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
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.]
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.
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.
The patent system rewards innovation, not development. So processes of repurposing or repositioning existing drugs usually attract little commercial interest.
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.
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.
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.].
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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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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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DOI: https://doi.org/10.1007/s10787-010-0056-2