Impact Factor 2021: 3.041 (@Clarivate Analytics)
5-Year Impact Factor: 2.776 (@Clarivate Analytics)
Immediacy Index: 0.927
  • Users Online: 770
  • Print this page
  • Email this page

 
Table of Contents
REVIEW ARTICLE
Year : 2022  |  Volume : 15  |  Issue : 5  |  Page : 196-205

New developments in the treatment of cutaneous leishmaniasis


Invamed RD Global, Ankara, Turkey

Date of Submission07-May-2022
Date of Decision19-May-2022
Date of Acceptance21-May-2022
Date of Web Publication31-May-2022

Correspondence Address:
Rasit Dinc
Invamed RD Global, Ankara
Turkey
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1995-7645.345944

Rights and Permissions
  Abstract 

Leishmaniasis, including the cutaneous form, poses an important public health threat around the world, while no vaccine is currently available against any form of leishmaniasis. The drugs used in the first line treatment of cutaneous leishmaniasis (CL) are commonly pentavalent antimonials despite their toxicities, long-term treatment duration and increasing resistance rates. Other alternatives are amphotericin B, pentamidine, miltefosine and paromomycine. Movement of the population, especially in endemic regions, increases the spread of the parasite and affectes the distribution of causative species, which requires re-evaluation the treatment regimen. Extensive researches are carried out on the treatment of leishmaniasis. The immunotherapeutic and targeted therapeutic approaches, formulations of carrier-loaded active drugs, local thermotherapeutic applications, the combination of antileishmanial drugs/compounds, the use of new synthetic and natural products are promising therapeutic options in the future. Herein, the author reviews the potential treatment modalities of CL with a brief overview of current treatments in the light of ongoing studies around the world.

Keywords: Cutaneous leishmaniasis; Current treatment; Potential treatments; Thermotherapy; Immunotherapy; Natural/ synthetic therapy


How to cite this article:
Dinc R. New developments in the treatment of cutaneous leishmaniasis. Asian Pac J Trop Med 2022;15:196-205

How to cite this URL:
Dinc R. New developments in the treatment of cutaneous leishmaniasis. Asian Pac J Trop Med [serial online] 2022 [cited 2022 Jul 2];15:196-205. Available from: https://www.apjtm.org/text.asp?2022/15/5/196/345944


  1. Introduction Top


Leishmaniasis is a serious, but preventable and treatable parasitic disease caused by Leishmania species[1],[2]. Depending on host and parasite characteristics, the clinical manifestations of leishmaniasis can be classified as cutaneous, mucocutaneous, and visceral leishmaniasis[3],[4],[5]. Leishmaniasis affects about 12 million people all over the world, mostly in developing countries[6]. However, their incidences vary widely amongst their geographical locations. The annual incidence of leishmaniasis is about 2 million cases, 1.5 million cases for cutaneous leishmaniasis (CL) and 500 000 cases for visceral leishmaniasis (VL). The skin lesions in CL tend to heal spontaneously, contrary to VL which can be fatal if not properly treated. CL may result in disfiguring and stigmatizing scars with a considerable impact on quality of life[3],[7]. The decision to treat CL, and to initiate a systemic or local treatment, depends on different factors related to the risk-benefit balance[8],[9]. The main aim of CL treatment is to decrease the recurrence, to reduce scarring, particularly in cosmetic sites of the body, and to prevent spread of the disease in the community[2]. Diverse Leishmania species is known to cause CL, at least five species have been reported on the Eurasian and African continents, and seven species in the Americas. The resolving period and severity of CL depends on the infecting species[10]. The most frequent species causes CL in the western countries are Leishmania (L.) mexicana, L. amazonensis, L. braziliensis, L. panamensis, and L. guyanensis, while in the developing countries are L. tropica, L. aethiopica, and L. major[7],[11].

No vaccine is currently available against any form of leishmaniasis[12]. In the clinical applications, there are around 25 compounds and formulations showing antileishmanial effects[13]. But, until now, none of the available drugs can be considered ideal due to their high toxicity and the emergence of resistant Leishmania associated with the lengthy treatment period[14],[15],[16]. The standard treatment recommendation is impossible due to the diversity of Leishmania infections worldwide. Optimal treatment regimens are best defined in consideration of demonstrated regional efficacy, available resources, and risk-benefit assessments for major syndrome in each geographic region[9]. Currently, the traditional approach in the treatment of CL is to use pentavalent antimonials; however, several other treatment modalities could be proposed based on epidemiological and geographical features of the regions[3].

Treatment is required if lesions are: multiple, in different locations, and large than 5 cm; complicated, metastatic spread to the lymph nodes; mucosal involvement and exposed skin in location; more invasive (e.g., those failing to respond to topical treatment); and patients are immunocompromised[9].

The population relocation related to several reasons such as wars and socio-economic anxiety, and environmental aspects like climate change result in the exposure of unimmunized individuals to different species of the parasite[17],[18]. Even if species-level diagnosis for guiding treatment has limited value by the current treatment methods, this kind of risk factors contribute to an epidemiological diversity and increased frequency of infection which requires to revise the treatment policy[16]. On the other side, rapid advances are made on the treatment of leishmaniasis, some of which represent new avenues for more effective, safer, easier and cheaper applications.

This review focuses on potential treatment modalities of CL with a brief overview of current treatments in the light of ongoing studies around the world.


  2. Current treatments for cutaneous leishmaniasis Top


2.1. Pentavalent antimonials

The drug of choice for all types of the infections caused by Leishmania species are pentavalent antimonials (SbV)[13], which are found as sodium stibogluconate and methylglucamine antimoniate (MA) formulations. Although the drugs has inhibitory effects on the glycolytic and oxidative pathways of fatty acids in amastigotes, their action mechanism is still not understood completely[19].

The drug is mainly administered intramuscularly (IM), intravenously (IV), or intralesional (IL). Generally, an uncomplicated CL treatment is initiated by local therapy, whereas systemic therapy is warranted for complicated CL[19]. Recommended dose by IM and IV is 15-20 mg SbV/kg of body weight daily for 21-28 days [Table 1] is distributed in high concentration in the plasma, liver and spleen, and 50% of the drug is excreted in 24-76 hours through urine[13],[20].
Table 1: Current therapy protocol of cutaneous leishmaniasis[7],[9],[13].

Click here to view


However, painful injection, high toxicity and the emergence of significant resistance due to the long-course treatment of the drug have reduced the use of antimonials[13],[14].

The therapeutic response is affected by multiple factors, including the host immune status, and Leishmania species. Decreased response to pentavalent antimony has been observed among Leishmania species, together with some geographic changeability[19]. Data obtained from various reports using intralesional methylglucamine antimoniate therapy show that the cure rates ranged between 50% and 92%[21],[22],[23],[24],[25],[26],[27],[28]; otherwise, intralesional sodium stibogluconate ranged from 58.3% to 94.6%[29],[30],[31],[32],[33] in CL patients.

Amphotericin B, pentamidine, miltefosine and paromomycin are the second line drugs for especially pentavalent antimony contraindicated or refractory patients [Table 1][13]. On the other hand, there are limitations for their use for CL treatment: the therapeutic efficacies of these second line drugs are less than the antimonials[13],[14],[19]. Besides, they have various toxicities in systemic or local therapy[14],[34],[35].

2.2. Other drugs clinically used

Over the last 35 years, many compounds have been investigated for their efficacies against leishmaniasis, including rifampicin, tamoxifen, doxycycline, monomycine, trimethoprim, some azole- derivatives, allopurinol (a purine analogue), and sitamaquine (an 8-aminoquinoline analogue). However, safisfying impact has not been observed in the cure results[4],[13]. Use of cryotherapy is another treatment choice, but often restricted to diseases caused by L. tropica and L. major et al. Cryotherapy with liquid nitrogen consists of a freeze, thaw, and freeze cycle, which causes destroy of parasites and other cells[21],[36]. Rifampin has been used at higher doses for CL, without reports of increased adverse effects, supporting the idea that the majority of rifampin’s adverse effects are idiosyncratic and not dose-related[37].


  3. New therapeutic alternatives for CL treatment Top


Increasing resistance to the current drugs, long-term treatment necessity, and the toxicity problems have resulted in the need to investigate new therapeutic alternatives, such as immunotherapy, local hyperthermic administrations, antileishmanial synthetic and natural products, and combination therapy[6],[9],[33],[38],[39],[40],[41],[42]. Some of these treatments has shown high effectivity, however, there is no standardized protocol.

3.1. Immunomodulatory and targeted therapeutic approaches

Macrophages are very important not only as effectors and antigen- presenting cells, but also as host cells for some microorganisms[12]. By inhibition of phagosome-endosome fusion, the macrophages could serve as hosts for long-term replication, survival and parasite spread (referred as “Trojan horse”)[43]. T lymphocytes also play a critical role in shaping the host immune response to direct both protective and non-protective immunity. The disease progression in CL is driven largely by the production of Th2-associated cytokines IL-4, IL-10, IL-13, and TGF-β[44]. In the experimental non-healing and disseminating infection models by L. major, a parasite-driven Th2 polarized response was observed[45]. Otherwise, the infection control is mainly mediated by IL-12-driven Th1-type immune response. The production of IFN-γ by CD4+ T cells plays a critical role in the activation of macrophages to kill the parasites by a nitric oxide mediated condition[44]. Despite these basic immunological mechanisms, the regulation of resistance varies widely between species, even within a given species. For example, L. mexicana and L. amazonensis, unlike L. major, have developed mechanisms to survive in conditions of limited Th1 immune responses in the host[46].

3.2. Immunotherapeutic/targeted approaches

The immunotherapy is experiencing a renaissance in various fields[47]. The immunotherapy of leishmaniasis, including CL, is not naive to this renaissance. In this context, the idea of modulation the immune response by the activation of macrophages and the increase of nitric oxide production and other mechanisms to eliminate the parasites has led to new investigations to supply an effective immune response[48],[49].

To achieve these goals, one of the approaches in the treatment of leishmaniasis is targeted therapy. Targeted therapies act by blocking basic biochemical or signaling pathways essential for growth and survival of the parasite[6]. In an experimental study, Cummings et al. demonstrated that PI3Kγ mediates the entry of L. mexicana into phagocytic host cells[50]; whereas in their another study that used the AS-605240, a PI3Kγ inhibitor, for the treatment of experimental L. mexicana infection in mice, it was observed significantly lower parasite burdens and lesion sizes than wild type untreated mice. Therefore, PI3Kγ may be a possible drug target for the management of L. mexicana and potentially other obligate intracellular pathogens. Further, in reducing parasite burdens, AS-605240 was as effective as sodium stibogluconate. The results of another experimental study by Oghumu et al. revealed that transgenic expression of CXCR3 on T cells exacerbates CL caused by L. major in BALB/c mice by amplifying Th2 host immune responses, increasing neutrophil and inflammatory monocyte infiltration to infected sites, and inhibiting monocyte maturation[51]. This observation can lead CXCR3 to be considered as a therapeutic target.

Targeting the mechanisms of which are regulated by Leishmania to evade or exploit host immune responses is another promising choice for therapeutic intervention[52]. To reverse the immunosuppressed milieu by parasite-driven Th2 cytokine production, it is important to identify the molecules that control Treg cell. Chowdhury et al. reported that Ara-LAM, a potent immunomodulatory which induces pro-inflammatory functions in a toll-like receptor 2-dependent manner, causing IFN-γ secreting CD4+ T cells in Leishmania- infected BALB/c mice, potentially correlated with impaired Treg cell functions[53]. Some of the other promising immuno-therapeutic strategies could be used as potential targets in future involve receptors expressed on Treg or its corresponding ligands on effectors cells, programed cell death domain-1 or its ligands (PD-L1, and B7- H1), and cytotoxic T lymphocyte antigen-4[6].

Another promising approach for targeted therapeutic treatment of CL is the release of the drug into macrophages cell to kill parasites reside and multiply within host macrophages. In this way, the drug is expected to improve the therapeutic index by increasing efficacy and reducing toxicity[54],[55]. In a study to evaluate in vitro efficacy of paromomycin sulfate (PM) against L. major and L. tropica, Kharaji et al. observed that solid lipid nanoparticles (SLN) as delivery system can enhance the capability of PM to penetrate into the macrophage. They reported that the efficacy of PM-loaded SLN is significantly more effective than that of PM in inhibiting parasite propagation and SLN is safe without any cytotoxicity[56]. In a visceral leishmaniasis experiment in mice, it was shown that liposomal resiquimod induced IFN-γ and IL-10, and decreased the parasitic load. The decreased parasitic load is potentially due to the large up-regulation of IFN-γ outweighs that of IL-10[57]. Collier et al. formulated AR-12, which is a host-mediated therapeutic investigational new drug-approved by the Food and Drug Administration for cancer treatment, into microparticles, a polymer microparticle coated celecoxib derivative kinase inhibitor (AR-12/MPs) using the novel biodegradable polymer acetylated dextran to use VL treatment. Following the treatment with AR-12/MPs, parasitic loads in liver, spleen, and bone marrow were significantly decreased. Moreover, combinatorial therapies with amphotericin B illustrated more significant effects[58].

A variety of nanomaterials (NMs) are used in the drug release approaching. NMs can act as drug carriers or selective agents against the parasite. NMs reduce the toxic effects, and can be used for any combination therapy or as adjuvants to improve immune response in vaccine studies[59].

In a study to evaluate fractional CO2 laser-assisted topical rifamycin drug delivery, Lodi et al. reported that this technique might be safe and effective in treating CL[60].

We consider that the immunotherapeutic choice against leishmaniasis should be targeted at least one of the three main goals: stimulation of the immune system to enhance leishmaniacidal activity, prevention of the parasite-driven milieu which promotes parasite survival in macrophages, and inhibition of the cells which act as a “Trojan horse” in order to reduce parasitic load.

In the first report about the use of immunomodulators, Badaro et al. observed the superiority of human IFN-γ as an adjunct antimony therapy for VL by explaining an enhanced intracellular killing of the parasites[11]. In murine leishmaniasis model, recombinant IFN-γ given alone or along with sodium stibogluconate resolved the infections caused by L. major and developed Th1-type responses. However, administration of anti-IL-12 antibodies reversed the therapeutic effects, which suggesting that IFN-γ promotes cure through an IL-12-dependent mechanism[61]. Tucaresol, an orally bioavailable immunopotentiatory drug, acts against infection caused by L. donovani by enhancing TH1 response and the production of IL- 12 and IFN- γ levels[62].

It would be logical and important to identify an immunomodulatory compound generating an oxidative burst within Leishmania-infected neutrophils to effectively eliminate parasites. It has been reported that berberine chloride has a leishmaniacidal activity both directly by inducing an oxidative burst in parasites and indirectly via an increase in IL-12[63]. It has obtained successful clinical outcomes via imiquimod, an FDA-approved toll-like receptor 7/8 agonist in treatment of CL[64],[65]. It may be beneficial in refractory CL in combination with other drugs[64]. Similarly, an imiquimod derivative and FDA-approved molecule resiquimod has also shown promising outcomes in treating CL. Resiquimod decreases the intracellular parasitic load by inducing the production of nitric oxide although it has no direct effect on the parasite[66]. Also, both of the molecules induce interferon-α, interleukin-1β, IL-6 and tumor necrosis factor-α in macrophages and monocytes[67].

The parasitized neutrophils undergo apoptosis and then will be upregulated by macrophages. Therefore, the parasite drives neutrophils as “Trojan horses” to infect macrophages and dendritic cells and initiate CL[53]. In experimental leishmaniasis models to evaluate whether neutrophils have a protective or non-protective role, inhibition of neutrophil recruitment in the infection site resulted in paradoxical impacts, depending on the genetic background of mice used for the experiments. Depletion of the neutrophils results in a reduced parasite load in BALB/c mice, whereas C57BL/6 mice show an exacerbated infection[68]. In an experimental visceral leishmaniasis study used chemokine receptor 2 antagonist RS- 504393, we observed decreased numbers of inflammatory monocytes and parasitic loads in spleen and liver. Besides, there was a decreased inflammatory monocyte response correlated with decreased numbers of IFN-γ+IL-10+CD4+ T cells percentage[69].

3.3. Cytokine therapy

Cytokines have a significant role in the shaping of CL by either the development of Th1 or Th2 response[44]. The idea of using immunostimulatory cytokines (e.g., IFN-γ, IL-12, and GM-CSF) or antibodies that target deactivating cytokines as therapy method in leishmaniasis should be considered an important development[49].

The use of anti-IL-10R mAb in chronic cutaneous L. major infection results in eliminated persisting parasites. The apparently enhanced antimicrobial action is mainly related to increased expression of activating cytokines such as IL-12, IFN-γ, iNOS induction, macrophage activation and generalized inflammation[70]. Likewise, in normally susceptible BALB/c mice, exogenous treatment with rIL-12 during L. major infection leads to resistance of the mice[71]. Neutralizing IL-10 or blocking its receptors in VL models yielded similar results. Suppression of IL-13, IL-4 and TGFAβ inhibited parasite replication[72].

3.4. Dendritic cell-based therapy

Dendritic cells (DCs) are the most potent antigen-presenting cells and play a critical role in the activation of T, B and NK cells[73]. In CL, DCs rather than macrophages prime T cell responses against L. major and induce protective immunity[74]. DCs play an important role in initial anti-Leishmania T cell responses and promoting their differentiation into memory T cell to achieve long-lasting immunity. Thus, DC-based immunotherapy appears as a promising application for the induction of antigen-specific T cell immunity[6]. In murine VL, dendritic cells- and antimony-based combined therapy has been found highly effective[75].

3.5. Thermotherapy applications in CL treatment

Thermotherapy application is a technique used to increase tissue temperature for whole or regional body. Radiofrequency, electromagnetic energy, ultrasonic waves, and other thermal- conduction-based devices could be used for the heating. The heating increases blood flow which facilitates tissue healing. The thermotherapeutical applications can be used in various medical conditions, including skin infectious lesions[76],[77],[78],[79].

Hyperthermia alone can damage Leishmania parasites, but more importantly, hyperthermia might potentiate the effectiveness of chemotherapeutics when used in combination[76],[77],[78],[79].

The ability of dermatotrophic Leishmania species to replicate is limited at higher temperatures, and almost completely eliminated over 39 °C[80]. Subsequently, thermotherapy has been evaluated in a variety of CL species[81]. The ThermoMed device (Thermosurgery Technologies, Inc., Phoenix, AZ), which utilizes radio-frequency technology has received the United States FDA approval for this purpose[82]. WHO recommended this instrument as an alternative therapy for all American CL species[83]. The device is portable, battery-operated, and delivers superficial heat to 50 °C via a set of prongs placed directly on the lesion. On other side, local anesthesia is required due to pain during the application[76],[83].

Another adapted technology of thermotherapy Hand-held Exothermic Crystallization Thermotherapy for Cutaneous Leishmaniasis (HECT-CL) (Pristech Products, San Antonio, TX) which is a sodium acetate heat pad calibrated to produce (52±2) °C for 3 minutes, in one to three fractions (depending on the pain tolerance of the patient)[76]. It costs less than 3 dollars, is simple to use, and is rechargeable by boiling for recurrent reuse[38]. However, thermotherapy should not be used for lesions with potential for lymphocutaneous or mucosal spread[83].

Although different ratios are represented based on heterogeneity among the applications related to personal experience, the definitive clinical cure rate of HECT-CL was generally reported to be 60%- 68.4% in the treatment of CL[38]. For radiofrequency thermotherapy, this rate ranges from 38% to 90% with a variety of species[81],[82],[83],[84],[85],[86],[87]. In a meta-analysis of controlled clinical trials, the overall efficacy of thermotherapy was 73.2%, whereas the efficacy of systemic treatment was 70.6%. Thermotherapy presents similar efficacy to that of systemic treatment, being safer, requiring a smaller number of treatments and no laboratory monitoring, improving adherence, and having a lower cost et al[88].

Photodynamic therapy (PDT) has become a novel important application for some skin infection, including leishmaniasis and it can also be used as combinations of the existing treatments[89],[90].

3.6. Combined therapy choice

The combined treatment of CL is one of the most important strategies, which not only increase antileishmanial effect, but also reduce the potential toxic adverse effects, the length of treatment and decrease drug resistance due to their synergistic effects[6],[13],[91],[92]. Several combinations exist for antileishmanial using, such as liposomal amphotericin B plus miltefosine, miltefosine plus paromomycin, miltefosine plus sodium stibogluconate, other new combinations, including the use of immune-chemotherapy[93],[94],[95],[96]. Combinations of drugs eliminate the parasites via different modes of action. One drug/compound in the combination could modulate the immunity of the host, while the second drug could target the parasite itself[6]. Using recombinant IFN-γ in combination with pentavalent antimonials has been reported as more effective parasitological and clinical in VL treatment, most probably due to the acceleration of parasitologic effect of SbV that depend on activated macrophage by IFN-γ[97]. In a study by Almeida et al., combined topically applied GM-CSF and antimony was found as effective and well tolerated in the treatment of relapsed CL[98]. In another study, it was indicated that meglumine antimoniate plus pentoxifylline could be more beneficial than meglumine antimoniate alone in the treatment of CL[39]. In comparison to the killing induced by amphotericin B alone, IL-12, anti-IL-10R or agonist anti-CD40 in combination with amphotericin B was more efficient than monotherapy and led to a reduction of the amphotericin dose[99]. In the patients suffering from L. donovani infection, combined chemotherapy of sodium stibogluconate and paromomycin[100] and liposomal amphotericin B combined with miltefosine[101],[102],[103] was found highly effective. Some candidates of the combination seems to take part in the future options for therapy of leishmaniasis, such as 1) Th1 cytokines like IL-12, IFN-γ and TNF+sodium stibogluconate; 2) granuloma remodeling exogenous cytokines IL-2 or GM-CSF+potent antileishmanial drug like paromomycin; 3) IL-10-receptor blockers+chemotherapy+sodium stibogluconate/paromomycin; and 4) amphotericin B+miltefosine[104].

Nevertheless, taken together, a lot of promising observations are available through immunomodulators and combined therapeutic approaches for the treatment of CL, their prices are exorbitantly high for especially poor population[13].

3.7. The advancement of promising synthetic and natural products

To identify the structural features and action mechanisms of the important drugs gives rise to develop new drugs, like derivatives, which is less toxic and more effective. The significant progress has been made on the advancement of new drugs due to recent technological advances. Similarly, the design and synthesis of specific inhibitors could control the parasites with minimal damage to the host[105],[106],[107],[108],[109],[110]. Topoisomerases[111], kinetoplast[112], mitochondria[113], phosphoinositide 3-kinase gamma[50], fatty acid and sterol pathways of the parasite are amongst the promising targets[114] for these specific inhibitors. Besides, plant extracts and plant-derived compounds are extensively preferred for the treatment of infectious diseases, including leishmaniasis, because of their fewer side effects, lower cost, and higher availability[115]. The plant extracts show biological activity through their various chemical groups such as alkaloids, flavonoids, phenylpropanoids, steroids, and terpenoids[116],[117],[118],[119],[120],[121]. Edelfosine and ilmofosine, new alkyl- lysophospholipid derivatives, revealed high in vitro activity against L. donovani[117]. Azasterols, which are synthetic products, have been demonstrated that are active against amastigotes of L. amazonensis by the inhibition of the enzyme sterol 24-methyltransferase[118].

Extensive studies have been carrying out on the activity of natural products sourced from marine, microorganism or more commonly plants against Leishmania during the last years. A glycoprotein from the sponge Pachymatisma johnstonii showed a high anti-leishmanial activity against promastigotes and amastigotes of various species, including a pentavalent antimonial-resistant strain[119]. A fungal metabolite aphidicolin, isolated from Nigrospora sphaerica, was found to be active on both promastigotes and amastigotes[120].

There are so many plants extract from different geographical regions representing anti-leishmanial acts. For example, it was shown that phenylpropanoid dimers isolated from the extract of the twigs of Nectandra leucantha have anti-leishmanial activity via an nitric oxide-independent mechanism[121]. The anti-leishmanial activities of some essential oil have been evaluated in some researches[122],[123],[124],[125]. A linalool-rich essential oil from the leaves of Croton cajucara, a plant used in folk Brazilian medicine, has been found that is a strikingly potent leishmanicidal plant extract, which inhibited the growth of L. amazonensis promastigotes at very low concentrations and presented no cytotoxic effects against mammalian cells[126]. Ardic N et al., in an unpublished study, have recently observed that Juniper tar (cade oil), one of the essential oils obtained from the genus Juniperus, inhibited the growth of promastigote forms at very low concentrations in vitro.


  4. Limitations of this review Top


The review is not a systematic review study and is vulnerable to selection bias. There are many new various studies mentioned in the article, but for which sufficient data could not be obtained in term of the risk-benefit. The other challenges are 1) most of the treatment methods mentioned are not standardized and 2) the effectiveness of alternative treatment strategies has not been adequately compared.

Cutaneous, and the other forms of leishmaniasis, continues to be a public health problem in many countries of the world. The drug for CL treatment is still for chemotherapeutic approaches, such as pentavalent antimonials, amphotericin B, pentamidine, and miltefosine. A method which is more cost-effective, has less toxicity and easy to use, can prevent resistance and shorten the treatment period, will challenge the others. Understanding of crucial pathways for the parasite survival and the host to combat against the parasite is significant in the development of therapeutic vehicles. The formulations of carrier-loaded active drugs, the combination of antileishmanial drugs/compounds, the use of new synthetic and natural products, thermotherapy applications, the immunotherapeutic and targeted therapeutic approaches are promising therapeutic options.

Conflict of interest statement

The authors declare no conflict of interest.

Funding

The authors received no extramural funding for the study.

Authors’ contributions

RD drafted, conceptualized, and finalized the manuscript structure and contents.



 
  References Top

1.
Saha S, Ramachandran R, Hutin YJ, Gupte MD. Visceral leishmaniasis is preventable in a highly endemic village in West Bengal, India. Trans R Soc Trop Med Hyg 2009; 103(7): 737-742.  Back to cited text no. 1
    
2.
Silva CFM, Pinto DCGA, Fernandes PA, Silva AMS. Evolution of acridines and xanthenes as a core structure for the development of antileishmanial agents. Pharmaceuticals (Basel) 2022; 15(2): 148.  Back to cited text no. 2
    
3.
Ramos-Milaré ÁCFH, Oyama J, Murase LS, Souza JVP, Guedes BS, Lera-Nonose DSSL, et al. The anti-Leishmania potential of bioactive compounds derived from naphthoquinones and their possible applications. A systematic review of animal studies. Parasitol Res 2022; 121(5): 1247-1280.  Back to cited text no. 3
    
4.
Mahender T, Pankaj W, Kumar SP, Ankur V, Kumar SS. Some scaffolds as anti-leishmanial agents: A review. Mini Rev Med Chem 2022; 22(5): 743-757.  Back to cited text no. 4
    
5.
Yeşilova Y, Aksoy M, Sürücü HA, Uluat A, Ardic N, Yesilova A. Lip leishmaniasis: Clinical characteristics of 621 patients. Int J Crit Illn Inj Sci 2015; 5(4): 265-266.  Back to cited text no. 5
    
6.
Singh OP, Sundar S. Immunotherapy and targeted therapies in treatment of visceral leishmaniasis: Current status and future prospects. Front Immunol 2014; 5: e296.  Back to cited text no. 6
    
7.
Oliveira-Ribeiro C, Pimentel MIF, Oliveira LFA, Vasconcellos ÉCFE, Conceição-Silva F, Schubach AO, et al. An old drug and different ways to treat cutaneous leishmaniasis: Intralesional and intramuscular meglumine antimoniate in a reference center, Rio de Janeiro, Brazil. PLoS Negl Trop Dis 2021; 15(9): e0009734.  Back to cited text no. 7
    
8.
Madusanka RK, Silva H, Karunaweera ND. Treatment of cutaneous leishmaniasis and insights into species-specific responses: A narrative review. Infect Dis Ther 2022; 11(2): 695-711.  Back to cited text no. 8
    
9.
Magill AJ. Leishmania species: Visceral (Kala-Azar), cutaneous, and mucosal leishmaniasis. In: Bennett JE. Dolin R, Blaser MJ, editors. Mandell, Douglas, and Bennett’s principles and practice of infectious diseases. 8th ed. Philadelphia: Saunders/Elsevier; 2015, p. 3091-3107.  Back to cited text no. 9
    
10.
Ben Salah A, Ben Messaoud N, Guedri E, Zaatour A, Ben Alaya N, Bettaieb J, et al. Topical paromomycin with or without gentamicin for cutaneous leishmaniasis. N Engl J Med 2013; 368(6): 524-532.  Back to cited text no. 10
    
11.
Palma D, Mercuriali L, Figuerola J, Montalvo T, Bueno-Marí R, Millet JP, et al. Trends in the epidemiology of leishmaniasis in the city of Barcelona (1996-2019). Front Vet Sci 2021; 8: 653999.  Back to cited text no. 11
    
12.
Nagill R, Kaur S. Vaccine candidates for leishmaniasis: A review. Int Immunopharmacol 2011; 11(10): 1464-1488.  Back to cited text no. 12
    
13.
Monzote L. Current treatment of leishmaniasis: A review. Open Antimicrobial Agents J 2009; 1: 9-19.  Back to cited text no. 13
    
14.
Zulfiqar B, Avery VM. Assay development in leishmaniasis drug discovery: A comprehensive review. Expert Opin Drug Discov 2022; 17(2): 151-166.  Back to cited text no. 14
    
15.
Santana W, de Oliveira SSC, Ramos MH, Santos ALS, Dolabella SS, Souto EB, et al. Exploring innovative leishmaniasis treatment: Drug targets from pre-clinical to clinical findings. Chem Biodivers 2021; 18(9): e2100336.  Back to cited text no. 15
    
16.
Saroufim M, Charafeddine K, Issa G, Khalifeh H, Habib RH, Berry A, et al. Ongoing epidemic of cutaneous leishmaniasis among Syrian refugees, Lebanon. Emerg Infect Dis 2014; 20(10): 1712-1715.  Back to cited text no. 16
    
17.
Ardic N, Ardic AF, Gunel Z. Leishmaniasis during the increased Syrian refugee traffic. Glob J Infect Dis Clin Res 2018; 4(1): 13-16.  Back to cited text no. 17
    
18.
Turan E, Yeşilova Y, Sürücü HA, Ardic N, Doni N, Aksoy M, et al. A comparison of demographic and clinical characteristics of Syrian and Turkish patients with cutaneous leishmaniasis. Am J Trop Med Hyg 2015; 93(3): 559-563.  Back to cited text no. 18
    
19.
Lindoso JA, Cota GF, Queiroz IA, Goto H. Review of the current treatments for leishmaniasis. Res Rep Trop Med 2012; 3: 69-77.  Back to cited text no. 19
    
20.
Berman JD, Gallalee JF, Gallalee JV. Pharmacokinetics of pentavalent antimony (pentostam) in hamsters. Am J Trop Med Hyg 1988; 39(1): 41-45.  Back to cited text no. 20
    
21.
Asilian A, Sadeghinia A, Faghihi G, Momeni A. Comparative study of the efficacy of combined cryotherapy and intralesional meglumine antimoniate (glucantime) vs. cryotherapy and intralesional meglumine antimoniate (glucantime) alone for the treatment of cutaneous leishmaniasis. Int J Dermatol 2004; 43(4): 281-283.  Back to cited text no. 21
    
22.
Martins SS, Barroso DH, Rodrigues BC, da Motta JOC, Freire GSM, Pereira LIA, et al. A pilot randomized clinical trial: Oral miltefosine and pentavalent antimonials associated with pentoxifylline for the treatment of American tegumentary leishmaniasis. Front Cell Infect Microbiol 2021; 11: 700323.  Back to cited text no. 22
    
23.
Asilian A, Sadeghinia A, Faghihi G, Momeni A, Amini Harandi A. The efficacy of treatment with intralesional meglumine antimoniate alone, compared with that of cryotherapy combined with the meglumine antimoniate or intralesional sodium stibogluconate, in the treatment of cutaneous leishmaniasis. Ann Trop Med Parasitol 2003; 97: 493-498.  Back to cited text no. 23
    
24.
Briones Nieva CA, Cid AG, Romero AI, García-Bustos MF, Villegas M, Bermúdez JM. An appraisal of the scientific current situation and new perspectives in the treatment of cutaneous leishmaniasis. Acta Trop 2021; 221: 105988.  Back to cited text no. 24
    
25.
Firooz A, Khatami A, Khamesipour A, Nassiri-Kashani M, Behnia F, Nilforoushzadeh M, et al. Intralesional injection of 2% zinc sulfate solution in the treatment of acute old world cutaneous leishmaniasis: A randomized, double-blind, controlled clinical trial. J Drugs Dermatol 2005; 4: 73-79.  Back to cited text no. 25
    
26.
Sadeghian G, Nilfroushzadeh MA, Iraji F. Efficacy of local heat therapy by radiofrequency in the treatment of cutaneous leishmaniasis, compared with intralesional injection of meglumine antimoniate. Clin Exp Dermatol 2007; 32: 371-374.  Back to cited text no. 26
    
27.
Bezemer JM, van der Ende J, Limpens J, de Vries HJC, Schallig HDFH. Safety and efficacy of allylamines in the treatment of cutaneous and mucocutaneous leishmaniasis: A systematic review. PLoS One 2021; 16(4): e0249628.  Back to cited text no. 27
    
28.
Salmanpour R, Razmavar MR, Abtahi N. Comparison of intralesional meglumine antimoniate, cryotherapy and their combination in the treatment of cutaneous leishmaniasis. Int J Dermatol 2006; 45: 1115-1116.  Back to cited text no. 28
    
29.
Bumb RA, Mehta RD, Ghiya BC, Jakhar R, Prasad N, Soni P, et al. Efficacy of short-duration (twice weekly) intralesional sodium stibogluconate in treatment of cutaneous leishmaniasis in India. Br J Dermatol 2010; 163: 854-858.  Back to cited text no. 29
    
30.
Azim M, Khan SA, Ullah S, Ullah S, Anjum SI. Therapeutic advances in the topical treatment of cutaneous leishmaniasis: A review. PLoS Negl Trop Dis 2021; 15(3): e0009099.  Back to cited text no. 30
    
31.
Solomon M, Baum S, Barzilai A, Pavlotsky F, Trau H, Schwartz E. Treatment of cutaneous leishmaniasis with intralesional sodium stibogluconate. J Eur Acad Dermatol Venereol 2009; 23: 1189-1192.  Back to cited text no. 31
    
32.
Sharquie KE, Al-Talib KK, Chu AC. Intralesional therapy of cutaneous leishmaniasis with sodium stibogluconate antimony. Br J Dermatol 1988; 119: 53-57.  Back to cited text no. 32
    
33.
Bumb RA, Prasad N, Khandelwal K, Aara N, Mehta RD, Ghiya BC, et al. Long-term efficacy of single-dose radiofrequency-induced heat therapy vs. intralesional antimonials for cutaneous leishmaniasis in India. Br J Dermatol 2013; 168: 1114-1119.  Back to cited text no. 33
    
34.
Solomon M, Pavlotzky F, Barzilai A, Schwartz E. Liposomal amphotericin B in comparison to sodium stibogluconate for Leishmania braziliensis cutaneous leishmaniasis in travelers. J Am Acad Dermatol 2013; 68(2): 284-289.  Back to cited text no. 34
    
35.
Pali S, Beijnen JH, Dorlo TPC. An update on the clinical pharmacology of miltefosine in the treatment of leishmaniasis. Int J Antimicrob Agents 2022; 59(1): 106459.  Back to cited text no. 35
    
36.
Hellier I, Dereure O, Tournillac I, Pratlong F, Guillot B, Dedet JP, et al. Treatment of Old World cutaneous leishmaniasis by pentamidine isethionate. An open study of 11 patients. Dermatology 2000; 200(2): 120-123.  Back to cited text no. 36
    
37.
Kochar DK, Aseri S, Sharma BV, Bumb RA, Mehta RD, Purohit SK. The role of rifampicin in the management of cutaneous leishmaniasis. Q J Med 2000; 93: 733-737.  Back to cited text no. 37
    
38.
Valencia BM, Miller D, Witzig RS, Boggild AK, Llanos-Cuentas A. Novel low-cost thermotherapy for cutaneous leishmaniasis in Peru. PLoS Negl Trop Dis 2013; 7(5): e2196.  Back to cited text no. 38
    
39.
Rashid HU, Ullah I, Adeeb H, Zeb M, Mohammad A, Rehman N. Synergistic effect of oral allopurinol and intralesional sodium stibogluconate in the treatment of cutaneous leishmaniasis. J Ayub Med Coll Abbottabad 2020; 32(4): 558-561.  Back to cited text no. 39
    
40.
Samant M, Sahu U, Pandey SC, Khare P. Role of cytokines in experimental and human visceral leishmaniasis. Front Cell Infect Microbiol 2021; 11: 624009.  Back to cited text no. 40
    
41.
Mota CA, Oyama J, Souza Terron Monich M, Brustolin AÁ, Perez de Souza JV, Murase LS, et al. Three decades of clinical trials on immunotherapy for human leishmaniases: A systematic review and meta-analysis. Immunotherapy 2021; 13(8): 693-721.  Back to cited text no. 41
    
42.
Anand A, Balodi DC, Ramalingam K, Yadav S, Goyal N. Immunological characterization of rLdTCP1γ for its prophylactic potential against visceral leishmaniasis in hamster model. Mol Immunol 2022; 141: 33-42.  Back to cited text no. 42
    
43.
Ritter U, Frischknecht F, van Zandbergen G. Are neutrophils important host cells for Leishmania parasites? Trends Parasitol 2009; 25(11): 505-510.  Back to cited text no. 43
    
44.
Cummings HE, Tuladhar R, Satoskar AR. Cytokines and their STATs in cutaneous and visceral leishmaniasis. J Biomed Biotechnol 2010; 2010: 294389.  Back to cited text no. 44
    
45.
Sacks D, Noben-Trauth N. The immunology of susceptibility and resistance to Leishmania major in mice. Nat Rev Immunol 2002; 2: 845-858.  Back to cited text no. 45
    
46.
Natarajan G, Oghumu S, Varikuti S, Thomas A, Satoskar AR. Mechanisms of immunopathology of leishmaniasis. In: Pathogenesis of leishmaniasis. New developments in research. New York: Springer Science; 2014.  Back to cited text no. 46
    
47.
Page DB, Naidoo J, McArthur HL. Emerging immunotherapy strategies in breast cancer. Immunotherapy 2014; 6(2): 195-209.  Back to cited text no. 47
    
48.
Mota CA, Oyama J, Souza Terron Monich M, Brustolin AÁ, Perez de Souza JV, Murase LS, et al. Three decades of clinical trials on immunotherapy for human leishmaniases: A systematic review and meta-analysis. Immunotherapy 2021; 13(8): 693-721.  Back to cited text no. 48
    
49.
Seth A, Kar S. Host-directed antileishmanial interventions: Harvesting unripe fruits to reach fruition. Int Rev Immunol 2022. doi: 10.1080/08830185.2022.2047670.  Back to cited text no. 49
    
50.
Cummings HE, Barbi J, Reville P, Oghumu S, Zorko N, Sarkar A, et al. Critical role for phosphoinositide 3-kinase gamma in parasite invasion and disease progression of cutaneous leishmaniasis. Proc Natl Acad Sci U S A 2012; 109(4): 1251-1256.  Back to cited text no. 50
    
51.
Oghumu S, Stock JC, Varikuti S, Dong R, Terrazas C, Edwards JA, et al. Transgenic expression of CXCR3 on T cells enhances susceptibility to cutaneous Leishmania major infection by inhibiting monocyte maturation and promoting a Th2 response. Infect Immun 2015; 83(1): 67-76.  Back to cited text no. 51
    
52.
Gupta G, Oghumu S, Satoskar AR. Mechanisms of immune evasion in leishmaniasis. Adv Appl Microbiol 2013; 82: 155-184.  Back to cited text no. 52
    
53.
Chowdhury BP, Das S, Majumder S, Halder K, Ghosh S, Biswas S, et al. Immunomodulation of host-protective immune response by regulating Foxp3 expression and Treg function in Leishmania-infected BALB/c mice: Critical role of IRF1. Pathog Dis 2015; 73(8): ftv063. doi: https://doi.org/10.1093/femspd/ftv063.  Back to cited text no. 53
    
54.
Van de Ven H, Paulussen C, Feijens PB, Matheeussen A, Rombaut P, Kayaert P, et al. PLGA nanoparticles and nanosuspensions with amphotericin B: Potent in vitro and in vivo alternatives to Fungizone and AmBisome. J Control Release 2012; 161: 795-803.  Back to cited text no. 54
    
55.
Jain K, Jain NK. Novel therapeutic strategies for treatment of visceral leishmaniasis. Drug Discov Today 2013; 18: 1272-1281.  Back to cited text no. 55
    
56.
Kharaji MH, Doroud D, Taheri T, Rafati S. Drug targeting to macrophages with solid lipid nanoparticles harboring paromomycin: An in vitro evaluation against L. major and L. tropica. AAPS Pharm Sci Tech 2016; 17(5): 1110-1119.  Back to cited text no. 56
    
57.
Peine KJ, Gupta G, Brackman DJ, Papenfuss TL, Ainslie KM, Satoskar AR, et al. Liposomal resiquimod for the treatment of Leishmania donovani infection. J Antimicrob Chemother 2014; 69(1): 168-175.  Back to cited text no. 57
    
58.
Collier MA, Peine KJ, Gautam S, Oghumu S, Varikuti S, Borteh H, et al. Host-mediated Leishmania donovani treatment using AR-12 encapsulated in acetalated dextran microparticles. Int J Pharm 2016; 499(1-2): 186-194.  Back to cited text no. 58
    
59.
Assolini JP, Carloto ACM, Bortoleti BTDS, Gonçalves MD, Tomiotto Pellissier F, Feuser PE, et al. Nanomedicine in leishmaniasis: A promising tool for diagnosis, treatment and prevention of disease-An update overview. Eur J Pharmacol 2022; 923: 174934.  Back to cited text no. 59
    
60.
Lodi G, Sannino M, Caterino P, Cannarozzo G, Bennardo L, Nisticò SP. Fractional CO2 laser-assisted topical rifamycin drug delivery in the treatment of pediatric cutaneous leishmaniasis. Pediatr Dermatol 2021; 38(3): 717-720.  Back to cited text no. 60
    
61.
Li J, Sutterwala S, Farrell JP. Successful therapy of chronic, nonhealing murine cutaneous leishmaniasis with sodium stibogluconate and gamma interferon depends on continued interleukin-12 production. Infect Immun 1997; 65(8): 3225-3230.  Back to cited text no. 61
    
62.
Smith AC, Yardley V, Rhodes J, Croft SL. Activity of the novel immunomodulatory compound tucaresol against experimental visceral leishmaniasis. Antimicrob Agents Chemother 2000; 44(6): 1494-1498.  Back to cited text no. 62
    
63.
McDowell MA, Rafati S, Ramalho-Ortigao M, Ben Salah A. Leishmaniasis: Middle East and North Africa research and development priorities. PLoS Negl Trop Dis 2011; 5(7): e1219.  Back to cited text no. 63
    
64.
Miranda-Verástegui C, Llanos-Cuentas A, Arévalo I, Ward BJ, Matlashewski G. Randomized, double-blind clinical trial of topical imiquimod 5% with parenteral meglumine antimoniate in the treatment of cutaneous leishmaniasis in Peru. Clin Infect Dis 2005; 40(10): 13951403.  Back to cited text no. 64
    
65.
Arevalo I, Ward B, Miller R, Meng TC, Najar E, Alvarez E, et al. Successful treatment of drug-resistant cutaneous leishmaniasis in humans by use of imiquimod, an immunomodulator. Clin Infect Dis 2001; 33(11): 1847-1851.  Back to cited text no. 65
    
66.
Buates S, Matlashewski G. Treatment of experimental leishmaniasis with the immunomodulators imiquimod and S-28463: Efficacy and mode of action. J Infect Dis 1999; 179(6): 1485-1494.  Back to cited text no. 66
    
67.
Dockrell DH, Kinghorn GR. Imiquimod and resiquimod as novel immunomodulators. J Antimicrob Chemother 2001; 48(6): 751-755.  Back to cited text no. 67
    
68.
Tacchini-Cottier F, Zweifel C, Belkaid Y, Mukankundiye C, Vasei M, Launois P, et al. An immunomodulatory function for neutrophils during the induction of a CD4+ Th2 response in BALB/c mice infected with Leishmania major. J Immunol 2000; 165(5): 2628-2636.  Back to cited text no. 68
    
69.
Terrazas C, Varikuti S, Oghumu S, Steinkamp HM, Ardic N, Kimble J, et al. Ly6Chi inflammatory monocytes promote susceptibility to Leishmania donovani infection. Sci Rep 2017; 7(1): 14693.  Back to cited text no. 69
    
70.
Murray HW, Moreira AL, Lu CM, DeVecchio JL, Matsuhashi M, Ma X, et al. Determinants of response to interleukin-10 receptor blockade immunotherapy in experimental visceral leishmaniasis. J Infect Dis 2003; 188(3): 458-464.  Back to cited text no. 70
    
71.
Heinzel FP, Schoenhaut DS, Rerko RM, Rosser LE, Gately MK. Recombinant interleukin 12 cures mice infected with Leishmania major. J Exp Med 1993; 177(5): 1505-1509.  Back to cited text no. 71
    
72.
Murray HW, Flanders KC, Donaldson DD, Sypek JP, Gotwals PJ, Liu J, et al. Antagonizing deactivating cytokines to enhance host defense and chemotherapy in experimental visceral leishmaniasis. Infect Immun 2005; 73(7): 3903-3911.  Back to cited text no. 72
    
73.
Soosaraei M, Hezarjaribi HZ, Fakhar M, Akhtari J, Emameh RZ. An overview on liposomal delivery and adjuvant development for leishmaniosis vaccines. Ann Parasitol 2021; 67(3): 367-386.  Back to cited text no. 73
    
74.
Ritter U, Mattner J, Rocha JS, Bogdan C, Körner H. The control of Leishmania major by TNF in vivo is dependent on the parasite strain. Microbes Infect 2004; 6(6): 559-565.  Back to cited text no. 74
    
75.
Ghosh M, Pal C, Ray M, Maitra S, Mandal L, Bandyopadhyay S. Dendritic cell-based immunotherapy combined with antimony-based chemotherapy cures established murine visceral leishmaniasis. J Immunol 2003; 170(11): 5625-5629.  Back to cited text no. 75
    
76.
Silva H, Liyanage A, Deerasinghe T, Sumanasena B, Munidasa D, de Silva H, et al. Therapeutic response to thermotherapy in cutaneous leishmaniasis treatment failures for sodium stibogluconate: A randomized controlled proof of principle clinical trial. Am J Trop Med Hyg 2021; 104(3): 945-950.  Back to cited text no. 76
    
77.
Refai WF, Madarasingha NP, Sumanasena B, Weerasingha S, De Silva A, Fernandopulle R, et al. Efficacy, safety and cost-effectiveness of thermotherapy in the treatment of Leishmania donovani-induced cutaneous leishmaniasis: A randomized controlled clinical trial. Am J Trop Med Hyg 2017; 97(4): 1120-1126.  Back to cited text no. 77
    
78.
Kämink S, Abdi A, Kamau C, Ashraf S, Ansari MA, Qureshi NA, et al. Failure of an innovative low-cost, noninvasive thermotherapy device for treating cutaneous leishmaniasis caused by Leishmania tropica in Pakistan. Am J Trop Med Hyg 2019; 101(6): 1373-1379.  Back to cited text no. 78
    
79.
Pinart M, Rueda JR, Romero GA, Pinzón-Flórez CE, Osorio-Arango K, Silveira Maia-Elkhoury AN, et al. Interventions for American cutaneous and mucocutaneous leishmaniasis. Cochrane Database Syst Rev 2020; 8(8): CD004834.  Back to cited text no. 79
    
80.
Berman JD, Neva FA. Effect of temperature on multiplication of Leishmania amastigotes within human monocyte-derived macrophages in vitro. Am J Trop Med Hyg 1981; 30(2): 318-321.  Back to cited text no. 80
    
81.
Ardic N, Yesilova Y, Gunel IE, Ardic IN. Leishmaniasis recidivans in pediatric patients. Pediatr Infect Dis J 2017; 36(5): 534.  Back to cited text no. 81
    
82.
Laboudi M, Sahibi H, Elabandouni M, Nhammi H, Ait Hamou S, Sadak A. A review of cutaneous leishmaniasis in Morocco: A vertical analysis to determine appropriate interventions for control and prevention. Acta Trop 2018; 187: 275-283.  Back to cited text no. 82
    
83.
Siadat AH, Iraji F, Zolfaghari A, Shariat S, Jazi SB. Heat therapy for cutaneous leishmaniasis: A literature review. J Res Med Sci 2021; 26: 15.  Back to cited text no. 83
    
84.
Vega JC, Sanchez BF, Montero LM, Montaña R, Mahecha Mdel P, Dueñes B, et al. The efficacy of thermotherapy to treat cutaneous leishmaniasis in Colombia: A comparative observational study in an operational setting. Trans R Soc Trop Med Hyg 2009; 103(7): 703-706.  Back to cited text no. 84
    
85.
Reithinger R, Mohsen M, Wahid M, Bismullah M, Quinnell RJ, Davies CR, et al. Efficacy of thermotherapy to treat cutaneous leishmaniasis caused by Leishmania tropica in Kabul, Afghanistan: A randomized, controlled trial. Clin Infect Dis 2005; 40(8): 1148-1155.  Back to cited text no. 85
    
86.
Safi N, Davis GD, Nadir M, Hamid H, Robert LL Jr., Case AJ. Evaluation of thermotherapy for the treatment of cutaneous leishmaniasis in Kabul, Afghanistan: A randomized controlled trial. Mil Med 2012; 177(3): 345-351.  Back to cited text no. 86
    
87.
López L, Robayo M, Vargas M, Vélez ID. Thermotherapy. An alternative for the treatment of American cutaneous leishmaniasis. Trials 2012; 13: 58.  Back to cited text no. 87
    
88.
Cardona-Arias JA, Vélez ID, López-Carvajal L. Efficacy of thermotherapy to treat cutaneous leishmaniasis: A meta-analysis of controlled clinical trials. PLoS One 2015; 10(5): e0122569.  Back to cited text no. 88
    
89.
Mackay AM. The evolution of clinical guidelines for antimicrobial photodynamic therapy of skin. Photochem Photobiol Sci 2022; 21(3): 385-395.  Back to cited text no. 89
    
90.
Marcolino LMC, Pereira AHC, Pinto JG, Mamone LA, Strixino JF. Cellular and metabolic changes after photodynamic therapy in Leishmania promastigotes. Photodiagnosis Photodyn Ther 2021; 35: 102403.  Back to cited text no. 90
    
91.
Trinconi CT, Reimão JQ, Coelho AC, Uliana SR. Efficacy of tamoxifen and miltefosine combined therapy for cutaneous leishmaniasis in the murine model of infection with Leishmania amazonensis. J Antimicrob Chemother 2016; 71(5): 1314-1322.  Back to cited text no. 91
    
92.
Chanmol W, Siriyasatien P, Intakhan N. In vitro anti-Leishmania activity of 8-hydroxyquinoline and its synergistic effect with amphotericin B deoxycholate against Leishmania martiniquensis. Peer J 2022; 10: e12813.  Back to cited text no. 92
    
93.
López L, Alvarez F, Ramos AP, Llanos-Cuentas A, Echevarria J, Vélez I, et al. A phase II multicenter randomized study to evaluate the safety and efficacy of combining thermotherapy and a short course of miltefosine for the treatment of uncomplicated cutaneous leishmaniasis in the New World. PLoS Negl Trop Dis 2022; 16(3): e0010238.  Back to cited text no. 93
    
94.
Das A, Jawed JJ, Das MC, Parveen S, Ghosh C, Majumdar S, et al. Lupeol and amphotericin B mediate synergistic anti-leishmanial immunomodulatory effects in Leishmania donovani-infected BALB/c mice. Cytokine 2021; 137: 155319.  Back to cited text no. 94
    
95.
Fernández OL, Rosales-Chilama M, Quintero N, Travi BL, Wetzel DM, Gómez MA, et al. Potency and preclinical evidence of synergy of oral azole drugs and miltefosine in an ex vivo model of Leishmania (Viannia) panamensis infection. Antimicrob Agents Chemother 2022; 66(1): e0142521.  Back to cited text no. 95
    
96.
World Health Organization. Post-kala-azar dermal leishmaniasis: A manual for case management and control. [Online]. Available from: https://www.who.int/publications-detail-redirect/9789241505215. [Accessed on 10 May 2022].  Back to cited text no. 96
    
97.
Squires KE, Rosenkaimer F, Sherwood JA, Forni AL, Were JB, Murray HW. Immunochemotherapy for visceral leishmaniasis: A controlled pilot trial of antimony versus antimony plus interferon-gamma. Am J Trop Med Hyg 1993; 48(5): 666-669.  Back to cited text no. 97
    
98.
Almeida RP, Brito J, Machado PL, DE Jesus AR, Schriefer A, Guimarães LH, et al. Successful treatment of refractory cutaneous leishmaniasis with GM-CSF and antimonials. Am J Trop Med Hyg 2005; 73(1): 79-81.  Back to cited text no. 98
    
99.
Murray HW, Brooks EB, DeVecchio JL, Heinzel FP. Immunoenhancement combined with amphotericin B as treatment for experimental visceral leishmaniasis. Antimicrob Agents Chemother 2003; 47(8): 2513-2517.  Back to cited text no. 99
    
100.
Thakur CP, Kanyok TP, Pandey AK, Sinha GP, Messick C, Olliaro P. Treatment of visceral leishmaniasis with injectable paromomycin (aminosidine). An open-label randomized phase- II clinical study. Trans R Soc Trop Med Hyg 2000; 94(4): 432-433.  Back to cited text no. 100
    
101.
Sundar S, Rai M, Chakravarty J, Agarwal D, Agrawal N, Vaillant M, et al. New treatment approach in Indian visceral leishmaniasis: Single-dose liposomal amphotericin B followed by short-course oral miltefosine. Clin Infect Dis 2008; 47(8): 1000-1006.  Back to cited text no. 101
    
102.
Araujo CF, N Oliveira IB, Silveira MB, Ribeiro-Dias F. Disseminated cutaneous leishmaniasis due to Leishmania (Leishmania) amazonensis in human immunodeficiency virus (HIV)-infected patients: A report of two cases. Asian Pac J Trop Med 2021; 14: 281-284.  Back to cited text no. 102
    
103.
Habib S, Azab M, Elmasry K, Handoussa A. Leishmania donovani: Immune response and immune evasion with emphasis on PD-1/PDL- 1 pathway and role of autophagy. Asian Pac J Trop Med 2021; 14: 195-208.  Back to cited text no. 103
    
104.
Jha TK. Drug unresponsiveness & combination therapy for kala-azar. Indian J Med Res 2006; 123(3): 389-398.  Back to cited text no. 104
    
105.
Ramos-Milaré ÁCFH, Oyama J, Murase LS, Souza JVP, Guedes BS, Lera-Nonose DSSL, et al. The anti-Leishmania potential of bioactive compounds derived from naphthoquinones and their possible applications. A systematic review of animal studies. Parasitol Res 2022; 121(5): 1247-1280.  Back to cited text no. 105
    
106.
Singh A, Raza A, Amin S, Damodaran C, Sharma AK. Recent advances in the chemistry and therapeutic evaluation of naturally occurring and synthetic withanolides. Molecules 2022; 27(3): 886.  Back to cited text no. 106
    
107.
Tempone AG, Pieper P, Borborema SET, Thevenard F, Lago JHG, Croft SL, et al. Marine alkaloids as bioactive agents against protozoal neglected tropical diseases and malaria. Nat Prod Rep 2021; 38(12): 2214-2235.  Back to cited text no. 107
    
108.
Brink JTR, Fourie R, Sebolai O, Albertyn J, Pohl CH. The role of lipid droplets in microbial pathogenesis. J Med Microbiol 2021. doi: 10.1099/jmm.0.001383.  Back to cited text no. 108
    
109.
Ashok P, Faheem F, Kumar BK, Chander S, Chandra Sekhar KVG, Sankaranarayanan M. Anti-infective potential of manzamine alkaloids-a review. Med Chem 2022; 18(6): 629-654.  Back to cited text no. 109
    
110.
Rahmanian V, Bokaie S, Haghdoost A, Barouni M. Predicting cutaneous leishmaniasis using SARIMA and Markov switching models in Isfahan, Iran: A time-series study. Asian Pac J Trop Med 2021; 14: 83-93.  Back to cited text no. 110
    
111.
Das BB, Ganguly A, Majumder HK. DNA topoisomerases of Leishmania: The potential targets for anti-leishmanial therapy. Adv Exp Med Biol 2008; 625: 103-115.  Back to cited text no. 111
    
112.
Motta MC. Kinetoplast as a potential chemotherapeutic target of trypanosomatids. Curr Pharm Design 2008; 14: 847-854.  Back to cited text no. 112
    
113.
Sen N, Majumder HK. Mitochondrion of protozoan parasite emerges as potent therapeutic target: Exciting drugs are on the horizon. Curr Pharm Design 2008; 14: 839-846.  Back to cited text no. 113
    
114.
Roberts CW, McLeod R, Rice DW, Ginger M, Chance ML, Goad LJ. Fatty acid and sterol metabolism: Potential antimicrobial targets in apicomplexan and trypanosomatid parasitic protozoa. Mol Biochem Parasitol 2003; 126: 129-142.  Back to cited text no. 114
    
115.
Mahmoudvand H, Ezzatkhah F, Sharififar F, Sharifi I, Dezaki ES. Antileishmanial and cytotoxic effects of essential oil and methanolic extract of Myrtus communis L. Korean J Parasitol 2015; 53(1): 21-27.  Back to cited text no. 115
    
116.
Tiuman TS, Santos AO, Ueda-Nakamura T, Filho BP, Nakamura CV. Recent advances in leishmaniasis treatment. Int J Infect Dis 2011; 15(8): e525-e532.  Back to cited text no. 116
    
117.
Azzouz S, Maache M, Garcia RG, Osuna A. Leishmanicidal activity of edelfosine, miltefosine and ilmofosine. Basic Clin Pharmacol Toxicol 2005; 96(1): 60-65.  Back to cited text no. 117
    
118.
Magaraci F, Jimenez CJ, Rodrigues C, Rodrigues JC, Braga MV, Yardley V, et al. Azasterols as inhibitors of sterol 24-methyltransferase in Leishmania species and Trypanosoma cruzi. J Med Chem 2003; 46(22): 4714-4727.  Back to cited text no. 118
    
119.
Le Pape P, Zidane M, Abdala H, Moré MT. A glycoprotein isolated from the sponge, Pachymatisma johnstonii, has anti-leishmanial activity. Cell Biol Int 2000; 24(1): 51-56.  Back to cited text no. 119
    
120.
Cortes S, Bruno de Sousa C, Morais T, Lago J, Campino L. Potential of the natural products against leishmaniasis in Old World-a review of in-vitro studies. Pathog Glob Health 2020; 114(4): 170-182.  Back to cited text no. 120
    
121.
Celes FS, Barud HS, Viana SM, Borba PB, Machado PRL, Carvalho EM, et al. A pilot and open trial to evaluate topical bacterial cellulose bio-curatives in the treatment of cutaneous leishmaniasis caused by L. braziliensis. Acta Trop 2022; 225: 106192.  Back to cited text no. 121
    
122.
Barros LM, Duarte AE, Morais-Braga MF, Waczuk EP, Vega C, Leite NF, et al. Chemical characterization and trypanocidal, leishmanicidal and cytotoxicity potential of Lantana camara L. (Verbenaceae) essential oil. Molecules 2016; 21(2): E209.  Back to cited text no. 122
    
123.
Tajbakhsh E, Khamesipour A, Hosseini SR, Kosari N, Shantiae S, Khamesipour F. The effects of medicinal herbs and marine natural products on wound healing of cutaneous leishmaniasis: A systematic review. Microb Pathog 2021; 161(Pt A): 105235.  Back to cited text no. 123
    
124.
Demarchi IG, Terron Mde S, Thomazella MV, Mota CA, Gazim ZC, Cortez DAG, et al. Antileishmanial and immunomodulatory effects of the essential oil from Tetradenia riparia (Hochstetter) Codd. Parasite Immunol 2016; 38(1): 64-77.  Back to cited text no. 124
    
125.
Saedi Dezaki E, Mahmoudvand H, Sharififar F, Fallahi S, Monzote L, Ezatkhah F. Chemical composition along with anti-leishmanial and cytotoxic activity of Zataria multiflora. Pharm Biol 2016; 54(5): 752-758.  Back to cited text no. 125
    
126.
do Socorro S, Rosa Mdo S, Mendonça-Filho RR, Bizzo HR, de Almeida Rodrigues I, Soares RM, et al. Antileishmanial activity of a linalool-rich essential oil from Croton cajucara. Antimicrob Agents Chemother 2003; 47(6): 1895-1901.  Back to cited text no. 126
    



 
 
    Tables

  [Table 1]



 

Top
 
  Search
 
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

  2. Current treat...3. New therapeut...4. Limitations o...
  In this article
Abstract
1. Introduction
References
Article Tables

 Article Access Statistics
    Viewed796    
    Printed12    
    Emailed0    
    PDF Downloaded139    
    Comments [Add]    

Recommend this journal