Animal Models for Assessing Countermeasures to Bioterrorism Agents (2011) / Chapter Skim
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5 Alternative Approaches to Animal Testing for Biodefense Countermeasures
5 Alternative Approaches to Animal Testing for Biodefense Countermeasures
Pages 61-76
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From page 61... ...
It briefly describes a number of in vitro and in vivo methods that support the Three Rs and humane endpoints. The Committee on Animal Models for Assessing Countermeasures to Bioterrorism Agents concludes that absolute replacement of animal models in countermeasure development is not possible at this time and that in vitro and in silico methods are not advanced enough yet (in part due to absence of human data)
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From page 62... ...
In other areas of research and development, especially in the agent discovery phase, replacement of older with more advanced methods is more common due to constant pressure for more predictive and less costly tests. In the case of developing countermeasures for bioterrorism agents where absolute dependence on animal models for efficacy testing serves to replace human clinical trials, the Three Rs provide a good framework to reduce animal use and minimize the animals'pain and distress.2 Because adoption of alternatives was driven by both animal welfare considerations and scientific advances in our understanding of biological phenomena, their utilization is often in the best interest of the study.
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From page 63... ...
can further reduce animal numbers and refine the experiments by minimizing pain and distress. Other noninvasive methods, such as imaging technologies and telemetry, that allow Biomarkers and signatures of toxicity that are often derived from nonanimal models are useful tools that make 6 animal studies more sensitive or facilitate earlier termination (with humane endpoints)
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From page 64... ...
Although this has been the standard practice in animal research protocols, such reliance solely on the test article to demonstrate efficacy may produce a misleading model of what the human counterpart may actually experience and lead to false or incomplete data on the effectiveness of the test product. Patients with dyspnea and acid and base imbalances due to pulmonary insufficiency, for example, would have to be provided with oxygen and intravenous electrolytes while enrolled in a trial to test the efficacy of a novel bronchodilator.
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From page 65... ...
In addition, longer survival of animal subjects due to an expanded repertoire of clinical support could result in better predictive models. If animals die too quickly,10 the pharmacokinetics and drug metabolism of the test product or the absence of effects of increased time on an effective immune response may not replicate or approximate the expected timelines in patients, resulting in misleading findings.11 Furthermore, subtle yet important differences in test products or dosages may become evident over a longer time frame of therapy due to prolonged animal survival.
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From page 66... ...
. In Vitro and In Silico Methods Biothreat agents are prime candidates for accelerated development and regulatory clearance of countermeasures by using animal models as alternatives to human clinical trials.
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From page 67... ...
and other effects identified through studies of the natural history of the disease, relevant human clinical trials, or other animal model work. These biosignatures and pathways so identified and tested could then be a bridge to IV/IS models.
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From page 68... ...
In this context, the computational approaches reduce animal testing by focusing future studies on the most promising leads and potentially by identifying biomarkers to develop humane endpoints for follow-up studies. In their current form, IV/IS tools and strategies cannot serve as complete replacements for animal models.
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From page 69... ...
1986, 1987a, 1987b) ; in this case, using surrogate animal models susceptible to monkeypox virus would be a more natural approach than the persistent use of variola virus on organisms with no natural affinity for this agent.
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From page 70... ...
Therefore, this information should be collected systematically, consistently, and accurately and be made available to the research community to enable progress toward standardization of methods and qualification of models, and to address ethical concerns regarding the potential nonproductive or duplicative use of animals or the unnecessary duplication of studies and waste of resources. • The provision of supportive veterinary care during animal efficacy trials for countermeasures is a means to improve data gathering from animal models to enhance the efficiency and productivity of this research field.
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From page 71... ...
In previous sections, the report outlines the need for the development of humane endpoints and biomarkers, for the administration of supportive clinical care, and for the alleviation of pain and distress. Medical countermeasures research and development for biodefense currently depends on the continued use of nonhuman primates, as discussed in chapter 2, and will probably remain so until such time that robust alternatives (either absolute or relative)
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From page 72... ...
2010. Gene expression profiling of monkeypox virus-infected cells reveals novel interfaces for host-virus interactions.
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Animal Models – Essential Elements to Address Efficacy Under the Animal Rule. Available online (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm 078923.pdf)
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Proc Natl Acad Sci USA 101(42)
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2000. Humane endpoints for infectious disease animal models.
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2004. Laboratory animal welfare: Cage enrichment and mouse behavior.
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