Developing oral chronotherapy for cortisol replacement in congenital adrenal hyperplasia.

Autor: Whitaker MJ; Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK., Debono M; Department of Endocrinology Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK., Ross RJ; Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK.
Jazyk: angličtina
Zdroj: Clinical endocrinology [Clin Endocrinol (Oxf)] 2024 Oct; Vol. 101 (4), pp. 311-317. Date of Electronic Publication: 2023 Sep 28.
DOI: 10.1111/cen.14976
Abstrakt: The sun imposes a 24-h periodicity to life and circadian rhythms have evolved to maintain homoeostasis through the day/night cycle. In humans, there is a central clock that controls the sleep/wake cycle which is paralleled metabolically by a fast/feed cycle. The clock maintains homoeostasis by synchronising metabolism to the time of feeding. Loss of synchrony between the clock and hormonal rhythms results in loss of homoeostasis as evidenced by obesity, depression, and diabetes in people undertaking shift work. Cortisol has a distinct circadian rhythm; peaking on waking and low at sleep onset. Loss of this rhythm in adrenal insufficiency is associated with a poor quality of life and increased mortality. To replace the cortisol rhythm requires chronotherapy and for this you need to define the key parameters of the target rhythm, create a formulation to replicate that rhythm, and then prove clinical benefit. The physiology of hormones is more complex than that of nonnative drugs. Hormones are secreted with varied rhythms, bound to multiple cognate binding proteins, and actively transported and cleared through enzymatic pathways in multiple organs. We have examined the diurnal rhythm of cortisol in healthy volunteers, created physiologically-based pharmacokinetic models, and tested various oral delayed and sustained formulations of hydrocortisone (development name, Chronocort) in clinical trials. The outcome from this work was the manufacture of modified-release hydrocortisone hard capsules (tradename Efmody, Diurnal Ltd), that replicate the cortisol diurnal rhythm and improve the disease control of congenital adrenal hyperplasia the commonest hereditary form of adrenal insufficiency.
(© 2023 The Authors. Clinical Endocrinology published by John Wiley & Sons Ltd.)
Databáze: MEDLINE
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