Lancet.
`no. 9421 (May 15 2004)
`General Collection
`'^1 LA453
`2004-05-27 14:49:46
`
`ANC "I rH
`
`www.thelancet.com
`
`'volume 363j Number 9421 • Founded 1823 • Published weekly • Sanirday May 15, 2004
`
`editorial
`1565 Political neglect in India's health
`COMMENTARY
`1566 Dangerous pathogens in the iaboratory; from smallpox to today’s
`SARS setbacks and tomorrow's polio-free world
`D L Heymann and others
`1568 How to prevent cannabis-induced psychological distress ... In
`politicians
`F Grotenhermen
`1569 Psychological, physiological, and drug interventions for type 2
`diabetes
`D J A Jenkins
`1570 Statins for the treatment of multiple sclerosis: cautious hope
`C H Polman, j Killestein
`ARTICLES
`1571 Breastmilk feeding and lipoprotein profile in adolescents born
`preterm
`A Singhal and others
`1579 Psychological and social sequelae of cannabis and other Illicit drug
`use by young people
`J Macleod and others
`1589 Systematic review and meta-analysis of randomised controlled trials
`of psychological Interventions to improve glycaemic control In
`patients with type 2 diabetes
`K Ismail and others
`1598 Efficacy of rectal artesunate compared with parenteral quinine in
`initial treatment of moderately severe malaria in African children
`and adults
`K I Barnes and others
`CASE REPORT
`1606 Progressive blnasal hemianopia
`E Pringle and others
`research lehers
`1607 Oral simvastatin treatment In relapsing-remitting multiple sclerosis
`T Vollmer and others
`1608 Serum lipopolysaccharide-binding protein prediction of severe
`bacterial infection In cirrhotic patients with ascites
`A Albinos and others
`
`NEWS
`1611 US criticises Bulgarian nurses'
`conviction
`1612 Central American trade pact may limit
`access to generics
`1614 World Trade Center rescuers face lung
`distress
`NIH panel calls for limits on
`consulting
`1615 WHO puts HiV/AIDS pandemic at top
`of its agenda
`Canada draws near to approving
`Africa drugs deal
`1616 Pregnancy complications kill 70 000
`teenagers a year
`Spanish HIV registry should be
`abolished, court rules
`1617 News in brief
`1618 Bush accused of financially
`neglecting research
`SEMINAR
`1619 Cerebral palsy
`L A Koman and others
`PERSONAL ACCOUNT
`1632 Yes, survive I did . . .
`J Geppert
`REVIEW
`1633 Preimplantatlon genetic
`diagnosis
`K Sermon and others
`VIEWPOINT
`1642 Early origins of
`cardiovascular disease: is
`there a unifying hypothesis?
`A Singhal, A Lucas
`Contents list continues
`inside
`
`PROPERTY OF THE
`NATIONAL
`LIBRARY OF
`MEDICINE
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`LANCET - INCLUDING INDEX
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`2004 VOLUnE 363 ISSUE 9421
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`SISACiililii:9421
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`IND
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`ON
`fM
`in
`Ov
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`-#
`
`Date;
`'o
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`^Exhibit-
`Exhibit No.;
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`©kSQUiRE a
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`mm
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`Ot/)
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`IPR 2018-01403
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`Page 1 of 5
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`

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`THE LANCET
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`CORRESPONDENCE
`1646 Post-traumatic stress in former Ugandan child soldiers
`S McKay, M G Wessells;
`I Derluyn and others:
`C Magambo, R Lett;
`K A L A Kuruppuarachchi, L T Wijeratne;
`S Singh
`1648 Unsafe injections and transmission of HIV-1 in sub-Saharan Africa
`D Gisselquist and others;
`G P Schmid and others;
`M Bulterys and others:
`M Thoma and others
`1651 Rising dengue death toll in Indonesia
`S C Arya, A Varma
`1651 Patients’ charges in Slovakia
`P Celec
`1651 European Clinical Trials Directive: the Italian position
`U Rlibeck and others
`1652 A need to rethink social psychiatry in Europe
`W RuU
`OBITUARY
`1653 Wayne Streilein T Tannen
`DISSECTING ROOM
`1654 More than I wanted to know j Hill
`1655 Lost in translation (and transcription and replication) f McLelian
`1656 A tug of war between ethics and commercialisation r Caine
`1656 Young people with dementia G Smith
`1657 Evidence M Edwards
`1658 Lifeline P Webb
`1658 Meeting fatigue j a Lee
`CLINICAL PICTURE
`1578 Cystic bronchiectasis E Coche and others
`
`Volume 363, Number 9421 • Founded 1823 • Published weekly • Saturday May 15, 2004
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`Page 3 of 5
`
`

`

`Research letters
`
`RESEARCH LETTERS
`
`Oral simvastatin treatment in relapsing-remitting multiple sclerosis
`Timothy Vottmer, Lyndon Key, Valerie Durkalski, William Tyor, John Corboy, Silva Markovic-Plese, Jana Preiningerova, Marco Rizzo, Inderjit Singh
`
`Many drugs have been approved for relapsing forms of multiple
`sclerosis but are only partly effective, are Injected, and are
`expensive. We aimed to investigate use of of oral simvastatin
`(80 mg) in 30 Individuals with relapsing-remitting multiple
`sclerosis. The mean number of gadolinium-enhancing lesions at
`months 4, 5, and 6 of treatment was compared with the mean
`number of lesions noted on pretreatment brain MRI scans.
`Number and volume of Gd-enhanclng lesions declined by 44%,
`(p<0 0001) and 41% (p=0 0018), respectively. Treatment was
`well tolerated. Oral simvastatin might Inhibit Inflammatory
`components of multiple sclerosis that lead to neurological
`disability.
`Lancet 2004; 363: 1607-08
`See Commentary page 1570
`Since 1993, five disease-modifying drugs have been approved
`for relapsing forms of multiple sclerosis.' All these are only
`panly effective for most patients, need regular injections, and
`are expensive. Statins are cholesterol-lowering drugs exten­
`sively used in medical practice for primary and secondary
`prevention of cardiovascular events due to atherosclerosis. In
`addition to their cholesterol-lowering effect, previously
`unrecognised immunomodulatory effects have been identi­
`fied.^ Statins inhibit lyonphocytc function associated antigen 1
`(LFA-1)—a ligand for intercellular adhesion molecule
`(ICAM) that enables inflammatory cells to pass through the
`blood-brain barrier—and the production of matrix metallo­
`proteinase 9, an enzyme associated with T-cell transmigration
`across endothelial barriers.’ Singh and his group (Pahan and
`colleagues,' Stanislaus and colleagues’) reponed the down-
`regulation of inflammatory' mediators (such as tumour
`necrosis factor a and inducible nitic o.xide synthase) in macro­
`phages and glial cells in culture and experimental autpimmune
`Baseline
`
`encephalomyelitis brain, a model for multiple sclerosis.'
`Furthermore, Youssef and co-workers’ showed that statins
`induce a shift from production of proinflammatory (T-helper
`[Th] 1) cytokines to anti-inflammatory (Th2) cytokines in
`autoaggressive T cells. Thus, statins could be beneficial for
`multiple sclerosis. We aimed to assess use of oral simvastatin
`in patients with relapsing-remitting multiple sclerosis.
`We designed a multi-centre, open-label, single-arm study to
`gather information on use of oral simvastatin. Between May,
`2001, and February, 2002, we enrolled into a pre-treatment
`phase individuals who were aged 18-55 years with clinically
`definite relapsing-remitting multiple sclerosis and no previous
`treatment with interferons or glatiramer in the previous
`3 months or corticosteroids within 30 days of screening. We
`monitored panicipants for 3 months, and did monthly brain
`MRI scans; those with at least one gadolinium-enhancing
`lesion detected during this phase were eligible to receive 80
`mg of simvastatin daily for 6 months. We repeated brain MRI
`at months 4, 5, and 6 of treatment. All MRI scans were read
`by two expert masked readers who manually established the
`location of Gd-enhancing lesions. We measured the volume of
`lesions with a threshold technique. We identified the number
`of nevv Gd-enhancing lesions per scan by comparison of the
`location of lesions on consecutive scans during pretreatment
`and treatment phases, with masked order of phase.
`The primary outcome measure was mean number of Gd-
`enhancing lesions on magnetisation transfer enhanced T1
`images pretreatment and during treatment. Secondary MRI
`outcomes were volume of Gd-enhancing lesions, number of
`new Gd-enhancing lesions, and total T2 lesion volume plus a
`brain atrophy measure, which were quantified by one operator
`with semiautomated software (MSClassifier). Secondary
`clinical outcomes were relapse rate and change in expanded
`Average mean difference
`Treatment
`P
`
`2-31(1-39)
`2
`
`1-37 (1-53)
`1
`
`1’30 (0-99)
`1
`
`0-71 (0-68)
`0-50
`
`234 (262)
`172-5
`
`139 (235)
`71
`
`Number of Gd-enhanclng lesions’
`Mean (SD)
`Median
`Number of new Gd-enhanclng lesions
`Mean (SD)
`Median
`Volume of Gd-enhanclng lesions (mm’)
`Mean (SD)
`Median
`T2 lesion volume (mm‘)
`Mean (SD)
`Median
`Brain parenchymal fraction
`0-87 (0-041)
`Mean (SD)
`0-88
`Median
`EDSS (mean)
`2-80
`Yearly relapse rate (mean)
`0-43
`EDSS=expanded disability status score. ’Primary outcome (per-protocol. n=28).
`MRI and clinical outcomes of participants
`
`27 019 (23 871)
`21 398
`
`27 994 (26 284)
`20 831
`
`0-86 (0-040)
`0-88
`2-98
`0-38
`
`THE LANCET • Vol 363 • Mnv 15. 200-t • w-ww.ihelancei.com.. .
`
`-1-01 (108)
`
`-0-679(1-54)
`
`-98-3 (183-8)
`
`862-5 (4605-5)
`
`-0-002 (0-005)
`
`<0-0001
`
`0-0295
`
`0-0018
`
`0-5634
`
`0-0467
`
`0-6125
`1-0
`
`ifinv
`
`Page 4 of 5
`
`

`

`RESEARCH LETl'ERS
`
`disability status score. We assessed adherence with monthly
`study drug records. We summarised all MRI outcome
`measures as the average of the mean values per participant and
`analysed them with the Wilcoxon signed rank test. We did
`exploratory immunology studies including serial measurement
`of cytokine production by in-vitro anti-CD3 plus anti-CD28
`monoclonal antibody-stimulated peripheral blood mono­
`nuclear cells. We monitored secretion of Thl (interferon 7,
`tumour necrosis factor a, interleukin 2, interleukin 12) and
`Th2 (interleukins 4, 6, and 10) cytokines. Further, we noted
`surface marker expression in a small cohort. Three-colour
`staining was done and we analysed results on lymphocyte­
`gated and monocyte-gated populations with Cell Quest
`sofnx'are (version 3.3) (Beckton Dickinson Immunocytometry
`Systems, San Diego, CA, USA).
`Of 45 people screened, 30 were eligible for treatment and
`nvo discontinued before completion of the three treatment
`MRI scans (one withdrew consent and one was lost to follow­
`up before the month 6 scan). Mean age was 44 years (SD 8),
`and 21 (70%) were women. Of the 28 per-protocol
`individuals, the average of the mean number of Gd-
`enhancing lesions was reduced by 44% during treatment
`compared with pretreatment (p<0 0001; table). Similarly,
`Gd-enhancing lesion volume fell by 41% after treatment
`(p=0 0018). Pretreatment and treatment phase yearly relapse
`rates did not differ. No relevant change between pretreatment
`and treatment expanded disability status scores was detected
`.during the 6 month treatment period (table).
`Mean baseline total cholesterol and T T)T. values were
`5-0 mmol/L (SD 1-0) and 3-1 mmol/L (0-7) respectively. By
`treatment month 6, these amounts had fallen to 3-5 mmol/L
`(0-6) and 1-8 mmol/L (0-5), respectively (p<0-0001).
`Treatment did not affect relative numbers of monocyte
`(CDI4+) and lymphocyte (CD3+, CD4+, CD8+, CD19+)
`subsets in the cohort of nine patients. Overall, the findings of
`the immunology studies did not indicate a change in
`secretion , of representative Thl and Th2 cytokines. No
`serious adverse events were reponed during the treatment
`phase. Two of the treated individuals had a clinically
`important increase in liver function tests during treatment
`and one had a clinically relevant creatinine phosphokinase
`concentration at month 1 of treatment that returned to
`normal for the rest of the treatment period. Three people
`reported muscle weakness possibly related to study drug.
`Tfiese findings suggest that an 80 mg daily dose of oral
`simvastatin over a 6 month period could inhibit the inflam­
`matory components of multiple sclerosis that lead to neuro­
`logical disability. Since individuals were enrolled on the basis
`of their disease activity on baseline MRI scans, noted
`reductions in a baseline versus treatment trial design could
`represent regression to the mean. However, our results,
`combined with the published work on the immunological
`effects of statins, lend support to the case for randomised
`controlled clinical trials to establish the safety and efficacy of
`statins in the treatment of relapsing-remitting multiple
`sclerosis.
`Contributors
`L Key and I Singh were the study chairmen. V Durkalski was the study
`statistician and project leader at the Clinical Innovation Group
`(coordinating center). T Vollmer, S Markovic-Plese, W Tyor, and
`J Corboy were site investigators. J Preiningerova and M Rizzo worked at
`the central MRI reading center.
`Conflict of interest statement
`The Medical University of South Carolina and IS are participants in US
`patent no 6 31 1 800, an unlicensed patent about use of statins for
`treatment of ncurodegcncrative and inflammatory diseases. If the patent is
`licensed, financial distribution will be due according to the Medical
`University of South Carolina’s intellectual property policy guidelines. IS is
`entitled to 25% of the income from this patent. TV, IS, and LK have
`received honoraria for speaking from Merck.
`
`Acknowledgments
`This research was supported by an unrestrieted educational grant from
`Merck to the Medical University of South Carolina. The sponsor had no
`role in study design, data collection, data analysis, data interpretation, or
`in the writing of the report.
`1 Goodin DS, Frohman EM. Garmany GP Jr, et al. Disease modifying
`therapies in multiple sclerosis: report of the Therapeutics and
`Technology Assessment Subcommittee of the American Academy of
`Neurology and the MS Council for Clinical Practice Guidelines.
`Ucumlogy 2002; 58: 169-78.
`2 Neuhavs O, Scrasser-Fuchs S, Fazekas F, et al. Statins as
`immunomodulators: comparison with interferon-beta lb in MS.
`Neurology 2002; 59: 990-97.
`3 Stanislaus R, Singh AK, Singh I. Lovasiadn treatment dcereascs
`mononuelear cell infiltration into the CNS of Lewis rats with
`experimental allergic encephalomyelitis. J Ncurosci Res 2001; 66:
`155-62.
`4 Pahan K, Sheikh F, Namboodiri A, Singh I. Lovastarin and
`phenylacetatc inhibit the induedon of nitric oxide synthase and cytokines
`in rat primary astrocytes, microglia and macrophages. J Cfiii Invest 1997;
`100:2671-79.
`5 Youssef S, Stuve O, Patarroyo JC, et al. The HMG-CoA reductase
`inhibitor, atorvastadn, promotes a Th2 bias and reverse paralysis in
`central nervous system autoimmune disease. Nature 2002; 420:
`78-84.
`Barrow Neurological Institute, St Joseph's Hospital and Medical
`Center, Phoenix, AZ, USA (T Vollmer md); Medical University of South
`Carolina, Charleston, SC, USA (L Key md, V Durkalski Pho, W Tyor md,
`I Singh PhD); Clinical Innovation Group, Charleston, SC, USA
`(V Durkalski); Department of Neurology, University of North Carolina,
`Chapel Hill, NC, USA (S Markovic-Plese md); Department of Neurology,
`Yale School of Medicine, New Haven, CT, USA (T Vollmer,
`S Markovic-Plese, J Preiningerova md, M Rizzo md); University of
`Colorado Health Sciences Center, Denver, CO, USA (J Corboy md);
`Neurology Service, Ralph H Johnson Veterans Affairs Medical Center
`Charleston, SC, USA (W Tyor); Denver Veterans Affairs Medical
`Center, Denver, CO, USA (J Corboy); and Vl/est Haven Veterans Affairs
`Medical Center, West Haven, CT, USA (J Preiningerova)
`Correspondence to: Dr Inderjit Singh, Medical University of South
`Carolina, 316 Clinical Science Building, 171 Ashley Avenue,
`Charleston, SC 29425, USA
`(e-mail: singhi@musc.edu)
`
`Serum lipopoiysaccharide-binding
`protein prediction of severe
`bacterial infection in cirrhotic
`patients with ascites
`Agustin Albinos, Antonio de-la-Hera, Melchor Alvarez-Mon
`
`Serum llpopolysaccharlde-binding protein Is Increased In a
`subset of non-Infected ascitic cirrhotic patients, a finding
`previously related to bacterial passage from the gut to the
`circulation without overt Infection. We prospectively analysed
`the risk factors associated with a first episode of severe
`bacterial Infection In 84 ascitic cirrhotics, followed up for a
`median of 46 weeks. The cumulative probability of such
`Infection In patients with raised and normal llpopolysaccharlde-
`binding protein was 32-4% and 8-0% (p=0-004), respectively.
`Increased llpopolysaccharlde-binding protein was the only
`factor Independently associated with severe bacterial Infection
`In a multivariate analysis (relative risk 4-49, 95% Cl
`1-42-14-1). Monitoring of serum llpopolysaccharlde-binding
`protein could, therefore, help to target cirrhotic patients with
`ascites for antibiotic prophylaxis.
`
`Lancet 2004; 363:1608-10
`
`1608
`
`THE LANCET • Vol 363 • May 15, 2004 • wwuMhelancci.com
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