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Anti-inflammatory glucocorticoid drugs: reflections after 60 years

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Abstract

This review considers the problem of the serious concomitant side effects of powerful anti-inflammatory drugs modelled upon the principal human glucocorticoid hormone, cortisol. The very nature of the original bio-assays to validate their cortisol-like hormonal and anti-inflammatory activities ensured that pleiotropic toxins were selected for clinical studies. Other complicating factors have been (1) considerable reliance on bio-assays conducted in laboratory animals that primarily secrete corticosterone, not cortisol, as their principal anti-inflammatory adrenal hormone; (2) some differences in the binding of xenobiotic cortisol analogues (vis á vis cortisol) to transport proteins, detoxifying enzymes and even some intra-cellular receptors; (3) the “rogue” properties of these hormonal xenobiotics, acting independently of—but still able to suppress—hormonal mechanisms regulating endogenous cortisol; and (4) problems of intrinsic/acquired “steroid resistance”, diminishing their clinical efficacy, but not necessarily all their toxicities. The rather gloomy conclusion is that devising new drugs to reproduce the effect of multi-potent hormones may be a recipe for disaster, in contexts other than simply remedying an endocrine deficiency. Promising new developments include “designed” combination therapies that allow some reduction in total steroid doses (and hopefully their side effects); sharpening strategies to limit the actual duration of steroid administration; and resurgent interest in searching for more selective analogues (both steroidal and non-steroid) with less harmful side effects. Some oversights and neglected areas of research are also considered. Overall, it now seems timely to engage in some drastic rethinking about (retaining?) these “licensed toxins” as fundamental therapies for chronic inflammation.

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Notes

  1. Over the years 1958–1961, the author was commissioned by the Institute of Scientific Information, Philadelphia, PA to read 17 mainline chemistry journals (published from the USA, UK, Switzerland, France, Italy, Czechoslovakia and Holland) to note all new structures that were non-progestational C21 oxysteroids, both chemical intermediates and hormonally active. They numbered well over 200/month. The patent literature at that time disclosed even more structures. [The published structures of these newly reported steroids were coded for an IBM computer database maintained at the US National Library of Medicine, Washington, DC which was then generously made available to research centres worldwide.]

  2. Until the very late 1960s this was the first practical experiment in pharmacology for medical students at UCLA; a convincing demonstration of both the difficulties in assaying some traditional drugs and more educationally, just how hazardous such drugs might be for human use.

  3. For example, it has been possible to re-induce a response to low-dose prednisone (5 mg) in COPD-patients by administering anti-inflammatory emu oils (AG Turner private communication) as supportive therapy.

  4. The patent system rewards innovation, not development. So processes of repurposing or repositioning existing drugs usually attract little commercial interest.

  5. Considerable data for this exercise undoubtedly exists—much of it not in the public domain—and that is a real difficulty. For those drugs now well out of patent protection, some generosity of disclosures would be most helpful.

  6. It is particularly unfortunate that access to (largely unpatentable) supportive phytotherapies and medicinal animal products has now come under so much prohibitive government regulation, largely at the behest of Big Pharma and Big Food in Europe and the USA. This is at a time when they might be most needed to help prevent/minimise the ravages of steroid therapy.

  7. A consortium of 20 rheumatologists (Hoes et al. 2007) presented an 11-item research agenda relating to the management of systemic glucocorticoid therapy. Six of these items posed question about GC-associated toxicities, with particular concerns about cardiovascular risk, altered lipid profiles, skin and opthalmic adverse effects and myopathy. [Regrettably this present review has failed to consider these particular issues. Perhaps other commentators can repair these omissions, preferably sooner than later.].

References

  • Adcock IM, Barnes PJ (2008) Molecular mechanisms of corticosteroid resistance. Chest 134:394–401

    Article  CAS  PubMed  Google Scholar 

  • Albrechtsen SJ (1991) Philip Showalter Hench. In: Magill FN (ed) The nobel prize winners: physiology or medicine, vol 2. Salem Press, Pasadena CA, pp 627–635

  • Alourfi Z, Donn RP, Stevens A, Berry A, McMaster A, Ray DW (2005) Glucocorticoids suppress macrophage migration inhibitor factor (MIF) expression in a cell-type-specific manner. J Mol Endocrinol 34:583–595

    Article  CAS  PubMed  Google Scholar 

  • Auphan N, DiDonato JA, Rosette C, Heimberg A, Karin M (1995). Immunosuppression by glucocorticoids: inhibition of NF-kappa B activity through induction of I kappa B synthesis. Science 270:286–209

    Google Scholar 

  • Baker JR, Barsh GS, Carney DH, Cunningham DD (1978) Dexamethasone modulates binding and action of epidermal growth factor in serum-free cultures. Proc Natl Acad Sci USA 75:1882–1886

    Article  CAS  PubMed  Google Scholar 

  • Barnes PJ (2006) How corticosteroids control inflammation. Br J Pharmacol 148:245–254

    Article  CAS  PubMed  Google Scholar 

  • Barraclough D (1983) Rheumatoid arthritis. Austr Fam Physician 12(Suppl):2–10

    Google Scholar 

  • Bartholome B, Spies CM, Gaber T, Schuchmann S, Berki T, Kunkel D et al (2004) Membrane glucocorticoid receptors (mGCR) are expressed in normal human peripheral blood mononuclear cells and up-regulated after in vitro stimulation and in patients with rheumatoid arthritis. FASEB J 18:70–80

    Article  CAS  PubMed  Google Scholar 

  • Berliner DL, Keller N, Dougherty TF (1961) Tissue retention of cortisol and metabolites induced by ACTH: an extra adrenal effect. Endocrinol 68:621–632

    Article  CAS  Google Scholar 

  • Bijlsma JW, Saag KG, Buttgereit F, da Silva JAP (2005) Developments in glucocorticoid therapy. Rheum Dis Clin N Am 31:1–17

    Article  Google Scholar 

  • Borski JR (2000) Nongenomic membrane actions of glucocorticoids in vertebrates. Trends Endocrinol Metab 11:427–436

    Article  CAS  PubMed  Google Scholar 

  • Bostrom H, Odeblad E (1953) The influence of cortisone upon sulphate exchange of chondroitin sulfuric acid. Arkiv Kemi 6:39–43

    CAS  Google Scholar 

  • Brandtzaeg P (1996) History of oral tolerance and mucosal immunity. Ann NY Sci 778:1–27

    Article  CAS  Google Scholar 

  • Braughler JM (1985) Lipid peroxidation-induced inhibition of gamma-aminobutyric acid uptake in rat brain synaptosomes; protection by glucocorticoids. J Neurochem 44:1282–1288

    Article  CAS  PubMed  Google Scholar 

  • Braughler JM, Pregenzer JF (1989) The novel 21-aminosteroid inhibitors of lipid peroxidation: reaction with lipid peroxyl and phenoxyl radicals. Free Radic Biol Med 7:125–130

    Article  CAS  PubMed  Google Scholar 

  • Bush IE (1962) Chemical and biological factors in the activity of adrenocorticoid steroids. Pharmacol Rev 14:317–445

    CAS  PubMed  Google Scholar 

  • Butters D, Whitehouse M (2009) Beyond DMARDs: extending TNF-regulant therapies to the vast majority/less privileged. Int J Rheum Dis 12:299–306

    Article  PubMed  Google Scholar 

  • Buttgereit F, Schaffold A (2002) Rapid glucocorticoid effects on immune cells. Steroids 67:529–534

    Article  CAS  PubMed  Google Scholar 

  • Buttgereit F, Saag KG, Cutolo M, da Silva JA, Bijlsma JW (2005) The molecular basis for the effectiveness, toxicity and resistance to glucocorticoids: focus on the treatment of rheumatoid arthritis. Scand J Rheumatol 34:14–21

    Article  CAS  PubMed  Google Scholar 

  • Buttgereit F, Doering G, Schaeffler A, Witte S, Sierakowski S, Gromnica-Ihle E et al (2010) Targeting pathophysiological rhythms: prednisone chronotherapy shows sustained efficacy in rheumatoid arthritis. Ann Rheum Dis 69:1275–1280

    Article  CAS  PubMed  Google Scholar 

  • Caldwell JR, Furst DE (1991) The efficacy and safety of low-dose corticosteroids for rheumatoid arthritis. Sem Arthr Rheum 21:1–11

    Article  CAS  Google Scholar 

  • Cardinali G, Cardinali G, Decaro BM, Handler AH, Aboul-Enein M (1964) Effect of high doses of cortisone on bone marrow cell proliferation in the Syrian hamster. Cancer Res 24:969–972

    CAS  PubMed  Google Scholar 

  • Castor CW, Dorstewitz EL (1966) Abnormalities of connective tissue cells cultured from patients with rheumatoid arthritis. I. Relative unresponsiveness of rheumatoid synovial cells to hydrocortisone. J Lab Clin Med 68:300–313

    CAS  PubMed  Google Scholar 

  • Charmandari E, Kino T, Ichijo T, Chrousos GP (2008) Generalized glucocorticoid resistance: clinical aspects, molecular mechanisms, and implications of a rare genetic disorder. J Clin Endocrinol Metab 93:1563–1572

    Article  CAS  PubMed  Google Scholar 

  • Cheng MY, Sun G, Jin M, Zhao H, Steinberg GK, Sapolsky RM et al (2009) Blocking glucocorticoid and enhancing estrogenic genomic signalling protects against cerebral ischemia. J Cereb Blood Flow Metab 29:130–136

    Article  CAS  PubMed  Google Scholar 

  • Chickanza IC, Kozaci DL (2004) Corticosteroid resistance in rheumatoid arthritis: molecular and cellular perspectives. Rheumatology 43:1337–1345

    Article  Google Scholar 

  • Coghlan MJ, Elmore SW, Kym PR, Kort ME (2003a) The pursuit of differentiated ligands for the glucocorticoid receptor. Curr Top Med Chem 3:1617–1635

    Article  CAS  PubMed  Google Scholar 

  • Coghlan MJ, Jacobson PB, Lane B, Nakane M, Lin CW, Elmore SW et al (2003b) A novel anti-inflammatory maintained glucocorticoid efficacy with reduced side effects. Mol Endocrinol 17:860–869

    Article  CAS  PubMed  Google Scholar 

  • Cohen IR (2000) Discrimination and dialogue in the immune system. Semin Immunol 12:215–219

    Article  CAS  PubMed  Google Scholar 

  • Cohen IR, Klareskog EL (2008) Anti-inflammatory therapy for rheumatoid arthritis. Arthr Rheum 58:1–4

    Article  Google Scholar 

  • Cowell A-M, Buckingham JL (2001) Glucocorticoids and the HPA-axis. In: Goulding NJ, Flower RJ (eds) Glucocorticoids. Birkhauser Verlag, Basel, pp 129–145

    Google Scholar 

  • Cury PR, Araujo VC, Canavez F, Furuse C, Araujo NS (2007) Hydrocortisone affects the expression of matrix metalloproteinases (MMP-1,-2,-3,-7, and -11) and tissue inhibitor of matrix metalloproteinases (TIMP-1) in human gingival fibroblasts. J Periodontol 78:1309–1315

    Article  PubMed  Google Scholar 

  • Da Silva JA, Jacobs JW, Kirwan JR, Boers M, Saag KG, Inês LB et al (2006) Safety of low dose glucocorticoid treatment in rheumatoid arthritis: published evidence and prospective trial data. Ann Rheum Dis 65:285–293

    Article  CAS  PubMed  Google Scholar 

  • De Bosscher K, Haegeman G (2009) Minireview: latest perspectives on antiinflammatory actions of glucocorticoids. Mol Endocrincol 23:281–291

    Article  CAS  Google Scholar 

  • Denko CW (1958) The effect of hydrocortisone and cortisone on fixation of 35S in the stomach. J Lab Clin Med 51:174–177

    CAS  PubMed  Google Scholar 

  • Derbes VJ, Weiss TE (1951) Untowards reactions of cortisone and ACTH. Oxford Blackwells Scientific Publications, 51 pp

  • Devogelaer J-P (2006) Glucocorticoid-induced osteoporosis: mechanisms and therapeutic approach. Rheum Dis Clin N Am 32:733–757

    Article  Google Scholar 

  • Dougherty TF, Berliner DL, Berliner ML (1961) Corticosteroid-tissue interactions. Metabolism 10:966–987

    Google Scholar 

  • Einstein M, Greenlee M, Rouen G, Sitlani A, Santoro J, Wang C et al (2004) Selective glucocorticoid receptor nonsteroidal ligands completely antagonize the dexamethasone-mediated induction of enzymes involved in gluconeogenesis and glutamine metabolism. J Steroid Biochem Mol Biol 92:345–356

    Article  CAS  PubMed  Google Scholar 

  • Eisjbouts AMM, Murphy EP (1999) The role of the hypothalamic-pituitary-adrenal axis in rheumatoid arthritis. Best Pract Res Clin Rheumatol 13:599–613

    Article  Google Scholar 

  • Fieser LF, Fieser M (1959) Adrenocortical hormones. In: Steroids. Rheinhold Publication Corporation, New York, pp 600–726

  • Filaretova L, Podvigina T, Bagaeva T, Morozova O (2009) Dual action of glucocorticoid hormones on the gastric mucosa: how the gastroprotective action can be transformed to the ulcerogenic one. Inflammopharmacol 17:15–22

    Article  CAS  Google Scholar 

  • Florey HW (1962) Influence of drugs on the inflammatory process. In: Florey HW (ed) General pathology, 3rd edn. Lloyd-Luke (Med Books), London, pp 1050–1052

    Google Scholar 

  • Fraser FC, Sajoo A (1995) Teratogenic potential of corticosteroids in humans. Teratology 52:45–46

    Article  Google Scholar 

  • Furukawa S, Usada K, Abe M, Ogawa I (2004) Histopathological findings of cleft palate in rat embryos induced by triamcinolone acetonide. J Vet Med Sci 66:397–402

    Article  CAS  PubMed  Google Scholar 

  • Ghosh P, Shimmon S, Whitehouse MW (2006) Arthritic disease suppression and cartilage protection with glycoaminoglycan polypeptide complexes (Peptacans) derived from the cartilage extracellular matrix: a novel approach to therapy. Inflammopharmacol 14:155–162

    Article  CAS  Google Scholar 

  • Gomez EC, Frost P (1976) Induction of glycosuria and hyperglycaemia by topical corticosteroid therapy. Arch Dermatol 112:1559–1562

    Article  CAS  PubMed  Google Scholar 

  • Gonzalo JA, Gonzalez-Garcia A, Martinez C, Kroemer G (1993) Glucocorticoid mediated control of the activation of and clonal deletion of peripheral T cells in vivo. J Exp Med 177:1239–1245

    Article  CAS  PubMed  Google Scholar 

  • Gossye V, Elewaut D, van Breneden K, Dewint P, Haegeman G, de Bosscher K (2010) A plant-derived glucocorticoid receptor modulator attenuates inflammation without provoking ligand-induced resistance. Ann Rheum Dis 69:291–296

    Article  CAS  PubMed  Google Scholar 

  • Goulding NJ (1998) Corticosteroids—a case of mistaken identity. Br J Rheumatol 37:477–483

    Article  CAS  PubMed  Google Scholar 

  • Gross KL, Cidlowski JA (2008) Tissue-specific glucocorticoid action: a family affair. Trends Endocrinol Metab 19:331–339

    Article  CAS  PubMed  Google Scholar 

  • Halliday WJ, Garvey JS (1964) Some factors affecting the secondary immune response in tissue cultures containing hydrocortisone. J Immunol 93:957–962

    Google Scholar 

  • Harbison SJ, Whitehouse MW (2000) Possible steroid-sparing effect of Lyprinol, a shellfish lipid extract. Med J Austr 173:560

    CAS  Google Scholar 

  • Harbuz MS, Jessep DOS (1999) Is there a deficit in cortisol production in rheumatoid arthritis? Rheumatology 38:298–302

    Article  CAS  PubMed  Google Scholar 

  • Hardy R, Rabbitt EH, Filer A, Emery P, Hewison M, Stewart PM et al (2008) Local and systemic glucocorticoid metabolism in inflammatory arthritis. Ann Rheum Dis 67:1204–1210

    Article  CAS  PubMed  Google Scholar 

  • Hench PS, Kendall EC, Slocumb CH, Polley HF (1950) Effects of cortisone acetate and pituitary ACTH on rheumatoid arthritis, rheumatic fever and certain other conditions. Arch Int Med 85:545–666

    CAS  Google Scholar 

  • Hetland MR, Christensen IJ, Tarp U, Dreyer L, Hansen A, Hansen IB et al (2010) Direct comparison of treatment responses, remission rates, and drug adherence in patients with rheumatoid arthritis treated with adalimumab, etanercept or infleximab. Arthr Rheum 62:22–32

    Article  CAS  Google Scholar 

  • Hillier SG (2007) Diamonds are forever: the cortisone legacy. J Endocrinol 195:1–6

    Article  CAS  PubMed  Google Scholar 

  • Hoes JN, Jacobs JWG, Boers M, Boumpas D, Buttgereit F, Caeyers N et al (2007) EULAR evidence-based recommendations on the management of systemic glucocorticoid therapy in rheumatic diseases. Ann Rheum Dis 66:1560–1567

    Article  CAS  PubMed  Google Scholar 

  • Hoes JN, Jacobs JWG, Verstalppen SMM, Bijlsma JW, Van der Heij den GJMG (2009) Adverse events of low- to medium-dose oral glucocorticoids in inflammatory diseases: a meta-analysis. Ann Rheum Dis 68:1833–1838

    Article  CAS  PubMed  Google Scholar 

  • Hoffman TG, Hehner SP, Bacher S, Droge W, Schmitz ML (1998) Various glucocorticoids differ in their ability to induce gene expression, apoptosis and to repress NF-kB dependent transcription. FEBS Lett 441:441–446

    Article  Google Scholar 

  • Hundertmark S, Buhler H, Rudolf M, Weitzel HK, Ragosch V (1997) Inhibition of 11β-hydroxysteroid dehydrogenase activity enhances the antiproliferative effect of glucocorticosteroids on MCF-7 and ZR-75-1 breast cancer cells. J Endocrinol 155:171–180

    Article  CAS  PubMed  Google Scholar 

  • Hyun E, Bulla M, Steinhoff M, Wallace JL, del Soldato P, Vergnolle N (2004) Anti-inflammatory effect of nitric oxide-releasing hydrocortisone NXC-1 022 in a murine model of contact dermatitis. Br J Pharmacol 143:618–625

    Article  CAS  PubMed  Google Scholar 

  • Ingle DJ (1954) Permissibility of hormone action; a review. Acta Endocrinol 17:172–186

    CAS  PubMed  Google Scholar 

  • Kavenagh RJ, Kam PCA (2001) Lazaroids: efficacy and mechanism of action of the 21-aminosteroids in neuroprotection. Br J Anaesth 86:110–119

    Article  Google Scholar 

  • Kendall EC (1951) The adrenal cortex and rheumatoid arthritis. Br Med J 2:1295–1299

    Article  CAS  PubMed  Google Scholar 

  • Kirwan JR (2007) Glucocorticoid resistance in patients with rheumatoid arthritis. Scand J Rheumatol 36:165–166

    Article  CAS  PubMed  Google Scholar 

  • Kirwan J, Power L (2007) Glucocorticoids: action and new therapeutic insights in rheumatoid arthritis. Curr Opin Rheumatol 19:233–237

    Article  CAS  PubMed  Google Scholar 

  • Leech M, Metz C, Hall P, Hutchinson P, Gianis K, Smith M et al (2001) Macrophage inhibitory factor in rheumatoid arthritis: evidence of pro-inflammatory function and regulation by glucocorticoids. Arthr Rheum 42:1601–1608

    Article  Google Scholar 

  • Liberman AC, Druker J, Garcia FA, Holsboer F, Arzt E (2009) Intracellular molecular signalling. Basis for specificity to glucocorticoid anti-inflammatory actions. Ann NY Acad Sci 1153:6–13

    Article  CAS  PubMed  Google Scholar 

  • Liggins GC, Howie RN (1972) A controlled trial of antepartum glucocorticoid treatment for prevention of respiratory distress syndrome in premature infants. Pediatrics 50:515–525

    CAS  PubMed  Google Scholar 

  • Lipsky PE, Tao XL (1997) A potential new treatment for rheumatoid arthritis: thunder god vine. Semin Arthr Rheum 26:713–723

    Article  CAS  Google Scholar 

  • Lofdahl C-G, Reiss TF, Leff JA, Israel E, Noonan MJ, Finn AF et al (1999) Randomised placebo controlled trial of effect of a leukotrienes receptor antagonist, montelukast, on tapering inhaled corticosteroids in asthmatic patients. Br Med 19:87–90

    Google Scholar 

  • Martich GD, Danner RL, Ceska M, Suffredini AF (1991) Detection of interleukin 8 and tumor necrosis factor in normal humans after intravenous endotoxin: the effect of antiinflammatory agents. J Exp Med 173:1021–1024

    Article  CAS  PubMed  Google Scholar 

  • McKenzie LS, Horsburgh BA, Ghosh P, Taylor TKF (1976) Effect of anti-inflammatory drugs on sulphated glycoaminoglycan synthesis in aged human cartilage. Ann Rheum Dis 35:487–497

    Article  CAS  PubMed  Google Scholar 

  • McKenzie MA, Hoefnagels WH, Jansen RW, Benraad TJ, Kloppenborg PW (1990) The influence of glycyrrhetinic acid on plasma cortisol and cortisone in healthy young volunteers. J Clin Endocrinol Metab 70:1637–1645

    Article  Google Scholar 

  • Miner JN (2002) Designer glucocorticoids. Biochem Pharmacol 64:355–361

    Article  CAS  PubMed  Google Scholar 

  • Mitra R, Sapolsky RM (2008) Acute corticosterone treatment is sufficient to induce anxiety and amygdaloid dendritic hypertrophy. Proc Natl Acad Sci USA 105:5573–5578

    Article  CAS  PubMed  Google Scholar 

  • Moraes LA, Paul-Clark PJ, Richman A, Flower RJ, Goulding NJ, Perretti M (2005) Ligand-specific glucocorticoid receptor activation in human platelets. Blood 106:4167–4175

    Article  CAS  PubMed  Google Scholar 

  • Morand EF, Leech M (2001) Hypothalamic-pituitary-adrenal axis regulation of inflammation in rheumatoid arthritis. Immunol Cell Biol 79:395–399

    Article  CAS  PubMed  Google Scholar 

  • Morita Y, Munck A (1964) Effect of glucocorticoids in vivo and in vitro on net glucose uptake and amino acid incorporation by rat thymus cells. Biochim Biophys Acta 93:150–157

    CAS  PubMed  Google Scholar 

  • Mummert ME (2005) Immunological roles of hyaluran. Immunol Res 31:189–206

    Article  CAS  PubMed  Google Scholar 

  • Munck A (2001) Historical introduction. In: Goulding NJ, Flower R (eds) Glucocorticoids (milestones in drug therapy). Basel Birkhauser Verlag, pp 17–34

  • Munck A, Naray-Fejes-Toth A (1992) The ups and downs of glucocorticoid physiology. Permissive and suppressive effects revisited. Mol Cell Endocrinol 90:C1–C4

    Article  CAS  PubMed  Google Scholar 

  • Munck A, Guyre PM, Holbrook NJ (1984) Physiological functions of glucocorticoids in stress and their relation to pharmacological actions. Endocr Rev 5:25–44

    Article  CAS  PubMed  Google Scholar 

  • Nalbant S, Akmaz I, Kaplan M, Avsar K, Solmazgul E, Sahan B (2006) Does rofecoxib increase TNF-alpha levels? Clin Exp Rheumatol 24:361–365

    CAS  PubMed  Google Scholar 

  • Naumann L, Huscher D, Detert J, Spengler M, Burmester G-R, Buttgereit F (2009) Anti-TNFα therapy in patients with rheumatoid arthritis results in a significant and long-lasting decrease of concomitant glucocorticocoid treatment. Ann Rheum Dis 68:1234–1236

    Article  CAS  Google Scholar 

  • Nayak S, Acharjya B (2008) Deflazacort versus other glucocorticoids: a comparison. Indian J Dermatol 53:167–170

    Article  PubMed  Google Scholar 

  • Newton R, Leigh R, Giembycz MA (2010) Pharmacological strategies for improving the efficacy and therapeutic ratio of glucocorticoids in inflammatory lung diseases. Pharmacol Ther 125:286–327

    Article  CAS  PubMed  Google Scholar 

  • Norman AW, Mizwicki MT, Norman DP (2004) Steroid-hormone rapid actions, membrane receptors and a conformational ensemble model. Nat Rev Drug Discov 3:27–41

    Article  CAS  PubMed  Google Scholar 

  • Panoulas VF, Douglas KM, Stavropoulos-Kalinoglou A, Metsios GS, Nightingale P et al (2008) Long-term exposure to medium-dose glucocorticoid therapy associates with hypertension in patients with rheumatoid arthritis. Rheumatology (Oxford) 27:72–75

    Article  CAS  Google Scholar 

  • Pariante CM (2008) The role of multi-drug resistance p-glycoprotein in glucocorticoid function: studies in animals and relevance in humans. Eur J Pharmacol 583:263–271

    Article  CAS  PubMed  Google Scholar 

  • Paul-Clark MJ, Mancini L, del Soldato P (2006) Potent anti-arthritic properties of a glucocorticoid derivative (NCS-1015) in an experimental model of arthritis. Proc Natl Acad Sci USA 99:1677–1682

    Article  CAS  Google Scholar 

  • Pazirandeh A, Xue Y, Rafter J, Sjovall J, Jondal M, Okrets S (1999) Paracrine glucocorticoid activity produced by mouse thymic epithelial cells. FASEB J 13:893–901

    CAS  PubMed  Google Scholar 

  • Perel P, Roberts I, Sena E, Wheble P, Briscoe C, Sandercock P et al. (2006) Comparison of treatment effects between animal experiments and clinical trials: systematic review. Br Med J. doi:10:1136/bmj.39048.407928.BE (publ. 15 December 2006)

  • Perretti M, D’Acquiolo F (2009) Annexin-A1 and glucocorticoids as effectors of the resolution of inflammation. Nat Rev Immunol 9:62–70

    Article  CAS  PubMed  Google Scholar 

  • Perry MG, Kirwan JR, Jessop DS, Hunt LP (2009) Overnight variations in cortisol, interleukin 6, tumour necrosis factor α and other cytokines in people with rheumatoid arthritis. Ann Rheum Dis 68:63–68

    Article  CAS  PubMed  Google Scholar 

  • Petersen HH, Andreassen TK, Breiderhofft T, Brasen JH, Schultz H, Gross V et al (2006) Hyporesponsiveness to glucocorticoids in mice genetically deficient for the corticosteroid binding globulin. Mol Cell Biol 26:7236–7245

    Article  CAS  PubMed  Google Scholar 

  • Popper TL, Watnick AS (1974) Anti-inflammatory steroids In: Scherrer RA, Whitehouse MW (eds) Anti-inflammatory agents, vol I. Academic Press, New York, pp 245–294

  • Premkumar V, Dey M, Dorn R, Raskin I (2010) MyD88-dependant and independent pathways of toll-like receptors are engaged in biological activity of triptolide in ligand-stimulated macrophages. BMC Chem Biol 10:3

    Article  PubMed  CAS  Google Scholar 

  • Quirk SJ, Gannell JE, Fullerton MJ, Funder JW (1986) Specificity and mechanism of biphasic action of glucocorticoids on alpha-lactabumin production by rat mammary gland explants. Endocrinology 118:909–914

    Article  CAS  PubMed  Google Scholar 

  • Rainsford KD (2005) The Coxib controversies. Inflammopharmacol 13:331–341

    Google Scholar 

  • Rainsford KD (2008) Review of “The resolution of inflammation”. In: Rossi AG, Sawatsky DA (eds) Inflammopharmacol, vol 16, Birkhauser, Basel, pp 100–102

  • Rhen T, Cidlowski JA (2005) Anti-inflammatory action of glucocorticoids—new mechanisms for old drugs. New Engl J Med 353:1711–1723

    Article  CAS  PubMed  Google Scholar 

  • Richard EM, Helbling J-C, Tridon C, Dermedt A, Minni AM, Cador M et al (2010) Plasma transcortin influences endocrine and behavioural stress responses in mice. Endocrinol 151:649–659

    Article  CAS  Google Scholar 

  • Rubin MR, Bilezikian JP (2003) New anabolic therapies in osteoporosis. Endocrinol Metab Clin N Am 32:285–307

    Article  CAS  Google Scholar 

  • Sadowski T, Steinmeyer J (2001) Effects of non-steroidal antiinflammatory drugs and dexamethasone on the activity and expression of matrix metalloproteinase-1, matrix metalloproteinase-3 and tissue inhibitor of metalloproteinases-1 by bovine articular chondrocytes. Osteoarthr Cartil 9:407–415

    Article  CAS  PubMed  Google Scholar 

  • Saldanha C, Tougas G, Grace E (1986) Evidence for anti-inflammatory effect of normal circulating plasma cortisol. Clin Exp Rheumatol 4:365–366

    CAS  PubMed  Google Scholar 

  • Schaaf MJM, Cidlowski JA (2002) Molecular mechanisms of glucocorticoid action and resistance. J Steroid Biochem Mol Biol 83:37–48

    Article  CAS  PubMed  Google Scholar 

  • Schacke H, Schottelius A, Docke W, Strehlke P, Jaroch S, Schmees N et al (2004) Dissociation of transactivation from transrepression by a selective glucocorticoid agonist leads to separation of therapeutic effects from side effects. Proc Natl Acad Sci USA 101:227–232

    Article  PubMed  CAS  Google Scholar 

  • Schacke H, Berger M, Rehwinkel M, Asadullah K (2007) Selective glucocorticoid agonists (SEGRAs): novel ligands with improved therapeutic index. Mol Cell Endocrinol 275:109–117

    Article  PubMed  CAS  Google Scholar 

  • Schäcke H, Döcke WD, Asadullah K (2002) Mechanisms involved in the side effects of glucocorticoids. Pharmacol Ther 96:23–43

    Article  PubMed  Google Scholar 

  • Schiller S, Dorfman A (1957) Mucopolysaccharides in animals: the effect of cortisone and hydrocortisone on rat skin. Endocrinology 60:376–381

    Article  CAS  PubMed  Google Scholar 

  • Schmidt M, Straub RH (2007) Altered expression of 11β-hydroxysteroid dehydrogenases in rheumatoid arthritis synovial cells. Arthritis Rheum 55:1720–1721

    Article  CAS  Google Scholar 

  • Selenke WM, Leung GW, Townley RG (1980) Non-antibiotic effects of macrolide antibiotics of the oleandomycin-erythromycin class with special reference to their “steroid-sparing” effects. J Allergy Clin Immunol 65:454–464

    Article  CAS  PubMed  Google Scholar 

  • Selye H (1946) The general adaption syndrome and the diseases of adaption. J Clin Endocrinol 6:117–230

    Article  CAS  Google Scholar 

  • Shepherd VL, Konish MG, Stahl P (1985) Dexamethasone increases expression of mannose receptors and decreases extracellular lysosomal enzyme accumulation in macrophages. J Biol Chem 260:160–164

    CAS  PubMed  Google Scholar 

  • Smolen JS, Landewe R, Breedveld FC, Dougados M, Emery P, Gaujoux-Viala C et al (2010) EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs. Ann Rheum Dis 69:964–975

    Article  CAS  PubMed  Google Scholar 

  • Sneader W (2005) Adrenal cortex hormones. In: Drug discovery, a history. Wiley, Chichester, pp 179–184

  • Sorrells SF, Sapolsky RM (2007) An inflammatory review of glucocorticoid actions in the CNS. Brain Behav Immun 21:259–272

    Article  CAS  PubMed  Google Scholar 

  • Spies CM, Bijlsma JWJ, Burmester G-R, Buttgereit F (2010) Pharmacology of glucocorticoids in rheumatoid arthritis. Curr Opin Pharmacol 10:302–307

    Article  CAS  PubMed  Google Scholar 

  • Stoughton RB (1972) Bioassay system for formulations of topically applied glucocorticosteroids. Arch Dermatol 106:825–827

    Article  CAS  PubMed  Google Scholar 

  • Swingle K (1974) Properties of steroidal anti-inflammatory drugs. In: Scherrer RA, Whitehouse MW (eds) Anti-inflammatory agents, vol II. Academic Press, New York, pp 85–89

    Google Scholar 

  • Thompson JS, Urist MR (1973) Effect of cortisone on bone metabolism in intact and thyroidectomized rabbits. Calcif Tissue Int 13:197–215

    Article  CAS  Google Scholar 

  • Trnavsky K (1974) Drug effects on connective tissue metabolism. In: Scherrer RA, Whitehouse MW (eds) Anti-inflammatory agents, vol II. Academic Press, New York, pp 303–326

  • Van der Laan S, Meijer OC (2008) Pharmacology of glucocorticoids: beyond receptors. Eur J Pharmacol 585:483–491

    Article  PubMed  CAS  Google Scholar 

  • Wang L, Wang J, Almqvist KF, Veys EM, Verbruggen G (2002) Influence of polysulphated polysaccharides and hydrocortisone on the extracellular matrix metabolism of human articular chondrocytes in vitro. Clin Exp Rheumatol 20:669–676

    CAS  PubMed  Google Scholar 

  • Weindl G, Schellar M, Schafer-Korting M, Korting HC (2004) Hyaluronic acid in the treatment and prevention of skin diseases: molecular, biological, pharmaceutical and clinical aspects. Skin Pharmacol Physiol 17:207–213

    Article  CAS  PubMed  Google Scholar 

  • Weissmann G, Thomas L (1963) Studies on lysosomes II. The effect of cortisone on the release of acid hydrolases from a large granule fraction of rabbit liver induced by an excess of vitamin A. J Clin Invest 42:661–669

    Article  CAS  PubMed  Google Scholar 

  • Whitehouse MW (1964) Some biochemical and pharmacological properties of anti-inflammatory drugs. In: Jucker E (ed) Progress in drug research, vol 8, pp 321–429

  • Whitehouse MW (1967) Evaluation of potential anti-rheumatic drugs in vitro using lymphocytes and epithelial cells. J Pharm Pharmacol 19:590–595

    CAS  PubMed  Google Scholar 

  • Whitehouse MW (1995) Inflammation, stress and environmental factors as determinants of NSAID efficacy and toxicity. Inflammopharmacol 3:373–377

    Article  CAS  Google Scholar 

  • Whitehouse MW (2005a) Coxibs and their aftermath: a commentary based on some historical viewpoints. Inflammopharmacol 13:403–417

    Article  CAS  Google Scholar 

  • Whitehouse MW (2005b) Prostanoids as friends, not foes: further evidence from the interference by Cox-inhibitory drugs when inducing tolerance to experimental arthritigens in rats. Inflammopharmacol 12:481–492

    Article  CAS  Google Scholar 

  • Whitehouse MW (2007) Adjuvant arthritis 50 years on. Inflamm Res 56:133–138

    Article  CAS  PubMed  Google Scholar 

  • Whitehouse MW, Butters DE (2003) Combination anti-inflammatory therapy: synergism in rats of NSAIDs/corticosteroids with some herbal/animal products. Inflammopharmacol 11:453–464

    Article  CAS  Google Scholar 

  • Whitehouse MW, Lash JW (1961) Effect of cortisone and related compounds on the biogenesis of cartilage. Nature 189:37–39

    Article  CAS  PubMed  Google Scholar 

  • Whitehouse MW, Rainsford KD (2006) Lipoxygenase inhibition: the neglected frontier for regulating chronic inflammation and pain. Inflammopharmacol 14:155–162

    Article  CAS  Google Scholar 

  • Xiao C, Zhou J, He Y, Jia H, Zhao L, Zhao N et al (2009) Effects of triptolide from Radix Tripterygium wilfordii (Leigongteng) on cartilage cytokines and transcription factor NF-kappa B: a study on induced arthritis in rats. Chin Med 4:13

    Article  PubMed  CAS  Google Scholar 

  • Yao W, Cheng Z, Busse C, Pham A, Nakamara MC, Lane NE (2008) Glucocorticoid excess in mice results in early activation of osteoclastogenesis and adipogenesis and prolong suppression of osteogenesis. Arthr Rheum 58:1674–1686

    Article  CAS  Google Scholar 

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Acknowledgments

I am profoundly indebted to my wife, Desley Butters, for much help with literature searches and preparing the typescript; and to my long-standing friend and colleague, K. Rainsford, for continuing support and encouragement.

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Authors and Affiliations

  1. School of Medicine, Griffith University, Gold Coast, QLD, Australia

    Michael W. Whitehouse

  2. Centre for Integrative Clinical and Molecular Medicine, University of Queensland, Brisbane, QLD, Australia

    Michael W. Whitehouse

  3. PO Box 68, Stones Corner, QLD, 4120, Australia

    Michael W. Whitehouse

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  1. Michael W. Whitehouse
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Correspondence to Michael W. Whitehouse.

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This article is dedicated to the memories of two innovative but largely unrecognised steroid chemists, Drs Lew Sarett (Merck and Co) and Max Ehrenstein (Univ. Pennsylvania).

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Whitehouse, M.W. Anti-inflammatory glucocorticoid drugs: reflections after 60 years. Inflammopharmacol 19, 1–19 (2011). https://doi.org/10.1007/s10787-010-0056-2

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