Ci a ion: Se e ino, P.; San ana, W.;
Lisboa, E.S.; San os, V.L.S.d.; Lima,
E.T.d.S.; Ca doso, J.C.;
Albuque que-Junio , R.L.C.d.;
Na e os, B.C.; San ini, A.; Sou o, E.B.;
e al. Cu aneous/Mucocu aneous
Leishmaniasis T ea men o Wound
Healing: Classical e sus New
T ea men App oaches. Mic obiol. Res.
2022,13, 836–852. h ps://doi.o g/
10.3390/mic obiol es13040059
Academic Edi o : Thomas Do lo
Recei ed: 20 Augus 2022
Accep ed: 14 Oc obe 2022
Published: 17 Oc obe 2022
Publishe ’s No e: MDPI s ays neu al
wi h ega d o ju isdic ional claims in
published maps and ins i u ional a il-
ia ions.
Copy igh : © 2022 by he au ho s.
Licensee MDPI, Basel, Swi ze land.
This a icle is an open access a icle
dis ibu ed unde he e ms and
condi ions o he C ea i e Commons
A ibu ion (CC BY) license (h ps://
c ea i ecommons.o g/licenses/by/
4.0/).
Re iew
Cu aneous/Mucocu aneous Leishmaniasis T ea men o Wound
Healing: Classical e sus New T ea men App oaches
Pa ícia Se e ino 1,2 , Wanessa San ana 1, E ika S. Lisboa 1, Vic o ia L. S. dos San os 1, E ica T. dos San os Lima 1,
Juliana C. Ca doso 1, Rica do L. C. de Albuque que-Junio 3, Bea iz C. Na e os 2,4,5 , An onello San ini 6,
Eliana B. Sou o 7,8,* and Sona Jain 1,*
1Ins i u e o Resea ch and Technology, Uni e si y Ti aden es, A . Mu ilo Dan as 300,
A acaju 49032-490, Se gipe, B azil
2Depa men o Pha macy and Pha maceu ical Technology, School o Pha macy, Uni e si y o G anada,
Campus o Ca uja s/n, 18071 G anada, Spain
3
Depa men o Pa hology, Fede al Uni e si y o San a Ca a ina, Flo ianópolis 88040-370, San a Ca a ina, B azil
4Ins i u e o Nanoscience and Nano echnology (IN2UB), Uni e si y o Ba celona, 08028 Ba celona, Spain
5Biosani a y Ins i u e o G anada, 18012 G anada, Spain
6Depa men o Pha macy, Uni e si y o Napoli Fede ico II, Via. D. Mon esano 49, 80131-20 Napoli, I aly
7Depa men o Pha maceu ical Technology, Facul y o Pha macy, Uni e si y o Po o, de Jo ge Vi e bo
Fe ei a, No. 228, 4050-313 Po o, Po ugal
8REQUIMTE/UCIBIO, Facul y o Pha macy, Uni e si y o Po o, de Jo ge Vi e bo Fe ei a, No. 228,
4050-313 Po o, Po ugal
*Co espondence: [email p o ec ed] (E.B.S.); [email p o ec ed] (S.J.)
Abs ac :
Cu aneous leishmaniasis (CL) and mucocu aneous leishmaniasis (ML) show clinical spec a
ha can ange om a localized lesion (wi h a spon aneous healing p ocess) o cases ha p og ess
o a gene alized sys emic disease wi h a isk o dea h. The ea men o leishmaniasis is complex
since mos o he a ailable d ugs show high oxici y. The de elopmen o an e ec i e opical d ug
o mula ion o CL and ML ea men o e s ad an ages as i will imp o e pa ien ’s compliance o he
he apy gi en he possibili y o sel -adminis a ion, as well as o e coming he i s pass me abolism
and he high cos s o cu en ly a ailable al e na i es. The mos common dosage o ms include solid
o mula ions, such as memb anes and semi-solid o mula ions (e.g., oin men s, c eams, gels, and
pas es). Topical ea men has been used as a new ou e o adminis a ion o con en ional d ugs
agains leishmaniasis and i s combina ions, as well as o exploi new subs ances. In his e iew, we
discuss he ad an ages and limi a ions o using opical d ug deli e y o he ea men o hese wo
o ms o leishmaniasis and he ele ance o combining his app oach wi h o he pha maceu ical
dosage o ms. Emphasis will also be gi en o he use o nanoma e ials o si e-speci ic deli e y.
Keywo ds:
cu aneous leishmaniasis (CL); mucocu aneous leishmaniasis (ML); opical o mula ions;
d ug deli e y; nanoma e ials
1. In oduc ion
Leishmaniasis, a ch onic pa asi ic disease is caused by he lagella e p o ozoa belong-
ing o he genus Leishmania. I is classi ied as a neglec ed disease by he Wo ld Heal h
O ganiza ion (WHO) and is globally dis ibu ed mainly in de eloping coun ies eaching
a leas 2 million new cases and causing a ound 30,000 dea hs pe yea [
1
]. Las ew yea s
ha e seen an inc ease in he numbe o cases mos ly because o u ban de elopmen , de-
o es a ion, clima e change, and he mig a ion o people o endemic a eas. Acco ding o
he T opical Diseases Resea ch P og am, leishmaniasis is classi ied as one o he six mos
impo an endemic diseases in he wo ld, due o i s complexi y in he clinical spec um and
epidemiological di e si y [1].
Mo e han 20 Leishmania species ha e been desc ibed o cause in ec ion in humans,
ansmi ed by he in e eb a e ec o o he Psychodidae amily [
2
]. The pa asi e can adap
Mic obiol. Res. 2022,13, 836–852. h ps://doi.o g/10.3390/mic obiol es13040059 h ps://www.mdpi.com/jou nal/mic obiol es
Mic obiol. Res. 2022,13 837
o di e en habi a s and clima e and p esen s wo o ms (p omas igo e and amas igo e)
du ing i s li e cycle. The p omas igo es a e lagella ed, mobile, and elonga ed in shape,
and de elop in he diges i e ac o he in e eb a e ec o . The amas igo es, on he o he
hand, a e non- lagella ed, measu ing abou 2–5
µ
m in diame e and de elop inside he
phagocy ic cells. The e a e no mo phological di e ences be ween pa asi e species, bu
geog aphical, biological, and clinical c i e ia, a e used o iden i y hem [3].
The clinical mani es a ions o leishmaniasis a y acco ding o he species o Leishmania
and i s i ulence, as well as he clinical condi ion o he hos , including hei nu i ional
s a us and immune esponse [
4
]. Clinical spec um can ange om a localized lesion, wi h
spon aneous cu e, o cases ha p og ess o a gene alized sys emic disease wi h a isk o
dea h. Based on he clinical symp oms leishmaniasis can be classi ied as isce al leishma-
niasis (VL) o kala-aza , cu aneous leishmaniasis (CL), and mucocu aneous leishmaniasis
(ML), wi h espec o he in ec ion o mac ophages h oughou he e iculoendo helial
sys em, localized in he de mis, o sp ead in he naso-o opha yngeal mucosa, espec i ely.
Fo all h ee o ms, in ec ion can ange om asymp oma ic o se e e. CL and ML can cause
subs an ial mo bidi y, whe eas VL can be li e- h ea ening [5].
The ansmission o he disease occu s when he emale sand lies unde ake blood
meal in he mammals and inocula e p omas igo es in he hos . The p omas igo es a e
encompassed by mac ophages and a e ans o med in o amas igo es wi hin a pe iod o 24
o 72 h. The amas igo es, inside he mac ophages, mul iply in ensely un il p omo ing he
up u e o phagocy ic cells. The eleased amas igo es in ec o he mac ophages, comple ing
he cycle [
6
]. The opposi e is also possible, ha is an insec bi es an in ec ed hos and
inges s he mac ophages pa asi ized by amas igo es. Then, he amas igo es p esen in he
in es ine o he in e eb a e a e ans o med in o p omas igo es, which a e in ec ious o he
e eb a e hos [7].
2. Cu aneous and Mucocu aneous Leishmaniasis
Wo ldwide cases o CL and ML a e es ima ed o be o e 1 million pe yea . CL is
he mos common o m o leishmaniasis and is caused mainly by Leishmania (Leishmania)
amazonensis,Leishmania (Viannia) guyanensis, and Leishmania (Viannia) b aziliensis [
8
]. The
skin lesions usually appea wi hin se e al weeks o mon hs a e he exposu e especially on
he exposed pa s o he body, such as he ace, a ms, and legs. They e ol e om papules o
nodula plaques ha may esul in ulce a i e lesions, showing a aised bo de and cen al
dep ession, ha can be co e ed by scab o c us . Some lesions pe sis as nodules. The
lesions a e usually painless bu can become pain ul, when in ec ed wi h bac e ia o when
p esen nea a join . The healing p ocess ypically esul s in a ophic sca ing [
9
]. Mucosal
leishmaniasis is a me as a ic sequela o he cu aneous o m, due o he dissemina ion o
he pa asi es om he skin o he naso-o opha yngeal mucosa, caused by species in he
Viannia subgenus (especially L. [V.] b aziliensis bu also L. [V.] panamensis and some imes
L. [V.] guyanensis. The isk ac o s o mucosal dissemina ion a e poo ly unde s ood and
epo ed o a y among geog aphic egions. ML becomes e iden wi hin se e al yea s o
he o iginal cu aneous lesions, especially hose no ea ed a all o ea ed poo ly. Nasal
and o al mucosa a e he mos equen ly a ec ed body lesions. The lesions in he o al ca i y
can sp ead o he o opha ynx and la ynx and may a ec ca ilage and ocal co ds. ML
lesions a e ulce a ed, and ea men is essen ial o con ol in ec ion. ML is a po en ially
li e- h ea ening and highly dis igu ing condi ion, due o he la e-s age des uc ion o he
o al-nasopha yngeal mucosa and ca ilage.
Also, he de elopmen o expe imen al models o he s udy o leishmaniasis has con-
ibu ed o unde s anding he pa hogenesis. In ecen yea s, se e al s udies ha e explo ed
pa e ns o esis ance and suscep ibili y o di e en s ains o mice in ec ed wi h di e en
species o Leishmania sp. The bes -s udied model o leishmaniosis egumen a y is he
in ec ion o mice wi h L. majo . This model employs a la ge numbe o pa asi es, which
a e inocula ed subcu aneously in he paw o he animals. Using his model, suscep ibili y
and esis ance o leishmaniasis we e c ea ed, due o a Th1- ype cellula immune esponse
Mic obiol. Res. 2022,13 838
in which lymphocy es p oduce high le els o IFN-
α
and low le els o IL-4, he e is he
de elopmen o a small lesion a he si e o inoculum, non-ulce a ed ha heals spon a-
neously. O he wise, expe imen al in ec ions in mice wi h a ious species o Leishmania sp.
can mimic se e al o ms o human cu aneous leishmaniasis. Depending on he pa asi e
species and mouse s ain, a conside able disease spec um can be p oduced. Some s ains
o mice such as BALB/c, a e highly suscep ible o L. majo in ec ion and ail o de elop
a Th1 esponse agains he pa asi e. In con as , o he mouse s ains such as C3H and
C57BL/6, in ec ed wi h L. majo , de elop spon aneously healing lesions associa ed wi h
s ong cellula immuni y. In ec ions in mice wi h o he species o Leishmania sp. can lead
o di e en models o esis ance and suscep ibili y. Fo example, s ains o mice esis an
o L. majo in ec ion (such as CBA, C3H o C57BL/6) a e suscep ible o in ec ion wi h
L. amazonensis
o L. mexicana, sugges ing ha pa asi e-speci ic ac o s play an impo an
ole in he cou se o he disease [10].
Al hough L. b aziliensis induces a disease ha is se ious in public heal h in Sou h
Ame ica, he e a e ew expe imen al wo ks ha cha ac e ize he immune esponse o his
pa asi e, p obably because mice a e unlikely. Mou a e al., 2005 de eloped a model o inoc-
ula ion o L. b aziliensis in he ea de mis o BALB/c mice leading o he de elopmen o an
ulce a ed lesion, wi h aised edges and nec o ic undus ha heals spon aneously, egional
lymphadenopa hy and pe sis ence o he pa asi e in lymphoid issues and de elopmen o
a Th1 esponse. In his way, his model is used in B azil as a e e ence [11].
3. Classical T ea men s
The ea men o leishmaniasis is complex [
4
]. Se e al d ugs a e desc ibed in he
li e a u e. The p ima y ea men can be aced back o 1920, based on i alen an imony
sal s (Sb III), bu hei oxici y, na ow he apeu ic window, and esis ance o pa asi es
esul ed in hei discon inuous use in se e al coun ies [12].
Pen a alen an imonials we e de eloped wi h imp o ed ea men po en ial and
less oxici y. An imonials a e well- ole a ed, bu some side e ec s, such as pain a he
injec ion si e, gas oin es inal dys unc ion, muscle pain, s i ening o join s, a hy hmias,
and panc ea i is ha e been epo ed [
13
]. In B azil, N-me hyl glucamine an imona e
(Glucan ime
®
) is he d ug dis ibu ed by he Minis y o Heal h. The p esc ibed dose o
Glucan ime
®
a ies be ween 10–20 mg/kg/day o child en and adul s o 20 o 30 days
unin e up ed ia in a enous o in amuscula adminis a ion ou es. Howe e , N-me hyl-
glucamine an imonia e has been associa ed wi h some mu agenic e ec s [
14
]. Ac i a ion
o an imonial d ug h ough educ ion om Sb(V) o Sb(III), ollowed by inhibi ion o
ypano hione educ ase and oxida i e s ess, is one o he easons why Leishmania pa asi es
a e suscep ible o o ganic an imonial d ugs [
15
,
16
]. F om he la es e sion o he guideline
o he ea men o Leishmaniasis in Ame ica (2nd Edi ion), pen a alen an imonials a e
ye ecommended o he ea men o mucosal o mucocu aneous leishmaniasis, ei he
wi h o wi hou o al pen oxi ylline [17].
Ampho e icin B and pen amidine ise hiona e a e also used especially du ing ea men
ailu e wi h pen a alen an imonial. Ampho e icin B is no sugges ed in pa ien s wi h hea
disease, li e disease, and neph opa hy. I s ecommended dose is 1–4 mg/kg/day, admin-
is e ed in a enously daily un il maximal dosage o ole ance. Mo e ecen ly, ampho e icin
B was loaded in unilamella esicles, consis ing o hyd ogena ed soy phospha idylcholine,
choles e ol, dis e oyl phospha idyl glyce ol, denomina ed comme cially, Ambisome
®
. This
nano echnology-based o mula ion was ound use ul o educe undesi able e ec s, such as
e e , chills, s i ness, d owsiness, sligh ele a ion o li e unc ion es s, enal dys unc ion,
and ca diopulmona y oxici y. This d ug is e ec i e in VL and ML [
18
]. Pen amidine
ise hiona e is also well- ole a ed and e ec i e in he ea men o ML caused by L. b azilien-
sis. Pen amidine ise hiona e is sugges ed in cases o poo esponse o N-me hyl glucamine
an imona e and in ole ance o ampho e icin B [19].
Mil e osine is he i s o al d ug used o bo h CL and ML. I s mechanism o ac ion is
no clea , howe e , Lux e al. (2000) [
20
] demons a ed ha his d ug inhibi s he enzyme 1-
Mic obiol. Res. 2022,13 839
acyl-2-lysoglyce o-3- phosphocholine acyl ans e ase in p omas igo e s age. Some ad e se
e ec s such as neph o oxici y, hepa o oxici y, and e a ogenici y ha e been obse ed [21].
The cu en he apeu ic op ions o he ea men o leishmaniasis a e linked o high
oxici y, low e icacy, di icul y in adminis a ion, and pa asi ic d ug esis ance [
4
]. The
pha maco he apy has been mos ly unchanged o decades, wi h ew d ug op ions, in
spi e o species di e si y and nume ous o ms o disease mani es a ion [
22
]. O e he
las decades, new d ugs o leishmaniosis ea men ha e been de eloped ocusing on
he imp o emen o e iciency, while keeping low cos and educed colla e al e ec s. An
example is isopen yl ca ea e which was desc ibed as p omising agains he mechanisms
ha pa asi es unde ake o hei su i al [
23
–
26
]. Mo e ecen ly, No ais e al. (2021) [
27
]
discussed he use o hos -di ec ed he apies ei he o enhance p o ec i e immune esponses
o o amelio a e excessi e cu aneous in lamma ion, i.e., hos -speci ic deli e y is hus
p oposed o be ailo ed acco ding o he ype o leishmaniosis.
The loading o con en ional d ugs in o inno a i e o mula ions (e.g., opical solid
dosage o ms, ilms and memb anes, nanoma e ials) has been p oposed o imp o e he
clinical ou comes, educe he oxicological isk and cos s, wi h he ul ima e aim o im-
p o e he pa ien s’ li e quali y (Figu e 1). Table 1summa izes ele an examples o d ugs
commonly used o he classical ea men o CL and ML.
Mic obiol. Res. 2022, 13, x FOR PEER REVIEW 4 o 17
comme cially, Ambisome®. This nano echnology-based o mula ion was ound use ul o
educe undesi able e ec s, such as e e , chills, s i ness, d owsiness, sligh ele a ion o
li e unc ion es s, enal dys unc ion, and ca diopulmona y oxici y. This d ug is
e ec i e in VL and ML [18]. Pen amidine ise hiona e is also well- ole a ed and e ec i e
in he ea men o ML caused by L. b aziliensis. Pen amidine ise hiona e is sugges ed in
cases o poo esponse o N-me hyl glucamine an imona e and in ole ance o ampho e i-
cin B [19].
Mil e osine is he i s o al d ug used o bo h CL and ML. I s mechanism o ac ion is
no clea , howe e , Lux e al. (2000) [20] demons a ed ha his d ug inhibi s he enzyme
1-acyl-2-lysoglyce o-3- phosphocholine acyl ans e ase in p omas igo e s age. Some ad-
e se e ec s such as neph o oxici y, hepa o oxici y, and e a ogenici y ha e been ob-
se ed [21].
The cu en he apeu ic op ions o he ea men o leishmaniasis a e linked o high
oxici y, low e icacy, di icul y in adminis a ion, and pa asi ic d ug esis ance [4]. The
pha maco he apy has been mos ly unchanged o decades, wi h ew d ug op ions, in spi e
o species di e si y and nume ous o ms o disease mani es a ion [22]. O e he las dec-
ades, new d ugs o leishmaniosis ea men ha e been de eloped ocusing on he im-
p o emen o e iciency, while keeping low cos and educed colla e al e ec s. An exam-
ple is isopen yl ca ea e which was desc ibed as p omising agains he mechanisms ha
pa asi es unde ake o hei su i al [23–26]. Mo e ecen ly, No ais e al. (2021) [27] dis-
cussed he use o hos -di ec ed he apies ei he o enhance p o ec i e immune esponses
o o amelio a e excessi e cu aneous in lamma ion, i.e., hos -speci ic deli e y is hus p o-
posed o be ailo ed acco ding o he ype o leishmaniosis.
The loading o con en ional d ugs in o inno a i e o mula ions (e.g., opical solid
dosage o ms, ilms and memb anes, nanoma e ials) has been p oposed o imp o e he
clinical ou comes, educe he oxicological isk and cos s, wi h he ul ima e aim o im-
p o e he pa ien s’ li e quali y (Figu e 1). Table 1 summa izes ele an examples o d ugs
commonly used o he classical ea men o CL and ML.
Figu e 1. Examples o opical s a egies o he ea men o cu aneous and mucocu aneous Leish-
maniosis and hei ad an ages.
Figu e 1.
Examples o opical s a egies o he ea men o cu aneous and mucocu aneous Leish-
maniosis and hei ad an ages.
Mic obiol. Res. 2022,13 840
Table 1. D ugs used o he classical ea men o cu aneous (CL) and mucocu aneous leishmaniasis (ML).
D ug Adminis a ion Rou e Dose Mechanism o Ac ion Side E ec s Re e ences
N-me hylglucamine
an imonia e
In a enous, o
in amuscula
CL: 15 mg/kg/day (20 days);
ML: 20 mg/kg/day;
Two mechanisms: (i) i binds wi h ibonucleosides o ming a complex,
p e en ing opoisome ases om ca ying ou hei unc ion in he
p ocess o DNA eplica ion and ansc ip ion; (ii) i inc eases
p o-in lamma o y cy okines in he hos , enhancing he phagocy ic
ac ion o neu ophils and monocy es.
Myalgia, li e changes,
abdominal pain and ca diac
diso de s.
[28]
Ampho e icin B
deoxychola e In a enous CL and ML: 1 mg/kg/day;
I binds wi h he e gos e ol o he pa hogens’ plasma memb ane. I will
cause he dys unc ion o he cells h ough o ming o ion po e channels.
The po e o ma ion will cause inhibi ion o glycolysis and apid e lux
o K+ and Mg+ ions inside cells leading o an inc ease in acidi y o
hese cells and cells dea h
Fe e and chills a he momen
o he in usion. Anemia,
neu openia,
h ombocy openia, and
changes in li e enzymes.
[29–31]
Ampho e icin B In a enous CL and ML: 1–4 mg/kg/day
(daily);
I is he same as Ampho e icin B deoxychola e, he di e ence happens
wi h he addi ion o lipid o mula ions ha help o dec ease side e ec s
and o each only a ge issues wi h maximum concen a ion and
selec i i y, se um concen a ion o he d ug should be kep low.
Loss o po assium and
magnesium, anaphylaxis,
e e s. Anemia and
neph o oxici y
[29,31]
Pen amidine ise hiona e
In a enous o in amuscula
CL and ML: 4 mg/kg/day;
I in e e es p oduc ion o polyamine, RNA polyme ase ac i i y,
causing he inhibi ion o p o ein and RNA syn hesis.
I has abili y o en e he pa hogen’s cell and bind he RNA ans e is
ca ied ou and hus block he syn hesis o p o eins, nucleic acids,
phospholipids and ola e.
Hypoglycemia, hypo ension,
a hy hmias, p olonged QT
in e al, a igue, nigh swea s,
ano exia, nausea, omi ing,
syncope, ash, neph o oxici y,
hepa o oxici y.
[32]
Mil e osine O al CL and ML: 2.5 mg/kg/day.
I ac i a es cy o oxic mac ophages, he abili y o in e e e wi h cell
signaling pa hways, ca y ou modi ica ions in he lipid memb ane, as
well as p og ammed cell dea h (apop osis). When adminis e ing he
d ug, i will ha e he abili y o in e e e wi h he pa hogen’s cell
memb ane, in luence he lipid composi ion, pe meabili y, and luidi y
o he memb ane, as well as he me abolism o phospholipids, causing
apop osis o be s imula ed.
Ano exia, nausea, omi ing
and dia hea, skin alle gy, high
concen a ions o li e
ansaminases and, in a e
cases, enal ailu e.
[33]
Imiquimod Topical 5%
The o -label use o opical imiquimod has been e alua ed as an agen
in he ea men o se e al in ec ious diseases. In cu aneous
leishmaniasis, i ac s on he s imula ion p ocess, causing TCD4
lymphocy es o sec e e in e e on-y, ac i a ing he elease o
mac ophages ha will ollow he in ec ion si e o phagocy ose he
amas igo e o ms o leishmania.
Some local side e ec s may
occu in high dose si ua ions,
such as i ching, e y hema,
bu ning, local i i a ion.
[34,35]
Pa omomycin Topical and pa en e al
I inhibi s he syn hesis o p o eins p esen in he p o ozoan s uc u e.
I binds o he 30S ibosomal uni causing an accumula ion o abno mal
ibosomal complexes leading o he dea h o he p o ozoan.
Neph o oxici y, o o oxici y and
li e dys unc ion [21,36,37]
Mic obiol. Res. 2022,13 841
Table 1. Con .
D ug Adminis a ion Rou e Dose Mechanism o Ac ion Side E ec s Re e ences
Azi h omycin O al 500 mg/day
(20 days)
I is an an ibac e ial ha wo ks by p e en ing p o ein p oduc ion and
in e e ing wi h bac e ial g ow h. I s an ipa asi ic ac ion is possibly
associa ed wi h i s immunomodula o y ac i i y p e en ing he
p oduc ion o cy okines and p o-in lamma o y media o s.
nausea, omi ing and dia hea [38]
Azoles O al
Ke oconazole: 200 o
400 mg/ wice a day ( o
h ee mon hs)
Fluconazole: 5 o 8 mg/kg
( o 4–12 weeks)
I aconazole: ML:
4 mg/kg/day ( o 6 weeks)
I s mechanism o ac ion is based on blocking he syn hesis o e gos e ol,
an essen ial molecule o bio egula ion and cell memb ane in eg i y.
I ching, nausea, omi ing,
alle gic and ano exia [21]
Sodium S iboglucona e In a enous [o
In amuscula 20 mg/kg/day ( o 20 days) I s mechanism o ac ion is based on he inhibi ion o glycolysis and
oxida ion o a y acids in p o ozoan cells.
Nausea, omi ing, abdominal
pain, a igue, muscle pain,
a hy hmias, li e diso de s.
[39]
Zinc sul a e O al 10 mg/kg/day
The e ec o zinc sul a e shows ela i ely posi i e bu a iable esul s
in he ea men o leishmaniasis. The e alua ion o he e ec o zinc
sulpha e in he ea men o leishmaniasis is s ill no well unde s ood,
he e ec may be ela ed o he ac ion o zinc sulpha e on p o ozoan
enzymes in e e ing wi h DNA syn hesis.
- [40]
Mic obiol. Res. 2022,13 842
4. Topical T ea men S a egies
The skin is a ba ie o ex e nal en i onmen al condi ions, p o ec ing he body agains
ul a iole adia ion, chemical agen s, mic oo ganisms, and alle gens. In addi ion o
egula ing he loss o mois u e and some nu ien s, i main ains body homeos asis, con ols
body empe a u e and blood p essu e, and allows he adminis a ion o pha maceu icals
o a sys emic e ec .
The de elopmen o an e ec i e opical dosage o ms o he ea men o CL and
ML would ep esen a signi ican ad ance in he he apy o his neglec ed disease [
4
].
The d ug mus be eleased om he o mula ion and emain e ained in he wound. The
ac ion o a d ug in o wound healing depends on a ange o ac o s, including he d ug’s
physicochemical p ope ies, he cha ac e is ics o he pha maceu ical dosage o m, and he
condi ions o he skin [41].
While challenging o ea opical leishmaniasis, se e al ad an ages can be poin ed ou
o he opical ea men , such as he possibili y o sel -adminis a ion, a oidance o he
i s -pass me abolism which helps o inc ease he d ug’s bioa ailabili y, in pa icula , hose
wi h a sho hal -li e and a na ow he apeu ic window, less plasma luc ua ion, imp o ed
e ec i eness wi h a lowe dosage, educed cos s, all p omo ing pa ien ’s [
42
,
43
]. Mo eo e ,
he possibili y o a ge he d ug in o he si e o ac ion (e.g., wi h nanoma e ials) educes
he oxicological isks. The mos common dosage o ms include ilms/memb anes and
semi-solid o mula ions (e.g., oin men s, oil-in-wa e emulsions and hyd ogels). Topical
ea men has been used as a new ou e o adminis a ion o con en ional d ugs agains
leishmaniasis and i s combina ions, and also o he deli e y o new compounds wi h
an i-leishmaniosis ac i i y [
41
]. Table 2summa izes CL ea men s acco ding o he ype o
o mula ion o skin ou e o adminis a ion.
5. Semi-Solid Fo mula ions
Oin men s a e s able, semi-solid pha maceu ical dosage o ms, so in consis ency,
in ended o ex e nal use, consis ing o one o mo e d ugs and monophasic excipien s
wi h lipophilic o hyd ophilic cha ac e is ics. Oin men s mus be plas ic and he mo-
e e sible, so ha wi h he inc ease o he empe a u e upon opical applica ion, hey
become less iscous, allowing he d ug o be eleased and each he skin. Acco ding o
he deg ee o pene a ion and he excipien used, hey a e classi ied as epide mal (i he
d ug ac s supe icially on he skin and he excipien s used a e pe oleum and mine al
oil), endode mal ( he d ug pene a es deepe in o he skin eaching he de mis, and he
excipien is a ege able oil) and hypode mic (i abso bed and can igge a sys emic e ec ;
he excipien is lanolin).
Bilbao-Ramos e al. (2020) [
44
] desc ibed he i s - ime
in i o
s udy epo ing he use
o u solic acid o ea leishmania. U solic acid was loaded in a semi-solid o mula ion
(e.g., c eam o oin men ) and compa ed o he comme cial O abase
®
(Fag on) in which
he u solic acid was dispe sed wi h glyce in:p opylene glycol. The semi-solid o mula ion
using 0.2% o u solic acid p omo ed a educ ion o ~50% o lesion size compa ed con ol
g oup, a e 28 consecu i e days. The ea men was howe e no e icien in comple ely
educing he L. amazonensis in ec ion, a ibu e o he occlusi e e ec o he oin men which
p omo ed u solic acid pe meabili y ac oss he skin wi h a p olonged he d ug deli e y.
In ano he s udy, Copas-López e al. (2016) [
45
] in ec oo o Sy ian hams e model
using L. opica s ain. The e ec o (
−
)-
α
-bisabolol by opical, o al and in alesional
adminis a ion was e alua ed. The oin men was composed o ce yl alcohol, lanolin, whi e
pe oleum jelly and (
−
)-
α
-bisabolol (1%, 2.5%, 5%) was applied on he oo pad lesion o
p e en mic obial in ec ion and educe he isk o sca s. (
−
)-
α
-bisabolol is a na u al o igin
wi h an i-in lamma o y, an i-mic obial and healing p ope ies.
Mic obiol. Res. 2022,13 843
Table 2.
Examples o o mula ions p oposed o cu aneous leishmaniosis, ype o d ug, p oduc ion
me hod and main esul s.
Type o
Fo mula ion D ug P oduc ion Me hod Resul s Re e ences
Polyme ic
nanopa icles
Meglumine
an imonia e Nanoemulsi ica ion
The o mula ion was able o con ol
a leishmaniasis in ec ion as he same
le el han he e e ence injec ed
Glucan ime®.
[46]
Film-Fo ming
(sp ay o mula ion)
Ni oimidazole
DNDI-0690
Dispe sion in
wa e /e hanol medium o
polyme and plas icize
The o mula ion educed he
pa asi es in he skin, bu did no
in luence he lesion size compa ed
wi h he con ol.
[47]
Emulsions (PEI25-CAN-γ-Fe2O3
NPs) Nano-Leish-IL Emulsion The elimina ion o in ec ion by L.
majo in i o assays was obse ed. [48]
Emulsion Ampho e icin B Emulsion
Cu e a es o 39.4% we e obse ed,
showing ha opical Ampho e icin
B was no e ec i e o he ea men
o CL.
[49]
Nanos uc u ed
lipid ca ie s
(NLCs)
inco po a ed in o a
hyd ogel
Ampho e icin B
NLC was p oduced by he
emulsi ica ion me hod,
polyme and plas icized
was added and
homogenized.
The o mula ion was a ound i e
imes slowe in he IC50 alues
in i o assays.
[50]
Nano ans e somes
inco po a ed in
chi osan gel
Ri ampicin
Film hyd a ion me hod
ollow, chi osan added and
homogenized
Nano ans e somes we e mo e
e ec i e compa ed o d ug p is ine.
Fu he mo e, he nano ans e somes
inco po a e in chi osan gel educed
he wound healing signi ican ly.
[51]
Memb anes
Die hyl
di hioca bama e
(DETC)
Bac e ial cellulose
memb anes we e ob ained
om cul i a ion o
Gluconace obac e hansenii
Reduc ion in signi icance o pa asi e
load and
o in ec ion o L. b aziliensis in
mac ophages
[52]
Memb anes ampho e icin B (AmB)
A poly inyl alcohol, (PVA)
hyd ogel p oduced by
cas ing
The leishmanicidal, an i ungal, and
cy o oxic ac i i y o he sys em
loaded wi h AmB we e signaled an
e icien pha macological ac i i y
and adequa e biocompa ibili y o
PVA-AmB hyd ogels wi h g ea
po en ial in he opical ea men
o CL.
[53]
Sel -
nanoemulsi ying
d ug deli e y
sys ems
bupa aquone (BPQ) Dispe sion o d ug, oil,
su ac an in sol en
Reduc ion o pa asi ism and
indica ed healing in animals [54]
Liposomes Ampho e icin B (AmB) Film hyd a ion me hod
Liposomal o mula ion was
conside ably highe han ha
obse ed o p is ine AmB
[55]
Liposomes s iboglucona e and
ke oconazole Film hyd a ion me hod In i o
and
in i o
an i- indica ed a
10.67- old lowe IC50 alue [56]
Mic obiol. Res. 2022,13 844
Table 2. Con .
Type o
Fo mula ion D ug P oduc ion Me hod Resul s Re e ences
Liposomes Azi h omycin and
glucan ine
dehyd a ion– ehyd a ion
esicle; (DRV) me hod
dehyd a ion– ehyd a ion
esicle; (DRV) me hod
Dehyd a a ion-
ehyd a a ion esicle
me hod
In i o assays showed a cu e a e o
77% o azi h omycin and 76% o
glucan ime.
[57]
Liposomes Ampho e icin B -
Liposomal o mula ion was s able
and showed capaci y o pene a e
in o he skin. I was also e icien
agains L. majo in i o and in i o.
[58]
Hyd ogels Mil e osine Dispe sion o d ug and
polyme in wa e .
The opical 0.5% mil e osine gel
o mula ion was e icacious and
non- oxic when adminis e ed
opically in i o assays.
[59]
Hyd ogels Meglumine
an imonia e
Polyme homogeniza ion
in aqueous medium
I showed high e en ion on he skin
and educ ion o IC50 compa ed
he con ol.
[60]
Hyd ogels Ampho e icin B
Homogeniza ion o
polyme wi h cons an
mechanical s i ing in
aqueous medium
No cy o oxic e ec s we e obse ed
in mac ophages. No in i o and
in i o assays we e done ye .
[61]
Oin men U solic acid mel ing
Reducing he L. amazonensis
in ec ion, a ibu e o he occlusi e
e ec o he oin men , which
p omo ed u solic acid pe meabili y
ac oss he skin wi h a p olonged he
d ug deli e y
[44]
Oin men (−)-α-bisabolol Mel ing
In i o assays p e en ed mic obial
in ec ion and in lamma ion,
leishmanial and healing p ope ies.
[45]
A e in ec ion, he animals we e ea ed o 7 days. The mos p omising esul was
ob ained wi h he opical ea men using 2.5% (
−
)-
α
-bisabolol oin men , which educed
~83% he lesion size and 80% pa asi e load. This ou come was a ibu ed o he an i-
in lamma o y ac i i y o d ug, oge he wi h he enhanced d ug bioa ailabili y upon
opical adminis a ion in he wound.
Rega ding he use o oin men s o leishmaniasis ea men So o e al. (2019) [
62
]
epo ed a ele an esul wi h opical applica ion o pen amidine in leishmaniasis caused
by L. b azilensis. A 15% pen amidine oin men was o mula ed in a hyd ophilic ehicle
gi e adso p ion p ope ies. The hyd ophilic o mula ion o pen amidine had a cu e a e o
77.5% compa ed o he posi i e con ol (in alesional injec ion o pen amidine adminis e ed
on days 1, 3 and 5 a a dose o 120
µ
g/mm
2
a he lesion si e) which had a a e o 70%.
These esul s sugges ha he oin men ac s posi i ely, inc easing he d ug bioa ailabili y.
In a Phase III ial desc ibed by Sosa e al. (2019) [
63
], an e icacy o 79% and 78% was
obse ed o he g oup ea ed wi h 15% pen amidine and 0.5% gen amicin oin men and
15% pen amidine oin men , espec i ely, when applied once a day o 20 days [35].
The i s medicine con aining pa omomycin o ea CL was an oin men based on
15% o pa omomycin and 12% o me hyl benze honium showing a sa is ac o y esul
in i o
, elimina ing he pa asi es and healing he lesion in 100% o he animals [
64
]. This
o mula ion is a ailable comme cially in Is ael, as Leoshcu an
®
. Mo e ecen ly, Ve aldi e al.
(2020) [
65
] de eloped pa omomycin (15%) oin men con en glyce in, aseline, sepigel 305,
Mic obiol. Res. 2022,13 851
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