Y Hpc TP. Hd Chi Minh * T | p 20 * Sd 6 * 2016 Nghien cmi Y hpc
NGHIEN CUtJ T H U C NGHIEM TAC DUNG HA ACID URIC MAU CUA CAC CAO CHIET Tt/ L A XA KE
Nguyen Hodng Minh*, Nguyht HodngAn*, Nguyen Thi Thu Huong*
TOMTAT
Dqt van de vd m^c tiiu nghien ciiu: Theo kinh nghiim dia Y hgc co' truyin Viit Nam, Id Xa ki (Artoairpus alHlis (Park.) Fosb.) diegc sie dung Hong cdc bdi thud'c dmi tri benh thong phong. LdXaki chiea rdiiiu steroid, terpenoid, saponin, flavonoid, alkaloid'^^vd dddugcchung minh cd hoqt tinh uc che enzym xanthine oxidase (enzyme tham gia qud trinh tao thdnh add uric) in viHo^^l Do dd, di tdi tim hdnh nghiin cieu tdc dung cua cdc cao chiei tieldXahx Hin thuc nghiem tang add uric mdu.
Phuong phdp nghien citu: Chudt nhdt trang dugc gdy tdng add uric mdu bang tiem phuc mqc kali oxonat (lieu 300 mg/kg). Tii'n hdnh dinh lugng acid uric mdu sau 1 ldn udng (diiu trj) vd sau 5 lan uong (du phdng) cua cdc cao chiii tie Id Xa ke(cao chiei con 45% b Heu 0,38-0,76 g/kg hay cao chiei nude a liiu 0,5-1,0 g/kg). Allopurinol, thud'c hq add uric mdu theo ca che iec che enzym xanthine oxidase, dugc sir dung ldm thuoc ddi chieu.
Kei qud: Cao chiii wn 45% hay cao chiii nude tieldXake deu co tdc dung ha add uric mdu trong thuc nghiim gay tdng add uric mdu bang kali oxonat a cd phdc do dmi Hi vd du phdng, tuang tu nhu tdc dung dia allopurinol (10 mg/kg).
Ket ludn: Cdc cao chia tieldXake deu co tdc dung hq add uric mdu Hin md hinh gdy tang add uric mdu thuc nghiim. Miec do gidm add uric mdu cua cao chiei cdn 45% Hong khodng 8,3-17,5% vd cua cao chiO. nude Hong khodng 19,4-27,5%.
Tie khoa: Ld Xa fce, add uric mdu, hdi oxonat, gout ABSTRACT
EXPERIMENTAL STUDY ON THE ANTI-HYPERURICEMIC EFFECTS OF THE EXTRACTS FROM ARTOCARPUS ALTJUS LEAVES
Nguyen Hoang Minh, Nguyen Hoang An, Nguyen Thi Thu Huong
* Y Hoc TP. Ho Chi Minh * Vol. 20 - No 6 - 2016:145 -150 Aims of study: Based on the ethnic use erf Vietnamese Haditional medidne, Artocarpus alHlis leaves have bem used for Heatmmt of gout Artocarpus alHlis leaves contain steroids, terpenoids, saponins, flavonoids, alkaloids, andthe in vitro inhibitory acHvity on xanthine oxidase (enzyme involved in uric add producHon) was reporte"^K Ther^ore, the aim of this study is to evaluate the anH-hyperuricemic effed of the exHacts fr^om Artocarpus alHhs leaves in mouse model of hyperuricemia.
Methods: The mouse model erf hyperuricemia was induced by intraperitoneal injecHon of potassium oxonate (300 mg/kg).The measuremmt of the plasma uric add was performed after single dose (Heatmmt protocol) or repeated doses (preHeatmmi protocol) (rf Artocarpus altilis leaves extracts (45% ethanol extract at the doses of 0.38-0.76 g/kg and theaqueous extract at the doses cf 0.5-1.0 g/kg). Allopurinol (10 mg/kg), a xanthine oxidase inhibitor, was used as r^ermce drug.
Results: The resultsshowed that dther single dose or repeated doses of the 45% ethanol exHad and
* Trung Tam Sam va Du<;jc lieu TP. Hb Chi Minh-Vien Dugc lieu
Tdc gid lien lac: PGS.TS. Nguyen Thj Thu Huong DT: 38274377 Email: [email protected]
NgJiien cuu Y hpc Y Hpc TP. Hb Chi Minh * Tap 20 * So 6 * 2016
theaqueous exHad from Artocarpus altilis leaves diminished plasma uric add in kali oxonat-mduced hyperuricemic model The effect of Artocarpus altilis leaves was the same as allopurinol.
Conclusion: The exHacts from Artocarpus altilis leaves exerted the anH-hyperuricemic effed on mouse model of hyperuricemia. The decrease levels of plasma unc add readied 8.3-17.5% for the 45% ethanol exHact and 19.4-27.5% for theaqueous extract
Keywords. Artocarpus alHlis leaves, plasma uric add, potassium oxonate, gout.
DAT VAN DE thang 11 d&i tiiang 12 nam 2014. La su dung la nhimg la gia, sau khi thu ve duoc xii ly sach bui Tang add uric mau keo dai la nguyen nhan ^ j , ^ pj^^ y , - ^.^ ^^ ^ ^ j ^ ^ ^ ^ ^^ ^ j , dan d m benh goul. Theo to ch,ic NHANES ^ a ke duoc so bo tieu chuan hoa va duoc lim (National Health and Nutrition Examination
Survey) cua My thong ke vao 2007-2008 ty le tang add uric mauo nguoi trucmg thanh la 8,3 trieu nguoi''"*. Tuy nhien viec dieu tri benh gout bang tan duoc trong thdi gian dai gay nhieu tac dung phu khong mong muon, dac biet chi phi dieu tricao. Vi the viec nghien ciiu dieu tri benh gout bang dugc lieu thien nhien thay the cho cac duoc thuoc tong hgrp ngay cang dugc quan tam bcri CO tmh uu the la it tac dving phu, chi phi dieu tri thap.
Theo luong y Nguyen Cong Diic {Khoa Y hgc CO truyen, DH Y Dugc, TP.HCM), la Xa ke (Artocarpus alHlis, thugc hg dau tam Moraceae) phoi hgp voi mgt so vi thuoc khac se tri dugc mgt so benh nhu soi than, cao huyet ap, benh thoai hoa khop, benh gout, dai thao dutmg, viem gan vang da, phii,... La Xa ke da dugc chiing minh co boat tinh tic che enzym xanthine oxidase {enzym tham gia qua trinh tao thanh add uric) in pifro"', Nhunghien nay chua co nghien ciiu thuc nghiem nao chiing minh tac dung dugc Iy ciia la Xa ke [Artocarpus alHlis) trong dieu tri benh gout. Do do, muc tieu d& tai la "Nghien cuu tac dung ciia cao diiet la Xa ke tren chugt nhat trang bi gay tang add uric bang kali oxonat", gop phan tim ra nguon dugc lieu moi trong ho trg dieu tri va giam chi phi cho viec dieu tri benh gout.
D6lTlJ<]NG-PHU"aNGPIIAPNGEnENaJtJ Doi tuong nghien cuu
La Xa ke dugc thu thap tai huyen Mo Cay Bac, tinh Ben Tre trong khoang tfioi gian ttr
mau tai Trung tam Sam va Dugc lieu TP. Ho Qii Minh. Bgt la Xa ke dugc chiet ngam kiet vcri cQn 45% (ty le 1:20) va dugc co giam ap cho ra cao chiet con 45% hoac dugc chiet sac ham 3 lan voi nuoc cat (ty le 1:25) va dugc co each thiiy cho ra cao chiet nuoc.
Cao chiet con 45% co hieu suat chiet la 15,2%
(da qui ve cao kho tuy^t doi); cao chiet nuoc co hieu suat chiet la 19,9% (da qui ve cao kho tuyet doi). Viec dinh tihh flavonoid bang phan iing mau va sac ky ban mong cho thay cho thay bpt dugc lieu, cao chiet con 45% va cao chiet nuoc deu chiia flavonoid. Ham lugng polyphenol tong tuong duong voi acid gallic (GAE) ciia cao chiet con 45% va cao chiet nuoc Ian lugt la 4,77 mg GAE/100 mg cao va 4,6 mg GAE/100 mg cao (da tru do am).
Dong v^t nghien cihi
Chugt nhat trang, chung Smiss albino, trudng thanh 5-6 hian tuoi, dugc cung cap boi Vien Vac xin va Sinh p h & i Y te - TP. Nha Trang. Chuot dugc nuoi bang thuc pham vien, nuoc uong d'Sy dli va dugc de on dinh it nhat mgt tuan truoc khi thu nghiem. The tich cho uong hay tiem phuc mac (i.p.) la 10 ml/kg the trgng chugt Thuoc thu'nghiem
Kali oxonat (Sigma-Aldrich Co., Ltd, USA), Allopurinol (vien nen chiia allopurinol lieu 300 mg cong ty co phan Dugc pham DOMESCO, Viet Nam).
146
Y Hpc TP. Hb Chi Minh * Tap 20 * So 6 * 2016 Nghien cuu Y hpc
Phuong phap nghien cuu Khdo sdt doc ttnh cap duang uong'^
Chugt nhat chia Ihanh cac 16 tuong tu, nhung chugt 6 cung mgt 16 se nhan cung mgt lieu chat khao sat Su danh gia dua vao phim ling toan iing hay bat iing (s&ig hay diet) n h | n thay is moi chugt trong nhom sau 72 gja. Chugt dugc tiep tuc theo doi sau 14 ngay uong d^ ghi n l ^ nhiing trieu chiing bat thuang (neu co).
Co 3 truong hgp co the xay ra:
Trudng hap 1: Sau khi cho chugt uong mau tfiii, so chugt trong 16 thii nghiem van bao toan, xac dinh lieu cao nhat co the bom qua kim ma khong lam chet chugt Lieu nay dugc ky hieu la Dmax va lieu tuong doi an toan Ds dimg trong cac thuc nghiem dugc ly co the bang 1/5 Dmax hoac Ion hon 1/5 Dm».
Truang hgp 2: Sau khi cho chugt uong mau thii, ti le tu vong la 100% thi day la lieu chet tuyet doi -LDioo. Tinh toan va gay 16 thii nghiem de tiep tuc xac dinh dugc Ueu khong lam chet con vat nao-LDo. Tit do, suy ra lieu LDso dugc tinh theo c6ng ihiic Karber-Behrens.
Truang hop 3: Sau khi cho uong mau thii, phan suat tii vong thap ban 100%, kh6ng xac dinh dugc lieu gay diet tuyet doi. Doi voi truong hgp nay, khong thS' suy ra Heu LDso, nhung co the xac dinh dugc lieu toi da khong gay chet chugt ggi la lieu duoi lieu chet-LDo. Lieu tuong dcfi an toan Ds dtmg cho thuc nghiem dugc ly co gia tri bang 1/5 hoac 1/10 LDo.
JOiflo sdt tdc dyng cua cdc cao chiei tuldXake tren mo hinh gdy tdng acid uric mdu^
Phdc do diiu Hi (Lieu dem)
Chudt nhat trang dugc chia 16 ngau nhi&i, nhu sau:
Nhom binh thitong: Tiem phiic mac NaCl 0,9 %
L6 chiing sinh ly: Uong nuoc cat; 16 thu uong cao chigt con 45% ( h ^ 0,38-0,76 g/kg) hay cao chiet nuoc (lieu 0,5-1,0 g/kg) tu la Xa ke va 16 doi
Nhom benh ly: Tiem phiic mac kcdi oxonat (lieu 300 mg/kg). Ti§h h&nh chia cac 16 chugt va thuc hien phac do nghien ciiu tuong tu nhu nhom binh thuong.
Sau 1 gio tiem phiic m6 kali oxonat (lieu 300 n^g/l*S)/ cho diugt uong cao chiet con ^% (lieu 0,38- 0,76 g/kg) hay cao chiet nuoc (h'eu 0,50-1,00 g/kg) tu la Xa k& mgt lieu duy nhat. Tigh hanh lay mau tinh mach duoi chu6t sau 2 gio tiem kali oxonat de dinh lugng add uric trong huygt tuong bang bg Kit Add Uric Liquidcolor ciia Human Diagnostic Ltd. Co (Germany).
Phdc do die phdng (Liiu lap lai)
Lo chiing sinh ly: Uong niroc cat lien tuc 4 ngay; ngay 5 tiem phiic mo N a Q 0,9%.
Lo chiing benh ly: Uohg nuoc cat Uen tuc 4 ngay; ngay 5 tiem phiic mo kali oxonat (Ueu 300 mgflcg).
Lo cao chiet con 45% (Ui&u 0,38-0,76 g/kg) hay cao chiet nuoc (lieu 0,5-1,0 g/kg) tii la Xa ke cho uong mgt Ian vao buoi sang trong 4 ngay Uen tuc; ngay 5 tiem phiic m6 kali oxonat {Ueu 300 mg/kg).
Lo doi chieu: Uong nude cat U&i tuc 4 ngay;
ngay 5 tiem phiic m6 kaU oxonat (Ueu 300 mg/kg) va 1 gio sau cho uong allopurinol {lieu 10 mg/kg).
Mgt gio sau khi tiem kali oxonat cho chugt chiing benh ly u6ng nuoc cat cac 16 Ihii cho uong cao chiet con 45% (Ugu 0,38-0,76 g/kg) hay cao c h i ^ nuoc (Ueu 0,50-1,00 g/kg) tii la Xa ke, 16 doi chieii cho uong allopurinol (lieu 10 mg/kg).
Tieh hanh lay mau du6i chugt sau 1 gio cho uong thuoc de dinh lugng ham lugng add uric trong huyet tuong.
Danh gia k^t qua
Cac so Ueu dugc bieu thi bang trj so trung binh: M ± SEM (Standard error of the mean - sai so chuan ciia gja tri trung binh) va xii ly tiiong ke dua vao phep kiem Qne-Way ANOVA va Student-Newman-Keuls test (phan mem SigmaStat 3.5). Ket qua thii nghiem dat y nghia
Nghien cuu Y hpc Y Hpc TP. Hb Chi M i n h * T^p 20 * Sb 6 * 2016
tiiong ke voi do tin cay 95% khi p < 0,05 so voi 16 chiing.
KET QUA-BAN LUAN Ket qua dpc tinh cap duong ubng
Ghi nhan sau 72 gio thii nghiem va sau 14 ngay ubng cao chiet la Xa ke thi so lugng chu6t thii nghiem co phan suat tii vong la 0% va kh6ng the xac djnh dugc LDso. Quan sat hanh vi va th^
trang tong quat cho thay khong co trieu chiing bat thuong nao tren chugt tiiii nghiem. Dua vao Ueu Ion nhat da thii, nhom nghien ciiu xac dinh
Dma.( (Ueu cao nhat cua mau thii co the bom qua kim ma khong lam chet chugt) ciia cao chiet cbn 45% la 28,0 g/kg va D™x cua cao chiet nuoc la 22,41 g/kg (da qui ve cao kh6 tuyet doi):
Tli do, de tai da lua chgn 2 Ueu fhii cho m6i cao chiet tuong iing voi 2,5 va 5 g dugc Ueu va da qui ve cao kho tuyet dbi nhu sau:
-Lieu cao chief con 45% la 0,38 g/kg va 0,76 g/kg the trgng chugt
-Lieu cao chief nuoc la 0,5 g/kg va 1,0 g/kg ihe trgng chugt
Ket qua khao sat tac dung cac cao chi^t tu: la >
Bdng 1. Hdm lugng add uric mdu ciia chugt nhat tran^
Nhdm
Binh thiFOTig
Benh ly
t o (n = 10) Chung sinh ly Cao c6n 45 % lilu 0,38 g/kg Cao con 45 % lilu 0,76 g/kg Cao nu'd'c lilu 0,5 g/l(g Cao ni/6^ lilu 1,0 g/kg Allopurinol lieu 10 mg/kg Chiang t ) ^ h ly Cao con 45% lilu 0,38 g/kg Cao con 45% lieu 0,76 g/kg Cao nuftnc lilu 0,5 g/kg Cao nu^^'dieu 1,0 g/kg Allopuiinol lilu 10 mg/kg
[a ke tren m6 hinh g^y tang acid uric mau d cdc Id thie nghiim
Ham luong acid uric (mg/dl) Phac dd dieu tn
3,09 ±0,09 2,46 ± 0,11 2,43 ±0,22 2,34 ±0,17 2,25 ±0,12 2,13 ±0,09 3.81 ± 0 , 1 ^ 3,02 ±0,33* (10,65%)
3,10 ±0,25-(8,28%) 2,61 ±0,21-(22,78%) 2,45*0,13* (27,51%) 2,52 ±0,12* (25,44%)
Phac do diF ph6ng 2.86 ±0,15 2,36 ± 0,20 2,60 ± 0,24 2,30 ±0,15 2,57 ±0,19 2.70 ±0,17 4,64 ±0,18*
4,00 ±0,12* (13,79%) 3,83 ±0,23'(17,45%) 3,56 ±0.15* (23,27%) 3,74 ±0.16* (19,39%) 2.86 ±0,13-(38,36%) '" p < 0,05 d<f.t y nghia tlwng ke so v&i 16 chimg sinh ly
''>p< 0,05 dat y nghia thShg ki so vdi Id dumg binh ly (...) Ph&n trdm hdm liegng acid uric gidm so v&i chiing benh ly
Ket qua Bang 1 cho fhay cac 16 uong cao chief tli la Xa ke kh6ng anh huong deh ham lugng add uric mau tren chugt binh thuong 6 ca phac do dieu fri va dv phong.
Chugt 6 16 chiing benh ly dugc tiem kaU oxonat lieu 300 mg/kg co ham lugng add uric mau fang (10,49- 38,36%) daf y nghia tiiong ke khi so sanh voi 16 chiing sinh ly. CJ ca 2 phac do dieu tri va du phong, 16 doi chieu cho uong allopurinol Ueu 10 mg/kg deu co fac dimg lam giam ham lugng add uric mau (25,44-38,36%) daf y nghia fhong ke so voi 16 chiing boih ly, phuc hoi ve miic binh fhuong.
d phac do dieu tri cac 16 cho uong cao chiet con 45% (lieu 0^8-0,76 g/kg) hay cao chiet niroc (Ueu 0,5-1,0 g/kg) CO miic do giam add uric mau dat y nghia tiiong ke so voi 16 chung benh ly lan lugt la 10,65%; 8,28%; 22,78% va 27,51%; ph^c hoi ve miic binh thuong. Trong do, cao chiet nuoc (Ueu 0,5-1,0 g/kg) co tac dimg tuong tu nhu fhuoc doi chieii allopurinol (giam 25,44%).
d phac do du phong cac 16 cho uong cao con 45% (Heu 0,38-0,76 g/kg) hay cao chiet nuoc (li&i 0,5-1,0 g/kg) CO miic do giam add uric huyet dat y nghia fhrang ke so voi 16 diiing benh ly lan lugt la 13,79%; 17,45%; 23,27% va 19,39%.
148
Y Hpc TP. Hb Chi M i n h * T | p 20 * So 6 * 2016 Nghien cmi Y hpc
BAN LUAN
O dgng vat gam nham, sy hien dien cila enzym uricase lam cho nong d6 acid uric trong huyet tucmg tiiap. Do do, de lam fang add uric o dgng vat g|im nham, hoat dgng ciia enzym uricase phiii dugc giam ho^c loai bo bang each dimg cac chat lic che enzym uricase, nhu mu6i ciia add oxonic ho^c cac chat tuong tu xanthine va hj'poxanfhine. KaU oxonat thuong dugc sii dung trong mo Wnh gay fang add uric cap tiieo CO die lie che canh tranh enz3Tn uricase voi urat do cau tnic phan fii ciia kaU oxonat tuong dong vdi cau tnic phan tii ciia urat lam cho qua trinh diuyai hoa fir add uric sang aUanfoin (co do hoa tan gap 10 Ian so voi acid uric nen de dang dugc t l ^ dao thai) bi <finh tre dan d&i tinh frEing fang add uric mau'*'. Add uric la san phain cuoi cung ciia qua trinh diuy&i hoa purin. Trong qua trinh thoai hoa purin, purin trong co fhe dugc chuyen hoa qua cac dang tnmg gian de trd thanh hypoxanthine. O giai doan cuoi ciia qua trinh fhoai hoa purin, dudi tac dung ciia enzym xanthine oxidase, h)'poxanfhine dugc bi&i doi thanh xanthine va cuoi cimg thanh add uric.
Trong la Xa ke co boat chat chinh la cac sakenin A-H, 5 geranyl dihydrochalcon va 4 geranyl flavonoid'*). Nam 2014, nhom nghien cihi Dai hgc Bach Khoa Ha Ngi cung da phan lap dugc 6 hgp chat nhom flavonoid va 3 hgp chat thugc nhom terpenoid trong la Xa ke'*'.
Theo nghien ciiu a i a Masayoshi va c6ng su, mgt so chat thugc nhdm flavonoid (myricetin, kaempferol, quercetin,...) cd kha nang lic die enzym xanthine oxidase trong thu nghiem in viHo'^\ Cac flavonoid nhu quercetin, puerarin, myricetin, morin and kaempferol dugc chiing minh cd fac dung lam giam ham lugng acid uric trong gan chugt bi gay tang acid uric bang kaU oxonat fheo ca che lie che enzym xanthine oxidase'^'. Nghien o i u gan day ciia nhdm nghien ciiu Dai hgc Can Tho da chiing minh la Xa k^ cd boat tinh lic che enzym xanthine oxidase in vitro^'^K Kef qua nghien cihi a i a de
chief nude tir la Xa ke, tuong tit allopurinol deu cd fac dung lie che sir fang a d d uric mau gay boi kali oxonat. Tong hgp cac dii Ueu cd the ggi y co che fac dung ha acid uric mau ciia la Xa ke co the tuong t u nhu allopurinol, mgt fhuoc dugc chi dinh trong dieu tri gout tiieo CO che lie che enzym xanthine oxidase. Day la tien de cho cac nghien ciiu tiep fheo nhu xac dinh nhdm boat chat trong cao chief cd tac dung ha acid uric mau va khao sat co che ha acid uric huyet ciia la Xa ke.
KETLUAN
Cao chief con 45% (Heu 0,38-0,76 g/kg) hay cao chief nude (Ueu 0,50-1,00 g/kg) tir la Xa ke deu cd tac dung lie die su tang add uric mau gay bdi kaU oxonat tren chugt nhat trang. Miic dp giam acid uric mau aia cao chief con 45%
trong khoang 8,3-17,5% va ciia cao chief nude trong khoang 19,4-27,5%. Cac ket qua aia de tai se cung cap nhiing dii Ueu khoa hgc cho viec dinh hirdng iing dgng la Xa ke trong h6 trg dieu fri benh gout
TAI LIEU THAM KHAO
1 Dai Thi Xuan Trang, Huynh Ngoc True, Nguyen Trong Tu3n (2014). Khao sat kha nang u c d i e enzym xanthine oxidase tir U Xa k@ Artocarpus altilis (Park.) Fosb. Ttfp chi Klioa hoc Trufmg DaiOxCSn Tha, tr.94-101.
2. D 6 Tnmg D a m (19%). Phumg phap xac dinh dgc Hnh cap cua thuoc. Nha xuift ban Y hgc. Ha Npi, tr,7-24.
3 IJo H Moriyama A, Matsumolo Y, Takaki N and Fukumoto M (1985) Inhibition of Xanthme Oxidase by Fiavonoids.
Agricultural and Biological Chemistry, 49(7);2173-2176.
4. Mo S F, Zhou F, L u Y . Z , H u Q H , Zhang DM, Kong LD (2007).
Hypouncenruc acUon of Selected Flavonoids in Mice' Structure - Activity Relationships. Biol. Pharm. Bull, 30(8); 1551-1556, 5 Newburget J, Combs AB, Hsu TF (1978). Diumal Variation m
Serum U n c A a d of Rats Fed Potassium Oxonate Drug and Chemical Toxicology, l(3):231-233
6 Nguyen MT, Nguyen NT, Nguyen KD, Dau HT, Nguyen H X Dang PH, Le XM, Nguyen Phan TH, Tran AH, Nguyen BD, Ueda JV, Awale S (2014). Geranyl dihydrochalcones feom Artocarpus altilis and their anhausteric activity. Planta l/ied., 80(2-3):193-200.
7 Pradhan C, Mohanty M., Rout A (2013). Assessment of the antibacterial potential of breadfiTiil leaf extracts against pathogenic bacteria. Intemational Joumai of Pharmacy, 3(2):374- 379.
8 Wang Y, Xu K, Lm L, Pan Y, Zheng X (2007). Geranyl flavonoids from the leaves al Artocarpus altilis Phylodiemislry, 68(9):1300-1306
Nghien ciiu Y hpc Y Hpc TP. Hb Chi Minh * Tap 20 * So 6 • 2016
9 Watabe S, Kimuia K, Fukui T (2006). Effect of Human Placenta Extract on Potassium Oxonate- iruluced Elevation of
Blood Unc Arid Concmtration. ;o«rr.«I 0/He.» SdoiB Ngoy llMji Ml t t o 3O/0S/20K 52(6).73S.742. Ngoy pWu fcim i i M t i ! « M i i»!0. 20/0912016 10, Young HE, Zhu Y, Choi ^(2011). The Epidemiology of Uric
Acid and Fmctose.»»«N,!pM,31(5).411419 Ngi) hat bao dmJC Mng 25/11/2016
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