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8/9/2019 Que es el AC-11
1/15
United
S t a t e s
Patent
[ 1 9 ]
Per0
US006039949A
6 , 0 3 9 , 9 4 9
Mar. 2 1 , 2 0 0 0
[ 1 1 ] P a t e n t
Number:
[ 4 5 ] Date o f
P a t e n t :
[ 5 4 ]
METHOD
OF PREPARATION
AND
COMPOSITION OF
A WATER
SOLUBLE
EXTRACT OF THE PLANT SPECIES
UNCARIA
[ 7 5 ] I n v e n t o r : Ronald W. P e r o , L u n d , Sweden
[ 7 3 ] A s s i g n e e :
CampaMed,
n c . , New
o r k ,
NY.
[ 2 1 ]
A p p l .
N o . : 0 8 / 8 0 7 , 3 7 3
[ 2 2 ]
F i l e d : F e b .
2 7 ,
1 9 9 7
[ 5 1 ] I n t . Cl.7 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
A61K
5/78
[ 5 2 ]
US. l . . . . . . . . . . . . . . . . . . . . . .
. . 4 2 4 / 1 9 5 . 1 ; 514/885; 514/886;
5 1 4 / 9 0 8
[ 5 8 ] Field
Of
Search
. . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . 424/1951; 435/4,
4 3 5 / 7 2 1 ,
7 . 2 3 , 7 . 2 4 ,
3 9 0 ;
5 1 4 / 8 8 5 ,
8 8 6 ,
908
[ 5 6 ] R e f e r e n c e s
C i t e d
U . S .
PATENT DOCUMENTS
4,844,901 7/1989 Keplinger e t
a l .
. . . . . . . . . . . . . . . . .
. 424/1951
4 , 9 4 0 , 7 2 5 7 / 1 9 9 0
K e p l i n g e r e t
a l . 5 1 4 / 4 1 1
5 , 3 0 2 , 6 1 1 4 / 1 9 9 4
K e p l i n g e r e t
a l . 5 1 4 / 4 1 1
5,411,733
5/1995
HoZumi
t
a l . . . . . . . . . . . . . . . . . . . . . . 424/ 195 1
FOREIGN PATENT DOCUMENTS
56032418 4/1981 Japan
W0 2 / 0 1 1 3 0
4 / 1 9 8 2
WIPO.
OTHER
PUBLICATIONS
K u r a m o c h i e t a l . , L i f e S c i e n c e s , 5 4 : 2 0 6 1 2 0 6 9 , 1 9 9 4 .
R i Z Z i
e t
a l . , J o u r n a l o f E t h n o p h a r m a c o l o g y , 3 8 : 6 3 7 7 , 1 9 9 3 .
K i u c h i
e t a l . ,
Chem.
P h a r m . B u l l . , 3 1 : 3 3 9 1 3 3 9 6 , 1 9 8 3 .
NeW P o l y h y d r o x y l a t e d T r i t e r p e n e s From U n c a r i a
Tomen
t o s a , R .
A q u i n o , F . De S i m o n e , F . F . V i n c i e r i ,
C .
P i Z Z a ,
J o u r n a l o f N a t u r a l P r o d u c t s , v o l . 5 3 , N o . 3 , p p . 5 5 9 5 6 4 ,
M a y J u n .
1 9 9 0 .
P l a n t M e t a b o l i t e s
S t r u c t u r e And
I n
V i t r o A n t i v i r a l
A c t i v i t y
Of Q u i n o v i c A c i d G l y c o s i d e s From U n c a r i a T o m e n t o s a
And
G u e t t a r d a P l a y t y p o d a , R .
A q u i n o ,
F . De
S i m o n e ,
C
P i Z Z a ,
J o u r n a l
o f
N a t u r a l
P r o d u c t s ,
v o l . 5 2 ,
N o .
4 ,
p p . 6 7 9 6 8 5 ,
J u l . A u g .
1 9 8 9 .
P l a n t
M e t a b o l i t e s
NeW
Compounds
And
A n t i ? a m m a t o r y
A c t i v i t y
o f U n c a r i a
T o m e n t o s a , R i t a A q u i n o , V i c e n Z o
De
F e o , F r a n c e s c o
De
S i m o n e , C o s i m o P i Z Z a ,
a n d
G i u s e p p e
C i r i n o ,
J o u r n a l o f N a t u r a l
P r o d u c t s ,
v o l . 5 4 ,
N o .
2 , p p .
4 5 3 4 5 9 ,
M a r . A p r . 1 9 9 1 .
F r a n c e s c o De S i m o n e , C o s i m o P i Z Z a , a n d G i u s e p p e C i r i n o ,
J o u r n a l
o f
N a t u r a l P r o d u c t s , v o l . 5 4 , N o . 2 ,
p p .
4 5 3 4 5 9 ,
M a r . A p r .
1 9 9 1 .
P l a n t D e r i v e d N a t u r a l P r o d u c t s i n D r u g D i s c o v e r y a nd
D e v e l o p m e n t , M a n u e l
F .
B a l a n d r i n ,
A .
D o u g l a s K i n g h o r n
a n d Norman
R .
F a r n s W o r t h , 1 9 9 3 American Chemical S o c i
e t y
( C h a p t e r
1 ) .
P h y t o m e d i c i n e s i n
W e s t er n E u r o p e P o t e n ti a l
I m p a c t
o n
H e r b a l M e d i c i n e i n
the
U n i t e d S t a t e s , V a r r o E . T y l e r
D e p t .
o f
M e d i c i n a l
C h em i s t r y a n d P h a r m a c o g n o s y , S c h o o l o f
P h a r m a c y
a n d Ph a r m a c a l S c i e n c e s , P u r d u e U n i v e r s i t y ,
W e s t
L a f a y e t t e , IN 4 7 9 0 7 1 3 3 3 , 1 9 9 3 A m e r i c a n C h e m i c a l S o c i
e t y
( C h a p t e r
3 ) .
R o l e
o f P l a n t s i n
t h e
N a t i o n a l
C a n c e r
I n s t i t u t e Drug
D i s
c o v e r y
a n d
D e v e l o p m e n t
P r o g r a m ,
G o r d o n
M. C r a g g ,
M i c h a e l
R .
B o y d e , J o h n H .
C a r d e l l i n a I I ,
a n d MattheW
S u f f n m e s s , P u b l i s h e d 1 9 9 3 A m e r i c a n C h e m i c a l
S o c i e t y
( C h a p t e r 7 ) .
Una
d e
G a t o ( C a t s C l a W ) R a i n f o r e s t h e r b g e t s s c i e n t i ? c a n d
i n d u s t r y
a t t e n t i o n ,
b y
Mark
B l u m e n t h a l ,
W h o l e
F o o d s
M a g a z i n e , O c t .
1 9 9 5 ,
p p .
6 2 , 6 4 , 6 6 , 6 8 &
8 .
A p o p t o s i s a n d a
r e i n v e s t i g a t i o n o f t h e b i o l o g i c
b a s i s f o r
c a n c e r
t h e r a p y ,
Anthony V .
DAmico,
W. G i l l i e s McKenna
R a d i o t h e r a p y
a n d O n c o l o g y 3 3 ( 1 9 9 4 )
3 1 0 .
A p o p t o s i s
i n
t h e
P a t h o g e n e s i s
a n d T r e a t m e n t
o f D i s e a s e ,
C r a i g B . T h o m p s o n , S c i e n c e ,
v o l .
2 6 7 ,
M a r .
1 0 , 1 9 9 5 .
P r i m a r y ExaminerJon P .
Weber
A s s i s t a n t ExaminerJanet M .
Kerr
A t t o r n e y , A g e n t , o r FirmCobrin
& i t t e s
[ 5 7 ]
ABSTRACT
The p r e s e n t
i n v e n t i o n
i s d i r e c t e d t o a method
o f
p r e p a r a t i o n
a n d t h e c o m p o s i t i o n
o f
a W a t e r s o l u b l e e x t r a c t
o f
t h e p l a n t
s p e c i e s
U n c a r i a . The p r e s e n t i n v e n t i o n i s a l s o
d i r e c t e d
t o t h e
p h a r m a c e u t i c a l u s e o f t h e
c o m p o s i t i o n
f o r t h e e n h a n c e m e n t
o f
t h e
immune, a n t i - i n ? a m m a t o r y , a n t i - t u m o r a n d DNA
r e p a i r p r o c e s s e s o f W a r m b l o o d e d a n i m a l s . The p r e s e n t
p r e p a r a t i o n
o f t h e
W a t e r
s o l u b l e e x t r a c t
o f
the p l a n t s p e c i e s
U n c a r i a r e s u l t s i n
t h e d e p l e t i o n
o f many o f
t h e
i n g r e d i e n t s
Which
l e a d
t o v a r i o u s t o x i c
s i d e
e f f e c t s
a s s o c i a t e d
W i t h
o t h e r
e x t r a c t s
o r
c o m p o s i t i o n s d e r i v e d
from
U n c ar i a . A l s o ,
t h e
p r e s e n t p r e p a r a t i o n l e a d s
t o
t h e d e p l e t i o n o f
many
o f t h e
a c t i v e
i n g r e d i e n t s commonly
a s s o c i a t e d
W i t h
o t h e r e x t r a c t s
a n d c o m p o s i t i o n s o f t h e p l a n t
s p e c i e s
U n c ar i a . T h e r e f o r e ,
t h e p r e s e n t i n v e n t i o n t e a c h e s t ha t
t h e
h o t W a t e r
e x t r a c t i o n
o f
t h e
c r u d e
p l a n t p a r t s
o f
U n c a r i a a n d
t h e
s u b s e q u e n t d i a l y s i s
o f
t h e s o l u b i l i Z e d
p r o d u c t s
y i e l d s a l o W m o l e c u l a r W e i g h t
c o m p o s i t i o n W h i c h m a i n t a i n s
a h i g h d e g r e e o f
t h e a n t i
t u m o r ,
i n ? a m m a t o r y a n d immune
s t i m u l a t o r y a c t i v i t i e s
a s s o c i a t e d W i t h
t h e
c r u d e
p l a n t
p a r t s .
1 8 C l a i m s ,
9
Drawing S h e e t s
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8/9/2019 Que es el AC-11
2/15
U.S.
Patent M a r . 2 1 , 2 0 0 0 S h e e t 1 0 f
9
6,039,949
m
E
92 ;
2 3 5 8
0
N
N
2 2 5 2
E 2m_2 2 8 1
?
n
2 - 8 2 6
E 2
n
2 9 5 - 0
s 3
d . 4 r .
O
O
( N O I T I I W ) N O l i V l ? d O d
1 1 3 0
3
E
9
2 :
5 8
0
N 3 2
B :
m2 - 5 2 6
O |
22 - 8 2 6
6 5 2 8?
6
e
N O I T I I W ) N O l i V ' l ? d O d
1 1 3 0
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-
8/9/2019 Que es el AC-11
4/15
U.S.
Patent M a r . 2 1 , 2 0 0 0 S h e e t 3 0 f 9 6,039,949
u :I
2 9
2 :5 5 80
w
5 5 5
?
a
_
2 6 1 8 1
?
m
5 E 5
5 5 5 m :
2 1 0 22 6 1 8 1
2m
2 8 2 . 0
1 5 04 1
J ;
( N O I T I I I N )
NOIiW?dOd
1 1 3 9
I n :
w I
2 9
2 :
5 8
u
w
E 2o g w z o?
2
2 9 . 2 0
6 5 2 8
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( N O I T I I W ) N O L L V l ? d O d 1 1 3 0
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8/9/2019 Que es el AC-11
5/15
U.S.
Patent M a r . 2 1 , 2 0 0 0 S h e e t 4 0 f
9
6,039,949
ONTROL
_
I - -
C-MED-10O
( 3 9 7
p g l m l )
o- H 2 0 2
( 1 0 0 p M )
P O P T O T I C
E L L S
-
8/9/2019 Que es el AC-11
6/15
U.S. Patent M a r .
2 1 , 2 0 0 0
S h e e t
5
0 f
9
6,039,949
2 1 0 p g / m l
0 . 9 9 6 9 , p = 5
i n
e a c h g r o u p ) .
F I G .
7 .
P h y t o h e m a g g l u t i n i n
( P H A )
s t i m u l a t e d
l y m p h o
c y t e p r o l i f e r a t i o n i n W/Fu
f e m a l e
r a t s s u p p l e m e n t e d
W i t h
C-MED-100
e x t r a c t
( E x a m p l e 1 ) f o r
8
a n d 1 6 m g / d a y
f o r 8
c o n s e c u t i v e
W e e k s .
S p l e n o c y t e s
W e r e
p r e p a r e d
b y s i n g l e
c e l l
s u s p e n s i o n ( O l s s o n e t a l . , 1 9 9 5 ,
C a r c i n o g e n e s i s
1 6 ( 5 ) :
10291035) a n d c u l t u r e d on a m i c r o l i t e r p l a t e a t 2 5 , 0 0 0
c e l l s / W e l l i n
200
l R P MI 1 6 4 0 -
1 0
f e t a l c a l f s e r u m - 1 0
p l
PHA t
3 7 C . , 5 CO2 o r
5 d a y s ,
t h e n p u l s e d
f o r
6 h o u r s
W i t h 0 . 5 p C i [ 3 H ] t h y m i d i n e / m l . L a b e l e d n u c l e a r m a t e r i a l
W a s
c o l l e c t e d o n g l a s s
?ber
? l t e r s i n a m i c r o l i t e r p l a t e c e l l
h a r v e s t e r ,
d r i e d
a n d
c o u n t e d i n s c i n t i l l a t i o n ? u i d . The e s u l t
i n g
cpm [ 3 H ] t h y m i d i n e
d a t a Was
l o g - t r a n s f o r m e d
t o g e t
a
n e a r
normal d i s t r i b u t i o n . R e s u l t s a r e shoWn by
a v e r a g e i n
column
and
SD
i n e r r o r b a r .
n=5
i n
e a c h g r o u p
e x c e p t
( l o W + h i g h ) n = 1 0 .
DETAILED
DESCRIPTION
OF THE
INVENTION
The
f o l l o W i n g
e x a m p l e s
a r e
some
p r e f e r r e d
f e a t u r e s
b u t
n o t
l i m i t a t i o n s
o f
t h i s
i n v e n t i o n .
EXAMPLE
P r e p a r a t i o n o f U n c a r i a
e x t r a c t s
( C - M e d - 1 0 0 ) .
One
h u n
d r e d
a n d ? f t y g r a m s
o f
a i r - d r i e d
b a r k ( c o l l e c t e d f r o m
Campa
I n d i a n s b y C a m p a M e d ,
I n c . ,
A r l i n g t o n ,
V t . ) o r p u l v e r i Z e d
b a r k p o W d e r ( s u p p l i e d c o m m e r c i a l l y b y MW n t e r n a t i o n a l ,
I n c . , H i l l s i d e , N . J . ) o f U n c a r i a
( W i l l d ) ,
a l s o knoWn com
monly
a s
U n a
d e Gata
o r
C a t s
ClaW,
Were
mixed
With 5
l i t e r s o f t a p W a t e r and h e a t e d i n a s t a i n l e s s s t e e l p o t t o
t h e
s u b b o i l i n g p o i n t ( a b o u t 9 0 1 0 0
C . )
f o r 2 0 2 4 h o u r s u n t i l
t h e h o t Water e x t r a c t W a s concentrated t o about 9 0 0 1 0 0 0
m i l l i l i t e r s
by
e v a p o r a t i o n . The
d a r k
broWn
e x t r a c t
Was t h e n
a d j u s t e d
t o
e x a c t l y
1 0 0 0 m i l l i l i t e r s , ? l t e r e d t h r o u g h common
c o f f e e
? l t e r s
( M e l i t t a
S c a n d i n a v i a A B ) , a n d
t h e n c e nt r i f u g e d
a t 3 0 0 0 > < g f o r
1 5
m i n u t e s a t
4 0
C . t o p r o d u c e a p a r t i c u l a t e
f r e e
W a t e r
e x t r a c t e q u a l
t o
150
grams c r u d e
b a r k p e r 1 000
m i l l i l i t e r s
o r
0 . 1 5
grams
p e r
m i l l i l i t e r . Next 50
m i l l i l i t e r
a l i q u o t s o f t h e W a t e r e x t r a c t Were t r a n s f e r r e d i n t o c e l l u l o s e
membrane
d i a l y s i s
t u b i n g ( p o r e
s i Z e
2 . 4 n m , e x c l u s i o n
l i m i t = < 1 2 0 0 0 m o l e c u l a r
W e i g h t ,
KEBO L a b ) a n d
d i a l y Z e d
a g a i n s t 1000
m i l l i l i t e r s d i s t i l l e d W a t e r f o r 24 h o u r s a t 4
C .
A f t e r
d i a l y s i s ,
t h e
h i g h m o l e c u l a r
W e i g h t
f r a c t i o n
( d a r k
b r o W n ) r e t a i n e d i n t h e d i a l y s i s t u b i n g Was d i s c a r d e d
a n d
t h e
loW m o l e c u l a r
f r a c t i o n
( l i g h t y e l l o W ) t h a t d i f f u s e d
o u t
Was
c o n c e n t r a t e d by a Water
vacuum e v a p o r a t i o n
a t 5 0 C .
t o
e q u a l a
volume
o f
50 i l l i l i t e r s . I t i s t h i s p r e p a r a t i o n
o f a
h o t
W a t e r ,
d i a l y Z a b l e
( l o W
m o l e c u l a r
W e i g h t )
e x t r a c t f r o m
U n c ar i a b a r k
t h a t h a s b e e n b i o l o g i c a l l y e v a l u a t e d i n t h i s
i n v e n t i o n
and hereby i s r e f e r r e d
t o
a s
C-Med-100
e x t r a c t .
T h e C-Med-100 p r e p a r a t i o n
i s
a p a l e y e l l o W t o l i g h t
br oWn c l e a r
s o l u t i o n With a s l i g h t
b i t t e r t a s t e
and no o d o r .
UV p e c t r a l
s c a n n i n g
s h o W s a p e a k a b s o r p t i o n
a t A l g g n m .
C-Med-100 i s s t a b l e t o h e a t o f
s u b b o i l i n g
f o r
24
h o u r s a n d
s t e r i l i Z a t i o n b y a u t o c l a v i n g ( 2 0 m i n u t e s a t 1 2 1 C . ) a n d
m a i n t a i n s
i t s b i o l o g i c a l a c t i v i t y
f o r
a t
l e a s t
6 months
When
f r o Z e n
i n
l i q u i d
f o r m
a t
2 0
C .
When
d r i e d
by
f r o Z e n
vacuum e v a p o r a t i o n , l i g h t broWn p a r t i c l e s a r e p r o d u c e d
y i e l d i n g
793310.249 m i l l i g r a m s p e r m i l l i l i t e r
o f
the
h o t
W a te r , d i a l y Z e d
e x t r a c t .
H e n c e , t h e y i e l d
f r o m
c r u d e
b a r k
W a s
7 . 9 3 3
mg
e r
m i l l i l i t e r d i v i d e d by 150 mg e r m i l l i l i t e r
or 5.3 .
-
8/9/2019 Que es el AC-11
13/15
6 , 0 3 9 , 9 4 9
5
EXAMPLE
A n t i - t u m o r
a c t i v i t y o f
U n c a r i a
e x t r a c t ( C - M e d - 1 0 0 ) . The
a n t i - t u m o r
a c t i v i t y
o f C-Med-100
e x t r a c t
p r e p a r e d a s i n
Example
1
Was e v a l u a t e d i n v i t r o u s i n g 2 human l e u k e m i c
c e l l
l i n e s (HL-60 a n d K-5
2 )
a n d a
mouse
l e u k e m i c
c e l l l i n e
( R a j i ) .
The
a n t i - p r o l i f e r a t i v e p o t e n c y o f
C-Med-100 Was
a s s e s s e d
b y
c o u n t i n g
t h e
t o t a l n u m b e r o f
c e l l s
b y m i c r o
s c o p i c
a n a l y s i s a t 4 0 0 > < m a g n i ? c a t i o n . The c a n c e r
c e l l l i n e s
Were s e e d e d i n d u p l i c a t e 2
i l l i l i t e r c u l t u r e s
a t a
c e l l d e n s i t y
o f 0 . 5 > < 1 0 5
c e l l s
p e r c u l t u r e i n 1 5 m i l l i l i t e r
F a l c o n
t e s t t u b e s .
The c u l t u r e
medium W a s
RPMI
ith
10 e t a l c a l f serum
and t h e
t e s t t u b e s
Were
i n c u b a t e d
under
s t a n d a r d c o n d i t i o n s
i . e .
3 7 C . , 5
CO2
a n d 80 h u m i d i t y ) . C - M e d - 1 0 0 e x t r a c t
W a s added
a t
198 and 397 p g p e r m i l l i l i t e r t o g e t h e r
W i t h
t h e
c e l l s e e d i n g ,
a n d t h e
i n c u b a t i o n Was c o n t i n u e d f o r 8 d a y s .
The t o t a l
number
o f
c e l l s i n e a c h c u l t u r e
W a s
d e t e r m i n e d
e v e r y d a y b y h e m o c y t o m e t e r c o u n t i n g i n t h e p r e s e n c e o f
t r y p a n b l u e . A f t e r 8
d a y s
o f g r o W t h a s s e s s m e n t , t h e c u l t u r e s
r e c e i v i n g 397
p g p e r m i l l i l i t e r
o f
C-Med-100
e x t r a c t
Were
spun
doWn, t h e
o l d c u l t u r e
medium
d i s c a r d e d a n d neW
c u l t u r e medium a d d e d
back
c o n t a i n i n g 1397 pg e r
m i l l i l i t e r
C-Med- 10 0 e x t r a c t . This Was done t o
a s c e r t a i n
i f
t h e
c e l l s
s u r v i v i n g
397
pg
p e r
m i l l i l i t e r C-Med-100 Were
a c t u a l l y
k i l l e d ( c y t o t o x i c ) o r
o n l y
g r o W t h i n h i b i t e d ( c y t o s t a t i c ) .
The d a t a
p r e s e n t e d i n F I G . 1
c l e a r l y
shoWs t h a t C-Med
100 e x t r a c t
h a s
a
profound
a n t i - p r o l i f e r a t i v e
e f f e c t o n a l l
t h r e e c a n c e r c e l l l i n e s . I n t e r e s t i n g l y , K-562 c e l l s , W e l l
knoWn
t o b e
r e s i s t a n t t o
i n d u c t i o n
o f a p o p t o s i s (DAmico
a n d
McKenna, R a d i o t h e r . O n o c o l .
3 3 : 3 1 0 ,
1 9 9 4 ) , W e r e
a l s o t h e m o s t r e s i s t a n t t o
g r o W t h
i n h i b i t i o n u s i n g C-Med
100
e x t r a c t . T h i s d a t a s u p p o r t s t h e e f f e c t s on a p o p t o s i s
p r e s e n t e d i n E x a m p l e 3 . F u r t h e r m o r e ,
t h e
r e g r o W t h e x p e r i
m e n t s
i n
F I G .
1 i n d i c a t e
t h a t
n o t
a l l
p h a s e s
o f
t h e
c e l l
c y c l e
o f c a n c e r c e l l s
a r e
e q u a l l y s u s c e p t i b l e t o C-Med- 10 0 e x t r a c t .
I t W a s
shoWn t h a t
even
Wh en
groWth
W a s
i n h i b i t e d
>95
over
a n 8 day
p e r i o d i n c u l t u r e , a s
W a s t h e c a s e
With H L - 6 0
a n d R a j i
c e l l s ,
When C-Med-100 e x t r a c t Was
removed from
t h e
medium a t l e a s t some c e l l s
began
t o g r o W a f t e r
a
feW
more d a y s
i n
c u l t u r e . T h i s
d a t a
i s c o n s i s t e n t W i t h
Example
3 and a l s o t e a c h e s t h a t s o m e tumor c e l l s
must
be i n
a s t a t e
o f
groWth s u c h t h a t t h e y
a r e
r e s i s t a n t t o C-Med-100 e x t r a c t
a n d n o t c a p a b l e o f u n d e r g o i n g d e a t h b y
a p o p t o s i s .
EXAMPLE
I n d u c t i o n
o f
a p o p t o s i s b y
U n c a r i a
e x t r a c t s ( C - M e d - 1 0 0 ) .
A p o p t o s i s i s a n a t u r a l o c c u r r i n g
form
o f c e l l d e a t h
o r s u i c i d e
o f
p a r t i c u l a r
s i g n i ? c a n c e
t o
m a i n t a i n i n g
c o m p e t e n t
homeo
s t a t i c in?ammatory
and
immune r e s p o n s e s n e c e s s a r y a s
a
p r i m a r y
d e f e n s e
a g a i n s t many
d i s e a s e s i n c l u d i n g c a n c e r ,
v i r a l i n f e c t i o n s , A I D S , a u t o i m m u n e a n d n e u r o d e g e n e r a t i v e
d i s o r d e r s . A g e n t s th at c a n
i n d u c e a p o p t o s i s
a r e p o t e n t i a l
a n t i - i n ? a m m a t o r y
a n d
a n t i - t u m o r
d r u g s
b e c a u s e
t h e y may
h a v e t h e a b i l i t y t o i n d u c e a p o p t o t i c d e a t h i n
m a l i g n a n t
o r
in?ammatory
macrophages
o r monocytes Which a r e kn o W n
t o
b e
p a r t i c u l a r l y s e n s i t i v e t o i n d u c t i o n
o f
a p o p t o s i s .
L i k e W i s e ,
s u c h
a g e n t s s i m u l t a n e o u s l y
s t i m u l a t e immune
e l l
f u n c t i o n b y l i m i t i n g o r r e d u c i n g t h e p r o d u c t i o n o f TNF-A b y
t h e in?ammatory c e l l s Which
a r e a
W e l l k n o W n n a t u r a l
o c c u r r i n g a g e n t t h a t i s c y t o t o x i c t o
l y m p h o c y t e s a n d
t h u s
i m m u n o s u p p r e s s i v e
( A p o p t o s i s
r e v i e W e d b y C . B .
T h o m p s o n ,
S c i e n c e
2 6 7 : 1 4 5 6 6 2 ,
1 9 9 5 ) .
T h e
d a t a
i n t h i s
E x a m p l e ( F I G . 2 ) d e m o n s t r a t e s a n d d i s c l o s e s t h a t C-Med
100 e x t r a c t
o f
U n c a r i a d e s c r i b e d i n Example
1
i s a n e f f e c t i v e
i n d u c e r o f a p o p t o s i s i n HL-60 l e u k e m i c c e l l s , a n d t h u s t h i s
p r e p a r a t i o n
p o s s e s s e s i m p o r t a n t
a n t i - t u m o r ,
a n t i
i n ? a m m a t o r y
a n d i m m u n e
s t i m u l a t i n g p r o p e r t i e s .
10
1 5
20
25
30
35
40
45
50
55
60
6 5
6
F o r
t h e
p u r p o s e o f
e v a l u a t i n g a p o p t o s i s
i n v i t r o ,
human
leukemic H L - 6 0 c e l l s Were c u l t u r e d
a t a
d e n s i t y o f
0 . 5 > < 1 0 6
c e l l s p e r m i l l i l i t e r i n 1 0 c a l f
serum
s u p p l e m e n t e d
RPMI
medium i n
a 5 CO2 a t m o s p h e r e a t 3 7 C . f o r 4 8 h o u r s . The
c e l l s
W e r e
h a r v e s t e d by c e n t r i f u g a t i o n
a n d
r e s u s p e n d e d i n a
f r e s h
medium a t
a
c o n c e n tr a t i o n o f 1 2 > < 1 0 6
c e l l s
p e r
m i l l i l i t e r i n 1 5
m i l l i l i t e r
F a l c o n t e s t t u b e s f o r b i o a s s a y
p u r p o s e s . Next t h e c e l l s Were exposed t o e i t h e r 100 pM
hydrogen
p e r o x i d e
a s a p o s i t i v e c o n tr o l o r 397 pg p e r
m i l l i l i t e r
C-Med-100 x t r a c t
p r e p a r e d a c c o r d i n g t o E x a m p l e
1 o r no exposure
f o r
072 h o u r s a t
37
C .
Samples
o f c e l l s
Were t a k e n from
t h e
c u l t u r e s a t
t h e
t i m e p e r i o d s
i n d i c a t e d
i n
F I G . 2 a n d t h e p o p t o s i s i n
t h e
t o t a l c e l l s c o u n t e d
Were
a n a l y Z e d a n d
s c o r e d b y p h a s e c o n t r a s t m o r p h o l o g i c a l c r i t e
r i a .
EXAMPLE
R e l a t i v e c y t o t o x i c
d o s e
p o t e n c y o f c r u d e b a r k v e r s u s
U n c a r i a h o t
W a t e r e x t r a c t i o n
(C-MED100).
Commercial
p r e p a r a t i o n s o f Uncaria a r e f o r m u l a t e d and s o l d a s c r u d e
b a r k
p h y t o m e d i c i n e s
g i v e n o r a l l y
u s u a l l y i n
c a p s u l e s a t t h e
d o s e
o f 1 3 g r a m s p e r d a y . T h e b i o a v a i l a b i l i t y o f i n g e s t e d
c r u d e
b a r k
h a s
n e v e r been d e t e r m i n e d
b u t
n e c e s s a r i l y Would
r e l y
on a n e f f i c i e n t
e x t r a c t i o n
a n d a b s o r p t i o n
o f
t h e a c t i v e
components u n d e r
t h e
a c i d i c
c o n d i t i o n s o f
t h e
s t o m a c h .
O n
t h e
o t h e r h a n d , C-Med-100
W a t e r
e x t r a c t Would n o t
have
i t s
b i o a v a i l a b i l i t y i n ? u e n c e d
b y t h e p a r t i c u l a t e
f r a c t i o n o f
U n c a r i a . To e s t i m a t e t h e r e l a t i v e b i o a v a i l a b i l i t i e s o f t h e s e
t W o p r e p a r a t i o n s o f
U n c a r i a , d o s e
r e s p o n s e a n t i p r o l i f e r a t i v e
a c t i v i t i e s
Were
e v a l u a t e d
a g a i n s t l e u k e m i c
H L- 60
c e l l s .
Crude b a r k
m a t e r i a l W a s ? r s t e x t r a c t e d
W i t h
1
N Cl
f o r
3 h o u r s
a t a c o n c e n t r a t i o n
o f
0 . 1 5
grams
p e r m i l l i l i t e r
Which
W a s
i d e n t i c a l t o
t h e
c o n c e n t r a t i o n o f crude bark
used
t o
produce C-Med-100
e x t r a c t .
N e x t ,
t h i s
a c i d e x t r a c t W a s
n e u t r a l i Z e d
W i t h
5
N
N a O H ,
c e n t r i f u g e d
a t 3000 > < g
t o
r e m o v e p a r t i c u l a t e m a t e r i a l ,
a n d
t h e s u p e r n a t a n t ( s o l u b l e
f r a c t i o n ) u s e d f o r c o m p a r i s o n
W i t h
C-Med-100 e x t r a c t .
C-Med-100 e x t r a c t
p r e p a r e d
a s i n Example 1 W a s t r e a t e d
i n
t h e
s ame
e x a c t Way s
t h e
a c i d i c crude bark p r e p a r a t i o n
s o
t h a t
t h e y c o u l d b e c o m p a r e d u n d e r
c o n t r o l l e d
e x t r a c t i o n
p r o c e d u r e s
f o r b i o l o g i c a l a c t i v i t y .
The a b i l i t y o f t h e s e
t W o U n c a r i a
p r e p a r a t i o n s t o
i n h i b i t
t h e p r o l i f e r a t i o n
o f HL-60 e l l s Was d e t e r m i n e d u s i n g e x p o
n e n t i a l l y g r o W i n g
HL-60 c e l l s c u l t u r e d
a t t h e
d e n s i t y o f
5 0 , 0 0 0 / m i l l i l i t e r
i n R P M I
1640
medium W i t h 1 0
f e t a l
c a l f
s e r u m ,
andimixed
W i t h t h e tWo d i f f e r e n t Uncaria
p r e p a r a
t i o n s
i n a
volume
o f
50
l
p e r
950
l o f
c u l t u r e
t o
e q u a l
t h e
? n a l
c o n c e n t r a t i o n s
f o r t h e d a t a p o i n t s
r e p o r t e d
i n F I G .
3
i . e . 0 6 0 0 pg
o f t h e d r y W e i g h t s o f
t h e r e s p e c t i v e a c i d i c
a q u e o u s e x t r a c t s p e r m i l l i l i t e r ) . 200
p l
o f t h e i t r e a t e d c e l l s
s u s p e n s i o n s
W e r e
s e e d e d
i n
9 6 - w e l l m i c r o l i t e r p l a t e s a n d
c u l t u r e d i n a n i n c u b a t o r a t 3 7 C . W i t h 6
CO2
a n d 8 0
h u m i d i t y f o r 3
d a y s .
A l i q u o t s o f 2 5 p l [ 3 H ] t h y m i d i n e ( 9
p C i / m i l l i l i t e r ) Were added f o r
a n o t h e r
6 0
m i n u t e s
b e f o r e
t h e
c e l l s Were
h a r v e s t e d
by vacuum a s p i r a t i o n o n t o g l a s s ? b e r
? l t e r s
( W h a t m a n G F / A ) .
W h i l e f r e e [ 3 H ] t h y m i d i n e i s
W a s h e d t h r o u g h
t h e ? l t e r s , t h e
[ 3 H ] t h y m i d i n e
i n c o r p o r a t e d
i n t o d e o x y r i b o n u c l e i c a c i d (DNA) s r e t a i n e d . T h e r a d i o a c
t i v i t y
r e t a i n e d
o n t h e
? l t e r s Was q u a n t i ? e d by
l i q u i d s c i n
t i l l a t i o n c o u n t i n g .
EXAMPLE
I n v i v o e v a l u a t i o n o f t o x i c s i d e
e f f e c t s a n d
h e m a t o l o g i c
p a r a m e t e r s o f U n c a r i a
e x t r a c t
( C - M e d - 1 0 0 ) . T h i s
i n v e n t i o n
d i s c l o s e s n o t
o n l y a
u n i q u e c o m p o s i t i o n o f ,
a n d a
p r e p a r a
t i o n
f o r ,
U n c a r i a
b u t
a l s o
t h a t t h e
c u r r e n t
p h y t o m e d i c i n a l
-
8/9/2019 Que es el AC-11
14/15
6 , 0 3 9 , 9 4 9
7
p r a c t i c e i s n o t c o n s i s t e n t W i t h a c h i e v i n g e f f i c a c i o u s t r e a t
ments o f
humans
b a s e d
on t h e d a i l y
d o s e s
o f
c r u d e b a r k
recommended
f o r
o r a l a d m i n i s t r a t i o n . As
a l r e a d y p o i n t e d
o u t i n t h i s i n v e n t i o n ,
t o
a c h i e v e s i n g l e e f ? c a c i o u s d o s e s o f
U n c a r i a
j u d g e d by i n d u c t i o n o f a p o p t o s i s o r i n h i b i t i o n o f 5
c e l l
p r o l i f e r a t i o n
( E x a m p l e s 2 a n d
3 ) ,
a t
l e a s t
2 6 2
t o
5 2 4
g r a m s
o f c r u d e b a r k
( c a l c u l a t i o n p r e s e n t e d
i n summary o f
t h e i n v e n t i o n s e c t i o n ) W o u l d n e e d t o b e i n g e s t e d e v e r y d a y .
H o W e v e r , C-Med-100 e x t r a c t
c o u l d
e a s i l y
b e
a d m i n i s t e r e d
o r a l l y a t
t h e s e d o s e
l e v e l s
i n
one
c a p s u l e ,
t a b l e t o r t h e
e q u i v a l e n t . I n o r d e r t o e v a l u a t e the
t o x i c o l o g i c a l
a n d
immu
n o l o g i c a l
c o n s e q u e n c e s
o f
d o s i n g
C-Med-100 e x t r a c t p r e
p a r e d
a s i n Example
1 i n t h i s c o n c e n t r a t i o n
r a n g e , W/Fu
a t s
i n i t i a l l y W e i g h i n g 1 5 0 2 0 0 g r a m s
W e r e
a d m i n i s t e r e d d a i l y
doses
o f
C-Med- 10 0 e x t r a c t by o r a l
gavage
o v e r
a n 8
c o n s e c u t i v e Week
p e r i o d .
The r a t s Were k e p t i n a m b i e n t
t e m p e r a t u r e o f
2 1 C . t o 2 3 C . L i g h t s Were
k e p t
on from 6
am o 6 pm nd t h e r a t s
Were
given
f r e e a c c e s s t o f r e s h t a p
W a t e r a n d
s t a n d a r d p e l l e t
f o o d a n d W e r e
g e n e t i c a l l y
a s s i g n e d
a s
a
h e a l t h
c h e c k .
The
p r o t o c o l
c o n t a i n e d
30
female
r a t s
r a n d o m l y a s s i g n e d i n t o 3 g r o u p s e a c h c o m p o s e d o f
1 0
a n i m a l s : G r o u p 1 = c o n t r o l s , 1
m i l l i l i t e r
s t e r i l e W a t e r b y
o r a l
g a v a g e ; Gro up 2=8 mg d r i e d
W e i g h t o f
C-Med-100 e x t r a c t
p e r m i l l i l i t e r b y
o r a l g a v a g e ;
G r o u p 3 = 1 6 mg
d r i e d W e i g h t
o f
C-Med-100 e x t r a c t
p e r
2 m i l l i l i t e r s
by
o r a l
g a v a g e .
Acute
t o x i c i t y
Was
m o n i t o r e d e v e r y
d a y by t h e
p r e s e n c e o r
a b s e n c e
o f
s y m p t o m s .
Body e i g h t Was
e c o r d e d
o n c e
p e r
W e e k , a n d
h e m a t o l o g i c a l
p a r a m e t e r s
Were
measured
e v e r y s e c o n d
W e e k . About 0 . 3
ml
b l o o d s a m p l e Was t a k e n f r o m t h e o p t i c a l
venous p l e x u s o f t h e r a t i n t o 2 ml
p o l y p r o p y l e n e
m i c r o c e n
t r i f u g e
t u b e c o n ta i n i n g 2 5
p l
2 5 0 0
L E .
h e p a r i n p e r m i l l i l i t e r
( 2 0 0 I . E . / m l i n
? n a l c o n c e n t r a t i o n )
a n d t h e n i m m e d i a t e l y
a n a l y Z e d b y
a n
a u t o m a t e d h e m a t o l o g y a n a l y Z e r ( S y s m e x ,
K - 1 0 0 0 ) .
The
r e l e v a n t i n v i v o d a t a
i s
p r e s e n t e d i n
F I G S .
4 a n d 5 .
No c u t e
s y m p t om s
Were observed
s o f a r
i n
t h e
r a t s a f t e r 6
Weeks o f d a i l y C-Med-100
o r a l
a d m i n i s t r a t i o n a t
t h e 8
o r
1 6
mg
d a i l y d o s e s . A l l t h e r a t s
g a i n e d W e i g h t o v e r
t h e e x p e r i
mental p e r i o d and no
s t a t i s t i c a l
d i f f e r e n c e W a s found a t
any
o f
t h e
t i m e p o i n t s
t e s t e d
among
h e
3 g r o u p s ( F I G .
4 ) .
T h e s e
d a t a t e a c h
t h a t t h e
r e l a t i v e l y h i g h d o s e s o f C-Med-100
e x t r a c t , Which
t o
o u r
knoWledge
h a v e
n e v e r
p r e v i o u s l y been
a d m i n i s t e r e d
i n v i v o f o r
U n c a r i a
p r e p a r a t i o n s , a r e s a f e and
f r e e
from
c a u s i n g any
g r o s s
o b v i o u s
a c u t e
o r
c h r o n i c t o x i c
r e s p o n s e .
I n a d d i t i o n ,
b o t h
t h e 8 a n d 1 6 mg o s e s
o f C-Med-100
e x t r a c t
shoWed
a
s t a t i s t i c a l l y s i g n i ? c a n t
i n c r e a s e
i n hemo
g l o b i n ( p < 0 . 0 0 0 1 f o r b o t h g r o u p s b y o n e t a i l e d t - t e s t )
a n d
W h i t e b l o o d
c e l l
c o u n t s ( p < 0 . 0 5 a n d p < 0 . 0 7 7
by
o n e t a i l e d
t - t e s t )
( F I G .
5 ) .
I n c r e a s e d
h e m o g l o b i n
c o u l d
b e s t i m u l a t o r y
t o r e s p i r a t i o n a n d
e n e r g y
p r o d u c t i o n W h i l e e l e v a t i o n s
i n
the
c o n s t i t u t i v e
WBC o u l d
h a v e immune e n h a n c i n g
e f f e c t s
b o t h
o f
Which Were i n d u c e d
by
t h e C-Med-100 i n t e r v e n t i o n .
H e n c e ,
the d a t a i n F I G S .
4 a n d
5 , t a k e n t o g e t h e r W i t h t h a t
r e p o r t e d i n
F I G S .
1
a n d 2 ,
d i s c l o s e
t h a t d o s e s o f C-Med-100
i n d u c i n g f a v o r a b l e
i n
v i t r o
b i o l o g i c a l r e s p o n s e s
a r e a l s o
b o t h s a f e
a n d e f f e ct i v e i n v i v o .
EXAMPLE
DNA e p a i r e n h a n c e m e n t
b y
C-MED-100 s u p p l e m e n t a
t i o n
i n r a t m o d u l e . T h i s example t e a c h e s t h a t i n v i v o
s u p p l e m e n t a t i o n
o f 8 o r
1 6
mg/day
C- MED- 100
e x t r a c t f o r
8 c o n s e c u t i v e Weeks i n
t h e
r a t
r e s u l t e d
i n
a n enhanced
a b i l i t y
t o c a r r y o u t DNA e p a i r a n d t h e r e b y t o remove DNA amage
t h a t i n t u r n i n h i b i t s
c e l l
r e p l i c a t i o n a n d immune f u n c t i o n .
T h i s
d a t a con?rms t h a t
C- MED- 100
e x t r a c t
s u p p l e m e n t a
t i o n h a s t h e
a b i l i t y
t o s t i m u l a t e t h e
r e m o v a l
o f DNA e s i o n s
8
t h a t
can
cause human
disease
such as cancer a s Well as
s t i m u l a t e immune c e l l r e s p o n s i v e n e s s .
EXAMPLE
PHA t i m u l a t e d
l y m p h o c y t e
p r o l i f e r a t i o n i n W/Fu f e m a l e
r a t s s u p p l e m e n t e d W i t h C-MED100. T h i s e x a m p l e d i s c l o s e s
t h e
immune
s t i m u l a t i n g p r o p e r t i e s o f
C-MED-100
e x t r a c t
s u p p l e m e n t e d
i n v i v o
W i t h
8 o r
1 6 m g / d a y .
S p l e n o c y t e s f r o m
t h e C - ME D - 1 0 0 t r e a t e d
r a t s
had a n enhanced a b i l i t y
t o
r e s p o n d
t o
t h e
g r o W t h s t i m u l a t i o n
i n d u c e d
b y
t h e
m i t o g e n ,
P H A .
V a r i o u s
m o d i ? c a t i o n s
o f t h e methods
o f
p r e p a r a t i o n , u s e
a n d
c o m p o s i t i o n o f
t h e W a t e r s o l u b l e e x t r a c t
o f U n c a r i a
t o m e n t o s a shoWn a n d d e s c r i b e d h e r e i n , W i l l
b e
r e a d i l y
a p p a r e n t t o t h o s e s k i l l e d i n
t h e a r t
f r o m
t h e
f o r e g o i n g
d e s c r i p t i o n s .
Such
m o d i ? c a t i o n s a r e a l s o i n t e n d e d
t o
f a l l
W i t h i n t h e s c o p e
o f
t h e
a p p e n d e d
c l a i m s .
What
i s
c l a i m e d
i s :
1 . A ethod f o r p r e p a r i n g a Water s o l u b l e e x t r a c t o f a n
U n c a r i a s p e c i e s c o m p r i s i n g :
( a ) h e a t i n g
a m i x t u r e
o f W a t e r
a n d a s u b s t a n c e s e l e c t e d
f r o m
t h e
g r o u p
c o n s i s t i n g
o f
d r i e d
r o o t s ,
b a r k a n d
b a r k
poWder o f s a i d U n c a r i a s p e c i e s a t
a
t e m p e r a t u r e o f
a p p r o x i m a t e l y
90100 C . f o r s u c h a t i m e and a t s u c h
a
r a t i o o f
s a i d s u b s t a n c e t o
s a i d
Water t o
y i e l d
a
? r s t
broWn e x t r a c t
o f
s a i d m i x t u r e
due
t o
e v a p o r a t i o n o f
s a i d
W a t e r ;
( b )
? l t e r i n g s a i d ? r s t
broWn
e x t r a c t
f r o m
s a i d
m i x t u r e ;
( c ) c e n t r i f u g i n g s a i d ? l t e r e d b r o W n e x t r a c t ;
( d )
d i a l y Z i n g
s a i d c e n t r i f u g e d
b r o W n
e x t r a c t a g a i n s t d i s
t i l l e d
W a t e r i n a d i a l y s i s t u b i n g
h a v i n g
a n e x c l u s i o n
l i m i t o f u p t o a p p r o x i m a t e l y
1 2 , 0 0 0
m o l e c u l a r W e i g h t
a t
a p p r o x i m a t e l y 4 1 5
C . f o r
2048
h o u r s t o s e p a r a t e
a W a t e r s o l u b l e e x t r a c t o f s a i d U n c a r i a s p e c i e s ; and
( e )
r e c o v e r i n g s a i d s e p a r a t e d W a t e r
s o l u b l e
e x t r a c t o f
a n
U n c a r i a
s p e c i e s .
2 . The method
o f
c l a i m 1 W h e r e i n s a i d
s u b s t a n c e
s e l e c t e d
f r o m t h e g r o u p c o n s i s t i n g o f b a r k a n d b a r k poWder o f
s a i d
U n c a r i a s p e c i e s i s
mixed
W i t h W a t e r a t a r a t i o o f 150 grams
o f
b a r k o r bark
poWder t o 5
l i t e r s
o f W a t e r .
3 . The method o f
c l a i m
1
W h e r e i n
s a i d U n c a r i a s p e c i e s
i s
s e l e c t e d f r o m t h e
g r o u p
c o n s i s t i n g
o f
t o m e n t o s a , g u i a n e n s i s ,
p t e r o p o d a ,
h o m o m a l l a , p e r r o t t e t i i a n d
r h y n c h o p y l l a .
4 .
The method o f c l a i m
1
W h e r e i n t h e s t e p o f
c e n t r i f u g i n g
t a k e s
p l a c e
a t 10003000 > < g f o r 1560
m i n u t e s .
5 . The method
o f c l a i m
1
W h e r e i n t h e s t e p o f d i a l y Z i n g
s a i d c e n t r i f u g e d broWn e x t r a c t a g a i n s t s a i d d i s t i l l e d W a t e r
t a k e s p l a c e a t a volume o f 50 10 0
m i l l i l i t e r s
o f s a i d p a r
t i c u l a t e
f r e e W a t e r
e x t r a c t p e r 50 0 150 0 m i l l i l i t e r s o f s a i d
d i s t i l l e d
W a t e r .
6 .
AWater
s o l u b l e e x t r a c t o f a n
U n c a r i a
s p e c i e s o b t a i n e d
by t h e method
o f c l a i m
1 W h e r e i n s a i d
e x t r a c t :
( a ) e x h i b i t s
UV axima
a t a p p r o x i m a t e l y
1 9 9
nm;
( b ) i s s t a b l e
t o t e m p e r a t u r e s l e s s t h a n
1 0 0
C .
f o r 24 h o u r s
a n d
s t e r i l i Z a t i o n by a u t o c l a v i n g f o r
up
t o
a t
l e a s t 2 0
m i n u t e s
a t a p p r o x i m a t e l y
1 2 1 C . ;
( c ) m a i n t a i n s b i o l o g i c a l a c t i v i t y
f o r a t
l e a s t 6
m o n t h s
When f r o Z e n i n l i q u i d f o r m a t a p p r o x i m a t e l y 2 0
C . ;
a n d
( d )
c o n s i s t s e s s e n t i a l l y
o f m o l e c u l e s h a v i n g a m o l e c u l a r
W e i g h t o f u p t o a p p r o x i m a t e l y 1 2 , 0 0 0 .
7 . AWater s o l u b l e e x t r a c t o f a n
U n c a r i a
s p e c i e s o b t a i n e d
by
t h e
method
o f c l a i m 1 .
8 .
A h a r m a c e u t i c a l c o m p o s i t i o n c o m p r i s i n g :
( a )
t h e
W a t e r
s o l u b l e
e x t r a c t
o f
a n
U n c a r i a
s p e c i e s
o f
c l a i m
7 ;
a n d
( b ) a
n o n t o x i c
i n e r t c a r r i e r
o r
d i l u e n t .
9 . The p h a r m a c e u t i c a l c o m p o s i t i o n o f c l a i m 8 W h e r e i n
s a i d
c a r r i e r o r d i l u e n t i s
s e l e c t e d
from t h e g r o u p
c o n s i s t i n g
o f
W h e a t s t a r c h
a n d s o d i u m c a r b o x y m e t h y l c e l l u l o s e .
10
20
25
30
35
40
55
-
8/9/2019 Que es el AC-11
15/15
6 , 0 3 9 , 9 4 9
9
1 0 . Amethod f o r e n h a n c i n g
t h e
immune competency o f a
mammal b y i n h i b i t i n g T N F - o t
p r o d u c t i o n
o r i n d u c i n g a p o
p t o s i s
o f
W h i t e
b l o o d
c e l l s c o m p r i s i n g a d m i n i s t e r i n g
t o s a i d
ma mma l
t h e p h a r m a c e u t i c a l c o m p o s i t i o n o f c l a i m
8
i n a n
amount e f f e c t i v e t o i n h i b i t TNF-ot p r o d u c t i o n o r t o i n d u c e
a p o p t o s i s o f
W h i t e
b l o o d
c e l l s .
1 1 . The method o f
c l a i m
10
Wherein
s a i d m a mm a l i s a
human.
1 2 . The
method
o f c l a i m 1 0 W h e r e i n
t h e s t e p
o f
admin
i s t e r i n g
s a i d
p h a r m a c e u t i c a l
c o m p o s i t i o n i s o r a l l y
a n d
W h e r e i n
s a i d p h a r m a c e u t i c a l
c o m p o s i t i o n i s i n a f o r m
s e l e c t e d f r o m t h e g r o u p c o n s i s t i n g
o f
c a p s u l e s ,
t a b l e t s ,
s y r u p s , a n d l i q u i d s .
1 3 .
A ethod
f o r
i n h i b i t i n g t h e i n ? a m m a t o r y r e s p o n s e o f
a
mammal by i n h i b i t i n g T N F - o t
p r o d u c t i o n
o r
i n d u c i n g
a p o p t o s i s o f W h i t e b l o o d c e l l s c o m p r i s i n g a d m i n i s t e r i n g t o
s a i d mammal the
p h a r m a c e u t i c a l c o m p o s i t i o n o f cl a i m 8 i n
an amount e f f e c t i v e
t o
i n h i b i t
TNF-ot
production
o r
t o
i n d u c e a p o p t o s i s o f W h i t e b l o o d c e l l s .
5
1 5
1 0
1 4 .
The method o f
c l a i m 1 3 Wherein s a i d
m a mm a l i s a
human.
1 5 . The method
o f c l a i m
1 3
W h e r e i n
t h e s t e p o f admin
i s t r a t i n g
s a i d
p h a r m a c e u t i c a l c o m p o s i t i o n i s o r a l l y a n d
W h e r e i n s a i d p h a r m a c e u t i c a l
c o m p o s i t i o n
i s i n
a f o r m
s e l e c t e d f r o m
t h e
g r o u p c o n s i s t i n g
o f
c a p s u l e s ,
t a b l e t s ,
s y r u p s ,
a n d
l i q u i d s .
1 6 . A e t h o d
f o r
d e c r e a s i n g t he p r o l i f e r a t i o n
o f l e u k e m i c
c e l l s i n a m a mm a l c o m p r i s i n g a d m i n i s t e r i n g
t o s a i d
mam
mal a n e f f e c t i v e amount o f
t h e
p h a r m a c e u t i c a l c o m p o s i t i o n
o f
c l a i m 8 .
1 7 .
The method o f
c l a i m 1 6 Wherein s a i d
m a mm a l
i s
a
human.
1 8 .
The
method
o f c l a i m
1 6
W h e r e i n
t h e
s t e p o f
admin
i s t e r i n g
s a i d
p h a r m a c e u t i c a l
c o m p o s i t i o n i s o r a l l y a n d
W h e r e i n s a i d p h a r m a c e u t i c a l c o m p o s i t i o n i s i n a f o r m
s e l e c t e d
f r o m
t h e
g r o u p c o n s i s t i n g
o f c a p s u l e s , t a b l e t s ,
s y r u p s ,
a n d
l i q u i d s .
