w ·1 .J O~.:1':;l J;'
`~u.1
`v-ol
`1~84
`~ .1,1--------SEQ: J 2884 UOOO
`,f I: JOUR NAl.. Uf' 'l'tt.i:; 1-l.t:l.lICAL
`ASSOC.Llt'l '. IUN Of' 'l'l!A.fLANI>
`
`1 of 9
`
`Almirall EXHIBIT 2047
`
`Amneal v. Almirall
`IPR2019-00207
`
`

`

`r1ru~m·nmn1Jnn'l 2527- 252s
`The Council of the Medical Association of Thailand: 1984-1985
`
`,q
`
`lHfl11ll l11Y1Ulll1t'J!
`
`V
`
`'
`
`...
`
`tnim
`President
`
`~i~9i1mnbmun
`
`President Elect
`
`tphnun
`
`Vice-President
`
`rn,ninn
`
`Secretary General
`'"
`...
`~'lf1UH'l'1111i011 ·
`Assistant Secretary General
`
`lllft'J!~O
`Treasurer
`
`tlijmJ 11ii::tl1::1irnH1utl1::,s11tllrl''ll~
`
`Songkram Supcharoen
`
`tl,::nt>u 1!rnfm1
`
`Prakorb Burapharat
`'
`(cid:141)
`OlHfl 11f!fl
`
`Narong Sadudi
`
`UOlfl
`
`lJfl::lll'll
`
`Panata Migasena
`
`1Ufl 1flflt)\lv'lliJ
`
`Vinit Rodanant
`"~ ......
`Yl~l,lflOfl 1l1U101
`
`Pongsak Viddayakorn
`
`'lftit>
`
`tiilflill'!
`
`House Master and Chalnnan : Public Relation
`
`Chalor Kupatawintu
`
`1.h~ [jTlJ llf-l'JJn
`Chairmen
`
`'
`111111101111Yll1U
`
`Publication
`
`011U1::'l(ll1'1f1011
`
`'
`,
`011fl0 Mllll'ITIUfllll f11 llti!: ll11Ullll'll1U
`
`Scientific Section
`..
`Medical Education and Ethics
`
`11111~011.
`
`Welfare Section
`,,
`l1tl~11)!fl
`
`Library
`
`011ll0110til~llti::tl1::1il'llfhU\1fll1lf!'ll
`
`Fund Raising
`
`011ll0110til~llti::tl1::1il'llH1Ul1111lll'tiO
`
`Membership
`
`tl,::11112 l'ltl~llllf\!
`Prasert Thongcharoen
`
`Ul::till.ll fl'1'llfl'lllfl
`
`Pralom Sakuntanaga
`, ......
`tlf!UU 11Ul1'1f'1ti
`Adulya Viriyavejakul
`(cid:141),/
`...
`,/
`tl11U
`lll1t'J!mfl
`
`Arrie Charoenphong
`
`ltl'llO (!1iifl~
`
`Anek Yuvachitti
`11rucrrn itum 11,s
`Kunthon Sundaravej
`l'lfU l'lfflii'Ml
`·v1chal Chokvlvat
`
`nnummm~
`Members of Council
`
`ll.1.1.1n11ii''lf flllil'lf
`
`M.R.Kraithavej Srithavej
`
`a~m 11111mr1
`
`Singha Soavapap
`
`1'1lfl ltlfltl'll'llfl
`'
`u
`"'"'
`
`Vinit Rodanant
`
`'lliifl tUt'J!t'J!l
`Kachit Choopanya
`
`fl::i'u 11~11umt1
`
`Tawan Kangwanpong
`(cid:141)
`1i'lll ltJU011'1ll
`
`Tana Erkarna
`
`•
`I
`""
`\llt,tl~ 1Jtll0fl
`
`Chumlong Bawkirt
`
`tl,::mm1 1,s11'1ltl1,s1
`
`Prakarsna Chaovanapricha
`
`-
`
`This m.atearia I ,va:s copie•d
`atthe NLM and may b-e
`Subjeirt US Copyright Laws
`
`2 of 9
`
`

`

`JOURNAL OF THE MEDICAL ASSOCIATION OF THAILAND
`
`OFFICE : The Medical Association of Thailand,
`New Pejburi·Rd., Bangkok 10, Tel. 314-4333
`
`EDITOR
`Prasert Thongcharoen
`
`Assistant Editor
`Ratana Eamsobhana
`
`EDITORIAL BOARD
`
`Pongsom Atthasampunna
`Urabala Boonyaprakob
`Wirapong Chatranon
`Hatai Chitanondh
`Vichien Diloksambandh
`Thep Himathongkam
`Dhanyasobhak Kashemsant
`Pornchi Matangkasombut
`Praphan Phanupak
`Anong Piankijakum
`Chawalit Preeyasombat
`Samruay Shuangshoti
`Visith Sitprija
`Charas Suvanwela
`Savanat Tharavanij
`Montri Tuchinda
`Apichati Vichayanrat
`
`ADVISORY BOARD
`
`Thavi Boonchoti
`Suphachai Chaithiraphan
`Kamheang Chaturachinda
`Somwang Danchaivijitr
`Prasit Futrakul
`Direk Israngkul
`Priya Khanjanasthiti
`Prasert Pacharec
`Boriboon Phornphibul
`Ukrist Plengvanich
`Sompone Punyagupta
`Kiija Sindt.vananda
`Prasit Srisomboon
`Vinai Suvatte
`Sommai Toongsuwan
`Atthasit Vejjajiva
`Puangtong Kraiphibul
`
`Suvit Areekul
`Vijit Boonpucknavig
`Thavom Charoonsmith
`Krungkrei Che1ipanich
`Supathana Dejatiwongse
`Sant Hathirat
`Parttraporn Israngkul
`Sophon Kongsamran
`Arun Pausawasdi
`Thada Piamphongsant
`Sakdichai Ponprasert
`Cham Satapanakul
`Stitaya Sirisinha
`Sabiang Srivannaboon
`Sidhi Techakampuch
`Mukd:i Trishnananda
`Preecha Vichitbandha
`
`Quay Ketusinh
`Vikit Viranuvatti
`
`Sood Sangvichien
`Uthai Dhutiyabhodi
`
`Sukhum Bhadrakom
`Natth Bhamarapravati
`
`CIRCULATION MANAGER
`Boonrueng Niyomporn
`
`BUSINESS MANAGER
`Ittipan Charoenpol
`
`3 of 9
`
`

`

`THE JOURNAL OF THE MEDICAL ASSOCIATION OF THAILAND (J. Med. Ass. Thailand)
`is the official journal published monthly (one volume a year) by the Medical Association of
`Thailand.
`
`SUBSCRIPTION RA TES
`
`CORRESPONDENCE
`
`PUBLICATION
`
`- Members of Med. Ass. Thailand
`: no additional charge.
`- Non-members : 400 baht per year (Foreign US. 8 20)
`payable in advance.
`- Medical Students : .100 baht per year payable in advance.
`
`- Single copies and duplicates : 40 baht each (Foreign US. 8 2)
`- Foreign : Postage included. (surface mail)
`
`- All correspondence concerning journal subscriptions, order
`for copies or reprints from the journal, notice of change of
`address, complaints, and advertising should be addressed to
`the Business Manager, Department -of Microbiology, Faculty
`of Medicine, Siriraj_ Hospital (Phone 4110241 ext. 243,
`4113111).
`- All articles and notices for publication, general correspondence,
`and inquiries should be addressed to the Editor, Department
`of Microbiology, Faculty of Medicine, Siriraj Hospital (Phone
`4110241ext. 448, 4113111).
`
`- For the type of material acceptable for this journal, and
`information regarding the processing of manuscripts, proofs,
`read "A Guide for Contributors' which is published in the
`January issue cf the J. Med. Ass. Thailand and may be
`obtained from the Editorial Office.
`
`4 of 9
`
`

`

`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`Incidence of Anemia in Leprosy Patients Treated with Dapsone*
`
`Siripen Puavilai, M.D., ** Saengsuri Chutha, M.D., ** Niwat Polnikom, M.D., **
`Penwadee Timpatanapong, M.D., ** Pariya Tasanapradit, M.D., **
`Somyot Charuwichitratana, M.D., ** Achara Boonthanom, M.D. **
`and Harn Wongwaisayawan, M.D. **
`
`Dapsone is cnmmonly used for the treatment of
`leprosy, but ii is known to have undesirable hematolo(cid:173)
`gical side effects. The most common one is hemolysis
`which occurs in almost every patient taking 200 tn 300
`mg depsone per day. Dosages o.f I 00 mg or less in
`normal healthy persnns and 50 mg or less in healthy
`individuals with glucose-6-phosphale dehydrogenase
`(G-6-PD) deficiency does not cause hemnlysis< 1>.
`Methemng!obin is also common and Heinz body forma(cid:173)
`tion might occur<2>. Leukopenia, agranulocytosis,
`and pseudoleukemia are rare toxic effets of dapsnne<24>.
`
`We have observed several patients treated with
`dapsone 50-100 mg daily who developed anemia inspite
`of nnrmal G-6-PD level. The purpose of this paper
`is tn find out the frequency, and nnset nf anemia in
`leprosy patients treated with dapsone.
`
`Material and Method
`
`One hundred new cases of leprosy patients seen
`at Ramathibodi Hospital during .1979-1983 were
`considered for this study. Patients under 50 kg body
`weight received 50 mg dapsone per day, for those over
`50 kg body weight, 100 mg per day nf dapsone was given.
`
`The hemoglobin (Hb), and hematocrit (Hct),
`glucose-6-phnsphate dehydrogenase
`(G-6-PD)
`level
`were determined before ihe administration of dapsone.
`
`Laboratory tests were done before taking dapsnne
`and at 6 months and one year thereafter. These included
`complete blooo count (CBC), urinalysis, stool examination,
`reticulocyte count, methemoglobin, Heinz body,
`Conmbs' test, blood urea nitrogen (BUN), creatinine,
`
`lactic dehydrogenase (LDH), serum g!utamic oxaloacetic
`transaminase (SGOT), serum glutamic pyruvic transa(cid:173)
`minase (SGOT), total protein, albumin, bilirubin and
`urine hemosiderin pigment. The CBC, reticulocyte count,
`methemoglobin and Heinz body were also determined
`at the 2nd week, and at the 1st, 2nd, 3rd, 9th and 12th
`month after treatment. Of the 100 patients, 43 cases
`who had hemoglobin below 11 g/100 ml with parasitic
`infestation and thnse who could not attend the clinic
`regularly were excluded from the study. A total of 57
`cases were included. The age ranged from 17-68 years .
`The types of leprosy diagnosed in these patients were
`indeterminate in 16 cases, tuberculoid 18 cases, border(cid:173)
`line tuberculoid 8 cases, borderline borderline 7 cases,
`borderline lepromatous 6 cases, and lepromatous leprosy
`2 cases.
`
`Methemoglobin was measured by the method of
`Evelyn and Malloy(5).
`The data was statistically evaluated by Student's
`T test.
`
`Result
`
`There were 51 cases with normal O-6-PD level
`and 6 with G-6-PD deficiency. Of the normal O-6-PD
`group there were 3 I males and 20 females. Anemia
`(hemoglobin dropped one gram per cent of more)
`developed in 40 cases (78.41t/o). These included 25
`males and 15 females. Of these 40 cases, 15 had a drop
`of hemoglobin I g/ 100 ml from the baseline, nine had
`2 g/100 ml drop, 3g/JOO ml drop in 12 and 4 g/ 100 ml
`drop in 4 cases. Significant anemia (P< 0.05) developed
`
`• Supported by The Faculty of Medicine, Research Foundation, Ramathibodi Hospital, Mahidol University,
`Grant Number D 38/1980.
`
`**Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok 10400,
`Thailand .
`
`5 of 9
`
`

`

`Vol. 67 No. 7
`July 1984
`
`16
`
`14
`
`12
`
`Hb
`
`10
`
`8
`
`6
`
`0
`
`Incidence of Anemia in Leprosy Patients Treated with Dapsone
`..
`
`,.
`
`,.
`
`*
`
`405
`
`,.
`
`•
`
`112
`
`2
`Mo!llhs
`
`3
`
`6
`
`9
`
`12
`
`Fig. 1 Demonstration of means and standard deviations of Hb in correlation with
`duration of dapsone administration in 25 male and 15 female patients with
`normal G-6-PD
`*P ( 0.05
`
`*
`
`*
`
`*
`
`*
`
`*
`
`14
`
`12
`
`10
`
`8
`
`6
`
`Hb
`
`0
`
`2
`
`3
`
`6
`
`9
`
`12
`
`Months
`
`Fig. 2 Demonstration of means and standard deviations of Hb in correlation with
`duration of dapsone administration in 5 patients with complete deficiency of
`G-6-PD
`*P ( 0.05
`
`6 of 9
`
`

`

`406
`
`S. Puavilai et al.
`
`J. Med. Ass. Thailand
`
`Table 1. Means ofMethemoglobin in correlation with dosage of dapsone .
`
`Dosage of dapsone
`(mg/day)
`
`Means Methemoglobin
`before treatment(%)
`
`Mea1;_s Methemoglobin
`after treatment(%)
`
`50 (n = 9)
`J00(n=7)
`
`*P ( 0.01
`
`1.33
`
`0.87
`
`0.8
`3.0*
`
`)
`
`between 1 month to 1 year after dapsone administration
`(Fig. I).
`
`Sixteen cases were evaluated for methemoglo(cid:173)
`binemia, significant rise in methemoglobin level was
`detected one month after
`therapy
`in
`those
`taking
`dapsonelQ0mg per day (P < 0.01) but not in those
`who took 50 mg per day (Table I).
`
`Hemolysis, characterized by reticulocytosis and
`increased indirect bilirubin were present in 17 patients .
`Heinz bodies were present in 13 patients. One had
`positive direct Coombs' test.
`
`For the patients with complete deficiency of
`G-6-PD, five in six had a hemoglobin drop of one g
`per cent or more. One had a drop of hemoglobin I g/100
`ml from the baseline, 3 g/100 ml dropped in 3 and 4
`g/ 100 ml dropped in one case. Anemia developed at the
`second week, 3rd, 6th, 9th and 12th month of dapsone
`administration (P < 0.05) (Fig . 2). Hemoiysis charac(cid:173)
`terized by reticulocytosis and increased indirect bilirubin
`were present in five. patients who developed anemia.
`Methemoglobin level did not increase in these patients.
`
`The white blood cell and platelet count, renal
`and liver function tests were all normal during the
`course of treatment. No patient developed significant
`anemia necessitating discontinuation of
`tre~tment.
`
`Discussion
`
`This study demonstrated that in normal G-6-PD
`individuals taking dapsone 50-100 mg per day, significant
`anemia developed in 78.4 per cent of cases. Hemolysis
`was present in 17 out of 51 cases (330Jo) and Heinz
`body positive anemia was detected in 13 of 51 cases
`(25.50Jo). These findings contrasted with the previous
`that
`studies done by De Gowin who demonstrated
`
`normal G-6-PD patients could take 100 mg dapsone per
`day without easily detectable hemolysis<6l. The mechanism
`of dapsone induced hemolysis and Heinz bodies forma(cid:173)
`tion might be due to the ability of dapsone to oxidise
`hemoglobin and reduced glutathione (GSH) despite
`increasd hexnse monophosphate shunt activity, thereby
`causing hemolysis of normal red blood cell; the old
`red blood cells wer<! more affected<7l . Dapsone also
`caused various membrane changes including decreased
`sulfhydryl group activity and lipid peroxidation<8).
`
`Methemoglobin level was significantly increased
`(P < 0.0 I) one month after dapsone administration
`only in the group taking 100 mg per day . This was in
`accordance with the study done by Manfredi who
`found good correlation between the dose of dapsone
`and the level of methemoglobin<9l. The mechanism of
`methemoglobin formation might be due to the toxic
`dapsone derivative, DDS-NHOH (4' amino 4' hydroxy
`amino diphenyl sulfone)(IO-l2) , In the patients studied,
`no one developed signs or sympt oms of cyanosis necessi(cid:173)
`tating discontinuation of dapsone.
`
`In the patients with complete deficiency_ of G-6-PD,
`five in six developed hemolyt ic anemia, but not severe
`enough to necessitate discontinuatio n of treatment.
`Though the number of patients in this group is rather
`small, we believe that patients with complete G -6-PD
`deficiency could take dapsone under close observation.
`
`No patients in the study developed severe anemia
`requiring discontinuation of dapsone. We concluded
`that long-term dapsone therapy is relatively safe at the
`dosage of 100 mg per day or less.
`
`Summary
`
`Fifty-seven patients with different types of leprosy
`treated with dapsone 50-100 mg per day were evaluated
`
`7 of 9
`
`

`

`Vol. 67 No .7
`July 1984
`
`Incidence of Anemia in Leprosy Patients Treated with Dapsone
`
`407
`
`in regard to the frequency, onset and etiology of anemia.
`Fifty-one patients had normal G-6-PD, six patients had
`complete deficiency of G-6-PD. Significant anemia
`developed in 40 cases out of 51 patients with normal
`G-6-PD (P < 0.0•5). The onset of significant anemia
`in this group was one month after dapsone administration
`and continued throughout the course of treatment for
`one year. The methemoglobin level rose significantly
`(P < 0.01) in correlation with the dose of dapsone
`administered. Seventeen patients had hemolysis, 13
`
`had Heinz bodies and one had positive direct Coombs'
`test. Hemolytic anemia developed in 5 out of 6 patients
`with complete deficiency of G-6-PD, but not severe
`enough to necessitate discontinuation of treatment.
`
`Acknowledgement
`
`The authors would like to thank Dr. Phongjan
`Hathirat and Mr. Weerasak Sasanakul for their assistance
`in the measurement of met hemoglobin level.
`
`(Received for publication on January 10, 1984)
`
`REFERENCES
`
`I. De Gowin RL . A review of the therapeutic and
`hemolytic effects of dapsone. Arch Intern Med 1967;
`120: 242-248.
`
`8. Rasbridge MR, Scott GL. The hemolytic action of
`dapsone : changes in the red-cell membrane. Br J
`Hematol 1973; 24 : 183-193.
`
`2. Graham WR, Jr. Adverse effects of dapsone. Int J
`Dermatol 1975; 14: 494-500.
`
`3. LL Col Ognibene AJ. Agranulocytosis due to dapsone.
`Ann Intern Med 1970; 72: 521-524.
`
`4. Levine PH, Weintraub LR. Pseudoleukemia during
`recovery from dapsone-induced agranulocytosis.
`Ann Intern Med 1968; 68: 1060-1065.
`
`5. Dubowski KM. Measurement of hemoglobin deri(cid:173)
`vatives. In : Hemoglobin, its precursors and metabo(cid:173)
`lites. Sunderman FW and Sunderman EW. Jr.
`(Eds.) J.B. Lippincott Co., Philadelphia 1%4: 272-274.
`
`6. De Gowin RL. Studies of sulfone-induced hemolysis.
`Clin Res 1965; 13: 270.
`
`9. Manfredi G, Panfilis GD, Zampetti M, Allegra F.
`Studies on dapsone induced hemolytic anemia.
`I Methemoglobin production and G-6-PD activity
`in correlation with dapsone dosage. Br J Dermatol
`1979; 100: 427-432.
`
`10. Hjelm M and De Verdier GH. Biochemical effects
`of aromatic amines. I Methemoglobinemia, hemolysi~
`induced by 4,4'(cid:173)
`and Heinz bodies formation
`Diaminodiphenyl sulphone. Biochem Pharmacol
`1965; 14: II 19-1128.
`
`11. Kramer PA, Glader BE, Li TK. Mechanism of
`methemoglobin formation by diphenylsulphones.
`Biochem Pharmacol 1972; 21 : 1265-1274.
`
`7. Rasbridge MR, Scott GL. The hemolytic action of
`dapsone : the effect on red cell glycolysis. Dr J
`Hematol 1973;24: 169-181.
`
`12. Scott GL, Rasbridge MR. The in vitro action of
`dapsone and its derivatives on normal and G-6-PD
`deficient red cells. Br J Hematol 1973; 24: 307-317.
`
`8 of 9
`
`

`

`408
`
`S. Puavilai et al.
`
`J. Med. Ass. Thailand
`
`~
`
`..,..
`
`.
`
`v,
`-It
`fll'jflfl1:11r>1JP1flTHU'lltMfll'j mvafln~ 1 '1ttP1iH 1ur-Rhu h r1I,r>'U
`ti"
`.JIii Vv
`V
`v
`YI t vi l 1Jtll '.i '.i fl 1:11 vi 1U U1 II vi
`t C)fl.J
`
`,!
`
`..
`
`..
`
`~
`
`iifrritu w''Jflo, n.v. *, lliW170 fJ't/1, w.v. *, iJiw Wfliim, n.v. *, IWtu')~ nmt'ilmmfl, w.v .•
`mtJ, 11F111z/,::~1;{ w.v. *, fl1Jl1f1 on1i1mf~nn, w.v. *, 1town vwourm, w.v. •
`tlf/:f 1ncy nnhf1tJ7'i'if)J, n. V. *
`
`....
`
`t
`
`"
`
`..,,
`
`t
`
`....
`
`'
`
`....
`
`'l,Wim,111111:: foii,rmluq1.hu hmtllwi::u::,h~ i
`57 fl\\ ~'l.ifonnfm,mi1uu1LLfltJhu'JJm.i'iull:: 50-100
`ijlliinf1JL\\Ld'JJllJfl111Jtl'JJllJnmii.i1111::: fov.mnJ, 1:::u::
`L 1m~Lii.i foiim1~v,i~;nn'l.ifurnL.itJhu 111Jfi~HlL v,~
`'llll~foii.irnluqt11mv,li1d qt11u 51 11uih::.'iun~1m1-
`-ilnvllllHvlfl~Ll! 1m~L\\HU7n~ 1in 6 1lU'JJ1flL5wnuMr1d
`1.iu~uL=rt~ ;nnm1iim:ndl'iu11 40 lu 51 11ui1ih5ui'u~
`du1n~ Lii.ihiimrnv,i~'l.ifuuiu.itJ1-n,lltl1Jjjuu1ht'ity
`
`(P< 0.05) qt11mii.ifoiim1~~~LL~ 1 LiiB\lLL1nVii~'l.ifo
`UlLL!l::Lnflfl!lllm::u:::L1!ll 1 u~'l.ifuu,d 1:::.i1.JLl.JliH1lJ-
`1nllut1'l,-inllltl1~ihtmht'ity (P <0.01) 1.iujjm11Ji1J~t1il'
`lll.J'JJ\llfl'llll~u1i1qt11u'l.ifu 11 11ujjLJj.i hiv..iufl~LLfln,
`13 11ujj'luif1.Jil~, 1 11un~!lLflL1flfJlJULYIH~Li'.lumn
`~tl1U~'JJlflL5wnu~n~1m,-iinvlaHLvlfl~Lll 1m~L\\H 5 L\l 6
`11ULnfl fov.m,~iiflL"flL i'lilflLLfl~LLflnLL~Lil~ULL1 ~l.Jln ilU
`.'iu~Vi~.iu1LL.itJ1'llu
`
`9 of 9
`
`