Modified-release hydrocortisone for circadian therapy: a proof-of-principle study in dexamethasone-suppressed normal volunteers.

2.50
Hdl Handle:
http://hdl.handle.net/10541/58679
Title:
Modified-release hydrocortisone for circadian therapy: a proof-of-principle study in dexamethasone-suppressed normal volunteers.
Authors:
Newell-Price, John; Whiteman, M; Rostami-Hodjegan, A; Darzy, Ken H; Shalet, Stephen M; Tucker, G T; Ross, R J M
Abstract:
BACKGROUND: All existing long-term glucocorticoid replacement therapy is suboptimal as the normal nocturnal rise and waking morning peak of serum cortisol is not reproduced. AIM: To test whether it is possible to reproduce the normal overnight rise and morning peak in serum cortisol using an oral delayed and sustained release preparation of hydrocortisone (Cortisol(ds)). SUBJECTS AND METHODS: Six healthy normal male volunteers attended on two occasions, in a single-dose, open-label, nonrandomized study. Endogenous cortisol secretion was suppressed by administration of dexamethasone. Cortisol(ds) (formulation A or B) was administered at 2200 h on day 1. Blood samples for measurement of cortisol were taken from 2200 h every 30 min until 0700 h, then hourly until 2200 h on day 2. Fifteen body mass index (BMI)-matched control subjects had serum cortisol levels measured at 20-min intervals for 24 h. Serum cortisol profiles and pharmacokinetics after Cortisol(ds) were compared with those in controls. RESULTS: Formulations A and B were associated with delayed drug release (by 2 h and 4 h, respectively), with median peak cortisol concentrations at 4.5 h (0245 h) and 10 h (0800 h), respectively, thereby reproducing the normal early morning rise in serum cortisol. Total cortisol exposure was not different from controls. CONCLUSIONS: For the first time we have shown that it is possible to mimic the normal circadian rhythm of circulating cortisol with an oral modified-release formulation of hydrocortisone, providing the basis for development of physiological circadian replacement therapy in patients with adrenal insufficiency.
Affiliation:
Academic Unit of Diabetes, Endocrinology and Metabolism, The University of Sheffield, Sheffield, UK. j.newellprice@sheffield.ac.uk
Citation:
Modified-release hydrocortisone for circadian therapy: a proof-of-principle study in dexamethasone-suppressed normal volunteers. 2008, 68 (1):130-5 Clin. Endocrinol.
Journal:
Clinical Endocrinology
Issue Date:
Jan-2008
URI:
http://hdl.handle.net/10541/58679
DOI:
10.1111/j.1365-2265.2007.03011.x
PubMed ID:
17803699
Type:
Article
Language:
en
ISSN:
1365-2265
Appears in Collections:
All Christie Publications ; Endocrinology

Full metadata record

DC FieldValue Language
dc.contributor.authorNewell-Price, John-
dc.contributor.authorWhiteman, M-
dc.contributor.authorRostami-Hodjegan, A-
dc.contributor.authorDarzy, Ken H-
dc.contributor.authorShalet, Stephen M-
dc.contributor.authorTucker, G T-
dc.contributor.authorRoss, R J M-
dc.date.accessioned2009-04-01T23:02:56Z-
dc.date.available2009-04-01T23:02:56Z-
dc.date.issued2008-01-
dc.identifier.citationModified-release hydrocortisone for circadian therapy: a proof-of-principle study in dexamethasone-suppressed normal volunteers. 2008, 68 (1):130-5 Clin. Endocrinol.en
dc.identifier.issn1365-2265-
dc.identifier.pmid17803699-
dc.identifier.doi10.1111/j.1365-2265.2007.03011.x-
dc.identifier.urihttp://hdl.handle.net/10541/58679-
dc.description.abstractBACKGROUND: All existing long-term glucocorticoid replacement therapy is suboptimal as the normal nocturnal rise and waking morning peak of serum cortisol is not reproduced. AIM: To test whether it is possible to reproduce the normal overnight rise and morning peak in serum cortisol using an oral delayed and sustained release preparation of hydrocortisone (Cortisol(ds)). SUBJECTS AND METHODS: Six healthy normal male volunteers attended on two occasions, in a single-dose, open-label, nonrandomized study. Endogenous cortisol secretion was suppressed by administration of dexamethasone. Cortisol(ds) (formulation A or B) was administered at 2200 h on day 1. Blood samples for measurement of cortisol were taken from 2200 h every 30 min until 0700 h, then hourly until 2200 h on day 2. Fifteen body mass index (BMI)-matched control subjects had serum cortisol levels measured at 20-min intervals for 24 h. Serum cortisol profiles and pharmacokinetics after Cortisol(ds) were compared with those in controls. RESULTS: Formulations A and B were associated with delayed drug release (by 2 h and 4 h, respectively), with median peak cortisol concentrations at 4.5 h (0245 h) and 10 h (0800 h), respectively, thereby reproducing the normal early morning rise in serum cortisol. Total cortisol exposure was not different from controls. CONCLUSIONS: For the first time we have shown that it is possible to mimic the normal circadian rhythm of circulating cortisol with an oral modified-release formulation of hydrocortisone, providing the basis for development of physiological circadian replacement therapy in patients with adrenal insufficiency.en
dc.language.isoenen
dc.subjectHydrocortisoneen
dc.subjectCircadian Therapyen
dc.subjectDexamethasoneen
dc.subjectCortisolen
dc.subjectGlucocorticoid Replacement Therapyen
dc.titleModified-release hydrocortisone for circadian therapy: a proof-of-principle study in dexamethasone-suppressed normal volunteers.en
dc.typeArticleen
dc.contributor.departmentAcademic Unit of Diabetes, Endocrinology and Metabolism, The University of Sheffield, Sheffield, UK. j.newellprice@sheffield.ac.uken
dc.identifier.journalClinical Endocrinologyen

Related articles on PubMed

All Items in Christie are protected by copyright, with all rights reserved, unless otherwise indicated.