Leukotrienes and anti leukotriene (part 1)

Basic
• Leukotriene
• Anti-leukotriene drugs
Clinical use of anti-leukotriene therapy
• Preschool wheezing
• Asthma
– AR co-morbidity
– Small airway disease
– Chronic asthma/ add-on therapy, step down
– Aspirin exacerbated respiratory disease
– Exercise-induced bronchospasm
– Smoking
– Elderly
• Other diseases

• Originally termed slow-reacting substance (SRS)
described first by Feldberg and Kellaway in 1938
– Observation made by demonstrating substances
released from perfused lung by antigen challenge
– Later time points after exposure to cobra venom when
the histamine declined, they further discovered that
contracted guinea-pig ileum with a slow onset and
sustained
Clinical and Experimental Allergy Reviews, 2001, Volume 1, Number 3
Wilhelm FeldbergCharles Kellaway in his laboratory at the
Walter and Eliza Hall Institute

• In 1959, Walter Brocklehurst, confimed that SRS-like
activity released following anaphylactic challenge of
sensitized tissues and named `slow-reacting substance
of anaphylaxis‘ (SRS-A)
• In 1979, the name leukotriene, introduced by Swedish
biochemist Bengt Samuelsson
Clinical and Experimental Allergy Reviews, 2001, Volume 1, Number 3

• “leuko” = white blood cells
• “trienes”= three conjugated double bond
• A family of eicosanoid inflammatory
mediators produced in leukocytes
• Comprise a family of products of the 5-lipoxygenase
pathway of arachidonic acid metabolism
Golden MP, et al. N Engl J Med 2007;357:1841-54.

• Leukotrienes are potent lipid mediators formed
from arachidonic acid through multiple enzymatic
steps
– Cysteinyl LT (cysLTs): LTC4, LTD4, LTE4
– LTB4
• Importance in the clinical course and physiologic
changes of asthma
Wanzel SE. Middleton’s Allergy, 8th edition

• Phospholipids, ubiquitous elements of cellular
membranes enzymatically metabolized by
phospholipases to arachidonic acid (AA)
• AA further metabolized:
1. Cyclooxygenase pathway
2. Lipoxygenase pathways (5-LO pathway)
• Which pathway depends on specific cell type and
stimuli

• Initiated by 5-lipoxygenase (5-LO) in concert
with 5-LO activating protein (FLAP)
• leads to the production of an unstable
intermediate known as LTA4
• LTA4 →LTB4 by LTA4 hydrolase
• LTA4 →LTC4 by LTC4 synthase
• LTC4 →LTD4 →LTE4

Drazen JM, et al. N Engl J Med 1999;340:197-206.

• LTC4 synthase
– metabolizes LTA4 to LTC4 through a glutathione
transferase
– resides on chromosome 5q, a region associated
with many other genes linked with asthma and
atopy
• LTC4 is then rapidly metabolized to LTD4 and
LTE4, through enzymes γ-glutamyl
transpeptidase and dipeptidase

• Based on distribution of the necessary
enzymes, leukotrienes are produced almost
exclusively by cells of the myeloid lineage
• LTC4 is produced primarily by mast cells,
basophils, and eosinophils
• LTB4 is produced primarily by neutrophils
and monocytes/macrophages

• LT act by binding to specific heptaheplical
receptors on outer membrane of
inflammatory cells
• Once ligated by LT, these receptors interact
with G proteins in cytoplasm by ↑
intracellular Calcium and ↓cyclic AMP

• LTB4 receptors
– BLT1 receptor
– BLT2 receptor
• CysLT receptors
– CysLT1receptor
– CysLT2receptor

Receptor Location Affinity Chromosome
BLT1
Monocyte, lymphocytes,
neutrophils, eosinophils,
High 14q11
BLT2
PMNs, monocytes,
endothelial cells
Low 14q
CysLT1
B lymphocytes, mast cell,
basophils, eosinophils,
monocyte/macrophages,
airway smooth muscle
LTD4 > LTC4 > LTE4 Xq13-21
CysLT2
Airway smooth muscle, lungs
macrophages, Purkinje cells,
peripheral leukocytes, mast
cells, brain
LTC4 = LTD4 > LTE4
13q14

• BLT1 is high-affinity receptor for LTB4 that
mediates chemoattractant and proinflammatory
action
• BLT2 is lower-affinity receptor for LTB4
• CysLT1 expression influenced at transcriptional
level by Th2 cytokines
– explains why CysLT1 is overexpressed in with asthma
or chronic rhinosinusitis who have aspirin sensitivity

The Journal of Biological Chemistry. Vol 288, No 16, ,April 2013

Proc Natl Acad Sci U S .A 2016 May, Vol113. No 22

Physiologic properties
• Role of CysLT
– Most of the actions is mediated by CyrLT1 receptor
– Potent bronchoconstrictors (100 to 1,000 times > histamine)
– Impact VQ mismatch and associated hypoxemia
• CysLT1 receptor antagonists effective in dose-dependent
reduction in the bronchoconstriction and V/Q mismatch
• LTB4
– No bronchoconstrictive or hyperresponsive qualities in
humans

Inflammatory properties
• CysLTs
– Chemoattractant properties
– Prolonging eosinophil survival
– Cofactors for enhanced production of eosinophils
from the bone marrow
• CysLTs : present in asthma and relate to inflammation
– Increased: patients with asthma, after allergen
challenge or exercise challenge
– Decreased: effective treatment

• LTC4 synthase knockout mice showed a marked effect to
levels of IgE and Th2 mRNA expression both in lung and in
parabronchial LN
• LTB4
– Potent chemoattractant for neutrophils, eosinophils
– Activator of neutrophils, enhance adhesion and
migration of the cells through endothelium
– Affect eosinophils less than cysLTs
• Both cysLTs and LTB4  active role in the early phases of
allergic responses, as well as later effectors of
bronchoconstriction

Fluid measurement
• CysLTs increased in
– Asthmatic BAL fluid after allergen and aspirin
challenges
– Asthmatic BAL fluid at night in nocturnal
asthmatic patients
– Nasal fluid after RSV infections
• LTs are increased in urine from asthmatic patients
with an acute exacerbation and are decreased with
resolution of the exacerbation

Concentrations of LTC4 in bronchoalveolar lavage fluid (BALF) before
and after endobronchial allergen challenge
LTC4 levels were significantly higher after
allergen challenge in atopic asthmatic
subjects than in prechallenge and control
groups (P < .05).

Drug Discovery Today, Volume 12, Numbers 9/10, May 2007

• Inhibitors of the 5-LO enzyme
– Block FLAP
• MK-886: atherosclerosis
• Veliflapon (BAY-X-1005, DG-
031): acute coronary
syndrome, phase 3
• MK-591
• ABT-080
• AM-103: phase 1
• AM643, AM679: ocular
inflammation diseases
– 5-LO inhibitors
• Zileuton
• Atreuloton
•Antagonism of cysLT1
receptors
•Montelukast
•Zafirlukast
•Pranlukast
Bioorg. Med. Chem. Lett. 25 (2015) 2607–2612

CysLT1 antagonists
• montelukast
• Zafirlukast
• pranlukast
Zileuton directly
inhibits 5-LO
FLAP inhibitor

Pharmacologic antagonism and inhibition
• Biologic difference between the LTRAs and the 5-LO inhibitors
– LTRAs inhibit the activity of cysLTs at CysLT1 only
– 5-LO inhibitors block the production and all downstream
activity of both LTB4 and cysLTs
*
*
*
*

FPL 55712 is a prototype antagonist
Mini-Reviews in Medicinal Chemistry, 2008, Vol. 8, No. 6

Mini-Reviews in Medicinal Chemistry, 2008, Vol. 8, No. 6

• Mechanism: binds with high affinity and selectivity to CysLT1
receptor
• Indication
1. Prophylaxis and chronic treatment of asthma in ≥12 mo
2. Acute prevention of EIB in ≥6 years
3. Relief of symptoms: seasonal AR ≥2 yr, perennial AR ≥ 6 mo
• Dosage
– ≥15 yr: one 10-mg tablet
– 6 to 14 years: one 5-mg chewable tablet
– 2 to 5 years: one 4-mg chewable tablet or one 4-mg granules
– 6 to 23 months: one 4-mg oral granules
– No adjustment is required in mild-to-moderate hepatic or renal
insufficiency
• Metabolism:
– mean Cmax in 2 to 2.5 hr, HL 2.7-5.5 hr
– excreted almost exclusively via the bile
– CYP3A4, 2C8, and 2C9
AAAAI, Allergy and Asthma medication guide, April 2016

• Adverse effects
– Most common: upper respiratory infection, fever,
headache, pharyngitis, cough, abdominal pain, diarrhea,
otitis media, influenza, rhinorrhea, sinusitis, otitis
– Neuropsychiatric events: agitation, aggressive behavior or
hostility, anxiousness, depression, disorientation,
disturbance in attention, dream abnormalities,
hallucinations, insomnia, irritability, memory impairment,
restlessness, somnambulism, suicidal thinking
– Eosinophilic conditions: systemic eosinophilia, Churg-
Strauss syndrome
– Phenylketonuria: chewable tablets contain phenylalanine
(component of aspartame)

• Drug interaction
– recommended clinical dose: no effect on theophylline,
prednisolone, oral contraceptives, Terfenadine, Digoxin, and
Warfarin
– CYP Enzyme Inducers: Phenobarbital dec concentration
• Geriatric: No overall differences in safety or effectiveness
observed, HL slightly longer
• Pregnancy and lactation: category B, excreted in rat milk,
not known in human

• Mechanism: competitive receptor antagonist of LTD4 and LTE4
• Indication: prophylaxis and chronic treatment of asthma in adults
and children 5 years of age and older
• Dosage
– >12 yr 20 mg, 5-11 y 10 mg twice daily
– Adjustment: not required for renal impairment, contraindicated in
hepatic impairment
– food can reduce the bioavailability (take 1 hr before or 2 hr after)
• Metabolism
– Peak concentration 3 hr, HL 10 hr (8-16 hr)
– excreted in the feces are formed through CYP2C9
AAAAI, Allergy and Asthma medication guide,
April 2016

• Adverse effect
– Hepatotoxicity: Cases of life-threatening hepatic failure have
been reported, periodic LFT
– Eosinophilic conditions: systemic eosinophilia, eosinophilic
pneumonia, or Churg-Strauss syndrome
– Neuropsychiatric events: insomnia and depression
• Drug interaction: ↑warfarin, theophylline level
• Geriatric: above 65 years ↓clearance
• Pregnancy and lactation: category B, excreted in BM
April 2016

• Mechanism: inhibit 5-LO
• Indications: prophylaxis and chronic treatment of
asthma in adults and children >12 years
• Dosage
• 600 mg extended-release twice daily, max 2400 mg
• Adjustment: not required for renal impairment,
contraindicated in hepatic impairment
• Food ↑ bioavailability- administered with food (WI 1 hr)
• Metabolism
• HL 3.2 hr
• Metabolised by CYP1A2, CYP2C9 and CYP3A4
April 2016

• Adverse effect
• Most common: sinusitis, nausea, pharyngolaryngeal pain
• Hepatotoxicity: ↑hepatic enzymes and bilirubin. LFT monthly
for first 3 mo, q 2-3 mo for 1st year, periodically thereafter
• Neuropsychiatric: sleep disorders and behavior changes
• Drug interaction: ↑ theophylline, warfarin, propranolol
levels
• Geriatric use: females ≥65 years ↑ risk of ALT elevations
• Pregnancy and lactation: category C, excreted in rat milk,
not known in human milk
April 2016

• All leukotriene modifier are metabolized by the liver and
interactions with other drugs metabolized by the cytochrome P-
450 enzyme system
• Food interfere absorption of Zafirlukast
• Zileuton: metabolized by specific CYP system that metabolizes
theophylline
• decrease the theophylline dose by 50%-monitor
theophylline level
• Montlukast not have any known drug interaction

• Possible associated with Churg-Strauss syndrome
–All these symptoms require assessment with a minimum of
CXR and peripheral eosinophil count
• In 2009 the FDA concluded that there were sufficient reports of
neuropsychiatric changes after initiation of therapy with
leukotriene-modifying drugs that this was added as a precaution
to consider when prescribing these agents
–However, this association remains controversial
–Asthma itself is associated with a higher rate of suicide and
other neuropsychiatric disorders, such that the true relevance
of this observation remains poorly understood.

Gluck JC, et al. American Journal of Obstetrics and Gynecology.2005; 192, 369e80
*
*
*

• Tendency for development of LT synthesis inhibitors as
therapeutics with focus on FLAP inhibitor
• FLAP inhibitors: GSK2190915, AZD6642, BRP-7
• 5-LO inhibitors: only Zileuton is launced, but suffers
from a short half life (3 hrs) and strong plasma protein
binding (93%), exhibits liver toxicity
• Only few LTA4 hydrolase and LTC4 synthase inhibitors
were reported
Expert Opinion on Therapeutic Patients, 2017

• Decrease circulating blood eosinophils
• Pranlukast
– reduction in EG2-positive cell in the tissue after 4 wks of
therapy
– reduction in eosinophils
– no significant impact on FEV1
• Montelukast
– decrease in tissue eosinophils compared to baseline,
compared to placebo was not statistically significant.
– no decrease in eosinophil numbers, less anti-inflammatory
effects than with fluticasone.

• play a role in response to anti-leukotriene therapy
• Certain mutations in the promoter region of 5-LO or LTC4 synthase
enzymes contribute to the level of response
• With the 5-LO promoter, certain polymorphisms may ↓production
of leukotrienes, thereby ↓response
• Polymorphisms in 5-LO: (ALOX5) response to montelukast was
greatest in patients (~36%) with mutant allele in the 5-LO promoter
• Polymorphisms in LTC4 synthase: A−444C polymorphism
associated with asthma, aspirin intolerance

• 5-LO is encoded by ALOX5, located on chromosome
10q11.21
• The ALOX5 gene encodes 5-LO—the rate-limiting
enzyme in cysLT biosynthetic pathway
• This polymorphism results from variable numbers of
copies of the Sp1 binding motif GGGCGG, whereby 5
Sp1 repeats are the major allele
• Classified as 5/5, 5/x and x/x
• Telleria et al. reported increased montelukast
responsiveness in adults with the 5/5 and the 5/x
genotype (compared with x/x)
Lancet Respir Med 2014; 2: 796–803
Clin Exp Allergy. 2013 May ; 43(5): 512–520

270 children 6-17 years old with poorly controlled asthma
Children who were homozygous for variant alleles had
significantly higher urinary LTE4 levels, significantly worse
FEV1% predicted and a trend toward worse asthma
Clin Exp Allergy. 2013 May ; 43(5): 512–520

Marcello and Carlo. Asthma Research and Practice 2016, 2:11

 Effect on allergen-induced inflammation
 Effect in nocturnal asthma
 Anti-inflammatory effects in chronic
asthma
 Exercise-induced bronchoconstriction
 Aspirin-induced asthma

Asthma
with AR
Asthma with
small airway
disease
Chronic
asthma
Obesity Smoking Elderly
EIB AERD
Preschool
wheezing

Pediatrics, Volume 137, number 6, June 2016

• 52-week, open-label, randomized, active-controlled,
multicenter study
• 202 patients, 2-4 yr, mild persistent asthma or >= 3 wheezing
episodes in 1 yr that lasted >1 day and affected sleep
• Budesonide inhalation suspension (BIS) 0.5 mg or
montelukast 4 to 5 mg once daily.
• Primary outcome: first additional asthma medication
Szefler et al. JACI in practice 2013, vol1, No1

no significant difference
between treatments in the
primary end point; however,
several secondary outcomes
showed statistically significant
differences

Summary
• Both BIS and montelukast are effective and well-tolerated asthma
medications in children 2 to 4 years of age with mild asthma, with
potentially greater benefits in terms of efficacy and asthma control
for BIS than for montelukast.

Bacharier et al. JACI 2008 December; 122(6): 1127–1135
• dbRCT, placebo-controlled, 12 month trial
• 238 children aged 12-59 months with moderate-severe intermittent
wheezing
• 7-days of either budesonide inhalation suspension (1mg bid),
montelukast (4mg OD), or placebos in addition to albuterol with each
identified respiratory tract illness
• Primary outcome: proportion of episode-free days (EFDs)

Summary
• In preschool children with moderate-to-severe intermittent
wheezing, episodic use of either budesonide or montelukast early in
respiratory tract illnesses, when added to albuterol, did not increase
the proportion of EFDs or decrease oral corticosteroid use over a 12-
month period.
• However, indicators of severity of acute illnesses were reduced,
particularly in children with positive API

• Szefler et al. JACI 2005
• INFANT trial, JACI 2016
• WAIT trial, Lancet Respir Med 2014
Burbanka and Szefler. Current and future management of the young child with early onset wheezing.
Curr Opin Allergy Clin Immunol 2017
Bacharier et al. Management of preschool recurrent wheezing and asthma: a phenotype-based approach.
Curr Opin Allergy Clin Immunol 2017

• 126 participants, 6 to 17 years with mild-to-moderate persistent
asthma
• Crossover sequence , 8 weeks of
1. Fluticasone propionate(100 mg bid)
2. Montelukast(5-10 mg)
• Outcome: improvement in FEV1
Szefler et al. JACI 2005
Burbanka and Szefler. Curr Opin Allergy Clin Immunol 2017

• Response to Montelukast: younger
age, shorter disease duration, lower
FeNO, peripheral eosinophil and
serum IgE level
• Response to Fluticasone: higher
exhaled nitric oxide, eosinophil
counts, serum IgE, and eosinophil
cationic protein and lower levels of
methacholine PC20 and pulmonary
function

Summary
• Children with low pulmonary function or high levels
of markers associated with allergic inflammation
should receive ICS therapy
• Other children could receive either ICSs or LTRAs

• Multicenter, randomized, double- blind, double-dummy trial
• 300 children 12-59 mo, step 2 treatment of asthma
• Randomized cross-over of three 16-week treatment
1. Fluticasone propionate 44 µg/dose bid
2. Montelukast 4 mg hs
3. As-needed ICS (FP 44 µg/dose bid) with SABA albuterol
sulfate
• Primary outcome: differential response to 3 therapies
– time from start of treatment to an exacerbation treated with
systemic corticosteroids
– annualized number of asthma control days (ACDs) within the
period
Fitzpatrick AM et al. JACI 2016

60/230 (26%) non-differential
responder
had indicators of less disease activity
(more ACDs and lower exacerbation
probability)
170/230 (74%) differential
responder
ICS As-
neede
d ICS
LTRA

Aeroallergen sensitization, but
not exacerbation history or sex,
was associated with a
differential response favoring
daily ICS

Blood eosinophils
≥300/µL also
associated with a
higher probability of
responding best to
daily ICS

Serum ECP levels ≥10 µg/L and dog and/or cat
sensitization also predicted better response to daily ICS

mAPI status, serum IgE and
urinary LTE4: not predict
differential response pattern

Summary
• Daily low dose ICS is the most effective therapy for the
majority of young children with asthma and recurrent
wheezing for whom with daily controller is warranted
• Phenotypic heterogeneity is associated with differential
responses
• Biomarkers of type 2 inflammation, namely aeroallergen
sensitization and blood eosinophils ≥300/µL, can be used to
identify whom daily ICS is beneficial

• Multicenter, parallel-group, randomised, placebo-controlled trial
• 1,358 children aged 10 months to 5 years with >=2 wheeze episodes
allocated to either a 5/5 or 5/x+x/x ALOX5 promoter genotype stratum
• Randomly assigned (1:1) to receive intermittent montelukast or placebo
at each wheeze episode over a 12 month period
• Primary outcome: unscheduled medical attendance for wheeze (USMA)
WAIT trial

Time to first unscheduled
medical attendance, reduced in
5/5 stratum but not in 5/x+x/x
Mean number of courses of
rescue oral corticosteroids
were lower in children given
montelukast

Urinary leukotriene E4 (log10
transformed) was higher in
children with the x/x genotype
than in those with the 5/5
genotype

Summary
• Highlight "personalized medicine" by
suggesting that genetic variability in the
arachidonate 5-lipoxygenase (ALOX5)
gene promoter
• no clear benefit of intermittent
montelukast in young children with
wheeze

Curr Opin Allergy Clin Immunol 2017 , 17:131–138
ICS:
aeroallergen
sensitivity,
blood
eosinophil >=
300/mL are
predictors of
good response
to daily ICS
LTRA
Recent studies-
no clear benefit,
WAIT trial -
identified a
genotype that
may increase
response

Leukotrienes and anti leukotriene (part 1)

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Leukotrienes and anti leukotriene (part 1)