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New pyranonaphthoquinone derivatives were synthesized and investigated for their activity against Trypanosoma brucei, Leishmania major, and Toxoplasma gondii parasites. The pentafluorophenyl derivative was efficacious against T. brucei with single digit micromolar EC50 values and against T. gondii with even sub-micromolar values. The 3-chloro-4,5-dimethoxyphenyl derivative showed an activity against amastigotes of Leishmania major parasites comparable to that of amphotericin B. In addition, antioxidant activities were observed for the bromophenyl derivatives, and their redox behavior was studied by cyclovoltammetry. Anti-parasitic and antioxidative activities of the new naphthoquinone derivatives appear uncorrelated.  相似文献   

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Mass drug administration (MDA) is a means of delivering safe and inexpensive essential medicines based on the principles of preventive chemotherapy, where populations or sub-populations are offered treatment without individual diagnosis. High-coverage MDA in endemic areas aims to prevent and alleviate symptoms and morbidity on the one hand and can reduce transmission on the other, together improving global health. MDA is the recommended strategy of the World Health Organisation to control or eliminate several neglected tropical diseases (NTDs). More than 700 million people now receive these essential NTD medicines annually. The combined cost of integrated NTD MDA has been calculated to be in the order of $0.50 per person per year. Activities have recently been expanded due, in part, to the proposed attempt to eliminate certain NTDs in the coming two decades. More than 1.9 billion people need to receive MDA annually across several years if these targets are to be met. Such extensive coverage will require additional avenues of financial support, expanded monitoring and evaluation focusing on impact and drug efficacy, as well as new diagnostic tools and social science strategies to encourage adherence. MDA is a means to help reduce the burden of disease, and hence poverty, among the poorest sector of populations. It has already made significant improvements to global health and productivity and has the potential for further successes, particularly where incorporated into sanitation and education programmes. However logistical, financial and biological challenges remain.  相似文献   

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Neglected tropical diseases (NTDs) have received increasing attention in recent years by the global heath community, as they cumulatively constitute substantial burdens of disease as well as barriers for economic development. A number of common tropical diseases such as malaria, hookworm or schistosomiasis have well-documented economic impacts. However, much less is known about the population-level impacts of diseases that are rare but associated with high disability burden, which represent a great number of tropical diseases. Using an individual-based model of Buruli ulcer (BU), we demonstrate that, through feedbacks between health and economic status, such NTDs can have a significant impact on the economic structure of human populations even at low incidence levels. While average wealth is only marginally affected by BU, the economic conditions of certain subpopulations are impacted sufficiently to create changes in measurable population-level inequality. A reduction of the disability burden caused by BU can thus maximize the economic growth of the poorest subpopulations and reduce significantly the economic inequalities introduced by the disease in endemic regions.  相似文献   

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Global efforts to address neglected tropical diseases (NTDs) were stimulated in January 2012 by the London declaration at which 22 partners, including the Bill & Melinda Gates Foundation, World Bank, World Health Organization (WHO) and major pharmaceutical companies committed to sustaining and expanding NTD programmes to eliminate or eradicate 11 NTDs by 2020 to achieve the goals outlined in the recently published WHO road map. Here, we present the current context of preventive chemotherapy for some NTDs, and discuss the problems faced by programmes as they consider the ‘endgame’, such as difficulties of access to populations in post-conflict settings, limited human and financial resources, and the need to expand access to clean water and improved sanitation for schistosomiasis and soil-transmitted helminthiasis. In the case of onchocerciasis and lymphatic filariasis, ivermectin treatment carries a significant risk owing to serious adverse effects in some patients co-infected with the tropical eye worm Loa loa filariasis. We discuss the challenges of managing complex partnerships, and maintain advocacy messages for the continued support for elimination of these preventable diseases.  相似文献   

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A new 3,4-difluorobenzylidene analog of curcumin, CDF, was recently reported, which demonstrated significantly enhanced bioavailability and in vivo anticancer activity compared with curcumin. For highlighting the antiparasitic behavior of CDF, we tested this compound together with its new O-methylated analog MeCDF against Leishmania major and Toxoplasma gondii parasites. Both CDF and MeCDF were tested in vitro against L. major and T. gondii. In addition, the in vitro cytotoxicity against Vero cells and macrophages was determined and selectivity indices were calculated. The DPPH radical scavenging activity assay was carried out in order to determine the antioxidant activity of the test compounds. Both compounds showed high activities against both parasite forms with EC50 values in the (sub-)micromolar range (0.35 to 0.8 μM for CDF, 0.31 to 1.2 μM for MeCDF). The higher activity of CDF against L. major amastigotes when compared with MeCDF can in parts be attributed to the antioxidant activity of CDF while MeCDF lacking any antioxidant activity was more active than CDF against T. gondii parasites. In conclusion, CDF and MeCDF are promising antiparasitic drug candidates due to their high activities against L. major and T. gondii parasites.  相似文献   

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Infections caused by parasitic worms impose a considerable worldwide health burden. One of the most impactful is schistosomiasis, a disease caused by blood-dwelling of the genus Schistosoma that affects more than 230 million people worldwide. Since praziquantel has also been extensively used to treat schistosomiasis and other parasitic flatworm infections, there is an urgent need to identify novel anthelmintic compounds, mainly from natural sources. In this study, the hexane extract from roots of Piper malacophyllum (Piperaceae) showed to be mainly composed for gibbilimbol B by HPLC/ESI-HRMS. Based on this result, this compound was isolated by chromatographic steps and its structure was confirmed by NMR. In vitro bioassays showed that gibbilimbol B was more active than praziquantel against larval stage of S. mansoni, with effective concentrations of 50 % (EC50) and 90 % (EC90) values of 2.6 and 3.4 μM, respectively. Importantly, gibbilimbol B showed no cytotoxicity to mammalian cells at a concentration 190 times greater than the antiparasitic effect, giving support for the anthelmintic potential of gibbilimbol B as lead compound for novel antischistosomal agents.  相似文献   

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A series of bis‐naphthoquinone derivatives prepared by condensation of aryl aldehydes with lawsone were tested for antiparasitic activities against Toxoplasma gondii and Trypanosoma brucei parasites. Monofluorophenyl derivative 1a , 3,4‐difluorophenyl analog 1c and furyl compound 1l exhibited significant activity against T. gondii cells and appear to be new promising drug candidates against this parasite. The 3,4,5‐trifluorophenyl derivative 1g and the isovanillyl derivative 1j displayed selective activity against Leishmania major amastigotes.  相似文献   

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Neglected tropical diseases are defined operationally as diseases that prevail in “tropical” regions and are under‐researched, under‐funded, and under‐treated compared with their disease burden. By analysing the adjectives “tropical” and “neglected,” I expose and interrogate the discourses within which the term “neglected tropical disease” derives its meaning. First, I argue that the term “tropical” conjures the notion of “tropicality,” a form of Othering which erroneously explains the disease‐prevalence of “tropical” regions by reference to environmental determinism, rather than colonialism and neocolonialism. Second, I examine the way in which this Othering enables the abjection of tropical regions and their peoples, leading to neglect. I recommend that the term “neglected tropical diseases” be more carefully contextualised within health scholarship, education, and policy.  相似文献   

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We have developed a new series of simple biaryl piperidine derivatives ( 11 – 19 ) based on biaryl naphthylisoquinoline alkaloid Ealamine-A. The target compounds were synthesized, analyzed by spectral data, and evaluated for antileishmanial activity against Leishmania donovani strain Ag83 by MTT assay. The compounds have shown the best to moderate antileishmanial activity. The 5′-fluoro-2′-methoxyphenyl derivative 14 and 3′,5′-difluorophenyl derivative 16 have inhibited the promastigotes by 86 % and 85 % after 24 h and 92 % and 91 % after 48 h incubation, respectively, at 400 μM concentration. The % inhibition was lower with the lowering of the concentration and increased with the incubation time. Compounds 12 , 15 , and 18 have solubility issues and proved to be less active than the rest of the compounds. Molecular docking studies were performed on selective active compounds and the results indicate that these compounds may act by binding to the Leishmanolysin and the docking scores are in good correlation with the antileishmanial activity. These results provide an initial insight into the design of new therapeutics for neglected tropical diseases.  相似文献   

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A series of synthetic 1,2,4-trioxanes related to artemisinin was tested against L. donovani and T. cruzi parasites. This screening identified some active compounds, with key common structural features. Interestingly, these selected trioxanes were efficient against both parasites, and achieved antiparasitic activities comparable or superior than those presented by the corresponding reference drugs, artemisinin and artesunate. This study represents the first example of synthetic trioxanes evaluated on T. cruzi and provides possible candidates for developing new drugs for the treatment of leishmaniasis and Chagas disease.  相似文献   

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Trypanosomiases and Leishmaniases are neglected tropical diseases that affect the less developed countries. For this reason, they did not and still do not have high visibility in Western societies. The name neglected diseases also refers to the fact that they often received little interest at the level of public investment, research and development. The drug discovery scenario, however, is changing dramatically. After a period in which different socioeconomic factors have prevented massive research efforts in this field, such efforts have increased considerably in the very recent years, with significant scientific advancements. In this context, we have embarked on a new drug discovery project devoted to identification of new small molecules for the treatment of trypanosomal and leishmanial diseases. Two complementary approaches have been pursued and are reported here. The first deals with a structure-based drug design, and a privileged structure-guided synthesis of quinazoline compounds able to modulate trypanothione reductase activity was accomplished. In the second, a combinatorial library, built on a natural product-based strategy, was synthesized. Using whole parasite assays, different quinones have been identified as promising lead compounds. A combination of both approaches to hopefully overcome some of the challenges of anti-trypanosomatid drug discovery has eventually been proposed.  相似文献   

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Reported in Haiti as early as 1923, Mansonella ozzardi is still a neglected disease ignored by the health authorities of the country. This review is an update on the geographic distribution of the coastal foci of mansonelliasis in Haiti, the epidemiological profile and prevalence rates of microfilariae in people living in endemic areas, the clinical impact of the parasite on health and the efficiency of the transmission of the parasite among three Culicoides biting-midge species identified as vectors in Haiti. Additionally, interest in establishing a treatment programme to combat this parasite using a single dose of ivermectin is emphasised.  相似文献   

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Eumycetoma, the fungal form of the neglected tropical disease mycetoma, is a crippling infectious disease with low response rates to currently available antifungal drugs. In this study, a series of natural naphthoquinones and anthraquinones was evaluated for their activity against Madurella mycetomatis, which is the most common causative agent of eumycetoma. The metabolic activity of Madurella mycetomatis as well as the viability of Galleria mellonella larvae upon treatment with quinones was investigated. Several hydroxy-substituted naphthoquinones exhibited activity against Madurella mycetomatis. In particular, naphthazarin (5,8-dihydroxy-1,4-naphthoquinone) was identified as a considerably active antifungal compound against Madurella mycetomatis (IC50=1.4 μM), while it showed reduced toxicity to Galleria mellonella larvae, which is a well-established in vivo invertebrate model for mycetoma drug studies.  相似文献   

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Introduction:

Snakebite is a relevant public health problem in Colombia, which is evident in epidemiological data at the Latin American level, where it ranks third place in the number of snakebites, after México and Brazil.

Objective:

To perform a retrospective analysis of snakebite accidents in the department of Cauca between 2009 and 2018 based on the data from the Public Health Surveillance System of Colombia reported to the Health Institute of Cauca.

Materials and methods:

We compiled and interpreted the information from the compulsory snakebite notification forms for the study’s 10 years period. We determined snakebite incidence and frequency according to the geographical distribution and the causal agents, and we analyzed related socioeconomic variables as well.

Results:

The records accounted for 1,653 cases and low mortality. Bothrops and Bothriechis species (77.43%) caused most of the accidents followed by Micrurus (2.9%). Most of the notifications came from the south of the department, and males and farmers were the most affected with bites mainly in the upper extremities. During poisoning, hemorrhagic manifestations predominated over necrosis and infections; serotherapy criteria were not always adequately applied, however, iatrogenic complications were not frequent.

Conclusions:

El Tambo and Piamonte municipalities, being male, and rural areas were the variables most affected by ophidism, mainly bothropic ophidism. The highest incidences occurred in the southern part of Cauca, in the Patía and Caquetá river basins.  相似文献   

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Pathogens have evolved numerous strategies to infect their hosts, while hosts have evolved immune responses and other defenses to these foreign challenges. The vast majority of host-pathogen interactions involve protein-protein recognition, yet our current understanding of these interactions is limited. Here, we present and apply a computational whole-genome protocol that generates testable predictions of host-pathogen protein interactions. The protocol first scans the host and pathogen genomes for proteins with similarity to known protein complexes, then assesses these putative interactions, using structure if available, and, finally, filters the remaining interactions using biological context, such as the stage-specific expression of pathogen proteins and tissue expression of host proteins. The technique was applied to 10 pathogens, including species of Mycobacterium, apicomplexa, and kinetoplastida, responsible for \"neglected\" human diseases. The method was assessed by (1) comparison to a set of known host-pathogen interactions, (2) comparison to gene expression and essentiality data describing host and pathogen genes involved in infection, and (3) analysis of the functional properties of the human proteins predicted to interact with pathogen proteins, demonstrating an enrichment for functionally relevant host-pathogen interactions. We present several specific predictions that warrant experimental follow-up, including interactions from previously characterized mechanisms, such as cytoadhesion and protease inhibition, as well as suspected interactions in hypothesized networks, such as apoptotic pathways. Our computational method provides a means to mine whole-genome data and is complementary to experimental efforts in elucidating networks of host-pathogen protein interactions.  相似文献   

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