50th anniversary of the discovery of ibuprofen: an ...

Platelets, September 2012; 23(6): 415–422 Copyright ß 2012 Informa UK Ltd. ISSN: 0953-7104 print/1369-1635 online DOI: 10.3109/09537104.2011.632032

REVIEW

50th anniversary of the discovery of ibuprofen: An interview with Dr Stewart Adams GAYLE M. HALFORD, MARIE LORDKIPANIDZE´, & STEVE P. WATSON

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Centre for Cardiovascular Sciences, Institute of Biomedical Research, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom

Abstract 2011 marks the 50th anniversary of the discovery of ibuprofen. This article is a focus on the personal reflections and career of Dr Stewart Adams OBE, the scientist whose research lead to the discovery of the cyclooxygenase inhibitor. When Dr Adams discovered ibuprofen, he was working as a pharmacologist in the Research Department for the Boots Pure Drug Company Ltd. Dr Adams was assigned to work on rheumatoid arthritis (RA) and chose in 1953 to search for a drug that would be effective in RA but would not be a corticosteroid. He was one of the first workers in this field that later became known as NSAIDs (Non-Steroidal Anti-Inflammatory Drugs). In 1961, Dr Adams with John Nicholson, the organic chemist, filed a patent for the compound 2-(4-isobutylphenyl) propionic acid, later to become one of the most successful NSAIDs in the modern world, ibuprofen. In this article, Dr Adams gives his modest insight into the early stages and initial observations which led to this world-wide success.

Keywords: Ibuprofen, NSAIDs, Non-Steroidal Anti-Inflammatory Drugs, cyclooxygenase inhibitor

Stewart Adams: The early years Stewart Adams (Figure 1) was born into a working class background in the village of Byfield, Northamptonshire. He was the son of a railway driver whose failing eyesight caused his job to be downgraded and the family to move to March in Cambridgeshire, where Stewart attended grammar school. As a young boy, Stewart was interested in biology and in nature, and he had naturally thought about veterinary surgery as a career. However, when he left school at 16 (which he later much regretted) he had no clear aspirations or ambitions: ‘‘I have great sympathy with young people today as I could have gone either into Arts or Sciences’’.

Stewart Adams obtained his first job through a family contact. His aunt was a Justice of Peace in Daventry and she had a contact at the bench whose nephew was an executive at Boots. Thus at the age of 16 in 1939, he began an apprenticeship in retail pharmacy with the intention of becoming a pharmacist. He initially enjoyed the work especially as he was

able to work with local farmers in the largely rural area. However he quickly realised that he needed a more challenging career and so, after a 3 year apprenticeship, he chose to go to University College Nottingham to study for a B. Pharm degree instead of the normal pharmacy diploma. He was supported by a scholarship from the company of £40 for one year only and supplemented this by working on Sundays at a day-and-night pharmacy and during the holidays. Stewart Adams was the first person from his family to attend university. As a pharmacy student, he was in a reserved occupation in World War II, and he graduated in 1945, the period when Florey and Chain were undertaking their Nobel Prize winning work on penicillin production [1]. Shortly after graduation, Stewart Adams was offered the opportunity to work on the production of the antibiotic in the penicillin factory in Daleside Road in Nottingham (the old factory is still there). He worked on penicillin production (surface fermentation in milk bottles) for 18 months but found the job routine and unrewarding with little research content.

Correspondence: Gayle Halford, Centre for Cardiovascular Sciences, Institute of Biomedical Research, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. Tel: þ44-(0)121-415-8680. Fax: +44(0)121-415-8817. E-mail: [email protected] (received in final version 11 October 2011)


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G. M. Halford et al.

Figure 1.

A recent photograph of Dr Stewart Adams.

Stewart Adams transferred to the Bioassay Division of the Research Department in Boots in 1947. It was there that he met his wife and in 1950 they were married. During his time in the Bioassay Division, Stewart became interested in heparin and devised a new rapid technique for its assay, which was his first research experience. During this work, he discovered that when heparin solutions were heated, high levels of histamine were released. This sparked an interest in the relationship between histamine and heparin which formed the basis of his PhD studies in the University of Leeds where he was supported by a scholarship of £300 from a Pharmaceutical Society Scholarship, which was made up to £600 by Boots. His thesis was on the relationship between Heparin and Histamine in mast cells and was undertaken under the supervision of Professor Bain.

Searching for a novel treatment for rheumatoid arthritis Stewart Adams finished his PhD in 1952 and returned to the Research Department at Boots. The laboratories had been relocated to old buildings on the outskirts of Nottingham in 1939 at the start of the war and resources hence were limited [2]. A front

room of an old Victorian house, which is now a nursery (Figure 2), served as his laboratory and in time he expanded into the kitchen and larder. He was finally relocated to new and more suitable premises 6 years later [2]. Stewart Adams was assigned to a project to search for new treatments for Rheumatoid Arthritis (RA) [2,3]. The challenge that he faced was how to be effective in a small company with limited resources, himself and one technician. In the USA, a vast amount of research was being undertaken on steroids and new derivatives were already being developed. Furthermore, Dr Adams felt that the Research Department in Boots was using a series of poorly characterised and inappropriate tests to identify novel steroids and that there would be issues with their safety in the treatment of chronic disease. In mid 1953, Dr Adams began to think about looking for an agent that would have an effect like cortisone/cortical steroids, but would ‘chemically’ be non-steroidal [2,3]. Thus, he began to search for a novel Non-Steroidal Anti-Inflammatory Drug (NSAID). The breakthrough came when he read in an obscure dental journal [4], a paper which set him thinking about anti-inflammatory activity and in particular the action of aspirin which, at the time in high doses, was being used for the treatment of RA [5,6]. Dr Adams was further influenced through discussions with a clinical rheumatologist, Professor Duthie in Edinburgh, who was of the view that there was something ‘special’ about aspirin. Dr Adams felt that it was aspirin’s anti-inflammatory activity that accounted for its efficacy [2,3,7]: ‘‘Nobody really talked about anti-inflammatory activity in those days; if you look at Pharmacopoeias, you’ll find that up until 1962 aspirin was always analgesic antipyretic, so it was original to be thinking about anti-inflammatory activity’’,

Dr Adams set about trying to devise techniques that might pick up this anti-inflammatory activity, but without success [2,3]. He admits that his thinking at the time was rather woolly, but it must also be remembered that very little was known about the cause of RA or the mode of action of aspirin [7,8]. He was also involved in other projects at this time ‘‘which was the way our research was run in those days’’

which further diluted the limited resources. A breakthrough came when a pharmacist in the Medical Department sent Dr Adams a paper in 1955 authored by Wilhelmi, who was working for Roche in Switzerland [9]. The paper described an ultraviolet


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Figure 2. The Victorian house where Dr Adams was first allowed to conduct research for Boots, now converted to a nursery. The laboratory was the bay window, bottom right.

(UV) erythema model using guinea-pigs. Dr Adams characterised and refined this UV erythema model to increase accuracy and throughput before the investigation of experimental molecules could be attempted. He looked at a large number of compounds to establish whether the UV erythema model was a suitable test to detect anti-inflammatory effects of non-steroidal drugs [2,3]. Hydrocortisone was inactive in this assay and so were anti-histamines. The group tested a whole range of other compounds including those claimed to be active in RA. This included phenylbutazone, which by this time was known to be anti-inflammatory. Phenylbutazone and aspirin were active in the model. Sodium salicylate was also active but it was significantly less potent than aspirin, in line with the reduced clinical efficacy of salicylates in RA. Dr Adams did not have a clear idea of the mechanisms involved, but he was certain that the test was specific and it had the potential to identify new drugs for RA. Interestingly, 2 years later, Steve Winder at Parke Davis in the US published a paper which revealed that he had also been using this model for the same reason and at the same time, with the same outcomes and conclusions [10]. In 1956, Dr Adams produced a seminal report which was the basis for all future work and in which he outlined a number of chemical approaches [11]. To realise this ambitious research programme, he highlighted the need for chemical support ‘for which a strong plea is made’.

As a result, Dr John Nicholson, a highly capable chemist within the Chemistry Division in Boots, joined Dr Adams. Dr Nicholson’s appointment was to prove crucial to the success of the project and, as a team, Stewart Adams, Colin Burrows (his technician) and John Nicholson worked together for over 20 years. The 1956 report made a strong case for the development of salicylate derivatives with increased potency and enhanced safety over aspirin [11]. This became the foundation of the first wave of studies into new anti-inflammatory drugs (Box 1). However, after testing over 200 compounds derived from salicylates, it became clear that this line of research was unlikely to yield drugs superior to aspirin [3]. This initial disappointment of ‘not finding anything better than aspirin’ led Dr Adams and his team to consider other molecules. The studies with salicylates indicated that the carboxylic acid group was important [3]. Dr Nicholson thus turned his attention to simple compounds with carboxylic acid groupings, several of which were available in the Chemistry Division having initially been developed as part of the herbicide research programme. Two of the phenoxypropionic acids showed anti-inflammatory activity and Dr Nicholson and his colleagues went on to make over 600 analogues [2,3]. The most potent of these, BTS8402, underwent clinical trial for RA but was inactive [2,3]. This was a serious blow, but further work into the reasons for this failure suggested that a triad of properties might be necessary for the drug to be an effective treatment for RA


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(anti-inflammatory, analgesic and antipyretic), and BTS8402 was far less analgesic and antipyretic than anti-inflammatory [2,3]. With slight chemical manipulation, Nicholson produced substituted phenylacetic acetic and phenylpionic acids which possessed the three required properties [2,3]. It was decided to proceed with the acetics because, mistakenly, there had been some earlier evidence that they might be better tolerated [2,3]. The three acetics BTS10335, BTS10499 and ibufenac were, to the great relief of the team, all active in RA but BTS10335 and BTS10499 provoked rashes in an unacceptable number of patients [2,3]. However, ibufenac did not produce a rash, and showed good gastric tolerance; it was launched as a prescription drug in 1966 in the UK [2,3]. But there was further disappointment when it was later withdrawn because of liver toxicity on prolonged dosing [2,3]. Interestingly, ibufenac remained on the market in Japan for several years without serious side effects and there has never been an explanation for this [2,3]. It seemed possible after four clinical failures that this might be the end of the project, but new radioactive studies (a new laboratory had recently been set up) indicated that the acetics concentrated in certain tissues but the propionics much less so [12]. It was optimistically postulated that this might be the reason for the toxicity of the acetics [3]. Hence it was decided to concentrate on the phenylpropionics. In 1961, Dr Nicholson and Dr Adams applied for a patent for ‘‘Anti-Inflammatory Agents’’ which covered a broad collection of compounds, including compound 2-(4-isobutylphenyl) propionic acid which was later to be called ibuprofen (Figure 3) [2,3,8,13]. Between 1961 and 1964, Dr Adams and his team looked at the toxicity of a number of propionic compounds, including ibuprofen [2,3]. Dr Adams commented ‘‘there was a lot of guess work involved’’ but ibuprofen was chosen for further investigation despite the fact that it was not the most potent propionic but on the available evidence seemed likely to be the best tolerated [12– 16]. Dr Adams himself was the first person to take ibuprofen and also some of the other antiinflammatories (health and safety regulations were very different in those days). ‘‘there are certain side effects that you can’t study from animal testing, for example rash, nausea and headaches’’.

He claims he was also the first to establish its value for a hangover – confirmed by many since then! Ibuprofen was the fifth compound to go to clinical trial and was effective in RA with good gastric tolerance [2,3]. In 1969, it was approved in the UK

Figure 3. Patent specification for the UK Patent No. 971,700.

as a prescription drug for the treatment of the rheumatic diseases [2,3,8]. In the 1970s, extensive trials were carried out world-wide in a range of non-rheumatic painful conditions and it is on the basis of these that ibuprofen was eventually approved as an over-the-counter drug [17].

Searching for novel indications for ibuprofen As new indications emerged for aspirin and other anti-inflammatory drugs, ibuprofen was tested for new properties and applications in medicine [18]. Among the earliest new indications considered, prevention of thrombosis proved to be a challenging field to study. Early in the 1970s, ibuprofen was shown to have antithrombotic effects, similar but not as reliable as those of aspirin studied in parallel [19–23]. The reason for this was later ascribed to the reversible action of ibuprofen on the cyclooxygenase (COX) enzyme, which would require dosing multiple times a day to afford the same protection as aspirin could with once-daily dosing [24,25].


50th anniversary of the discovery of ibuprofen What also became quickly obvious was that there was competition for the active site of platelet COX-1 between ibuprofen and aspirin, and administering ibuprofen before aspirin precluded the latter from reaching its pharmacological target [26]. This resulted in premature recovery of the ability of platelets to form clots, and could thus leave patients at risk of thrombosis unprotected [25,27–29]. Recent studies have found NSAID use to be associated with increased risk of death and cardiovascular complications in patients at risk, and their use should thus be avoided in patients with previous history of cardiovascular disease [30,31]. A more successful application for ibuprofen is in the treatment of patent ductus arteriosus in preterm and/or low birth weight infants [32]. During foetal development, the foetus depends on the placenta for oxygenation of blood, and as a consequence, the foetal circulation bypasses the lungs through an arterial shunt called ductus arteriosus. However, after birth, circulation into the lungs is required, and the ducturs arteriosus is rapidly closed. Often in preterm or low birth weight infants, the ductus arteriosus remains patent which may lead to severe complications, and potentially death [32]. The mainstream of therapy has for a long time been indomethacin [33], a potent anti-inflammatory, but its severe side effects limit its use [32]. In a recent meta-analysis, ibuprofen was shown to be as effective as indomethacin in the treatment of arteriosus in preterm and/or low birth weight infants, and because it is associated with significantly less severe side effects, ibuprofen is recommended as the drug of choice in this condition [32]. Finally, another potential clinical avenue for ibuprofen is in the prevention of Parkinson’s disease. A number of observational studies have reported a protective effect of NSAID exposure, especially with ibuprofen, on the development of Parkinson’s disease [34–37]. It is too early to tell whether ibuprofen will be recommended as a prophylactic agent for Parkinson’s disease, however this interesting possibility opens yet new unexplored opportunities for ibuprofen use in the future.

Looking back on the path of ibuprofen discovery Dr Adams describes his work throughout his search for NSAIDs as ‘‘very much applied biology’’. The objectives were clear and he admits that he was ‘‘obsessed’’ in the search for the right compound even though nobody knew anything about how aspirin worked (it would be more than a decade before John Vane would uncover its mechanism of action [38]) or the major determinants of the UV erythema assay. Although these questions were of great interest to

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Dr Adams, his pragmatic approach and available resources kept him focused on the search for a new drug candidate. As he would later state: ‘‘Later as a senior scientist, I always encouraged my younger colleagues to take a walk in the woods and explore basic concepts, as long as they came out further along the road towards the development of a new drug’’.

Along the same lines, Dr Adams did not use sophisticated statistical methods to analyse his data at any stage in the project; he believed the extent of the effect he was looking for was sufficiently large to render complex statistical testing unnecessary. Boots was not renowned as a research company, even though it had had a pharmacology division since 1926. This may in part explain why, in the early days, Dr Adams was allowed to proceed with a large amount of freedom though few resources. This, he believed, sharpened his thinking. Dr Adams had an excellent relationship with members of the Medical Division and particularly its Head who gave him much encouragement and many contacts with rheumatologists. The many discussions he held with another member of the Medical Division, Ray Cobb, also sharpened his thinking. They discussed many ideas together and went on to publish a paper in Nature on ‘A Possible Basis for the Anti-inflammatory Activity of Salicylates and other Non-Hormonal Anti-Rheumatic Drugs’ [7]. This was the only significant publication from Dr Adams during this time, as he had little time to publish and nor did he wish to give away data on the compounds he was working on. Life after the discovery of ibuprofen From 1962 to 1969, the group moved from the Victorian house to a new, larger building, where the team began to grow [2,3]. The search for more compounds continued. Among the propionics, the second candidate to be recommended for clinical testing was flurbiprofen, later commercialised but with disappointing success given the promise from pre-clinical and clinical testing [2,3]. From 1969 to retirement from research (14 years), Dr Adams moved firstly to Head of Pharmacology at Boots and then to Head of Pharmaceutical Sciences where he was responsible for chemistry and biological research. His interest in non-steroidals remained throughout this period. He felt that too many NSAIDs were being introduced on the market, and that many should not have been marketed at all for reasons of toxicity, and he spoke and wrote about this [39,40]. When asked why he had stayed at Boots during almost his entire career, Dr Adams replied that he

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Box 1. Ibuprofen development and its way through the clinic. From an early stage, the objectives set out by Dr Adams for the research and development effort which produced a series of compounds including ibuprofen by the Boots Pure Drug Company Ltd were clear: to find a drug for the treatment of rheumatoid arthritis that (a) could be administered by mouth; (b) was effective in doses much lower than those inducing toxicity; (c) was not corticosteroid-like in chemistry or biological action; (d) had a novel chemical structure; (e) would be more effective than aspirin; and (f) would have a good safety profile, especially in the gastrointestinal tract. With the purpose to test the anti-inflammatory properties of various chemical compounds synthesised by Dr John Nicholson, the research team led by Dr Adams investigated the potency of these chemicals on the UV erythema model on guinea pigs [9]. It became apparent that the carboxyl group held an importance in the anti-erythemic activity of aspirin [2,3]. More than 600 phenoxyacids were studied, and some were found to be up to 10 times more potent than aspirin [2,3]. Compound BTS8402 was selected as a lead and was tested in patients suffering from rheumatoid arthritis, but was found ineffective [2,3]. Later investigation into the properties of BTS8402 has shown it to be highly anti-erythemic, but lacking the analgesic and antipyretic properties required [2,3]. Nicholson decided to look at close relatives of phenoxyacids and produced phenylacetic and phenylpropionic acids which possessed the triad of properties now deemed essential (anti-inflammatory, analgesic and antipyretic). Among them, BTS 10335 was sent to clinical trials and was found effective in patients suffering from rheumatoid arthritis, but further development of the drug was abandoned when half of the exposed patients developed a severe rash [2,3]. The encouraging data in terms of efficacy of BTS 10335 paved the way towards a new candidate drug, ibufenac, which was tried in patients with rheumatoid arthritis and found active, without side effects on the skin, nor evidence of gastric irritation [2,3]. The drug was marketed, but later withdrawn from the UK market because of liver toxicity in a minority of patients. It remained on the market in Japan, where it became a leading drug until the late 1960s [2,3]. The next compound to be clinically tested, BTS 10499, was found effective in treating rheumatoid arthritis, but like BTS 10335 provoked a rash in one fifth of patients which halted its development [2,3]. For this reason, Dr Adams decided to abandon the 4-substituted pheylacetics, and to concentrate on 4-substituted phenylpropionics in search of a new lead compound. Among the vast family of propionics tested, ibuprofen was selected in 1961 on the basis of reasonable potency and a promising safety profile [2,3]. Clinical testing of ibuprofen showed that it was effective in treating patients with rheumatoid arthritis, with a good safety margin. Ibuprofen was introduced on the market in 1969 in the UK and in 1974 in the USA with the indication of the treatment of rheumatic diseases [2,3]. In recognition of its safety profile, ibuprofen achieved over-the-counter status in the UK in 1983 and in the USA in 1984 [17].

Box 2. Ibuprofen use in clinic. Ibuprofen’s success in providing relief of pain and inflammation with a strong safety profile has made it among the most popular overthe-counter (OTC) analgesics [17]. Although the pattern of use of OTC analgesics varies from country to country, ibuprofen remains especially popular in treating minor aches and pains, particularly if these are accompanied by an inflammatory state [17]. The main indications of OTC use of ibuprofen include treatment of mild to moderate pain associated with inflammation including dental pain, headache and migraine, osteoarthritis, dysmenorrhoea, postoperative analgesia, and aches and fever associated with immunisation [17,41]. The drug is also commonly used for fever with discomfort and pain in children [41]. Nevertheless, new research continues to unearth unexpected benefits of ibuprofen. For example, it is replacing indomethacin as therapy in the closure of ductus arteriosus in preterm and/or low birth weight infants and has been associated with a reduced risk of Parkinsons disease [32,37].

had received other job offers but was never tempted to move. His view at that time was that many companies were ‘‘using unethical marketing methods’’ and ‘‘Boots had always been a very ethical company’’ and this was very important to him. Reflections and inspirations Throughout Dr Adams’ career, it was apparent that medical professionals influenced his work a great

deal. He found rheumatological meetings to be particularly important because of contact with clinicians. He talks fondly about numerous discussions with clinical rheumatologists, most notably Dr Duthie at Edinburgh, Dr Bywaters at Taplow and Dr Hill at Stoke Mandeville. In contrast, he seldom attended meetings of, for example, the British Pharmacological Society because at that time they had no interest in anti-rheumatic drugs or aspirin.


50th anniversary of the discovery of ibuprofen In Stewart Adams’s view, the peak of this story was the launch in the UK of ibuprofen in 1983 as an over-the-counter (OTC) drug, 30 years after he began [3,17]. It was one of the earliest prescription drugs to successfully switch to OTC status based on good safety and good clinical efficacy [17]. Ibuprofen is among the most commonly used NSAIDs in the world and continues to be used for an ever increasing number of indications (Box 2) [41]. Looking at the development of drugs in the modern era, Dr Adams feels that many companies and research departments are too big, which makes him wonder whether they are fully focussed on the goal of drug discovery. When asked about advice to a young person starting out today, he recommended doing additional research in University, trying and studying for a PhD and possibly joining a small company ‘‘because they are small and need to survive by producing promising drugs and an individual can have influence’’.

Dr Adams’ hero was Louis Pasteur as he put ‘‘good academic research to practical use’’. But Dr Adams emphasised very strongly that he and Nicholson were only at the beginning of the process and that many people were involved in the success of ibuprofen. As the project proceeded, more people from different disciplines were involved, e.g. toxicologists, biochemists, clinicians, and even chemists developing new synthetic routes for a factory built specifically for the manufacture of the drug. All of these people contributed to ibuprofen’s success. Concluding remarks The journey to the discovery of ibuprofen had no sudden flashes of perception but was far from ‘‘woolly thinking’’. Above all, it was achieved by determination and clarity in thought, avoiding unnecessary distractions such as basic research and the writing of papers. Dr Adams maintains that team work was crucial to the accomplishment, but the liberty within Boots to act on his own ideas with minimal hierarchal input was also instrumental in the success – Dr Adams was allowed to pursue his goal and as a result he succeeded. Dr Adams likes to think that, as Louis Pasteur said ‘‘Chance favours the prepared mind’’.

Acknowledgement We are grateful to Dr Stewart Adams for sharing his personal reflections and thoughts for discussion.

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Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

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