The ethics of research involving animals - Nuffield Council on ...
The ethics of research involving animals - Nuffield Council on ...
The ethics of research involving animals - Nuffield Council on ...
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T h e e t h i c s o f r e s e a r c h i n v o l v i n g a n i m a l s<br />
Box 8.1: <str<strong>on</strong>g>The</str<strong>on</strong>g> characterisati<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g> promising<br />
candidate medicines (stages 3 and 4): example<br />
<str<strong>on</strong>g>of</str<strong>on</strong>g> animal <str<strong>on</strong>g>research</str<strong>on</strong>g> undertaken during <str<strong>on</strong>g>of</str<strong>on</strong>g> the<br />
development process <str<strong>on</strong>g>of</str<strong>on</strong>g> a new medicine<br />
Jin, Q, Nie H, McCleland BW et al. (2004) Discovery <str<strong>on</strong>g>of</str<strong>on</strong>g><br />
potent and orally bioavailable N,N’-diarylurea<br />
antag<strong>on</strong>ists for the CXCR2 chemokine receptor Bioorg<br />
Med Chem Lett 14:4375-8.*<br />
<str<strong>on</strong>g>The</str<strong>on</strong>g> aim <str<strong>on</strong>g>of</str<strong>on</strong>g> this <str<strong>on</strong>g>research</str<strong>on</strong>g> was to test the ability <str<strong>on</strong>g>of</str<strong>on</strong>g> a series<br />
<str<strong>on</strong>g>of</str<strong>on</strong>g> compounds to bind to the CXCR2 chemokine<br />
receptor (thus blocking its functi<strong>on</strong>). CXCR chemokines<br />
are signalling molecules that play an important role in<br />
transporting neutrophils (a type <str<strong>on</strong>g>of</str<strong>on</strong>g> white blood cell) to<br />
sites <str<strong>on</strong>g>of</str<strong>on</strong>g> inflammati<strong>on</strong> in disease processes involved in<br />
arthritis, asthma and reperfusi<strong>on</strong> injury (where the<br />
body’s attempt to restore blood flow to an injury causes<br />
damage by oxidati<strong>on</strong>).<br />
A n<strong>on</strong>-animal in vitro assay was used to identify<br />
compounds which may bind to the CXCR receptor. Six<br />
compounds were identified and their affinity for the<br />
CXCR2 receptor, as well as their effect in a living body, was<br />
investigated. <str<strong>on</strong>g>The</str<strong>on</strong>g> degree <str<strong>on</strong>g>of</str<strong>on</strong>g> binding to the CXCR2<br />
Box 8.2: <str<strong>on</strong>g>The</str<strong>on</strong>g> characterisati<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g> promising<br />
candidate medicines (stages 3 and 4): example<br />
<str<strong>on</strong>g>of</str<strong>on</strong>g> animal <str<strong>on</strong>g>research</str<strong>on</strong>g> undertaken during the<br />
development process <str<strong>on</strong>g>of</str<strong>on</strong>g> a new medicine<br />
Irving EA, Vins<strong>on</strong> M, Rosin C et al. (2005) Identificati<strong>on</strong><br />
<str<strong>on</strong>g>of</str<strong>on</strong>g> neuroprotective properties <str<strong>on</strong>g>of</str<strong>on</strong>g> anti-MAG antibody: a<br />
novel approach for the treatment <str<strong>on</strong>g>of</str<strong>on</strong>g> stroke? J Cereb<br />
Blood Flow Metab 25: 98–107.*<br />
It had been previously hypothesised that a protein<br />
called myelin-associated glycoprotein (MAG) was a<br />
c<strong>on</strong>tributing factor to the lack <str<strong>on</strong>g>of</str<strong>on</strong>g> regenerati<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g> the<br />
CNS after injury, such as stroke. This <str<strong>on</strong>g>research</str<strong>on</strong>g> project<br />
dem<strong>on</strong>strated that the antibody specific to this protein,<br />
anti-MAG, possessed the ability to neutralise the<br />
inhibitory effect <str<strong>on</strong>g>of</str<strong>on</strong>g> MAG <strong>on</strong> neur<strong>on</strong>s following an<br />
induced stroke and, in additi<strong>on</strong>, protected certain CNS<br />
cells from cell death in vitro. Rats given the antibody<br />
improved in their motor functi<strong>on</strong> ability after the stroke<br />
compared with c<strong>on</strong>trol <str<strong>on</strong>g>animals</str<strong>on</strong>g>, measured by their<br />
ability to walk al<strong>on</strong>g a cylindrical beam. <str<strong>on</strong>g>The</str<strong>on</strong>g> authors<br />
c<strong>on</strong>cluded that the data indicated potential for the use<br />
receptor was then assessed in cell lines originally derived<br />
from the kidneys <str<strong>on</strong>g>of</str<strong>on</strong>g> Chinese hamsters.<br />
In a further test, the compounds were injected into<br />
groups <str<strong>on</strong>g>of</str<strong>on</strong>g> three rats. This was first d<strong>on</strong>e intravenously<br />
and then, in a later experiment, injected into the<br />
perit<strong>on</strong>eal cavity. This experimental format is designed to<br />
both reduce the number <str<strong>on</strong>g>of</str<strong>on</strong>g> <str<strong>on</strong>g>animals</str<strong>on</strong>g> used and<br />
experimental variati<strong>on</strong>. At various intervals after<br />
administrati<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g> the compounds, blood samples were<br />
taken from the lateral tail vein <str<strong>on</strong>g>of</str<strong>on</strong>g> the rats. Further in vitro<br />
studies using comp<strong>on</strong>ents <str<strong>on</strong>g>of</str<strong>on</strong>g> rat and human liver cells<br />
were carried out to investigate the way that the liver<br />
metabolises these compounds. <str<strong>on</strong>g>The</str<strong>on</strong>g>se cells were obtained<br />
from euthanised rats and from human tissue which had<br />
been removed during surgery. <str<strong>on</strong>g>The</str<strong>on</strong>g> <str<strong>on</strong>g>research</str<strong>on</strong>g> yielded a new<br />
class <str<strong>on</strong>g>of</str<strong>on</strong>g> CXCR2 compounds that are potent and effective<br />
in binding and blocking CXCR2 receptor functi<strong>on</strong>.<br />
* This is an example <str<strong>on</strong>g>of</str<strong>on</strong>g> animal <str<strong>on</strong>g>research</str<strong>on</strong>g> that has been carried out<br />
in the UK and published in a peer-reviewed journal. Details<br />
relate to this specific example and should not be taken to<br />
represent a ‘typical’ animal experiment. It is important to note<br />
that individually published experiments usually form <strong>on</strong>e part<br />
<str<strong>on</strong>g>of</str<strong>on</strong>g> a c<strong>on</strong>tinuing area <str<strong>on</strong>g>of</str<strong>on</strong>g> <str<strong>on</strong>g>research</str<strong>on</strong>g>, and the significance <str<strong>on</strong>g>of</str<strong>on</strong>g> the<br />
results may therefore be difficult to interpret.<br />
<str<strong>on</strong>g>of</str<strong>on</strong>g> the antibody as a therapeutic agent for the<br />
treatment <str<strong>on</strong>g>of</str<strong>on</strong>g> stroke.<br />
Under anaesthesia, small tubes were inserted into the<br />
brains <str<strong>on</strong>g>of</str<strong>on</strong>g> rats to enable the inducti<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g> a stroke. Two<br />
weeks later the rats were anaesthetised and a stroke<br />
was induced by causing a transient blockage <str<strong>on</strong>g>of</str<strong>on</strong>g> an<br />
artery in the brain for 90 minutes. Rats that displayed<br />
circling stereotypic behaviour <strong>on</strong>e hour following the<br />
surgical procedure were judged to be suitable models<br />
and therefore <strong>on</strong>ly these rats were included in the<br />
study. During the following week, the rats were<br />
administered with the test antibody at 1, 24 and 72<br />
hours after the stroke either into the brain or<br />
intravenously. <str<strong>on</strong>g>The</str<strong>on</strong>g>y were then euthanised.<br />
* This is an example <str<strong>on</strong>g>of</str<strong>on</strong>g> animal <str<strong>on</strong>g>research</str<strong>on</strong>g> that has been carried out<br />
in the UK and published in a peer-reviewed journal. Details<br />
relate to this specific example and should not be taken to<br />
represent a ‘typical’ animal experiment. It is important to note<br />
that individually published experiments usually form <strong>on</strong>e part<br />
<str<strong>on</strong>g>of</str<strong>on</strong>g> a c<strong>on</strong>tinuing area <str<strong>on</strong>g>of</str<strong>on</strong>g> <str<strong>on</strong>g>research</str<strong>on</strong>g>, and the significance <str<strong>on</strong>g>of</str<strong>on</strong>g> the<br />
results may therefore be difficult to interpret.<br />
8.17 Informati<strong>on</strong> about <str<strong>on</strong>g>research</str<strong>on</strong>g> carried out during stages 3 and 4 is <str<strong>on</strong>g>of</str<strong>on</strong>g>ten provided through oral<br />
communicati<strong>on</strong>s and posters at scientific meetings, and is later reported in scientific<br />
publicati<strong>on</strong>s. 22 Many thousands <str<strong>on</strong>g>of</str<strong>on</strong>g> such posters and publicati<strong>on</strong>s are published annually by<br />
industry. More recently, the Home Office has begun to make available abstracts <str<strong>on</strong>g>of</str<strong>on</strong>g> licensed<br />
<str<strong>on</strong>g>research</str<strong>on</strong>g> (see Box 13.4), which are likely to include many types <str<strong>on</strong>g>of</str<strong>on</strong>g> experiment undertaken to<br />
identify and optimise pharmaceutical leads. We c<strong>on</strong>sider issues relating to publicati<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g><br />
<str<strong>on</strong>g>research</str<strong>on</strong>g> in more detail in Chapter 15 (see paragraph 15.35).<br />
CHAPTER 8 THE USE OF ANIMALS FOR RESEARCH IN THE PHARMACEUTICAL INDUSTRY<br />
22 See PubMed, a service <str<strong>on</strong>g>of</str<strong>on</strong>g> the US Nati<strong>on</strong>al Library <str<strong>on</strong>g>of</str<strong>on</strong>g> Medicine, which includes over 15 milli<strong>on</strong> citati<strong>on</strong>s for biomedical articles<br />
dating back to the 1950s, available at: http://www.ncbi.nlm.nih.gov/pubmed. Accessed <strong>on</strong>: 26 Apr 2005.<br />
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