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International Journal of Risk & Safety in Medicine 20 (2008) 5-36 DOI 10:3223/JRS-2008-0431 IOS Press

Fatal neuropsychiatric adverse reactions to oseltamivir: case series and overview of causal relationships 543-0002 3-2-17 902 E-mail: gec00724nifty.com OP PubMed Web(PMDA) FDA 8 5 14 10 15 5 80 50 8 1) OT OT OCB

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2) OCB 3) 1) 2) (1)CNS delayed neuronal cell damage (2) (3) 3 1 1 Key words: Tamiflu, oseltamivir, adverse drug reaction, sudden death, influenza, animal toxicity, fever, delirium, organ damage, encephalopathy OCB: Oseltamivir carboxylate NAP: New drug approval package() MHLW PMDA [8,69] [9] 2000 (NSAIDs) / [37]

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2002/2003 [8][84] OCB [33,34] 8 10 3 2005 11 [35] 5 3 2005 [35] 3 2007 8 5 8 e-mailPubMed Web PMDA FDA NAP[13-15] 2007 12 10 (1) (2) (3) (4) (5) (6) (7) (8) / (9) (10) OCB (11) OCB (12) (13) (14)

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EpiInfo(version 3-2-2) (NSAIDs) StatDirect 2.1 8 7 1

1 2 3

/ 14 17 2/9 M M M A A A A 75mgx1 75mgx1 2mg/kg 1 2mg/kg 1

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** 37.5 39.2 34.0 ?

4

3/3

M

B 5 39 M

150mg x1

?

A 6 14 M ?* 7 0/10 F

75mg x1

37.5

? (

2mg/kg 1 B 75mg 1 +752

5 6 / 3

8

15

M

4 + 75mg 1

* : ( 6 ) **:

4

7 3 2.2 14 2005 2 4 38.0 39.4 2 37.5 1 75mg 98.5mg 1.5 30 9 9 9 17 2004 2 4 39 1 50mg1 1 39.7 1.5 39.2 1 2 () cm 3 45 50mg 9 2.3 2 9 13kg2005.2 4 38.3 25.5mg 39.2 10 1.5 4050 2 20 2 45

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10 2 55 30 34.0 28 AST/ALT/LDH/CK 13.5kg 2002 12 27 38.5 39.6 50mg 1 55mg4.1mg/kg 14 27.5mg 1 16 16 34 10 1mL(0.1mg) 1mL(1mg) 11 17 15 ( 1361g) + GFAP -Blood-Brain-Barrier 16 41 196mg/dL 16 52 466mg/dL

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39 2005 2 25 1930 37.5B 500mg 1g+ 500mL 2 75mg 100mg 100mg 2 22 , (448g) 500mL 2 2.4 2 1 1 14 3 2005 12 31 39 11 8 8 1 37.5 38.8 80 36.7 2 7 2 15

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2002 3 12 3324g 10 69 10 2002 12 26 71.2cm 9.0kg 2003 1 16 HI 0.1L 38.6 19 37.9 1 20 1 22 38.6 18mg 15 30 16 20 16 45 4mg 10 1.5 38.622 25 38.9 26 22 2 2 10m 22 2 3

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3 5 5 2006 4 MRI Sylvius 2006 EEGspike QTc0.397 2.5 15 39.2 B 75mg 1 2 400mg2007 2 8 38.010 3712 13 10 CT MRI 2 17 23 19 SPECT 23 26 27 18 16 14 13 3 7 3 14

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hCE-1 OCBRo64-0802 -BBB [13-15]OCB A B OCB 79(SD11.6) [13-15] 3.1 (1) AR 2005 6 136 [85] [16] 1 1 -BBB (2) 10 2004 6 [62] 2005 6 69 [16]PMDA 2005 10 8 [77] 2005 11 2006 1 35 [77] 2001 2 2007 5 31 1377 [63,64] 567 211 71 2007 9 30 1432 635 282 2 71

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71 8 5 10 3 20 FDA[27]103 3 95 75 (73) n=58 0.5 =12(21%)1-1.5 =12(21%)2-2.5 =8(14%) 38 (66%) 4 54 93 6 12 2006 10 2005/2006 2846 [63] 11.9 / 10.6 1.1695% 0.90-1.49 6 / / 0.45 1.82 0.38% 2.00 0.005 0.66 0.60 2.34 0.55 2.03 95% 4.02 (1.52-10.53), 5.22 (1.85-14.68), 11.99 (1.57-91.30), 3.89 (1.56-9.62), 3.69 (1.40-9.67) 2 7 FDA[26] 2007 12 25 2006/07 10316 [98] 0.38295% 0.338-0.432p<0.0001 1.37 95% 1.18-1.58

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2.561.83-3.61p<0.000001[39] (3) 71 [64] 13 39 [65] 41 41 1 80 71 9 [38] [29] 1 2 71 80 50 10 18 32 20 2007 84 52 21 13 17 8 3 6 7 [29] 2005 11 50 E-mail 1 53 1 60 8 18 9 2

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1 2 MHLW-B04026215 VP 18mg/ 5 4 3520 34 the latter 85 2 MHLW-B05005388 16.5mg/ 10

-B04036215) -B05005388) 1

(4) 30 34.1

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[86] 37.4 7 100 80 36.7 FDA case#5769078[26] 75mg 15 38.1 37.6 2 (5) 1 [44] A 22 [63,64] ([59,60]) 9 75mg 6 80 8 3 2 10 30 [63,64] 4 [63,64] NAP[13] (6) 80 2

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1 DLST [63,64] DLST [100] (7) 1) (a)(): (b) 2) 5 OCB 1 3) TEN 3.2 (1) 3 [14,15] (a) 7 OP1000mg/kgOT 761mg/kg 24 18 7 18 9 500mg/kg OT 381mg/kg (b) OP 700mg/kg OT 533mg/kg 14 2 1000mg/kg OT 761mg/kg 14 700mg/kg 14 6 1000mg/kg 14 12 1000mg/kg 14 1

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(c) Toxico-Kinetics TK OP 1000mg/kg 7 OP 10 4 56 7 56 8 14 28 10 21 42 28 (2) (3) OT 64 7 OT Cmax42 64 7 OT Cmax OT Cmax 0.81 OCB 42 Cmax 7 Cmax 3.1 7 OCB Cmax OCB Cmax 0.072 0.72 [15,17 17 ] (4) 1020 OP 500mg/kgmg/kg OP 5.3mg/kg/ OT 4mg/kg/ 100 OCB AUC 1020 7 1 (5)[13] 100mg/kg OCB 2 6 3 14 OCB 100mg/kg AUC0- 53.9gh/mL 75mg 1 AUC0-244.6gh/mL 12 20mg/kg AUC0- 8.55gh/mL AUC 2 OP 2000mg/kg 2 10 1 2000mg/kg OP 7 4 2 4

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2 2000mg/kg OP 1000mg/kg OP 500mg/kg 100mg/kg NOAEL Non-observed adverse effects level 500mg/kg NOAEL Cmax AUC 75mg 1 2 AUC0-24 AUC0-24 4 6 7 10 OCB 2 (6) 28 3.3g/kg 50mg/kg Loss of righting reflexLORR [46] CA1 100M (population spike) paired-pulse facilitationPPFM OCB GABA [46][42] OCB 8 75mg OCB 11mg 3.3mg/kg 2025g= 1 3.3

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// ** 11 8 18 9 500mg/kg 700 mg/kg 1000mg/kg 18 9 BBB 4 * * * *

400 2000mg/kg 2 4 2 2 CmaxAUC ) * **

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3.4 [7] [7] 3.5 2000 NSAIDs [37] NSAIDs 30 10 30 10 2002 9 2 NSAIDs 9 15 [21,25,49,50,43,56,78,79,90] ([19,23,45,46,49,52,71, 72,83]) NSAIDs 1 14 NSAIDs NSAIDs Peto 7.5495%CI4.50-12.66p<0.0001I2 inconsistency995%CI0-52.1[36] NSAIDs [81]4 NSAIDs 84 5 6.0 NSAIDs NSAIDs 47.495%CI3.29-1458p=0.0019[36] NSAIDs 2.2595%CI0.19-58.6[36 74 ] [85] 1

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10 2002/2003 [85] 2001 2 2001 3 [ B01-529]60 39.0 75mg2 2 NSAIDs NSAIDs [57] [25] 3.6 2002/2003 6 [84]3 4 1 8 1 7 [84] [99] [7,24] 25mg/kg 100mg/kg [58][52] [95] 1 7

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[99] 1 [99] 3.7 [72] [86] 3435 67 15 52 12 35 80 12 =44.095%CI4.37-1081.12p=0.000018

AB 95%*b p *c

*c: Fisher EpiInfo Version 3-3-2

A. 1 *a(8 %) 11 (92 %) 44.0 (4.37-1081) p=0.000018

B. 8 (37.0 %) 138 (63.0 %) 6.81 (2.68-18.02) p=0.0000018

28 (80%) 7 (20%)

*a: *b: Cornfield 95%EpiInfo Version 3-3-2

PubMed "fever""delirium" Web 4 [48,72,73,88] 226 219

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NSAIDs 39.0 37.081/219 80 28/35 6.81 95%CI 2.68-18.02p=0.0000018 4B38 10.924/219 3.8 (1) - CNS-BBB- [4,7,87] 7 42 64 [15] (2) 5 30 [26]2 2 8 [26] BBB [15] Number Needed to HarmNNH) 25 24 55 3.495%CI:1.9-6.1[14] NNH 15 2 0.895%CI0.47-1.4 (3) [54,45,75][5,54,75]

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AQPs [5,45,51,54,60,75]AQP4 upregulate [54,75] AQP4 [54] (4) Na+ENaC Na+/K+-ATPase active transport ALI ALI ALI AFC [102] (5) 2 [63,64] #576078[26] [63,64]() 1 1 [6][11,12,10,28,98][2,41,42,94] [47][70,83]([64,76])[19,83] [41] (HAPE)[20,76] ENaC Na+/K+-ATPase downregulate [20,76] [20,76] AQP-

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AFC[91] 3.9 2 B04024215 B05005388 3 [3,22,55]acute disseminated encephalomyelitisADEM[23,31] [71,93] apparent life threatening events(ALTE)[61] [22]()[55] [3] 129 30 35[22] 116 25 (24) [22] 12 6 7 CA1 [55] MRI ADEM ADEM [23,31] MRI ADEM 6 [71] gastro-oesophageal reflux disease (GORD)respiratory syncytial virus (RSV) (URTILRTI)

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QT McGovern[61] 11 1.5 - RSV (URTILRTI) QTc 0.397 3.10 OCB Li dbSNP (nonsynonymous single nucleotide polymorphismSNP) R41Q HsNEU2 OCB SNP OCB SNP (R41Q) 9.29 SNP CA1 GABA OCB [46] [46,59] OCB [63,64] NEU1 NEU2 NEU3 NEU4 [96,97] NEU3 PPAR- [101] [103]([66])

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conformation sialoglycoconjugates [66,67,80]([62,73])

T [92] [82,89,92] DIC 2 125mg/kg OCB AUC 6 OCB ) 2 0mg/kg 2 50mg/kg 150mg/kg500mg/kg 75 0,1,1,1,3 0.1.1.2.3 2,1,1,3,5 50mg/kg OCB AUC 1.6 5.8 80 1 2.5 WSN WSN A/WSN/33(WSN) [31] OCB DIC

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3.11 OCB 2006 7 3 13 OCB HPLC-UV HPLC-UV [30] 100ng/g ng/mL OCB OCB 400ng/mL 18300ng/g 75mg max 60ng/mL 2060 24 PLC/MS/MS 1ng/g 3.12adverse reaction EU ICH[43]adverse reaction adverse reaction

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FDA 2007 2 10 OCB 3.13 8 2 1 1 1 2 TK [17]. 2 10 adverse reaction[84] 2 1 [35] 71 [83,64]

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3.14 5 5060 2007 10 1. 1020 AUC / 2. 3. 10 4. delayed neuronal cell damage 5. 5 OCB 1

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6. 2 14 17 2005 11 12 37 [35] 2007 [40]1 44 29 34 [40] [65]- P- [18,68,74] 84 52 5 4 8 10 Graham Dukes [9] E.D. Belay, J.S. Bresee, R.C. Holman, A.S. Khan, A. Shahriari, L.B. Schonberger. Reye's syndrome in the United States from 1981 through 1997. N Engl J Med. 340 (1999) 1377-82. 103 [103] T.Miyagi, K.Kato, S.Ueno and T.Wada. Abberant Expression of Sialidase in Cancer. Trends in Glycoscience Glycotechnology 16 (2004) 371-381.

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