Pentavalent Antimonials Research Articles

Imported Cutaneous Leishmaniasis from Peru Caused by Leishmania (Viannia) guyanensis in a Brazilian Patient: Case Report and In Vitro Drug Susceptibility Analysis

In South America, cutaneous leishmaniasis is caused by several species of the parasite of the genus Leishmania. Here, we describe an imported case of cutaneous leishmaniasis acquired in Peru by a Brazilian patient during her travel to Iquitos. Infection by Leishmania parasites was confirmed by histopathologic examination, and the patient was treated with pentavalent antimony (Pentostam), without clinical response. Molecular typing was performed by sequencing the ribosomal DNA internal transcribed spacer and heat-shock protein 70 gene, which identified the parasites as Leishmania guyanensis. The clinical isolate was similarly susceptible to amphotericin B, pentamidine, and miltefosine as the reference strain, while for pentavalent antimony, this clinical isolate was more susceptible than the reference strain, even though its susceptibility in vitro was still considered low. The patient was then treated with liposomal amphotericin B, with clinical improvement of the lesions.

Immunotherapeutic Strategies as Potential Treatment Options for Cutaneous Leishmaniasis.

Cutaneous leishmaniasis (CL), caused by protozoan parasites of the Leishmania genus, is prevalent in tropical and subtropical regions, with important morbidity, particularly in low- to middle-income countries. Current systemic treatments, including pentavalent antimonials and miltefosine, are associated with significant toxicity, reduced efficacy, and are frequently ineffective in cases of severe or chronic CL. Immunotherapies leverage the immune system to combat microbial infection and offer a promising adjunct or alternative approach to the current standard of care for CL. However, the heterogeneous clinical presentation of CL, which is dependent on parasite species and host immunity, may require informed clinical intervention with immunotherapies. This review explores the clinical and immunological characteristics of CL, emphasising the current landscape of immunotherapies in in vivo models and clinical studies. Such immune-based interventions aim to modulate immune responses against Leishmania, with additive therapeutic effects enabling the efficacy of lower drug doses and decreasing the associated toxicity. Understanding the mechanisms that underlie immunotherapy for CL provides critical insights into developing safer and more effective treatments for this neglected tropical disease. Identifying suitable therapeutic candidates and establishing their safety and efficacy are essential steps in this process. However, the feasibility and utility of these treatments in resource-limited settings must also be considered, taking into account factors such as cost of production, temperature stability, and overall patient access.

Comparative Efficacy of Current and Emerging Therapies for Cutaneous and Visceral Leishmaniasis: A Global Perspective

Leishmaniasis treatment has faced challenges with pentavalent antimonials, historically used but now showing resistance and high failure rates. The World Health Organization (WHO) recommended higher doses, but resistance in Nepal and misuse persist. Antimonials are no longer the preferred treatment for visceral leishmaniasis (VL) in the Indian subcontinent but are still used for cutaneous leishmaniasis (CL). Amphotericin B, especially liposomal amphotericin B (L-AmB), has become the preferred treatment for VL in the Indian subcontinent, with high efficacy and shorter treatment courses. Genetic insights into leishmaniasis reveal that parasite species and host immune responses are key factors in disease variation. Genetic analysis of atypical parasite isolates shows that genetic variations can lead to different disease patterns. Whole genome sequencing and proteomic analyses offer fresh insights into how parasite genes and proteins impact drug resistance, post-kala-azar dermal leishmaniasis (PKDL), and unusual disease presentations. Variations in hereditary unit copy numbers and single nucleotide polymorphisms contribute to genetic diversity and distinct tissue distribution, leading to distinct disease patterns. Genomic markers for drug resistance in Leishmania parasites include ATP-binding cassette (ABC) transporters, amino acid permease 3 (AAP3), and proteins like phosphoglycerate kinase (PGK) and mitogen-activated protein kinase (MAPK). These markers are associated with efflux of thiols and metals, antimony resistance, and protection against oxidative stress. Additionally, key proteins and enzymes in antioxidant defense mechanisms, such as iron superoxide dismutase-A (FeSOD-A), folate transporter 1 (FT1), and heat shock protein 83 (HSP83), play roles in drug resistance and parasite survival.

Antimicrobial Peptides and Their Anti-Leishmanial Efficacies on Leishmania tropica Promastigotes In vitro.

Antimicrobial resistance is a real threat to humanity. Pentavalent antimonials are reported non-effective in leishmaniasis treatment today, in countries like India. New treatment options have been assessed worldwide lately. Antimicrobial peptides (AMP) are the leading antibiotic candidates due to their large spectrum, fast efficacy, and low resistance risks. Cathelicidins are the AMP with well-documented antimicrobial activities against bacteria, fungi, and protozoa, over their positively charged membranes. Here, we aim to design cathelicidine-like helical peptides (CLHP), and compare their anti-Leishmanial efficacies in vitro, with meglumine antimoniate (MA) on Leishmania tropica. A total of five study [TN-1-5] and two control (MA and non-drug) groups were formed. Cryopreserved L. tropica isolate was thawed and cultivated in Novy-MacNeal-Nicolle medium and then in RPMI. Five different CLHPs (TN1-5) were diluted in dimethyl sulphoxide. A total of 150 uL of CLHPs and MA were added into the first wells of the test plaques, followed by serial dilutions that revealed doses within 4 and 512 ug/mL. Then, 100 uL of cultures including 1x108/mL of L. tropica promastigotes were added into each well. Viability of promastigotes was checked with XTT, while the parasite count was assessed at 24th and 48th hours. TN3 was effective at 32 ug/mL. All tested CLHPs exhibited varying degrees of anti-Leishmanial activities, except TN5, even at its highest dose. TN3 showed a particular efficacy against L. tropica in vitro. Further studies including in vivo testing of the candidate's both efficacy and toxicity are essential.

Analysis of the Relative Effectiveness of Curcumin Loaded Chitosan Nanoparticles and Pure Curcumin Compound in the Treatment of Leishmaniasis.

Aim: A proficient drug conveyance plan is expected to treat cutaneous leishmaniasis (CL). Regardless of their deficient solvency, significant expense, low assimilation, and rising medication-safe Leishmania spp., pentavalent antimonials and curcumin (CC) may fix leishmaniasis. Drug conveyance frameworks (DDS) might be utilized to treat CL without these worries. Methodology: We tried free CC and Curcumin-stacked nanoparticles produced using chitosan (CC-CNPs) for antileishmanial movement in-vitro. Nanoparticles of Chitosan (CNPs) were produced by tripolyphosphate (TPP), which are negatively charged ionic gelation. CC was added to the CNPs mix. The size, surface shape, epitome adequacy (EE), drug stacking content (DLC), and surface charge of the NPs were characterized using various approaches. The MTT test was performed to evaluate their effectiveness against Leishmania tropica promastigotes and axenic amastigotes after characterization. Results: Round CC-CNPs with a typical molecule size of 276 nm, a zeta capability of (+18.74 mV), and 88% embodiment viability were integrated. Following 72 hours, free CC restrained promastigotes and axenic amastigotes parasite load by 64 and 70%, separately, though CC-CNPs repressed parasites by 91 and 86%. CC-CNPs diminished parasite suitability better than free CC. The half-maximal inhibitory focus (IC50) of CC-CNPs was a lot of lower than that of free CC. Conclusion: In a portion-time subordinate way, CC-CNPs showed more antileishmanial action than unbound CC. In-vivo testing is expected for CL nearby treatment with this detailing.

Development of Amphotericin B Decorated Gold Nanoparticles as a Promising Antileishmanial Nanoconjugate.

Leishmaniasis, attributed to the protozoan parasite Leishmania, manifests in diverse clinical forms, including cutaneous, mucocutaneous, and visceral leishmaniasis; VL constitutes a significant global health menace. Prevalent in tropical and subtropical regions, this affliction disproportionately impacts individuals below the poverty threshold, transmitted through the bite of female sandflies. Existing treatments, such as pentavalent antimony, miltefosine, and Amphotericin B, exhibit limitations. Despite the emergence of liposomal Amphotericin B (AmBisome) as a promising antileishmanial agent, its utility is impeded by adverse effects, elevated production expenses, and cytotoxicity. To address these challenges, our investigation introduces a potential remedy─a citrate-coated gold Amphotericin B nanoparticle formulation. Characterized using dynamic light scattering and transmission electron microscopy, this pioneering formulation exhibited efficacy against L. donovani Ag83 promastigotes as demonstrated by MTT cell viability testing. Evaluating internal reactive oxygen species (ROS) levels and dual staining with acridine orange and ethidium bromide unveiled its consequential impact on cell death. Significantly, our study discloses this novel nanoformulation's unprecedented inhibition of the trypanothione reductase enzyme. The findings posit the citrate-coated gold Amphotericin B nanoformulation as a promising and targeted antileishmanial agent, representing potential advancements in leishmaniasis therapeutics.

American Cutaneous Leishmaniasis: Imported cases in Berlin 2000-2023.

American Cutaneous Leishmaniasis (ACL) shows variable response to therapy, but data on species-specific treatment efficacy is scarce. We describe the clinical characteristics and outcome of patients with ACL imported to a tertiary centre in Germany and determine whether species-specific therapy according to the 2014 "LeishMan" group recommendations is associated with cure. A retrospective chart review was conducted at the Charité Institute of International Health in Berlin. We analysed data on PCR-confirmed ACL cases collected between 2000 and 2023. Systemic therapy included liposomal amphotericin B, miltefosine, pentavalent antimony, ketoconazole or itraconazole. Localized therapy included perilesional pentavalent antimony or paromomycin ointment. Cure was defined as re-epithelialization of ulcers or disappearance of papular-nodular lesions after 3 months of treatment. Logistic regression models were used to quantify the effect of species-specific systemic therapy on the outcome. 75 cases were analysed. Most patients were male (62%), median age was 35 years, no patient had a history of immunosuppression. The most common reason for travel was tourism (60%), the most common destination was Costa Rica (28%), the median duration of illness was 8 weeks, and most patients presented with ulcers (87%). Lesions were complex in 43%. The most common Leishmania (L.) species was L. braziliensis (28%), followed by L. panamensis (21%). 51/73 (70%) patients were cured after initial therapy and 17/21 (81%) after secondary therapy. Cure after systemic therapy was more frequent when species-specific treatment recommendations were followed (33/45; 73%), compared to when not followed, (6/17; 35%, P = 0.008). This association was independent of age, sex, previous therapy, complex lesions, and Leishmania species (adjusted OR, 5.06; 95% CI, 1.22-24.16). ACL is a rare, imported disease in Germany. Complex lesions were common, challenging successful therapy. This study highlights the importance of identifying the parasite species and suggests that a species-specific approach to treatment leads to better outcomes.

Articulate Chemotherapeutic Strategies for the Development of Effective Drugs against a Fatal Disease, Visceral Leishmaniasis.

Visceral Leishmaniasis (VL) control relies mainly on chemotherapy in the absence of no effective vaccines. However, available anti-VL drugs are limited in number, having toxicity issues, adverse reactions, low efficacy, and resistance observed against antileishmanial. A significant decrease in efficacy (~tenfold increase in dosage and duration) was reported against the usual treatment with Pentavalent antimonials (the most recommended antileishmanial drug discovered 90 years ago). Amphotericin B is the second line of treatment but limits wider use due to its high cost. Pentamidine is another anti-VL drug, but its therapeutic efficacy has decreased significantly in different areas. These conventional therapeutics for VL have become almost outdated due to a significant increase in therapeutic failure in terms of percentage. Due to this, the search for an effective future anti-VL drug spans several decades, and now it is in high demand in the current situation. Some conventional therapeutics are modified, but they are also not satisfactory. Therefore, this article aimed to discuss conventional and modified therapeutics while emphasizing innovative chemotherapeutic measures against VL that could speed up the slow pace of antileishmanial drugs and overcome the drug resistance problem in the future.

Clinical pattern and treatment outcome of cutaneous leishmaniasis patients in Somali region, eastern Ethiopia

AbstractBackgroundNeglected tropical diseases, affecting over a billion people, include leishmaniasis, a protozoan parasite found in over 20 species. It is classified into three types: visceral, cutaneous, and muco‐cutaneous leishmaniasis, with cutaneous leishmaniasis being the most common. Dogs and rodents are the primary reservoirs of leishmaniasis, which is transmitted by infected female sandflies. Cutaneous leishmaniasis, found on exposed parts such as the arms, face and legs, presents with diverse clinical manifestations, including erythematous lesions, large, painless nodules, ulceration and an eventual volcanic form.ObjectiveTo assess the clinical pattern and treatment outcome of cutaneous leishmaniasis patients in the Somali region of eastern Ethiopia.MethodsThis descriptive study was conducted in the Somali region using neglected tropical disease surveillance data collected from 1 September 2023, to 8 February 2024. The data were cleaned and then exported to STATA version 17 for analysis.ResultsFrom 1 September 2023, to 8 February 2024, 900 patients were diagnosed with cutaneous leishmaniasis. Of these, 105 (11.67%) patients had localised cutaneous leishmaniasis, 741 (82.33%) had disseminated cutaneous leishmaniasis, 20 (2.22%) had diffuse cutaneous leishmaniasis, 8 (0.89%) had mucocutaneous leishmaniasis, 12 (1.33%) had mucocutaneous and disseminated leishmaniasis and 14 (1.56%) had localised and mucocutaneous leishmaniasis. All of the cases were male; the most common signs and symptoms the patients showed were papule, nodule, ulcer and crust 791 (87.89%) and itching, fever and discharges 758 (84.22%), respectively. Most of the patients, 823 (93.34%), were given systemic pentavalent antimonials, and the cure rate was 886 (98.44%). Of the patients, 14 (100%) who were defaulted on had diffuse cutaneous leishmaniasis.ConclusionsAll the participants had travelled to an area where sandflies were common. The majority of patients complained of itching, fever and discharges, with over two‐thirds having disseminated cutaneous leishmaniasis (DCL) and 0.89% having mucocutaneous leishmaniasis. The regional health bureau should set up a strong surveillance system and launch educational campaigns to raise awareness about cutaneous leishmaniasis, its transmission, symptoms and preventive measures. Furthermore, patients should be advised to strictly adhere to their treatment schedule and follow‐ups.

In vitro and in silico antileishmania activity of voriconazole (Vfend)

American Cutaneous Leishmaniasis (ACL) is a public health problem in 88 countries. The treatment of ATL is based on pentavalent antimony, which has several adverse effects. And through new alternatives for the treatment of leishmaniasis, the use of off-label medications appears. The objective of this work was to evaluate, through in vitro and in silico tests, the activity of voriconazole in tablet form as off-label against the promastigote forms of Leishmania amazonensis and Leishmania guyanensis. In the bioassay, species of Leishmania (L.) amazonensis and Leishmania (V.) guyanensis were used, cultivated in RPMI medium with 10% SFBi. The 50% inhibitory concentration (IC50) of voriconazole was evaluated by the inhibition of promastigotes exposed to voriconazole at concentrations of 6.25 to 200 µg.mL-1 diluted in culture medium and fluconazole at 25 to 400 µg.mL-1. In the experiment, parasites plus culture medium and pentamidine isethionate at 3 µg.mL-1 were used as controls for 24, 48 and 72 h in triplicate. The concentrations of voriconazole used in the test showed antileishmanial activity against promastigotes of both Leishmania species, with an IC50 of 5.34 µg.mL-1 for L. amazonensis and 5.66 µg.mL-1 for L. guyanensis. Therefore, the study showed that off-label voriconazole presented better results than fluconazole against Leishmania species, in addition to showing better enzymatic coupling of new targets.

Computational and experimental approaches manifest the leishmanicidal potential of α-mangostin resourced from Garcinia cowa

Owing to the persistent number of parasitic deaths, Visceral leishmaniasis continues to haunt several economically weaker sections of India. The disease causes over 30,000 deaths and threatens millions annually on a global scale. The standard pentavalent antimonials, on the other hand, are associated with health adversities and disease relapse. The current study is focused on the search for the most potential natural bioactive phytocompound from the bark extract of the Northeastern Indian plant, Garcinia cowa, that shows potent anti-leishmanial properties. The High Resonance Liquid Chromatography followed by Mass Spectrometry (HR-LCMS) study followed by an in silico molecular docking using computational tools revealed that α-mangostin might potentially possess antiparasitic activity. To validate the anti-leishmanial efficacy of the compound, a cell viability assay was performed, which demonstrated the parasite-specific inhibitory activity of α-mangostin; with IC50 values ranging from 4.95 - 7.37 µM against the different forms of Leishmania donovani parasite. The flow cytometric analysis of the phytocompound treated parasites indicated an oxidative and nitrosative stress-mediated apoptotic cell death in the parasites, by the suggestive surge in nuclear fragmentation and mitochondrial dysfunction. Simultaneously, a cytokine profiling study suggested approximate two-to-three-fold upregulated levels of pro-inflammatory cytokines post-compound treatment, which is predicted to actively contribute to parasite-killing. α-mangostin was also found to reduce the chances of parasite survival by inhibiting arginase enzyme activity, which in favorable conditions facilitates its sustenance. This study thereby substantiates that α-mangostin significantly possesses anti-leishmanial potentiality that can be developed into a cure for this infectious disease.

Revolutionizing Leishmaniasis Treatment with Cutting Edge Drug Delivery Systems and Nanovaccines: An Updated Review.

Leishmaniasis, one of the most overlooked tropical diseases, is a life-threatening illness caused by the parasite Leishmania donovani that is prevalent in underdeveloped nations. Over 350 million individuals in more than 90 different nations worldwide are at risk of contracting the disease, which has a current fatality rate of 50 000 mortalities each year. The administration of liposomal Amp B, pentavalent antimonials, and miltefosine are still considered integral components of the chemotherapy regimen. Antileishmanial medications fail to treat leishmaniasis because of their numerous drawbacks. These include inadequate effectiveness, toxicity, undesired side effects, drug resistance, treatment duration, and cost. Consequently, there is a need to overcome the limitations of conventional therapeutics. Nanotechnology has demonstrated promising outcomes in addressing these issues because of its small size and distinctive characteristics, such as enhanced bioavailability, lower toxicity, biodegradability, and targeted drug delivery. This review is an effort to highlight the recent progress in various nanodrug delivery systems (nDDSs) over the past five years for treating leishmaniasis. Although the preclinical outcomes of nDDSs have shown promising treatment for leishmaniasis, further research is needed for their clinical translation. Advancement in three primary priority domains─molecular diagnostics, clinical investigation, and knowledge dissemination and standardization─is imperative to propel the leishmaniasis field toward translational outcomes.

Py-CoMFA, docking, and molecular dynamics simulations of Leishmania (L.) amazonensis arginase inhibitors

Leishmaniasis is a disease caused by a protozoan of the genus Leishmania, affecting millions of people, mainly in tropical countries, due to poor social conditions and low economic development. First-line chemotherapeutic agents involve highly toxic pentavalent antimonials, while treatment failure is mainly due to the emergence of drug-resistant strains. Leishmania arginase (ARG) enzyme is vital in pathogenicity and contributes to a higher infection rate, thus representing a potential drug target. This study helps in designing ARG inhibitors for the treatment of leishmaniasis. Py-CoMFA (3D-QSAR) models were constructed using 34 inhibitors from different chemical classes against ARG from L. (L.) amazonensis (LaARG). The 3D-QSAR predictions showed an excellent correlation between experimental and calculated pIC50 values. The molecular docking study identified the favorable hydrophobicity contribution of phenyl and cyclohexyl groups as substituents in the enzyme allosteric site. Molecular dynamics simulations of selected protein–ligand complexes were conducted to understand derivatives’ interaction modes and affinity in both active and allosteric sites. Two cinnamide compounds, 7g and 7k, were identified, with similar structures to the reference 4h allosteric site inhibitor. These compounds can guide the development of more effective arginase inhibitors as potential antileishmanial drugs.

Nanostructured Lipid Carriers for oral treatment of leishmaniasis: Design and preclinical evaluation

Pentavalent antimonials are the primary treatment for leishmaniasis due to their proven efficacy and cost-effectiveness. However, they present poor oral absorption, parenteral administration, and serious adverse effects due to prolonged use. Nanostructured Lipid Carriers (NLC) offer a promising solution, providing prolonged release, enhanced intestinal permeability, and oral bioavailability. This study aimed to address these issues by developing Nanostructured Lipid Carrier loaded with meglumine antimoniate (NLC-MA) for oral leishmaniasis treatment. We used design of experiments (DoE) for optimization. The chosen NLC-MA was characterized assessing size, polydispersity index (PdI), zeta potential (ZP), entrapment efficiency (EE), pH, and by analytical techniques such as DSC, FTIR, XRD, and TEM. Stability under simulated gastrointestinal conditions, in vitro release kinetics, cytotoxicity in RAW 264.7 macrophages, and leishmanicidal activity were assessed. NLC-MA presented 41.13 nm, PdI 0.227, ZP −27.9 mV, EE of 62.43%, and pH 5.23. Characterization techniques confirmed drug incorporation and nanoparticles with reduced crystallinity. TEM images showed spherical morphology. NLC remained stable in gastrointestinal pH and under refrigeration storage, while lyophilized formulations retained their initial properties. MA release from NLC followed the Peppas-Sahlin model, an anomalous transport mechanism. Importantly, MA showed no cytotoxicity in macrophages, but the NLCs exhibited cytotoxicity beyond 50 µg/mL. NLC-MA displayed improved efficacy against Leishmania infantum. Overall, these results highlight the potential of utilizing a lipid nanocarrier incorporating meglumine antimoniate as an innovative drug delivery platform for oral treatment against leishmaniasis.

Comparison of Intralesional Sodium Stibogluconate versus Intralesional Meglumine Antimoniate for the Treatment of Leishmania major Cutaneous Leishmaniasis.

Israel is endemic for Old-World cutaneous leishmaniasis. The most common species is Leishmania major. However, the available treatment options are limited. This study's objective was to compare the authors' experience with different antimony intralesional treatments of Leishmania major cutaneous leishmaniasis. A retrospective evaluation was undertaken for cases of Leishmania major cutaneous leishmaniasis treated by pentavalent antimony in a university-affiliated medical centre in Israel. The previous treatment of intralesional sodium stibogluconate (Pentostam®) was compared with the current treatment of meglumine antimoniate (Glucantime®). One hundred cases of cutaneous leishmaniasis were treated during the study period, of whom 33 were treated with intralesional sodium stibogluconate and 67 were treated with intralesional meglumine antimoniate. The patients were 78 males and 22 females, mean age 24 (range 10-67) and there was a total of 354 skin lesions. Within 3 months from treatment, 91% (30/33) of the intralesional sodium stibogluconate group and 88% (59/67) of the intralesional meglumine antimoniate group had complete healing of the cutaneous lesions after an average of 3 treatment cycles (non-statistically significant). In conclusion, the 2 different medications have the same efficacy and safety for treating cutaneous leishmaniasis. Pentavalent antimoniate intralesional infiltration treatment is safe, effective, and well tolerated with minimal side effects for Old-World cutaneous leishmaniasis.

Post-kala-azar dermal leishmaniasis (PKDL) drug efficacy study landscape: A systematic scoping review of clinical trials and observational studies to assess the feasibility of establishing an individual participant-level data (IPD) platform.

Post-kala-azar dermal leishmaniasis (PKDL) is a dermatosis which can occur after successful treatment of visceral leishmaniasis (VL) and is a public health problem in VL endemic areas. We conducted a systematic scoping review to assess the characteristics of published PKDL clinical studies, understand the scope of research and explore the feasibility and value of developing a PKDL individual patient data (IPD) platform. A systematic review of published literature was conducted to identify PKDL clinical studies by searching the following databases: PubMed, Scopus, Ovid Embase, Web of Science Core Collection, WHO Global Index Medicus, PASCAL, Clinicaltrials.gov, Ovid Global Health, Cochrane Database and CENTRAL, and the WHO International Clinical Trials Registry Platform. Only prospective studies in humans with PKDL diagnosis, treatment, and follow-up measurements between January 1973 and March 2023 were included. Extracted data includes variables on patient characteristics, treatment regimens, diagnostic methods, geographical locations, efficacy endpoints, adverse events and statistical methodology. A total of 3,418 records were screened, of which 56 unique studies (n = 2,486 patients) were included in this review. Out of the 56 studies, 36 (64.3%) were from India (1983-2022), 12 (21.4%) from Sudan (1992-2021), 6 (10.7%) were from Bangladesh (1991-2019), and 2 (3.6%) from Nepal (2001-2007). Five (8.9%) studies were published between 1981-1990 (n = 193 patients), 10 (17.9%) between 1991-2000 (n = 230 patients), 10 (17.9%) between 2001-2010 (n = 198 patients), and 31 (55.4%) from 2011 onwards (n = 1,865 patients). Eight (14.3%) were randomised clinical trials, and 48 (85.7%) were non-randomised studies. The median post-treatment follow-up duration was 365 days (range: 90-540 days) in 8 RCTs and 360 days (range: 28-2,373 days) in 48 non-randomised studies. Disease diagnosis was based on clinical criterion in 3 (5.4%) studies, a mixture of clinical and parasitological methods in 47 (83.9%) and was unclear in 6 (10.7%) studies. Major drugs used for treatment were miltefosine (n = 636 patients), liposomal amphotericin B (L-AmB) (n = 508 patients), and antinomy regimens (n = 454 patients). Ten other drug regimens were tested in 270 patients with less than 60 patients per regimen. Our review identified studies with very limited sample size for the three major drugs (miltefosine, L-AmB, and pentavalent antimony), while the number of patients combined across studies suggest that the IPD platform would be valuable. With the support of relevant stakeholders, the global PKDL community and sufficient financing, a PKDL IPD platform can be realised. This will allow for exploration of different aspects of treatment safety and efficacy, which can potentially guide future healthcare decisions and clinical practices.

Pentavalent Antimony Associated with G-CSF in the Treatment of Cutaneous Leishmaniasis Caused by Leishmania (Viannia) braziliensis.

This study compares the effectiveness of G-CSF associated with MA in the treatment of CL. A total of 32 patients aged between 18 and 50 years with CL confirmed for L. braziliensis were included in this study. G-CSF or placebo (0.9% saline) was applied by intralesional infiltration at four equidistant points on the edges of the largest ulcer on days 0 and 15 of treatment associated with intravenous MA. Males predominated in the G-CSF group (59%), while females predominated in the control group (53%). Injuries to the lower limbs predominated in both study groups. The cure rate in the G-CSF group was 65% and in the control group it was 47%, 90 days after initiation of therapy. Our data indicate that the association of G-CSF with MA is not superior to MA monotherapy. Although not significant, the potential benefit of this combination deserves further investigation. The use of higher doses or other routes of application of G-CSF in a greater number of patients should contribute to a definitive response.

Insights into the trypanothione system in antimony-resistant and sensitive Leishmania tropica clinical isolates

Pentavalent antimonials are the mainstay treatment against different clinical forms of leishmaniasis. The emergence of resistant isolates in endemic areas has led to treatment failure. Unraveling the underlying resistance mechanism would assist in improving the treatment strategies against resistant isolates. This study aimed to investigate the RNA expression level of glutathione synthetase (GS), Spermidine synthetase (SpS), trypanothione synthetase (TryS) genes involved in trypanothione synthesis, and thiol-dependent reductase (TDR) implicated in drug reduction, in antimony-sensitive and -resistant Leishmania tropica isolates. We investigated 11 antimony-resistant and 11 antimony-sensitive L. tropica clinical isolates from ACL patients. Drug sensitivity of amastigotes was determined in mouse macrophage cell line J774A.1. The RNA expression level in the promastigote forms was analyzed by quantitative real-time PCR. The results revealed a significant increase in the average expression of GS, SpS, and TrpS genes by 2.19, 1.56, and 2.33-fold in resistant isolates compared to sensitive ones. The average expression of TDR was 1.24-fold higher in resistant isolates, which was insignificant. The highest correlation coefficient between inhibitory concentration (IC50) values and gene expression belonged to the TryS, GS, SpS, and TDR genes. Moreover, the intracellular thiol content was increased 2.17-fold in resistant isolates compared to sensitive ones and positively correlated with IC50 values. Our findings suggest that overexpression of trypanothione biosynthesis genes and increased thiol content might play a key role in the antimony resistance of L. tropica clinical isolates. In addition, the diversity of gene expression in the trypanothione system and thiol content among L. tropica clinical isolates highlighted the phenotypic heterogeneity of antimony resistance among the parasite population.

Comment on “High‐Efficient Blue Emission and Bandgap Engineering from Jahn‒Teller Distorted Halide Double Perovskites”

AbstractIn a recent publication, Liu et al. investigated the doping strategy of pentavalent antimony (Sb5+) in the benchmark material Cs2NaInCl6, achieving a bright blue emission with a high photoluminescence quantum yield of ≈90% at low doping concentrations and bandgaps as low as 1.24 eV at high doping concentrations (Adv. Opt. Mater. 2024, 12, 2301576). In this comment, by reanalyzing Liu et al.' data and conducting hybrid density functional theory calculations, the study provides evidence supporting the incorporation of Sb3+ ions rather than “Sb5+ ions”, as the cause of the efficient blue emission observed in the lightly‐doped Cs2NaInCl6 samples. Furthermore, it is proposed that the narrowing of the bandgap in the “heavily‐doped Cs2NaInCl6” samples is a result of the formation of a new phase related to a mixed‐valence salt, Cs4SbIIISbVCl12.

Genomic Insight of Leishmania Parasite: In-Depth Review of Drug Resistance Mechanisms and Genetic Mutations.

Leishmaniasis, which is caused by a parasitic protozoan of the genus Leishmania, is still a major threat to global health, impacting millions of individuals worldwide in endemic areas. Chemotherapy has been the principal method for managing leishmaniasis; nevertheless, the evolution of drug resistance offers a significant obstacle to therapeutic success. Drug-resistant behavior in these parasites is a complex phenomenon including both innate and acquired mechanisms. Resistance is frequently related to changes in drug transportation, drug target alterations, and enhanced efflux of the drug from the pathogen. This review has revealed specific genetic mutations in Leishmania parasites that are associated with resistance to commonly used antileishmanial drugs such as pentavalent antimonials, miltefosine, amphotericin B, and paromomycin, resulting in changes in gene expression along with the functioning of various proteins involved in drug uptake, metabolism, and efflux. Understanding the genetic changes linked to drug resistance in Leishmania parasites is essential for creating approaches for tackling and avoiding the spread of drug-resistant variants. Based on which specific treatments focus on mutations and pathways could potentially improve treatment efficacy and help long-term leishmaniasis control. More study is needed to uncover the complete range of genetic changes generating medication resistance and to develop new therapies based on available information.