Reducing animal use in complex systems: using nausea and vomiting as a test case

Nausea and emesis (vomiting) are complex conditions that involve multiple organ systems including the brain, gastrointestinal system and the circulatory system. For this reason, animals (including mouse, rat, ferret, dog and non-human primate) have previously been considered the only possible model for:

  1. Understanding basic mechanisms which underlie the pathophysiology of nausea and emesis.
  2. Developing novel drugs  to treat nausea and emesis (anti-emetics).
  3. Assessing the potential for new chemicals to have nausea and emesis as side effects (emetic liability).

The utility of these models in predicting the human condition is questionable given the paucity of effective anti-emetic drugs clinically available and the number of marketed drugs (around 50%) which include nausea and vomiting as side effects.

Using nausea and emesis as a test case, we have demonstrated how 3Rs approaches can be employed to reduce reliance on animals in complex, multi-organ systems.

  • We have invested in research to develop imaging approaches to identify reliable biomarkers of nausea susceptibility in human subjects. Information generated in these studies can be used to better identify correlative biomarkers in animal models of nausea, potentially improving predictivity of the models and refining their use, and ultimately replacing them all together.
     
  • Through our CRACK IT Solutions technology partnering hub we have supported the development of a social amoeba (Dictyostelium discoideum) model for predicting the emetic liability and palatability of new drugs. This is now being further developed with GlaxoSmithKline for pharmaceutical industry application.

Working with Pfizer, we have funded a comparative study of the response induced by emetic compounds across species to investigate whether dogs, ferrets and rats are all similarly predictive of humans. This work provides an evidence base for species choice for assessing emetic liability of specific compound classes and was published in the British Journal of Pharmacology.

A hypothetical tiered approach to illustrate the assessment of potential emetic liability of novel chemicals that could reduce animal use.

Percie du Sert N, Holmes AM, Wallis R, et al (2012) Predicting the emetic liability of novel chemical entities: a comparative study. British Journal of Pharmacology 165: 1848-1867 doi: 10.1111/j.1476-5381.2011.01669.x

Holmes AM, Rudd JA, Tattersall FD, et al (2009) Opportunities for the replacement of animals in the study of nausea and vomiting. British Journal of Pharmacology 157: 865-80 doi: 10.1111/j.1476-5381.2009.00176.x

Robinson V (2009) Less is more: reducing the reliance on animal models for nausea and vomiting research. British Journal of Pharmacology 157: 863-864 doi: 10.1111/j.1476-5381.2009.00280.x

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