• Nghien CLFU - Ky thuat
d i l u tri amikacin d i u r i t cao (>90%) d ca 4 bdnh Vidn khao sat vd khac bipt cd y nghTa thdng ke giua cdc bpnh vidn. Ty lp cd gidm sdt trong dieu tn r i t cao d Thanh Nhdn (93%). khd cao d BV Bgch Mai (75%) vd t h i p n h i t d BV Xanh Pdn vd 108 (khodng 1/3 tong sd bdnh dn can gidm sat).
D l vide s d dyng khdng sinh amikacin cd hipu qua, an todn vd hpp ly, cac benh vipn nen tdng c u d n g gidm sat dieu tri bdng cdch ghi nhdn d i y du cdc thdng sd ve can nang. chieu cao eua bpnh nhdn vd thue hien cdc xet nghipm chuc nang thdn day diJ t r u d c va trong qud dieu tri.
S u m m a r y
Rational use of amikacin was retmspectlvely studied at 4 hospitals. Central Military Hospital l\fl08, Bach Mai. Thanh Nhan and Xanh Pon W^ere/n, Gr(-) bacteria were dominant causatives, accounting for up to 81%; 67% and 72.1% in Bach Mai, Military 1^108 and Thanh Nhan, respectively.
Amikacin was used in more than 95% of therapeutic regimens, almost in combination with beta-iactamin. The difference in dose regimen
between these hospitals were significantly great.
The doses were not per body-weigh. The therapeutic monitoring were not conducted at all in these 4 hospitals. It suggests that for enhancemence of therapeutic efficacy and drug- use safety of amikacin, important informations concerning drug monitoring should be supplemented to medication histories.
Tai lieu tham khao 1, BO Y t l (2002). Duyc thw Qu6c gia. NXB Y hpc, tr, 130-132,500-502.
2, Bd Y t l (2006), Hudng din diiu tri. NXB Y hpc, tr. 101-107.
3, Aronoff G. R, (2007), "Drug prescribing in renal failure: Dosing guidelines for adults and children", /American College of Physician, 5th edition
4, Bauer L. A, (2008). Applied Clinical Pharmacokinetics, McGraw-Hill Medical. 2nd ed , p 97-206,
5 Chambers H F. (2006), "Aminoglycoside", in Goodman and Gilman's - The pharmacotogical baisis of therapeutics Laurence L Brunton, et al,. Editors, McGraw-Hill MEDICAL, Chapter 45:Aminoglycosid, (E-book),
Ngliien cij"u bao ciie vien nen trimetazidin giai piiong keo dai lie cot tlian nirac
O a t v a n d e
Thude gidi phdng keo ddi (GPKD) ngdy cang phat t r i l n vd cd nhieu u u diem hon dgng thuoc quy u d c . Trong do, he trj lieu GPKD s d dyng HPMC tgo cdt than n u d c cd nhidu uu diem nhu:
he cdt nay gidi phdng d u p c c h i t theo nguydn tac k h u l c h tdn qua hang rdo gel, vd Idp gel se bj hda tan - an mdn t d t d nen trdnh d u o c s y bung l i l u vd thudng se I n ^ n h giua cac 16 me khi khong ehe d u y c cac thdng s i ky thugt va tang sinh kha dyng cua d u o e c h i t .
Trimetazidin hydrodorid (TRI) Id t h u l c d i l u tri bdnh dau that ngye d mpi t h i benh d u y e s u dung nhu mdt thuoc md hinh trong nghien cuu,
r^J* CHI Dl/gfC HQC - 07/2012 (S6 435 NAM 52)
Nguyen Thi Thanli Duyen', Hodng Van Ddc^
'Truang Dgi hoc Du(rc Hd Ngi Cue Qudn Iy Duac TRI thupe nhdm 1 trong he t h i n g phdn loai sinh d u p c hpe ed tinh tan r i t tdt trong n u d c . h i p thu nhanh qua d u d n g tidu hda, thdi gian bdn thai ngdn. Trong cdng trinh nghien edu ndy, ehung tdi tidn hdnh nghien cdu bao c h i vien ndn trimetazidin hydrodorid 35 mg gidi phdng keo ddi 12 gid hd cot than nudc.
N g u y e n l i $ u v a p h y a n g p h a p n g h i e n CLPU
Nguydn lipu
Trimetazidin hydrodorid (TRI) (An Dd), HPMC K4M CR (My), dicald phosphat (DCP) (An DO), magnesi stearat (MagS), aerosil (Trung
• Nghien CIFU - Ky thuat
Quoc); PVP K30 (My); eroscarmellose (Cros) (My); avicel PH101 (Trung Qudc), ethanol 96%
(Vipt Nam): cdc nguyen lidu ndy d i u dgt tidu c h u i n d u y c dyng.
P h u o n g phdp nghidn c u t i Phuxmg phdp bao che vien ndn Vien ndn tnmetazidin d u y c bdo e h i theo phuong phdp xdt hgt udt: cdn lupng td dup'c trong cdng thdc (tn> td d u p c tron) trdn d i u theo nguyen tdc d i n g l u p n g , Tgo hgt bdng dung djch PVP trong ethanol 96%. Xdt hgt qua rdy s i 1000. Say se trong 15-20 phut. Sua hgt qua rdy s i 1000. S l y d 55-60"C d i n dd I m 2-5 %. Sua hgt khd qua rdy 1000. Trdn td d u y c tron. Ddp vidn, dudng kinh 0 = 9 mm vdi lyc ddp 2 t i n .
Phuxmg phap (ht> tfp hda tan
S u dyng mdy thd dd hda tan ERWEKA DT 60 (Ddc): mdi trudng hda tan Id 500 ml dpm phosphat pH 6,8, nhipt dp 37±0,5°C, t i c dd khuay 50±1 vdng/phut, 10 ml d|ch hda tan d u p c l l y ra d cdc thdi d i l m nghidn edu, li tdm vdi t i c do 5000 v/p trong 5 phut, Ipc qua mdng Ipc 0,45 ym va do quang vi sai' do dp hap thy cua dung djch chuan vd dung d|ch thu d hai b u d e sdng 2 7 0 n m v d 3 0 0 n m .
Ydu c l u giai phdng d u p c chat: sau 1 gid: 25- 45%; sau 2 gid, 45-60%; sau 4 g i d ' 60-80 %;
sau 8 g i d : > 80%.
Banh gia SIP giong nhau giCra hai do thj giai phong
f2 dupe tinh theo cdng t h d o / - 5 0 x l g
H -t(R.-T.y
Trong dd: i : sd t h d t u d i l m l l y mau; n : so d i l m lay mau; R, vd T, : % TRI giai phdng tgi thdi d i l m i cua vidn thye nghidm vd vidn ddi e h i l u . f2 ed gid tn t u 50-100 thi hai do thj gidi phdng Id gidng nhau, fa cdng Idn thi 2 dd thj cdng giong nhau '^'^l
K e t q u a n g h i e n c i r u
K h d o sat dp hda tan trimetazidin tip vien
ddi e h i l u vastarel MR 35 m g
T h d hda tan vidn ddi e h i l u Id vastarel MR 35 mg (Les Laboraroires Servler, s i Id 869483 VN 7243-08, hgn dung 07/2013), k i t qud trinh bdy d bdng 1,
Bdng 1 : % du^e chit gidi phdng tir vi§rt vastarel MR 35 mg
Thdi gian (gl") TB (n=6)
(%)
RSD (%) 1
36,44 2,75
2
53.15 2.47
4 74.06
1,30 6
86.11 0.37
a
93.06 1.17 Nhdn xdt: Vidn d i i e h i l u gidi phdng dupc c h i t t u o n g ddi d i u ddn vd phu hpp vdi tigu c h u i n gidi phdng eua vidn ndn trimetazidin GPKD 12 gid, RSD (%) eua cdc vidn n i m trong khodng t u 0,37-2,57 % (<5%) eho t h i y cdc vidn trong cung mdt Id gidi phdng d u p c c h i t tucrng ddi d i n g d i u .
Nghidn c d u t h i e t k l c d n g thuPC vidn nin trimetazidin gidi p h d n g kdo ddi
Dya vdo mdt s6 tdi lidu tham khao '^' ^ chung tdi lya ehpn cdc td d u y c sau d l nghien c d u bdo e h i vidn ndn TRI GPKD hp e l t :
- HPMC K4M CR: td d u p e k i l m sodt giai phdng TRI theo eo ehe t r u o n g n d trong nudc tao thdnh hdng rdo gel, Idm chdm t i e dd giai phdng d u p c c h i t .
- Dicalci phosphat: td d u p c dpn ddm bSo khoi lupng vidn d i n g thdi k i l m sodt gidi phdng d u p c c h i t theo co c h i tgo hd c i t tro khdng tan, Idm chdm t i e dd gidi phdng d u p c c h i t
- Avicel PH 101: td d u p c ddn, hOt nudc theo eo chd vi mao qudn - truong n d tgo kdnh dan giup gidi phdng d u y c c h i t .
- Aerosil vd magnesi stearat: td dupe tran nham cdi thidn dd tron ehdy cua khdi hgt. giam ma sdt, c h i n g dinh ehdy c i i . Idm b l mdt vien bdng dpp, gdp phan k i l m sodt giai phdng dupc chat (GPDC).
Thdnh phan cdng thuc c o ban d u p c thilt ke nhu sau:
STT 1 2 3 4 5
Ten nguyen lieu Trimetazidin hydrodond
HPMC K4M Dicalci phosphat (DCP)
PVP K30 eroscarmellose (Cros)
Kl/vien (mg) 35.0 Thay doi Thay doi 6.0 Thay doi
STT 6 7 8 9
Ten nguySn Ii0u Avicel PH101
Aerosil Magnesi stearat
Ethanol 96%
K l V / i n (mtl Thayd6i
1.3 3.2 " * VCradil J |
TAP CHi Dtfqc HQC - 07/2012 (S6 435 NA
• Nghien cipu -- Ky thuat
Thiet ke c6c cong thCpc trong nghi&n CLPU sang igc du'gc di^a ra d bSng 2.
B a n g 2 : Thiet ki cong thOc vien ndn TRI GPKD va dg hda tan diroc chat C6ng
thtipc
CTI CT2 CT3 CT4 CT5 CT6 CT7 CT8 CT9 CT10 CT11 CTI 2
CTI 3 CTI 4 CTI 5 CTI 6
HPMC K4M (mg)
140,0 150.0 160.0 140.0 130.0 125,0 130,0 130,0 130.0 130.0 130.0 130.0
120.0 80,0 108.0 100.0
DCP (mg)
60.0 60.0 60.0 52,5 48,75 46,87 48.75 48.75 48.75 48.75 29.0 9.0
80.0 120.0 86.4 72.0
Cros Avicel (mg) (mg)
- -
1,2 2,4 5,0 9.5
23,0 47.0
20 Lifcd^p
(tin)
2.0 2.0 2.0 2.0 2,0 2,0 2,0 2,0 2,0 2,0 2,0 3mi>c:
2.0 1.0;
1,5;
2.0 2.0 2.0 2.0
% trimetazidin glii phdng tai (
( g i * 32.57 30.21 28.63 31.68 32.44 32.65 34.65 35.94 34.37 34.88 36.40 34.10 37.81 36.39 36.97 45.48 35.77 37.53
2gid' 44.56 42.18 41,56 44.23 44.85 45.58 45.58 45.34 46.17 45.98 45.45 45.40 46.28 45.62 49.78 55.75 52.19 51.96
4gl&
62.84 62.07 62.40 62.59 62.19 65.25 65,25 65.73 65.63 63,48 67.20 65.46 65.82 63,58 68.76 81.81 68,26 68,78
6gi&
73,88 73,35 73,88 74,32 76,29 77,28 77.28 76.06 77.12 74.53 77.59 75.39 75,54 72,35 81,32 93,48 83,85 83,79
:ac th&i tSiem
a gidt 81.62 80.84 81.62 81.66 83.09 85.43 85.43 82,03 83,53 82,54 83,82 82,73 83,92 83,33 35,58 99,29 90,76 92,17
t2 51,96 49,63 49.68 49.68 51.79 49.68 58.26 55,56 67,45 53,96 58,65 55,33 56,88 52,96 67,06 59,61 76,67 78,70 Khao sat anh huvng cua HPMC K4M toi
giai phong du'gv chat
Cac cdng thuc C T I , CT2 vd CT3 duoe t h i l t
kd nhu d bang 2 Bao c h i vien nen, ddnh gid dp hda tan d u p c c h i t , k i t qua d u p c trinh bay d bang 2 vd hinh 1.
Hinh 1 : Do thj gidi phdng trimetazidin tu-vidn ndn Hinh 2: D6 thi gidi phdng tnmetazidin tir vidn nen thi/c nghidm vdi iirgng HPMC K4M khac nhau thyc nghidm vdi ti Id cot khdc nhau
Nhdn xdt: Khi l u o n g HPMC K4M tang t u 140-160 mg (kl/vien) vd d i n g thdi giu nguyen khoi lupng cdc thanh phan khdc thi toe dd GPDC giam. Do HPMC K4M cd dp nhdt cao.
truong nd tgo gel, khi Idp gel cang ddy - e h i l u ddi khulch tan cdng Idn lam chgm GPDC, CT3 k i l m sodt % TRI giai phdng ngay t u gid dau tidn (28,63%), kha deu dan vd h i n g djnh d cdc gid
T^P CHf DlTgfC HQC - 07/2012 (SO 435 NAM 52)
• Nghien CIFU - Ky thuat
tiep theo, tuy nhien d nhung gib- sau toe i50 gi^i phong dup'c chat cbn th^p so vdi vi6n d6i chi^u.
Vi vgy. ehpn CT3 de t i l p tyc nghifin CLTU.
Khio sit inh hu^g cua ly /# cdt tdi glii phdng du^o chit (gdm HPMC vi DCP)
C4c cdng thuc CT3, CT4, CT5 vi CT6 dipp'c t h i l t k l nhu * bang 2: ti 1$ HPMC/DCP = 8/3, kh6i l u v n g e6t t u a n g Cmg ti 220; 192.5; 178,75;
171.87 mg. B^o e h i vi§n n6n, thi> dO h6a tan.
k i t q u i trinh b i y i) b i n g 2 v i hinh 2. Khi ty 1$
c6t g i i m tit 220 mg d i n 171.87 mg (kl/viin) thi
% g i i i ph6ng TRI t$i e i c th&i d i l m da t i n g (1- 4%). v i h§ s6 tz cQng da tang Ifin, tuy nhign sif thay d6i khSng n h i l u , Chpn CT5 d l t i l p tgc nghidn c u u .
Khio sit inh hu^g eda eroscarmellose vi avicel PH101
- Vdi cros, c i c c6ng thCrc CT5, CT7, CIS, CT9 v i CT10 (tuang ung v&'i ty l§ cros trong vi6n lan l u v t l i 0,53 %; 1,06%; 2,17%; 4,04%) duvethi^
k l nhu 6* b i n g 2. B i o e h i viSn n i n , thO d0 h6a tan, k i t q u i trlnh b i y 6 b i n g 2 v i hinh 3.
Thin giaji (gtir^
Hinh 3: Do thi gidi phdng trimetazidin tir Hinh 4: Dd thi gidi phdng trimetazidin tCr vidn ndn vidn ndn thi/c nghidm v6i luxmg cros khdc nhau thyc nghidm vdi ti 1$ avicel khdc nhau
Khi dua them mpt l u o n g cros vdo trong vidn (0,53-4.04%) thi khdng cd s y khde biet rd rdng ve l u p n g TRI giai phdng d cdc thdi d i l m . Mdt khac, khi bdo che vd bdo qudn t h i y be mgt vien cua cae CT nay rdp, s i n sCii, r i t de hut I m khi de d d i l u kipn h d , dgc bidt Id vien CT9 vd CT10.
- Vdi avicel PH101, cdc cdng thdc CT5, CT11 vd CT12 dutre t h i l t k l n h u d bdng 2.
Theo k i t qud d bdng 2 vd hinh 4 eho t h i y : Khi
t a n g t y i p avicel l i n luprt Id 10% vd20%(CT11, C T I 2) thi % GPDC tdng nhp t u 1-3% d cdc thoi d i l m dau so vdi cdng thue khdng cd avicel. M^t khdc, cdng thuc s u dgng avicel d l tgo hgt hon cdng thdc khdng cd avicel, thu|ln Ipi cho qua trinh bao c h i vidn,
Khio sdt dnh hwong cua lyc d$p Chpn cdng thue C T I 2, dap vidn d 3 mi)c:
1,0; 1.5; 2,0 t i n . T h u dd hda tan, k i t qud trinh b d y d bang 2 vd hinh 5.
Thm gian (gii)
Hinh 5: Do thj giai phdng trimetazidin tu vien ndn thyc nghiem vai lyc dap vidn khdc nhau
T h ^ eian (ei^>
Hinh 6: Do thi giii phdng tnmetazidin tO vien nin thuc nghidm vdi tile HPMC-DCP khic nhau
20
T4P CHi mrqc HQC - 07/2012 (s6 435 NAM 52)
• iManien ciyu - i\y tnuat
Khi lyc dap vidn gidm t u 2 - 1 , 5 - 1 tan tuong ung vdi luc gay v d vidn trung binh Id 62,8 N;
50,7 N vd 37,3 N thi % dupe c h i t giai phdng d gid dau tang t d 2-4%, eac gid sau h i u nhu it thay doi. D i l u nay ed t h i d u y c lugn giai nhu sau:
L y c nen giam thi b l ddy vien tdng, tdng didn tich bd mat vien, he vi mao qudn Idn hon, n h i l u han ndn khi mdi t i l p xOc vdi mdi trudng hda tan s y GPDC d gid dau tang nhp, nhung GPDC d nhung gid sau gan n h u khdng khde nhau. Vi vay, khi t r i l n khai dgng vidn ndn hp cot ndy trdn quy md Idn hon thi GPDC tgi ede thdi d i l m it thay ddi so vdi d quy md phdng thi nghidm, d l dam t)ao ddng d i u GPDC giua ede Id md.
Khao sat anh htrcmg cua tl 10 HPMC K4M vaDCP
Cdc cdng thdc C T I , CT13 vd CT14 dupe t h i l t k l nhu d bang 1. Bdo e h i vien nen. t h u dp hda tan, k i t qua trinh bay d bang 2 va hinh 6.
Khi luyng HPMC giam t u 140 - 80 mg, d i n g thdi lupng DCP tang t d 60-5-120 mg (tuong ung vdi gidm ty Id HPMC/DCP t d 7: 3 (CTI) xudng 3 : 2 (CTI 3) vd 2: 3 (CTI 4)) thi % gidi phdng TRI tang dan d ca 5 thdi d i l m (tu 4-20%). K i t qua ndy cho thay ty Id HPMC/DCP trong cdng thdc ed dnh hudng r i t Idn den GPDC. Ca 2 cdng thuc d i u cd he so tz cao. D y dodn he cdt vdi ty lp HPMC/DCP khoang t d 3/2 d i n 2/3 se eho dd thj GPDC gidng vidn doi ehilu hon.
Lya chon cong thirc
T u cdc k i t qua trdn, dgc bidt Id khao sat v l ti Id HPMC/DCP va k i t hpp vdi nghidn cdu sdng Ipc khi s u dung avicel, cac cdng thuc CT15 vd CT16 d u o e thiet k l nhu d bang 2. Bao chd vidn nen. t h u dp hda tan. k i t qua trinh bay d bdng 2 va hinh 7.
- • | 6 0 -
^•. J 2 0
—•—CT 15
—1»—CT 16
—*— Vien DC
Th&i gian (giii) H i n h 7: Dd thi giai phdng trimetazidin tu- vidn nen thyc nghidm vol tile HPMC/DCP thay dii
TAP CHI DirgfC HQC - 07/2012 (SO 435 NAM 52)
Cd 2 cdng thuc l y a chpn d i u dgt ydu c l u v l GPDC, hp s i t u o n g d i n g f2 eua ed 2 cdng thuc t u o n g doi cao (76,67 vd 78,70), Trong dd, CT 16 cd chua avicel PH 101 d l tgo hgt hon CT15, fa Idn hon. Do vgy, ehpn CT16 bdo che vidn trimetazidin trdn quy md 1000 vien/md vdi 3 me M l , M2, M3. K i t qud thd hda tan cua 3 me d u p e thd hidn trong bang 3.
Bdng 3: Ty Id % trimetazidin gidi phdng tie vidn ndn bdo chi theo CT 16 (3 md) (X, n=6)
Thdi gian 1 2 4 6 8 f!
( 2 *
Ml 40,15
56,4 75,31 89,92 97,02 74,64 66,09
RSD 2,20
%
1,7 3,74 2,66 2,05
M2 39,82 59,12 74,11 89,54 96,1 72,72 65.85
RSD 0.84
%
2.86 2.86 2.6 2.12
m
42.56 55.13 77.58 88.29 94,21 74.01 65.56
RSD%
3.58 2.32 3.06 2.77 2.35
Ghi chu: fa la hp so tuong dong cua dd thj giai phdng eua cdc me 1000 vidn so vdi do thj gidi phdng cua vien ddi e h i l u , fa* Id hp s i tuong dong cua dd thj me 1000 vidn so vdi do thj giai phdng cua me 50 vien.
Nhan xet Ca 3 mau ddu ed he sd tuong dong fa so vdi vidn ddi ehilu deu cao (> 70) eho t h i y vien nen trimetazidin bdo ehd theo CT16 tren quy md 1000 vien/me cd dd thj GPDC tuong duong vdi vidn ddi chieu Vastarel MR.
RSD cua 3 m i u vien deu thap (<5 %), cdc vidn trimetazidin bdo c h i trong mpt me giai phdng t u o n g d l l dong deu.
He sd tuong ddng fa* giua do thi giai phdng cua 3 me khi ndng d p quy md so vdi dd thj giai phdng eua me 50 vien lan l u p l la 66,09; 65,85 vd 65,56 (>60) cho t h i y khi ndng d p quy md t u 50 vien/me Idn 1000 vidn/me thi do thi giai phdng d u p e c h i t Id giong nhau.
Mo h i n h d o n g hoc cua vien doi e h i l u va vidn thijrc nghipm
Bang 4: Phirang trinh dpng hoc giai phdng dirqic chit cua vidn DC va vidn thyc nghidm
w i n Md hinh M6 hinh d^ng hoc ^ ~ ] Higuchi Y=33.701 X + 2,6986 0.9908 Vidn doi
ehilu °^ng hpc
bdcO Y=10,532X+20,277 0,8601 Vidn thyc Higuchi Y=34,735 X -i- 3.6911 0,9908
nghipm odng hpc
(Cri6,me1) bdcO Y=10,823X•^ 21,921 0,8550
