Glatiramer Acetate and Neuroprotection

1
??????? ?????? ??????????? ? ?????????
?????????? ????????.

• ???????? ?? ?????? ??
• ?.?.?. ?????? ?.?.

2
???????????? ????????Currency of problem

• ?c?o?? ? ????? ????????????? ?????? 2,5 ???.
  ?????? ?? ??. ? ??????? ????????????? 18,5 ???.
  ?????? ?? ??.
• ?? ???????????????? ????????????, ??
  ???????????????? ??????????????? ????? ????????
  ???
• ?????????????? ??????? ???????????????
• ????? 15 ????? ????? ??????? ????????????
  ????????
• gt 80 ????? ????????? ???????
• gt 50 ?? ?????? ???????????? ??? ??????????
  ????????
• gt 70 ????? ???????? ??? ??????????????????

3
????????? ?? MS Pathogenesis
4
???????? ?? ?????????????? ?????
?????????????-?????????????
????????-???????????????
??? ???????????
???? ????????????????
?????????? ??????????????????/????????
?????
????? ?????
??????????????? MRI lesion burden
??????????? ??????????
T1 ??????????? (??)
??????? ??????????????????
?????? (????? ? Gd) ??? ??????????
?? ?????? ???? Gd ?????????? ???
????????-??????????? ??????????.
Noseworthy et al. N Engl J Med. 2000343938
Weinshenker et al. Brain. 1989112133 Trapp et
al. Curr Opin Neurol. 199912295.
5
???????????????? ????????? ??
6
??????????? ????????? ???????????, ??????????????
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.
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??????????, ???????????? ??? ?????????????? ??????
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7
????????? ????? ?????? ????? ????????????
Growing immobilization and dependence on
assistance
Unilateral assistance, can walk up to 100 m
Distance the patient is able to walk
Stages evaluated by functional disabilities scale
/ Normal neurological status
8
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8
9
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Gd ????? ??????????????? ?? ???????? ????????
??????????.
?2-????? ????, ?????? ???????? ????? ????????
????? (????? ? ?????? T2 ?? ???). ?????????????
???? ???????.??? ????? ????? ?????????
??????????? ? ?????????????.
????? ? ??????? ?????.
10
??????????????? ?????????? ?? ??? ??????? ????
????????? (Gd)
10
11
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11
12
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??????? ????????? ?????
??????? ? ???? ??????? 40 ??? ???????????? ??
12 ??? EDSS 5,5
12
13
??????? ?????????????? ?? ?? ????????-????????????
?
? ??????????? ????????? ? ???, ?? ??????????
???????, ?????????? ??????? ? ????
??????? ??? ? ???? ()
???????????? ??????? ?? (????)
Weinshenker et al. Brain. 1989112133.
14
?????? ?????? ??????? ?? ????? ?????????
?????????? ????????????? ?? ????????? ?
???????????? ???????? ???????

• Treatment at diagnosis may interrupt the disease
  course prior to onset of neurologic degeneration
  and may thus reduce CNS atrophy

???????????? ??????? ??
?????????????
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5
10
15
????? (????)
?????? ??????????
Adapted from Trapp BD, et al. Curr Opin Neurol.
199912295-302 Trapp BD, et al. Neuroscientist.
1999548-57 Jeffery DR. J Neurol Sci.
20021971-8 Cohen JA, et al. J Neuroimmunol.
19999829-36.
15
???????? ?????????????? ??????? ???
??Pathogenetic Therapy Objectives for MS
???????? ?? ?????- ???????????? ??????
??????????? ?????????????- ?????????????
??????? ????????????? ????????

• Influence the immunopathological process.
• Delay disability.

16
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17
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??????? ???????? 3 ???? ? ?????? 1 ??? ? ?????? ????? ???? ?????? ???? 1 ??? ? ?????
?????? ???????? ???????? ??????? ????????????? ???????? ???????? ???????????? ???????
????????? ???????????? ??? ??? ?? ??? ???
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?????? ???? 29G 23G 30G 29G
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????????? ?????????????? ????????? ????????? ??? ??? ?? ??? ???
??????????? ????????????? ??????? ??? ?? ???? ?? ?? ?? ?? ?????? ? ???????? ??????????-????????? ??????????
18
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????????? (??????????-????-1b)
165 ??????????? (????????????? E.coli) ????????
???????? ????? ???? ???????????????????
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?????? ?????????????????
????? (??????????-????-1?)
166 ??????????? (?????????????? ?????????? CHO
??????) ????????? ???????? ????? ????
19
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20
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21
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22
??????????? ?????? (??)

• ??????????????????? ????? ?????????????
  ????????????, ?????????? ?????? ????????????
  L-???????????? ???????, L-?????, L-?????? ?
  L-??????? ? ???????????? ???????? ???????????,
  ???????????? ???????? ????? ??????? (???) -
  myelin basic protein (MBP)

23
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  ?????? ??????? (???).
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  (??????????? ??????, ????????). ????????, ???
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  ?? ?? ???????? ???????? ???????? ????????????.

24
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  ????? ?? ???????? ???????-??????, ????????????,
  ????? ???????, ???????? ??????????????????
  ??????????? ? ???.

25
??????????? ?????? ?? ???????? ?? ???????????
??
??
??? ???????-?????????????? ??????
Ziemssen T et al., 2007 International Review of
Neurobiology (in press)
26
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??????(???????- ? ???????????????)
??? I F N ß
TCR
IFNßR
??
MHC
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ß - ???????????
TCR ?-????????? ????????, ?HC ????????
???????? ??????????????? , ???IFN
?????????????? ???
27
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(???????????)
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?????????? 1 ?????, ????????? ????????????? ??
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• ???????????? - ??? ?? CD4-?????????, ??????????
  ?????? ??? ?? ??? ?? ??????? ???????????? ? ??
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• ???????? ????????? ?????????? ????? ???.,?????.,
  ? ????? ? ?????? ? ????????????? ???? ??
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• ???????-???? ??????????? ? ????????? ??
  (????????????? ????????)

28
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• ????????????? ???????? ?????? ?????????????? ?
  ?????????, ? ????? ??? ??????? ??????????? ?
  ????????? ????????? ??????????? (????????????
  ??????, ???????, ????????? ???????)
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• - ?-?????????? ?D25, ?D52 ?????????
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• - ?D18 ???????????? ???????? ?????????? ?
  ???????? ????????? ?? ????.

29
????????????? ???????? ?????????? ????????
(??????????????), ?? ?????????? ??????????
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• ????? ????????????? ???????? ????? ????? ?????
  ??????????? ?? ???????? ??????? ???????

IL-2
?D-20
?D-52
30
????????????? ????????

• ?-???????
• Natalizumab
• ????????? ? 2006 ????
• Daclizumab
• ?lemtuzumab
• Ustakinumab

• ?-???????
• Rituximab
• Ocralizumab
• Ofatumumab
• Ataccept

31
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?4-?????????, ?.?. ??????????? ????????
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32
????????? ??????????? ??????? ??????? (SAM)
Natalizumab (Tysabri)

• ????????, ???? ??????????? ?? ??????????????
  ????? ?????????????? ???????
• ????? ????????????? ????????, ??? ????
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  ?? ?????????? ??????????? ??????? ???????
  (SAM)
• ???????????? ?????????????
• ???????? ????? ?4- ?????????

Rudick RA, Sandrock A. Expert Rev
Neurotherapeutics 20044571-580.
33
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• ?? ?????? ??????? 2009 ???? 52 ???.????????? ?
  ?????? ????? ???????? ??????????? (??????????? ?
  ? ????????? ????????????)
• ??????????? ?????? ????? ?????????????
  ????????????? ?? 42, ??????? ????????? ?????????
  ?? 68 ?? ???, ??? ??????????? ?? 92 ??????
  ?????? ????????? ? ??????? (?FFIRM)
• ????? ??????? (1 ??? ?? ???.)
• ???? ????????? ? ???????? ???????? ??? (?????,
  ???????, ???????) ?????????????? ?????????
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  (?????????? ???., ?????????,?????????? ????????)
• ? 2 ?????????, ?? ?????????? ??????????? ???????
  ????????????? ? ?FNß-1a ??????????? ???????????
  ?????????????? ?????????????????? .

34

• ??????????? ??????????????????
• ??? ???????????? ??? ??????????????? ??????
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• ??????? ???????? ??? ????? ????????? ???????
• 1.2/10 000 ?????????
• - ???????? ????????? ????????????? ??
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• - ?? ????????? ????? ?? ?? ? ????????
  ????????????, ????????? ?????????? ? ?????? ????,
  ?????????????? ???????????????? 1000 ?? ?3, ?/?
  ????. ? ?????????? ???????????? ??????
  mefloquine, mitazapin
• - ??? ?????????? ???????????? ???????? ????????
  ??? ???????????? ????????? ???? ?????? ? ???????
  ????? ??????????.

35
????????? ????????? ??? ?????????? ??????? ??
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94.9
100
???????
4Xvs. ???????
???????
80
58.3
57.7
56.6
60
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40
14.9
14.2
20
0
n290
n583
n296
n593
n296
n593
??? Gd ??????
??? T2 ??????
??????? ?? ???
???????? ?????? ??? ?????????? ??????? ?? ??????
??? ???????????? ?? ????, ? ???? ?? ???? Gd
?????? ???????? 1 ? 2-? ?????, ? ????? ????? ???
?????, ?? ???????????? ? ????????,
T2-???????????????? ?????? Galetta SL, et al.
Presented at 60th Annual Meeting of the American
Academy of Neurology April 12-19, 2008 Chicago,
IL, USA.
36
??????? ???????? ??????????? ??????

• ???????? ????????
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• ?????????
• ???????? ??????-
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• ?????????? ??????
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• ( 1.2/ 10 000 ?????????)

Yousry TA, et al. N Engl J Med. 2006354924-933.
37
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• ????????
• -?????? ?????????????
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• -???????? ????? ?? ?????? ?????????
• -?????, ??? ???????? ??????? ??? (
  ??????????????????, ????????????)

38
????????? ?????? ?????????? ????????? ?????? ??
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68
70
Plt0.001
60
50
40
34
32
32
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30
P0.002
Plt0.001
P0.055
Plt0.001
20
10
0
?????????
????? 22 ??? TIW
???????
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????? 44 ??? TIW
?????????? ?? ????????? ??????????? ????????????
?? ????? ???? ???????? ????????. ??? ?????????
? ??????? ?????? 2-? ??? Polman CH, et al. N
Engl J Med. 2006354899-910 TYSABRI package
insert. Cambridge, MA Biogen Idec, Inc. 2004
Nov. Intent to treat Patients who completed
2 years in the study Jacobs et al. Ann Neurol.
199639285 IFNB Multiple Sclerosis Study Group.
Neurology. 199343655 Betaseron package insert.
Emeryville, CA Chiron Corporation 2003 Oct.
Johnson et al. Neurology. 199850701 Copaxone
package insert. Bloomington, IN TEVA
Neuroscience, Inc. 2004 Feb. PRISMS Study
Group. Lancet. 19983521498 Rebif package
insert. Rockland, MA Serono, Inc 2005 Jan.
39
??????? ????? ?? ??????? ??????? ????????? ?????
???????? ??????? ?????
??????? ? 55 (2-? ???)
????????? (8 MIU) ??? ??????
????? (44???) ?? ?????????? (p??)
???????? 2 ?????????????? ???????????? (1 ? ????????????? ??????????? ? 1 ? ?????????????) ? 25 (18 ???.) p?? ? 40 (? 9 ?? 18 ???. ????????? ????? SIENA)
??????????? ? 44 (2-? ???, p0.004)
Galetta et al. Arch Intern Med. 20021622161
Jacobs et al. N Engl J Med. 2000343898 Simon
et al. Neurology. 200055185 Li et al. Ann
Neurol. 199946197 PRISMS Study Group.
Neurology. 2001561628 Comi et al. Ann Neurol.
200149290 Stone et al. Neurology. 199749862
Rudick et al. Neurology. 1999531698 Jones et
al. Neurology. 200156(suppl 3)A379 Sormani et
al. Neurology. 2004621432-34.
40
GAP ??????? ?????????? ?????????????? ? ???????
??
32 ????????? ???????? , ??? ???????? ? ?????????
????????? ???????? ???????? ??????????? ???
????????? ???? ?????
??????? ????? ???????? ????? ????? ???????
????????? ?????? ???????. ??? ???????? ???????
??????? ? ????????? ?????? ??????? ??????????
?????? ???? ???. Devonshire et al. ECTRIMS,
2006. Abstract and Poster 316.
41
GAP ??????? ?????????? ?????????????? ? ???????
??

• ??????????????? 50
• ????? ??? ????????? ??????? -20
• ???????????? ???????? -13
• ???? ? ????? ??????? 12
• ???????? ???? 10
• ?????? ??????? -10
• ?????? ??????? -10

42
???????? ?????????? ??????? ??? ????????? ??????
?? ?? ?????????? ?? ????????? ????????? ? ?.?????
? 2008 ?.
43
????????? ?????????, ?? ???????? ???????????
????????? ? 2008 ?.
44
?????????? ???????? ?????????? 2008 ????
45
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• ???? ? ?????? ???????? ??????-
• ??????? ?????????? ? ????? ???????

????? 2. ?????????? ????????? ????? ?? ??????
EDSS. 3. ? 6 ????????? ? 9 ?? ??????????????
??????? ??????????? ???????? 3 ?????. 4. ? 3-?
????????? ? ??????????? ??????????? ????
??????????????

1. ?????????? ??????? ?????-

46
????????Conclusions

• ?? ??? ??????? ???????????? ?????????? ? ?????? ?
  ?? ???????????? ???????????? ??????????????
  ???????? ?? ?????? EDSS ? ?????????? ?????????
  ??????????.
• ????????? ?????????????? ???????
  ????????????????????????? ???????????? ? ?????? ?
  ??

47
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