The document discusses anti-leukotriene drugs for treating asthma and other conditions. It provides details on:
1) How leukotrienes are synthesized from arachidonic acid by the 5-lipoxygenase pathway in leukocytes and other cells. This involves enzymes like 5-lipoxygenase, FLAP, and LTA4 hydrolase.
2) The receptors that leukotrienes act on, including CysLT1, CysLT2, CysLT3, BLT1, and BLT2. CysLT1 mediates effects like bronchoconstriction while BLT1 mediates leukocyte recruitment.
3) Ways to block
Eicosanoids is the class of lipids derived from arachidonic acid. Eicosanoids play an important role in the growth and development, cellular signalling, drug response, platelet action and maintenance of body homeostasis.
This presentation introduces a brief and rapid review for an important research area (oxidative stress) and its relation to liver fibrosis.
Liver fibrosis is very important for us as we are facing a very dangerous and continuously growing problem in Egypt, HEPATIC PATIENTS COMPLICATIONS.
Molecular hydrogen has been studied extensively and has been found to affect cell signalling. This presentation summarizes the major points of the studies.
Presented by AlkaWay International at http://www.alkaway.com, http://www.alkaway.com.au and http://www.alkaway.co.uk
Eicosanoids is the class of lipids derived from arachidonic acid. Eicosanoids play an important role in the growth and development, cellular signalling, drug response, platelet action and maintenance of body homeostasis.
This presentation introduces a brief and rapid review for an important research area (oxidative stress) and its relation to liver fibrosis.
Liver fibrosis is very important for us as we are facing a very dangerous and continuously growing problem in Egypt, HEPATIC PATIENTS COMPLICATIONS.
Molecular hydrogen has been studied extensively and has been found to affect cell signalling. This presentation summarizes the major points of the studies.
Presented by AlkaWay International at http://www.alkaway.com, http://www.alkaway.com.au and http://www.alkaway.co.uk
Retinal Pigment epithelial cells perform a multitude of functions to protect the retina and maintain normal vision. Any kind of RPE malfunction leads to a variety of ocular diseases.
This PPT explains the various functions performed by RPE to maintain normal vision.
Epidermal Growth Factor use in Diabetic Foot UlcersG H PRABHU
EGF is used by many diabetologists to treat Diabetic Foot Ulcers. If used early EGF can prevent progression of DFU resulting in amputations and related morbidity and mortality.
Retinal Pigment epithelial cells perform a multitude of functions to protect the retina and maintain normal vision. Any kind of RPE malfunction leads to a variety of ocular diseases.
This PPT explains the various functions performed by RPE to maintain normal vision.
Epidermal Growth Factor use in Diabetic Foot UlcersG H PRABHU
EGF is used by many diabetologists to treat Diabetic Foot Ulcers. If used early EGF can prevent progression of DFU resulting in amputations and related morbidity and mortality.
micro teaching on communication m.sc nursing.pdfAnurag Sharma
Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
New Drug Discovery and Development .....NEHA GUPTA
The "New Drug Discovery and Development" process involves the identification, design, testing, and manufacturing of novel pharmaceutical compounds with the aim of introducing new and improved treatments for various medical conditions. This comprehensive endeavor encompasses various stages, including target identification, preclinical studies, clinical trials, regulatory approval, and post-market surveillance. It involves multidisciplinary collaboration among scientists, researchers, clinicians, regulatory experts, and pharmaceutical companies to bring innovative therapies to market and address unmet medical needs.
Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
Title: Sense of Taste
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the structure and function of taste buds.
Describe the relationship between the taste threshold and taste index of common substances.
Explain the chemical basis and signal transduction of taste perception for each type of primary taste sensation.
Recognize different abnormalities of taste perception and their causes.
Key Topics:
Significance of Taste Sensation:
Differentiation between pleasant and harmful food
Influence on behavior
Selection of food based on metabolic needs
Receptors of Taste:
Taste buds on the tongue
Influence of sense of smell, texture of food, and pain stimulation (e.g., by pepper)
Primary and Secondary Taste Sensations:
Primary taste sensations: Sweet, Sour, Salty, Bitter, Umami
Chemical basis and signal transduction mechanisms for each taste
Taste Threshold and Index:
Taste threshold values for Sweet (sucrose), Salty (NaCl), Sour (HCl), and Bitter (Quinine)
Taste index relationship: Inversely proportional to taste threshold
Taste Blindness:
Inability to taste certain substances, particularly thiourea compounds
Example: Phenylthiocarbamide
Structure and Function of Taste Buds:
Composition: Epithelial cells, Sustentacular/Supporting cells, Taste cells, Basal cells
Features: Taste pores, Taste hairs/microvilli, and Taste nerve fibers
Location of Taste Buds:
Found in papillae of the tongue (Fungiform, Circumvallate, Foliate)
Also present on the palate, tonsillar pillars, epiglottis, and proximal esophagus
Mechanism of Taste Stimulation:
Interaction of taste substances with receptors on microvilli
Signal transduction pathways for Umami, Sweet, Bitter, Sour, and Salty tastes
Taste Sensitivity and Adaptation:
Decrease in sensitivity with age
Rapid adaptation of taste sensation
Role of Saliva in Taste:
Dissolution of tastants to reach receptors
Washing away the stimulus
Taste Preferences and Aversions:
Mechanisms behind taste preference and aversion
Influence of receptors and neural pathways
Impact of Sensory Nerve Damage:
Degeneration of taste buds if the sensory nerve fiber is cut
Abnormalities of Taste Detection:
Conditions: Ageusia, Hypogeusia, Dysgeusia (parageusia)
Causes: Nerve damage, neurological disorders, infections, poor oral hygiene, adverse drug effects, deficiencies, aging, tobacco use, altered neurotransmitter levels
Neurotransmitters and Taste Threshold:
Effects of serotonin (5-HT) and norepinephrine (NE) on taste sensitivity
Supertasters:
25% of the population with heightened sensitivity to taste, especially bitterness
Increased number of fungiform papillae
Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journeygreendigital
Tom Selleck, an enduring figure in Hollywood. has captivated audiences for decades with his rugged charm, iconic moustache. and memorable roles in television and film. From his breakout role as Thomas Magnum in Magnum P.I. to his current portrayal of Frank Reagan in Blue Bloods. Selleck's career has spanned over 50 years. But beyond his professional achievements. fans have often been curious about Tom Selleck Health. especially as he has aged in the public eye.
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Introduction
Many have been interested in Tom Selleck health. not only because of his enduring presence on screen but also because of the challenges. and lifestyle choices he has faced and made over the years. This article delves into the various aspects of Tom Selleck health. exploring his fitness regimen, diet, mental health. and the challenges he has encountered as he ages. We'll look at how he maintains his well-being. the health issues he has faced, and his approach to ageing .
Early Life and Career
Childhood and Athletic Beginnings
Tom Selleck was born on January 29, 1945, in Detroit, Michigan, and grew up in Sherman Oaks, California. From an early age, he was involved in sports, particularly basketball. which played a significant role in his physical development. His athletic pursuits continued into college. where he attended the University of Southern California (USC) on a basketball scholarship. This early involvement in sports laid a strong foundation for his physical health and disciplined lifestyle.
Transition to Acting
Selleck's transition from an athlete to an actor came with its physical demands. His first significant role in "Magnum P.I." required him to perform various stunts and maintain a fit appearance. This role, which he played from 1980 to 1988. necessitated a rigorous fitness routine to meet the show's demands. setting the stage for his long-term commitment to health and wellness.
Fitness Regimen
Workout Routine
Tom Selleck health and fitness regimen has evolved. adapting to his changing roles and age. During his "Magnum, P.I." days. Selleck's workouts were intense and focused on building and maintaining muscle mass. His routine included weightlifting, cardiovascular exercises. and specific training for the stunts he performed on the show.
Selleck adjusted his fitness routine as he aged to suit his body's needs. Today, his workouts focus on maintaining flexibility, strength, and cardiovascular health. He incorporates low-impact exercises such as swimming, walking, and light weightlifting. This balanced approach helps him stay fit without putting undue strain on his joints and muscles.
Importance of Flexibility and Mobility
In recent years, Selleck has emphasized the importance of flexibility and mobility in his fitness regimen. Understanding the natural decline in muscle mass and joint flexibility with age. he includes stretching and yoga in his routine. These practices help prevent injuries, improve posture, and maintain mobilit
Basavarajeeyam is a Sreshta Sangraha grantha (Compiled book ), written by Neelkanta kotturu Basavaraja Virachita. It contains 25 Prakaranas, First 24 Chapters related to Rogas& 25th to Rasadravyas.
- Video recording of this lecture in English language: https://youtu.be/kqbnxVAZs-0
- Video recording of this lecture in Arabic language: https://youtu.be/SINlygW1Mpc
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
Knee anatomy and clinical tests 2024.pdfvimalpl1234
This includes all relevant anatomy and clinical tests compiled from standard textbooks, Campbell,netter etc..It is comprehensive and best suited for orthopaedicians and orthopaedic residents.
The Gram stain is a fundamental technique in microbiology used to classify bacteria based on their cell wall structure. It provides a quick and simple method to distinguish between Gram-positive and Gram-negative bacteria, which have different susceptibilities to antibiotics
Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
Dr. Vidisha Kumari, a leading epidemiologist in Bangalore, emphasizes the importance of getting vaccinated. "The flu vaccine is our best defense against the influenza virus. It not only protects individuals but also helps prevent the spread of the virus in our communities," he says.
This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
2. Contents
• Synthesis of leukotrienes
• Leukotriene receptors
• Blockade of leukotriene synthesis and receptors
• Anti-leukotriene in asthma
• Anti-leukotriene in allergic rhinitis
• Anti-leukotriene in AERD
• Anti-leukotriene in urticaria
3. • Leukotrienes are primarily formed in various types of leukocytes, especially granulocytes,
monocytes/macrophages, mast cells, and dendritic cells
• Leukotrienes are paracrine mediators exerting their actions in the local cellular environment
• Leukotrienes are divided into two major classes
• Cysteinyl-leukotrienes (Cys-LTs) - LTC4, LTD4, and LTE4: powerful spasmogenic agents
• Dihydroxy acid leukotriene B4 (LTB4): one of the most potent chemotactic agents
Leukotrienes
Haeggstrom JZ, Funk CD. Chem Rev 2011;111:5866-98.
4. Synthesis of leukotrienes
• Metabolism of arachidonic acid leads to lipid mediators, including prostaglandins, thromboxane,
leukotrienes, and lipoxins, along two major metabolic pathways, the cyclooxygenase (COX) and
lipoxygenase (LO) pathways.
• These compounds, known as eicosanoids, are involved in maintenance of normal hemostasis,
regulation of blood pressure, renal function, reproduction and host defense.
• When formed in excess under pathological conditions, these molecules can elicit pain, fever, and
inflammation and play roles in many acute and chronic endemic diseases.
Haeggstrom JZ, Funk CD. Chem Rev 2011;111:5866-98.
5. • Arachidonic acid is liberated by cytosolic phospholipase A2
• Classical lipoxygenation: Oxygen is introduced at C-5 to form 5(S)-hydroperoxy-6-trans-
8,11,14-cis-eicosatetraenoic acid (5-HpETE)
• Pseudolipoxygenation: Abstraction of the pro-R hydrogen at C-10 is followed by radical
migration to C-6 and rearrangements of the double bonds
• Radical combines with the hydroperoxy group in a dehydration step to form the epoxide moiety
of Leukotriene A4 (LTA4)
Synthesis of leukotriene A4 (LTA4)
Haeggstrom JZ, Funk CD. Chem Rev 2011;111:5866-98.
7. 5-lipoxygenase-activating protein (FLAP)
• 5-Lipoxygenase (5-LO) becomes activated and translocates to
membranes in response to Ca2+
• Cellular 5-LO activity is dependent on 5-lipoxygenase-activating
protein (FLAP)
• Mechanism of action for FLAP is not fully understood
• Presents or transfers free arachidonic acid to 5-LO
• Stimulates the utilization of arachidonic acid by 5-LO
• Increases the efficiency with which 5-LO converts 5-HpETE
into LTA4
Haeggstrom JZ, Funk CD. Chem Rev 2011;111:5866-98.
9. • LTA4 is a highly unstable molecule that has to be shielded from hydrolytic attack by water
• Several molecules, e.g., albumin, liposomes, and fatty acid binding protein, have been shown to
act as chaperones against LTA4 breakdown and could potentially facilitate transcellular trafficking
of LTA4 during cell–cell interactions
Haeggstrom JZ, Funk CD. Chem Rev 2011;111:5866-98.
Synthesis of leukotrienes
10. LTA4 hydrolase
• Detected in almost all mammalian cells, even in
cells lacking 5-LO activity such as erythrocytes,
fibroblasts, endothelial cells, keratinocytes, and
airway epithelial cells
• Neutrophils, monocytes and erythrocytes are rich
sources of the enzyme
• Eosinophils, basophils and platelets seem to lack
LTA4 hydrolase
- Haeggstrom JZ, Funk CD. Chem Rev 2011;111:5866-98.
- Peters-Golden M, Henderson WR, Jr. N Engl J Med 2007;357:1841-54.
Synthesis of leukotrienes
11. LTC4 synthase
• High levels of enzyme expression and capacity to
synthesize LTC4 are observed in eosinophils, mast
cells, and monocytes
• LTB4 and LTC4 are exported from the cell by
specific transporter proteins
• Released LTC4 is converted to leukotriene
D4 (LTD4), which undergoes conversion to
leukotriene E4 (LTE4) by sequential amino acid
hydrolysis
Synthesis of leukotrienes
- Haeggstrom JZ, Funk CD. Chem Rev 2011;111:5866-98.
- Peters-Golden M, Henderson WR, Jr. N Engl J Med 2007;357:1841-54.
13. • Nonleukocyte cells generally do not have sufficient 5-lipoxygenase and FLAP to synthesize
appreciable amounts of leukotrienes from arachidonate
• Transcellular biosynthesis: Cells expressing distal LTA4-metabolizing enzymes can take up
leukocyte-derived LTA4 and metabolize it into bioactive leukotrienes
• Neutrophil (the donor cell) containing 5-lipoxygenase provides LTA4 to the endothelial cell
• Endothelial cell (the acceptor cell) lacks 5-lipoxygenase but expresses LTC4 synthase and
can metabolize the donated LTA4 to LTC4
Synthesis of leukotrienes
Peters-Golden M, Henderson WR, Jr. N Engl J Med 2007;357:1841-54.
14. • Amount of free arachidonate that phospholipase A2 releases from cell-membrane phospholipids
• Level of each of the proteins in the 5-lipoxygenase pathway
• Catalytic activity per enzyme molecule (modulated by protein kinase–directed phosphorylation)
• Availability of small molecules (ATP, nitric oxide, and reactive oxygen intermediates) that
modulate 5-lipoxygenase activity
• Intracellular localization of 5-lipoxygenase
Regulation of leukotriene synthesis
Peters-Golden M, Henderson WR, Jr. N Engl J Med 2007;357:1841-54.
16. Leukotriene receptors
• There are 3 cysteinyl LT receptors: CysLT1,
CysLT2, and CysLT3
• There are 2 LTB4 receptors: BLT1 and BLT2
• Signaling through the LT receptors results in
increased intracellular calcium and decreased
intracellular cyclic AMP
Peters-Golden M, Henderson WR, Jr. N Engl J Med 2007;357:1841-54.
18. Cysteinyl LT receptor 1 (CysLT1)
• CysLT1 is expressed on airway smooth muscle cells, eosinophils, B lymphocytes, mast cells,
monocytes, and macrophages
• Maps to X-chromosome (Xq13-21)
• Binding affinity for cysLT1 is LTD4 > LTC4 = LTE4
• Signaling through cysLT1 elicits bronchoconstriction, mucus secretion, and airway edema
• Therapeutic cysLT1 antagonists include montelukast, pranlukast, and zafirlukast
Burks AW, Peebles RS. In: Middleton's allergy: Principles and practice. Elsevier; 2020.
19. Cysteinyl LT receptor 2 (CysLT2)
• CysLT2 is expressed on lung macrophages, airway smooth muscle, peripheral blood leukocytes,
mast cells, and brain tissue
• Mouse study showed that CysLT2 is also expressed in the lung on bronchial smooth muscle,
alveolar macrophages, conventional dendritic cells, and eosinophils
• Maps to chromosome 13 (13q14)
• Binding affinity for cysLT2 is LTD4 = LTC4 > LTE4
• Gemilukast which reportedly inhibits both cysLT1 and cysLT2, is being evaluated in phase-2
trials for the treatment of asthma
Burks AW, Peebles RS. In: Middleton's allergy: Principles and practice. Elsevier; 2020.
20. • CysLT3 was detected on lung and nasal epithelial cells in mice
• Predominant ligand for cysLT3 is LTE4
• CysLT3-deficient mice
• Loss of LTE4-mediated vascular permeability
• Fully protected against profound epithelial cell mucin release and swelling
• Reduced baseline numbers of goblet cells, suggesting a function of this receptor in
regulating epithelial cell homoeostasis
• No known human cysLT3 antagonists
Cysteinyl LT receptor 3 (CysLT3)
Burks AW, Peebles RS. In: Middleton's allergy: Principles and practice. Elsevier; 2020.
21. LTB4 receptor
BLT1
• High-affinity receptor for LTB4 is BLT1
• Mediates most of the chemoattractant and proinflammatory actions
• Signaling enhances leukocyte recruitment to infected sites and involved in the elimination of
pathogen
BLT2
• Much less affinity for LTB4 compared with BLT1
• Highly expressed in epithelial cells in various tissues including intestine and skin
• Signaling promotes cell-cell junctions, protects against trans-epidermal water loss, and prevents
entry of environmental substances into the body
Burks AW, Peebles RS. In: Middleton's allergy: Principles and practice. Elsevier; 2020.
22.
23. Blockade of leukotriene synthesis and receptors
• CysLT1 antagonists
• Montelukast, zafirlukast, and pranlukast
Burks AW, et al. Middleton's Allergy: Principles and Practice: Elsevier Health Sciences; 2019.
24. Blockade of leukotriene synthesis and receptors
• Zileuton
• Directly inhibits 5-lipoxygenase
• Blocks production of cysteinyl leukotrienes and LTB4
• Inhibits an estimated 26-86% of endogenous leukotriene production
• Need to monitor hepatic enzyme levels
• Direct toxic effect that is unrelated to inhibition of 5-lipoxygenase
• Need to administer the drug 4 times daily
• A twice-daily sustained-release form of zileuton has recently received FDA approval
Peters-Golden M, Henderson WR, Jr. N Engl J Med 2007;357:1841-54.
25. • FLAP inhibitor
• DG031 is being reformulated for use in phase 3 trials for the prevention of myocardial
infarction
• Selective BLT1 antagonists
• Tested in animal models of disease, but none have emerged for clinical use
Blockade of leukotriene synthesis and receptors
Peters-Golden M, Henderson WR, Jr. N Engl J Med 2007;357:1841-54.
27. Anti-leukotriene in diseases
• FDA-approved antileukotriene with association in large-scale
randomized DBPC trials
• Asthma
• Allergic rhinitis
• Association in small scale or nonrandomized placebo-controlled trials
• Atopic dermatitis, Urticaria
• Viral bronchiolitis, OSA, COPD
• Interstitial cystitis
• Rheumatoid arthritis, SLE
• Atherosclerosis
Peters-Golden M, Henderson WR, Jr. N Engl J Med 2007;357:1841-54.
28. Antileukotriene drugs as controller agents
• Benefits of antileukotriene therapy (montelukast, zafirlukast, zileuton)
• Improved pulmonary function
• Decreased daytime and nocturnal symptoms
• Reduced need for short-acting rescue β2 agonists
• Fewer exacerbations of asthma
• Increased quality of life
• Inhaled corticosteroids are more potent than antileukotriene and favored as 1st line treatment
• Antileukotriene therapy can be used initially in a patient who cannot or will not take
corticosteroids
Anti-leukotriene in asthma
Peters-Golden M, Henderson WR, Jr. N Engl J Med 2007;357:1841-54.
32. Montelukast: 12 weeks of treatment of patients aged 2 to 5 years
• Significant improvements compared with placebo
• Daytime asthma symptoms (cough, wheeze, trouble breathing, and activity limitation)
• Overnight asthma symptoms (cough)
• Percentage of days with asthma symptoms
• Percentage of days without asthma
• Need for β-agonist or oral corticosteroids
• Physician global evaluations
• Peripheral blood eosinophils.
• Clinical benefit of montelukast was evident within 1 day of starting therapy
Anti-leukotriene in younger children
Knorr B, et al. Pediatrics 2001;108:E48.
35. Chauhan BF, Ducharme FM. Cochrane Database Syst Rev 2012;2012:CD002314.
Anti-leukotriene vs ICS
Inhaled corticosteroids are favored than antileukotrienes in
• Decreased in experience of an exacerbation requiring hospital admission
• Improvement from baseline in FEV1 (L) at all points of time
• Improvement from baseline daytime symptom scores
• Change from baseline night-time awakenings
• Reduction from baseline mean daily use of β2-agonists
• Change in proportion of symptom-free days
• Change in quality of life at all points in time
• Reduction in blood eosinophils
36. • Antileukotriene agents have an additive benefit in patients whose disease is not adequately
controlled by inhaled corticosteroids
• Montelukast:
• History of at least 1 year of intermittent or persistent asthma symptoms treated with inhaled
corticosteroids for at least 6 wk, aged 15 years and older
• 16 weeks of treatment
• Addition of montelukast (10 mg) to inhaled beclomethasone (200 mg twice daily) resulted in
improved asthma control compared with beclomethasone alone
Anti-leukotriene as additive agents
Laviolette M, et al. Am J Respir Crit Care Med 1999;160:1862-8.
37. • Improvement of FEV1, daytime symptoms score, morning and nocturnal awakenings, fewer days
with asthma exacerbations and fewer asthma attacks compared with beclomethasone alone
• Decrease in the eosinophil counts compared with beclomethasone alone
Anti-leukotriene as additive agents
Laviolette M, et al. Am J Respir Crit Care Med 1999;160:1862-8.
39. Substitution of LTRA for ICS as Step-Down Strategy
• Comparing LTRA versus placebo in patients with stable asthma when reducing ICS found a
decreased risk ratio of treatment failure of 0.57 (95% CI, 0.36–0.90; I2 = 0%)
Rank MA, et al. Allergy Asthma Proc 2015;36:200-5.
40. Antileukotriene drugs in acute asthma
• Limited evidence in acute asthma
• Administration of oral montelukast
results in a significantly higher PEF
the morning after admission
Anti-leukotriene in acute asthma
Ramsay CF, et al. Thorax 2011;66:7-11.
41. • Next-generation ARIA guidelines
• Practice parameter 2020
• BSACI guideline 2017
Anti-leukotriene in allergic rhinitis
44. • ARIA guideline based on GRADE and real-world evidence: Treatment initiation
• Intermittent allergic rhinitis with any VAS
• Persistent allergic rhinitis with VAS <5
Bousquet J, et al. J Allergy Clin Immunol 2020;145:70-80 e3.
Next-generation ARIA guidelines
45. Recommendations
• Against select the oral leukotriene receptor antagonist (LTRA) montelukast for the initial
treatment of AR
• Reduced efficacy when compared with other agents
• Serious neuropsychiatric events (suicidal thoughts or actions) have been reported
• Montelukast should be used to treat AR only in patients who are not treated effectively
with or cannot tolerate other alternative therapies
• Against select an oral LTRA for the treatment of NAR
• Use an INCS over an LTRA in initial treatment of moderate/severe SAR in patients ≥15 years
Dykewicz MS, et al. J Allergy Clin Immunol 2020;146:721-67.
46. Oral LTRAs with oral antihistamines
• Against combine the oral LTRA montelukast with an oral antihistamine for symptoms not
controlled with an oral antihistamine
Oral LTRAs with INCS
• Against the addition of the oral LTRA montelukast to an INCS for AR
• Lack of adequate evidence of improved efficacy and concerns for serious neuropsychiatric
events from montelukast
Rhinitis 2020: A practice parameter update
Dykewicz MS, et al. J Allergy Clin Immunol 2020;146:721-67.
50. BSACI guideline 2017
• LTRAs reduce the mean daily rhinitis symptom
scores by 5% more than placebo
• Combination of LTRA plus OAH has no advantage
over either drug used alone and not any more
effective than INS alone
• LTRAs may have a place in asthma patients with
seasonal allergic rhinitis
Scadding GK, et al. Clin Exp Allergy 2017;47:856-89.
51. • Nasal congestion and rhinorrhea in allergic rhinitis are reduced by montelukast to a degree
similar to that with antihistamines but inferior to that with topical corticosteroids
• Montelukast had greater improvements in their symptoms of SAR and PAR than placebo
• Montelukast exhibited efficacy similar to loratadine, but less than intranasal fluticasone
propionate
• Montelukast in combination with antihistamines such as loratadine or cetirizine has generally
resulted in greater efficacy than used alone
Anti-leukotriene in asthma and allergic rhinitis
Nayak A, Langdon RB. Drugs 2007;67:887-901.
52. • Improvement of daytime nasal symptom (DNS), night-time symptoms relating to sleep quality,
daytime eye symptoms, global end-of-study evaluations by both patients and physicians, and
RQLQ scores compared to placebo
Nayak A, Langdon RB. Drugs 2007;67:887-901.
53. Allergic rhinitis symptoms
• Montelukast plus inhaled fluticasone propionate/salmeterol (FP/S) showed significantly greater
improvement in total DNS scores than did those who received placebo plus FP/S
Asthma symptoms
• Neither montelukast nor fluticasone propionate aqueous nasal spray (FPANS) provided any
further benefit over inhaled FP/S in controlling asthma (morning and evening peak expiratory
flow)
Anti-leukotriene in asthma and allergic rhinitis
Nayak A, Langdon RB. Drugs 2007;67:887-901.
54. Anti-leukotriene in exercise-induced bronchoconstriction
Exercise-induced bronchoconstriction
• Acute onset of bronchoconstriction occurring during or minutes
after exercise
• Urine concentration of LTE4 increased significantly 2 hours
after exercise challenge during placebo treatment
- Reiss TF, et al. Thorax 1997;52:1030-5.
- Kemp JP. Ther Clin Risk Manag 2009;5:923-33.
55. • Exercise-induced bronchospasm (EIB)
is blunted by both cysLT1 antagonists and
5-LO inhibitors
• Protection against EIB with montelukast is
detectable as early as 2 hours after a single
oral dose and persists for up to 24 hours
Anti-leukotriene in exercise-induced bronchoconstriction
- Burks AW, Peebles RS. In: Middleton's allergy: Principles and practice. Elsevier; 2020.
- Pearlman DS, et al. Ann Allergy Asthma Immunol 2006;97:98-104.
56. • Effect of montelukast in this setting was significantly
superior to the long-acting β-agonist (LABA) salmeterol
over the same time frame in two 8-week trials
Anti-leukotriene in exercise-induced bronchoconstriction
Edelman JM, et al. Ann Intern Med 2000;132:97-104.
57. - Weiler JM, et al. J Allergy Clin Immunol 2016;138:1292-5 e36.
- Burks AW, et al. Middleton's Allergy: Principles and Practice: Elsevier Health Sciences; 2019.
58. Anti-leukotriene in AERD
Aspirin
• Inhibition of cyclooxygenase type 1 (COX-1)
• Decreased generation of protective PGE2
• Diminished expression of EP2 receptors on
the respiratory tissue granulocytes
• Activation of inflammatory cells
• Release of inflammatory mediators
• Development of bronchial and/or nasal
symptoms
Burks AW, et al. Middleton's Allergy: Principles and Practice: Elsevier Health Sciences; 2019.
59. Anti-leukotriene in AERD
• Enhance LTC4 synthesis by
eosinophils and mast cells
• Increase the neutrophil-derived
LTA4 available for conversion to LTC4
• Promote activation of mast cells
• Baseline impairment of local
PGE2 generation and EP2 receptor
• Promote persistent inflammation
and tissue remodeling
Laidlaw TM, Boyce JA. Immunol Allergy Clin North Am 2013;33:195-210.
60. Anti-leukotriene in AERD
• 10% of adults with asthma will have asthma symptoms
and reduction in pulmonary function after ingesting
aspirin or other NSAIDs >> AERD
• There was a mean 4-fold increase in urinary LTE levels
at 3-6 hours after aspirin provocation but not placebo
• Leukotriene release may play a central role in the
mechanisms of asthmatic attacks produced by aspirin
ingestion
- Burks AW, et al. Middleton's Allergy: Principles and Practice: Elsevier Health Sciences; 2019.
- Christie PE, et al. Am Rev Respir Dis 1991;143:1025-9.
61. • Treatment with both cysLT1 antagonists and 5-LO
inhibitors reduced AERD pulmonary function
abnormalities and symptoms
• LTs are involved in AERD pathogenesis
• Zileuton significantly increased FEV1 compared with
standard therapy, including inhaled corticosteroids
• Patients with AERD have additive gains in both FEV1
and symptom improvement with 5-LO inhibitor or a
cysLT1 antagonist
Anti-leukotriene in AERD
Burks AW, Peebles RS. In: Middleton's allergy: Principles and practice. Elsevier; 2020.
62. Anti-leukotriene
in urticaria
• Development of wheals and angioedema in
CSU is dependent on mast cell-activating
signals and receptors, signaling pathways,
inhibitory receptors and mediators
• CSU symptoms occur mainly due to the
release of histamine, other mediators
Kolkhir P, et al. Nat Rev Dis Primers 2022;8:61.
63. Anti-leukotriene in urticaria
• Significant differences in UASs and weekly antihistamine counts per patient between the
montelukast and placebo treatment periods
Erbagci Z. J Allergy Clin Immunol 2002;110:484-8.
65. - Bernstein JA, et al. J Allergy Clin Immunol 2014;133:1270-7.
- Kulthanan K, et al. Asian Pac J Allergy Immunol 2016;34:190-200.
66. Montelukast
Indication Age Dose
Asthma 12 months - 5 years 4 mg oral once daily
6-14 years 5 mg oral once daily
≥ 15 years and adult 10 mg oral once daily
Allergic rhinitis (Perennial) 6 months - 5 years 4 mg oral once daily
6 years - <15 years 5 mg oral once daily
≥ 15 years and adult 10 mg oral once daily
Allergic rhinitis (Seasonal) 2-5 years 4 mg oral once daily
6 years - <15 years 5 mg oral once daily
≥ 15 years and adult 10 mg oral once daily
Exercise-induced bronchospasm 6 years - <15 years 5 mg oral at least 2 hours prior to exercise
≥ 15 years and adult 10 mg oral at least 2 hours prior to exercise
Urticaria (chronic and delayed pressure) ≥ 15 years and adult 10 mg oral once daily
67. Montelukast
Indication Age Dose
AERD (Chronic management) Adult 10 mg oral once daily
AERD (Aspirin desensitization/challenge) Adult 10 mg oral once daily 3 days before desensitization/challenge
Hypersensitivity reactions,
rapid chemotherapy/biologics desensitization
Adult 10 mg oral once daily 1-2 days before desensitization
68. Zafirlukast
Indication Age Dose
Asthma 5-11 years 10 mg oral twice daily
≥ 12 years and adult 20 mg oral twice daily
Chronic urticaria Adult 20 mg oral twice daily
Zileuton
Indication Age Dose
Asthma ≥ 12 years and adult - Immediate release 600 mg oral 4 times daily
- Extended release 1200 mg oral twice daily
69. • Counsel all patients receiving montelukast about mental health side effects, and advise them to
stop the medicine and contact a health care professional immediately if they develop any
symptoms
Food and Drug Administration 2020
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