Topical Treatment Of Cutaneous Leishmaniasis Research Articles

Microemulsions strongly promoted the activity of α-bisabolol against different Leishmania species and its skin permeation

This study aimed to develop microemulsions (MEs) containing α-bisabolol for the topical treatment of cutaneous leishmaniasis (CL). Initially, pseudoternary phase diagrams were developed using α-bisabolol as the oil phase, Eumulgin® CO 40 as the surfactant, Polymol® HE as the co-surfactant, and distilled water as the aqueous phase. Two transparent liquid systems (TLS) containing 5% of α-bisabolol were selected and characterized (F5E25 and F5EP25). Next, skin permeation and retention assays were performed using Franz cells. The interaction of the formulation with the stratum corneum (SC) was evaluated using the FTIR technique. The cytotoxicity was evaluated in murine peritoneal macrophages. Finally, the antileishmanial activity of microemulsions was determined in promastigotes and amastigotes of L. amazonensis (strain MHOM/BR/77/LTB 0016). As a result, the selected formulations showed isotropy, nanometric size (below 25 nm), Newtonian behavior and pH ranging from 6.5 to 6.9. The MEs achieved a 2.5-fold increase in the flux and skin-permeated amount of α-bisabolol. ATR-FTIR results showed that microemulsions promoted fluidization and extraction of lipids and proteins of the stratum corneum, increasing the diffusion coefficient and partition coefficient of the drug in the skin. Additionally, F5E25 and F5EP25 showed higher activity against promastigotes (IC50 13.27 and 18.29, respectively) compared to unencapsulated α-bisabolol (IC50 53.8). Furthermore, F5E25 and F5EP25 also showed antileishmanial activity against intracellular amastigotes of L. amazonensis, with IC50 50 times lower than free α-bisabolol and high selectivity index (up to 15). Therefore, the systems obtained are favorable to topical administration, with significant antileishmanial activity against L. amazonensis promastigotes and amastigotes, being a promising system for future in vivo trials.

Preparation and characterization of paromomycin encapsulated in lecithin-chitosan nanoparticles for the topical treatment of cutaneous leishmaniasis

Introduction: Leishmaniasis is a disease caused by the Leishmania protozoa, with Cutaneous Leishmaniasis (CL) being the most common form of the illness. Paromomycin (PM) has recently garnered increased interest for its effectiveness against Leishmania, but it is hindered by limited efficacy, low oral bioavailability, and rapid clearance. As far as we know, there have been no studies examining the impact of nano lecithin-chitosan-containing paromomycin (Nano-PM) on CL. Therefore, the objective of the present study was to create Nano-PM and assess its effects on the promastigotes in vitro and on the lesions caused by Leishmania major in the BALB/c mice model in vivo. Methods: The loading of PM into lecithin-chitosan nanoparticles was achieved using the ionic gelation method, and the resulting nanoparticles were characterized. The IC50 values for PM, Glucantim, and Nano-PM against promastigotes were determined after 24, 48, and 72 hours of treatment. The viability of promastigotes was assessed using the MTT assay. The Nano-PM formulation was administered intramuscularly to mice for a period of 28 days, during which lesion sizes were measured weekly. Furthermore, the parasite load in the infected mice was quantified using quantitative realtime polymerase chain reaction (qPCR). Results: IC50 of Nano-PM was significantly lower than Glucantim (p < 0.0001 after24 h incubation, p = 0.013 for 48h and p < 0.0001 for 72 h) and PM (p < 0.0001 after24 h, p = 0.003 for 48h and p < 0.0001 for 72h). All concentrations of Nano-PM had the highest toxicity on promastigotes in comparison with other groups after 24, 48, and 72 h treatment. Moreover, a significant reduction in the lesion size was found in the Nano-PM group in comparison with the control group after three (p = 0.0369) and four (p = 0.0009) weeks of treatment. More importantly, Nano-PM significantly reduced the parasite load compared to the control and the lecithin-chitosan groups (p = 0.001 for both). Conclusion: Our findings showed that Nano-PM had lower toxicity (lower IC50) on promastigotes compared to Glucantim and PM. Moreover, Nano-PM treated mice showed reduced lesion size compared to the control group. Additionally, Nano-PM led to a significant decrease in parasite burden compared to the control group and the lecithin-chitosan group. Nevertheless, more complementary research is needed to approve our findings.

Piperine, quercetin, and curcumin identified as promising natural products for topical treatment of cutaneous leishmaniasis

Leishmania braziliensis (L. braziliensis) causes cutaneous leishmaniasis (CL) in the New World. The costs and the side effects of current treatments render imperative the development of new therapies that are affordable and easy to administer. Topical treatment would be the ideal option for the treatment of CL. This underscores the urgent need for affordable and effective treatments, with natural compounds being explored as potential solutions. The alkaloid piperine (PIP), the polyphenol curcumin (CUR), and the flavonoid quercetin (QUE), known for their diverse biological properties, are promising candidates to address these parasitic diseases. Initially, the in vitro cytotoxicity activity of the compounds was evaluated using U-937 cells, followed by the assessment of the leishmanicidal activity of these compounds against amastigotes of L. braziliensis. Subsequently, a golden hamster model with stationary-phase L. braziliensis promastigote infections was employed. Once the ulcer appeared, hamsters were treated with QUE, PIP, or CUR formulations and compared to the control group treated with meglumine antimoniate administered intralesionally. We observed that the three organic compounds showed high in vitro leishmanicidal activity with effective concentrations of less than 50 mM, with PIP having the highest activity at a concentration of 8 mM. None of the compounds showed cytotoxic activity for U937 macrophages with values between 500 and 700 mM. In vivo, topical treatment with QUE daily for 15 days produced cured in 100% of hamsters while the effectiveness of CUR and PIP was 83% and 67%, respectively. No failures were observed with QUE. Collectively, our data suggest that topical formulations mainly for QUE but also for CUR and PIP could be a promising topical treatment for CL. Not only the ease of obtaining or synthesizing the organic compounds evaluated in this work but also their commercial availability eliminates one of the most important barriers or bottlenecks in drug development, thus facilitating the roadmap for the development of a topical drug for the management of CL caused by L. braziliensis.

Nanoemulsions containing amphotericin b and paromomycin for the treatment of cutaneous leishmaniasis

Cutaneous leishmaniasis (CL) is a vector-borne disease characterized by skin lesions that can evolve into high-magnitude ulcerated lesions. Thus, this study aimed to develop an innovative nanoemulsion (NE) with clove oil, Poloxamer® 407, and multiple drugs, such as amphotericin B (AmB) and paromomycin (PM), for use in the topical treatment of CL. Methods: Droplet size, morphology, drug content, stability, in vitro release profile, in vitro cytotoxicity on RAW 264.7 macrophages, and antileishmanial activity using axenic amastigotes of Leishmania amazonensis were assessed for NEs. Results: After optimizing the formulation parameters, such as the concentration of clove oil and drugs, using an experimental design, it was possible to obtain a NE with an average droplet size of 40 nm and a polydispersion index of 0.3, and these parameters were maintained throughout the 365 days. Furthermore, the NE showed stability of AmB and PM content for 180 days under refrigeration (4 °C), presented a pH compatible with the skin, and released modified AmB and PM. NE showed the same toxicity as free AmB and higher toxicity than free PM against RAW 264.7 macrophages. The same activity as free AmB, and higher activity than free PM against amastigotes L. amazonensis. Conclusion: It is possible to develop a NE for the treatment of CL; however, complementary studies regarding the antileishmanial activity of NE should be carried out.

Proposal of a topical alternative for Cutaneous Leishmaniasis

Leishmaniasis is a group of diseases caused by a flagellated protozoan belonging to different species of the genus Leishmania, causing infections of the skin (cutaneous Leishmaniasis), mucous membranes (mucocutaneous Leishmaniasis) and internal organs (visceral Leishmaniasis)1 . This disease is present in 88 countries worldwide, mainly in South and Central America, Africa, Asia and Southern Europe 2. In Honduras, this infection is endemic3, and by 2022, 1,565 new cases of cutaneous Leishmaniasis were reported4 . The treatment of choice for all forms of this disease has been meglumine antimoniate, known commercially as Glucantime® (AMG), which is distributed for intravenous (IV) administration and produces adverse effects such as fever, nausea, vomiting, abdominal pain and nephrotoxicity. In some cases, it may be necessary to adjust the dosage of the drug or discontinue treatment if side effects are severe5 . Another therapeutic option for the treatment of cutaneous Leishmaniasis is Amphotericin B deoxycholate (AMB), which, like AMG, is administered by IV but produces immediate adverse effects such as fever, chills, nausea, vomiting, headache, anaphylactic shock, arrhythmias and liver failure6 . Although lipid formulations of AMB have been developed to reduce the toxic effects of the molecule and improve its effectiveness (liposomal, lipid complex, colloidal suspension), these presentations are expensive and make it impossible for patients to purchase this treatment. Likewise, there are less risky alternatives such as intralesional application with AMG and thermotherapy7 . However, despite the efforts to research and develop new treatments, no topical treatment for cutaneous Leishmaniasis has been marketed. Topical treatments offer several advantages, including localized action, reduced systemic side effects, convenience of use and rapid absorption, making them a practical option for treating various medical and dermatological conditions. In this regard, we propose the development of a potential product that can be easily and rapidly prepared in a magistral formulation as a therapeutic alternative to Cutaneous Leishmaniasis.

Nitazoxanide and quercetin co-loaded nanotransfersomal gel for topical treatment of cutaneous leishmaniasis with macrophage targeting and enhanced anti-leishmanial effect

PurposeAnti-leishmanial medications administered by oral and parenteral routes are less effective for treatment of cutaneous leishmaniasis (CL) and cause toxicity, hence targeted drug delivery is an efficient way to improve drug availability for CL with reduced toxicity. This study aimed to develop, characterize and evaluate nitazoxanide and quercetin co-loaded nanotransfersomal gel (NTZ-QUR-NTG) for the treatment of CL. MethodsNTZ-QUR-NT were prepared by thin film hydration method and were statistically optimized using Box-Behnken design. To ease the topical delivery and enhance the retention time, the NTZ-QUR-NT were dispersed in 2 % chitosan gel. Moreover, in-vitro drug release, ex-vivo permeation, macrophage uptake, cytotoxicity and anti-leishmanial assays were performed. ResultsThe optimized formulation indicated mean particle size 210 nm, poly dispersity index (PDI) 0.16, zeta potential (ZP) −15.1 mV and entrapment efficiency (EE) of NTZ and QUR was 88 % and 85 %, respectively. NTZ-QUR-NT and NTZ-QUR-NTG showed sustained release of the incorporated drugs as compared to the drug dispersions. Skin permeation of NTZ and QUR in NTZ-QUR-NTG was 4 times higher in comparison to the plain gels. The NTZ-QUR-NT cell internalization was almost 10-folds higher than NTZ-QUR dispersion. The cytotoxicity potential (CC50) of NTZ-QUR-NT (71.95 ± 3.32 μg/mL) was reduced as compared to NTZ-QUR dispersion (49.77 ± 2.15 μg/mL. A synergistic interaction was found between NTZ and QUR. Moreover, in-vitro anti-leishmanial assay presented a lower IC50 value of NTZ-QUR-NT as compared to NTZ-QUR dispersion. Additionally, a significantly reduced lesion size was observed in NTZ-QUR-NTG treated BALB/c mice, indicating its antileishmanial potential. ConclusionIt can be concluded that nanotransfersomal gel has the capability to retain and permeate the incorporated drugs through stratum corneum and induce synergetic anti-leishmanial effect of NTZ and QUR against cutaneous leishmaniasis.

Tratamiento tópico de leishmaniasis cutánea con crema- nanoemulsión de un compuesto genérico antimonial pentavalente. Caso clínico.

Introduction. An effective vaccine against cutaneous leishmaniasis has yet to be developed. Treatment of the disease relies on painful intramuscular administration of high doses of compounds based on pentavalent antimony, causing adverse effects. New therapeutic options effective, easy to apply, cheap and without adverse effects are urgently required. Case report. A 26-year-old male patient showing a large facial ulcer, presumptively by cutaneous leishmaniasis, diagnostic confirmed by Montenegro’s skin test and microscopical observation of amastigote forms. Due to the ulcer’s location and size, topical treatment with a nanoemulsion cream-based on a generic antimony-compound was attempted. The cream was applied twice daily and was rapidly absorbed. After 2 months of treatment, no discomfort or other adverse effects were detected. The ulcer was replaced with healthy skin tissue and a soft, clean scar. Conclusion. The novel cream, which was rapidly absorbed, effective, cheaper than standard systemic therapy and self-applied by the patient, showed potential value in the treatment of cutaneous leishmaniasis.

Microemulsion based on methyl 3,4,5-trihydroxybenzoate for the topical treatment of cutaneous leishmaniasis: an in vivo assay

ABSTRACT Cutaneous leishmaniasis, caused by protozoa of the genus Leishmania, presents diverse clinical manifestations, and current therapeutic options have limitations, including long treatment periods, potential hospitalization, and excessive pain during treatment. Methyl gallate, a phenolic compound found in plants such as Libidibia ferrea, presents promising antileishmanial activity. Combining this compound with existing leishmaniasis medications could lead to reduced dosages and the minimization of side effects. This study aimed to assess the efficacy of a microemulsion containing methyl gallate, either on its own or in combination with Glucantime®, for the experimental treatment of cutaneous leishmaniasis in a 30-day in vivo assay using golden hamsters infected with Leishmania (Leishmania) amazonensis. The control groups included an untreated positive control and an uninfected, untreated negative control. After treatment, we evaluated clinical, parasitological, and biochemical parameters. While none of the treatments achieved clinical or parasitological cure, notable improvements were observed in the combined group, with significant reductions in snout skin lesions and parasite load when compared to the control. Biochemical parameters such as creatinine, CK-MB, GOT, and GPT remained unchanged, but urea and CPK levels significantly increased in all the experimental groups relative to the control. In conclusion, the integration of a topical methyl gallate microemulsion with intralesional Glucantime® showed potential as an effective treatment for cutaneous leishmaniasis. Further investigations into optimal dosages and therapeutic schemes are warranted in order to enhance treatment outcomes.

Emulgel-loaded mannosylated thiolated chitosan-coated silver nanoparticles for the treatment of cutaneous leishmaniasis

Topical treatment of cutaneous leishmaniasis holds great promise for decreasing drug associated side effects and improving efficacy. This study was aimed to develop mannosylated thiolated chitosan-coated silver nanoparticles (MTCAg) loaded emulgel for the treatment of cutaneous leishmaniasis. MTC-Ag were synthesized via a chemical reduction method and were loaded into the emulgel. The nanoparticles had a zeta potential of +19.8 mV, an average particle size of 115 nm and a narrow polydispersity index of 0.26. In-vitro release profiles showed controlled release of silver ions from both the MTC-Ag and the emulgel-loaded MTC-Ag nanoparticles after 24 h. An ex-vivo retention study indicated 5 times higher retention of silver by the emulgel-loaded MTC-Ag than by the MTC-Ag nanoparticles. The in-vitro anti-leishmanial assay revealed that MTC-Ag had an excellent inhibitory effect on intracellular amastigotes, leading to ~90 % inhibition at the highest concentration tested. A 4-fold reduction in the IC50 value was found for MTC-Ag compared to blank Ag nanoparticles. Cytotoxicity assay showed 83 % viability of macrophages for MTC-Ag and 30 % for Ag nanoparticles at a concentration of 80 μg/mL, demonstrating the improved biocompatibility of the polymeric nanoparticles. Drug release and retention studies corroborate the great potential of MTC-Ag-loaded emulgel for the treatment of cutaneous leishmaniasis.

Triple-combination therapy for cutaneous leishmaniasis using detergent-free, hyaluronate-coated elastic nanovesicles.

Aim: To develop and evaluate detergent-free, triple-drug-loaded, hyaluronate-coated elastic nanovesicles (H-ENVs) for the topical treatment of cutaneous leishmaniasis. Materials & methods: H-ENVs were developed and evaluated for vesicle size, entrapment efficiency, skin permeation and antileishmanial potential. Results: A 15.7 and 28.6% decrease in the cytotoxicity of paromomycin and amphotericin B, respectively, was observed in detergent-free ENVs compared with conventional ENVs. H-ENVs improved the efficacy of paromomycin against promastigote and amastigote models of leishmaniasis by 4- and 7.5-fold, respectively. In vivo investigation of H-ENVs demonstrated efficient topical management of cutaneous leishmaniasis. Conclusion: The results indicate the potential of H-ENVs as a safe topical treatment choice for cutaneous leishmaniasis.

Surfactant free synthesis of cationic nano-vesicles: A safe triple drug loaded vehicle for the topical treatment of cutaneous leishmaniasis

The basic aim of the study was to develop and evaluate the triple drug loaded cationic nano-vesicles (cNVs), where miltefosine was used as a replacement of surfactant (apart from its anti-leishmanial role), in addition to meglumine antimoniate (MAM) and imiquimod (Imq), as a combination therapy for the topical treatment of cutaneous leishmaniasis (CL). The optimized formulation was nano-sized (86.2 ± 2.7 nm) with high entrapment efficiency (63.8 ± 2.1% (MAM) and 81.4 ± 2.3% (Imq)). In-vivo skin irritation assay showed reduced irritation potential and a decrease in the cytotoxicity of cNVs as compared to conventional NVs (having sodium deoxycholate as a surfactant). A synergistic interaction between drugs was observed against intracellular amastigotes, whereas the in-vivo antileishmanial study presented a significant reduction in the parasitic burden. The results suggested the potential of surfactant free, triple drug loaded cNVs as an efficient vehicle for the safe topical treatment of CL.

Amphotericin-B-loaded polymer-functionalized reduced graphene oxides for Leishmania amazonensis chemo-photothermal therapy

Two platforms based on reduced graphene oxide (rGO) functionalized with Pluronic® P123 (rGO-P123) and polyethyleneimine – PEI (rGO-PEI) polymers and loaded with amphotericin B (AmB) were fabricated and tested against Leishmania amazonensis, which can cause cutaneous and diffuse cutaneous leishmaniasis. The materials rGO-P123 and rGO-PEI were efficiently loaded with AmB – a polyene antibiotic – which resulted in rGO-P123-AmB (0.078 mg per mg of material) and rGO-PEI-AmB (0.086 mg per mg of material). Under near-infrared (NIR) light irradiation, the amount of AmB released from rGO-PEI-AmB at pH 5.0 and 7.4 doubled in comparison to AmB released in the absence of NIR light under identical conditions. It was accompanied by a photothermal effect. Otherwise, rGO-P123-AmB did not show a significant change in AmB released in the presence and absence of NIR light. Cytotoxicity studies in mammalian host macrophages revealed that rGO-PEI and rGO-PEI-AmB were nontoxic to the host cells, whereas rGO-123 and rGO-P123-AmB were very toxic, particularly the latter. Therefore, only rGO-PEI and rGO-PEI-AmB were tested against L. amazonensis promastigotes in the presence and absence of NIR light. In vitro antiproliferative effects revealed that rGO-PEI-AmB showed a more pronounced activity against the parasite than rGO-PEI, which was improved under NIR light irradiation. Scanning-transmission electron microscopy of L. amazonensis promastigotes after incubation with rGO-PEI or rGO-PEI-AmB suggested autophagic and necrotic cell death. Thus, the facile synthesis, high AmB loading capacity and good photothermal effect make the rGO-PEI-AmB platform a promising candidate for the topical treatment of cutaneous leishmaniasis.

Nano-Leish-IL: A novel iron oxide-based nanocomposite drug platform for effective treatment of cutaneous leishmaniasis

Kinetoplastids are infamous parasites that include trypanosomes and Leishmania species. Here, we developed an anti-Leishmania nano-drug using ultra-small functional maghemite (γ-Fe2O3) nanoparticles (NPs) that were surface-doped by [CeLn]3/4+ to enable effective binding of the polycationic polyethylenebyimine (PEI) polymer by coordinative chemistry. This resulting nano-drug is cytolytic in-vitro to both Trypanosoma brucei parasites, the causative agent of sleeping sickness, as well as to three Leishmania species. The nano-drug induces the rupture of the single lysosome present in these parasites attributed to the PEI, leading to cytolysis. To evaluate the efficacy of a “cream-based” version of the nano-drug, which was termed “Nano-Leish-IL” for topical treatment of cutaneous leishmaniasis (CL), we developed a rapid screening method utilizing T. brucei parasites involved in social motility and demonstrated that functional NPs arrested the migration of the parasites. This assay presents a surrogate system to rapidly examine the efficacy of “cream-based” drugs in topical preparations against leishmaniasis, and possibly other dermal infectious diseases. The resulting Nano-Leish-IL topical preparation eliminated L. major infection in mice. Thus, this study presents a novel efficient nano-drug targeting the single lysosome of kinetoplastid parasites.

Efficacy of topical risedronate and risedronate - Eudragit E complex in a model of cutaneous leishmaniasis induced by Leishmania (Leishmania) amazonensis

An efficacious topical treatment for cutaneous leishmaniasis (CL) is highly desirable but still an ongoing challenge. Systemic risedronate (Ris) has been reported to have anti-leishmanial properties and Eudragit EPO (EuE) has shown in vitro activity against L. (L.) amazonensis. The aim of this work was to investigate the in vivo efficacy of topical Ris and EuE-Ris complexes on CL. Surface charge and Ris release kinetics from the different dispersions were analyzed. BALB/c mice were infected intradermally with promastigotes of L. (L.) amazonensis. Ulcers were treated with Ris or EuE-Ris hydrogels. All the lesions that received topical Ris or EuE-Ris showed an improvement with respect to control: reduction of ulcer average size, cicatrization, flattened edges and no signs of necrosis. In addition, a marked parasitic inhibition of 69.5 and 73.7% was observed in the groups treated with Ris and EuE-Ris, respectively, with the IgG2a levels indicating a tendency towards cure. The results are promising and the system should now be enhanced to achieve total parasite elimination.

Therapeutic advances in the topical treatment of cutaneous leishmaniasis: A review

Cutaneous leishmaniasis has been endemic since decades. Millions of cases are reported worldwide specially in developing and underdeveloped countries. There are 2 major types of cutaneous leishmaniasis based on the causating species found in different regions of the world. These include New and Old World cutaneous leishmaniasis, which are self-healing, but if not treated, these may cause severe scars and many other complications like mucosal involvement. The conventional gold standard treatment for both types is mainly intralesional or parenteral administration of antimonial. Lately, a great deal of research has been done on development of topical treatment based on single agent or combination therapy. This review summarizes the current state of literature regarding therapeutic outcome of topical treatment against cutaneous leishmaniasis caused by different species in different regions.

Topical Treatment of Cutaneous Leishmaniasis: A Case Treated with A Glucantime-Based Lotion Experienced in Ecuador and A Mini Review

Cell shrinkage is a biological process and when it started naturally or by any means, it indicates programmed cell death. A proper understanding of cell volume regulation, and routes involved in the movement of ions at the activation spot of apoptosis in the cell, can disclose the cell shrinkage process. Focused research on the concentration of potassium and sodium ions further leads to disclose the concerned process in maintaining the normal physiological intracellular concentration.

Efficacy of nanoemulsion with Pterodon emarginatus Vogel oleoresin for topical treatment of cutaneous leishmaniasis

Cutaneous leishmaniasis (CL) is a neglected tropical skin disease caused by the protozoan genus Leishmania. The treatment is restricted to a handful number of drugs that exhibit toxic effects, limited efficacy, and drug resistance. Additionally, developing an effective topical treatment is still an enormous unmet medical challenge. Natural oils, e.g. the oleoresin from P. emarginatus fruits (SO), contain various bioactive molecules, especially terpenoid compounds such as diterpenes and sesquiterpenes. However, its use in topical formulations can be impaired due to the natural barrier of the skin for low water solubility compounds. Nanoemulsions (NE) are drug delivery systems able to increase penetration of lipophilic compounds throughout the skin, improving their topical effect. In this context, we propose the use of SO-containing NE (SO-NE) for CL treatment. The SO-NE was produced by a low energy method and presented suitable physicochemical characteristic: average diameter and polydispersity index lower than 180 nm and 0.2, respectively. Leishmania (Leishmania) amazonensis-infected BALB/c mice were given topical doses of SO or SO-NE. The topical use of a combination of SO-NE and intraperitoneal meglumine antimoniate reduced lesion size by 41 % and tissue regeneration was proven by histopathological analyses. In addition, a reduction in the parasitic load and decreased in the level of IFN-γ in the lesion may be associated, as well as a lower level of the cytokine IL-10 may be associated with a less intense inflammatory process. The present study suggests that SO-NE in combination meglumine antimoniate represents a promising alternative for the topical treatment of CL caused by L. (L.) amazonensis.

Evaluation of a New Topical Treatment for the Control of Cutaneous Leishmaniasis.

Leishmania major (L. major) causes cutaneous leishmaniasis in the Old World. The infection mostly induces a localized lesion restricted to the sand fly bite. The costs and the side effects of current treatments render imperative the development of new therapies that are affordable and easy to administrate. Topical treatment would be the ideal option for the treatment of cutaneous leishmaniasis. MF29 is a 3-haloacetamidobenzoate that was shown in vitro to inhibit tubulin assembly in Leishmania. Here, we tested a topical cream formulated with MF29. BALB/c mice were infected in the ear dermis with L. major metacyclic promastigotes and once the lesion appeared, mice were treated with different concentrations of MF29 and compared to the control group treated with the cream used as the vehicle. We observed that topical application of MF29 reduced the progression of the infection while control groups developed an unhealing lesion that became necrotic. The treatment decreased the type 2 immune response. Comparison with SinaAmphoLeish, another topical treatment, revealed that MF29 treatment once a day was sufficient to control lesion development, while application SinaAmphoLeish needed applications twice daily. Collectively, our data suggest that MF-29 topical application could be a promising topical treatment for cutaneous leishmaniasis.

Preparation and Characterization of Nanostructured Lipid Carriers for Improved Topical Drug Delivery: Evaluation in Cutaneous Leishmaniasis and Vaginal Candidiasis Animal Models.

The present study aimed to develop, characterize and evaluate the amphotericin B-loaded nanostructured lipid carriers (AmB-NLCs) for topical treatment of cutaneous leishmaniasis (CL) and vulvovaginal candidiasis (VVC). AmB-NLCs were characterized for particle size, zeta potential, encapsulation efficiency and surface morphology. Prepared NLCs were also characterized for in vitro drug release, ex vivo skin permeation and deposition before evaluating their in vitro and in vivo efficacy. Cytotoxicity of NLCs was assessed on MRC-5 cells, whereas skin irritation potential was evaluated in vivo using rats. Significant accumulation of drug in to the skin supported the topical application potential of drug-loaded NLCs. Encapsulation of AmB in NLCs resulted in enhanced in vitro potency against promastigotes and intracellular amastigotes of L. major JISH 118 (IC50 ± SEM = 0.02 ± 0.1μM for both) compared with free drug (IC50 ± SEM = 0.15 ± 0.2 & 0.14 ± 0.0, respectively). Similar improved potency of AmB-NLCs was also observed for other Leishmania and fungal strains compared with drug solution. Topical application of AmB-NLCs on L. major-infected BALB/c mice caused a significant reduction in parasite burden per mg of lesion (65 × 108 ± 13) compared with the control group (> 167.8 × 108 ± 11). Topical AmB-NLCs gel demonstrated superior efficacy in the vaginal C. albicans rat model for VVC as compared with plain AmB gel. Moreover, results of in vitro cytotoxicity assay and in vivo skin irritation test confirmed AmB-NLCs to be non-toxic and safe for topical use. In conclusion, NLCs may have promising potential as carrier for topical treatment of various conditions of skin and mucosa.

Nano-elastic liposomes as multidrug carrier of sodium stibogluconate and ketoconazole: A potential new approach for the topical treatment of cutaneous Leishmaniasis

The present study evaluates the efficacy of sodium stibogluconate (SSG) co-loaded with ketoconazole (KTZ) in nano-elastic liposomes (NELs) for the topical treatment of cutaneous leishmaniasis (CL). SSG-KTZ co-loaded NELs were developed and assessed for various physicochemical properties and anti-leishmanial potential. The optimized nano-vesicles have an average size of 212.8 ± 3.1 nm and entrapment efficiency of 61.2 ± 2.9%. SSG-KTZ co-loaded NELs displayed 5.37-fold higher skin permeation of SSG as compared to drug solution. SSG and KTZ displayed a synergistic interaction and flow cytometry revealed enhanced killing of DsRed Leishmania mexicana in infected macrophages. In-vitro and in-vivo anti-leishmanial studies indicated a 10.67-fold lower IC50 value and a 35.33-fold reduced parasitic burden as compared with plain SSG solution, respectively. SSG-KTZ co-loaded NELs were found to be a promising approach for the topical treatment of CL.