Treatment Of Cutaneous Leishmaniasis Research Articles

Protocol for a prospective observational cohort study of cutaneous leishmaniasis in Ethiopia

Background Cutaneous leishmaniasis (CL) is a skin neglected tropical disease, with an estimated 40,000 new cases each year in Ethiopia. CL causes ulcers, nodules, and plaques on the skin, and in some instances the destruction of the nasopharyngeal mucosa and cartilage. Some CL lesions may heal spontaneously, whilst other lesions may require therapies which are associated with discomfort, adverse effects, prolonged treatment, and a frequent lack of a complete response. Scarring, a sequela of CL, causes permanent disfigurement and is associated with stigma linked with a reduction in health-related quality of life. The choice of treatment for CL is based upon factors including the causative species; the number, extent, size, and location of lesions; and the availability of treatments. The development of robust evidence for CL treatment is hindered by a lack of validated and appropriate outcome measures and few data to support hypothesis-generation and trial design. There is a paucity of prospective data with well-defined treatment outcomes for CL caused by L. aethiopica. Aim The overall aim of this study is to improve the understanding of the health and economic burden of CL. Methods We have designed an observational, multi-centre cohort study to examine treatment outcomes for CL in Ethiopia which includes clinical outcomes, laboratory outcomes, patient reported outcome measures, scar assessments and cost effectiveness. We aim to recruit up to 750 participants across two hospital sites. We present here the protocol for this cohort study with a 12-month follow up period for each participant. Conclusions These data will inform the design of randomized controlled trials to evaluate new treatment strategies, with appropriate economic evaluations. This will help improve evidence-based guidelines and support evidence-led policy decisions, not only in Ethiopia but also globally.

In vitro Antileishmanial Effect of Scrophulariabavanatia Extract on Leishmania (L) tropica [MHOM/NADIM3

Background: Cutaneous Leishmaniasis (CL) is a widespread parasitic disease that causes skin lesions and ulcers. Although the World Health Organization recommends Glucantime as a treatment for CL, this remedy presents unexpected side effects and high costs. This study investigates the in vitro antileishmanial effect of Scrophulariabavanatia hydroalcoholic extract on Leishmaniatropica promastigotes. Objectives: This study aims to evaluate the in vitro antileishmanial effects of a local Scrophulariabavanatia hydroalcoholic extract on Leishmania (L.) tropica [MHOM/NADIM3] promastigotes. Methods: Various concentrations (0.2, 1, 5, 25, and 125 mg/mL) of Scrophulariabavanatia methanol extract were prepared and added to cultures containing the parasite. The amastigote form of the L. tropica strain [MHOM/IR/NADIM3] was isolated from mouse spleens and transformed into promastigotes in Novy-Nicolle-Mac Neal medium. The antileishmanial activity of Scrophulariabavanatia extract was then compared to Glucantime using cell proliferation ELISA. Results: The LC50 values in the stationary stage for both Scrophulariabavanatia extract and Glucantime (mg/mL) were greater than in the dynamic stage. The extract at concentrations of 0.2, 1, 5, 25, and 125 mg/mL did not show significant differences after 24 and 48 hours (P > 0.05) compared to negative controls but did show a significant effect after 72 hours (P = 0.000). The extract demonstrated increased effectiveness with higher concentrations and longer exposure times. Conclusions: Scrophulariabavanatia extract inhibits the survival and growth of Leishmania promastigotes. Future studies should further explore its effects on in vivo survival of the parasite.

REASONS OF ABANDONMENT TREATMENT IN PATIENTS WITH LEISHMANIASIS

The goals of this study that examined patients with Cutaneous Leishmaniasis (CL) who were diagnosed and treated at the Sanliurfa Cutaneous Leishmaniasis Diagnosis and Treatment Center (SCLDTC), were to determine the frequency of treatment discontinuation and the reasons for discontinuation. This was a descriptive study that included individuals who visited the SCLDTC for diagnosis and treatment in 2020 and were diagnosed with CL. The study’s data collection phase took place between July 1, 2020 and December 31, 2020. The study comprised 370 patients who were diagnosed with CL and under treatment as of January 1, 2020. It was found that 187 of these patients discontinued treatment. The frequency of treatment discontinuation was 50.5%. Of those who discontinued treatment, 50.8% were women. It was determined that 3.7% of those who discontinued treatment did not speak Turkish, and 41.1% had not received formal education. Among the patients who discontinued treatment, 21.4% had no job, and 83.9% belonged to the lower socioeconomic status and unemployed group. Of those who discontinued treatment, 54.6% stopped before completing the first course, while 39,0% did not attend the follow-up examination after completing the first course. In cases of cutaneous leishmaniasis, the most common reasons for discontinuing treatment were believing that they do not require treatment (28.9%), disregarding the disease (27.3%), and a lack of medication in SCLDTC (26.7%). In the present study, the most common reasons for discontinuing treatment were a lack of belief in the necessity for treatment, disregarding the disease, and a shortage of medication. Patients’ and society’s knowledge and awareness of CL should be increased, public education programs should be organized, patients admitted to SCLDTC and their relatives should be informed, and the importance of completing the treatment should be explained, especially in neighborhoods where CL cases are densely distributed.

Development and validation of ultra-performance liquid chromatography tandem mass spectrometry methods for the quantitative analysis of the antiparasitic drug DNDI-6148 in human plasma and various mouse biomatrices

DNDI-6148 is a promising new oral drug for the treatment of cutaneous leishmaniasis (CL), a parasitic neglected tropical disease that affects impoverished populations worldwide. Preclinical target site pharmacokinetics (PK) studies are necessary to evaluate the actual exposure to DNDI-6148 of Leishmania parasites in the skin. To facilitate these investigations, we have developed and validated a reversed phase ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) method to quantify DNDI-6148 in relevant target site PK samples, adhering to the relevant International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) M10 guideline on bioanalytical method validation. Full validation was performed for the surrogate biomatrices human K2EDTA plasma, enzymatic digestion buffer and skin microdialysate. Partial validation was conducted for mouse K2EDTA plasma and tissues. The tissue samples, including mouse skin, liver and spleen, were homogenized using a collagenase A-based enzymatic homogenization workflow. This method was found to be 2.9-fold more effective in extracting DNDI-6148 from skin than the commonly used mechanical homogenization. Protein precipitation was subsequently carried out for all biomatrices. A surrogate biomatrix was used for each method and the range was specifically developed for its intended application, resulting in a linear concentration range of 5.00–2,000 ng/mL, 2.00–1,000 ng/mL, and 3.00–600 ng/mL for human K2EDTA plasma, enzymatic digestion buffer and microdialysate, respectively. Each biomatrix had intra- and inter-run accuracy and precision within 15 % for all concentration levels. Matrix effects did not affect the determination of DNDI-6148, since the stable isotopically-labelled internal standard for DNDI-6148 effectively compensated for these matrix effects. Total recovery across all methods was between 73.5 % and 81.3 % (CV ≤4.5 %). DNDI-6148 was stable under various conditions in all the tested biomatrices. However, a decrease in its concentration was observed during homogenization, for which the internal standard corrected adequately. The suitability of the method for use in future preclinical research involving DNDI-6148 was demonstrated in a preclinical target site PK study using a CL-infected murine model.

Aspidosperma nitidum reduces parasite load and modulates cytokines in BALB/c mice infected with Leishmania (Leishmania) amazonensis.

The lack of vaccines shows the need for alternative leishmaniasis treatments. In vitro study previously demonstrated the leishmanicidal activity of A. nitidum extracts. This study describes for the first time, the antileishmanial activity of A. nitidum extracts in infected Balb/c mice and its immunomodulatory effect. The extract (EE) was obtained by maceration of the peel powder with ethanol, which was fractionated by acid-base partition, originating the alkaloid (FA) and neutral (FN) fractions. EE and FA were analyzed using mass spectroscopy. Daily intragastric treatment was performed with EE and FA, at doses of 200mg/kg and 400mg/kg, in Balb/c mice with 28days of infection by Leishmania amazonensis. A thickness gauge was used to assess the progression of the lesion and the MTT method to determine the parasite load in the spleen. The quantification of IL-10 and IFN-γ was performed by ELISA. Analysis of the mass spectrum of EE indicated the presence of the alkaloids corynantheol and yohimbine, while in FA the alkaloid dihydrocorynantheol was identified. To elucidate the mode of interaction of these alkaloids with the TR protein, molecular target of antileishmanial drugs, we used molecular modeling approaches such as docking, molecular dynamics simulations and free energy affinity. Treatment with EE for 28days at the highest dose tested, significantly reduced the size of the lesion. EE and FA after 28days of treatment showed dose-dependent antileishmanial activity, which reduced the parasite load in the spleen of infected mice by 42.5% and 22.1%, respectively. Both EE and FA presented immunomodulatory effect, as they decreased IL-10 expression and increased IFN-y levels. The effectiveness of A. nitidum in the treatment of cutaneous leishmaniasis was proven in this study. The results obtained in silico demonstrated that the compounds are capable of interacting with the catalytic residues of the TR. The affinity energy results demonstrated that the complexes formed are favorable for enzymatic inhibition. The alkaloids present in the plant have demonstrated not only antileishmanial activity, but also the ability to modulate the host's immune response. These promising results open perspectives for developing more effective and comprehensive treatments against cutaneous leishmaniasis.

Effectiveness of Antileishmanial Treatments in Three Endemic Areas of Colombia: A Community-Based Cohort Study.

The effectiveness of treatment of cutaneous leishmaniasis (CL) in rural settings remains underexplored. This study assessed the effectiveness of standard antileishmanial treatments using a community-based approach supported by mobile health (mHealth) in three rural areas of Colombia. From January 2018 to September 2021, we assessed treatment outcomes, adherence, and adverse drug reactions in CL patients, with the support of the Guaral+ST app. Treatment decisions were made by providers at health facilities at each site in accordance with national guidelines, whereas treatment follow-up and presumptive case identification were made by trained community leaders and health agents at the community level. In total, 231 participants received antileishmanial treatment (63 received miltefosine, 110 meglumine antimoniate, and 58 pentamidine). Disease presentation was mild (median number of lesions = 1, interquartile range [IQR]: 1-2) and of short duration (1.5 months, IQR: 1-3). The strategy yielded information on the therapeutic outcomes in 81% of study participants. Effectiveness, measured as the proportion of cure at 90 to 180 days, was 86.3% (95% CI: 73.3-93.48) for miltefosine; 77.6% (67.5-85.3) for meglumine antimoniate, and 73.1% (59.0-83.6) for pentamidine. The effectiveness of pentamidine in children ≤10 years old was 79.4% (61.6-90.3). This is one of the few reports of effectiveness of pentamidine in children with prospective data collection in the Americas. Adverse drug reactions occurred in 32% of patients, most frequently with meglumine antimoniate. Our findings demonstrate that standard antileishmanial treatments are effective in rural areas where the disease is endemic and that mHealth has a pivotal role in improving patient follow-up and data collection on therapeutic outcomes.

Effects of Amphotericin B-Conjugated Functionalized Carbon Nanoparticles in the Treatment of Cutaneous Leishmaniasis.

Leishmaniasis is a parasitic disease spread by the bite of an infected sandfly and caused by protozoan parasites of the genus Leishmania. Currently, there is no vaccine available for leishmaniasis in humans, and the existing chemotherapy methods face various clinical challenges. The majority of drugs are limited to a few toxic compounds, with some parasite strains developing resistance. Therefore, the discovery and development of a new anti-leishmanial compound is crucial. One promising strategy involves the use of nanoparticle delivery systems to accelerate the effectiveness of existing treatments. In this study, Amphotericin B (AmB) was incorporated into functionalized carbon nanotube (f-CNT) and evaluated for its efficacy against Leishmania major in vitro and in a BALB/c mice model. The increase in footpad thickness was measured, and real-time PCR was used to quantify the parasite load post-infection. Levels of nitric oxide and cytokines IL-4 and IFN-γ were also determined. We found that f-CNT-AmB significantly reduced the levels of promastigotes and amastigotes of the Leishmania parasite. The nanoparticle showed strong anti-leishmanial activity with an IC50 of 0.00494 ± 0.00095 mg/mL for promastigotes and EC50 of 0.00294 ± 0.00065 mg/mL for amastigotes at 72 h post-infection, without causing harm to mice macrophages. Treatment of infected BALB/c mice with f-CNT-AmB resulted in a significant decrease in cutaneous leishmania (CL) lesion size in the foot pad, as well as reduced Leishmania burden in both lymph nodes and spleen. The levels of nitric oxide and IFN-γ significantly increased in the f-CNT-AmB treated groups. Also, our results showed that the level of IL-4 significantly decreased after f-CNT-AmB treatment in comparison to other groups. In conclusion, our results demonstrate that AmB loaded into f-CNT is significantly more effective than AmB alone in inhibiting parasite propagation and promoting a shift towards a Th1 response.

Investigation of the in vitro and in vivo therapeutic activity of Tarantula cubensis extract (Theranekron ® ) on Leishmania major.

Cutaneous leishmaniasis (CL) is a vector-borne parasitic disease caused by several species of the protozoan parasite Leishmania. The need for new anti-leishmanial drugs for the treatment of CL is highlighted by factors such as high cost, toxicity, potential for resistance and limited long-term use of existing anti-leishmanial drugs. The aim of this study was to investigate the therapeutic effect of Tarantula cubensis alcoholic extract (TCE), which has been shown to have wound-healing, anti-inflammatory, regenerative, resolving and epithelialising effects, on L. major promastigotes in vitro and in vivo in an experimental mouse model of CL. The effect of TCE on L. major promastigotes in vitro was investigated after determination of non-cytotoxic concentrations of TCE using the XTT method. To establish a CL model, L. major amastigotes were injected into the paws of BALB/c mice. Lesion size and histopathological evaluation were used to assess the effect of treatment. TCE was found to be effective against L. major promastigotes at 24 h and 48 h at concentrations of 250 μg/mL, 125 μg/mL and 62.5 μg/mL ( P <0.05). TCE was found to be more effective than meglumine antimonate in treating CL in the experimentally induced CL model in BALB/c mice. The results suggest that TCE holds promising potential therapeutic agent for the treatment of CL. However, further extensive investigations are required to substantiate and expand understanding in this area.

Improved Topical Delivery of Sorafenib-Meglumine Antimoniate: Elastic Nano-Liposomal Formulation for the Treatment of Cutaneous Leishmaniasis

Background: Cutaneous leishmaniasis (CL) is a widespread parasitic disease with significant health and social impacts. Current systemic treatments have severe side effects, highlighting the need for effective topical alternatives.Objective: This study aimed to develop and evaluate the effectiveness of sorafenib (SF) and meglumine antimoniate (MM) dual-loaded transferosomes (TRs) for topical treatment of CL.Methods: TRs were prepared using a thin film hydration method and incorporated into a carbopol gel. The formulations were characterized for vesicle size, zeta potential, entrapment efficiency, and deformability index. In vivo and ex vivo skin permeation studies were conducted, along with anti-leishmanial efficacy testing on an intramacrophage amastigote model using BALB/c mice.Results: The TRs exhibited a vesicle size of 186.1 ± 65.89 nm, zeta potential of -27.9 mV, and entrapment efficiency of 71.7 ± 3.9% for MM and 78.6 ± 4.2% for SF. Ex vivo studies showed enhanced skin permeation with cumulative permeation of 327.6 ± 29.4 µg/cm² for MM and 291.6 ± 28.3 µg/cm² for SF. In vivo results indicated a significant reduction in lesion size (0.1 ± 0.12 mm) and parasite load (2.7 ± 0.3 log scale).Conclusion: The MM-SF dual-loaded TRs demonstrated effective topical delivery and therapeutic potential for CL, providing a promising alternative to systemic treatments.

Tolerability and Safety of Miltefosine for the Treatment of Cutaneous Leishmaniasis.

Miltefosine, an orally administered drug, is an important component of the therapeutic arsenal against visceral and mucosal forms of leishmaniasis. However, data regarding the safety and tolerability of miltefosine treatment for cutaneous leishmaniasis (CL) are relatively limited. The aim of this study was to evaluate the tolerability, safety, and adverse events (AEs) of miltefosine treatment in patients with CL. In this cohort study, we reviewed the medical records of all miltefosine-treated patients between 1 January 2016 and 31 December 2022, at Israel Defense Forces military dermatology clinics and the dermatology and Tropical Medicine Clinics at Chaim Sheba Medical Center, Ramat-Gan, Israel. A total of 68 patients (54 males, 79%) with a median age of 30.3 ± 15.6 years (range: 18-88) were included in this study. Leishmania species were identified as L. major (n = 37, 54.4%), L. tropica (n = 12, 17.6%), L. braziliensis (n = 18, 26.5%), and L. infantum (n = 1, 1.5%) using polymerase chain reaction (PCR). Miltefosine tablets were administered orally at a dose of 50 mg, three times daily, for 28 days. Overall, 44 patients (65%) completed the 28-day treatment, and the remaining patients required dose reduction or early discontinuation of treatment. AEs (of any degree) were common, reported in 91% of patients. Both previously reported and previously unreported AEs were documented. Gastrointestinal symptoms (66.1%) and malaise (23.5%) typically occurred during the first two weeks of treatment and tended to subside. Other AEs, including acute renal failure (20.6%), sudden and severe pleuritic chest pain (7.6%), acne exacerbation (11.8%), suppuration of CL lesions (17.8%), and AEs related to the male genitourinary system (39.6% of males), typically occurred towards the end of treatment. The latter included testicular pain, epididymitis, diminution or complete absence of ejaculate, inability to orgasm, and impotence. Severe AEs necessitated treatment discontinuation (29.4%) or hospitalization (10.3%). URTI-like symptoms, arthritis, cutaneous eruption, pruritus, and laboratory abnormalities were also observed. Overall, the cure rate (for all patients combined) evaluated 3 months after the completion of treatment was 60%. The tolerability of miltefosine treatment for CL is low. Close clinical and laboratory monitoring is required during treatment, as severe AEs are not uncommon. As new insights regarding its toxicities emerge, further studies are required to define the role of miltefosine in the treatment of CL.

Photodynamic therapy in management of cutaneous leishmaniasis: A systematic review.

This systematic review evaluated the efficacy and safety of photodynamic therapy (PDT) in the management of cutaneous leishmaniasis (CL). The electronic search for identification of relevant studies, adhered to the PICOS (Population, Intervention, Comparator, Outcomes and Study type) framework, was conducted through PubMed, Google scholar, Dimensions, X-mol, and Semantic Scholar till December 2023. All types of studies reporting PDT in the management of CL with no language restriction were included. Methodological quality appraised of the selected studies was performed using Jadad index. Of the 317 identified studies, 21 reported PDT for the treatment of CL lesions, consisting of two randomized controlled trials (RCTs), four single-center open study, one case series and 14 case reports. Collectively, these studies presented a total of 304 patients with ages ranging from 1 to 82years, undergoing varying number of PDT sessions (3-28) and follow-up durations spanning 4weeks to 24months. The CL lesions predominantly manifested on the exposed body areas, such as face, limbs, neck, ear and nose, and characterized with the use of clinical variables, such as plaques, papules, erythema and ulceration. PDT protocols differed in the photosensitizer type, incubation time, light source characteristics (e.g., wavelength, output power, and energy density), duration of light illumination, number of PDT sessions and their respective frequencies. Treatment response was assessed through the clinical presentation (i.e., at the baseline and after PDT completion) or by the absence of Leishmania parasites. Adverse effects comprised of pain, burning and tingling sensation experienced during PDT, followed by erythema, pigmentation changes and edema post-treatment. This systematic review revealed that PDT is an efficacious and safe modality for the treatment of CL, with mild and transient side effects.

In Vivo Evaluation of Sepigel-Based Meglumine Antimoniate and Amphotericin B for Cutaneous Leishmaniasis Treatment.

Cutaneous leishmaniasis (CL) poses a significant public health concern in endemic regions due to its increasing prevalence and substantial impact on affected individuals. This disease is primarily caused by the Leishmania protozoa, which are transmitted through insect bites, and it manifests as a range of symptoms, from self-healing lesions to severe disfigurement. Current treatments, which often involve the parenteral administration of antimonials, face challenges such as poor compliance and adverse effects. This study investigates the efficacy of topical formulations containing meglumine antimoniate (MA) and amphotericin B (AmB), using Sepigel as an excipient, for treating CL. In the in vivo study, BALB/c mice infected with L. amazonensis developed lesions at the injection site five weeks post-infection. Subsequently, the mice were divided into eight groups: untreated mice, mice treated orally with miltefosine, mice treated intraperitoneally with MA, and mice treated topically with 15%, 22.5%, and 30% MA-Sepigel, as well as those treated with AmB-Sepigel. Treatments were applied daily for two weeks, and the results revealed a significant reduction in lesion size and parasite burden following topical application, particularly with the AmB-Sepigel formulations and 30% MA-Sepigel. Additionally, Sepigel-based treatments demonstrated improved patient compliance and reduced toxicity compared to systemic therapies. These findings underscore the potential of Sepigel-based formulations as a promising alternative for CL treatment. They offer enhanced efficacy and tolerability, while reducing the systemic toxicity associated with conventional therapies.

Semen Cannabis and Oleum Hyperici: Antileishmanial activity against Leishmania tropica promastigotes and intracellular amastigotes

The exploration of alternative agents and novel drug candidates for the effective treatment of cutaneous leishmaniasis has garnered significant attention, driven by the high cost, toxic effects, and the emergence of drug resistance associated with current therapeutic options. Plant extracts derived from Semen Cannabis, the seeds of the Cannabis sativa L. (hemp) plant, and Oleum Hyperici, the oily macerate of Hypericum perforatum L. (St. John's Wort) plant, were prepared by using solvents of varying polarity (n-hexane, chloroform, ethanol, and 60% aqueous ethanol). The primary objective of this study was to research in vitro and ex vivo antileishmanial efficacy of Semen Cannabis and Oleum Hyperici plant extracts against Leishmania tropica promastigotes and intracellular amastigotes. The efficacy of plant extracts against promastigotes were assessed using the cell counting by hemocytometer and the CellTiter-Glo assay. Additionally, their impact on infected THP-1 macrophages and the quantity of intracelluler amastigotes were investigated. Cytotoxicity was evaluated in THP-1 macrophages. Among the tested plant extracts, chloroform extract of Oleum Hyperici demonstrated significant antileishmanial activity against promastigotes (SI: 12.6) and intracellular amastigotes (SI: 16.8) of L. tropica without inducing cytotoxic effects and hold promise for further investigation as potential antileishmanial agents.

Use of topical rSm29 in combination with intravenous meglumine antimoniate in the treatment of cutaneous leishmaniasis: A randomized controlled trial

BackgroundCutaneous leishmaniasis (CL) caused by Leishmania (Viannia) braziliensis is associated with an inflammatory response. Granzyme (GzmB) and IL-1β play a key role in the pathology. Meglumine antimoniate (MA) is the first-choice drug for the treatment of CL, but therapy failure is observed in up to 50% of the cases. The protein, rSm29 of Schistosoma mansoni, down-modulates pro-inflammatory cytokine production. We evaluate if the combination of topical rSm29 plus MA increases the cure rate of CL. MethodsIn this randomized clinical trial, 91 CL patients were allocated in 3 groups. All cases received MA (20 mg/kg/weight) for 20 days. Group 1 used topical rSm29 (10 µg), group 2 a placebo topically applied, and group 3 received only MA. ResultsThe cure rate on day 90 was 71% in subjects treated with rSm29 plus MA, and 43% in patients who received MA plus placebo or MA alone (P < 0.05). There was a decrease in GzmB and an increase in IFN-γ (P < 0.05) in supernatants of skin biopsies of the lesions obtained on D7 of therapy (P < 0.05) in patients who received rSm29. ConclusionrSm29 associated with MA reduces GzmB levels, is more effective than MA alone, and decreases CL healing time. Clinical trials registrationClinicalTrial.gov under NCT06000514.

The Therapeutic Effect of Shirvan Herbal Ointment on Human Cutaneous Leishmaniasis Compared with Glucantime.

Cutaneous leishmaniasis (CL) infection is caused by the Leishmania major (L. major) parasite and affects 1.5 to 2 million people worldwide each year. Although research into vaccines and antiparasitic drugs has been somewhat successful, their adverse effects include high toxicity, prolonged regeneration, and scarring. This has highlighted the importance of research to replace natural products with antibacterial and antioxidant properties, such as vegetable extracts and oils. Since, the anti-leishmaniasis effect of each of the components of Shirvan herbal ointment (aloe vera, Brazembel, Nigella sativa, propolis, lavender, and olive oil) has been separately studied and confirmed, it seems that the combination of these components can have an increasing anti-leishmanial effect to treat CL. Therefore, this study investigated the therapeutic impact of Shirvan herbal ointment on Iranian patients with leishmaniasis in comparison with glucantime (meglumine). Sixty patients with leishmaniasis were divided into the control and test groups. The control and test groups received intralesional glucantime and Shirvan herbal cream (two times daily), respectively. The size mean of the lesion was 51.5 ± 32.5 before and 11.11 ± 16.28 after treatment in the control group and 50.8 ± 31.2 before and 0.0 ± 0.0 after treatment in the test group. In addition, the period mean of treatment was 43.9 ± 14.4 days and 30.5 ± 7.4 days in the control and test groups, respectively. There was a significant difference in lesion size between the two groups after treatment. Data suggested that Shirvan herbal ointment can be an alternative drug in the treatment of human CL.

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 &lt; 0.0001 after24 h incubation, p = 0.013 for 48h and p &lt; 0.0001 for 72 h) and PM (p &lt; 0.0001 after24 h, p = 0.003 for 48h and p &lt; 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.

Intraperitoneal Administration of 17-DMAG as an Effective Treatment against Leishmania braziliensis Infection in BALB/c Mice: A Preclinical Study.

Leishmaniasis is a significant global public health issue that is caused by parasites from Leishmania genus. With limited treatment options and rising drug resistance, there is a pressing need for new therapeutic approaches. Molecular chaperones, particularly Hsp90, play a crucial role in parasite biology and are emerging as promising targets for drug development. This study evaluates the efficacy of 17-DMAG in treating BALB/c mice from cutaneous leishmaniasis through in vitro and in vivo approaches. We assessed 17-DMAG's cytotoxic effect on bone marrow-derived macrophages (BMMΦ) and its effects against L. braziliensis promastigotes and intracellular amastigotes. Additionally, we tested the compound's efficacy in BALB/c mice infected with L. braziliensis via intraperitoneal administration to evaluate the reduction in lesion size and the decrease in parasite load in the ears and lymph nodes of infected animals. 17-DMAG showed selective toxicity [selective index = 432) towards Leishmania amastigotes, causing minimal damage to host cells. The treatment significantly reduced lesion sizes in mice and resulted in parasite clearance from ears and lymph nodes. It also diminished inflammatory responses and reduced the release of pro-inflammatory cytokines (IL-6, IFN-γ, TNF) and the regulatory cytokine IL-10, underscoring its dual leishmanicidal and anti-inflammatory properties. Our findings confirm the potential of 17-DMAG as a viable treatment for cutaneous leishmaniasis and support further research into its mechanisms and potential applications against other infectious diseases.

Hydrophobic binary mixtures containing amphotericin B as lipophilic solutions for the treatment of cutaneous leishmaniasis

Cutaneous leishmaniasis, caused by Leishmania parasites, requires treatments with fewer side effects than those currently available. The development of a topical solution based on amphotericin B (AmB) was pursued. The considerable interest in deep eutectic solvents (DESs) and their remarkable advantages inspired the search for a suitable hydrophobic excipient. Various mixtures based on commonly used hydrogen bond donors (HBDs) and acceptors (HBAs) for DES preparations were explored. Initial physical and in-vitro screenings showed the potential of quaternary phosphonium salt-based mixtures. Through thermal analysis, it was determined that most of these mixtures did not exhibit eutectic behavior. X-ray scattering studies revealed a sponge-like nanoscale structure. The most promising formulation, based on a combination of trihexyl(tetradecyl)phosphonium chloride and 1-oleoyl-rac-glycerol, showed no deleterious effects through histological evaluation. AmB was fully solubilized at concentrations between 0.5 and 0.8 mg·mL−1, depending on the formulation. The monomeric state of AmB was observed by circular dichroism. In-vitro irritation tests demonstrated acceptable viability for AmB-based formulations up to 0.5 mg·mL−1. Additionally, an ex-vivo penetration study on pig ear skin revealed no transcutaneous passage, confirming AmB retention in healthy, unaffected skin.

Use of miltefosine in the treatment of cutaneous leishmaniasis in French Guiana

Use of miltefosine in the treatment of cutaneous leishmaniasis in French Guiana