# Nghien CIFU - Ky thuat
Tai lieu tham khao
1. A. Afkhami and Morteza Bahram (2005), "Mean centering of ratio spectra as a new spectrophotometric method for the analysis of binary and ternary mixtures", Talanta, 66, pp. 712 - 720.
2. A-A. M. Wahbi and Hoda Mahgoub (2003),
"/application of fourier functions to ratio spectra of absorption curves: theory and application", Bulletin of Faculty af Pharmacy Cairo University, 44 (^).
3. D. L. Massart, B. G. M. Vandeginste, L. M. C Buydens, S. D. E. Jong, P. J. Lewi, J. Smeyers-
Verbeke (1997), Handbook of Chemometrics and Qualimetrics: Part A, Elsevier Science, p. 238.
4. M. A. Korany, M. A. Elsayed, M. M. Bedair and H. Mahgoub (1990), "Computer-assisted spectrophotometry: Muiticomponent analysis with a discrete Fourier transfomi", Talanta, 37 (12), pp. 1183 - 1 1 8 8 .
5. R. M. Youssef and H. M. Maher (2008), "A new hybrid double divisor ratio spectra method for the analysis of ternary mixtures", Spedrochimica Acta Part>*,70. pp. 1152-1166. •
Danh gia tac dung giam dau va trung hoa acid ciia thuoc Vi quan khang tren thyc nghiem
Vfl Minh Hoan^', Nguyen Tr9ng Thdng^
Nguyin Nhirgrc Kim ^ Vu Th| Nggc Thanli^
' Benh vien Da khoay hgc co truyen Hd Ngi
^ Truang Dai hgc Y Hd Ngi E.mail: [email protected] S u m m a r y
Analgesic and acid-neutralizing effects of Vi quan l<hang were experimentally studied. In mice, for the analgesic effect, at daily doses of 22g and 44g/kg given orally for 5 consecutive days, Vi quan khang showed equivalent to a single injection of morphine hydrochloride of lOmg/kg and to aspegic lOOmg/kg. The acid-neutralizing effect of Vi quan khang was ca. 42.9% in comparison with that of ff/taalox.
Keywords: Vi quan khang, analgesic effect and neutralize acid, experimental.
D a t v a n d e
Oau, g hoi, g chua la mgt tridu c h y n g t h y d n g ggp cua benh vidm ioet dg day td trdng.
Do do, myc tieu trong d i l u tri Id phai giam d y g c c o n dau v d trung hda acid djch vj. Oe lam gidm do acid djch vj c6 2 cdch hoge la trung hda acid dieh vi hoac i>c ehe bdi t i l t acid djch vj. Bai thude Vj qudn khang trong thdnh p h i n cd mdt sd vi thudc cb tac dyng ly khi khoan hung, che toan gidm thdng t y c Id gidm dau, trung hda acid.
Oe lam sdng td tac dung ndy cua thude tren thyc nghigm chung tdi tien hdnh nghien c i i u v d i cdc myc tieu sau: Danh gia tac dung giam dau va tac dicing trung hda acid ciJa thuoc Vj quan khang tren f/iyc nghiem.
C h a t l i d u v a d o i t u ' O ' n g n g h i e n ciPU T h u o c n g h i e n c i r u
Cao n y d c chiet xuat tO bdi thudc Vj qudn khang cd ty 1^ 1:1, d y g c bao che tgi Bgnh vien Oa khoa Y hgc cd truyen Ha Ndi. Thdnh phan cua bdi thudc gdm hodng lien, cam thdo, huyen ho, nga t r u l t , a tgc cdt, ban hg ehe, phye linh:
12 g, ngo thu, tran b l . . . D d i tu'O'ng n g h i e n c i r u Nghidn cmi tac dung giam dau - Chugt nhdt trdng chung Swiss, cd 2 gidng, khoe mgnh, trgng l y g n g 18 - 22 g do Vi§n V#
sinh djch t l Trung y o n g cung cap. ChuOt d y g c nudi trong phdng thf nghiem cua B d mdn Dygc ly 3 ngdy t n r d c khi nghidn cil'u v d trong sudt thdi gian nghidn eO-u bang t h y c an c h u i n ddnh
T ^ CHi Dl/glC HQC-08/2013 (SO 448 N A M 53)
• Nghien CIFU - Ky thuat
rieng cho chuOt (do Vign V g sinh djeh te Trung y o n g eung cap), udng n y d c t y do.
Thude, hod ehat vd may mde phuc vu nghidn c y u .
Aspegie (DL-lysin aeetylsalicylat) gdi bot 100 mg cua hang Sanofi Aventis, Phap. Morphin hydroclorid dng 10 mg/ml cua Xf nghiep D y g c pham Trung y o n g 2. Dung djch acid acetic 1 % . Mdy Hot plate model - DS37 eua Hang Ugo- Basiie (Italy).
Nghien c i h / tac dung trung hoa acid - Thuoc thCpVj qudn khang t y l g 1:1 5 mi.
- Maaiox (chya magnesi hydroxyd va nhom hydroxyd): pha 1 vien vi>a dCi 22,5 ml n y d c (lieu dung tren ngydi mdi ian 2 vien)
L y g n g thudc trong 5 mi cua cd 2 thudc d i u t y o n g d y o n g 1/9 iieu dung mdt (In cua ngydi.
Phu'O'ng phap nghien ci>u
- Nghien ciiu tac dung giam dau eua Vj quan khang theo 2 phyang phap "mam ndng" (hot plate) va phyong phdp gdy quan dau bang acid acetic (phyong phap Koster).
- Nghien cijv tac dung trung hoa acid L i y 5 ml dung djeh thude t h y khdng acid.
Cho them dung djch HCi 0,1M (cho nhieu dng, vdi sd HCI tang dan). Bo pH cua hdn hgp de xac dinh sd l y g n g HCI 0,1 M da them vdo de dat d y g c pH khoang 3,0. Do pH trong 3 gid (vao cac thdi diem 15 phut, 30 phut, 1 gid, 2 gid, 3 gid) bang mdy Jenway 3510 pH Meter (Anh), so sanh vdi thude ddi chieu (Maalox).
Xu" ly sd lieu
Cae s6 lieu dugc x y iy thdng kd theo tfiuat toan thdng ke t-test Student bang phan mem Microsoft Excel. Sy khac biet cd y nghTa thdng Ire khi p < 0,05.
K e t q u a n g h i e n cCru
Tac d y n g giam dau cua Vj quan khang theo phyo>ng phap mam n d n g
Bang 1: Anh hu^ng cua Vi quan khang len thai gian phan irng vai nhiet cua chugt nhat tring LS chu^t
L6 1: (chi>ng) L6 2: {tiem morphin hydrodorid 10mg/kg)
P2-1
Lo 3: (uong Vi qufin ktiang 22g duq/c ii#u/kg/ngfiy) P3-1
P3-2
L6 4: (u6ng Vj quan khang 44g dyg-c lieu/kg/ngay) P4-1
Pw P4-3
N - 10 10
10
10
Thm gian phan Ceng voi nhi^t Trum: Sau 23,61 ± 6,57
23,67 ± 4,35
>0,05 23,23 ±4,19
>0,05
>0,05 23,75 ± 4,89
>0,05
>0,05
>0,05
23,95 ± 7,63 33,03 ± 7,59
<0.05 32,85 ± 8,74
<0.05
>0,05 31,23 ±6,94
<0.05
>0,05
>0,05
-p trufdfc-sau
>0,05
<0,01
<0.01
<0,05
Nhan x6t: - V| quan khang d 16 3 va 4 cd tac dyng keo - Morphin eo tac dyng Idm keo dai rd ret thdi dai rd ret thdi gian phan upng vdi nhiet cua chudt gian phdn yng vdi nhigt cua chugt (p2.i < 0,05 so vdi tardc khi udng thudc (p < 0,01 va p <
va p so vdi t r y d c khi tiem morphin < 0,01). 0,05) va so vdi 16 ehO-ng (p < 0,05).
Tac d y n g g i d m dau cua Vj qudn khang theo Phu'O'ng phap gay dau bang acid acetic Bang 2: Anh hiedng cOa Vi quan khang ten so con quSn dau ciJa chudt nhit tring
Lo chu^t L61 (chijng)
L6 2 (aspegiclOOmg/kg)
P!-1 N
10
10 Q'Sphut 5,60 ± 2,46
2,50 ±1,51
<0,01
So ccn qu$n dau (so ccm/ SphCit)
5-10 phut 10-15 phot 15-20 phut 20 - 25 phut 25 - 30 phUt 15,60 ± 5,04 16,30 ± 5,91 14,40 ± 5,83 10,80 ± 4,37 8,00 ± 3,83
9,90 ±2,23 11,00 ±2,83 9,40 ±2,37 6,70 ±2,36 4,80 ±2,39
<0,01 <0,05 <0,05 <0,05 < 0,05
TAP CHi DU'DC HOC - 08/2013 (S6 448 NAM 53>
• Nghien cirv
1 -Ky thuat
Lo chugt L6 3 (Vl quan khang 22g dugc lieu/kg/ngay)
P3-1 P3-2 L6 4 (uong Vl quan khang 44g dugc lieu/kg/ngay)
P4-1 P4-2 P4-3
JV
10
10 0-5phut
2,80 ±1,81
<0.05
>0,05
3,09 ±1,76
<0.05
>0,05
>0,05
So ccm qu^n 6au (so con/ 5 phut) 5-10 phut 10-15 phut
12,10 ±3,84 12,20 ±2,97
<0,05 <0.05
> 0,05 > 0,05
11,36±2,01 12,00±4,07
<0.05 <0.05
> 0,05 > 0,05
> 0,05 > 0,05 15-20phLlt
9,70 ± 2,36
<0.05
>0,05
9,00 ± 3,44
<0.05
>0,05
>0,05
20-25 pha
7,10 ±1,91
<0.05
>0,05
6,73 ± 3,07
<0.05
>0,05
>0,05
25-30 phut
4,10±1,85
<0.01
>0,05
4,09 ± 2,95
<0.05
>0,05
>0,05 Nhan xet: Aspegic lieu 100 mg/kg cd tac
dung lam giam sd c o n quan dau d tdt cd cdc thdi diem nghien e y u (p< 0,01 hoac p< 0,05). Vj qudn khang d 16 3 va 4 tde dyng Idm giam sd Tac dung trung hoa acid cua Vj quan khang Cao Vj quan khang 1:1 cd pH = 4 , 5 1 .
c o n qudn dau ro rgt d tat cd cdc thdi diem nghien e y u so vdi Id chCrng (p< 0,05 hoac p<
0,01); tac dyng giam dau nay t y o n g d y o n g vdi aspegic (p3.2 vd P4.2 > 0,05).
Bang 3;
Ong 1 2 3 4 5 6 7
Tac dung trung hoa acid cua
15 pha 1,5 4,35 2,0 4,25 2,5 4,17 3,0 4,10 6,0 3,67 9,0 3,27 12.0 3,03
Vi quan iihang
30 phut 4,44 4,35 4,26 4,18 3,78 3,30 3,16
pH 1 gia 4,51 4,40 4,29 4,19 3,78 3,27 3,13
2 9 » 4,35 4,26 4,17 4,10 3,70 3,23 3,11
3 giil 4,34 4,26 4,19 4,10 3,71 3,26 3,11 Nh$n xet: Cao Vj quan khang cd tac dung
duy tri pH ^ 3 it nhdt 3 gid. Tac dung trung hoa acid nhanh sau 15 phut, sau dd pH tang rdt nhe trong khoang thdi gian do 3 gid.
Bdng 4: Tac dung tmng hoa acid cua hAaalox
Tac dyng trung hoa acid cua Maalox Pha 1 vien Maalox trong vCra dCi 22,5 ml n y d c (tyong d y o n g 2/9 vien v y a du 5 ml n y d e ) , dung djch cd pH = 8,62.
6ng 1 2 3 4 5
So ml HCI 0,1 M 5 28 25 20 15
15 phut 4,35 3,02 3,70 4,10 4,20
30 phut 6,50 4,94
pH 1 gia 7,34 5,69
2gic>
7,53 6,22
Khong do tiep
3 g » 7,57 7,14
Nhan xet: Tae dyng trung hoa acid nhanh sau 15 phut, sau do pH tiep tye tang dan trong khoang thdi gian do 3 gid.
B a n i u a n
Dau Id mgt eo c h l bdo v g c o thd. Oau Id do cdc ngpn ddy than kinh cdm gidc bj kfch thieh
T ^ CHi Dirpc HQC-08/2013 (S6448 NAM 53>|
• Nghien CCFU - Ky thuat
qud dO bdi tde nhdn vgt ly hay hda hpe. Cd n h i l u nguydn nhdn vd c o c h l gdy dau ndn tren ttiyc nghidm ed nhidu md hinh nghidn c d u tde dgng gidm dau cua thudc. Mdi md hinh gdy dau se dgi di$n cho mgt logi eo c h l dau nhat djnh vd d y g c dung d l ddnh gid tde dyng cua mpt ioat CO chd gidm dau cOa thudc"^. P h y o n g phdp gdy dau b i n g acid acetic- p h y o n g phdp Koster t h y d n g d y g c dCing d l ddnh gia tac dyng giam dau ngi tgng. P h y o n g phdp " mam ndng" (hot plate) Id mdt p h y o n g phdp t h y d n g d l nghien cdu ddnh gid tde dgng gidm dau tmng y o n g . Phyong phdp ndy d y g c tien hdnh tren chudt tiem mdng byng morphin hydroclorid vd udng thude tht> nghidn cdu, do thdi gian phdn yng vdi nhi^t dd cCia chugt t n r d c khi udng thudc va sau khi udng thudc '^.
Ket qud d bdng 1 cho thay morphin cd tae dyng Idm kdo ddi ro rgt thdi gian phan yng vdi nhigt cCia chuOt (P2-1 < 0,05 vd p so vdi tryde khi tidm morphin < 0,01), cdn Vj qudn khang cd 2 l i l u 22 g vd 44 g d y g c lidu/kg/ngdy udng trong 5 ngdy iidn tyc c6 tde dyng kdo ddi rd ret thdi gian phdn yng vdi nhi$t cCia chuOt so vdi t r y d c khi udng thudc (p < 0,01 vd p < 0,05) vd so vdl 16 chyng (p < 0,05).
K i t qud d bdng 2 cho thay, Aspegie iieu lOOmg/kg cd tde dyng Idm gidm sd con qugn dau d t i t cd ede thdi d i l m nghidn cdu (p < 0,01 h o l e p < 0,05).Vj qudn khang cd 2 lieu 22 g vd 44 g d y g c IJdu/kg/ngdy udng trong 5 ngdy lien tyc ddu c6 tde dyng Idm gidm sd c o n qudn dau ro rgt d t i t cd cdc thdi d i l m nghien cdu so vdi id chdng (p < 0,05 hoge p < 0,01); tde dgng gidm dau ndy t y o n g d y o n g vdl aspdgic (P3.2 va P4.2 > 0,05). Tde dgng gidm dau d 2 Id udng Vj qudn khang lieu t h i p vd Vj qudn khang lieu eao khdng c6 s y khdc bl^t cd y nghTa thdng ke (p >
0,05).
K i t qud d bdng 3 vd 4 cho thay cao Vj quan khang cd tde dgng duy tri pH ^ 3 it n h i t 3 gid, tde dyng tmng hda acid nhanh sau 15 phOt, sau dd pH tang rdt nhg trong khoang thdi gian do 3 g i d . Maalox cd tde dgng duy tri pH ^ 3 ft n h i t 3 gid, tde dyng tmng hda acid nhanh sau 15 phOt, sau dd pH t i l p tyc tang d i n trong khodng thdi gian do 3 gid
Vdi k i t qud nghidn edu tren eho t h i y Vj qudn khang ed tde dgng gidm dau tdt tren thyc
nghiem qua hai phyong phdp "hot plate" v d
"Koster^ va tde dyng trung hda acid. Trong bdi thudc Vj qudn khang co mdt sd vj thudc co tde dgng ly khi hogt huyet tde la cd tde dgng giam dau n h y nga tmdt, t r i n bi, h u y l n hd '^' ^' ^\ Cde vj thudc nay Id nhdng vi thudc cd tde dyng ly khi, kien ty, tdo thdp, ehi thdng vdi mde dp khde nhau, trong do nga tmgt vd huyen hd ngoai tde dung hdnh khi con ed tae dyng hogt huylt. T r i n bi Id vj thudc trong nhdm thudc hdnh khi gidi u l t de ehya cdc ehdng khi trg d ty vj vd ean khi u l t ket nen ed tde dyng giam dau, kich thich tieu hda, lam h i t cdc trieu chdng d i y c h y d n g , g hoi, ndn mda, giam tao bon do t r y o n g lyc eo bj gidm. Ngodi ra trong thudc Vj quan khang cdn c6 mdt sd vj cd tde dung che toan chJ thdng, tham t h i p nhy 6 tae cdt, bgch linh. Mpt sd tdi ligu cho thdy 6 tgc cdt ed tde dung thu liem chi huyet, cd tmh ehi ddi, ehe toan ehf thdng, thu thap liem sang. La thudc lam giam c h i t chua, dCing cd hieu qua ddi vdi eae chyng aeid djch vj cao, loetdaddyf^'^l
Vdi ket qua nghien edu tren thyc nghidm tren cang minh chdng tde dung gidm dau va trung hda acid ciJa thude, khi nghien edu ridng ie tdng vj thudc cho t h i y cdc tae dyng gidm dau nhyng khi phdi hgp thanh bdi thude Vj qudn khang thi chung vdn cdn tac dyng tdt. Day cung ia tien de de danh gid tde dyng eua thudc trdn lam sdng.
K e t i u a n
Ket qua nghidn cdu cho thay Vj qudn khang vdi l i l u 22 g d y g c ligu/kg/ngdy va 44 g d y g c ligu/kg/ngdy cho ehupt nhat trang udng trong 5 ngdy cd tde dyng gidm dau t y o n g d y o n g vdi tde dgng 0 16 chudt tiem mgt lan morphin hydroclorid 10 mg/kg va vdi tde dgng d 16 chuOt udng Aspegie 100 mg/kg. S y khac bigt d hai lieu 22 g va 44 g d y g c lidu/kg/ngay khdng cd ed y nghTa thdng ke.
Vj qudn khang cd tde dgng trung hda acid bang 42,9% so vdl tae dyng cOa Maaiox. Tde dung tmng hda aeid cua Vj qudn khang dgt gan tdi da ngay trong 15 phCit d i u vd duy tri trong it n h i t 3 gid, trong khi tac dgng trung hba aeid cua Maalox nhanh sau 15 phut, sau dd pH tidp tyc tdng dan trong khoang thdi gian do 3 gid.
(Xem tiep trang 55)
TAP CHf DiraC HOC - 08/2013 (S6 448 NAM 53^
• Nghien ciru - Ky thuat
cau hoa, vd gidi phong ban dau cua PRE ACE ti>
vi cdu PLGA tuong irng Id 7,83 pm, 88,28% and 20,40%. Vdi khd ndng kidm sodt gidi phfing ddi ngdy, vi cau PLGA ehii'a PRE ACE thich hgp de bdo chd hdn djeh tifim dudi da eho nhiing benh nhan bj viem khdp man tinh,
T a i i i e u t i i a m i t i i d o 1, Iran V.T, Benolt J.P., Venier-Julienne M.C. (2011),
"Why and tiow lo prepare biodegradable, monodispersed, pdymeric microparticles in the field of pharmacy?".
IntemationalJoumal (^ Pharmaceutics, 407,1-11.
2. Liu R., Ma G., Meng F.T. & Su Z.G, (2005),
"Preparation of uniform-sized PUV microcapsules by combining Shirasu Porous Glass membrane emulsification technique and multiple emulsion- solvent evaporation method", Journal of Controlled Release. 103, 31-43.
3. Kukizaki M. & Baba Y, (2008), "Effect of surfactant type on microbubble formation behavior using Shirasu porous glass (SPG) membranes".
Colloids and Surfaces A: Physicochemical and Engineering Aspects, 326, 129-137.
D a n h g i a . . . (Tidp theo trang 9) T a i i i e u t h a m i t i i a o 1. 86 Y te (2002), Dugc didn Vl$t Nam III. nha xuat ban Y hpc. Ha Nfii.
2. Bp mon Dugc ly, Trudng Ogi hpc Y Ha N6i (2003), Duoc ly hgc lam sang, Nha xuat ban Y hpc, tr 400-413.
3. Vien DUO'C lieu (1993), Tdi nguyfin cdy thudc
Viet Nam. Nha xuat ban Khoa hpc va Ky thugt.
4. Do Tdt Lgi (2006). "Nhung cdy thudc va vj thudc Viet Nam", Nha xuat ban Y hgc.
5- Do Minh Quang vd CS (2000). "Tham do mpt s6 tac dung dugc ly cOa chd phim Magaldrak (Malumix) tn viem Ioet da ddy td trang", T^p chi Duoc hgc. sd4, tr.15-17.
T a c d o n g c u a . . . (Tidp theo trang 59) (Biopharmaceutieal Classification System- BCS) FDA vd EMA dd ra duge qui ^ n h ve "nhdn nhugng sinh hge" (biowaiver) cho phfip chap nhgn thCr do khueeh tdn so sdnh, bang each thay thd t h u BE tren ngudi {in vivo) bang dang thudc phdng thieh theo thdi gian qui dinh, Ky thuat ndy cd Igi cho ea nhd nghifin cuu sdn xuat ian eo quan quan ly Id da thdng nhat duge each tinh tuong quan BA trong in vitro va in vivo {In Vivo - In Vitm Correlation - IVIVC) de tien dodn BA eua dgng bdo ehd udng tde dung keo ddi.
Vdo nhQ'ng nam 60 khong cd yeu cau qudn ly gi vd BA/BE ddi vdi thudc, cung khfing cd gi dam bdo cho bdc sT vd bgnh nhdn co the hy vgng hieu qua t u o n g d u o n g vd an todn, khi chuyen t u thude nay sang thudc khdc khi chung c6 cung hoat chat vd hdm lugng. Ngay nay do cfi yfiu eau eua c o quan qudn ly d u g c v d BA/BE ma bfinh nhan eo thd hi vgng vao hifiu qua tu'O'ng duong va an todn cda thufic generic so vol brand eung nhu ed the tin t u d n g vdo cdc thude mdi d u g c phe duy$t khi da t h u BE so vdi thude da qua t h u Idm sdng giai dogn 3.
2. ADME/PK-PD
Nhiing ndm 60-80 bat ddu cd khdi n i ^ ve PK vd chuyen hod. sau dfi Id nhu-ng tidn bp ram rfi ve ky thudt, lien kdt PK-PD. Nam 1974 do cb sg tham gia tich cge eua cdc duge sT ldm sdng da bugc eo quan qudn ly dugc Thyy €)idn chdp nh§n md phong hod
PK-PD va quan adm bat ehudc Id nen tdng de ddnh gia hieu qua, an todn ci!ia thudc. Nam 1992 hOi nghi cae nhd qudn ly dugc da thdo lugn vige dp dyng mo phong quan thd PK/PD vd phuong phdp bdt chude.
Trong 20 nam qua FDA vd EMA da khuydn khieh s u dyng rgng rdi mo phdng PK/PD.
Phuang phdp md phong PK/PD da ddy manh ky thuat thCr Idm sang bdt ehude.
Vdn hod khoa hge d u g e vdo thdi gian ndy khdng ehi xam nhgp vdo eo quan qudn ly md con lan toa ra cdc doanh nghifip dugc. Vdo giua nhirng nam 90 phong D u g c ly Idm sang vd sinh d u g c hgc eua FDA da ung dyng cde nghien euu vao hudng dan quan ly^ vd d u g c ly Idm sdng. Da dfi xudt: Cdc cau hdi ve d u g c \'^ lam sdng; Thu thgp sau giai dogn 2 t h u Idm sdng, tdng quan cac nhan td khoa hgc thu Idm sdng giai dogn 2 va giai doan 3; Thanh ldp Ban tich hgp sd lieu PK/PD t u eae thu nghifim nghifin cdu da dang,.
Tat cd nhung vige lam ndy da lam co sd cho vigc quan ly nhieu van de nhu: can c d phdp ly cho vific djnh lieu dung, phdt hign tuong tac thude, qui dinh nfii dung nhan thude, hd trg viec phe duyet lidu dung cho trfi em, ngudi Idn ma khong qua t h u lam sdng giai dogn 3.
(Cdn nira) Nguyen X u a n H i i n g (Theo tdi li^u cua FIP gui cfio cdc hoi vien, thdng 3/2013)
