The earliest descriptions of inflammatory joint diseases were first recorded on Ebers papyrus dating back to around 1500 BC, which also described the use of copper to reduce inflammation. A millennium later, the ancient Greek physician Hippocrates described a type of arthritis that involved joint swelling and pain that started in middle age and affected hands and feet (possibly gout). Galen, between 129 and 216 AD, introduced the term rheumatismus. Yet it wasn’t until 1858 when Alfred Baring Garrod demonstrated that increased blood uric acid was responsible for gout, thereby providing a differential diagnosis between gout and “rheumatoid arthritis”.1

The history of anti-inflammatory drugs also stretches back to antiquity and is an amalgam of natural products isolation, medicinal chemistry and clinical exploitation. Medicines made from willow bark appeared in Egyptian pharonic pharmacology papyri from the second millennium BC.3 The ancient Greeks chewed the bark of willow trees to alleviate pain and fever, and around 400 BC3 Hippocrates referred to their use to reduce fevers.

However, it was not until the 1800’s that the active ingredient in willow bark, salicin, which is metabolised to salicylate, was isolated.4 In 1899, Aspirin (acetylsalicyclic acid) the more palatable form of salicyclic acid was introduced into the market by Bayer.5

In 1830, discovery of copper in the blood fostered the beliefs of a causal link between copper deficiency and rheumatism.6 This lead to the evolution of metallotherapy, involving various applications of copper, gold and other metals in the treatment of joint inflammation. In 1879, James Compton Burnett, a medical doctor, homeopath, and prolific author, published a lengthy treatise on the use of gold in medicine and recommended a dosage of gold between 3-9/100 of a grain (a grain is 65 milligrams) which is equivalent to 1.95mg to 5.85mg.7 Yet the first scientific reports on the use of gold primarily to reduce inflammation and to slow progression of rheumatoid arthritis did not appear until 1935.8 Interestingly, in spite of lack of scientific evidence, devices such as bracelets and insoles, incorporating magnets, copper or other metals are still widely promoted and used for relieving pain and combating the progression of chronic musculoskeletal disorders, including most notably rheumatoid arthritis.9

The use of cortisone as an anti-inflammatory agent in the treatment of rheumatoid arthritis dates back to 1929 when Edward C. Kendall, a rheumatologist and Philip S. Hench, a biochemist, began isolating chemical moieties from bovine adrenal glands and experimenting with them in humans. In the 1930’s Kendall succeeded in isolating 6 hormones, each identified by a letter A through F. Four of the compounds were observed to have anti-inflammatory activities (A, B, E, and F). Compound A (11-dehydrocorticosterone) and Compound E (cortisone) were chosen for their initial studies owing to their structural simplicity. For their discovery, in 1950 Kendall and Hench shared the Nobel Prize in Physiology or Medicine together with Tadeus Reichstein, a Swiss scientist who also independently isolated hormones of the adrenal cortex.10

This was quickly followed by the isolation and structure identifications of prednisone and prednisolone by Arthur Nobile in 1950, and the first commercially feasible synthesis of prednisone was carried out in 1955 in the laboratories of Schering Corporation.11

However, during the subsequent years, permanent side effects of steroids proved challenging to patients and clinicians, and their long term use as a workable treatment for rheumatoid arthritis was abandoned. This led to the ensuing rise to prominence of the non-steroidal anti-inflammatory drugs (NSAIDs) from the 1970’s onwards.

The actions of NSAIDs can be divided into three categories: non-narcotic / non addictive analgesia; antipyretic; and in higher doses, anti-inflammatory effects.

Until the mid-1960’s, steroids, salicylates, phenacetin and the pyrazole phenylbutazone, and its metabolite oxyphenbutazone, were the most commonly used drugs in the treatment of joint-inflammation.

In 1963, Hart and Boardman published their finding on the anti-inflammatory effect of indomethacin.12 The development of indomethacin was quickly followed by the market release of ibuprofen in 1966 in the UK by the Boot Company (1974 in the US).

However in 1971, the two pharmacologists John Vane and Priscilla Piper discovered when inflammation was induced, the affected organ unexpectedly develops an enormous capacity to generate prostaglandins.13 The anti-inflammatory effects of aspirin and NSAIDs were due to their abilities in blocking the production of prostaglandins.14 15 For this discovery, in 1982 Vane was awarded a Nobel Prize in Physiology or Medicine.

Such a discovery led to the quick development of other novel NSAIDs for human use such as ketoprofen in 1972, diclofenac in 1973, naproxen in 1976, and piroxicam in 1977. However, taken long term, all NSAIDs were found to share a significant ulcerogenic gastrointestinal side-effect profile.

In 1973 the cyclooxygenase reaction through which arachidonic acid is enzymatically cyclized to prostaglandin was identified by Samuelsson & Hamberg.16 However, it was not until the late 1980 and early 1990’s that important discoveries by Daniel L. Simmons were made from elegant molecular and cellular biological studies confirmed the existence of two cyclooxygenase enzyme systems (COX) controlling the production of prostanoids: the constitutive COX-1 that produces prostaglandins, and thromboxane which regulate gastrointestinal, renal, vascular and other physiological functions, and the inducible COX-2 that produces prostaglandins involved in inflammation, pain and fever.17

Independent from the works of Daniel L. Simmons, the Dupont company had developed an oral compound, DuP-697, that was potent in many anti-inflammatory assays but did not have the ulcerogenic effects of NSAIDs. Once the COX-2 enzyme was identified Dup-697 became the building-block for synthesis of selective COX-2 inhibitors.18 Celecoxib, the first COX-2 inhibitor took less than eight years from development to market entry (December 1998 in the US). Rofecoxib (launched in the US in May 1999) and valdecoxib (launched in the US in 2001) were withdrawn from the market in September 2004 and April 2005 respectively due to significant increases in cardiovascular risks. Lumiracoxib (launched in Australia in 2006) was withdrawn from the market in August 2007 due to serious liver adverse reactions. Etoricoxib (launched in Australia in August 2009 as non-PBS medication) is the only other COX-2 inhibitor in the Australian market today.

By 2008, consensus was reached that long term administration of COX-2 selective medications could cause imbalance of prostaglandins in the vasculature leading to increased cardiovascular risk when compared to placebo.19

Do we have the last word on anti-inflammatories?

Although we are not there yet, we do see an exciting road ahead for more targeted anti-inflammatories.

Over the past two decades, the use of tumor necrotic factor inhibitors and monospecific monoclonal antibodies (MoAb) have demonstrated significant benefits in a subset of patients with joint inflammatory disorder (e.g. in rheumatoid arthritis). Excitingly, we are now seeing increasing research interest in the use of bispecific monoclonal antibodies (BsAb) and dual variable domain immunoglobulin (DVD-Ig) in the field osteoarthritis.20

In the meantime, lifestyle modification such as weight loss and exercise with the judicious short term use of anti-inflammatories during episode of flare are our recommended approach to managing mankind arthropathies.

References:

  1. G. D. Storey: Alfred Baring Garrod (1819–1907) Rheumatology. 2001. 40 (10):1189-1190.
  2. Lawrence J. Marnett The COXIB Experience: A Look in the Rearview Mirror Annu. Rev. Pharmacol. Toxicol. 2009. 49:265–90.
  3. Nunn, John F. “7”. Ancient Egyptian Medicine. Norman, OK, USA: University of Oklahoma Press. 996. pp. Ch. 7: Table 7.2. ISBN 0-8061-2831-3.
  4. Rajnish A. Gupta & Raymond N. DuBois Colorectal cancer prevention and treatment by inhibition of cyclooxygenase-2 Nature Reviews Cancer 1, 11-21 (October 2001).
  5. J. R. Vane. The fight against rheumatism: from willow bark to COX-1 sparing drugs. J Physiol Pharmacol, 51:573-586, 2000 and reference cited therein.
  6. Fox PL. The copper-iron chronicles: the story of an intimate relationship. BioMetals. 2003  16: 9–40.
  7. Douglas G. Richards, David L. McMillin, Eric A. Mein, Carl D. Nelson. Gold And Its Relationship To Neurological/Glandular Conditions International Journal of Neuroscience 2002, Volume 112, pages 31-53.
  8. Forestier J. Rheumatoid arthritis and its treatment with gold salts – results of six years experience.J Lab Clin Med. 1935. 20: 827–40.
  9. Stewart J. Richmond, Shalmini Gunadasa, Martin Bland, Hugh MacPherson. Copper Bracelets and Magnetic Wrist Straps for Rheumatoid Arthritis – Analgesic and Anti-Inflammatory Effects: A Randomised Double-Blind Placebo Controlled Crossover Trial PLoS ONE 8(9): e71529. doi:10.1371/journal.pone.0071529.
  10. Amy K. Saenger. Discovery of the Wonder Drug: From Cows to Cortisone The American Association for Clinical Chemistry 2010. 56:8 1349–1350.
  11. Merck Index, 14th Edition, p.1327. Published by Merck & Co. Inc.
  12. INDOMETHACIN: A NEW NON-STEROID ANTI-INFLAMMATORY AGENT – British Medical Journal 1963:965-970. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1873102/pdf/brmedj02520-0043.pdf
  13. Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat. New Biol. 1971.231:232–35.
  14. Smith JB,Willis AL. Aspirin selectively inhibits prostaglandin production in human platelets. Nat. New Biol.1971.231:235–37.
  15. Ferreira SH, Moncada S, Vane JR. Indomethacin and aspirin abolish prostaglandin release from spleen. Nat. New Biol.1971.231:237–39.
  16. Hamberg M and Samuelsson B. Detection and isolation of an endoperoxide intermediate in prostaglandin biosynthesis. Proc Natl Acad Sci USA. 1973.70:899-903.
  17. Daniel L. Simons, Regina M. Botting & Timothy HLA. Cyclooxygenase Isozymes: The Biology of Prostaglandin Synthesis and Inhibition. Pharmacol Rev 2004. 56:387–437.
  18. Gans KR Galbraith W,Roman RJ,Haber SB,Kerr JS,Schmidt WK, Smith C, Hewes WE, Ackerman NR. Anti-inflammatory and safety profile of DuP 697, a novel orally effective prostaglandin synthesis inhibitor J Pharmacol Exp Ther. 1990 Jul;254(1):180-7.
  19. Li, H., M. Hortmann, et al.Cyclooxygenase 2-Selective and Nonselective Nonsteroidal Anti-Inflammatory Drugs Induce Oxidative Stress by Up-Regulating Vascular NADPH Oxidases. J Pharmacol Exp Ther 2008. 326(3): 745-753.
  20. Susan E. Lacya, Chengbin Wug, Dominic J. Ambrosid, Chung-Ming Hsieha, Sahana Bosea, Renee Millera, Donna M. Conlonc, Edit Tarcsae, Ravi Charif, Tariq Ghayurd & Rajesh V. Kamathb Generation and characterization of ABT-981, a Dual Variable Domain Immunoglobulin (DVD-IgTM) molecule that specifically and potently neutralizes both IL-1α and IL-1β MAbs. March 2015. http://www.ncbi.nlm.nih.gov/pubmed/25764208

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