YHgcTP.HoChiMinh'Tapl7*S63*2013 NghiencmiYhpc
NGHIEN Clfu MO DA TRUNG TAM VOI LIEU LINH HOAT DE DANH GIA HIEU QUA VA SU" DUNG NAP CUA DON TRI LIEU TOiPIRAMATE 6 NHU'NG BENH NHAN DONG KINH MCH CHAN DOAN
Pham Quynh Diep*, Ninh Thi 1%**, Le Thj Khanh Van***
TOMTAT
Muc tieutDdidi gid khd ndng dung nap va hieu qud am don tri lieu Topamax vdi lieu linh hoat a nhung benh nhdn dgng kinh moi dugc chan dodn, chua dieu tri hoac Bmt hai v&i dim tri lieu bang mgt thuoc khdng dgng kinh khdc.
Phuong phdp nghien cihi: Nghien ahi ma can thiep da trung tam su dungtopiramate lieu linh hoai don tri lieu trong 16 tuan tren benh nhi> 5 tuoi mai dugc chan dodn dgng kinh, chua duoc dieu tri hoac dd thai bai voi 1 thud'c khdng dgng kinh khdc.
Ke't qud: Topiramate vai lieu trung binh 2,97mg/kg co hieu cpta trong 88,9% trucmg liap co con dgng kinh toan thi'lan can dgng kinh cue bg, dgng kinli mai chua dugc dieu tri cung nhu dd that bai vai 1 chn tri lieu;
trong do 70,1% hH ccm hodn todn, 16,2% giam >75% am vd 2,6% gidm >50%. Topiramate dung nap tdi vai 43,2% truang hap co tdc dung ngoai y nhe va khong dnh huong deii huyei do, chuc nang gan th&n, diin tim
Tir khoa: Topiramate, dan trj lieu, dgng hnh mai chdn dodn ABSTRACT
MULTICENTER OPEN-LABELED TRIAL WITH FLEXIBLE DOSAGE TO ASSESS TOLERABimY AND EFFICACY OF TOPIRAMATE MONOTHERAPY IN NEWLY DL\GNOSED EPILEPSY
PATIENTS
Pham Quynh Diep, Ninh ThiUng, Le Thi Khanh Van
* Y Hoc TP. Ho Chi Minh * Vol. 17 - No 3 - 2013:131 - 136 Objectives: Evaluation efficacy and safety of Topirainate monotherapy with flexible dosage in newly diagnosed epilepsy patients not yet treated or failed monotherapy with another antiepileptic drug.
Methods: Multicentei- open-labeled interventioiml trial cf using flexible dose of Topirainate monotherapy pr 16 vxeks in pediatric patients aged >5 years who liaue nezv onset epilepsy, not yet treated or foiled monotherapy with another antiepileptic drug.
Results: Topiramateat low average liose of 2.97 mg/kg shows effective in 88.9% cases remaining in the trial, including generalized and partial seizures, newly diagnosed not treated epilepsy and epilepsy having foiled previous monotherapy with one antiepileptic drug. Among the good response cases, 70.1% are completely seizure free, 16.2% reduce > 75% seizure rate and 2.5% reduce >50% sazure rate. Topiramate are also well tolerated with 43,2% of cases have mild adverse events and have no influence on hematology, liver and kidney function, electrocardiogram.
Keywords: Topiramate, monotherapy, newly diagnosed epdepsy
GIOI THIEU nghiem trong thuong gap nhat {ty le moi mSc Dpng kinh la mpt roi loan than kinh khoang 30-50/100000 dan nam; ty le b^nh lim
• Benh vien Tam than, TP Ho Chi Minh, ** Benh vien Nhi Tnmg ucmg. Ha npi *** BV Nhi Dong 2 Tdc gia lien lac: BS CK 2 Pham Quynh DiepDT: 0908414963 Email: [email protected]
NghiencmiYhoc YHpcTP.HoChiMinh*Tapl7*So3*2013 hanh 0,6-0,8%)<". Cac thuoc chong dpng kinh
kinh dieh da giiip kiem soat cac con dpng kinh 6 phan Ion cac benh nhan. Tuy nhien, cac thuoc nay co nhieu tac dung phu va co tiem nang gay dpc tinh he than kinh trung uong hoac CO the gay ra cac phan iing dac iing nghiem trpngO^. Tu nam 1992, nhieu thuoc chong dpng kinh moi vol cac co che khac voi CO che cac thuoc kinh dieh va co cac tac dung phu dupe cai thien da dupe dua vao sii dung;
dieu nay giup viec xu tri dpng kinh dat dupe cac miic dp cao hon ve tinh hieu qua va an toan*^'. Topiramate la mpt trong cac thuoc nay.
Hieu qua va s^r an toan ciia topiramate da dupe chiing minh trong nhieu thii nghiem co doi chiing ngau nhien mil doi 6 ngirdi Ion va tre em, ca nhu la don tri lieu va dieu tri ket hpp cho cac con dpng kinh ci^c bp co hay khong CO toan the hoa thii phat, va cho cac con dpng kinh toan the h6a(''>.
"Thii nghiem mo can thi^p da tnmg tam voi lieu linh hoat de danh gia s\r dung nap va hieu qua ciia don tri lipu topiramate 6 nhung benh nhan dpng kinh moi dupe chah doan chua dupe dieu tri hoac that bai voi don trj lieu sii dung thuoc chong dpng kinh khac" da dupe tien hanh de mo ta viec sii diing "thuoc trong thuc te" va tinh thiet thuc ciia viec dieu tri nay 6 Viet Nam.
Thii nghiem ma da trung tam nay da dupe hen hanh tu Biang 5 nam 2008 6 khoa Than kinh cua benh vien Nhi trung uong 6 Ha Npi, khoa Npi than kinh oia benh vi§n Nhi dong 2 6 Tp.HCM va phong kham ngogi tni nhi oia benh vien Tam than a Tp.HCM.
Muc tieu nghien ciiu
Nham danh gia sy dung nap va hifu qua ciia don tri lieu topiramate voi lieu linh hoat a nhung benh nhan dpng kinh moi dupe ch£i doan, chua dupe dieu tri hoac don tri li^u that bai voi mpt thuoc chong dpng kinh khac.
D^Tl/ONG-mi/CflVGIHAPNGHIENCUlJ Thiet ke nghien oiu
Thti n ^ e m mo can thiep da trung tam.
Doi tupng nghien dm
Nhiing benh nhi bi dpng kinh thoa man cac tieu chuan chpn b|nh va tieu chuah loai trii dupe liet ke ben duoi tir 3 trung tam tham gia nghien oiu (khoa Tliian kinh ciia benh vien Nhi Trung Ucmg (Vi^t Nam - Thuy Dieh), khoa Npi than kinh cua b^nh v i ^ Nhi Dong 2 6 Tp.HCM va phong kham ngoai tni nhi ciia benh vien Tam Than 6 Tp.HCM).
Tiew chuan chon benh
- Tuoi > 5 tuoi va < 18 tuoi va can nang > 25 kg.
- Dupe chah doan dpng kinh co ciing co gigt toan the hoa nguyen phat hoac cac dpng kmh cue bp CO hoac khong co toan the hoa ttiu phat (theo ILEA) trong vong 5 nam gan day.
- Chua bao gjo duoc dieu tri, hay that bai voi don tri lieu dau tien vdi cac thuoc chong dpng kinh khac do khong co hieu qua hoac khong dung nap, khong doi hoi tri lieu ket hpp.
Tieu chuan lo^i trie
- Nhung b^nh rJian bi cac con gia dpng kinh hoac cac con dpng kinh trieu chiing voi cac nguyen nhan co the dieu tii dupe.
- Nhung benh nhan co bat ky benh ly nghiem trpng hope ti&i tnen nao ma no c6 the can tro su hoan thanh thii nghiem.
- Nhiing benh nhan co thai hoac cho con bii.
- Nhung benh nhan voi tien can hoac nghi ngo lam dyng ruou hoac chat gay nghien.
- Nhiing b#nh nhan tham gia trong mpt thii nghiem thuoc khac trong vong 30 ngay truoc khi bat dau thir nghiem nay.
- Nhiing benh nhan da sii dung topiramate hoac hon mpt thuoc chong dpng kinh truoc do.
- Nhiing benh nhan nhay cam voi bat ky thanh phan nao ciia thuoc
- Nhiing benh nhan dang dimg cac chat lie che MAO, hirosemide, hydrochlorothiazide.
Cac benh nhan trong nghien ciiu nay da dupe dieu tri bang topiramate trong vong 16 tuan voi lieu khoi dau la 0,5mg/kg can nang 152
YHpcTP.HoChiMinh*Tapl7*S63*2013 NghiencmiYhpc dimg duong uong vao buoi toi, sau do tang
0,5mg/kg/ngay moi tuan trong vong 6 tuan cho den khi dat lieu muc tieu 3mg/kg/ngay. Lieu hep theo da duac dieu chinh bang each tang 0,5mg/kg/ngay moi tuan de dat dupe lieu ten uu tiiy theo hieu qua va sy dung nap, nhung khong vupt qua lieu tong cpng la 9mg/kg/ngay.
Neu benh nhan da duoc dieu tri voi thuac chong dpng kinh khac liic khoi dau cua ihu nghiem, thuoc nay se dupe gjam dan de ngung hoan toan sau 3 tuan de dam bao rang tat ca nhiing benh nhan se dimg don tri lieu topiramate vao cuoi tuan thii 4.
Lieu, giam lieu thuoc chong dpng kinh, chinh li§u deh lieu toi da la 9mg/kg/ngay neu con dpng kinh khong dupe kiem soat lieu co the gjam neu khong dupe dung nap tot
Cac tieu chi danh gia la su ttiay doi ti le con dpng kinh 6 tuan ihii 4, tuan 12 va tuan 16 so voi liic ban dau, su giam con dpng kinh > 50%, >
75%, 100% (khong con con dpng kinh) va su thay doi oia diem so danh gia lam sang tong quat (Clinical Global Impression CGI) a ngay cuoi cimg so voi ngay bat dau. Tat ca cac tac dyng ngoai y trong suot thii n ^ e m da duoc ghi nhan 6 moi Ian tham kham. Phan tich thong ke mo ta da dupe sii dyng de danh gia cac dii lieu quan sat. Do dac tinh mo ciia thii nghiem va khong CO nhom chiing hoac phan nhom dieu tri ngau nhien, v i ^ tinh toan gia tri p oia y nghia thong ke da khong dupe thuc hien.
KET QUA Cae dac diem dan so hpc
Tir thang 8 nam 2008 deh ttiang 1 nam 2010, 139 b#nh nhi thoa man cac tieu chuan chpn benh va tieu chuah loai trir tii 3 trung tam da dupe dua vao nghien cuu: 132 b^nh nhan tham gia vao phan b'ch an toan thuoc, 117benh nhan hoan tat thir nghiem dupe phan tich hieu qua va 22 b?nh nhan nit lui khoi thii nghiem, chiem 15,8%
tat ca cac tnrong hgp.
Phan bo be trai (51,1%) va be gai (48,9%) thi gan nhu bang nhau, Tuoi trung binh ciia
dan so nghien ciiu la 10,1 ± 3,1 tuoi, trang khi do tuoi trung binh ciia khai phat b?nh la 8,9 ± 3,4 tuoi, cho thay rang phan Ion cac truong hpp CO khoi phat dpng kinh gan day. Hon 40%
cac benh nhan da dupe ghi nhan la c6 cac finh trang tien benh ly chang ban nhu chah thuang dau (15,9%), cac can dpng kinh do sot (12,9%), viem mang nao (2,2%), cham phat trien tam than (1,4%), xuat huyet nao (0,7%) va cac tinh trang khac.
Dya tren phan loai ciia ILAE ve cac con dpng kinh, 58,3% cac truang hpp da duoc chah doan la cac con dpng kinh cue bp co holic khong CO toan the hoa ttiii phat va 41,7% cac tnrong hpp la cac con dpng kinh co ciing co giat toan ttie hoa nguyen phat. Phan Ion cac can dpng kinh la vo can (56,9%); cac con dpng kinh con lai la can nguyen ah (18,7%), co trieu chiing (17,3%), va khong xac dinh (7,1%).
Hai phan ba cua dan so nghien cuu la cac truong hpp dpng kinh moi duoc chan doan chua dupe dieu tri va chua baa gio dupe dteu tri voi mpt fhuoc chong dpng kinh trong qua khii. Mpt phan ba con lai da dupe dieu tri voi mpt thuoc chong dpng kinh tnroc khi di vao thii n ^ e m . Cac thuoc chong dong kinh dupe sir dyng truoc do ttiudng gap nhat la valproate (16,5%) va carbamazepine (10,1%). Cac ly do oia viec chuyen sang topiramate la khong co hieu qua (77%), khong dung nap (5,8%), va ca khong co hieu qua va khraig dung nap (5,8%).
Tan so oia con dpng kinh trung binh moi thang tnroc khi bat dau voi topiramate trong nhom nghien cihi thi cao, 36,6+96 moi thang, vcd 41% cac tnrong hpp co hem 10 con dpng kinh moi thang va 59% cac trudng hcrp co ti le con dpng kinh duoi 10 con dpng kinh moi thang.
Hieu qua oia topiiamate
O tuan 16, lieu trung binh ciia topiramate dupe dimg trong thii nghiem fhi thap (2,97mg/kg/day), gan b3ng lieu muc tieu la 3mg/kg/ngay.
Danh gia hieu qua dieu tri o tuan 4, tuan 12, va tuan 16 vdd cac ti le dap iing dieu tn 133
NghiencmiYhpc YHpcTP.HoChiMinh*Tapl7*So3*2013 (giam con dong kinh it nhat 50%) trong nhom
nghien oiu lan luat la 85,9%, 86,2%, 88,9%. Ti le khong con con dpng kinh tuong iing la 58,6%, 66,9%, va 70,1%.
Ba nhom con dong kinh eye bp, toan the hoa thii phat, CO ciing co giat toan &\e hoa nguyen phat ttii dap iing tot voi dieu tri (giam ti I? con dpng kinh it nhat 50% Ian lupt la 85%, 90%, va 92%; khong con con dpng kinh Ian luot la 65%, 60%, va 80%) (Bieu do 1).
Con ci^c Con toan t h i Ccm co cirng co
^ hda thip phat gilt toan the i nauvSnohal [
Biai do 1:
Sau 16 tuan, nhiing benh nhan voi tan so con dpng kinh hang thang thap (< 4 con moi thang) truoc khi dua vao thii nghiem co ti 1? het con dpng kinh cao hon so voi nhiing benh nhan co >
10 con dpng kinh moi thang (743% so voi 66%)(Bieu do 2).
Hipu qua ciia topiramate nhu la don tri lipu trong 2 nhom benh nhan - moi dupe chan doan va chua dupe dieu tri, hoac that bai vol mpt thuoc chong dpng kinh khac - thi tuong tu nhau vai ti le khong con con dpng kinh la khoang 70%(Bieu do 3).
Hi?u qua dieu tri fhi ciing diroc phan anh qua viec danh gia diein so lam sang tong quat (Clinical Global Impression CGI) tnroc va sau khi dieu tri. Sau 4 thang dieu tri, phan Ion cac truong hpp dupe danh gia tir kha fot den rat tot (17,9% dupe danh gia nhu la rat tot, 52,8% tot, va 25,2'!o kha tot) trong khi phan lan cac danh gia liic ban dau thi tuang doi xaii.
134
• 100% con
• £75% can , a O % a m
<Acof\l 4-10 00-0/ > 1 0 c o ' n / [ .tfiapg _tha_na thanQ_.
Bieu do 2:
Giam.
> 100% con , a 75% con 2 50% con
Chira di^i tri _ Biiu do 3:
Sy dung nap
Da CO 43,2% cac trudng hop duoc ghi nh|n la CO 1-7 tac dung ngoai y xay ra trong suot thu nghiem. Khong co tac dung nga^ y nang nao dupe ghi nhan.Phan Idn cac tac dung ngoai y dupe bao cao dupe danh gia la nhe, thoang qua, tu gidi han va khong can phai dieu tri. Cac tac dung ngoai y hay gap nhat la sut can, chan an, cac roi loan da day rupt, tang than nhiet, met m6i,...(Bieu do 4).
E>oi vdi tac dung ngoai y sut can, can nang CO the da dupe ghi nhan la mat dudi 8%, trung binh 1,26kg ± 1,22kg, it nhat la 0,5kg va nhieu nhat la 7kg (d mot benh nhan qua can liic bSt dau dieu tq). Cac dac diem tac dyng ngoai y tuong ty vdi cac ket qua ciia cac tac gja khac. Sau 4 ttiang dieu tri bang topiramate d lieu thich hpp, khong CO mpt su thay ddi bat thudng cd y nghia da dupe ghi nhan tren cac ket qua xet
YHpcTP.HoChiMinh*Tapl7*Sd3*2013 NghienciruYhpc nghiem ve huyet hpc, sinh hda doi vdi cac chiic
nang gan va than, ion do, NHs, phan tich nude tieu va dien tam do.
Rit lM Tit Kh lit Trmt
Bieu do 4:
Hoan thanh nghien cuu
Ti le nhiing benh nhan van dimg topiramate sau 4 Ihang nghien ciiu la 84,2%, ket qua nay tuang tu vdi ket qua ciia cac nghien ciiu bdi cac tac gja khac sir dung Ueu linh haat topiramate dudi dang don tri lieu. Ti le nay thi cao hon ti le ciia cac nghien cuu sir dung cac thuoc chong dpng kinh khac (vi du, 57% vdi cac thuoc chong dpng kinh co dien, < 68% vdi lamotrigine, va 43% - 56% vdi gabapentin).
Trong so 22 trudng hpp (15,8%) nit lui khoi thii nghiem, khdng co trudng hpp nao la do khong dung nap thuoc: ba trudng hpp nit khdi nghien ciiu do hieu qua kem, va phan Idn cac trudng hpp con lai la do khong tuan ttiu dieu tri- BANLUAN
Da han 20 nam ke tir khi bao cao dau tien nam 1988 ve dimg Topiramate trong dieu tri dpng kinh, Hieu qua va dp an toan oia Topiramate trong don tri lieu cac con dpng kinh mdi chah doan, dpng kinh khang tri da dupe danh gia bang cac thu nghiem lam sang co kiein saat dupe tien hanh tren nhieu quoc gia.
Trong nghien ciiu nay, lieu khdi dau dieu tri tir 0,5 mg/kg/ngay tang lieu them 0,5 mg/kg/ngay sau 2 tuan, cii 2 tuan tang ttiem 0,5 mg/kg/ngay phii hpp vdi cac tac gia Glauser<^, Cappolat^'.
E>di vdi con co that gap da tang len 29
mg/kg/ngay van dung nap dupe (Glauser<'^).
Ng^en ciiu oia Yann Mikaeloff, OKvier Dulac*'^
cho thay Topamax cd hieu qua tot khi dieu tri tre em dudi 4 tudi nhimg phai yeu cau tang lieu that cham. Dieu tri ca dpng kinh khang thuoc d tre dirdi 12 tuoi dang can cue bp, dpng kinh giat ca nang. Nhieu nghien ciiu md da dupe bao cao ve dieu tri dpng kinh cue bp bing Topiramate (Privitera et al"*"; Reife and Pledger<i«; Faughf^;
Ben-menachem«; Coppola et al.P>) cha ttiay 50%
CO dap ling khi dieu tri ket hpp vdi Topiramate, giam con co.giat sau 3 thang dieu tri vdi lieu trung binh 4,8 - 9 mg/kg/ngay. Mpt vai nghieu etiu cho rang Topiramate cd hieu qua tuang duong cho tat ca cac loai dpng kinh, tuy nhien Wei-Ping Liao^^* nhan xet hieu qua tren dpng kinh eye bp, cue bo toan the hoa.
O nghien ciiu oia chiing toi, 65% het con trong nhdm benh nhan bi can cue bp, 60% het con trong nhom benh nhan bi con toan the hoa thii phat va 80% het con d benh nhan bi con co cting CO giat toan the nguyen phat.
Tuy nhien da c6 nhiing tranh luan ve lieu va chuah lieu oia thuocCac bao cao gan day khang dinh rang lieu thap Topiramate cd the cd hi^u qua tot. Nhiing khac biet nay cd le do sy khac biet trong timg ca the doi vdi Topiramate Idn hon cac thuoc chong dpng kinh khac. Sy khac biet ve chiing tpc va trpng lupng ca the co ttie la nhiing yeii to khac anh hudng d&i hieu qua.
Thea tac gia Wei-Ping Uao, Topiramate lieu 2,7 mg/kg/ngay cat dupe con, khuyen cao lieu khdi dau 1 mg/kg/ngay vdi chuan Ueu 0,5 mg/kg/ngay moi tiian co le la phac do dieu tri tot cha tie em.
Con theo nghien ciiu ciia chiing toi tien 139 benh nhan, Ueu thuoc Tapiramate trung binh sir dung la 2,97 mg/kg/ngay; Ueu khdi dau trung binh la 0,73 mg/kg/ngay vdi chuah Ueu trung binh la 0,4 mg/kg/ngay.
Privitera et al<'^ nghien oiu 613 benh nhan (20% benh nhan cd tuoi Ion hon 6 va nhd hon 16) bi can dpng kinh toan the hay cue bp, ngau nhien mil doi vdi topiramate 100 mg/ngay hay
NghiencmiYhpc YHpcTP.HbChiMinh*Tapl7*S63*2013 200 mg/ngay, so vdi valproate 1250 mg/ngay va
carbamazepine 600 mg/ngay, cho ttiay khong cd khac biet dang ke giiia topiramate 100 mg, tapiramate 200 mg, valproate hay caibamazepine, nhung nhdm topiramate 100 mg/ngay bi it tac dung phu hon.
Tuy nhiea d nghien oiu ngay cd 52 benh nhan timg su dung cac ttiudc khang dpng kinh khac trudc do nhu valproate, phenobarbital, caihamazepine nhung khong hieu qua, dupe chuyen sang sir dung topiramate thi thay co 70,5% benh nhan dt duoc 100% can, va 13,7%
benh nhan c3t dupe > 50% so con. Theo Kwan P., Brodie M.J^^^ benh nhan khdng dap iing vdi ttiuoc khang dpng kinh dau tien la mot yeii to tien lupng khang tri.
KETLUAN
Topiramate vdi Ueu tnmg binh 2,97 mg/kg/ngay hieu qua tiong \'iec lam giam so lupng cac con dpng kinh: 70,1% hoan toan khdng cdn con dpng kinh, 16,2% giam ty le con dpng kinh >75% va 2,5% giam ti le can dpng kinh > 50%.
Topiramate hieu qua trong con dpng kinh toan the co ciing co gilt vk cac con dpng kinh eye bp cd hay khong cd toan the hoa thii phat, va trong ca 2 nhdm benh nhan: dpng kinh mdi dupe chah doan chua dupe dieu tii va dgng kinh that bai vdi cac thuoc chong dpng kinh khac dudi dang don tri Ueu.
Topiramate ciing dupe dung nap tot bdi vi khong CO tnrdng hpp nao bj tac dyng ngoai y nang hoac nit lui khoi thii nghiem do tac dung ngoai y. Cac tac dung ngo^ y da dupe bao cao nhu dian an, giam can, tang than nhiet roi loan tieu hda nhe, thoang qua, va tu gidi ban.
Lot cdm ate d i m cm cong ty }aiissen Cdag Viet Nam da lai tra itghiena'nininf.CmiianBS}^giiyenLeMaihTrangv(iBSD3 Vii Liiii Hittmg. CO vSii y Idioa jansscn Cilag Viet Nam, da ho tra viec bien tap bdo cao nghihi cuu my.
TAI LIEU THAM KHAO
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