emerging therapies in bronchial asthma

7/30/2019 Emerging Therapies in Bronchial Asthma

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By Dr Ashok Kumar


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Asthma is a syndrome characterized byairflow obstruction that varies markedly,both spontaneously and with treatment.

Asthma is a heterogeneous inflammatorydisease of the airways. that makes themmore responsive than non-asthmatics to a

wide range of triggers, leading toexcessive narrowing with reduced airflow,symptomatic wheezing and dyspnea.


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Asthma is a heterogeneous disease with

interplay between genetic and environmental

factors.

Several risk factors and triggers have beenidentified.

Upper respiratory tract virus infections such

as rhinovirus, respiratory syncytial virus, and

coronavirus are the most common triggers ofacute severe exacerbations.


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There is chronic inflammation in therespiratory mucosa from the trachea to

terminal bronchioles.

The airway mucosa is infiltrated with

activated eosinophils and T lymphocytes, and

there is activation of mucosal mast cells.

Airway Remodeling with increased airway

smooth muscle, fibrosis, angiogenesis, andmucus gland hyperplasia.

The airway inflammation in asthma is

associated with airway hyper-responsiveness.


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The diagnosis of asthma is usually apparent

from the symptoms of wheezing, dyspnea, and

coughing.

Variable and intermittent airways obstruction,and airway hyperresponsiveness are

diagnostic.

Confirmed by objective measurements of lung

function.


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Simple spirometry confirms airflow limitation

with a reduced FEV1, FEV1/FVC ratio, and

Peek Expiratory Flow.

Reversibility is demonstrated by a >12% and200-mL increase in FEV1 15 minutes after an

inhaled short-acting B2-agonist or in some

patients by a 2 to 4 week trial of oral

corticosteroids.


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The increased airway response is normally

measured by methacholine or histamine

challenge with calculation of concentration

that reduces FEV1 by 20%. This is rarely useful in clinical practice.


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Non-Pharmacological

Treatment begins with the identification and

elimination of possible environmental inhalant

allergens that can trigger symptoms. Substantially reducing exposure to these

allergens significantly reduces lung inflammation,

improves clinical symptoms, and decreases the

need for medications. Allergen Immunotherapy is another option that

has been shown to provide similar effects.


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Numerous agents are used, including

1. Inhaled corticosteroids (ICSs)2. 2 agonists (short and long acting)

3. Leukotriene antagonists,4. Cromones,5. Monoclonal antibodies.

Of these, ICSs remain the mainstay oftreatment for persistent asthma according tovarious guidelines.


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ICS decrease airway inflammation and

remodeling, hyper-responsiveness, improve

asthma symptoms and decrease morbidity.

These are now considered first-line therapy in

the management of persistent asthma. ICS

therapy has been shown to have long-term

efficacy in adults as well as children.


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There are currently 6 ICSs approved by the US FDA

1. Beclomethasone dipropionate (BDP)

2. Budesonide (BUD),

3. Triamcinolone acetonide (TA)

4. Flunisolide,

5. Fluticasone propionate (FP), and

6. Mometasone furoate (MF).

All of these ICSs are effective and safe, althoughtherapeutic profiles differ slightly among ICSs.


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Local :oral candidiasis, dysphonia, and cough.

Systemic :Skin thinning and bruising.Bone mineral density can be reduced with

long-term, high-dose therapy.

Risk of cataracts and glaucoma may beincreased. In children, growth suppression and

adrenal suppression are seen with highdoses.


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Step 2

Step 1

Step 3

Step 4

Step 5


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Class Examples Mechanism of

action

ICS Ciclesonide Local activation,

depot formation,rapid metabolism.

Dissociated steroids Transrepression

without

Transactivation.Soft steroids Drug inactivated

when not in lungs

IgE and Mast

Cell Targets

Omalizumab Anti-IgE therapy

Lumiliximab Anti-CD23 antibody

Spleen tyrosine kinase

(Syk) inhibitorsInhibits Mast cell

signaling.


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Novel

Anti-

InflammatoryAgents

Roflumilast PDE4 inhibitor

Cytokine

Inhibitors

Soluble IL-4 receptor IL-4 antagonist

Mepoluzimab IL-5 antagonist

Suplatast tosilate Suppresses IL-4 and

IL-5

Daclizumab IL-2 receptor

antagonist

Etanercept TNF- antagonist

Vaccines AIC vaccine (DNA

vaccine)

Toll-like receptor 9

agonists


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The anti-inflammatory action of Corticosteroidsare mediated by inhibition of transcription(transrepression), whereas associated sideeffects are mediated by transactivation of geneexpression.

Dissociated steroids have only transrepressionactivity without transactivation

Soft steroids : These unique steroids are pharmacologically

active at the desired site, but their distributionaway from the site results in rapid metabolicdeactivation that prevents toxicity.


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Ciclesonide is a prodrug soft steroid that isactivated in the lungs to active metabolite

des-ciclesonide (des-CIC).

Des-CIC has 100 times greater affinity for theGR than CIC. Once in the circulation undergoes

extensive first-pass metabolism (>99%) by the

liver. Bioavailability of CIC is


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Omalizumab is a recombinant humanized

monoclonal anti-IgE antibody approved

for clinical use in severe asthma. It binds

circulating IgE and thereby prevents itfrom attaching to mast cells.

It does not affect IgE bound to mast cells,

it can take weeks to months for IgE bound

to mast cells to disappear.


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Lumiliximab : An anti-CD23 antibody, acts as

an immunomodulator, reduces IgEconcentrations in patients with mild asthma.

Spleen tyrosine kinase (Syk) is involved in the

activation of mast cells through IgE-

dependent pathway.R112 is inhibitor of Syk, has been shown to

decrease nasal symptoms in patients with

allergic rhinitis. More studies are needed to

test its efficacy in asthma.


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Th2 cells produce interleukins IL-4, IL-5, and IL-13, all of which are important in asthma and

other allergic diseases.

Mepolizumab is a monoclonal antibody that

targets IL-5, it effectively reduced eosinophillevels in blood and sputum.

Pitrakinra is a recombinant IL4 that acts as a

competitive antagonist at IL4 and IL13.Nebulized pitrakinra has improved FEV1 and

decreased inflamation.


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Etanercept shown a decrease in bronchial

hyperresponsiveness, improved FEV1 and

athma related quality of life.

Infliximab did not show any improvementin peak expiratory flow rates.

Long term treatment with anti-TNF

agents can cause reactivation of chronic

infections like Tuberculosis.


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Theophylline was commonly used in themanagement of asthma in the past. is anonselective phosphodiesterase (PDE)inhibitor has significant side effects.

Roflumilast is a selective PDE4 inhibitorgiven orally, inhibit both early and lateasthmatic responses, effects arecomparable to low doses of inhaledsteroids.

Cilomilast is another PDE4 inhibitor underevaluation


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Smooth muscle hypertrophy is an important

finding in severe athma. smooth muscle mass

can be reduced with controlled delivery of

thermal energy to bronchial wall during

bronchoscopy. Studies have shown that

Thermoplasty reduces severe exacerabations

and improves quality of life.

Bronchial Thermoplasty


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Allergen immunotherapy represents the only

disease-modifying treatment that can potentially

alter the natural course of asthma.

A new form of immunotherapy is using

oligodeoxynucleotides (short single-stranded

synthetic DNA molecules) as conjugates.

CpG oligonucleotides (CpG-ODN, resembling

bacterial DNA) engage Toll-Like Receptor 9 on B-

cells, dendritic cells resulting in induction ofTh1-type and T-regulatory-type immune

responses.


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There will be shift of Th2 IgE to Th1 CMIresponse for the conjugated antigen, after

repeated exposure.

CpG-Oligonucleotides are potent inhibitors ofatopic responses, suppressing Th2 cytokine

and, reducing airway eosinophilia, systemic

levels of IgE.


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Amb a1 (a ragweed-pollen antigen)Immunostimulatory oligonucleotide

Conjugated(AIC) vaccine

was shown to offer long-term clinical

efficacy in the treatment of ragweed

allergic rhinitis.

Immunotherapy found to be moreeffective for allergic rhinitis than for

asthma


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It is estimated that about 40% of cases

asthma is based on neutrophilic airway

inflammation.

Possibly triggered by environmental exposureto bacterial endotoxin, particulate air

pollution, and ozone, as well as viral

infections.

Patients with non-eosinophilic athma haveincreased neutrophils and IL8 in their

airways.


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Cartocosteroids are of limited efficacy in

non-eosinophilic athma.

Macrolides like Clarithomycin and

Telithromycin are active against Atypicalbacteria, which are known to cause acute

exacerebations.

They also have anti-inflammatory action,

have been shown to be effective in acuteexacerbations of asthma.


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Magnesium sulphate is smooth musle

relaxant.

Intravenous magnesium sulphate is a safe

treatment for acute asthma. Doses of up to40 mg/kg/day (maximum 2 g) by slow

infusion have been used.

It can also given by nebulisation.


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Theoretically furosemide can produce

bronchodilation.

Studies failed to show any significant benefitof treatment with nebulised furosemide

compared to 2 agonists.


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emerging therapies in bronchial asthma

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