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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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.

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.

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.

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.

Discovery of New Broad-Spectrum Anti-Infectives for Eukaryotic Pathogens Using Bioorganometallic Chemistry.

Drug resistance observed with many anti-infectives clearly highlights the need for new broad-spectrum agents to treat especially neglected tropical diseases (NTDs) caused by eukaryotic parasitic pathogens, including fungal infections. Herein, we show that the simple modification of one of the most well-known antifungal drugs, fluconazole, with organometallic moieties not only improves the activity of the parent drug but also broadens the scope of application of the new derivatives. These compounds were highly effective in vivo against pathogenic fungal infections and potent against parasitic worms such as Brugia, which causes lymphatic filariasis and Trichuris, one of the soil-transmitted helminths that infects millions of people globally. Notably, the identified molecular targets indicate a mechanism of action that differs greatly from that of the parental antifungal drug, including targets involved in biosynthetic pathways that are absent in humans, offering great potential to expand our armamentarium against drug-resistant fungal infections and neglected tropical diseases (NTDs) targeted for elimination by 2030.

How correlations between treatment access and surveillance inclusion impact neglected tropical disease monitoring and evaluation-A simulated study.

Neglected tropical diseases (NTDs) largely impact marginalised communities living in tropical and subtropical regions. Mass drug administration is the leading intervention method for five NTDs; however, it is known that there is lack of access to treatment for some populations and demographic groups. It is also likely that those individuals without access to treatment are excluded from surveillance. It is important to consider the impacts of this on the overall success, and monitoring and evaluation (M&E) of intervention programmes. We use a detailed individual-based model of the infection dynamics of lymphatic filariasis to investigate the impact of excluded, untreated, and therefore unobserved groups on the true versus observed infection dynamics and subsequent intervention success. We simulate surveillance in four groups-the whole population eligible to receive treatment, the whole eligible population with access to treatment, the TAS focus of six- and seven-year-olds, and finally in >20-year-olds. We show that the surveillance group under observation has a significant impact on perceived dynamics. Exclusion to treatment and surveillance negatively impacts the probability of reaching public health goals, though in populations that do reach these goals there are no signals to indicate excluded groups. Increasingly restricted surveillance groups over-estimate the efficacy of MDA. The presence of non-treated groups cannot be inferred when surveillance is only occurring in the group receiving treatment.

Perceptions of the roles, impact, challenges and needs of community drug distributors in the control and elimination of neglected tropical diseases in difficult-to-access communities in Ghana.

INTRODUCTION: The success of mass drug administration (MDA) campaigns to control and eliminate neglected tropical diseases (NTDs) in Ghana depends, to a large extent, on the essential role community drug distributors (CDDs) play. This study aimed to investigate community's perceptions of CDDs' roles, impact of CDDs' work, challenges faced by CDDs, and views on resources required to enhance CDDs' work to sustain MDA campaigns. METHODS: A cross-sectional qualitative study employing the use of focus group discussions (FGDs) with community members and CDDs in selected NTD endemic communities together with individual interviews with district health officers (DHOs) was conducted. We interviewed 104 people aged 18 and over, purposively selected, through eight individual interviews, and 16 focus group discussions. RESULTS: Participants in the community FGDs noted that health education and the distribution of drugs were the main roles of CDDs. Participants also perceived that the work of CDDs had prevented the onset of NTDs, treated symptoms of NTDs, and generally reduced the incidence of infections. In the interviews with CDDs and DHOs, lack of cooperation/non-compliance by community members, demands by community members, lack of working resources and low financial motivation were mentioned as the main challenges to the work of CDDs. Moreover, the provision of logistics and financial motivation for CDDs were identified as factors that will enhance their work. CONCLUSIONS: Incorporating more attractive schemes will incentivise CDDs to improve output. Addressing the challenges highlighted is an important step for the work of CDDS to be effective in controlling NTDs in difficult-to-access communities in Ghana.

Individual longitudinal compliance to neglected tropical disease mass drug administration programmes, a systematic review.

Repeated distribution of preventative chemotherapy (PC) by mass drug administration forms the mainstay of transmission control for five of the 20 recognised neglected tropical diseases (NTDs); soil-transmitted helminths, schistosomiasis, lymphatic filariasis, onchocerciasis and trachoma. The efficiency of such programmes is reliant upon participants swallowing the offered treatment consistently at each round. This is measured by compliance, defined as the proportion of eligible participants swallowing treatment. Individually linked longitudinal compliance data is important for assessing the potential impact of MDA-based control programmes, yet this accurate monitoring is rarely implemented in those for NTDs. Longitudinal compliance data reported by control programmes globally for the five (PC)-NTDs since 2016 is examined, focusing on key associations of compliance with age and gender. PubMed and Web of Science was searched in January 2022 for articles written in English and Spanish, and the subsequent extraction adhered to PRISMA guidelines. Study title screening was aided by Rayyan, a machine learning software package. Studies were considered for inclusion if primary compliance data was recorded for more than one time point, in a population larger than 100 participants. All data analysis was conducted in R. A total of 89 studies were identified containing compliance data, 57 were longitudinal studies, of which 25 reported individually linked data reported by varying methods. The association of increasing age with the degree of systematic treatment was commonly reported. The review is limited by the paucity of data published on this topic. The varying and overlapping terminologies used to describe coverage (receiving treatment) and compliance (swallowing treatment) is reviewed. Consequently, it is recommended that WHO considers clearly defining the terms for coverage, compliance, and longitudinal compliance which are currently contradictory across their NTD treatment guidelines. This review is registered with PROSPERO (number: CRD42022301991).