Efficacy and Safety of Tribendimidine Against Clonorchis sinensis
M A J O R A R T I C L E
Ef ?cacy and Safety of Tribendimidine Against Clonorchis sinensis
Men-Bao Qian,1,a Peiling Yap,2,4,a Yi-Chao Yang,5Hai Liang,6Zhi-Hua Jiang,5Wei Li,6Yu-Guang Tan,5Hui Zhou,3,4
Jürg Utzinger,2,4Xiao-Nong Zhou,1and Jennifer Keiser 3,4
1National Institute of Parasitic Diseases,Chinese Center for Disease Control and Prevention,WHO Collaborative Center for Malaria,Schistosomiasis
and Filariasis,Key Laboratory of Parasite and Vector Biology,Ministry of Health,Shanghai,People ’s Republic of China;2Department of Epidemiology
and Public Health,3Department of Medical Parasitology and Infection Biology,Swiss Tropical and Public Health Institute,4University of Basel,Basel,
Switzerland;5Guangxi Center for Disease Control and Prevention,Nanning,and 6Binyang Center for Disease Control and Prevention,Binyang,People ’s
Republic of China
Background .Clonorchiasis is of considerable public health importance,particularly in the People ’s Republic
of China (PR China),where most of the 15million individuals infected with Clonorchis sinensis are currently
concentrated.Praziquantel is the drug of choice,but tribendimidine might be an alternative.
Methods .We performed a randomized open-label trial in Guangxi,PR China,to assess the ef ?cacy and safety
of 400mg tribendimidine once,400mg tribendimidine daily for 3days,and 75mg/kg praziquantel in 1day
divided in 3doses against parasitological-con ?rmed C.sinensis infections.Cure and egg reduction rates were
determined 3weeks posttreatment using available case analysis.Clinical symptoms were documented at baseline,
and adverse events were recorded and graded 3and 24hours after each dose.
Results .A total of 74patients were included in the ?nal analysis.Single-dose tribendimidine achieved a cure
rate of 44%,whereas cure rates of 58%and 56%were obtained for tribendimidine administered for 3days and
praziquantel,respectively.High egg reduction rates (97.6%–98.8%)were observed for all treatment regimens.
Single-dose tribendimidine was the best-tolerated treatment scheme.Patients treated with praziquantel experi-
enced signi ?cantly more adverse events than did tribendimidine recipients (P <.05).
Conclusions .Tribendimidine has an ef ?cacy comparable to praziquantel in the treatment of C.sinensis infec-
tion and resulted in fewer adverse events compared to https://www.wendangku.net/doc/02384308.html,rger clinical trials are warranted among
C.sinensis –infected patients to determine the potential of tribendimidine against clonorchiasis and other helmin-
thiases.
Clinical trials registration https://www.wendangku.net/doc/02384308.html,,ISRCTN80829842.
Keywords .Tribendimidine;praziquantel;Clonorchis sinensis ;clonorchiasis;People ’s Republic of China.
INTRODUCTION An estimated 15million people,most of them living in the People ’s Republic of China (PR China),are infected with the liver ?uke Clonorchis sinensis ,result-
ing in a global burden of at least 275370disability-
adjusted life-years (DALYs)[1].The consumption of
raw freshwater ?sh is a popular tradition not just in
PR China but also in Vietnam and South Korea.Infec-
tions occur when raw freshwater ?sh,harboring infec-
tive metacercariae,are consumed.Pathological
changes caused by C.sinensis infection are largely
con ?ned to the bile duct,liver,and gallbladder.Indi-
viduals with heavy infections often suffer from unspe-
ci ?c symptoms,such as fever,fatigue,weakness,
nausea,or abdominal pain,but more severe conse-
quences,namely obstructive jaundice and biliary colic,
Received 6September 2012;accepted 19November 2012.a M.-B.Q.and P.Y.contributed equally to this work.Correspondence:Jennifer Keiser,PhD,Department of Medical Parasitology and Infection Biology,Swiss Tropical and Public Health Institute,PO Box,CH-4002
Basel,Switzerland (jennifer.keiser@unibas.ch).Clinical Infectious Diseases ?The Author 2012.Published by Oxford University Press on behalf of the Infectious Diseases Society of America.All rights reserved.For Permissions,please e-mail:
journals.permissions@https://www.wendangku.net/doc/02384308.html,.DOI:10.1093/cid/cis1011
Clinical Infectious Diseases Advance Access published January 3, 2013 at Fudan University on January 3, 2013
https://www.wendangku.net/doc/02384308.html,/Downloaded from
might occur[2].The most serious complication of C.sinensis infection is cancer of the bile ducts,cholangiocarcinoma[3]. Praziquantel,administered at3doses of25mg/kg each at 5-hour intervals,is the drug of choice against clonorchiasis [4].This treatment schedule is highly ef?cacious,with an egg reduction rate(ERR)of99%[5].However,transient adverse events,such as dizziness,sleepiness,headache,and diarrhea, are commonly observed after praziquantel administration[4]. Effective alternative drugs with a good safety pro?le are not available.
The Chinese anthelmintic drug tribendimidine might be a potential new drug candidate for treating infections with C.sinensis.Tribendimidine was observed to be highly effective in C.sinensis–infected rats[6]and in vitro[7].In a random-ized open-label trial in Lao People’s Democratic Republic(Lao PDR),tribendimidine administered as a single oral dose of 200mg(subjects<14years of age)or400mg(subjects aged ≥14years)to patients with parasitologically con?rmed Opis-thorchis viverrini infections,a related liver?uke,was found to be as ef?cacious as praziquantel(75mg/kg given in2doses) [8].Clinical trials with tribendimidine have therefore been suggested to determine the ef?cacy and safety of this drug in patients infected with C.sinensis[4,9].Tribendimidine is reg-istered for human use for the treatment of infections with soil-transmitted helminths in PR China.A consortium com-posed of Chinese,Swiss,and US partners are currently seeking regulatory approval for the use of tribendimidine outside PR China[10],as studies in PR China have demon-strated that the drug is safe and ef?cacious against hookworm and Ascaris lumbricoides infections[11,12].
The aim of this trial was to study and compare the ef?cacy and safety of tribendimidine,given as a single-dose or3-day regimen,the latter already tested for the treatment of Trichuris trichiura infection[13],with the standard treatment of prazi-quantel in C.sinensis–infected individuals.
PATIENTS AND METHODS
Ethics Statement
The study was approved by the ethics committees in Basel, Switzerland(EKBB;reference nos.209/09and375/11),the Liverpool School of Tropical Medicine(reference no.
12.02RS),and the National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention(reference no.2012–02).
Drugs
Tribendimidine(200mg enteric-coated tablets)was purchased from Shandong Xinhua Pharmaceutical Co,Ltd(Zibo,PR China).Praziquantel(200mg?lm-coated tablets)was the product of Nanjing Pharmaceutical Factory Co,Ltd(Nanjing,
PR China).
Study Area and Participants
The study was conducted from June to July2012in a C.sinen-
sis–endemic village(Hezhuang)located under the township of Gantang,Binyang county,Guangxi Zhuang Autonomous Region,PR China.Most villagers belong to the Zhuang ethnic
group and are farmers.Living standards are relatively low as compared to the more developed regions of the country but
literacy rate is high,with all villagers having received at least primary-school education.
Eligible individuals were adults of both sexes,aged≥18 years.During the clinical examination by physicians,villagers
who had no major systemic,acute,or chronic illnesses,no
known or reported psychiatric or neurological disorders,or hypersensitivity to tribendimidine or praziquantel,and were
not pregnant,were invited to join the study.Individuals were excluded from trial participation if they had used any anthel-
mintic within the past month or were attending other clinical
trials during the same period.Only participants with written informed consent,who provided2stool samples at baseline,
and were willing to provide another2stool samples3weeks posttreatment were?nally included in the study.
Study Flow,Sample Size,and Randomization
Our study was a randomized,open-label trial aiming to recruit
20–25patients per treatment arm[14],similar to our earlier
study focusing on O.viverrini[8].Villagers were invited to provide a fresh morning stool sample in a container labeled
with a unique identi?er.Stool samples were transferred to the laboratory of Binyang Center for Disease Control and Preven-
tion(CDC)and examined for the presence of C.sinensis eggs. Patients with a parasitologically con?rmed C.sinensis infection
were asked to provide another stool sample over the next5days.
Written informed consent was obtained from C.sinensis–infect-
ed patients,and only consenting individuals were examined clinically,which included a physical examination and the mea-surement of height,weight,axillary temperature,blood pressure,
and pulse.Study participants were randomly allocated,using a computer-generated randomization code prepared by an inde-pendent statistician,into3treatment arms:(i)tribendimidine
400mg once,(ii)tribendimidine400mg daily for3days,and
(iii)praziquantel75mg/kg divided into3doses administered
within a day(Figure1).All patients were treated on the same
day.Three and24hours after each dosing,each patient was
asked open-ended questions for the presence and severity of adverse events.In a next step,the physicians asked for speci?c adverse events.Adverse events were graded(ie,mild,moderate, severe,and life threatening)[15],recorded in the case report forms (CRFs),and remedial measures were taken if necessary.For
at Fudan University on January 3, 2013
https://www.wendangku.net/doc/02384308.html,/
Downloaded from
each patient,the same physician performed the clinical exami-nation and collected adverse events throughout all https://www.wendangku.net/doc/02384308.html,boratory Procedure From each stool sample,triplicate Kato-Katz thick smears,
using 41.7mg templates,were prepared [16]and quantitatively examined for C.sinensis eggs under a microscope by experi-enced technicians,who were blinded to treatment allocation.The number of A.lumbricoides ,T.trichiura ,hookworm,and other helminth eggs were recorded separately.For quality control,the 3slides were independently read by different tech-nicians,and the results compared.Slides were reread if incon-sistencies were detected.Outcome Measures and Statistics Statistical analyses were performed with Stata version 10.0(Sta-taCorp,College Station,Texas).Available case analysis was em-
ployed and thus,only those patients who had primary outcome
data were used for analysis.Cure rate (CR)was de ?ned as the proportion of C.sinensis egg –positive patients at baseline,who became egg-negative 3weeks after treatment.CRs represent-ed as odds ratio (OR)between different treatment arms and calculated from logistic regressions were also determined.Fecal egg counts,as expressed as eggs per gram of stool (EPG),were
calculated by multiplying the sum of the egg counts from the 6
Kato-Katz thick smears by a factor of 4.Infection intensity of C.sinensis was categorized as light (1–999EPG),moderate
(1000–9999EPG),and heavy (≥10000EPG)according to Yu and colleagues [17].ERRs for each treatment group were deter-mined based on the geometric mean (GM)fecal egg counts before and 3weeks after treatment.The 95%con ?dence inter-vals (CIs)of ERR were calculated with bootstrap resampling.The average dose (mg/kg)of tribendimidine was also deter-mined and analyzed with a logistic regression to assess whether the dose of treatment had an in ?uence on the CR.
Other test statistics included χ2test,Fisher exact test,and anal-ysis of variance,as appropriate.
RESULTS
Adherence and Baseline Characteristics
From a recruitment pool of 96individuals assessed for eligibil-ity,20patients were excluded because they did not
participate
Figure 1.Trial ?ow diagram demonstrating patient compliance in a randomized open-label trial assessing the ef ?cacy and safety of tribendimidine against C.sinensis in Guangxi,PR China,from June to July 2012.
at Fudan University on January 3, 2013
https://www.wendangku.net/doc/02384308.html,/Downloaded from
at the clinical examination(n=18)or presented with chronic or severe illnesses(n=2).In total,76participants were ran-domized to the3treatment arms.One patient discontinued praziquantel treatment after2doses due to adverse events and 2patients were lost to follow-up,giving an overall compliance with treatment and follow-up of96%(73/76).
Stool samples of the patient who discontinued praziquantel treatment were collected at the follow-up,and hence this patient was included in the available case analysis.Demo-graphic and laboratory baseline characteristics of the74pa-tients are summarized in Table1.Fifty-seven participants (77.0%)were male and17were female.Only2women were randomized to the praziquantel treatment group.The mean age in the3treatment arms ranged from49.9to51.2years.The height ranged from156to162cm.Most of the patients (n=41)harbored a moderate C.sinensis infection(1000–9999 EPG).Fecal egg counts ranged from124to31244EPG with a GM of2816to4051EPG according to treatment arms. Overall,12,2,and1patients were concurrently infected with hookworm,T.trichiura,and A.lumbricoides,respectively. Given the small number of soil-transmitted helminth infec-tions,these were not considered further.
Ef?cacy Against C.sinensis
Single-dose tribendimidine(400mg)achieved a CR of44%, while CRs of58%and56%were obtained for400mg tribendi-midine administered for3days and praziquantel,respectively (Table2).All patients harboring a light C.sinensis infection
Table1.Demographic and Laboratory Baseline Characteristics of Clonorchis sinensis–Infected Patients in Guangxi,PR China,From June to July2012(N=74)
Treatment Group
Parameter Tribendimidine
400mg Once
(n=25)
Tribendimidine
400mg Once
Daily for3d
(n=24)
Praziquantel
75mg/kg
Divided in3
Doses(n=25)
Males/females(no.)19/615/923/2 Mean(SD)age,years51.2(8.8)49.9(10.1)50.5(10.0) Mean(SD)weight,kg61.9(10.8)58.3(7.6)60.4(12.3) Mean(SD)height,cm157(6)156(8)162(8) C.sinensis infection intensity
Overall GM fecal egg counts,EPG338728164051 Fecal egg counts(range),EPG(124–29624)(184–18772)(212–31244) No.of light infections(1–999EPG)544
No.of moderate infections(1000–9999EPG)111713
No.of heavy infections(≥10000EPG)938 Abbreviations:EPG,eggs per gram of stool;GM,geometric mean;SD,standard deviation.
Table2.Effect of Tribendimidine Single and Triple Dosages and Praziquantel in Patients Infected With Clonorchis sinensis in Guangxi,PR China,From June to July2012(N=74)
Treatment Group
Parameter Tribendimidine400mg
Once(n=25)
Tribendimidine400mg
Once Daily for3d
(n=24)
Praziquantel75mg/kg
Divided in3Doses
(n=25)
No.of patients cured(%)11(44)14(58)14(56) No.of patients cured of light infection(%)5(100)4(100)4(100) No.of patients cured of moderate infection(%)6(54)10(59)7(54) No.of patients cured of heavy infection(%)003(38) C.sinensis infection intensity
Overall GM fecal egg counts,EPG80.035.150.0 Fecal egg counts(range),EPG(0–3636)(0–1296)(0–1876) Egg reduction rate(%)(95%CI)97.6(93.0–98.6)98.8(96.9–99.6)98.8(97.0–99.6)
Abbreviations:CI,confidence interval;EPG,eggs per gram of stool;GM,geometric mean. at Fudan University on January 3, 2013 https://www.wendangku.net/doc/02384308.html,/ Downloaded from
(1–999EPG)were cured regardless of the treatment adminis-tered.In all 3treatment arms,CRs of 54%–59%were observed against moderate (1000–9999EPG)infections.Praziquantel was able to cure 3of 8patients with a heavy C.sinensis infec-tion (≥10000EPG),while tribendimidine failed to cure such heavy infections regardless of dose.High ERRs (97.6%–98.8%)were observed for all treatments.Tribendimidine administered once daily for 3days had 10%higher odds of curing a C.si-nensis infection than praziquantel.On the other hand,single-dose tribendimidine had 38%and 44%lower odds of curing C.sinensis infection than praziquantel and the 3-day tribendi-midine regimen,respectively.However,no signi ?cant differ-ences were observed for the treatment outcomes in the praziquantel treatment arm vs tribendimidine single-dose or given for 3days,and between both tribendimidine regimens.The actual dose of tribendimidine administered ranged from 4.9to 9.1mg/kg for the single-dose and 16.9–29.6mg/kg for the 3-day regimen.No signi ?cant association between CRs and dose was observed.Adverse Events No life-threatening adverse events were observed following
treatment.One patient treated with praziquantel experienced
severe vomiting and discontinued treatment (the patient did
not take the third dose).Most adverse event episodes were mild (n =121),with 9moderate or heavy adverse events either at 3hours (n =2)or 24hours (n =7).Table 3summarizes the number of patients experiencing adverse events,strati ?ed by treatment arm at the different examination time points,while Supplementary Table 1presents the number of adverse events reported at different time points after treatment.
Single-dose tribendimidine was the best-tolerated treatment scheme.Eleven patients treated with a single dose of tribendi-midine complained of adverse events,with dizziness/faintness the predominant adverse event reported by 5patients.However,this symptom was already stated by 3patients before treatment.Adverse events were reported among 16patients
who were given tribendimidine daily for 3days,dizziness/faintness being the most commonly reported symptom.Patients treated with praziquantel experienced signi ?cantly more adverse events than patients given tribendimidine (P <.05).Dizziness/faintness was signi ?cantly more often re-ported by patients treated with praziquantel than in patients treated with tribendimidine (P <.05).Praziquantel-treated pa-tients also experienced abdominal pain,vomiting,and nausea.Adverse events labeled as “others ”that were commonly re-
ported by praziquantel-treated and tribendimidine-treated pa-
tients were bloatedness and dry mouth,respectively.DISCUSSION
Clonorchiasis is a public health problem in PR China,yet only a single treatment —praziquantel —is currently available [18].
Table 3.Number of Patients With Adverse Events Among the 3Treatment Arms,as Assessed at Different Time Points,in a Randomized Open-Label Trial Assessing the Ef ?cacy and Safety of Tribendimidine Against Clonorchis sinensis in Guangxi,PR China,From June to July 2012a
Treatment Group
Time Point Tribendimidine 400mg Once Tribendimidine
400mg Once Daily for 3d Praziquantel 75mg/kg
Divided in 3Doses Related symptoms before treatment 3(12)1(4)4(16)No.of patients with adverse events (%)
3hours after first treatment 5(20)b 9(38)12(48)24hours after first treatment 7(28)10(42)NA 3hours after second treatment NA 2(8)c 16(64)24hours after second treatment NA 4(16)NA 3hours after third treatment NA 3(12.5)NA d 24hours after third treatment NA 1(4)c 17(71)Overall number of patients experiencing adverse events at any time point
11(44)b 16(67)b 23(92)Abbreviation:NA,not applicable.
a P values were calculated using χ2or Fisher exact test,as appropriate.
b Significantly different from praziquantel group (P <.05).
c Significantly different from praziquantel group (P <.001).
d Th
e third treatment o
f praziquantel was administered in the evenin
g and it was logistically impossible for the patients to report back 3hours after treatment.Thus,adverse events were only recorded 24hours after treatment.
at Fudan University on January 3, 2013
https://www.wendangku.net/doc/02384308.html,/Downloaded from
Repurposing existing medicines cuts drug development costs and might provide alternative treatments in a timely manner [19,20].We studied tribendimidine,a Chinese broad-spectrum anthelmintic drug marketed for the treatment of soil-transmitted helminthiases,against infections with the liver?uke C.sinensis in a randomized open-label trial.
We found that single-dose tribendimidine(400mg) achieved a high ERR and moderate CR in patients infected with C.sinensis,an ef?cacy pro?le comparable to standard triple-dose praziquantel.Moreover,tribendimidine was better tolerated than triple-dose praziquantel.Indeed,and in line with?ndings from previous studies[21,22],praziquantel-treated patients commonly reported dizziness,abdominal pain,nausea,and vomiting.It is interesting to note that dizzi-ness has also been reported previously in praziquantel-treated patients infected with O.viverrini[8]and Hymenolepis nana [23].To our knowledge,it is not known why praziquantel causes dizziness.More investigation into this issue is warrant-ed,as praziquantel is routinely used in preventive chemother-apy,and dizziness as a common adverse event is not desirable. Our results con?rm recent results obtained with single-dose tribendimidine in patients infected with O.viverrini in Lao PDR.Indeed,in that proof-of-concept study,19of27O.viver-rini–infected-patients were cured(70%)and an ERR of over 99%was achieved.In line with our?ndings,tribendimidine was better tolerated than praziquantel[8].
Though our study was not designed as an equivalence trial, our?ndings hint that single-dose tribendimidine is equally ef-?cacious as3doses of the drug.Note that in preventive che-motherapy programs,which aim to prevent morbidity due to helminthiases using the available armamentarium of anthel-mintics,drugs are administered as single doses to entire at risk-populations without prior diagnosis,often in remote rural areas where access to public services is a formidable challenge [24].A clonorchicidal drug,which is effective as a single dose, would therefore greatly facilitate preventive chemotherapy programs.
In terms of CR,all3treatment regimens had an excellent ef?cacy against light infections and a reasonable ef?cacy against moderate infections,but a poor ef?cacy against heavy C.sinensis infections.The differing susceptibility to prazi-quantel depending on infection intensity of trematode infec-tions is well known[22,25],and therefore different doses and treatment schedules have been proposed[22].For example, praziquantel given at3×25mg/kg was found to be superior to a single dose of40mg/kg,in particular for C.sinensis infec-tion of heavy intensities[22].It has been suggested that genetic polymorphism might be a reason for the low ef?cacy of praziquantel against heavy C.sinensis infection.For example,patients with a particular single-nucleotide polymor-phism of their cytochrome P450gene revealed lower CRs than patients without[26].In addition,genetic diversity of C.si-
nensis could also play a factor in the success of praziquantel treatment,with strains in Southeast Asia showing lower sus-ceptibility to the drug than strains from East Asia[27,28].
Because soil-transmitted helminthiases and clonorchiasis
often overlap geographically[29],praziquantel and albenda-
zole have been coadministered in areas where trematode(eg,
C.sinensis and O.viverrini)and nematode infections(eg,soil-transmitted helminths)coexist[30].Our?ndings point to an additional bene?t of tribendimidine;because of the broad spectrum of activity of this drug,concurrent infections with
soil-transmitted helminths and liver?ukes could be targeted
in one go.In the present setting,only few C.sinensis–infected patients were coinfected,and hence the ef?cacy and safety of tribendimidine in patients infected with both soil-transmitted helminths and liver?ukes remains to be investigated.
In conclusion,our results suggest that single-dose tribendi-
midine is comparable to triple-dose praziquantel,both in
terms of ef?cacy and safety,in the treatment of C.sinensis https://www.wendangku.net/doc/02384308.html,rger clinical trials,which have been initiated with
O.viverrini–infected patients in Lao PDR,should also be planned in C.sinensis–infected patients.
Supplementary Data
Supplementary materials are available at Clinical Infectious Diseases online
(https://www.wendangku.net/doc/02384308.html,/our_journals/cid/).Supplementary materi-
als consist of data provided by the author that are published to bene?t the
reader.The posted materials are not copyedited.The contents of all sup-plementary data are the sole responsibility of the authors.Questions or messages regarding errors should be addressed to the author.
Notes
Acknowledgments.We thank the people of Hezhuang village for their participation.The smooth execution of this study would not have been pos-
sible without dedicated efforts from the local staff of Guangxi CDC,
Binyang CDC,and Gantang township hospital.Statistical support from Mr Dimitrios Alexios Karagiannis Voules and Mr Benjamin Speich is deeply appreciated.We are grateful to Prof Peter Odermatt and Dr Somphou Saya-
sone for their continuous support and leading role in the grants funded by
DFID/MRC/Wellcome Trust Joint Global Health Trials Scheme.
Financial support.This work was supported by DFID/MRC/Well-
come Trust Joint Global Health Trials Scheme.J.K.is?nancially support-
ed by the Swiss National Science Foundation(SNSF;project nos.PPOOA-
114941and PPOOP3_135170).The funders had no role in study design,
data collection and analysis,decision to publish,or preparation of the manuscript.
Potential con?icts of interests.All authors:No reported con?icts.
All authors have submitted the ICMJE Form for Disclosure of Potential
Con?icts of Interest.Con?icts that the editors consider relevant to the
content of the manuscript have been disclosed.
References
1.Fürst T,Keiser J,Utzinger J.Global burden of human food-borne
trematodiasis:a systematic review and https://www.wendangku.net/doc/02384308.html,ncet Infect Dis
2012;12:210–221.
at Fudan University on January 3, 2013
https://www.wendangku.net/doc/02384308.html,/
Downloaded from
2.Fürst T,Sayasone S,Odermatt P,Keiser J,Utzinger J.Manifestation,
diagnosis,and management of foodborne trematodiasis.BMJ2012;
344:e4093.
3.Hong ST,Fang Y.Clonorchis sinensis and clonorchiasis,an update.
Parasitol Int2012;61:17–24.
4.Choi MH,Park SK,Li Z,et al.Effect of control strategies on preva-
lence,incidence and re-infection of clonorchiasis in endemic areas of China.PLoS Negl Trop Dis2010;4:e601.
5.Rim HJ.The current pathobiology and chemotherapy of clonorchiasis.
Korean J Parasitol1986;24:1–141.
6.Keiser J,Xiao SH,Chollet J,Tanner M,Utzinger J.Evaluation of the
in vivo activity of tribendimidine against Schistosoma mansoni,Fascio-la hepatica,Clonorchis sinensis,and Opisthorchis viverrini.Antimicrob Agents Chemother2007;51:1096–8.
7.Xiao SH,Xue J,Xu LL,Zheng Q,Qiang HQ,Zhang YN.The in vitro
and in vivo effect of tribendimidine and its metabolites against Clo-norchis sinensis.Parasitol Res2009;105:1497–507.
8.Soukhathammavong P,Odermatt P,Sayasone S,et al.Ef?cacy and
safety of me?oquine,artesunate,me?oquine-artesunate,tribendimi-dine,and praziquantel in patients with Opisthorchis viverrini:a rando-mised,exploratory,open-label,https://www.wendangku.net/doc/02384308.html,ncet Infect Dis2011;
11:110–8.
9.Keiser J,Utzinger J.The drugs we have and the drugs we need against
major helminth infections.Adv Parasitol2010;73:197–230.
10.Olliaro P,Seiler J,Kuesel A,et al.Potential drug development candi-
dates for human soil-transmitted helminthiases.PLoS Negl Trop Dis 2011;5:e1138.
11.Xiao SH,Wu ZX,Zhang JH,et al.Clinical observation on899chil-
dren infected with intestinal nematodes and treated with tribendimi-dine enteric coated tablets.Chin J Parasitol Parasit Dis2007;25:372–5 [in Chinese].
12.Zhang JH,Xiao SH,Wu ZX,et al.Tribendimidine enteric coated
tablet in treatment of1,292cases with intestinal nematode infection—
a phase IV clinical trial.Chin J Parasitol Parasit Dis2008;26:6–9[in
Chinese].
13.Wu ZX,Fang YY,Liu YS.Effect of a novel drug—enteric coated tri-
bendimidine in the treatment of intestinal nematode infections.Chin J Parasitol Parasit Dis2006;24:23–6[in Chinese].
14.Julious S.Sample size of12per group rule of thumb for a pilot study.
Pharm Stat2005;4:287–91.
15.Cancer Therapy Evaluation https://www.wendangku.net/doc/02384308.html,mon Toxicity Criteria,
Version2.0.DCTD,NCI,NIH,DHHS1998.
16.Katz N,Chaves A,Pellegrino J.A simple device for quantitative stool
thick-smear technique in schistosomiasis mansoni.Rev Inst Med Trop S?o Paulo1972;14:397–400.17.Yu SH,Kawanaka M,Li XM,Xu LQ,Lan CG,Rui L.Epidemiological
investigation on Clonorchis sinensis in human population in an area of
South China.Jpn J Infect Dis2003;56:168–71.
18.Lun ZR,Gasser RB,Lai DH,et al.Clonorchiasis:a key foodborne zoo-
nosis in https://www.wendangku.net/doc/02384308.html,ncet Infect Dis2005;5:31–41.
19.Dakshanamurthy S,Issa NT,Assefnia S,et al.Predicting new indica-
tions for approved drugs using a proteochemometric method.J Med
Chem2012;55:6832–6848.
20.Keiser J,Utzinger J.Antimalarials in the treatment of schistosomiasis.
Curr Pharm Des2012;18:3531–8.
21.Rim HJ,Lyu KS,Lee JS,Joo KH.Clinical evaluation of the therapeutic
ef?cacy of praziquantel(Embay8440)against Clonorchis sinensis in-
fection in man.Ann Trop Med Parasitol1981;75:27–33.
22.Rim HJ,Lee YM,Lee JS,Joo KH.Therapeutic?eld trial with prazi-
quantel(Biltricide?)in a rural population infected with Clonorchis si-
nensis.Korean J Parasitol1982;20:1–8.
23.Rim HJ,Park CY,Lee JS,Joo KH,Lyu KS.Therapeutic effects of pra-
ziquantel(Embay8440)against Hymenolepis nana infection.Korean J
Parasitol1978;16:82–7.
24.WHO.Preventive chemotherapy in human helminthiasis:coordinated
use of anthelminthic drugs in control interventions:a manual for
health professionals and programme managers.Geneva:World Health
Organization,2006.
25.Augusto G,Magnussen P,Kristensen TK,Appleton CC,Vennervald
BJ.The in?uence of transmission season on parasitological cure rates
and intensity of infection after praziquantel treatment of Schistosoma
haematobium–infected schoolchildren in Mozambique.Parasitology
2009;136:1771–9.
26.Kim CH,Lee JK,Chung BS,Li S,Choi MH,Hong ST.In?uencing
factors for cure of clonorchiasis by praziquantel therapy:infection
burden and CYP3A5gene polymorphism.Korean J Parasitol2011;
49:45–9.
27.Tatonova YV,Chelomina GN,Besprosvannykh VV.Genetic diversity
of nuclear ITS1–5.8S-ITS2rDNA sequence in Clonorchis sinensis
Cobbold,1875(Trematoda:Opisthorchidae)from the Russian Far
East.Parasitol Int2012;61:664–74.
28.Tinga N,De N,Vien HV,et al.Little effect of praziquantel or artemi-
sinin on clonorchiasis in northern Vietnam.A pilot study.Trop Med
Int Health1999;4:814–8.
29.Utzinger J,Keiser J.Schistosomiasis and soil-transmitted helminthia-
sis:common drugs for treatment and control.Expert Opin Pharmac-
other2004;5:263–85.
30.WHO.Report of the WHO expert consultation on foodborne trema-
tode infections and taeniasis/cysticercosis.Vientiane:World Health Organization,2011. at Fudan University on January 3, 2013
https://www.wendangku.net/doc/02384308.html,/
Downloaded from