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`~ ~
`• PROPERTY OF THE
`NATIONAL
`LIBRARY OF
`MEDICINE
`
`VOl.4 1
`
`Editor: P. J. MEHTA
`
`JUNE 1993
`
`321
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`323
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`325
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`327
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`329
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`333
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`335
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`337
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`339
`
`IN T ill<.: ISSl 1;
`H >l I O IU ALS
`Toxicit y of O r a l Iro n Ch elator L 1
`SK llic/1ile, Pl Melrra. S1111i/ J Pareklr
`S tre ptokinasc in Acute M yocn rdinl Infarctio n
`RS Rajagopalo11
`Co ntinu ous Artc riovenous llaemofiltrnti on and
`MK Ma11i
`Haemod ia lysis
`RJ Daslr,.
`E nd emic C retinism : Th e Indian Scene
`V Gupta
`OIU<;J N \l.Alffl<'I ES
`Assessment o fl11tr:ivcno11s S tre ptok inase Therapy in
`P Garg, R Saigal,
`Acute Myocardi al Infarction
`SC Mathur
`Con t i nuou ~ Re na l Re placeme nt The ra py in C ritic ally Ill
`I) Mnlakar, PP 111omas,
`Patients with Renal Fi1il11rc
`CK )(ICOb, JCM Slwstry
`C linical S tud y of End emic C retin ism In South Sikkim
`R Snnkw. T Pulger, JJ Rai, G Sankar, TR Gyatso, BM Roi
`Autoant ihodi es in Thala ssnemia Maj or: Relations hip
`J Melrta, A Clwblani,
`wit h O ral I ron C h ela tor L1
`R Reporter. S Si11g11a/, /JC Melrta
`342
`lmmun osurvcill a ncc of T ra nsfusion l)cp cncle nt
`M Maz.111111/er.
`Tlrnlassacm ia a nd lle patilis B Va ccimllion
`IJ Se11g11pw. M De. P u1/riri, DK 81w11aclral)'O
`KD Nilra/011i,
`C-P cptid e Pro fil es in Youn g Diabetics
`PK Vartlrokavi. KL Patel. l'C Mercl1a11t
`P rognosis a nd Ma n agem en t o f Membranous Nephropa thy
`DK f'<1lwri , S Das, /JN D1111r1. D IJanerjee
`Sero logica l Ch aractcris11 tion o f Ncisse riu G ono rrh oea c
`MG K11lkomi,
`By Co - Agi:l11t in a tio n T echnique
`RA Rudie. S Join, PK M11rti
`354
`l'o ly111yosilis - A l~ cv iew a nd Follow Up S tudy of 24
`Ca~cs AS Naray111w.111•w11y. M /\klrwr, N K11111ar. Al Lazar
`357
`E va luation of l\ la nni ng's C rit eria in t h e l)iagnosis of
`KP Rao. S G11p1t1, AK Jain.
`Irritable Bowel Sy nd r ome
`AK Agarwal, JP G11p1t1
`Tnms rccta l F ine Needle Aspirati on of Prostate
`G J11y<1ru111, N Nakra. AK Ven1111, GD Goel
`367
`C liclazidc in th e Trea tment of O h csc Non-Ins ulin
`V Sesl1ialr, S Ve11katra111a11,
`Depe ndent Diabetic Pi1tie nt
`K SureJ·/r
`369
`Scrum l mmunoglob in E Agains t l'l'D A nti gen in
`AV l'lrerwa11i,
`Pat hi cnts with Pulmona r y Tubercu losis
`I. lllyram. MA fl•la.rnod
`37 1
`An ti-Lymp hocyte G lobul in Therapy in Acqu ired
`/VllJ Agurll'al, UM Ag11nv11I. AB fllwve,
`A pl asti c An em ia
`C Vi.r/11v<11111tlw11
`Sl' I C'I \I 'il·. IOl .S
`Ad verse Dru g lk a c tio n Monitorin i: In I nd ia
`NA KJ/iiramgar, SC Karamle. CN l'mkar
`
`K NNares/i,
`
`377
`
`379
`38 1
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`386
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`389
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`397
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`398
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`399
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`400
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`400
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`401
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`401
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`401
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`363
`324
`344,373,390,396.402
`
`S HOUT ARTICLE
`Platelet Func tion in Acut e L e ukaemias
`P Sivasa11karo11, Al Ve/iath
`\Jl'))A n . AR'I ICl.Kl.i
`BM Hegde
`Congesti ve Heart Fa ilure · An O verview
`AM Amarap1;rkor, SC Slrah,
`Subacute Hepatic Failure
`SRS!ralr
`RE\ 11, \ \ ARI Jl'I I·
`Recent Trends in t h e Diagn os is of Amoebias i.s SC Parija 383
`CAS I•; REl'OR rs
`Macroglossia · T h e Presenting Feature of Primary
`S Gaikwad. P Vartlrakavi, M Chandalia,
`Amyloidosis
`KO Nihala11i
`Pers is tent Comple te Hem·t Block Followin g Acu te
`CK Shalr,
`Rheunmtic Fever in a 12 Yea r Old Girl
`RG11pta
`A Bhansu/i
`A Pseudo Adernal T umo r in a n Obese I nfant
`39 1
`R M11ralidlrara11. N Klla1idelwal, SK Mitra, RJ Dash
`393
`Mu lt iple My el oma Prese ntin g us Acute Parnplegiu
`S Aganval, R Avasthi, S Gupta, BK Ram
`395
`Von Will cbrand 's Disease with Gas trointes tinal
`VR Dhamidlrarka, SK Bic/1ile, SS Vaidya
`Tel a ng icctasia
`ll lrn•. F C ,\S I· R El'O RT<.;
`Acute Pancr eatilis with Disseminated I ntravascula r
`K Jayaclra11dra11, L Ve11ka1akrisl1na11,
`Coaguhl lion
`S Nagaraja11
`No n-Cardiac Pulmona r y O ed ema in Scorpion Bite
`A Matlrur, G Ven11a, RS Gehlot, JS Ujj1val
`Uron chogcnic Ciirc inoma in volving the Aortn , s uperi or
`Ven a Ca va, Mediastinum a nd Pe rica rdium
`VP Sa11z.giri. CR Mere/ram, JV Ma 11dke, AM Phatak
`C 'Olt lU~S l'ONl>EM . 1· S
`Poncct's Disease P Dileep Kumar, PK Sasidhara11.
`BJ Patti, G Tharinn, PV Bhargavan
`Associa te of T hy roid Disorders with Acrom egaly and
`with the Develo pment of lly pe rplastic/Dysplastic Breast
`Ajay K Slrarma, SK G11pta, SK Mislrra
`Disor d ers
`S K11111ar, S Rao,
`A Case of Ncurotox ic ity l>u e to lNll
`I Ramiah, A Jaymm
`Atypical Lymph ocy tes in Acute Falcipa rnm Ma laria
`RC Jai11, V Jai11
`E ffi cacy and Safety of ll uma n lli osynthe tic I ns ulin of
`N Rias. CClwri,
`Saccharomyt.'Cs Ccrcvis iae O rig in
`A Kapur
`(}l.,I/
`llOOh. IU .VlF WS
`374
`This mat,.rial W"1"<~40ttl NCEI\ I ENTS
`at the NLM and may be
`Subject US Copyri,gfit Laws
`
`345
`
`350
`352
`
`364
`
`
`1 of 4
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1031
`
`

`

`ORIGINAL ARTICLE.
`
`AUTOANTIBODIES IN THALASSAEMIA MAJOR: RELATIONSHIP WITH
`ORAL IRON CHELATOR Ll
`
`J Mehta"'. /\ Chablani * ·~ . R Reporter* * * , S Singhal*, BC Mehta****
`
`/\HS I H1\ ( I
`Nine ty pa ticnlS with thalaso;acmia major were inveo;tigatcd for the occurrence or antinuclear :mtihodics (ANA), a nd those
`with AN/\ were tested for an tihodic<> to his toncs (A II ,\ ). AN/\ were d etected in 7 o f 27 thalasscmics on oral iron chelator LI,
`and in 2 of(1J th:ilas .. acmics not on LI (p < 0.01). AllA \\ere seen in 4 or 7 tha la""cmics rcceivini: LI with positive ANA, rmd
`in no ne or the 2 not re1:civing I.I (p < 0.03). J oint pain" were seen in patient-; receivi ng L I, but in none of the patients not
`rccl'ivini: I.I. T her e was no rnrrl'lation hetwccn hepatitis JI or lll V positivity and presence or ANA or joint pai ns. 'While some
`amount or background ANA -positivity w;1s funnd in paticnto; with thalas .. acmia major, ii was significantly more in patients
`rcecivi ni: I.I. Laboratory cviden1:e or drug-indncecl l11 p11o;-like reaction wao; seen only in p<itients who received LI. In view or
`serious concerno; about the safety of 1. 1 and wide variationo; in the incidmcc and wvcrity of adverse reactions repor ted by dif(cid:173)
`ferent sourcco;, an urgent rcg11la111ry audit of all trial centrl'o; i\ l's .. ential.
`
`I NT l~O l>l l ( TH >N
`
`L ong-term
`iron chelation therapy with desfcr(cid:173)
`rioxaminc
`in patients with 1ransfuslon-dependcn1
`thnlnssaemi a io; wcll-cstabli-;hed. generally sarc· nnd
`reduces or prevents iron-induced organ dysl'unction.1
`Dcsfcn-ioxamine is the standard against which the
`risks and benefits or any new form or chelation
`therapy
`including oral
`iron chelators should he
`measured.2
`Of the large number of' drug~ that have been
`evnlunted as potential oral
`iron chela1ors.
`the
`hydroxypyridinone family has been the most exten(cid:173)
`sively swdied.1 1.2-dimcthyl-3-hydroxypyridin-4-one
`(LI or CP20) ha!. been the most widely studied oral
`chclator. While some investigators have found ii to be
`a sal'e drug in animal studies.4.5 others have en(cid:173)
`countered substantial animal
`toxicity such as
`potentiation or th.! action of barbiturates in rats,6 in(cid:173)
`creased sali vation, severe sweating, muscular spasms,
`7
`and hyperactivity. 3·
`/\granulocytosis and
`throm(cid:173)
`bocytopoenia developed in one LI recipient with
`syndromc.8
`I31ackfan -Diamond
`Agranulocywsis
`developed in 3 of34 patients receiving LI in London.9
`We have described a case of fatal LI -induced sys(cid:173)
`temic
`lupus crythcmatosuo;. tO The
`reports of
`occurrence of au1oa111ibodics in thalassaemics rcceiv-
`
`"'Blood Researc h Centre. Vivi11:1 Bldg 3A, SV Rond. llu111hay 400
`058: Leukae mia Unit. Royal MaNde n llo~pi1:1l. Su11o n. Surrey.
`•• 11111111111op:ithological Di agnn~llc ('e n1 re. 14 Pare kh Mah:1!. IJ
`Road. Bombay 400 01 C>:
`• u T :11a Blood Dank. JJ 110\pital.
`..... N.111ava11 l h1,p11:,J.SV Road. Vik l':nlc. Uombay400054.
`Received. 17.2. 1993: Revl'ed: I 0.5 1991: Acc.: pied: 21 .5. 1993
`
`JAi'/ J9YJ. \IOI .IJ, NO. fl
`
`ing LI have been conflicting, 11 •20 and questions have
`been raised ahcmt a backgound occurrence of an(cid:173)
`tinuclacr antibodies
`(ANA)
`in patients wi th
`thalassacmia major. 13·20 Antibodies to nuclear his(cid:173)
`tones (AHA), which arc supposed to be relatively
`specific for drug-induced lupus,2 1 have been described
`in patients with thalassaemia major not receiving
`Ll. 17
`The present study was undertaken to determine the
`frequency of occurrence of ANA in thalassaemics ir(cid:173)
`respective of the kind of chelation therapy they were
`receiving, and to see if the presence of ANA wns
`drug-related by determining AHA. The data have been
`presented in abstract form.22
`
`l\IATEIOJ\ I. ,\NI> \IETllOl>S
`All 1he 1lt:tl:Mae111ics aucnding 1wo major blood 1ransfu sio n
`cen1re~ (Nan:1vati I lospital 131ood 13:mk a nd Tata Blood B:1nk. JJ
`Hospiwl) in Bomb:iy were investigated. Detailed inquiry w;1~
`made about arthralgia and the n;tture of c helation therapy. lnfor·
`mation abou t the llB~Ag (ELISA) and HIV (ELISA with Western
`llloi conlirma1io n of positive n:sults) status was obt:nned from
`rece nt record \ .
`ANA were csti111a1cd in all p:tticnts by immunonuoreseencc
`using HEp·2 cells a~ subs1ra1e. All the samples found 10 be posi·
`tive
`for AN A were
`further
`s1udicd
`for antibodies 10
`doublc-~tr;tnded DNA (AdsDNA) by immuno nuorcsccnce using
`Cri1/1idi11 /11c1/i<1e as substr:11e. :tnd for I\ llA by ELISA (Sigma).
`
`IH<;l ' l.TI\
`A IOlal o f 90 1halassaemics were inves1igated. o f who m 27
`were receiving LI and 63 were nul receiving L I. Of 1hc ln11er. 2 1
`were 0 11 regular desl'crrioxamine. The dose of LI was 500 mg 10
`4 g per day.
`Eigh1 patient~ 111 1he LI group had a rthralgia while on LI , ;111d
`one had joint ,wcllings. One o f the patie nts ~ad a~hralgia e vc.n
`before \ l:trting LI and this was aggr:watcd after starting LI. In this
`
`339
`
`
`2 of 4
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1031
`
`

`

`patient and in two other~. LI h:1d to be Ol\l·un1111ued du.: 10 thc
`severity of the pain. LI wa\ re\tarted in one ol 1lu.:.l:111cr. n:,ull1'.l!'
`in severe arthrnlgia neeessi1ating LI di,co111inua11on once ag:nn
`LI was restarted in the latter two al low do'c 1500- ICX)O mg per
`day) without recurrence of .11 thralgia. Joint pain wu' not pr.:...:n1 111
`any of the patients not receiving LI. Seven patient~ were lllhAg·
`positive and five were HIV-positive. None of thc'c 12 had
`arthralgia.
`The pattern of autoantibo<Jic~ detected b \ hown in Table ~
`AdsDNA were not detected in any of the 111110.: patient' w11h JXl\I·
`live ANA. The ANA titre was I :40 and I :!!O 111 the two patienh
`1101 receiving LI. and ranged from I :80 10 I: 160 in the 'even
`pmien1s receiving L I. None of the H BsAg·JXl\ itive patient' had a
`positive ANA, while one of the HIV-po~iuvc patient\ had ;i P°''·
`tivc ANA but negative AHA.
`Table t : lmmunoloi:icul i nnstii:ti un~ in 90 thul:""""mk'
`
`ANA·p<h11tvc
`
`A ll A I"""" c
`
`Thalass:icmics on L1 In= 27)
`Thalass:icmics no1 on L 1(n =63>
`
`,,
`
`7125 9'.I)
`2 (3.31il I
`<0.01
`
`t (llK'f)
`
`0 '°")
`
`<0 01
`
`Five months aflcr discontinuation of LI on our advic.:. one of
`the patic111s who had po~i1ive ANA and Al IA hcc:unc 111:ga11vc for
`both. Four months after di,co111inua1iun of L I. one pa1ic111 who
`had positive ANA and a negative AHA hec.::11111: ncgulive lu1 /\NA
`
`l)ISCUSS ION
`Bartlell Cl al reported the development or transient
`arhralgia in 5 of 13 patients on LI; I
`!WO or whom be(cid:173)
`came seropositive for RA . One pa1icn1 developed
`ANA ( 1:40) during L I therapy, and the othcr showed
`no change in a pre-LI posi tive ANA (1:20). The
`remaining three were ANA-neg:nivc.
`There has l5een much conl1ict and inc.on'>istcncy in
`the way all three groups involved with human trials ol
`LI have addressed the issue of autoimmunity a<; a
`result of the drug. T he Canadian group investigating
`LI did not describe any immunological abnornwli1ics
`in their detailed repon, 12 but later reported pos11i ve
`ANA in 5 of 12 thalassacmics with negati ve anti (cid:173)
`dsDNA and AHA before starting L 11:1 in response 10
`our report of LI -induced SLE. 10 No mention was
`made of the subsequent evolution of these abnor(cid:173)
`malities during the course of therapy with L I .
`A 1-Refaic et al reported presence or ANA in 2 of
`12 patients prior tQ. ,'>tarting LI , and in 4 or 12 after
`conclusion of the tliai. 14 However, no mention was
`made of AHA despi te the foci that the presence or
`AHA is supposed to be specific for drug-induced
`lupus. This was an omission which we had to point out
`in view of serious concern about LI-induced SLE 23
`The most striking contradictions have come from
`the Bombay-based group in vestigating L I. Three of
`24 Ind ian patients with thalasscmi:i major on LI
`
`J./O
`
`di.:vdopcd 1rn11,il.!nt 111u,cu lo-.h.clctal palll and arthral(cid:173)
`gia.15 All th1 ec \.\C.:n: n.:portedly negmivc r'.1r ANA,
`Ad-.DN A. and RA factor. The pha'c 11 LI trial report
`on 52 1h:il:1-. ... ae1111c:'
`India 1 '•
`' howcd GI tract
`111
`... ymptom' in ll.5'h and ;111hra lgi:i rn 21. 1%. In the
`same report. Agarwal et al found no "significant
`toxicity" on "ex1en,in.: di nical and
`la.bora~ory
`monitoring" of 'iC\eral orcan 'Y'Icm-. and luncuons
`I u·
`.
`I
`16
`lllC U mg l lC 1rnmune \)'lelll.
`I lowevcr, our in ve,ti!'atinn of two patients fr~m
`Agarwal el :ii· s cohon d1,t:lmcd cvitknce of drug-tn(cid:173)
`duced
`~I.I~ 1n Aut'u't 1990 One had severe
`con,1itu11onal 'iymptom' ol '\ LE and du:d 1wo 1110111.hs
`after the dial!nmi-; ol 'ii.I:,, ith m·ti ve di-.ce1se despite
`·
`·
`·0 10 1·1 • other
`aggrcssrvc thcrapy wi th crn 11cns1cro1 s.
`lC
`.. cl of
`patient \\a' •") mptolllalll, and onl) had the lrl·1
`invc-.tigat1011' 1.:ons1dc1ed ,uggc.,lf\ c of drug-ind~i~ed
`lupus: po'\iti vc ANA. ni.:!•a1i vi.: Ad.,DNA. and posiuve
`All A :?I
`
`i.;
`
`. NAl7 19 and
`Agarn ,ti ct al tl1d rqmr t pre,Clll'C ol A
`7
`I
`11 17
`. I The
`A A
`alter we tle,c11hl·d I.I 1nd11ccd upu'i.
`ques1ion ol i1nn111nolo"1l· ;tl1cr:1111111' observed in In(cid:173)
`rcc:ef\ i~t"
`dian pa11cnh
`I I wa' not adcquaicly
`addrc,.;i.:d Ill :111y ol the'l' 111 ;1 d ·tailed report on ~he
`ei'licaey ol thc drug. 1X Agal\\al l'l al made no mcnll~i
`ol the pa1icn1 who had d1cd due to L I -ind uced SLE.
`· 1·
`·
`I
`II
`I n·1de no
`19
`n
`lc1r 1nal trial 1cpo11. Agarwal cl a r •
`mention ol Al IA at all \\ 1ch could havc shed some
`light on the dntg-induced lupus conlrO\ crsy.
`·1·1
`I
`tll'lt the
`let al pn:-:<.:nted hy A ••arwal cl al <;uggcsts
`•
`·
`·0
`. "'
`· 1hahs(cid:173)
`j7:t9
`rncr cnc:e ol ANA po,11 i, 11y i'
`,1 milar 111
`\acmrc' receiving LI and tho'e not n:ceiving LI.
`17
`.ind that All A may be 'l'l'n in patienl'> noI or~ LI.
`·1·11 • l·1t1 · ·
`I I
`·
`.
`d 1-.. 11ef that
`• c1 wmr t conl 111:1 w11h thl' .1ccepte
`.
`·~
`. r· .,t ()ur work
`AllA ·
`·1-
`.ire 'Pecr re 101 d11tl! induced S L ~.-
`pri.:,cnted Ill 1111, papcr \\ ~Jh 'ome patient' on the LI
`trhl
`.
`I
`I
`111 . sarnc
`011er
`thala,'iacmic'
`lnllll
`c
`·
`•
`·llH
`soc ioec:o110111ic and ethnic hackl!n>Ulld ~hows th:ll
`I ·1
`. ·1y oc-
`w 11 I.! 'Ollle amount ol hacl,,g111,;11d ANA po.,111vi .
`.
`1
`cur' in thalassaemit.\ not
`tal,,rn1• LI . there is .'
`·
`· •
`e-
`· ·
`t)' Ill
`'>tgnilil'.an1ly hi 0 hcr 11H..1dc11cc ol ANA po'111"1
`thalassac111ics i:king 1.1 W e c:ould not dcJCt.:l any
`All A in patients not tah.ing I. I.
`.
`ln:qucnc.:) ~I
`Bcrclouka ... hypothc\11cd 1ha1 h11.!11
`hcp:ttllis B po-;itivc hloocl ·1dmini,;1a11on.; ;it iran"·
`r ·
`·
`1 . 1n1c
`us1on centres in Bombay and the n.:sull ant c ~r <
`hcp·11i1i ·
`I y 111 In
`•
`s may account 101 -;ystcmic .1nhrop:tl 1
`. '
`1
`dian th·1l·1··s· •
`·
`,,, .
`• enl ,tu< Y
`_
`' ' "'· .1c1111l.!s rccc 1v1111' LI . -
`I he pre'
`frnds no · . I ·
`"'
`111 V ;;tallls
`·
`c:or re a11on between the 1 IBsAg or
`of the p·1t"tc111 · d · ·
`·
`·... 1·cc
`'
`.1n JO!ll t pains or :1111oant111e>t 1 '
`When the tlr\t sci il'trs doubt'> about ihc U'C of LI in
`
`~
`
`JM'I l'ilJ.I. VOi
`
`.JI NO 6
`.
`
`
`3 of 4
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1031
`
`

`

`human subjects were raised by us with a call for halt(cid:173)
`ing human trials gcnding detailed immunulugical
`testing of patients, 1 Herdoukas 'felt that our concerns
`were unsupported and that the value of immunological
`investigations was "unclear".20 Bertloukas et al now
`feel that there is "serious doubt" about the safety or
`this agent and that funher development of this com(cid:173)
`is "not justi f'ied".24 This
`is based upon
`pound
`extensive an imal studies which show that the pattern
`of toxicities of L 1 is similar to that of a cytotoxic
`a(fent with teratogcnicity. rnutagenicity and <lose-de-
`24
`b
`pendent myclosupprcssion.
`In light of the animal and human toxicity data
`reported with LI so far, it is surprisi ng that the Inter(cid:173)
`Iron Chelation
`national Study Group on Oral
`(ISGOJC)
`feels
`that discontinuation of
`further
`development of LI is "prcmature".25 Considering the
`obvious reported inconsistent:ies in various types of
`adverse reactions and con llicts of interest. it is pos(cid:173)
`sible that LI is in fact more toxic in human subjects
`than has been reported so fnr. Before the appeal of the
`ISGOIC to carry out further trials wi th L 1 is con(cid:173)
`sidered, in the interest of patients. all the three major
`human trials of L 1 in thalassnemia major (India, UK
`and Canada) need to be audited urgently by the
`relevant regul::itory drug authorities and independent
`investig::itors to !'cc if any ::idditional important aspects
`need to be highlighted.
`
`I{ EFl.;l{E NC' l'.S
`I. Hoflbrnnd AV. Wnnke B. Ri.:sults of long.-tern1 suht·ut:tncous
`desfcrrioxamine therapy. /JailliNI' -.~ Cli11 //111:11111111/ t 9!N: 2 :
`345-36'2.
`2. Cohen ,\. Cum:rll staius of inm \.'hc laiion ihcr:1py with
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`
`in patients taking
`
`JAPI 1993. VOL .// . NO. f>
`
`341
`
`
`4 of 4
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1031
`
`