International 2017

Allergology International, April 2017

• LTRAs improve respiratory function and reduce the frequency of exacerbations
within 1st weeks after administration
• In patients with mild persistent asthma, LTRAs are as effective as ICSs. (Ref:
Mosaic study 2005, Ann Allergy Asthma Immunol. 2003)
• Efficacy of LTRAs as add-on therapy to ICSs has also been demonstrated.

• The Montelukast Study of Asthma in Children
• 12-month, multicenter, randomized, double-blind, noninferiority trial
• 6 to 14 years of age, mild persistent asthma
– once-daily, oral montelukast (5 mg) (n=495)
– twice-daily, inhaled fluticasone (100 mg) (n=499)
• Percentage of asthma rescue-free days (RFDs)
Garcia M, et al. Pediatrics 2005;116:360–369
MOSAIC study

Efficacy End Points
▪ Montelukast: not inferior to fluticasone in
increasing the percentage of RFDs among
6- to 14-year-old patients with mild
asthma.
▪ Secondary end points: percentage of
predicted FEV1, days with b2-receptor
agonist use, and quality of life, improved
in both groups but were significantly
better in the fluticasone treatment group.
Garcia M, et al. Pediatrics 2005;116:360–369

Ann Allergy Asthma Immunol. 2003
• Open-label, prospective, observational study
• Method: Children 6 - 15 years with mild asthma, not currently
receiving controller therapy, assigned to fluticasone two 44 mcg puffs
twice or montelukast 10 mg ->questionnaire at 6 and 12 months
• Primary objective: rate of asthma attacks requiring emergent medical
care

Ann Allergy Asthma Immunol. 2003
• Adherence significant better for Montelukast
Summary: oral montelukast and
inhaled fluticasone have similar
real-world efficacies in the
treatment of children with mild
asthma, possibly as a result of
the significantly better
adherence

Cochrane Database Syst Rev 2017 Mar 16;3
37 studies representing 6128 adult and adolescent participants (most with mild to
moderate asthma)
• For adolescents and adults with persistent asthma, with
suboptimal asthma control with daily use of ICS, the addition of anti-
leukotrienes is beneficial for reducing moderate and severe asthma
exacerbations and for improving lung function and asthma control
compared with the same dose of ICS.
• We cannot be certain that the addition of anti-leukotrienes is superior,
inferior or equivalent to a higher dose of ICS.
• Scarce available evidence does not support anti-leukotrienes as an ICS
sparing agent

• The addition of LABA (compared to LTRA) to ICS was associated with a
statistically greater improvement from baseline in lung function, as well
as in symptoms, rescue medication use and quality of life, although the
latter effects were modest.
• LTRA was superior in the prevention of exercise-induced
bronchospasm
18 RCTs (7208 participants), of which 16 recruited adults and adolescents
(6872) and 2 recruited children 6 to 17 years of age (336)
Cochrane Database Syst Rev 2014 Jan 24;(1)

• Histamine has long been implicated as a major mediator
• In contrast to histamines, LTs such as LTC4 and LTD4 contribute to
vascular permeability and vasodilation, resulting in mucosal
swelling, which causes rhinorrhea and nasal congestion
• Nasal congestion in the early phase and late phase is accompanied
by a significant increase in CysLTs in nasal lavage fluid from AR
patient
• In recent animal studies, nasal LTD4 challenge was shown to
increase nasal airway resistance
Marcello and Carlo. Asthma Research and Practice 2016, 2:11

• Montelukast is comparably
effective to oral AHs (loratadine
as usual comparator),
combination may have a small
additive effect
• In AR with asthma, montelukast
may be advantageous over AHs
because potential to offer
benefits in both conditions
• LTRA could be beneficial as
adjunctive or even sole
treatment for nasal polyps
Allergy 2015; 70: 474–494.

Allergic Rhinitis and its Impact on Asthma (ARIA)
Guidelines – 2016 Revision

Curr Opin Allergy Clin Immunol 7 Jun 2017

• Leukotriene receptors are differently expressed in
fibroblasts from peripheral compared to central airways
• Mechiche et al. reported that the CysLTs were about
30-fold more potent in small than in large bronchi
• Studies suggested CysLT driven remodeling mainly in
the peripheral airways and possibly resulting in a
predominant effect of montelukast on the small airways
Marcello and Carlo Asthma Research and Practice 2016, 2:11

• Randomized, open-label, parallel comparison study
• 60 patients with stable asthma receiving ICS
• Intervention: 24-week add-on with 1) ciclesonide 400 mcg od (n =
19), 2) montelukast 10 mg od (n = 22), or 3) none (n = 19)
• Outcome: small airway markers- extended nitric oxide analysis, PFT,
blood eosinophil counts and asthma control tests (ACTs)
Nakaji H et al. Ann Allergy Asthma Immunol. 2013;110(3):198–203.

AX levels in montelukast group improved over time
compared with control (P=0.05)
Ciclesonide and montelukast add-on
therapy may act differently, but both
separately can improve small airway
abnormalities and provide better asthma
control
PFT, eosinophils-no significant differences
ACT improve in both groups
Nakaji H et al. Ann Allergy Asthma Immunol. 2013;110(3):198–203.

J Allergy Clin Immunol 2017;139:764-6.

• In AERD, subjects display dramatic upregulation of 2
essential enzyme involved in CysLT synthesis, LO and
LTC4S
• CysLTs demonstrate important proinflammatory and
profibrotic effects that contribute to the extensive hyperplastic
rhinosinusitis and nasal polyposis
• Lipid mediators (CysLTs), responsible for differentiation,
survival, and activation of eosinophils

• 10% of adult asthmatic patients sensitive to aspirin
• Bronchoconstriction associated with increased
production of cysLTs at baseline and after aspirin
challenge
• Mechanism: not clear, although studies suggest that
– increase in mast cells
– increase activated eosinophils
– increase expression of LTC4 synthase and CysLT2

• Antileukotrienes should be a part of any treatment course for
AERD to deal with the actual dysregulation of leukotriene
production
• Both LTRAs (montelukast, zafirlukast) and inhibitors of LT
synthesis (zileuton) work well for AERD
• As a practical matter, most physicians choose „„an oral LTRA‟‟
for initial therapy, as opposed to zileuton (requires twice-daily
administration, need periodic monitoring of liver function,
some potential drug interactions
Eur Arch Otorhinolaryngol (2017) 274:1291–1300

Practice parameter; Exercise-induced bronchoconstriction update, JACI2016
• Strong evidence that leukocyte-
derived eicosanoids, including
CysLTs and PGD2, are released
into airways after an exercise
challenge
• LTD4 mediate airway narrowing at
a lower concentration than other
mediators, such as PGD2,
histamine, or methacholine

• Consider daily leukotriene inhibitors because not lead to tolerance
and shown to attenuate EIB in 50% (30-80%)
• Can be used for intermittent or maintenance prophylaxis
• No response: other mediators (eg, PGD2, histamine) may be
involved
• Most studies examined specific LTD4 receptor antagonists,
particularly montelukast
– Bronchoprotective within 1-2 hr, also accelerates recovery
• Lipoxygenase inhibitors shown to attenuate EIB but duration of
inhibition is relatively short- not currently recommended

If the maximal percent
decreases of
FEV1>15% and
PEF>20%, a diagnosis
of EIA is confirmed

• In asthmatic children, exposure to tobacco smoke
(higher cotinine levels) is associated with higher
urinary LTE4
• Rabinovitch et al.
– followed 27 school-children for 5 months with urinary
LTE4, cotinine, FENO, albuterol use
– randomized to receive daily montelukast or placebo
without change in current controller
– Montelukast was more effective in tobacco exposure
group, suggesting CysLT might play a role

• Worse asthma control
– Different type of airway inflammation
– Comorbidities such as OSA and GERD
– Mechanical factors
– lack of fitness and reduction in lung volume due to
abdominal fat
• Increased expression of 5-LO pathway and key
members of the LT synthesis pathway are
overexpressed in adipose tissue during obesity,
resulting in increased LTs levels in this tissue
GINA guideline 2017

• ICS are the mainstay of treatment in obese patients
(Evidence B), although their response may be reduced
Peters-Golden et al.
• In lean patients, beclomethasone: higher asthma control
than montelukast, at 18.6 % versus 9.5 % (P < 0.001).
• beneficial effect of ICS vs LTRA became less as BMI in-
creased, 18.8 % vs 15.7 % in overweight (P = 0.25), and
13.9 vs 13.4 (P = 0.90) in obese
• Authors concluded that obese patients with asthma had a
better response to montelukast
GINA guideline 2017
Peters-Golden M. Eur Respir J. 2006;27:495–503

Peters-Golden M. Eur Respir J. 2006;27:495–503

• Asthma is highly frequent, ranging from 4.5 to
12.7 %
• Multiple comorbid conditions, prone to have
poor inhaler technique/adherence, lack of
care-givers and cognitive impairment
• Montelukast, compared with the inhaled
agents, could represent a more effective,
given that unintentional nonadherence

Allergy Asthma Immunol Res. 2015 September;7(5):440-448
• A randomized, open-label, parallel-designed trial 12 weeks
• Either 800 μg of inhaled budesonide (800BUD) or 400 μg of
budesonide plus 10 mg of montelukast (MON-400BUD)
• The primary endpoint was the rate of “well-controlled asthma
status” after the 12-week
efficacy of 12-week MON- 400BUD in older
asthmatics was comparable to 800BUD

The numbers of asthma exacerbations requiring oral corticosteroid treatment (20
vs 8) and sore throat (22 vs 11) significantly higher in 800 BUD group than MON-
400BUD.
Allergy Asthma Immunol Res. 2015 September;7(5):440-448

EAACI/GA2LEN/EDF/WAO urticaria guideline

• "leukotriene receptor antagonists can
be considered for patients with CU with
unsatisfactory responses to second-
generation antihistamine monotherapy"
JACI. Vol 133. Number 5

• Objectives: To assess the available evidence for an effect of
leukotriene receptor antagonists (LTRAs) on the ocular symptoms of
allergic eye diseases.
• 6 studies were suitable for meta-analysis, in patients with seasonal
AC
• Conclusions: In seasonal AC, LTRAs are more efficacious than
placebo but less efficacious than oral antihistamines in adult patients.
Gane J, et al. J AllergyClin Immunol: In Practice 2013;1:65-74

▪ Two double-blind studies of montelukast in atopic
dermatitis showed no efficacy over placebo.
Recommendation
• Because of the contradictory results from the
published trials, montelukast is currently not
recommended for the treatment of moderate-to-
severe AD.
Roekevisch E, et al. J Allergy Clin Immunol 2014;133:429-38
Veien NK, et al. J Am Acad Dermatol 2005;53:147-9
Friedmann PS, et al. Clin Exp Allergy 2007;37:1536-40.

• 5 studies with a total of 1296 participants under two
years of age hospitalized with bronchiolitis
• Primary outcomes:
1. Length of hospital stay. 2. All-cause mortality
Cochrane Database of Systematic Reviews 2015, Issue 3

The current evidence
does not allow definitive
conclusions to be made
about the effects of
leukotriene inhibitors on
length of hospital stay
and clinical severity
score in infants and
young children with
bronchiolitis
Cochrane Database of Systematic Reviews 2015, Issue 3

• 4 trials, 1430 infants with confirmed diagnosis of acute
bronchiolitis
• Primary outcome of this analysis was incidence of
recurrent wheezing
Pediatr Allergy Immunol 2014: 25: 143–150.

• Incidence of recurrent wheezing -not significant RR 0.78 (95% CI: 0.55–1.12)
• 2 trials reduce the frequency of recurrent wheezing (29,31)
• no significant effects on symptom-free days, reducing the usage of
corticosteroids
• side effects of rash, vomiting, insomnia occurred in 1.5%
Pediatr Allergy Immunol 2014: 25: 143–150.

Allergic Rhinitis and its Impact on Asthma (ARIA) Guidelines –
2016 Revision

Biomedicine & Pharmacotherapy. July 2016. 989–997
• Montelukast has a significant influence in improving patients' nasal
symptoms quality of live but is not as effective as antihistamine
• may have a slight advantage SAHs in relieving nighttime symptoms
significantly
• Combined therapy is more effective in improving patients' day time
symptom than Montelukast alone

Antileukotrienes may be useful for children with adenotonsillar hypertrophy due to
their anti-inflammatory effects, which help to reduce adenotonsillar inflammation.
Eur Arch Otorhinolaryngol (2016) 273:4111–4117

• Cys-LT, important inflammatory mediator, postulated to
contribute to CVDs such as atherosclerosis and ischemia
inducing the proliferation of endothelial and SMCs, thus
provoking vasoconstriction and reduction of coronary blood flow
• Studies give evidence of a potential protective role through its
antiapoptotic and anti- inflammatory activities
• limited number of studies in human
Eur J Clin Pharmacol (Apr 2017) 73:799–809

• Overexpression of 5-LOX and CysLT1 increase cell migration
and metastasis in pancreatic, lung, and breast cancers.
• Expression of 5-LOX, CysLT1, and CysLT2 is upregulated in
human glioma cells
• Both montelukast and zafirlukast inhibited migration and invasion
of glioma
• Suggest a role, potential drugs to reduce migration and invasion
Cell Mol Neurobiol, 6 Jun 2017

Leukotriene and antileukotriene part 2

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