FRONTIERS IN MEDICAL CASE REPORTS - Volume 1; Issue 1, (Jan-Jun,2021), Archives of Medical and Clinical Research
Pages: 01-15
Print Article
Download XML Download PDF
Topical Treatment of Cutaneous Leishmaniasis: A Case Treated with A Glucantime-Based Lotion Experienced in Ecuador and A Mini Review
Author: Yoshihisa Hashiguchi, Lenin V. Nieto, Nancy C. Villegas, Eduardo A. Gomez, Hirotomo Kato
Category: Medical and Clinical Research
Abstract:
A 1.5-year-old male patient living in a remote community in the southeast of Manabí province of Ecuador was diagnosed as cutaneous leishmaniasis (CL) caused by Leishmania (Viannia) guyanensis. He was treated with a lotion, meglumine antimoniate Glucantime plus Merthiolate chloride, applying four to five times a day during eight weeks. The complete cure of lesion was obtained. This childhood-CL case did not respond against systemic therapy with Glucantime for the first cycle of regimen administered before the current topical treatment. Although systemic administration of pentavalent antimonials still remain as the first choice of treatment, it may often cause severe side effects, in addition to various disadvantages, such as painful injections, long-term regimens, difficulty to access health centers for patients living in remote/mountainous endemic areas. Therefore, as the alternatives, effective, easy-applicable and patient-compliant treatment is urgent need, especially for childhood-CL patients, who are highly vulnerable for toxic, systemic administrations of the drug. The current Glucantime plus Merthiolate lotion could be recommended as a future topical therapy of CLs, because of several advantages, easy-application, already-used drug as systemic therapy for the disease for a long time, more than 70 years.
Keywords: Cutaneous Leishmaniasis, Topical Treatment, Meglumine Antimoniate, Ecuador
DOI URL: https://dx.doi.org/10.51941/AMCR.2021.1103
Full Text:
Introduction
Leishmaniasis is a vector-borne disease that is transmitted by the bite of infected female of a tiny blood-sucking insect phlebotomine sand fly in tropical and subtropical areas of 98 countries and territories in the world (Alvar et al., 2012; WHO, 2018). The disease is principally divided into three clinical manifestations, cutaneous (CL), mucocutaneous (MCL), and visceral (VL), the fatal form if not treated (Alvar et al., 2012; WHO, 2018). Nearly 350 million people are at the risk of infection and 12 million are affected by the disease worldwide; among them, CL is the most prevalent and approximately 0.7 to 1.2 million cases occurring each year (Alvar et al., 2012; WHO, 2018).
In Ecuador, CL is the most predominant, followed by few numbers of MCL, 5-7% of the total cases, and other atypical clinical forms such as diffuse-CL, disseminated-CL, recidiva cutis, sporotrichoid-CL/pian-bois, and etc. (Hashiguchi and Gomez, 1990; Calvopiña et al., 2004, 2006, 2013a,b, 2014; Hashiguchi et al., 2016, 2017); no VL case is available. The disease is prevalent in 22 of the country’s 24 provinces at both sides of the Andes, Pacific and Amazonian regions, including Andes valleys where Andean-CL exists, and it remains as one of the important public health concerns (Hashiguchi et al., 1991, 2017, 2018).
In the 2016 outbreak in Manabí province, Ecuador (Molares, 2017), an infantile patient presented to a rural health center of the Ministry of Health and he was diagnosed as CL. The patient received systemic therapy with meglumine antimoniate Glucantime; however, no improvement was observed, suggesting a resistant case for the systemic therapy of the drug. Thus, childhood-CL are frequently resistant against systemic therapy with antimonial compared to adult-CL (Layegh et al., 2011a; Aksoy et al., 2016). This study describes a complete healing of a childhood-CL case which was resistant for systemic therapy with Glucantime, and then treated topically with a lotion of Glucantime plus Merthiolate.
Besides, paromomycin ointment/cream was recently shown to be effective for the treatment of both Old World and New World CL caused by L. (L.) major and L. (V.) panamensis, respectively (Ben-Sarah et al., 2013; Sosa et al., 2013, 2019).
A Case Experienced In Ecuador: Clinical Images
A 1.5-year-old male patient presented to a rural health center of the Ministry of Health, with a crusted ulcer lesion (20 mm x 15 mm) on the left cheek very close to the mouth (Fig, 1A). The patient was parasitologically and microscopically diagnosed as CL in the health center, by observing Leishmania amastigotes on smear specimen taken from the ulcer lesion, in addition to the typical clinical manifestation. His primary lesion appeared six months before as mosquito-bite-like papule that gradually ulcerated. The patient received intramuscular Glucantime injection for 21 consecutive days without any improvement, thereafter the patient’s parents refused to continue further cycle of regimens of the systemic treatment at the health center, because of different reasons, such as various side effects and painfulness of the injections, remoteness of patients dwelling site, etc. We searched for the patient living in a remote and newly established community surrounded by dense forest where no health services are available. The patient’s parents gave informed consent, to participate in the current topical treatment, because of daily worth and advanced evolution of their baby’s lesion. A comprehensive clinical history was taken by LVN, Ministry of Health, and a physical examination was performed by EAG, Ministry of Health, under the parent's informed consent. Before commencement of the current treatment, for the aim of determination of the causative Leishmania species, residual tissue materials were taken from the ulcer margin and spotted onto FTA Classic Card, Whatman Newton Center, MA. Using the clinical FTA samples, the parasite was identified as L. (Viannia) guyanensis by a polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) and cytochrome b (cyt b) analysis (Kato et al., 2019). The patient received topical treatment of a lotion of Glucantime mixed with white Merthiolate chloride, half and half concentration four to five times a day for eight weeks at his house (Calvopiña et al., 2013a,b). The lesion improved remarkably (Fig. 1B) and healed completely leaving scars (Fig. 1C, D).
Figure 1: Childhood cutaneous leishmaniasis (1.5-year-old male patient) and its topical treatment with a lotion of Glucantime plus Merthiolate chloride lotion A. Severe, profound and advanced stage of the lesion as of our first examination, before the treatment with the lotion. (Photo: 2017.10.05.). B. Partly healed lesion, during the topical treatment (6 weeks of application), the lesion improved remarkably but still leaving papules at the periphery; the treatment continued further two weeks (8 weeks in total). (Photo: 2017.11.16.). C. Two months of follow-up of B, complete cure was observed, but unexpectedly leaving typical scars of CL, probably due to severe, profound and advanced stage of the lesion as seen in A. (Photo: 2018.01.12.). D. Five months of follow-up of C, complete cure was observed, leaving depressed, depigmented and retracted scars typical for CL. (Photo: 2018.06.09).
Unfortunately, however, this case leaved an unexpectedly large scar typical for CL, probably because of the severity and profoundness of the primary lesion which could be caused by; 1) careless attending for a long time after unresponsiveness of the patient to the systemic antimonial therapy, 2) thereby, hesitation of the patient’s parents to search for further treatment; and living in a remote area surrounded by dense forest (Personal communication: Drs. LVN & EGL). Therapeutic response of the present case was in agreement with our previous cases which were also resistant against systemic therapy with Glucantime, before topical treatment with the same lotion (Calvopiña et al., 2013a, b).
Thus, the current topical lotion may be one of the alternative therapies for CL, even in those cases unresponsive to the systemic injection of Glucantime, lack of medical care systems, lower age groups impossible to tolerate for a long course of systemic regimens, etc. The current patient received half and half concentration of Glucantime per Merthiolate for eight weeks in total. However, this concentration of the lotion would be able to modify depending on the disease and/or patient conditions, such as sizes, numbers, sites, evolution times of lesions, patient’s ages, etc (Calvopiña et al., 2013a,b). Besides, this is an interesting and noticeable case of childhood-CL in which the lesion located very close to the mouth, the initial site of infection; the sand fly’s bite site; the lesion involved gradually labial mucosa. Such a case, especially in the progressed stage, is frequently diagnosed as mucosal leishmaniasis (ML) or erroneously MCL in the New and Old Worlds.
A Brief Review on The Available Topical Treatment
Systemic pentavalent antimonials, or meglumine antimonite Glucantime or sodium stibogluconate Pentostam, remain the standard therapy for CL including other clinical forms of the disease in the world, though the alternatives include amphotericin B, pentamidine, and miltefosine depending on the causative Leishmania species and clinical manifestations (Reithinger et al., 2007; Rosal et al., 2010). However, the systemic therapy with antimonials reveals serious side effects or toxicity such as musculoskeletal pains, renal failure, hepatotoxicity and cardiotoxicity, frequently requiring admission to hospital (Blum et al., 2004). Therefore, under the standard protocol of treatment with antimonials, many patients fail to complete the full course of treatment with poor compliance, in addition to yearly increase of non-responsive cases against the drugs (Croft et al., 2006; Reithinger et al. 2007; Rosal et al., 2010). Other factors such as a long course of painful injections, remoteness of patients’ dwelling sites to medical care systems are also roles as reasons of poor compliance of the systemic therapy (Croft et al., 2006; Reithinger et al., 2007). Besides, the cure rate of CL-cases with the recommended regimens is not necessarily acceptable; thus, further limiting the patients from completing a full course of the administration of antimonials (Gasser et al., 1994; Sosa et al., 2019). For these reasons, different topical treatments of CL have been conducted against the patients from the Old and New World endemic areas. Topical and oral formulations, topical paromomycin, topical niosomal zinc sulphate, and oral terbinafine are also prescribed, because of absence of pain and more or less acceptable efficacy (Reithinger et al, 2003). In the rural endemic areas of CL, however, these drugs are not easy for the patients to access. Under such circumstances, more effective, easy applicable and patient-compliant topical treatment is an urgent need especially for childhood-CL patients who are highly vulnerable for the available therapy. In this brief review, we focus on the topics of the available topical treatment of CL cases, especially on those performed in the New World.
Intralesional Infiltration
Intralesional antimonial therapy remains the gold standard of treatment for CL-patients including childhood-CL cases. However, this intralesional injection is also suffering pain in the same way as systemic therapy, because of repeated, multiple shots, and may result in poor patient-compliance; therefore, the patients and/or physicians may prefer a single intramuscular dose/shot (Aksoy et al., 2016). Intralesional injections of antimonial have been administered frequently for CL-patients in both the New and Old Worlds, obtaining a good or acceptable/tolerable result. Notably, such a topical treatment has been recommended to use only in geographical regions where CL causing Leishmania species have low potential for mucosal spread (Rosal et al., 2010). Recently, however, an important and interesting comment was given, addressing the question of whether the risk of developing ML/MCL warrants systemic treatment in all patients with New World CL or whether local treatment might be an acceptable alternative (Blum et al., 2012). The results were given as follows: local treatment might be considered as a valuable treatment option for subjects suffering from the New World CL, provided that there are no risk factors for developing ML/MCL such as multiple lesions, big lesions (>4 cm2), localization of the lesion on the head or neck, immunosuppression or acquisition of infection in the high Andean countries, notably Bolivia (Blum et al., 2012). To answer the question of whether the risk of developing severe, metastatic MCL appears or not, it is important to know the Leishmania species or genotypes circulating in given endemic areas of the New World CL, performing molecular- and clinico-epidemiological studies, including other MCL-causing factors; Leishmania RNA virus may control the severity of MCL (Ives et al., 2011). Besides, here an important note have to be given on this intralesional infiltration, that this treatment should be avoid or prohibited, when the CL-lesions localized on the face especially close to the eyes. The antimonial infiltration to such a lesion could cause serious toxic side effects affecting visual sight, finally losing eyesight (Hashiguchi et al., 2007a).
Ointment/Cream Treatment
As topical treatment of CL, more effective, easy-applicable and patient-compliant methods are urgent need for the localized self-limiting clinical forms. Considerable numbers of topical treatment of CL, such as paromomycin-gentamicin ointment, have been reported in both the New and Old Worlds until now (Ben-Sarah et al., 2013; Sosa et al., 2019). Trial of topical treatment was first implemented for the Old World CL in which the causative Leishmania parasites belong to the subgenus L. (Leishmania) which mainly causes simple and self-limiting CL. On the other hand, the trial for the New World CL was postponed, because of different species of the causative parasites which belong to the subgenera L. (Leishmania) and L. (Viannia). Among them, L. (L.) mexicana, and L. (L.) amazonensis belong to the former, and L. (V.) braziliensis, L. (V.) guyanensis, L. (V.) panamensis and L. (V.) peruviana, to the latter causing more severe ML and/or metastatic MCL clinical forms in the New World. Very few trials have been conducted for the New World CL caused by L. (L.) amazonensis and L. (L.) mexicana (Hendriksen and Lende, 1983; El-On et al., 1985, 1986).
At the early phase of trials of topical CL treatment using ointments/creams, some were found to be effective in healing the CL-lesions. Those were chlorpromazine ointment against diffuse-CL due to L. (L.) aethiopica, and paromomycin plus methylbenzethonium chloride against recurrent- or advanced-CL caused by L. (L.) major or L. (L.) aethiopica (El-On et al., 1985, 1986; Weinrauch et al., 1987). Lipid formulations of amphotericin B could also be useful as a topical treatment for Old World CL in children (Zvulunov et al., 2003), and topical treatment with nanoliposomal amphotericin B reduces early lesion growth but fails to induce cure in an experimaental model of cutaneous leishmaniasis caused by L. (L.) mexicana (Varikuti et al., 2017). Among these, a pioneering study on the topical treatment of CL using ointment was noted, that a preparation of antibiotics of the aminoglycoside class, paromomycin, using 15% paromomycin sulphate and 12% methylbenzethonium chloride in a hydrophobic base, was employed for the treatment of CL caused by L. (L.) major, proposing the possibility that the topical formulation could be an alternative method for the disease (El-On et al., 1986). However, it is still remain problems that need to be investigated, such as low penetration of most compounds through the human skin, though the transdermal transport of drugs against CL-lesions has many advantages over other routes of administration (Rossi-Bergmann et al., 2011). Nowadays, two paromomycin ointments especially for the Old World CL are commercially available but the use is limited due to toxicity or lack of remarkable efficacy (Ben-Sarah et al., 2013; Sosa et al., 2019). Several topical formulations have been in clinical trials, but many results have still been equivocal, and no major breakthroughs have been achieved yet (Garnier and Croft, 2002). Under such a circumstance, a randomized, hydrophilic vehicle-controlled trial of topical treatments containing 15% paromomycin, with and without 0.5% gentamicin, for ulcerative CL caused by L. (L.) major was conducted in Tunisia (Ben Sala et al., 2013). The results revealed that either formulation was an effective treatment for the disease by 20 days medication, without showing superiority of paromomycin-gentamicin combination. Recently, the two formulations, paromomycin-gentamicin and paromomycin alone, were also tested for the New World CL caused by L. (V.) panamensis in Panama, demonstrating similar results to those reported in Tunisia, and the previous results reported with systemic antimonial therapy (Sosa et al., 2019).
Lotion/Solution Treatment
Topical treatment with a lotion for CL could be desirable alternatives especially for infantile, childhood-CL, because of its easy and non-invasive natures, increasing accessibility and patient’s adherence and satisfaction, thus resulting in a higher cure rate of the disease (Ben-Sarah et al., 2013; Sosa et al., 2019). Efficacy of topical treatment for CL with ethanolic lipid amphotericin B was reported (Vardy et al., 2001). In Israel, furthermore, a 1.5-year-old infant who did not respond to repeated courses with paromomycin-containing ointment, then the patient was treated with topical ethanolic lipid amphotericin B, applied twice daily, one drop to each lesion, for three weeks, resulted in cure of the CL-lesions, with no local or systemic side effects; in the case three months after the treatment, no signs of recurrence were observed (Zvulnov et al., 2003). Furthermore, one of such topical trials provided that liposomal amphotericin B solution had the same efficacy as intralesional Glucantime infiltration in the CL-cases caused by L. (L.) tropica and L. (L.) mexicana (Layegh et al., 2011b).
Cryotherapy and Thermotherapy
Cryotherapy was compared with intralesional Glucantime infiltrations for childhood-CL treatment in Iran (Layegh et al., 2009). The results revealed that 1) cryotherapy is an effective treatment for the CL, 2) no serious post-treatment side effects were observed in either group, 3) at six months of follow-up, no recurrence of disease was observed in cured patients in either group, 4) because of its simplicity, lower cost, low rate of serious complications and greater tolerability, and thus, 5) cryotherapy should be recommended as an appropriate alternative treatment for childhood-CL. The efficacy of thermotherapy for the treatment of 401 CL-patients with a single lesion due to L. (L.) tropica was tested in a randomized, controlled trial in Kabul, Afghanistan, comparing the treatment with sodium stibogluconate (SSG) (Reithinger et al., 2005). The results of thermotherapy/SSG comparison revealed that no statistically significant difference was observed in the odds of cure in comparison of intralesional SSG and thermotherapy treatments, and the time to cure was significantly shorter in the thermotherapy group than in the intralesional SSG or intramuscularly SSG group, and concluding that thermotherapy is an effective, comparatively well-tolerated, and rapid treatment for CL, and it should be considered as an alternative to antimony treatment. Recently, this was further evaluated that thermotherapy can be considered as a therapeutic alternative in localized cutaneous leishmaniasis, especially in cases of single cutaneous lesions and with formal contraindications to conventional treatment with pentavalent antimonials (Goncalves and Costa, 2018).
Topical Treatment in Ecuador
Intralesional Infiltration
In Ecuador, topical treatment by using antimonial (Glucantime) intralesional infiltration against CL-patients was carried out countrywide until now. As seen in other leishmaniasis-endemic countries, intralesional injections of Glucantime to CL-patients were performed for a long time in the country, depending on the patient’s conditions. It is noteworthy to mention that during the 1984 and 1985 outbreaks of CL, after El Niño phenomena, a lack of antimonials was occurred in the country, and the outbreaks forced the use of this topical treatment; the method resulted in several advantages, with much low dose and undesired side effects, shorter treatment period, etc., together with its good and acceptable result (Gomez and Hashiguchi, 1990; Hashiguchi et al., 2017). Recently, this intralesional, topical treatment was applied to recidiva cutis type of CL-lesions and resulted in an excellent result with a high cure rate (Calvopiña et al., 2017). However, as mentioned above, this topical treatment should be considered more seriously or prohibited, when the CL-lesions localized on the face especially close to the eyes, because the antimonial infiltrations cause severe and/or toxic side effects affecting visual sight; for example, we reported one case who lost her right eyesight after receiving intralesional infiltration on the lesions located on her right cheek, losing eyesight (Hashiguchi et al., 2007a).
Ointment/Cream Treatment
Paromomycin (PM) ointment as a monotherapy for CL with clinical cure of 10%-54% patients (Nonaka et al., 1992); topical PM plus methylbenzethonium (MB) for CL with 85% cure rate with 9% cure in placebo (Krause and Kroeger, 1994); topical PM-MB and PM-urea ointment for CL with clinical cure in 79.3% and 70% respectively (Armijos et al., 2004). Topical treatment with nitric oxide donor was shown for CL with 100% cure (Lopez-Jaramillo et al. 1998), but disappointingly resulted in low cure rate and local adverse reaction in another trial (Davidson et al. 2000).
Lotion/Solution Treatment
Topical treatment with a lotion, Glucantime diluted with saline solution, was for the first time administered in the Andean type of CL-endemic areas, where the causative agent is L. (L.) mexicana and the lesions are small and superficial ulcers mostly in children less than 5-year-old (Hashiguchi et al., 1991; Nonaka et al., 1992). In these patients, usual systemic injection of Glucantime was not effective for the CL lesions, in addition to strong adverse reactions for the infant patients. Then, the lotion was prepared and applied directly to the lesions, in order to avoid painful injection and systemic adverse reactions, resulted in an excellent cure. Recently, two clinical cases of CL in Ecuador, both were quite resistant for the repeated Glucantime systemic injections, were treated by the lotion, and the results showed excellent healing, suggesting a future alternative treatment (Calvopiña et al., 2013a,b). Those cases are briefly summarized as follows. The first one is a 7-year-old female with four small crusted papules in the periphery of a large central scar on her cheek, diagnosed as CL (recidiva cutis) due to L. (V.) guyanensis; she received intramuscular antimonial (Glucantime) for 15 consecutive days but no improvement was observed, and finally treated with a topical lotion comprised of Glucantime plus Merthiolate (half and half concentration), healing completely after two months of application (Calvopiña et al., 2013a). The other one is an 18-year-old female case with a severe ulcerative lesion on her right ear. Her ear was edematous and erythematous with a large, painless ulcerative lesion covering a third of the pinna and satellite papular lesions on the posterior. She was diagnosed with chiclero’s ulcer demonstrating abundant Leishmania amastigotes in smear specimens. Because of preferences of the patient and the large volume (21 mL or 4 ampoules/day) of antimonials against her weight for systemic therapy needed, we recommended topical treatment with a lotion of Glucantime mixed half and half with white Merthiolate. After applying the lotion three to four times a day for six weeks, the lesion healed completely (Calvopiña et al., 2013b).
Thermotherapy, Cryotherapy and Other Treatment
Topical thermotherapy was applied to Andean type of a CL case with excellent healing without resurgence (Hashiguchi et al., 2007b). Topical cryotherapy treatment with nitrogen liquid is also used in limited private hospitals or research projects (Gomez et al., 2007). Besides, there exist many traditional medications for CL. In a subtropical area endemic for CL, about 150 therapies were reported (Weigel et al., 1994). These included the indigenous plants, chemicals, acids, antibiotics, heat treatments or petroleum byproducts, and some of these treatments could have clinical value. Almost 70% of the subjects with a past or present CL history were treated solely by traditional methods; notably, only 12% received a full course of systemic therapy with Glucantime, and the premature drug discontinuance was frequent in the CL endemic areas of Ecuador (Weigel et al., 1994; Weigel and Armijos, 2001).
Discussion
In this study, a childhood-CL case was treated with a lotion composed of Glucantime plus Merthiolate and resulted in complete cure. The case was no responder for systemic therapy with Glucantime. Although systemic and/or intralesional administration of the drug remain as the first choice of CL treatment, but these therapies need repeated painful injections, long-term regimens, various side or toxic effects, and etc. Therefore, an effective, easy-applicable, and patient-compliant treatment is urgent need especially for infantile, childhood-CL patients who are highly vulnerable for systemic or intralesional administrations of the antimonials. Recently, paromomycin ointment/cream was shown to be effective for the treatment of both Old World and New World CL caused by L. (L.) major and L. (V.) panamensis, respectively (Ben Sarah et al., 2013; Sosa et al., 2013, 2019).
On the other hand, there is no recommended treatment for childhood-CL less than two years of age yet (Tuon et al., 2008). Limited therapeutic options and increased incidence of childhood-CL force the development of more effective treatment for this vulnerable population (Askoy et al., 2016; Castro et al., 2017). Topical treatment including intralesional antimonial infiltration has been recommended to use only in geographical regions where CL-causing Leishmania species have low potential for mucosal spread (Rosal et al., 2010). However, topical/local treatment might be considered as a valuable treatment option for those people suffering from the New World CL, provided that there are no risk factors for developing ML/MCL (Blum et al., 2012). For obtaining precise information on these potential factors or risks, it is important to know the causative Leishmania species or genotypes circulating in given endemic areas of the disease, performing molecular- and clinico-epidemiological studies, including other MCL-causing factors.
In Ecuador, for example, only 5% to 7% of all the CL cases were found/reported countrywide (Hashiguchi and Gomez, 1990; Hashiguchi et al., 2017). Furthermore, our retrospective studies demonstrated that any case of MCL was detected, except one or two ML but not MCL cases in the Amazonian CL endemic areas for 27 years (1986-2012) (Olalla et al., 2015). Besides, in the Ecuadorian Andes regions, there exist Andean childhood-CL caused by L. (L.) mexicana mainly affecting children less than 10 years of ages (Hashiguchi et al., 1991). Those childhood-CL cases are mostly resistant for systemic antimonial therapy but susceptible for the lotions (Glucantime plus Merthiolate or Mercury chrome) applied directly onto the lesions (Hashiguchi, Gomez and Nonaka, unpublished data). Under such a situation of the disease, it could be possible to consider topical treatment in the areas where no MCL or more severe cases are reported. Regarding intralesional antimonial infiltrations, again, it should be avoided or prohibited, when the CL-lesions localized on the face especially close to the eyes, causing serious toxic side effects affecting visual sight, losing eyesight (Hashiguchi et al., 2007a).
Our previous trials using the lotion of Glucantime plus Merthiolate resulted in a good or complete cure of CL lesions in Ecuador (Calvopiña et al., 2013a,b), similarly as observed in the current clinical case. Thus, the topical treatment with Glucantime plus Merthiolate lotion could be one of the alternative therapies for CL, even in those cases unresponsive to conventional systemic antimonial injection, especially for childhood-CL patients impossible to tolerate for a long course of systemic regimens etc. The current patient received half and half concentration of Glucantime plus Merthiolate. However, this concentration would be able to be modified depending on the disease conditions, including other combinations than Merthiolate as anticeptics. Further studies are needed to get more precise information on the current Glucantime lotion, based on randomized research protocols. In addition, combination with nanoparticles (NPs) could enhance local skin accumulation of the drugs (Espuelas et al., 2016). Recently, nano-deformable liposomes (NDLs) for the dermal delivery of sodium stibogluconate (SSG) against CL was tested, indicating that the targeted delivery of SSG could be accomplished by using topically applied NDLs for the effective treatment of CL (Dar et al., 2018). Those are useful information for the development of future ideal topical treatment of CL prevalent worldwide as serious health concerns.
Conclusions
The current Glucantime-based lotion could be able to recommend as a future topical therapy of CL, because of the following advantages: 1) it needs very small amount of Glucantime, in comparison with systemic injection or intralesional infiltration, 2) there exist no side effects, 3) it is easy to apply at patient’s house or working place in remote endemic areas, 4) the drug itself has been used for a long time as the first choice of the treatment of different clinical forms of leishmaniasis in the world, and etc. Thus, more ideal and efficient combinations of the drugs for CL should be developed, employing NDLs or others, especially for infantile, childhood-CL.
Conflict of Interest: The authors have no conflict of interest to declare.
Authors’ Contributions: Y.H and H.K. designed and organized the study and wrote the paper. L.N.V., N.V.V. and E.A.G.L. collected data. H.K. tested the Leishmania parasite by PCR.
Acknowledgements: We thank medical and co-medical personnel of Subcentro de Salud de Pedro Pabro Gomez, Jipijapa, Manabi, Ecuador for technical support and patient parents for giving informed consent to participate in this study.
References:
Aksoy M, Doni N, Ozkul HU, Yesilova Y, Ardic N, Yesilova A, Ahn-Jarvis J, Oghumu S, Terrazas C, Satoskar AR. Pediatric cutaneous leishmaniasis in an endemic region in Turkey: A retrospective analysis of 8786 cases during 1998-2014. PLoS Negl Trop Dis 2016; 10: e0004835.
Alvar J, Velez ID, Bern C, Herrero M, Desjeux P, Cano J, Jannin J, den Boer M, “the WHO Leishmaniasis Control Team”. Leishmaniasis worldwide and global estimates of its incidence. PLoS One 2012; 7: e35671.
Armijos RX, Weigel MM, Calvopiña M, Mancheno M, Rodriguez R. Comparison of the effectiveness of two topical paromomycin treatments vs meglumine antimoniate for New World cutaneous leishmaniasis. Acta Trop 2004; 91: 153-160.
Ben Salah A, Messaoud NB, Guedri E, Zaatour A, Alaya NB, Bettaieb J, Gharbi A, Hamida NB, Boukthir A, Chlif S, Abdelhamid K, Ahmadi ZE, Louzir H, Mokni M, Morizot G, Buffet P, Smith PL, Kopydlowski KM, Kreishman-Deitrick M, Smith KS. Topical paromomycin with or without gentamicin for cutaneous leishmaniasis. N Engl J Med 2013; 368: 524-532.
Blum J, Desjeux P, Schwartz E, Beck B, Hatz C. Treatment of cutaneous leishmaniasis among travellers. J Antimicrob Chemother 2004; 53: 158-166.
Blum J, Lockwood DNJ, Visser L, Harms G, Bailey MS, Caumes E, Clerinx J, van Thiel PPAM, Morizot G, Hatz C, Buffet P. Local or systemic treatment for New World cutaneous leishmaniasis? Re-evaluating the evidence for the risk of mucosal leishmaniasis. Int Health 2012; 4: 153-163.
Calvopiña MH, Armijos RX, Hashiguchi Y. Epidemiology of leishmaniasis in Ecuador: current status of knowledge - a review. Mem Inst Oswaldo Cruz 2004; 99: 663-672.
Calvopiña MH, Armijos RX, Marco JD, Uezato H, Kato H, Gomez EAL, Korenaga M, Barroso PA, Mimori T, Cooper PJ, Nonaka S, Hashiguchi Y. Leishmania isoenzyme polymorphisms in Ecuador: relationships with geographic distribution and clinical presentation. BMC Inf Dis 2006; 6: 139.
Calvopiña MH, Cevallos W, Paredes Y, Puebla,E, Flores J, Loor R, Padilla J. Intralesional infiltration with meglumine antimoniate for the treatment of leishmaniasis recidiva cutis in Ecuador. Am J Trop Med Hyg 2017; 97: 1508-1512.
Calvopiña MH, Kato H, Hashiguchi Y. Leishmaniasis recidiva cutis and its topical treatment from Ecuador. Trop Med Health 2013b; 41: 93–94.
Calvopiña MH, Martinez L, Hashiguchi Y. Cutaneous leishmaniasis. Chiclero ulcer in subtropical Ecuador. Am J Trop Med Hyg 2013a; 89: 195-196.
Calvopiña MH, Romero-Alvarez D, Kato H, Hashiguchi Y. Leishmaniasis cutanea esporotricoide (pian bois) causada por Leishmania (Viannia) guyanensis en el Ecuador. Rev Enfermed Inf Microbiol Clin 2014; 32: 465-466.
Castro MM, Gomez MA, Kip AE, Cossio A, Ortiz E, Navas A, Dorlo TPC, Saravia NG. Pharmacokinetics of miltefosine in children and adults with cutaneous leishmaniasis. Antimicrob Agents Chemother 2017; 61: e02198-16.
Croft SL, Sundar S, Fairlamb AH. Drug resistance in leishmaniasis. Clin Microbiol Rev 2006; 19: 111-126.
Dar MJ, Din FU, Khan GM. Sodium stibogluconate loaded nano- deformable liposomes for topical treatment of leishmaniasis: macrophage as a target cell. Drug Deliv 2018; 25: 1595-1606.
Davidson RN, Yardley V, Croft SL, Konecny P, Benjamin N. A topical nitric oxide-generating therapy for cutaneous leishmaniasis. Trans R Soc Trop Med Hyg 2000; 50: 296-311.
El-On J, Livshin R, Even-Paz Z, Hamburger D, Weinrauch L. Topical treatment of cutaneous leishmaniasis. J Invest Dermatol 1986; 87: 284-288.
El-On J, Weinrauch L, Livshin R, Jacobs GP, Even-Paz Z. Topical treatment of recurrent cutaneous leishmaniasis with paromomycin-methylbenzethonium chloride ointment. Br Med J 1985; 291: 704-705.
Espuelas S, Schwartz J, Moreno E. Nanoparticles in the topical treatment of cutaneous leishmaniasis: gaps, facts, and perspectives. Nanosci Dermatol 2016; 11: 135-155.
Garnier T, Croft SL. Topical treatment for cutaneous leishmaniasis. Curr Opin Investig Drugs 2002; 3: 538-544.
Gasser RA Jr, Magill AJ, Oster CN, Franke ED, Grögl M, Berman JD. Pancreatitis induced by pentavalent antimonial agents during treatment of leishmaniasis. Clin Infect Dis 1994; 18: 83-90.
Gomez EAL, Briones MI, Ibarra LV, Almeida RF, Martini LR, Flor T, Muzzio J, Chum YYW, Sud RA, Kato H, Uezato H, Hashiguchi Y. A case report of cutaneous leishmaniasis caused by Leishmania (Viannia) guyanensis, resistant to antimonial chemotherapy but cured with later cryosurgery in Ecuador. In: Hashiguchi, Y. (Ed.), Studies on New and Old World Leishmaniases and their Transmission, With Particular Reference to Ecuador, Peru, Argentina and Pakistan (Res. Rep. Ser. 8). Kyowa Print. & Co. Ltd., Kochi, Japan. 2007; p: 163-168.
Gomez EAL, Hashiguchi Y. Treatment and protection of leishmaniasis in Ecuador. In: Hashiguchi, Y. (Ed.), Studies on New and Old World Leishmaniasis and Its Transmission, With Particular Reference to Ecuador (Res. Rep. Ser. 2). Kyowa Print. & Co. Ltd., Kochi, Japan. 1990; p: 190-192.
Gonçalves SVCB, Costa CHN. Treatment of cutaneous leishmaniasis with thermotherapy in Brazil: an efficacy and safety study. An Bras Dermatol 2018; 93: 347-355.
Hashiguchi Y, Cáceres AG, Criollo ML, Gomez EAL, Yamamoto Y, Kato H. A brief note on the American cutaneous leishmaniasis at an Andean community, Lanca, Province of Huarochiri, Department of Lima, Peru. In: Hashiguchi, Y. (Ed.), Studies on New and Old World Leishmaniases and their Transmission, With Particular Reference to Ecuador, Peru, Argentina and Pakistan (Res. Rep. Ser. 8). Kyowa Print. & Co. Ltd., Kochi, Japan. 2007a; p. 203-208.
Hashiguchi Y, Gomez EA, Velez LN, Villegas NV, Kubo M, Mimori T, Hashiguchi K, Kato H. Anthropophilic phlebotomine sand fly Lutzomyia species and search for the natural Leishmania infections in an area endemic for cutaneous leishmaniasis in Ecuador. Acta Trop 2020; 203: 105287.
Hashiguchi Y, Gomez EAL, A brief comment on combating leishmaniasis in Ecuador –general situation-. In: Hashiguchi, Y. (Ed.), Studies on New World Leishmaniasis and its Transmission, With Particular Reference to Ecuador (Res. Rep. Ser. 2). Kyowa Print. & Co. Ltd., Kochi, Japan. 1990; p: 185-189.
Hashiguchi Y, Gomez EAL, A review of leishmaniasis in Ecuador. Bull Pan Am Health Org 1991; 25: 64-76.
Hashiguchi Y, Gomez EAL, Cáceres AG, Velez LN, Villegas NV, Hashiguchi K, Mimori T, Uezato H, Kato H. Andean cutaneous leishmaniasis (Andean-CL, uta) in Peru and Ecuador: the causative Leishmania parasites and clinico-epidemiological features. Acta Trop 2018; 177: 135-145.
Hashiguchi Y, Gomez EAL, Coronel VV, Mimori T, Kawabata M, Furuya M, Nonaka S, Takaoka M, Alexander JB, Quizhpe AM, Grimaldi GJr, Kreutzer RD, Tesh RB. Andean leishmaniasis in Ecuador caused by infection with Leishmania mexicana and L. major-like parasites. Am J Trop Med Hyg 1991; 44: 205-217.
Hashiguchi Y, Gomez EAL, Kato H, Martini-Robles L, Velez LN, Uezato H. Diffuse cutaneous and disseminated cutaneous leishmaniasis: cases experienced in Ecuador and a brief review. Trop Med Health 2016; 44: 2.
Hashiguchi Y, Gomez EAL, Mimori T. An adult case report of cutaneous Andean leishmaniasis “Ecuadorian uta, usually affects lower age groups in Ecuador, caused by Leishmania (Leishmania) mexicana parasites. In: Hashiguchi, Y. (Ed.), Studies on New and Old World Leishmaniases and their Transmission, With Particular Reference to Ecuador, Peru, Argentina and Pakistan (Res. Rep. Ser. 8). Kyowa Print. & Co. Ltd., Kochi, Japan. 2007b; p: 169-174.
Hashiguchi Y, Velez LN, Villegas NV, Mimori T, Gomez EAL, Kato H. Leishmaniases in Ecuador: comprehensive review and current status. Acta Trop 2017; 166: 299-315.
Hendriksen TH, Lende S. Treatment of diffuse cutaneous leishmaniasis with chlorpromazine ointment. Lancet 1983; 1: 126.
Ives A, Ronet C, Prevel F, Ruzzante G, Fuertes-Marraco S, Schutz F, Zangger H, Revaz-Breton M, Lye LF, Hickerson SM, Beverley SM, Acha-Orbea H, Launois P, Fasel N, Masina S. Leishmania RNA virus controls the severity of mucocutaneous leishmaniasis. Science 2011; 331 :775.
Kato H, Gomez EAL, Seki C, Furumoto H, Martini-Robles L, Muzzio J, Calvopiña M, Velez LN, Kubo M, Tabbabi A, Yamamoto DS, Hashiguchi Y. PCR-RFLP analyses of Leishmania species causing cutaneous and mucocutaneous leishmaniasis revealed distribution of genetically complex strains with hybrid and mito-nuclear discordance in Ecuador. PLoS Negl Trop Dis 2019; 13: e0007403.
Krause G, Kroeger A. Topical treatment of American cutaneous leishmaniasis with paramomycin and methylbenzethonium chloride: a clinical study under field conditions in Ecuador. Trans Roy Soc Trop Med Hyg 1994; 88: 92-94.
Layegh P, Pezeshkpoor F, Soruri AH, Naviafar P, Moghiman T. Efficacy of cryotherapy versus intralesional meglumine antimoniate (glucantime) for treatment of cutaneous leishmaniasis in children. Am J Trop Med Hyg 2009; 80: 172-175.
Layegh P, Rahsepar S, Rahsepar AA. Systemic meglumine antimoniate in acute cutaneous leishmaniasis: children versus adults. Am J Trop Med Hyg 2011a; 84: 539–542.
Layegh P, Rajabi O, Jafari MR, Malekshah ETP, Moghiman T, Ashraf H, Salari R. Efficacy of topical liposomal amphotericin B versus intralesional meglumine antimoniate (Glucantime) in the treatment of cutaneous leishmaniasis. J Parasitol Res 2011b; 2011: 656523.
Lopez-Jaramillo P, Ruano C, Rivera J, Teran E, Salazar-Irigoyen R, Esplugues JV, Moncada S. Treatment of cutaneous leishmaniasis with nitric-oxide donor. Lancet 1998; 351: 1176–1177.
Molares M. Reporte de casos de leishmaniasis disminuyen en Manabi. Reduccion medica, Salud Publ 2017.
Nonaka S, Gómez EAL, Sud RA, Alava JJ, Katakura K, Hashiguchi Y. Topical treatment of cutaneous leishmaniasis in Ecuador. In: Hashiguchi, Y. (Ed.), Studies on New World Leishmaniasis and its Transmission, With Particular Reference to Ecuador (Res. Rep. Ser. 3). Kyowa Print. & Co. Ltd., Kochi, Japan. 1992; p: 115-124.
Olalla HR, Velez LN, Kato H, Hashiguchi K, Cáceres AG, Gomez EAL, Zambrano FC, Romero-Alvares D, Guevara AG, Hashiguchi Y. An analysis of reported cases of leishmaniasis in the southern Ecuadorian Amazon region, 1986-2012. Acta Trop 2015; 145: 119-126.
Reithinger R, Dujardinm JC, Louzir H, Pirmez C, Alexander B, Brooker S. Cutaneous leishmaniasis. Lancet Infect Dis 2007; 7: 581-596.
Reithinger R, Mohsen M, Aadil K, Sidiqi M, Erasmus P, Coleman PG. Anthroponotic cutaneous leishmaniasis, Kabul, Afghanistan. Emerg Infect Dis 2003; 9: 727-729.
Reithinger R, Mohsen M, Wahid M, Bismullah M, Quinnell RJ, Davies CR, Kolaczinski J, David JR. Efficacy of thermotherapy to treat cutaneous leishmaniasis caused by Leishmania tropica in Kabul, Afghanistan: a randomized, controlled trial. Clin Infect Dis 2005; 40: 1148-1155.
Rosal T, Artigo FB, Miguel MJG, Lucas R, Castillo F. Successful treatment of childhood cutaneous leishmaniasis with liposomal amphotericin B: report of two cases. J Trop Paediatr 2010; 56: 122-124.
Rossi-Bergmann B, Falcão CAB, Zanchetta B, Bentley MVLB, Santana MHA. Performance of elastic liposomes for topical treatment of cutaneous leishmaniasis. Nanocosmet Nanomed 2011; 9: 181-196.
Sosa N, Capitán Z, Nieto J, Nieto M, Calzada J, Paz H, Spadafora C, Kreishman-Deitrick M, Kopydlowski K, Ullman D, McCarthy WF, Ransom J, Berman J, Scott C, Grogl M. Randomized, double-blinded, phase 2 trial of WR 279,396 (paromomycin and gentamicin) for cutaneous leishmaniasis in Panama. Am J Trop Med Hyg 2013; 89: 557-563.
Sosa N, Pascale JM, Jimenez AI, Norwood JA, Kreishman-Detrick M, Weina PJ, Lawrence K, McCarty WF, Adams RC, Scott C, Ransom J, Tang D, Grogl M. Topical paromomycin for New World cutaneous leishmaniasis. PLoS Negl Trop Dis 2019; 13: e0007253.
Tuon FF, Amato VS, Graf ME, Siqueira AM, Nicodemo AC, Amato Neto V. Treatment of New World cutaneous leishmaniasis -a systematic review with a meta-analysis. Int J Dermatol 2008; 47: 109-124.
Vardy D, Barenholz Y, Naftoliev N, Klaus S, Gilead L, Frankenburg S. Efficacious topical treatment for human cutaneous leishmaniasis with ethanolic lipid amphotericin B. Trans Roy Soc Trop Med Hyg 2001; 95: 184-186.
Varikuti S, Oghumu S, Saljoughian N, Pioso MS, Sedmak BE, Khamesipour A, Satoskar AR. Topical treatment with nanoliposomal amphotericin B reduces early lesion growth but fails to induce cure in an experimaental model of cutaneous leishmaniasis caused by Leishmania mexicana. Acta Trop 2017; 173: 102-108.
Weigel MM, Armijos RX, Racines RJ, Zurita C, Izurieta R, Herrera E, Hinojosa E. Cutaneous leishmaniasis in subtropical Ecuador: popular perceptions, knowledge, and treatment. Bull Pan Am Hlth Org 1994; 28: 142-155.
Weigel MM, Armijos RX. The traditional and conventional medical treatment of cutaneous leishmaniasis in rural Ecuador. Rev Panam Salud Publica 2001; 10: 395-404.
Weinrauch L, Katz M, El-On J. Leishmania aethiopica: topical treatment with paromomycin and methylbenzethonium chloride ointment. J Am Acad Dermatol 1987; 16: 1268-1270.
World Health Organiztion (WHO), 2018. Global Health Observatory data repository: Number of cases of cutaneous leishmaniasis reported. https://apps.who.int/gho/data/view.main.NTDLEISHCNUMv.
Zvulunov A, Emanuala C, Shoshana F, Yehezkel B, Daniel V. Topical treatment of persistent cutaneous leishmaniasis with ethanolic lipid amphotericin B. Pediatric Infect Dis J 2003; 22: 567-569.
|