The RVC is committed to the 3Rs principles of in-vivo research - reduction, replacement and refinement. Recent research conducted at the RVC has led to developments in the way anti-sickness medications are developed and tested.
The study was designed to improve the standard protocol for this type of research by refining the dose to limit the negative side-effects and allowing for repeated doses - thus reducing the number of animals needed for research.
The dog is the closest species to humans in its response to stimuli that cause nausea, and therefore is the best species to screen new anti-sickness drugs before commencing human trials. Currently, when testing anti-sickness drugs, nausea is induced by administering a dose of cisplatin, a drug used in chemotherapy for both human and veterinary medicine. However, the dose customarily used to induce nausea has negative side-effects. The RVC research sought to reduce these and improve the welfare of the animals involved.
The research demonstrated that a reduced dose of cisplatin still causes measurable nausea and vomiting but significantly decreases its severity and reduces the side effects the drug has on kidney function and bone marrow. Having reduced the adverse side-effects, this lower dose allows for the safe administration of repeated doses of cisplatin in more powerful cross-over study designs. This means that as well as reducing the number of animals needed in anti-sickness drug development, dogs used in this type of research may be re-homed at the end of the studies.
The dogs used in the RVC studies of nausea were all healthy at the end of the study and were re-homed. This was possible because of the high quality care provided by the research team and because the dogs were socialised to make them suitable for domestic life as pets after the study. In addition to refining the model for future anti-sickness drug development, the research has also identified biomarkers of nausea that will benefit both veterinary clinical practice and pre-clinical screening of new drugs for both human and veterinary use.
Benefits for canine patients
As discussed above, the research has informed the development of a biomarker which is measurable in the blood. This is now being applied to clinical patients to facilitate the recognition and treatment of nausea in dogs.
As a subjective experience that animals are unable to verbalise, nausea is a significant welfare issue in veterinary medicine. Studies are ongoing in clinical patients, with their owner's consent, on dogs receiving different types of therapy thought to be associated with nausea. This will help us to see objectively which do suffer from this problem and will hopefully improve our ability to recognise nausea. As the biomarker reduces in the blood with effective treatment, it will also help us determine how best to treat nausea in veterinary medicine. Our research already suggests that there may be better drugs to manage nausea in dogs than those routinely used in clinical practice.
Benefit for pre-clinical drug development programmes
This biomarker may also make the screening of drugs in the research and development process for human use more objective. Dogs are used in this process at the present time as they best predict adverse effects of drugs on many organ systems in humans. At the present time, drug-induced nausea is one of the most common reasons for a new drug failing in development for human use when it enters Phase 1 Clinical trials. Better ways of detecting nausea in the dogs used to screen drugs under development for human use would prevent new drugs continuing in development at an early stage of their pre-clinical screening and therefore further reduce the number of animals required for the purpose of developing new drugs in the future.
The biomarkers we discovered in our research may provide this more accurate and objective assessment preventing further unnecessary testing of drugs that will prove to be unsuitable for chronic human use because they cause side effects of nausea.