This document summarizes recent advances in the pharmacotherapy of bronchial asthma. It discusses improvements to inhaled corticosteroids like ciclesonide that have fewer systemic side effects. New drug classes like phosphodiesterase inhibitors (roflumilast), monoclonal antibodies targeting cytokines like omalizumab (anti-IgE), mepolizumab (anti-IL5), and dupilumab (anti-IL4) are described. Long acting beta agonists (LABAs) and their combination with inhaled corticosteroids in single inhalers are covered. Novel bronchodilators involving ion channels and peptides are mentioned. Overall the document provides an overview of guideline-based management and new targeted bi
Educational and therapeutic topic on asthma for MBBS and MD pharmacology students. other students like BDS , BHMS, BAMS etc can use for knowledge. and academic purpose.
Bronchial Asthma - Epidemiology, Pathogenesis and ManagementShashikiran Umakanth
Bronchial asthma is a chronic disease with airway inflammation as a central theme in its pathogenesis. Prevalence of this condition is gradually increasing, especially in developed countries and in countries that are getting "westernized". With early diagnosis, regular monitoring and prompt and rational treatment, most patients with asthma can lead a symptom-free life.
Bronchial Asthma- Recent advances in management by Dr. Jebin AbrahamJebin Abraham
Bronchial asthma, Asthma phenotypes, newer bronchodilators, personalised medicine in asthma, pharmacogenetics of current drugs, immunotherapy, vaccination, bronchial thermoplasty, surgical management
Educational and therapeutic topic on asthma for MBBS and MD pharmacology students. other students like BDS , BHMS, BAMS etc can use for knowledge. and academic purpose.
Bronchial Asthma - Epidemiology, Pathogenesis and ManagementShashikiran Umakanth
Bronchial asthma is a chronic disease with airway inflammation as a central theme in its pathogenesis. Prevalence of this condition is gradually increasing, especially in developed countries and in countries that are getting "westernized". With early diagnosis, regular monitoring and prompt and rational treatment, most patients with asthma can lead a symptom-free life.
Bronchial Asthma- Recent advances in management by Dr. Jebin AbrahamJebin Abraham
Bronchial asthma, Asthma phenotypes, newer bronchodilators, personalised medicine in asthma, pharmacogenetics of current drugs, immunotherapy, vaccination, bronchial thermoplasty, surgical management
ASTHMA etiology, risk factors, pathophysiology and it's managementPoovarasanA5
Asthma is a common disease which we come across all over the world, certain factors helps to avoid and try to improve livelihood by changing life style modifications
Ozempic: Preoperative Management of Patients on GLP-1 Receptor Agonists Saeid Safari
Preoperative Management of Patients on GLP-1 Receptor Agonists like Ozempic and Semiglutide
ASA GUIDELINE
NYSORA Guideline
2 Case Reports of Gastric Ultrasound
New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
Ethanol (CH3CH2OH), or beverage alcohol, is a two-carbon alcohol
that is rapidly distributed in the body and brain. Ethanol alters many
neurochemical systems and has rewarding and addictive properties. It
is the oldest recreational drug and likely contributes to more morbidity,
mortality, and public health costs than all illicit drugs combined. The
5th edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-5) integrates alcohol abuse and alcohol dependence into a single
disorder called alcohol use disorder (AUD), with mild, moderate,
and severe subclassifications (American Psychiatric Association, 2013).
In the DSM-5, all types of substance abuse and dependence have been
combined into a single substance use disorder (SUD) on a continuum
from mild to severe. A diagnosis of AUD requires that at least two of
the 11 DSM-5 behaviors be present within a 12-month period (mild
AUD: 2–3 criteria; moderate AUD: 4–5 criteria; severe AUD: 6–11 criteria).
The four main behavioral effects of AUD are impaired control over
drinking, negative social consequences, risky use, and altered physiological
effects (tolerance, withdrawal). This chapter presents an overview
of the prevalence and harmful consequences of AUD in the U.S.,
the systemic nature of the disease, neurocircuitry and stages of AUD,
comorbidities, fetal alcohol spectrum disorders, genetic risk factors, and
pharmacotherapies for AUD.
MANAGEMENT OF ATRIOVENTRICULAR CONDUCTION BLOCK.pdfJim Jacob Roy
Cardiac conduction defects can occur due to various causes.
Atrioventricular conduction blocks ( AV blocks ) are classified into 3 types.
This document describes the acute management of AV block.
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
Report Back from SGO 2024: What’s the Latest in Cervical Cancer?bkling
Are you curious about what’s new in cervical cancer research or unsure what the findings mean? Join Dr. Emily Ko, a gynecologic oncologist at Penn Medicine, to learn about the latest updates from the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer. Dr. Ko will discuss what the research presented at the conference means for you and answer your questions about the new developments.
ARTIFICIAL INTELLIGENCE IN HEALTHCARE.pdfAnujkumaranit
Artificial intelligence (AI) refers to the simulation of human intelligence processes by machines, especially computer systems. It encompasses tasks such as learning, reasoning, problem-solving, perception, and language understanding. AI technologies are revolutionizing various fields, from healthcare to finance, by enabling machines to perform tasks that typically require human intelligence.
These lecture slides, by Dr Sidra Arshad, offer a quick overview of physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar leads (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
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
Recent advances in the management of bronchial asthma
1. Recent Advances in the
Pharmacotherapy of Bronchial Asthma
Dr Pritam Biswas
2. As we go along
• Introduction
• Pathophysiology
• Current Management Guidelines.
• Recent Advances
Pharmacotherapy
Monoclonals & Anti cytokines
Immunotherapy
Non Pharmacological
3. Introduction
• Asthma represents a global public health issue due to high
prevalence rates in the general population( 1% to 18% of
the population in different Countries),
• Affects approximately 300 million people worldwide
• Rising prevalence in developing countries which is
associated with increased urbanization.
4. Asthma is defined as a chronic inflammatory disease
Airway hyper responsiveness
Recurrent symptoms such as wheezing, dyspnea
(shortness of breath), chest tightness and coughing.
Episodes are associated with widespread ,variable,
airflow obstruction within the lungs that is reversible
spontaneously or with appropriate asthma treatment
13. Current Management of Asthma .
Short acting beta 2 agonist for symptom reliefStep
1
Mild
intermittent
asthma
Mild
Persistent
asthma
Moderate
Persistent
asthma
Severe
asthma
ICS+ Leukotriene modifier add on
Step
2
Step
3 Low dose ICS +LABA
High dose ICS+ LABA
Leukotriene modifier
Step
4
Severe
Persistent
asthma
Step
5
Oral steroid+ high
dose ICS+ LABA
14. Inhalational corticosteroids &
Advances in Steroid resistance
Beta 2 agonists
Phosphodiesterase Inhibitors
Methyl xanthines
Anticholinergics
Anti IgE
Anti cytokines
Novel class of
bronchodilators
Immunomodulatory therapies
Newer anti-inflammatory
therapies
Miscellaneous approaches
CTRH
Toll like receptors
Marcolides
Endothelin antagonists
15. Inhalational corticosteroids
ICS Pharmacokinetics Safety
Triamcinolone Greater systemic side
effectsBeclomethasone
Fluticasone High first Pass
Metabolism (liver )
Fewer systemic side
effects
Safe at higher doses
Budesonide
Momethasone
Ciclesonide Prodrug
High First Pass
metabolism
High plasma protein
binding
Minimal systemic side
effects
16. Ciclesonide
Prodrug, converted to active ingredient
des-ciclesonide by lung esterases
Oral Bioavailability <1 %
Highly Plasma protein bound 99%
Half-life: 0.71 hr (ciclesonide); 6-7 hr
(des-ciclesonide)
Clearance: 152 ML/hr high
Lipid Binding to fatty acids in lung
Decreased
systemic toxicity
Increased Local
action
17.
18. Soft steroids
They have improved local, topical selectivity and have
much less steroid effect outside target area.
Lactone GCS conjugate
Glucocorticoid with a lactone ring
Stable in the lung , not metabolized by lung esterases
Metabolized quickly by plasma paraoxonase
Soft steroids
Loteprednol
Approved for ophthalmic use
Phase 2 development in Germany
Lactone GCS
Butixocort/ Tipredane Lack clinical efficacy
Rofleponide Preclinical phase
19. SEGRA- Selective Glucocorticoid
receptor agonist
Desirable anti-inflammatory and immuno suppressive properties of classical
glucocorticoids drugs but with fewer side effects .
Transactivation
annexin
A1, angiotensin-
converting
enzyme, neutral
endopeptidase
Transrepression
COX,NO
synthase, TNF, TG
F BETA, ICAM-1
20. Mapracorat ( SEGRA )
• Topical treatment of atopic dermatitis and
inflammation following cataract surgery.
• New frontier for asthma research .
21. Advances in Steroid resistance
About 5-10% of asthmatics are resistant to steroids
Definition
Failure to improve baseline FEV1by more than 15% after treatment with
prednisolone (30– 40 mg daily) for 2 weeks
Type I Steroid Resistant Asthma
Reduction in glucocorticoid receptor‐binding affinity
High concentrations of IL‐2 and IL‐4 or by IL‐13 alone
Type II Steroid Resistant Asthma
Due to low numbers of glucocorticoid receptors
22.
23.
24. IV immunoglobulins:
Steroid-sparing effect appears to be present but is not used, as it is
prohibitively expensive.
IL-2 & IL-4 levels can be lowered by IV immunoglobulins: 2-3 mg / kg /
wk / 4wks
Methotrexate:
Methotrexate causes inhibition of T cell proliferation through inhibition
of enzyme Amidophosphoribosyltransferase.
Concomitant weekly methotrexate therapy causes clinically
significant reduction in oral prednisolone doses 15mg/day to
5mg/day.
Methotrexate therapy also increases peripheral blood T cell sensitivity
to prednisolone inhibition.
25. Cyclosporine:
selectively inhibits T lymphocyte proliferation, IL-2 and other cytokine
production and response of inducer T cells to IL-1.
It is used as a second line immunomodulator drug in steroid resistant
asthma.
Gold:
Has been used in Japan, and isolated studies in
Europe and America have shown decreased use of steroids,
improved symptoms but no change in FEV 1
Leflunomide:
A disease modifying agent for rheumatic diseases, it also causes selective
suppression of Th cytokine expression. They have a steroid sparing effect.
27. SIT - Single Inhaler therapy
• LABA monotherapy has been associated with an
increased risk of asthma-related morbidity and mortality,
• Should only be used along with an ICS
Combination therapy
Inhalational corticosteroid +LABA
Maintenance
28. Rational of ICS + LABA
Common combinations
Beclomethasone+ salmeterol
Fluticasone + salmeterol
ICS
1. Prevents down regulation of Beta receptors
2. Prevents desensitization
LABA
Helps In enhancing the binding of Glucocorticoids to GCR
Maintenance Levosalbutamol
29. SMART – Single Inhaler Maintenance
and reliever therapy
Formoterol has a fast onset of action <1min compared to
other LABA like salmeterol with a onset of 30min
Therefore ICS+ LABA Combinations that contain
formoterol
Budesonide + formoterol
Fluticasone + formoterol
Maintenance and
reliever
30. Advances in Beta 2 agonists
Ultra LABA’s
Ultralong acting LABA . Duration > 24 hrs.
Indacaterol
Bambuterol
carmoterol,
vilanterol
olodaterol,
Indacaterol
Initial trials
Safe
Improvements in FEV1 at 4 weeks ,
Long term studies – Not established the effect
on asthma disease control
Asthma exacerbations
32. CysLT 2 Receptor antagonists
• Studies have revealed that Cyst LT2 mRNA is
abundantly expressed on activated eosinophils.
• Raised the possibility that Cyst LT2 antagonists
would be more effective in ameliorating the LT’s
response explaining the relative failure of the
existing Cyst LT1 antagonists.
33. Methyl xanthines
Low dose Sustained release theophylline
Plasma values 5 to 10 mg/l – Anti-inflammatory / Less side effects .
Mechanisms :
Histone deacetylase activation- Steroid resistant asthma
Effects on apoptosis
Interleukin-10
Inhibition of NF-KB
Indications
Low dose sustained release theophyline as a add on to ICS in severe asthma
34. Doxofylline
• Novel xanthine bronchodilator
Mechanism of action
• Inhibition of phosphodiesterase 4,
• Decreased affinities towards adenosine A1 and A2
receptors,
Comparative Safety Profile
No CNS stimulation
No cardiac arrhythmias
35. Phosphodiesterase Inhibitors
PDE4 inhibition is thought to lead to elevated levels of
intracellular cAMP,
• suppression inflammatory cell function
• inhibition of mucin production epithelial cells
• alterations in airway smooth muscle tone
Selective PDE inhibitors
Roflumilast , Cilomilast, Rolipram, Ibudilast,
Piclamilast, Luteolin
38. Results
Long acting Muscarinic Agonists ( Tiotropium )
1. In moderate to severe asthma , as a add on when no response to
ICS+ LABA
2. In mild persistent asthma as a add on to ICS .
Important outcomes that are not evaluated in all studies published until
now are the reduction of exacerbations and the anti-inflammatory
effects of tiotropium
Currently available data on the efficacy of tiotropium in asthmatic patients are
not sufficient to recommend the use of this drug
39. Novel classes of bronchodilators
Magnesium sulfate
MOA
• Reduces cytosolic calcium in airway smooth
musclebronchodilatation
USES :
Useful as an additional drug to SABA in A/c severe asthma
can be given by IV/nebulisation
Side effects
Include flushing and nausea
Not suitable to be employed alone as clinical benefit is small
40. Potassium channel openers
Potassium channel openers that open calcium activated
large conductance K+ channels in smooth muscle
Calcium channel blockers Nifedipine, verapamil
-Prevent calcium entry into smooth muscle
-Inhibit stimuli induced bronchoconstriction
41. VIP analogs
- VIP binds to VPAC1(smooth muscles of blood vessels) &
VPAC2(airway smooth muscle)couple to Gs
adenylyl cyclase stimulated-smooth muscle
relaxation
- VIP potent bronchodilator in vitro studies but in patients
it is rapidly metabolized and also has vasodilator Side
effects
Stable analog of VIP (RO 25-1533) selectively stimulate
VPAC2-produces rapid bronchodilatation but effect is
not prolonged .
42. ANP & related peptide Urodilatin
- Activates membrane guanylyl cyclase cGMP
bronchodilatation
- Bronchodilator effects comparable to SABA.
- Useful for additional bronchodilatation in Acute severe
asthma
44. Route : S/c or IV every 2- 4 weeks
Use :
severe persistent extrinsic asthma who are resistant to
other forms of treatment.
Reduces exacerbations and requirement of oral and
inhaled steroids in them
Drawback : high cost
S/E : local reaction at inj. Site
urticarial, rash, flushing
rarely anaphylactic reaction
46. Anti IL-5
IL-5
Anti IL-5 Antibodies
Mepholizumab
Humanized Monoconal antibody
Phase 3 trials
Reduced Eosinophil entry in the airways
Decrease asthma exacerbation
Reslizumab
Phase 2
Pronounced in a subgroup
of patients with highest blood &sputum
eosinophils,
IL5 Receptor antibodies
Benralizumab
Pre-clincial stage
Decrease of circulating eosinophills
47. Anti IL-4
IL-4
Th2 differentiation
Switching of B cells to IgE synthesis
Eosinophil recruitment
Development of mast cells
Anti IL4
Pitrakinra ( s.c / inhaled )
Pascolizumab
Dupilumab decrease in asthma exacerbation rate during
withdrawal of inhaled therapy with
corticosteroids and long-acting 𝛽2-
adrenergic agonists,
marked improvement of respiratory function
TH2
48. Anti IL-13
Lebrikizumab ( PHASE 3)
Improvement of lung function in patients
with moderate-to severe asthma
Improvement of FEV1 from baseline
Tralokinumab ( s.c) -- Phase 3
Decrease need for rescue medication
Anti IL-9
MEDI -528
Improved Asthma Symptom scores
In Trial for exercise induced asthma
TH2
49. Anti TNF alpha Th1 TNF alpha
Recruitment neutrophils and eosinophils via upregulation of
epithelial and endothelial adhesion molecule
Anti TNF alpha Evidence from phase 2
trials
Concern
infliximab circadian oscillations in
peak expiratory
flow
active tuberculosis,
pneumonia, sepsis, and
several different
malignancies
(breast cancer, B-cell
lymphoma, metastatic
melanoma, cervical
carcinoma, renal cell
carcinoma, basal cell
carcinoma,
and colon cancer)
golimumab Not conclusive
etanercept improve lung function,
airway hyper-
responsiveness, and
quality of life
50. Anti IL-17
TH1 IL-17
Neutrophilic inflammation, airway remodeling, Steroid resistant
Secukinumab Humanized anti IL17 antibody
Brodalumab Il-17 receptor antibody
On Going Phase 2 trials in severe asthma that is not adequately
controlled by ICS+LABA
IL-17 is also involved in immune protection against infectious and
carcinogenic agents
51. In vitro studies human anti-GM-CSF monoclonal
IgG1 antibody (MT203) has been developed,
capable of significantly decreasing survival and activation
of peripheral human eosinophils
Anti GM-CSF
GM-CSF is a growth factor over expressed in asthmatic
airways
54. CRTH2
CRTH2 (Chemo attractant Receptor-homologous
molecule expressed on Th2 cells)
G-protein coupled receptor expressed by Th2
lymphocytes, eosinophils, and basophils.
The receptor mediates the activation and chemotaxis of
these cell types in response to prostaglandin D2 (PGD2),
produced by mast cells.
Contributes to the so-called “Th2 polarization”
55. CRTH2 antagonists
Using indomethacin, a CRTH2 agonist, as a starting block
and have prepared novel CRTH2 DP2-selective
antagonists
An oral CRTH2 antagonist (OC0000459) showed a 7.4%
improvement in FEV1 at 28 days (p=0.037).
led to a reduction in total IgE concentration and a trend
toward decreasing sputum eosinophils
57. Statins are now under evaluation in asthma therapy by
AAAAI
It was observed that asthmatics with co-morbidities who
are on statins have 30% lower risk for ER visits &
hospitalizations due asthma than controls.
58. Miscellaneous approaches
Endothelin antagonists may improve structural changes in asthma.
However not tested.
Antioxidants more potent than Vit C&E, N-Acetyl cysteine in development
as oxidative stress important in asthma.
Bitter taste receptors agonists ---chloroquine,saccharine
60. Bronchial thermoplasty
Concept:
Passing RF pulses
through the airway
tissues generates heat
due to tissue resistance
debulking of ASM
Devices :
thermoplasty apparatus
and RF compatible FOB
61.
62. • In a double-blind, randomized, sham-controlled
clinical study of bronchial thermoplasty
• Improved Qol
• Reduction in asthma attacks
• Reduction in emergency room visits for
respiratory symptoms
• Reduction in days lost from work, school,
• Reduction in hospitalizations for respiratory
symptoms
FDA approved 2010
63. Immunotherapy
• Administration of increasing doses of allergen extracts to
induce persistent immune tolerance in patients with
allergen-induced symptoms
• Recently SubLingual immunotherapy (SLIT) is preferred
and claimed to be more effective in asthma
64. Benefits include: ↓ in symptom scores, ↓ in
medication usage and ↓ airway reactivity
Mechanism:
Increased regulatory T cell activity
Restoration of Th1- Th 2 balance
Switching of allergen-specific B
cells towards IgG4 production.
Usual course:
3-5 years on maintenance therapy.
65. Allergen peptides:
The active peptides of allergens are used → down
regulation of T cells without co-stimulatory signals
1. Short T cell epitope peptides: induce tolerance without
mediator release (no IgE binding)
2. B cell epitope derived peptides: stimulate B cells to
produce blocking IgG 1 without IgE binding
Recombinant allergens:
Reconstructed with reduced allergenic activity
66. CpG-DNA based immunotherapy:
• Giving cytosine guanine plasmid DNA with allergen
extract produce a strong Th-1 response with increase of
mucosal IF-ϒ and decrease IgE production
67.
68. Is the insertion of a functional gene in a target cell
to exert the gene function
Genes transferred to target cells by a viral vector
or a liposome (? nanocarrier)
Target cells in the lungs are respiratory epithelium
69. Cytokine encoding genes:
Genes encoding for IL-12, IF-ϒ, IL-18:
Cause marked reduction in eosinophilic inflammation, IgE
production and airway hyper responsiveness
Genes encoding for IL-10 and TGF-β:
Cause suppression of both Th-1&Th-2 response
β2 receptors encoding genes:
To over express β2 receptors and potentiate bronchodilation
Glucocorticoid R genes:
Over expression overcomes GCR resistance and decrease systemic
SEs
70. Cloned Th -1 cells are now under Phase 2 trials
Aim: correction of Th1-Th2 imbalance in
asthma with correction of cytokine profile:
↑↑ IL-12, IF-ϒ & ↓↓ IL-4, IL-5, IL-13
T cell Therapy