• Nghien ciru - Ky thuat
Danh gia tac dung ha glucose mau tren thuc nghiem cua 4 loai Gymnema R. Br.
d Viet Nam
Phiing Thanh Huong, Pham Ha Thanh Tiing
TiifOtig Dgi ligc Dirac Ha Noi Email. [email protected]
Summary
21 Vietnamese Gymnema ecotypes of 4 species (G. sylvestre, G. latifolium, G. yuhanense and G.
inodorum) were evaluated for hypoglycemic effect in streptozocin-induced hyperglycemic mice. After 7 days of treatment at the dose 10 g/kg, b.w., all of the Gymnema species samples reduced the glycemia at various levels. For each species, the hypoglycemic activity was quite variable from samples to samples of different origins. Several Gymnema samples of the most significant hypoglycemic activity were sorted out, which may serve as valuable sources of medicinal materials for anti-diabetic drugs.
Keywords: Gymnema R. Br, diabetes, streptozocln.
Dat van de
Chi Gymnema R, Br hoTnjcdao (-4pocy/iaceae) c6 khoang 25 lodi, phan bo d viing Tay Chau Phi, Australia, chdu A. Trong chi Gymnema R. Br, loai Gymnema sy/ves(re(Retz.)R Br. ex Schult da dugc nghien cipu nhieu ve tac dung ha glucose mau va dupe s u dyng rgng rai d l d i l u trj dai thao dudng (DTD) d nhieu nude tren the gidi. 0 Vi$t Nam, da phdt hign s y ed mat ciia mgt so loai thuoc chi ndy I'-^i. Ngodi Gymnema sylvestre (Retz.) R. Br.
ex Sehult, cdc lodi cdn lai hau nhu it duac nghien edu ve tac dung dieu trj DTD tren the gidi. Lieu cac lodi ndy co tac dyng ha glucose mau hay khong?
Mdt khde, ban than loai Gymnema sylvestre (Retz.) R Br. ex Sehult mac dii da duac dua vao nhieu che pham thuoc va thuc pham chifc nang d l d i l u trj DTD nhung tac dyng to ra khong on djnh, dong nhdt. ed t h i la do nguon nguyen lieu chua dupe chudn hda. O l co the ddnh gia dupe tdc dyng hg glucose mau cua cac loai Gymnema vd gdp phdn cho edng tac nghien cdu phat tnen, chudn hda ngu6n dupe lieu d i l u trj DTD trong nude, bdi bdo ndy cdng bo cae k i t qua nghien
cdu nham danh gia tac dung hg glucose mau ciia cac m l u thuoc bon loai Gymnema sylvestre (Retz.) R Br ex Schult, Gymnema latifolium Wall, ex Wight, Gymnema yunnanense Tsiang, Gymnema inodorum (Lour.) Decne thu hai d cac viing khac nhau ciia Viet Nam va lya chgn mdt so mau cd tac dung ha glucose mau uu the nhat trong chi Gymnema R Br d Viet Nam d l cd t h i bao t i n . phat tnen, khai thac lam nguyen lieu san xuat thulc va thyc pham chdc nang cho ngudi benh DTD,
Doi tirang va phu'cng phap nghien ci>u
Nguyen lieu, hoa chat
Nguyen lieu la la ciia cdc mau thuge 4 loai trong chi Gymnema R. Br. dupe thu hai d cac dia phuang khac nhau. Cac m l u thu v l deu d u g c phai se Irong bong ram, say kho d 45 - 50''C, xay nhd thanh bgt, ham am khong qua 5%. Th6ng tin ve danh phap, nai thu mdu va ma ky hieu ciia cac m l u s u dyng trong nghien cdu duac trinh bay Irong bang 1.
T A P C H i DUgfC HQC-10/2014(S6462 N A M 54)
Nghien CLFU - Ky thuat
Bang 1 : Cac mau s d dung trong nghien cuu
Ma miu Non thu mau Stt Ma mau Noi thu miu
S.QN Quang Ninh 12 L.ThN Thdi Nguyen
3 Gymnema sylvestre 4 (Retz.) R.Br ex Schult 5
Gymnema yunnanense Tsiang
SPY S.VP SND S.QT S-ThN Y.GL1 YKT YDL1 Y G L 2
Phu Yen VTnh Phuc Nam Binh Quang Tn Thai Nguyen Gia Lat Kon Turn Dak Lak Gia Lai
13 14 15 16 17 18 19 20
Gymnema latifolium Wail, ex Wight
Gymnema inodorum (Lour.) Decne
LHB L.TQ L.GL L.TN L. NB
I.HN LBK I.VP
Moa Binh Tuyen Quang Gia Lai TSy Ninh Ninh Binh Ha Noi Bac Kan VTnh Phuc Y. DL2 Dak Lak
Chuot nhat t r l n g chiing Swiss khde manh, g i l n g dye, trong lugng trung binh 25 ± 2 g, mua tai Hgc vien Quan y, ehugt d u g c chia thanh cae 16, moi 16 7 - 1 0 eon.
Streptozocln (Sigma); gliclazid (Stada).
P h u a n g phap nghien c d u Phu-ang phap chiet xuat du-gc lieu Duge lieu d u g c c h i l t bdng phuang phap ngdm kiet vdi dung m6i ethanol 80", djch c h i l t thu d u o c c i t thu hoi dung mdi d u d i ap s u i t giam eho tdi can, sau do pha hdn djch can vdi nude cdt ti le 1:1, s u dung NaCMC 0,5% d l on djnh h6n dich.
Phwang phap djnh Iwgng glucose huyet Phuong phap enzym glucose oxidase vdi may t u dgng va que thd Aceu - chek Active (Roche).
Phu-ang phap nghien cu-u tac dung ha glucose mau tren dgng vat thi nghiem
Danh gia tac dung ha glucose mau cua dich c h i l t d u a c lieu tren mo hinh chu6t tang glucose mau thyc nghiem bdng STZ (tiem mang bung lieu 150 mg/kg the trgng). 72 gid sau khi tiem mang bung dung djch STZ (150 mg/kg), tien hanh dmh lugng glucose mau luc ddi cua ehugt,
lya chpn ehugt cd glucose mau ^ 11 mmol/L cho thi nghiem. Chudt tang glucose mdu thue nghiem d u a c chia thdnh edc 16, mdi Id 10 con: L6 chiing trdng udng dung dich NaCMC 0,5%. Ld chiing d u a n g udng gliclazid (20 mg/kg the trgng). Cac 16 t h u udng hdn dich can d u a e lieu vdi lieu tuang d u a n g 10 g d u a e lieu kh6/kg the trong chupt. Cho ehugt udng mau t h d trong vong 7 ngdy (vao 8 gia sang m6i ngay), trong 7 ngay dd cho ehugt an uong binh t h u d n g . So sanh s u thay doi glucose mau cua cae 16 thi nghiem.
Xu- li so lieu
S6 lieu d u a c x d li bdng test Anova. Sy khac biet CO y_nghTa t h i n g ke khi p < 0,05. Bieu dien s l lieu: X ± SE.
Ket qua nghien CLPU va ban luan
Tac d u n g ha g l u c o s e mau cua Gymnema sylvestre (Retz.) R.Br, ex Schult
Chia ehugt thanh cae 16 g l m : 11d chirng trlng;
1 16 chdng d u a n g ; 6 16 t h u (uong hdn djch can d u g c lieu vdi l i l u 10 g/kg cua 6 mdu G. sylvestre thu d u a c d 6 viing. So sanh s u thay doi glucose mau cua cac 16 sau thdi gian dieu trj.
Bang 2: Si/ thay ddi glucose mau cua cac 16 chuot uong G. sylvestre Lo
1 2 3 4 5 6 7 8
ChLing trang Chu'ng duong SON SPY SVP SND S.QT SThN
Glucose mau NgayO 17,5 ±1,7 17,7 + 1,9 16,9±1,2 16,5 ±0,8 16,8 ±1,4 16,8 ±0,8 16,8 ±0,6 17,7 ±1,6
(mtnol/i) Ngay 7 16,8±1,7 10,1±0,8 10,8±0,9 9,6 ±0,9 11,8+1,0 11,3±0,6 12,6±0,6 10,8+0,8
- Ty le ha glucose mau (%) 3.47±1.81 41,75+2,88 35,97±2,46 42,24±3,09 29,94±2,08 32,42±2,Z0 25,19+2,30 38,46±2,08
P., I'r Pr P, Pr P, P«
p so voi 16 1
<0,001
<0.001
<0,001 ,<0,01 ,<0,01 , <0.05 ,<0,001
2
p„>0,05 p,,>0,05 p„<0,05 p„<0,05 P,,*"."!
p.,>0,05
T^P CHi DUPC HQC - 10/2014 (SO 462 NAM 54)
• Nghien CCPU - Ky thuat
Ket qua bang 2 cho thay cde mau G. sylvestre deu cd tdc dyng ha glucose mdu khdc biet ed y nghT thong ke so vdi Id ehung trang. Khi so sdnh edc Id t h d vdi Id chung d u a n g , ket qua la mue ha glucose mau ciia 3 Id t h d vdi cac mdu G. sylvestre Quang Ninh, Phu Yen, Thai Nguyen khdng khac biet vdi mdc ha ciia 16 chung d u a n g (p > 0,05). Ba mdu cdn lai eho tae dung kem han gliclazid 20 mg/kg (p < 0,05). Trong cac mdu G.
sylvestre, m l u Phu Yen cho ty le ha glucose mau
cao n h l t (42,24%), mdu Quang Trj cho mdc ha glucose mau thdp n h l t (25,19%).
Tac d u n g ha g l u c o s e mau cua Gymnema latifolium Wall, ex Wight
Chia chuot thdnh cae 16 g l m 116 chung t r l n g , 1 Id chdng duang va 6 16 thir (uIng hdn djch e l n duge lieu vdi l i l u 10 g/kg eua 6 mdu G. latifolium thu d u a c d 6 viing. So sanh s u thay ddi glucose mau cua ehugt sau thdi gian dieu tri.
Bang 3: Si/ thay doi glucose mau cua cac 16 chuot u6ng G. latifolium
1 2 3 4 5 6 7 8
Chiang trlng ChLrng du'ang
LThN L H B L.TQ L.GL L.TN L N B
Glucose mau (mmol/l) Ngay 0
17,5±1,7 17,4±1,4 16,7±1,3 16,1±1,2 16,6±1,3 16,8±1,0 16,3±0,7 16,0±1,3
Ngay 7 16,8 ±1,7
9,8 ±0,7 10,3 ±1,0 9,0 ±0,9 10,2 ±1,0 9,9 ± 0,7 10,3 ±0,5 12,7 ±1,7
Ty le ha glucose mau 3,47±1,81 43,17±1,58 38,25±4,10 44,24±1,04 39,09±2,60 41,04 ±2,14 36,92±2,21 24, 95+4,3
p so v&i 16 1
p,,<0,001 p,,< 0,001 p., < 0,001 p,,< 0.001 P,, < 0,001 p,,< 0,001 Pfii ^0.01
2
Pj,>0,05 p. 2 > 0.05 p „ > 0 , 0 5 p^2>0,05 p „ < 0 , 0 5 P,,<0,05 K i t qua bdng 3 eho thay 6 mau G latifolium cao n h l t (44,24%).
deu lam gidm glucose mau khac biet cd y nghla thong ke so vdi 16 t r l n g Khi so sanh cde Id thd vdi Id chdng d u o n g , chi co 16 thd m l u G, latifolium Tdy Ninh va Ninh Binh cd s y khac biet cd y nghTa t h i n g ke (p < 0,05), cac 16 mau thy c6n lai so vdi 16 chung duang s y khdc biet khong cd y nghTa thong ke (p > 0,05). Trong cac m l u G.
latifolium, mdu H6a Binh cd mdc ha glucose mau
Tac dung ha glucose mau cua Gymnema inodorum (Lour.) Decne
T i l n hanh thi nghiem vdi 1 16 chung trdng, 1 16 chdng duang va 4 Id thd udng h I n djch e l n d u g c lieu lieu 10 g/kg eiia 4 mdu Gymnema inodorum. So sanh s y thay doi glucose mdu sau thdi gian thu' nghiem.
Bang 4: Su' thay doi glucose mau cua cac 16 chuot uSng G. inodorum L 6
1 2 3 4 5 6
ChLpng trSng Chung ducrng
L V P l,HN I B K l,HB
Glucose NgayO 13,9±1.0 16,0±1.6 14.0±1,7 14.3±1,r 14.3±1,2 15,1±1,5
mau (mmol/l) Ngay 7 14.2 ±1.1 9,2 ±0,7 10,0 ±0,7 10,5 + 0,9 10,5 ±0,7 10,2 ±1,0
- Ty ie ha glucose mau -1,89±1,80 41,33±2,75 27,00+2,70 32.82+2,32 25.72±3,26 30,11±3,8
(%)
P , , P, P.
P^
P,
p so vol 16 1
< 0,001 ,<0,05 ,<0,05 ,<0,05 , < 0,05
2
P3j<0,05 P.,<0,05 p „ < 0 . 0 5 P^j<0.05 K i t qua bdng 4 cho t h I y edc mdu G. inodorum
ddu cd tdc dpng hg glucose mdu khac biet cd y nghTa t h i n g ke so vdi 16 trdng (p < 0,05). Tdc dyng hg glucose mdu cao nhat la eua mdu G. inodorum Hd Npi (32.82%). So vdi 16 ehung duong, muc hg glucose mdu eiia cde Id m l u
T/SPCHi DU<?C HQC - 10/2014 ( S 6 462 N VM 54)
thu thap han co y nghTa so vdi 16 chdng duong (P < 0,05).
Tac d u n g ha glucose mau cua Gymnema yunnanense Tsiang
Chia ehugt thanh cae 16 vdi 1 16 chu'ng trang, 1 16 ehdng duang va 4 16 thd (uong hon dich
45
Nghien CLFU - Ky thuat
can d u a c lieu vdi l i l u 10 g/kg cua 5 mdu G. cua edc 16 sau thdi gian dieu trj, ket qua thu du'ac yunnanense. So sanh s y thay doi glucose mdu the hien d bang 5.
Bang 5: Si/ thay d6i glucose mau cua cac 16 chuot uSng G. yunnanense
L6 Glucose mau (mmol/l)
Ngay0 Ngay7
Ty le ha glucose mau _
(%)
p so voi Id2 3 4 5 6 7
Chung duang YKT YGL1 Y.DL1 Y G L 2 Y DL2
14,6±1,4 16,9±1,6 14,0+1,1 16,4±1,4 16,2±1,7 16.2+0,9
8.4 ± 0,5 13,8±1.0 11,3+0.6 13,3±1,3 13,3±0,8 12,7±1,5
41,23±2,75 22.03±2,43 18,86+2,67 19,39+1,55 17,83±2,3 21,2±1,4
P2, P i P.
P, P, P,
<0,001
<0,05
<0,05
<0,05
<0,05
<0,05 P, P.
P, P, P,
, <0,001
<0,001 ,<0,001 J <0,001 , <0,001 Ket qua bang 5 eho thay cdc mau
G. yunnanense co tae dung ha glucose mau khde biet eo y nghTa thong ke so vdi Id trdng (p <
0,05). M l u G yunnanense Kon Turn eho ty le ha glucose mau cao n h l t (22,03%). Ty le ha glucose mau eua cac 16 t h u thdp han va khae biet so vdi 16 chdng duong (p < 0,001).
Ban luan
Vdi l i l u 10 g/kg the trong ehugt thi nghiem, tat ca cac mdu G. sylvestre thu d u a c d i u lam ha glucose mau co y nghTa tren mo hinh ehugt tang glucose mau thuc nghiem bdi STZ. Dieu nay khang djnh Gymnema sylvestre d Viet Nam cung cd tac dung ha glucose mau nhu eac nghien cdu ve G. sylvestre da eong bd tren t h i gidi '^•''l Trong cac mau thu d u a c thi mdu G. sylvestre Phil Yen cho mi^e ha glucose mau cao n h l t (42,24%), 2 mdu G. sylvestre Quang Ninh va Thai Nguyen cung cho tac dung tot vdi mdc ha glucose mau l l n lugt la 35,97% va 38,46% Ca 3 mau d i u CO tac dung tuang d u a n g vdi giiclazid lieu 20 mg/kg. Cac m l u nay cung eho k i t qua tdt hon k i t qua ma Truang Thj Tam (2008) c6ng bd tren m l u G. sylvestre Thanh Hda (32,21%) vdi cung lieu diing va md hinh thyc nghiem (Truang Thj Tam (2008), Nghien cu'u thanh phin hoa hoc va buac dau thu' hoat chit cac phan doan djch chiit cua cay day thia canh (Gymnema sylvestre R.Br ex Schult). Khoa luan tot nghiep d u a e sy, Trydng Dai hgc Dugc Ha Npi). Ddng thdi, khi so sanh vdi k i t qua thuc nghiem cua Sathya S.
va^cgng s u (2008) thi mdc ha glucose mau cua mdu G sylvestre Phii Yen (42,24%) Idn han mdc ha glucose mau eua G. sylvestre ma Sathya S.
va edng s u dd cdng bo (39,97%)i^J. G, sylvestre la mgt loai d u a c lieu da va dang duae su dung rpng rai trong thue te de dieu trj DTD. Do vay c^c ket qua nay r l t cd y nghTa trong viec lua chpn m d rgng cac viing nguyen lieu hien ed. Su khac nhau v l muc ha glucose mau eua cae mau G.
sylvestre thu hdi d eac viing dja ly khac nhau ed the do ehung ed nguon gen khae nhau, hoac chju anh h u d n g bdi cae dieu kien khi hau, th6 n h y d n g khac nhau. Cdn ed them cac nghien ciiu v l cae y l u to anh h u d n g nay nhdm thu duvc nhung ngudn nguyen lieu Gymnema sylvestre cho c h i t luang va san luang cao.
Cac mdu G. latifolium vdi lieu 10 g/kg deu CO tdc dung ha glucose mdu tren md hinh chupt tang glucose mau t h y c nghiem bdi STZ. Trong do, mau G. latifolium d Hoa Binh cho mdc h?
glucose mau eao n h l t (44,24%) ciing vdi ba m l u d Thai Nguyen (38,25%), Tuyen Quang (39,09%), Gia Lai (41,04%) t u a n g duang v&i gliclazid 20 mg/kg, mau d Ninh Binh tac dyng thdp nhdt (24,95%). K i t qua ndy hoan toan phii hap vdi k i t qua ma Pham Van Hai (2010) da tiln hanh t h u nghiem tren md hinh t u a n g ty, mau G.
latifolium thu d Hda Binh eho mdc ha glucose mau sau 10 ngay s d dung Id 40,84% (Phgm Van Hai (2010), Nghien ciru dac diem thi/c v$t, thanh phin hoa hoc va tac dung sinh hgc ciia cay day thia canh la to a Hoa Binh. Khoa lu|n tot nghiep d u a e sy, T r u d n g Dai hge Dupe Hd Npi). Gymnema latifolium vdi ten thudng gpi Id day thia canh la to ed dae diem t h y c vgl ddng chu y la luang sinh khoi Id Idn han nhieu sovcri day thia canh (Gymnema sylvestre). Trong khi dd thdnh p h i n cd tdc dung ha glucose mdu lai
TAP CHI DUgfC HQC - 10/2014 (SO 462 NAM54)
• Nghien cipu - Ky thuat
tdp trung phan Idn d Id, vi thd vdi k i t qua cho thay tdc dyng ha glucose mau tot thi G. latifolium hodn toan cd the t r d thanh mdt nguon d u a c lieu quan trpng dieu tri DTD ben canh G. sylvestre.
Han nua, hien nay, ngoai Viet Nam, tren t h i gidi hau nhu ehua co cdng bo ve tae dung ha glucose mdu cua G. latifolium. Do vay, k i t qua nay cd ddng gdp nhat dinh, gdp phdn m d ra nhung t n I n vpng khai thac ngudn nguyen lieu nay d l dieu tri DTD.
Tren m6 hinh chudt tang glucose mau bdi STZ, ea 4 mau G. inodorum d i u cd tac dung ha glucose mau. K i t qua phii hap vdi nghien cdu eua Shimizu K. chdng minh G. inodorum cd tac dyng ha glucose mdu. Theo Shimizu K. va cgng sy, dich chiet G inodorum lam giam 60% kha nang h i p thu glucose tren chupt c6ng sau 30 phiif^i. Tuy lodi G. inodorum chua d u a c nghien cdu nhieu ve tae dyng ha glucose mau, nhung vdi mdc gay ha glucose mau cao n h l t la 32,82%
ciia mdu G. inodorum thu d Ha Noi thi no cung la mgt nguon nguyen lieu tiem nang trong dieu tri DTD. Can t i l n hanh them cac nghien cu'u d l co the danh gia day du han tac dyng cua loai nay
Ket qua thuc nghiem vdi mau G, yunnanense thu hai d Kon Tum cho tac dung tot nhat (22,03%) so vdi cac m l u trong loai. K i t qua chii'ng mmh tdc dyng ha dudng h u y l t cua loai G. yunanense tren thuc nghiem, ciing c l them cho k i t qua nghien cdu cua Jmg-Tian Xie va cgng s y tren ehugt tdng glucose mau thyc nghiem, nhom chupt s u dyng djch chiet 6. yunnanense cho tde dyng hg glucose mau cao han 22% so vdi nhdm doi chdng'^l Mac dii ty le ha glucose mau khong eao nhu eac loai cdn lai trong chi, nhung vi^e nghien cdu tac dung ha glucose mau ciia 6.
yunnanense vua eung cap them mgt d u g c lieu cd the dung Irong d i l u tn DTD, vii'a giiip danh gia khdi quat v l tac dung ciia chi Gymnema R Br d Vidt Nam. Tii' dd ed cai nhin tong quat hon cho cdc nghien edu t i l p theo v l chi Gymnema R. Br T u k i t qua so sanh tren cd t h i giup lua chgn mdt so m l u Gymnema co tac dung ha glucose mdu uu t h i trong edc mau da dupe thy nghiem, dd Id edc m l u : G. sylvestre (Phii Yen, Quang Ninh, Thdi Nguyen) vd G. latifolium (Thai Nguyen, Hda Binh, Tuydn Quang, Gia Lat) Hien nay Iren
thj trudng da cd nhieu san pham thuoc vd thyc pham chdc nang hd tra d i l u tn DTD. Tuy nhien, viec khai thac nguyen lieu cho cac san pham nay chua ed mgt ca s d khoa hoe ma chu y l u dua vdo tinh thuan tien cCia nai san x u l t , nen hieu qua thue t l cua cdc c h i pham tren con chua on dinh va ddng nhdt. Do dd, k i t qua lya chgn eua d l tdi nay ed the d u a c s d dyng cho eac nghien cuu t i l p theo n h I m bao tdn, nhan g i l n g va khai thac CO hieu qua nguIn d u a c lieu quy trong dieu trj DTD.
Ket luan
21 mau ciia 4 loai Gymnema thu hai d cac viing khac nhau cua Viet Nam deu co tac dung ha glucose mau tren chuot tang glucose mau thyc nghiem bdi STZ. Mue do ha glucose mau cua cac m l u khac nhau tiiy theo loai va trong cung mgt loai, mdc ha glucose mau ciia cac mdu d cac vung khac nhau tuang d6i khac nhau.
Da lya chpn d u g c mpt so mdu co tac dung ha glucose mau uu t h i nhat de c6 the t i l n hanh bao ton, nhan giong va khai thac lam nguyen lieu: G.
sylvestre (Phii Yen, Quang Ninh, Thai Nguyen) va G. latifolium (Thai Nguyen, Hoa Binh, Tuyen Quang, Gia Lai).
Tai lieu tham khao 1. Trln Thi Bach (2007), "Nghien CLKU phan loai ho Thien ly a Viet Nam", Luan an tien sy sinh hgc, Vien Sinh thai va Tai nguyen sinh vat
2. Pham Hoang Hp (2000), Cay co Viet Nam. NXB Tre, quyiin 2, tr 738-740,
3. Sathya S., Kokilavani R„ Gurusamy K (2008),
"Hypoglycemic effect of Gymnema sylvestre (retz.) R Br leaf in normal and alloxan induced diabetic rats".
Ancient Science of Life. 28(2), p 12 - 14.
4 Shailendra G,, et al (2007), "Pharmacognosy phyto chemistry, pharmacology and clinical application of Gymnema sylvestre". Pharmacognosy reviews, 1(2), p 338-343.
5. Shimizu K„ Ozeki M , Tanaka K , Itoh K , Nakajyo S. etal. (1997), "Suppression of glucose absorption by extract from the leaves of Gymnema inodorum". J. Vet Med. SCI . 59(9), p 753 - 757.
6 Xie J. T., Wang A., Mehendale S„ Wu J., Aung H. H., Dey L, et al (2003), "Anti-diabetic effects of Gymnema yunnanense extract", Pharmacological Research The official journal ol Italian Pharmacological Society. 47, p 323 - 329.
(Ngay nh$n bai: 23/07/2014 - Ngay duyet dSng 06/10/2014) T A P C H i D t g f C HQC - 10/2014 (S6 462 N \ M 54)