補遺 A

A A

X X X 2 X 3X 2K i1 (nM)X 2K i2 (nM)X 3K i1 (nM)X 3K i2 (nM)1 538 2730 691 45502 2699 1050 2.0 1813 578 14.4 141 104004 20 100 10.7 7.95 2100 3.1 281 286 7.5 8.4 44 2.87 3.11 3.76 1.94 1.93K i1 K i2

X mmHgSHR a X1mL/kg 12 7 14X25mg/kg 12 7 14SHR 53mg/kg Xp0.05 p0.01 s.e.m.aSHR5

X X210 30mg/kg mg/kgC maxng/mLT maxhAUC 0-tng.h/mLAUC 0-infng.h/mL2 10 30 2 10 304.9 20.4 30.7 5.5 12.9 28.60.8 0.4 0.3 0.4 0.5 0.321.6 80.5 267 33.3 80 29828.3 112 297 40.2 90 3273X [ 14 C]X mg/kg * 2.8 88.17.4 5.50.7 93.66.98.8 89.44.7 6.91.4 95.33.4168 S.D.n5* 22.1%21.7%

X[ 14 C]X 1.75mg/kg ng equiv.*/g 1 6 24 48 72 105 96.6 2.34 2.34 3.65 142 175 3.12 ND ND 656 49.2 14.3 9.63 ND 359 31.5 ND ND ND 116 9.37 ND ND ND 124 28.9 4.69 ND ND 490 44.0 10.2 6.25 5.47 105 26.6 ND ND ND 1280 651 21.6 13.3 9.63 570 2470 39.3 12.0 ND 875 380 133 87.7 64.6 234 59.1 7.55 ND ND* 1gX ngN5ND

X [ 14 C]X mg/kg 1.75 61.39.3 30.34.1 - 95.25.01.75 57.43.8 37.03.4 - 95.21.52 72.30.8 26.91.9 - 99.51.120 23.56.3 0.50.2 76.05.9 1000.8220 67.19.0 24.85.0 - 93.36.8 Wistar168S.D. n5

XXAUCmg/kg/dayC maxng/mLngh/mL#0.48$ 36.7 557 X 8.8 68.9 (1.9)* 72.7 (0.2)* Y21.9 267 (7.3)* 207 (0.5)*43.8 430 (11.7)* 325 (0.7)* 50 479 (13.0)* 1580 (2.8)* Z 1.5 5.58 (0.2)* 15.9 (< 0.1)* V5 24.8 (0.7)* 69.3 (0.1)*15 184 (5.0)* 511 (0.9)*6014113# AUC 0-6AUC 0-tAUC 0-tx2450kg 1*

XLeydig 3 mg/kg 30 mg/kg 100 mg/kgx/50x/50x/50x/50 x/50x/50x/50x/50 x/50x/50x/50x/50 * x/50x/50x/50x/50*

2.3.32.3.3.1 2.3.3.2 *2.3.3.3 *2.3.3.4 2.3.3.5 2.3.5 2.3.5.1 2.3.5.2 *2.3.5.3 2.3.5.4 2.3.5.5 2.3.5.6 2.3.5.7 2.3.5.8 2.3.5.9 In Vivo2.3.5.10 In Vitro2.3.5.112.3.5.122.3.5.132.3.5.142.3.5.152.3.5.16 2.3.7 2.3.7.1 2.3.7.2 2.3.7.3 2.3.7.4 2.3.7.5 2.3.7.6 2.3.7.7 2.3.7.8 In Vitro 2.3.7.9 In Vivo 2.3.7.10 2.3.7.11 2.3.7.12 2.3.7.13 2.3.7.14 2.3.7.15 a2.3.7.16

2.3.7.17 *a2.3.7.15

2.3.3.1 : (1) (3) (4) Vol.. Page(2) : (1) (INN)(2)CTD GLP (3)CTD (4)(

2.3.3.4 (1) : (2)a / (mg/kg) / GLP (3) : (1)(2) (INN)(3)(a -

2.3.5.1 : (1) (2) (3)Vol..Page : (1) (INN).(2)CTD GLP (3)CTD

2.3.5.3 : : CTD (4) (/) / / (mg/kg) (2)PK : : (3) : (1) (INN)(2) , 14 C-HPLC, LSC(3) , , , , , (4)

2.3.5.4 : :[ 2.3.5.3 ]

Format A2.3.5.5 : :CTD : Vol.. Page . : (/) / : : / : : (mg/kg): : : : / (1) (2) (3) (4) (5) t 1/2 :

2.3.5.5 : :CTD : Vol.. Page . : (/) / : : / : : (mg/kg): : :/ :C t / conc. T/P 1) Conc. T/P 1) time AUC t 1/2 :1) [ ]/[ ]

2.3.5.6 : : :, : % CTD Vol.. Page :

2.3.5.7 : : CTD : Vol.. Page . : / : / : : (mg/kg):: : (hr) / () (3): (3): :CTD : Vol.. Page . : / : : / : : (mg/kg):: : [hr] : : : / : : :

Table 2.3.5.7 (INN); , ,

2.3.5.8 : :

2.3.5.9 : In Vivo : (/) / : : / : : (mg/kg): : :% CTD M1 M2 Vol. Page ::

2.3.5.10 : In Vitro :CTD : Vol.. Page . : :M-1M-2 ::

2.3.5.11 : :()

2.3.5.12 : / :CTD : Vol.. Page . :: . : : :

2.3.5.13 : : (/) / (3) / (mg/kg) (4) 0 - T hrCTD : (2) : (1) (INN)(2) , , , , , (3)(4)

2.3.5.14 : :[ 2.3.5.13 ]

2.3.5.15 : :CTD : Vol.. Page . : : : :

2.3.5.16 : :CTD : Vol.. Page . : : : :

2.3.7.1 : (1) / (mg/kg a ) (3)GLP Vol.. Page (2) : (1) (INN)(2)CTD (3)CTD a - NOAEL

2.3.7.2 : (1) (2) (mg/kg) (3)GLP Vol.. Page : (1) (INN)(2)CTD (Section 3, )(3)CTD

2.3.7.3 : (1)(2) : (1) (INN)(2)/

2.3.7.4 : (1). (%) ( ) :(2) (3) : (1) (INN)(2)(3)

2.3.7.5 (1) : (2) / / (mg/kg) (mg/kg) (mg/kg) : (1)CTD (2) (INN)

2.3.7.6 (1) : (2)a / ( / ) (mg/kg) (mg/kg) : (1)CTD ICH M3 GLP (2) (INN)________a - No Observed Adverse-Effect Level

2.3.7.7 (1) (2) : : (3) / : : .: : CTD : Vol.. Page: : GLP : / : : : (mg/kg/)0 ( )M:: AUC ( ) (4) (5) (% a ) (% a (5))(5) ( )F: M: F: M: F: M: F:- + ++ +++ (6)(7) * - p

2.3.7.7 (1) . (mg/kg/)0 ( )M: F: M: F: M: F: M: F: a (%)(9): (8)- (7) * - p

Table 2.3.7.7 (1): 2.3.7.7A, 2.3.7.7B, 2.3.7.7C (2)ICH M3 (3) (INN)(4) AUC, Cmax, (5)(6)(7)(8)(9)

2.3.7.8 (1) In Vitro : : (2): : : : CTD : Vol.. Page: / : GLP : : : : : : : : (3)(4) : (1): 2.3.7.8A,2.3.7.8B, (2) (INN)(3)(4)(5)(5) * - p

2.3.7.9 (1) In Vivo : : (2) : : . / : : CTD : Vol.. Page : : GLP :: / : : / : : / : : : (mg/kg) : (1)2.3.7.9A2.3.7.9B(2) (INN)(3)(3) * - p

2.3.7.10 (1) : : (2) / : : .: : CTD : Vol.. Page: / : GLP : :: (3) : (mg/kg/): AUC ( ) (4) / (%) (% a )(5) (% a )0 ( ) (6) * - p

2.3.7.10 (1) . (mg/kg/)( ) 0 ( ) :(7):: : : : : : : : : :– - * - p

2.3.7.10 (1): 2.3.7.10A, 2.3.7.10B, (2) (INN)(3)ICH S1C (4) AUC, Cmax, Css, (5)(6)(7)/

2.3.7.11 (1) : (2) /( / ) mg/kg : (1)CTD ICH M3 GLP

2.3.7.12 (1) - : : (2)(3) :ICH 4.1.1 :: . / : : (8) : CTD : Vol. Page: : GLP :: : : / : :F 0 :F 0 :F 1 : (mg/kg/)0 ( ): AUC ( ) (4) (% a ) (% a )(5)- + ++ +++ (6)(7) * - p

2.3.7.12 (1) . (mg/kg/)0 ( ): AUC ( ) (4)(% a ) (% a )(% a ) (% a ) /14 - + ++ +++ (6)(7) * - p

Tables 2.3.7.12, 2.3.7.13 2.3.7.14 (1): 2.3.7.12A, 2.3.7.12B, 2.3.7.13A, 2.3.7.13B, (2) (INN)(3)(4) AUC, Cmax (5)(6)(7)(8)01

2.3.7.13 (1) - : : (2)(3) :ICH 4.1.3 : . : (8) / : : CTD : Vol.. Page: : GLP :: / : : :F 0 :F 1 : (mg/kg/) / : : AUC () (4)0 ( ) (% a ) (% a )(5)- + ++ +++(6) G = (7) * - p

2.3.7.13 (1) . (mg/kg/)0 ( ) : (g) :( )- * - p

2.3.7.14 (1) - : : (2)(3) :ICH 4.1.2? : . : (8) / : : CTD : Vol.. Page / : GLP :: / : : :F 0 :F 1 :F 1 : (mg/kg/)0 ( )F 0 :: AUC ( ) (4) (% a ) (% a ) (% a ) (% a ) ( )(5)- + ++ +++(6) G = (7) * - p

2.3.7.14 (1) . (mg/kg/)0 ( )F 1 :( )F 1 :( ) / /a (g)/b (g) (% c ) - + ++ +++ (6) (7) *- p

2.3.7.14 (1) . (mg/kg/)0 ( )F 1 :( )F 2 :a (g)(g)(% b ) (% b )( ) / (g) (% )- + ++ +++ (6)(7) : *- p

2.3.7.14 (1) . (mg/kg/)0 ( )F 1 :( )a (g)(g)(% b ) (% ab )( ) : F 2 / / /a (g)- + ++ +++(6)(7) * - p

2.3.7.15 (1) : (2) / (mg/kg) : (1)(2) (INN)

2.3.7.16 (1) : (2) / (mg/kg) : (1)(2) (INN)

2.3.3.1 : Curitol Sodium Vol..PageVZV In vitrosponsor Inc.VZV In vitrosponsor Inc.HSV In vitrosponsor Inc.In vitrosponsor Inc.CMV sponsor Inc.VZV ICR sponsor Inc.SVV 954019540295406954089541195420111111120304555100; In vitro sponsor Inc. 95602 1 200a , , , , i.v.sponsor Inc.sponsor Inc.957039570622175HIV AZT T In vitro sponsor Inc. 95425 2 200a -GLP

2.3.3.4 : Curitol Sodium / (mg/kg)a / GLP CD-1 0, 10, 50,250, , CD-1 0, 10, 50, ,25010M6M92201(10 mg/kg) , , , ,92205 (50 mg/kg) ( ), , , ( ) 0, 3, 10, 30 3M 92210()30 mg/kg , a -

2.3.5.1 : Curitol Sodium Vol..Page , i.v. sponsor Inc. , i.v. sponsor Inc. , i.v. sponsor Inc.93302933049330611112550sponsor Inc.sponsor Inc. , , , , In vitro sponsor Inc. , , / /sponsor Inc.933079330893311933121111100125150200sponsor Inc.sponsor Inc.934029340711250300 , i.v. sponsor Inc. , i.v. sponsor Inc. , i.v. sponsor Inc.93302933049330611112550aAZT sponsor Inc. 94051 1 350a -GLP

2.3.5.3 : : Curitol Sodium 95104 CTD Volume 1, Page 258 (/) / 4M 3M 4F 2M 6M / 10% 10% 10% (mg/kg) 15 8 5 5 4 mg TRA a MM-180801 MM-180801 MM-180801 MM-180801 LSC HPLC HPLC HPLC HPLCPK :Tmax (hr) 4.0 1.0 3.3 1.0 6.8Cmax (ng/ml or ng-eq/ml) 2,260 609 172 72 8.2AUC (ng or ng-eq x hr/ml) 15,201 2,579 1,923 582 135( – hr) (0-72) (0-24) (0.5-48) (0-12) (0-24)T 1/2 (hr) 10.6 3.3 9.2 3.2 30.9( – hr) (7-48) (1-24) (24-96) (1-12) (24-120) : , , , 30 5 a - , 14 C

2.3.5.5 : : Curitol SodiumCTD : Vol. 21 Page 1 . 95207 (/) / 3M/ / / (mg/kg) 1014 C2x10 5 Bq/mg0.25, 0.5, 2, 6, 24, 96, and 192 hr / 0.25 0.5 2 6 24 t 1/2? 9.2 3.7 1.8 0.9 0.1 16.5 7.1 3.2 1.6 0.2 0.3 0.3 0.2 0.1 nd 9.6 14.1 7.3 2.9 0.1 73.0 54.5 19.9 12.4 3.2 9.6 13.2 4.9 3.8 0.6 0.3 0.5 0.6 0.5 0.1 1.0 1.2 0.8 0.3 nd : , , , , , ,… .nd = .

2.3.5.5 : : Curitol SodiumCTD : Vol.. 21 Page 1 . 95207 (/) / 3M/ / / (mg/kg) 1 :/ /HPLC10 min, 1, 4, 8, 24, 48, 96, and 168 hrC 1hr / Conc. T/P 1) conc. T/P 1) AUC t 1/2? 1.4 0.08 0.44 22 48 57.3 37.3 4.5 6 1.85 92.5 48 290 51.7 2.8 0.20 1.07 53.5 48 126 36.3 6.5 8.6 3.5 175 48 410 46.9 :1) [ ]/[ ]

2.3.5.6 : : Curitol SodiumIn vitro , % -CTD Vol..Page 1 – 100M 82.1 - 85.4 95301 21 150 1 – 100M 83.5 - 88.2 95301 21 150 1 – 100M 75.2 - 79.4 96-103-03 45 1 :

2.3.5.7 : : Curitol SodiumCTD : Vol.. 22 Page 1 . 95702 : / : 14 19 / 3 / : / : (mg/kg): 5: , 14 C : LSC (hr) 14 days/30 min 14 days/24 hr 19 days/30 min 19 days/24 hr / () 12.4 0.32 13.9 0.32 3.8 0.14 3.3 0.32 0.07 0.04 0.04 0.13 0.54 0.03 0.39 0.10 : , , , , CTD : Vol.. 22 Page 102 . 95703 : / : day 7/3 : / : / : (mg/kg): 5: , 14 C : LSC [hr] 1 2 4 6 8 24 : : 0.6 0.8 1.0 1.1 1.3 0.4 : 1.5 1.4 1.2 0.8 0.6 0.1 / : 0.40 0.57 0.83 1.4 2.2 4.0 :

2.3.5.9 : In Vivo : Curitol Sodium (/) / : : 4M : 3F : 8M : / : : / : : 75-mg : : * : * : (mg/kg): : 5 mg/kg : 5 mg/kg : 75 mg : 14 C : 2 x 10 5 Bq/mg% of CTD or Period M1 M2 Vol.Page0.5 hr0-24 hr0-4 hr--2.128.0-87.20.615.5-6.1n.d.7.2-3.40.25.1-9507626261010.5 hr0-24 hr0-4 hr--6.632.0-92.86.428.5-n.d.n.d.2.8-7.2n.d.n.d.-95082 26 3011 hr0-24 hr---5.5--87.52.4--trace2.9--12.5n.d.--CD-102 42 1* - n.d. -

2.3.5.13 : : Curitol Sodium (/) / 4M 4M 3M 3M / (mg/kg) 10 5 10 5 TRA a TRA a TRA a TRA a LSC LSC LSC LSC 0 - 24 hr0 - 48 hr0 - 72 hr0 - 96 hr263031315765656783959798222728296369707085969899202526262965737449909910023282929427872736596101102 95102 95156CTD Volume 20, Page 75 Volume 20, Page 150 :a - ; , 14 C

2.3.5.14 : : Curitol Sodium (/) / 4M 4M / (mg/kg) 10 5 TRA a TRA a LSC LSC 0 - 2 hr37 - 37 75 - 750 - 4 hr50 - 50 82 - 820 - 8 hr62 - 62 86 - 860 – 24 hr79 9 86 87 11 980 – 48 hr83 10 93 88 11 99 95106CTD Volume 20, Page 150a - ; , 14 C

2.3.7.1 : Curitol Sodium (mg/kg a )GLP Vol. Page3.1 CD-1 --0, 1000, 2000, 50000, 100, 250, 500Sponsor Inc.CRO Co.9604696047111100Wistar --0, 1000, 2000, 50000, 100, 250, 500Sponsor Inc.CRO Co.9605096051112003003.2 CD-1 3 0, 62.5, 250, 1000, 4000,7000CRO Co.9401821Wistar 2 0, 1000, 2000, 40002 0, 500, 1000, 20000, 200, 600, 18003 0, 100, 300, 9006 0, 10, 40, 1001 0, 5, 20, 509 0, 500, 10005 Sponsor Inc.Sponsor Inc.Sponsor Inc.Sponsor Inc.Sponsor Inc.Sponsor Inc.CRO Co.9401994007942149500194020960419400833456781200111113.3 S.typhimuriumE. coliIn Vitro-0, 500, 1000, 2500,5000 mcg/plateSponsor Inc.9671891 In VitroWistar -3 0, 2.5, 5, 10, 20, and 40mcg/ml0, 1000, 2000CRO Co.Sponsor Inc.a - NOAEL( )976349603799100200

2.3.7.1 : Curitol Sodium / (mg/kg)GLP Vol. Page CD-1 21 0, 0, 25, 100, 400Wistar 24 0, 0, 25, 100, 400CRO Co.Sponsor Inc.9501295013101211Wistar a0, 5, 30, 180Wistar F: G6 - G15 b 0, 10, 100, 1000NZW F: G6 - G18 b 0, 1, 5, 25F: G6 - L21 b 0, 7.5, 75, 750Wistar CRO Co.Sponsor Inc.CRO Co.Sponsor Inc.96208942119702895201141516171111NZW 1 0, 15 mg Sponsor Inc. 95015 18 1 3 0, 5 mg CRO Co. 97012 18 20Wistar 2 0, 1000, 2000 Sponsor Inc. 97025 18 200________a - : - 7b - G = L =

2.3.7.2 : Curitol Sodium (mg/kg) GLP Vol.Page62.5, 250, 1000, 4000, 7000500, 1000, 2000100, 300, 90010, 40, 1005, 20, 5025, 100, 40025, 100, 4001, 5, 259401894007950019402096041950129501397231235671012161200111111

2.3.7.3 : Curitol Sodium(mg/kg)15102025405062.51002503004005009001000200040007000 AUC (mcg-hr/mL)a10 12 6 835401208152,1034,9758,24140481355701,8703,9877,680b c25 d , 20 e689012520025032727 d , 22 e72851201902403213410101240b 925273f3__________a - b - c - d - e - f - 147-007

2.3.7.3 : Curitol Sodium100010010HumansMale MiceFemale MiceMale RatsFemale RatsDogs10.10.01 0.1 1 10 100Dose (mg/kg), 1, 2.5, 5 mg OD MM-180801AUC 24

2.3.7.4 : Curitol Sodium. (%) A B Ca : >95 0.1 0.2 0.3LN125 98.2 0.1 0.1 0.2 94007940089671894NA103 99.1 0.2 0.1 0.2 960469605094214940209763495NA215 97.3 0.1 0.3 0.1 960479605196037942119702895NB003 94.6 0.2 0.3 0.4 940199701296NB101 99.0 0.4 0.1 0.0 94018950019500295012950139620895015--Ames In Vitro 1 a - %.

2.3.7.5 : Curitol Sodium / ( /) (mg/kg) / (mg/kg) (mg/kg) CD-1 ()0,1000,2000,500010M10F50005000>50002000: 960465000: , , ()0,100,250,50010M10F250250>2502000250

2.3.7.6 : Curitol Sodium / / (mg/kg) / (mg/kg) aCD-1 3 0, 62.5,250, 1000,4000,700010M, 10F M:4000F: 10004000: ; 94018 /7000: 4M 6F / ; ; Wistar 2 0, 1000,2000,40005M, 5F10002000: 940194000: 2M 1F 2 ()0, 500,1000,20005M, 5F10002000: ; 94007 5 0, 500, (CMC )10001M, 1F

#12.3.7.7A : MM-180801: : Curitol Sodium / : Wistar : 3 . 94214: 5 : 1 CTD : Vol. 4 Page 1: 1994 1 15 : / : GLP : : : 200 mg/kg/day (mg/kg/)M:30: AUC (mcg-hr/mL):Day 1-Day 28-Day 90- 0 (% a )394 g (% a )20.4 g- , , - , , --0 ( ) 200 600 1800F:30---0244 g17.2 g----M:20305250000----F:202847510-1-1----M:201301451600-10*-1----F:201251401480-11*-8*+---M:303284005110-25**-30**++---F:303023804750-45**-50**++++++-- + ++ +++ Dunnett's Test: *- p

#12.3.7.7A . 94214 (mg/kg/)0 ( ) 200 600 1800 (g/dl) (10 6 /mm 3 )MCHMCHC (10 3 /mm 3 )M:3015.88.1--846F:3015.0-2234799M:2015.77.9--825F:2014.9-2134814M:2015.88.1--914F:2014.6-2234856M:3014.0*7.4*--931*F:3013.1*-19*30*911* (IU/L) (g/dl)(mg/dl)ALT(IU/L)AST(IU/L) (mg/dl) (mEq/L) (mEq/L)0.7-9667880.18-9.30.76.7-56920.2010.7-0.7-8660*960.17-9.30.76.6-52900.2010.8-0.7-9055*87*0.18-9.30.76.6-47*84*0.2010.8-1.1*-105*53*85*0.22**-8.2*1.1*5.0***-58930.26**9.8**- (mg/dl)PH (mg/dl) (g/dl)2607.5--49-0181027.5--34-0181237.2--54-2016126*6.3**--22*-98**12*- Dunnett's Test: *- p

#12.3.7.7A . 94214 (mg/kg/) b (%) : : : : : (% a ) b (%)M:303.01 g15.9 g2000200000-10422 g3.24 g0 ( ) 200 600 1800F:301.75 g8.01 g2000200000-10265 g1.81 gM:20002000200000-0--F:20+5*+12000200000-0--M:20+1+10*2000200000-0--F:20+8**+12*2051206602-0--M:30+12**+12*2011203122-10-10*+8*F:30+20**+20**2024204049-10-20**+10- Dunnett's Test: * - p

#22.3.7.7B : MM-180801: : Curitol Sodium / : : 1 . 94020 : 5-6 : CTD : Vol. 6 Page 1: 1994 2 2 : / : Gelatin GLP : : . : 10 mg/kg (mg/kg/)M:3: AUC (mcghr/ml):Day 1-Day 28-0 ( ) 10 40 100F:3--M:354F:365M:3108F:31211M:34035F:34845 (% a ) :( )ALT(IU/L): Week 2 Week 409.8 kg----222509.2 kg----252700----242600----27250-1----21230-19**----242500+---48*54*0-18**++---69**84**- + ++ +++ Dunnett's Test: * - p

#22.3.7.7B . 94020 (mg/kg/)M:3a (%)339 g-3 : 0 -0 ( ) 10 40 100F:3337 g-30-M:3+1-30-F:3-1-30-M:3+17**-30-F:3+16**-30-M:3+23**-32-F:3+21**-33-- Dunnett's Test: * - p

#12.3.7.8A In Vitro : MM-180801: Salmonella E. Coli Ames : Curitol Sodium: : 2 . 96669 : S. typhimurium E. coli : 3 CTD : Vol. 10 Page 211: Arochlor-S9, 7.1% / : - : : DMSO : DMSO GLP : : 48 hr. : 1996 : . : .(mcg/plate)Assay #1(Mean ±SD)TA 98 TA 100 TA 1535 TA 1537 WP2 uvrA DMSO MM-1808012-NitrofluoreneSodium azide9-AminoacridineMMS100 mcl/plate312.5625125025005000 a211002.5 mcl/plate24 ± 924 ± 632 ± 930 ± 427 ± 530 ± 3696129 ± 4128 ± 11153 ± 9152 ± 12140 ± 6137 ± 2154215 ± 412 ± 49 ± 29 ± 39 ± 315 ± 14684 ± 24 ± 28 ± 29 ± 25 ± 17 ± 251517 ± 314 ± 217 ± 518 ± 419 ± 113 ±4573 DMSO MM-1808012-Aminoanthracene100 mcl/plate312.5625125025005000 a2.51027 ± 631 ± 430 ± 133 ± 235 ± 831 ± 41552161 ± 12142 ± 8156 ± 15153 ± 13160 ± 4153 ± 5148712 ± 512 ± 517 ± 213 ± 310 ± 29 ± 42145 ± 14 ± 29 ± 58 ± 28 ± 27 ± 16121 ± 817 ± 323 318 ± 319 ± 517 ±4366a -

#22.3.7.8B In Vitro : MM-180801: : Curitol Sodium : : 1 . 96668 : : 2 CTD : Vol. 10 Page 245: Arochlor-S9, 5% / : 100 : : DMSO : DMSO GLP : :S9 24 ; 5 : 1996 S9 24 . : : S9 10 20 µg/ml, S9 50 200 µg/ml (mcg/ml)Cytotoxicity a(%)Aberrant Cells % Abs / CellTotal polyploidcellsDMSO MM-180801-2.551020100785936322.03.04.016.5**35.0**0.020.030.050.200.5543423MITOMYCIN0.105238.5**0.645DMSOMM-180801-2.51050200100918880434.04.54.59.5*34.0**0.040.050.050.100.6633243CYCLOPHOSPHAMIDEDunnett's Test: * - p

#12.3.7.9A In Vivo : MM-180801: : Curitol Solution : : . : 96683 / : Wistar : 24 CTD : Vol. 10 Page 502 : 5 : .: / : . GLP : / : 2000 : 1996 7 : . / : 2000 mg/kg , , PCEs . : . : 2000 mg/kg .(mg/kg)PCEs %(±SD)MN-PCEs %(±SD) 0 5M 52 ± 1.9 0.20 ± 0.12MM-180801 2 5M 54 ± 3.7 0.25 ± 0.1620 5M 49 ± 3.1 0.20 ± 0.07200 5M 50 ± 2.1 0.26 ± 0.082000 3M 31 ± 2.5 0.12 ± 0.03Cyclophosphamide 7 5M 51 ± 2.3 2.49 ± 0.30**Dunnett's Test: * - p

#22.3.7.9B In Vivo : MM-180801: DNA : Curitol Solution : DNA : . : 51970 / : Wistar : 2 16 CTD : Vol. 11 Page 2 : 5 Weeks : .: . / : . GLP : / : 100 : 1997 : . / : . : . : - . 94007, Nuclear(mg/kg) Mean ± SDCytoplasmMean ± SDNGMean ± SD% IRMean ± SDNGIRMean ± SD 0 3M 16 3.5 ± 0.2 7.3 ± 0.3 -3.8 ± 0.4 0 ± 0 -MM-180801 222020200200200020003M3M3M3M3M3M3M3M2162162162163.0 ± 1.14.1 ± 0.53.9 ± 0.23.6 ± 0.34.2 ± 0.23.1 ± 0.34.8 ± 0.42.7 ± 0.15.5 ± 1.46.5 ± 0.86.9 ± 0.36.3 ± 0.47.5 ± 0.35.3 ± 0.38.2 ± 0.74.8 ± 0.3-2.6 ± 0.4-2.4 ± 0.2-3.0 ± 0.1-2.7 ± 0.2-3.4 ± 0.2-2.2 ± 0.1-3.4 ± 0.4-2.1 ± 0.30 ± 00 ± 01 ± 00 ± 00 ± 00 ± 00 ± 00 ± 0--5.7 ± 0.4-----DMN 10 3M 2 10.7 ± 3.0 5.8 ± 1.0 4.9 ± 2.1 41 ±15 11.4 ± 0.4Nuclear = ; Cytoplasm = ; NG = /; % IR = 5 NG %NGIR = /

2.3.7.10 : MM-180801: : Curitol Sodium / : CD-1 : 21 . 95012: 6 : CTD : Vol. 4 Page 1: 1995 9 20 / :: GLP : : . : TK 12 12 (mg/kg/):28 AUC (mcg-hr/ml a )180 Css (mcg/ml) : /M--6016440 ( ) 25 100 400F--601644M F10 120.4 0.560 c 6015 1344 c 47 (%) 67 73 75 80 71 68 56 59 (% b ) 33g 31g 0 0 -7* 0 -13** -19** (% b ) 6g/ 5g/ 0 0 -9* -8* -17** -15**M401.7601842F480.3602040M81534602733F57024602535Dunnett's Test: * - p

2.3.7.10 . 95012 (mg/kg/) 0 ( ) 25 100 400 M: 60 F: 60 M: 59 F: 60 M: 60 F: 60 M: 60 F: 60 : : 01 : 40 + 40: 00 : , 0 : 0 : 4 : 1 : 323+ 13: /4 /15 + 1310101100221121001012202000113041411111020000100010223111126 b9404100003233514215111313100004011272913 b18 a303000103040413113024 a1011000010111415a - Trend analysis, p

2.3.7.10 . 95012 (mg/kg/)0 ( ) 25 100 400M: 60F: 60M: 59F: 60M: 60F: 60M: 60F: 60 : , 0 : : 1 : 1 : 0: 0 : 0 : 0 : : 6 : 111000111130: - - - - - - - -– 000100040010010001100010000301000001212100000005000010000110 : : 412 322 415*1 40**30**45**- Fisher Exact Test: * - p

2.3.7.11 : Curitol Sodium /( / ) mg/kgWistar ()G6 G150, 500, 1000,20001000: ; ; ;;94201NZW 13 0, 5,15, 45 15: 97020 (CMC )45: G =

2.3.7.12 - : MM-180801: : Curitol Sodium ICH 4.1.1 : M: . 97072 / : Wistar F: CTD : Vol. 6 Page 1: 10 Weeks : Day 0: 1997 3 3 : 16 GLP : : : : / : .F 0 : 100 mg/kgF 0 : 100 mg/kgF 1 : 1000 mg/kg (mg/kg/)0 ( ) 10 100 1000: AUC b (mcg-hr/ml)-1.825320 : (% a )220--452 g2.72221220--02.52121220+-02.32221220++--12*2.82221- + ++ +++Dunnett's Test * - p

2.3.7.12 . 97072 (mg/kg/)0 ( ) 10 100 1000: AUC b (mcg-hr/ml)-2.127310(% a ) (% a ) (% a ) (% a ) /14 220--175 g225 g14 g15 g3.92.1212115.914.58.813.31.208.3221--00003.82.3222115.814.011.413.30.705.0220--00003.82.5222216.815.38.914.31.006.5220+--5*-12**-6*-15**3.92.2212015.313.89.812.81.007.2- + ++ +++Dunnett's Test * - p

2.3.7.13 - : MM-180801: : Curitol Sodium ICH 4.1.3 : G6-G18 . 97028 : Day 0 / : NZW : G29 CTD : Vol. 6 Page 200: 5 : : 1997 8 7 / : GLP : : . :F 0 : 1 mg/kgF 1 : 5 mg/kg (mg/kg/)0 ( ) 1 5 25 / : : AUC b (mcg-hr/ml)-2.631345 (% a ) (% a )2000--3.2 kg60 g/day9.47.915.81910--009.38.113.12010---15*-9*9.49.14.02003++--20**-16**10.49.48.9- + ++ +++ G = Dunnett's Test * - p

2.3.7.13 . 97028 (mg/kg/)0 ( ) 1 5 25 : (g) (% ) : : (%)(%): (%)(%) : (%)(%) : (%)(%) : (%)(%)181400.214.344.8246.30000002 (1.4)1 (5.6)2 (1.4)2 (11.1)161260.302.842.4457.7000000001 (0.8)1 (6.3)171480.405.442.1457.40000001 (0.7)1 (5.9)001886*4.7**049.0**42.3952.87 (8.0)*5 (27.8)**6 (6.9)*6 (33.3)**10 (11.5)**8 (44.4)**001 (1.2)1 (5.6)- Fisher Exact Test * - p

2.3.7.14 - : MM-180801: : Curitol Sodium ICH 4.1.2 : G6 - L21 . 95201 : Day 0 / : Wistar : CTD : Vol. 10 Page 1: 9-10 / : : 1995 10 8 / : 4// GLP : : :F 0 : 7.5 mg/kgF 1 : 75 mg/kgF 1 : 75 mg/kg (mg/kg/)0 ( ) 7.5 75 750F 0 :: AUC b -(mcg-hr/ml)230--225 g (% a )210 g (% a )15 g (% a )16 g (% a )22.1 ( )-2.4210--000022.2-21220++-000022.1-150238+++--25**0-12*023.5 +-- + ++ +++ G = L = Dunnett's Test * - p

2.3.7.14 . 95201 (mg/kg/)0 ( ) 7.5 75 750F 1 :( ) / / /a (g)(% ).2313.613.50.1--6051--2113.813.80.0--5853--2214.914.60.3--6249--1511.2 ++9.4 ++1.8 +--53*51--F 1 :( )b (g) (% b ) 23---20015 g----2.4232321---1950----3.3212122---1950----2.9211915---186*-11*----3.52320- + ++ +++Dunnett's Test * - p

2.3.7.14 . 95201 (mg/kg/)0 ( ) 7.5 75 750F 1 :( )F 2 :a (g)(g)(% b ) (% b )( )230--22615315 g16 g----2.4232316.415.83.8211--23016000----3.3212116.215.26.3220--23514400----3.1212015.814.412.3230--196*158-13*0----3.5232115.514.93.7/ (g) (% )15.00.805.13.6953-14.90.302.23.6549-13.60.805.23.7554-14.40.503.43.8154-- + ++ +++Dunnett's Test * - p

2.3.7.17 : Curitol Sodium / (mg/kg) 0, 5 mg 5M, 5F 970123 ; 1Wistar 2 0, 1000,200010M, 10F MM-180801 2%Z- 97025 ; MM-180801