Chronotherapy of maxacalcitol on skin inflammation induced by topical 12-O-tetradecanoylphorbol-13-acetate in mice

Abstract

In general, chronotherapy is desirable for a more effective and/or safe dosage regimen. In this study, a daily rhythm of skin vitamin D receptor (VDR) and chronotherapeutic profiles of maxacalcitol, a vitamin D analogue, were evaluated using mice with skin inflammation induced by topical 12-O-tetradecanoylphorbol-13-acetate (TPA). This study showed that skin nuclear VDR expression in TPA-treated mice has a daily rhythm with the peak at the middle of active period. The effects of maxacalcitol were greater after dosing during early to middle of active period than those after dosing during early to middle of inactive period. These data suggest that chronotherapeutic profiles of maxacalcitol partly depend on the daily rhythm of skin nuclear VDR in TPA-treated mice. Because TPA-treated mice are considered as one of animal models of psoriasis, these animal data might be helpful for establishing chronotherapeutic approach of maxacalcitol in clinical practice.

The circadian clock and diseases of the skin

“…Moreover, all rhythms in infection are abolished in clock-deficient macrophages and mice lacking the circadian clock in immune cells [47]. Additionally, the diurnal pattern of T-cell recruitment and function parallels nocturnal itching and exaggeration in atopic dermatitis (AD) [48].…”

“…Hence, more clinical studies should be conducted to assess how time of application impacts treatment efficacy and side effects. Experiments done in mice show that maxacalcitol, a vitamin D3 analogue for psoriasis symptom relief, is more effective when applied during the early to middle active phase of mice than during the early to middle resting phase [48]. For AD, application of topical treatment in the evening is proposed to improve symptoms [156].…”

Circadian rhythms in psoriasis and the potential of chronotherapy in psoriasis management

“…59,60 Studies using a murine model of psoriasis-like inflammation demonstrated that the expression of the vitamin D receptor (VDR) exhibits diurnal variation with VDR levels peaking in the middle of the active period (night-time for nocturnal animals such as mice). 61 Using this model, the authors demonstrated that the efficacy of topical vitamin D analogues, one of the first-line treatments for psoriasis, was enhanced when administered during early to middle active period compared with dosing during early to middle inactive period. 61 A recent study demonstrated greater efficacy of topical corticosteroids when applied to plaques of psoriasis in the evening.…”

“… 61 Using this model, the authors demonstrated that the efficacy of topical vitamin D analogues, one of the first‐line treatments for psoriasis, was enhanced when administered during early to middle active period compared with dosing during early to middle inactive period. 61 A recent study demonstrated greater efficacy of topical corticosteroids when applied to plaques of psoriasis in the evening. 62 Similar observations come from several small clinical studies, in which administration of corticosteroids for the treatment of asthma 63 and rheumatoid arthritis 64 in the afternoon or evening is more efficacious than in the morning.…”

The Impact of the Circadian Clock on Skin Physiology and Cancer Development

“…Over the years, the circadian regulation of drug metabolism and processing has been employed in the treatment of a range of disease states, including diabetes, hypertension, peptic ulcers, and allergic rhinitis [ 58 ]. There is also interest in using chronotherapeutic approaches for skin disease, including psoriasis [ 110 ] and atopic dermatitis [ 111 ]. Although time-dictated drug administration had been demonstrated many decades ago, its application in cancer treatment was limited due to insufficient mechanistic data supporting experimental results and inconsistency among clinical trials.…”