`

`Supplement to
`
`] UR
`
`L OF
`
`AllergyANn Clinical
`Immunology
`
`VOLUME lOR
`
`NUMBER 5
`
`ALLERGIC RHINITIS AND ITS
`IMPACT ON ASTHMA
`
`ARIA WORKSHOP REPORT
`
`In collaboration with the
`World Health Organization
`
`Chair
`Jean Bousquet, MD, PhD
`
`Co-Chair
`Paul van Cauwenberge, MD, PhD
`
`WHO
`Nikolai Khaltaev, MD
`
`www.whiar.com
`
`Supported through a grant from
`the American Academy of Allergy, Asthma, and Immunology
`and the World Health Organization
`
`HIGHLY CONFIDENTIAL-
`SUBJECT TO STIPULATED PROTECTIVE ORDER
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`

`

`ARIA Workshop Group
`
`Jean Bousquet, Chair
`Paul van Cauwenberge, Co-Chair
`Nikolai Khaltaev (WHO)
`
`Nadia Ai:t-Khaled
`Isabella Annesi-Maesano
`Claus Bachert
`Carlos Baena-Cagnani
`Eric Bateman
`Sergio Bonini
`Giorgio Walter Canonica
`Kai-Hakon Carlsen
`Pascal Demoly
`Stephen R. Durham
`Donald Enarson
`Wytske J. Fokkeus
`Roy Gerth van Wijk
`Peter Howarth
`Nathalia A. Ivan ova
`.Tamt::s P. Kemp
`Jean-Michel K.Jossek
`Richard F. Lockey
`Valerie Lund
`Ian Mackay
`Hans-Jorgen Mailing
`Eli 0. Meltzer
`Niels Mygind
`Minoru Okuda
`Ruby Pawankar
`David Price
`Glenis K. Scadding
`F. Estelle R. Simons
`Andrzcj Szczcklik
`Erkka Valovirta
`Antonio M. Vignola
`De-Yun Wang
`John 0. Warner
`Kevin B. Weiss
`
`HIGHLY CONFIDENTIAL-
`SUBJECT TO STIPULATED PROTECTIVE ORDER
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`

`

`Authors
`
`Jean Bousquet, MD, PhD, Chair
`Depanmem of Allergy and Respirawry Diseases
`University Hospital and JNSERM
`Montpellier
`France
`
`Paul B. van Cauwenberge, MD, PhD
`Co-Chair
`Departmem of Oto-rhino-laryngology
`Ghem Universiry
`Ghenr
`Belgium
`
`Nikolai Khaltaev, MD
`World Health Organisation (WHO)
`Geneva
`Switzerland
`
`Nadia A'it-Khaled, MD
`International Union Against 1uberculosis and Lung Disease
`(IUATLD)
`Paris
`France
`
`Isabella Anncsi-Macsano, MD, DSc, PhD
`INSERM U472 : Epidemiology and BiosmtiS<ics
`Villejuif
`Prance
`
`Claus Rachert, MD, PhD
`Departmenr of Oto-rhino-laryngology
`Universiry Hospital Ghcnr
`Belgium
`
`Carlos E. Baena-Cagnani, MD
`Division of Immunology and Respiratory Medicine
`Infantile I lospiral
`Curdoba
`Argentina
`
`Eric Bateman, MD, PRCP
`University of Cape 1own
`CapeTown
`South Africa
`
`Sergio Bonini, MD
`Second University of Naples and leal ian National Research
`Council (CNR)
`Rome
`Iraly
`
`Giorgio Walter Canonica, MD
`Allergy and Respiratory Diseases
`-DJMI- Dept. of lmemal Medicine
`Universiry of Genoa
`Genoa
`Italy
`
`Kai-Hak.on Carlsen, MD, PhD
`Voksenroppen Narional Hospiral of Asthma, Allergy and
`Chronic Lung Diseases in Children
`Oslo
`Norway
`
`Pascal Dcmoly, MD, PhD
`Deparrment of Allergy and Respiratory Diseases
`University Hospital and INSERM
`Montpellier
`France
`
`Stephen R. Durham, MA, MD, FRCP
`Upper Respiratory Medicine
`Narional Heart & Lung lnsrinare
`London
`United Kingdom
`
`Donald Enarson, MD
`International Union Against Tuberculosis and Lung Disease
`(IUATLD)
`Paris
`France
`Wytske J. Fokkens, MD, PhD
`Department of Oro-rhino-laryngology
`Erasmus University Medical Cenrre Rotterdam
`Rotterdam
`The Netherlands
`
`J ALLERGY CLIN IMMUNOL
`
`Continued on page 4A
`
`November 2001
`
`3A
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`HIGHLY CONFIDENTIAL-
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`Authors (Continued)
`
`Roy Gerth van Wijk, MD, PhD
`Deparm1enr of Allergy
`Erasmus Universiry Medical Centre Rorrerdam
`Ronerdam
`The Netherlands
`
`Peter Howarth, BSc(Hons), DM, FRCP
`Universiry of Sourhampron
`Southam pron
`United Kingdom
`
`Nathalia A. lvanova, MD
`Clinic of Children's Diseases
`Sr. Petersburg
`Russia
`
`James P. Kemp, MD
`Universiry of California School of Medicine
`San Diego, California
`USA
`
`Jean-Michel Klossek, MD
`ENT and Maxillofacial Department
`Universiry Hospital Poitiers
`Poi[iers
`France
`
`Richard F. Lockey, MD
`Universiry of South Florida and James A. Haley Veterans
`Hospital
`"Jampa, Florida
`USA
`
`Valerie Lund MD
`Royal National Throat Nose & Ear Hospital
`Institute of Laryngology and Otology
`London
`United Kingdom
`
`Jan S. Mackay, MB, BS, FRCS
`Consul tam ENT Surgeon
`Royal Brompton and Charing Cross Hospitals
`London
`United Kingdom
`
`Hans-J argen Mall ing, MD
`National University 1-Jospiral
`Copenhagen
`Denmark
`
`Eli 0. Meltzer, MD
`Allergy and Asthma Medical Group and Research Cemer
`San Diego, California
`USA
`
`Niels Mygind, MD
`Depanment of Respil amry Medicine
`Aarhus Universiry Hospital
`Denmark
`
`Minoru Okuda, MD, PhD
`Nippon Medical School
`Japan Allergy & Asthma Clinic
`Tokyo
`Japan
`
`Ruby Pawankar, MD, PhD
`Nippon Medical School
`Department of Otolaryngology
`Tokyo
`Japan
`
`David Price, MR, RChir, MRCGP
`Department of General Practice & Primary Care
`Universiry of Aberdeen
`United Kingdom
`
`Glenis K. Scadding, MD, FRCP
`Royal National Throat, Nose & Ear Hospital
`London
`United Kingdom
`
`E Estelle R. Simons, MD, FRCPC
`Section of J\Jiergy & Clinical Immunology
`Universiry of Jvbniroba
`Winnipeg
`Cmada
`
`4A November 2001
`
`J ALLERGY CLIN IMMUNOL
`
`HIGHLY CONFIDENTIAL-
`SUBJECT TO STIPULATED PROTECTIVE ORDER
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`Authors (Continued)
`
`Andrzej Szczeklik, MD, PhD
`Deparnnent of Medicine
`Jagellonian University
`Cracow
`Poland
`
`Erkka Valovina, MD, PhD
`European Federation of Asthma and Allergy AssociaTions
`Turku Allergy Cente1
`Turku
`Finland
`
`Antonio M. Vignola, MD
`Imlian National Research Council and
`University of Palermo
`Palermo
`Italy
`
`De-Yun Wang, MD, PhD
`Depanmem of Otolaryngology
`The National University of Singapore
`Singapore
`
`John 0. Warner MD, FRCP, FRCPCH
`Allergy & Inflammation Sciences Division (Child Health)
`University of Southampton
`Southampton
`United Kingdom
`
`Kevin B. Weiss, MD
`Northwestern University
`Chicago, Illinois
`USA
`
`J ALLERGY CLIN IMMUNOL
`
`November 2001 5A
`
`HIGHLY CONFIDENTIAL-
`SUBJECT TO STIPULATED PROTECTIVE ORDER
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`

`Endorsing Organisations
`
`American Academy of Allergy, Asthma and
`Immunology (AAAAI)
`U.S.A.
`
`British Thoracic Society
`United Kingdom
`
`Bulgarian Society of Allergology
`American College of Allergy, Asthma & Immunology Bulgaria
`(ACAAI)
`U.S.A.
`
`Danish Society for Allergology
`Denmark
`
`All India Rhinology Society
`India
`
`Allergy and Immunology Society ofThailand
`Thailand
`
`Allergy Society of South Africa
`South Africa
`
`Argentine Association of Allergy and Immunology
`(AAAI)
`Argentina
`
`Deutsche Gese\lschaft ftir Hals-Nasen(cid:173)
`Ohren-Heilkunde, Kopf- und Hals-Chirurgie
`Germany
`
`ENT India
`India
`
`European Academy of Allergy and Clinical
`Immunology (EAACI)
`
`European Federation of Asthma and Allergy
`Associations (EFA)
`
`Asia Pacific Association of Allergology and Clinical
`Immunology (APAACI)
`
`European Respiratory Society (ERS)
`
`Asociacion Argentina de Medicina Respiratoria
`Argentina
`
`Emopcan Rhinology Society (ERS)
`
`Belgian Society for Allergology and Clinical
`Immunology
`Belgium
`
`Brazilian Society of Pediatrics
`Brazil
`
`British Association of Otorhinolaryngologists -
`Head and Neck Surgeons (BAO-HNS)
`Unitt:d Kingdom
`
`British Society for Allergy and Clinical Immunology
`(BSACI)
`United Kingdom
`
`European Society of Paediatric Allergy and Clinical
`Immunology (ESPACI)
`
`Gennan Society for Allergology and Clinical
`Immunology (DGAI)
`Germany
`
`Hong Kong College of ENT
`Hong Kong
`
`Indont:sian Otorhinolaryngology Ht:ad & Nt:ck
`Surgery Society (INDO-HNS)
`Indonesia
`
`lnterasma
`
`6A November 2001
`
`J ALLERGY CLIN IMMUNOL
`
`HIGHLY CONFIDENTIAL-
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`MEDA_APTX01331424
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`

`

`Endorsing Organisations (Continued)
`
`International Association of Allergology &
`Clinical Immunology - The World Allergy
`Organization (IAACI- WAO)
`
`Philippine Society of Allergy, Asthma &
`Immunology, Inc. (PSAAI)
`The Philippines
`
`International Union Against Tuberculosis and Lung
`Disease (IUATLD)
`
`Polish Society of Allergology
`Poland
`
`Italian Society of Respiratory Medicine (SIMeR)
`Italy
`
`Rhinology Society of the Philippines
`The Philippines
`
`Japan Allergy foundation
`Japan
`
`Japan Rhinology Society
`Japan
`
`Rhinology Society ofTmkey
`Turkey
`
`Royal Belgian Society for Oto-rhino(cid:173)
`laryngology, Head and Neck Surge1y
`Belgium
`
`Japan Society of Allergy and Immunology in
`Otolaryngology
`Japan
`
`Singapore ENT Society
`Singapore
`
`Japanese Society of Allergology
`Japan
`
`Korean Rhinologic Society
`Korea
`
`Latin American Society of Pediatric Allergy, Asthma
`and Immunology (SLAAIP)
`
`Malaysian Society of Otorhinolaryngology - Head
`and Neck Surgeons
`Malaysia
`
`National Asthma Campaign
`United Kingdom
`
`Netherlands Society of Allergology
`The Netherlands
`
`Philippine ENT Society
`The Philippines
`
`Sociedad Mexicana de Neumologia y Cirugia de
`T6rax
`Mexico
`
`Sociedade Po1tuguesa de Alergologia e Imuuologia
`Clinica (SPAIC)
`Pmtugal
`
`Societe de Pneumologie de Langue Franc;aise (SPLF)
`France
`
`Soci~t~ Fmn~aise d'Allergologie et d'Immunitt!
`Clinique (SFAIC)
`France
`
`Societe Franc;aise d'Oto-Rhino-Lmyngologie et de
`Chimrgie de Ia Face et du Cou
`France
`
`Societe Roumaine d 'Allergologie et d 'lmmunologie
`Clinique (SRAIC)
`Romania
`
`J ALLERGY CLIN IMMUNOL
`
`Continued on page 8A
`
`November 2001 7A
`
`HIGHLY CONFIDENTIAL-
`SUBJECT TO STIPULATED PROTECTIVE ORDER
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`CIPLA LTD. EXHIBIT 2009 PAGE 8
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`

`

`Endorsing Organisations (Continued)
`
`Societe Tunisienne d' Allergologie et d'Immunologie Thai Rhinologic Society
`Clinique (STAIC)
`Thailand
`
`South African Thoracic Society
`South Africa
`
`Turkish ENT Society
`Turkey
`
`Spanish Society of Allergology and Clinical
`Immunology (SEAIC)
`Spain
`
`8A November 2001
`
`J ALLERGY CLIN IMMUNOL
`
`HIGHLY CONFIDENTIAL-
`SUBJECT TO STIPULATED PROTECTIVE ORDER
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`MEDA_APTX01331426
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`CIPLA LTD. EXHIBIT 2009 PAGE 9
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`

`

`

`

`n
`0
`~
`
`____ ..
`= .. ""
`
`CONTENTS
`
`CONTINUED
`
`3-l-3-2- Pollens ......... ~.···•·~··· ····· .. ·•·····- ·· ... ........ : ....... 5 163
`3-1-3-3- Animal danders .......... .................................. .... 5 164
`3-1-3-3-1- C::~t ami dog alleq,l:ens .... .................... .......... .... S 164
`... 5164
`3-1-3-3-1-Horse.
`.
`.. ···· -~·-· ·• · .. .
`J-1-J-J-J. cattle ......................... ................................. . 5 164
`J-1·3·3-4· Rabbit ...... ........... . _ ... . . .. ..... . . . . ......... 5164
`... S164
`3-L-3-J-5- Other rotlcnrs ., ...
`.. . .•.••. .. ·•• ···· • . ,._ . .. . ,
`•. •· .. ............ .. ... 5165
`3-1-3-4- f1mgnl nllergens . .... .
`. ......... ................. 5165
`3-J-].:).Jnsecls ......... .
`. ... , .... 5 165
`3-1-3-6- Olher inhala11ls
`... ,....... .... .
`3-1-4- rood allergens .. ......... ......... ..... ................ ....... 5166
`3-1-5- Cross-reactive allergens between food and inhalant
`allergens ....................................................... - .. 5 166
`3-1-6- Occupational allergens ... ............... ................... 5166
`3-1-6-1- Latex .. ........ ...... ..................... .. ................. 5166
`3-1-6-2- Low molecul<tr weight compounds .. ..... ,., ......... .. S 167
`3-1-6-3- 0~1er occupational allergens .... ......... ............. 5167
`3-2- Pollutants .. ....... .................. .......................... .. 5167
`3-2-1- Characteristics of air pollution ........ ............. 5167
`3-2-J-J. Evolution of outdoor air poJ\ution .... ... ... ............ S 167
`3-2-1-2- Automobile polhllion ....................... .... ...... ..... 5 167
`J-2-1-3- Cbamcteristics of diesel emission .... ... .. ...... ..... 5168
`3-2-1-4- Indoor nir pollution .. . .. .................................. 5 168
`3-2-2- Pollutants of possible relevance in allergic
`..... 5168
`rhinilis
`3-2-2-1-0zone .. .. .......... ............ .. ........ .. .......... . ... 5168
`. ....... .. ... S J 68
`3-2-2-2- Sulphur dioxide (S02) .,.
`... ....................... ..... 5169
`3-2-2-3- NiLric dimiue (N02) .. ... .
`3-2·2·4· Particulate matler (PM) .. .. ... ......... ................. 5 169
`3·2·2·5- Volatile or~:mic compounds (VOC) aud
`fonnnldclwde ............... ........................ ...... ..... 5 169
`3-2·2·6· Aulotnobile pollution ........................... ............. 5 169
`3-2-2-7- Tobacco smoke ... ........................ ......... ........... S 169
`3-3- Dnlgs ............... - ........ ~ ......... - ..................... - .. 5 170
`3-3-1- Aspirin ullolerancc ... - .................. .... ... .. ........... 5 170
`. ...... ... .. 5170
`3-3-2- OU1cr drugs .... ... .
`........ , ........ ,. ..
`
`4- Mechanisms ............................................. ... 5171
`4-1- The normaluasal mucosa .......................... 5171
`4-1-1- Anatomy and physiology oftbc nose ............. 5171
`4-1-2- Nosal microvnsculohlre. __ , . ..................... 5172
`4-1-3- Mucous glands ..................................... . S173
`. ..... . . 5173
`4-1-3-1- Goblel cells nnd lniiCOliS slnnds
`.. , 5173
`4·1-3·2- StJLifC(!s ofu.;ts;tl fluid iu rhiuorrht~a.
`...... 5173
`4-1-.1-.1- Curllrol nllhe secrelory process ..
`......... .
`.. ..... 5 173
`4-1-4- Cells nf the nose
`4-1-5- Nerves of the nose ................................. .......... 5173
`4-2- Cells, mediators, cytokines, chemokines
`and adhesion molecules of nasal
`inflammation .. _ .................................................... 5174
`4-2-1- Cells ................... ........................... ... ...... ......... 5174
`4-2-1-1 Most cells ........... .................... .. ......... .............. 5174
`4-2-1-2- Dnsophils ........ , ........ ............ . ... .... ..... .. ... S 175
`4-2-1-3- Eosinophils ......... ... ........ ......... ~ ... - .............. 5 175
`4-2-1-4- T-l)"nphocyles ......... ............. ........................... 5 176
`.5177
`4-2-1-5- B-lympilocytes.... ... ... ..... .. . ... .... ........
`4-2-l-6- Macroplmges cmd de11drilic. cells ... .. ............. , .. . S 177
`
`.
`
`4-2-1-6·1- Macmphages , .. , .. , ..... " "' "'" ...... ...................... S 177
`4-2-l-6-2- Dmllritic c~:lls .. ...... .... .. ... ... ~ ....... .... .... ..... ... ..... S 177
`4-2-1-7- Epitltelial cells ......... ........ ....... ........ ... ............. 5178
`.. ...................... .... .. ... 5 178
`4-2-1-8- Endothelial cells ..
`4-2-1-9-Fibroblasts .. ...... .. ........................ ...... ............. 5178
`.... ...... - ..... 5 178
`4-2-2- Pro-inflammatory mediators ........
`. .................. .... 5178
`4-2-2-t- Histamine.. ............
`..S 179
`4-2-2-2 Arnchidonic ncid rnetnboliles .. .
`4-2-2-2-l- Cyclooxygcnnsc pathways: Biosynlhc~is and biological
`. ..•. ___ __ S 180
`rrnpertirs nf rm1-ot:moids.. ..... ...... ..
`4-2-2-2-2- Lil'oxyg,en<Jse pathways: Biusyntllesis and biolo(!ical
`. 5 180
`propertie.~ of leukorriene\ •..•. .•.. ••..... & . . . . . . . . . . . . . . . . . . . . . . . . . .
`4-2-2-2-3- Leuko1riene rcceptofli .. .. . ......... . .. . .. .................... S 181
`4-2-2-2-4-1\spirin-im.lucec..l :mhma ami rhinitiH ............... \ ....... 5 181
`4-2-2-3- Kinins ............ ......... ............ ....... ................. S 181
`4-2-3- Cytokines .......... ...................... ....................... S 182
`4-2-3-1- Pro-inflammatory cytoklnes ................. .............. S 182
`4-2-3-2- Tit2-retaled cylokines .. ................. ............... .... S 183
`4-2-3-3- O~ter cylokines and growth fuctors ................... 5 183
`4-2-4- Chcmukines ................................ ...................... 5183
`4-2-5- Adhesion molecules ... .... ................ ................... S 184
`4-2-5-1- Endothelial adhesion molecules ........... .... , ..... 5184
`4-2-5-2- lCAM-1 ............................. ............................. 5 184
`. .... ~ ......... ...... S 185
`4-2-5-3- Soluble adhesion molec.ules .
`.... 5185
`4-2-6- Survival of inflammatory cells
`..... .......... .. .... 5185
`4-2-7- Conclusions ...
`4-3- Neurotransmitters.. ........... ...
`. .. ......... .. S 185
`4-J-1- Non-adrenergic, non-cholinergic system .......... 5 185
`4-3-2- Nitric oxide ........................ .... ...................... .. 5185
`4-4- The IgE immune response .. . .................... 5186
`4-4-1- Regulation ot' the 1gE immw1e response .......... 5186
`4-4·1·1· Alttigen presenting cells .. ..... .. ... ........... .......... 5186
`4-4-t-2- Tit2 cy1okines ......................... ............. .... .. .. S186
`4-4-1-3- Co-Siimulotory signols .......... ......... , .... ..... ........ 5 187
`4-4-1-4- Cells involved in llt2-c.ytokine >yntltesis ............ 5187
`.. ........ S187
`4-4-2- LocallgE immune response .
`4-4-J- Systemic lgE immune response ............... .. ... S 188
`4-4-4- IgE receptors ............................................ S 188
`4-4-4-t- TI1c high nrunily receplor for l~E (fceRJ) ......... 5188
`4-4-4-2- I he low nflinity receptor for l~E (fccJUI, CD23) ... 5189
`4-5- From nasal challenge to chronic rhinitis .. 5189
`4-5-1- Nasal challenge: early and late-phase reactions .. S 189
`4-5·1·1· llte early-phase reaction ....... .. ...... ................... 5 189
`4-~-1-1-l- l{ele-Jsc of va~c.raclh·c m~Jiulo/); . .... ...... ... ... . .. .... S 189
`4-S-1·1 ·2- l'lu:~ma exw.Jation ..... .......................... .............. 5 189
`4-S-l-1-3- l\crh·a1ion of epi thelial c:ells ............... ... .... .... ..... S 189
`4-5-1·1-1- Ne11ruro1>tiJes ........... ........... .......................... 5 189
`4-5-l-1-S- Relc-.1sc ofchemolactic factors ... , .. , .. . ........... ... ... S 189
`4-5 · 1·2· Late·phasc reaction .................. .. .............. ........ 5191
`4-5-l-2-l- Cell u~;tivation and rcka:\c ofpro-innammatory
`meJI"'""' ..... . .. .... ... .. .. ..................... .... ... ...... ....... 5191
`4-5-l-2-2- C)1okin~. chcmokincs ;mcl the hllc-phasc reaction ..... S 192
`4-5-1-2-3- Recruitment of inflammatory cells am.l adlcsion molecules 5192
`. ,.,_, . .. , . .... .. _ .. . S 192
`4-5-l-2-4· Survival orinnammatory cells
`4-5-2- The priming effect .......................... .......... ... 5192
`4-5-3- Minimal persistent inflammation ...................... 5193
`...... 5193
`4-5-4- Persistent inflammation
`
`10A November 2001
`
`J ALLERGY CLIN IMMUNOL
`
`HIGHLY CONFIDENTIAL-
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`MEDA_APTX01331428
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`PTX0326-00011
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`CIPLA LTD. EXHIBIT 2009 PAGE 11
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`

`

`CONTENTS
`
`CONTINUED
`
`"' ..
`
`c
`! - E:--------
`0 u
`
`4-5-4-1- Seasonal allergic rhinitis .... ................... ....... 5193
`5193
`4-5-4-1-1- rnnammalory cells
`..... 5193
`4-5-4-1-2- Erilhclial cells ....
`.
`. .......... 5193
`4-5-4-1-J- Pro-inflammatory mediators ... . .
`4-S-4-1-4- CyJokinea and chemokinet> .. ,., .... ,, ,, ,, .. ,,, . ._.,, ... .•• ~Sl93
`4-5·4-t·S- E~•ma ... ........ ,. ... ... ............. ........... . ... .. . ...... .. 5J93
`4-5-4- t -6- N•umr•rrid" ....... ........................................ 5194
`4-5-4-2- Perennial allergic rhinitis .......... ... .. ...... .. .......... 5194
`4-5·4·2· t- rnnammotory cdl> .. ............... ... ......... ......... ..... 5 194
`4-5·4-2-2- Epithelial cells ..... ... , ..................... _ ............... 5194
`4-5-4-2-3- Pro-inflammatory mediator.~ ...... ..... . ......... .... ... 5194
`4-5-4-2·4· Cytokioe• ......... , ...... , ..... , ...... ................ ...... 5194
`4-S-4-2-S- Adhesil)n molecules ....... ... .... ... .......... L·•· · ..•.. .. 5194
`4-6- Aspirin induced rhinitis..... . .. ............ .. 5194
`4-7- Nasal hyperreactivity .......... .. ... ............... 5195
`4-8- Non-specific triggers .. _ ....... ---...... . 5195
`
`5- Non-infectious, non-allergic rhinitis .. S 196
`5-1- Prevalence and natural history ................ 5196
`S-2- Pathophysiology ........... ...
`.......
`5196
`5-2-1- Drug response and mediators ....................... 5196
`5-2-2- Nasal hyperreactivity .............. ......................... 5196
`5-3- Symptoms .......................... - ........ _ ............ 5196
`. 5196
`5-3-1- Sneezers ............ , ................................ , ..........
`~~ .. 5196
`5-3-2- Rwmers..
`5-3-3- Blockers ......................................................... 5196
`5-4- Causes and classification ...
`................... 5197
`5-4-1- Physiological symptoms .............................. 5197
`5-4-2- Aetiology of non-allergic, non-infectious rhinitis .5 197
`5-4-J- Inappropriate awan:ncss ofnonualuasal
`symptoms ........................ ... . ............................ . 5197
`5-4-4- Anatomical abnormalities ...... ................... ... .. 5197
`S-5- JJ mgnos•s ........................................................... Sl97
`5-6- Dificr<:ntial diagnosis ................................. 5197
`.. S 197
`5-7- Conclusions .................... ......... ....... . ,..
`
`6- Co-morbidity and comp1ications .. 5198
`6-1-Asthma ......
`....................................... ..... .... 5198
`6-1-1- lntroducliou .. ........... ........................ .......... S 198
`6-1-2- Epidemiology .. ......................... . .................. Sl98
`6-1-2·1- A"ociution between a'Liuna and rl1initis ........... 5198
`6·1·2·2- Association between rhinilis and non-specific
`broncl>ial byperreaclivity .................... .............. 5 198
`6-1-J- The same trigger.s can cause rhinitis and asthma .. S 199
`6-1-4- Natural history of tl1e diseases ....... .................. . S 199
`6-1-5- The mucosa of the airways ...................... ...... 5199
`6-1-&- Relationships and dillerences between rhinitis
`and asUtma ....... ............................................. ... .... 5200
`6-1-7- Physiological relationships between rhinitis ami
`asthma ........................................................... ........... S200
`6-1-8- Clinical relationships between rhinitis and
`... 520 l
`asllmHt
`. ...... 5201
`6-1-9- Costs .............. .... ... ............ .. .. ..........
`......... 5201
`6-1-10- Conclusion . ....... .. .......................... .
`6-2- Conjunctivitis ................. ................. ........... .. 5201
`6-2-1- Prevalence of the association ....................... . 520 I
`6-2-2- Mechanisms ............ ... ........... _ ...................... 5203
`
`.. .. 5203
`6-2-3- Clinical aspects......... ............. ....
`6-3- Sinusitis and nasal polyposis
`.... 5203
`6-3-1- Sinusitis ......... ................. , .... , .. .... , .. ......... ...... 5203
`6-3-1-1- RelatiOJJship between allergy and sinusilis ........ .. 5203
`6-3-1-2-Relation!-ihip between asthma and sinusitis - .. . -.,.., .. 5204
`6-3-2- Nasal polyps ...... ............................................... S204
`..... 5204
`6-3-2-1- Relationship between allelJI,y and polyposis .
`6-3-2-2- Relation!ihip between aspirin intolerance and
`polyposis .............. ... ......... ................ ...... ...... .......... 5204
`6-3-2-3- Relatim1>hip between astl1ma and polyposis ....... 5204
`6-4- Otitis media ....................................... - ........ 5205
`6-4-1- Introduction , ... ............................. ........... 5205
`6-4-2- Definition and classification of otitis mcdia ..... S205
`6-4-3- Epidemiological relation between rhinitis and
`otitis media ...... ............................... .......... .......... .... 5206
`6-4-3-1 lnfectious rbinitis nnd otitis media ...... .............. . . 5206
`5206
`6-4-3-2-Allergy and otitis media witl.1 effitsion.
`6-4-4- Potential intemctions ~etween rhinitis ;md otitis
`media .. _ ................................. _ ..................... ... 5206
`(i-4-4-1- Enst1chian htbe dysfunction &·----··-·-·····"··· .. ·-&·5206
`... . 5206
`6-4-4-2-Jnloction- ..... .. ..... · -·--· .... - .• --......... -
`. 5206
`6-4-4-3- Allergy Hw.l allergit: inflummatiou .. .. .••. , .
`..... ,
`6-4-4-4-llle relatiotLo.;hip between food allergy and OME .5207
`6-4-5- Conclusion .............................................. ..... .. 5207
`
`7- ~~~~:~~~~.),a~-~ ... ~~~-~~~~~~-~-~~-~~~~~~~- ~i~~
`
`7-1-1- Symptoms of rhinitis and complications ........ 5208
`7-1-2- Other historical background . .... ................ .. 5208
`7-2- Examination of the nose .............................. 5209
`7-2-1- Methods ........................................................... 5209
`7-2·2· 1'111dlns.s ........................................................... 209
`7-3- Allergy diagnosis .................... - ...................... S209
`7-3-1- Mctl10ds .......................... ................. ................ 5209
`7-3-t-2- Skin tc.;ts ..... ... ........... ... ..... ... ...... ... . 521 0
`.. ... 521 0
`7-J+2·t· Methoos ..... .. .. ..
`. .. 5211
`7-J-l-2-2- Factor,.; affecting skin ttstin,u. .
`.521 1
`7-J-1-2-J- rntcrprctation of~killl~l:-1 ..
`5211
`7-J-1-2-4- Clinic<! I \":rim: ~lfllkin IC:<~1.~ ....... . ... ... ... .
`5212
`7-3-1-3-lgE
`. .... 5212
`7-3·1 -3-1- Serum tut.JIIgE
`...
`. ..... 5212
`1·3· 1·3·2· Ser"""l""i~o I~E .. ......
`7-3-1-3-3- Screening test~> using senun SJ)t!l:il'ic lgE . ... ...... ..... 5212
`7-3-J-4- OUt<r lcsls ........... ...... .................. .... .............. . 5213
`7-l· 1-H- tsG "'d lsG 4 .. ...... .... ~ ....... ....... ... ....... .... ~ ..... 5213
`7-3-1·4-2· 'Perirher:~l blood :::acti\:rtion nmkcrli .. ... ....... ...... .. . 5213
`7-l·l·o·l- Na'"l <Occir.c lsE ........ .. ............ . ............ - .... S213
`. 5213
`7-3-1·4·4- Mer.Ji:.rtors rcle-Jscd UurinQ allergic reactions ...... . & ..... .
`.. ........... 5213
`7-l· 1·4·5· Cytology an<l histolo~)' ..... ,.... ..
`. 5213
`7·3-1·4·6- Mca:-.•rrcmcnt of nitric Ol'.it.lc in c~halcJ air ,. ..
`. .. 52\3
`7-J-1-5- Nn<al challenge . ....
`..5213
`7-J-1-5-1- Nas;_rl challrnQ-c with allergen ... ... ·-· ··- .... ••. .
`7-J-l-5-1-1- "Provokinj! agent . ......... •· ···· ..... ....... 5213
`7-J-l-5-l-2- Dcrmtition in the nose ..... ... ... .... , .... .. ... ...... .. 5214
`. 5214
`7-3-l-1-l-3-A~sessmentofthe response
`.. . . ......
`.... ··· ·-
`7-3·1-5-1-4- Mea.-;urement of metliators ;_rntl cells during t.:hallenge 5215
`Continued on page 12A
`
`J ALLERGY CLIN IMMUNOL
`
`November 2001
`
`11A
`
`HIGHLY CONFIDENTIAL-
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`MEDA_APTX01331429
`
`PTX0326-00012
`
`CIPLA LTD. EXHIBIT 2009 PAGE 12
`
`

`

`CONTENTS
`
`CONTINUED
`
`7-3-1-5-t-5- Factor:; affecting nat-kll challenge ... .• ..
`
`7-3-1-5-1- Nas:.~l challenge with ron-spccifie agents
`
`- ~· ··· ... 5215
`.. 5215
`.... . .. 5215
`7-3-l-5-3- Challenge with occupational agents
`... 5215
`7-3-l-5-4- A:;,pirin-induccd rhinitis and asthma .
`7-3-2- lnterpretatjon of tests and recommendatio11s ... 5216
`................... .......... 5216
`7-3-2-1- Comlation between teols
`7-3-2-2- Diag.nosis of inhalant allergy ·· ···-·~----·· ··· ·· .. -- ..... 5216
`7-3-2-3- Dia~;nooio of food allerb'Y ................... ............. 5216
`7-3-2-4- Diagnooio of occupational allergy .. ........ .... ... ... 5216
`7-4- Other ENT diagnosis ................................... 5216
`· .. -·~-................. _,, .. ,_ ... , .. 5216
`7-4-1- Bacteriology -
`.. ................. . ... 5216
`7-4-2- Imaging .......... ......
`7-4-2· [.Plain oinus radiograplt< .. .. ............. ................ 5216
`.. .... .......... 5217
`7-4-2-2- Computerised tomography (CT) . .
`... 5217
`7-4-2-3- Magnetic resonance imagiJJg (MRI)
`................................. ... 5217
`7-4-3- Mucociliary function
`.5217
`7-4-4- Nasal airway assessment __ , .. , ,.
`7-4-5- Olfaction ....... ,,. ........................................ 5217
`7-5- Diagnosis of Asthma ..............
`..5217
`7-5-1- History and measurement of symptoms .... ..... 5217
`7-5-2- Physical examination ........................ ..... ........... 5218
`7-5-3- Measurement of lung function .......... .. .............. 5218
`. ....... 5218
`7-5-3-1- Recording airflow obstn1ction .
`7-5-3-2- Asse.'i.'ii[]g the reversibility of airflow ob~tmctiou .5218
`7-5-3-3- A~'e"inH ti1e diurnal variation of oirllow obotmction .. 5218
`7-5-3-4- Non-specific challenge tc:~ti[lg .......... .. ....... .. ... 5219
`7-5-4- Special considerations in difficult groups ...... S219
`7-6- Assessment of severity of rhinitis ............ 5219
`
`8~ Management ................. _ ................................. 5220
`8-1- Allergen avoidance ....................................... 5220
`8-J-J. House dust mites ..................... ........ ................ 5220
`8·1-2· Cats and dogs .................................................. .. 5221
`8-1-3- Cockroaches .. ........... ... ................................ ..... 5221
`8-1·4- Outdoor allergens . . ..... .. ... .. ... .... .. .. .......... . 5221
`....... ........... . .. 5221
`8-l-5-lndoor moulds ......... .... ...... ..... .
`8-J -6- Occupational agents .... ... ........... .. .. ... .......... . 5221
`8-1-7- Food allergens ............... .. .. ..... ..... .. ...... ... . 5222
`.. . .......... .. .. 5222
`R-1-R- Conclusion . .... ..... .... ......
`B-2- M~diL:ation ..................... . ............ ........... . 5222
`...S222
`8-2-1- Routes of administration ..
`8-2-1-J- Advantage:-; ofilltranasal<~dministmtion .. ... ........ 5222
`8·2·1·2· Problems of intranasal administration ............. 5222
`8·2-2- Oral HI-antihistamines .... .... ......... .. ......... ..... 5223
`8-2-2-1- Mechanisms of actio11 nnd rationale .................. 5223
`8-2-2-1-1- H 1-blo,k;ng offect ,. ........ , .... ..... ............ ......... ... S223
`8-2-2-1·2· /\nt;·allct~ic effecl' .. .. .... ............ ........ , ......... .... 5223
`8·2·2·2· Clinical and rhannacological effects .. . ........ .... 5224
`8·2·2-3· Side effect< of H l·amihistamincs .. .... ............. 5224
`... .. ... 5224
`6·2·2·3·1· Crntrul ncnou:i ~y:-tcm :iide cffccL'I
`.... ..... . ..
`. . . . S225
`R-2-2-3-2- C:1nJia~: ~ide cffed:-. .~ ... ..... ...... . ... ...... ..... .. H
`S-2-2-3-3- C:~rcinogcnic ciTccts .. . ..... ..... ........ ...... . .. .. ........ ~ 5225
`8-2-2-3-4- Other side rn-Crts ... .. ................ , ................ ....... 5225
`.. .......... ............. 5226
`R-2-2-4- MolecHieo used ...
`. .. . . 5226
`R-2-2-4-1-1\cri\;lstinc.. ... . ..
`.. ....... 5226
`s~n 0~ ""tem;zole...
`.,5226
`S-2-2-4-3- .1\2el:Jstine.
`8·2-2-4·4- Cet;,;,;ne ........ . ..... , ......... ........ ..... . ........... 5226
`
`8~2-2~4-5- Eb"''"" ............... ... . , .................. , ........ .. 5227
`. .. 5227
`8-2-2-4-6- Emedastinc .... ~- -
`. ··- · .•..
`B-2-1-4-7- Er;n,so;ne ..... ... ... . ......... .... " "" ... ............ 5227
`...... .. .... ·--·· · - · ·•· •·· ··----··• ... .. 5227
`B-2-2-4-8- Fexofcnadinc
`B-2-2-4-9 Levocabm;tine ....... . .. . ...... ... .. . . ................ . .. .... 5228
`8-2·2·4-10- Locaoau;ne ........... .. , ... .. ......... , ... M .......... .. .... 5228
`R-2-2-4-11- Mequit:J2ine ........ . .. ....... . .. .. ........ . ........... .. .... 5228
`8-2·2·4-12- M;wi>Stine ................... .................... ......... 5228
`8·2-2-4-13- Terfenau;ne ... , .. , . .... .. , .... , ......... , . ....... ,. , .... ,.,.5228
`8-2-2-4-14· Ketotifen ....................... ..... ........................ 5229
`.. , ... .... ,.,.,.5229
`B-2-:2-rl-15· Oxutomid~ .. .. ,, .. . ........ ,
`...... 5229
`8-2-2-4-l(i- Other mo\~cules . .... ....... .. .. .......... , .........
`8-2-2-5- The future of Hl-antihiotamines ....... ...... ......... 5229
`8-2-2-<t- Rccmruncndatioos ........ ................ .................. 5229
`S-2-3- Tupical HI-antihistamines .. ...................... ... .... 5229
`8-2-J-1- Rationale ........ .... , . ............................... ...... 5229
`8-2-J-2- Efficocy ~ ............... _ , __ ....................... 5229
`5229
`R-2-3-2-1- Nasal :u.Jministr.ltion
`. ., ............... ,
`..... .. , . .. ... ... ... ... . 5230
`8-2-J-2-l- Ocular utlministnltion ..........
`8-2-J-J- Safety ....... ....... .... , ................... ....... : .. ...... . 5230
`8-2-3-4- RecmmneJJdalioos ........... ... ... ...... .................. .. 5230
`8-2-4- Topical glucoeorticosteroids .. .......................... 5230
`8-2~-1- Mechanisms of action and ratimmle .............. .. 5230
`8-2-4-1·1· Molecular enecL' ................ . . .......................... 5230
`S-2-4-l-2- Anti-innamm:~Lory efreL:Ifi on cell:.; ...... . ....... ... ....... 5231
`B-2-4-L-3-.Anti-inflarnmatory effect:; on cylokines .................. 5231
`8-2-4-1-4- Oth~r cff~ct'l of intrann.'i<il g\ucocortico.~t~roid.~ ..... .... 5231
`8-2-4-2- Clinical and phannacologieal effects .. ............... 5231
`8-2-4-3- Side cffcc.t< of intranaoal ghlcocortieoslcroids .. .... 5232
`...... ...... .... 5232
`8-2-4-J-1- Local siue e~'e,tx .. .. .........