TAP CHI DITOC HOC ISSN 0866 - 7861

6/2017 (So 494 NAM 57)

MUC LUC NGHIEN CLPU - KY THUAT

MAI N G U Y E N N G O C TRAC, N G U Y E N P H U O N G DUNG, DO TH!

H O N G TOOL Khuyen cao ve nghien cuu tiromg tac thuoc in vitro va in vivo trong qua trinh phat then thuoc mai 2 N G U Y E N KHAC DONG, T R A N T H U THUY, O A O T H U TRANG,

NGUYEN VAN DOAN. BUI VAN DAN, NGUYEN HOANG ANH: SO sanh 3 phirang phap quy ket hoi chiing Stevens-Johnson va hoai tu-thuwig bi nhiem doc gay ra bdi thuoc trong co so dO lieu bao cao ADR cua Viet Nam 6 PHAM VAN TAT, VAN TH| MY HUE: Thiet ke va do doan hoat tinh gay doc t§ bao ung thu- bieu mo ciia dan chat 2-arylquinazolin-4-on so dung mo hinh QSAR 11 NGUYEN TH! CAM VI, TRiNH QUYNH DIEU, TRAN PHI HOANG YEN, THAI KHAC MINH, TRAN THANH OAO: Khao sat kha nang chong oxi hoa va cai thien tri nho ngSn han cua dan chat benzylaminochalcon tren chupt nhAt 17 L£ KHAC TUAN, PHAM OiNH DUY: Dieu che gia mang lipid cau true nano chua miconazol nitrat blng phoong phap vi nhu toong 21 NGUYEN TH! KIM THU. MAC DiNH HUNG: Tong hop p-methan-3,8-diol va thi> nghiem hoat tinh xua mu6i 26 VO BiNH DUONG, NGUYEN XUAN TRUNG, NGO XUAN TRiNH, PHAM VAN HlEN, NG6 TH| TUYET MAI: Nghien cou djnh logng mangiferin trong tri mau {Rhizoma Anemarrhenae) bdng sSc ky long hieu nang cao 29 TRAN HUU GlAP, HA TH! THOA, CAO TH! HUE, NGUYEN TH| TU OANH, VG TH! KIM OANH, NGUYEN TH! MINH HANG, NGUYEN VAN HUNG, NATALIA S. MISHCHENKO, SERGEI A. FEDOREEV, LE NGUYEN THANH: Hpp chat flavan va acid beo phan lap to vo than cay mau cho trai day (Knema pachycarpa de Wilde) 33 NGUYEN THj LAR PHAM THj NGUYET HANG: Nghien cii-u tac dung oc ch§ so ti'ch tu lipid gay boi acid oleic cua cao chiet con to Ganoderma sp\ tang ky sinh va dai hoa te tan tren te bao HepG2 36 TRAN LE HANG, NGUYEN NHAT LAM, LY MINH HUY, LE NGUYEN BAO KHANH, TRUONG NGOC TUYEN: Tong hop dan chit halogen cua acid anthranilic bang phoong phap su dung Oxone® 40 LE TUAN, NGO HONG THAI. NGUYEN DINH NGA, HUYNH TH! NGQC PHUONG: Tong hpp va thu* hoat tinh khang nam cua mot so din chit ((2-benzoylhydrazono) methyl) pyridinium va ((2-pheny-Ihydrazono) methyl) pyridinium 43 VO TH! KIM THU, NGUYEN TH! THAO TRAN, DOAN NGOC NHUAN, LE NGOC THACH: Thanh phan hoa hoc va mot so hoat tinh sinh hoc cua tinh dau la 6i Dai Loan 48 NGUYEN THj THU TRANG, 00 THj THUY, PHAM NGOC TUAN ANH: Tong hpp va danh gia hoat tinh khang khuln cua cac dan chit mdi 2 salicyloylbenzofuran 51 NGUYEN VAN RU: Tao che phlm insulin pegyl hoa va danh gia mot so dac tinh cua che phlm de dung trong y doge 55 NGUYEN TH! KIM THU, BUI THANH TUNG: Oanh gia kha nang Crc che enzym acetylcholinesterase cua cac phan doan dich chiet bim bim trlng (Convolvulus pluricaulis Choisy) 59 TRAN ANH VO, DUONG TH! MONG NGOC, NGUYEN TH! THU HANG: Xay dung tieu chuan cho dupe lieu kho qua loai qua nho (Momordica charantia L var. abreviata Sen) 63 N G U Y E N TH! MAI: Adenosin va hai hpp chit lignan phan lap tu phan tren mat dlt cua cay gle - Momordica cochinchinensis (Lour.) Spreng 67 N G U Y E N TH! THANH D U Y E N , D A M THANH XUAN: Nghien cuu bao mang khang dph vi cho pellet pantoprazol 71 NGUYEN VAN LINH, D U ONG TH| HAl YEN, HOANG LE TUAN ANH, VO MANH HUNG, PHAM THANH KY: Hai hpp chit phenolic glycosid phan lap tu phln tren mat dlt cay tien hac thao (Agrimonia pilosa Ledeb. var. pilosa) 76 TRAN TR|NH CONG, DAM THU HlEN: Nghien cuu he vi nlm tren vj thuoc kha tu (Fmctus Terminaliae) dang luu hanh o mot so hieu thuoc Dong dupe tren dja ban Ha Npi 78

PHARMACEUTICAL JOURNAL ISSN 0866 - 7861

6/2017 (N° 494 Vol. 57)

CONTENTS R E S E A R C H - T E C H N I Q U E S

MAI NGUYEN NGOC TRAC, NGUYEN PHUONG DUNG, 00 TH| HONG TU'OI: Recommendations on the in vitro and in vivo research of drug interaction in development of novel drugs 2 N G U Y E N K H A C D G N G . T R A N T H U T H U Y D A O T H U T R A N G . N G U Y E N

VAN DOAN, BUI VAN DAN, NGUYEN HOANG ANH: Comparasion of 3 imputation methods for identifying drugs-induced Stevens-Johnson syndrome and toxic epidermal necrolysis by retrospective analysis of the relevant data from the national pharmacovigilance database in Vietnam 6 PHAM VAN TAT, VAN TH| MY HUE: Structural design and cytotoxic prediction of new 2-aryl-quinazolin-4-one derivatives against the KB cell line using QSAR model 11 NGUYEN TH| CAM VI, TRiNH QUYNH DIEU. TRAN PHI HOANG YEN, THAI KHAC MINH, TRAN THANH DAO: Experimental antioxidant and memory-improving property of benzylaminochalcon in mice 17 LE KHAC TUAN, PHAM O'lNH DUY: Preparation of miconazole nitrate loaded nanostructured lipid carriers by microemulsion 21 NGUYEN TH! KIM THU, MAC DiNH HUNG: Synthesis and culicifuging activity of p-methane-3,8-diol 26 VG BiNH DUQNG, NGUYEN XUAN TRUNG, NGO XUAN TRiNH. PHAM VAN HlEN, NGO THj TUYET MAI: An HPLC procedure for quantitative analysis of mangiferin in Rhizoma Anemarrhenae 29 TRAN HUU GlAP, HA TH! THOA, CAO THI HUE, NGUYEN THI TU OANH, VU THj KIM OANH, NGUYEN TH! MINH HANG, NGUYEN VAN HUNG, NATALIA S. MISHCHENKO, SERGEI A. FEDOREEV, LE NGUYEN THANH: Flavans and fatty acids isolated from the stem barks of Knema pachycarpa (de Wilde) 33 NGUYEN TH! LAP, PHAM THj NGUYET HANG: Inhibitory activity of the ethanol extracts from Ganoderma sp\ Scurrula parasitica (L. Merr. and Asarum maximum (Hemsl.) on the lipid accumulation in the HepG2 cell line 36 TRAN LE HANG, NGUYEN NHAT LAM, LY MINH HUY, LE NGUYEN BAO KHANH, TRUO'NG NGQC TUYEN: Synthesis of some halogen derivatives from anthranilic acid and Oxone® 40 LE TUAN, NGO HONG THAI. NGUYEN OINH NGA, HUYNH TH| NGOC PHUO'NG: Synthesis and evaluation of antifungal activity of some derivatives of ((2-benzoylhydrazono) methyl) pyridinium and ((2-phenylhydrazono) methyl) pyridinium 43 VO TH! KIM THU, NGUYEN TH! THAO TRAN, DOAN NGOC NHUAN, LE NGOC THACH: Phytochemical composition and some bioactivities of the leaf oils of the plant Taiwan guava (Psidium guajava L.) 48 NGUYEN TH! THU TRANG, DO THj THUY, PHAM NGOC TUAN ANH: Synthesis and antibacterial activities of novel 2-salicyloylbenzofuran derivatives 51 NGUYEN VAN RU: Preparation and characterization of PEGyl insulin by covalent conjugation with methoxy polyethylene glycol aldehyd (mPEG-CHO) 55 NGUYEN TH! KIM THU, BUI THANH TUNG: Acetylcholinesterase inhibitory activity of various fractions of extracts from Convolvulus pluricaulis Choisy 59 TRAN ANH VO, DUONG TH! MONG NGOC. NGUYEN TH! THU HANG: Establishment of the quality control standards for the fruits of Momordica charantia L. var. abreviata Ser. 63 NGUYEN TH! MAI: Isolation of adenosine and two lignan compounds from the aerial parts of Momordica cochinchinensis (Lour.) Spreng 67 NGUYEN TH! THANH DUYEN, DAM THANH XUAN: Formulation of film coated pellets for enteric delayed release capsules of pantoprazole 71 NGUYEN VAN LINH, DUONG TH! HAl YEN, HOANG LE TUAN ANH, VU MANH HUNG, PHAM THANH KY: Isolation and identification of two phenolic glycosides from the aerial parts of Agrimonia pilosa Ledeb. var. pilosa 76 TRAN TR|NH CONG. DAM THU HlEN: Fungal contamination of the herbal item Fructus Terminaliae curremtly circulated in traditional oriental drug stores in Hanoi 78

• Nghien cu»u - Ky thuat

interaction studies: Regulatory guidance and an industry and labeling recommendations, February. Perspective", The AAPS Journal, 15(3), 629-645. 1 2 V 6 p h 0 n g N g u y ^ n ^ c s ( 2 Q 1 7 ) ^ p h ^ p c 6 n g

11. ^ D e p a r t m e n t of Health and Human Services (2012^ h § t h 6 t j n h 6 t k § d a n v ^ ^ S j S t „ a n - B ^ 0 ^ „ 6 / Food and drug administration, Center for Drug Evaluation and .7 . , . . „ , j n A ~ . w - r

Research (CDER)", Guidance for industry, drug interaction ^ 3 P ° X ' ^ ' ^ Q C ^ P ' studies-study design, data analysis, implications for dosing, H° Chi Minh.

(Ngay nhan bai: 09/12/2016 - Ngay phan bien: 08/03/2017- Ngay duyet dang: 02/06/2017)

r

So sanh 3 phirong phap quy ket hoi chung Stevens-Johnson mt r

va hoai tu* thirong bi nhiem doc gay ra bdi thuoc trong co* so* dfr lieu bao cao ADR cua Viet Nam

Nguyen Khac Dung1 % Tran Thu Thiiy1 , Dao Thu Trang1

Nguyen Van Doan3, Bui Van Dan3 , Nguy en Hoang Anh1* 'Trung tarn Quae gia ve Thong tin thuoc vd Theo cloi phan irng co hai cua thuoc,

Tnrang Dai hoc Dugc Ha Not •'Trung tarn Cdnh gidc Dugc khu vuc Midi-Pyrenees, Toulouse, Phdp

'Trung tarn Di irng vd Mien dich him sang, Benh vien Bach Mai 'E-mail: anh90tk@yahoo.com

Summary In view that though Stevens-Johnson's syndrome and Toxic epidermal necrolysis (SJS/TEN) are serious ADR

with high mortality rate is high (up to 25%), the imputability methods for these reactions seemed not so reliable, and occasionally, the clinical expert judgements in some specific cases were quite different; and from 174 reports on 2 severe muco-cutaneous reactions SJS/TEN in national database of pharmacovigilance in the period 2006-2013, 355 ADR-drug pairs were identified, a new imputability method (ADLEN) specified for SJS/TEN (ALDEN) was investigated in comparison with the former WHO and Najanro's methods, to estimate the corresponding causality relationship and calculate the correlation. A low correlation was revealed between ADLEN method and WHO and Najanro's methods for the 174 cases in question (0.38 and 0.23, respectively). For estimating SJS/TEN reactions, in comparison with ALDEN method, the specificity of WHO method was low (Sp=36%) and Najanro's method was even absolutely nonspecific (Sp=0%). This suggested the ALDEN method should serve as a powerful tool for assessment of the causalities of drug-induced SJS/TEN not only in pharmacovigilance imputation but also in clinical practice.

Keywords: ALDEN, Pharmacovigilance database, SJS/TEN, Naranjo, WHO method.

Dat van de ti> vong trung b inh cua loai phan u n g nay len td i Hoi Chung Stevens-Johnson va hoai t u t hugng 20-25% '2 «. Viec chl ro chinh xac nguyen nhan SJS/

bi nhidm doc (SJS/TEN) la nhung phan u n g tren da T E N 9 i C |P b a c s T d i a u t r ! r a d ! n h k !P t h 6 > i v a v i P c

nghiem trong, d u g c dac t rung bd i ti le t u vong cao va ngung s u dung thuoc nghi n g d la nguyen nhan trong thuoc d u g c cho la nguyen nhan chinh gay ra hoi chung k h i d d v i n d u Y t r i t i a P tM c n h Q , n 9 t h u ° c d i a u t r ! c a n t h i a t

nay ^ Nhung nam gan day, Trung tarn Quoc gia ve k h a c - d a c b i a t l a t r o n 9 9 ' f ' d o a n P h a t c d a P h a n

Thong tin thuoc va Theo ddi phan u n g co hai cua thuoc ur ig. Tuy nhien, viec chan doan nguyen nhan SJS/ (Trung tarn DI&ADR Quoc gia) nhan d u g c n h i i u bao TEN trong thuc hanh con gap nhieu khd khan khi nhan cao t u nguyen lien quan tdi loai phan u n g nay (nam vien y te s u dung p h u o n g phap chung cho tat ca cac 2013 ghi nhan 46 bao cao). Viec quy ket chinh xac moi loai phan u n g nhi r ph i r ong phap quy ket nhan qua quan he nhan qua g iua thuoc nghi n g d va SJS/TEN con cua To chuc Y te the gidi ( thang W H O ) hay thang cua gap nhieu t rd ngai do benh nhan trong nhieu bao cao Naranjo de danh gia loai phan u n g nay. Vi vay, nghien co xu h u d n g si> dung nhieu thuoc dong thdi (dac biet cuu nay d o g e tien hanh vo i muc t ieu: so sanh m u c do la cac benh nhan cao tuoi) va ban chat cua SJS/TEN la t u o n g dong g iua p h u o n g phap A L D E N (Algorithm for phan u n g qua man mugn (thdi gian t iem tang Kr luc bat Assessment of Drug Causality in Epidermal Necrolysis dau s u dung thuoc tdi luc xuat hien phan u n g dac t rung - thang chuyen biet danh gia hoi chung SJS/TEN) vd i dao dong trong mot khoang thdi gian dai t u vai ngay tdi p h u o n g phap cua W H O va cua Naranjo trong quy ket vai t u 3 n ) w . SJS/TEN can phai nhan d u g c s u quan tarn moi quan he nhan qua phan u n g tren da nghiem trgng dac biet khi danh gia Igi ich/nguy c o cua thuoc do ti le gay ra bdi thuoc.

6 T A P C H I DU'gfC H Q C - 6/2017 (SO 494 N A M 57)

• Nghien ci>u - Ky thuat

D o i tu 'gng v a p h u o n g p h a p n g h i e n c u u

Doi tuor ig nghien CLFU Toan bo bao cao v§ phan u n g tren da nghiem trong

trong C o s o d o lieu (CSDL) bao cao t u nguyen luu t ru tai Trung tarn DI&ADR Quoc gia trong giai doan t u 01/2006 td i 12/2013.

Tieu c h u a n l y a c h o n Bao cao vd i thuat n g u d u g c mo ta ve SJS/TEN

d u g c sang loc trong CSDL vdi cac thuat n g u mo ta bao gom: "hoi chung Stevens-Johnson", "hoi chung Lyell" hay "hoai ti> t h u g n g bi nhiem doc", hoac trong bao cao mo ta ton t h u o n g da kieu trot loet /tuot da tung mang tren 3 0 % dien t ich c o the hoac loet 2 hoc t o nhien kern ton t h u o n g ngoai da kieu trot loet tren da/mun bong n u d e .

Tieu c h u a n loai trip Bao cao th ieu thong tin ve mo ta phan u n g , khdng

gh i /khdng xac dinh d u g c thuoc nghi n g d , th idu thong tin ngay bdt dau dieu tri hoac ngay xuat hien phan u n g .

P h u o n g phap nghien cu»u Danh gia moi quan he nhan qua g iua thuoc nghi

n g d d u a tren hoi c u u CSDL bao cao A D R t u nguyen. Danh sach cac thuoc nghi n g d va ket qua tham dinh cuoi cung cua chuyen gia theo thang W H O d u g c tn'ch xuat ra d u a tren bao cao goc luu t r u tai Trung tarn. Bao cao A D R goc lien quan d u g c tiep tuc danh gia moi quan he nhan qua g iua thuoc nghi n g d va SJS/TEN theo p h u o n g phap A L D E N va Naranjo. Viec danh gia d u g c thuc hien bdi nhom nghien c u u trong do cd 2 bac sT lam sang chuyen nganh Di u n g - M i i n dich lam sang. Thang A L D E N d u g c dinh nghTa la thuat toan chuyen de danh gia cac phan u n g tren da nghiem trong n h u SJS/TEN d u a tren bo 6 tieu chi : thd i gian t iem tang, s u cd mat cua thudc trong c o the vao ngay xuat hien phan ung , s u ngung dung thuoc, tien s u xay ra phan u n g vd i thuoc hoac phan u n g tai dien khi tai s u dung thuoc, m u c nguy c o cua thuoc va yeu to benh nguyen khac (bang 1) [ 3 -5 1 . Tong diem thu d u g c t u ket qua sau khi danh gia 6 tieu chi nay se d u g c quy doi t u o n g u n g vd i mot m u c quy ket thuoc-ADR (bang 2).

Bang 1. Thang danh gia ALDEN danh gia phan (mg SJS/TEN151

Tieu chi Cho diem Quy tac ap dung

Thai gian tiem tang: Thai gian tir khi bat dau diing thudc den khi xuat hien phan ung

Rat co kha nang: +3 Tir 5 den 28 ngay CcKh3 nariij +2 Tir 29 den 56 ngay Cd the: +1 Tir 1 den 4 ngay Khdng chac chan: -1 Tren 56 ngay Loai tn>: -3 Thuoc dirac bat dau sir dung vao ngay hoac sau ngay xuat hien phan dng Neu trirdc day benh nhan da tang cd phan irng vdi thuoc nay: Rat cd kha nang: Cd the:

+3 Tu-1 cen 4 ngay +1 Ti> 5 den 56 ngay

Sir cd mat cua thuoc trong ca the vao ngay xuat hien phan ung

Chac chan:

Nghi ngd:

Loai tru:

+0

-3

Thuoc dirge tiep tuc sir dung cho den ngay xuat hien phan ung hoac da dirge ngirng trade ngay xult hien phan dng it han nam Ian thdi gian ban thai Thuoc da dirge ngirng trirdc ngay xuat hien phan Lrng nhidu han nam Idn thdi gian ban thai. Nghi ngd xay ra tirang tac thuoc hoac thay doi chdc nang gan than lam anh hirdng tdi nong do cua thuoc trong ca the

Thuoc da dugc ngirng trirdc ngay xuat hien phan dng nhieu han nam Ian thdi gian ban thai. Khdng nghi ngd xay ra tirang tac thudc, chirc nang gan than khdng thay doi.

Sir ngirng sir dung thuoc

Trung tinh: +0 Ngirng dung thudc hoac khdng rd Am tinh: -2 Thuoc tiep tuc dirge dung ma phan dng cai thien hoac khdng xay ra phan ung

Da tdng xay ra phan ung vdi thuoc hoac phan ung tai dien khi tai sir dung thuoc

Xdp hang cua thuoc theo nguy ca xay ra ra phan ung

Daang tinh dac hieu doi vdi benh va thuoc:

+4 SJS/TEN xay ra khi dung chinh thuoc nay

Dirang tinh dac hieu ddi vdi benh hoac thuoc:

+2 SJS/TEN xay ra khi dung thudc taang tg hoac phan ung khac tirang tg xay ra khi dung chinh thuoc nay

Dirong tinh khdng dac hieu: +1 Phan ung khac tirang tg xay ra sau khi dung thudc tirang tg Khdng lam/ Khdng rd: +0 Khdng biet tien sir dung thuoc nay/ Khdng dung lai thuoc Am tinh: -2 Pa dung thuoc nay ma khdng xay ra phan irng/ Dung lai thuoc ma khdng xay ra phan dng Rat lien quan: +3 Thudc thudc danh sach "nguy cacao" Lien quan: +2 Thuoc thudc danh sach "nguy ca co y nghia"

Thuoc thudc danh sach "chira danh gia duoc nguy co/ hoac da cd ghi nhan xay ra phan dng vdi thudc theo ket qua mot vai bai bao, bao cao dich t§ Nghi ngd: +1

Khdng nghi ngd: Thuoc thudc danh sach "khdng cd nguy co/ Khdng rd: +0 Cac thudc khac (bao gom ca nhCrng thuoc mdi liru hanh va thuoc gay nhieu)

Oiem trung gian = Tong diem tdt ca cac tieu chi tren Nguyen khac

nhan Cd the: Trong mot ca bao cao, neu cd it nhat mot thuoc cd diem trung gian > 3 thi trir mot diem tir

diem trung gian cua cac thuoc cd diem trung gian < 3

Tong diem : -12 den 10

T A P C H I D U O C H O C - 6/2017 (SO 494 N A M 57) 7

• Nghien C C P U - Ky thuat

Bang 2. Bang quy ddi diim- mire danh gia cua thang ALDEN

Tong diem Mux; danh gia Quy uuc mire danh gia >6 Rat co kha nang

4 - 5 Co kha nang 2 - 3 Co the 0 - 1 Khong chdc chan <0 Rat khong chac chan

Ket qua tham dinh d u g c phan loai thanh 4 m d c vdi s u t u u n g dong thuat ngO quy ket g iua 3 thang A L D E N , W H O va Naranjo (bang 3).

Bang 3. Quy ket muc danh gia va gia tri chan doan cua cac phuung phap

Mipcquyket ALDEN NARANJO WHO Gia tri chan doan Rat co kha nang Chac chan Chac chan

Co kha nang Co the

Co kha nang Co the

Co kha nang Dirong tinh (ADR) Co the

Khong chac chan

Rk khong chdc chdn Khong chdc

Khong chac chan Chaa phan loai Am tinh (Khong ADR)

Khong the phan loai

Ket qua thu d u u c d u p e x u ly va phan tich bang phan m e m thong ke R (phien ban 3.3.1). Moi t u u n g quan g iua 3 p h u o n g phap d u p e t inh toan theo p h u o n g phap Spearman thong qua gia tri rho va gia tri p t u u n g u n g cua cac cap p h u o n g phap. He so t u u n g quan rho nay the hien s u t u o n g dong cua cac p h u o n g phap danh gia doi vd i phan u n g tren da nghiem trpng n h u SJS/TEN. Gia tri chan doan cua thang W H O , thang Naranjo va thang A L D E N d u p e xac dinh thong qua cac chi so dp dac hieu, dp nhay, gia tri d u doan d u o n g t inh, gia tri d u doan am tinh t u o n g u n g .

Ket qua nghien cu u Trong CSDL bao cao A D R t u nguyen giai trong

doan 2006-2013, co 174 bao cao A D R ve SJS/TEN thoa man tieu chi lua chpn va loai t ru , t u o n g u n g vdi 355 cap quy k§t thuoc nghi ngd-ADR. Trong 355 cap thuoc-ADR nay, thuoc khang sinh xuat hien nhieu nhat vd i 75 t r udng hpp (22,1%), tiep do la thuoc giam dau, ha sot, chdng viem vdi 55 t rudng hpp (16,2%), thuoc h u d n g tarn than 45 t rudng hpp (13,3%), thudc chong lao 41 t rudng hpp (12,1%), thuoc tri gut 20 t r udng hpp (5,9%), thuoc co nguon goc d u p e lieu/thuoc y hoc co truyen 14 t r udng hpp (4,1%) va cac nhom thuoc con lai xuat hien vd i ti le nho (0,3-3,2%). Paracetamol la thuoc d u p e ghi nhan nhieu nhat vdi 38 bao cao, tiep do la carbamazepin (26 bao cao), cotr imoxazol (15 bao cao) va allopurinol (12 bao cao) (bang 4). Trong 355 cap quy ket thuoc-ADR, ket qua danh gia moi quan he nhan qua cd s u khac biet dang ke g iua 3 p h u o n g phap (hinh 1). So cap quy ket thu6c-ADR s u dung thang A L D E N co quy ket m u c 1 va 2 thap h o n so vdi thang W H O , trong khi do m u c 2 va 4 lai thap h o n so vd i thang W H O . Khi s u dung thang Naranjo, khong co cap quy ket thuoc-A D R d m u c 1 va m u c 4 trong khi do m u c quy ket phan Ion la mu'C 2 (87%). Ve moi t u o n g quan cua giQ'a ket qua tham dinh bao cao SJS/TEN theo thang A L D E N so vdi W H O va Naranjo kha thap vd i gia tri rho bdng 0,38 va 0,23 t u o n g u n g (hinh 2). D p nhay cua thang Naranjo

t u o n g d u o n g vdi A L D E N tuy nhien hoan toan khong dac hieu khi danh gia loai phan u n g nay. D p nhay cua W H O so vd i A L D E N d m u c t u o n g d6i tuy nhien dp dac hieu van con thap (Sp = 36%) (bang 5).

Bang 4. Cac thuoc nghi ngd trong cac bao cao SJS/TEN (tin suit>1)

Hoatchat So bao cao (%)

N=174 Hoaf chat

So bao cao (%) N= 174

Paracetamol 38 (21,8%) Levomepromazin 3(1,7%) Carbamazepin 26(14,9%) Piracetam 3(1,7%)

Cotrimoxazol 16 (9,2%) Serratiopeptidase 3(1,7%)

Thuoc nguon g6c duvc lieu

14(8%) Chymotrypsin 2(1,1%)

Allopurinol 12(6,9%) Azithromycin 2(1,1%)

Isoniazid 9 (5,2%) Cefadroxil 2(1,1%)

Colchicin 8 (4,6%) Chlorpheniramin 2(1,1%)

Pyrazinamid 8 (4,6%) Doxycycl - 2(1,1%)

Rifampicin 8 (4,6%) Erythromycin 2(1,1%)

Amoxicillin 7(4%) Gabapentin 2(1,1%)

Ethambutol 7(4%) Glucosamin 2(1,1%)

Streptomycin 7 (4%) Multivitamin 2(1,1%)

Ciprofloxacin 6 (3,4%) Nevirapin 2(1,1%)

Cefuroxim 5 (2,9%) Nifedipin 2(1,1%)

Meloxicam 5 (2,9%) Penicillin 2(1,1%)

Acid clavulanic 4 (2,3%) Phenobarbital 2(1,1%)

Ampicillin 4 (2,3%) Piroxicam 2(1,1%)

Ofloxacin 4 (2,3%) Prednisolon 2(1,1%)

Vitamin 3B 4 (2,3%) Promethazin 2(1,1%)

Cefixim 3(1,7%) Roxythromycin 2(1,1%)

Cefotaxim 3(1,7%) Spiramycin 2(1,1%)

Cephalexin 3(1,7%) Sulbactam 2(1,1%)

Chloramphenicol 3(1,7%) Vitamin C 2(1,1%)

Chlorpromazin 3(1,7%) Vitamin PP 2(1,1%)

s T A P C H I DUgfC H Q C - 6/2017 (SO 494 NAM 57)

• Nghien cu>u - Ky thuat

300

Hinh 1. Tile mire quy ket thuoc-ADR thim dinh theo 3 thang

B 4' 1#

• • » 3

NARANJO WHO

rho= 0.23

VAHO

M4 rtio= 0.38

ALDEN

2

1 u . ; ?

•. •

•••

1 2 1 4 ALDEN Uechod

1 2 J ALDEN Method

4

Hinh 2. A - Muc do tuung quan giira phuung phap Naranjo so vdi phuung phap ALDEN; B - Muc do tuung quan giue phuung phap WHO so vdi phuung phap ALDEN

Bang 5. Muc do tuung quan va gia tri chin doan cua thang WHO va Naranjo so vdi ALDEN

Gia tri chan doan cua cap phuwng phap

WHO-ALDEN Naranjo-ALDEN

Do nhay Se 85,8% 100%

Do dac hieu Sp 36,2% 0,0%

Gia trj da doan daong tinh 59,2 % 51,6%

Gia tri da doan am tinh 70,2 % 100%

He so taong quan Spearman [rho) 0,38 0,23

Gia tri p < 0,0001 < 0,0001

Ban luan T u nam 1976, tren the gidi da co nhieu h u d n g

tiep can trong quy ket moi quan he nhan qua thuoc-ADR, chu yeu d i rge chia thanh 3 nhom Idn: y kien cua chuyen gia d u a theo tieu chi lam sang, ti§p can theo xac suat va thuat toan M . Quyet dinh cua chuyen gia hoac nhan vien y te d u a tren tieu chi lam sang t hudng

d u g c ap dung trong thuc hanh t h u d n g quy. Tuy nhien, y kien cua chuyen gia d mot goc do nao do t iem an nhieu khiem khuyet n h u mang dam t inh chu quan va thieu s u chuan hoa [ 9 ) . D ieu nay co xu h u d n g dan td i do lap lai t h l p trong danh gia moi lien quan thuoc-ADR. H o n nua , tien tr inh d u a ra quyet dinh cua chuyen gia t h u d n g khong d u g c dien giai ro rang, vi the thieu "minh bach" va khong "bdt c h u d c " d u g c [ 9 ] . Ben canh do, h u d n g tiep can xac xuat la hien con gap nhieu kho khan trong viec ap dung trong thuc hanh t h u d n g quy do c i n phai d u a theo phan phoi mau ve xac suat. Vi vay, p h u o n g phap s u dung thuat toan d u d n g n h u la mot p h u o n g an de dang ap dung nhat trong thuc hanh vd i viec cho diem cac tieu ch i va danh gia d u a vao ket qua tong diem thu d u g c . Khi s u dung thuat toan kieu n h u A L D E N hay Naranjo, s u dong thuan cua cac Ian danh gia khac nhau cua cung mot n g u d i danh gia hoac g iua cac ngud i danh gia khac nhau t u o n g doi cao, tuy nhien ket qua phu thuoc chu yeu vao trong so d u g c gan cho moi tieu ch i , day chinh la yeu to d u a tren kinh nghiem

T A P C H I D U O C H O C - 6/2017 (SO 494 N A M 57) 9

• Nghien cCru - Ky thuat

Hinh 1. Vie muc quy kit thuoc-ADR thim dinh theo 3 thang

• 4

3 NARAHJO

rfio= 0.23 z ALDEN o

2

WHO

rho= 0.38 ALDEN

Hinh 2. A - Muc dp tuung quan giua phuung phap Naranjo so v&i phuung phap ALDEN; B - Muc do tuung quan giua phuung phap WHO so voi phuung phap ALDEN

Bang 5. Muc do tuung quan va gia tri chin doan cua thang WHO va Naranjo so v&i ALDEN

Gia tri chan doan cua cap phuwg phap

WHO-ALDEN Naranjo-ALDEN

06 nhay Se 85,8% 100%

Do (Jac hieu Sp 36,2% 0,0%

Gia tri da doan daong tinh 59,2 % 51,6%

Gia tri da doan am tinh 70,2 % 100%

He s6 taang quan Spearman (rho) 0,38 0,23

Gia tri p < 0,0001 < 0,0001

Ban luan T u nam 1976, tren the gidi da co nhieu h u d n g

tiep can trong quy ket moi quan he nhan qua thuoc-ADR, chu yeu d u g c chia thanh 3 nhom Idn: y kien cua chuyen gia d y a theo tieu chi lam sang, tiep can theo xac suat va thuat toan 16-91. Quyet dinh cua chuyen gia hoac nhan vien y te d y a tren tieu chi lam sang t hudng

d i rge ap dung trong t h y c hanh th i rdng quy. Tuy nhien, y kien cua chuyen gia d mot goc do nao do tiem an nhieu khiem khuyet nhir mang dam tinh chu quan va thieu s y chuan hoa [ 9 1 . D ieu nay cd xu h i rdng dan tdi do lap lai thap trong danh gia moi lien quan thu6c-ADR. Hun nua , tien tr inh d i ra ra quyet dinh cua chuyen gia th i rdng khong d i rge dien giai ro rang, vi th§ thieu "minh bach" va khong "bat ch i rdc" d i rge [9 ). Ben canh do, h i rdng tiep can xac xuat la hien con gap nhidu kho khan trong viec ap dung trong thuc hanh t h u d n g quy do can phai d u a theo phan phoi m i u ve xac suat. Vi vay, p h u u n g phap sir dung thuat toan d u d n g n h u la mot p h u u n g an d§ dang ap dung nhat trong thuc hanh vd i viec cho diem cac tieu ch i va danh gia d u a vao ket qua tong diem thu d u g c . Khi s u dung thuat toan kieu n h u A L D E N hay Naranjo, s u dong thuan cua cac Ian danh gia khac nhau cua cung mot ngud i danh gia hoac g iua cac ngud i danh gia khac nhau t u u n g doi cao, tuy nhien ket qua phu thugc chu y§u vao trong so d u g c gan cho m6i tieu ch i , day chinh la yeu to d u a tren kinh nghiem

T A P C H I D U O C H O C - 6/2017 (SO 494 NAM 57) 9

• Nghien C C F U - Ky thuat

chuyen mdn. Cac p h u u n g phap loai nay co the ap dung rang rai (muc dich de danh gia tat ca cac A D R va tat ca cac thuoc) hoac cu the trong tung t r udng hup (tire la ap dung cho A D R cu the va thuoc lien quan t u u n g ung) .

Trong nghien c y u nay, nhom nghien c i m da b u u c dau ap dung thang A L D E N de danh gia phan i rng SJS/ TEN trong CSDL bao cao A D R nham vu i muc dich so sanh mi>c do t u u n g dong vu i cac p h u u n g phap chung khac. Naranjo mac du la p h u u n g phap d u u c ky vgng la mot cdng cu nhay ben de phat hien cac tin hieu canh giac d u u c (khach quan, do lap lai cao), tuy nhien thang nay lai hoan toan khong phu h u p de danh gia SJS/ TEN do do dac hieu cua Naranjo so vui A L D E N bbng 0. T r u u c do, nghien c i ru cua Nguyen Thj Thu Thuy va CS. nam 2011 ("So sanh tham dinh moi quan he nhan qua phan u n g co hai cua thuoc trong bao cao t y nguyen ve Trung tarn DI&ADR Quoc gia b l n g p h u u n g phap cua Naranjo va p h u u n g phap cua To chdc Y te the giui" , Khoa luan tot nghiep Ducrc sy, Tru&ng Dai hoc Duac Ha Noi) tren bao cao A D R cua Viet Nam (n = 100) cho rdng 2 thang Naranjo va W H O kha t u u n g dong trong danh gia cac bao cao A D R (K =0,52). Tuy nhien khi ap dung d6i vu i cac bao cao SJS/TEN thl thang W H O co do dac hieu cao hun so vu i Naranjo trong danh gia cac bao cao SJS/TEN, n h i m g thang Naranjo lai d y doan cac bao cao "khong ADR" tot h u n su vu i thang W H O (do nhay Se = 100%). Doi vu i danh gia ve phan u n g ngoai da nghiem trong, rd rang la It co s y t u u n g dong g iua W H O va A L D E N va gan nhir khong co s y t u u n g dong g iua thang Naranjo va thang A L D E N . Do sir khac nhau trong c l u true, tieu chuan quy ket va each l i r yng gia tieu chuan co s y khac biet giCra cac loai phan ting co hai, viec ap dung 1 thang chuyen biet nhir A L D E N se co y nghTa rat Ion trong t h y c hanh lam sang vi thang nay d i r y c cong nhan la cb the xac dinh chinh xac thudc gay ra SJS/TEN va khong can ngt ing dieu tri vu i cac thuoc dieu tri k h a c [ 5 ] .

S y khac biet lun nhat cua 2 thang W H O vu i A L D E N tap trung u moi lien he ve mat thu i gian (thai gian t iem tang cua SJS/TEN t h u d n g tir 4 ta i 28 ngay), dieu nay gay nhieu doi va gay anh h u d n g tui y kien danh gia chu quan cua chuyen gia l 4 ) . Ben canh do, ydu to tai s ir dung thudc khdng d i r y c phep ap dung do mire do nghiem trong cua A D R d i n tu i it mi re quy ket mi re " c h i c c h i n " ddi vu i cac bao cao nay khi dung thang W H O . S y khac biet lun n h i t giCra thang Naranjo so vu i A L D E N la khdng loai tr ir d i r y c cac yeu to gay nhieu nhir benh m i c kern, thuoc sir dung dong thu i , ng i rng thuoc ct ing luc vui tat cac cac dieu tri dong thui hoac ngi rng thuoc ma khdng cd tien then. Do ban chat dac thu cua SJS/TEN bao gom tap h y p cua nhieu trieu chung dac hieu va khdng dac hieu, viec phat hien va phan biet vu i cac A D R khac cung dat ra thach th i rc doi vu i ng i ru i bao cao cung nhir chuyen gia tham dinh. Dieu nay cd

the giai thich s y khdng dac hieu khi ap dung cac thang khdng chuyen biet trong danh gia quan he nhan qua cua cac bao cao SJS/TEN.

Ket luan Day la nghien c i ru ddu t ien van dung thang A L D E N

de danh gia cac bao cao SJS/TEN trong CSDL bao cao A D R cua Viet Nam. Nghien ci>u cung chi ra thang W H O va thang Naranjo cd mi re do t i rung dong kha thap khi so sanh vu i thang A L D E N khi danh gia cac bao cao lien quan tui loai phan ting nay. D o dac hieu cua thang W H O kha thap va thang Najanro hoan toan khdng dac hieu khi danh gia moi quan he nhan qua SJS/TEN gay ra bui thuoc khi so sanh vu i thang A L D E N . Nghien c u u da bo sung mot ph i r ung phap mt i i chuyen biet hun de danh gia cac phan ting tren da nghiem trgng nhir SJS/ TEN trong he thong cac ph i rung phap tham dinh A D R hien tai u Viet Nam va h i rung den viec can nhac ap dung A L D E N trong t h y c hanh canh giac d i r y c cung nhir trong t h y c hanh lam sang.

Tai lieu tham khao 1. Nguyen Van Doan (2005), "Nghien ci>u hoi chirng

Stevens-Johnsson va Lyell do di ting thudc tai Khoa Di ting-MDLS Benh vien Bach Mai (1997-2002)", Tap chi Nghien cuu Yhoc, 33, 57-63.

2. Rzany B. et al. (1996), "Epidemiology of erythema exsudativum multiforme majus, Stevens-Johnson syndrome, and toxic epidermal necrolysis in Germany (1990-1992): structure and results of a population-based registry", J. Clin. Epidemiol., 49, 769-773.

3. Mockenhaupt,M. et al. (2008), "Stevens-Johnson syndrome and toxic epidermal necrolysis: assessment of medication risks with emphasis on recently marketed drugs. The EuroSCAR-study", J. Invest. Dermatol., 128, 35-44.

4. Marotti M. (2012), "Severe cutaneous adverse reactions (SCAR) syndromes", Rev. Assoc. Medica Bras. Engl. Ed., 58, 276-278.

5. Sassolas B. et al. (2010), "ALDEN, an algorithm for assessment of drug causality in Stevens-Johnson syndrome and toxic epidermal necrolysis: Comparison with case-Control analysis", Clin. Pharmacol. Then, 88, 60-68.

6. Irey N. S. (1976), "Diagnostic problems in drug-induced diseases", Ann. Clin. Lab. Sci., 6, 272-277.

7. Edwards I. R., Lindquist M., Wiholm B. E. & Napke E. (1990), "Quality criteria for early signals of possible adverse drug reactions" Lancet, 336, 156-158.

8. Clark J. A., Klincewicz S. L. & Stang P. E. (2001), "Spontaneous adverse event signaling methods: classification and use with health care treatment products", Epidemiol. Rev, 23, 191-210.

9. Arimone Y. et al. (2006), "A new method for assessing drug causation provided agreement with experts' judgment", J. Clin. Epidemiol., 59, 308-314.

{Ngay nhan bai: 28/12/2016 - Ngay phan bien: 22/03/2017 - Ngay duyet dang: 02/06/2017)

1 0 T A P C H I D U O C H Q C - 6/2017 (SO 494 N A M 57)