Nghiên Cứu Dạng Bào Chế Và Tiền Lâm Sàng Của Thuốc Artesunat Kết Hợp Với Piperaquin Để Làm Thuốc Chữa Sốt Rét.docx

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g h o t toankhacv6ic:iethuocsGtréthie:ndangco,lamottrongnhfmgquanIDhangd6ukhfi ngchiriengcuaVietNammaconcuan h i é u niioctrenth

eg i c i i Tro ngailérnnhfitdfiivéithuoccocaun6iperoxidlatyletiiiphiitcao.(10-

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tiicdungphu(CV8),hoaccothedephMhuydodihydrroartemisinin(artekin) Hiennayartesunatdangdvocsitdungrongr5itaiViétNamv i gia thanhre,dfibénvfmgcaohonsovéic:iedanchatkhiic.Nghién c t i u keth o p artesunatva piperaquinnhamt a o r a m o t d a n g th uo c c h o n g t : i i p h a t , d e b é o q u

é n v a s i r dung,g i a thanht h 4 p l a d i é u r a t c a n t h i é t c h o c h i e n l i i o c s i r d

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Motsoccscrdasanxu6t thuocsotre’tvadong

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gopvematkhoahocchoChuongtrinhQuocgiaphongchongsotrét.Vi(nSotrét-'nccsosituxuatdattiéuchuanGMP(doDit:inPCSRVi(tUcHitrcrtruocday)desénxu6tthuocsotrétm6icohi(o quécao.D6yclinglanghie‘ncirumodaudecosoli(ugiiipchoviecxinkinhphicacnghiéncilritic:ptheosédunekethppv6itruéngDH

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Piperaquind u o c RhoneP o u l e n c t o n g hpptitnhfmgnam1 9 5 0 vamotth6pkysaudfida

duocVténNghiénciiuCongnghi(pDuocThuongHii,T r u n g Q u o c s i r dung.N o t h a y t h é c h o chloroquinn h i i lat h u o c s i t dungchotuyénd dut r

o n g n h i é u v i i ngoTrungQ u o c t r o n g n h tmnam1970va1980.NgoairamotsonhfikhoahocTrungQuoccondnaradangthuock é t h p p g i i i a p i p e r a q u i

n v a a r t e m i s I n i n ( 3 0 0 m g + 5 0 m g ) g o t l a artequick,cohi(uliictfitv6ikysinhtriingsotrét.TrongthciigianchongMythaocsotrétdachieucua

TrungQuocdiingchobodfiiVi(tNamlaViénphongIII,trongdficokéthppchuyéuv6ipiperaquin

Conhie‘unghiénelmve'cécph:iedfike"thopgifrathuoccocaunoiperoxidvéritha0csotrétkhac.TaiThaiLandake"ihppthuocartesunatv6imefloquinth6ycohi(uquacaovoiKSTsotre’t,tyl(I:iiph:it thap

CTTI.I,kitquachothdyartemisinintothon4-5lansov6imefloquin,28-30l6nsovéiic h l o r o q u i n va1 0 lansovciiquinin( N g u y ‹ : n D uy Syvacongsu,1992)

Hauhétcactiicgiénghienciiudenconh"anxétchungladiilieuthapvoitong1i‹:ulal g haylieucao5gthiartemisinindc:u catso1vasachKSTtruoc48giosaukhiufi ng

thuoc(NgoyénDuySyvacongsu,1992).C h o dennayd i é u t r i s o t rétactinhchin y é u d na vaocacthuocs o t réttiém,truyénnhuquinin,artesunat ,dieanaykhfi ng thudntien otuyenccs o

Mfitsonghiénelmchothayvoiartesunattiémbapthitlieu240mgJ3ngay,360mg/5ngay,480mg/

nay.Hu6ngnghi6nciiuchinyentiptrungkéodaithéigianbénthaiciiathuocde"nongdothuocduytritrongin:iulauhon.Dieunayconghiacmkethppchiingvéimot thuocsotre’tco théigianb:inthiidaihon

Nghiénelmgind:Iydaphoihppdihydroartemisininvoipiperaquin,primaquin,trimethoprim(viénCV8)doVi(tnamsénxuatchothaycotiredungcho ng I:i i p h : i t , n h u r i g v a n cot:ied un g phun h u : b u f i n n f i n,da u

9

Vi(nSotrétkéthppvoimob

soccrs‹s é n xuatdathirnghiémthuocArterakin( h o n h p p t h u o c k e t hp

pg i f i a d i h y d r o a r t e m i s i n i n 40mgv a piperaqain320mg),cohi(uluccaovoikysinhtrilngsotrétvasitdungantoan.Phacdhsirdungcuaarterakinla2viensau0,8,24va36gio.Tonglieula8vién

Trongdc:tdinay,TruongdaihocDuocHaNfiivdVi(:nS0trét-KST-CTTUnghienctiudangthuocke“thppgiiiapiperaquinv a thuoccfihieulvccaov6iKSTsotrét,ddylahittingnghiénciiumcritimrathuficsfitrétcohieuluccao,chong Laiphét,giathanhthdpvaantoanchonguéisirdung

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Duoc dién Viet Nam III Duoc dien Viét Nam III Tinh khiét ph:in tichTinh khiét phlri tich

Tinh khiét ph8n tich

Artésiinat‘ Dihydroartemisinin Doxycyclin Piperaquin

Lactose

Tinh bot mi

Microcrystalline cellulosePolyvinyl pyrolidonTween 80

PolyethylenTalc

glycol 6000

Magnesi stearat Acid chlohydric Triphenyl phosphin Natri bicarbonat Aceton

Ethanol Ether ethylic n-hexan Ethyl acetat

Tr‹in bot kép

Polyvinyl pyrolidone Ethanol tuy(t dfii

Tao hat :im

3.ID.2.Biroche““viénnénphihppartesunatv‹ipiperaquinb a n g phu:engphap taohatamviiphu:engphtipdcipthang

a) Phvongpha ptaohatam

S:iyhat

.Tate

:Magnesis t e a r a t

q u i t d u n g s a i 5 9oV a k h f i n g d u o c viénn a o cochénhlechg a p dfiidungsai

— Docimg:Deroitvdo3vientitchieucaolm1‘eninitmatph:ingchac,khongviénnaodvocglyvo.Néumiitvia:ncovetranthicoinhirbivfi.Ne‘iil4nthiinhatkhfingdatyéucauthilhmlaiv6i3vi6nkh:ic

CfitRP18: 25cmx4,6mm,kichthuochat:5Jim

d]chdemphosphatpH5,8:acetonitril(83:17)Tocdddong: 1ml/phiitDetectorUV:

3.2.1.5 Dungenytévadungciichuyénd u n g dii ngtrongthu:nghiém.

15

- ChuanbiKST:NufiicitykysinhtriingtrongmoitruéngRPMI1640,hepes,gentamicin,NaHCO,val09«huyetthanhnguirichodinkhi

datintdfitoithieuShesednavaodethit thuoc

(dfiivériongchimg)vamoi triiéngcficacnongdfithufickh:ienhau.Sau72giolaylam,nhu0mgiemsa

vade"mhfingcdunhiémkysinhtriingtrénlamgiotmongtheo10.000hongcauocacgic:rigchiingvac:icnongdothuockh:ienhau

- Xacdinhnongdfiticché509oKSTph:ittrien(ICSO)sov6ichiiiigdnatheophan

mémdaduoccaidattrénmaytinh

16

chit: Ar : Arteraquin

4.1.3 Docling:Lam3l4nmoifan:3vienthuocthatitdocao1metxuongmatdat,trong4maulhuocdéudatkhongcoviénnaobisutmé

20

TT M:inthuiic Thiiigianr:i Kétqué

7.0

21

Dungmoichay:acetonitril:acetatebuffer(55 ;45)

ArtesunatciiaAr3

5,2Rf= -=0.747,0

7.0

PiperaquincliaAr2

4,3Rf= -—,6I

7,0

22

4,6Rf= -=0,66

7,0

PiperaquinciiaAr4

4,8Rf= ————— =0,6S

7,U

Nh:in x ét:Dungphuongphapsackjl6pmongdedinhtinhva

bandinhlupngchoth6yvetciiaartesunatvapiperaquintrongc:icviénthuocdéutuongduongvéiiartesunatvapiperaquinchum

4.1.5.Dinhlupng haml irongartesunatvapiperaquin:

1 2 3 4 5 6 7 8 9 10[ 310,0 320,0 319,0 320,2 319,9 316,8 318,0 320,0 316,4 319,1

Chit thich: (":Dondongnhay

chloroquin"':Chfingkhangchloroquin

²"':DonvitinhnM/L4):Donvitinhtheopiperaquin4.2.2.NghiénelmI:iedungdoivéiky'sinhtriingsiitréttrénchuotthnc

5.BANLUANDaconhie’utécgiinghienermvepiperaquinkethppvéimotsothuocSOtr é t k h : i c m a

d a c b i ( t l a t h u o c c o c a u n o i p e r o x i d n h i r C V 8 , a r t e k i n , artecom,artecan,artequick cacthuocde‘ucotacdungtrenkysinhtriingsotrét.Trongcfingngh(baoché,vande

tainsaodéthuoccotacdungtotmalaiitdficlamoiquantaindautrongc:icnghiénciiu.Caccfingthiicbaochéchin yéu dna trén t:ic dung ciia hop chatpiperaquin két hpp v6idihydroartemisininlach4titbénvingkhi

chuyénhoatrongccthéngircii[5] t:icgiéchorangk h i u f i n g a r t e s u n a t v a

o c c then o s é ch uy én h o a thanhdihydroartemisininc o t:icdungv‹iikysinhtriingsotrét[SJ.Dnatrénngayénlydfi,c h u n g t f i i da

nghienciiukéthppp i p e r r a q u i n voiartesunatva• motthuockh:icdetimkiémcongthirccotaedungtottre‘nkysinhtriingsotrétvacodfibénviiiigcao.Chiingtfiidakéthopcacdangthuoc:

STchiingkhangchloroquin.

Chfingtfiidilngladuocvachatddnchocacc0ngthilcthuocnhirb-c y Chfingtfiidilngladuocvachatddnchocacc0ngthilcthuocnhirb-c l o d e x t r i n (hoaChfingtfiidilngladuocvachatddnchocacc0ngthilcthuocnhirb-ctween80),polyvinylpyrrolidon,bottalChfingtfiidilngladuocvachatddnchocacc0ngthilcthuocnhirb-c,magnesistearat,lactose+ t i n h b o t m i + m i c r o c r y s t a l l i n e c e l l u l o s e K e t q aékiémt

r a c h d t l irongthufictheoDuocdiénVietNamIIIladattiéuch0anvecactie‘uchi:dot anra,dinhtinh

vadinhlupnghoatch4tchinh.Cacliidunenayde‘udekie"m,rétrénvardtthongdungdirncsirdungtaiVie‘tNam

Dinhtinhbangsackjl‹ipm o n g chothaycachoatchatchinhlaartesunatvapiperaquindéuchosackydonhvchatchu6n,Rfcuachatthitvach6tchu6nlamongduongnhau.

Dinhluonghoatchitbangsackylongcaoapchokétquanhubang2va3.Hamluonghoatchattrongviéndinhluongduocsovéihamluongdpvie‘nlakhfingsaikhaccfiynghiathongké(P>0,05)

o p c h o tuyénytéccsositdung

Trongnghiénciiunayartekindiéutrib(nhnhausotrétnhiémk y sinhtriingtyIe‘khfiibenhla1009o(N=137).Thuoccohieuluctrongdiéutrtdoiv‹:iicfcloaik

ysinhtriingP.falcif›arum,P.rivexvanhic:inphoihop.Ketq u é nayphiihopvéiitaen ghi

én ciiuciiaTranTinhHiencfingbotyléchiiakhfiila95-1009o[2]

Lind4uVi(nSitrét-KST-CTTOnghiénciiuringdungthuoca r t e k i n diettrichobe‘nhnhansotrétchu abiénchtmgdoP.falciparumtaithucdiaVi(tNamliéudoivéiinguéi1éin8viénnongtrong3ngay,chothaythooccohi(uqué,anioanthun tienchoviecsirdungdiéutrib(nhnhfinsotréttaituyen ccso,dacbiétchoviingsotrétnang,viings6uviingxa [2]

Kc:tquanghiénemuciiachiingtfiitrén/nvi/

io:Phantichsoli(uIC50ciiaartesunatvapiperaquintrénchiingnhayvakhangchloroquinkhacnhaukhfingcfiynghiathongkc:P>0,05

Vénghién emuinvite:Lochufituongartesunatchiccit:icdungiiccheKSTphéttriencrtuand6udiéutri.Sau

khike‘tthiic7ngayu0ngthuoc,matdoKSTtiéptuctangcaovachuotchét100Qotinhdenngay28

-LochuotuongpiperaquincfitaedungsachKSTtrongtuandimdieutri.KSTxuathientrolaititngay10den28,nhungmatdfiKSTtangchain.Tinhdénngay28cfi809•sochuott:iiphatlaiKST,chufitthucnghie‘mconsong959o

-Lochuotnongman

arieraquin1,cotacdungsachKSTsau3ngaydiéuIn.KSTxutlthiéntrcrlaitirngay14,nhimginitdfiKSTtrongmauthap.Tinhdinngay28cci659csochufittaiphfitlaiKSTnhimgchufit thucnghic:incfinsong1009o

nghic:inconsong1009« Ke"tquénaygringiongnhuketq0anghiénemuciiaaitekin[2]

-Lochufituongmauarteraquin3,cfitacdungsachKSTsau3ngaydiéutri.Tinhdenngay28caclochuotthiinghiemkhfiib6nh1009o.Kétquanaytuongduongv ciin

g h i é n ciiucuaPGS.TS.DoanHanhNhanv6ilieu227,2mg/

kgthetrong[2]

Diéutriartesunatdonthuanchufitchit1009osaul4ngaydiéutri

Dieutripiperaquindonthudndénngay28vanconkysinhtriing

1 Baochéthuoc:

Dabaochéduoc4dangthuocartesunatkéthppv6ipiperaquindattie‘uchuanthuocvién theoDuocdiénVietNamIII

2.T:i cdungtréniriritrovainrivo.

- Thuocarteraquin1,2,3va4cotacdungtic chéKSTSRtrénchiing

nhaychloroquintothon1,5-2tansov6ichiingkhang

TacdungticchéKSTciiac:icthuocphoihpptothonsovoidiingdonthuan,dacbie‘Ivérichiingnhychloroquin

)3.12 7-130.

5 Artemisininkineticsanddynamicsduringoralandrectaltreatmento funcomplicatedm a l a r i a AshtonM,SyND,GordiT,HaiTN,NieuNT,H

uongNVandHuongDX.Clinicalpharmacology&lherapetics.(1998

).Vol63,No4

7.ChenQ,DengJ,WuD(1979)Studyonabsorption,distributionand exci‘etionof" C-piperacjiiinep h o s p h a t e a n d "C-f›if›eraquine

inmice.Ph a r ma c e u t I n d u s t r y 8 : 1 9 - 2 3

8 GiaoPT,deVriesPJ,HungLQ,BinhTQ,NamNV,KagerPA(2004)CV8,ane wcombinationofdihydroartemisinin,piperaquine,trimetoprimandprimaquine,compare dwithatovaquone-proguanil

Dihydroartemismin -piperaquinea8ainstm u l t i d r u g - r e s t s tant

plasmodiumfalciparummalariainVietnam.‘randomizedclinicaltrial.

Lancet 363:18-22

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