A b f lio A u g u s t o F r a g a t a F ilh o , M a r c o A u r e lio D ia s d a S ilv a , E lia s B o a in a in ( '0 ')
E th io lo g ical treatm en t o f acu te
an d ch ro n ic C h ag as' h eart d isease
Instituto Dante Pazzanese de Cardiologia •
S liDPaulo, Brazil
T h e u n c e rta in ttie s in th e e th io lo g ic a l tre a tm e n t o f C h a g a s ' D is e a s e a re c o n s e q u e n c e o f th e la c k o f e n tire k n o w le d g e o f its p a th o g e n y a n d th e n o e x is te n c e o f a h e a lin g c rite riu m . T h e re is a c o n s e n s u s th a t a n tip a ra s ite d ru g s s h o u ld b e u s e d in th e a c u te
p h a s e o f th e in fe c tio n , re g a rd le s s o f th e in fe c tio n ro u te , in n e w c ris is , in p a tie n ts u n d e r im m u n o s s u p p re s s io n a n d in o rg a n s tra n s p la n ta tio n . T h e re is s till c o n tro v e rs y re g a rd in g s u b a c u te , c h ro n ic o r in d e te rm in e d p h a s e o r c a s e s w ith m ild c a rd ia c /d ig e s tiv e
fo rm s , n o t in c lu d e d in th e s itu a tio n s lis te d a b o v e n e ith e r in a re s e a rc h p ro to c o l.
T h e tre a tm e n t in c lu d e s o ra l b e n z o n id a z o l 5 m g /k g /d a y , b id o r tid fo r 6 0 d a y s . In 7 1 p a tie n ts m o n ito re d in th is fa s h io n , th e a u th o rs h a v e fo u n d 6 0 % o f n e g a tiv e x e n o d ia g n o s tic a t th e e n d o f tre a tm e n t. It is s till n e c e s s a ry , h o w e v e r, to c o n tin u e to in v e s tig a te a n d
a c c o m p lis h in g m o re ra n d o m iz e d tria ls to c o n firm th e e ffic a c y o f s u c h m e th o d , a n d a ls o to try to o b ta in e ffe c tiv e a n d le s s to x ic a g e n ts . It is a ls o fu n d a m e n ta l to s ta n d a rd iz e a m o re re lia b le h e a lin g c rite riu m .
U N IT E R M S : C h a g a s 's d is e a s e . B e n z o n id a z o l. C a rd io m y o p a th ie s .
T
h ep a ra s itic id ic d ru g s fo r C h a g a s 'c o n tro v e rs y d is e a s e , e s p e c ia llyo v e r in th e c h ro n ic fo rm , is g ro u n d e d in th e d o u b ts a b o u tth e p a th o g e n e s is a n d th e re a l im p o rta n c e o f th e p a ra s ite .
T h e d o c u m e n ta tio n o f p a ra s ite m ia is d iffic u lt, a n d th e re is
n o w a y to te s t th e re a l p a ra s itic id ic a c tio n o f th e d ru g s .
A d d r e s s f o r c o r r e s p o n d e n c e : A b ilio A u g u s t o F r a g a t a F ilh o
I n s t it u t o D a n t e P a z z a n e s e d e C a r d io lo g ia A v . D r . D a n t e P a z z a n e s e , 5 0 0
S a o P a u lo - S P - B r a s il- C E P 0 4 0 1 2 - 0 0 1
E lia s B o a in a in - ('ll')d e c e a s e d
T h e tH e u b ts a b o u t th re P fu h « > ~ R i$ s a re g ro u n d e d
an
th e u s u a l little s ig n ific a n c e a s c rib e d to th e a c u te p h a s e
a n d th e b ig g e r im p o rta n c e g iv e n to th e c h ro n ic p h a s e .
A d d itio n a lly , th e p a ra s ite is ra re ly fo u n d in th e p e rip h e ra l
b lo o d o r in th e tis s u e s d u rin g th e c h ro n ic p h a s e . T h e re fo re ,.
M a rg a rin o T o rre s ' h y p o th e s is (1 1 ) th a t d e fe n d e d th e
a lle rg ic m e c h a n is m s a n d th e a u to im m u n e m e c h a n is m s a s
th e m o s t im p o rta n t p a th o g e n ic fa c to rs fo r th e c h ro n ic p h a s e
b e c a m e s tro n g e r. R e c e n t in v e s tig a tio n s s h o w e d th e h ig h
a n tig e n ic p o te n tia l o f
Trypanosoma
cruzi
a n d th eim p o rta n c e o f th e e x is tin g re a c tio n s a n d c h a n g e s (a p u d
5 ). T h is in fo rm a tio n 'is th e m o s t im p o rta n t is s u e in th e
v a lid ity o f e tio lo g ic tre a tm e n t o f th e c h ro n ic p h a s e .
M o re re c e n tly , w ith th e re a c tiv a tio n o f th e d is e a s e in
p a tie n ts w ith a h e a rt tra n s p la n t a n d im m u n o s s u p re s s io n
th erap y , th e im p o rtan ce o f th e p arasite assu m es g reater
im p o rtan ce an d so d o es th e n ecessity o f elim in atio n o f th e
p arasite w ith p arasiticid ic d ru g s.
H I S T O R I C A L B A C K G R O U N D
C lin ical an d ex p erim en tal etio lo g ical treatm en t w as
tried a lo n g tim e ag o in stu d ies w h ich w ere n o t scien tifically
co n tro lled (ap u d 3 ). P ack ch an ian tested 4 7 n itro fu ran ic
co m p o u n d s in in fected m ice, an d o n ly th ree d ru g s w ere
effectiv e at elim in atin g th e p arasitic b lo o d fo rm s:
n itro fu razo n e, fu raltad o n e an d fu raso lid in e. N o n eth eless,
th e p arasitic tissu e fo rm s w ere n o t elim in ated b y th o se
d ru g s.
E m p lo y in g th e k n o w led g e ab o u t th e
Trypanosoma
cruzi
b io lo g ical cy cle in th e h o st, B ren er (4 ) su g g ested in1 9 6 1 lo n g er treatm en t trials in o rd er to m ain tain a h ig h er
co n cen tratio n o f th e d ru g in th e p erip h eral b lo o d to
ex term in ate th e p arasite b y "p arasitic ex h au stio n ". B ren er
(4 ) co n firm ed th is in fo rm atio n ex p erim en tally ,
d o cu m en tin g th at th e u se o f d ru g fo r 5 3 d ay s w as m o re
effectiv e th an fo r 2 9 d ay s.
E tio lo g ic treatm en t o f C h ag as' d isease w as o n ly .
m ad e u n ifo rm w h en th e "S tu d y G ro u p ab o u t C h ag as'
D isease" m et in R io d e Jan eiro in 1 9 6 2 . S in ce th at m eetin g ,
sev eral d ru g s h av e b een tested in b o th ch ro n ic an d acu te
p h ases o f th e d isease em p lo y in g th e g u id elin es p ro d u ced
b y th e stu d y g ro u p . A m o n g eig h t d ru g s tested , o n ly tw o
w ere ap p ro v ed : n ifu rtim o x an d b en zo n id azo le. B o th d ru g s
w ere tested w ith th e sam e m eth o d s in m an y d ifferen t
clin ical assay s in th e search o f th e h ig h est efficacy w ith
th e lo w est rate o f sid e effects. T h e resu lts g av e cred en ce
to m an y o th er co n clu sio n s, b u t o n e in p articu lar w as th at
th ere w as a "g eo g rap h ic d ifferen ce" in p arasiticid ic actio n .
N ifu rtim o x w as effectiv e in 8 0 % o f th e p atien ts (acu te
an d ch ro n ic p atien ts) in C h ile, A rg en tin a an d R io G ran d e
d o S u I. It w as o n ly 4 0 % effectiv e in ch ag asic p atien ts fro m
o th er lo catio n s w ith in th e B razilian territo ry . T h is
g eo g rap h ic d ifferen ce w as n o t reco rd ed fo r b en zo n id azo le,
p erh ap s b ecau se th ere w ere sev eral d ifferen t strain s o f
Trypanosoma
cruzl.
In ad d itio n to n itro fu rtim o x an d b en zo n id azo le, n ew
d ru g s h av e b een tested su ch as k eto co n azo l, itraco n azo l
an d allo p u rin o l-rib o sid e. T h e o u tco m e d o es n o t allo w a
d efin itiv e co n clu sio n at th is tim e. O u r ex p erien ce lead to
th e co n clu sio n th at itraco n azo l an d allo p u rin o l-rib o sid e
w ere in effectiv e, b u t o u r p atien t test sam p le w as a sm all
o n e (6 ,7 ). O th er au th o rs b eliev e th at allo p u rin o l-rib o sid e
m ay b e a u sefu l th erap eu tic altern ativ e in selected cases
o f C h ag as' d isease (1 ).
P resen tly , th e o n ly d ru g av ailab le fo r th e treatm en t
is b en zo n id azo le, a co m p o u n d th at h as b een u sed fo r b o th
acu te an d ch ro n ic fo rm s o f th e d isease.
T H E R A P E U T I C I N D I C A T I O N S A N D P A T I E N T
S E L E C T I O N
Acute phase:
A ll p atien ts in th e acu te sh o u ld b e treated p h ase
reg ard less o f th e m o d e o f in fectio n . A cco rd in g to M alta
(8 ), it is th e u n an im o u s o p in io n o f sev eral B razilian
sp ecialists o n th is issu e th at treatm en t is in d icated in th is
p h ase.
Chronic phase:
E tio lo g ic treatm en t o f th is p h ase is m o re
co n tro v ersial, an d sev eral criteria are req u ired to q u alify
th e p atien ts fo r treatm en t. T ab le I d ep icts th e co n clu sio n s
d raw n b y th e "S tu d y G ro u p ab o u t C h ag as' D isease" d u rin g
th e. S eco n d M eetin g o f A p p lied R esearch to C h ag as'
D isease h eld in A rax a (M G ) in 1 9 8 6 . T h ese
reco m m en d atio n s ack n o w led g ed a treatm en t in d icatio n fo r
th e ch ro n ic fo rm s o f th e d isease, in d eterm in ate an d card iac
T a b l e 1
E t i o l o g i c t r e a t m e n t f o r C h a g a s ' d i s e a s e : i n d i c a t i o n s 1 . A c u t e p h a s e w it h a n y t r a n s m is s io n m e c h a n is m . 2 . R e a c t iv a t io n in p a t ie n t s o n im m u n e d e p r e s s a n t m e d ic a t io n t h e r a p y .
3 . C h ild r e n o r a d u lt s in t h e c h r o n ic p h a s e w it h a r e c e n t in f e c t io n .
4 . I n d e t e r m in a t e a n d m ild c a r d ia c f o r m in c lin ic a l r e s e a r c h p r o t o c o l
5 . C h r o n ic d ig e s t iv e f o r m a lo n g w it h o r n o t w it h m ild c a r d ia c f o r m in a c lin ic a l in v e s t ig a t io n p r o t o c o l. I f m e g a e s o p h a g u s is a ls o p r e s e n t , t h is c o u ld n o t in t e r f e r e w it h d r u g a b s o r p t io n .
S . O r g a n t r a n s p la n t .
(w ithout great dam age), only in clinical investigations. W e
understand by cardiac form w ithout great dam age w hen
the heart is norm al sized or show s a m ild enlargem ent of a
chest film , w hen there are no severe arrhythm ias, no
advanced heart blocks, heart failure or syncope.
A t the Instituto D ante Pazzanese de C ardiologia in
Sao Paulo, w e em ploy the criteria show n in table I to
prescribe treatm ent. T he exclusion criteria are show n on
table 2.
W e indicate this treatm ent in the indeterm inate and
m ild cardiac/digesti"ve form s independently of the research
T a b le 2
E xclu sio n crite ria to
e tio lo g ic tre a tm e n t in th e ch ro n ic p h a se
1 . S e ve re ca rd ia c d ise a se .
2 . S e ve re m e d ica l co n d itio n th a t co m p ro m ise s th e p a tie n t's o u tlo o k.
3 . M a ln u tritio n
4 . O ld e r th a n 5 0 ye a rs.
5 . R e sid e n t in a h ig h -risk fo r re in fe ctio n a re a .
protocol because side effects are w ell tolerated and because
there is a theoretical and potential benefit from the drug.
W e also explain to the patient the unknow n efficacy of the
treatm ent and the drug toxicity.
B ased on the research protocol, w e should
dem onstrate the presence of the parasite in the peripheral
blood. H ow ever, these tests (xenodiagnosis and blood
cultures) are expensive and carry several technical
problem s as low specificity (40% ). In this situation, w e
treat the patients even w ithout parasite dem onstration.
T H E R A P E U T IC S
W IT H B E N Z O N ID A Z O L E
Side effects and toxicity:
T hey are: derm atitis, peripheral polineuropathy,
appetite loss, leukopenia. A high prevalence of m alignant
lym phom a w as observed in m ice that received the drug in
the peritoneum . O ther studies did not confirm this
com plication (apud 10). M oya registered c1astogenic
effects w ith N ifurim ox and B enzonidazole in three
patients. T his inform ation lacks further confirm ation.
T he derm atitis w as allergic in nature, and it could
also be w idespread. It occurs regardless the dosage and it
m anifests usually in the second w eek of treatm ent. T he
severity is variable and som etim es requires discontinuation
T a b le 3
B e n zo n id a zo le th e ra p y - ch ro n ic p h a se
A n a lyse d se rie s 1 9 7 4 -8 0
• n u m b e r o f p a tie n ts: 7 1 • m a le s: 4 9 (6 9 % )
• a g e : 8 -5 2 ye a rs (3 6 ,7::t9 ,1 )
C lin ic fo rm
• in d e te rm in a te : 3 0 (4 2 % ) • m ild ca rd ia c fo rm : 4 1 (5 8 % ). C a rd ia c X -ra y
• N o rm a l: 5 5 (7 7 % )
• L ig h t ca rd io m e g a ly: 1 6 (2 3 % ) E le ctro ca rd io g ra m
• N o rm a l: 3 0 (4 2 % )
• R ig h t b u n d le b lo ck + U p a n te rio r d ivisio n b lo ck: 1 6
(22% )
• R ig h t b u n d le b lo ck: 1 3 (1 8 ,5 % ) • A n te rio r d ivisio n b lo ck: 4 (5 ,5 % ) • O th e rs: 8 (1 1% )
T a b le 4
B e n zo n id a zo le th e ra p y - S id e e ffe cts in 7 1 p a tie n ts
Dosage:
In either the acute or in the chronic phase, w e use
benzonidazole at 5m g/kg/day tw o or three tim es a day for
60 days (each tablet carries 100 m g of benzonidazole).
D ia g n o sis
d e rm a titis p o lin e u ro p a th y a p p e tite lo ss o th e rs n o n e
p a tie n ts
27
26
12
5
21
%
3 8 % 3 6 % 1 7 % 7% 3 0 %
of the treatm ent. In our series of 71 treated patients (tables
3 and 4),27 patients (38% ) developed derm atitis, w hich
is usually treated w ith anti-histam ine m edication. N o
patient had to stop the treatm ent.
T he peripheral polineuropathy m ainly in the low er
lim bs is a m ore serious com plication. It occurred in 26
patients (36% ). W hen severe, it could render the patient
incapable of w alking, and the sym ptom s can rem ain for
several m onths after it is stopped. N o patients in our series
had to discontinue treatm ent because of the developm ent
of peripheral polineuropathy. Peripheral neuropathy
sym ptom s m ay subside a little w ith B vitam ins.
A ppetite loss w ith occasional loss of w eight occurred
in 12 (17% ) patients. D rug treatm ent w as discontinued
only in the m ore severe cases.
L eukopenia and granulocytopenia are rare
com plications. A periodic w hite cell count (W B C ) is
m andatory each 15 or 20 days. T his com plication m ay
occur betw een the second and the fourth w eeks of
treatm ent and the drug m ust be stopped (10). N one of our
patients developed this type of com plication.
O ther side effects of less im portance include nausea,
vom iting and insom nia.
CURE CRITERIA
T here are no cure criteria accepted by all authors to
certify that the treatm ent w as effective.
W e em ploy three criteria, nam ely: serological,
parasitic and clinical.
In the acute phase, the serology alw ays becom e
negative, expressing a state of cure. In the chronic phase,
it rarely becom es negative and w hen it happens, it is
difficult to ascribe to the effects of the therapy. In our series
of patients only 2 out of 71 patients (3.8% ) had negative
tests.
T he parasitic criterion requires negative tests. In the
chronic phase, the xenodiagnosis and blood cultures are
em ployed to determ ine the presence of the parasite.
H ow ever, these tests display low sensibility and reliability
rates. T herefore, it is difficult to confirm the absence of
the
T.
cruzi.
B lood cultures show in the chronic phase a positive
yield of 45% after a 90-day period for the results.
X enodiagnosis show s less than 40 diagnostic yield. It is
m ade in three sessions w ith a tw o-w eek interval. W e
em ploy 40 third internship nym phs of
T.
infestans
fortesting. T he results becom es available only after 30 and
60 days.
Finally, the clinical criterion dem onstrates dam age
to different organs either by physical exam ination or by
laboratory m eans such as a electrocardiogram or a chest
film . It is the w orst of all three criteria. In the acute phase,
the clinical m anifestations disappear in tw o to three m onths
w ith or w ithout treatm ent. In the chronic phase, the organ
dam age is irreversible.
RESULTS
T here is no cure criterion beyond question.
T herefore, it is difficult to assess the results. T he
recom m endations of the discussion m eeting about C hagas'
disease published in 1963 are still used presently require
the follow ing: B oth the blood tests and the parasitem ia
becom e negati ve after treatm ent.
R assi (10) stated that the therapeutic efficacy w ith
serological tests and xenodiagnosis could be evaluated in
both acute and chronic cases w ith a recent infection. B oth
tests have tw o possibilities:
a) If, a long tim e after treatm ent, both tests are
negative, w e acknow ledge the infection is cured. N egative
blood tests are not im m ediate but it happen one or three
years later or even longer.
b) If both tests becom e positive, the treatm ent failed.
In this case, the xenodiagnosis becom es positive in six to
24 m onths.
T hree situations could happen in the chronic phase:
a) A fter the treatm ent, both tests becom e positive,
show ing treatm ent failure.
b) Several negative xenodiagnostic tests w ith positive
serological tests (dissociated cases). T his is the m ost
com m on situation. T o som e authors, this m eans treatm ent
failure. T o other authors, this is the equivalent of a
serological scar (antibodies w ithout the parasite) as seen
w ith FT A B S in syphilis infection and serological tests in
B ouba.
c) T he third situation concerns the patients w ho
becom e negative in the xenodiagnosis after treatm ent.
H ow ever, serological tests are doubtful (serological
oscillation). T his could persist perm anently. In these
cases, an "im m unologic m em ory" could be the
explanation.
In our unit, the parasitic criterion in em ployed to
record cure. If w e obtain 24 consecutive negative
xenodiagnostic tests perform ed at a 30-day interval after
treatm ent is term inated, w e consider it a cure. A ccording
to this criterion, w e have a 61 % parasitic cure rate (table
3). T hese data are sim ilar to other published series.
POST-TREATMENT FOllOW-UP
T h e a im o f tre a tm e n t in th e c h ro n ic p h a s e is to h a v e
a b e tte r c lin ic a l fo llo w -u p p ic tu re w h e n c o m p a re d to
u n tre a te d p a tie n ts . A c o m p re h e n s iv e ra n d o m iz e d
in v e s tig a tio n is n e c e s s a ry to c o n firm th is h y p o th e s is .
In th e m e a n tim e , a ll th a t it is s ta te d a b o u t tre a tm e n t
is h y p o th e tic a l.
O u r re tro s p e c tiv e a s s e s s m e n t e m p lo y in g
e le c tro c a rd io g ra p h ic a n d ra d io lo g ic a l c rite ria s h o w th a t
w ith in 7 ,1 9
:t
5 ,3 6 y e a rs o f fo llo w -u p , 6 0 p a tie n ts (8 4 % )b e c a m e e q u a l. T h a t m a y b e a s ig n o f g o o d p ro g n o s is .
B e fo re tre a tm e n t, 4 2 % o f th e p a tie n ts w e re in th e
in d e te rm in a te fo rm a n d 5 8 % d is p la y e d a m ild c a rd ia c fo rm
o f th e d is e a s e . F iv e p a tie n ts (7 % ) d e te rio ra te d , a n d in th re e
o f th e m th e x e n o d ia g n o s is b e c a m e p o s itiv e . O n e p a tie n t
d ie d in th is p e rio d fro m c a u s e s u n re la te d to C h a g a s '
d is e a s e .
CONCLUSIONS
T h e e tio lo g ic tre a tm e n t o f C h a g a s ' d is e a s e
d e m o n s tra te s s e v e ra l d o u b tfu l p o in ts . E v e n in s itu a tio n s
w h e re tre a tm e n t is a c o n s e n s u s (a c u te p h a s e , re a c tiv a tio n
w ith th e u s e o f im m u n e d e p re s s a n t m e d ic a tio n a n d b e fo re
o rg a n tra n s p la ta tio n ) th e re a re n o c o n tro lle d a n d
ra n d o m iz e d s tu d ie s c o n firm in g th e s c ie n tific v a lid ity .
In th e c h ro n ic p h a s e , e x c e p t in im m u n e s u p re s s io n
a n d o rg a n tra n s p la n ta tio n , th e d o u b ts a b o u t tre a tm e n t a re
b a s e d o n th e tru e a c tio n o f th e p a ra s ite a s w e ll a s th e
im m u n o lo g ic a l, a n d h y p e rs e n s ib ility m e c h a n is m s th a t th e
T. cruzi
e lic it fro m th e h o s t. C o m m o n s e n s e ta k e s in toa c c o u n t th e p a ra s ite in th e c h ro n ic p h a s e a n d th e p o s s ib ility
o f a n tig e n ic s tim u la tio n . W e a d m it th a t th e re a re s im ila ritie s
w ith rh e u m a tic d is e a s e w h e n w e k n o w th e re a l im p o rta n c e
o f th e im m u n o lo g ic s itu a tio n b u t w e u s e p e n ic illin to
e lim in a te th e
Streptococcus.
In d e p e n d e n t o f th e th e o re tic a l v a lu e o f th e e tio lo g ic
h y p o th e s is in th e c h ro n ic p h a s e , w e s h o u ld e v a lu a te th e
e ffic a c y o f b e n z o n id a z o le , th e o n ly d ru g a v a ila b le . O th e r
s tu d ie s a n d o u r e x p e rie n c e s h o w a g re a t tre a tm e n t fa ilu re
w h e n th e p a ra s itic c rite rio n is e m p lo y e d . If w e e m p lo y th e
s e ro lo g ic a l c rite rio n , a fe w p a tie n ts c o u ld h a v e a s u c c e s s fu l o u tc o m e .
F in a lly , w e h a v e to p e rfo rm o th e r s tu d ie s to :
a ) d e v e lo p a n e w p a ra s itic id d ru g w ith h ig h e r k illin g
p o w e r o n tis s u e a n d p e rip h e ra l b lo o d fo rm s o f th e
T'ypanosoma
cruzi;
b ) d e v e lo p a g o o d c u re c rite ria ;
c ) d e te rm in e th e v a lid ity o f s h o rt- o r lo n g -te rm
tre a tm e n t.
In th e m e a n tim e , if th e s e re s p o n s e s a re u n a v a ila b le ,
th e p re s e n t e v id e n c e a c c o u n ts fo r th e u s e o f b e n z o n id a z o le
in th e a c u te p h a s e o f C h a g a s ' d is e a s e a s w e ll a s in s o m e
c h ro n ic fo rm s . W e n e e d to b e a w a re , a n d s o d o th e p a tie n ts ,
a b o u t th e u n c e rta in ty o f th e re s u lts .
REFERENCES
I. A G U ILER A , X .; A PT, W .&A R R IB A LD A , A . - Evaluaci6n del alopurinol en Ie enferm edad de C hagas' cronica hum ana
en C hile. ParasitoI1l:32-4, 1987.
2. B ELLO TTI, G . & PILEG G I, F. - Tryposonom iase e
cardiopatia chagasica cronica. A rq B ras C ardiol 61:203-5,
1993.
3. B O A IN A IN , E. - Tratam ento etiol6gico nas doen~as de
C hagas na fase cronica. Tese apresentada
a
Faculdade de M edicina da U niversidade de G oias, 1977.4. B R EN ER , Z. - A tividade terapeutica do
5-nitro-flltaldefdo-sem i-carbozona (nitrofurazona) em esquem as de dura~ao
prolongada na infec~ao experim ental do cam undongo pelo Trypanosoma cruzi. R ev Inst M ed Trop Sao Paulo 3:4-49,
1961.
5. B R EN ER , Z. - Im m une response and im m unepathology in T cruzi infection. In: W endel, S.; B rener, Z.; C am argo, M .E.
& R assi, A . eds. C hagas' D isease (A m erican
Tryposonom iasis): H is im pact on transfusion and clinical
m edicine. ISB T B razil 92:31-47.
6. FR A G A TTA P.,A .A .; B O A IN A IN , E.; N A IFR IN O , L.B .M . et ai. - Itraconazol in treatm ent of C hronic C hagas' disease.
M en Inst O sw aldo C ruz 88:243, 1993.
7. FR A G A TTA FO ., A .A .; B O A IN A IN , E.; PER EIR IA
C H IO C C O LA , V .C . et al. - A llopurinol riboside in C hronic
C hagas' D isease. N om Inst O sw aldo C ruz 88:242, 1993.
8. M A LTA , 1. - Terapeutica da D oen~a de C hagas'. C onsensos
e D ivergencias. A rq B ras C ardioI61:201-2, 1993.
9. PA C K C H A N IA N , A .O . - C hem otherapy of experim ental
C hagas' disease w ith nitrofuran com pounds. A ntibiotic and
C hem other 7: 12-23, 1957.
10. R A SSI, A . & LU Q U ETTI, A .O . - Therapy of C hagas' D isease. In: W endel, S.; B rener, Z.; C am argo, M .E. &R assi, A . eds. C hagas' D isease (A m erican Tryposonom iasis): H is
im pact on transfusion and clinical m edicine. ISB T B razil
92:31-47.
11. TO R R ES, C M . - Endocarditic parietale dans la m aladie de
C hagas. C R Soc B ioI 99:886-7, 1928.
Sao Paulo Medical Journal/RPM 113(2} Mar/Apr 1995
= 1 -:\$ il$ l$ lllllK l$ li$ liW ,ll:i~ = * ,1 0 "ID M m ::~ lre"~ = -..m = = .M w .= ~ ~ $ )!'.$ _ :W ;= < l"'i= ,* "-= l= W ,!$ liW ,$ ;$ i$ ";II* W .M w .w .r& m * ,l!'= {m » K $ l* ,,= .m ;w .W = :::l'~ .w .w ,;$ ;$ W ~ W ,,,,'"?$ * ,;$ ;$ iW ~ ~ ~ '{,* ,< $
