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    EEE Relationship of Urinary Myelin Basic Protein—Like Material With Cranial Magnetic Resonance Imaging in Advanced Multiple Sclerosis John N. Whitaker, MD; Jerry S. Wolinsky, MD; Ponnada A. Narayana, PRD; Alfred A. Bartolucci, PRD; John H. Noseworthy, MD; Fred D. Lublin, MD; Anders Linde, MB; Per Gjorstrup, MD, PhD; Herman C. Sullivan, MD; {for the North American Linomide Investigators Background: 4 significant correlation exists between disability and the volume of black holes (BHL VOL), de- fined as hypointense lesions on T1-weighted cranial mag- netic resonance imaging. A consistent correlation bas also been reported between urinary myelin basic protein like material (MBPLM) and the transition toward sec- ‘ondary progression (SP) from relapsing-remitting (RR) multiple sclerosis (Ms) Objectives To improve the management of MS through a noninvasive and cost-effective test for monitoring dis- cease activity oF disease status, Design and Methods: From 662 patients with MS (86 with RR MS, 259 with SP MS without continued at- tacks, and 317 with SP MS with continued attacks), 24- hour urine samples were obtained at enrollment in the phase 3 Linomide (roquinimex) drug study. The urine specimens were analyzed for MBPLM and correlated with, clinical features and findings on cranial magnetic reso- nance imaging, Results: Significant but weak correlations existed be- ‘oven urinary MBPLM and BHL VOL in all patients with MS (r=0.114, P=.003; n=662), patients with SP MS with- outattacks (r=0.185, P= 003;n=250) andall patients with SP MS (r=0.122, P2003; n=576). No significant correla- tions were detected in the RR MS group or any of the dis- case groups of subgroups whose Expanded Disability Sta- tus Seale score was 5.0 or lower. In subgroup analysis, the ‘most significant correlation was detected between urinary MBPLM alter adjustment for creatinine and BHL VOL in palicnts with SP MS with an Expanded Disability Status Seale score of 5.5 of higher but without continued relapses: (r=0417, P<.001; n= 138). Conelusions: In patients with advanced SP MS, uri- nary MBPLM may possibly serve as an indicator of failed remission and axonal damage. Urinary MBPLM corre- lates with disease status in MS, especially the transition of RR MS to SP MS with advancing disability Arch Neurol. 2001;58:49-54 From the Departments of ‘Neurology (Dr Whitaker) and Biostatistics (Dr Bartluc), University of Alabama at Birmingham; Neurology and Reseach Services, Birmingham Veterans Administration Medical Genter (Dr Whitaker Departments of Neurology (Dr Wolinsky) and Radology (Dr Narayana), Universty of Texas at Houston Health Science Genter; Departent of ‘Neurology, Mayo Clini Rochester, Minn (Dr Noseworthy); Department of ‘Newrology, Allegheny University ofthe Health Sciences, Philadephia, Pa (Dr Lublin) «and Pharmacia and Upjohn, (Drs Gorstrup and Sullivan and (MrLinde). complete list ofthe investigators who contributed to this multicenter tal appears in cabo on page 32, ANY IMPORTANT ad vances have been rade in recent years in the clinical manage- ment of patients with smuliple sclerosis (MS). Among those are the increased accuracy and certainty of di- agnosis,"= recognition of clinical sub- types, and the introduction of 2 types of immunomodulatory agents, type 1 inter- feronsand glatiamer acetate, which have been shown to improve the natural hi tory of MS by reducing the number ofr lapses! and slowing progression’ of x. lapsing-remitting (RR) MS and slowing progression of secondary progressive (SP) MS.’ Numerous tals with a number of agents are now in progress oF being planned. This new stage in managing MS has increased the awareness of the need to be able to condutct clinical trials more rapidly and reliably and to monitor pa- tients with MS to determine treatment fail cris particularly important, ture. The lat (©2001 American Med since RR MS changes to SP MS and the pa- tient becomes increasingly disabled. For editorial comment see page 30 |A surrogate marker is defined as & nonclinical assessment that may predict ul- imate clinical change.” Among the vari- cous procedures that might be used as such a marker in MS, cranial magnetic reso- nance imaging (MRI) has been firmly es- tablished as 4 noninvasive means to aid {im the diagnosis and gauge the dynamic changes occurring in MS.” Although gado- linium-enhancing TI lesions on cranial MRI imply active phases with distuption of the blood-brain barrier with perivenu- lar inflammatory collections,” correla- Lions with progression of disease have been more difficult o ascertain, For example, spatial mapping of T2 and gadoliniuim= enhancing TI lesion volumes does not appear directly linked and suggests that Association, All rights reserved. PATIENTS, MATERIALS, AND METHODS PATIENTS ‘The North American Linomide Study vasa phase 3 tal of patients with RR and SP MS conducted in 27 centers in aran- ‘domized, double-blind, placebo-contrlled and malidoselsh- fon." Of718 patients entering the rial, 24-hour urine speci- mens were obtained from 662 patients at enrollment (fable 1)-The study population was95.2% whiteand 483% nonwhite, with a female-male rao of 1.1. Of the 662 pa- tients, 86 had RRMS, and 576 had SP MS.*Of the group with SP MS, 317 were noted to have accompanying relapses and 259 « have no relapses, All patients were scored as to dis. ability on the Expanded Disability Status Seale (EDSS). PERFORMANCE AND ANALYSIS OF CRANIAL MRL Cranial MR were performed atthe time of enrollment. All patients underwent maging (Signa 15-1 scanner, General Ercan, Milwaulce, Wis) tsing version 34 or higher op- erating system, according to' defined protocol” Se- quences were applied to obtain T2-weighted, fluid- ‘Menuated iverson recovery and magnetization arse, {Tsweighted with gadolinium, magnet resonance angog- raphy, and posigadolinium Tl-weighted images” Auto- inated segmentation analysis was performed, an compos- ite score was derived.” Low-gnal intensity lesions, designated aback hole” were determined by exper den: fication and local thresholding on posigadelinium T1- ated magescudon tener age ek les mex ture a heterogeneous population of lesions. They were Segmented bed on having an intensity ess than that of the ‘ormal-sppesring white matter and greater than that of c= ‘hrespinalfulon the pos T1-weighted images Black haes {ppeat to include the most permanent and lest reverable ‘tue destruction, especially when gadolinium-enhanced se is excluded as was done tn this sty.” As noted.” de- {crmination of BHL VOL was not part ofthe original study design and these determinations onthe MRI dat obtained were no inated unl well after the study was begun Inanatempt to compile the various abnormalities de- tected on cranial MRI, an MRI composite score, desig hated a the composite 24, wae determined.” The 24 was derived from the volume of enhanced ussue, the normal ized plague volume, the normalized cerebrospinal id vol- me, and the BHL VOL. The more positive the 24 num- ber: the worse the subject son MBI ative to ish pees DETERMINATION OF URINARY MBPLM. At the time of preenrollment, 3: plastic hot was i= sued to the patient who, daring the 24 hours before the Cnrollment or second stidy vit, collected hither wine The total volume and duration of collection were deter sine. and ater thorough mixing, a alight of mob rine was place ina plastic contne (Borex: Fisher, Sa vanes Ga) with I boric aid tablet. The vial was sent to ‘hecental laboratory of Qaim, the contact esearchor- fomzation forthe ta, stored fosen at "20°C, and sue Gem shipped focen othe laboratory ofthe primary at- thor NW for analysis Stade were conducted Cats fot shown) to demonstrate tha this processing of rine id nov alter the quantitative results of urine MEPL Urinary MBPLM was determined by a double- antibody radioimmunoassay in which radiolabeled oe tan MBP peptide 69-89 served a the radioligand. abit (E110) ane? served a primary antibody, and man MBm peptide 83-89 served tv asny standard" The per formance, valdation, snd variation ofthis adoimno- tssny havc been deseibedegewhere-" Urinary MBPLM fas expres as haopains per mle of unpeocemed thine ar at nanograms per nlligain of Geatiine mene Sued by standard methods" The statement of MBPUM in febibeaip vo ceatinin: was to tse creatinine waa jistment fr real function and dilution of rine Since 2 Kotrunnecollctons were made. 24-hour rales of BLM designated as otal MBPLML were lo eae olatd BIOSTATISTICS Alleorrelations were performed on the comprehensive clini- cal and MRI dataset available from the entire study” and. the measurement of urinary MBPLM. Becatise ofthe early termination ofthe trial due to cardiac toxic effects, only a cross-sectional study was performed, Staisties mentioned. for the cranial MRI results have been previously re- ported.” For the analyses and correlations of the urinary MBPLA data, group and subgroup comparisons were made primarily by using the general linear model approaches of §nalysis of variance with post hoc comparisons. Correla- tions were performed using Pearson or Spearman rank pro- cedures where appropriate progressive gliosis and wallerian degeneration may’ o¢- ‘cur without an inflammatory disruption of the blood- ‘brain barrier." Attempis to measure a variety of changes ‘on cranial MRI and loss of central nervous system tsse volume accompanying atrophy are addressing the onset and progression of disability in MS." The presence of decreased signals, commonly referred to asblack holes," fon Tl-weighted images and cervical spinal cord atro- phy inthe upper segments! appear o be the best neu- roimaging correlates of disability, and inferentialy pro- igression, of MS, Diminished N-acetylaspartate detected bby magnetic resonance spectroscopy relates directly to discase disability and progression’ and correlates with the severity of the hypointense T1 lesions." ‘epausteD) IRCTNEDROL VOUS TaN SOT (©2001 American Med jamanetwork.comy/ on 01/03/2021 Urinary myelin basic protein-like material (MBPLM) also correlates with disease progression." Urinary MBPLM has been used to designate an immunoreactive substance(s) detected by antibodies reactive with MBP. The major chemical component of urinary MBPLM has recently been identified as p-eresol sulfate.” tis known that MBPLM in urine represents material that (1) eross- reacts with a cryptic epitope in MBP peptide 83-89": (2) is normally present in low levels in neonates that Fise above adult levels in childhood”; (3) is normal in RR MS but elevated in SP MS and, toa lesser degree, in pri- rary progressive MS"; (4) does not correlate with disease activity in MS; (5) when elevated, correlates with a transition to the SP phase of MS from RR MS" Association, All rights reserved. Table 1. Correlations of Urinary Myelin Basle Proteln-Like Material and Black Hole Volume on Cranial Magnetic. Resonance Imaging in Multiple Sclerosis Tear RAMS sPMs SP MS with lapses) SP MS without relapses) 1). = 0371, and (6) when elevated, correlates with lesion number and volume of T2-weighted central nervous system lesions manually identified and quantitated on 0.15-T ‘cranial MRI” The predictive value ofthe level of urinary MBPLM. in a large prospective trial was planned as an “add-on study in the multicenter Linomide (roquinimex) rial on RR and SP MS. In this article, the results at enrollment oof that investigation are described with evidence pre- sented to demonstrate that urinary MBPLM, alone or af- teradjustment for creatinine (MBPLM/Cr), correlates well with black hole volume (BHL VOL) detected on T1- weighted cranial MRI, especially in SP MS and, more spe- cifically, in those without relapses and with more ad- vanced disease. (as In this cross-sectional study, urinary MBPLM and MBPLM/Cr showed no dilferences in the population of| patients with an EDSS score of 5.0 of lower oF an EDSS score of 5.5 or higher, whereas BHL VOL was greater (P=.02) in the group with the higher EDSS scores (5.5). ‘A series of correlations were made for BHL VOL (Table 1) and the MRI composite 24 score (Table 2) with urinary MBPLM. A weak direct correlation existed between the level of urinary MBPLM and BHL VOL in all patients with MS (Table 1). The fact that the corre lations with MBPLM were not evident or as strong with MBPLM/Cr or total MBPLM presumably reflects the lack oflinearity of the measurement of MBPLM using a stan- dard of MBP peptide 83-89.°" When analyzed among Ms subtypes, this correlation was restricted to those with SP MS, specifically those without relapses, and most sig- nificantly when the EDSS score was 5.5 or higher. The (©2001 American Med Table 2. Corelations of Urinary Myelin Basi Potein-Like Material and 24 Score (Magnetic Resonance Imaging Composite) on Cranial Magnetic Resonace ‘Imaging in Multiple Seerosis* Toad ARMS sms 3 MS ith lapses) SP MS uithout relapses) DSS ctor <5 EDSS ctor =55 ~ MBPLIM indeaes myelin Basl protelo-tke materia MBPLUUCr, MBPLMY ster adustnet or creatine, A MS, reapsing-ertng mufpe Sclerosis SPS, second progression mule sls and EDSS, Expanded Dsainy Status Seale. The numbers in boa ar stately Sinient Frou EDSS 5.0 (0 = 180), x = 105 and = 20: fr rey EOSS ode reais inge =r ° ‘Ho rai or sex tferences wee detected later correlation was highly significant regardless of the ‘manner in which urinary MBPLM was expressed (Table 1. The greatest significance was for urinary MBPLM/ x. The group of patients with SP MSwith relapses showed no differences in urinaty MBPLM related to EDSS scores of 5.5 or higher or less than 5.5 in regard to T1- weighted BHL VOL. The population of patients studied was predomi nantly white, but no racial differences in the correlations were noted (data not shown). For correlations of MBPLM or total MBPLM, there were no differences between sexes; however, for MBPLM/Cr, in the group of patients with SP MS (02 females and 46 males), both females and males showed the same correlations, which were more signifi cant for females. This is presumably related to the known lower body mass and urinary creatinine in females.”* Although not asstrong, similar correlations were noted between the expressions of urinary MBPLM and the MRL composite 24 score (Table 2). No racial or sex differences were noted, Since BHL VOL is included in the 24 compos- ite score and since there was no significant correlation of urinary MBPLM and any of the other cranial MRE mes surements (data not shown), this weaker relationship of the 2+ score and urinary MBPLM is presumably due to the {impact of the BHL VOL component on the composite score. The composite 24 score (Table 2) but not the BHL VOL measurement (Table 1) showed a weak correlation with MBPLM in patients with SP MS. This significant relation- ship of 24 was present only in those with an EDSS score of 5.5 or higher. The correlation with the Z4 score and not with BHL VOL implies an impact of another component, not yet identified, on the composite Z4 score ‘No correlations for urinary MBPLM and any of the era- ected for the RRMS group, nal MRI measurements were Association, All rights reserved. mn American Linom MRI-Analysis Center Assistants [MBI-Analysts Center, University of Texas Health Science Center, Houston: Jonathan Carlson, Jennifer Chambers, Bran Dec, Lucy Mendis, skip Slatenow, Tom Thomas “The North American Linomide Investigators University Hospital Univers of Alabama, Birmingham: Jon N. Whitaker, MD (clinical principal investigator), Galen W. Michell MD, Christopher C. LaGanke MD, Beverly Layton, RN, University of Alabama, Birmingham, ME imaging, Taber ELGamial, MD Gmaging principal investigator), Cleve Crews, Wladyslaw Sobol, PhD; Arizona Health Scences Center Tucson : William A. Sibley. MD (clinieal principal investigator, Scolt Sherman, MD, Barbara Geese, MD, Jean Kunkel” “Thomas, MD, janet Mar, RN, Todd McGregor, University Medical Center MR, Joachim Seeger, MD (imaging principal i= ‘etigator, Joseph Berg, Arthur Gmitro, PHD, Bill bern; The Bowman Gray School of Medicine, Salem, NE: Douglas R.Jel- irey, MD (clinical principal investigator), B. Todd Troost, MD, D.Letkowitz, MD, Wilam McKinney, MD, Loraine Hai, RN. MRI Center, Department of Radllogy, Allen Elster, MD (imaging principal investigator) Lisa mith, Elaine James; Bu. {alo General Hospital alflo, NY Lawrence Jacobs, MD (linia prinlpal investigator), Reza Fordel, MD, Predevick E Mun Schauer Il, MD, Elzabeth Doherty, MD, Steven} Greenberg, MD, Susan Krantz, RN, Roswell Park MR, Henry Z. Wang, MD. PAD, Wendy Zimmer, MD (imaging principal investigators), Carol Kaminski, Richard Macurchek, PhD, Mark Smerk The University of Calgary: Luanne Metz, MD (clinical principal investigator, David Patty, MD, Rober Bell MD, W, F. Mur- phy, MD, Amanda Pits, RN, Sandy McGultness, MN, Magnetic Resonance Imaging Cente, Foothills Hospital, Carla Wal- face, MD (imaging principal investigator), Pierre LaForge, RINM, Ken Bot, The Univers of California, Davis Medical Cn ter, Dave Marke Av Agivs, MD (clinical principal investigator), David Richman, MD. N. Vijayan, MD, Lee Eun Kyu, MD, Janelle Adams, RN, University of California, Davis Medical Center, MRI Center, Michael Buonocore, MD, PAD (imaging Principal investigator), Stephen Hecht, MD, Cindy DuPreeThompcon, Lisa Wal, Jose Gacayan, John Tinker, John Ryan Banna Whitheld David A. Weber, PAD Jim Deal The University of California at Los Angeles Lawrence Myers, MD (clinical principal investigator), joanna Girard, MD, Robert Baummhelner, MD, Lois Rosner, MD, Sharon Craig RN. UCLA MR Int- ging Center John R. Henson, MD (imaging principal investgaon), Valerie Gausche, BRST. Mary An Burs, CRT, Angela Wallace, CRT, Shantan Sinha, PHD; The University of Chicago, chicago, It Anthony Redex. MD (clinical principal invest- {ato)Avertano Noronha, MD, Bary Amason, MB, Gaven Jacob, RN, The University of Chicago Hospital Department of Radiology, Daniel Huddle, DO (imaging principal investigator, Vence Edmonds, Rober Meyers Georgetown University Medi- fal Cenler, Washington, DC: John Richer MD (clinica principal investigator), Carlo Tornatore, MD, Riren Kresa Real, MD, Jorge Katia, MD, Andrew Pachner, MD, Tara Gustason, Shady Grove MRI, Robert Isaacs, MD Gaging principal inves {an Je Previte: Kevin Quinn, University Hospital, Landon, Ontario: George Ric, MD clinical principal investigator), George Ebers,MD, Pj Wilma Koop, University Hospital imaging, Donal Lee MD (maging principal investigator), Karen Kennedy RRINM, Brian Rutt, PHD; Maimonides Medical Center, New York: Aaron blr, MD (cial principal investigator, Marchal Keilon, MD, Keri Bruining, MD, Elen Drexler, MD, Linds Scars, BN, MSc, The New York Hosptal-Corell Medial Cen ter, New York Brian Apatoll MD (clinical principal investigator), batty Singer, M, Justine Wheatley, RN, Pisa Pericon, MPA, The New York Hospial-Cornell Medical Center maging, Michael D. F, Deck, MD (imaging principal investigator). John A Matkisz, MD, PAD, Michael Aqua, RT; The Univers of Maryland Hospital, Baltimore ChrsopherBever, Je MD (clinical principal investigator), Kenneth Pjohnson, MD, Omar Khan, MD, Hillel Panitch, MD, Subay Jalbut, MD, Eleanor Katz, RN” Cathy Conway, RN, Anna Gutsy MRI Center, Michael Rothman, MD (amaging principal investiga), Erma ‘Owens, Moriel Nessaiver PAD, Steve Crum; MCP Hahnemann University: Fred D. Lubin, MD (cna principal investga- tor), Fo Trans, RN, Leth Kelly, RN, PAD, Thomas Jerson Universi, Philadelphia, Pa: Robert Knobler, MD, Jllerson Imnaging-Bala, Carlos Gonzales, SD (imaging principal invesigato), Lynn Adil, BSRT(R), Simon Vink, PRD, Keith Kodash: Mayo Clinic, Rochester, Min: John H. Noseworthy. MD (linia principal investigator), Claudia Lucchinet, MD, Brin Weinehenker, MD, Moses Rodriguez, MD, Andrea Adams, MD, Mind) Arneson, RN, Mayo Clinic MR Imaging. Bradley). Erickson, MD, PAD (maging principal investigator), john Rasmason, Joc ,Flmnie, PhD, Richard Westlund, Mayo Clini, Scotisdae Ari: jonathan Carter, MD (clinical principal investigator), Richard Caselly MD, Kathryn, Hrschorn, MD, Timothy J gall MD, Alycia Metcalf RN, Carre Meshulam, CA, MRI Center, Kent. Nelson, MD Gimagig principal investigator), Kay Binoncour, Dan Peterson, The Mellon MS Center~levland Clini, Cleveland, Ohi Jelley Cohen, MD (clinical principal investigator), Thomas Masaryk, MD, Bianca Guttman, MD, Revere P.Kinkel, MD, Richard Rudi, MD, Patricia Adler, RN, MSN, Lakewood MRI Center. Jelrey Ross, MD (imaging principal investigator), Judy Wilms, RT Jean “hack, PAD, Steve Bowers, The Univesity of Minnesota, Minneapolis: Gary Birnbaum, MD (linia prinlpal investigator) Randall Shapiro, MD, David Knopman, MD, Crispin se, MD. Rosemary Nelson, RN, Midwest MRI, David Kiser, MD Gime aging principal investigator, Kimberly Carley, Pat Miller, John Gaughan; Montreal Neurological Insitute: Gordon Franc, MD Clinical principal investigator), Wiliam Barkas, MD, Yves Lapierre. MD, Rozie Arnaoutcis, Montreal General Hosp Raquel Del Carpio-O'Donovan, MD (imaging principal investigator, Laurian Rohoman, Christopher Henri, Gennare Du tante; UMD New Jersey Medal Scho Newark. Ststt Cook, MD (chinkal principal investigator), Shalit Bars, MD, Mary ‘Ann Picone, MD, Annete Jotkowit, james Quinless, Department of Radiology, Leo J. Wolansky, MD imaging principal investigator) Janice Comiskey, Wen Ching Lin, PAD, The University of Rochester heal Center, Rochester, NY Ante Good tian, MD (clits principal investigator) David H. Mattson, MD, PRD, Steven R Schvvid, MD, Eileen Scheid, RN, Depart- tment of Radiology David shrier, MD (maging principal investigator), Constance H White, BSRT, Edmund Wing-Chi Kwok, Rsh-PresbyterianSt Lake's Medial Center, Chicago, Dusan stlosk, MD (clinical principal investigetor), Flay A. Davis MD, Karyn Karlin, MD, Jean Rush, RN, Greg Podraa, RN, ARSC-Citcle Imaging Center, William Greenice, MD (imaging Principal investigator), Ginny Flynn, 1. Jin-Zhao Wang, PhD, Brad Phillps St Michaels Hospital, Toronto, Ontari: Fal 4W- O'Connor, MD (clinical principal investigator, Trevor Gra, MD, Paul Marchet, MD, Jue Hall, Sunnybrook Health 5 AN TY WHWARCTNEUROL COW (©2001 American Medical Ass Downloaded From: https:/jamanetwork.com/ on 0103/2021 lation, All rights reserved. an Science Center MRI Centre, Gordon Cheung, MD (imaging principal investigator), Pauline Houston; University Medical Cen: ter SUNY at Stony Brook: Patricia K_ Coyle, MD (clinical principal investigator), Lauren Krupp, MD, O. Gerber, MD, Carol Doscher, NP, Department of Radiology, Robert G. Peyster, MD (imaging principal investigator), Robert Day, Hailang Li PAD, Christopher Runz; The University of Texas-Houston, Health Science Centr: J. William Lindsey, MD (clinical principal investigator), Staley Brod, MD, Mazen Dimachikie, MD, Emily Cerreta, RN, MSN, Hermann Hospital MRI Department, Larry Kamer, MD (imaging principal investigator), June Garcia, RT, Scot Dunc, RT; Vanderbilt University Medical Center, Nas ville, Tenn: Jane E- Howard, MD (clinical principal investigator), Subramanian Sriram, MD, Howard Kirshner, MD, Renee Browning, RN, Vanderbilt University Magnetic Resonance Imaging, Robert Kessler, MD (imaging principal investigator) Richard Paulsen, MD, Ric Andal, Joe Knuutila, Ronald R. Price, PRD, Dan West; Wayne State Univesity School of Medicine, Detroit, Mich: Robert P. Lisak, MD (clinica principal investigator), Alex C. Tselis, MD, PhD. John Kambollz, MD, PRD, James ‘Garber MD, PhD, Richard Lewis, MD, Linda Tvardek, RN, Children's Hospital of Michigan, Cristie J. Becker, MD (imaging principal investigator), Barbara Peters, Greg Moore External Data Safety Monitoring Committee Henry McFarland, MD, Chair; Walter H. Carter, Jr, PRD, Charles Flexnor, MD, Stephen L. Hauser, MD, John Petkau, PhD, Stephen Reingold, PAD. Pharmacia and Upjohn Per Gjorstrup, MD, Director of Clinical Research; Anders Linde, MB, Study Director; Herman Sullivan, MD, Clinial Pro- gram Leader. cc ‘ment, especially at the medium dose of Linomide of 2.5 mg/d, persuasive effectiveness of treatment could not be r demonstrated with the brevity ofthe wal. Nevertheless, investigation revealed that in patients with more ad- vanced MS, thats those withan EDSsscoreo!3.5orhigher important experience was gained from that tril. As re and without relapses, urinarylevelsofMBPLMare signifi. ported elsewhere.” there was evidence of slowing of pro- ‘cantly correlatedwithBHL VOL hypolntenseareasonT1- gressive accumulation of lesion burden and of gadolinium Weighted images on cranial MRI. The slightly less strong _posivity im patients who were treated with Linomidecom- Correlation ofurinary MBPLM with the MRI composite 24 pared with placebo. Iv adlition, the MRI measrement of Scoreismost likely theresultoftheinchisionofother MRI BHLVOLalsoshowed anelfectof treatment. fter3 months methods, along with BHL VOL, in that composite: These of treatment inthis tal, the proportion of lesions catego- findings-anextensionofpreviousstudiesreatingincreased _rizedas blac holes was reduced by reatinent, with thee levels of urinary MBPLM to the progressivephase of Ms fect most prominent for patents with MS taking higher doses so provide addtional evidence forthe possible utility of of drug (P= 05 for active treatment and P=03 overall)” Urinary MBPLM topredictor reflect the more disablingform The biological relationship of BHL VOL on Ti- ‘OfMS. The recent identieation of p-

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