Revista da Sociedade B rasileira de M edicina Tropical 18(3): 18(3): 187-198, Jul-Set, 1985
REVISÃO
PENTAVALENT ANTIMONIALS: OLD DRUGS FOR NEW DISEASES
Philip Davis Marsden
I N T R O D U C T I O N
C l in ic ia n s lik e m y s e l f f e e l a s e n s e o f p r e s s u r e b e c a u s e th in g s c h a n g e s o s lo w ly f o r th e p a t i e n t in s p ite o f th e v o lu m e o f c u r r e n t r e s e a r c h . T h is is c u r r e n tl y th e c a s e in th e c h e m o th e r a p y o f le is h m a n ia s is w h e r e th e d ru g f o r m u la tio n s u s e d in th e f ir s t lin e t r e a t m e n t h a v e n o t c h a n g e d f o r f o u r d e c a d e s . N e i t h e r is a p r a c tic a l a lte m a tiv e o n t h e h o r iz o n . T h e r e is n o m o n e y to b e m a d e in tr e a t i n g t h e p o o r p e o p l e o f r u r a l a r e a s s u ffe rin g fro m th is d is e a s e . T h e s m a ll e f f o rts t h a t h a v e b e e n e x te n d e d in th is d ir e c tio n h a v e n o t m e t w ith s u c c e s s . T h e r e f o r e w e m u s t t r y to u s e a n tim o n ia ls m o r e e ffic ie n tly f o r th e b e n e f it o f th e p a t i e n t a n d th is is th e c h ie f p u r p o s e o f th is r e v ie w .
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W e a r e i n d e b te d t o D r . E d g a r d d e C e r q u e ir a F a l c ã o2 3 f o r a m o n o g r a p h s u m m a r is in g th e c o n tri- b u tio n s o f G a s p a r V ia n n a w ith a c o l le c tio n o f h is sc ie n tific p a p e r s . T h e o r ig in a l c o m m u n ic a tio n o n th e u s e o f t a r t a r e m e tic in c u t a n e o u s a n d m u c o s a l le is h m a n ia s is is r e p r o d u c e d 7 2 . A l s o , in a le s s w e ll k n o w n p a p e r , V ia n n a ill u s tr a te s a v e r y g o o d r e s u l t in a p a t ie n t w ith s e v e r e m u c o s a l d i s e a s e 7 3 . H e u s e d a 1 % s o lu tio n o f t a r t a r e m e tic a lth o u g h t h e o r ig in o f th e d r u g is n o t s ta te d . E a r l y p r e p a r a t i o n s o f t a r t a r e m e tic w e r e m a d e b y a llo w in g a n t im o n y g o b le ts t o s ta n d w ith w h ite w in e a n d e x t r a c ti n g t h e s u p e m a t a n t . C o n f ir m a tio n o f V ia n n a ’s f a v o u r a b le r e s u lt s fo llo w e d in s e v e r a l B r a - z ilia n p u b lic a t io n s62 2 ^ 9 j n 1 9 1 5 th e e f f e c tiv e n e s s o f t a r t a r e m e tic in th e t r e a t m e n t o f in f a n tile k a l a - a z a r in I ta l y w a s r e p o r t e d 1 9 . T h e d r u g w a s th e n w id e ly u s e d d u r in g th e e p id e m ic o f k a l a - a z a r o n th e t e a e s t a t e s in A s s a m 4 5 .
N ú c l e o d e M e d i c i n a T r o p i c a l e N u t r i ç ã o , U n iv e r s id a d e d e B r a s ília - 7 0 9 1 0 B r a s í l i a - D F , B r a s il.
R e c e b id o p a r a p u b l i c a ç ã o e m 2 3 / 5 / 8 5 .
T h e m a i n s u p p o r t o v e r t h e y e a r s f o r th e s e c lin ic a i s tu d ie s h a s b e e n f ro m a U n i t e d S t a te s P u b l i c S e r v ic e G r a n t ( A I 1 6 2 8 2 ) , a d m i n is te r e d b y th e D e p a r t m e n t o f I n t e r n a ti o n a l M e d ic in e , C o m e ll M e d i c a i C o lle g e , N e w Y o rk .
F o r th o s e o f u s w h o h a v e u s e d t a r t a r e m e tic it is o b v io u s t h a t its s e v e r e s id e e f f e c ts m a d e a n a l te m a tiv e d e s ir a b le . B r a m a c h a r i in 1 9 2 0 d e v e lo p e d th e firs t p e n t a v a l e n t a n tim o n ia l: u r e a s tib a m in e 5 5 . A m o re s ta b le p e n t a v a l e n t a n t im o n ia l b y S c h m id t in G e r m a n y in 1 9 3 6 u n d e r th e n a m e S o lu s tib o s a n ( s o d iu m a n - tim o n y l (V ) g lu c o n a te 6 3 ) h a d t h e a d v a n ta g e o v e r th e e a r lie r N e o s t i b o s a n in t h a t i t w a s s ta b le in w a te r a n d c o u l d b e s to r e d in s o lu tio n u n til r e a d y f o r u s e . A ls o it c o u l d b e g iv e n in tr a m u s c u l a r ly , in tr a v e n o u s ly a n d s u b c u ta n e o u s ly s in c e it w a s n o t i r r i ta n t to tis s u e s e v e n in a h y p e r to n i c s o lu tio n . I t w a s f ir s t p r o d u c e d b y B a y e r a n d s h o w n t o b e e ffe c tiv e in k a l a - a z a r in í n d i a a n d C h i n a 3 6 4 6 . T h e W e llc o m e p r o d u c t P e n to s t a m is s o d iu m a n tim o n y g lu c o n a te . A n a lte m a ti v e p e n t a v a l e n t a n tim o n ia l, G l u c a n t i m e ( N - m e th y l- g lu c a m in e a n t im o n ia te ) w a s d e v e lo p e d a t th e e n d o f th e S e c o n d W o r l d W a r . E a r l y s tu d ie s o f its e f f ic a c y in b o th c u t a n e o u s a n d v is c e r a l le is h m a n ia s is a p p e a r e d in F r e n c h l it e r a tu r e2 1 5 7 . I ts v a lu e in p a t ie n t s w ith m u c o s a l le s io n s w a s r e p o r te d f ro m B r a z il in 1 9 5 2 1 5 . T o d a y G l u c a n tim e is p r o d u c e d b y R h o d ia in B ra z il a n d is w id e ly u s e d . P e n t o s t a m is n o t a v a ila b le h e re .
T h e m o d e o f a c tio n o f th e s e d ru g s in le is h m a n ia s is is u n k n o w n .
G l u c a n tim e a n d P e n t o s t a m
T h e s e a r e th e o n ly tw o p e n t a v a le n t a n tim o n ia ls a v a ila b le c o m m e r c ia lly . B o t h a r e in itia lly m a n u - f a c tu r e d a s w h ite p o w d e r s ( a p p r o x im a te ly 3 4 % a n t im o n y c o n t e n t) a n d a r e r e a d ily s o lu b le in w a te r. B o t h s o lu tio n a r e b e s t k e p t in t h e d a r k s in c e th e y m a y u n d e r g o c h e m ic a l c h a n g e i f e x p o s e d to th e lig h t.
S in c e th e y d o n ’t h a v e d e f in e d c h e m ic a l fo r- m u la e th e y a r e d if fic u lt to s ta n d a r d is e . S te c k6 7 g iv es th e f o r m u la e f o r th e tw o c o m p o u n d s illu s tr a te d in F i g u r e 1 . I t h a s b e e n s u g g e s te d t h a t to x ic ity is n o t n e c e s s a r ily r e la te d to a n t im o n y c o n t e n t3 1 . A c tiv ity a n d to x ic ity m a y v a r y f ro m b a t c h t o b a t c h 3 . T h e a u t h o r h a s p e r s o n a l e x p e r ie n c e o f th is w ith b o th d ru g s. I t is w o r t h c itin g a c o m m e n t o n th e p e n ta v a le n t a n t im o n ia ls 3 2 .
Revisão. M arsdert PD, P entavalent antim onials: o ld drugs fo r new diseases. R evista da Sociedade B rasileira de M edicina Tropical 1 8 :1 8 7 -1 9 8 , Jul-Set, 1985
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“ T h e s e d r u g s , u n d e r w h a te v e r n a m e , a r e s im p ly s o lu tío n s o f a n t im o n y p e n t o x id e in a h ig h ly h y d r o - x y la te d o r g a n ic m e d iu m a n d m a k in g th e m is c o o k e r y , n o t c h e m is try . O n e c a n m a k e s u c h a d ru g t o c o n ta m a n y a m o u n t o f a n t im o n y , a n d t o h a v e a n y d e g r e e o f to x ic ity ; o n e h a s t o c h o o s e a m e th o d o f m a k in g i t w h ic h p r o v id e s a r e a s o n a b le p r o d u c t, w ith r e a s o n a b le a c tiv ity a n d r e a s o n a b ly lo w to x ic ity . W h e n o n e p u ts it in to a p a t ie n t a b o u t 8 0 o r 9 0 % o f t h e a n tim o n y it c o n ta in s is e x c r e te d b y t h e k id n e y s in th e f ir s t fe w h o u r s , s o o n e is r e ly in g o n w h a t is le ft in t h e a n im a l, s o a k e d in to th e tis s u e c e lls , w h ic h l a t e r r e d u c e it to tr iv a le n t a n tim o n y ( G o o d w i n & P a g e 1 9 4 3 ) . T h is is th e k ille r, h o p e f u lly , o f t h e p a r a s i t e b u t u n f o r tu n a te ly s o m e tim e s o f th e p a t i e n t . ” A v a r ia tio n in a n ti- le is h m a n ia l a c tiv ity in d if f e r e n t a m p o u le s o f G l u c a n - tim m e h a s b e e n n o te d in a n
in vitro
s y s t e m 4 3 . A r e v a lu a tio n o f th is p r o b le m is lo n g o v e r d u e s in c e p e n t a v a le n t a n tim o n ia ls r e m a in t h e d r u g s o f c h o i c e 1. T h e r e a p p e a r s t o b e little d if f e r e n t in a c tio n b e t w e e n P e n to s t a m a n d G l u c a n t i m e8 a lth o u g h a g o o d c o m - p a r a tiv e tr i a l h a s y e t t o b e d o n e .G lu c a n tim e is m a r k e te d in 5 m l a m p o u le s c o n ta in in g 1 .5 g r a m s o f t h e d r u g m e g lu m in e a n ti- m o n ia te a n d 4 2 5 m g p e n t a v a l e n t a n tim o n y ( t h e e q u iv a le n t o f 8 5 S b v m g p e r m l). P e n t o s t a m is p r e s e n te d in 1 0 0 m l f la s k s e a c h m l c o n t a in i n g 1 0 0 m g S b v . T h e a m p o u le h a s a n a d v a n ta g e o v e r t h e f la s k fo r t r ç a tm e n t in t h e f ie ld s in c e a m p o u le s a r e le s s lia b le to c o n ta m in a tio n b y lo c a l p e o p l e a p p ly in g r e p e a te d in je c tio n s f o r p a t ie n t s . T h e s e a p p l ic a to r s u s u a lly c a n o n ly g iv e i n tr a m u s c u l a r in je c tio n s . T h e v o lu m e u s in g P e n to s t a m is 1 5 % le s s , r e d u c in g lo c a l p a i n a little w h e n la rg e d o s e s a r e a p p lie d in tr a m u s c u l a r ly .
Revisão. M arsd en PD. P entavalent antim onials: o ld drugs fo r new diseases. R evista da Sociedade B rasileira de M edicina Tropical 18: 187-198, Jul-Set, 1985
I n 1 9 8 4 S U C A M b o u g h t 3 9 2 ,3 2 9 a m p o u le s o f G lu c a n tim e . T h e M in i s tr y o f H e a l t h h a s c a l c u la t e d it w ill b u y 6 0 0 , 0 0 0 a m p o u le s in 1 9 8 5 ( J B F V ie ira : p e r s o n a l c o m m u n ic a ti o n ) . R h o d i a s ’ 1 9 8 5 p r ic e to S U C A M p e r a m p o u le s is 6 , 7 3 2 c r u z e ir o s ( a b o u t 1 .2 A m e r ic a n d o lla r s ) . H o w m u c h p r o f it R h o d i a m a k e s p e r a m p o u le is n o t k n o w n . W e llc o m e h a v e n o in te r e s t in m a r k e tin g P e n t o s t a m in B r a z il. T h e a u t h o r k n o w s o f tw o a t te m p ts b y th e B r a z ili a n g o v e m m e n t to p r o d u c e th e d r u g n e i th e r o f w h ic h h a s b e e n s u c c e s s fu l. í n d i a is p ro d u c in g a s a tis f a c to r y s o d iu m s ti b o g lu c o n a te ( R A N e a l: p e r s o n a l c o m m u n ic a ti o n ) a n d th is m ig h t b e a c h e a p e r s o u r c e o f d r u g , i f d e m a n d c o n t in u e s to in c re a s e .
Absorption, distribution a n d excretion
S o m e a s p e c ts h a v e b e e n r e v ie w e d b y B e v e rid g e ^ . M a n y a n tim o n y d r u g s lik e t a r t a r e m e tic a r e to o i r r i ta n t to b e g iv e n b y m o u th b u t P a n a y o t a t o u5 3 c u r e d a c a s e o f in f a n tile k a l a - a z a r b y in s t illa tio n p e r r e c tu m o f a tr iv a le n t s a lt. I n o u r c u r r e n t s itu a tio n p e r h a p s h e r o b s e rv a tio n s s h o u ld b e f o llo w e d u p a n d th e v a lu e o f th e o ra l r o u te f o r p e n t a v a l e n t a n t im o n ia ls r e v ie w e d in s u ita b le a n im a l e x p e r im e n ts .
P a r e n t e r a l p e n t a v a l e n t a n tim o n y a c h ie v e s p e a k b lo o d le v e is w ith in a n h o u r . I n t r a m u s c u l a r in je c tio n re s u lts in a s lig h tly lo w e r , l a t e r p e a k t h a n in tr a v e n o u s a p p lic a tio n b u t th is m a k e n s little d if f e r e n c e 1 2. T h e d ru g is r a p id l y e x c r e te d in t h e u r in e 2 ^ 51 A f t e r 6 h o u r s b lo o d le v e s h a v e f a ll e n t o le s s t h a n 1% o f p e a k v a lu e s a n d m o r e t h a n 8 0 % h a s b e e n e x c r e te d in th e u r in e 5 9 . T h u s p a t ie n t s a r e v o id in g t h e g r e a te r p a r t o f th e d r u g th e y re c e iv e . T h i s r a i s e s th e in te r e s ti n g p o s s ib ili- ty o f in te r f e r in g w ith th is r a p id e x c r e tio n a n d th e re - fo re u s in g s m a lle r d o s e s to a c h ie v e th e s a m e e ffe c t. B e c a u s e o f th e p o te n tia l to x ic ity o f a n tim o n ia ls th is im p lie s a n o t h e r s e r ie s o f a n im a l s tu d ie s . T h e h a m s te r is n o t a g o o d m o d e l f o r s u c h s tu d ie s s in c e th e k id n e y is c o m p o s e d a l m o s t e n tir e ly o f lo n g lo o p n e p h r o n s . T h e d o g w o u ld b e a m o r e s u it a b le m o d e l to m im ic t h e h u m a n s itu a tio n .
A b o u t 1 2 % o f th e a n t im o n v d o s e is r e ta in e d w ith a h a lf-life o f 3 2 .8 ± 3 .8 h o u r s 1 2 . W i t h r e p e a te d in je c tio n s a r is e in th e b a s e lin e le v e i o f r e ta in e d a n tim o n y c a n b e o b s e r v e d o v e r th e in itia l fiv e d a y s o f tr e a tm e n t. S o m e o f th is a n t im o n y is th o u g h t to b e r e d u c e d t o t h e t r i v a l e n t sta te ^ O a n d t r i v a l e n t a n tim o n y c o m p o u n d s m a y b e le s s e f f e c tiv e t h a n p e n t a v a l e n t in k illin g L e i s h m a n i a 3 5 . M u c h t h e r e ta in e d a n tim o n y is c o n c e n t r a te d in t h e liv e r a n d s p le e n2 7 58 T h e s e is n o
in f o r m a tio n o n h o w m u c h o f th is a n tim o n y is p r e s e n t in t h e s k in o r m u c o u s m e m b r a n e s a lth o u g h it is p r o b a b ly a v e r y s m a ll a m o u n t. Y e t in s k in o r m u c o s a l le s io n s it is th is f r a c tio n t h a t m u s t b e im p o r ta n t. T h e r e is so m e r a ti o n a le th e n f o r a t te m p tin g lo c a l a n tim o n y tr e a tm e n t in s k in u l c e r s1 6 5 . S o m e s u c c e s s in a n im a is h a s b e e n n o te d w ith P e n t o s t a m c r e a m4 2 w h ic h is n o w b e in g tr ie d in m a n . O b v io u s ly s u c h lo c a l t r e a tm e n t is in s u f f ic ie n t f o r o r g a n is m s c a u s in g s y s te m ic d is e a s e o r th o s e w h ic h p r o d u c e m e ta s t a t i c le s io n s .
I t is th e a n t im o n y r e ta in e d in th e tis s u e s w h ic h is th o u g h t to b e r e s p o n s i b le f o r to x ic e ffe c ts . T r i v a le n t c o m p o u n d s b in d m o r e to tis s u e s (
eg
. r e d c e lls ) a n d th e ir to x ic ity is m a r k e d in c o m p a r is o n to p e n t a v a le n t c o m p o u n d s t h a t a r e r a p id l y e x c r e te d in t h e u r in e . F o r th is r e a s o n p e n t a v a l e n t a n tim o n ia ls a r e r e c o m m e n d e d to d a y in h ig h e r u n in te r r u p te d d o s e s t h a n in th e p a s t.C om plications o f a ntim ony therapy
W h i le th e to x ic ity o f p e n t a v a l e n t a n tim o n ia ls is m u c h le s s t h a n t r iv a le n t c o m p o u n d s it is n o t n e g lig ib le . M o s t s id e e f f e c ts a p p e a r a t th e e n d o f c o u r s e s o f th e r a p y s u g g e s tin g th e y a r e th e r e s u lt o f c u m u la tiv e e f f e c ts o f tis s u e a n tim o n y . H o w e v e r th e r e a r e e x c e p - tio n s . W e h a v e s e e n a sin g le in tr a v e n o u s d o s e o f 5 m l P e n to s t a m g iv e n to a m a n w ith c u ta n e o u s le is h m a n ia s is r e s u l t in p r o f o u n d c a r d io v a s c u la r c o l la p s e w ith m a r k e d fa li in b lo o d p r e s s u r e , s w e a tin g , a n d c lo u d in g o f c o n c io u s n e s s . A s im ila r d o s e th e n e x t d a y g a v e th e s a m e r e s u lt. T h e r e w a s n o h is to r y o f p re v io u s a n tim o n y th e ra p y e s p e c ia lly P e n to s ta m . F o r th is re a s o n w e n o w a d v is e a 1 m l in tr a v e n o u s t e s t d o s e b e fo re c o m m e n c in g a c o u r s e o f t h e r a p y . W e h a v e r e p o r te d in th e lit e r a tu r e a n u r ia f o llo w in g a to ta l d o s e o f o n ly 3 3 g r a m s o f G l u c a n tim e d r u g ( 9 .3 g r a m s S b v)61. R e c e n tly w e h a v e s e e n a w o m a n w ith m u c o s a l d is e a s e w h o d e v e lo p e d s u c h s e v e r e s h o u ld e r a r th r a lg ia a f te r 8
d a y s P e n t o s t a m th e r a p y s h e c o u l d n o t r a is e h e r a rm s . T h is im p r o v e d w ith in a d a y o f c e s s a tio n o f th e r a p y . F u r t h e r a t te m p ts t o c o m m e n c e a n tim o n y th e r a p y r e s u lt e d in h e r d e v e lo p in g th is s y m p to m a f te r a sin g le d o s e o f a n t im o n y a n d t r e a t m e n t w ith th is d r u g h a d to b e a b a n d o n e d 7 .
A n o c c a s io n a l c o m p lic a ti o n o c c u r in g d u r in g th e f ir s t w e e k o f tr e a t m e n t is o e d e m a a n d e r y th e m a o f g r a n u lo m a s , a s s o c ia te d s o m e tim e s w ith h a e m o r r h a g e , a n d w e h a v e ill u s tr a te d a n d r e p o r te d th is fin d in g in m u c o s a l d i s e a s e 6®. T h is is a p a r ti c u la r l y s e rio u s c o m p lic a ti o n i f th e la r y n g e a l a p e r tu r e is a a lr e a d y r e d u c e d . F o r th is r e a s o n w e r e c o m m e n d e d t h a t a
Revisão. M arsden PD. P entavalent antim onials: o ld drugs f o r new diseases. R evista da Sociedade B rasileira de M edicina Tropical 18: 187-198, Jul-Set, 1985
T a b l e 1
-D e ta ile d side effects using 5 different treatm ent schedules in m ucocutaneous leishm aniasis.
Side effects
A
B
CD
E
30 cases
20 cases
18 cases
21 cases
7 cases
A r th r a lg ia 17 1 8
2
1 0M y a lg ia 8 9 4
A n o r e x ia 7 6 8 5 4
N a u s e a 3 8 2 1
V o m itin g 2 1 1 1
F u lln e s s 1
E p ig a s tr ic p a i n 1
W a te r b r a s h 1
A b d o m in a l p a in 1
Itc h in g 1 1
F e v e r 2
W e a k n e s s 2 1
H e a d a c h e 3 2 2 4
D iz z in e s s 1
P a lp it a tio n s 1 1
I n s o m n ia 2
N e r v o u s n e s s 1
P y ro g e n ic s h o c k 4
F a c i a l o e d e m a 1
H e r p e s z o s te r 1 2
A ) G lu c a n tim e 2 8 m g /k g / d a y S b v f o r 1 0 to 1 2 d a y s in s e r ie s w ith in te r v a ls o f 15 d a y s . B ) G lu c a n tim e o r P e n t o s t a m 2 0 m g /k g / d a y o f S b v d u r in g a m e a n o f 3 0 d a y s .
C ) G l u c a n tim e a n d N if u r tim o x ( L a m p i t) in d o s e s o f 2 9 m g /k g / d a y S b v f o r 15 d a y s a n d l O m g /k g / d a y f o r 3 0 d a y s re s p e c tiv e ly . D ) P e n to s ta m lO m g /k g /d a y o f S b v fo r 3 0 d a y s .
E ) A m p h o te r ic in B in a m e a n o f 2 .3 g r a m s to ta l d o s e .
tr a c h e o s to m y s e t b e b y th e b e d o f th e p a tie n t, d u r in g th e firs t w e e k o f th e r a p y w ith f a c ilitie s t o d o a n e m e r g e n c y tr a c h e o s to m y . A s im ila r s y n d r o m e o c c u r s w ith a m p h o te r ic in B th e r a p y s o it is n o t a d r u g e ffe c t. O n e p o s s ib ility is t h a t th e d e a t h o f th e tis s u e L e i s h m a n i a p r o m o te s th is r e a c tio n in a m a n n e r s im ila r to th e J a r is c h - H e r x h e i m e r r e a c tio n . A lth o u g h c o r tic o s te - ro id s h a v e b e e n r e c o m m e n d e d to c o n t r o l s u c h re a c tio n s w e h a v e h a d n o o c c a s io n to u s e th e s e to d a t e a n d th e y c o u ld h a v e a d v e r s e e ffe c ts ^ 35 S im p ly s to p p in g th e d r u g fo r a fe w d a y s is s u f fic ie n t a s th is p h e n o m e n o n n e v e r re c u rs .
S a m p a io6 2 h a s r e c e n tly a n a ly s e d th e o c c u r re n c e o f s y m p to m a tic s id e e f f e c ts w ith f o u r d if fe r e n t a n tim o n ia l s c h e d u le s ( T a b le 1) a m o n g p a t ie n t s a d m itte d to o u r u n iv e r s ity h o s p it a l in B r a s ília . C o m m o n s y m p to m a tic s id e e ffe c ts a r e a r th r a lg ia ,
m y a lg ia , a n o r e x ia , n a u s e a , v o m itin g a n d h e a d a c h e 1. T h e s e s id e e f f e c ts a r e c o m m o n e s t w ith h ig h c o n tin o u s d o s e s o f a n tim o n y ( T a b l e 2 ) . H e r p e s in f e c tio n o f th e s k in is a r e c o g n is e d c o m p lic a ti o n o f h e a v y m e ta l th e r a p y a n d o c c u r r e d in o u r e a r lie r s e r i e s 6 2 .
A g ra n u lo c y to sis h a s b e e n n o te d4 a n d w e h a v e se e n lo w w h ite b lo o d c e ll c o u n t s d e v e lo p w h ile o n p e n t a v a le n t a n tim o n ia l th e r a p y .
Revisão. M arsden PD. Pentavalent antim onials: o ld drugs fo r new diseases. Revista da Sociedade Brasileira de M edicina Tropical 18: 187-198, Jul-Set, 1985
s tu d ie d t u b u l a r f u n c tio n a f te r a n tim o n y th e r a p y a n d it r e c o v e r s r a p id l y in n e a r ly a li p a t i e n t s ^ '. T h e tu b u la r d e f e c t a p p e a r s to b e b a s e d o n tw o m e c h a n is m s , in te r fe re n c e w ith th e a c tio n o f a n t id iu r e tic h o r m o n e a n d a d ir e c t to x ic e f f e c t o n th e t u b u l a r c e lls 2 6 . I f lo w e r d o s e s o f a n tim o n y a r e u s e d th is r e n a l c o m p lic a tio n is u n c o m m o n 3 4 .
E l e c tr o c a r d i o g r a p h ic a b n o r m a litie s a r e a js o lis te d in T a b l e 2 a n d a p p e a r t o b e m o r e f r e q u e n t w ith s c h e d u le A . I n o u r e a r ly h o s p it a l s tu d ie s w e tr ie d to g iv e th is d o s e s c h e d u le c o n t in u o u s ly b u t r e p o r te d e l e c tr o c a r d io g r a p h ic c h a n g e s in a li th r e e p a t ie n t s a f te r 2 0 d a y s c o n tin u o u s th e r a p y 6 ^. 2 8 m g S b v/ k g / d a y is a p p r o a c h in g th e t o x ic s in g le d o s e o f 3 0 m g S b v/ k g / d a y 1. T h e f r e q u e n c y o f c a r d ia c a r r h y th m ia s is r e la te d to th e to t a l d a i ly d o s e o f a n tim o n y 14. T h e c o m m o n E C G c h a n g e s a r e T w a v e in v e r s io n a n d a p r o lo n g e d Q T in te r v a l b u t r a r e l y s e v e r e e v e n f a ta l a r r h y th m ia s h a v e o c c u r r e d1 4 I t m u s t b e e m p h a s i s e d t h a t a li th e s e s id e e f f e c ts o c c u r a t h ig h d o s a g e in t h e p a t i e n t w ith n o r m a l o r g a n f u n c tio n ; a t lo w e r d o s e s e l e c tr o c a r d io g r a p h ic e f f e c ts a r e n o t s e e n 4 4 .
M a n y o f th e s e s id e e f f e c ts o c c u r to g e th e r w ith m a x im a l th e r a p y . A n illu s tr a tio n is o u r p a t i e n t w h o r e s is te d 3 0 d a y s c o n tin u o u s P e n t o s t a m th e r a p y ( 1 0 m g S b v/k g / d a y ) a n d 2 .5 g r a m s a m p h o te r ic in B b u t w a s e v e n tu a lly c u r e d b y 8 5 d a y s th e r a p y a t a d a i ly d o s e o f 2 0 m g S b v/ k il o g r a m p e r d a y . O n th e 8 5 th d a y h e h a d
T a b le 2 -
Side effects o f 5 different treatment schedules
in m ucosal leishmaniasis.
A B C D E
% S y m p to m a tic 5 7 8 0 6 6 6 6 1 0 0
% B io c h e m ic a l 2 3 2 6 3 7 2 6 4 0 % A b n o r m a l E C G s 4 0 3 0 2 0 2 0 0
T r e a tm e n t s c h e d u le A - 2 8 m g S b v / k g / d a y fo r 1 0 -1 2 d a y s r e p e a te d 3 tim e s w ith a n in te r v a l o f 15 d a y s .
T r e a tm e n t s c h e d u le B - 2 0 m g S b v / k g / d a y fo r a m e a n o f 3 0 d a y s .
T r e a tm e n t s c h e d u le C - 2 8 m g S b v / k g / d a y fo r 15 d a y s p lu s o r a l N i f u r tim o x l O m g /k g /d a y fo r 3 0 d a y s .
T r e a tm e n t s c h e d u le D - lO m g S b v / k g / d a y f o r 3 0 d a y s . T r e a tm e n t s c h e d u le E - A m p h o t e r i c i n B m e a n t o t a l d o s e 2 . 3
g r a m s .
a r th r iti s w ith e ffu s io n o f th e le ft w ris t a n d s h o u ld e r, a p a l p a b le liv e r a n d r a is e d t r a n s a m in a s e a n d a lk a lin e p h o s p h a ta s e le v e is , d iffu s e a lte r a tio n s o f re p o la ri- s a tio n o n th e e le c tr o c a r d io g r a m a n d a r e n a l tu b u le c o n c e n t r a tin g d e f e c t4 1.
T o x ic e n c e p h a lit is a s s o c ia te d w ith h e a v y m e ta l th e r a p y w e h a v e n o t s e e n n o r c a n I t r a c e a r e f e r e n c e in th e lit e r a tu r e a s s o c i a t e d w ith p e n t a v a le n t a fitim o n ia ls . O n e e ld e r ly la d y in th e fie ld a r e a w h o w a s g iv e n a d a ily d o s e in e r r o r e x c e e d in g 3 0 m g S b v/k g / d a y o f G lu c a n tim e d e v e lo p e d p e r ip h e r a l n e u r itis a n d e x fo lia tiv e d e r m a titis . F o r t u n a t e l y b o th im p r o v e d a f te r c e s s a tio n o f th e r a p y . P e r h a p s it is w o r th m e n tio n in g t h a t w e h a v e n e v e r p e r m a n e n tl y p r e ju d ic e d o r lo s t a p a t i e n t a s a r e s u lt o f p e n t a v a l e n t a n tim o n y th e r a p y in s p ite o f u s in g r e la tiv e ly h ig h d o s e s in o v e r 1 ,0 0 0 p a tie n ts .
R e a lly th e s itu a tio n w ith r e g a r d to th e u s e o f a n tim o n ia ls , s p e c ia lly in th e fie ld , h a s n o t c h a n g e d fro m th e o b s e r v a tio n o f P e s s o a a n d B a r r e t t o - ^ q u o te d b e lo w w ith r e la tio n t o t a r t a r e m e tic .
“ C l in ic a i e x p e r ie n c e in b o th v is c e r a l a n d c u t a n e o u s A m e r i c a n le is h m a n ia s is s h o w s t h a t th e m o s t s a tis f a c to r y r e s u lt s a r e o b ta in e d u s in g la rg e d o s e s in th e s h o r te s t p e r io d s o f tim e e v e n i f c e r ta in s y m p to m s o f in to le ra n c e a r e p ro d u c e d . W e w ish to c a ll th e a tte n tio n o f c lin ic ia n s in g e n e r a l to th is p o in t f o r o u r e x p e r ie n c e s h o w s th a t, m a n y c lin ic ia n s in th e in te rio r o f th e State,
w h e re th e d is e a s e is p re v a le n t, u se , fo r fe a r o f p ro d u c in g a c c id e n ts d u e to in to le ra n c e to ta r ta r e m etic , ex ce ssiv e ly s m a ll d o s e s o f th e p r o d u c t r e s u ltin g in lo w tr e a tm e n t e ff ic ie n c y a n d a p r o lo n g e d t r e a tm e n t tim e ” ^ 4 .
D rug delivery in m an o f pentavalent antim onials
A li d r u g d o s e s a r e n o w e x p r e s s e d in m illig ra m s o f p e n t a v a le n t a n tim o n y p e r k ilo g r a m p e r d a y so th a t s c h e m e s a r e s ta n d a r d is e d ir r e s p e c tiv e o f th e p re - p a r a t i o n 1.
A s m ig h t b e e x p e c t e d th is is a m o s t c o n - tr o v e r s ia l a r e a . N o t o n ly c lin ic ia n s v a r y w id e ly in th e ir o p in io n s a s to th e d o s e o f p e n t a v a l e n t a n tim o n ia ls th a t s h o u ld b e u s e d b u t e v e n th e tw o p r in c ip a l d ru g c o m p a n ie s h a v e d if f e r e n t r e c o m m e n d a tio n s . F o r P e n t o s t a m th e W e llc o m e L a b o r a t o r ie s L td , B e c k e n h a m , E n g la n d , r e c o m m e n d t h a t a d u lts ( 6 0 k g) b e g iv e n in tr a v e n o u s o r in tr a m u s c u l a r in je c tio n s o f 1 0 m g S b v/ k g / d a y f o r 7 - 1 0 d a y s a n d t h a t 2 -3 c y c le s b e s e p a r a te d w ith t e n d a y r e s t in te r v a ls if a d d itio n a l t r e a t m e n t is n e c e s s a r y . F o r G lu c a n tim e R h o d ia S A ,
Revisão. M arsden PD. P entavalent antim onials: o ld drugs f o r new diseases. R evista da Sociedade B rasileira de M edicina Tropical 18: 187-198, Jul-Set, 1985
S ã o P a u lo , B r a z il,r e c o m m e n d a d u lts b e g iv e n in - tr a m u s c u la r in je c tio n s o f 1 7 - 2 8 m g S b v/ k g / d a y fo r 1 0 - 2 0 d a y s f o llo w e d b y a 1 5 d a y r e s t in te r v a l a n d a s e c o n d c y c le if n e e d e d . B o t h r e c o m m e n d a tio n s a r e n o w o b s o le te s in c e th e w o rk d o n e in K e n y a s h o w e d th a t s u c h r e s t p e r io d s a r e p h a r m a c o lo g i c a lly u n s o u n d s in c e b o th d ru g s a r e r a p id ly e x c r e te d in t h e u r in e . T h is w o rk w h ic h I h a v e r e v ie w e d e l s e w h e r e 3 9 , s in c e it s h o r te n s tr e a tm e n t tim e , is th e o n ly p r a c tic a l a d v a n c e f o r th e p a tie n t in th e t r e a t m e n t o f l e is h m a n ia s is to a p p e a r in th e la s t d e c a d e .
Y e t o n e c a n s y m p a th is e w ith th e d r u g c o m - p a n ie s s in c e th e s e r e c o m m e n d a tio n s a r e a n e n o r m o u s p r o b le m a s e v id e n c e g ro w s o f d iffe rin g s u s c e p tib ilitie s t o a n tim o n ia ls o f v a r io u s le is h m a n ia l s p e c ie s a n d th e c lin ic a i s y n d r o m e s c a u s e d b y th e s e p a r a s ite s . U n fo r - tu n a te ly c o m p a ra tiv e s tu d ie s o f d iffe re n t ta x o n o m ic a lly d efin e d le s h m a n ia l in fe c tio n s in m a n w h e re s im ila r d o s e s h a v e b e e n u s e d d o n o t e x is t in th e lite ra tu re alth o u g h a stu - d y is b e in g p r e p a re d fro m P a n a m a 13. M a n y w o rk e rs c a n ’t m o u n t s u c h s tu d ie s . F o r e x a m p le , i n o u r w o r k in C e n tr a l B ra z il
L eish m a n ia braziliensis braziliensis
( L b b ) in f e c tio n is s o c o m m o n w e h a v e v e r y fe w o th e r sp e c ie s in d e n tific a tio n s in p a tie n ts w ith m u c o c u ta n e o u s d is e a s e . R e c e n tly 1 h a v e tr i e d to d e s ig n a s im p le ta b le
a s a g u id e f o r a n t im o n ia l u s e f o r C o n n ’s
Current
Therapy,
a d id a c ti c t r e a t m e n t te x t, a n d th is is s h o w n in T a b l e 3 . I t r e p r e s e n ts a n o v e r s im p lif ic a tio n a n d th e f a c t is t h a t th e c lin ic ia n h a s to e x e r c is e c o n s id e r a b l e s k ill in th e u s e o f a n tim o n ia ls ta k in g in to a c c o u n t th e n a t u r e o f th e le s io n , th e p r o b a b le in f e c tin g o r g a n is m ( th is in f o r m a tio n is n o t a v a ila b le a t th e tim e o f th e t r e a t m e n t d e c is io n ) , th e a g e a n d w e ig h t o f th e p a t i e n t a s w e ll a s a n y e v id e n c e o f o r g a n d is f u n c tio n .T h e s m a lle s t a d u l t d o s e o f G lu c a n tim e r e c o m m e n d e d in B r a z il is o n e a m p o u le o f G lu c a n tim e tw o tim e s a w e e k 4 9 . W h i le t h i s s e e m s h o m e o p a th i c t o s o m e a n d c a n n o t b e r e c o m m e n d e d it is p o s s i b ly th e o n ly d o s e a v a ila b le , f o r r e a s o n s o f c o s t, f o r a c h ild w ith a d v a n c e d k a l a - a z a r , a n a e m ic a n d m a ln o u r is h e d w h o h a s t o b e tr e a t e d a t h o m e in o n e o f t h e
fa v e la s
in th e c itie s o f B r a z il w h e r e k a l a - a z a r is c u r r e n tl y e n d e m ic . T h e f a c t t h a t B r a z ili a n k a l a - a z a r r e s p o n d s to s u c h a d o s e s h o w s it h a s a h ig h s e n s itiv ity a lth o u g h th e r e la p s e r a te m u s t b e h ig h . T h e h ig h e s t d a ily d o s e a d v o c a t e d in B r a s il is s ix a m p o u le s o f G lu c a n tim e a d a y 1®. T h is is w e ll o v e r t h e t o x ic lim it m e n tio n e d b y th e W o r ld H e a l t h O r g a n i z a t i o n1 f o r a s in g le d o s e a n d it is c u r io u s t h a t fe w to x ic e f f e c ts w e r e o b s e r v e d . I t c a n n o t b e r e c o m m e n d e d . A B r a z ili a n M in i s tr y o fT a b le 3 -
G uide to the treatm ent response o f different leishm anial species causing clinicai syndrom es with
p entavalent antim onials.
Treatment response
E a sy to treat
Group A
M ore difficult
Group B
M o st difficult
Group C
C lin ic a i fo rm
C u t a n e o u s L im ite d c u t a n e o u s le s io n s
L.
L.
L.
L.
tropica
m ajor
m. m exicana
m. am azonensis
V is c e r a l o r m u c o s a l fo rm s
L. peruana
L . b. pana m en sis
L . b. guyanensis
L. b. braziliensis
P o s t K a l a - a z a r D e r m a l le is h m a n ia s is
(
L . donovani)
V is c e r a l le is h m a n ia s is
(L. donovani)
D if f u s e c u t a n e o u s le is h m a n ia s is
L. aethiopica
L. m. p ifa n o i
L . m. am azonensis
L e i s h m a n i a s is r e c id iv a n s
S k in g r a n u lo m a d u e to
L. aethiopica
M u c o s a l l e is h m a n ia s is
L. b. braziliensis
L. b. pana m en sis
L. b. ?
K e y . L = L e i s h m a n ia L . m . = L eish m a n ia m exicana g r o u p L . b . = L eish m a n ia braziliensis g ro u p .
N o te . O v e r s im p lif ie d , th is g u id e d o e s n o t ta k e in to a c c o u n t th e e x c e p tio n s to th e r u le . R e la p s e c a n o c c u r in i n d iv id u a l p a ti e n ts in a li c a te g o r ie s .
T r e a tm e n t G r o u p A - lO m g S b v/ k g / d a y f o r 1 0 -1 5 d a y s .
” G r o u p B - lO m g S b v/ k g / d a y f o r 3 0 d a y s o r 2 0 m g S b v/ k g / d a y f o r 1 5 d a y s .
Revisão. M a rsd en PD. P entavalent antim onials: old drugs fo r new diseases. R evista da Sociedade Brasileira de M edicina Tropical 18: 187-198, Jul-Set, 1985
H e a l t h r e c o m m e n d a tio n is o n e a m p o u le o f G l u c a n - tim e d a i ly f o r 7 - 1 0 d a y s ; th e c o u r s e b e in g r e p e a te d if n e c e s s a r y . I n o u r r e c e n t e x p e r ie n c e it a p p e a r s t h a t th is w ill c lo s e m a n y s k in u lc e r s d u e t o L b b ; b u t w ill it p r e v e n t m u c o s a l d is e a s e ? S in c e in t h e p a s t y e a r w e h a v e h a d little G lu c a n t i m e , w e h a v e m a n y p a t ie n t s w ith L b b w h o h a d t o b e t r e a t e d w ith s u c h a s c h e d u le (7 m g S b v/ k g / d a y ) . T h e y a r e u n d e r lo n g itu d in a l o b s e r v a tio n . W e h a v e u s e d f o u r tim e s th is d o s e in th e e n d e m ic a r e a o f T r ê s B r a ç o s f o r y e a r s ( 2 8 m g /k g / d a y ) a n d in o u r r e c e n tly p u b lis h e d s tu d i e s m u c o s a l r e la p s e w a s a l m o s t u n k n o w n o n s h o r t te r m fo llo w -u p 3 7 . T h e p r a c tic a l d if fic u ltie s o f g iv in g s u c h h ig h d o s e s u n d e r fie ld c o n d itio n s a r e c o n s id e r a b l e ( 2 0 c m 3 d a i ly in tr a m u s c u l a r d o s e ) b u t th e y c a n n o t b e d is c u s s e d h e r e . P r a t a h a s n e v e r s e e n a k a l a - a z a r p a t i e n t r e la p s e in B r a z il u s in g s im ila r d o s e s in o v e r 1 0 0 p a t ie n t s ( A R P r a ta : p e r s o n a l c o m m u n ic a ti o n ) b u t th e y d o r a r e ly o cc u r^ Õ 68
O n t h e w h o le in te r m s , o f f r e q u e n c y o f t r e a tm e n t p r o b le m s in h o s p it a is in B r a z il, i t is m u c o s a l le is h m a n ia s is w h ic h c a u s e s m o s t c o n c e m . T a b l e 4 s h o w s o u r r e s u lt s w ith th e f o u r a n tim o n y s c h e d u le s p r e v io u s ly m e n tio n e d in r e la tio n t o m u c o s a l d is e a s e in o u r h o s p it a l in B r a s í l i a 6 3 . O u r a n a ly s i s o f t h e r e s u lt s o f t r e a tm e n t w ith c u t a n e o u s le s io n s f a ile d to s h o w a d if fe r e n c e b e t w e e n t h e f o u r s c h e d u le s b u t t h e r e is a d if fe r e n c e b e t w e e n th e s e in m u c o s a l p a t ie n t s . S u c h d a t a is e x t r e m e l y d if fic u lt to c o l le c t d u e to f o llo w -u p p r o b le m s a n d a s y e t it d o e s n o t le n d it s e l f t o s ta tis t ic a l a n a ly s is . H o w e v e r i t s u g g e s ts t h a t 2 0 m g /S b v/ k ilo g r a m b o d y w e ig h t f o r a m e a n o f 3 0 d a y s is t h e b e s t r e c o m m e n d a tio n . B r y c e s o n in L o n d o n h a s r e c e n tly s t a r t e d t o u s e th is d o s e tw ic e a d a y t o f u r th e r r e d u c e h o s p it a l s t a y ( A D M B r y c e s o n : p e r s o n a l c o m m u n i
c a tio n ) . E v id e n tly w e s till h a v e to d e fin e o p tim a l s c h e d u le s f o r a n tim o n y u s e .
B o th P e n t o s t a m a n d G lu c a n tim e a r e b e s t g iv e n b y s lo w in tr a v e n o u s in f u s io n o v e r a t le a s t th r e e m in u te s . N o d ilu e n t is u s u a lly n e c e s s a r y u n le s s th e p a t i e n t d e v e lo p s a v e n o u s th r o m b o s is a t a n in o c u la tio n s ite . I n t r a m u s c u l a r in je c tio n is p a in fu l b u t o f te n n e c e s s a r y u n d e r fie ld c o n d i tio n s w h e r e n o d o c t o r c a n b e p r e s e n t f o r d a i ly in je c tio n . O n e lo t o f G lu c a n tim e u s e d in T r ê s B r a ç o s p r o d u c e d s e v e r a l m u s c le a b s c e s s e s . P h a r m a c o k in e t ic s tu d ie s s h o w little d if fe r e n c e in p e a k s e r u m le v e is a f te r a p p lic a tio n b y th e s e tw o r o u t e s 1^ . A n in te r e s tin g s tu d y c a r r ie d o u t a t th e W a l t e r R e e d A r m y M e d ic a i C e n t e r c o m p a r e d th r e e m e th o d s o f d r u g d e liv e r y in A m e r i c a n s o ld ie r s w ith le is h m a n ia s is . W h i le a li s u b je c ts w e re g iv e n th e s a m e to t a l d o s e o f 6 0 0 m g S b v/ d a y th is w a s a d m in is te r e d e i th e r a s a c o n t in o u s 2 4 h o u r s in f u s io n , in th r e e d iv id e d e ig h t h o u r ly d o s e s o r a s a s in g le in tr a v e n o u s d o se^O . T h e l a t t e r m e th o d w a s s h o w n to b e m o r e e ffe c tiv e in te rm s o f c u r e a n d in c id e n c e o f s u b je c tiv e c o m p la in ts .
I n p a t ie n t s w ith e v id e n c e o f r e n a l, c a r d ia c o r h e p a tic d is e a s e a n a l te r n a t iv e m a y h a v e to b e s o u g h t d e p e n d in g o n t h e c lin ic a i a s s e s s m e n t o f t h e p a tie n t. P a t i e n t s w ith r e n a l in s u f f ic ie n c y b e c o m e le th a rg ic , a n o r e x ic , d r o w s y a n d w e a k a f te r a n tim o n ia l
t h e r a p y 5 9 . A l t e m a t i v e s a r e th e r e c o m m e n d e d s e c o n d lin e d r u g s 1 n a m e ly P e n ta m id in e w h ic h h a s few re n a l s id e e f f e c ts o r a m p h o te r ic in B w h ic h is fre e o f h e p a tic to x ic ity a n d c a r d ia c e f f e c ts a r e o n ly r e la te d to p o ta s s iu n in b a la n c e .
F in a ll y e v e n h ig h d o s e p e n ta v a le n t a n tim o n ia l w ill n o t c u r e a li p a t ie n t s . W e h a v e r e p o r te d a g irl w h o
T a b l e 4 -
Cure rate o f fiv e treatm ent schedules in m ucosal leishm aniasis.
N
pfa il e d /
A
B
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to ta l num ber
1 1 /2 6
1 /12
3 /7
7/18
2 /8
% C u r e 5 8 % 9 2 % 5 7 % 6 1 % 7 5 %
M e a n f o llo w u p p e r io d ( m o n th s ) 1 8 8 1 9 1 2 12
T r e a t m e n t s c h e d u le A - 2 8 m g S b v/ k g / d a y f o r 1 0 - 1 2 d a y s r e p e a te d 3 tim e s w ith a n in te r v a l o f 1 5 d a y s . ” ” B - 2 0 m g S b v / k g / d a y f o r a m e a n o f 3 0 d a y s .
” C - 2 8 m g S b v / k g / d a y f o r 1 5 d a y s p l u s o r a l N i f u r t im o x l O m g /k g / d a y fo r 3U d a y s . ” ” D - lO m g S b v/ k g / d a y f o r 3 0 d a y s .
” ” E - A m p h o t e r i c i n B m e a n t o ta l d o s e 2 .3 g ra m s .
Revisão. M arsden PD. P entavalent antim onials: o ld drugs fo r new diseases. R evista da Sociedade B rasileira de M edicina Tropical 18: 187-198, Jul-Set, 1985
d e v e lo p e d m u c o s a l g r a n u lo m a s d u r in g a n tim o n ia l tr e a tm e n t f o r h e r s k in le s io n d u e t o L b b 4 ®.
Unresponsiveness
I n b r ie f r e c e n t w o r k r e g a r d in g d is e a s e r e s p o n s e to to ta l a n tim o n y d o s e s u g g e s ts t h a t h ig h c o n tin u o u s a n tim o n y th e r a p y is th e b e s t a p p r o a c h in r e c a l c i t r a n t d is e a s e f o r a f a v o u r a b le r e s p o n s e . S y n d r o m e s s u c h a s a r e m e n tio n e d in g r o u p C o f T a b l e 3 r e q u ir e th is a p p r o a c h . T h is is n o t t o s a y t h a t h ig h d o s e a n tim o n y w ill a lw a y s m e e t w ith s u c c e s s p a r ti c u la r l y in p a t ie n t s w ith m u c o s a l d is e a s e ^ 4 4 0 . A n e r g ic H a n s e n o i d le is h m a n ia s is w ill fa il to r e s p o n d s in c e th e p a t i e n t c a n ’t m o u n t a n im m u n e r e s p o n s e . T h e im p o r ta n c e o f u n r e s p o n s iv e n e s s is d if fic u lt to a s s e s s s in c e h ig h e n o u g h d o s e s h a v e n o t b e e n w id e ly e m p lo y e d to d a te .
T h e te r m u n r e s p o n s iv e is u s e fu l s in c e r e s is ta n c e is o f te n t a k e n to im p ly p a r a s i t e r e s is ta n c e w h ic h is n o t n e c e s s a r ily th e c a s e . P a t i e n t s w ith f a ta l a n tim o n y u n r e s p o n s iv e k a l a - a z a r h a d p a r a s ite s w h ic h s h o w e d a n o r m a l r e s p o n s e to a n t im o n ia ls in a n im a l m o d e ls in d ic a tin g a h o s t d e f e c t 2^ 32 O n t h e o t h e r h a n d a t l e a s t in K e n y a n k a l a - a z a r th e r e is e v id e n c e in c e ll c u ltu r e s ^ a n d in a n im a l m o d e ls o f p a r a s ite r e s is ta n c e to
a n t i m o n y 3 3 . U n f o r tu n a te l y s im ila r e x p e r im e n ts h a v e n o t b e p o s s ib le w ith L b b s in c e it c a n n o t b e in d u c e d to g ro w in
in vivo
c e ll lin e s . H o w e v e r M o r e i r a 4 3 h a s e x a m in e d o n e o f o u r m o s t s u s p e c t L b b is o la te s in te r m s o f r e s is ta n c e a n d it s h o w s d im in is h e d s e n s itiv ity in h e r p r o m a s tig o te c u ltu r e s y s te m .T h e W o r l d H e a l t h O r g a n i z a t i o n 1 s u g g e s ts w e c o n s id e r p r im a r y u n r e s p o n s i v e n e s s a s n o c lin ic a i o r p a r a s ito lo g ic a l im p r o v e m e n t o n in itia l th e r a p y a n d s e c o n d a r y u n r e s p o n s iv e n e s s w h e r e r e la p s e o c c u r s a f te r o n e o r m o r e c o u r s e s o f a p p a r e n tly s u c c e s s fu l t r e a t m e n t T o illu s tr a te h o w d if fic u lt it is to d is c u s s th is s u b je t w ith th e r e c e n t c h a n g e s in d o s a g e s c h e d u le s í n d i a w h ic h r e c o r d e d a 1 3 % r e la p s e r a te in k a l a - a z a r is s a id to h a v e r e d u c e d it to z e r o b y d o u b lin g th e a n tim o n y d o s e 1. C e r t a in l y a r is k o f m in im a l d o s e th e r a p y is th e e m e r g e n c e o f p a r a s ite r e s is ta n c e to a n tim o n ia l tr e a tm e n t.
C oncluding rem arks
T h e la s t tw o d e c a d e s h a v e s e e n g r e a t a d v a n c e s in o u r u n d e r s ta n d in g o f th e ta x o n o m y o f L e i s h m a n i a u s in g b io c h e m ic a l2 9 a n d i m m u n o l o g i c a l ^ m e th o d s . T o d a y th is is s e e n a s a n e s s e n ti a l f ir s t s te p to u n r a v e llin g th e c o m p le x itie s o f th e e p id e m io lo g y a n d
c lin ic a i p ic tu r e o f h u m a n d is e a s e . A t th e U n iv e r s it y o f B r a s ília w e w e r e t h e f ir s t t o u s e th e m o n o c lo n a l te c h n o lo g y d e v e lo p e d a t H a r v a r d in s u c h fie ld s t u d i e s 1 7 . W e a r e d e a lin g in T r ê s B r a ç o s , B a h ia , w ith w h a t a p p e a r s t o b e v ir tu a lly a m o n o tr a n s m is s i o n to m a n o f L b b . W e a r e s till d e f in in g th e c lin ic a i p ic tu r e b a s e d o n th is ta x o n o m y . S im ila r d a t a o n o t h e r im - p o r t a n t p a r a s ite s in B r a z il s u c h a s
L eish m a n ia
braziliensis guyanensis
w ill d o u b tle s s b e a v a ila b le s o o n . N e w c lin ic a i e n titie s a r e b e in g d e f in e d ; fo r e x a m p le w e a r e p r e p a r in g a r e p o r t o n d is s e m in a te d c u t a n e o u s le is h m a n is is c a u s e d b y L b b 16.I n c o n t r a s t to th is e x c itin g fie ld in e p id e m io lo g y , p r o s p e c ts f o r a d v a n c e s in th e c h e m o th e r a p y o f le is m a n ia s is a r e g lo o m y . I n e v e r im a g in e d w h e n I q u a lif ie d in m e d ic in e 2 5 y e a r s a g o t h a t I w o u ld re v ie w a n t im o n ia l th e r a p y in 1 9 8 5 . H e a v y m e ta l th e r a p y w a s th e m a in s ta y o f 19 t*1 c e n tu r y m e d ic in e . T h e e x p e r ts in th is fie ld t o d a y a r e p h y s ic ia n s tr e a tin g le is h m a n ia s is . T h e r e h a s b e e n n o a d v a n c e in d r u g f o r m u l a ti o n s fo r p r im a r y th e r a p y t h a t h a s b e n e f ite d t h e p a t i e n t f o r f o rty y e a r s . P a r e n t a l p e n t a v a l e n t a n tim o n ia ls a r e s till th e d r u g s o f c h o i c e f o r m o s t o f th e f o rm s o f le is h m a n ia s is .
I w ill n o t d is c u s s w h y th is is s o , a lth o u g h I h a v e d e f in ite v ie w s a f te r c o n f r o n tin g h u n d r e d s o f p a t ie n t s w ith L b b in f e c tio n s a n d o f te n n o t h a v in g e v e n a n tim o n y to o f fe r th e m . L e t u s a d o p t a m o r e p o s itiv e a p p r o a c h . T h e f a c t is t h a t th e r e is o n ly o n e p h a r m a - c e u tic a l c o m p a n y a n d o n e r e s e a r c h in s titu te s e rio u s ly in v o lv e d in d e v e lo p in g n e w d ru g s ; n a m e ly th e W e llc o m e R e s e a r c h L a b o r a t o r i e s in A m e r i c a a n d E n g la n d a n d th e W a l t e r R e e d A r m y I n s titu t e o f M e d ic a i R e s e a r c h in W a s h in g t o n . T w o d r u g s , a n 8 a m in o q u in o lin e ( W R 6 0 2 6 ) , 0 f ro m th e l a tte r a n d A llo p u r in o l r ib o s id e f ro m th e f o rm e r47 h a v e e n te r e d c lin ic a i tr ia ls . P r e lim i n a r y in f o r m a tio n s u g g e s ts t h a t n e i th e r m a y b e s u it a b le f o r o u r p r o b le m s w ith L b b , b u t e v e n i f t h is is n o t s o , I m a y w e ll b e a n o ld m a n b e f o r e I s e e s u c h o r a l p r e p a r a tio n s u s e d in o u r fie ld c lin ic . T h is is b e c a u s e c lin ic a i e v a lu a tio n is a le n g th y p r o c e s s a n d in v o lv e s te s tin g in itia lly in k a l a - a z a r a n d lim ite d s k in le is h m a n ia s is b e f o r e i t c a n b e u s e d f o r a n o r g a n is m c a u s in g m e ta s ta tic d is e a s e . A ls o w e o u rs e lv e s r o u tin e ly d o a tr ia l in h o s p it a l in B r a s ília b e f o r e a d r u g c a n b e ta k e n to th e fie ld . T h e e v a lu a tio n o f e a c h o f th e s e tr ia ls w ill ta k e s e v e r a l y e a r s .
Revisão. M arsd en PD. Pentavalent antim onials: o ld drugs fo r new diseases. R evista da Sociedade Brasileira de M edicina Tropical 18: 187-198, Jul-Set, 1985
o n e p a t i e n t w ith K e n y a n k a l a - a z a r u n r e s p o n s iv e to fre e a n tim o n y tr e a t e d w ith lip o s o m é s f a ile d to r e s p o n d 3 5 . B o th th e r e s e a r c h g ro u p s m e n tio n e d a r e in v o lv e d in t h is d e v e lo p m e n t. A lth o u g h if it e v e r c a m e to h u m a n tr i a l th is a p p r o a c h w o u ld s till im p ly in je c tio n th e r a p y it w o u ld a b o lis h t h e n e e d f o r th e s e p a in fu l, p ro lo n g e d , in je c tio n s c h e d u le s . I h a v e n o d o u b t t h a t th e sin g le m o s t im p o r ta n t a d v a n c e in th e c o n tr o l o f le is h m a n ia s is is th e d e v e lo p m e n t o f m o r e e ffic ie n t d r u g t h e r a p y 38 in te r m s o f a n o r a l in e x p e n s iv e t r e a t m e n t o f s h o rt d u r a tio n . S u c h a d r u g w o u ld b e e q u a lly u s e fu l b o th in k a l a - a z a r a n d in t h e m u c o c u ta n e o u s in f e c tio n s o f r u r a l a r e a s . W i t h m in is tr y s u p p o r t w e a r e c u r r e n tly te s tin g k e t o c o n a z o le b u t th is h a r d ly f a lls in to th is c a te g o ry .
T h e la s t w o r d is p e r h a p s b e t t e r s a id b y th e f a th e r o f o n e o f o u r p a t ie n t s in t h e e n d e m ic a r e a o f T r ê s B ra ç o s w h e r e th e y a r e a s f a m ilia r w ith G lu c a n tim e a s w e a r e w ith a s p ir in 4 8 . H e a s k e d m e w h y i f w e h a d b e e n w o rk in g th e r e f o r te n y e a r s w e w e r e s till u s in g th is d ru g a n d h a d n o t f o u n d a m o r e c o n v e n ie n t t h e r a p y . I e x p la in e d t h a t w e w e r e d e p e n d e n t in th e fie ld , a t th e e n d o f th e lin e a s it w e r e , o n th e r e s e a r c h o f o th e r c o lle a g u e s a n d n o th in g h a d a p p e a r e d t o d a te . “ B u t w ill it” , h e in s is te d “ s o t h a t I d o n ’t h a v e to w a lk 5 k ilo m e tre s w ith m y d a u g h t e r to g e t h e r in je c tio n ? ”
R E F E R E N C E S
1. A n o n y m o u s . T h e l e is h m a n ia s e s . W o r ld H e a l t h O rg a - n iz a tio n T e c h n ic a l R e p o r t S e r ie s n.° 7 0 1 , G e n e v a , 1 9 8 4 . 2 . B e r m a n J D . I n v itr o s u s c e p tib ility o f a n tim o n y r e s i s t a n t
L eish m a n ia t o a lt e m a ti v e d r u g s . J o u r n a l o f I n f e c tio u s D i s e a s e s 1 4 5 : 2 7 9 , 1 9 8 2 .
3 .B e v e r id g e E . C h e m o t h e r a p y o f l e is h m a n ia s is . In : S c h n itz e r R J , H a w k in g F ( e d ) E x p e r i m e n t a l c h e m o th e r a p y , v o l. 1 , A c a d e m ic P r e s s , N e w Y o rk , 1 9 6 3 .
4 . B r a h m a c h a r i P N , M a i ti C R , K o r C C . A g r a n u lo c y to s is f o llo w in g a n tim o n y th e r a p y in k a la - a z a r . J o u r n a l I n d i a n M e d i c a i A s s o c ia t io n 2 5 : 4 0 8 - 4 1 0 , 1 9 5 5 .
5 . B r y c e s o n A D M . T h e r a p y in m a n . In : P e t e r s W , K illic k K e n d r i c k R ( e d ) T h e l e is h m a n ia s is in b io lo g y a n d m e d ic in e , A c a d e m ic P r e s s , L o n d o n , in p r e s s .
6 . C a r in i A . T r ê s c a s o s d e le is h m a n io s e . A r c h iv o s d a S o c ie d a d e d e M e d i c i n a e C i r u r g ia d e S ã o P a u l o 5 : 8 -9 , 1 9 1 4 .
7 . C a s t r o C N , C o s t a J M L , S a m p a i o R N R , M a r s d e n P D . U n u s u a l s id e e f fe c ts fo llo w in g p e n ta v a l e n t a n tim o n ia l
t h e r a p y . R e v is ta d a S o c ie d a d e B r a s ile ir a d e M e d ic in a T r o p ic a l, in p r e s s .
8 . C a s t r o R M . T r a t a m e n t o d a l e is h m a n io s e te g u m e n ta r a m e r ic a n a . A n a i s B r a s ile ir o d e D e r m a to lo g ia 5 5 : 8 7 - 8 9 ,
1 9 8 0 .
9 . C h a n c e M L , N e w R R C . T h e u se o f lip o s o m é s in th e tr e a tm e n t o f e x p e r im e n ta l c u ta n e o u s a n d v is c e r a l le is h m a n ia s is . In : V a n d e B o s s c h e ( e d ) T h e H o s t P a r a s i te I n t e r p l a y , p . 6 5 9 . E l s e v i e r / N o r t h H o l l a n d B io m e d ic a l P r e s s , A m s t e r d a m , 1 9 8 0 .
1 0 . C h a p m a n W L , H a n s o n W L , W a i t s V B , K in n a m o n K .E. A n ti le i s h m a n i a l a c tiv ity o f s e le c te d c o m p o u n d s in d o g s e x p e r im e n ta lly in f e c te d w ith L eish m a n ia donovani.
R e v is ta d o I n s t i tu t o d e M e d i c i n a T r o p ic a l d e S ã o P a u lo 2 1 : 1 8 9 - 1 9 3 , 1 9 7 9 .
1 1 . C h a p m a n W L , H a n s o n W L , A lv in g C R , H e n d r ic k s L D . A n ti le i s h m a n i a l a c tiv ity o f lip o s o m e e n c a p s u la te d m e g lu m in e a n tim o n a te in th e d o g . A m e r ic a n J o u r n a l o f V e te r in a r y R e s e a r c h 4 5 : 1 0 2 8 - 1 0 3 0 , 1 9 8 4 .
1 2 . C h u l a y J . C lin ic a i p h a r m a c o k in e tic s o f c u r r e n tly u s e d c o m p o u n d s a n d t h e i r s id e e ffe c ts . I n f o r m a l m e e tin g o n C h e m o th e r a p y o f V is c e ra l L e is h m a n ia s is . M im e o g ra p h e d d o c u m e n t. N a i r o b i, 1 9 8 2 .
1 3 . C h u la y J D , O s te r C N , M c G r e e v y P B , K r e u t z e r R D , H e n d r ic k s L D . A m e r ic a n c u ta n e o u s le is h m a n ia s is . C lin ic a i p r e s e n t a ti o n a n d p r o b le m s o f p a tie n t m a - n a g e m e n t J o u r n a l o f I n f e c tio u s D i s e a s e , in p re s s . 1 4 . C h u l a y J D , S p e n c e r H C , M u g a m b i M . E le c tr o c a r -
d io g r a p h ic c h a n g e s d u r in g tr e a tm e n t o f le is h m a n ia s is w ith p e n ta v a l e n t a n tim o n y ( S o d iu m s tib o g lu c o n a te ) . A m e r ic a n J o u r n a l o f T r o p ic a l M e d ic in e a n d H y g ie n e 3 4 : 7 0 2 - 7 0 9 , 1 9 8 5 .
1 5 . C o r r ê a A , E li z a b e ts k y M . A ç ã o d e a n tim o n ia to d e N - m e th y l g lu c a m in a s o b r e a s le s õ e s m u c o s a s d e le is h m a - n io s e t e g u m e n ta r a m e r ic a n a . P u b lic a ç õ e s M é d ic a s d e S ã o P a u l o 2 2 : 1 3 - 2 1 , 1 9 5 2 .
1 6 . C o s t a J M L , M a r s d e n P D , L la n o s - C u e n t a s E A , N e tto E M , C a r v a l h o E M , B a r r a i A , R o s a A C , C u b a C C , M a g a lh ã e s A V , B a r r e t o A C . D is s e m i n a t e d c u ta n e o u s l e is h m a n ia s is in a f ie ld c lin ic . R e p o r t o f 8 c a s e s . J o u r n a l o f T r o p ic a l M e d ic in e a n d H y g ie n e , in p re s s .
1 7 . C u b a C u b a C A , M a r s d e n P D , B a r r e t o A C , R o itm a n I, V e x e n a t A , D e L im a L M P , D e S á M H P . I d e n tif ic a tio n o f h u m a n s to c k s o f L e i s h m a n ia s p p . i s o la te d fro m p a tie n ts w ith m u c o c u t a n e o u s le is h m a n ia s is in T r ê s B r a ç o s , B a h ia , B ra z il. T r a n s a c t i o n s o f th e R o y a l S o c ie ty o f T r o p ic a l M e d ic in e a n d H y g ie n e 7 8 : 7 0 8 - 7 1 0 , 1 9 8 4 . 1 8 . C u c e L C , F r e i t a s T H P , O li v e i r a Z N P , S a m p a io S A P .
Revisão. M arsden PD. P entavalent antim onials: old drugs f o r new diseases. R evista da Sociedade B rasileira de M edicina Tropical 18: 187-198, Jul-Set, 1985
T r a t a m e n to d a l e is h m a n io s e te g u m e n ta r a m e r ic a n a p e lo a n tim ô n io p e n ta v a l e n te ( e s q u e m a r á p id o ) . A n a i s B r a s ile iro s d e D e r m a t o lo g i a 5 7 : 1 0 7 - 1 0 8 , 1 9 8 2 .
1 9 . D i C h r i s t in a G , C a r o n i a G . S u lla t e r a p ia d e lia le is h m a n io s i in te r n a . B u lle tin d e la S o c ié tè d e P a th o lo g ie É x o tiq u e 8 : 6 3 - 6 6 , 1 9 1 5 .
2 0 . D ie tz e R , A r a ú j o R C , L im a M L R , V e x e n a t J A , M a r s d e n P D , B a r r e t o A C . E n s a io t e r a p ê u t i c o c o m g lu c a n tim e e m s a g ü is (C allith rix ja cc h u s) i n f e c ta d o s c o m u m a c e p a á e L e is h m a n ia d o novani a p a r e n te m e n te r e s is te n te a o tr a t a m e n to . R e v is ta d a S o c ie d a d e B r a s ile ir a d e M e d i c i n a T r o p ic a l 1 8 : 3 9 - 4 2 , 1 9 8 5 .
2 1 . D u r a n d P , B e n m u s s a S , C a r u a n a M . T r a i t e m e n t d u k a l a - a z a r p a r u n n o v e a u c o m p o s é s tib ié 2 , 1 6 8 R P ( p r e m ie r s ré s u lta ts ) . B u lle tin S o c ié tè M e d ic in e H ô p i t a l P a r is 6 2 : 3 9 9 - 4 0 9 , 1 9 4 6 .
2 2 . D u t r a e S ilv a O . S o b r e a le is h m a n io s e te g u m e n ta r e se u tr a ta m e n to . M e m ó r ia s d o I n s t i tu t o O s w a ld o C r u z 7: 2 1 3 - 2 4 8 , 1 9 1 5 .
2 3 . F a l c ã o E C , O p e r a O m n i a d e G a s p a r V ia n n a . E m p r e s a G r á f ic a d a R e v is ta d o s T r ib u n a i s , S ã o P a u l o , 1 9 6 2 . 2 4 . F u r t a d o T A . A n a p p r a i s a l o f c h e m o t h e r a p y o f A m e r ic a n
le is h m a n ia s is . D e r m a t o lo g i a I b é r i c a L a t i n o - A m e r i c a n a 3: 2 5 7 - 2 6 8 , 1 9 6 8 .
2 5 . F u r t a d o T , V ie ir a J B F . G e o g r a f i a d a l e is h m a n io s e te g u m e n ta r a m e r ic a n a n o B r a s il. A n a i s B r a s ile ir o d e D e r m a to lo g ia 5 7 : 1 3 5 - 1 4 0 , 1 9 8 2 .
2 6 . G a g lia r d i A R T , V e ig a J P R , R o s a T T , M a r s d e n P D . P e n t a v a l e n t a n tim o n y in h ib itio n o f w a te r t r a n s p o r t b y th e to a d b la d d e r . B r a z ilia n J o u r n a l o f M e d ic a i a n d B io lo g ic a l R e s e a r c h , in p r e s s .
2 7 . G e l h o r n A , V a n D y k e H B . T h e c o r r e la tio n b e tw e e n d is tr ib u tio n o f a n tim o n y in tis s u e s a n d c h e m o th e r a p e u tic e f fe c t in e x p e r im e n ta l le is h m a n ia s is . J o u r n a l o f P h a r - m a c o lo g y a n d E x p e r i m e n t a l T h e r a p e u t i c s 8 8 : 1 6 2 - 1 7 2 , 1 9 4 6 .
2 8 . G e l h o r n A , T u p ik o v a N A , V a n D y k e H B . T h e t is s u e d is tr ib u tio n a n d e x c r e ti o n o f f o u r o r g a n ic a n tim o n ia ls a f te r s in g le o r r e p e a te d a d m in is tr a tio n to n o r m a l h a m s te r s . J o u r n a l o f P h a r m a c o lo g y a n d E x p e r i m e n t a l T h e r a p e u tic s 8 7 : 1 6 9 - 1 8 0 , 1 9 4 5 .
2 9 . G o ld f r e y D G . M o l e c u l a r b io c h e m ic a l c h a r a c t e r i z a t i o n o f h u m a n p a r a s ite s . In : G i l le s H M ( e d ) R e c e n t A d v a n c e in T r o p ic a l M e d ic in e . C h u r c h ill L iv in g s to n e , E d in b u r g h , p . 2 8 9 - 3 1 9 , 1 9 8 4 .
3 0 . G o o d w in L G , P a g e J E . A s tu d y o f th e e x c r e tio n o f o rg a n ic a n tim o n ia ls u s in g a p o la r g r a p h ic p r o c e d u r e . B io c h e m ic a l J o u r n a l 3 7 : 1 9 8 - 2 0 9 , 1 9 4 3 .
3 1 . G o o d w in L G . T h e t o x ic ity a n d t r y p a n o c id a l a c tiv ity o f s o m e o r g a n ic a n tim o n ia ls . J o u r n a l o f P h a r m a c o lo g y a n d E x p e r i m e n t a l T h e r a p e u t i c s 8 1 : 2 2 4 - 2 3 4 , 1 9 4 4 .
3 2 . G o o d w in L G . C o m m e n t a r y . In : T r y p a n o s o m i a s i s a n d L e is h m a n ia s is . C i b a F o u n d a t i o n S y m p o s iu m 2 0 . E l- s e v ie r , N o r t h H o l l a n d , A m s t e r d a m , p . 3 3 1 , 1 9 7 4 .
3 3 . H a n s o n W L , W a i t s V B . R e la tiv e in s e n s itiv ity o f a K e n y a n s t r a in o f L eish m a n ia d o novani to p e n ta v a l e n t a n tim o n y t h e r a p y in h a m s te r . J o u r n a l o f P a r a s i to l o g y 6 9 : 4 4 6 - 4 4 7 , 1 9 8 3 .
3 4 . J o llif f e D S . N e p h r o t o x ic it y o f p e n ta v a l e n t a n tim o n ia ls . L a n c e t 1: 5 8 4 , 1 9 8 5 .
3 5 . K a g e r P A , R e e s P H . C lin ic a i a s p e c t s o f k a l a - a z a r in K e n y a I C G P r i n t in g D o r d r e c h t , 1 9 8 3 .
3 6 . K ik u th W , S c h m id t H . C o n t r ib u t i o n t o t h e p r o g r e s s o f a n tim o n y t h e r a p y o f k a la - a z a r . C h in e s e M e d i c a i J o u r n a l 5 2 : 4 2 5 - 4 3 2 , 1 9 3 7 .
3 7 . L la n o s - C u e n t a s E A , M a r s d e n P D , L a g o E L , B a r r e to A C , C u b a C C , J o h n s o n W D . L e is h m a n io s e m u c o - c u tá n e a h u m a n a e m T r ê s B r a ç o s , B a h ia . U m a á r e a d e t r a n s m i s s ã o d e L e ish m a n ia braziliensis braziliensis. II D o e n ç a c u tâ n e a : a p r e s e n t a ç ã o e e v o lu ç ã o . R e v is ta d a S o c ie d a d e B r a s i le i r a d e M e d i c i n a T r o p ic a l 1 7 : 1 6 9 - 1 7 7 , 1 9 8 4 .
3 8 . M a r s d e n P D . S e le c tiv e p r i m a r y h e a l t h c a r e : s tr a te g ie s f o r c o n tr o l o f d is e a s e in t h e d e v e lo p in g w o r ld . X I V L e is h m a n ia s is . R e v ie w s o f I n f e c tio u s D i s e a s e 6 : 7 3 6 - 7 4 4 , 1 9 8 4 .
3 9 . M a r s d e n P D . N e w lig h t o n p e n ta v a l e n t a n tim o n ia ls in th e t r e a tm e n t o f l e is h m a n ia s is . R e v is ta d a S o c ie d a d e B r a s i le i r a d e M e d i c i n a T r o p ic a l 1 6 : 1 7 2 - 1 7 4 , 1 9 8 3 .
4 0 . M a r s d e n P D , L l a n o s - C u e n t a s E A , L a g o E L , C u b a C C , B a r r e t o A C , C o s t a J M , J o n e s T C . H u m a n m u c o - c u ta n e o u s l e is h m a n ia s is in T r ê s B r a ç o s , B a h ia - B r a z il. A n a r e a o f L eish m a n ia braziliensis braziliensis
t r a n s m is s io n . I I I M u c o s a l d is e a s e : p r e s e n t a ti o n a n d i n itia l e v o lu tio n . R e v is ta d a S o c ie d a d e B r a s i le i r a d e M e d i c i n a T r o p ic a l 1 7 : 1 7 9 - 1 8 6 , 1 9 8 4 .
4 1 . M a r s d e n P D , S a m p a i o R N R , C a r v a l h o E M , V e ig a J P R , C o s t a J L M , L la n o s - C u e n t a s E A . H ig h c o n tin u o u s a n tim o n y th e r a p y in tw o p a ti e n ts w ith u n r e s p o n s iv e m u c o s a l l e is h m a n ia s is . A m e r ic a n J o u r n a l o f T r o p ic a l M e d ic in e a n d H y g ie n e , 3 4 : 7 1 0 - 7 1 3 , 1 9 8 5 .
