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`Page 1
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`Liquidia's Exhibit 1094
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`Liquidia's Exhibit 1094
`Page 1
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`
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`Yo! 110, No 17, October 26, 2004
`CoNeee
`fittp://circ.ahajournals.org _~‘
`
`SUPPLEMENT TO
`
`American Heart
`BUILBC
`Reem ahve
`
`JOURNAL OF TH AMERICAN HEART ASSOCIATION
`
`scientific
`Abstracts Ts
`
`from
`
`Circulation
`
`Page 2
`
`Sessions: November 7—10
`Exhibits: November 7—9
`New Orleans, Louisiana
`scientificsessions.org
`
`Named and Invited Lectures 2004
`
`& basic science
`ym
`-
`a a | Pisce
`CHANICAL SCIENCE
`at
`jae)a)ul aton science
`
`-
`
`2004 Russell Ross Memorial Lectureship in Vascular Biology * 2004 George Lyman Duff Memorial Lecture + 2004 Sol Sherry
`Distinguished Lecture in Thrombosis * 2004 Thomas W. Smith Memorial Lecture « 2004 George E. Brown Memorial Lecture
`» 2004 Dickinson W. Richards Memorial Lecture * 2004 Katharine A. Lembright Award * 2004 William W. L. Glenn Lecture
`© 2004 William J. Rashkind Memorial Lecture + 2004 T. Duckett Jones Memorial Lecture * 2004 Charles T. Dotter Memorial
`Lecture * 2004 Laennec Society Lecture * 2004 Ancel Keys Lecture + 2004 Lewis K. Dahl Memorial Lecture * 2004 Robert
`I. Levy Endowed Lecture in Lipid Metabolism
`
`New and YoungInvestigator Award/Prize Abstract Finalists
`Lewis N. and Arnold M. Katz Basic Science Research Prize for Young Investigators * Mclvin L. Marcus Young Investigator
`Awards in Cardiovascular Science * Cournand and Comroe Young Investigators Prizes in Cardiopulmonary and Critical
`Care * Outstanding Research Awardin Pediatric Cardiology « Melvin Judkins Young Investigator Award in Cardiovascular
`Radiology » Vivian Thomas Young Investigator Award * Martha N. Hill New Investigator Awards * Elizabeth Barrett-
`ConnorResearch Award in Epidemiology and Prevention for Investigators in Training * Samuel A. Levine Young Clinical
`Investigator Awards ¢ Laennee Society Young Clinician Award « NPAM New Investigator Award
`
`Abstracts From the Scientific Sessions 2004
`
`Liquidia's Exhibit 1094
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`Liquidia's Exhibit 1094
`Page 2
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`
`
`
`
`can og
`.
`
`Worldwhee-
`
`with proven safety
`
`as an adjunct to diet for manypatients with dyslipidemia
`
`)%
`Proven safety similar to other leading statins’
`© Adverse reactions were mild and transient; incidence and discontinuation rates 2, 2
`similar to placebo and other statins**
`ane
`Na
`we
`O The most frequent adverse events were myalgia (3.3%), constipation (1.4%). 4 6 %
`asthenia (1.3%), abdominal pain (1.3%), and nausea (1.3%)?*
`: La
`soe
`CRESTORwasevaluated in over 10,000 patients in ee .
`preapprovalclinical trials—more than any other statin
`prior to approval**"
`Overall, more than 42,000 patients have taken
`CRESTORin clinicaltrials, including ongoingtrials
`in the GALAXY” Program”
`O The GALAXYProgram is a large, comprehensive, long-term evolving global research
`initiative evaluating the efficacy and safety of CRESTOR and demonstrating the
`AstraZeneca confidence in, and commitmentto, this important therapeutic option
`
`It is recommendedthatliver function tests be performed before and at 12 weeks
`following both the initiation of therapy and any elevation of dose, and periodically
`(eg, semiannually) thereafter.
`
`The effect of CRESTOR on cardiovascular morbidity and
`mortality has not been determined; long-term outcome
`
`studies are currently under way.
`
`Please see brief summary of full Prescribing
`
`Information on reverse side of this advertisement.
`
`/}
`K
`CRESTOR
`rosuvastatin calcium
`
`.
`
`,
`
`Liquidia's Exhibit 1094
`Page 3
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`Liquidia's Exhibit 1094
`Page 3
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`
`
`Supplementto
`CirCULAatiON sone ri nurvers7 cctover 2200
`
`Abstracts From Scientific Sessions 2004
`Morial Convention Center
`New Orleans, Louisiana
`November 7-10, 2004
`
`Named and Invited Lectures
`
`
`2004 Russell Ross Memorial Lectureship in Vascular Biology
`Garret A. FitzGerald) MDS OU 8 9h) OMT OEE DNs bed caepansen vice yehvcreranstenats vee Bivbaxeutets TH-A
`
`2004 George Lyman Duff Memorial Lecture
`Henry N. Ginsberg, MD |... 00.020. 0 0.00... Pe Pers ee 00, See em com ames oie, rene TH-A
`
`2004 Sol Sherry Distinguished Lecture in Thrombosis
`Denisa’ Ds Wagner,"RAD\ 2°) 5 UR A REA TH ale craom nual cid ane Ree waite ater ersso aeee, I-A
`2004 Thomas W. Smith Memoria! Lecture
`DonaldgVi bersa)Dae en Re rp en ne Seen e cise aie Oerianeaee Ament te III-B
`
`i
`2004 George E. Brown Memorial Lecture
`David A. Kass, MD) FAA ec ae es yet varies gene See ieelerones mem nome umn II-B
`
`2004 Dickinson W. Richards Memorial Lecture
`Kenneth Weir, MD, FAHA (1d cc ec eee ee eee es thls Nel OHIO RNIN: Mie ROUEN RW sata T-C
`
`2004 Katharine A, Lembright Award
`DianelMeBecker ARN) MPHSCDSPAHA (ee aSkhi) Se alec bs Hen Le ater Sea ree ere 1-C
`
`2004 William W. L. Glenn Lecture
`imothy Gardner, MD)
`Mig Wea ee ee egg Wie nan Perens Suey ej earosun cis free arenes mg nin koa lriera ceaiel cicets I-C
`
`2004 William J. Rashkind Memorial Lecture
`Betsy Dresser, PRD ooo ooo cee ee Ee DAME REGS A EGE SEMIN: uViseReee tals betaua Ii-D
`
`2004 T. Duckett Jones Memorial Lecture
`GRE RW INCWOULRCTV) VUEe
`meee
`tine Sere treet. el acncece-wedea Fe (eaaport
`
`es
`
`syeca soeraney Siscerssile rH eran rane ne Ned ene eTeeVan heed Hentas Il-D
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`2004 Charles T. Dotter Memorial Lecture
`LewisWexler, MID emcee) i ene eres Ween ee ET gids $251 Gis saentVS fb OAC paiva sR ITC EGE Coats. I-D
`
`2004 Laennec Society Lecture
`Nanette K. Wenger,iMD,FAHA \ eho k. 2 id. 0 eevee interac Pathaaheolnes Hiteaielen tilts IlI-E
`
`2004 Ancel Keys Lecture
`Darwin R. Labarthe, MD, MPH, PRDcn eee ete een een en baer neennas TII-E
`
`Note: Abstract numbers are arranged to coincide with abstracttitles in the American Heart Association's Scientific Sessions 2002 Program.
`Subject and author indexes are keyed to abstract numbers. Authors of all Named and Invited Lectures and New and YoungInvestigator
`Award/Prize Abstracts are presented in the expanded Table of Contents within this Abstracts issue.Indexesare located at the backofthis issue.
`All other supplements to this volume of Circulation will be indexed in the last Decemberissue.
`
`
`CIRCULATION (ISSN 0009-7322)is published weekly except combinedthefirst two weeks in January and the last two weeks in Decemberby Lippincott Williams & Wilkins at 16522
`Hunters Green Parkway, Hagerstown, MD 21740. Businessoffices are located at 530 WalnutStreet, Philadelphia, PA 19106-3621. Productionoffices are located at 351 West Camden
`Street, Baltimore, MD 21201-2436.Individuals may subscribefortheir personal use at the following rates: $206 for members of an American Heart Association scientific council and
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`and additional mailing offices. POSTMASTER: Send address changes ta CIRCULATION, American Heart Association, Lippincott Williams & Wilkins, 16522 Hunters Green Parkway,
`
`Hagerstown, MD 21740.
`
`Liquidia's Exhibit 1094
`Page 4
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`Liquidia's Exhibit 1094
`Page 4
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`
`
`2004 Lewis K. Dahl Memorial Lecture
`Rhian M. Touyz MD, PAD ooo... ces ve nnseuts tune tnneean gut vv4uuendesteunanuenecies IlI-F
`2004 Robert I. Levy Endowed Lecture in Lipid Metabolism
`Ronald M. Krauss, MD, FAHA 10000 ccc ce ceed y eet bu bebe bbb bb bbb bb beees Ill-F
`
`IL-1
`
`New and Young Investigator Award/Prize Abstract Finalists
`Lewis N. and Arnold M. Katz Basic Science Research Prize for Young Investigators
`Karl-Ludwig Laugwitz, Alessandra Moretti, Jason Lam, Peter Gruber, Yinhong Chen, Sarah Woodard, Lizhu
`Lin, Chen-Leng Cai, Michael Reth, Sylvia Evans, Kenneth R. Chien .....................-............... T-G
`Patrick Most, Mirko Voelkers, Sven T. Pleger, Erhe Gao, Melanie Boerries, Andrew Remppis, Hugo A. Katus,
`CACC ee ereee I-G
`Sathyamangla V. Naga Prasad, Aruni Jayatilleke, Howard A. Rockman .................................. Il-H
`Da-Zhi Wang, Dongsun Cao, Zhigao Wang, Shijie Li, Eric N. Olson © o.oo ooo oe ccc ccc cee cece ee. HI-H
`Min Xie, Sam C. Wang, Dou Zhang, Arun J.C. Prahash, Hidemasa Oh, Motoaki Sano, Xiaozhen Wang, Jennifer
`S. Pocius, George E. Taffet, Lloyd H. Michael, Tse-Hua Tan, Mark L. Entman, Michael D. Schneider ......... JI-H
`Melvin L. Mareus Young Investigator Awards in Cardiovascular Science
`Roselle Abraham, Peter Lim, Charles A. Henrikson, Roland Emokpae, Ronald Li, Leslie Tung, Eduardo Marbdén ....
`Garvan C. Kane, Atta Behfar, D. Fearghas O’Cochlain, Roy B. Dyer, Xiao-Ke Liu, Denice M. Hodgson,
`Santiago Reyes, Takashi Miki, Susumu Seino, Andre Terzic 2.0.0.0 o.oo ooo ooo ccc ccc ccc ccceceee Il-I
`Ryoji Koshida, Petra Rocic, Shuichi Saito, William M. Chilian 2.00000 ooo voce cc cece ccc ce ee.
`Ili-I
`Gangjian Qin, Masaaki li, Andrea Wecker, Evelyn Bord, Hong Ma, David A. Goukassian, Yung-sup Yoon, Raj
`Kishore, Yan Zhu, Douglas W. Losordo . 0.6.c cect c ccc ccc cece, T-J
`Yao Liang Tang, Yi Tang, Keping Qian, Y. Clare Zhang, Leping Shen, M. lan Phillips ..................... Til-J
`Subodh Verma, Chao-Hung Wang, William Stanford, Shu-Hong Li, Richard D. Weisel ...................... It-J
`Cournand and Comroe Young Investigators Prizes in Cardiopulmonary and Critical Care
`Kimberly A. Boddicker, Yi Zhang, Loyd R. Davies, Richard E. Kerber ..................-.-......-2.2 0 TH-K
`Sebastien Bonnet, M. Evangelos D. Michelakis, Sean McMurtry, Gwyneth Harry, Sandra Bonnet, Alois Haromy,
`RVGAHA0 IE; ARALIP. | oko obane Hb Baga DAbo sbeaonpnas dhondanspeeransodooubennedaencsccorote tan. HI-K
`Pietro Catroni, Fumito Ichinose, Rong Liu, Rosemary C. Jones, Kenneth D. Bloch, Warren M. Zapol ......... IH-L
`Junyan Gu, Deyanira Prastein, Charles White, Jeffrey Manchio, Richard N. Pierson, Bartley P. Griffith, Paul
`Gurbel, Udaya Tandry, Robert Poston. 200... 6 ccc ccc cee eects n cece beet tect e cee e eee eeey TH-L
`Christopher J. Mingone, Sachin A. Gupte, Noorjahan Ali, Richard A. Oeckler, Susan C. Olson, Michael S. Wolin .... TH-L
`Outstanding Research Awardin Pediatric Cardiology
`Brian Feingold, Seda Selamet, Sang C. Park, Beth F. Printz, C. Becket Mahnke, Shing Lee, Charles S.
`Kleinman, Donna M. Timchak, William H. Neches, Welton M. Gersony ...... 0.000.000.0000 0-0-2022.0... IlI-M
`Marco Stramba-Badiale, Karine Goulene, Giuliano Bosi, Roberta Bini, Silvia G. Priori, Raffaella Bloise, Lia
`Crotti, Patrizia Salice, Vlasta Fesslova, Savina Mannarino, Giuseppe Latini, Roberto Giorgetti, Peter J. Schwartz ........ Il-M
`Wayne Tworetzky, Audrey C. Marshall, Laura B. Myers, Lisa J. Bergersen, Russell T. Jennings, Carol B.
`Benson, Louise E. Wilkins-Haug, James E. Lock 00.0.0c cece cc eceeccecveecee. ItI-N
`Melvin Judkins Young Investigator Award in Cardiovascular Radiology
`Fabao Gao, Bensheng Qiu, Sourav Kar, Xiangcan Zhan, Lawrence V. Hofmann, Xiaoming Yang ............. III-N
`C. Javidan-Nejad, D.C. Lesniak, G.S. Chrysant, J. Zheng, R.J. Gropler, TK. Pilgram, P.K. Woodard ......... TI-O
`Saman Nazarian, David A. Bluemke, Albert C. Lardo, Menekhem M. Zviman, Katherine C. Wu, Stanley Watkins,
`Cleria Azevedo, Timm L. Dickfeld, Glenn R. Meininger, Ronald D. Berger, Hugh Calkins, Joao A. Lima, Henry
`RPE nena cms gem ge qeue ves foees nee... emmend penne pemuaaa Il-O
`Monvadi B. Srichai, Chelif Junor, L. Leonardo Rodriguez, Arthur E. Stillman, Richard A. Grimm, Michael L.
`Lieber, Joan A. Weaver, Nicholas G, Smedira, Richard D. White 20.00.00 ooo ooo ccc ccv ccc ccccec ccc. II-O
`Vivian Thomas Young Investigator Award
`Sydney L, Gaynor, Hersh S. Maniar, Jeffrey B. Bloch, Paul Steendijk, Marc R. Moon .... eee c cee Il-P
`Faraz Kerendi, Michael E. Halkos, Hajime Kin, Joel S. Corvera, Daniel J. Brat, Mary B. Wagner, Jakob
`Vinten-Johansen, Zhi-Qing Zhao, Joseph M. Forbess, Kirk R. Kanter, Paul M. Kirshbom ................... I-P
`Paul V. Kochupura, Evren U. Azelogli, Damon J. Kelly, Sergey V. Doronin, Stephen F. Badylak, Irvin B.
`Krukenkamp, Ira S. Cohen, Glenn R. Gaudette ....................... Fe ee casa oe IlI-P
`Stephen Kolakowski Jr, Mark F. Berry, Todd Grand, Omar Fisher, M. Astrid Moise, Jeffrey Cohen, Vivian Hsu,
`OED CORSO REDD BBE BennnOMEOL cob coe 54 bo 0bod bond uaonueddecnwhconscnsdhaol seMbanineta..- ItH-Q
`Frank Langer, Filiberto Rodriguez, Saskia Ortiz, Allen Cheng, Mary K. Zasio, David Liang, George T.
`Daughters, Netl B. Ingels, D. Craig Miller 000.c ccc ceebebetevecccee. III-Q
`Pierre Voisine, Jian Li, Cesario Bianchi, Tanveer A. Khan, Marc Ruel, Shu-Hua Xu, Jun Feng, Audrey
`Rosinberg, Tamer Malik, Yasunari Nakai, Frank W. Sellke 00.000 ooo ooo occ voc ce ccc cecc cece cee. IW-R
`
`Liquidia's Exhibit 1094
`Page 5
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`Liquidia's Exhibit 1094
`Page 5
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`
`
`Martha N.Hill New Investigator Awards
`Wen-Wen Li, Anita L. Stewart, Nancy Stotts, Erika S. Froelicher ©... 1.0.0... ees TI-R
`Philip Moons, Kristien Van Deyk, Kristel Marquet, Els Raes, Leentje De Bleser, Sabina De Geest, Werner Budts .... TU-R
`Lorraine S. Evangelista, Kathleen Dracup, Lynn Doering, Debra K. Moser, Jon Kobashigawa ............... IlI-S
`Elizabeth Barrett-Connor Research Award in Epidemiology and Prevention for Investigators in Training
`Matthew Allison, Michael Criqui, Elena Ho, Julie Denenberg .....0 0.00 ccc ett tnee I-T
`Khawaja Afzal Ammar, Steven J. Jacobsen, Richard J. Rodeheffer 2.0.00... cc cc cc eee ee W-T
`Apoor S. Gami, Daniel E. Howard, Eric J. Olson, Virend K. Somers ©. 0.0.0.0... 2.0 cece cece cee ees II-T
`Frederick A. Masoudi, Charles Baillie, Yongfei Wang, Edward P. Havranek, JoAnne Micale Foody, John F.
`Steiner, Harlan M. Krumholz 1.00.0 eee en etn ete TH-U
`Nona Sotoodehnia, David Siscovick, Matteo Vatta, Bruce Psaty, Russell Tracy, Jeffrey Towbin, Rozenn Lemaitre,
`Thomas Rea, Peter Durda, Joel Chang, Thomas Lumley, Lewis Kuller, Greg Burke, Susan Heckbert .......... Il-U
`Tianying Wu, Susan E. Hankinson, Walter C. Willett, Edward Giovannucct ... 0.0.0... 0 0c cece eee W-V
`Samuel A. Levine Young Clinical Investigator Awards
`Michaela Scheuermann-Freestone, Damian Tyler, George K. Radda, Stefan Neubauer, Kieran Clarke ......... TII-w
`Michelle M. Kittleson, Shui Q. Ye, Rafael A. Irizarry, John V. Conte, Giovanni Parmigiani, Leslie W. Miller,
`Yingjie Chen, Jennifer L. Hall, Joe G.N. Garcia, Joshua M. Hare... ccc teenies TII-W
`Hidenobu Koga, Seigo Sugiyama, Kiyotaka Kugiyama, Keisuke Watanabe, Hironobu Fukushima, Tomoko
`Tanaka, Tomohiro Sakamoto, Michihiro Yoshimura, Hideaki Jinnouchi, Hisao Ogawa .......... 0... eee es T-w
`Francesca Nesta, Maire Leyne, Charles Simpson, Daisy Dai, Jane E. Marshall, Chaim Yosefy, Judy Hung, Susan
`A. Slaugenhaupt, Robert A, Levine 0000enn nt nent nen ens WI-x
`Khim Leng Tong, Sanjiv Kaul, Xin-Qun Wang, Diana Rinkevich, Saul Kalvaitis, Todd Belcik, Wolfgang Lepper,
`William A. Foster, Kevin Wei 00.0.ee enn e rete eet r eter ees III-X
`
`Laennec Society Young Clinician Award
`.. 0.00... m-Y
`Marcus Y. Chen, William A. Baker, Bryan R. Haugen, Robert A. Quaife
`Andrew C. Lee, Elyse Foster, Yerem Yeghiazarians
`...........0. 000s. essee Patera aise See I-Y
`Molly Ware, Eric Awtry, Michael Klein, Thomas Ryan... 00.060ee T-Y
`
`NPAM NewInvestigator Award
`M. Robinson, M. Scheuermann-Freestone, P. Leeson, K. Clarke, S. Neubauer, F. Wiesmann oo. 00000 c ee III-Z
`
`Abstracts From the Scientific Sessions 2004 ........................04.
`
`Il-1
`
`Author Indexes fea oe os cto es 68 6 ped ge pe a Se es a Il-837
`
`Subject Index 0.055 sce vs soe 5 eae Oh We ew ok ae I1I-893
`
`Abstracts From the Resuscitation Science Symposium ................. TIT-1095
`
`
`
`American Heart Association Embargo Policy for Scientific Sessions Abstracts
`
`Abstracts, lectures, and other presentations includedin the Scientific Sessions 2004 Supplementpublished in the
`Oct. 26 issue of Circulation: Journal of the American Heart Association are embargoedforrelease at the time of
`presentation at the American Heart Association’s Scientific Sessions 2004 (Nov. 7-10) and information may not
`be released before then. Presentation times are listed in the Scientific Sessions 2004 Final Program.
`
`
`
`Liquidia's Exhibit 1094
`Page 6
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`Liquidia's Exhibit 1094
`Page 6
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`
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`Circulation
`
`JOURNAL OF THE AMERICAN HEART ASSOCIATION
`
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`Liquidia's Exhibit 1094
`Page 7
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`Liquidia's Exhibit 1094
`Page 7
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`
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`Basic Science
`
`
`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`
`Abstracts From Scientific Sessions 2004
`Ill-295
`
`hypolha-
`hypotha-
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`
`
`
`
`plasma TNF-a=TNF-a1p Lp IL-6 iL1g ew Jung/BW
`
`
`
`AhoA in angiotensin |I-treated rats and SHA.
`In addition, Y-27632 or valsartan reduced the
`
`
`
`
`plasmaIL (paymg=(pg/mg)Ss ipg/mg=(pa/mgLs tpgmg (eg/mg Ratio Fatlo
`
`
`
`expression levels of phosphorylated ERM in both groups. Subcutaneous infusion of phenyl-
`
`
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`
`
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`
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`ephring increased SBP to the same level of angiotensin II Infusion in WKY, However,it did not
`MI+VEH
`ABLITIO9
`1195497
`5446765
`471779
`68207
`61409 671-101
`264441
`72402
`135406
`alter the expression levels of membranous RhoA and phosphorylated ERM, Conclusions: Thesa
`in=7)
`results suggest that 1) the pressor response induced by central infusion of angiatensin II
`is
`MI+SL
`S575231"
`S3StB6"
`32.6758" 26.4251 3606"
`25205°
`394255°
`256452 64+03'
`121206°
`substantially mediated by activation of Rho/Rho-kinase pathway in brainstem via ATI
`ren
`SHAM+SL
`482236
`99,7126
`237-65
`174246
`28207
`21708
`25.3748
`243749
`33201
`52403
`receptors, 2) this pathway may also be involved in hypertensive mechanism in SHR.
`‘SHAM+
`53924
`36,1226
`276-54
`186240
`32209
`24408
`28.0287 2366S 3420.1
`51209
`
`1412
`
`Endothelial Nitric Oxide and Hypertension in Autonomic Failure
`
`Alfredo Gamboa, Cyndya Shibao, Andre Diedrich, Bonnie K Black, Ginnie Farley, Satish R
`Raj, David Robertson,Italo Biaggioni; Vanderbilt Univ, Nashville, TN
`More than half of patients with autonomicfailure (AF) have severe supine hypertension despite
`low or unresponsive norepinephrine tevels and often undetectable plasma renin activity. Supine
`hypertensionis related to increased vascularresistance but the mechanism is not known. To
`test the hypothesis thatnitric oxide deficlency contributes to supine hypertension we blocked
`endogenousnitric oxide synthase with L-NMMAin 5 AF patients and 7 normal controls (supine
`SBP 17346 and 107+5 mmHg,respectively}. Systolic blood pressure (SBP) was normalized
`to 110 mmHg in AF with graded head-up tilt, and baroreflexes were eliminated with
`trimethaphan In normal controls to mimic autonomic failure. The pressor response to graded
`doses of L-NMMA wasshifted to the left in AF (Figure); The dose necessary to increase SBP
`by 30 mmHg was 3.4-fold lower in AF comparedto controls (136+24 and 4654103 ua/k/min
`respectively, p<0.02).In conclusion, contrary to ouroriginal hypothesis, our results suggest an
`increased tonic release ofnitric oxide in AF. Thus, NO deficiency does not contribute to supine
`hypertension In autonomicfailure. On the contrary, this enhanced tonic NO maycontribute to
`orthostatic hypotension in these patients.
`
`60
`
`
`
`ASBP(mmHg}
`
`oe
`=NnwaryeoSOooS
`
`33
`
`a6
`
`250
`166
`L-NMMA dose(p/k/min)
`
`500
`
`1413
`Oral Administration of a Mineralocorticoid Receptor Antagonist Reduces
`Brain, Heart, and Blood-borne Proinflammatory Cytokines in Heart Failure
`
`Yu-Ming Kang, Carver College of Med, Univ of lowa, lowa City, IA; Ralph F Johnson, Uniy of
`lowa, lowa City,
`iA; Zhi-Hua Zhang, Carver College of Med, Univ of lowa,
`lowa City, 1A;
`Robert M Weiss, Carver College of Med, Univ of lowa and VA Med Ctr, lowa City, IA; Alan K
`Johnson, Univ of lowa,
`lowa City,
`IA; Robert B Felder; Carver College of Med, Univ of lowa
`and VA Med Ctr, lowa City,
`IA
`
`Introduction: Brain and blood-borne cytokines may contribute to neurohumoral excitation in
`heart failure (HF). We previously reported that blockade of mineralocorticaid receptors (MR) in
`{he central nervous system with spironolactone (SL) reduces clreulating tumor necrosis factor
`(THF)-c in HF rats. The effect of SL on proinflammatory cytokines (PIC) in the brain and on
`Other Important circulating PIC - interleukin (IL}=1 andIL-6 - was not determined. Hypothesis:
`Chronic treatment with oral SL will reduce brain and blood-borne PIC in rats with HF following
`ML. Methods and Results; Rats underwent coronary artery ligation to induce Ml (48.2--2.0%
`Of lett ventricle, with ejection fraction of 35.5+4,1% by echocardiography), or sham surgery
`(SHAM). Six weeks later,
`immunohistochemistry of
`the paraventricular nucleus (PVN) of
`YPothalamus, a region critical to cardiovascular regulation, revealed more PVN neurons (Ml vs
`MAM, **P<0.01) positive for TNF-c (69.52-3.3"* vs 10.8+0.9) and IL-TB (0723.9ys
`13.82°4.2) (ry Mi (n=6) than in SHAM (n=6) rats. Double staining demonstrated that these
`eurons were distributed among PVN neurons expressing Fra-like immunoreactivity, indicating
`fe Tonic heuronal activation. Mi rats (n=6)treated with SL.(1 ma/ka/dayorally for 6 weeks) had
`me (MI-+SL vs Ml, #?<0.01) Fra-like positive PVN neurons (85.5+5.4 vs 183.8+5.0}, and
`ewer PYN neurons positive for TNF-ce (22.45 1.8%i ve 32.4: 1.7%) and IL-1. (19.121.34%#
`et =2.1%), Levels of TNFecr, IL-1 8 and IL-6 in brain and heart tissues and in plasma were
`© lower in Ml rate treated with SL (see table). Conclusion:in rats’ with ischemia-induced
`Part failure, orally administered SL has a global
`inhibitory influence ‘on the appearance of
`Proinfiarnmatory cytokines in brain, heart and plasma, The beneficial
`influence of MR
`onus in patients with HF may result at least in part from blocking aldosterone-induced
`kine synthesis, (Table: "P<0.05 MI+SL vs MI+-VEH)
`
`
`
`
`
`Pulmonary Arterial Hypertension: New
`Therapies
`Subspecialty: Integrative Biology
`Wednesday
`Ernest N Morial Convention Center, Hail 12
`Abstracts 1414-1418
`
`1414
`
`Inhaled Treprostinil Sodium (TRE) For the Treatment of Pulmonary
`Hypertension
`
`Robert Voswinckel, Beate Enke, Andre Kreckel, Frank Reichenberger, Stefanie Krick,
`Henning Gall, Tobias Gessler, Thomas Schmehl, Markus G Kohstall, Friedrich Grimminger,
`Hossein A Ghofrani, Werner Seeger, Horst Otschewski; Univ Hosp Giessen, Giessen,
`Germany
`
`Objective: To evaluate the effects of inhaled TRE on pulmonary hemodynamics and gas
`exchange in severe pulmonary hypertension (PH) and to assess safety, tolerability and clinical
`efficacy in patients with severe PH. Background: TREis a stable prostacyclin analogue that has
`been approved for treatment of pulmonary arterial hypertension as a continuous subcutaneous
`infusion.
`lloprost, another prostacyclin analogue, has been shown to beefficacious in a
`randomised controlled study as repetitive inhalation. Methods:
`In an open-label study a
`preservative free solution of inhaled TRE was applied to 17 patients with severe pulmonary
`hypertension during Swan-Ganz catheter investigation. Patients received a TREinhalation by
`use of the pulsed OptiNeb® ultrasound nebulizer (3 single breaths, TRE solution 600 j.g/ml).
`Hemodynamics were observed for 2 hours, Two patients with idiopathic PAH received
`compassionate treatment with 4 inhalations of TRE per day after the acute test. Results:
`Patients (male/female= 4/13) suffered from iPAH (n=5)}, PAH other (n=8) and CTEPH (n=4);
`PVR 948 + 112 dyn*s*cm’®, PAP 48.3 + 2.7 mmHg, PAWP 8.9 + 0.5 mmHg, CVP 10.8 + 1.6
`mmHg, CO 3.8 = 0.3 l/min, Sv02 61.8 + 1.8 %. TRE inhalation resulted in a sustained, highly
`pulmonary selective vasodilatation over 120 minutes, Maximum PVR decrease was -31,2 + 4.5
`% after 30 min. PVR and SVR at 120 minutesafter inhalation were 89.2 + 4.2 % and 101.0 +
`4.0 % of the baseline vatues, respectively. The AUC for the observation period (120min) was
`-22.9 + 3.8 % for PVR and -4.9 + 3.2%for SVR. The compassionate use patients have been
`treated for more than 3 months. In both patients NYHA class improved (from IV to Ill and from
`Il to Il}, and six minute walk increased (from 0 m (bedridden) to 143 m, and from 310 m to
`486 m, respectively). No side effects have been observed by the patients during long-term
`treatment. Conclusion: Inhaled TRE shows strong pulmonary selective vasodilatory efficacy
`with a long duration ofeffect following single acute dosing. Tolerability is exceltent even at high
`drug concentrations and short inhalation times (3 breaths). Long-term treatment effects are
`very promising. The current results warrant controlled studies investigating this approach in a
`larger series of patients. Supported by Lung RX
`
`1415
`
`Rho-kinase in Pulmonary Hypertension
`
`Ken Ishikura, Norikazu Yamada, Akihiro Tsuji, Satoshi Ota, Mashio Nakamura, MasaakiIto,
`Naoki isaka, Takeshi Nakano; Mie Univ Sch of Med, Tsu, Japan
`
`Objectives: Pulmonary hypertension (PH) is a poor prognostic disease with limited treatment.
`Rho-kinase is involved in the pathophysiology of several diseases underlying smooth muscle
`hypercontraction. But the role of is unknown. The purpose of this preliminary report was to
`indicate the efficacy of fasudil, a Aho-kinase inhibitor in patients with pulmonary hypertension
`using interventional hemodynamic assessment. Methods: Fasudil was intravenously injected in
`10 patients (9 female, mean + SD, 46 + 15 years, NYHA II n=2,Ill n=7, IV n=1) with primary
`{n=5) and secondary (n=5) PH who were not
`received any vasodilator. Fasudil was
`administrated 30mg with 1mg/min. Hemodynamic data were measured using Swan-Ganz
`catheter until 60 minutes after starting administration of fasudil. Hemodynamic and arterial
`blood gas data of baseline and the lowest
`total pulmonary resistance (TPR)
`time were
`compared. Results: The lowest TPR time was within 30 to 60 minutes after administration.
`Administration of fasudil significantly decreased TPR from 13.6 + 6.8 Uto 10.3 + 4.9 U (-23.2
`+ 9.2 %, p < 0.001) and mean pulmonary arterial pressure (mPAP) from 43.6 + 14.5 mmHg
`to 38.8 + 13.9 mmHg (-11.6 + 10.4 %, p < 0,02). Cardiac index (Cl) was significantly
`increased from 2.39 + 0.66 Lmin/m? to 2.74 + 0.73 Limin/m? (+16.5 + 15.1 %, p < 0.01).
`Although TPR was equally decreased in both primary and secondary PH, the changes in the
`parameters that prescribed TPR, namely C! and mPAP, were different between the two groups
`subjects, Increased Cl was a major factor into reducing TPR in primary PH, while reduced mPAP
`
`
`
`Liquidia's Exhibit 1094
`Page 8
`
`
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`RY OF CONGRESSny0 017 694
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`29
`
`SSSaS
`
`i
`
`das
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`Page 9
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`NORVASCis indicated for the treatment of hypertension and angina.
`in clinical trials, the most commonside effects versus placebo
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`Please seebriefsummary ofprescribing information
`forNORVASContheadjacentpage.
`
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`
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