Extracts and Terpenoids from Stevia Species as Potential Anthelmintics for Neglected Tropical Diseases Caused by Cestode Parasites.

Cestodes are etiological agents of neglected diseases such as echinococcosis and cysticercosis, which are major public health problems. Antiparasitic treatment relies on a small number of approved drugs, which are often only partially effective, poorly tolerated and require prolonged administration. Thus, the discovery of novel potential treatments is critical. The Stevia genus (Asteraceae) includes species that are recognized as a source of bioactive compounds, with many species associated with medicinal uses. In this study, the cestocidal activity of four South American Stevia species that previously showed antiprotozoal activity was analyzed using a motility assay on the laboratory cestode model, Mesocestoides vogae. The four Stevia extracts showed cestocidal activity, with S. alpina var. alpina as the most active. The sesquiterpene lactones estafietin and eupatoriopicrin were purified from S. alpina var. alpina and S. maimarensis, respectively, and tested on M. vogae. Estafietin showed cestocidal activity, inhibiting parasite viability in a dose-dependent manner, even from the first day of incubation. Consistent with the motility effects, the extract of S. alpina var. alpina and estafietin induced marked alterations in the morphology of the parasite. The results of this report show that Stevia species represent a source of new molecules with potential for the treatment of neglected tropical diseases caused by cestodes.

Neglected Tropical Diseases: A Chemoinformatics Approach for the Use of Biodiversity in Anti-Trypanosomatid Drug Discovery.

The development of new treatments for neglected tropical diseases (NTDs) remains a major challenge in the 21st century. In most cases, the available drugs are obsolete and have limitations in terms of efficacy and safety. The situation becomes even more complex when considering the low number of new chemical entities (NCEs) currently in use in advanced clinical trials for most of these diseases. Natural products (NPs) are valuable sources of hits and lead compounds with privileged scaffolds for the discovery of new bioactive molecules. Considering the relevance of biodiversity for drug discovery, a chemoinformatics analysis was conducted on a compound dataset of NPs with anti-trypanosomatid activity reported in 497 research articles from 2019 to 2024. Structures corresponding to different metabolic classes were identified, including terpenoids, benzoic acids, benzenoids, steroids, alkaloids, phenylpropanoids, peptides, flavonoids, polyketides, lignans, cytochalasins, and naphthoquinones. This unique collection of NPs occupies regions of the chemical space with drug-like properties that are relevant to anti-trypanosomatid drug discovery. The gathered information greatly enhanced our understanding of biologically relevant chemical classes, structural features, and physicochemical properties. These results can be useful in guiding future medicinal chemistry efforts for the development of NP-inspired NCEs to treat NTDs caused by trypanosomatid parasites.

Emerging therapeutics: The imidazo[1,2-b]pyridazine scaffold as a novel drug candidate for eumycetoma, a neglected tropical disease.

Mycetoma is a neglected invasive infection endemic in tropical and subtropical regions, presenting as a chronic subcutaneous inflammatory mass that can spread to deeper structures, leading to deformities, disabilities, and potentially mortality. The current treatment of eumycetoma, the fungal form of mycetoma, involves antifungal agents, such as itraconazole, combined with surgical intervention. However, this approach has limited success, with low cure rates and a high risk of recurrence. This study addresses to the urgent need for more effective therapeutics by designing and synthesising 47 diversely pharmacomodulated imidazo [1,2-b]pyridazine derivatives using a simple synthetic pathway with good yields and purity. Of these, 17 showed promising in vitro activity against Madurella mycetomatis, the prime causative agent of eumycetoma, with IC50 ≤ 5 µM and demonstrated significantly lower cytotoxicity compared to standard treatments in NIH-3T3 fibroblasts. Notably, compound 14d exhibited an excellent activity with an IC50 of 0.9 µM, in the same order then itraconazole (IC50 = 1.1 µM), and achieved a favourable selectivity index of 16 compared to 0.8 for itraconazole. These promising results warrant further research to evaluate the clinical potential of these novel compounds as safer, more effective treatments for eumycetoma, thus addressing a profound gap in current therapeutic strategies.

Aminopyridines in the development of drug candidates against protozoan neglected tropical diseases.

Neglected tropical diseases (NTDs) pose a major threat in tropical zones for impoverished populations. Difficulty of access, adverse effects or low efficacy limit the use of current therapeutic options. Therefore, development of new drugs against NTDs is a necessity. Compounds containing an aminopyridine (AP) moiety are of great interest for the design of new anti-NTD drugs due to their intrinsic properties compared with their closest chemical structures. Currently, over 40 compounds with an AP moiety are on the market, but none is used against NTDs despite active research on APs. The aim of this review is to present the medicinal chemistry work carried out with these scaffolds, against protozoan NTDs: Trypanosoma cruzi, Trypanosoma brucei or Leishmania spp.

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Assessing the integration of skin screening into a mass drug administration campaign against neglected tropical diseases: A cross-sectional observational study from two districts in Côte d'Ivoire, 2023.

BACKGROUND: The World Health Organization advocates integrating neglected tropical diseases (NTDs) into common delivery platforms to combat them in resource-constrained settings. However, limited literature exists on the benefits of integration. This study examines the feasibility and impact of adding skin screening to a mass drug administration (MDA) campaign in Côte d'Ivoire. METHODS: In June 2023, the Ministry of Health and Public Hygiene of Côte d'Ivoire piloted screening for skin-related NTDs alongside a national MDA campaign targeting soil-transmitted helminthiases and schistosomiasis. Two districts, Fresco and Koro, were selected for the pilot. The study applied both quantitative and qualitative assessments. The quantitative aspect focused on campaign costs and outputs, using an ingredient approach for costing. The qualitative evaluation employed an empirical phenomenological approach to analyze the campaign's operational feasibility and appreciation by stakeholders. FINDINGS: MDA activities cost $0·66 per treated child and skin screening $0·62 per screened person, including medical products. The MDA campaign exceeded coverage targets in both districts, whereas skin screening coverage varied by locality and age group. Both the service delivery team and the beneficiaries expressed appreciation for the integrated campaign. However, opportunities for improvement were identified. CONCLUSION: Integrating MDA and skin NTD screening proved operationally feasible in this context but had not recorded cost-saving effects. The performance of the MDA campaign was not negatively affected by additional skin screening activities, but effective integration requires thorough joint planning, strengthened training, and proper supervision.

Multitarget Compounds for Neglected Diseases: A Review.

Neglected diseases are a group of infectious diseases, many of them parasitic, that mainly affect the poorest populations with limited access to health services, especially those living in remote rural areas and slums. According to the World Health Organization (WHO), neglected diseases put the lives of more than 200 million people at risk, and treatment is made difficult by the occurrence of resistance to existing medications, as well as the high level of toxicity. In this way, the potential of multitarget compounds is highlighted, defined as compounds designed to modulate multiple targets of relevance to disease, with the overall goal of enhancing efficacy and/or improving safety. Thus, the objective of our study is to evaluate existing multitarget compound approaches for neglected diseases, with an emphasis on Leishmaniasis, Chagas Disease, and Arboviruses. A literature review was performed by searching the database "Web of Sciences". In relation to the diseases covered in this work, Leishmaniasis, individually, was the one that presented the largest number of articles (11) that dealt with the topic, which can be justified by the high prevalence of this disease in the world, the second most common disease was Dengue, followed by Chagas disease, Chikungunya virus, and Zika virus. Furthermore, the multitarget potential of phenolic compounds was observed in all diseases under study, with the mechanisms related to the nucleus and transcription being the most reported mechanisms. From this perspective, it is worth highlighting the effectiveness of approaches related to multitarget drugs in discovering new therapeutic agents for neglected diseases.

Drugs in preclinical and early clinical development for the treatment of Chagas´s disease: the current status.

INTRODUCTION: Chagas disease is spreading faster than expected in different countries, and little progress has been reported in the discovery of new drugs to combat Trypanosoma cruzi infection in humans. Recent clinical trials have ended with small hope. The pathophysiology of this neglected disease and the genetic diversity of parasites are exceptionally complex. The only two drugs available to treat patients are far from being safe, and their efficacy in the chronic phase is still unsatisfactory. AREAS COVERED: This review offers a comprehensive examination and critical review of data reported in the last 10 years, and it is focused on findings of clinical trials and data acquired in vivo in preclinical studies. EXPERT OPINION: The in vivo investigations classically in mice and dog models are also challenging and time-consuming to attest cure for infection. Poorly standardized protocols, availability of diagnosis methods and disease progression markers, the use of different T. cruzi strains with variable benznidazole sensitivities, and animals in different acute and chronic phases of infection contribute to it. More synchronized efforts between research groups in this field are required to put in evidence new promising substances, drug combinations, repurposing strategies, and new pharmaceutical formulations to impact the therapy.

Privileged small molecules against neglected tropical diseases: A perspective from structure activity relationships.

Neglected tropical diseases (NTDs) comprise diverse infections with more incidence in tropical/sub-tropical areas. In spite of preventive and therapeutic achievements, NTDs are yet serious threats to the public health. Epidemiological reports of world health organization (WHO) indicate that more than 1.5 billion people are afflicted with at least one NTD type. Among NTDs, leishmaniasis, chagas disease (CD) and human African trypanosomiasis (HAT) result in substantial morbidity and death, particularly within impoverished countries. The statistical facts call for robust efforts to manage the NTDs. Currently, most of the anti-NTD drugs are engaged with drug resistance, lack of efficient vaccines, limited spectrum of pharmacological effect and adverse reactions. To circumvent the issue, numerous scientific efforts have been directed to the synthesis and pharmacological development of chemical compounds as anti-infectious agents. A survey of the anti-NTD agents reveals that the majority of them possess privileged nitrogen, sulfur and oxygen-based heterocyclic structures. In this review, recent achievements in anti-infective small molecules against parasitic NTDs are described, particularly from the SAR (Structure activity relationship) perspective. We also explore current advocating strategies to extend the scope of anti-NTD agents.

Current drug strategies for the treatment and control of schistosomiasis.

INTRODUCTION: Schistosomiasis, one of the current Neglected Tropical Diseases (NTDs) affects over 230 million people globally, with nearly 700 million at risk in more than 74 countries. Praziquantel (PZQ) has served as the primary treatment for the past four decades; however, its effectiveness is limited as it solely eliminates adult worms. In regions where infections are frequent, PZQ exhibits only temporary efficacy and has restricted potential to disrupt the prolonged transmission of the disease. AREAS COVERED: A comprehensive exploration using the PubMed database was conducted to review current pharmacotherapy approaches for schistosomiasis. This review also encompasses recent research findings related to potential novel therapeutics and the repurposing of existing drugs. EXPERT OPINION: Current schistosoma treatment strategies, primarily relying on PZQ, face challenges like temporary effectiveness and limited impact on disease transmission. Drug repurposing, due to economic constraints, is decisive for NTDs. Despite PZQ's efficacy, its failure to prevent reinfection highlights the need for complementary strategies, especially in regions with persistent environmental foci. Integrating therapies against diverse schistosome stages boosts efficacy and impedes resistance. Uncovering novel agents is essential to address resistance concerns in tackling this neglected tropical disease. Integrated strategies present a comprehensive approach to navigate the complex challenges.

Pull me - push you? The disparate financing mechanisms of drug research in global health.

BACKGROUND: There is an inconsistency in the way pharmaceutical research is financed. While pull mechanisms are predominantly used to incentivize later-stage pharmaceutical research for products with demand in the Global North, so-called neglected diseases are chiefly financed by push funding. This discrepancy has so far been ignored in the academic debate, and any compelling explanation for why we draw the line between push and pull at poor people is lacking. MAIN BODY: Clinical development of new pharmaceuticals is chiefly financed by free market pull mechanisms. Even in cases where markets fail to deliver adequate incentives, demand enhancement mechanisms are used to replicate pull funding artificially, for example, with subscription models for antibiotics. Push funding in clinical research is almost always used when the poverty of patients means that markets fail to create sufficient demand. The general question of whether push or pull generally is the more efficient way to conduct pharmaceutical research arises. CONCLUSIONS: If the state is efficient in directing limited budgets for pharmaceutical research, push funding should be expanded to global diseases. If private industry is the more efficient actor, there would be enormous value in experimenting more aggressively with different approaches to enhance market demand artificially for neglected diseases.

Exploring the Potential of Natural Products as Antiparasitic Agents for Neglected Tropical Diseases.

Recent developments in the use of natural product-based molecules as antiparasitic agents for Malaria, leishmaniasis (LE), Chagas disease (CD), and Human African trypanosomiasis (HAT) are reviewed. The role of diverse plants in developing bioactive species is discussed in addition to analyzing the structural diversity of natural products as active agents and the diverse biological applications in CD, HAT, LE, and Malaria. This review focuses on medicinal chemistry, emphasizing the structural characteristics of natural molecules as bioactive agents against parasitic infections caused by Leishmania, Trypanosoma, and Plasmodium parasites.

Knowledge of tropical diseases and response capabilities of healthcare providers in Kaduna State, Nigeria.

BACKGROUND: The public health impact of neglected tropical diseases (NTDs) is quite substantial. The objective of this study was to assess the knowledge and response capability of health professionals regarding NTDs in Kaduna State, Nigeria. METHODS: A pre-tested questionnaire with a Cronbach's α coefficient of 0.716 was administered to 350 health professionals. The questionnaire assessed the knowledge, resource availability and capacity to handle NTD cases. RESULTS: Only 38 (12.6%) respondents were familiar with the World Health Organization's definition of NTDs. Although self-reported knowledge was highest for physicians (37 [82.2%]), there was no statistically significant knowledge disparity between cadres of health professionals. Only 12 (46.2%) practitioners in private health facilities reported adequate knowledge. The tier of practice was significantly associated with management of NTDs (χ2 = 10.545; df 2; p = 0.005). Only 24 (47.1%) medical laboratory scientists and 18 (40.0%) physicians had adequate clinical resources for management of NTDs. Nearly three-quarters (211 (70.1%)] of respondents had never been trained in the management of NTDs. More than half (177 [58.8%]) of facilities lacked pharmaceuticals or standard operating procedures for management of NTDs. CONCLUSIONS: Self-reported knowledge of NTDs was suboptimal. Physical and clinical resources for the diagnosis and treatment of NTDs were inadequate. Targeted training, increased funding and provision of adequate resources are needed in order to ameliorate the situation.

Synthesis of findings from the literature and a qualitative research study on the impacts of gender, disability, and ethnicity in Neglected Tropical Diseases programs.

INTRODUCTION: Act to End NTDs | West, a USAID-funded program that supports national governments to eliminate or control five neglected tropical diseases (NTDs) in West Africa including trachoma, lymphatic filariasis (LF), onchocerciasis, schistosomiasis and soil-transmitted helminthiasis, conducted a gender and social inclusion analysis to determine how NTDs differentially impact various populations and how gender and social norms impact NTD programs to inform future programming. METHODS: The study used a mixed methods approach including a literature review; primary qualitative data collection; and monitoring data in Côte d'Ivoire, Sierra Leone, and Ghana. RESULTS: Women and girls face additional health risks from many NTDs compared to men and boys. In addition to differential health burden, the social and economic impacts of NTD-related disability or infertility can be particularly dire for women and girls. Men were somewhat less likely to participate in mass drug administration (MDAs) due to: lack of information about campaigns, lack of access due to work, and higher levels of mistrust of the government and concerns about side effects of the medicines. Pregnant and breastfeeding women were sometimes excluded by community drug distributors (CDDs) from certain types of MDAs for which they are eligible. Training participation rates for CDDs and supervisors were nearly universally higher for men than women, even though feedback on the effectiveness of female CDDs was overwhelmingly positive, and female CDDs often have more access to other women in conservative households. The role of a CDD can lead to career and social opportunities for women. However, challenges faced by CDDs were seen as a greater barrier for women, including transportation, safety, household responsibilities, lower education levels, and low or lack of wages. DISCUSSION: Programs to address NTDs can promote equity and improve programming by increasing women's participation as CDDs and providing financial compensation. Additionally, programs should prioritize inclusive training for CDDs, and inclusive messaging about MDA for communities.

The pipeline for drugs for control and elimination of neglected tropical diseases: 2. Oral anti-infective drugs and drug combinations for off-label use.

In its 'Road map for neglected tropical diseases 2021-2030', the World Health Organization outlined its targets for control and elimination of neglected tropical diseases (NTDs) and research needed to achieve them. For many NTDs, this includes research for new treatment options for case management and/or preventive chemotherapy. Our review of small-molecule anti-infective drugs recently approved by a stringent regulatory authority (SRA) or in at least Phase 2 clinical development for regulatory approval showed that this pipeline cannot deliver all new treatments needed. WHO guidelines and country policies show that drugs may be recommended for control and elimination for NTDs for which they are not SRA approved (i.e. for 'off-label' use) if efficacy and safety data for the relevant NTD are considered sufficient by WHO and country authorities. Here, we are providing an overview of clinical research in the past 10 years evaluating the anti-infective efficacy of oral small-molecule drugs for NTD(s) for which they are neither SRA approved, nor included in current WHO strategies nor, considering the research sponsors, likely to be registered with a SRA for that NTD, if found to be effective and safe. No such research has been done for yaws, guinea worm, Trypanosoma brucei gambiense human African trypanosomiasis (HAT), rabies, trachoma, visceral leishmaniasis, mycetoma, T. b. rhodesiense HAT, echinococcosis, taeniasis/cysticercosis or scabies. Oral drugs evaluated include sparfloxacin and acedapsone for leprosy; rifampicin, rifapentin and moxifloxacin for onchocerciasis; imatinib and levamisole for loiasis; itraconazole, fluconazole, ketoconazole, posaconazole, ravuconazole and disulfiram for Chagas disease, doxycycline and rifampicin for lymphatic filariasis; arterolane, piperaquine, artesunate, artemether, lumefantrine and mefloquine for schistosomiasis; ivermectin, tribendimidine, pyrantel, oxantel and nitazoxanide for soil-transmitted helminths including strongyloidiasis; chloroquine, ivermectin, balapiravir, ribavirin, celgosivir, UV-4B, ivermectin and doxycycline for dengue; streptomycin, amoxicillin, clavulanate for Buruli ulcer; fluconazole and isavuconazonium for mycoses; clarithromycin and dapsone for cutaneous leishmaniasis; and tribendimidine, albendazole, mebendazole and nitazoxanide for foodborne trematodiasis. Additional paths to identification of new treatment options are needed. One promising path is exploitation of the worldwide experience with 'off-label' treatment of diseases with insufficient treatment options as pursued by the 'CURE ID' initiative.

Public-private partnerships influencing the initiation and duration of clinical trials for neglected tropical diseases.

Public-private partnerships (PPPs) for neglected tropical diseases (NTDs) are often studied as an organizational form that facilitates the management and control of the huge costs of drug research and development. Especially the later stages of drug development, including clinical trials, become very expensive. This present study investigates whether and how the type of PPPs influences the initiation and duration of NTD clinical trials. Using the ClinicalTrials.gov database, a dataset of 1175 NTD clinical studies that started between 2000 and 2021 is analyzed based on affiliation information and project duration. For the NTD clinical trials that resulted from PPPs, the collaborating types were determined and analyzed, including the public sector-, private sector-, governmental sector-, and nongovernmental organization-led collaborations. The determinants for the discontinuation of all stopped clinical trials were categorized into scientific-, funding-, political-, and logistic dimensions. The results reveal that public sector-led PPPs were the most common collaborative types, and logistic and scientific issues were the most frequent determinants of stopped clinical trials. Trial registration: ClinicalTrials.gov.