Ti^ chi Khoa hgc Tnrang Dgi hgc C:&n Tha Phan A: Khoa hgc Tv nhien. Cdng nghf vd Mdi iruang: 31 (2014): 85-89
Tap chf Khoa hoc Tru'dng Oai hpc Can Thd website: sj.ctu.edu.vn
KHAO SAT NONG DO THU6C KHANG LAO RIFAMPICIN TREN BENH NHAN LAO PHOl TAI DIEU TRI
BANG PHlTONG PHAP SAC KY LONG HIEU NANG CAO Duong Thi Loan', Tran Ngoc Dung' va Tran Nhan Dung"
' Khoa Y. Trudng Dgi hgc Ydugc Cdn Tha
^ Vien Nghien ciru & Phdt trien Congnghe Sinh hgc. TrudngDgi hgc Cdn Tha Thong tin chung:
Ngdy nhgn: 21/02/2014 Ngay ch^p nhdn: 28/04/2014 TUle:
Monitoring rifampicin concentration in plasma of re-treated pulmonary tuberculosis patients by the method of high performance liquid chromatography Tir khoa:
Rifampicin. sdc ky long hiiu ndng cao. lao phdi tdi diiu trj, ndng do diiu tri Keywords:
Rifampicin, high performance liquid
chromatograph}'.
re-treatment of tuberculosis, therapeutic concentrations range
ABSTRACT
Rifiimpicin concenlradon in plasma of re-trealed pulmonary tuberculosis patients ca the Can Tho Tubercuhsis and Pulmonary Disease Hospital was determined by high performance liquid chrtmiatogrc^j/iy (HPLC) method. Thirty jive patients were investigated in this slucty to understcmd factors which are
related to the drug concenlralions in plasma of re-treated pulmonary- tuberculosis patients compared to the stanchrd concentratitm recommended by the national pro-am for anti-tuberculosis disease. Cross-sectional descriptive stucfy (a stuefy in a certain period) wtis contiucted with 70 plasma samples. The samples were taken at two events: 2 hours and 3 hours t^er swallowing.
Average concentrations of rifampicin in plasma at 3 hours (4.23±5.21 i^ml) was si^icficantly hi^r (with p <0.05) thtm that of rifampicin in plasma at the time of 2 hours (2.6~±3.32 )Jg/mlJ. Only 8.6% of patients at the time of2 hours and 22.9% of patients at the time of 3 hours lined between the therapeiaic concentrations range (8-24 fJ^ml). There is a significant relation between concentrations of rifampicin in plasma of re-trealed pulmonary tuberculosis patients with therapeutic doses and the age ofpalienls Qr^0.05).
TOM TAT
Dimg phrang phdp sdc ky long di xdc dinh ndng do thudc rifampicin tren b4nh nhdn lao phdi ldi diiu tri tgi Binh vien Lao vd B^nh phdi Thanh phd Cdn Tho. Tim hiiu cdc yiu td liin quan din viic ndng do thudc dgt hay khdng dgt nong dg chudn irong huyit luang binh nhdn mdc lao phdi tdi diiu tri. Nghiin cuu md td edt ngang dugc tiin hdnh vdi 70 mdu huyet tuang dugc ldy a 2 thai diem 2 gid vd 3 gid sau khi udng thudc rifampicin (RMP) ciia 35 binh nhdn lao phdi tdi diiu tri dem phdn dch bdng sdc ky long (HPLC). Kit qud chi rdng ndng do RMP huyit tuang trung binh a thdi diim 3 gid (4.23±5.2I pg/ml) cao han so vdi d thm diem 2 gia (2.67±3.32 pg/ml) vdip<0.05. Chi cd 8.6% binh nhdii a thai diem 2 gid vd 22.9% benh nhdn d thai diim 3 gid dgt phgm vi ndng do diiu tri (8-24 ftg/ml). Co mdi twang quan thudn chiiu giira ndng dd RMP huyit tuang vdi liiu diiu tri vd vai ludi cua nhdm benh nhdn nghiin cuu (p<0.05).
I GioriTHieu
Benh Iao Id rapt frong ba benh tmyen nhiira eav tii vong cao nfaat d cdc nudc dang pfait uiln.
Nara 2011, Viet Nara xep thii i 2121 Quoc gia cd so benh nhin nhiera lao eao nhdt tfal gidi, xip thii 14/27 nudc cd gdnh ning benh lao da Idling tfaudc
Tgp chi Khoa hgc Truang Dgi hgc Cdn Tho Phdn A: Kboa hgc Tv nhiin. Cdng nghf vd Mdi trudng: 31 (2014): 83-S9 cao frln toin ciu (WHO, 2012). Cd rdt nhilu
nguyin nfain dan din tinh frang lao khang tfaudc vd ndng do tfaudc cfadng iao frong mau tfadp Ii mot frong nfaung nguyin nfain dan din kfad nang dap ling dieu tri kem ciia benfa nfadn. Thudc rifampicin dugc phit failn vio ndra 1963 va cho din nay tfaudc van giii vai frd cfaii ylu frong vile dieu tri benh lao.
Thudc dugc hip thu tdt qua dudng tiiu fada va chuyin fada qua gan. Trong miu, ndng dp thudc dugc xem Ii dat pham vi dieu trj trong kfaoing 8- 24 ^ig/ral (Peloquin CA, 2002)
Le Thi Luyln, 2006 di nghien cuu sinh khd dung ciia rifampicin frln ngudi tinh nguyen va ndng dp rifampicin frong huylt tuong benh nhdn lao phdi, kit qud chi ra rdng sinh khd dung frong vien fadn hgp 2-FDC vd 3-FDC frln ngudi tinh nguyin mac dii dugc udng cung mpt lilu vi do d Cling thdi diim cd ndng dp RMP trong fauyet tuong khdc nhau giua cac cd tfal, cdn frln nfadra benfa nfain cd 91,3% benfa nfain d tfadi diem 2 gid va 84% benfa nfain d thdi diim 3 gid cd ndng dp RMP tfaip faon so vdi ndng do pfaam vi dieu tri.
Nguyin Tfai Kilu Anh va ctv. (2007) di xiy dung nipt qui frinh dinh lugng ddng thdi rifampicin va pyrazinamid frong huylt tuong bdng phuang phdp sdc ky Idng faieu nang eao, phuong phdp nay di dugc tham dinh day du vl cdc tieu chudn cua FDA qui dinh ve phucmg phdp phdn tich thuoc frong dich sinh hpc vol dg tin c^y eao dugc iing dung dinh gid tinh sinh khd dung ciia thudc ciing nhu gidm sat ndng do rifampicin huylt tuong ciia benh nhan frong qud trinfa dilu tri dl tii dd giiip cdc bac sT cd tfal dilu chinfa lieu dilu fri rifarapicin kip tfadi va hgn cfae tinfa frang kfadng tfauoc.
Chiing tdi dp dung qui frinh dinh lugng rifampicin frong huylt tucmg bing phuong pfaip sic k^ Idng ciia Nguyen Thj Kilu Anfa vd ctv, 2007 nhdm thuc hiln de tdi "Kfaio sat ndng dp thudc khang lao rifampicin fren benh nhan Iao phoi tdi diiu frj tai benh vien Lao vi Benh phdi Thdnh phd Cdn Tho" nfadm hai muc tiiu; (I). Diing phuong phdp HPLC de xac dinh ndng d^ thudc rifampicui frln benh nfain Iao phdi tai diiu fri tai BliUi vien Lao va Benh phoi Tfaanfa phd Cdn Tho. (2). Tim hieu cic ylu td Uln quan din vile ndng do thudc dgt hay kfadng dat ndng dp cfaudn frong fauyit luong benfa nhin mic Iao phdi tdi diiu tri.
2 DOI TU'<;yNG VA PHU^ONG PHAP 2.1 Doi tugng
Ba muoi ldm (35) benh nhin da dugc chdn dodn xac dinh la lao phdi tdi diiu tri tgi Benh
vien Lao vd Benh pfadi Thanfa phd Cdn Tfao, dugc fade sT chi dinh dieu tri theo phic dd 2SHRZE/
IHRZE/5H3R3E3 Diy la phdc dd chuin tiieo chuong trinfa cfadng lao Qudc gia qui dinh (Bd Y Tl, 2009), tiidi gian thuc hiln tir thing 3/2012 din tiling 5/2013.
2.2 Phinmg pbap Pbuong phdp md td cat ngang.
2.2.1 Thiit bi vd hda chdt thi nghiim Bao gdm he thdng mdy HPLC (Sfairaadzu SPD-10 Avp), may lac co hpc, mdy silu ira dudi khi, miy Iy tim, cdn phin tich 4 sd le. Hda chat gom Methanol, Acetoiutril, Kali dihydrophosphale (Merck), rifarapicin cfaudn, fauyit tuong frdng, thudc dang viin cd chiia rifampicin benh nfadn dang udng vd fauyit tuong ciia benfa nfadn sau khi uong rifarapicin. Thudc udng Tuberzid viit tit RHZ Ii dang thudc nen hdn hgp ba thdnh phdn (3- FDC) bao gdm Rifampicin 150 mg; Isoniazid 75 mg; Pyrazinamid 400 mg, faoic Turbe viet tdt RH, Id dang tfaudc nen fadn hgp hai thdnh pfaan (2-FDC) bao gdm Rifampicin 150 mg vd Isoniazid 100 mg, cd 2 loai tfaudc deu do nfaa sdn xuit Cty cd phin Dugc phim Nara H i (Nam Dinh-Vilt Nam)
2.2.2 Phuang phdp dinh lugng rifampicin irong huyet tuong
a. Cdch lay mdu
Qui frinh ldy mlu dugc tien fadnh theo cic budc sau (i) Cdc benfa nfadn tfaam gia diu dugc udng viin tiiudc khdng lao dang hon hgp 2 h o ^ 3 thdnh phdn khi tiln hinfa nghien ciiu. Thudc dugc udng liic 6-7 gid sdng vdi 200 raL nude dun sdi di ngudi (ii) radi benh nfadn dugc lay 2 raau mdu tai cdc thdi dllm 2 gid va 3 gid sau kfai udng thuoc.
Tgi mdi thdi diim 2,5 mL mdu tinh macfa dugc cho vdo dng nghiim cd cfaiia cfaat cfaong ddng (Heparin), mdu dugc bdo qudn Ignfa, Iy tira (4000 vdng/phiit) ldy 1 mL huylt tuong. Phdn huyit tuong niy dugc bdo qudn -20^0 cho din kbi djnh lugng ciing Mc 70 mdu
b Djnh lirgng rifampicin huyit tuong bdng HPLC (i) Chiet RMP: hiit chinh xic 1 mL huyet tuong CO chiia RMP vd 1,5 mL acetonitril cho vdo ciing I dng nghiim cd nip day, lac ky bing mdy ldc frong 1 phiit vd ly tim dung djch niy bing mdy ly tim vdi tdc dg 3500 vdng/phiit frong 30 phiit di dugc phan dung dich hiiu co cd chiia RMP (Nguyen TTij Kieu Anh, 2008). Diing bom tilm ImL hiit phdn dich frong sau dd bom tii tii qua raing lpc OASiim dk dugc dich chiit RMP. (ii) Tbi fr'ch mau tilra Id 30 pL. Su hiln dien ciia rifampicin vd hdm lugng
Tgp cbi Khoa hgc Truang Dgi hgc Cdn Tha Phan A: Khoa hgc Tv nhien, Cong nghf vd Moi trudng: 31 (2014): 85-89 cua nd frong miu huylt tucmg dugc xic dmh dua
vao thdi gian luu ciia rifampicin chuin vi dudng chudn eiia rifarapicin dugc thiit Igp d cic ndng do 3 Mg/raL, 7.5 pg/mL va 15 (ig/mL (R^.9963).
I.. Phuangphdp xir ly sd lieu trong nghien cuu Diing phin mim tiidng ke SPSS 18.0 di xii ly so lipu thu thgp
3 K^TQUA
3.1 Dac diem nhdm benh nhdn nghien ciru 3.1.1 Tudi, gioi tinh vd cdn ngng Trong tdng sd 35 b|nh nhdn nghien ciiu 29 benfa nfadn Id nam (82,9%), cd 6 b|nh nhdn nir (17,1%). Tudi cua nhora ngfailn ciiu tir 25 din 72 tiidi, trung binh 49,89±11,73. Da s6 cdc benh nhin (74,3%) thudc nfadm cdn ning 40-55 kg, cin ndng frimg binh 48,3±7,8 kg.
3.1.2 Dgc diem ldm sdng vd can ldm sdng cua nhdm binh nhdn
Cd 34/35 benh nhan cd biiu failn frilu cfaiing ho khac ddm (97,1%), ki din Id m^t radi (65,7%), sut can (60%), ran phdi (54,3%), sdt nhe vi chiiu (42,9%), cdc trieu chiing dau ndng nggc vi khd tfad chiira ty II kha thap (<32%). Cdc benh nfain diu dugc soi ddm trgc tiip trudc khi tiin hdnh diiu tri vdi ty 11 duong linh la 91,4%, 100% benh nhdn cd hinh anfa tdn thuong tren phim X-quang phdi cfaudn.
Bang 2: Ty II fainh nhdn theo khodng ning dp d 2 t
3.1.3 Tiin sir benh vd thai gian tdi phdt Trong tdng sd 35 benh nfadn tfaam gia nghien ciiu, chiing tdi gfai nhin da sd benh nhdn cd thdi gian tdi phdt >5 nam.
3.2 Lieu dilu tri rifampicin tfaeo can nang Nhin xet: Lieu diiu tri tfaudc RMP trung binfa cua benfa nfadn frong nfadm nghiin ciiu tbeo can ndi^ la 9,42±0,82 mg/kg. Tdt cd cdc benh nhan diu duac dilu fri theo diing khuyin cdo ciia cfauong frinh chdng lao Qudc gia (CTCLQG).
Bang I: Liiu diiu tri RMP theo can nang Lieu khuyin cdo Lieu dilu trj thuc tk cua Chuong trinh (mg/kg) n = 35 chong lao Quoc gia Liiu TB ± Th^p nhat
(mg/kg) [1] SD - Cao nhdt 8-12 9,42±0,82 8,10-10,98 3.i Nong dg rifampicin huyet tuong thdi diem 2 gid va 3 gid sau kfai u^ng thuoc
Nhdn xet: Ty le benh nhin dat pfagm vi ndng dp diiu fri thdp, 8,6% d tfadi diim 2 gid, 22,9% d thdi diim 3 gid. Pfain Idn b|nh nfadn (77,1% d tiidi diim 2 gid, 68,5% d tfadi diim 3 gid) cd ndng dp RMP fauyit tuong dudi 4 jig/ml. 6 ci 2 thdi diim, khdng cd benh nhan ndo vugt ngudng ndng do RMP frong huylt tuong (> 24 jig/ml).
Khoang nong do R M P (fig/ml)
< 4 4 - < 8
8 - 2 4
> 2 4 Tong cong
S o b n 27 5 3 0 35
2Rior
Thoi diem lay Ty II (%)
77,1%
14,3%
8,6%
0,0%
100%
mau sau none S o b n
24 3 8 0 35
RMP 3 gior
Ty II (%) 68,5%
8,6%
22,9%
0,0%
100%
Bang 3: So sanh nong dp RMP huyet tmmg d 2 thdi diem
Nong dO RMP huyet tmmg
Thoi diem 2 gid (n=35) Trung binh
Trung vj D^ Ilch chuin
3 gid (»=35) 2,67 4,23 1.37 1,51 3,32 5.21 0,015 Pham vi none do 0,00-15,88 0,00-18.06
Nhgn xet: Ndng dp RMP trung binh d tiidi diim 2 gid Ii 2.67±3,32 fig/ml, cdn d tiidi diim 3 gid li 4.23±5,21 pg/ml. DO I|ch chuin Idn cho thdy cd su dao dpng rit nhilu ve ndng do frong huyit tucmg
giiia cac ca thi. Do dd, chiing tdi diing kilm dinh Wiicoxon cho phin phdi khdng cfauin dl so sinfa ndng dp RMP tgi hai thdi dllm 2 gid vd 3 gid sau khi udng thuic, kit qui cho thdy ndng dp RMP d thdi diim 3 gid cao hon so vdi d tfadi diira 2 gio va sy kfaac bill ndy cd y nghTa thdng kl vdi ; K 0 , 0 5 (Z = -2,424,n = 35,p = 0,OI5).
3.4 M^i lien quan giira nong dp rifampiciD huylt tuong vdi mpt so yiu t6
3.4.1 Lien quan giira ndng do rifampicin huyit luang vdi lieu dieu Iri theo cdn ngng vd vdi ludi ciia nhdm binh nhdn nghien cuu
Khi phan tich tuong quan don biin cfao thdy d Cling 1 thdi diim cd su tuong quan thuan chiiu
T^ chi Khoa hgc Trudng Dgi hgc Cdn Tho Phan A: Khoa bgc Tv nhien, Cdng nghe vd Mdi truang: 31 (2014): 85-89 miic dg ylu giiia ndng dg RMP huylt tuong vdi
liiu dieu tri tfaeo cdn nang vdi p < 0,05, r = 0,34 d thdi diim 2 gio, r = 0,4 d thdi diim 3 gid.
3.4.2 Liin quan giira ndng dg rifampicin tdi da trong huyet tuang vdi tudi binh nhdn
Qua phan tich tuong quan don biln vi qua Hinh 3 cho tfaay cd su tuong quan tfaugn efaiiu raiic do yiu gi&a ning do RMP toi da frong huyit tuong va tudi ciia nhdm benh nhin tham gia nghiin ciiu (r = 0.34,/)<0,05).
Hinh 1: Liln quan giua nong dd RMP trong huyet tuong d thdi diim 2 gid vdi lieu dilu tri
theo can ndng
Hinh 2: Lien quan giua nlng dd RMP trong huyet tmrng d thM diim 3 gid vdi lilu dieu trj
theo can ndng
Bang 4: Liln quan gii>a ndng dp RMP vdi gidi, thdi gian tai phat, ngay lay mau
Hinh 3: Liln quan giua n^ng dp RMP toi da trong huyet tinmg vdi tuoi cua nhom b|nfa nhan
nghien cuu 3.4.3 Liin quan giua ndng do RMP huyit tuong vdi ede yeu td khdc
Nhin xet: Kfadng cd sy liln quan giiia ndng do RMP fauyet tuong vdi gidi tinh, tfadi gian tii phit va ngay lay mlu (p>0,05).
Yeu to khao sdt Nong dp RMP huyet tuone
Trung binh±SD Trung vi Nam (n=29)
Ng (n=6)
4,76±5,51 3,00±l,77
3,14 1,71 Thdi gian tdi
phat
< 1 nam (n=7) I - 5 nim (n=9)
>5nam(n=19)
3,67±5,77 2,49±4,74 5,69±4,90
1,19 0,48 3,91
0,170
Ngay lay radu <90ngiy(n=18)
>90ngiy(n=17)
4,89±5,46 4,01 ±4,79
3,23 1,37 4 THAO LUAN
Tai thdi diira 2 gid sau khi udng thudc, RMP se dgt nong dp cao nhat frong huylt tuong (Peloquin CA, 2002) va ddy Id thoi diem thich hop cd thi liy mdu de giam sat ndng dp tfaudc frong diiu fri. Tuy nhiin, frong nghien ciiu nay cfaiing tdi ghi nhdn ndng do tiiudc RMP d tiidi diim 3 gid sau khi uing cao hon so vdi d thdi diira 2 gid vd sy khdc bilt nay co y nghia thing ke vdi /7<0,05, diiu niy phii
hgp vdi nghiin ciiu (Ll Tfal Luyln va ctv (2005).
Mac dii tdt ci cic benfa nfadn frong nfadra ngfaien ciiu diu dugc diiu tri dung theo liiu khuyin cao cua CTCLQG (8-12 mg/kg) nhung hi kit qui d Bang 2 va Bing 3 cho tfaay da sd cic binfa nhin diu kfadng dat pfaam vi ndng dp dilu frj. Cd den 91,4% benh lifadn d ttidi diim 2 gid va 77,1 % benh nhan d tlidi diim 3 gid cd ndng do RMP huyit tirong dudi 8 jig/ml. Ndng dp RMP huyit tirong
Tgp chi Khoa hgc Tru&ng Dgi hgc Cdn Tho Phan A: Khoa hgc Tu nhien. Cong nghf vd Mai tru&ng: 31 (2014): 85-89
d i l u fri c i n dat Id 8 - 2 4 pg/ml, n i u n d n g d o tfadp faon 8 ng/ml thi nguy eo tdi pfadt benh cd thi x ^ ra vi quin the vi kfaudn gdy benfa kfadng dugc tiiu diet hit se gdp pfadn quan frgng frong tii pfadt benh Iao.
Kit qud niy khi pfaii fapp vdi ngfaien cuu trudc diy trin ddi tugng fainfa nfain mdc Iao mdi tai Tfainh pho Can Tfao sau 2 gid cd 87,5% vd sau 3 gid 82,5% binfa nfaan cd ndng dp rifampicin frong huyet tuong dudi pham vi dilu tri (Nguyin Thi Hdng Nhung va ctv., 2012). Vi viy, ngfaien eiiu ciia chiing tdi cho thdy viec sii dung phuong phdp HPLC de do ndng dp rifampicin trong huylt tuong la cin thilt, cd the ap dung gidm sat ndng dp rifampicin nhdm failu chinh lieu mdt each phii hgp trin tiing benh nhdn mac benh lao khi sii dung tfaudc RMP frong dilu fri.
Tii Hinfa 1 v i Hinh 2 qua phan tich tucmg quan don biln cho thay cd radi tuong quan thuin chieu rairc dp yiu giiia ndng do RMP trong huyit tuong vdi liiu diiu tri tinfa theo mg/kg can n ^ g , kit ^ua niy pfau fagp vdi ngfailn ciiu ciia Nguyin Tfai Hdng Nfaung vd ctv. 2012 vd S.W.Um, 2007. Ngoii yiu to lieu dilu frj, cfaiing tdi cung ghi nfaan tir Hinh 3 cd sy tuong quan d miic dp yeu giUa ndng dO thudc RMP vdi tuoi ciia nhdm benh nhdn nghiin ciiu. Dilu ndy ciing pfaii hgp vdi nghien cuu ciia Le Thi Luyln (2011), tdc gid cho rdng kfai tudi benh nfadn cdng eao thi ndng do tfaudc frong huylt tuong cdng Idn.
5 KET LUAN
Qua ngfaien curu ndng do rifampicin frln 35 b^nh nhin lao phdi tdi fri dieu fri tai Binh vien Lao vi B^nh phdi Thanh phd Cin Tho, chiing tdi dgt dugc mdt sd ket qud sau:
- Ty Ip benh nhdn cd ndng do rifampicin huyit tuong dudi ndng do dilu fri chilm ty 11 cao d cd thdi diim 2 gid (91,4%) vi thdi diim 3 gid (77,1%).
- Ndng do rifarapicin huyit tuong d thdi diem 3 gid cao hon so vdi d tfadi dllm 2 gio vdi /?< 0,05.
Cd sy kliac bill rit ldn ve ndng dp rifampicin frong huyit frrong giiia cic ci tiii
Cd radi tuong quan thudn chieu miic dd yeu giiia ndng d^ rifampicin huyit tuong vdi lilu diiu fri ttieo mg/kg cdn ning vdi;?< 0,05.
• Khi tudi cua b|nh nhdn cdng cao thi ndng dp rifampicin huyit frrong cing ldn vi ngugc lai.
TAI LI$U THAM KHAO
1 Bp Y ti, 2009. Hudng dan chin dodn, diiu trj vi pfadng b|nfa lao, (Ban hdnfa kem theo
Quylt dinh sd 979/QD-ByT ngdy 24 tiidng 3 nim 2009 ciia Bd trudng Bd Y ti) 20 trang.
2. Ll Thi Luyln, Trdn Vdn Sdng, Hoing Thi Kim Huyin, Nguyin Thj Liln Huong, Tong Van Tudn, 2005. Ngfailn cihi nong dp Rifarapicin fauyit tuong tai tfadi diim 2 gid va 3 gid sau kfai udng d benfa nfadn lao pfadi AFB (+) tai tn. Tgp chiy hgc thuc hdnh 6: 49-5 i.
3. Ll Tfaj Luyln, 2006. Nghiin ciiu sinfa khi dung ciia Rifampicin fren nguoi tinh nguyin v i nong do Rifampicin frong huylt tuong benh nhin lao phdi. Lugn dn tien si Y hgc, Chuyin ngdnh lao vd benh phdi, Trudng Dai hpc Y Hi Ngi.
4. Ll Thi Luyln vd ctv, 2011. Phin tich rapt sd yeu td dnfa hudng din ndng dp Rifampicin, Isoniazid vi Pyrazinamid huyet tuong benh nhin lao. Tgp chi Yhgc ViitNam 378 (1): 1-5.
5. Nguyin Thi Kilu Anh, Le Thi Luyln, Nguyen Thj Lien Huong, 2007. Nghiin cOnj xiy dyng qui frinfa dinfa lugng ddng tfadi Rifampicin va Pyrazinamid frong fauyet tuong bdng phuong phdp sic ky ldng hieu nang cao. Trudng Dgi hgc Dugc Hd Ngi- Hgi nghi khoa hgc cdng nghi tudi Ire ldn thirXIV.
6. Nguyen Thi Hdng Nhung, Duong Thi Loan, Trin Ngpc Dung, 2012. Khdo sdt ndng dp thuoc khang lao Rifarapicin trin benh nhdn lao phdi mdi dilu fri tai Benfa vien Lao vd Benh phdi thdnfa phd Can Tho. Tgp chiy hgc thitc hdnh 821 (5): 87-89.
7. Peloquin Charles A., 2002. Therapeutic Drug Monitoring in the Treatraent of Tuberculosis. Drug; 62(15): 2169-2183 8. Rovina Ruslami, Hanneke M. J. Nijland, Bacfati Alisjafabana, Ida Parwati, Reinout van crevel, and Rob E. Aamoutse, 2007.
Pharmacokinetics and tolerability ofa higher Rifampin dose versus the standard dose in pulmonary mberculosis patients.
Antimicrobial Agents and Chemotherapy 51 (7): 2546-2551.
9. S-W. Ura, S. W. Lee, S. Y. Kwon, H. I. Yoon, K. U. Park, J. Song, C.T. Lee, 2007. Low serura concenfrations of anti-tuberculosis drugs and determinants of theu' serum levels.
The IntemationalJoumal of Tuberculosis and Lung disease 11 (9): 972-978.
10. WHO, 2012- Global tuberculosis report.
