ReÐ.Inst. Med.. trop.

Stio Paulo
29(5): 305 311, se¿e7¡¿bro-outubro, 1981

EFFICACY OF OXAMNIOUINE, PRAZIOUANTEL AND A COMBINATION OF BOTH DRUGS

IN SCHISTOSOMIASIS MANSONI IN BRAZIL

K. ZWINGiENBERGER (1), J. A. NOGUEIR,A QUEIROZ (2), U. POGGENSEE (I), J. E. ALENCAR (2),

J. VALDEGUNAS (3). F. ESMERALDA (3) & H. FELDMEIER (T)

SUMMARY

A rândomized clinicâl trialÏvas carried out to compâ¡e the efficâcy ofa low-dosage
combinâtion of oxâmniquine (7.5 mg/kg) plus prâziquantel (20 mg/kg) against either
agent, oxamniquine (15 mg/kg) or praziquantel (40 mg/kg) alone, in the treatment
of schistosomiâsis mansoni in the Brazilian north-east.
The drugs v¡ere rândomly administered per os to 91 patients. Six and twelve
months after treatment 89% of those admitted to the trial were reexamined by
Kâto-Katz method (ten slides) and MIF technique (one gram ofstool)
The achieved cure râtes, âs defined by absence of S. mansoni eggs in the faeces
of individual pâtients at alt points during the parasitological follou¡ up, v¿ere 8l.gvo,
81.2% and 67.6Ea for prazíquattel, oxâmniquine and the combination respectively.
The reduction of eggs excretion in non-cured patients six months after therapy
ran ged from 93 .8-96.8% wi th prâziquan tel,32.5 97 Ea urith ox âmniquine an d ? 6.9-99 .59.
v/ith the combinâtion.
It is concluded that, at the used dosages, the three therâpeutical regimens give
similar ând satisfactory results in the treatment ofuncomplicâted S- mansoni infec-
tion in Brazil.

KEY-WOßDS: Schistosoma mansoni; Oxâmniqui¡e; Oxamniquine resistance; Pra-

ziquantel.

INTRODUCTION
Two compounds â¡e currently recommen-
ded for ùhe treatment of schistosomiasis manso-
ni52. Oxâmniquine has been used in large scale
mâss l,real,ment in Brâzil, in an attempt 1,o cur-
tail the transmission of this helminthiâsis ând
to achieve eradicâtion3o 45 43 5r. ïrhe drug was ad-
vantageous from the point of vie\tr of cost-eflecti
viness, since satisfying cure râtes have been ac-
complished in this country with a single oral do.
se of15 mg/kg body weight33 40. fn contrast, doses
up to 60 mg/kg are required in Africa to attâi¡
similar therapeutical efncacy in schistosomiasis
mansoni3e. Oxamniquine is usually well tolera-
ted35 a'z and clinical imÞrovement has been ob-
served in advanced cases of this parasitosis3 '3.
Nevertheless serious central nervous adverse

(1) LatrdesiDstitut i¡r Tropenmedizin Berlin, {¡est Berlin, Federâl Republic oIGermâny.
(2) Núcleo de Medicina Tropical, Centlo de Ciénciâs da Sâúde, Universidade Federâì do Ceará, Fo$âleza, Ceará, Brasil.
(3) Sì¡perintendência de campånÌ¡as de Saúde Pública {SUCAM), Ministélio da Saúde, Cmto, Ceârá, BmslÌ.
A¡laltcss for conesDoDrlerce: H. Feldmeier, Depårtment oflmmunodiagnosis ând Immunopârâsitology, Landesinstitut fr:r TÌo-
penmedizin. Königin-Elisabeth-Stlâsse 32 42, D'1000 Bedtx 19, Federâl Republic of Gelmâny.
 ZWINGENBERGER, K,: NOGUEIRA QUEIROZ, J. A.I POGGENSEE, U.I ALENCAR, J. E.: VALDEGUNAS, J.i ESMERALDA.
F. 3¿ FELDMEIER, H.
- Emcact of oxamniqui¡e, prâziquântel and â combination of both drues ìn schistosomrasis mânsoni
in B¡azù- R€v. lnst. Med. trop. São Paulo,29:305 3tr, 198?.
reactions have been reported following its admi-
nistrations 16 ¡6 37 47. Unfortunâtely it also beca-
me âpparent already at early stages of the eradi-
câtion campaign in Brazil that S, mansoni
strains resistant to oxâmniquine exist32. Such
resistance hâs been confi¡med by other investi
gators'z re æ' 41.
Prâziquantelis a novel antihelminthic agent
active against all schistosome species pathoge-
nic to manr 26 ae âs well as a variety of other
huma¡ tremâtode50 and cestode2T infections. It
proved to be a safe drugca zs :e -n has been
"n
administered to schistosomiasis pâtients with
hepatosplenomegaly without inducin g any seve-
re untoward effects'r 13. Moreover, it has been
successfu lly used in oxamniquine-resistant câ-
ses of schistosomiasis mânsonia e 20.
Recentlyithas been suggested that the com
bination of oxamniquine and praziquantel, even
at low dosages, produces a synergistic action
âgainst S. mansoni3 r3 20 44. Tlhese preliminary
findings have not yet been clinically ilvestiga-
ted in northeastern BraáI. Thus we have carried
out â field trial at this endemicâl region in order
to compare the efficacy of â half-dose combina-
tion on these two drugs âgâinst each one alone.
PATIENTS AND METHODS
A total of 93 subjects living at an area ende-
mic for schistosomiasis in the municipality of
Crato, situated in the interior ofCeara state, Bra-
zil, were diâgnosqd as infected þy S. mansoni
in a parasitologicâl survey. All of them, 70 males
and 23 females, presented the uncomplicated
form of the disease. The median age was 21 ran-
ging from 10 to 62 yeafs. Only 20% were younger
than 16 or older than 30 yeâ.rs. Two females allo
cated to the praziquantel group were exempted
ftom treâtment at the beginning of the study
because of pregnancy. They received therapy
post-partum butwere excluded from the evâlua-
uon.
lne worm bt¡rden was quantified on the ba,
sis of faecal egg counts using the Kato thick
smear technique as modiñed by KATZ et al.3¡.
306
The number of eggs per gram of fâeces prior to
treâtment was calculated from five slides (equi-
valent to 210 mg ofstool). Parasitological follow-
up exâminations performed on a single speci
men obtai¡ed three, six and twelve months post-
treatment, comprised a minimum of ten slides
(corresponding to 420 mg of stool) per patient.
In âddition, approximately I g of stool salltple
was examined by the merthiolate formol lMlf')
concentrâtion technique6. This methoqôlogy
was bâsed on the rationale that a single Kalo
thick smeâr reliably indicates the intensity of
infection only if egg excretion is highet than 50
ova per gram of faeces, whereas below this level
fâìse-negative results are frequenta6.
Subjects with previous history of seizures were
excluded ftom the trial. The patients were then
rândomly allocâted to.one ofthe following treat-
ment group: (a) oxamniquine 15 mg/kg in a sin
gle dose; (b) prâziquantel 40 mg/kg in two split
doses, taken 4 hours apârt; and (c) a combination
of oxamniquine ?.5 mg/kg plus praziquantel 20
mg/kg, taken simultaneously. Tabtets of both
drugs were used in âdults; in children, oxamni-
quine was administered in the form of syrup.
Thfuty-two individuals vsere ¿reated with oxam
niquine,24 Í¡ith praziquântel and 3b received
the combinâtion. The Unequal number of pa-
tients within lhe three groups was due to the
non-prefixed limitâtion in the âmount of cases
entering the trial. In such event it may occur
that at a certain moment the open random allo
cation brings about a disproportional distribu-
tion of patients âmongst groups.
The mâi¡ characteristics of the patients en
rolled in the three groups are shown in Table
I. They did not differ in age or sex composition,
and there v,¡as no significant difference in pre-
treatment worm burden. The overall mediân
numbe¡ ofeggs per gram ofstool prior to therapy
was 168, range 42-964. Fewer than 100 eggs per
gram were encountered in 279a of the indivi-
duals, whereas in 26Eo, egg, excretion exceeded
300 per gram.
Statistical evaluation was performed accor-
dingto Fisher's exact test for comparison ofrela-
tive frequencies, and Mann-Whitney signed -rank
test to compare reductions in egg exc¡etion.
ZWINGENBERGER.K.iNOGUEIR'AQUEIIÙOZ,J-A,POGGENSEEU:ALENCARJE-VALÐEGIIN-AS,J-;ESMERALDA
Ir. & FELDMEIEI¿, H. Eñcacy of oxamDiquine, praziquântel ând a combi¡âtion of.both d¡ugs in schlstosomiâsis mânsoni
-
lll Braziì. Bev.Inst. Med. troÞ. Sáo Pauto,29:305 311, 198?

TABLE I
Chârâcteris üics of the pâtients wìthin th e three drug groups ( OXM = oxâmniqume, PZQ
: pÌâziquantel
EPG = number ofs. mansoni eggs per grâm orfaecesl

Drug groups Orâmniquine oxM & PzQ

Dosages (mg/kg) 40+ 15 'L5 + 20

Treâted câses 24 32

Sex Mâle/female 16/8 25t7 29t6

Median 22ys. 21 ys. 20 ys.

R ânge 12: 50 ys. 10 . 62 ys. 12 54 ys-
< ys.
16 225ô 2tsc 785ô
16 30 ys. 564. 6I7. 6t./o
> 30 ys. 22Va lBq. 2LVô

Med¡ân 13? EPG I56 EPG 176 EPG

bùrden Limits** 100 - 216 EPG 132 - 230 EPG 120 216 EÞG
< EPG
1OO 328 28V. 25V.
100 300 EPG 455. 449/. 507.
> 3OO EPG 235. 24./. 25V.

* Twice 20 mg, four hours apalt.

** 957. conJidence intervâl.

R,ESULTS Table II shows the number of examined pa

Ctinical tolerability to all three medications
was uneventfull as no difference was noticed i¡
regard to the usual side-effects already reported
in Brazil with praziquantel, oxâmniquine, and
inclusively with the combinationr0 rs 2l.
tients, positive cases ând eggs excreted pe¡gram
of fâeces at different points of the follotr¡-up pe
riod. Seventy-two percent, 89% and 897, respec-
tively, of the treated patients could be reexa
mined three, six and twelve months after therâ-
phy. The cure râtes, i. e., failure to detect ova

TABLE II
paúsitotogicat findings 3, 6 and 12 montbs after treâtmenb (for iegative stool sâmples þy Kâto-Kâtz but posiüive by MIF
concentration. an EPG of 5 wâs â36umed i¡ order ,o calculate the reduction in ova excrctlotr¡

Foltow-up Dose groups

Findinss
Controls Praziquantel oxM & PzQ
Examined paüents* ta (11L, 26 t811êt 2t (6tqol
3rd. 0 2 t 8q.) I I 5q.'
Month EPG in non-cured câses ¡ange 24 r88 48
Reduction ofEPG
-
range 46.r
- 81.8qô 87.7c/.
- -
Examined pâtients+ 20 ta3sal 30lg4Sot 3219L5.l
8th 3lSSat 6 (20Val 8l2í7.t
Montb EPG tr
non-cu¡ed cases - range 5-10 5
-230
Reduction ofEPG rânge 93.8 96.87c 32.5 ,97.OSa ?6.9
- 99.5%
-
Examined patients* 22 (92C.) 30 (9450) 2A ßOS"t

12 th. 2 t 99ô) 4 tlSqot 4 (14%)

Mohth EPG ln non-cu¡ed câ6es
- rânge 5-45 to
-25 l5-25.
Reductlon ofEPG ra¡ge
- 39.2
- 96.9'lo 72.2
- 94.Oqo 42.5
- 93.7c.

* ln brackets, the Dercentage ofreexamined cases in ælatlon to Feâted Þatients

*r In brackets ttìe perceniâge ofpositive cases in relation to reexamined pafients-

307
 ZWINGENBERGER, K.i NOGUEIR¿. eUE'*OZ, J. A.; pOGGENSEE. U.t AI_ENCAR, J. E.i
F & FELDMETER Tl Eflicacv of oxamniquine, prâziq u antel ând â com bin â tion o l bo rhVALDEGUNAS,
-
i¡ Blâzil. Rev. tnst. Med. troD. Sáo pauto, 29:305 Bll. tg8?
in the faeces, corresponding to these conrrol ìn
tervâls were: 100Ea,85EÒ, glEa for praziqu ntel.,
92Eø, 80Ea, 87 Ea for oxamniquine; and gEVo, l iVa,
86% for tlle combination, âccording to the Kato
Katz method. Taken into account the findings
of the MIF concentration in addition to the re
sults by Kâto Katz, and embraceing the whole
twelve months ofparasitologicâl follow up, cure
rates of 81.8%, 81.2qa and 62.62¿ were achieved
wiôh praziquantel, oxamniquine and the combi_
nation respectively, as shown in Tat te III. The
relative frequencies of parasitological cures did
not differ statistically bet{¡een the groups.
TABLE III
OverâU æsults of the pâlâsibotogicat exâminations by
Kato-Kâtz ând MIF methods, du¡ns
the entùe 12 month follou/ Lrp.
Drug goups Pmziquântel Oxâmniquine
Negâtive cases l8 26 ¿3
4 6 ll
8r.85ô 8t.2V. 67 _6Vo
* Onepatientilrthe oxâmntquine and one in the combination
group was found posit¡ve by the MIr' concentration ontv.
In those patients still excreting eggs after
treatment, considerable reductions in egg
counts were observed. They also did not differ
signiflcantly between the three groups, and the
number of remaining positive câses was too
small to allow statistical comparison of persis_
ting excretion of S. mansoni. It is visualized in
Figure 1, however, that the reincrease of egg ex
cretion in non-cured Þâtients âppears to be stee_
per in those treated with oxamniquine than in
those who received prâziquantel.
DISCUSSION
Our results confirm the similar efficâcy of
praziquantel and oxamniquine \¡/hen used in
conventional dosages for tleating S. mansoni i¡_
fection, as already demonst¡ated in double blind
comparative trials ca.rried out in Brazil 14 22 34.
In addition, it has been disclosed that a low_
dose combination ofboth drugs is effective, Í'ith
6?.6% of patients no longer excreting ova âfter
the treatment and an average ¡eduction of egg
counts of 88.?7¿ in those patients in whom no
308
J.; ESMERALDA,
dru gs in schis tosomiâsis m ansoni
Frg. t S. MANSONT OVA EXCR.ETION IN INDTVTDUAL
PATIENTS (po¡nts indrcatb the Epc ofeâch case, those nega-
Cive ât the filstfollo\¡/-up buLpositive on subsequent examina
crons edenoted byopencirctes. Mediânsand gb¿l. conñdence
Iimits prior Lo bhenpy are indicated byhorizontal bars. FoÌtow
up examina¿ions posiiive by MI¡' concenhation only are not
quantüled)-
PZQ
complete pâ¡asitologÍcal cure was accomþli_
shed.
A similat dosage to the one !¡¡e used in this
trial has previously shown to be advantageous
in a dose-hnding study conducted in Malawia3-
The children treated in this country had 2 to
4 times higher egg counts prior to treatment,
and many were concomitanfly infected with S.
haematobium. In thât study, the ¡eduction of
ova excretion three months after therâpy was
marginâlly los¡er using ?.b mg/kg oxamniquine
plus 15 mglkg praziquantel, as compared to the
group treated with 10 mg/kg oxamniquine.plus
20 m g/k g praziq ua nT,el (98% vs.97Ea). Six months
after treatmenú lit e difference was appârent
betvr'een the two dosage schemes (95Vo vs.96gù.
In our trial the post-treatment decrease of
S. mansoni ova excrelion and cure ¡âte seemed
more favourable for the group treated with prazi
quantel alone, hor¡rever, the initial egg count was
slightly lov,/e¡ than in the tv/o remaining groups.
In this connection, â statistically significant dif_
ference in the reduction of the mean numbers
of eggs Fer grâm of faeces afteÌ heatment with
praziquantel in compârison to oxamniquine has
been reported in a much larger sized samplel?.
A reincreâse in egg counts upon reexâmiúation
six and twelvemonths aftertreatment wasnoted
in two to three patients in eâch group in whom
the counts had fallen to nought or 10 eggs per
ZWNGENBERGER. K.; NOGUEIRA QUEIIùOZ, J AiPOGGENSEE U;-A.LENCAR. J E-: VALDEGUN-A.S J;¡SMERAIDA'
F. & FELDMEIER. H. Efücacy of oxâmniqume, pmziquanüel ând â combinâlion of both drugs in schistosomias$ mânson¡
-
in Brazil. Rev. Inst. Med. troÞ. Sáo Pãüto, 29:305_311, 198?
gram 3 months post therapy. This finding was
most pronounced on the 6th. month after treat-
mentin the oxamniquine group. Actually, in two
cases treâted with this drug the egg counts rea-
ched pre therapeutical levels. This could be due
to a diminished susceptibility of S. mansoni
strâihs to this drug but the possibility ofreinfec
tion or relapse cannot be ruled out either. In
regâ¡d to this, the assessment of oxamniquine
efücâcy by the quantitative oogram technique
hâs been indicative ofpersistance ofegg ptoduc-
tion four months on after treatment12.
In conclusion, a single dose administration
ofoxamniquine mg/kg or praziquantel40 mg/
15
kg or a half-dose combination of both drugs pro
ved to be similarly effective in schistosomiasis
mansoni in Brâzil, as anâlogous cure rates and
reductions of egg excretion in non-cured cases
were achieved. It remains speculative whether
this combination v¡ill prevent fl¡rther develop-
ment of oxamniquine resistance, which could
turn into a serious hazard for schistosomiasis
control in Brazil. Finally it should be empha-
not
sized that these are only preliminary results
to be extrapolated to large scale therapy.
R,ESUMO
Eficácia ala oxamniquine, alo praziquantel e ala
combinaçáo ile ambas as drogas na
esquistossomose mansônica no Brasil.
Conduziu-se um ensaio clínico Þara compa
râr a eficácia de uma combinaçáo em baixas do-
ses de oxamniquine (7,5 mg/kg) mais praziquan-
tel r20 mg/kg, com ambas as drogas - oxamni-
quine (15 mg/kg) e praziquantel (40 mg/kg)
empregadâs isoladamente, no tratamento da es
-
quistossomose mansônica em uma área endê-
mica do nordeste brasileiro.
Os medicâmentos foram administrados,
aleatoriamente, por via oral, a 91 pâcientes. Seis
e doze meses depois do tratâmento 89% dos ad-
mitidos no ensaio foram reexaminados segundo
os métodos de Kato-Katz (dez lâminas) e MIF
(um grâma de fezes),
Os Índices de cuta alcançâdos, representan-
do â ausência de ovos nas fezes em todos os con-
troles durante o acompanhamento parasitoló
gico individuâlizado dos pacientes, foram de
Al,AVo, 81,21ø e 67,6Ea com, respectivamente, o
praziquantel, a oxamniquine e â combinaçáo.
A reduçáo do número de ovos eliminado por gra-
ma de fezes nos casos náo.curados, variou de
93,8-96,8% com o praziquantel, 32,5-979a com a
oxamniquine e ?6,9 99,5Va collr a combinaçáo.
Concluiu-se que os trés regimes terapêuti-
cos, nas doses utilizadas, dáo resultados similâ-
res e satisfâtó¡ios no tratamento da esquistos-
somose mânsônica náo complicada, no B¡asil.
ACKNOWLEDGEMENTS
The collaboration ofSUCAM held microsco
pists, Romulo M. do Nascimento ând Maria A.
de S. Bento is greatly âppreciâted. Technical as-
sistance wâs âlso frroyided by E. Adusu, J. ïqe-
ber-Adusu and K. Stórzel. Prof. Nâidu, Univer
sidade Federal do Ceârá, Fo¡taleza, gave valua-
ble advises.
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