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`JOURNAL Ur” Tflr.‘ MEDICAL
`ASSOClA‘lIUN OF THAXLAND
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`Almirall EXHIBIT 2011
`Almirall EXHIBIT 2011
`Amneal V. Almirall
`Amneal v. Almirall
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`IPR2018-00608
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`fl~Uf133~lil131J3~13 2527- 2528
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`The Council of the Medical Association of Thailand : 1984-1985
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`JOURNAL OF THE MEDICAL ASSOCIATION OF THAILAND
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`THE JOURNAL OF THE MEDICAL ASSOCIATION OF THAILAND (J. Meal. Ass. Thailand)
`is the official journal published monthly (one volume a year) by the Medical Association of
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`4 of 9
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`This material may be protected by Copyright law (Title 27 U.S. Code) J
`
`Inciddnce of Anemia in Leprosy Patients Treated with Dapsone*
`
`Siripen Puavilai, M.D., ** Saengsuri Chutha, M.D., ** Niwat Polnikorn, M.D., **
`Penwadee Timpatanapong, 3I.D.,** Pariya Tasanapradit, M.D., **
`
`Somyot Charuwichitratana, M.D., ** A chara Boonthanom, M.D. **
`and IIarn Wongwaisayawan, M.D. **
`
`Dapsone is commonly used for the treatment of
`
`leprosy, but it is known to have undesirable hematolo-
`
`gical side effects. The most common one is hemolysis
`
`which occurs in almost every patient taking 200 to 300
`
`mg depsone per day. Dosages of 100 mg or less in
`
`normal healthy persons and 50 mg or less in healthy
`
`individuals with glucose-6-phosphate dehydrogenase
`
`(G-6-PD) deficiency does not cause hemolysis(l),
`
`Methemoglobin is also common and Heinz body forma-
`tion might occur(2). Leukopenia, agranulocytosis,
`
`and pseudoleukemia are rare toxic effets of dapsone(2"4),
`
`lactic dehydrogenase (LDH), serum glatamic oxaloacetic
`
`transaminase (SGOT), sernm glutamic pyruvic transa-
`
`minase (SGOT), total protein, albumint 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 those 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.
`
`We have observed several patients treated with
`
`The types of leprosy diagnosed in these patients were
`
`dapsone 50-100 mg daily who developed anemia inspite
`
`indeterminate in 16 cases, tuberculoid 18 cases, border-
`
`of normal G-6-PD level. The purpose of this paper
`
`line tuberculoid 8 cases, borderline borderline 7 cases,
`
`is to find out the frequency, and onset of anemia in
`
`borderline lepromatous 6 cases, and lepromatous leprosy
`
`leprosy patients treated with dapsone.
`
`2 eases.
`
`Material and Method
`
`One hundred new eases 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 of dapsone was given.
`
`The hemoglobin (Hb), and hematocrit (Hct),
`
`glucose-6-phosphate dehydrogenase (G-6-PD) level
`were determined before the administration of dapsone.
`
`Labnratory tests were done before taking dapsone
`and at 6 months and one year thereafter. These included
`
`complete blood count (CBC), urinalysis, stool examination,
`
`reticulocyte count, methemoglobin, Heinz body,
`
`Coombs’ test, blood urea nitrogen (BUN), creatinine,
`
`Methemnglobin was measured by the method of
`(5)
`Evelynand Malloy .
`
`The data was statistically evaluated by Student’s
`
`T test.
`
`Result
`
`There were 51 cases with normal G-6-PD level
`
`and 6 with G-6-PD deficiency. Of the normal G-6-PD
`
`group there were 31 males and 20 females. Anemia
`
`(hemoglobin dropped one gram per cent of more)
`
`developed in 40 cases (78.4Ve). These included 25
`
`males and 15 females. Of these 40 cases, 15 had a drop
`
`of hemoglobin 1 g/100 ml from the baseline, nine had
`
`2 g/100 ml drop, 3g/100 ml drop in 12 and 4 g/100 ml
`
`drop in 4 cases. Significant anemia (P<~ 0.05) developed
`
`* Supported by Tile Faculty of Medicine, Research Foundation, Ramathibodi Hospital, Mahidol University,
`Grant Number D 38/1980.
`
`**Department of Medicine, Faculty of Medicine, Ramathibodi ttospital, Mahidol University, Bangkok 10400,
`
`Thailand.
`
`"
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`Vol. 67 No. 7
`July 1984
`
`Incidence of Anemia in Leprosy Patients Treated with Dapsone
`
`405
`
`Hb
`
`10,
`
`6
`
`1/2
`
`I
`
`i
`2
`Months
`
`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
`
`1
`
`14
`
`10
`
`8.
`
`6-
`
`Hb
`
`0
`
`I/2 1
`
`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
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`406
`
`S. Puavilai et al.
`
`J. Med. Ass. Thailand
`
`Table 1. Means of Methemeglobin in correlation with dosage of dapsone.
`
`Dosage of dapsone
`(mg/day)
`
`Means Methemoglobin Means Methemoglobin
`after treatment (%)
`
`before treatment (%)
`
`50 (n = 9)
`
`100 (n = 7)
`
`*P ( 0.01
`
`1.33
`
`0.87
`
`0.8
`
`3.0*
`
`between 1 month to 1 year after dapsone administration
`
`normal G-6-PD patients could take 1(30 mg dapsone per
`
`(Fig. 1).
`
`day without easily detectable hemolysis(6). The mechanism
`
`of dapsone induced hemolysis and Heinz bodies forma-
`
`Sixteen cases were evaluated for methemoglo-
`
`finn might be due to the ability of dapsone to oxidise
`
`binemia, significant rise in methemoglobin level was
`
`hemoglobin and reduced glutathione (GSH) despite
`
`detected one month after therapy in those taking
`
`increasd hexose mnnophosphateshunt activity, thereby
`
`dapsonel00mg per day (P ’(0.01) but not in those
`who took 50 mg per day (Table 1).
`
`causing hemolysis of normal red blood cell; tile old
`
`red blood cells wer~ more affected(7). Dapsone also
`
`Hemolysis, characterized by reticuIocytosis and
`
`increased indirect bilirubin were present in 17 patients,
`
`Heinz bodies were present in 13 patients. One had
`
`positivedireet Coombs’ test.
`
`caused various membrane changes including decreased
`, Io (8).
`sulfhydryl group activity and lipid perox’dat" n
`
`Methemog!obln level was significantly increased
`
`(P "~ 0.C l) one month after dapsone administration
`
`For the patients with complete deficiency of
`
`only in the group taking 100 mg per day. This was in
`
`G-6-PD, five in six had a hemoglobin drop of one g
`
`accordance with the study done by Manfredi who
`
`per cent or more. One had a drop of hemoglobin 1 g/100
`
`found good correlation between the dose of dapsone
`
`ml from the baseline, 3 g/100 ml dropped in 3 and 4
`
`and the level of methemoglobin(9). Tile mechanism of
`
`g/100 ml dropped in one case. Anemia developed at the
`
`methemoglobin formation might be due to the toxic
`
`second week, 3rd, 6th, 9th and 12th month of dapsone
`
`dapsone derivative, DDS-NHOH (4’ amino 4’ hydroxy
`
`administration (p ,~ 0.05) (Fig. 2). Hemolysis charac-
`
`amino dlphenyl sulfone)(10"12). In the patients studied,
`
`terized by reticulocytosis and increased indirect bilirubin
`
`no one developed signs or symptoms of cyanosis necessi-
`
`were present in five patients who developed anemia,
`
`tating discontinuationofdapsone.
`
`Methemoglobin level did not increase in these patients.
`
`In the patients with complete deficiency of G-6-PD,
`
`The white blood cell and platelet count, renal
`
`five in six developed hemolytic anemia, but not severe
`
`and liver function tests were all normal during the
`
`enough to necessitate discontinuation of treatment.
`
`course of treatment. No patient developed significant
`
`Though the number of patients in this group is rather
`
`anemia necessitating discontinuation of treatment,
`
`small, we believe that patients with complete G-6-PD
`
`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 (33%) and Heinz
`
`body positive anemia was detected in 13 of 51 cases
`
`deficiency could take dapsone under close observation.
`
`No patients in the study developed severe anemia
`
`requiring discontinuation of dapsnne. We concluded
`
`that long-term dapsone therapy is relatively safe at the
`
`dosage of 100 mg per day or less.
`
`Summary
`
`(25.507"0). These findings contrasted with the previous
`
`Fifty-seven patients with different types of leprosy
`
`studies done by De Gowin who demonstrated that
`
`treated with dapsone 50-100 mg per day were evaluated
`
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`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,
`
`had Heinz bodies and one had positive direct Coombs’
`
`Fifty-one patients had normal G-6-PD, six patients had
`
`test. Hemolytic anemia’developed in 5 out of 6 patients
`
`complete deficiency of G-6-PD. Significant anemia
`
`with complete deficiency of G-6-PD, but not severe
`
`developed in 40 cases out of 51 patients with normal
`
`enough to necessitate discontinuation of treatment.
`
`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
`
`Acknowledgement
`
`one year. The mcthemoglobin level rose significantly
`
`The authors would like to thank Dr. Phongjan
`
`(P ~ 0.01) in correlation with the dose of dapsnne
`
`Hathirat and Mr. Weerasak Sasanakul for their assistance
`
`administered. Seventeen patients had hemolysis, 13
`
`in the measurement ofmethemoglobinlevel.
`
`(Received for publication on January 10, 19841
`
`REFERENCES
`
`1. De Gowin RL. A review of the therapeutic and
`
`8. Rasbridge MR, Scott GL. The hemolytic action of
`
`hemolytic effects of dapsone. Arch Intern Med 1967;
`
`dapsone : changes in the red-cell membrane. Br J
`
`120 : 242-248.
`
`Hemato11973; 24 : 18J-193.
`
`2. Graham WR, Jr. Adverse effects of dapsone. Int J
`
`9. Manfredi G, Panfilis GD, Zampetti M, Allegra F.
`
`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-
`
`vatives. In : Hemoglobin, its precursors and metabo-
`
`lites. Sunderman FW and Sunderman EW. Jr.
`
`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, hemolysis
`
`and Heinz bodies formation induced by 4,4’-
`
`Diaminodiphenyl sulphone. Biochem Pharmacol
`
`1965; 14: 1119-1128.
`
`(Eds.) J.B. Lipplncott Co., Philadelphia 1964 : 272-274.
`
`11. Kramer PA, Glader BE, Li TK. Mechanism of
`
`6. De Gowin RL. Studies of sulfone-induced hemolysis,
`
`Clin Res 1965; 13 : 270.
`
`methemoglobin formation by diphenylsulphones.
`
`Biochem Pharmaco11972; 21 : 1265-1274.
`
`7. Rasbridge MR, Scott GL, The hemolytic action of
`
`12. Scott GL, Rasbridge MR. The in vitro action of
`
`dapsone : the effect on red cell glycolysls. Br 3
`
`dapsone and ils derivatives on normal and G-6-PD
`
`Hematol 1973; 24 : 169+181.
`
`deficient red cells. Br J Hematol 1973; 24 : 307-317.
`
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