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B Y T

TR N G I HC

Dc

H N I

***********

L TH NGA

TNG QUAN V CC M HNH NGHIN cu


TC DNG CHNG VIM CA THUC
(KHA LUN

T T N G H I P DU c S K H A 2 0 0 3 -2 0 0 8 )

Ngi hng dn : T S . o Th Vui


Ni ihc hin

: B m n D c l

Trng i h c D c H N i
Thi gian thc hin: 022008 - 05/2008

V
I A V ^L.

H NI, THNG 5-2008

hi cm 0R
B c kt' qu bo co nh ngy hm nay, ti xin by lng bit
1 su s c ti T I. S o Thi Vui - Rg thy n tnh du dt v
hng dn ti hon thnh Kha lun ny.
Ti xin chn hnh cm n c c thy c gio trong B mn Bc l
to mi iu hin v nhit tinh gip li trong sut thi gian hc
tp v lm Kha lun.

T xin chn thnh cm n tp th Th vin trng i T)C Dc


Hi gip d t rt nhiu trong qu Irnh lm hha lun ny.
Ti xn chn thnh cm n Ban flt*m hiu trng Di c c
T Hi lun to mi iu kin thun lt cho ti hon thnh tt Kha
lun
V cui cng, ti xn by t lng bit n v hn ti gin nh, ngi
Han T bn b l nhng ngi lun c v, ng vin, ch da tinh
thn cho li nhng lc hh hhn trong hc tp v cuc sng.

T Hi. ngy 2 1 /0 5 /2 0 0 8
Sinh vin: li Th ga

MC LC
T VN ......................................................................................................................... 1
1. V I M V T H U C C H N G V I M ........................................................................ 2
1.1. T CNG V V I M .............................................................................................2
1.1.1. Khi n i m .............................................................................................................. 2
1.1.2. Nguycn nhn gy v ic m .....................................................................................2
1.1.3. Phn l o i .................................................................................................................2
1. .4. Din bin phn ng viin ................................................................................. 3
1.1.5. Cc yu t tham gia vo phn ng v ic m ....................................................5
1.2. T H U C C H N G V I M ....................................................................................... 1 ]
1.2.1. Ha dc chng v ic m ...................................................................................
1.2.2. ng dc chng vim ................................................................................ 14

2. MT S M HNH NGHIN c u TC DNG CHNG VIM


C A T H U C ...................................................................................................................... 16
2 . 1 M hnh gy vim cp v bn c p ...................................................................... 16
2.1 .1 . M hnh gy ph hn chn c h u t .......................................................... 16
2. .2. M hnh gy ph tai ch ul........................................................................ 18
2. ] .3. M hnh gy tng tnh thm thnh m c h ................................................21
2.1 .4 . M hnh gy vim mng phi................................................................... 23
2 . 1.5. M hnh gy ban ...................................................................................... 2 4
2.1 .6 . M hnh to ti u h t .................................................................................... 25

2.2. M hnh gy

vim mn t n h ...............................................................................2 6

2.2 .1 . M hnh gy u ht thc nghim ............................................................... 2 6

2.2.2. M hnh gy vim a khp thc n g h i m ..............................................28


2.3. M hnh nghin cu c ch chng v i m ..........................................................3 0
2.3 .1 . Gy kt tp bch cu a n h n ..................................................................... 3 0
2.3 .2 . Gy ha ng ng i thc b o ................................................................. 30

2.3.3. Th nghim v cc cht chuyn ha ca acid a ra ch id o n ic........... 31


2 .3 .4 . Gy gii phng cc cytokin t t bo bch c u .................................... 34
3 . B N L U N ........................................................................................................................3 6
3.1. Bn lun v m hnh nghicn cu tc dng chng vim ca th u c ...... 3 6
3.1.1. M hnh gy vicm cp v bn c p ............................................................36
3.1.2. M hnh gy vim mn t n h ....................................................................... 39
3.1 .3 . M hnh nghin cu c c h chng vim ................................................4 0
3.2. Hng la chn m hnh nghin cu thuc chng vim Vit N a m . 42

4. KT LUN V XUT.......................................................................... 45
4.1. Kt l u n .......................................................................................................................... 4 5
4.2. xut.............................................................................................................................4 6
T I L I U TH A M KH O
PH U L C

CH THCH CC T VIT TT

C O X -1

C y c lo o x y g c n a sc -1

C O X -2

C yclooxygenase-2

DM SO

Dimethyl Sulfoxid

FM LP

Form yl-L-m ethionyI-L-leucyl-Lphcnylam in

IL -]

Incrlcukin-1

IL -6

Interleukin-6

IL -8

Inlerleukin-8

LOX

Lipooxygcnasc

LPS
LTB4
N SA ID s

Lipopolysaccharid
Lcucotrien B4
Non-Stcroidal Anti-Inriammalory Drugs Thuc chng vim
khng steroid

PAF

Platclct Acivating Faclor- yu l hoi ha tiu cu

PG

Prostaglandin

P G Ej

Prostaglandin E|

PCi E 2

Prostaglandin E 2

PGE3

Prostagiandin E,

P G I2

Prostacyclin

TNF

Tumor Nccrosis Factor- yu t hoi t u

TXA2

Thromboxan A ,

T VN
Vim l mt hin tng bnh l ph hin, theo thng k c 1/3 bnh nhn n
khm hay nhp vin l c tnh trng vim. Ngy nay, nh s pht trin ca y dc
hc, con ngi c nhng hiu bit su hn v c ch phn t ca phn ng vim.
T gip tm ra cc c ch tc dng ca thuc chng vim, ng thi gi ra nhng
hng mi trong nghin cu pht trin ihuc chng vim mi. Hin nay c nhiu
thuc chng vim c s dng nh NSAIDs. glucocorticoid, enzym chng vim,
dc liu chng vim, trong NSAIDs v glucocorticoid l hai nhm thuc chng
vim kinh in, c tc dng tt trn nhiu loi vicm v c s dng ph bin.
Nhng cc thuc ny cng c nhiu lc dng khng mong mun: gy vim lot
ng tiu ha, nh hng qu trnh ng mu, to mu, xp xng...gy nguy
him cho cc bnh nhn c bit l vi cc bnh nhn vim mn tnh. V vy, vic
tm kim, nghin cu cc thuc chng vim mi c hiu qu tt. t tc dng khng
mong mun l yu cu cp thit i vi cc nh khoa hc. T lc pht hin ra ti m
nng ca mt dc liu cng nh ha dc chng vim n lc bin n tr thnh
mt ch phm thuc hon chnh l c mt chng ng di, trong giai on tin
lm sng-th tc dng dc l l khu rt quan trng. V thc hin vic th
khng th thiu cc m hnh thc nghim ph hp gip chng minh thuc thc
s c tc dng hay khng? liu lng trong khong no? c ch tc dng ra sao?
Hin nay ti Vit Nam cc m hnh nghin cu tc (lng chng vim ca
thuc cn t v hn ch cng nh cha c thng kc mt cch y . V vy
chng ti tin hnh thc hin ti "Tng quan v cc m hnh nghin cu tc
dng chng vim ca thuc" vi mc tiu:
+ Tng quan v cc m hnh nghin cu tc dng chng vim ca thuc.
+ nh gi cc m hnh nghin cu tc dng chng vicm ca thuc.
+ Bc u la chn mt s m hnh nghin cu tc dng chng vi m ca
thuc ph hp vi iu kin thc t Vit Nam.

1. VIM V THUC CHNG VIM


1.1. I CNG V V IM
1.1.1. Khi nim
Theo t in Bch khoa Dc hc: Vim l phn ng li ch ca c th do
cc m b kch thch hoc tn thng. l mt phn ng phc tp cua cc m lin
kt v ca tun hon mao mch ni h tc ng, c biu hin bng cc triu
chng sng, nng, , au v ri lon chc phn [23].
Theo V Triu An: Vim l tp hp cc phn ng t bo. phn t, m v dch
th m c th pht ng phn ng vi mi kh nng gy tn thng n tnh ton
vn ca n hay ch ng. hn ch, b hot, tiu hy nhn t tn cng ri dn sch
m b tn thng [9].
1.1.2. Nguyn nhn gy vim [21]
Nguyn nhn ngoi sinh
- Do vi sinh vt: vi khun, virus, mt s loi nm, cc vi sinh vt n bo, k
sinh trng v cn trng.
- Do cc cht ha hc: do ha cht (acid. baz..

o thuc...

-D o yu t vt l: chn thng, d vt, nhit (hng nng, hng lnh), tia phng
x. bc x...
Nguyn nhn ni sinh
- Sn phm chuyn ha: nh ur mu tng gy vim mng phi, mng lim;
aicd uric tng gy vim khp trong bnh Gt.
- H oi t kn gy vim v trng: nh hoi t chm xng i.
- Phn ng t min-, nh bnh thp khp, vim cu thn.
- Vim xung quanh t chc ung th ...
1.1.3. Phn loi
- Theo nguyn nhn: vim nhim trng v vim v trng.
- Theo v tr: vim nng, vim su hoc vim bn ngoi, vim bn trong.
- Theo dch r vim: vim Ihanh dch, vim t huyt, vim mu...ty theo dch r
vim ging huyt thanh, huyt tng hay cha nhiu bch cu thoi ha.

- Theo tin trin ca vim gm c: vim cp v vim mn. Vim cp c 4 triu


chng in hnh l sng, nng, , au v c c im l tng mnh s lng
hch cu a nhn ti m b tn thng. Vim mn c c im ltng

lng cc i thc bo. lympho bo, tng bo v bch cu i toan.


1.1.4. Din bin phn ng vicm
Qu trnh in bin ca vim c th chia thnh nm giai on, cc giai on t
nhiu an xen ln nhau hn l xy ra lin tip.
/ . 1.4.1. Giai on cm ng
Khi yu t gy vim xm nhp vo c th ti mt im no th nhng t bo
ho v li ch v h thng dch th tip xc (ng mu, b th) s gy ml phn ng
tc

khc. Nhng phn ng ban u phng ra cc tn hiu ha hc khuych tn ti

mi t bo c kh nng phn ng li nhm khoanh vng tn thng li.[9]


/ . 1.4.2. Giai on phn ng m ch mu
Phn ng ny xy ra rt sm sau tn thng v phi trin mc khc nhau
ph thuc vo s trm trng ca tn thng m. u tin l s co mch chp
nhong xut hin cc tiu ng mch do hng phn thn kinh co mch. Sau i
hin tng gin cc mch mu theo th t t cc tiu ng mch, mao mch ri n
tiu tnh mch. S gin mch dn n tng tun hon ti ch gy nn cc triu
chng nng v .
Phn ng tun hon qu mnh tln ti cc ri lon nghim trng nh gin
mch cc , dng mu chy chm li. gy tng tnh Ihm thnh mch lm thot
dch ri vim giu protein vo cc m quanh huyt qun. Do s chcn p ca dch r
vim v do mt s yu t mch mu (lit thn kinh vn mch, t ho ni mc sng
to, tng nht ca m u...) gy mu lm mt tun hon t ng mch sang tnh
mch, thiu oxy, gy ri lon chuyn ha. lm tn thng t chc v vicm pht tri n
lon din (biu hin lm sng l ph v au). [6. 15].

1.1.4.3. Giai on phn ng t bo


Phn ng t ho l phn ng c bn nht phn nh kh nng bo v ca c th
chng vicm. trong bch cu ng vai tr quan trng nht. Hot ng ca bch
cu ti vim gm hai hin tng xy ra k tip nhau:

Bch cu thot mch


Bnh thng bch cu ch dnh vi ni m mc thp. Khi c vim, di tc
ng ca cc cht trung gian ha hc (yu t hoi t u (TNF), intcrlcukin-1 (IL-1),
prostacyclin (P G I,)...) th bch cu tng kh nng bm dnh vi t bo ni m. Sau
khi dnh vo cc t bo ni m, bch cu chuyn ng nh dc theo b mt ni m,
lun nhng chn gi vo k h gia cc t bo ni m ri xuyn qua vo khong
gian bo ngoi mao mch. Tip theo, bch cu di chuyn Irong m k v pha m
vim do kch thch ha ng ng. Cc cht gy ha ng ng bch cu l: cc sn
phm cua vi khun (cc peptid c cc acid amin ln cng l N-formyl-methionin);
cc sn phm ca h Ihng b th b hot ha (C3a, C5a); prostaglandin, leucotrien:
cc cytokin; fibrin v cc sn phm phn hy ca fibrin [5. 6. 15].
Hin tng thc bo v thot ht
Khi ti vim, bch cu nhn bit v dnh vi i tng b thc bo. Sau .
bo tng ca thc bo ko di ra to thnh gi tc tin n bao quanh ly i tng
(nut), sp gi tc li to thnh hc thc bo. Mng ca hc thc bo st nhp vi
mng bo tng ca ht lysosom. ri cc thnh phn ca lysosom vo h thc
bo phn hy i tng thc ho (bch cu mt ht).[7].

1.1.4.4. Giai on ton thn


Khi vim chim mt th tch m ln th n pht tn cc yu t hot ha i xa
qua tun hon mu vi s lng lm cc trung tm thn kinh chuyn bit tham
gia. Cc trung tm y gi i xung ng thn kinh lm hav i b my n nhit ca
c th v kch thch vng lin yn l b phn iu ha c ch p ng i vi cc
tn cng. Kt qu l c cc phn ng ton thn nh: st. tng hch cu. tng tc
mu lng, ri lon chuvn ha (glucid. lipid, protcin)....[9J.

. 1.4.5. Giai on thnh so hay chuyn sang mn tnh


Sau mt thi gian nhng hot ng thoi ha ngng, thay vo l phn ng
tng hp. Khi y nguyn bo x gi mt vai tr ch yu. Chng hnh thnh si
collagen v nhng phn l proteoglycan cn cho vic sa cha m b vim. Khi
vim kco di nhiu ngy th vim chuyn sang mn tnh, Irong qu trnh ph hy
v hn gn tn thng m xy ra ng thi. Vim u ht l mt hnh thi c hit ca

vim mn tnh, trong i thc bo chim u th v chuyn thnh cc t bo dng


biu m (epitheloid cell)- l cc t bo khng c kh nng thc bo nhng c Ih bt
gi cc mnh nh. Cc i thc bo cng c th hp li thnh cc t ho khng l
gip chng c kh nng thc bo nhng i tng ln. u ht c bao bc bi v
bc x gm collagen, proteoglycan lm cho khi u ht khng mu ti, thuc
khng thm nhp c vo trong nn vim kh cha v ko di.[5. 9]
1.1.5. Cc yu t tham gia vo phn ng vim
Vim l mt phn ng phc tp, c s tham gia ca nhiu yu t t bo v Ih
dch.

. 1.5.1. Cc t bo tham gia vo phan ng vim


Bch cu a nhn trung tnh
Bch cu a nhn trung tnh chim khong 60-70% tng s bch cu, c chc
nng chnh l tm kim ph hy vi khun, l hng ro bo v u ticn ca c th vi
nhim trng. Cc bch cu ny cha nhiu ht bn trong t bo. Thnh phn chnh
ca cc ht ny l cc cnzym c kh nng ticu ha cc thnh phn cu trc ca vi
khun cng nh phn hy m ca vt ch.[7,21 ]
Bch cu i kim v dng bo
L nhng t bo quan trng trong phn ng vim. Bch cu i kim tun hon
trong mu v c huy ng khi c d ng. Dng bo c tr v thun thc ti m.
Cc ht a kim cha cc cht trung gian nh histamin, serin protease, sulatase,
glycosidasc v carboxypeptidase A.[ 13]
Bch cu i toan
Bo tng cha cc ht c hiu a acid. trong cha nhiu protcin c hot tnh
sinh hc, c bit l protein EBP (eosinophilic basic protein) rt c vi k sinh
trng. Bch cu i toan cn c tc ng iu ha v kim sot qu trnh vim.[5]
Bch cu n nhn v i thc bo
Bch cu n nhn lu hnh trong cc mao mch v c th thot khi vng
tun hon i vo m. Ti m chng c bit ha thnh cc i thc bo. Bch cu
n nhn v i thc ho l nhng t ho u tin b thu ht li vim bi nhiu
cht ha ng ng nh sn phm thoi ha ca m v mng vi khun, cc thnh

phn b th b hoi ha. phc hp khng nguyn-khng th, mnh si collagcn.


Ti v tr vim, i thc bo sn xut cc cht trung gian ha hc gy vim nh [ L - l .
IL-6, TNF-a, PG...lm khuych i phn ng ra xa.[9,13]
Lvmpho bo B, T v t bo NK [7]

Lympho bo B: tham gia vo min dch dch th. Khi khng nguyn vo c
th s gn vi t bo B c khng thd b mt tng ng ri kch thch bit ha t bo
B thnh tng bo c kh nng sn xut khng th (IgE, IgG, IgA, IgD, IgM).

Lympho bo T. l t bo chu trch nhim p ng min dch qua irung gian t


bo. C 2 dng t bo T :
- Mt dng cha khng nguyn CD4: sinh ra cc lymphokin tiu dil th l
bng cch tuyn m. hot ha cc t bo lympho khc, ng thi kch thch tng
hp globulin min dch v kch thch phn ng vim qu mn chm.
- Mt dng cha khng nguyn CD8: nhn bit khng nguyn, tn cng trc
tip cc t bo c khng nguyn l trn b mt (t bo ch), iu ha min dch, c
ch hot ng ca cc lympho khc.

T bo NK: l nhng lympho bo khng bit ha thnh lympho B hay ympho


T v tham gia vo p ng min dch qua trung gian t bo do gy c t bo.
Tiu cu
Tiu cu c th tham gia vo mi giai on ca qu trnh vim. Chng cha
nhiu cnzym v cc thnh phn ht c hot tnh vim mnh.
C c thnh phn ca m m
Gm cc l bo ni m, nguyn ho x v cc t bo c trn. Chng gi vai
tr tch cc trong vim do khng ch p ng vi cc tn hiu phin t ca bch cu
m cn iu ha c chc nng ca bch cu. Cc t bo ni m ph mt trong tt c
cc huyt qun v to thnh hng ro u tin gia cc thnh phn mu v m m.
ng vai tr l cc t bo vim quan trng.[13]

. 1.5.2. Cc cht trung gian ha hc trong phn ng vim


C c cht c ngun gc l bo

Prostaglandin
Khi t bo b tn thng, mng pho.spholipid ca l bo s b hot ha bi
phospholipase A2 to ihnh acid araehidonic. Prostaglandin l sn phm chuyn ha
ca acid arachidonic theo con ng cyclooxygenase (C O X ). C hai loi cnzym
c o x ng phn l COX-1 v COX-2. C O X -1 l en/ym c mt hu ht cc m,
chu trch nhim tng hp prostaglandin sinh tham gia vo cc chc nng bnh
thng ca mt s c quan trong c Ihc (c bit ng tiu ha, tiu cu v thn),
n nh ni m v bo v t' bo. C O X -2 c xcm l enzym tin vicm, ch xut
hin ti cc t chc b tn thng v c vai tr to ra cc prostaglandin gy vim.
Bnh Ihng nng COX-2 trong t bo rt thp. Trong cc m vim, kch thch
vim gy cm ng cc t bo tham gia vo phn ng vim (bch cu n nhn, i
thc bo, t bo ni m c...) t hot ha mnh COX-2 v nng COX-2 c th
tng cao gp 80 ln bnh thng.[ 13,20]
Trong vim cp, cc m v mch mu ti ch sn xut PGE, v PGI2. Trong vicm
mn, cc bch cu n nhn v i thc bo gii phng PGE, v T X A 2.

Prostaglandin c nhiu tc dng khc nhau 9


P (E ', c receptor trn t bo ni m, t ho c trn thnh mch, t ho trung
tm iu nhit vng di i. N gy tng tnh thm mch, gy st.
P G E , : c receptor trn cc t ho c trn. N c tc dng gin mch gy han
v au.
P G E V c rcceptor trcn t bo ni m mch m n lm tng tnh thm, trcn cc t
bo nim mc d dy v trong mt s nron.
P G I : c rcccptor trcn mng t' bo ni m mch v t bo C trn. N c tc
dng gin mch v tng tnh thm thnh mch gy ph. ban , tng au. st.
TXA-t: c gii phng sau khi tiu cu kt dnh vi ni mch b tn thng.
TXA? kch thch s kt tp tiu cu v c tc dng co mch.
Leucotrien
Ngoi con ng c o x . acid arachidonic c thc c chuyn ha theo con
ng lipooxvgenase (L O X ) to ra cc leucotrien. Cc lcucotrien c tng
hp ch yu hi cc t bo vim nh bch cu a nhn, i thc ho v ng bo.

Leucotrien B 4 c tnh ha ng ng vi hch cu a nhn irung tnh, bch cu n


nhn v mt s t bo lympho; kch thch bm dnh bch cu a nhn trung tnh vo
t ho ni m. kch thch i thc ho v lympho bo tng sinh v sn xut cytokin

[9J.
Cc acid amin hot mch

Histamin
Ngun gc: histamin c ngun gc ch yu t dng bo, ngoi ra cn c
trong bch cu i kim v tiu cu. N c to thnh v d tr Irong cc ht ca
cc t bo ny. Histamin c gii phng do qu trnh mt hl ca cc t ho khi
p ng vi cc kch thch.[9, 13]
Vai tr trong vim: histamin gy gin tiu ng mch v c coi l cht trung
gian chnh trong giai on khi u tng tnh thm thnh mch. N gv co cc t
bo ni mc ca tiu tnh mch, gin rng vng ni gia cc t bo ny v cho huyt
tng thm qua vo ni m.[5. 13]

Serototiin
Ngun gc: serotonn c ngun gc t tiu cu v cc t ho a crom rut.
S kt dnh tiu cu s gii phng serotonin. 13)
Vai tr Irong vim: lng t histamin.
Yu t hot ha tiu cu (PA F)
PAF c hnh thnh trong mng cc tiu cu. t bo ni m. hch cu a
nhn trung tnh (sau khi b kch thch), bch cu i toan, t bo cn nhn, t bo li
v cu thn t mt loi phospholipid nh phospholipase A2.
Tc dng ca PAF l hot ha bch cu a nhn trung lnh nhm kch thch
chng bm dnh vo t ho ni m. PAF cng gv v ht, m u cho vic tit cc
enzym Iv gii v gii phng superoxyd. Mt tc dng khc l lm tng tnh thm
thnh mch, gy ph. Ngoi ra n c tc dng co tht phc' qun lm cho cn hen
nng hn v cng tc dng ln cc t bo mu (gim bch cu, gim tiu cu) [9J.

Cc thnh phn ca lysosom


Cc ht lysosom cha trong cc bch cu a nhn trung tnh v bch cu n
nhn. Trong phn ng vicm cc ht ny c gii phng. Thnh phn chnh ca cc
ht ny l cc enzym c kh nng ticu hy cc thnh phn cu trc ca vi khun v
m ca vt ch [21 ].
Cc cytokin
Cvtokin bn cht l nhng glycoprotein. do nhiu loi t bo sn xut nhng
ch yu t lvmpho bo v i thc bo b hot ha. Cytokin do t ho lympho to
ra gi l cc lymphokin, do t bo n nhn to ra gi l monokin v c gi di
mt tn chung l cc interleukin (IL). Chng iu ha hoi ng trn mi h thng
c quan v tham gia iu khin mi giai on ca p ng vicm l khi u n sa
cha [9].
Ti v tr tn thng: IL-1. IL-6. TNF-a tc ng ln cc nguyn bo x, t bo
ni m. gy tn thng t bo, gii phng nhiu cht c hot tnh sinh l gy gin
mch, tng tnh thm thnh mch, tp trung bch cu ti vicm. L-8 c tc dng
ha ng ng c bit mnh vi hch cu a nhn trung tnh.
Ton thn: IL -I, IL-6, TNF-a tc ng ln vng di i lm tng thn nhit
(gy st), tng tng hp ACTH. hvdrocortison. Cc cytokin cn kch thch t bo
gan sn xut protein phn ng c (CRP). Cc CRP ny nhanh chng gn vo vi
khun kco thm h Ih vo to Ihnh mt phc hp hp dn cho cc thc bo vy
bt. x l [13].
C c gc oxv t do
Gc oxy t do hnh thnh trong li th i thc bo hot ha. Chng tiu hy
i tng thc bo. Trong vim khi i thc bo b ly gii s gv trn gc t do ra
ngoi, to iu kin cho qu trnh pcroxyd ha lipid mng t bo gy tng lnh (hm
mch, lo iu kin thun li cho vic gii phng acid arachidonic t phospholipid
mng t bo tng hp cc cht trung gian ha hc 15].
Oxyd nit (NO)
NO gn vi na Hem trn guaniyl cyclase v hot ha enzym ny. Di tc
ng ca cc kinase. guanosin phosphat vng c tng sinh, gy gin c trn ca

huyt qun v gy gin mch, lng tnh (hm Ihnh mch, tng sn xul cc PG
vicm. Ngoi ra NO cn lm gim t lp v kl dnh tiu cu.
NO do i thc bo sn xut s tc ng nh cc gc t do l yu t c vi t
bo vi khun, nm, virus, t bo u. Tuv nhin, nu cc i thc bo b hot ha sn
xut qu nhiu NO s gy hi cho c th nh gin mch nng v chong trong sc
nhim khun [13].
C c cht trung gian c ngun gc huyt tng /5 , 7]
Bao gm: h thng b th, h thng ng mu, h thng tiu t huyt, h
thng kinin v cc globulin min dch. Trong 4 h thng u licn c to thnh
theo kiu dng thc v c mi tng quan ln nhau.
H thng b th
Vai tr: dit khun nh cc thnh phn cui ca h thng b th; gia tng phn
ng vicm nh cc sn phm ph nh C3a, C5a khi hot ha t C1 n C5 bao gm
s opsonin ha. ha hng ng bch cu, thot ht t bo mast.
H thng ng mu
Vai tr: ngn s pht tn ca vi khun; gi vi khun v vt l ni m hot
ng thc bo mnh nht; lo thnh b khung to iu kin cho s sa cha v lnh
vt thng.
H thng kinin
Kinin cn bn l bradykinin, c vai tr: gy gin mch: cng tc ng vi PCi
gy au; gy co Iht c trn ngoi mch mu; gy tng tnh thm thnh mch do
cng tc ng vi PG nhm E trong giai on sau ca qu trnh vim: tng ha ng
ng bch cu.

H thng tiu

t huyt

Enzym gv ticu t huyt in hnh l plasmin, n c to thnh do s phn


tch plasminogen. Plasmin c vai tr quan trng Irong tiu cn t huyt. Trong phn
ng vim, n khi ng s hot ha ca h thng b the do phn lch C3 thnh cc
on, phn hy ibrin v lm tng tnh thm thnh mch.
C c globulin min dch (khng th)
Bao gm: IgG, IgA, IgM, IgE, IgD.

10

i i chim u th trong huyt thanh, vai tr [ opsonin ha, hot ha b th, gy


c t bo ph thuc khng th, trung ha ngoi c t, gy ngng kt t bo vi
khun, trung ha virus.
IgA: chim u th trong cc dch tit ph ln b mt nim mc ng h hp trn
v di, ng tiu ha. ng tit niu, sa. Vai tr l trung ha cc tc nhn gy
bnh, hot ha b th theo ng nhnh.
IgM : lm thy ch yu trong huyt thanh. N c kh nng hoi ha b th mnh
hn IgG.
IgE : nng trong huyt thanh thp, tng ln khi d ng, nhim k sinh trng.
IgE gn vi cc th th trn b mt dng ho v hch cu i kim, kch thch cc t
bo ny giai phng cc cht trung gian ha hc nh histamin, serotonin,
leucolrien...
IgD: c rt t trong huyt thanh. V tr khu tr l trn b mt t bo B. N cng
vi IgM l nhng globuiin min dch xuvn mng. IgD b mt c vai tr trong thun
thc l bo B.

1.2.

THUC CHNG VIM

1.2.1. Ha dc chng vim


1.2.1.1. Thuc chng vim khng sterod (NSAIDs) [4, 8]
Bao gm mt s thuc: aspirin, phcnlbuta/.on. indomethacin, piroxicarru
ibuprocn, celecobxid...

C ch chng vim
NSAIDs gn vo v tr hot ng dnh cho acid arachidonic trn c o x gy c
ch cnzym c o x lm cho aci arachidonic khng chuyn thnh prostagandin- cht
trung gian ha hc gy vim nn NSADs c ch phn ng vim (hnh I ).
Ngoi ra NSAIDs c ch h enzym phn hy proiein trong lysosom, lm vng
bn mng lysosom v i khng tc dng ca cc cht trung gian ha hc nh
bradykinin. histamin, serotonin. c ch ha hirng ng bch cu, c ch s di
chuyn ca bch cu ti vim.

Hnh 1: S c ch chng vim ca NSAIDs v glucocorticoid

Tc dng khng mong mun


NSAIDs gy lot d dy-t trng, ko di thi gian chy mu, gy vim thn,
gy cn hen gi, gy d tt thai nhi nu dng thuc trong 3 thng u ca Ihai
k...

C h nh chung
Chng vim: c vim cp v mn (vim khp dng ihp, thp khp, vim ct
sng dnh khp, hnh gt...)
Ngoi ra thuc cn dng gim au v h st.
1.2.1.2. Thuc chng vim steroid [4, 8]
Thuc chng vim steroid cn gi l cc glucocorticoid, bao gm mt s
thuc: hydrocortison, prednisolon, methylprcdnisolon, triamcinolon. dcxamcthason,
betamethason...

12

C ch chng vim
Glucocorticoid c ch phospholipase A2 thng qua kch thch tng hp
lipocortin lm gim tng hp acid arachidonic. do lm gim tng hp leucotrien
v prostaglandin, v vy c ch phn ng vim.
Ngoi ra n cn c tc dng c ch dng bch cu n nhn, trung tnh,
lympho bo i vo m gy khi phi phn ng vim.

Tc dng khng mong mun


Glucocorticoid gy nhiu tc dng khng mong mun nh ph, lot d dv t
trng, long xng-xp xng, teo c, ri lon phn b m. suy Ihng thn cp khi
ngng thuc t ngt, ...

C h nh
iu tr vicm khp, vim da. vim c...
Ngoi ra cn dng iu tr Ihay th hormon trong suy thng thn, iu tr cc
bnh t min, ng, sc phn v...
1.2.1.3. Enzvm chng vim
Bao gm mt s cnzym: a-chymotrypsin. trypsin, serratiopeptidase. amylase.
papain, bromelain.

C ch chng vim
Thy phn protein huyt tng, tiu hy mnh vn si to keo, cc mnh t
bo v cc fibrin kt t ti vng b tn thng ng thi kch thch hin tng thc
bo. V vy chng lm gim ph vim, ci thin kh nng lu Ihng ca mu. phc
hi lun hon mao mch m ho cung cp oxv V1 dinh dng cho cc vng
b tn thng.
iu ha cc cht trung gian ha hc ca vim nh cc protein ca pha cp,
cc cytokin. cc th th gy kt dnh trn mng bch cu.
c ch cc protcase. cc protcin thu dn gc t do.
Gim kh nng hot ha h thng b (h ca phc hp min dch mng t ho,
lm gim s nguy him ca cc phn ng qu mn [13].

Tc dng khng mong mun


Mt s enzym c h gy d ng, ri lon tiu ha (tiu chv, chn n,...)

13

C h nh
Chng vim, chng ph n sau phu thut, chn thng, trong tit niu, sn
ph khoa, tai mi hng.
1.2.2. ng dc chng vim
Theo quan im ca ng y, vim l triu chng ca c th khi b nhim c.
Nguvn nhn nhim c c the do bn trong (ph tng hot ng yu, khng sc
thanh thi cht c) hoc do bn ngoi (cn trng cn. hi ha cht, ng c thc
n...)* V th. trong ng y cc v thuc chng vim thng l cc Ihuc thanh, tiu
v hot nh thuc ihanh nhit gii c, thuc tr thp, thuc hot huvt tiu ...
C rt nhiu dc liu v bi thuc c truyn c tc dng chng vim c
s dng rng ri trong dn gian v hin nay ang c nghin cu tm ra cc
hot cht c kh nng chng vim cng nh c ch chng vim ca cc hot cht
.
Mt s dc liu chng vim [2, 3]

Kim ngn
Tn khoa hc: U m icera aponica Thunb. Capritbliaccae
B phn dng: hoa, phn trn ml l phi hay sy kh
Cng dng: Kim ngn hoa c dng ch yu cha mn nhl, mn nga,
st nng, st rt, t l v vim nhim trng ng h hp trn, vim da, vim mng
kt do sicu vi...

H e hoa
Tn khoa hc: Sophora aponica L. Fabaceac.
B phn dng: n hoa hc
Cng dng: ch yu phng nhng bin c ca bnh x va ng mch, iu
tr cc trng hp suy yu tnh mch, cc Irng hp xut huyt nh chy mu cam,
ho ra mu, t cung xut huyt, cc trng hp tn thng ngoi ra do bc x, chng
d ng. thp khp, lm vt thng chng lnh so.

Nc nc
Tn khoa hc: Oroxyum imicum Bignoniaceae.
B phn dng: v thn v ht phi hay sy kh.

14

Cng dng: cha ho, vicm ph qun, au gan, au d dy.


Ngoi ra cn c cc v dc liu c tc dng chng vim khc nh: Hong
cm, Ngu tt, Cam tho. Tam tht. Khng hot, Ct toi b. Dy au xng. Bch
hoa x, Lo quan tho di thc...
Mt s bi thuc chng vm [13]

Ngn kiu tn
Thnh phn:

Kim ngn hoa

Trc dip

Lin kiu

Kinh gii

m u x

Thng ma

Ngu bng t

Ct cnh

Bc h

Cam tho

Ch tr: cm cm, vim nhim v cc chng mn nht.

Cao tiu vim


Thnh phn:

T mc

Ngi cu

L mng tay

Ngh vng

Huyt gic
Ch tr: cm cm, mn nhl

c hot tang k sinh thang


Thnh phn:

c hot

T tn

Thc a

Phc linh

Tang k sinh

ng quy

trng

Cam tho

Tn giao

Thc dc

Ngu tt

u tm

Phng phong

Xuvn khung

Nhn sm

Ch tr: au u gi, au lng, tc lnh, thp khp lu ngy co dui kh khn.

15

2.

MT S M HNH NGHIN c u TC DNG CH NG VIM CA


THUC
Da trn nhng hiu bit v nguyn nhn gy vim, lin trin ca phn ng

vim, triu chng lm sng ca vim, ngi ta to ra cc m hnh vicm thc nghim
dng nghin cu tc dng chng vim ca thuc. Cc m hnh ny c the chia
thnh 3 loi:
- M hnh gy vim cp v bn cp
- M hnh gy vicm mn tnh
- M hnh nghin cu c ch chng vicm
2.1.

M HNH G Y V IM C P V BN C P
Vim c th do nhiu nguyn nhn gy ra nh nhim khun, thiu mu cc b,

tng tc khng nguyn-khng th, tn thng do ha cht, nhit , c hc. Tuy


nhin, d do nguyn nhn no th pha cp tnh ca phan ng vim cng xut hin
4 triu chng in hnh l sng, nng, , au. Trong Ihc nghim, ngi ta dng
cc cht ha hc to ra cc triu chng vim lng t Irn lm sng nghin cu
tc dng cua thuc. Thuc lm gim c cc triu chng ny c coi l c lc
dng chng vim cp. Trong cc phng php th gy ph (sng) l phng php
hay c s dng nht.
2.1.1. M hnh gy ph bn chn chut

Nguyn tc
M hnh ny c th dng nhiu cht gv vim khc nhau nh carrageenin,
dextran. kaolin. formaldehy. men bia, albumin trng...Khi tim cc cht ny vo
bn chn chut s kch thch gii phng cc cht trung gian ha hc nh histamin.
prostaglandin, serotonin...v kt qu l gy ph. Thuc c kh nng c ch ph bn
chn chut c coi l c tc dng chng vicm.
2.1.1.1. (y ph chn chut bng carrageenin [29]

Tin hnh
S dng chut cng c 2 ging, trng lng khong 100-150 g. chia ngu
nhin thnh cc l:

16

L chng: dng dung mi pha thuc


L i chiu: dng thuc chng vim bit
L ih: dng thuc ang nghin cu tc dng chng vicm
Chut c i qua m. Cho chut ung thuc hoc dung mi. Sau 30
phl. ticm 0.05ml dung dch carrageenin 1% vo gan bn chn tri sau ca chut.
o th tch chn chut ti cc thi im: trc khi gy vim; 1. 2. 3. 4, 5. 6. 7 v 24
gi sau khi gy vim.

nh gi
T l % tng th tch bn chn ca mi chut biu th mc vim cp c
tnh theo cng thc (1):

V -V
X % = ~ L ------ X 100
y
o

tu

Trong :

x%: t l % tng th tch chn chut


V0: th tch chn chul trc khi gy vim
V,: th tch chn chut sau khi gy vim t gi
Sau tnh trung bnh t l % tng th tch chn ca cc chut trong mi l.
T l % c ch ph ca l th so vi l chng c tnh Ihco cng thc (2):

Y % - Vt%
% = C 1 Xt
0/

X 100(2)
v 7

Trong :

%: t l % gim mc ph bn chn chut

%: trung hnh t l % tng th tch chn chut l chng

% : trung hnh t l % tng th tch chn chut l th.


Cc m hnh tng t
Tng t vi cch tin hnh V1 cch nh gi nhu m hnh gy ph bn chn
chut bng carrageenin, nhiu nh nghin cu ci s dng cc cht gy vim

khc nh: hn dch kaolin 5%; dung dch lng trng trng 1%; formalin 1% (Turner
1965); dextran 1% n 3% (Turner 1965); dextran 6% (Winter, 1963); dung dch

carrageenin % thm 00 ri PGE2 hoc PG, hn dch bt men bia 2,5% : 0,1 ml
dung dch trvpsin 0,1% : dung dch coagenase ; dung dch serotonin 0,02%;

bradxkini 0,005% ; prostaglandin E2 0,1 mg/ml; gcl bentoniv, 0,1 ml Nxstatin


15000 n v: adriamycin 0,5% (gy ph chn chui nht).
2.1.1.2. Gy ph chn chut do chn thng [12, 25, 37]

Nguyn tc
Khi tc ng lc c hc mnh ln bn chn chut s gy tn thirng m v t
bo chn chut, lm hot ha phospholipase A7 gy gii phng acid arachidonic l
phospholipid mng. Acid arachidonic s chuyn ha thnh prostaglandin nhen/ym
c o x v kt qu l gy ph. M hnh ny m phng tnh trng tng t trn lm
sng khi c th b chn thng nh bong gn, ng, va p...

Tin hnh
S dng chut cng trng, chut c chia ngu nhin thnh cc l:
L chng: ung dung dch nc mui sinh l
L i chiu: ung thuc chng vim bit
L th: ung thuc ang nghin cu tc dng chng vim
Cho chut ung thuc hoc nc mui sinh l vo mi bui sng trong 4 ngy
lin tc. n ngy th 5. sau khi cho chut ung thuc hoc nc mui ln cui 1
gi th gy vim bng cch th 1 qu nng 100 g t cao 50 cm xung bn chn
chut. o thc lch bn chn chut ti cc thi im: trc khi gy vim, sau khi gy
vim 1, 3, 5 gi [18].

nh gi
Tnh t l % tng th tch chn chut, ri tnh t l % c ch ph ca l th
so vi l chng theo cng thc (1) v (2) tng t nh mc 2.1.1.1.
2.1.2. M hnh gv ph tai chu
2.1.2.1. Gy ph tai chut bng oxazolon [29]

18

Nguyn tc
M hnh gy ph tai chut hng oxazolon do Evans gii thiu ln u tin nm
1971. y l m hnh da trn phn ng qu mn chm ca c th vi oxazo1on. kt
qu l kch thch lm v ht t bo mast, gii phng cc cht trung gian gy ph.

Tin hnh
S dng chut nht c 2 ging, trng lng Irung bnh khong 25 g, chia ngu
nhin thnh cc l:
L chng: bi 0,01 ml oxa?,olon 2% trong accton
L i chiu: bi 0 . 0 1 ml oxazolon 2% trong aceton d ha tan thuc
chng vim bit ( hydrocortison 0.03% hoc indomethacin 1%)
L th: hi 0,01 ml oxazolon 2% trong aceton ha tan thuc ang
nghin cu.
Gy m chut hng halothan. Bi 0 J ml oxazolon ln vng da bng co
lng hoc bi 0,01 ml oxazolon ln phn trong ca c 2 tai chut lm chut nhy
cm vi cht kch thch oxazolon. Sau 8 ngy, gy m chut ri kch thch gy
vimbng cch bi ln pha trong

tai phi chut dung dch tng ng ca cc l

(chng, i chiu, th). Tt c cc tai tri u c gi nguyn. Sau 24 gi, git


chut ri bm 1 vng trn ng knh 8cm vng bi thuc ca c 2 tai, cn ngay
lp tc, Irng lng khc nhau th hin mc ph trong vim.
Bailey v cng s (1995) cng m la m hnh gy qu mn do tip xc chut
nht. Bi 20 |il oxazolon 2% vo mt trong v mt ngoi ca mi tai (mi mt 10 l)
chut nhy cm vi oxazolon. Sau 7 ngy, kch thch chut bng cch bi
dung dch oxazolon 2% trong aceton v du liu (aceton:du liu = 4:1) vo c 2
mt cua tai phi. Ngay sau , l i chiu v l th c bi thuc. Tai tri gi
nguyn. Sau 24 gi, git chut, bm I vng trn ng knh 6mm mi tai ri cm
i cn ngay.

nh gi
Tnh t l % lng khi lng ca tai phi so vi tai tri ri tnh gi tr trung
bnh t l % tng khi lng tai chut trong mi l. Sau tnh t l % c ch ph
ca l th so vi l chng. Cng thc tnh tng t mc 2 .1 .1 .1.

19

2 .I.2.2. (y ph tai chu bng du ba u [29]

Nguyn tc
M hnh gy ph tai chut hng du ba u do Tonelli v cng s xul
(1965) dng nh gi ng thi tc dng chng vim v tc dng tco tuyn

ca cc stcroid. Theo kt qu nghin cu dc l hin i, du ba u dng lich


gy gii phng histamin l cht gv gin mch, tng tnh thm thnh mch v kt
qu l gy ph.

Tin hnh
Th nghim c th thc hin trn chut nht c trng lng 22 g hoc chut
cng c trng lng 70g. chut c chia ngu nhin thnh cc l:
L chng: dng dung mi pha thuc
L i chiu: dng thuc chng vim bit.
L th: dng thuc ang nghin cu tc dng chng vim.
Chun b hn hp dung mi gm c du ba u: ethanol: pyridine: ethyl ether
(t l 1:10:20:69 chut nht v 4 :10 :20 :6 6 chut cng). Thuc di chiu v thuc
th dc ha tan trong dung mi ny vi nng 0,03 n 1 mg/ml nu th nghim
trn chut nht v nng cao hn t 3 n 10 ln nu th nghim trcn chut cng.
Gy m chut ri bi ln c 2 mt ca tai phi cc dung dch tng ng cho
mi l (0,01 ml vi chut nht v 0,02 ml vi chut cng). Tt c cc tai tri c
gi nguyn. Sau 4 gi, git chut hng thuc m, ct 2 tai v bm 1 vng trn
dng knh 8mm mi tai ri em cn ngay, trng lng khc nhau th hin mc
ph trong vim. nh gi nh hng trcn tuyn c th 48 gi sau khi bi thuc
s git chut ri ct luyn c v cm cn, tnh ra s mg tuyn c/100 g th trng
chut.

nh gi
Tnh t l % tng khi lng ca tai phi so vi tai tri v t l % c ch ph
ca l th so vi l chng theo cng thc tng t nh mc 2 .1 .1 .1.
Tnh t l % gim trng lng tuyn c ca l th so vi l chng c nh gi
tc dng lm teo tuyn c ca thuc.

20

Tng t vi cch tin hnh trn ta cng c th dng cc m hnh gv ph tai


chut bng acid arachidonic, phorbol myristate acelat. telradccanoyl phorbol acctat,
capsaicin, xylene.
2.1.3. M hnh gv tng tnh thni thnh mch

Nguyn tc
Cc cht gy vicm kch thch gii phng cc cht trung gian nh histamin,
prostaglandin. leucotricn s lm gin cc tiu ng mch v tiu tnh mch, tng
tnh thm thnh mch. Kt qu l dch v protein huyt tng b thot ra gy ph.
Cc thuc c kh nng c ch tng tnh thm thnh mch s c tc dng gim ph,
chng vim.
2.1.3.1.G y tng tnh thm bng phenethvlainn [29]

Tin hnh
S dng chut cng c, trng lng 160-200 g, chut c chia ngu nhin
thnh cc l:
L chng: dng dung mi pha thuc
L i chiu: dng thuc chng vim bit
L Ih: dng thuc ang nghin cu tc dng chng vim
Co lng vng bng chut, tim tnh mch dung dch xanh Evan ]% vi liu 5
mg/kg. Sau 1 gi, cho chut ung thuc hoc dung mi. Sau 30 pht, gy m
chut bng clhcr ri tim trong da 0,05 ml dung dch phenethylamin 0,01% c 3 v
tr phi, tri v Ircn bng. Sau 90 pht, git chut bng ether ri tin hnh o ng
knh vng da b nhum xanh hoc ct vng da b nhum xanh em ngm vo dung
dch natri clorid 0.9% . sau khong 24 gi lc ly dch ri em o quang.

nh gi
o ng knh tnh din tch vng da b nhum mu xanh hoc tnh nng
dung dch xanh Evan thot mch. Tnh gi tr trung hnh cho tng l. Sau
tnh ti l % c ch s thot mch xanh Evan ca l th so vi l chng theo cng
thc tng t cng thc (2) mc 2.1.1.1.

21

2.1.3.2. Gy tng tnh thm thnh mch hng acid acetic [17]

Tin hnh
S dng chut nht trng, trng lng 8-22 g, chut c chia ngu nhin
thnh cc l:
L chng: dng nc mui sinh l
L i chiu: dng thuc chng vim c bit
L th: dng thuc ang nghin cu tc dng chng vim
Cho chut ung thuc hoc nc mui sinh l. Sau 30 pht, lim tnh mch
ui chut 0,2 ml dung dch xanh methylen 0.5% pha trong nc mui sinh l. Sau
3 phl. tim mng bng 4 ml dung dch acid acctic 0.3%. Sau 1 gi, gil chut, dch
bng c ht ring vo tng ng nghim, l tm, kh c v o mt quang
trn my o quang d nh lng cht mu thot ra khi lng mch [24].

nh gi
Tnh nng xanh mcthylen thot mch trn mi chut. Tnh gi tr trung
bnh cho tng l. Tnh t l % c ch thot mch ca l th so vi l chng theo
cng thc tng t cng thc (2) mc 2 . I .I .I .
2.1.3.3. Gv tng tnh thm thnh mch bng oxazolon [29]
Zentel v Topert (1994) dng oxazolon gy ihot mch xanh Evan nh gi
tc dng chng vim ti ch ca glucocorlicoid.

Tin hnh
S dng chut nht c, chut c chia ngu nhin thnh cc l:
L chng: dng dung mi pha thuc
L i chiu: dng thuc chng vicm bit
L th: dng thuc ang nghin cu lc dng chng vicm
Co lng sn tri chut ri bi vo 50 nl dung dch oxazolon 40% trong
ethanol (din tch bi khong 4 cm2) chut nhy cm vi cht kch thch. Sau
13 ngy, tim tnh mch chut 0,2 ml dung dch xanh Evan 0,5%. Ngay sau , bi
20 p.1 oxazolon 4% trong ethanol vo sn phi chut co lng (din tch bi
khong 6 cm2). Sau 3 gi, bi thuc hoc dung mi vo vng da b kch thch. Sau

22

24 gi. git chut v ct vng da b kch thch, ngm trong dung dch NaCI 0,9%
khong 24 gi, lc ly dch em i o quang bc sng 623 nm.

nh gi
Tnh nng dung dch xanh Evan thoi mch. Tnh t l % c ch s thot
mch xanh Evan ca l th so vi l chng theo cng chc tng t cng thc (2)
mc 2.1.1.1.
2.1.4. M hnh gv vim mng phi [29]

Nguyn tc
Vim mng phi l mt hin tng v vim r dch ph bin ngi. Trong
cc th nghim trn ng vl. c Ihc gy vim mng phi bng cc cht kch Ihch
nh histamin, bradykinin. prostaglandiru yu t gy mt ht t ho mast, dextran,
khng nguyn, vi khun v cc cht kch thch khng c hiu nh turpentin hay
carrageenin. Vim mng phi gy ra bi carragcenin chut c xcm l mt m
hnh gv vim cp rt tt m trong s thot dch, s di chuyn ca hch cu v
cc ch s sinh ha khc licn quan ti phn ng vim c th c o d dng trong
dch r.

Tin hnh
S dng chut cng c. trng lng 220-260 g, chia ngu nhin thnh cc l:
L chng: dng dung mi pha thuc
L i chiu: dng thuc chng vim bit
L th: dng thuc ang nghin cu tc dng chng vim.
Gy m chut bng ether. co lng bn sn phi ri lau cn, rch mt vt nh
vo trong da di chn phi trc gia xng sn 7 v 8. m rng vl rch, bc
l C lin sn ri rch m t vt nng hn trn , thng qua vt rch tim vo

khoang mng phi 0.1 ml dung dch carragecnin 2%, vic tim phi c thc hin
nhanh trnh gy tn Ihng phi, vt thng c ng kn li bng mt kp.
Sau cho chut dng thuc hoc dung mi vo cc thi im 1, 24, 48 gi
sau khi lim carragccnin.
72 gi sau khi tim carragcenin tin hnh git chut bng cthcr, ht hc dch r
mng phi vo trong mt ng c chia vch xc nh th tch dch r.

23

Ngoi m hnh trn, c th gy vicm mng phi chut cng bng tinh du
thng vi cch tin hnh v nh gi kt qu tng t [ 19|.

nh gi
Tnh gi Ir trung bnh ca th tch dch r vim mi l v so snh l th vi
l chng. Dng cc liu khc nhau c ih xc nh c ED50.
Mt s thng s c th xc nh:
Xc nh s lng hch cutrong dch r bng mt my dm
Xc nh hot lnh ca cc enzym trong lysosom

Xc nh bronectin

X c nh PGE2

2.1.5. M hnh gy ban [29]

Nguyn tc
M hnh gy ban bng tia u v c Wilhelmi m t ln u tin (1949),
ng nhn thy kh nng lm chm s pht trin ban do tia u v ca
phenylbutazon v cc thuc chng vim khng steroid. Sau cc nh khoa hc
khc m rng v ci tin phiig php ny bng cc cch kch thch khc.

Tin hnh
S dng chut lang trng c 2 ging, trng lng khong 350 g, chut c
chia ngu nhin thnh cc l:
L chng: dng dung mi pha thuc
L i chiu: dng thuc chng vim bit (indomethacin liu 1,5
mg/kg: phenylbutazon liu 4 mg/kg: acid acetylsalicylal liu 60 mg/kg).
L th: dng ihuc ang nghin cu tc dng chng vim.
Trc khi tin hnh th nghim 18 gi, chut dc co lng 2 bn sn v Irn
lng. Cho chut ung 1/2 lng thuc nghin cu hoc dung mi. Sau chut
c t vo trong ] li da c c 16 (kch thc 1.5 X 2.5 cm) cho php tia
u v ch chiu vo vng ny. S dng n t ngoi nguyn bn Hanau 600W, lm
nng n 30 pht trc khi dng v t n c nh, cch cc con vt 20cm. Chiu
tia u v trong 2 pht ri cho chut ung nt 1/2 lng thuc hoc dung mi cn li.
Ban c ghi li ti thi im 2 gi v 4 gi sau khi chiu tia u v .

24

Ngoi tia u v , tia X cng c s dng l vu t kch thch gyban (m


hnh do Ilirabayashi v Graham xut, 1969) [39].

nh gi
Da vo phng php tnh im nh gi mc ban trn mi chut :
0 = khng ban
1 = ban yu
2 = ban mnh
4 = ban rt mnh.
Tnh im trung bnh ca mi l. Sau tnh t l % c ch ban ca l th
so vi l chng theo cng thc tng t cng thc (2) mc 2 .1 .1 .1.
Nhng chut vi kt qu l 0 v 1 c xem l c bo v. Cc kl qu
thu c sau 2 v 4 gi c th s b cho bit khong thi gian tc dng v c th
tnh c EDS().
2.1.6. M hnh to ti II ht [29, 39]

Nguyn tc
M hnh to ti 11 ht do Selye pht minh (1953) v c Roberl v Nezamis
ci tin (1957). M hnh s dng du ba u [ cht kch thch gy ra mt vim bn
cp tng t tnh trng vim v khun do tng mt th tch ln dch Ihol mch.

Tin hnh
S dng chut cng c 2 ging, trng lng 150-200 g, chut c chia ngu
nhin thnh cc l:
L chng: dng dung mi pha thuc
L i chiu: dng thuc chng vim bit (indomethiicin)
L th: dng Ihuc ang nghin cu tc dng chng vim
Lng chut dc co lng v st trng. Gy m chut, dng mt kim rt mng
tim 20 ml khng kh vo vng da gia lng. Sau , tim 0.5 ml dung dch du ba
u 1% trong du vrng vo trong ti khng kh. trnh lt kh. Sau 48 gi. rt
khng kh trong ti. Sau , hng ngy cho chut dng thuc hoc dung mi.
nh gi tc dng ti ch, thuc c tim trc tip vo ti khng kh cng thi

25

im kch Ihch. Vo ngy Ih 4 hoc th 5. git chut, m ti v thu dch vo trong


xilanh thy tinh.
M hnh trn c th dng cc cht kch thch khc nh carrageenin (Boris v
Stevenson.1965), D-a-tocopherol (Glcnn v cng s. 1963).

nh gi
Tnh th tch trung hnh dch thu c ca cc l. Tnh ti ] % c ch vim ca
l th so vi l chng theo cng thc tng t cng thc (2) mc 2.1.1.1.
2.2. M HNH C.Y V IM MN TNH
2.2.1. M hnh gy u ht (hc nghim

Nguyn tc
Khi a vo c thc mt vt l khng c kh nng hp thu c nh amian.
bng...th c the s phn ng bng cch tp trung nhiu loi t ho lo ra m bo
li v nguyn bo si bao quanh vt l, to Ihnh mt khi u gi l u ht thc
nghim. Qu trnh tin trin to u ht thc nghim tng t vi tin trin ca mt
vim mn tnh. Mt thuc c kh nng c ch s hnh thnh u ht s gp phn iu
tr cc bnh vicm mn lnh. Vi cc cht kch thch khc nhau ta c cc m hnh gy
u ht thc nghim khc nhau.
2.2.1.1. (y u ht thc nghim bng amian [1 8 ,1 1 ]
M hnh tin hnh theo phng php ca Ducrol. Julou v cng s (1963).

Tin hnh
S dng chut cng trng c 2 ging, trng lng 100-140 g. chut c chia
ngu nhin thnh cc l
L chng: dng nc mui sinh l
L i chng: dng Ihuc chng vim bit
L th: dng thuc ang nghin cu lc dng chng vim.
Dng I mu si amian ng knh khong 2 mm. trng lng 30 I mg c
v trn v sy tit khun trong 2 gi 160"C.
Chut c gy m, co sch lng vng lng pha trn. Dng mi ko bm
mi l nh da ri un mi ko vo tch da lng ra khi c. cy si amian vo

26

ni bc lch. t kp hoc khu ni lin ch m trn lng. Phu thut lin hnh
trong iu kin v khun.
Cho chut ung hoc tim di da thuc hoc nc mui sinh l vo mi bui
sng trong 5 ngy lin lc, ln du cho thuc ngay sau khi cy si amian. Chiu
ngy th 5 k t ngy cy amian. git chut hng cloroform. bc tch khi u v cn
ti ngay.

nh gi
Tnh trng lng thc ca u ht bng Irng lng cn c tr i trng lng
ca si amian cy vo. Tnh trng lng trung bnh ca u ht cc l. Tnh t l %
c ch u ht ca l th so vi l chng.
2.2.1.2. (jrv u ht hc nghim bng bng [29]
y l m hnh gy u ht thc nghim u tin do Mcicr v cng s (1950)
tin hnh.

Tin hnh
S dng chut cng c, trng lng Irung bnh khong 200g, chia ngu nhin
thnh cc l
L chng: dng nc mui sinh l
L i chiu: dng thuc chng vicm bit
L th: dng thuc ang nghin cu tc dng chng vicm
Gy m chut, co lng lng v st trng bng ethanol 70". Rch 1 vt tht
lng, dng mt km to nhng ng di da v t lit vin gc bng c tit
Irng vo c 2 bn xng b vai. Cho chul ung thuc hoc dung mi lin tc
trong 7 ngy. Ngy th 8, git chut, bc tch u ht v sy kh n khi lng
khng i ri cn.
Theo kinh nghim ca cc nh nghicn cu th s to thnh u ht s mnh hn
khi gc bng c tm carrageenin.

nh gi
Tnh trng lng kh thc ca u ht ri tnh gi tr trung hnh ca mi l. Tnh
t l % c ch u ht ca l th so vi l chng.
2.2.1.3. Mt s m hnh gy 11 ht thc nghim khc [29, 39]

27

Vi cch tin hnh v nh gi tng t cc m hnh trn, cc nh nghin cu


xut, ci tin thm nhiu m hnh gy u ht thc nghim khc nh gy p xc
bng tinh du thng (Levy, 1968); gy u ht bng mnh knh (Vogcl, 1970): gy u
ht bng bt bin (Saxena. 1960); gy u ht hng carraggecnin trn chut lang
(Robcrtson v Schwartz,1953), trn th (McCandless, 1960), chut cng (Prodi v
Romeo, 1967); gy u ht hng polyvinylclorid (Rudas, 1960)....
2.2.2. M hnh gv vim a khp thc nghim
2.2.2.2. Gy vim a khp thc nghim bng cht b tr Freund [19, 39]
M hnh tin hnh theo phng php ca Ncvvbould B. B. (1963). Cht h tr
Freund l hn hp ca cc vi khun Mxcohacterium M. bntyricum, M. tubercosis,

M.phlei) cht c pha trong paran lng hoc du khong hoc du thc vi.
Khi tim cht ny vo trong c th chut cng s gy hi chng ging vim khp.

Tin hnh
S dng chut cng c trng, trng lng trung hnh khong 200 g, chut
c chia ngu nhicn Ihnh cc l:
L chng: dng nc mui sinh l
L i chiu: dng thuc chng vim bit
L th: dng thuc ang nghin cu tc dng chng vim.
Cho chut ung thuc hoc nc mui sinh l. Sau 1 ngy, o dy bn chn
phi sau ca chut. Tim vo gan bn chn phi sau 0.05 mi cht b tr. Cho chut
ung thuc 13 ngy lin tc k t khi tim cht b tr. n ngy th 13, o dy
bn chn phi sau ca chut.
VVard v cng s (1962) tin hnh gy vim a khp bng cht sp D phn
lp t trc khun lao vi cch lm tng l trcn.

nh gi
Tnh li l % tng dy chn chul trc khi tim v 13 ngy sau khi licm
cht b tr. Sau tnh trung bnh t l % tng dy chn ca cc chut trong mi
l. T tnh t l % c ch tng dy ca l th so vi l chng. Cc cng thc
tnh tng t mc 2.1.1.1.

28

Ngoi ra c th nh gi cc tn thng th pht (nh sng bn chn tri sau,


sng cc bn chn trc, sng cc lai v sng ui) da vo mc nghim trng
ca tn thng: bnh thng, nh. nng va v nng.

2.2.2.X Gy vim da khp thc nghim bng Mycoplasma arthritis [19]


M hnh tin hnh theo phng php ca Ward v Russel (1962), Wiesinger
(1964).

Tin hnh
S dng chut cng trng, trng lng 120-150 g, chut c chia ngu nhin
thnh cc l
L chng: dng dung mi pha thuc
L i chiu: dng thuc chng vim bit
L th: dng thuc ang nghin cu tc dng chng vim.
Chun b Mycopasm arthritis: nghin mt mnh sarcom lympho Murphy c
cha Mycopiasma arthris. Sau pha thnh hn dch trong NaCl 0,9% v cho
thm 400.000 n v penicillin v 1.000.000 n v colislin mclhansulonat. Hn
dch c ly tm trong 30 pht, gi li dch ni pha trn.
To dch r gy vim khp: Tim 30 ml khng kh v khun vo di da lng
chut e to 1 ti kh, ri tim 2 ml dch cha Mxcopsma arthritis thu c trn
vo ti kh. Sau 6-10 ngy, ht dch t trong ti, dch ny c cha nhiu vi khun

Mvcopasma rthritis, th nghim lin hnh trong iu kin v khun.


Gy vim khp: tim mng bng chut iml hn hp ng the tch thuc hoc
dung mi v dung dch deXtran 6%. Sau cho chut ung hoc ticm di da thuc
hoc dung mi hng ngy trong 8 ngy icn tc. Hng ngy quan sl v ghi li cc
ch s vim.

nh gi
Quan st hng ngy cc nhm khp: khp chy-e chn trc v sau; khp
xng c chn trc v sau; khp gia cc t ngn chn trc v sau. T xc
nh ch s vim khp da vo phng php tnh im:
0: bnh thng
1: ban nh

29

2: va ban d va sng
3: sng ty.
Cng s im ca cc ngy ta c mt ch s vim khp.
Tnh t l % c ch vim khp ca l th so vi l chng theo cng Ihc tng
t cng thc (2) mc 2.1.1.1.
2.3. M HNH NGHIN CXi c C H CHNG VIM
2.3.1. Gy kt tp bch cu a nhn [29]

Nguyn tc
Khi c lc nhn gy vim tn cng vo c th. chng s to ra cc cht ha
ng ng thu ht v tp trung bch cu li ni c cc cht ha ng ng . S c
mt qu nhiu bch cu s lm khuch i phn ng vim gy ra nhng tn thng
trm trng cho m v c th. V vv. mt trong nhng c ch chng vicm l c ch
ha ng ng bch cu. Trong m hnh ih nghim ny s dng cht gy ha ng
ng bch cu l fo)Tnyl-L-mcthionyl L"lcucyl-L-phcnylamin (FMLP).

Tin hnh
Chun b t bo bch cu a nhn: Tim vo mng bng chut cng 10 ml
dung dch casein natri 6%. Sau 17 gi. Ihu dch r mng bng to hn dch cc
t bo bch cu a nhn. Cc t bo c ra 2 ln trong dung dch nc mui ng
trng ri pha thnh hn dch vi nng 15 X 106 t bo/ml.
Gy kt tp bch cu a nhn: Thuc th v thuc i chiu (pcntoxiphvllin)
c ha tan trong dung dch nc mui ng trng. Hn dch t ho c li vi
thuc trong 10 pht ri thm FMLP pha trong dimethvl sulfoxid (DMSO) gv kt
p bch cu. S kl tp bch cu a nhn c thc hin irong my tp trung Born.

nh gi
So snh s kt tp bch cu da nhn gia nhm th v nhm chng da Irn
kt qu o t my.
2.3.2. Gy ha ng ng i thc bo [30]

Nguyn tc
M hnh s dng mt cht gv ha ng ng i thc ho v qua nh gi
kh nng c ch ha ng ng i thc bo ca thuc.

30

Tin hnh
S dng chut cng c. trng lng 200-220 g. Dng Ihioglycolk l cht
gy ha ng ng i thc bo.
Chun b cc t bo i thc ho: tim mng bng chut 5 ml canh
thi og lyco Hat 3%. 3 ngy lin tip sau khi tim thioglycollat cho chut ung thuc
hoc nc mui, Vo ngy Ihr 4, ihu ly cc t bo trong dch r mng bng bng
cch ra khoang mng bng vi dung dch nc mui ng trng. Cc t bo c
ra 2 In vi nc mui ri pha thnh hn dch nng 1X 10fi t bo/ml trong mi
trng lnh RPM I-1640 khng c phcnol v c b sung huyt thanh b 10%.
pcnicillin 100 Ul/ml v streptomcin 100 ig/ml.
Gy ha ng ng i thc bo: cc t ho c 3 7 c v 5% C 0 2 trong 2
gi cho cc i ihc bo bm vo b mt a nui cy. Cc t bo khng bm sc
b loi b hng cch ra mnh vi nc mui dng trng m. 90% cc t bo bm
vo a l cc i thc ho.

nh gi
S lng i thc bo c m bng my huyt tc k. So snh kt qu gia
mu th v mu chng.
2.3.3. Th nghim v cc cht chuyn ha ca acid arachidonic [29]
2.3.3.I. Th nghim oxv ha acid arachidonic bi CO X-1

Tin hnh
Ly 50 Jil cnzym COX-1 ti t hp tinh khit nng 1 ng/ml pha vo trong
Tris-HCl 100 mM, EDTA 0,5 mM pH 8,0. phcnol 1 mM, hcmatin 1-iM ri vi 2
dung dch cht c ch hoc DMSO (mu chng) trong 15 pht. Sau phn ng
c bt u bng cch thm 5 |j1 [ MC1- acid irachidonic 1 f.iM (0.005 jiQ) thu
c nng cui cng l 0.1 jM. nhit phng. Sau 7 pht, phn ng c
dng li hng cch thm 5 [li MCI ] M v 50 jLil acetonitril. Ly 50 nl mu phn ng
cho ln ct sc k HPLC tch cc cht. Cc cht chuyn ha ca acid Ltraehidonie
v acid arachidonic c tch ra v c nh lng bng mv pht hin sc ph
phng x.

31

nh gi
Tnh t l % acid arachidonic chuyn ha thnh prostaglandin. So snh ti l
gia mu th c cht c ch v mu chng khng c cht c ch.
2.3.3.2. To cc eicosanoid t l4C-acid arachidonic t bo iu cu
Eicosanoid l tn gi chung cho cc sn phm chuyn ha ca acid
arachidonic, bao gm prostaglandin. leucotrien, thromboxan. Prostaglandin gy tng
tnh thm thnh mch, gy ph. han . gy au. Lcucotrien c tnh ha ng ng
bch cu. kch thch hm dnh t ho bch cu vo l bo ni m...Thromboxan
kch thch s kt tp tiu cu. Do , c ch s hnh thnh cc cht ny l mt c
ch chng vim quan trng.

Tin hnh
Chun b cc t bo tiu cu: ly mu tnh mch cnh tay ca ngi tnh
nguyn khe mnh v tp trung trong cc ng nghim cht do c sn nalri citrat
(nng cui cng l 0,38% ). Khng qu 1 gi trc khi lm th nghim, ly tm
mu 100 g trong 15 pht thu c huyt tng giu tiu cu (khong 2,5 X 10"
tiu Cu/I),

bo q u n

20c.

To cc eicosanoid: huyt tng giu tiu cu c trn ng th tch vi dung


dch citrat trong glucose (27,35 g rinatri citrat.2HiO, 1,47 g acicl citric v 27,74 g
g!ucose.2H20 v 1 lt nc) v c ly tm 1000 g trong 20 pht (4C). Cn c
pha thnh hn dch trong dung dch nc mui bng th tch ban u. Ly 0,495 ml
hn dch tiu cu ny vi thuc th 37C trong 15 pht.. Sau ht u lo cc
eicosanoid bng cch thm 5 nl dung dch l - l4C-acid arachidonic (5 0 Ci/mol, 9 X

10 4 Ci/1). Sau 5 phl. dng phn ng hng cch thm 0.5 ml aceton lm lnh/o.l
ml HC1 IN, lm lnh ti 0"C v chit 2 ln vi 3 ml ethylacetat/ln. Dch chit c
lm bav hi dung mi. sau ha tan cn trong 0,2 ml mcthanol ri a ln ct sc
k HPLC tch cc cht. Xc nh cc l4C-eicosanoid to thnh bng my plt
hin nhp nhy.

nh gi
So snh s to thnh T X B : v PGE gia mu th v mu chng.

32

2.3.3.3. To prostaglandin bch cu a nhn trung tnh

Nguyn tc
M hnh s dng lipopolysaccharide (LPS) kch thch sinh PGE2. Cch tin
hnh do Herrmann v cng s xut ln u (1990). sau Weithmann v cng s
ci tin (1994).

Tin hnh
Nui cy cc t bo hch cu a nhn trung tnh vi ml 2.5 X 109 t bo/1
trong mi trng RPMI 1640 c b sung natri pyruvat 1 mmol/l. huyt Ihanh b 5%,
glutamin 2 mmol/1 v 100 Ul/ml pcnicillin/slreptomycin. Tin hnh bch cu a
nhn trung tnh trong mi trng RPMI 1640 vi acid acctyl salicylic 100 |amol/l
trong 60 pht (37c, 5% C 0 2). v sau ra 4 ln vi mi trng. Lv 0,25 ml mu
(2,5 X 10 bch cu a nhn/1 mi trng) vi LPS 0,1 mg/ml cng vi thuc Ih
trong 18 gi (ca 96-well, 37c. 5% c o ? )- To cc eicosanoid bng cch thcm 7 X
10'5 mol/1 cht mang ion calci A 23 187. 30 pht 37"C. Sau cc a c ly
tm 400 g trong 15 pht. PCiE, to thnh nm trong phn ch ni pha trn, c
xc nh bng ki ELISA.

nh gi
So snh nng PGE2 to thnh gia mu c thuc ih v mu chng khng
c thuc.
2.3.3.4. To leucotrien B4 t bo bch cu

Tin hnh
Chun b cc t ho hch cu: ly 40 ml mu ti citral ha c trn ln
vi 8 ml m PM16 gm c dcxtran 6% (trng lng phn t l 480 000) v c
f nhit phng trong 1 gi. Dch ni pha trn gm c cc t ho hch cu, ly
dch ra v pha long 1:1 vi PM16 ri ly tm 300 g trong 15 pht. Phn cn c
ha trong P M 16 v iu chnh c 10' t bo/1.
To leucotrien: ly 0,3 ml hn dch t bo trn tin hnh th nghim
chuyn ha acid arachidonic ni sinh thnh LTB4 ( 37"C). ng nghim phn ng
gm c 2 mrnol/1 CaCI2, 0,5 mmol/l MgCU v thuc nghin cu. Sau khi 15 pht,
phn ng c ht u bng cch thcm 12,5 g cht mang ion calci 23 187 v 2 g

33

glutathionc. Sau 5 phl, phn ng c dng li bng cch thm 30 il HCI 0.1 M
0l,c . Sau ly lm 2 pht C. phn dch ni pha trn c cm i sc k HPLC
tch lcucotrien B4. Dng cc thuc chun bit xc nh cc ng phn cis-,
trans-, v Cpi-LTB4. Vic phn hit 3 ng phn c th theo di hng phcp o quang
hc sng 278 nm.

nh gi
So snh kt qu gia mu c thuc th vi mu chng khng c thuc v mu
c thuc bil Cc dng.
2.3.4. Gy gii phng cc cyokin t t bo bch cu [29]

Nguyn tc
Cc cvtokin i din cho mt nhm cc peptid c hot tnh sinh hc cao.
Chng lin quan ti nhicu qu trnh t bo nh phn ng vicm. min dch v nhiu
p ng khc. Vic kha cc 1L-1 v TNF-tt gip iu tr thnh cng bc u
trn cc bnh nhn vim khp dng thp, vim rut hoc cc bnh thi manh ghp.
M hnh gy gii phng cytokin c dng pht hin cc thuc m tc dng vi
lipopolysaccharid trong qu trnh gii phng cytokin t t bo bch cu om nhn,

Tin hnh
Chun b t ho hch cu: ly 10 ml mu ti cilrat ha pha long 1:1 vi
m PM 16 v c lt vi 15 ml dung dch Lymphoprcp*. sau ly tm 400 g
trong 30 pht 20 "C. Phn t bo l mt vng trng xut hin gia 2 pha v c
ly ra cn thn bng 1 ng tim, pha long 1:1 vi PM 16 ri ly tm li trong 15
pht. Cn c ra sch vi 10 mi trng RPMI 1640 c thm L-glutamin 300
mg/1. Phn t bo ra c cho vo trong 1 ml mi trng RPMI 1640 c Ihm
L-glutamin

300

mg/1.

HEPES

25

mmol/l.

huyt

thanh

5%

penicillin/streptomycin 100 IU/mi. iu chnh hn dch t ho ti khong 5 X lo** l


bo/ml.
To cc cytokin: tin hnh trong cc a 96-vvell rt nh. Ly 0,23 ml hn dch
t bo, 500 ng LPS, thuc nghicn cu ha vo Irong 0,01 ml DMSO/nuc (1:10).
Hn dch t bo c trong t thng 37C/5% C 0 2. thi gian thng 20 gi
(xc nh IL-6 th 4 gi, IL-8 th 1 gi). Phn ng dng li bng cch t a vo

34

trong bt nc . Sau l tm a ti 2000 rpm trong 2 pht. Dng kit ELI SA


thch hp xc nh nng cytokin.

nh gi
Xc nh nng cytokin v so snh gia mu dng thuc vi mu chng khng
dng thuc.

35

3. BN LUN
3 .1 .Bn lun v m hnh nghicn cu tc dng chng vim ca thuc

3.1.. M hnh gy vim cp v bn cp


3.1.L I . M hnh gy ph bn chn chut
M hnh gy ph bn chn chut bng carrageenin
Sau khi lim carragccnin, p ng vim tin trin theo 2 pha (Vinegar v cng
s. 1969). Pha u tin c c trng bng s gii phng histamin. serotonin v
cc kinin. Pha th hai c trng bi s gii phng prostaglanin. Cc cht irung gian
ny gy nn ph chn chut. V vy, cc thuc c tc dng lm gim ph trn m
hnh ny c th c tc dng c ch ring lc hoc ng Ihi cc cht trung gian ha
hc trn.[39]
M hnh gy ph chn chut bng carrageenin l mt m hnh n gian, dc
lm, thi gian tin hnh nhanh. Carragccnin l chl tan trong nc lo ihnh dung
dch, do s tim c liu chnh xc, to ph n nh. Tuv nhin, khi o th
tch bn chn chut ph thuc vo yu t ch quan l ngi tin hnh th nghim
nn kt qu c chnh xc cha cao. M hnh thng c ng c sng lc thuc
mi. Carrageenin l cht r tin, sn c nhiu ni trn th" gii, Vit Nam
carrageenin c nhiu trong mt loi to b bin. V vy, m hnh ny c th p
dng rng ri Vit Nam. [10]
M hnh gv ph chn chut khc

Gy ph bng kaolin: C ch gv vicm ca kaolin cng tng t nh


carrageenin. M hnh ny hin nay t c s dng do mt s han ch: kaolin gy
ph rt mnh v vy nh gi kh nng c ch ph ca thuc s gp kh khn,
nht l vi cc thuc c ngun gc dc liu; hn na. kaolin khng tan trong nc
v to thnh hn dch nn lng tim kh chnh xc. ph to thnh khng u v n
nh.

Gy ph bn g/orm alin : y cng l mt m hnh dng nh gi tc dng


chng vim ca thuc. Trn thc nghim ngi ta thu c kt qu: phenylbutazon
khng c tc dng c ch ph to thnh do ormalin; indomcthacin v acid
lucnamic khng c ch ph liu c lc dng trn cc

36

IT 1

hnh khc;

methdilazin v cyproheptadin c kh nng c ch ph trn m hnh ny. Do vy c


ch gy ph trong m hnh ny c th l do ormalin kch thch lm v t ho mast.
gii phng histiimin v serotonin, khng c s tham gia ca prostaglandin.

Gy ph bng dextran: c ch gy ph chn chut bng dextran thng qua


vic gii phng histamin v scrolonin (Parratt v Wcsl. 1957). Theo nghin cu ca
Wintcr, phcnvlbutazonc khng c tc dng gim ph trn m hnh nv. ngoi tr
iu th m hnh gy ph bng dcxtran ging m hnh gy ph bng carrageenin
hn cc m hnh khc. y cng l m hnh c s dng nhiu Vit Nam.

M hnh gy ph bng cc cht trung gian ha hc (histamin. prostaglandin.


bradvkinin..): m hnh gy ph chn chut hng cc chl trung gian ha hc l a
trc tip cc yu t ca phn ng vim vo c th. pht dng v khuch i phn
ng vim. T nh gi c thuc nghin cu lc dng theo c ch no? M
hnh ny hin nay cn s dng rt hn chc Vit Nam.
M hnh gy ph du chn tling
M hnh m phng tnh trng chn thng tng t trong lm sng khi c
th b ng. va p...Khi . mng t bo b kch thch gii phng aci arachidonic,
acid arachidonic chuyn ha thnh prostaglandin gy sng, ph n, Cc nghin cu
thc nghim cho thy m hnh gy ph chn chut do chn thng to ph n
nh, mc ph va phi (thng 25%). trnh c ph qu mnh i khi khng
hi phc ca carrageenin. v l m hnh tt nh gi tc dng chng vim ti
ch ca cc thuc (thuc dn ngoi tla. cn xoa bp. cao xoa bp.. . M hnh ny
n gin, d thc hin, rt ph hp trong nghin cu Vit Nam-ni c nhiu v
thuc, hi thuc c tru vn c tc dng iu tr chn thtmg (bong gn, ng gv bm
tm. t m u ...).[25]

3.1.1.2. M hnh gy ph tai chut


Tng t vi m hnh gy ph chn chut, cc m hnh gy ph tai chut
cng da trn nguyn tc l cc cht gy vim kch thch giai phng cc cht trung
gian ha hc nh hisliimin, prostaglandin...lm gin mch, tng tnh thm, thot
dch v gy ph. Do c th s b bit c cc thuc c tc dng trn m hnh
ny l theo c ch no? Phng php tin hnh v nh gi cc m hnh gy ph tai

37

chul n gin, d Ihc hin. M hnh thng dng nh gi tc dng ti ch


ca cc thuc. Tuy nhin hin nay m hnh ny t c s dng ti Vit Nam.
Trong cc m hnh gy ph tai chut, m hnh gy ph bng oxazolon da
trn phn ng qu mn mun ca c th vi oxazolon ncn thng thch hp trong
nghin cu cc Ihuc chng vim slcroid v m hnh ny i hi thi gian tin
hnh di hn cc m hnh khc. M hnh gy ph tai chut bng du ba u l m
hnh rt lt nh gi tc dng ca cc Ihuc chng vim steroid khi c th xc
nh ng thi tc dng c ch ph v tc (lng lm teo tuyn c ca thuc.

3.1. . 3. M hnh gy tng tnh thm thnh m ch


C ch gy tng lnh thm thnh mch cng ing t nh c ch gy ph chn
chut v tai chut. Do vy cc thuc c lc dng trn m hnh ny c c ch chng
vim l c ch gii phng cc cht trung gian ha hc hoc i khng trc tip vi
cc cht y trn reccptor. M hnh ny thng dng trong sng lc thuc mi.

3.1.1.4.

M hnh gy ban

Trong p ng vim do tia u v gy ra xut hin c ban v s thay i tnh


thm thnh mch. Tuy nhin, thi gian tin trin ca hai triu chng ny khc
nhau. Thng thng ban xut hin sau 1 gi v mnh nhl sau khong 2-4 gi.
Cn tnh thm thnh mch t ln nht sau 12-20 gi. Hn na s tng tnh thm
thnh mch trong m hnh ny yu hn nhiu so vi cc m hnh tim cht kch
thch vo trong da. V vy, mc tng tnh thm khng phi l Ihng s thch
hp nh gi mc ban do tia uv gy ra. Qua nghicn cu. ngi ta nhn thy
cc glucocorticoid khng c tc dng c ch ban trong m hnh ny. Nh vy
cc yu t gy stress khng tham gia vo p ng vim trong m hnh ny. Cc
NSAIDs c thy l c tc dng c ch ban , tuy nhin NSAIDs ch c tc
dng trong thi gian u v hiu lc gim dn d Ihuc c dng nhc li. iu
ny a ra gi thit rng trong giai on u ca p ng vim proslaglandin l
ch chu trch nhim ch yu v khi NSAIDs th hin c tc dng. Sau .
cc yu t khc tham gia vo p ng m NSATDs khi khng cn tc dng.
Cc yu t ny hin nay vn dang c nghin cu v s m ra nhng hng mi
trong vic nghin cu thuc chng vim.

Trong nh gi kt qu, mc ban c tnh hng phng php lnh


im, phng php ny mang tnh ch quan v khng chnh xc. V vy cn
nghin cu phng php tnh chnh xc hn. Hin nay c mt s nh nghicn cu
xut phng php xc nh mc han da vo cc yu l lin quan nh
nhit . mu sc ban .

3.1.1.5.

M hnh to ti u ht

y l m hnh to mt vim bn cp dng nh gi ng thi lc dng


chng r dch v chng lng sinh ca thuc qua s pht trin ca ti u ht. S tng
sinh t bo th hin qua dy thnh ti. S r (lch c Irng bi s thm nhim
cc hch cu vo trong vim. Theo kt qu nghin cu, cc thuc chng vim
steroid c tc dng mnh hn hn cc thuc chng vim khng steroid trn c s
tng sinh t bo v s r dch. Do m hnh ny thch hp cho nghin cu cc
thuc chng vim stcroid c ton thn v ti ch.

3.1.2. M hnh gy vim mn tnh


3.1.2.1. M hnh gy u ht thc nghim
Khi a vo c th tc nhn gv vicm tr nh amian, hng...th c th phn
mg bng cch tp trung nhiu loi t ho xung quanh d vt v to thnh u ht. u
ht [ mt trng hp c bit cua vim mn lnh, t chc ny b bao bc bi mt
lp x gm collagen, proteoglycan...nn khng mu ti n. thuc kh thm
nhp vo, vic iu tr thng kh khn v lu di. Mt thuc c kh nng c ch u
ht ng ngha thuc c tc dng chng vicm mn. Cc m hnh gy u ht thc
nghim tin hnh n gin, cho kt qu tng i tin cy nn hay c p dng
trong nghin cu thuc chng vim mn tnh.
M hnh gy u ht bng amian: amian l vt liu tr khi a vo c th. d to
hnh dng, kch thc ng u, d hc tch v sn c, rc tin ncn y l nguyn
liu gy u ht thc nghim hay c s dng. M hnh ny hin nay c s dng
ph bin Vit Nam.
M hnh gy u ht bng bng: y l m hnh gy u ht thc nghim u tin
v n nay vn dc s dng nhiu trn Ih gii. Cc nh nghin cu thy rng
qu trnh tng sinh t bo to u ht hng m hnh ny gm 3 giai on: giai on 1

39

l giai on thm dch, xut hin irong 3 gi u tin, vin bng s ngm dch v
t bo ha; giai on 2 l giai on r dch, xut hin sau 3-72 gi cy bng, pha 3
l pha tng sinh vi s xut hin ca collagen trong u ht. Do c th nghin cu
c ch lc dng ca cc Ihuc thng qua cc giai on ny. M hnh ny rt nhy
vi cc thuc chng vim slcroid.

3.1.2.2. M hnh gy vim a khp thc nghim


Vim a khp l mt bnh vim mn tnh ph bin trn th gii v Vit Nam.
Mc d tm c nguyn nhn, c ch bnh sinh ca bnh nhng qu trnh iu
tr vn gp nhiu kh khn. M hnh gy vim a khp (hc nghim m phng
tnh trng bnh ging nh trong thc t v cch s dng thuc v cng tng t
vi cch s dng thuc ca bc s lm sng. c hit m hnh gy vim khp bng
cht b tr Freund hin nay c coi l m hnh lt nht nghin cu vim khp
dng thp. Cc thuc chng vim sleroid v chng vim khng steroid u thy c
tc dng lm gim cc triu chng ca bnh trn m hnh ny, tuy khng cha khi
hon ton. Nh vy, cc m hnh gy vim a khp thc nghim gp phn quan
trng trong vic tm ra thuc iu tr bnh. Tuy nhin, c th cha c bnh
hon ton cn tm ra nhng m hnh hiu qu hn na gip cho cng tc nghin
cu pht trin thuc mi t kt qu lt nht.

3.1.3. M hnh nghin cu c ch chng vim


3.1.3.1. Kt tp bch cu da nhn bi F M L P
Trong phn ng vim, cc bch cu a nhn b thu ht hi nhiu cht ha ng
ng Irong c FMLP - mt cht c gc N-formyl-methionyl- l cu trc c th

cc peptic ca vi khun m ngi khng c. FMLP lm thay i mng li vi


si aclin ca bch cu a nhn v lm thay i hnh Ih, s di chuvn ca bch cu
ti khu vc vim, ri bm dnh vo thnh mch v thot mch. Khi bch cu tp
trung ti ni c nng cht ha ng ng cao. bch cu c th dnh vo nhau lm
nghn mch gy cn tr tun hon mao mch v tnh mch, cui cng gy ph hy
ni m do cc bch cu gii phng cc prolease v cc gc t do cha oxy gy c
cho m. Do c ch s kt tp bch cu l c ch cn thit bo v c th. Cc

40

thuc c tc dng c ch ha ng ng trong m hnh ny c th c c ch l gn


cnh tranh vi FM LP trcn cc rcccptor mng t bo bch cu.[9]
3.1.3.2. Ha ng ng i thc bo
i thc bo l nhng l bo u tin b thu ht v hot ha bi cc cht gy
ha ng ng. Ti vim chng tit ra cc yu t gy vim nh IL-1. IL-6 gy
khuych i phn ng vim ra xa; chng tit cc cnzym tiu protcin, glucid nh
gelalinase, collagenase, elastinasc...tit NO v cc gc t do c oxy. Theo nghin
cu ca Dy M. v cng s, thioglycollat lm tng s lng i thc bo do tc
dng ha ng ng, dn n lm tng nng cc enzym ti vim. Thuc c tc
dng trn m hnh ny s c c ch l c ch' s ha ng ng i thc bo hoc
lm bn vng mng lysosom ngn gii phng cc cnzym phn gii.[28]
3.1.3.3. Th nghim v cc cht chuvn ha ca acid arachidonic
Cc cht chuyn ha ca acid arachidonic l nhng cht c vai tr ln trong
cc p ng vim v l nhng mc tiu m thuc chng vim hng ti. V vy
nhng m hnh lin quan ti cc cht ny l ihc s cn thit lm sng c thm
c ch chng vim ca thuc.
Prostaglandin 11 cht c nhc li u lin v vai tr ca n trong phn ng
vim rt quan trng. Prostaglandin Iham gia vo mi phn ng ca vim, to nn
cc triu chng in hnh cho vim nh sng, nng, , au. M hnh oxy ha
acid arachidonic bi COX-1 hoc m hnh to prostaglandin t bo bch cu cho
phcp tm hiu c ch chng vim ca mt thuc thng qua tc dng c ch to
prostaglandin. Tuy nhin nh chng ta bit v vai tr ca COX-I trong hot
ng sinh l ca c th, cc thuc c ch COX-1 mnh s gv ra nhiu tc dng
khng mong mun nh lot d dy t trng, vim thn...Xu hng hin nay l tm
cc thuc c ch chn lc trn COX-2 lm gim tc dng khng mong mun
trn ng tiu ha. trn mu. trn thn...nhng liu cc thuc tc dng u ticn
trn COX-2 c t tc dng khng mong mun hn cc thuc NSAIDs kinh in
vn cn l vn cn nghin cu k. Do cc ITI hnh nghin cu v COX-1 v
COX-2 l nhng m hnh cn thit trong nghin cu v cc thuc chng vim.

41

Leucotrien B4 l mt lcucolricn in hnh cho Iihin lcucotrien vi hot tnh


ha ng ng bch cu a nhn kh mnh, do thc y phn ng vim lin
trin. V vy c ch s to thnh leucotrien cng l 1 c ch chng vim cn c
quan tm nghin cu. V m hnh to leucotrien B4 thch hp nh gi kh
nng c ch .
3.1.3.4.

Gy gii phng cytokin t t bo bch cu ngi

Cylokin l nhm cc cht c hot tnh sinh hc mnh v nh hng ti rt


nhiu giai on ca phn ng vim. TNF-a l mt cytokin vicm mnh. N Iham
gia trong cc bnh mn tnh nh vim khp dng thp, x cng b h thng. l
yu t khuych i phn ng vim do ha ng ng bch cu n nhn v a nhn
trung tnh, lm v ht v phng thch cc supcroxyd. thoi ha m. tc ng ln
trung tm iu nhit gy st... IL-1. IL-6. IL-8 tng cng phn ng vim ti ch
v ton thn ha phn ng. V vy vic gii phng nhiu cc cytokin s gy hi
cho m, cho c th. Do cn phi c ch s tng sinh cc cytokin ny bo v
c th. M hnh cho php nh gi kh nng c ch cc cytokin ca thuc, nhng
c ch vo cytokin no, theo c ch phn t ra sao th cn l vn cn phi
nghicn cu ihm.
3 .2 .Hng la chn m hnh nghin cu thuc chng vim Vit Nam
Trong giai on th tc dng lin lm sng ca thuc, ngoi vic chng minh
thuc mi c tc dng dc l. cn phi tm ra c ch' lc dng ca thuc. V vy,
vic la chn m hnh nghin cu ph hp l thc s cn thit, c bit trong iu
kin cng ngh, k thut Vit Nam. Sau y l xut ca chng li v cch tin
hnh nghin cu mt thuc chng vicm

M hnh gy vim cp v bn cp
Theo chng ti, mun chng minh mt thuc (thuc y hc c truyn hay hot

cht mi) c tc dng iu tr vim, Ire ticn nn tin hnh chng minh tc dng
chng vim trn cc m hnh gy vim cp v bn cp. Cc kt qu thu c trn
cc m hnh ny s cho php nh gi mt cch s b thuc c lc dng chng vicm
hay khng v mc tc dng ca chng. Ch tiu nh gi cc ih nghim ny
ch yu thng qua kh nng c ch ph (chn chut hoc tai chut) hoc thng

42

qua lm gim cc du hiu ban hoc thng qua c ch s thot mch ca huyt
tng hoc thng qua c ch s tng lit dch r vim...

M hnh gy vim mn tnh


Sau khi c cc kt qu v tc dng ca thuc trn m hnh gy vim cp v

bn cp, tip tc nh gi trcn cc m hnh gy vim mn nh to u hl thc


nghim, gy vim a khp thc nghim...Ch tiu nh gi trong cc m hnh ny
thng qua kh nng c ch lo u ht hoc c ch cc triu chng vim khp.
Cc ch tiu nh gi trong cc m hnh gy vim cp. bn cp v m hnh gy
vim mn thc cht [ cc triu chng ca vicm thng gp trn lm sng. V vy.
cc kt qu thu c s cho bit thuc nghin cu c lm gim cc triu chng vim
hay khng v t khng nh thuc c tc dng chng vicm hav khng.

M hnh nghin cu c ch chng vim


Tuy nhin, nu vic nghin cu ch dng li cc m hnh gy vim cp, bn

cp v m hnh gy vim mn th vn l ra l khng bit thuc tc ng vo


khu no ca qu trnh vim vic s dng thuc c hiu qu hn, ng bnh
hn v trnh c tc dng khng mong mun ca thuc. V vy cn thit phi
nghin cu thm v c ch tc dng ca thuc.
tm bit thuc c tc dng chng vicm theo c ch no trc tin phi hiu
r c ch gy vim cng nh cc yu t lin quan n phn ng vim. Hin nay c
rt nhiu m hnh nghin cu c ch chng vim, mi m hnh ch cp n mt
c ch no v vy lu iheo iu kin v yu cu cng nh kt qu nghicn cu s
b c ch chn mt s m hnh nh gi cho ph hp. Theo chng ti cc yu t
c nh gi c lin quan nhiu ti c ch gy vim v chng vim l:
prostagandin, enzym c o x , leucotricn B., i thc bo. bch cu a nhn... V vy
cc m hnh nghin cu vc c ch chng vim ca thuc quan trng l: nghin cu
nh hng ca thuc i vi vic to ra prostaglandin. leucotrien B4, kh nng c
ch enzym c o x c hit l c ch COX- 2, kh nng c ch s tp trung ca bch
cu a nhn, i thc bo hoc c ch gii phng cytokin.
Tuy nhin cc phng php ny i hi phng tin v k thut cao ncn kh
nng p dng Vit Nam cn hn ch. Thc t. qua thu thp ti liu chng ti nhn

43

thy Vit nam cha c cng Irnh no i su nghin cu c ch chng vim ca


thuc. V vy y cng l phn nghin cu cn nhanh chng trin khai d cc
nghin cu v thuc chng vicm ni ring v cc nghin cu khc Vit Nam c
chnh xc cao hn.

44

4. K T LUN V XUT
4.1. Kt lun

ti tng kt c ml s m hnh nghin cu tc dng chng vim

ca thuc ang c p dng ti Vit Nam v trn Th gii, chia thnh 3 nhm:
+ M hnh gy vim cp v hn cp gm:
M hnh gy ph bn chn chut
M hnh gy ph tai chut
M hnh gy tng tnh thm thnh mch
M hnh gy vicm mng phi
M hnh gy ban
M hnh to li u hl
+ M hnh gy vim mn tnh gm:
M hnh gy u ht thc nghim
M hnh gy vim a khp thc nghim
+ M Knh nghin cu c ch chng vim gm:
Gy kt tp bch cu a nhn
Gy ha ng ng i thc bo
Th nghim v cc cht chuyn ha ca acid arachidonic
Gy gii phng cytokin t t bo bch cu.
ti nh gi tng m hnh, kh nng p (lng m hnh trong nghin
cu tc dng chng vicm ca thuc.
ti xut hng la chn cc m hnh nghin cu p dng vo
iu kin thc t ca Vit nam
4.2. xut
T kt qu thu c v da vo icu kin c Ihc, chng li nhn thy hon
thin h thng cc m hnh nghin cu tc dng chng vim phc v cho nghin
cu th cn tip tc:
Nghin cu su hn v c ch phn t ca cc m hnh t a ra
c c ch tc dng ca Ihuc.

45

Cp nht, thng k, phn lch y hn v cc m hnh nghin cu tc


dng chng vicm ca ihuc hin nay trn th gii
Xy dng quy trnh cc m hnh p dng trong nghin cu lc dng chng
vim ca thuc l hiu qu tt v ph hp vi iu kin Vit Nam.

46

T I L I T H A M K H O
Ti liu ting Vit

1.

V Hng Anh (1999), Gp phn nghin cu tc dng chng vim ca ch' phm
cha papain. Lun vn Thc S Dc hc

2.

B mn Dc hc c truyn- trng i hc Dc H Ni (2005). Dc hc r

truyn, tr. 201-202.


3.

B mn Dc liu- trng i hc Dc H Ni (2004). Bi i Dc liu, tp


1. tr.292-293.

4.

B mn Dc l- trng i hc Dc H Ni (2004), Dc l hc, tp 2. Ir. 231244. 255-260.

5.

B mn Min dch- Sinh l bnh-1rng i hc Y Dc Thnh Ph' H Ch Minh


(1999). Min dch sinh l bnh . tp 1. NXB Thnh Ph H Ch Minh. tr. 120-133.

6.

B mn Min dch v sinh l bnh- trng i hc Y H Ni (1991). Sinh l bnh,


NXB Y hc, tr. 68-76.

7.

B mn sinh l hc- trng i hc Y H Ni (2006). Sinh l hc, tp 1, NXB Y


hc, . 118-126.

8.

B y t (2006). Dc lm sng. NXB Y hc, tr.205-234.

9.

Borel J. B., F-X Maquart. Ph. Gillcry. M.Exposito (2006), Ha sinh cho thv

thuc tm sng, NXB Y hc, tr.21-61.


10. Trung m (1996), nh gi m hnh gy ph thc nghim hng kaolin v
caragenin nghin cu tc dng chng vicm cp ca thuc. Tp ch Dc liu.
s 2, tr.49-51.
11. Trung m (1996), Tc dng chng vim mn tnh ca bi thuc cha thp
khp SASP-5221, Tp ch Dc hc . s 10, tr.23.
12. Trn Mnh Dng (2005), Nghin cu s b thnh phn ha hc v tc dng
chng vim, gim au ca huyt gic (Dracena camboiina Pierre ex Gapnep..

Draciienaceae), Kha lun t! nhip dc .v di hc.


13. Nguyn Th Mai Hng (206), Tng quan v ha sinh vim v thuc ieu tr
viem, Kha lun tt nghip Dc s di hc
14. Nguyn Hong Hi (2001), Nghin cu tc dng chng vim ca Nc nc kt
hp vi a-chymotrypsin, Lun vn Thc s Dc hc
15. L Th Dim Hng (2002), Gp phn tm hcu tc dng chng vim ca hoa cy
kim

ngn

{Lonicera japonica

Thunb..

Caprioliaceae)

kt

hp

vi

a-

chymotrvpsin. Lun vn Thc s Dc hc


16. L Th Dim Hng, Nguyn Th Hng Nhin, Nguvn Th Hng Vn. Nguvn
Vit Thn, Nguyn Xun Thng (2007), Nghin cu tc dng chng vim mn
ca saponin v lavonoid cy kim ngn, Tp ch Dc hc , s 10. tr.24-25.
17. V Mnh Hng (1996), Nghin cu lc dng khng khu n chng vim ca Hch
hoa x v tc dng cua n i vi mi s ch tiu chng vim trn dng vi thc
nghim nhiem Dichlor diethylsul, Lun (h Ph Tin s Y Dc.
18. Mai Lc Hoa, Nguyn Gia Chn, Nguvn Thng Dong. Nguyn Th Dung (] 998).
Nghin cii tc dng chng vim ca cy lo quan di thc Vii Nam (Genuum

ihunbeni Sieb. Et 7.UCC., Geraniaceae)", Tp ch Dc liu, s 3, ir. 78-81


19. on Th Nhu. Trung m. Phm Duy Mai (2006). Phng php nghin cu

tc dng dc l ca thuc l dc tho , NXB Khoa hc v Kv thut. r. 139-149.


20. o Vn Phan (2004), Cc thuc ii au chong vim, NXB Y hc, tr. 49-51.
21. L nh Roanh. Nguyn nh Mo (1997), Bnh hc vim v nhim khun, NXB
Y hc, tr. I -132.
22. V Th Minh Thc, i Hng Ngii, i Duy Ban (2000), Ha sinh phn t ca

min dch di ng, NXB Y hc.


23. T in bch khoa dc hc (1999). NXB T in Bch Khua, tr.630,
24. Phm Vn Ty (2001), Min dch hc . NXB i hc Quc gia H Ni. tr. 21-22.
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PH LC
1.

M i tr n g R P M I 1640

Ca(NO,)2

L-Isoleucine

Polic acid

M g S 0 4 (anhyd)

L-Leucine

Glutathionc

KCI

L-Lvsinc HC1

mvo-Inositol

NaHCO,

L-Methionine

Niacinamide

NaCI

L-Phenylalanine

D-Pantothenic acid

Na2H P 0 4 (anhyd)

L-Proline

Pvridoxinc

L-Argininc

L-Serine

Ribolavin

L-Asparagine

L-Thrconine

Thiaminc HCI

L-Aspartic acid

L-Tryptophan

Vitamin B12

Cystinc 2HCI

L-Tyrosine 2Na

D-Glucosc

L-Glulamic acid

dihydrate

HEPES

L-Glutaminc

L-Valine

Phcnol rcd

Glycine

p-Aminobcnzoic acid

L-Glulaminc

L-Histidine

D-Biolin

NalCO,

Hydroxy-L-proline

Choi ine chloridc

2.

L y m p h o p rep "

Sodium Diatrizoate

9,1% (w/v)

Polysaccharide

5.7% (vv/v)