Effects and Interactions of Liquorice and Grapefruit on Glucocorticoid Replacement Therapy in Addison's Disease

Addison Disease Clinical Trial

Official title:

Use of Liquorice and Grapefruit in Patients With Addison's Disease

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01271296
• Other study ID #: 3.2007.2620 (REK)
• Secondary ID: 17775 (NSD)07/58
• Status: Completed
• Phase: N/A
• First received: December 22, 2010
• Last updated: January 13, 2011
• Start date: April 2008
• Est. completion date: January 2009

Study information

• Verified date: December 2010
• Source: Haukeland University Hospital
• Contact: n/a
• Is FDA regulated: No
• Health authority: Norway:National Committee for Medical and Health Research EthicsNorway: Norwegian Social Science Data Services (NSD)Norway: Directorate for Health and Social Affairs (SHdir)
• Study type: Interventional

Clinical Trial Summary

Addison's disease is a rare disease, wherein the adrenals can not produce sufficient steroid hormones (cortisol and aldosterone). Patients with Addison's disease report impaired subjective health status, and they have increased all-cause mortality. Conventional therapy is by oral replacement of glucocorticoid and mineralocorticoid hormones, but this strategy imperfectly mimic the diurnal cortisol variations, and render the patients both over- and under-treated. Anecdotally, some patients with adrenal insufficiency may benefit from the use of various nutritional compounds. We hypothesised that liquorice and grapefruit altered the metabolism and absorption of cortisone acetate.

Description:

In the present study, cortisone acetate absorption and metabolism are assessed in subjects with Addison's disease on three occasions. On the first occasion, the subjects are on their regular diet, but avoid ingestion of grapefruit and liquorice. At the end of the baseline assessment the order of the nutritional compounds (liquorice-grapefruit juice or grapefruit juice-liquorice) to be investigated in the next two assessments are randomised.

On the two next occasions, the absorption and metabolism of cortisone acetate is studied when study subjects consume liquorice and grapefruit juice. Between the use of grapefruit and liquorice there is a wash out period of at least 3 weeks.

For studies on liquorice effects, the subjects ingest 24-gram liquorice per day (equivalent of 150-mg glycyrrhizinic acid per day). For studies on grapefruit juice effects, subjects drink 200-ml grapefruit juice three times a day for three days. They maintain their regular medication and usual diet.

Time-series of cortisol and cortisone are obtained in serum and saliva samples on the third day of liquorice/grapefruit juice use. 24-hour urine is also collected.

Measurements of cortisol and metabolites in serum and saliva are used to calculate pharmacokinetical parameters. The measurements from samples obtained when using the investigated nutritional compounds are compared to the baseline assessment in each subject. Metabolites in 24-hour urine are compared similarly to investigate changes in urinary excretion, and to estimate the activity of enzymes involved in the metabolism of cortisol (5alfa-reductase, 5beta-reductase, cytochrome P450 3A4 system, 11-beta hydroxysteroid dehydrogenase).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 17
• Est. completion date: January 2009
• Est. primary completion date: January 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 80 Years

Eligibility

Inclusion Criteria:

• Verified diagnosis of adrenal insufficiency (Addison's disease)

• Stable cortisone acetate replacement therapy

• Written informed consent

Exclusion Criteria:

• Malignant disease

• Pharmacological treatment with other glucocorticoids

• Pregnancy

• Current minor disease (ie the flu)

• Major disease or accident requiring hospitalization the last three months

• Use of grapefruit juice or liquorice the last two weeks before study start

• Blood pressure above 150mmHg systolic or 90 mmHg diastolic.

Study Design

Allocation: Randomized, Endpoint Classification: Pharmacokinetics Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Supportive Care

Related Conditions & MeSH terms

• Addison Disease

Intervention

Dietary Supplement:
• Liquorice
24 gram liquorice eq. to 150 mg glycyrrhizinic acid, taken orally, for three days.
• Grapefruit Juice
200 ml pink grapefruit juice three times a day, taken orally, for three days.

Locations

Country	Name	City	State
Norway	Haukeland University Hospital, Helse-Bergen HF	Bergen

Sponsors (1)

Lead Sponsor	Collaborator
Haukeland University Hospital

Country where clinical trial is conducted

Norway, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	AUC Serum Cortisol - Levels of cortisol in serum during the first 2.6 hours after oral administration of cortisone acetate.	The area under the curve (AUC) of cortisol is calculated based on serum time-series sampling (every 20 minutes for 2.6 h after oral administration of cortisone acetate). The AUCs obtained during liquorice and grapefruit juice intakes are compared to the baseline assessment (without these nutritional compounds). All other pharmacokinetic properties (primary and secondary outcome measures) are compared analogously.	Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start.	No
Secondary	Serum Cortisol levels at the end of time-series sampling (t=160min)	At the end of time series sampling (160 minutes after orally administered cortisone acetate) on all three assessments	Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start.	No
Secondary	Serum Cortisone levels at the end of time-series sampling (t=160min)	At the end of time series sampling (160 minutes after orally administered cortisone acetate) on all three assessments	Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start.	No
Secondary	Saliva Cortisol levels at the end of time-series sampling (t=160min)	At the end of time series sampling (160 minutes after orally administered cortisone acetate) on all three assessments	Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start.	No
Secondary	Saliva Cortisone levels at the end of time-series sampling (t=160min)	At the end of time series sampling (160 minutes after orally administered cortisone acetate) on all three assessments	Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start.	No
Secondary	Time of maximum concentration of serum Cortisol	Based on time-series sampling at each of the three assessments	Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start.	No
Secondary	Time of maximum concentration of serum Cortisone	Based on time-series sampling at each of the three assessments	Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start.	No
Secondary	Time of maximum concentration of Saliva Cortisol	Based on time-series sampling at each of the three assessments	Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start.	No
Secondary	Time of maximum concentration of Saliva Cortisone	Based on time-series sampling at each of the three assessments	Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start.	No
Secondary	Half life of serum cortisol	Based on time-series sampling at each of the three assessments	Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start.	No
Secondary	Half life of serum cortisone	Based on time-series sampling at each of the three assessments	Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start.	No
Secondary	Urinary aTHF/THF-ratio	Measured in 24h urine obtained at the three assessments.; aTHF = allo-tetrahydrocortisol, THF = tetrahydrocortisol	Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start.	No
Secondary	AUC Serum Cortisone	Similar to primary outcome Serum AUC Cortisol	Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start.	No
Secondary	Urine total metabolites (Urinary cortisol+cortisone+6OHF+aTHF+THF+THE)	24-hour urine collected on each of the three assessments; aTHF = allo-tetrahydrocortisol, THF = tetrahydrocortisol, THE = tetrahydrocortisone, 6OHF = 6beta-hydroxycortisol	Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start.	No
Secondary	Urinary ratio (aTHF+THF)/THE	Assessed in 24h urine obtained at the three assessments (baseline, after liquorice and after grapefruit juice). It is an index of 5-reductase activity.; 24-hour urine collected on each of the three assessments; aTHF = allo-tetrahydrocortisol, THF = tetrahydrocortisol, THE = tetrahydrocortisone	Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start.	No
Secondary	Urinary Ratio Cortisol/6beta-OH-Cortisol	Assess the enzymatic activity of CYP3A4 by the index urinary cortisol/6beta-oh cortisol ratio obtained at the three assessments (baseline, after liquorice and after grapefruit juice.; 6OHF = 6beta-hydroxycortisol	Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start.	No
Secondary	Urine total metabolites (Urinary cortisol+cortisone+6OHF+aTHF+THF+THE)	24-hour urine collected on each of the three assessments; 24-hour urine collected on each of the three assessments; aTHF = allo-tetrahydrocortisol, THF = tetrahydrocortisol, THE = tetrahydrocortisone, 6OHF = 6beta-hydroxycortisol	Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start.	No
Secondary	AUC Saliva cortisone	Similar to primary outcome Saliva AUC Cortisol, but for cortisone.	Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start.	No
Secondary	AUC Serum Cortisone	Similar to primary outcome Serum AUC Cortisol, but for cortisone.	Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start.	No
Secondary	AUC Saliva Cortisol	Similar to AUC Serum Cortisol, but measurements are on saliva.	Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start.	No