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The Influence of Silver Nanoparticles Against Toxic Effects of Philodryas olfersii Venom
research-article
Author(s):
Jaqueline de Cássia Proença-Assunção
1 ,
Anna Paula Farias-de-França
2 ,
Natalia Tribuiani
1 ,
Jose Carlos Cogo
3 ,
Rita de Cássia Collaço
4 ,
Priscila Randazzo-Moura
5 ,
Sílvio Roberto Consonni
6 ,
Marco Vinicius Chaud
1 ,
Carolina Alves dos Santos
2 ,
Yoko Oshima-Franco
1
Publication date (Electronic):
25 May 2021
Publisher:
Dove
There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.
Abstract
Purpose
A silver nanoparticle obtained by reducing salts with solid dispersion of curcumin (130 nm, 0.081 mg mL −1) was used to counteract against the toxic – edematogenic, myotoxic, and neurotoxic – effects of Philodryas olfersii venom.
Methods
The edematogenic effect was evaluated by plasma extravasation in rat dorsal skin after injection of 50 µg per site of venom alone or preincubated with 1, 10, and 100 µL of AgNPs; the myotoxicity was evaluated by measuring the creatine kinase released into the organ-bath before the treatment and at the end of each experiment; and neurotoxicity was evaluated in chick biventer cervicis using the conventional myographic technique, face to the exogenous acetylcholine (ACh) and potassium chloride (KCl) added into the bath before the treatment and after each experiment. Preliminarily, a concentration-response curve of AgNPs was carried out to select the concentration to be used for neutralizing assays, which consists of neutralizing the venom-induced neuromuscular paralysis and edema by preincubating AgNPs with venom for 30 min.
Results
The P. olfersii venom-induced edema (n=6) and a complete neuromuscular blockade (n=4) that includes the total and unrecovered block of ACh and KCl contractures. AgNPs produced a concentration-dependent decrease the venom-induced edema (n=6) from 223.3% to 134.4% and to 100.5% after 10 and 100 µL AgNPs-preincubation, respectively. The preincubation of venom with AgNPs (1 µL; n=6) was able to maintain 46.5 ± 10.9% of neuromuscular response under indirect stimuli, 39.2 ± 9.7% of extrinsic nicotinic receptors functioning in absence of electrical stimulus and 28.3 ± 8.1% of responsiveness to potassium on the sarcolemmal membrane. The CK release was not affected by any experimental protocol which was like control.
Conclusion
AgNPs interact with constituents of P. olfersii venom responsible for the edema-forming activity and neuromuscular blockade, but not on the sarcolemma membrane-acting constituents. The protective effect of the studied AgNPs on avian preparation points out to molecular targets as intrinsic and extrinsic nicotinic receptors.
Most cited references56
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Improving Bioscience Research Reporting: The ARRIVE Guidelines for Reporting Animal Research
Carol Kilkenny, William J Browne, Innes Cuthill … (2010)
In the last decade the number of bioscience journals has increased enormously, with many filling specialised niches reflecting new disciplines and technologies. The emergence of open-access journals has revolutionised the publication process, maximising the availability of research data. Nevertheless, a wealth of evidence shows that across many areas, the reporting of biomedical research is often inadequate, leading to the view that even if the science is sound, in many cases the publications themselves are not “fit for purpose,” meaning that incomplete reporting of relevant information effectively renders many publications of limited value as instruments to inform policy or clinical and scientific practice [1]–[21]. A recent review of clinical research showed that there is considerable cumulative waste of financial resources at all stages of the research process, including as a result of publications that are unusable due to poor reporting [22]. It is unlikely that this issue is confined to clinical research [2]–[14],[16]–[20]. Failure to describe research methods and to report results appropriately therefore has potential scientific, ethical, and economic implications for the entire research process and the reputation of those involved in it. This is particularly true for animal research, one of the most controversial areas of science. The largest and most comprehensive review of published animal research undertaken to date, to our knowledge, has highlighted serious omissions in the way research using animals is reported [5]. The survey, commissioned by the National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs), a UK Government-sponsored scientific organisation, found that only 59% of the 271 randomly chosen articles assessed stated the hypothesis or objective of the study, and the number and characteristics of the animals used (i.e., species/strain, sex, and age/weight). Most of the papers surveyed did not report using randomisation (87%) or blinding (86%) to reduce bias in animal selection and outcome assessment. Only 70% of the publications that used statistical methods fully described them and presented the results with a measure of precision or variability [5]. These findings are a cause for concern and are consistent with reviews of many research areas, including clinical studies, published in recent years [2]–[22]. Good Reporting Is Essential for Peer Review and to Inform Future Research Scrutiny by scientific peers has long been the mainstay of “quality control” for the publication process. The way that experiments are reported, in terms of the level of detail of methods and the presentation of key results, is crucial to the peer review process and, indeed, the subsequent utility and validity of the knowledge base that is used to inform future research. The onus is therefore on the research community to ensure that their research articles include all relevant information to allow in-depth critique, and to avoiding duplicating studies and performing redundant experiments. Ideally scientific publications should present sufficient information to allow a knowledgeable reader to understand what was done, why, and how, and to assess the biological relevance of the study and the reliability and validity of the findings. There should also be enough information to allow the experiment to be repeated [23]. The problem therefore is how to ensure that all relevant information is included in research publications. Using Reporting Guidelines Measurably Improves the Quality of Reporting Evidence provided by reviews of published research suggests that many researchers and peer reviewers would benefit from guidance about what information should be provided in a research article. The CONSORT Statement for randomised controlled clinical trials was one of the first guidelines developed in response to this need [24],[25]. Since publication, an increasing number of leading journals have supported CONSORT as part of their instructions to authors [26],[27]. As a result, convincing evidence is emerging that CONSORT improves the quality and transparency of reports of clinical trials [28],[29]. Following CONSORT, many other guidelines have been developed—there are currently more than 90 available for reporting different types of health research, most of which have been published in the last ten years (see http://www.equator-network.org and references [30],[31]). Guidelines have also been developed to improve the reporting of other specific bioscience research areas including metabolomics and gene expression studies [32]–[37]. Several organisations support the case for improved reporting and recommend the use of reporting guidelines, including the International Committee of Medical Journal Editors, the Council of Science Editors, the Committee on Publication Ethics, and the Nuffield Council for Bioethics [38]–[41]. Improving the Reporting of Animal Experiments—The ARRIVE Guidelines Most bioscience journals currently provide little or no guidance on what information to report when describing animal research [42]–[50]. Our review found that 4% of the 271 journal articles assessed did not report the number of animals used anywhere in the methods or the results sections [5]. Reporting animal numbers is essential so that the biological and statistical significance of the experimental results can be assessed or the data reanalysed, and is also necessary if the experimental methods are to be repeated. Improved reporting of these and other details will maximise the availability and utility of the information gained from every animal and every experiment, preventing unnecessary animal use in the future. To address this, we led an initiative to produce guidelines for reporting animal research. The guidelines, referred to as ARRIVE (Animals in Research: Reporting In Vivo Experiments), have been developed using the CONSORT Statement as their foundation [24],[25]. The ARRIVE guidelines consist of a checklist of 20 items describing the minimum information that all scientific publications reporting research using animals should include, such as the number and specific characteristics of animals used (including species, strain, sex, and genetic background); details of housing and husbandry; and the experimental, statistical, and analytical methods (including details of methods used to reduce bias such as randomisation and blinding). All the items in the checklist have been included to promote high-quality, comprehensive reporting to allow an accurate critical review of what was done and what was found. Consensus and consultation are the corner-stones of the guideline development process [51]. To maximise their utility, the ARRIVE guidelines have been prepared in consultation with scientists, statisticians, journal editors, and research funders. We convened an expert working group, comprising researchers and statisticians from a range of disciplines, and journal editors from Nature Cell Biology, Science, Laboratory Animals, and the British Journal of Pharmacology (see Acknowledgments). At a one-day meeting in June 2009, the working group agreed the scope and broad content of a draft set of guidelines that were then used as the basis for a wider consultation with the scientific community, involving researchers, and grant holders and representatives of the major bioscience funding bodies including the Medical Research Council, Wellcome Trust, Biotechnology and Biological Sciences Research Council, and The Royal Society (see Table 1). Feedback on the content and wording of the items was incorporated into the final version of the checklist. Further feedback on the content utility of the guidelines is encouraged and sought. 10.1371/journal.pbio.1000412.t001 Table 1 Funding bodies consulted. Name of Bioscience Research Funding Body Medical Research Council Biotechnology and Biological Sciences Research Council Wellcome Trust The Royal Society Association of Medical Research Charities British Heart Foundation Parkinson's Disease Society The ARRIVE guidelines (see Table 2) can be applied to any area of bioscience research using laboratory animals, and the inherent principles apply not only to reporting comparative experiments but also to other study designs. Laboratory animal refers to any species of animal undergoing an experimental procedure in a research laboratory or formal test setting. The guidelines are not intended to be mandatory or absolutely prescriptive, nor to standardise or formalise the structure of reporting. Rather they provide a checklist that can be used to guide authors preparing manuscripts for publication, and by those involved in peer review for quality assurance, to ensure completeness and transparency. 10.1371/journal.pbio.1000412.t002 Table 2 Animal Research: Reporting In Vivo experiments: The ARRIVE guidelines. ITEM RECOMMENDATION TITLE 1 Provide as accurate and concise a description of the content of the article as possible. ABSTRACT 2 Provide an accurate summary of the background, research objectives (including details of the species or strain of animal used), key methods, principal findings, and conclusions of the study. INTRODUCTION Background 3 a. Include sufficient scientific background (including relevant references to previous work) to understand the motivation and context for the study, and explain the experimental approach and rationale.b. Explain how and why the animal species and model being used can address the scientific objectives and, where appropriate, the study's relevance to human biology. Objectives 4 Clearly describe the primary and any secondary objectives of the study, or specific hypotheses being tested. METHODS Ethical statement 5 Indicate the nature of the ethical review permissions, relevant licences (e.g. Animal [Scientific Procedures] Act 1986), and national or institutional guidelines for the care and use of animals, that cover the research. Study design 6 For each experiment, give brief details of the study design, including:a. The number of experimental and control groups.b. Any steps taken to minimise the effects of subjective bias when allocating animals to treatment (e.g., randomisation procedure) and when assessing results (e.g., if done, describe who was blinded and when).c. The experimental unit (e.g. a single animal, group, or cage of animals).A time-line diagram or flow chart can be useful to illustrate how complex study designs were carried out. Experimental procedures 7 For each experiment and each experimental group, including controls, provide precise details of all procedures carried out. For example:a. How (e.g., drug formulation and dose, site and route of administration, anaesthesia and analgesia used [including monitoring], surgical procedure, method of euthanasia). Provide details of any specialist equipment used, including supplier(s).b. When (e.g., time of day).c. Where (e.g., home cage, laboratory, water maze).d. Why (e.g., rationale for choice of specific anaesthetic, route of administration, drug dose used). Experimental animals 8 a. Provide details of the animals used, including species, strain, sex, developmental stage (e.g., mean or median age plus age range), and weight (e.g., mean or median weight plus weight range).b. Provide further relevant information such as the source of animals, international strain nomenclature, genetic modification status (e.g. knock-out or transgenic), genotype, health/immune status, drug- or test-naïve, previous procedures, etc. Housing and husbandry 9 Provide details of:a. Housing (e.g., type of facility, e.g., specific pathogen free (SPF); type of cage or housing; bedding material; number of cage companions; tank shape and material etc. for fish).b. Husbandry conditions (e.g., breeding programme, light/dark cycle, temperature, quality of water etc. for fish, type of food, access to food and water, environmental enrichment).c. Welfare-related assessments and interventions that were carried out before, during, or after the experiment. Sample size 10 a. Specify the total number of animals used in each experiment and the number of animals in each experimental group.b. Explain how the number of animals was decided. Provide details of any sample size calculation used.c. Indicate the number of independent replications of each experiment, if relevant. Allocating animals to experimental groups 11 a. Give full details of how animals were allocated to experimental groups, including randomisation or matching if done.b. Describe the order in which the animals in the different experimental groups were treated and assessed. Experimental outcomes 12 Clearly define the primary and secondary experimental outcomes assessed (e.g., cell death, molecular markers, behavioural changes). Statistical methods 13 a. Provide details of the statistical methods used for each analysis.b. Specify the unit of analysis for each dataset (e.g. single animal, group of animals, single neuron).c. Describe any methods used to assess whether the data met the assumptions of the statistical approach. RESULTS Baseline data 14 For each experimental group, report relevant characteristics and health status of animals (e.g., weight, microbiological status, and drug- or test-naïve) before treatment or testing (this information can often be tabulated). Numbers analysed 15 a. Report the number of animals in each group included in each analysis. Report absolute numbers (e.g. 10/20, not 50%a).b. If any animals or data were not included in the analysis, explain why. Outcomes and estimation 16 Report the results for each analysis carried out, with a measure of precision (e.g., standard error or confidence interval). Adverse events 17 a. Give details of all important adverse events in each experimental group.b. Describe any modifications to the experimental protocols made to reduce adverse events. DISCUSSION Interpretation/scientific implications 18 a. Interpret the results, taking into account the study objectives and hypotheses, current theory, and other relevant studies in the literature.b. Comment on the study limitations including any potential sources of bias, any limitations of the animal model, and the imprecision associated with the resultsa.c. Describe any implications of your experimental methods or findings for the replacement, refinement, or reduction (the 3Rs) of the use of animals in research. Generalisability/translation 19 Comment on whether, and how, the findings of this study are likely to translate to other species or systems, including any relevance to human biology. Funding 20 List all funding sources (including grant number) and the role of the funder(s) in the study. a Schulz, et al. (2010) [24]. Improved Reporting Will Maximise the Output of Published Research These guidelines were developed to maximise the output from research using animals by optimising the information that is provided in publications on the design, conduct, and analysis of the experiments. The need for such guidelines is further illustrated by the systematic reviews of animal research that have been carried out to assess the efficacy of various drugs and interventions in animal models [8],[9],[13],[52]–[55]. Well-designed and -reported animal studies are the essential building blocks from which such a systematic review is constructed. The reviews have found that, in many cases, reporting omissions, in addition to the limitations of the animal models used in the individual studies assessed in the review, are a barrier to reaching any useful conclusion about the efficacy of the drugs and interventions being compared [2],[3]. Driving improvements in reporting research using animals will require the collective efforts of authors, journal editors, peer reviewers, and funding bodies. There is no single simple or rapid solution, but the ARRIVE guidelines provide a practical resource to aid these improvements. The guidelines will be published in several leading bioscience research journals simultaneously [56]–[60], and publishers have already endorsed the guidelines by including them in their journal Instructions to Authors subsequent to publication. The NC3Rs will continue to work with journal editors to extend the range of journals adopting the guidelines, and with the scientific community to disseminate the guidelines as widely as possible (http://www.nc3rs.org.uk/ARRIVE).
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Strategy for a globally coordinated response to a priority neglected tropical disease: Snakebite envenoming
In one of his final essays, statesman and former United Nations secretary general Kofi Annan said, ‘Snakebite is the most important tropical disease you’ve never heard of’ [1]. Mr. Annan firmly believed that victims of snakebite envenoming should be recognised and afforded greater efforts at improved prevention, treatment, and rehabilitation. During the last years of his life, he advocated strongly for the World Health Organisation (WHO) and the global community to give greater priority to this disease of poverty and its victims. Snakebite envenoming (SBE) affects as many as 2.7 million people every year, most of whom live in some of the world’s most remote, poorly developed, and politically marginalised tropical communities [2]. With annual mortality of 81,000 to 138,000 and 400,000 surviving victims suffering permanent physical and psychological disabilities, SBE is a disease in urgent need of attention [2–4]. Like many diseases of poverty, SBE has failed to attract requisite public health policy inclusion and investment for driving sustainable efforts to reduce the medical and societal burden. This is largely due to the demographics of the affected populations and their lack of political voice [5]. Devising a consensual pathway to the goal of halving deaths and disability by 2030 Despite decades of concern over the impact of SBE in low-middle-income countries (LMICs), a lack of any clear mandate from member states has made it difficult for WHO to take substantial action [4, 6–9]. Indeed, it wasn’t until 2015 when alarm over the possible therapeutic vacuum in Africa, caused by Sanofi-Pasteur’s decision to cease production of their FAV-Afrique antivenom, galvanised renewed calls for urgent action [9, 10]. In 2017, after intense advocacy by concerned stakeholders including Médecins Sans Frontières [10, 11], the Global Snakebite Initiative [5, 12–14], Health Action International, and a detailed submission by more than 20 countries, WHO listed SBE as a priority neglected tropical disease (NTD) [15, 16]. In May 2018, the 71st World Health Assembly adopted a robust resolution (WHA71.5) on SBE, providing WHO with a strong mandate to take action [17]. The inclusion of SBE in the WHO NTD portfolio donates powerful attention to this disease. Even before the resolution was adopted, WHO’s Department of the Control of Neglected Tropical Diseases had already established a 28-member SBE Working Group (SBE-WG) to support WHO in drafting a road map to implement strategies to prevent, reduce, and control the snakebite burden. In June 2018, WHO convened a Wellcome-hosted meeting of the SBE-WG to review a first draft of the road map document. Central to the design of this strategic plan is the ambitious goal of halving the deaths and disability caused SBE by 2030 (Fig 1). The consensus of the SBE-WG was that implementing an integrated program based on building capacity and directing response to snakebite-affected regions offers the most effective approach to achieving this goal. Rather than risk this initiative being perceived as a standalone issue, the SBE-WG considered that efforts to combat SBE need to be incorporated within national and regional health plans and aligned with global commitments to achieving universal health coverage and the Sustainable Development Goals (SDG). With this in mind, four key pillars (Fig 1; Table 1) have been prioritised: Ensuring that safe and effective treatment is accessible and affordable for all; Empowering regional, national, and local communities to take proactive action; Strengthening health systems to deliver better outcomes; and Building a strong global coalition of partners to build advocacy, mobilise resources, coordinate action, and ensure that implementation of the roadmap is successful. 10.1371/journal.pntd.0007059.g001 Fig 1 Summary of WHO snakebite envenoming road map objectives, impact goals, and timeline phases. 10.1371/journal.pntd.0007059.t001 Table 1 Summary of overall program areas. Objective Safe and effective treatment Empowering and Engaging communities Stronger health systems Partnership, coordination and resources Key activities Programme-wide resource mobilisation to support all WHO activities and work plans Make safe, effective antivenoms available, accessible, and affordable to all Active community engagement and participation Strengthening community health services Supporting governance and leadership Better control and regulation of antivenoms Improve SBE prevention, risk-reduction and avoidance Facilitating research and policy development around healthcare cost mitigation Promoting advocacy, effective communication and productive engagement Prequalification of antivenoms Effective prehospital care and ambulance transport Improving infrastructure, services and health facilities Enhancing integration, coordination and cooperation Integrated health worker training and education Accelerate development of prehospital treatments Country-level implementation via national and sub-national health plans Build strong regional partnerships and alliances Improving clinical decision-making, treatment, recovery and rehabilitation Improve health care-seeking behaviours Enhanced disease burden monitoring and surveillance Coordinated data management and analysis Investing in innovative research on new therapeutics Build a strong understanding of socio-cultural and economic factors affecting outcomes Research on SBE ecology, epidemiology, clinical outcomes and therapeutics Research to build a strong and sustainable investment case The scale of this challenge is considerable and its achievement requires a globally coordinated and implemented strategy, with the WHO best positioned to coordinate this effort. Safe and effective treatment SBE is a medical emergency that particularly afflicts the world’s poorest people living in communities with the lowest quality of life indices [18]. The sooner a victim receives effective treatment, the greater the likelihood of a full recovery and an early return to normal life. For more than 120 years, the cornerstone of snakebite treatment has been the administration of animal-derived immunoglobulins (antivenoms) [2]. Most antivenoms are produced from the hyperimmune plasma of horses or sheep, and the methods used have changed very little in the last 50 to 60 years [19]. Consequently, the quality and safety of some antivenoms remain poor. Production inefficiencies, inadequate market demand, low manufacturing volumes, storage limitations, and distribution problems have combined with inadequate funding for procurement, poor health-worker training, and local bias towards traditional healing to create a fragile market at risk of collapse in many parts of the world [20]. These market fragilities explain why, for much of the last century, antivenom production has largely been the domain of public health laboratories, few of which have been adequately capitalised to keep pace with modern pharmaceutical manufacturing technologies. And while private manufacturers have gained an increasingly important role during the last four decades, especially in Asia and in Africa, the nature of the market limits their capacity to resource infrastructure and innovation [20, 21]. As a consequence, there has previously been little incentive for innovation or investment in new technology. Comprehensively addressing these issues is a key priority for WHO. The SBE-WG, concerned by the current critical situation in sub-Saharan Africa, have set a target of delivering at least 500,000 effective antivenom treatments to that region each year by 2024. By the end of 2030, the target is to deliver, globally, 3 million effective regionally specific treatments per year. To achieve this, WHO will work to strengthen the production of antivenoms, improve regulatory control, and most importantly, rebuild and reinvigorate the market by ensuring that safe and effective products are available, accessible, and affordable. WHO has already begun this process by undertaking a comprehensive product risk assessment for sub-Saharan Africa. Its results are expected to be published in early 2019. This evaluation included robust preclinical evaluation of products and site inspections to evaluate compliance with good manufacturing practice (GMP). The result will be a WHO-recommended list of products suitable for procurement across sub-Saharan Africa, providing purchasers and end-users with confidence that products are fit-for-use, and providing manufacturers with incentive to improve the quality of products and comply with GMP and other regulatory requirements as a pathway to restoring investment confidence in the market and generating income commensurate with sustained delivery. As funding becomes available, WHO plans to undertake similar antivenom risk–benefit assessments for other regions and to consider the introduction of antivenom prequalification as a tool for further strengthening the production of these life-saving drugs. Such a pathway will only be possible if technical barriers—such as the need to establish appropriate reference standards, minimum product design specifications, and pathways for acquiring robust clinical evidence—are resourced and overcome. A range of other initiatives (Box 1) will also be implemented to reinvigorate investment in antivenom production and to establish an environment that attracts new manufacturers, stimulates research, and encourages innovation. WHO will take key lessons from highly effective vaccine stockpiling ventures, such as the Oral Cholera Vaccine Stockpile [22, 23], to model and then establish an African Antivenom Stockpile as a pathway to creating a stable supply of quality-assured WHO-recommended antivenom products in sub-Saharan Africa. This stockpile is designed to reshape the current market: converting it from one in which low production at high unit cost has driven weak demand and distribution that culminated in poor accessibility and affordability; to one in which there is equitable access and affordability because of higher production at lower cost as a result of increased market confidence, higher demand, improved procurement, and wider distribution. Box 1. Priority actions to ensure sustainable supply and accessibility of safe, effective, and affordable antivenoms Resource actions Identify and mobilise resources to reshape the market for sustained antivenom delivery; Galvanise funding for research to improve existing antivenom technologies; Prioritise investment in clinical research, including clinical trials of the safety and effectiveness of treatments; Increase resources to reduce treatment-associated patient financial and social vulnerability. Actions to improve quality, safety, and effectiveness of antivenoms Global risk–benefit assessments of antivenom products to ensure that at least three quality-assured and fit-for-use antivenoms are accessible in each region; Strengthen the capacities of antivenom manufacturers to increase production, improve research and development, and meet GMP and quality control requirements and compliance with regulatory standards; Development and introduction of target product profiles (TPP’s), venom and antivenom reference standards, and an appropriate prequalification pathway; Provide essential guidance, regulatory and technical support to National Regulatory Authorities (NRAs), National Control Laboratories (NCLs), and National Health Authorities (NHAs) to strengthen and build capacity for effective regulation of antivenoms in all regions; Stimulate enhanced collaboration between research and manufacturing sectors to improve all aspects of antivenom design, production, quality control, and evaluation. Actions to increase accessibility and affordability of antivenoms Establish an antivenom stockpile programme initially for countries in sub-Saharan Africa; Working with countries, partners and donors, apply a range of initiatives (in addition to establishing revolving stockpiles) to reshape regional antivenom markets, increase confidence, incentivise demand, and expand the availability, accessibility, and affordability of WHO-recommended antivenoms; Deliver cost-mitigation and financing schemes to ensure access to effective treatment and healthcare. Actions to ensure long-term sustainability of antivenom supply Galvanise LMIC countries to support investment in local antivenom manufacturing; Work with communities to improve health-care seeking behaviours, and with governments to support health worker training and education around the use of antivenoms. The SBE-WG also agreed that there needs to be a range of actions to encourage increased collaboration between academia, clinicians, and industry to improve potency, specificity, and safety of current antivenoms, with an additional focus on development of new treatments. Research involving robust preclinical and clinical evaluation of antivenoms and other treatments for SBE will be encouraged, with clinical research prioritised for funding investment along with identifying sentinel sites where clinical trials can be conducted to high standards. Refining preclinical models to improve their reliability and relevance, and wider adoption of the 3R’s (reduction, refinement, and replacement) relating to the use of experimental animals in the production and testing of antivenoms are research priorities. With promising preclinical research on new therapeutic solutions to SBE management emerging, the need for investment in next generation therapies and diagnostics also needs funding support [24, 25]. The WHO will work with antivenom manufacturers, with national regulatory agencies, and with ministries of health to build capacity to ensure that all treatments for SBE are properly controlled and regulated. The SBE-WG also concurred that any effort to control the SBE burden requires broader efforts at improving the overall management of snakebite victims. It is essential that standard approaches be developed and implemented across all tiers of health systems. There should be clear criteria for judging the success (or otherwise) of treatment. Currently there is little assistance or support available to SBE survivors suffering residual disability. Establishment of dedicated rehabilitation programs, addressing both psychological and physical disability, will improve recovery of survivors, enabling more of them to return to useful, productive lives, therefore increasing economic productivity. Empowering and engaging communities As well as effective engagement with health decision makers at regional and national levels, there is strong evidence linking the success of disease interventions to engagement with local communities to engender trust in outcomes and hence productive participation [26–28]. A major barrier to improving the treatment of SBE is the perception across many LMIC communities that rather than being a physical illness amenable to medical treatment, snakebites, like many other unexpected illnesses, are associated with deity punishment, witchcraft, or other powerfully persuasive phenomena that are often very locally specific [29, 30]. Context-appropriate engagement with local communities is therefore important to overcome these misconceptions and create a balance between traditional customs and modern healthcare. It is equally vital that local hospitals and/or health centres are equipped with effective, affordable, and safe antivenom. Funding should be made available to study the human–snake conflict interface, the social and cultural barriers to allopathic medicine, and the development and deployment of effective prehospital care interventions that can improve ‘first mile’ care and sustain life. WHO will propose engagement with local champions who can lead efforts to introduce acceptable prehospital ‘first aid’, encourage earlier presentation to primary health care centres, facilitate safe transport, and provide basic life-support. Accelerating preclinical and clinical testing of promising prehospital adjunctive treatments, such as the phospholipase A2 inhibitor, Varespladib, as part of the WHO SBE research agenda may lead to early improvements in prehospital survival [25]. Coupled with improved training of primary healthcare workers in emergency treatment of SBE, safe referral of envenomed patients, and better access to basic life support commodities, antivenom, and adjunctive medicines, there is great potential to save lives in even the most remote settings. In many settings, community-level training about basic airway protection and safe transport to healthcare could save thousands of lives. The WHO road map recommends strong local engagement with communities to promote prevention, safe prehospital care, and improved healthcare-seeking behaviour combined with participation by traditional healthcare providers within the health system rather than outside it. This would mirror similar approaches that have been applied in some settings for other diseases such as Buruli ulcer and malaria [31, 32]. Stronger health systems Many of the components of a functional and responsive health system needed to improve the outcomes for snakebite victims are no different to those that improve access to universal healthcare for all people. Strengthening healthcare capacity and performance at community and higher national levels is vital and integral to achieving UHC2030 [33]. There is good evidence that such activities can have a substantial impact on the health of women and children, two groups who are vulnerable to poor outcomes after SBE due to reduced access and other factors [34]. Myanmar communities identified improved healthcare accessibility to antivenoms and greater affordability of health care as key priorities [35]. In Nepal, rapid access to healthcare positively improved outcomes after SBE [30, 36]. The SBE-WG agreed that integrated steps that build capacity of healthcare systems to better manage SBE and other diseases should be prioritised and that synergies should be identified and exploited to advance progress towards achieving SDGs for health and moving closer to UHC2030. The components that are directly relevant to snakebite victims range from access to prehospital care and ambulance transport through to effective diagnosis, the availability in hospital of essential medicines (including antivenoms), consumables and medical services (emergency, intensive care, radiology, pathology, renal care, paediatrics, surgical, etc.), complemented by rehabilitation and recovery support. There was strong agreement that increasing access to clear guidelines that standardise the diagnosis and treatment of snakebite patients and improving the training of doctors and other health workers was fundamental to ensuring better outcomes for patients. The road map calls for countries to increase training for all health workers in an integrated manner and to work towards improving infrastructure and resourcing of health facilities—steps that benefit entire communities. One of the major difficulties associated with SBE is the relative paucity of high quality epidemiological surveillance data and the impact this has on being able to accurately report the burden of disease [2, 3]. Having access to accurate information, research data, and the results of surveillance is fundamental to health planning, monitoring, and assessment and is a key component of a strong health system and the elimination or control of NTDs [36, 37]. Globally, much needs to be done to improve the surveillance of SBE. Under the proposed road map, WHO will recommend inclusion of SBE as a ‘notifiable disease’. To support adoption of this designation, and to improve data quality and comparability, standardised clinical criteria adapted to specific regional needs will be developed and minimum data set definitions for community-acquired and hospital-acquired data introduced. A number of public health tools already used to control other diseases can be valuably adopted for building higher resolution systems to monitor progress to control SBE [38–40]. Research to develop and deploy new data-collection tools, or which broaden our knowledge of the health- and socio-economic impacts of SBE, the cost-benefit and cost-effectiveness of interventions, patient care financing, and effective monitoring and evaluation of road map progress is needed. The WHO will include SBE data in the Global Health Observatory (www.who.int/gho/) repository and will work with countries and partners to improve the collection, analysis, and reporting of surveillance data. Partnership, coordination and resources Achieving the ambitious goal of reducing SBE mortality and disability by 50% by 2030 requires strong leadership from WHO, provision of requisite funding, identification and allocation of adequate resources, and the development of a dynamic global partnership to drive policy change, implementation, and evaluation of outcomes. Building a strong multidisciplinary and participatory collaboration is essential to increase effectiveness of interventions and mobilise resources to reduce the burden of SBE [41, 42]. Effective advocacy, built on robust data, will be vital to generate and mobilise the resources needed to implement the road map and to ultimately ensure the sustainability of the approaches being proposed. Stimulating research in priority areas where there are currently major gaps will ensure that appropriate tools are developed, and creating strategic partnerships will help ensure that research outcomes are effectively translated into new clinical and public health tools to reduce the burden of SBE. The resolution on SBE (WHA71.5) passed at the 71st World Health Assembly in May 2018 robustly calls on countries to increase their efforts to prevent and control this disease, just as it requests that WHO also takes specific steps in this regard [17]. The WHO road map for SBE will set out pathways for the incorporation of this disease in regional- and country-level health plans and will focus on horizontal integration, complementary activities, and local stakeholder inclusion and participation. In-country and regional coordination mechanisms that integrate SBE with interventions for other diseases, such as wound care programmes for Buruli ulcer [43], promotion of footwear to prevent soil-associated diseases such as hookworm or podoconiosis [44], or the use of malaria bed nets (which can prevent nocturnal snakebites in places where people are sleeping) [45] will be promoted. Similarly, the success of programmes such as WASH that improve sanitation and human behaviours can help to reduce the risk of SBE [46]. Next steps and key actions The road map has been revised by the SBE-WG and will be shared with key stakeholders before it is published and officially launched in May 2019. WHO is preparing a budget for implementing resolution WHA71.5, which will require strong financial commitment from stakeholders. The roll-out of the road map is incremental, and as efforts scale up, the strategy will require increased investment to support expanded WHO activities and in-country implementation. Additional modelling of implementation costs and benefits of specific components of the strategy are being undertaken, and together with the road map, these will be used to make the investment case for prevention, control, and reduction of SBE. The challenge of building an argument for an NTD that cannot be eliminated, and for which no single universal ‘cure’ is available, is substantial. But the reality is that there is good evidence demonstrating that effective treatment can dramatically reduce mortality by as much as 85% to 88% and also increase positive healthcare-seeking behaviours [47, 48]. In contrast to some other NTD vectors, venomous snakes cannot be eliminated, but SBE can be effectively prevented and controlled so that the burden of injury and the impact on those affected are substantially reduced. Funding is the only barrier to achieving rapid positive and sustainable change. A strong transformational funding investment from both public and private sectors that addresses the short-, medium-, and long-term needs of delivering effective solutions can ensure that SBE becomes a global public health success story. The WHO strategy of improving the production, quality control, and regulation of these life-saving medicines through a comprehensive program to stimulate modernisation, research and development, and to reinvigorate the market, represents a strong advance on the road to achieving a 50% reduction in global mortality and disability and is a compelling case for such investment. Combined with parallel efforts on community engagement and education, health systems strengthening towards universal healthcare and SDG3, effective partnerships at local, national, regional, and global level, and critically-needed funding, the WHO SBE road map can be transformative and enable many of the world’s poorest and most vulnerable communities to have a chance at living healthy and productive lives.
- Record: found
- Abstract: found
- Article: found
Targeting autophagy using metallic nanoparticles: a promising strategy for cancer treatment
Marco Cordani, Álvaro Somoza (2018)
Despite the extensive genetic and phenotypic variations present in the different tumors, they frequently share common metabolic alterations, such as autophagy. Autophagy is a self-degradative process in response to stresses by which damaged macromolecules and organelles are targeted by autophagic vesicles to lysosomes and then eliminated. It is known that autophagy dysfunctions can promote tumorigenesis and cancer development, but, interestingly, its overstimulation by cytotoxic drugs may also induce cell death and chemosensitivity. For this reason, the possibility to modulate autophagy may represent a valid therapeutic approach to treat different types of cancers and a variety of clinical trials, using autophagy modulators, are currently employed. On the other hand, recent progress in nanotechnology offers plenty of tools to fight cancer with innovative and efficient therapeutic agents by overcoming obstacles usually encountered with traditional drugs. Interestingly, nanomaterials can modulate autophagy and have been exploited as therapeutic agents against cancer. In this article, we summarize the most recent advances in the application of metallic nanostructures as potent modulators of autophagy process through multiple mechanisms, stressing their therapeutic implications in cancer diseases. For this reason, we believe that autophagy modulation with nanoparticle-based strategies would acquire clinical relevance in the near future, as a complementary therapy for the treatment of cancers and other diseases.
Author and article information
Journal
Journal ID (nlm-ta): Int J Nanomedicine
Journal ID (iso-abbrev): Int J Nanomedicine
Journal ID (publisher-id): ijn
Journal ID (pmc): intjnano
Title:
International Journal of Nanomedicine
Publisher:
Dove
ISSN
(Print):
1176-9114
ISSN
(Electronic):
1178-2013
Publication date
(Electronic):
25
May
2021
Publication date Collection: 2021
Volume: 16
Pages: 3555-3564
Affiliations
[1
]Post-Graduate Program in Pharmaceutical Sciences, University of Sorocaba (Uniso) , Sorocaba, SP, Brazil
[3
]Bioengineering and Biomedical Engineering Programs, Technological and Scientific Institute,
Brazil University , São Paulo, Brazil
[4
]Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas
(Unicamp) , Campinas, SP, Brazil
Author notes
Author information
Sílvio Roberto Consonni
http://orcid.org/0000-0003-3149-021X
Marco Vinicius Chaud
http://orcid.org/0000-0003-3618-8415
Yoko Oshima-Franco
http://orcid.org/0000-0002-4972-8444
Article
Publisher ID: 293366DOI: 10.2147/IJN.S293366
PMC ID: 8164871
SO-VID: e2a9011b-9bd4-4606-b743-e84b3ee85fb3
Copyright © © 2021 Proença-Assunção et al.
License:
This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).
History
Date
received
: 25
November
2020
Date
accepted
: 27
April
2021
Page count
Figures: 5,
References: 57,
Pages: 10
Categories
Subject:
Original Research
ScienceOpen disciplines: Molecular medicine
Data availability:
ScienceOpen disciplines: Molecular medicine