Search Results (57)

Background/Objectives: Drugs for human use require several studies for the assessment of their efficacy and safety. An important property is cytotoxicity, which should be tested in different environments and models in closer proximity to the final use of the drug, with greater reliability. Thus, we proposed to evaluate the toxicity of rifampicin, the only bactericidal drug in the anti-leprosy multidrug therapy, using skin cells and skin explant cultures. Methods: Cell viability was tested by the MTT method using primary keratinocytes and fibroblasts and immortalized skin cells (HaCaT and 3T3) at 24, 48, and 72 h of treatment. For the skin explant, we used the TTC assay to determine viability (24, 48, 72, and 96 h), hematoxylin and eosin staining to analyze the structure and architecture of the tissue, and TUNEL to assess apoptotic cells at 3, 6, 12, 24, 48, 72, and 96 h. Results: Regarding the toxicity of primary and immortalized cells, viability was above 70% up to a concentration of 50 μg/mL at 24, 48, and 72 h, and at the concentration of 200 μg/mL, all cells showed greater sensitivity, especially at 72 h. Tissue viability analysis revealed a high percentage (above 96%) of viable tissue at the concentrations of 100, 150, and 200 μg/mL at the time points studied. Histological analysis showed that tissue architecture was maintained, with no apoptotic cells being observed. Conclusions: Thus, our results showed the importance of evaluating drug toxicity using different cell types, with the ex vivo skin model proving to be an alternative to animal use. Full article

Background: Vasculonecrotic reactions in leprosy are typically associated with type 2 reactions. Differentiating between necrotizing erythema nodosum leprosum (nENL) and Lucio’s phenomenon (LP) can be difficult, as overlapping clinical and histopathological features have been reported. Mycobacterium lepromatosis, a recently identified species causing leprosy, has been sporadically linked to LP. While type 1 reactions are more commonly observed in HIV-coinfected individuals, reports of LP or ENL occurring outside the context of immune reconstitution inflammatory syndrome (IRIS) remain rare. Methods: We report a case of a vasculonecrotic leprosy reaction due to M. lepromatosis in an antiretroviral-naive patient with advanced HIV infection. Results: The patient presented with a two-month history of papules and nodules that progressed to painful necrotic ulcers, accompanied by systemic symptoms. Clinically, the presentation was consistent with nENL; however, histopathological analysis supported a diagnosis of LP. The patient rapidly deteriorated, developing septic shock and dying shortly thereafter. To our knowledge, this is the first reported case of a leprosy-associated vasculonecrotic reaction caused by M. lepromatosis in an HIV-infected individual not associated with IRIS. Conclusions: Vasculonecrotic reactions in leprosy are life-threatening emergencies due to their potential for rapid clinical deterioration and sepsis. In individuals with advanced HIV infection, recognition of these reactions may be challenging, as they can mimic other opportunistic infections, including fungal diseases, malignant syphilis, and disseminated mycobacterial infections. Early identification and prompt treatment are critical to improving outcomes. Full article

Drug repurposing is a cost-effective and innovative strategy for identifying new therapeutic applications for existing drugs, thereby shortening development timelines and accelerating the availability of treatments. Applying this approach to the development of cosmeceutical ingredients enables the creation of functional compounds with proven safety and efficacy, adding significant value to the cosmetic industry. This study evaluated the potential of rifampicin, a drug widely used for the treatment of tuberculosis and leprosy, as a cosmeceutical agent. The anti-melanogenic effects of rifampicin were assessed in B16F10 melanoma cells, showing no cytotoxicity at concentrations up to 40 µM and a significant reduction in intracellular tyrosinase activity and melanin content. Mechanistically, rifampicin reduced the expression of melanogenic enzymes, including tyrosinase, tyrosinase-related protein (TRP)-1, and TRP-2, via a protein kinase A (PKA)-dependent pathway, leading to the suppression of microphthalmia-associated transcription factor (MITF), which is a key regulator of melanogenesis. Additionally, rifampicin inhibited the p38 signaling pathway but was independent of the PI3K/protein kinase B (Akt) pathway. Furthermore, it decreased Ser9 phosphorylation, enhancing glycogen synthase kinase-3β (GSK-3β) activity, promoted β-catenin phosphorylation, and facilitated β-catenin degradation, collectively contributing to the inhibition of melanin synthesis. To evaluate the topical applicability of rifampicin, primary human skin irritation tests were conducted, and no adverse effects were observed at concentrations of 20 µM and 40 µM. These findings demonstrate that rifampicin inhibits melanogenesis through multiple signaling pathways, including PKA, MAPKs, and GSK-3β/β-catenin. This study highlights the potential of rifampicin to be repurposed as a topical agent for managing hyperpigmentation disorders, offering valuable insights into novel therapeutic strategies for pigmentation-related conditions. Full article

Background/Objectives: Treating chronic wounds incurs substantial costs for Brazil’s Unified Health System. Natural compounds, particularly propolis, are increasingly explored as low-cost alternatives due to their healing properties. Brazilian green propolis, distinct in its chemical composition, has garnered scientific interest. This study aimed to assess the healing effects of green propolis ointment on lower-limb ulcers from leprosy. Methods: A blinded, randomized clinical trial included 18 wounds in two groups: propolis ointment (G1) and control (G2), with evaluations conducted weekly for 61 days. Wound progress was monitored using morphometry and the Pressure Ulcer Scale for Healing (PUSH). Results: No participants exhibited sensitivity to the propolis. G1 showed significant initial healing: average wound area reduction (%) for G1 vs. G2 included 56.38 vs. 6.13–p < 0.001 (week 1); 79.51 vs. 24.16–p = 0.022 (week 4); and 84.33 vs. 39.73–p = 0.051 (week 7). In G1, the PUSH scores decreased from the beginning, whereas in G2, reductions were observed after three weeks. By week 5, 71.4% of G1 wounds scored below eight points, versus 33.3% in G2. G1 wounds exhibited a reduced area and exudate, as well as revitalized granulation tissue without adverse effects. Conclusions: The findings suggest that green propolis ointment is safe, supports tissue repair and may offer cost-effective treatment benefits. Standard wound dressings are selected to support all healing stages, with an emphasis on antimicrobial action, hemostasis to reduce exudate, and pain-reducing and non-irritant properties. Green propolis ointment meets these criteria, offering a cost-effective treatment that accelerates lesion reduction and encouraging leprosy patients to follow the therapeutic regimen. Full article

Community engagement has emerged as a critical component in the effective control and elimination of neglected tropical diseases (NTDs), particularly in regions with persistent stigma and limited healthcare access. Drawing on case studies from Brazil, India, and Nigeria, this opinion piece explores how community-driven initiatives have successfully improved leprosy awareness, reduced stigma, and fostered early case detection and treatment adherence. The importance of culturally sensitive, inclusive approaches in health education and stigma reduction campaigns is highlighted, emphasizing the potential for community engagement to enhance national leprosy programs and contribute to the World Health Organization’s Zero Leprosy Strategy. By examining these examples, this article illustrates how integrating community participation into leprosy control and elimination programs can drive sustainable outcomes for achieving Zero Leprosy, even in resource-limited settings. Full article

Background/Objectives: Clofazimine (CFZ) is a Biopharmaceutics Classification System (BCS) II drug introduced in the US market in 1986 for the treatment of leprosy. However, CFZ was later withdrawn from the market due to its extremely low aqueous solubility and low absorption. In the literature, the intrinsic solubility of CFZ has been estimated to be <0.01 μg/mL, and solubilities of its different salt forms in simulated gastric and intestinal fluids are <10 µg/mL. These are extremely low solubilities for the dissolution of a drug administered orally at 100–200 mg doses. Methods: In the present investigation, seven weak organic acids (adipic, citric, glutaric, maleic, malic, succinic, and tartaric) were tested by determining the aqueous solubility of CFZ as the function of acid concentration to investigate whether any of the acids would lead to the supersolubilization of CFZ. Results: There were only minimal increases in solubilities when concentrations of acids in water were increased up to 2.4 M. The solubilities, however, increased to 0.32, 1.23, and 10.68 mg/mL, respectively, in 5 M solutions of tartaric, malic, and glutaric acids after equilibration for 24 h at 25 °C. Crystalline solids were formed after the equilibration of CFZ with all acids. Apparently, salts or cocrystals were formed with all acids, except for glutaric acid, as their melting endotherms in DSC scans were in the range of 207.6 to 248.5 °C, which were close to that of CFZ itself (224.8 °C). In contrast, the adduct formed with glutaric acid melted at the low temperature of 77 °C, and no other peak was observed at a higher temperature, indicating that the material converted to an amorphous state. Conclusions: The increase in CFZ solubility to >10 mg/mL in the presence of 5 M glutaric acid could be called supersolubilization when compared to the intrinsic solubility of the basic drug. Such an increase in CFZ solubility and the conversion of the glutarate adduct to an amorphous state are being exploited to develop rapidly dissolving dosage forms. Full article

Background and Objectives: Leprosy primarily affects peripheral nerves, leading to significant neurological complications such as polyneuritis, mononeurosis, and autonomic dysfunction, which contribute to severe disabilities and impaired quality of life for patients. This scoping review aims to investigate the neurological manifestations and main treatments of leprosy patients. Materials and Methods: Studies were identified from an online search of PubMed, Web of Science, Cochrane Library, Embase, and Scopus databases. This review has been registered on OSF (n) PQBYH. Results: Neurological complications of leprosy, such as neuropathy and paralysis, necessitate accurate diagnosis and treatment, as immunological reactions can exacerbate nerve damage. Various studies highlight the effectiveness of personalized therapies, such as corticosteroids, multi-drug therapy (MDT), and surgical interventions, in improving symptoms and neurological function in leprosy patients. Conclusions: Managing neurological complications of leprosy necessitates careful diagnosis and treatment, as many patients experience unresolved peripheral neuropathy despite multidrug therapy. Future research should focus on improving diagnostic tools, exploring the link between neuropathic pain and psychological issues, and developing effective vaccines and treatments to enhance patient outcomes. Full article

This study aims to estimate the prevalence and analyze the factors associated with leprosy-related disabilities at the Kindia Disability Prevention and Physical Rehabilitation Centre (PIRP) in Guinea. It is a cross-sectional study using routine data from the centre from 2017 to 2021. Of 115 patients, 76% had a disability, 49% of which were grade II and 27% grade I. The age range of 15 to 30 years was the most represented (43.5%), with the average age (standard deviation) being 38 (16.5) years. Children under 14 years of age represented 3.5% of the total. Most (89%) patients had newly diagnosed leprosy. The majority (66.1%) had never come in contact with people with leprosy symptoms. Almost all (99.1%) patients had type 1 reactions on admission. Patients with multibacillary leprosy were in the majority (83.5%), and those with symptoms lasting 7–12 months represented 56.5% of the sample. In total, 79.1% of the patients received corticosteroid therapy, and 92.1% were reported cured at discharge. This neglected tropical disease continues to be a challenge in Guinea, even though leprosy care is free. Full article

Currently, over 200,000 new cases of leprosy are reported annually worldwide. Although leprosy was thought to have been eradicated in Taiwan, a few new cases still occur annually. Protean clinical manifestations of leprosy and immunological reactions result in delayed diagnoses. In addition, drug-resistant leprosy is emerging and poses treatment challenges. In this retrospective study, we collected and analyzed the clinicopathological features, leprosy type, treatment response, and relapse rate of patients with leprosy in our hospital between January 2009 and November 2022. We found that 54% of patients were Indonesian, and borderline lepromatous leprosy was predominant (39%); moreover, histoid leprosy and the Lucio phenomenon were also reported. Polymerase chain reaction analysis identified four positive cases, including a dapsone-resistant (4%) case. Our findings indicated good control of leprosy and a lower rate of dapsone resistance than that reported by the World Health Organization (4% vs. 13%) from 2009 to 2015. We found that the patient profile in terms of the treatment duration, recurrence rate, systemic symptoms, and neurological symptoms did not differ between before and during the pandemic. We report the recent advances in leprosy diagnosis, drug-resistant gene mutations, post-exposure prophylaxis, vaccination, and the effect of coronavirus disease 2019 on leprosy to facilitate updated leprosy diagnosis and management. Full article

Mycobacterium leprae is the etiological agent of leprosy. Macrophages (Mφs) are key players involved in the pathogenesis of leprosy. In this study, immunohistochemical analysis was performed to examine the phenotype of Mφ subpopulations, namely M1, M2, and M4, in the skin lesions of patients diagnosed with leprosy. Based on the database of treatment-naïve patients treated between 2015 and 2019 at the Department of Dermatology of the University of the State of Pará, Belém, routine clinical screening samples were identified. The monolabeling protocol was used for M1 macrophages (iNOS, IL-6, TNF-α) and M2 macrophages (IL-10, IL-13, CD163, Arginase 1, TGF-β, FGFb), and the double-labeling protocol was used for M4 macrophages (IL-6, MMP7, MRP8, TNF-α e CD68). To confirm the M4 macrophage lineage, double labeling of the monoclonal antibodies CD68 and MRP8 was also performed. Our results demonstrated a statistically significant difference for the M1 phenotype among the Virchowian (VV) (4.5 ± 1.3, p < 0.0001), Borderline (1.6 ± 0.4, p < 0.0001), and tuberculoid (TT) (12.5 ± 1.8, p < 0.0001) clinical forms of leprosy. Additionally, the M2 phenotype showed a statistically significant difference among the VV (12.5 ± 2.3, p < 0.0001), Borderline (1.3 ± 0.2, p < 0.0001), and TT (3.2 ± 0.7, p < 0.0001) forms. For the M4 phenotype, a statistically significant difference was observed in the VV (9.8 ± 1.7, p < 0.0001), Borderline (1.2 ± 0.2, p < 0.0001), and TT (2.6 ± 0.7, p < 0.0001) forms. A significant correlation was observed between the VV M1 and M4 (r = 0.8712; p = 0.0000) and between the VV M2 × TT M1 (r = 0.834; p = 0.0002) phenotypes. The M1 Mφs constituted the predominant Mφ subpopulation in the TT and Borderline forms of leprosy, whereas the M2 Mφs showed increased immunoexpression and M4 was the predominant Mφ phenotype in VV leprosy. These results confirm the relationship of the Mφ profile with chronic pathological processes of the inflammatory response in leprosy. Full article

The antimycobacterial drug clofazimine (CFZ) is used as a single agent at high doses, to suppress the exaggerated inflammation associated with leprosy. Paradoxically, increasing doses of CFZ leads to bioaccumulation of CFZ in the spleen and other organs under physiologically relevant dosing regimens, without accompanying dose-dependent elevation in the concentrations of the circulating drug in the blood. In long-term oral dosing regimens, CFZ induces immunological and metabolic changes resulting in splenomegaly, while the mass of other organs decreases or remains unchanged. As an organ that extensively sequesters CFZ as insoluble drug precipitates, the spleen likely influences drug-induced inflammatory signaling. To probe the role of systemic drug concentrations vs. drug bioaccumulation in the spleen, healthy mice were treated with six different dosing regimens. A subgroup of these mice underwent surgical splenectomies prior to drug treatment to assess the bioaccumulation-dependent changes in immune system signaling and immune-system-mediated drug distribution. Under increasing drug loading, the spleen was observed to grow up to six times in size, sequestering over 10% of the total drug load. Interestingly, when the spleen was removed prior to CFZ administration, drug distribution in the rest of the organism was unaffected. However, there were profound cytokine elevations in the serum of asplenic CFZ-treated mice, indicating that the spleen is primarily involved in suppressing the inflammatory signaling mechanisms that are upregulated during CFZ bioaccumulation. Thus, beyond its role in drug sequestration, the spleen actively modulates the systemic effect of CFZ on the immune system, without impacting its blood concentrations or distribution to the rest of the organism. Full article

Leprosy (Hansen’s disease) is an infectious, neglected tropical skin disease caused by the bacterium Mycobacterium leprae (M. leprae). It is crucial to note that the dynamic behavior of any living microorganism such as M. leprae not only depends on the conditions of its current state (e.g., substrate concentration, medium condition, etc.) but also on those of its previous states. In this article, we have developed a three-dimensional mathematical model involving concentrations of healthy Schwann cells, infected Schwann cells, and M. leprae bacteria in order to predict the dynamic changes in the cells during the disease dissemination process; additionally, we investigated the effect of memory on system cell populations, especially on the M. leprae bacterial population, by analyzing the Caputo–Fabrizio fractionalized version of the model. Most importantly, we developed and investigated a fractionalized optimal-control-induced system comprising the combined drug dose therapy of Ofloxacin and Dapsone intended to achieve a more realistic treatment regime for leprosy. The main goal of our research article is to compare this fractional-order system with the corresponding integer-order model and also to distinguish the rich dynamics exhibited by the optimal-control-induced system based on different values of the fractional order $\zeta \in (0,1)$. All of the analytical results are validated through proper numerical simulations and are compared with some real clinical data. Full article

The two polar clinical forms of leprosy, termed tuberculoid and lepromatous, have polarized cellular immune responses with complex immunological distinctions. The predominance of DCs in tuberculoid leprosy has been reported, while the lepromatous pattern of illness is associated with weak activation of local populations of DCs. TiO₂ nanoparticles have previously been shown to induce maturation of these cells, leading to an inflammatory response similar to adjuvant usage in vaccine administration. We aimed to evaluate the effect of potassium-incorporated Ti oxide nanostructures, namely KTiO_xs, in the response of human monocyte-derived DCs to live M. leprae. Human monocytic cell line dual THP-1, which harbors two inducible reporter plasmid systems for transcription factor activation of NF-κB and interferon regulating factor (IRF), was treated with titanium control or with 1 mol/L KOH-treated Ti or 10 mol/L KOH for 24 h. Subsequently, cells were infected with M. leprae. KTiO_x nanoparticles increase DC phagocytic activity without inflammation. KTiO_x exposure of DCs led to an increase in IRF activation with modulation of the inflammatory response to live M. leprae. It also led to differential secretion of the critical components of innate immune response and the development of cell-mediated immunity against intracellular pathogens. This study demonstrates the effect of nanostructures of KTiO_xs and the usefulness of nanoparticle technology in the in vitro activation of human DCs against an infectious disease with a puzzling immune spectrum. Our findings may prompt future therapeutic strategies, such as DC immunotherapy for disseminated and progressive lepromatous lesions. Full article

An intense effort has been focused on new therapeutic approaches and the development of technologies for more efficient and rapid wound healing. The research for plants used for long time in traditional medicine in the treatment of wound has become a promising strategy to obtain drugs therapeutically useful in the acute and chronic wound management. In this context, Centella asiatica (Apiaceae) has been used to treat a variety of skin diseases, such as leprosy, lupus, varicose ulcers, eczema and psoriasis, in Asiatic traditional medicine for thousands of years. Studies have shown that Centella asiatica extracts (CAE) display activity in tissue regeneration, cell migration and wound repair process by promoting fibroblast proliferation and collagen synthesis. Preliminary findings have shown that the asiatic acid is one of the main active constituents of C. asiatica, directly associated with its healing activity. Thus, this study discusses aspects of the effects of Centella asiatica and its active component, asiatic acid, in different stages of the healing process of cutaneous wounds, including phytochemical and antimicrobial aspects that contribute to its therapeutic potential. Full article

Leprosy can lead to blood depletion in Zn, Ca, Mg, and Fe and blood enrichment in Cu. In late medieval Europe, minerals were used to treat leprosy. Here, physiological responses to leprosy and possible evidence of treatment are investigated in enamel, dentine, and cementum of leprosy sufferers from medieval Denmark (n = 12) and early 20th century Romania (n = 2). Using SXRF and LA-ICP-TOFMS, 12 elements were mapped in 15 tooth thin sections, and the statistical covariation of paired elements was computed to assess their biological relevance. The results show marked covariations in the Zn, Ca, and Mg distributions, which are compatible with clinical studies but cannot be directly attributed to leprosy. Minerals used historically as a treatment for leprosy show no detectable intake (As, Hg) or a diffuse distribution (Pb) related to daily ingestion. Intense Pb enrichments indicate acute incorporations of Pb, potentially through the administration of Pb-enriched medication or the mobilization of Pb from bone stores to the bloodstream during intense physiological stress related to leprosy. However, comparisons with a healthy control group are needed to ascertain these interpretations. The positive correlations and the patterns observed between Pb and essential elements may indicate underlying pathophysiological conditions, demonstrating the potential of SXRF and LA-ICP-TOFMS for paleopathological investigations. Full article