Retrospective study of 1 5 1 patients with cutaneous leishmaniasis
treated with meglumine antimoniate
Estudo retrospectivo de 1 5 1 pacientes com leishmaniose cutânea
tratados com antimoniato de meglumina
Armando de Oliveira Schubach
1, Keyla B. Feldman Marzochi
1, João Soares Moreira
1,
Tânia Maria Pacheco Schubach
1,
Marcelo Lodi Araújo
4, Antônio Carlos Francesconi do Vale
2,
Sonia Regina Lambert Passos
1,3and Mauro Célio de Almeida Marzochi
1ABSTRACT
We re tro spe c tive ly a n a lyze d a se rie s o f 151 c a se s o f c u ta n e o u s le ishm a n ia sis tre a te d b e twe e n 1967 a n d 1982. On e - hu n dre d-a n d- thirty- n in e ( 92%) pd-a tie n ts pre se n te d with d-a c tive le sio n s d-a n d we re tre d-a te d with dd-a ily do se s o f m e glu m in e d-a n tim o n id-a te : 81 a du lts re c e ive d a 5- m l via l IM a n d 58 c hildre n re c e ive d 1 to 5m l. Fo rty- five ( 32.4%) pa tie n ts u n de rwe n t c o n tin u o u s tre a tm e n t with m e glu m in e a n tim o n ia te fo r 25 to 116 da ys witho u t re st in te rva ls, a n d 94 ( 67.6%) in te rm itte n t tre a tm e n t with 2 to 5 se rie s o f m e glu m in e a n tim o n ia te . In te rm itte n t se rie s c o u ld in c lu de sc he du le s o f da ily IM a pplic a tio n s fo r 10 to 25 da ys e a c h a n d in te rva ls va ryin g fro m 10 to 60 da ys. An tim o n y do se wa s c a lc u la te d fo r 66 ( 47.5%) pa tie n ts a n d ra n ge d fro m 3.9 to 28.7 Sb5+
/k g/da y. Of the se , 35 pa tie n ts re c e ive d > 10m g a n d 31 pa tie n ts < 10m g Sb5+
/k g/da y. Me dia n tim e o f he a lin g wa s lo n ge r fo r le sio n s o n the le gs a n d fe e t – 67.5 da ys versus 48.7 da ys ( p < 0.001) fo r o the r site s. Ho we ve r, the re we re n o sign ific a n t diffe re n c e s in the m e dia n tim e o f he a lin g b e twe e n a du lts a n d c hildre n , in te rm itte n t a n d c o n tin u o u s re gim e n s o r high a n d lo w a n tim o n y do se s. Fifty- o n e pa tie n ts we re re a sse sse d 5 to 14 ye a rs a fte r tre a tm e n t a n d sho we d n o e vide n c e o f dise a se . The se re su lts su ppo rt fu rthe r in ve stiga tio n ( c lin ic a l tria ls) o n tre a tm e n t u sin g lo w do se s o f a n tim o n y.
Ke y-wo r d s: Cu ta n e o u s Le i sh m a n i a si s. Le is h m a n ia ( Via n n ia ) b r a zilie n s is. Dru g th e ra p y. Me glu m i n e a n ti m o n i a te . Th e ra p e u ti c sc h e d u le s.
RESUMO
De sc riç ã o de u m a sé rie re tro spe c tiva de 151 c a so s de le ishm a n io se c u tâ n e a a te n dido s e n tre 1967 e 1982. De ste s, 139 ( 92%) pa c ie n te s a pre se n ta va m le sõ e s a tiva s e fo ra m tra ta do s c o m a n tim o n ia to de m e glu m in a dia ria m e n te : 81 a du lto s re c e b e ra m u m a a m po la de 5m l e 58 c ria n ç a s re c e b e ra m 1 a 5m l. Qu a re n ta e c in c o ( 32,4%) pa c ie n te s re c e b e ra m tra ta m e n to a n tim o n ia l c o n tín u o du ra n te 25 a 116 dia s e 94 ( 67,6%) re c e b e ra m tra ta m e n to in te rm ite n te c o m 2 a 5 sé rie s de a n tim o n ia to de m e glu m in a , c a da u m a de la s c o m du ra ç ã o de 10 a 25 dia s e c u jo s in te rva lo s de de sc a n so e n tre a s sé rie s va ria ra m de 10 a 60 dia s. A do se de a n tim ô n io , c a lc u la da re tro spe c tiva m e n te e m 66 ( 47,5%) c a so s, va rio u e n tre 3,9 e 28,7m g Sb5+/k g/dia .
De sse s pa c ie n te s, 35 re c e b e ra m > 10m g e 31 re c e b e ra m < 10m g Sb5+
/k g/dia . Nã o ho u ve dife re n ç a sign ific a tiva n o te m po de cica triza çã o e ntre a dulto s e cria nça s, e ntre e sq ue m a s inte rm ite nte s e ininte rrupto , ne m e ntre do se s a lta s e b a ixa s. Entre ta nto , o te m po de c i c a tri za ç ã o n a s pe rn a s e pé s ( 67,5 di a s) f o i su pe ri o r a o e n c o n tra do e m o u tra s lo c a li za ç õ e s ( 48,7 di a s) ( p < 0,001) . Cinq üe nta e um pa cie nte s fo ra m re a va lia do s e ntre cinco e 14 a no s a pó s o tra ta m e nto e m a ntinha m -se clinica m e nte cura do s. Essa sé rie o rigino u e nsa io s clínico s pro spe ctivo s utiliza ndo do se s b a ixa s de a ntim ô nio no Rio de Ja ne iro .
Pal avr as-chave s: Le i sh m a n i o se Cu tâ n e a . Le ishmania ( Viannia) b r azilie nsis. Te ra p ê u ti c a . An ti m o n i a to d e m e glu m i n a . Esq u e m a s te ra p ê u ti c o s.
1 . Ce ntr o de Re fe r ê nc ias e m Le ishmanio se s do Instituto de Pe sq uisa Clínic a Evandr o Chagas da Fundaç ão Oswaldo Cr uz, Rio de J ane ir o , RJ , B r asil. 2 . Se r viç o de Espe c ialidade s Clínic as do De par tame nto de Do e nç as Infe c c io sas do Instituto de Pe sq uisa Clínic a Evandr o Chagas da Fundaç ão Oswaldo Cr uz, Rio de J ane ir o , RJ , B r asil. 3 . De par tame nto de Epide mio lo gia do Instituto de Pe sq uisa Clínic a Evandr o Chagas da Fundaç ão Oswaldo Cr uz, Rio de J ane ir o , RJ , B r asil. 4 . Se r viç o de Endo sc o pia Pe r o r al do Ho spital Ge r al de B o nsuc e sso , Rio de J ane ir o , RJ , B r asil.
Addr e ss to: Dr. Ar mando Sc hub ac h. IPEC/FIOCRUZ. Av. B r asil 4 3 6 5 , 2 1 0 4 0 - 9 0 0 Rio de J ane ir o , RJ , B r asil. Te l: 5 5 2 1 3 8 6 5 - 9 5 3 6 ; fax: 5 5 2 1 3 8 6 5 - 9 5 4 1
Sc huba c h AO e t al
In Rio de Janeir o , Amer ic an tegumentar y leishmaniasis ( ATL) is c aused by Le ishm a nia ( Via nnia ) b ra zilie nsis, whose tr ansmissio n is de pe nde nt o n the adaptatio n o f the ve c to r Lutzo m yia inte rm e dia to the peridomiciliary environment1 9. The
disease affec ts the skin and muc osae. Cutaneous leishmaniasis ( CL) presents as skin ulcers in body sites exposed to the sandflies’ bite. These ulcers may regress without any treatment after a period of several months to years7. The patients may remain c ured or
reac tivation of sc ars or development of muc osal lesions may oc c ur4 0. Muc osal leishmaniasis ( ML) presents as c hronic and
destruc tive lesions of the oral, nasal, pharyngeal and/or laryngeal tissues. A higher risk of reac tivation and development of ML is b e lie ve d to b e asso c iate d with inc o m ple te o r inade q uate treatment1 6 1 7 1 8 4 1.
Pentavalent antimonials have been used in the treatment of le ishmaniasis fo r mo r e than 6 0 ye ar s1 1. De spite the b r o ad
spec tr um o f c linic al and i n vi tro se nsitivity to pe ntavale nt a ntim o nia ls e xhib ite d b y diffe r e nt spe c ie s a nd str a ins o f Le ishm a nia around the world, some therapeutic guidelines have been suggested1 0 1 3 4 2. However, c linic al assays c ontinue to be
perfo rmed to define the therapeutic regimen best suited to different regions of the globe3 3. The main differenc es between
the therapeutic regimens available relate to the use of meglumine antimoniate or sodium stibogluconate, continuous or intermittent administration, total daily dose, duration of treatment, the criteria used for disc ontinuation or prolongation of treatment, and the Le ishm a nia spec ies and strains involved4.
Until the mid-eighties, the treatment protoc ol for adult ATL at Evandro Chagas Clinic al Researc h Institute ( IPEC) c onsisted of one daily 5 -ml vial IM of meglumine antimoniate, irrespec tive of body weight3 7. We present here a retrospec tive series of CL
c ases treated with fixed doses of antimony independent of body weight, 5 1 of these were reassessed several years after treatment. The objec tive of this paper was to present the retrospec tive series of c ases that enc ouraged prospec tive c ohort studies and c linic al trials in Rio de Janeiro ( Southeast Region of Brazil) using low doses of antimony2 9 3 0.
MATERIAL AND METHODS
The study was appro ved by the Ethic s Co mmittee o f the Os wa ldo Cr uz Fo un da tio n ( Fio c r uz) a n d wa s c o n duc te d ac c ording to Resolution # 1 /8 8 of the National Health Counc il2 4. Retr ospective study ( r ecor d r eview) . The records and charts of patients with ATL seen at IPEC from 1 9 6 7 to 1 9 8 2 were reviewed. To be included, the following information had to be available: a) an epidemiologic history consistent with ATL acquired in the State of Rio de Janeiro; b) presence of cutaneous lesions suggestive of CL; c) diagnosis based on a positive Montenegro skin test ( MST) and/or demonstration of the parasite in culture, by direct examination or by histopathology; and d) treatment with meglumine antimoniate. Additionally, data about Le ishm a nia spec ies c harac terization based on monoc lonal antibody, and isoenzyme analysis1 2 2 5 were obtained from the charts. Of the 3 3 3
records reviewed, only 1 5 1 ( 4 5 .3 %) fulfilled the inclusion criteria.
Frequenc y distributions and medians with perc entiles 2 5 and 7 5 are presented. We performed an analysis of treatment effec tiveness. The results of treatment c omprised presenc e or absenc e of a good therapeutic response, defined as a written r e c o r d o f c o mple te sc ar r ing ( he aling) o f the le sio ns afte r treatment. The time in days to ac hieve the results of treatment with meglumine antimoniate sinc e the beginning of treatment was c ompared, ac c ording to the presenc e or absenc e of the following variables: age ( > or < 1 8 years) , body site of the lesions ( le gs o r fo o t ve r sus o the r ) , do se o f antimo ny administe r e d ( > o r < 1 0 mg/kg/day) , and c o ntinuo us versus intermittent treatment. The Kolmogorov Smirnov test rejec ted all the null hypothesis c onc erning the normality of c ontinuous variables distribution. Therefore, we c hose the nonparametric Mann-Whitney test to c ompare median times of healing between groups.
Cr oss- sectional study ( r eassessment of the patients) .
Between September 1 9 8 6 and January 1 9 8 8 , an ac tive searc h for these patients was c onduc ted. Fifty-one patients were loc ated again and reassessed after signing the informed c onsent form to partic ipate in the c ross-sec tional study. The patients were seen at IPEC for medic al history and physic al, dermatologic and ENT ( ears, nose and throat) examinations. The latter included anterior rhinosc opy, posterior rhinosc opy and laryngosc opy with Hopkins optic s 0 º and 9 0 º. Leishmanin was provided by the Institute of Biologic al Sc ienc es, Federal University of Minas Gerais2 2 for MST.
All tests and measurements with a ballpoint pen3 8 were performed
by a single observer. An indirec t immunofluoresc enc e assay ( IFA) was performed for the detec tion of anti-Le ishm a nia antibodies5.
Pr o m a s tigo te s o f th e B r a zilia n s tr a in MHCM/B R /7 6 /J OF, phenotypic ally similar to L. m a jo r2 6, were used as antigen.
RESULTS
Retr ospective study ( r ecor d r eview) . Of the 3 3 3 rec ords reviewed, 1 5 1 fulfilled the inc lusion c riteria, with 1 3 7 ( 9 0 .7 % ) of them from the metropolitan region of Rio de Janeiro. Patients we r e 7 4 m e n a nd 7 7 wo m e n, m e dia n a ge 1 6 ye a r s with perc entiles 2 5 and 7 5 of 8 to 3 0 .8 years for age and 1 to 1 0 months ( median = 3 months) for duration of disease.
Th e m e dia n n um b e r o f le s io n s pe r pa tie n t wa s o n e . One-hundr ed-and-five ( 6 9 .5 % ) patients had single lesio ns, 2 2 ( 1 4 .5 % ) had two lesions and 2 4 ( 1 6 % ) had three or more le sio ns. Upo n tr e atme nt, 1 2 ( 8 % ) patie nts had o nly sc ar s suggestive of CL and 1 3 9 ( 9 2 % ) had ac tive lesions. The twelve patients ( 8 adults and 4 c hildren aged up to 1 2 years) with c ic atric ial lesions at the beginning of treatment were exc luded fr o m the analysis o f tr eatment effec tiveness. These patients underwent prophylac tic treatment to prevent the development of ML and rec eived 5 0 -1 2 5 doses of meglumine antimoniate. Le ishm a nia was isolated from the sc ar of one of these patients 8 years after treatment with an intermittent sc hedule3 6.
known in 1 3 2 patients, thirty-four ( 2 6 % ) of whic h had ac tive lesions in the feet or legs.
The MST was positive in 1 4 3 ( n = 1 4 7 , 9 7 .2 % ) patients. IFA revealed serum titers between 1 :4 0 and 1 :3 2 0 in 2 7 ( n = 4 0 , 6 7 .5 %) patients. The parasite was detected by direct examination, histopathology or c ulture in 3 8 ( n = 6 1 , 6 2 .3 % ) patients. Nine out of 2 1 positive c ultures were identified as L. ( V.) b ra zilie nsis. All pa tie n ts r e c e ive d da ily in tr a m us c ula r m e glum in e antimoniate. Of the 1 3 9 patients with ac tive lesions, 8 1 adults rec eived a full 5 -ml vial daily and 5 8 c hildren rec eived a frac tion of the vial, ranging from 1 to 5 ml ( median 2 ml) , doses being determined empiric ally. In 6 6 ( n = 1 3 9 , 4 7 .5 % ) c ases for whic h body weight was recorded, the median antimony dose 11mg/kg/day ( 7 .5 mg/kg/day to 1 5 .3 mg/kg/day) c ould be c alc ulated. Thirty-five ( 5 3 % ) of these 6 6 patients rec eived > 1 0 mg Sb5 +/kg/day
and 3 1 ( 4 7 % ) patients rec eived < 1 0 mg.
F o r ty- fi ve ( n = 1 3 9 , 3 2 . 4 % ) p a ti e n ts u n d e r we n t c o ntinuo us tr e atme nt with me glumine antimo niate fo r 2 5 to 1 1 6 days, witho ut r e st inte r vals, and 9 4 ( 6 7 .6 % ) unde r we nt i n te r m i tte n t tr e a tm e n t, c o n s i s ti n g o f 2 to 5 s e r i e s o f me glumine antimo niate with 1 0 to 2 5 days dur atio n e ac h, and inte r vals o f 1 0 to 6 0 days b e twe e n e ac h se r ie s. Ho we ve r, 1 6 pa tie nts c o ns ide r e d to ha ve unde r go ne a c o ntinuo us regimen were in fac t patients who did no t return fo r additio nal the r apy, b e c ause le sio ns he ale d afte r a single 2 5 -day se r ie s. Overall, the median time to healing after the beginning of treatment was 5 0 days ( 3 0 - 6 0 days) . The median time ( and per c entiles 2 5 and 7 5 ) o f healing was lo nger – 6 7 .5 days ( 4 3 .8 - 9 1 .3 days) – for lesions in the legs and feet than for lesions at other sites – 4 8 .7 days ( 3 0 - 6 0 days) ( p < 0 .0 0 1 ) .
Apparent differenc es in the median time of healing between adults ( 5 0 days) and c hildren ( 4 0 days) ( p = 0 .5 3 ) ; intermittent ( 5 0 days) and c ontinuous ( 4 0 days) regimen ( p = 0 .6 3 ) ; or high ( 5 0 days) and low ( 5 0 days) antimony doses ( p = 0 .8 8 ) did not reac h statistic al signific anc e ( Table 1 ) .
Overall, the median number of injec tions per patient was 6 6 ( ranging from 2 5 to 1 2 5 and the median duration of treatment
was 9 0 . 0 days with 5 0 % o f o b se r vatio ns in the fo llo wing interquartile interval ( 5 0 days - 1 1 0 days) .
In the subgroup of patients undergoing c ontinuous treatment ( n = 4 5 ) , there was a c orrelation between median duration of treatment – 4 0 days ( 2 5 - 5 8 days) , median number of antimony injec tions rec eived – 4 0 ( 2 5 - 5 0 ) ( r = 0 .9 9 ; p = 0 .0 0 0 ) and median time to healing – 4 0 days ( 3 0 - 6 0 days) ( r = 0 .6 9 ; p = 0 .0 0 0 ) .In the subgroup of patients undergoing intermittent treatment, median duration of treatment was obviously longer – 1 0 0 days ( 9 0 - 1 2 0 ) than the median number of antimonial daily injec tions – 7 5 ( 6 0 - 7 5 ) . However, in this sub-group, both the median duration of treatment – 1 0 0 days ( 9 0 - 1 2 0 days) and the median number of antimony injec tions – 7 5 ( 6 0 - 7 5 ) were greater than time until healing – 5 0 days ( 3 0 - 6 0 days) and they did no t c o r r e la te with e a c h o the r ( p = 0 . 1 9 ; p = 0 . 2 2 , respec tively) .
Cr oss- sectional study ( r eassessment of the patients) .
Fifty-one patients were reassessed at a median of seven years after treatment. Thirty-three of these patients had been treated with a known dose of antimony: 1 7 patients with > 1 0 mg Sb5 +/kg
body weight/day and 1 6 with < 1 0 mg. All patients were still living in their area of origin. There were 2 5 men and 2 6 women ranging from 1 0 to 6 3 years of age ( median = 2 3 ) . All patients remained asymptomatic and presented atrophic c utaneous sc ars and no muc osal lesions. The MST was positive in 5 0 ( n = 5 0 , 1 0 0 % ) patients. The IFA was positive ( IgG = 1 :4 0 ) in the serum of 5 ( n = 5 1 , 1 0 % ) patients.
DISCUSSION
We studied 1 5 1 patients with CL from Rio de Janeiro who had rec eived one ampoule or less of meglumine antimoniate intramusc ularly daily. The limitations of this study are related to bias inherent in unc ontrolled real settings of treatment suc h as: diffic ulties in r ec o ver ing data fr o m c har ts o f patients seen b y diffe r e nt physic ians; ir r e gular data r e c o r ding; diffe r e nt therapeutic sc hedules and variable c riteria to evaluate response to therapy.
For the treatment of CL, the World Health Organization4 2 has
rec ommended the use of 1 0 -2 0 mg Sb5 +/kg body weight/day,
without interruption until c ure, for at least three weeks3 1. In
Brazil, the same daily dose for 2 0 days, with a maximum of 3 ampo ule s daily, is r e c o mme nde d. Re -tr e atme nt sho uld b e c onsidered in c ases in whic h c omplete sc arring is not ac hieved thr e e mo nths afte r the e nd o f the initial tr e atme nt1 0. It is
interesting to note that both fixed doses of antimony used in patients desc ribed in the present study and restric tion of the maximum daily dose in contemporary official Brazilian guidelines c an lead to the use o f do se s lo we r than 1 0 mg Sb5 +/k g b o dy
we ight/day.
Continuous or intermittent schedules with 2 0 mg Sb5+/kg body
weight/day are well tolerated, and intravenous administration has been preferred bec ause pain and disc omfort at the site of in j e c tio n a r e fr e q ue n t wh e n la r ge vo lum e s a r e in j e c te d intramusc ularly2 3 4 1 3 3 5. Other authors have reported renal tubular
Table 1 - Median , an d percen tiles 25 an d 75 of tim e to healin g sin ce be gin n in g of the r apy with m e glu m in e an tim on iate to tr e at active cu tan eou s leishm an iasis, Rio de Jan eiro ( n = 139) .
Median time Percentiles p value of
Mann-Variable to scarring ( days) 2 5 - 7 5 Whitney test*
Age
adult > 1 8 years ( n= 8 1 ) 5 0 .0 3 0 .0 - 6 0 .0 0 .5 3
children < 1 7 years ( n= 5 8 ) 4 0 .0 3 0 .0 - 6 0 .0
Schedules
continuous ( n= 4 5 ) 4 0 .0 3 0 .0 - 6 0 .0 0 .6 3
intermittent ( n= 9 4 ) 5 0 .0 3 0 .0 - 6 0 .0
Daily doses
> 1 0 mg Sb5+/Kg/ day ( n= 3 5 ) 5 0 .0 3 0 .0 - 7 0 .0 0 .8 8
< 1 0 mg Sb5+/Kg/ day ( n= 3 1 ) 5 0 .0 3 0 .0 - 6 0 .0
Location of lesions
legs and feet ( n= 3 4 ) 6 7 .5 4 3 .8 - 9 1 .3 0 .0 0 1
other ( n= 9 8 ) 4 8 .7 3 0 .0 - 6 0 .0
dysfunc tio n, c ardiac , hepatic , panc reatic and hemato lo gic al alterations1 8 9 3 4. In Rio de Janeiro, c ontinuous sc hedules with
5 mg Sb5 +/kg body weight/day has been safe and effec tive for
treatment of ATL2 8 2 9 3 0. In this study, no signific ant differenc e in
the time o f he aling was o b se r ve d b e twe e n the the r ape utic sc hedules used and high and low doses. Unfortunately, adverse effec ts wer e no t r ec o r ded o n a r egular b asis in the c har ts reviewed.
It was reported that pentavalent antimony is rapidly exc reted in urine6. Miekeley et al2 3 c onfirmed these results. However, in
c ontrast to previous reports, this rapid exc retion phase was followed by a slower one with a half-life > 5 0 days. These authors fo und e vide nc e o f the i n vi vo c o nve r s io n o f m e glum ine antimoniate into the ionic spec ies Sb5 + and Sb3 +, leading to
c onsiderable c onc entrations of Sb3 + in body fluids as suggested
pr e vio usly4 3. This finding suppo r ts the hypo the sis that the
formation of Sb3 + may be responsible for both the observed
long-term toxic ity of the drug and its therapeutic ac tion3 2.
In the present study, lesion healing had oc c urred within the period established by Brazilian therapeutic guidelines1 0 in 9 7 .1 %
o f the patients, despite the fac t that healing time c o uld b e overestimated due to time elapsed from sc arring to medic al observation and rec ording on the c hart. In the subgroup of patie nts who unde r we nt c o ntinuo us tr e atme nt, dur atio n o f treatment and time until healing were similar and sc arring de te r mine d the inte r r uptio n o f antimo nial administr atio n. However some patients in this subgroup had shorter duration of treatment than time intervals until healing, suggesting that it may not been nec essary to c ontinue antimonial applic ation until total he aling o f CL le sio ns o c c ur s. In the sub -gr o up o f patie nts undergoing intermittent treatment, both the duration of treatment and the number of injec tions per patient were higher than time of healing, suggesting that, in these c ases, one or more of the additional series were unnec essarily administered after lesion healing. Other studies have shown that c utaneous lesions whic h do not heal until the end of treatment c ould heal without the need for re-treatment4. Lesions loc ated on legs and feet take
longer to heal, suggesting venous stasis c ould be a delaying fac tor, as previously reported1 8.
Pe r siste nc e o f the par asite in o ne patie nt witho ut signs o f ac tive dise ase de mo nstr ate s that tr e atme nt did no t always e liminate the par asite and that this might no t b e ne c e ssar y to e stab lish c linic al he aling.
The 5 1 patients reassessed 5 to 1 4 years after treatment remained asymptomatic and fulfilled the c riteria used to define clinical cure of ATL4 2, i.e., healed skin lesions, absence of mucosal
lesions and a positive MST. Five ( 1 0 %) patients presented positive IFA at low titers ( 1 :4 0 ) . Some investigators have suggested that a negative IFA should also be inc luded in the c riteria of c ure3 9.
Ho wever, the c linic al value o f persistent antibo dy levels fo r p r e di c ti n g ATL r e c u r r e n c e i n e n de m i c a r e a s h a s b e e n questioned1 5 4 1. Other authors have obtained similar results with
th e r a p e utic s c h e m e s diffe r e n t fr o m th e o n e s c ur r e n tly r ec o mmended2 0 2 1. Mar sden1 8 sugge ste d that a lo w do se o f
meglumine antimoniate for the treatment of CL might prevent
invo lve me nt o f the muc o sae . Othe r inve stigato r s o b se r ve d c utaneous relapse and evolution to ML in 3 to 9 .1 % of c ases followed up for a period of 6 years after treatment1 4 2 7 4 1. Walton
et al4 0 has suggested the need for longer periods of observation.
The present study indic ates that lower doses of antimony c ould be as effec tive as higher doses.
ACKNOWLEDGMENTS
We wish to thank Dr. Thyedimo de C. Peixoto (in m e m o ria m) and Dr. Manoel Paes de Oliveira-Neto for the indication of the r e c o r ds o f h is pa s t pa tie n ts , th e dr ive r Ma n o e l So a r e s (in m e m o ria m) ; the social assistants Ana Luiza C. Oliveira, Ana Mariela G. Soares and Maria da Graça Soaresfor their performance in finding and rec overing the patients; the medic al students Aline Pac hec o Sc hubac h and Renata de So uza Co utinho fo r including the data in the databank; and Gabriel Grimaldi Jr and Hooman Momen for identification of the Le ishm a nia isolates.
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