sem mk sem asthma new developments

8/8/2019 SEM MK Sem Asthma New Developments

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Recent advances in asthma

treatment

Dr Madhu .K Post graduateDepartment of Pharmacology

SJMC Bangalore



Over view

• Problem statement

• Definition and pathogenesis

• Current therapy

• Future prospects Drugs

Drug delivery systems• Changes in guide lines

• Conclusions

• References



• Asthma is a common chronic disorder of theairways that is complex and characterized by variable and recurring symptoms, airflow obstruction, bronchial hyperresponsiveness, andan underlying inflammation.



• 300 million people world wide

• One out of 250 deaths world wide

• Enormous indirect cost and total heath carecosts



Current Asthma Treatment



Classification

• Long-term control medications (listed inalphabetical order)▫ Corticosteroids

▫ Cromolyn sodium and nedocromil

▫ Immunomodulators

▫ Leukotriene modifiers▫ LABAs

▫ Methylxanthines



• Quick-relief medications (listed inalphabetical order)▫ Anticholinergics

▫ SABAs

▫ Systemic corticosteroids



Name Indications /Mechanisms

Potentialadverse effects

Therapeuticissues

Inhaled Inhaled (ICS):BeclomethasonedipropionateBudesonide

FlunisolideFluticasonepropionateMometasonefuroateTriamcinolone

acetonide

IndicationsLong-term prevention of symptoms; suppression,control, and reversal of inflammation.

Anti-inflammatory.

Block late reaction toallergen and reduce Airway

hyperresponsiveness.

Reverse beta2-receptordownregulation. Inhibitmicrovascular leakage

Cough, dysphonia,oral thrush(candidiasis).In high doses…….

Spacer/holdingchamber

Preparations are notabsolutely interchangeable“Adjustable dose”

approachto treatmentRisk vs benefit




Potentialadverseeffects

Therapeutic issues

Systemic:Methylprednisolone

PrednisolonePrednisone

IndicationsFor short-term (3–10

days) “burst”.

For long-termpreventionof symptoms insevere

persistent asthma

MechanismsSame as inhaled

Short-term useLong-term use

Use at lowest effectivedose. For long-term

use, alternate-day a.m. dosing producesthe least toxicity (Beam et al. 1992).




Potentialadverse

effects

Therapeutic issues

CromolynSodiumand Nedocromil

IndicationsLong-term prevention of symptoms in mild persistentasthma

Preventive treatment prior toexposure to exercise or knownallergen

Mechanisms Anti-inflammatory:Interferes with chloride channelfunction.Stabilizes mast cell

membranes

Inhibits acute response toexercise, cold dry air, andSO2

Cough and irritation.

15–20 percent of patients complain of an unpleasanttaste from

nedocromil

Safety is the primary advantage of theseagents



Name Indications /

Mechanisms

Potential

adverseeffects

Therapeutic issues

Omalizumab(Anti-IgE)For subcutaneous

use

IndicationsLong-term control andprevention of symptoms

Preventive treatment prior toexposure to exercise or knownallergen

MechanismsBinds to circulating IgE,preventing it from binding tothe high-affinity (FcεRI)

Decreases mast cell mediatorDecreases the number of FcεRIs

Pain and bruising of injection sites has been reported in 5–20

Anaphylaxis has beenreported in 0.2%

Malignant neoplasms were reported in0.5%

Monitor patients followingInjection

The dose is administeredeither every 2 or 4 weeks

Needs to be stored underrefrigeration at 2–8 °C.



Name Indications /

Mechanisms

Potential

adverseeffects

Therapeutic issues

LeukotrieneReceptor

Antagonists

(LTRAs)

Montelukasttablets andgranules

Zafirlukasttablets

Indicationsselectivecompetitive inhibitor of CysLT1 receptor.

MechanismsLong-term control andprevention of symptomsin mild persistent asthmafor patients ≥1 year of

age.

No specificadverseeffects have been

identified.

reportedcases of reversibleHepatitis

May attenuate EIB in somepatients, but less effectivethan ICS therapy

Do not use LTRA + LABA asa substitute for ICS + LABA

Zafirlukast is a microsomalP450 enzyme inhibitor thatcan inhibit the metabolismof warfarin.



Name Indications /

Mechanisms

Potential

adverseeffects

Therapeutic issues

5-LipoxygenaseInhibitorZileuton tablets

IndicationsInhibits the productionof leukotrienes fromarachidonic acid, bothLTB4 and the cysteinylleukotrienes.

Mechanisms

Long-term control and

prevention of symptomsin mild persistent asthmafor patients ≥12 years of age.

Elevation of liverenzymes

Zileuton ismicrosomal P450enzyme inhibitor thatcan inhibit themetabolism of warfarin andtheophylline.



Name Indications /

Mechanisms

Potential

adverseeffects

Therapeutic issues

Long-ActingBeta2-Agonists(LABA) Inhaled LABA:FormoterolSalmeterolOral: Albuterol,sustained-release

IndicationsLong-term prevention of symptoms, added to ICSPrevention of EIB. Not to be used to treat acute symptoms or exacerbations.

Mechanisms

Bronchodilation.Smooth musclerelaxation followingadenylate cyclaseactivation and increase incyclic AMP

Tachycardia,skeletalmuscle tremor,hypokalemia,prolongation of QTcinterval inoverdose.

Not to be used to treatacutesymptoms orexacerbations.

Should not be used asmonotherapy for long-term control of asthma or as anti-inflammatory therapy.



Name Indications /

Mechanisms

Potential

adverseeffects

Therapeutic issues

MethylxanthinesTheophylline,sustained-releasetablets andcapsules

IndicationsLong-term control andprevention of symptomsin mild persistent asthmaor as adjunctive with ICS,in moderate or persistentasthma.

Mechanisms

Bronchodilation.

Smoothmuscle relaxation fromphosphodiesteraseinhibition and possibly adenosine antagonism.

Dose-relatedacutetoxicities includetachycardia,nausea and vomiting,tachyarrhythmias (SVT),

Maintain steady-stateserumconcentrations between 5 and15 mcg/mL.





Therapeutic issues

Short-ActingBeta2-

Agonists(SABA) Inhaled SABA: AlbuterolLevalbuterolPirbuterol

IndicationsRelief of acute

symptoms;quick-relief medication.Preventive treatment forEIB prior to exercise.

Mechanisms

Bronchodilation.Binds tothe beta2-adrenergicreceptor

Tachycardia,skeletal

muscle tremor,hypokalemia,increasedlactic acid,headache,hyperglycemia

Drugs of choice foracute bronchospasm

For patients who haveintermittent asthma,regularly scheduleddaily use neitherharms nor benefits

asthma control





Therapeutic issues

Anticholinergics

Ipratropium bromide

IndicationsRelief of acute

bronchospasm Mechanisms

Bronchodilation.Competitive inhibition of muscarinic cholinergic

Receptors.

Drying of mouthand

respiratory secretions,increased wheezing

Reverses only cholinergically

mediated bronchospasm;does not modify reaction to antigen.Does not block EIB.





Therapeutic issues

Corticosteroids Systemic:

MethylprednisolonePrednisolonePrednisone

IndicationsFor moderate or severe

exacerbations to preventprogression of exacerbation, reverseinflammation, speedrecovery, and reducerate of relapse.

Mechanisms

Anti-inflammatory.

Short-termuse

Short-term therapy should continue until

patient’s symptomsresolve.



New targets for drug

development in asthma



Future prospects

• Need ?Combinations not effective in all

In mild to moderate asthmaSub types of asthma

Relative corticosteroid insensitivity

Altered expression of epithelial markers



Improvement of current therapies

• New long acting bronchodilators▫ Indacaterol

▫ Carmoterol▫ GSK159797

• New corticosteroids with reduced systemic sideeffects

▫ Ciclesonide



Lipid mediator blockade

• Leucotrine inhibitorsMontelukast, Zileuton (5lipoxygenase inhibitor) Ivalukast etc

• Lipoxygenase inhibitors LD-2138 , ABT 761



FLAP inhibitors

• 5 lipoxygenase activating protein inhibitors

• MK 0591; Bay X 1005;MK 886

• BAY X 1005 is a selective inhibitor of both 5-HETE andleukotriene (LTB4, LTC4) synthesis in various in vitrosystems

Mode of action of the leukotriene synthesis (FLAP) inhibitor BAY X 1005: Implications for biologicalregulation of 5-1ipoxygenase* A. Hatzelmann~ R. Fruehtmann, K. H. Mohrs, S. Raddatz, M. Matzke, U.Pleiss, J. Keldenich and R. Miiller-Peddinghaus Bayer AG, Pharma Research Center, Institute forCardiovascular and Arteriosclerosis Research, P.O. Box 101709, D-42096 Wuppertal,Germany



Isoenzyme selective

• PGD2 G protein coupled DP2

• Thromboxane selective Ramatroban• Leukotreine B4 – receptor BLT1 –

chemoattractant – LY293111– not effective insmall group of asthma patients



Chemokine

modulators

CCL11 Blocks eosinophil

recruitment/activation

CAT-213 (preclinical)

CCR3 Blocks eosinophil recruitment/activation Met-RANTES (phase II,moderate/severe asthma)

CXCR4 Blocks Th2 activation AMD070, AMD3100, SP01A (allpreclinical for asthma, all phase II

HIV, AMD3100 phase III for multiplemyeloma)

CXCR1/2 Blocks neutrophil recruitment/activation Repertaxin (preclinical, phase IIfor graft vs host disease)



Inflammatory cytokinesInterleukin 5 Blocks eosinophil

recruitment/activationMEDI-563 (phase I,severe asthma),mepolizumab (phase II)

Interleukin 12 Interleukin 12 (phase II, no eff ect on lung function, adverseside-eff ects, notdeveloped further

Interleukin 10 Endogenous anti-inflammatory agent

Interleukin 10 (preclinical forasthma, approved forpsoriasis/Crohn’s disease,recruited in 1999 for asthma)

Interferon $ Interferon $ (phase II, no eff ect on lung function in severeasthma, notdeveloped further)

Interleukin 13 Key driver of asthmatic inflammation

Pitrakinra (interleukin-4/13mutein), CAT-354, IMA-638

(both in phase II)



VLA inhibitors• Very late antigen 4, α4β integrin involvement in

recruitment of eosinophil and T cells ICAM -1

• Natlizumab Progressive multifocal leucoencephalopathy

• Ban lifted wide spread implications



Other therapeutic areas• Infections Telithromycin

Clarithromycin• Intracellular signalling pathway PDE4 inhibitors generation of cytokines, oxidants,

proinflammatory , eosinophilic migration,

degranulationRoflumilast

Cilomilast



Kinase inhibitors• 4 types Serine, Cysteine, Aspartate and Trypsine

• Role in expression, activation of inflammatory mediators in theairway remodelling

Protease inhibitors in respiratory disease: focus on asthma and chronic obstructivepulmonary disease Venkatasamy, Radhakrishnan; Spina, Domenico,

Expert Review of Clinical Immunology , Volume 3, Number 3, May 2007 , pp. 365-381(17)

The targeting of proteases, including mast cell tryptase, neutrophilelastase and matrix metalloprotease with low-molecular-weightinhibitors APC 366 Phase 2 clinical trial

http://www.ingentaconnect.com/content/ftd/eci

http://www.ingentaconnect.com/content/ftd/eci



Kinase inhibitors



Thromboxane A2 inhibitor

• Facilitates effect of acetylcholine on the airways &may be involved in hyper responsiveness

• Prevent airway reactivity after exposure to↑allergens and irritants.

• Ozagrel hydrochloride– Japan reduce dose of steroids

• Ramatroban - perrinnial rhinitis Japan

Role of thromboxane A 2 synthetase inhibitors in the treatment of patients

with bronchial asthmaKUROSAWA M ;Gunma univ. school medicine, dep.

dermatology, div. allergy clin. immunology, 3-39-22 Showa-machi, Maebashi1 JAPAN



Gene therapy



Oxidative stress• Driving force behind inflammatory response and

lack of corticosteroid sensitivity in severe

asthma Nitric oxide synthase inhibitor

Resveratrol

Curcumin Phase I Clinical trial



Immuno modulation and anti allergy

treatment• Omalizumab

• Lumiliximab low affinity Ig E receptor

• Sublingual immunotherapy

• Dendritic cellsmain role

• Vaccine BCG and Th 1



New drug delivery systems• CFC MDIs will be reformulated with HFC

• Breath-actuated nebulizers,

• Adaptive aerosol delivery inhaler, and

• Metered-dose liquid inhaler (MDLI).

• Dry powder inhalers (DPIs)– Battery powered

and patient driven• Portable ultra sonic neubulizer



Current and New drug delivery systems



Conclusions• Highly specific target directed treatment –

receptor/ enzyme/ mediators

• Test for diagnosing subtypes• Vaccine against Treg and Th 17 cells

• Understanding multiple mechanisms



References• Hansel TT, Barnes PJ (eds): New Drugs for Asthma, Allergy and COPD.Prog

Respir Res. Basel, Karger, 2001, vol 31, pp 170–172• Ian M Adcock , Gaetano Caramori, K Fan Chung, New targets for development

of asthma The Lancet Vol 372 Sep 20 2008• Mode of action of the leukotriene synthesis (FLAP) inhibitor BAY X 1005: Implications for

biological regulation of 5-1ipoxygenase*A. Hatzelmann~ R. Fruehtmann, K. H. Mohrs, S.Raddatz, M. Matzke, U. Pleiss, J. Keldenich andR. Miiller-Peddinghaus M. J. Parnham 30

August 1994• Gene therapy strategies for asthma P Demoly1,2, M Mathieu2, DT Curiel3, Ph Godard1,2, J

Bousquet1,2 and FB Michel1,2 1 Maladies Respiratoires and 2INSERM U454, Hoˆpital Arnaud de Villeneuve, 34295 Montpellier Cedex, France; 3Gene Therapy Program, The

University of Alabama at Birmingham, Birmingham, AL, USA• New anti-asthma therapies: suppression of the effect of interleukin (IL)-4 and IL-5 J.C.

Kips, K.G. Tournoy, R.A. Pauwels New anti-asthma therapies: suppression of the effect of interleukin (IL)-4 and IL-5. J.C. Kips, K.G. Tournoy, R.A. Pauwels. #ERS Journals Ltd2001.

• PDE isoenzymes as targets for anti-asthma drugs C. Schudt, H. Tenor, A. Hatzelmann PDE isoenzymes as targets for anti-asthma drugs. C. Schudt, H. Tenor, A. Hatzelmann. ERS

Journals Ltd 1995.



• CYTOKINE MODULATORS IN ASTHMA: CLINICALPERSPECTIVES UTKARSH DOSHI, PINKY SALAT, VINAY PARIKHDepartment of Biological Research, Sun Pharma Advanced Research

Centre, Akota Road, Akota,Vadodara - 390 020. Gujarat, INDIA • Hansel TT, Barnes PJ (eds): New Drugs for Asthma, Allergy and COPD.

Prog Respir Res. Basel, Karger, 2001, vol 31, pp 170–172

• National Heart, Lung,and Blood Institute National Asthma Education andPrevention Program Expert Panel Report 3: Guidelines for the Diagnosisand Management of Asthma Full Report 2007

• Dolovish M, Eng P. The evolution of drug delivery: a review. Program andabstracts of the 1999 Annual Meeting of the American College of Allergy, Asthma Immunology; Chicago, Ill; November 12-17, 1999. Symposium:Delivering the next generation of asthma therapy.

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