• Nghien CLFU - Ky thuat
Nam 2011 tong gia tn tien thudc s d dyng g i n 27 ty dong, thuoc san xuat trong n u d c c h i l m 43,3 % so lup'ng nhung chi c h i l m 13,6% trj gia.
Ty Id thuoc mang ten goc d u p c s u dyng Id 39,5
% va chiem 34,9% gid trj tidn thuoc.
Hoat dpng giam sat t h y c hipn danh myc thudc cd hieu qua. Hopt ddng d u p c Idm sdng chiJ y l u Id k i l m tra. phe duypt p h i l u ITnh thudc, kidm tra tij tryc. Binh bdnh an tan suat t h i p . 1 lan/thdng.
Hopt dpng thdng tin thudc d u p c chu trpng v d i 54 lan thdng tin, 7 ADR d u p e bdo edo.
Be x u a t
D l hodn thipn hon cdng tdc cung ung thudc, bpnh vipn C tinh Thdi Nguyen c i n :
- Tang ty lp thudc chu y l u trong danh myc thudc bdnh vipn nham thyc hipn tdt chfnh sdch, quy djnh eua Bp Y te.
- Xay dyng e l m nang danh mye thuoc - Xem xet de loai bd cdc thudc khdng d u p c s u dyng trong danh myc.
T i l n hdnh phdn tfch tinh hinh s u dung khdng sinh tai bdnh vipn,
- Dau t u trang t h i l t bj (phan mem tra c u u thdng tin thuoc, sdch chuydn ngdnh...) va kinh phf cho hopt dpng d u p c Idm sang va thdng tin thude.
- Bd sung ngudn nhdn lyc d u p c , dpc biet Id d u p c sTIam sang.
- Bdnh vipn can tang eudng kidm tra vide thuc hidn quy chd kd don.
S u m m a r y
With regard that using drugs in safe, adequate, efficient, economic way plays an important role in improving the hospital examination and treatment
quality, the dnig supply In Provincial Hospital C of Thai Nguyen in 2011 was studied in this sense by the regression modeL in general, the hospital pmcess for drug use was appropnate. The drug list consisted of 396 active elements, being categohzed into 21 effect sub-groups according to 20 chapters of diseases and illnesses to treat. Of these, 90.4% were single-elements and 86.9%
were core drugs, in 2011, the total value of drug consumption was 27 billion VND; domestic drugs accounted for 43.3% of the total quantity but made up only 13.6% of the total value. The drugs in generic names were 39.5% and so responsible for 34.9%> of the total value. Main clinical pharmacy activities were checking, approving prescriptions and checking emergency drug resources. Low- frequency medical reports were made once per month. The medical information activities were concentrated to 54 times of information, with 7 ADR reports.
T a i l i e u t l i a m k h a o 1. Benh vien C tfnh Thai Nguyen, Bao cao tdng ket ve cong tac cung ijng thuoc {lO^Q, 2011),
2. BO Y t l (2001), Quan ly dwcyc benh vien, Nha xuat ban Y hoc
3 Bo Y te (2001), Quy che b^nh vi§n. Nha xuat ban Y hoc.
4 Bo Y te (2008), Danh muc thuoc chus benh chu yeu SLf dung tai cac co sa kham chu^ benh. Ban hdnh kem quyet dinh 05/2008/QD-BYT ngdy 01/2/2008.
5. Vu Thj Thu Hucng, Nguyin Thanh Binh (2011),
"Oanh gia hoat apng xay dung danh mijc thuoc cua bdnh vien E nam 2009", Tap chi DUK?C hQC. 12/2011, tr. 7.
6 Jonathan D. Quick, James R. Rankin et al.
(2010), Managing drug suply, Kumanan press.
Tham tach micro va ung dung trong
r r
nghien cuu thuoc chong ung thu tai mo dich
Nguyin Sinh Thai, Nguyen Thanh Hai, Thai Nguyin Hung Thu
Tnrong Dai hoc Duac Hd NoiD a t v a n d e
Nhiing nam gan day, ung t h u la mpt benh ly dup'c r i t nhieu cac nhd nghien cuu khoa hpc
tren the gidi d i u t u , quan tdm nhdm co gdng dieu trj tript de cdn bdnh nay. Oieu tri ung t h u cd rat nhieu phuong phap khac nhau, trong do hda
• N g h i e n C I F U - Ky t h u a t tri lidu ung t h u Id mpt trong nhung lidu phdp v d cCing quan trpng, Lipu phdp ndy dang d u y e dp dyng d u d i dpng t r u y i n hodc tidm tryc tilp cdc thudc chdng ung t h u v d o hd t u I n hodn ndn v i n cdn cd rdt nhidu mdt hgn c h i n h u gdy ddc vdi t l bdo t h u d n g trdn ngudi bdnh, cdc tdc dyng khdng mong mu6n v d de tpo ra s y khdng t h u l c d i i vdi cdc t l bdo ung t h u . Gdn ddy. cdc nhd nghidn c u u bdt d i u d l cdp v d tdp trung n h i m cdi tiln lipu phdp hda tq lidu theo 2 h u d n g : Mdt Id, tpo ra cdc thudc c h u y i n giao tgi dich (targeted drug delivery); Hai Id, nghidn c u u d i l u tri ung t h u ngay tgi md ung t h u (local chemotherapy). D i l u ndy cho phdp thudc dpt d u p c n i n g dO cao hon tgi m d ung t h u , ndng cao hidu qud d i l u tn, ldm gidm cdc tdc dyng khdng mong mu6n so vdi vide dung thuoc theo d u d n g todn thdn, hpn c h i s y khdng thudc.
Nham giCip ich cho s y phat trien cdc hudng nghidn cuu ndy, t h i m tdch micro dang Id mpt ky thudt mdi cd tinh tdi uu va hipu qua nhit. Ky thudt ndy khdng nhung cho phdp djnh luong nong dp t y do cae phdn t u thudc tpi md ung t h u ma cdn ed t h i dua cac phan t u thudc ung thu den md dfch d n thidt hay cdn goi Id phuong phap dieu tri ung thu tpi dfch. Trong bdi v i l t ndy, chCing tdi trinh bdy sau hon ky thudt tham tdch micro (microdlaiysis) vd cdc ung dung ky thudt ndy trong dinh luong ndng dp thuoc t y do tai m d dfch eua cdc thudc chong ung t h u eung nhu md ta m d hinh mdi cho vipc dieu trj ung thu ngay tai md ung thu.
Nguyen ly cua ky thuat tham tach micro
Nguyen l y 00* b d n
T h i m tdch micro Id ky thudt cho phdp xdc djnh d u p c n i n g d0 cdc c h i t nOi sinh (cdc ch&
d i n t r u y i n t h i n kinh, glucose..) v d ngogi sinh (cdc phdn t u t h u l c ) tgi m 6 dich tdc dyng. di;a vdo s y k h u l c h tdn thy ddng cua cdc phdn td ai trpng lup'ng t h i p khi qua cdc Id cOa mdt mdng bdn t h i m trdn mdt kim thdm dd dup'c c l y vdo t i chuc dich'^'.
c l u tpo mftt kim thdm dd bao g6m 3 bO phdn: ddy t r u y i n djch vdo, mdng bdn thim d d i u kim v d ddy dd l l y djch ra. Mdt s6 hang t h u o n g mpi sdn x u i t cdc logi kim thdm dd vdi n h i l u kich c d , k i l u ddng vd vdt lidu khdc nhau.
Kim thdm dd t h u d n g ed 4 hinh dgng: dudng t h i n g (linear), vdng mdc (loop), sdng ddi (side- by-side) v d d i n g tdm (concentric) (hinh 1). Vi$c lya ehpn hinh dpng cua kim thdm dd phy thuftc vdo VI tri c l y cCia kim'^. Dgng kim dudng thing vd vdng mde t h u d n g thich h p p cho l l y m i u m6 m I m n h u gan, da, c o v d k h I i u, Vdi kim thSm dd dang sdng ddi v d ddng tdm, ddy truyin djch vao v d ddy Idy djch ra cd vj tri song song vdi nhau v i vdy ehi can cay mdt d i l m trdn md dich, Kim tham dd dpng ddng tdm t h u d n g cung chic, la logi hay d u p e s u dyng pho b i l n n h i t trong cdc nghidn c u u c l y tgi m d nao, cdn kim thdm do dang sdng ddi cd chat lipu da dgng hon, thudng dung l l y mau tTnh mgch. Mdng bdn t h i m du^c Idm bang cdc vdt lidu n h u cellulose acetat, polycarbonat-ether (hdn h p p polymer), polyacrylonitril v d suifonat polyether. Trpng l u v n g phdn t u gidi hgn cho mdng bdn tham trong khodng t u 5 d i n 100 kDa, do dd cd the dung ky thugt tham tdch micro v d i nhilu ch^
khdc nhau.
rr'
li
L mi)n<: l):in thiim JDudng thang Vong moc Song doi
Hinh 1: Cac dang kim thdm dd thuung dung trong nghien cuvT^P CHi DlTgfC HQC - 07/2012 (S6 435 NAM 51)
• Nghien CCFU - Ky thuat
Hieu suit djnh lu^yng cOa kim tham do Ky thudt thdm tdch micro d y a vao s y k h u l c h tan cdc phdn t u t h u l c theo gradient nong dp qua mdng bdn tham nen nong dd thudc trong dich thu d u p c chua phan dnh d u p c nong dd thuoc thuc chat tpi mo dich. Mudn bidt chinh xdc ndng dp tpi md dich can d u p e hidu ehinh Igi thdng qua cac nghidn c u u ve hipu s u i t in vitro hope in vivcP\ Hipu s u i t kim thdm dd in vitro cd t h i tinh todn t u ty lp giOa nong dp thude trong djch thu d u p c va nong dp thudc b i l t d u p c khi dpt kim tham dd vdo dung djch ndy. Hidu s u i t kim thdm dd in vivo se phuc tgp hon do dnh h u d n g cua nhieu ydu td, trong dd cd dgc d i l m sinh ly cua md vd tuong tdc giua md dfch vdi phan t u thude'^'. Cdc phuong phdp d u p e dung de tinh hidu s u i t in vivo hipn dang d u p c s u dung gom: tdc dd ddng ehdy r i t ehpm (SFR, very slow flow rate)™, ngogi suy tdc dp ddng chay (ZFR, extrapolation to zero-flow rate)'*', zero-net-flux (ZNF)'^'. t h i m tdch nghjch (RD, retrodialysis)'^ va vgn c h u y i n c h i t phdn tich in vivo. Trong so dd. ZNF vd RD Id hai phuong phdp hay dup'c s d dyng n h i t ,
O'ng d u n g ky thugt t h a m tach micro t r o n g d j n h lu'p'ng n d n g dp t h u o c t y d o tgi m d d i c h va n g h i e n CIFU dup'c d o n g hoc cua cac t h u o c c h o n g u n g t h u '
Ky thugt t h i m tach micro da d u p e ung dyng t u n h i l u nam qua nham djnh lupng ndng dp thudc t y do tgi md dich eung nhu nghien c u u ve d u p c ddng hpc cua thudc trdn ddng vdt thuc nghiem vd ca tren n g u d i . T r u d c day, khi chua cd ky thuat nay de bidt d u p c qud trinh phan bo cua phdn t u thuoc d i n dich tdc dung nhu the nao, ngudi ta d y a vao phuong phdp chyp dnh phdng xa (vdi thuoc gan nguydn td ddnh d i u H^, r^^), tuy nhien phuong phdp ndy Igi chi djnh tinh ma khdng cho biet nong dp thuc cua thudc tai m d tdc dyng. Vi vdy, vipc ddnh gid hidu qud cua thude t h u d n g d y a tren quan sat qua cdc thdng sd d u o c dpng hpc (PK) eiia thudc thu d u o c t u mdu va mdi lien quan giua d u p c ddng hpc- d u o c l y c hpe (PK/PD) cua thude. Mdt sd trudng hp'p thudc cd t h i khdng tuan theo d u p c dpng hpc thu dirac t u mau hope khdng cd mdi lidn hd t u o n g quan chat vdi ddp dng d i l u tii'^'- Gan day, n h d s y phdt t r i l n cdc phuong phdp djnh l u p n g mdi, ky thudt tham tdch micro cho phep thu d u g e ede phan t d thuoc d dgng t u dc, dang
ed tdc dyng d u p c ly, ngay tgi djch ke eCia t l bdo, hay tgi md bao quanh cac thy t h i tdc dyng eua thudc.
Thdng thudng, thudc chdng ung thu dupe dua vdo CO t h i theo dudng tidm hay truyen tTnh mgch tryc tidp vdo hp t u I n hodn. D d djnh lupng t h u l c t u mdu phdn bd ddn md ung thu, mdt kim thdm dd se dup'c c l y vdo md dich c i n nghien cuu, Djch truydn vdo la mpt c h i t Idng sinh ly g i l n g vdi djch cd trong t l chuc md c l y kim thdm dd, chang hgn nhu dung djch Ringer cho md gan hay dung djch gid vd nao tuy cho cdc vung trong nao, vdi t i e dd truyin djch r i t chgm, t u 1-10 pl/phut''l Tai vj tri md c l y kim thdm dd, nong dp thudc trong md cao hon nong dd thuoc bdn trong mdng bdn t h i m ndn theo gradient ndng dp cdc phdn t u thudc k h u l c h tdn t u md vdo phia trong cua mdng vd theo djch t r u y i n di ra ngodi, sau dd ngudi ta se l l y djch thu d u p c cd chua cd phdn t d thudc dem djnh lupng bdng phuong phap sdc ky Idng hidu nang cao (HPLC) de xdc djnh ndng dp. Bang cdch s d dyng ky thugt ndy, cd the tiln hanh l l y mau djnh lupng lien tyc khoang 15-20 phiit/mlu vd ve d u p e dudng cong ndng dd thudc theo thdi gian.
Vdi kfch thudc cua Id mdng bdn tham tuong ddi nhd, chi eho phep cae phdn t u cd kich t h u d e t u dudi 100 KDa k h u l c h tdn qua, cdc phdn t u Idn nhu protein se khdng t h i qua mdng bdn tham, do dd dung dich thu d u p c khdng can phdi x u ly d l logi bd tgp protein, cho phep khdng mat qud n h i l u thdi gian vao qua trinh x u ly va phdn tich mdu'^l Lupng mdu lay rat nhd nen s y m i t mdt djch sinh hpc tgi md c l y Id khdng ddng ke.
Tuy nhidn, phuong phap djnh lupng ddi hdi can phdi ed dp nhay cao nhu sac ky Idng hipu ndng cao (HPLC) vdi detector thich hpp, sac k j Idng kdt hpp khdi phd (LC-MS-MS). Ket qua thu d u p c can hipu chinh lai bang hipu s u i t in vitro hoac in vivo.
Trong nhung nam g i n day, van de t h d nghipm cdc thude dieu trj ung t h u dang dgt ra nhieu thdeh thdc. Dac bipt, cdc nghidn c u u tren bpnh nhdn phdi phu hpp vdi cdc yeu cau ve dgo due. Ld mpt ky thuat bdn xdm l i n , t h i m tdch micro thda man d u p c dieu kidn ndy vd ngay cdng d u p c dng dyng n h i l u trong cdc nghien cuu Idm sdng. Djnh lupng ndng dd thuoc trong djch ke md ung t h u b i n g ky thugt t h i m tdch micro in vivo cho phep d u dodn d u p c ddp ung
• Nghien CCFU - Ky thuat
cua phuong phdp hda trj lidu, gidi thIch dupc sy khdng thuoc tren mdt sd bdnh nhdn, giup tii uu hda lieu dung vd ljch trinh dilu tq Mdt hd thing lly mdu vd djnh lupng tryc tilp (microdlaiysis online) da dup'c su dyng d l gidm sdt ndng dp thuoc chdng ung thu trong khdi u tgo ra khd ndng dieu chinh tuc thdi lilu dung eua thulc trdn bpnh nhdn cy thl'^'.
Su dyng ky thudt thim tdch micro de lly miu djnh lupng thudc chdng ung thu cd hudng ddn dich (targeted anticancer drugs delivery) tgi cdc md ung thu nhim xdc t^nh logi thulc dd cd thye sy den dich nhu mong mudn khdng Id mdt cdch tilp cgn ddc ddo, cung d p ede thdng tin ed gid trj v l sy phdn phdi thudc. tuong tdc thulc vd vdn chuyin thulc (hinh 2). Ong dyng
cua nd khdng chi ddng igi d vide nghidn cdu dupe d|ng hpc cua cdc hda chit tri lidu truyin thing. Ngdy nay. vdi sy phdt tnln cCia cdng nghd bdo chi nano da md ra mdt hudng di mdi, thilt k l cdc vidn thulc thdng mmh cd khd ndng hudng phdn b l din md ung thu nhilu hon, c6 thd k l din nhu cdc thulc gidl phdng cd kilm sodt tgi khIi u, hd vdn chuyin thulc liposome, cdc tilu phdn nano cua cdc hogt chit nhif:
cisplatin, duxorubicin. 5-fluorouraxin... Vide ling dyng ky thudt thim tdch micro cho phdp xdc djnh dupc ning dd thulc ching ung thu tgi cdc md ung thu, tu dd cd thi cdi tiln cdch thuc thilt k l cua cdc dgng bdo chi cd hudng din dfch tdc dyng, ddy Id ylu t l thudn lpi giup cho cdng nghd ndy phdt triln.
Hinh 2: Md hinh chuyen giao thudc din dich vd dinh iuvng ndng dp thudc ty do (g/ md ung thw gai^
Cfng dung liy thugt tham tdch micro trong hoa trj lipu ung thu tgi mo dich
Cdch truyen hoge tidm tryc tiep cdc thudc chdng ung thu vdo hd tuIn hodn cd nhilu cdc tac dyng khdng mong muln vd ddc tinh dipt t l bdo ung thu khdng ehpn Ipc. Bidn phap tii uu nhit d l tieu didt t l bdo ung thu ma Igi han chi dup'c tii da tac dyng phy cua thudc chong ung thu la hda tri lipu khu trij ngay tgi khdi u (local chemotherapy). Dilu ndy cd thi dat dupc bdng nhieu cdch khac nhau. nhu tidm thuoc ed hp thong kidm sodt gidi phdng vdo md ung thu hay mdi hon ca Id dp dyng ky thudt thim tdch micro trong hda tri lieu tai md ung thu '^
Trong dilu tri ung thu tgi md dfch sd dyng ky thuat tham tdch micro, thulc duoe pha thanh
dung djch cd ndng dp thich hp-p vd truyin vdo qua kim thdm dd vdi tie dp rit chdm, 2 thdng s6 ndy cin dupc nghidn cuu khang djnh cho mSi logi thulc chdng ung thu. Dung djch thulc dupc truyin vdo lidn tuc, duy tri sy chenh Idch ning dp giua hai phfa cua mdng. Luc ndy, tgi mang bdn thim trdn kim tham dd cdc phdn tu thulc khulch tdn td trong kim tham dd ra djch ke mo va di vdo trong t l bdo (hinh 3). Nhy vgy, thulc dupc phdn b l tdp trung tai md dich thay vi phai vdo mdu rli mdi khulch tan ra khoang gian bao, sau dd mdi ddn md dich. Mgt khdc. lupng thu6c tu djch ke md xung quanh vj tri cly kim tham do di vdo mdu rat it, do dd nong dd thulc tai m6 dich dgt dupe cao hon, dong thdi cung hgn ch^
dupc tdc dyng khdng mong muln trdn cdc m6 khdng bj bpnh.
10 T^P CHi DlTgfC HQC - 07/2012 (S6 435 NAM 52)
' Nghien CCFU - Ky thuat
Hidu qua dieu tri phy thudc vdo d i l u kien truyen (nong dp thudc, thdi gian vd sd lan truyen. tdc dp t r u y i n djch, dd ddi mdng ban tham, kich t h u d c lo mdng, vj tri c l y kim tham
do...) vd dac tinh eua khoi u (kich thudc, loai ung thu). Tat cd cac yeu to nay can d u o c nghien c u u trong tung trudng hpp cy the de thu d u y c mpt phde dd d i l u tri thich hpp n h i t .
Hinh 3; Md iiinh iida tn lidu tai md ung Vide s u dyng ky thugt tham tdch micro vdi myc dfch hda tri lidu tuong ddi don gidn trong trudng hop k h l i u dd tidp cgn vd nghien cdu, nhu ung thu vu, ung thu da, ung thu tinh hoan dudi dang kim thdm dd la dudng thang (linear). Cdc loai ung t h u khdc nhu ung thu c l t u cung, ung thu dudng tieu hda ( t n ^ trdng, da ddy, thyc quan, tyy), ung t h u dudng hd hap, dudng tilt nipu da dupc thd nghipm tiln lam sdng vd Idm sdng bang phuong phdp cay kim thdm dd qua ndi soi. Dgc bipt, cd the dgt kim tham dd vdo khoi u nao, duy tri trong vdi ngay'^"^ vd cho phep d i l u tri bdng nhieu hda c h i t tn lipu khdc nhau. Hgn c h i Idn n h i t cua ky thuat ndy la khd cd the dp dyng vdi cdc khdi u lan tda (disseminated tumour)'^.
Ndi Chung, cdc t h u l c c h i n g ung t h u cd h u d n g d i n dfch (targeted anticancer drugs delevery) tuy da dup'c nghien c d u rat nhieu trong vai thdp ky v d a qua, nhieu thudc trong so do da dup'c t h u nghidm Idm sdng vd cho k i t qua ddng khich lp cd khi k i t h y p l i n dung don le trong cdc lieu phdp hda trj lieu, Tuy nhidn.
viec tgo ra y l u to hudng d i n dfch gan tren thudc n h u hien nay v i n chua hodn todn ehpn Ipc d l d u a t h u l c d i n dfch tdc dyng ndn chiing van cd the gay ra cdc tdc dyng khdng mong mudn khi dung d u d n g todn thdn. Chfnh vl vdy van c i n phai than trpng vd theo doi khi l y a ehpn cdc nhdm t h u l c ndy. T u do ed t h i t h i y rang, ky thudt t h i m tach micro, mpt ky thudt cho phdp
thw phoi di,ra vdo ky thuat tham tach micro didu tri khu tru ngay tai md ung t h u (local chemotherapy), dudng nhu la con dudng an todn hon, hidu qua hon de dua "cac tdc nhan hudng d i n dung dich tac dyng, md khdng phdn tan thudc den ede md khdc".
K e t l u a n
T h i m tdch micro la mdt cdng cu r i t huu ich trong vide xac djnh dudng cong nong dp - thdi gian cung nhu dgc tfnh dupc ddng hpc cua cdc thudc chdng ung thu. Xac djnh vt tri cay kim tham dd va t h i l t ke nghien cuu hpp ly se tgo dieu kidn thugn lyi de thu dupe nhung thdng sd cd gia trj, giup md ta chinh xdc s y phan bd thude tgi md dfch. Vide k i t hpp ky thudt tham tdch micro vdi sieu am hai chieu, ba chieu, chyp cdt Idp phat xg positron (PET, positron emission tomography) m d ra mpt hudng di mdi trong nghidn cdu d u p c ddng hpc-dupc lyc hpc (PK/PD) cua cdc thuoc, tgo CO s d eho vide lya ehpn thudc vd l i l u ddng t i i u u . D i n g thdi, ky thugt ndy cung Id mdt cdng cy d i e lye trong hda trj lieu khu ti-u tai md ung thu, nham giup phdn t d t h u l c phdt huy hipu qud tgi dich tdc dyng vdi ndng dp t h u l c tgi md dich cao hon, trong khi tac dung khdng mong m u l n dup'c hgn c h i d i n muc t h i p nhat. Cung vdi vide khang ^ n h cdc gid trj khoa hpc va ung dung thyc tien tren Idm sdng. ky thudt tham tdch micro hda hen nhung bude tiln xa hon nua trong cude c h i l n chdng ung thu.
• Nghien CLFU - Ky thuat
Summary
Chemotherapy has an important role in cancer treatment. Although there have been developments and good results, chemotherapy still has many limitations mainly due to its toxicity and to the resistance mechanisms of tumour cells. Therefore, recent researches have focused on the development of chemotherapy agents (e.g. targeted drug delivery) or iocoregional administration techniques, with which therapeutic weapons can reach the tumour with a higher concentration and fewer side-effects. In this study, we will describe a microdlaiysis technique for quantitative determination of unbound drug concentration at the target tissues and the applications in pharmacokinetic studies of anti-cancer drugs and new local cancer chemotherapy method.
Keywords: Microdlaiysis technique, anti- cancer drug, pharmacokinetic, targeted drug
Tai lieu tham khao
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