N(O5
`
`f‘ 17 January 2006 ‘ Annals inflntcrnal Medicine Volume 144 Numberz
`
`
`
`
`
`
`
`
`
`7 IETIERS 145
`COMPLETE couriers 1:5
`
`z
`(:5
`‘71:;
`;:
`::-
`E'
`-‘;
`‘— ii
`s": L
`:
`—.
`i:
`J1
`g
`
`if,
`
`135%
`"1:2.
`":1
`iii;—
`T17 5,
`5:5
`a (i
`r-
`
`1;
`
`
`
`www.annals.org
`
`ESTABIISI—IH)
`
`IN 1927 M 'l‘HF AMirniCAN COLLECT-I 0F PHYSICLANS
`
`‘ AR'I‘ICLES
`
`Exercise Is Associated with Reduced Risk for Incident Dementia
`
`among Persons 65 Years of Age and Older
`l.Alt.\c)N, WANG, BOWEN, MCCOILMH‘K. THtL Ctumt, AND Kuxuu
`
`Socioeconomic Status and Mortality after Acute Myocardial Infarction
`AITixk, CHONG, Auxrw, MLLH'I‘Mtu, hum, Wu I mm, AND OTHERS
`
`Blarithromycin—Resistant Genotypes and Eradication of Helicobacter
`pylon DE FRANCl-b‘co‘ MatuuuTTA, 71mm, l-InssAN, AND UTI—II-Rh
`
`Brief Communication: Tamoxifen Therapy for Honmalignant
`Retroperitoneal FthUSiS VAN “(mm-1.. Hi-NIHUKSZ‘ ANI) OTHERS
`
`IMPROVING PATIENT CARE
`Prohtem Doctors: Is There a System-Level Solution?
`LEAP}: AND FRDMSI)N
`
`REVIEW
`
`Systematic Review: Antimicrobial Urinary Catheters To Prevent
`Catheter-Associated Urinary Tract Infection in Hospitalized Patients
`JOHNSON, Kusxnwsxt, AND VVII’I'
`
`PERSPECTIVE
`
`Acute Pain Management for Patients Receiving Maintenance
`Methadone or Buprenorphine Therapy
`ALI-'(JRD, Crmrrun‘, ANT) SAMFT
`
`EDITORIALS
`
`MEIIS Sana in fiorpore Sano l’nmwus AND GUALLAR
`..
`.
`.
`.
`Going Back To Understand the Future: Socioeconomic Posmon and
`Survival after Myocardial Infarction Kan.“
`.
`.
`.
`Improving Helrcoiracter pylon” Eradication Regimens
`FitANcms ANI) “mm-n
`
`ON BEING A DOCTOR
`(If Poems and Patients
`SFm—‘R
`
`Azila Kim.
`
`CURRENT CLINICAL Issuns
`Health and the Environment after Hurricane Katrina
`E‘IsIII-R VVIIMLN
`
`13
`
`32
`
`94
`
`101
`
`10?
`
`IIB
`
`121
`
`'35
`
`137
`
`I40
`
`142
`
`143
`
`153
`
`Liquidia's Exhibit 1009
`Page 1
`
`Liquidia's Exhibit 1009
`Page 1
`
`

`

` ARTICLES
`
`CONTENTS Annals of Internal Medicine
`
`BIarithromycin-Resistant Genotypes and Eradication
`of Helicoiracfer pylori
`V. De Francesco, M. Margiotta, A. Zullo, C. Hassan, L. Troiani,
`0. Burattini, F. Stella, A. Di Leo, F. Russo, S. Marangi,
`R. Monno. V. Stoppino. 5. Morini, C. Panella, and E. ierardi
`The authors compared Helicobacter pylori eradication rates
`among strains with different point mutations that confer
`clarithromycin resistance. Antibiotics eradicated Helicobacter
`pylori infection in 11 of 23 patients (48%) with the A21436
`mutation and in 14 of 15 patients (93 %) with either
`A214ZG or A2142C strains. A sequential triple—therapy
`regimen achieved a higher cure rate than simultaneous triple
`therapy in A21436 mutation strains.
`Continued on page i-6
`
`
`Exercise is Associated with Reduced Risk for Incident
`llementia among Persons 65 Years of Age and Older
`E.B. Larson, L. Wang, J.D. Bowen, W.C. McCormick, L. Teri,
`P. Crane. and W. Kukull
`
`13
`
`The authors folIOWed 1740 persons who did not have
`cognitive impairment at baseline. During a mean follow-up
`of 6.2 years, 158 participants developed dementia; the
`incidence rate was 13.0 per 1000 person-years for those
`who exercised 3 or more times per week at baseline and
`19.7 per 1000 person-years for those who exercised less
`frequently. The results were similar in the 107 participants
`who developed Alzheimer disease.
`Summary for Patients
`
`I-20
`
`82
`
`Socioeconomic Status and Mortality after Acute
`. Myocardial Infarction
`D.A. Alter, A. Chang, P.C. Austin, C. Mustard, K. Iron,
`1.1. Williams, C.D. Morgan. J.V. Tu. J. Irvine, and C.D. Naylor,
`for the SESAMI Study Group
`The true causes of income-related health disparities are not
`known. In 3407 Canadian patients who were hospitalized for
`acute myocardial infarction, high income was associated with
`alower 2—year mortality rate (crude hazard ratio, 0.45 [95%
`Cl, 0.35 to 0.57]; P < 0.001). However, adjusting for
`income-related differences in age and the prevalence of
`preexisting cardiovascular events or risk factors substantially
`reduced the effect of high income (adjusted hazard ratio,
`0.77 [CI, 0.54 to 1.10]; P = 0.150).
`
`Summary for Patients
`
`L42
`
`94
`
`17 January 2006 144 2 73—156
`
`101
`
`Brief Communication: Tamoxifen Therapy for
`Nonmalignant Retrcneritoneal Fibrosis
`E.F.H. van Bommel, T.R. Hendriksz, A.W.L.C. Huiskes, and
`A.G.M. Zeegers
`Retroperitoneal fibrosis is a progressive disease that can
`respond to corticosteroids but is sometimes steroid-resistant.
`Among 19 patients with retroperitoneal fibrosis who received
`tamoxifen, 20 mg twice daily, 15 reported substantial
`symptom resolution after a median of 2.5 weeks. Repeated
`computed tomography showed mass regression in 14 of 15
`clinical responders. Treatment failed in 5 patients, and 1
`patient developed severe hepatitis while receiving treatment.
`Summary for Patients
`l-51
`
`IMPROVING PATIENT CARE
`
`Problem Doctors: Is There a System-Level Solution?
`LL. Leape and J.A. Fromson
`
`11]?
`
`Three ideas frame an effective system for managing poorly
`performing physicians: Subpar performance can be objectively
`defined; routine monitoring of the entire medical staff is
`necessary to detect problems fairly and early; and responses to
`deficiencies should be prompt, constructive, and sustained. The
`long-term objective is to enable physicians to continue to
`practice effectively and safely, not to “weed them out."
`
`REVIEW
`
`116
`
`Systematic Review: Antimicrobial Urinary Catheters To
`Prevent Catheter-Associated Urinary Tract Infection
`in Hospitalized Patients
`J.R. Johnson. M.A. Kuskowski, and TJ. Wilt
`The authors assessed the efficacy of currently marketed
`antimicrobial urinary catheters. In this systematic review of
`12 trials, they concluded that antimicrobial urinary catheters can
`prevent bacteriuria in hospitalized patients during short-term
`catheterization. The cost implications of these catheters and
`their effect on infectious complications remain undefined.
`
`PERSPECTIVE
`
`127
`
`Acute Pain Management for Patients Receiving
`Maintenance Methadone or Buprenorphine Therapy
`D.P. Alford, P. Compton, and J.H. Samet
`The number of patients with opioid addiction who receive
`opioid agonist therapy (OAT) with methadone and
`buprenorphine is increasing, so that physicians will more
`frequently encounter such patients who have acutely painful
`conditions. This paper acknowledges the complex interplay
`
`Postmaster: Send damages of address to Customer Servrce. Ammo qfilnrrma! Medicine. 1‘30 N. Independence Mall West. l’hiiadclphia, PA 19106,} 572. I Amzafi oflnrrmal Mrdirr‘ne is published twice
`mondtly and copyrighted © 2006 by the American College oFPhysicians, 190 N. independence Mall West, Philadelphia, PA 19106-1572, USA. Basic member subscription price is $20.00 per year.
`Periodicals postage paid at Philadelphia. Pennsylvania. and at additionaJ mailing offices. Canadian Publications Mail Agreement #4003031}. (ACl'meRcrs, [03] Helen: Street. Fort Erie, Ontario LIA
`5N8. Canada) GST [039128512151 - AIMEAS 144(2)737156(2006i ' US ISSN 0003-4819.
`
`Liquidia's Exhibit 1009
`Page 2
`
`Liquidia's Exhibit 1009
`Page 2
`
`

`

`CONTENTS Arvials of Internal Medicine continued
`17 lanuary zoos 144 2 73-156
`
`Aziza
`R. Kannal
`
`143
`
`During the physical examination, Aziza read me with astute
`observation: She sensed my aversion to physical contact with
`her and my attempt to end the session peacefully. I tried to
`understand the contents of her thoughts, since she easily
`transferred from the world of delusions to our world. complete
`with National Insurance forms. Why couldn't I, the sane one,
`identify with her hallucinations?
`
`LETTERS
`
`tommem‘s and Responses
`
`National Health Information Network Cost and
`Structure
`
`I45
`
`R.H. Dolin and AM. Wiesenthal; R.B. Doherty: .I.M. Kretz;
`M.M. Rothkopf and HS. Jackson: R. Kaushal, D.W. Bates, and
`D. Blurnenthal
`
`Prevention of Exacerbations of Chronic Obstructive
`Pulmonary Disease with Tiotropium
`C.B. Good and L. Longo; A.B. O'Connor; D.E. Niewoehner,
`K. Rice, and S. Kesten
`
`Exorcising Ghosts and Unwelcome Guests
`5.5. Daskalopoulou and D.P. Mikhailldls: A. Jacobs
`
`Clinical observations
`
`Inhaled Treoostinil for Treatment of Chronic
`Pulmonary Arterial Hypertension
`
`141
`
`149
`
`I49
`
`R. Voswlnckel, HA. Ghofrani, F. Grimmlnger. W. Seeger. and
`H. Olschewski
`
`Heurocysticercosis in Kansas
`T.L. Daniels and Mt. Moore
`
`Correction
`
`150
`
`Correction: Advanced Lipoprotein Testing in Young Adults
`
`152
`
`CURRENT CLINICAL Issues
`
`among addictive disease, CAT, and acute pain management;
`describes 4 misconceptions that lead to suboptimal treatment
`of acute pain; and gives clinical recommendations for providing
`analgesia when a patient receiving OAT develops acute pain.
`
`EDITORIALS
`
`Mons Sana in Corpore Sana
`LJ. Podewils and E. Guallar
`
`I35
`
`Larson and colleagues provide important evidence that more
`physical exercise is associated with lower rates of dementia,
`adding significantly to several other recent studies on the
`association between physical activity and dementia risk. We
`now need randomized trials to examine the effect of physical
`activity on cognitive function measures, and we need
`researchers to include clinical dementia end points in
`ongoing trials of lifestyle modification.
`
`137
`
`Going Back To Understand the Future: Socioeconomic
`Position and Survival after Myocardial Infarction
`G.A. Kaplan
`Do we really need another paper on socioeconomic inequalities
`in health? Alter and colleagues have added to our knowledge,
`but the assumption that we can reduce socioeconomic
`inequalities in survival after cardiovascular disease (CVD) by
`reducing morbidity and risk factors in poor people begs the key
`question. We must integrate our knowledge of the upstream
`social determinants that lead to differential burdens of CVD
`and its risk factors and the downstream, proximal biological
`factors that drive health outcomes. Building a bridge between
`these bodies of knowledge could provide a way to decrease
`socioeconomic inequalities in survival.
`
`Improving Helicabacter pylori Eradication Regimens
`F. Francois and MJ. Blaser
`
`Ml]
`
`The work by De Francesco and colleagues showing the
`enhanced efficacy of sequential therapy is a timely advance
`for patients with peptic ulcer disease or mucosa-associated
`lymphoid tissue lymphoma, in whom Helicobacter pylori
`eradication is clearly indicated. A larger question is whether
`the relatively indiscriminate practice of “test and treat" for
`H. pylori infection treats the patient or the physician. In their
`zeal to remedy many ailments with antibiotics, physicians are
`contributing to new problems of antibiotic resistance and to
`changing human microecology.
`
`ON BEING A DOCTOR
`
`lit Poems and Patients
`D. Seder
`
`142
`
`Health and the Environment after Hurricane Katrina
`.l. Fisher Wilson
`
`153
`
`Recendy, my wife and I were out listening to a folk singer, and
`I realized how hard it is to listen to live music without leaning
`across a bar. It wasn't so long ago that 4 or 5 night a week I
`poured beer and shook drinks while customers came and went.
`That life is so different from my current one that it could have
`been led by another person entirely.
`I-6
`
`Cover photograph by Robert L. Meyer
`
`Authors' Form I-19
`CME Bulletin Board 1—31
`Subscription and Business Information 1-46
`Classified Services Begin on [-53
`
`Liquidia's Exhibit 1009
`Page 3
`
`Liquidia's Exhibit 1009
`Page 3
`
`

`

`AIMEAS 144(2)73-156(2006) US ISSN 0003-4819
`
`Annals of Internal Medicine
`ESTABLISHED IN 1927 BY THE AMERICAN COLLEGE or- PHYSICIANS
`
`Subscriptions
`Annals ofInternalMedicine (ISSN 0003-4819)
`is issued twice monthly by the American
`College of Physicians; new volumes begin with
`the first issues ofJanuaty and July each year.
`
`To subscribe to Annalr qurttrmal Medicine,
`call 800-523-1546, extension 2600. or write to
`Annals qflnnemal Medicine, Customer Service,
`190 N. Independence Mall West,
`Philadelphia, PA 19106-1572.
`
`Advertising
`To advertise in Annals qflmemal Medicine or
`request a media hit, all 800-523-1546,
`extension 2440, or write to Advertising Sales
`DCPartmcnt, 190 N. Independence Mall
`West. Philadelphia, PA 19106,
`
`Editorial Correspondence
`Editorial cortapondence should be
`addressed to:
`The Editor
`
`Admit qflntaml Median:
`190 N. Independence Mall West
`Philadelphia, PA 19106-1572, USA
`Fax 215651-2644
`
`Reprint Information
`Helen Canavan. Reprints Coordinator
`190 N. Independence Mall West
`Philadelphia, PA 19106—1572. USA
`Phone 800-523—1546, extension 2663
`Fax 215—351—2686
`
`For Canadian and translated reprints
`worldwide, contact Marsha Fogler. Reprint
`Sales Representative
`Phone 800-482-1450; 01 356-489-4446
`(outside the USA)
`Fax 856-489-4449
`E—tnail mfogler@medicalreptints.com
`
`mannalsntl
`
`Editorial Staff
`Editor: Harold C. Sox, MD
`Editors Emeriti: Frank DavidolT, MD,
`Robert H. Fletcher, MD, MSc,
`Suzanne W. Fletcher, MD, MSc,
`Edward J. Hutlt, MD
`Senior Deputy Editor: Christine Lainc, MD, MPH
`Deputy Editors: Michael Berkwits, MD. MSCE.
`Paul Epstein, MD,
`Cynthia D. Mulrow, MD. MSC
`Associate Editors: Elias Abrut'yn, MD.
`E. Victor Adlin, MD.
`Robert G. Badgett. MD (electronic publications),
`Martin Black. MD.
`Leonard E. Brain-nan. PhD, David Goldmann, MD,
`Steven N. Goodman. MD. PhD. MHS,
`Michael E. Griswold. PhD,
`Eliseo Guallar, MD. PhD.
`DuPont Guetry 1V, MD. Anne Hudson Jonas, PhD,
`William G. Kussmaui III, MD,
`Michael A. LaCombe. MI),
`Andrew S. Levcy. MD, A. Russell Incalio. JD,
`Catharine Stack, MS, PhD.
`Barbara]. Turner. MD, MSEd, MA,
`Sankey V. Williams, MD
`Associate Editor Emeritus: John 1.. Abruzzo. MD
`Managing Editor: Mary Beth SchaeEer
`Editorial fifties.- Robert Blaclmvell. Nicole Briglia.
`Ruth Burrows, Jill Jackson,
`Nicole Massone, Arm Paul
`
`Barry J. Marshall, Crawly, Australia
`Robert J. Mayer, MD, Boston
`Clement J. McDonald. MD, Indianapoln
`David Meltzer, MD, PhD, Chicago
`Santiago Pavlovsky, MD, Burner/lire:
`Lewis J. Rubin, MD. San Diego
`Margaret A. Tucker, MD, Rackville, Maryland
`
`Publication Committee, ACP
`Willem B. Applegate, MD, Chair
`Clara Bloomfield, MD
`David B. Duggan, MD, Vic! Chair
`Erin E. Dunnigan, MBA
`John P. Fitzgibbons, MD
`Benjamin]. George. MD
`Phyllis A. Cure. MD
`Stephen G. Paukct, MD
`Brian 1.. Strum, MD
`
`Publishing Staff
`Publisher: Robert Spanier
`Associate Publisher: Diane McCabe
`Director. Editorial Production: Linda Drumheiler
`Manlzlnl Editor: Mary E. Boyltm
`Supervisor, Edit-rial Production:
`Jennifer Kearney-Strouse
`Senior Production Editor: Laura Altobeilj
`Productlon Editors: Beth A. Hummel.
`Christine Kucowski
`Assistant Production Editor: Kimberly S. Rah
`
`Editorial Board
`Martin Blaser. MD, New York
`Clara Bloomfield. MD, Columbus. Ohio
`Harry R. Bullet, MD, PhD, Amsterdam
`Christopher Callahan, MD. Indianapoin
`Christine Cassel. MD, Philadelphia
`Janice Douglas. MD, Brammll Obie
`Ezekiel J. Emanuel. MD. PhD, MSC. Barbuda
`David P. Fasten, MD. Chicago
`Lisa H. Fish. MD, Edina. Minnesota
`Bevra H. Hahn, MD, [.05 Angela
`Alessandro Liberati, MD. Milan
`
`
`Advertising Operations
`Manager: Brian S. Barker
`lltlllal'tlsiltg Production: Helen Canavan
`“vault-in: Billit’lfl: Penny Quartapella
`Supervisor. Recruitment Sales: Margaret Gardner
`
`Advertising Sales
`Rational Account Managers: Tom Terreri (Catalyst
`Communications), Frank Cox (PMI). Kathleen
`Harrison (PMi), Betty Ann Gilchrist (PMI)
`
`Editorial Policy
`Annalt oflnrema! Medicine publishes original articles, reviews, clinical conferences, editorials, letters,
`and other information relevant to internal medicine and related fields. Further details on the kinds
`of manuscripts that are considered for publication are given in “Information for Authors."
`Portions of the content ofAnmzls aflnrmlMedicine are protected by copyright. Papers without a
`copyright symbol are in the public domain. Manuscripts are accepted for publication with the
`understanding that their contents, all or in part, have not been published elsewhere and will not be
`published elsewhere, except in abstract form or by the express consent of the Editor.
`Statements expressed in Annals affmemal Medicine reflect the views of the authors and not neces—
`sarily the policies of the journal or of the American College of Physicians, unless so identified
`Annals ofInternal Medicine and the American College of Physicians accept no responsibility for
`statements made by contributors or claims made by advertisers, nor does the publication of adver-
`tisements constitute or imply endorsement. The information contained herein should never be used
`as a. substitute for clinical judgment.
`17 January 2006 .‘\|'lll.lln of lntcmnl Medium»
`
`
` Volume 144 . Number 2| I‘9
`
` l
`
`l
`1
`
`1
`,
`
`F—.—
`
`Liquidia's Exhibit 1009
`Page 4
`
`Liquidia's Exhibit 1009
`Page 4
`
`

`

`
`in normal may be momma Mconrvnghtlzw little )7 us (may
`
`
`
`
`(Boehringer Ingelheim Pharmaceuticals); Consultancies: DE. Nicwoeh—
`net (Boehringcr Ingclheim Pharmaceuticals); Hormmria: DE. Niewoehv
`ner (Boehringer Ingeiheim Pharmaceuticals). K. Rice (Boehringer In-
`gciheim Pharmaceuticals).
`
`References
`In chronic obstructive
`Inhalation Aerosol Study Group.
`I. COMBIVEN’I‘
`pulmonary disease. a combinaliun ofipratmpium and albiitcrol is more effec»
`tive than either agent alone. An 85-day multicenter trial. Chest
`I‘J‘J‘lHUS:
`I4lle9.lI’MID13IBI328]
`2. COMBIVENT Inhalation Solution Study Group. Routine nebulired iprattopium
`and albuterol together are better than either alone in COPD. Chest. I99?“ [2:15I4»
`2|. [PMID: 9404747}
`3. National Heart. Lung and Blood Institute. Global Initiative for Chronic Obstructive
`Lung Disease: Global Strategy for the Diagnosis. Management and Prevention of
`Chronic Obstructive Pulmonary Disease (NHLBIJ’WHO workshop report). Bethesda,
`MD: National Hmrt. Lung and Blood Institute; 2001.
`4. O'Donnell DE. Aaron S. Bourheau }. Hernandea P. Marciniuk D. Balm M, e! ail.
`State of the Art Compendium: Canadian Thoracic Society recommendations for the
`management of chronic obstructive pulmonary disease Can Respir J. 2004:]l Suppl
`B:7B»59B, lPMID: liS‘lOSSll
`5. Anthonisen NR. Connert JF. Kiley JP. Altose MD, Bailey WC. Buist A5. et al.
`Effects of smoking intervention and the use of an inhaled anticholinut'gic bronchodie
`lator on the rate ofdeclinc of FEV I. The Lung Health Study. JAMA. 1994172: 14977
`505. [I’MID: 796684ll
`(1. Sin DD, McAlister FA. Man Sl“. Anthonisen NR. Contemporary management of
`chronic obstructive pulmonary disease: scientific review. JANIA 2003;290:23lll712,‘
`ll’MlD: 14600189]
`7. Wth T). Niewoehncr D. Kim C. Kane RI... Linabery A. Tacklind J. or .11. Use ul’
`Spirontetry for Case Finding. Diagnosis. and Management of Chronic Ohstrlictivt
`Pulmonary Disease (COPD). Evidence ReporthechnoIogy Assessment No.
`[2|
`AHRQ Publitsttion No. 0571501772. Rockville. MD: Agency for Healthcare Research
`and Quality; 2005.
`
`
`Exorcising Ghosts and Unwelcome Guests
`
`TO THE EDITOR: We applaud the editors ofAmer for their effort to
`increase awareness regarding ghostwriting (1). Drs. Laine and Muir
`row cite our editorial (2). but a slight correction is needed;
`they
`imply that the GATE principles were proposed by the European
`Medical Writers Association. Actually, we initially proposed these
`guidelines ourselves in our editorial (2). However. we were inHu»
`enced by the association’s statements and by our own experience
`when we formulated these guidelines.
`There is increasing concern about ghostwriters because it is dif—
`ficult to prove their existence. Therefore, whenever help from pro-
`fessional writers is necessary. it is imperative that the GATE princi-
`ples are maintained. Maybe a uniform policy should be implemented
`by journals (in our editorial. we proposed a formula of acknowledg-
`ment statements to achieve maximum transparency). One key issue
`not addressed by Laine and Mulrow is the possibility of regulating
`professional writers. In other words. writers would need to be l‘EgIS‘
`tered and evaluated to maintain minimum standards (2).
`The earliest article on ghostwriting that we identified through a
`search of I‘ubMed was published in 1934 (3). It is about time that
`we sort out this issue. Professional writers,
`if they have to be used.
`should have a legitimate role in assisting (not replacing) experts to
`provide a quality document while maintaining high ethical stan-
`dards. However. the experts should always play ct key role and have
`mannalutl
`
`LETTERS
`
`the final say on content. Hidden ghosts, unwelcome guests. and
`hired experts do not have any place in the medical literature.
`
`Stella S. Dmkalopaulou, MD, M56. DIC. PM)
`Dimitri 1". Mid/Jailidit. MD. MS!
`Royal Free Hospital
`London NW3 ZQG, United Kingdom
`
`Potential Financial Conflicts of Interest: None disclosed.
`
`References
`1. Lame C. Mulrow CD. Exercising ghosts and unweicnme guests {Editorial}. Ann
`Intern Med. ZOUS:I43:(iII-.Z. [I’MID: 16230729)
`2. Daskalopoulou SS. Mikhailidis UP. The involvement ofprolewional medical writers
`in medical publications {Editorial}. CLUT Med Res Opin. 2005;21:307-111.
`[I‘MIDz
`15802002)
`3. Place F. Ghost writing. Bull Med Libr Assoc.
`16016210]
`
`1934;22:200-213.
`
`[PMID:
`
`I was pleased to read Drs. Laine and Mulrow’s
`TO THE EDITOR:
`editorial about ghosts and guests, which I thought steered a very
`sensible course through a difficult topic (1). I feel that 1 minor point
`of clarification is required, however. The GATE principles referred
`to in the editorial were not described by the European Medical
`Writers Association but were described in an editorial (2) that no
`companied the association’s guidelines. Readers ofArmaLs may also
`be interested in the original guidelines (3). which were not cited by
`Drs. Laine and Mulrow in their editorial.
`
`Adam jarobr, PM), MSr
`Dianthus Medical Limited
`
`London SW19 3T2, United Kingdom
`
`Potential Financial Conflicts 01 Interest: Dr. Jacobs is a former presi-
`dent of the European Medical Writers Association and is a coauthor of
`the association‘s guidelines on the role of medical writers in developing
`peer~teviewed publications.
`
`References
`1. [nine C. Mulrow CD. Exercising ghosts and unwelcome guests {Editorial}. Ann
`Intern Med. 2005;143:61172. [PMID: 16230729]
`2. Dasltalopoulou SS. Mikhailidis DP. The involvement of professional medical writers
`in medical publications [Editorial]. Curr Med Res Opin, 200521507710. [PMID
`15802002]
`3. Jacobs A. Wager E. European Medial Writers Association (EMWAJ guidelines on
`the role of medical writers in developing perrereviewed publications. Curr Med Res
`()pin. 2005;21:311er [PMID: 15802003]
`
`CLINICAL OBSERVATIONS
`
`
`
`Inhaled Ttepostinil for Treatment at Chronic Pulmonary
`Arterial Hypertension
`
`is a stable prostacyclin
`TO THE EDITOR: Bar/aground: Treprostinil
`analogue that is approved for the treatment of pulmonary arterial
`hypertension when administered by continuous subcutaneous infu»
`sion (1). Inhalation of the stable prostacyclin analogue iloprosr has
`17 lanunry 2006 Annals ofinternal Medicine Volume I44 ' Number 2 149
`
`
`
`Liquidia's Exhibit 1009
`Page 5
`
`

`

`nary hypertension; mean pulmonary vascular resistance (i SE) was
`1355 I 286 dyne/s per cmfis. Inhalation of nitric oxide resulted in
`a mean reduction (1 SE) in pulmonary vascular resistance of 26%
`i 22.8%. Inhalation of treprostinil substantially reduced pulmonary
`vascular
`resistance (mean maximum change [1' SE],
`‘45.2%
`t 17.5%) for a sustained period (duration of effect, >180 min).
`Pulmonary selectivity of the approach was reflected by a substantially
`reduced ratio of pulmonary vascular resistance to systemic vascular
`resistance; the mean area under the curve (1 SE) was 30% i 1 1%
`For pulmonary resistance and 16% i 3% for systemic ICSiSIaflCt'.
`One patient had a favorable vasodilator response (shown in the Fig-
`ure) and was therefore given high—dose calcium-channel blocker ther-
`apy.
`
`The other 2 patients were oFfered long-term inhaled treprostinil
`therapy (on a compassionate treatment basis). consisting 01:4 daily
`1511.3 doses. Over the first 3 months of treprostinil therapy, the func-
`tional status of both patients improved dramatically (New York Heart
`Association class improved from IV to 111 and From 111 to II, respec-
`tively; 6—minute walking distance increased from 0 to 143 m and From
`310 to 486 in, respectively). No side effects were observed.
`Conclusion: In this preliminary report. single applications ofin—
`haled treprostinil induced highly pulmonary selective and sustained
`vasodilatarion. The drug was clinically eFfective. safe. and well toler-
`ated when 15 ug was inhaled in 3 breaths 4 times daily. The current
`results warrant controlled studies to investigate this approach in .1
`larger group of patients.
`
`Rabm Varminckel, MD
`Hussein A. Gbafi'tmi. MD
`Friedrich Grimmingm MD
`Werner Sager, MD
`University of Giessen Lung Center
`35392 Giesseu, Germany
`
`Horst Olrcbawei, MD
`Medical University Graz
`8036 Graz, Austria
`
`Potential Financial Conflicts of Interest: Comulmnricr: HA. Ghofmni
`(LungRX), W. Seeger (LungRX), H. Oisdtewslti (LungRX); Honoraria:
`HA. Ghofrani (LungRX); Grants receiueci‘ W. Seeger (LungRX).
`
`References
`1. Simonnmu G. Ham R], Gillie N. Naeije R. Rich 3, Bourge RC, et :1. Continuous
`subcutaneous infusion of treprostinil, a pmsracyclin analogue. in patients with pulmo-
`nary arterial hypertension: a doublehlind, randomized. placebo-oontmlled trial. Am]
`Respir Crit Care Med. 2002;165:8004. [PMID: 11897647]
`2. Olschewski H. Simonnmu G. Cali: N, Higenbot‘tam T. Naeiie R. Rubin L]. et al.
`Inhaled iloprost for severe pulmonary hypertension. N Englj Med. 2002;347:322-9.
`[PMID: 12151469]
`
`
`
`Neurocysticercosis in Kansas
`
`TO THE EDITOR: Background: In the United States, neurocysticer—
`cosis is a disease that is most often identified in persons of Hispanic
`Ethnicity. Cases of the disease have been reported from large urban
`areas (I); however, no studies have evaluated neutocysticercosis in
`rural areas.
`
`mandarin
`
`Liquidia's Exhibit 1009
`Page 6
`
`
`
`M
`2
`-
`E
`g
`i
`i
`e
`g
`E
`E
`
`
`
`o
`
`20
`
`40
`
`so
`
`too 120
`so
`11m.mln
`
`1&0
`
`160
`
`180
`
`100
`tn
`9° g
`n
`80
`_
`70
`E
`60
`u
`50
`1
`..
`t
`30
`-
`5
`a
`3
`GE
`
`2“
`10
`0
`
`g
`i
`E
`3
`
`n0
`gI
`
`a
`"i
`g
`.2
`3!
`
`70
`
`..
`5°
`
`120
`
`140
`
`150
`
`180
`
`100
`30
`11me.min
`
`
`E
`I I“
`'I
`two
`'u
`-
`1200 -
`i
`‘
`E
`3
`g
`g
`g
`a
`
`0
`
`20
`
`4O
`
`60
`
`
`
`Asterisks indicate administration of nitric oxide, and daggers indicate
`administration of trepostinil. Pulmonary artery pressure was substantially
`reduced with nitric oxide and even further reduced with trepostitlil (tap.
`squares). Systemic arterial pressure was not afl'ected by either substance
`(tap. circles). Pulmonary vascular resistance was substantially reduced
`with nitric oxide and even further reduced with trepostinil; the eflect of
`treprostinil outlasred the observation time of 180 minutes (battens.
`squares). long-lasting improvement of mixed venous oxygen saturation
`represented improved cardiac output in absence of gas exchange deteri-
`oration (bottom. circles).
`
`proven cliniml efficacy in patients with pulmonary hypertension in a
`randomized, controlled trial (2).
`Ogre-titre: To characterize the effects of inhaled treprostinil with
`special regard to safety.
`tolerability, and efiicacy in patients with
`severe pulmonary arterial hypertension.
`Mabodr and Findings: Three patients with severe pulmonary
`hypertension underwent catheterization of the right heart and Fern-
`oral artery lb: evaluation of pulmonary and systemic hemodynamics.
`The protocol consisted of asseSsment of baseline values; administra-
`tion of nitric oxide at a concentration of 20 parts per million; and
`administration of a single lS-ug dose of treptostinil,
`inhaled in 3
`breaths through a modified OptiNeb ultrasonic inhalation device
`(Nebu-Tec, Elsenfeld, Germany). All 3 patients had severe pulmo-
`150 17 January 2.006 Annals of lntemal Medicinel Volume 144 0 Number 2
`
`Liquidia's Exhibit 1009
`Page 6
`
`