Editorials
`
`should limit the scope of subject matter that can be
`patented and provide extensive safeguards to ensure
`that patent rights are not exploited inappropriately.
`The agreement signed on 30 August 2003 falls far
`short of this recommendation.
`Lastly the UK commission, again, has drawn atten-
`tion to the complexity of the legal and administrative
`architecture of
`the WTO and the way in which
`developing countries are disadvantaged in the negotia-
`tions and by the absence of civic dialogue and public
`debate.7 Until these issues are put at the top of the
`
`WTO agenda the real effect of this and any future trade
`rounds will continue to be the entrenchment of the
`interests of western countries and their industries.
`
`Allyson M Pollock professor
`(allyson.pollock@ucl.ac.uk)
`David Price senior research fellow
`Public Health Policy Unit, School of Public Policy, University College
`London, London WC1H 9QU
`
`Competing interest: None declared.
`
`1 WTO. Declaration on the TRIPS agreement and public health. Geneva: WTO,
`20 November 2001 (WT/MIN(01)/DEC/2).
`2 Raghavan C. Medicines won’t be cheaper under TRIPS and public health
`decision. Geneva: Third World Network, 31 Aug 2003. www.twnside.
`org.sg/title/5409b.htm (accessed 7 Sep 2003).
`3 Koivusalo M, Rowson M. Who will inherit the earth? Health Matters
`2000;41. www.healthmatters.org.uk/stories/rowson2.html
`(accessed 8
`Sep 2003).
`4 Braithwaite J, Drahos P. Global business regulation. Cambridge: University
`Press 2000:39-87.
`5 WTO takes first step. Lancet 2003;362:753.
`
`6 WTO. Implementation of paragraph 6 of the Doha declaration on TRIPS and
`public health. Geneva: WTO, August 2003 (W/TL/540).
`7 Commission on Intellectual Property Rights. Integrating property rights
`and development policy. London: CIPR, 2002. www.iprcommission.org/
`graphic/documents/final_report.htm (accessed 8 Sep 2003.)
`8 Drahos P. Biotechnology patents, markets and morality. European Intellec-
`tual Property Review 1999;21:441-9.
`9 Trouiller P, Olliaro P, Torreele E, Orbinski J, Laing R, Ford N. Drug devel-
`opment for neglected diseases: a deficient market and public health
`policy failure. Lancet 2002;359:2188-94.
`
`What are all the things that aspirin does?
`This fascinating but simple and cheap drug has an assured future
`
`Ask any medical student and he or she will tell
`
`you that aspirin reduces fever, pain, and
`inflammation but may cause ulcers. Students
`may also recollect that it prolongs bleeding, and may
`prevent strokes and heart attacks, but would be unlikely
`to know of its use in cancer or Alzheimer’s disease.
`A defining point in the history of aspirin was the dis-
`covery that it inhibited the prostaglandin forming cyclo-
`oxygenase.1 Prostaglandins cause inflammation, fever,
`and pain; have gastric cytoprotective actions; and are
`implicated in platelet aggregation, so this discovery pro-
`vided a unified explanation for the effects of aspirin (and
`most other non-steroidal anti-inflammatory drugs).
`However, events took an even more interesting turn
`when a further isoform of cyclo-oxygenase, cyclo-
`oxygenase-2, was discovered.2 While similar in many
`ways to the original enzyme (COX 1) there were impor-
`tant differences, including the fact that COX 2 was
`induced in cells by inflammatory insults. COX 2
`therefore seemed to be the most relevant target in
`inflammation, which led to the notion that the constitu-
`tive COX 1 generated prostaglandins required to main-
`tain physiological functions (such as protection of the
`gastric mucosa, platelet aggregation) whereas COX 2
`generated pro-inflammatory mediators.3 Aspirin inhib-
`ited both isoforms, as did most non-steroidal anti-
`inflammatory drugs, perhaps explaining why these
`compounds were not only effective therapeutically but
`also had characteristic side effects.
`The ensuing search by the pharmaceutical industry
`for selective COX 2 inhibitors culminated in the recent
`introduction of new, safer anti-inflammatory drugs as
`well as the rediscovery of older drugs that had COX 2
`selective actions. But, as aspirin inhibits both isoforms,
`why does it continue to be used and why is there con-
`tinuing interest in its pharmacology?
`The answer to the first part of this question is partly
`down to aspirin’s unique mechanism of action that
`inhibits both COX 1 and COX 2 irreversibly. The effects
`
`of this are evident in platelets where cyclo-oxygenase
`cannot be replaced, explaining why a single aspirin can
`depress platelet aggregation for many days. The half life
`of aspirin in plasma is short; esterases remove the acetyl
`group leaving free salicylate, which may have a
`secondary pharmacological effect
`through cyclo-
`oxygenase inhibition or other mechanism, adding to the
`complexity of aspirin’s action.
`The current interest in aspirin stems from the fact
`that many animal experiments and human epidemio-
`logical studies now link aspirin (and other non-steroidal
`anti-inflammatory drugs) with beneficial effects in
`various cancers, including breast, ovarian, oesophageal,
`and colorectal cancer. Recent meta-analyses supported
`the idea that the overall relative risk of colorectal cancer
`is reduced in people taking long term aspirin.4 Another
`meta-analysis of observational data confirmed a protec-
`tive effect in oesophageal cancer and provided evidence
`of a relation with dose and duration of treatment, and
`other studies showed a beneficial effect in ovarian can-
`cer.4 5 How aspirin or other non-steroidal anti-inflam-
`matory drugs produce this effect is not entirely clear, but
`the synthesis or activity of COX 2 is increased in many
`tumours, and inhibition could activate apoptotic mecha-
`nisms or suppress angiogenesis.6 It has even been
`suggested that the link between diet and the prevention
`of colorectal cancer is attributable to the presence of
`salicylic acid in plant and vegetable foodstuffs.7
`Evidence from longitudinal studies of long term
`users of non-steroidal anti-inflammatory drugs origi-
`nally pointed to a reduced risk of Alzheimer’s disease,8
`and these findings are supported by other, more recent
`data,9 where an inverse relation was found between
`taking
`aspirin (and
`other non-steroidal
`anti-
`inflammatory drugs) and Alzheimer’s disease, but not
`other
`forms of dementia. The mechanism is
`uncertain—Alzheimer’s has an inflammatory compo-
`nent and therefore COX 2 may be the target, although
`other mechanisms have been suggested.10
`
`BMJ 2003;327:572–3
`
`572
`
`BMJ VOLUME 327 13 SEPTEMBER 2003 bmj.com
`
`Cosmo Ex. 2166, Page 1
`CFAD v. Cosmo; IPR2015-00988
`
`

`
`Editorials
`
`Two questions bedevil what is otherwise an exciting
`therapeutic prospect. What
`is the minimum dose
`required to achieve these effects, and how can we assess
`the relative risk and benefit of a preventive treatment
`that will entail treating healthy people for many years
`with a drug known to have gastric and other side
`effects? It is here that aspirin’s grandchildren may have
`a role. COX 2 seems to be the main culprit in both
`cancer and Alzheimer’s, so the selective COX 2 inhibi-
`tors, which have reduced gastric side effects, are natural
`choices for such long term prophylactic treatment.
`What of the future of aspirin itself? Because of its
`profound effects on platelets it
`is unlikely to be
`supplanted as a cheap and effective prophylactic treat-
`ment for those patients at risk from excessive platelet
`aggregation, but in view of its venerable history, it is
`surprising that aspirin is still the subject of ongoing
`medicinal chemistry effort. Attaching a nitric oxide
`donor to the molecule seems to ameliorate the side
`effects of
`the drug while boosting its therapeutic
`effects.11 The discovery of a third form of cyclo-
`oxygenase,12 mainly confined to the central nervous
`system and heart, which is also inhibited by aspirin, will
`no doubt provide yet another twist to the continuing
`story of this fascinating but simple drug.
`Rod Flower professor of biochemical pharmacology
`William Harvey Research Institute, London EC1M 6BQ
`
`Competing interests: RF is on the scientific advisory board of
`Nicox Spa and has received consulting fees and research
`support from this company. He has appeared as an expert wit-
`ness for Searle-Monsanto, manufacturer of Celebrex.
`
`1 Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action
`for aspirin-like drugs. Nat New Biol 1971;231:232-5.
`2 Xie WL, Chipman JG, Robertson DL, Erikson RL, Simmons DL. Expres-
`sion of a mitogen-responsive gene encoding prostaglandin synthase is
`regulated by mRNA splicing. Proc Natl Acad Sci U S A 1991;88:2692-6.
`3 Mitchell JA, Akarasereenont P, Thiemermann C, Flower RJ, Vane JR.
`Selectivity of nonsteroidal antiinflammatory drugs as inhibitors of consti-
`tutive and inducible cyclooxygenase. Proc Natl Acad Sci U S A 1993;
`90:11693-7.
`4 Bosetti C, Gallus S, La Vecchia C. Aspirin and cancer risk: an update to
`2001. Eur J Cancer Prev 2002;11:535-42.
`5 Corley DA, Kerlikowske K, Verma R, Buffler P. Protective association of
`aspirin/NSAIDs and esophageal cancer: a systematic review and
`meta-analysis. Gastroenterology 2003;124:47-56.
`6 Thun MJ, Henley SJ, Patrono C. Nonsteroidal anti-inflammatory drugs as
`anticancer agents: mechanistic, pharmacologic, and clinical issues. J Natl
`Cancer Inst 2002;94:252-66.
`7 Paterson JR, Lawrence JR. Salicylic acid: a link between aspirin, diet and
`the prevention of colorectal cancer. QJM 2001;94:445-8.
`8 Stewart WF, Kawas C, Corrada M, Metter EJ. Risk of Alzheimer’s disease
`and duration of NSAID use. Neurology 1997;48:626-32.
`9 Broe GA, Grayson DA, Creasey HM, Waite LM, Casey BJ, Bennett HP, et
`al. Anti-inflammatory drugs protect against Alzheimer disease at low
`doses. Arch Neurol 2000;57:1586-91.
`10 Gao F, Bales KR, Dodel RC, Liu J, Chen X, Hample H, et al. NF-kappaB
`mediates IL-1beta-induced synthesis/release of alpha2-macroglobulin in
`a human glial cell line. Brain Res Mol Brain Res 2002;105:108-14.
`11 Burgaud JL, Ongini E, Del Soldato P. Nitric oxide-releasing drugs: a novel
`class of effective and safe therapeutic agents. Ann N Y Acad Sci 2002;
`962:360-71.
`12 Chandrasekharan NV, Dai H, Roos KL, Evanson NK, Tomsik J, Elton TS,
`et al. COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and
`other analgesic/antipyretic drugs: cloning, structure, and expression. Proc
`Natl Acad Sci U S A 2002;99:13926-31.
`
`The Wanless report and public health
`Wanless’s fully engaged scenario means a bigger role for public health
`
`Poor levels of health in the population will put
`
`considerable pressure on the NHS that risks
`swamping the government’s efforts to meet tar-
`gets and achieve solid gains through its sizeable injec-
`tion of money. Not surprising, then, that former banker
`Derek Wanless’s
`report on long term funding
`challenges for the NHS, which was published last year,
`struck a chord with ministers and advisers.1 In his 2003
`budget the chancellor invited Wanless to provide an
`update of the long term challenges in implementing
`the fully engaged scenario.2 This scenario was the most
`ambitious and optimistic of
`the three scenarios
`described in Wanless’s first report and has been
`endorsed by the government.
`It contains heroic
`assumptions about the ability of people to take greater
`responsibility
`for
`their health, and services
`to
`transform themselves
`through efficient use of
`resources and a high rate of uptake of technology. A
`dramatic improvement in health status is anticipated
`with life expectancy going beyond current forecasts.
`But the real appeal of the scenario for the government
`lies in an estimated saving to the NHS of some £30bn
`($47bn; €43bn) if it succeeds.
`The plea of
`the former health secretary Alan
`Milburn for a better balance between prevention and
`treatment
`in health policy seems
`to have gone
`unheeded.3 The government remains preoccupied with
`downstream acute care. The call for a “sea change in
`attitudes” has not happened. Public health remains mar-
`ginalised and lacks capacity, especially in primary care
`
`trusts, to challenge effectively the prevailing orthodoxy.
`Yet the outpouring of policy statements testifying to the
`grim picture of the nation’s health continues. The latest
`is an action plan designed to promote “often minor
`changes in the way . . . services are provided,” in the hope
`of “making today’s inequalities a thing of the past.”4
`The action plan concedes that “health inequalities
`are stubborn, persistent and difficult to change.” But
`they are also widening “and will continue to do so
`unless we do things differently.” The health gap
`between rich and poor is growing in line with the
`income gap, and a generation of overweight and
`underexercised individuals is maturing.
`The scenario will be unpicked and developed in the
`progress report on which Wanless is engaged, to identify
`cost effective public health interventions. But the review
`contains two further key features. Firstly,
`it will be
`concerned with assessing how public health policy is
`formed. Secondly, it will examine national and local gov-
`ernmental arrangements for delivering the public health
`agenda set out in the NHS Plan (chapter 13) and in sub-
`sequent guidance and targets.5 This means Wanless’s
`reach will go well beyond the NHS and embrace local
`government, regional bodies, and others engaged in
`health improvement and tackling health inequalities.
`With his private sector background, Wanless is
`regarded as someone the government can trust. He is
`respected and listened to. His progress report, to be
`completed by late February, will be presented not just
`to the chancellor but also to the prime minister and the
`
`BMJ 2003;327:573–4
`
`BMJ VOLUME 327 13 SEPTEMBER 2003 bmj.com
`
`573
`
`Cosmo Ex. 2166, Page 2
`CFAD v. Cosmo; IPR2015-00988