Journal of research in viet nam traditional medicine and pharmacy No 40 - 2014
^ X A C D I N H T I N H AN T O A N C U A B A I T H U O C Q U Y E N T Y T H A N G G I A G I A M ( Q T T G G ) T R E N T H l T C N G H I E M Study on t h e safety of " Q u y e n ty t h a n g gia g i a m " ( Q T T G G ) r e m e d y in
e x p e r i m e n t a l model
* Vu Tuan Anh ', ** Nguy8n Nhuoc Kim ^ ' Benh vien Da Jdioa Da Ndng, ^ Khoa YHCT Trudng Dgi hoc Y Hd Npi T6m Tat:
Mftc tiiu nghi&n ciiru: Ddnh gid dgc tinh cdp vd bdn trircmg diin cda cao long "Quyen ty thang gia gidm " trin thj^c nghiem Phuffng phdp nghien cuu: Xdc dinh liiu gdy chit 50% (LDsy) cua cao long "Quyen ty thang gia gidm " tren thuc nghiem vd 30 con tho chia 3 lo theo cdc liiu khdc nhau theo doi sau 30 ngay. Ket qud nghien cuu: Khong xdc dinh duac liiu LD;o vd thuSc khong gdy thay doi vi hinh dang chung tren Idm sdng, cung nhu chirc ndng tao mdu, chuc ndng gan vd thgn chua co su thay doi ve mo binh hoc Kit luan: Cao long "Quyen ty thang gia gidm " khong gdy dgc tinh cdp vd dpc tinh bdn truang diin tren thirc nghiem
TCr kh6a: Cao 16ng "QuyIn ty thang gia giam", d6c tinh cap, doc tinh ban truorng diln.
Summary
S T U D Y O N T H E S A F E T Y O F Q U Y E N T Y T H A N G G I A G I A M ( Q T T G G ) R E M E D Y I N E X P E R I M E N T A L M O D E L
Objectives: To investigate acute and sub-chronic toxicity of "QTTGG" extract on experimental model. Methods: Determine lethal doses 50% (LDjo) of "QTTGG" extract on experimental animals. 30 rabbits were split up into 3 groups under different doses were monitored in 30 days.
Results: LD50 of the "QTTGG " extract has not been determined. The extract did not cause changes in general status clinically, ft also did not cause damage to hematopoietic, liver and kidney function in rabbits. Conclusions: "QTTGG" extract did not cause acute and sub-chronic toxicity on experimental animals.
Keywords: "Quyen ty thang gia giam" extract, acute toxicity, sub-chronic toxicity.
Dja chi lien hf: Nguyen Nhiicrc Kim- Truong Dai hoc Y HaN6i Ngay nhan bai: 22/01/2014 i>ia chi email: [email protected] Ngay phan bien: 12/02/2014 Ph^n bien khoa hpc: PGS.TS. Nguyin VSn Toai Ngay dang bao: 24/3/2014
*BSCKU;** PGS.TS
Nghien cim YDHCT Viet Nam Sd 40-2014
I. DAT VAN DE
Viem khap dang thSp (VKDT Rheumatoid Arthritis) la mot benh khap man tinh hay gap nhlt trong cac benh v6 khop. Hien nay, thu6c diSu tri VKDT cua y hgc hien dai (YHHD) CO rit nhieu loai: nhom chong viem giam dau khong nhan steroid va nhom co nhan steroid;
(corticoid). Mgt so thu6c co tac dung lie chi miln dich de chOa VKDT nhu Metrotrexat, nhung cac thu6c nay ben canh tac dung chua benh t6t, co khi cung gay tai bien: xult huySt tieu hoa va suy giam mien dich. Mgt trong nhirng hucmg tim thuoc moi dugc luu y nhieu trong nhirng nam gan day la thira ke, phat huy nhihig bai thuoc eua y hgc c6 truyen di6u tri co hieu qua VKDT, dong thoi giam tai biSn khi diing thuoc. Bai thuoc "Quyen ty thang" CO xult xir tir: "Bach nhat tuyen phuong", co c6ng nang khu phong, trir thap, tan han, th6ng lac.
Chii tn chiing ty do phong ban thap.
Dua vao dac diem benh tat ciia ngugi Viet Nam tir bai thuoc "Quyen ty thang" , chung toi gia giam mgt so vi thuoc cho phu hgp va ggi la "Quyen ty thang gia giam".
Mue tieu nghien ciru:
Bdnh gia toe iinh c&p va bdn Iritdng dien cUu cao long "Quyen ty thang gla gidm" tren thu-c nghiem.
II. CHAT LIEU, DOI TLTONG VA PHirONG PHAP NGHIEN ClTU
2.1. Chat lieu nghien cmi tren thirc nghiem
- Cao 16ng "Quyen ty thang gia giam" [3], [4]
Khuanghoat 16g Qu6 chi 08g Bae mgc huang 06g Xuyen khung lOg Hai phong dang 40g Phong phong 12g Dgc boat 12g Tan giao 12g Xuyen khung 12g Chich cam thao 06g Tang chi 30g Ydt 16g - Dung dich NaCL 0,9%
- Hoa chat
+ Kit djnh lugng cac enzyme va chat chuydn boa trong mau: ALT (alanin aminotransferase), AST (aspartat aminotransferase), bilirubin toan phan, albumin, cholesterol va ereatinin ciia hang Hospitex Diagnostics (Italy) va hang DIALAB GmbH (Ao), dinh lugng tren may Screen master cua hang Hospitex Diagnotics (Italy).
+ Dung dich xet nghiem mau ABX Minidil LMG cua hang ABX Diagnotics, dinh lugng tren may Vet abc ™ Animal Blood Counter
+ Cac hoa chat xet nghiem va lam tieu ban m6 benh hoc
Journal of research in viet nam traditional medicine and pharmacy No 40 - 2014
+ Nghien curu dugfc tien hanh 6 Bo mon Dirgfc ly - Truang Dai hoc Y HaNoi.
2.2. Phirong phap nghien cihi 2.2. L Xdc dinh doc tinh cap Theo phircmg phap Litchfield - Wilcoxon. Chuot nhat trang (chiing Swiss 20 ± 2g), nhin doi 12 gia, dirgfC chia thanh cac 16 khac nhau, moi 16 10 con. Chupt dugc uong cao long
"Quyen ty thang gia giam" vai Heu tang dan trong cung mpt khoi lirgng de xac dinh lieu thap nhat gay chet 100% chupt va lieu cao nhat gay chet 0%.
Chupt dupc theo doi tinh trang chung trong suot 7 ngay va ty le chet trong 72 gia ciia timg 16 sau khi uong thuoc.
2.2.2. Xdc dinh dgc tinh bdn trtr&ng dien [1], [2]
Tho thi nghiem duac chia deu thanh 3 16, moi 16 10 con (chung Newzeland l,8-2,5kg)
+ L6 doi chung (n^lO): U6ng dung moi la NaCL 0,9% voi 5ml/kg/ngay.
+ Lo nghien cuu 1 (n=10): U6ng cao "Quyen ty thang gia giam" lieu 15g/kg/ngay (tuang duong voi lieu dung cho nguai)
+ L6 nghien cuu 2 (n=10): U6ng cao "Quyen ty thang gia giam" lieu 30g/kg/ngay (tuong duong voi hai lieu dung cho nguoi).
Tat ca cac con tho dupc uong thuoc trong 4 tuan Hen, moi ngay mpt lan vao buoi sang, vai lupng hang dinh 5 ml/kg
- Cac chi tieu theo doi truoc va trong qua trinh nghien cuu
+ Tinh trang chung, the trang ciia tho
i- Danh gia chuc phan tao mau th6ng qua cac chi so: S6 lupng hong cau, ham luong hemoglobin, hematocrit, so lupng bach cau, cong thuc bach cau va so luong tieu cau
+ Danh gia ton thuang gan; ALT, AST
+ Danh gia chiic nang than theo chi so ereatinin huyet thanh
Tat ca cac xet nghiem tren dupc danh gia tai 3 thofi diem: truac uong thu6c, sau 2 tuan va sau 4 tuan u6ng thuoc.
- Mo benh hpc: Sau 4 tuan u6ng thu6c, tho duoc mo de quan sat dai the toan bp cac co quan. Kiem tra ngau nhien cau tnic vi the gan, than ciia 30% so tho o moi 16 sau dot nghien cuu.
Xet nghiem vi the dupc thuc hien tai Bp m6n Giai phau benh - Truang Dai hpc Y Ha Npi.
2.2.3. Xu ly so lieu:
Xu ly so lieu thu dupc theo thuat toan thong ke y sinh hpc (chuong trinh Epi - info 6.04)
Nghien citu YDHCT Viet Nam So 40-2014
- Tinh n, ty le (%), tinh s6 trung binh thuc nghiem X, do lech chuin SD.
- So sanh 2 gia tri hung bmh cua 16 chirng va 16 nghien ciiu tren thuc nghiem dimg test t-student
Su khac biet co y nghia th6ng ke vai p<0.05
III. KET QUA NGHIEN CUtJ VE BOC TINH CAP VA BAN TRir6NG DIEN
i . l . Ket qua doc tinh cap tren chuot nhat trang
Chugt nhit trang ca 2 gi6ng, nang 18-22 gam dugc uong cao "QTTGG"
vai lieu tang dan tir 24g/kg den 240g/kg, vol the tich toi da ma chugt CO the dung nap dugc. Theo doi chugt trong 72 gig a dieu kien phong thi nghiem thay: Sau khi uong thu6c, chugt a cac 16 hoat dgng binh thuang.
Bang 3.1: Anh hu-gng ciia cao
an u6ng t6t, kh6ng thay chugt nao co biSu hien ngg dgc. Kh6ng co chugt nao ch6t a tit ca cac 16 nghien ciiu, vi th6 khong tinh duge LD50.
3.2. Dgc tinh ban triromg dien 3.2.1. Ket qud nghien curu mot s6 chi sd cdn nang, huyet hoc vd sinh hoa mdu cda tho
* Tinh trang chung: Trong su6t thoi gian thuc nghiem, tho a ca 3 16 boat dgng binh thucmg, nhanh nhen, an uong t6t, 16ng mugt, phan kho.
Khong thay bieu hien bat thuong 6 ca 3 16 tho trong su6t thoi gian nghien ciru.
* Ket qua nghien cuu trgng lugng, cac chi s6 huyet hgc va sinh hga mau danh gia chiirc nang gan, than ciia tho trong va sau 30 ngay diing thu6c "QTTGG" dugc trinh bay tren cac bang sau:
•QTTGG" den thi trang tho Trong lirgng (kg)
Thai diem Truac u6ng thuoc
(a) Sau 2 tuan (b)
P (a-b) Sau 4 tuan (c)
p(.-=,
Lo chirng (1) x ± S D 2,18±0,09
2,28±0,11 n
10
10
>0,05 2,38±0,09 10
>0,05
Lo NC (2) x±SD 2,30±0,13
2,32±0,16 n
10
10
>0,05 2,51±0,23 10
>0,05
Lo NC (3) x±SD 2,30±0,21
2,34±0,15 n
10
10
>0,05 2,54±0,15 10
>0,05
p P(i-2)>0,05 P(i-3)>0,05 P(2.3)>0,05 P(i-2)>0,05 P(i-3)>0,05 P(2-3)>0,05 P(i-2)>0,05 P(i-3)>0,05 P{2-3)>0,05
Journal of research in viet nam traditional medicine and pharmacy
Nhan xet: Sau 2 va 4 tuan u6ng thuoc, trgng lugng tho a 2 16 diing thu6c
"QTTGG" va 16 chirng deu co xu hugng tang so vdi truoc khi nghien ciiu, sir thay doi kh6ng co y nghia thong ke (p>0,05). Khong co su khac biet v6 miic do gia tang h-gng lugng tho giila 16 chimg va cac 16 dung thu6c (p>0,05)
Bang 3.2: Anh huomg ciia cao "QTTGG" dgn so Iiromg hong cau trong mau tho
Hong cau (trieu/mm^)
Thoi diem Truoc uong thu6c
(a) Sau 2 tuan
(b)
P fa-bl
Sau 4 tuan (c) p <«>
Lo chirng (1) x ± S D
4,90±0,46
4,71±0,32 n
10
10
>0,05 4,08±0,37 10
>0,05
Lo NC (2) x ± S D
4,93±0,39
4,92±0,43 n
10
10
>0,05 4,94±0,54 10
>0,05
Lo NC (3) x ± S D
4,96±0,84
4,94±0,58 n
10
10
>0,05 4,89±0,66 10
>0,05
p P(i-2)>0,05 P(i-3)>0,05 P(2j)>0,05 P(i-2)>0,05 P(i-3)>0,05 Pa-3)>0,05 P(i-2)>0,05 P(i-3)>0,05 P(2j)>0,05 Nhan xet: Sau 2 va 4 tuan uong thu6c, s6 luong hong cau trong mau tho 6 2 16 dung thu6c "QTTGG" va 16 chiing co thay d6i so voi truoc khi nghien ciiu, su thay doi khong co y nghia thong ke (p>0,05). Khong co su khac biet vh s6 lupng h6ng cau trong mau tho giua 16 chiing va cac 16 ditng thu6c (p>0,05).
Bang 3.3: Anh hirovg cua cao "QTTGG" den ham lirong huyet sic td trong mau tho
Hb(g/dl) Thoi diem
Truoc u6ng thuoc
(a) Sau 2 tuan
(b)
P (..b)
Sau 4 tuan
( 0 )
P (.-cl
Ld chung (I) x ± S D 10,11±1,30
9,73±0,87 n 10
10
>0,05 9,80±1,31 10
>0,05
Lo NC (2) x ± S D 10,33±0,59
9,90±1,21 n 10
10
>0,05 10,27±1,17 10
>0,05
Lo NC (3) x ± S D 10,18±1,63
I0,02±l,03 n 10
10
>0,05 9,96±0,44 10
>0,05
P P(i-2)>0,05 P(i-3)>0,05 P(2-3)>0,05 P(i-2)>0,05 P(i-3)>0,05 Pf2-3)>0,05 P(i-2)>0,05 P(i-3)>0,05 P(2-3,>0,05
Nghien ciru YDHCT Viit Nam So 40 - 2014
Nhan xet: Sau 2 va 4 tuan uong thu6c, ham lugng huygt sic t6 trong mau tho 6 2 16 diing thuoc "QTTGG" va 16 chirng co thay d6i so vol miac khi nghien ciiu nhung kh6ng co y nghia thong ke (p>0,05). Kh6ng eo su khac biet ve ham lugng buySt sic t6 trong mau tho giira 16 chiing va cac 16 dimg thuoc (p>0,05)
Bang 3.4: Anh huo'ng cua cao "QTTGG" din so Xvtqng bach cau trong mau tho
Bach cau (nghin/mm^)
Thd'i diem T r u a c uong thuoc
(a) Sau 2 tuan
(b) P (.-b) Sau 4 tuan
(c) P (a-cl
Ld chirng ( I ) x ± S D
4,77±1,12
4,57±1,00 n
10
10
>0,05 4,51 ±0,96 10
>0,05
Lo N C (2) x ± S D
4,98±0,81
4,97±0,48 n
10
10
>0,05 4,88±0,60 10
>0,05
L o N C (3) x ± S D
4,80±0,95
4,97±0,58 n
10
10
>0,05 4,98±0,45 10
>0,05
P
P(i-2)>0,05 P(i.3)>0,05 P(2-31>0,05 P(i.2)>0,05 P(i-3)>0,05 P(2-3)>0,05 P(i-2)>0,05 P(i-3)>0,05 p,2-31>0,05 Nhan xet: Sau 2 va 4 tuan uong thuoc, so lugng bach cau trong mau tho 6 2 16 dimg thu6c "QTTGG" va 16 chirng co thay doi so vol truoc khi nghien cuu nhung khong CO y nghia th6ng ke (p>0,05). Khong co su khac biet v6 so lugng bach clu trong mau tho giira 16 chiing va cac 16 dung thuoc (p>0.05)
Bang 3.5: Anh hirvng ciia cao "QTTGG" den chi so AST trong mau tho A S T (U/I)
Thoi diem T r u a c u6ng thuoc
(a) Sau 2 tuan
(b) P (a-bl Sau 4 tuan
(c) P (.-c)
Ld chirng (1) x ± S D
48,60±4,05
48,10±6,02 n
10
10
>0,05 46,53±2,17 10
>0,05
L o N C (2) x ± S D
46,10±6,37
46,41±5,27 n
10
10
>0,05 46,98±3,50 10
>0,05
L o N C (3) x ± S D
46,53±2,61
46,34±4,0i n
10
10
>0,05 47,66±3,10 10
>0,05
P P(i-2)>0,05 P(i-3)>0,05 P(2.31>0,05 P(i-2)>0,05 P(i-3)>0,05 P(2-31>0,05 P<i-2)>0,05 P{i-3)>0,05 J Q J ] ^ 0 J ( ) 5 _
Journal of research in viet nam traditional medicine and pharmacy No 40 - 2014
Nh^n xet: Sau 2 va 4 tuan uong thu6c, chi s6 AST trong mau tho a 2 16 dung thuoc "QTTGG" va 16 chiing co thay doi so vai truac khi nghien ciiu nhung khong CO y nghia th6ng ke (p>0,05). Kh6ng co sir khac biet ve chi so AST trong mau tho giGa 16 chiing va cac 16 diing thu6c (p>0.05)
Bang 3.6: Anh hiring cua cao "QTTGG" den chi so ALT trong mau tho ALT (U/I)
Thoi diem Truac u6ng thuoc
(a) Sau 2 tuan
(b)
P (.-bl
Sau 4 tuan (c)
P fB-Cl
L6 chirng (I) x ± S D 61,65±5,09
58,96±5,00 n 10
10
>0,05 59,32±2,92 10
>0,05
Lo NC (2) x ± S D 57,60±4,79
57,92±4,86 n 10
10
>0,05 59,20±9,41 10
>0,05
Lo NC (3) x ± S D 58,65±2,61
59,60±5,94 n 10
10
>0,05 59,53±9,23 10
>0,05
p P(i-2)>0,05 P(i-3)>0,05 p,2.3,>0,05 P(i-2)>0,05 P(i-3)>0,05 P(2-31>0,05 P(i.2)>0,05 P(i-3)>0,05 P(2-31>0,05 Nhan xet: Sau 2 va 4 tuan u6ng thu6c, chi s6 AST trong mau tho 6 2 16 diing thuoc "QTTGG" va 16 chiing co thay doi so vai truoc khi nghien cmi nhung khong CO y nghia th6ng ke (p>0,05). Kh6ng co su khac biet ve chi s6 AST trong mau tho giira 16 chirng va cac 16 diing thu6c (p>0.05)
Bang 3.7: Anh hu'dng ciia cao "QTTGG" den ham lugng Creatinin trong mau tho
Creatinin (mg/dl) Thoi diem
Truac u6ng thuoc
(a) Sau 2 tuan
(b)
Sau 4 tuan (c)
P f.-cl
Ld chirng x ± S D
1,03±0,05
1,05±0,05 fl)
n
10
10
>0,05 1,06±0,05 10
>0,05
Ld NC (2) x ± S D
1,04±0,05
1,03±0,04 n
10
10
>0,05 1,04±0,05 10
>0,05
Ld NC (3) x ± S D
1,02±0,04
1,03±0,04 n
10
10
>0,05 1,04±0,05 10
>0,05
p
P(i.2)>0,05 P(i-3)>0,05 P(2-31>0,05 P(i-2)>0,05 P(,.3)>0,05 Pf2.31>0,05 P(i-2)>0,05 P(i-3)>0,05 P(2-31>0,05
Nghien cim YDHCT Viet Nam So 40 • 2014
Nhan xet: Sau 2 va 4 tuSn uong thuoc, ham lugng creatinin trong mau tho a 2 16 dung thu6c "QTTGG" va 16 chung CO thay doi so vai truoc khi nghien ciiu nhung kh6ng co y nghia thong ke (p>0,05). Kh6ng co sir khac biet ve ham lugng creatinin trong mau tho giira 16 chirng va cac 16 diing diu6c (p>0.05)
IV. BAN LUAN:
Bai thu6c "Quyen ty thang gia giam" dua tren ca so ciia bai thuoc c6 phuong "Quyen ty thang" bo di vi thuoc NhQ huang va gia 2 vi thuoc mai: Phong phong, Y dT. Cac vi thu6c da dugc lira chgn theo diing tieu chuan Dugc dien Viet Nam IV va che bien theo phuang phap ciia YHCT.
Thu6c dugc sac tren he th6ng may chiit xult ky thuat cao cua Han Quoc, dam bao tieu chuan ve sinh va v6 triing.
* Tinh an toan xac dinh tren thue nghiem
Bai thu6c "Quyen ty thang gia giam" dugc thii nghiem dgc tinh d p vol LD50 tai Bg mon Dugc ly Trudng Dai hgc Y Ha Ngi. Kit qua theo doi lien tuc trong 72 gio g dieu kien phong thi nghiem da cho thiy:
Tat ca chugt thir nghiem deu an u6ng va hoat dgng binh thuang, khong co chugt nao co bieu hien ngg dgc dii lieu thu6c tren chugt gap 66 lan lieu tuang duong tren nguoi (la the tich
toi da ma chugt c6 the dung nap dugc). Dg vay thu6c kh6ng co dgc tinh cap va kh6ng xac dinh dugc lieu LD50.
Trong thuc te lam sang, benh VKDT can phai dieu tri lau dai, diing thu6c lien tuc nhieu ngay mai c6 ket qua de ban che benh va giam cac bien chirng cua benh doi vdfi benh nhan.
Do vay, de danh gia tinh an toan ciia bai thu6c "Quyen ty thang gia giam"
khi su dung dai ngay d6i vai co the, nghien ciiu dgc tinh ban truoTig dien tren tho thire nghiem vai lieu 15g/kg/24 gig (tuang duang lieu dimg tren nguai) va lieu 30g/kg/24 gia (tucmg duang 2 lan lieu diing tren nguai) da dugc danh gia sau 4 tuin u6ng thu6c.
Trong thai gian u6ng thu6c 4 tuan kSt qua tren nhom doi chirng va 2 nhom nghien cim cho thay rang: ea 2 lieu thu6c thu deu kh6ng gay anh huong xau d6n tinh trang chung cung nhu trgng lugng cua tho giira 16 chung va cac 16 dung thu6c (p>0,05).
Sir thay d6i eac chi so huylt hgc (so lugng h6ng cau, ham lugng huyet sic to, s6 lugng bach cau va tieu cau), xet nghiem hoa sinh danh gia su t6n thuong gan (chi s6 AST, ALT), chiic nang than (ham lugng creatinin, ure) truoc, trong va sau khi u6ng thu6c co su thay doi kh6ng dang ki va kh6ng CO y nghia th6ng ke (p>0,05). [5]
Journal of research in viet nam traditional medicine and pharmacy
Dong thai, cac xet nghiem vi the vl m6 hgc ciia gan va than cua th6 sau 4 tuin u6ng thu6c eiing cho thay thu6c kh6ng gay ton thuang ve hinh thai.
Nhu vay, bai thuoc "Quyen ty thang gia giam" da dat yeu cau ve tinh an toan va dugc phep su dung cho benh nhan theo tieu chuan quy dinh
V. KET LUAN
Cao long "Quyen ty thang gia giam" CO do an toan tren thir nghiem dugc ly qua khao sat dgc tinh cap va ban truong diln tren thuc nghiem.
1. Cao long "Quyen ty thang gia giam" vai lieu tang dan 24g/kg den 240g/kg (gip 66 lln lieu tuong duong
tren nguoi) va cung la the tich t6i da ma chugt c6 the dung nap dugc ma kh6ng thay co bilu hien ngg dgc va kh6ng CO chugt nao chet. Do do chua xac dinh dugc LD50 cua cao long
"QTTGG" tren chugt nhlt hing theo duang u6ng.
2. Nghien ciru dgc tinh ban truong dien cua cao long "Quyen ty thang gia giam" tren tho voi lieu 15g/kg/24h (tucmg duong voi liiu dimg tren nguai) va liiu 30g/kg/24h (tuang duang 2 lan heu dimg tren ngucri) kh6ng gay thay d6i vl tinh trang chung vl cac chirc nang sinh hoa cua gan, than, ve chirc nang tao mau va chua co su thay d6i ve m6 benh hgc.
TAI LIEU THAM KHAO 1. Bo Trung Dam (2006),
"Phircmg phdp nghien cuu doc tinh ban trucmg diin", Phucmg phap nghien ciiu tac dung Dugc ly ciia thuic tir Dugc thao - Vien Dugc heu, NXB Khoa hgc va Ky thuat, tr 311- 313.
2. Dd Trung Dam (2006),
"Phucmg phdp ngoai suy lieu co hieu qud tucmg ducmg giiia nguai vd dong vgt thi nghiem ", Phucmg phap nghien ciiu tac dung dugc ly eua thuoc tir
dugc thao - Vien Dugc lieu, NXB Khoa hgc va Ky thuat, tr 385.
3. Nguyen Nhugc Kim, Hoang Minh Chung (2009), "Duac hoc co truyin ", NXB Y hgc, tr 32-119.
4. Nguyen Nhugc Kim (2009),
"Phuang ti hpc ". NXB Y hgc, tt 60- 66.
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