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PRACTICE: Hywel C Williams Established corticosteroid creams should be applied only once daily in patients with atopic eczema BMJ 2007; 334: 1272 [Full text]

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Once daily administration and chronobiology

Martin S. Knapp   (10 July 2007)

Once daily administration and chronobiology 10 July 2007
Martin S. Knapp, Peripatetic Nephrologist 12 Townsend Street, Melbourne, Vic., 3079, Australia Send response to journal: Re: Once daily administration and chronobiology	A change in the medical management of eczema is proposed by Dr Hywel Williams (June 16). He makes a strong case that cutaneous administration of corticosteroids should be once daily. In neither his proposals, nor in those of his references which are available to me, is the question of what time of day or night should the once daily administration be applied. Halberg and others documented circadian rhythms in skin cell cycles almost 50 years ago (1) but rather little has been reported on whether this rhythmicity is disturbed in eczema or other skin conditions or whether there are circadian variations in the response to cutaneous corticosteroids or other treatments. There is an extensive bibliography on the responses and side effects of other therapeutic substances, including corticosteroids given systemically, which are variable dependent on the time of administration in relation to circadian cycles and other biological rhythms. There are known to be dramatic circadian variations in some skin responses that suggest that the chronobiology of eczema, which involves immune and inflammatory responses, might be variable and outcomes influenced by the timing of treatment. Pownall and I reported eightfold variations in the cutaneous response to applications of oxazalone to the skin of oxazalone-sensitized rats (2) and, with Cove-Smith and Kabler, an almost three fold variation in the response of humans to intradermal tuberculin given to BCG immunized nurses (3). These are immune mediated responses. Studies by Reinberg, Labreque and others (4,5) demonstrated that there are also circadian variations in the skin response to the application of substances. One study of the modification of skin inflammation induced chemically observed that there was no suppression at one circadian time-point with indomethacin with variations in suppression at other circadian time points dependant on the time of administration of the indomethacin(5). We confirmed these observations of circadian variations in the ability of agents to influence cutaneus inflammatory responses and established that the ability of immune suppressing medications to suppress cutaneous immune responses in rats and mice was also influenced by the time of administration (6,7). We demonstrated chronobiological variations in the clinical manifestations of some clinical events thought to be mediated by immune and inflammatory processes, including renal transplant rejection and rheumatoid arthritis, with variations in the responses to medication variable with circadian time (8,9,10). Other planned studies of this phenomena in human disease , including some in dermatology, were aborted when our Chronotherepeutics Research Group in Nottingham closed due to loss of funding. There has been too little attention given to the chronobiological aspects of pharmacology and therepeutics in clinical care or in clinical research. Many randomized controlled trials protocols still do not specify the time of administration even when administration is only once daily. Randomised trials contrasting alternative times of administration, which should be obligatory with once daily administration, are almost never published and retrospective post-trial analysis to study the possibility of the timing of therapy influencing outcome is uncommon. In 1978 an editorial, based on a submission from myself, introduced BMJ readers to the concept of chronopharmacology (11) an area of investigation named by Halberg . Chronopharmacology, the study of the influence of body time on the effect and side effects of medications, is linked to chronothereputics, the impact of time on administration of medications. In 1984 Pownall and I stated with confidence that “lymphocytes are rhythmic” but asked “is this important” and should it influence the timing of medication (12). In that BMJ editorial we referenced some of the many papers and symposia that report clinical and experimental data indicating that circadian time, and other aspects of body rhythmicity. can be relevant to prescribing for optimal effect and minimal side-effects. I hope that Dr Williams, who writes from the Queens University Centre in Nottingham where in 1983 we formed our short-lived Chronotherepeutics Research Group, will promote studies to establish the optimal time of day to apply once daily corticosteroid and other dermatological medications. This may encourage other specialties to reconsider whether they too should be giving moe attention to this aspect of therepeutics. 1.Halberg F,HalbergE,BarnumCP,BittnerJJ, Physiologic 24-hour periodicity in human beings and mice. In photoperiodism and related phenomena in plants and animals, publ.No 55, 1959; American association for advancement of science, Washington, DC. 803-878. 2.Pownall R, KnappMS, Circadian variations of delayed hypersensitivity to oxazolone, Clin. Sci.Med, 1978; 54:447-449. 3.Cove-SmithJR, KablerP, PownallR, KnappMS, Circadian variation in an immune response in man, Brit Med J,1978;2:253-254, 4.Reinberg A,Zagulla-Mally Z, Ghata J, Halbarg F, Circadian reactivity rhythms of human skin to house dust, penicillin and histamine. J.Allergy, 1969; 44: 292-298 5.LabrecqueG, Laperriere A, Perusse F, and BelangerP ,Variations in the carrageenin-induced oedema, in the action of the plasma levels of indomethacin. In: Chronopharmacology. 1979; Oxford: Pergamon; 231-238. 6. PownallR, KnappMS,Chronobiologic evaluation of hypersensitivity reactions and the influence of circadian variations in endogenous corticosteroids. Allergologie,1980;3(4):231-236. 7 PownallR, KnappMS,A circadian study of corticosteroid suppression of delayed hypersensitivity, Int J Immunopharmacol,1980;1:293-298, 8 KowankoIC, PownallR, KnappMS, MahoneyPGC, SwannellAJ, Circadian variations in the signs and symptons of rheumatoid arthritis and in the therapeutic effectiveness of flurbiprofen at different times of day. Brit J Clin Pharmacol:1981;11 (5):477-484, 9 Knapp,MS, Byrom,NP, Pownall, R,Mayor,Time of day of administration of immunosuppressive after renal transplantation, a possible influence of graft survival Br Med J,1981;281:1382-1385, 10 KowankoIC, PownallR, KnappMS, Swannell AJ,MahoneyPGC, The time of day of prednisolone administration in rheumatoid arthritis, Annals Rheum. Diseases,1982; 41: 447-452, 11 Editorial, Chronotherapeutics, a new science, Br Med J,1978;1376:1, 12 Knapp,MS, Lymphocytes are rhythmic: is this important, Br Med J, 1984;289: 1328-1330 Competing interests: None declared