129 research outputs found
Assessing Environmental Risks during the Drug Development Process for Parasitic Vector-Borne Diseases: A Critical Reflection
No full textParasitic vector-borne diseases (VBDs) represent nearly 20% of the global burden of infectious diseases. Moreover, the spread of VBDs is enhanced by global travel, urbanization, and climate change. Treatment of VBDs faces challenges due to limitations of existing drugs, as the potential for side effects in nontarget species raises significant environmental concerns. Consequently, considering environmental risks early in drug development processes is critically important. Here, we examine the environmental risk assessment process for veterinary medicinal products in the European Union and identify major gaps in the ecotoxicity data of these drugs. By highlighting the scarcity of ecotoxicological data for commonly used antiparasitic drugs, we stress the urgent need for considering the One Health concept. We advocate for employing predictive tools and nonanimal methodologies such as New Approach Methodologies at early stages of antiparasitic drug research and development. Furthermore, adopting progressive approaches to mitigate ecological risks requires the integration of nonstandard tests that account for real-world complexities and use environmentally relevant exposure scenarios. Such a strategy is vital for a sustainable drug development process as it adheres to the principles of One Health, ultimately contributing to a healthier and more sustainable world
Association between <i>IL1</i> gene polymorphism and human African trypanosomiasis in populations of sleeping sickness foci of southern Cameroon
No full textBackgroundHuman African Trypanosomiasis (HAT) is a neglected tropical disease caused by infections due to Trypanosoma brucei subspecies. In addition to the well-established environmental and behavioural risks of becoming infected, there is evidence for a genetic component to the response to trypanosome infection. We undertook a candidate gene case-control study to investigate genetic associations further.MethodologyWe genotyped one polymorphism in each of seven genes (IL1A, IL1RN, IL4RN, IL6, HP, HPR, and HLA-G) in 73 cases and 250 controls collected from 19 ethno-linguistic subgroups stratified into three major ethno-linguistic groups, 2 pooled ethno-linguistic groups and 11 ethno-linguistic subgroups from three Cameroonian HAT foci. The seven polymorphic loci tested consisted of three SNPs, three variable numbers of tandem repeat (VNTR) and one INDEL.ResultsWe found that the genotype (TT) and minor allele (T) of IL1A gene as well as the genotype 1A3A of IL1RN were associated with an increased risk of getting Trypanosoma brucei gambiense and develop HAT when all data were analysed together and also when stratified by the three major ethno-linguistic groups, 2 pooled ethno-linguistic subgroups and 11 ethno-linguistic subgroups.ConclusionThis study revealed that one SNP rs1800794 of IL1A and one VNTR rs2234663 of IL1RN were associated with the increased risk to be infected by Trypanosoma brucei gambiense and develop sleeping sickness in southern Cameroon. The minor allele T and the genotype TT of SNP rs1800794 in IL1A as well as the genotype 1A3A of IL1RN rs2234663 VNTR seem to increase the risk of getting Trypanosoma brucei gambiense infections and develop sleeping sickness in southern Cameroon.</div
Sedimentary diatom assemblages in the northern part of Lake Tanganyika
No full textSurface sediment diatoms from the northern part of Lake Tanganyika were analysed with several ordination and classification techniques. Three sample groups characterized by four diatom assemblages were recognized. The first sample group occurs in a rather shallow area near the delta of the Rusizi River on a coarse-grained sand substrate. The second and most important sample group occurs on the silty bottom of an underwater depression situated off the delta of the Rusizi River in the north-eastern part of Lake Tanganyika; its diatom composition has a great affinity to the Rusizi River diatom population. The third sample group contains all the other samples and covers an area corresponding to the west-, east- and southward continuation of the area of the second group: its diatom composition is also related to the Rusizi River diatom population, but in a less pronounced manner
Water quality in the Bay of Bujumbura (Lake Tanganyika) and its influence on phytoplankton composition
No full textEnhancing tsetse fly refractoriness to trypanosome infection using a symbiont-based delivery approach
No full textMouse models for pathogenic African trypanosomes: unravelling the immunology of host-parasite-vector interactions
No full textAfrican trypanosomiasis is a parasitic disease that affects a variety of mammals, including humans, on the sub-Saharan African continent. To understand the diverse parameters that govern the host-parasite-vector interactions, mouse models for the disease have proven to be a cornerstone. Despite the fact that most trypanosomes cannot be considered natural pathogens for rodents, experimental infections in mice have shed a tremendous amount of light on the general biology of these parasites and their interaction with and evasion of the mammalian immune system. Different aspects including inflammation, vaccine failure, antigenic variation, resistance/sensitivity to normal human serum and the influence of tsetse compounds on parasite transmission have all been addressed using mouse models. In more recent years, the introduction of various 'knock-out' mouse strains has allowed to analyse the implication of various cytokines, particularly TNF, IFNgamma and IL-10, in the regulation of parasitaemia and induction of pathological conditions during infection
Synthesis and Anti-Trypanosoma cruzi Activity of 3-Cyanopyridine Derivatives
No full textChagas disease (CD) is a parasitic neglected tropical disease (NTD) caused by the protozoan Trypanosoma cruzi that affects 6 million people worldwide, often resulting in financial burden, morbidity, and mortality in endemic regions. Given a lack of highly efficient and safe treatments, new, affordable, and fit-for-purpose drugs for CD are urgently needed. In this work, we present a hit-to-lead campaign for novel cyanopyridine analogues as antichagasic agents. In a phenotypic screening against intracellular T. cruzi, hits 1 and 2 were identified and displayed promising potency combined with balanced physicochemical properties. As part of the Lead Optimization Latin America consortium, a set of 40 compounds was designed, synthesized, and tested against T. cruzi intracellular amastigotes and relevant human cell lines. The structural modifications were focused on three positions: cyanopyridine core, linker, and right-hand side. The ADME properties of selected compounds, lipophilicity, kinetic solubility, permeability, and liver microsomal stability, were evaluated. Compounds 1–9 displayed good potency (EC50 T. cruzi amastigote <1 μM), and most compounds did not present significant cytotoxicity (CC50 MRC-5 = 32–64 μM). Despite the good balance between potency and selectivity, the antiparasitic activity of the series appeared to be driven by lipophilicity, making the progression of the series unfeasible due to poor ADME properties and potential promiscuity issues.Fil: Slafer, Brian W.. Universidade Estadual de Campinas; BrasilFil: Dessoy, Marco A.. Universidade Estadual de Campinas; BrasilFil: de Oliveira, Ramon G.. Universidade Estadual de Campinas; BrasilFil: Mollo, María Cruz. Universidade Estadual de Campinas; Brasil. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Lee, Eun. Universidade Estadual de Campinas; BrasilFil: Matheeussen, An. Universidade Estadual de Campinas; BrasilFil: Maes, Louis. Universidade Estadual de Campinas; BrasilFil: Caljon, Guy. Universiteit Antwerp; BélgicaFil: Ferreira, Leonardo L. G.. Universidade de Sao Paulo; BrasilFil: Krogh, Renata. Universidade de Sao Paulo; BrasilFil: Andricopulo, Adriano D.. Universidade de Sao Paulo; BrasilFil: Cruz, Luiza R.. No especifíca;Fil: Mowbray, Charles E.. No especifíca;Fil: Kratz, Jadel M.. No especifíca;Fil: Dias, Luiz C.. Universidade Estadual de Campinas; Brasi
Seasonal and spatial aspects of phytoplankton along the north-eastern coast of Lake Tanganyika
No full textPhytoplankton was sampled over 10 month sat five stations along the north-east ern coast of Lake Tanganyika. The biomass is composed chiefly of diatoms to g ether with blue-green algae and,occasionally, green algae and Euglenophytes. Seasonal changes in phytoplankton composition and densities are discussed in relation with abiotic factors
Dual N6/C7-substituted 7-deazapurine and tricyclic ribonucleosides with affinity for G protein-coupled receptors
No full textVarious purine-based nucleoside analogues have demonstrated unexpected affinity for nonpurinergic G protein-coupled receptors (GPCRs), such as opioid and serotonin receptors. In this work, we synthesized a small library of new 7-deazaadenosine and pyrazolo-[3,4-d]-pyrimidine riboside analogues, featuring dual C7 and N-6 modifications and assessed their affinity for various GPCRs. During the course of the synthesis of 7-ethynyl pyrazolo-[3,4-d]-pyrimidine ribosides, we observed the formation of an unprecedented tricyclic nucleobase, formed via a 6-endo-dig ring closure. The synthesis of this tricyclic nucleoside was optimized, and the substrate scope for such cyclization was further explored because it might avail further exploration in the nucleoside field. From displacement experiments on a panel of GPCRs and transporters, combining C7 and N-6 modifications afforded noncytotoxic nucleosides with micromolar and submicromolar affinity for different GPCRs, such as the 5-hydroxytryptamine (5-HT)(2B), kappa-opioid (KOR), and sigma(1/2) receptor. These results corroborate that the novel nucleoside analogues reported here are potentially useful starting points for the further development of modulators of GPCRs and transmembrane proteins
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