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

• ClinicalTrials.gov Identifier: NCT01271296
• Recruitment Status: Completed
• First Posted: January 6, 2011
• Last Update Posted: January 17, 2011
• Sponsor: Haukeland University Hospital
• Information provided by: Haukeland University Hospital

Study Description

Brief 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.

Condition or disease	Intervention/treatment	Phase
Addison Disease	Dietary Supplement: Liquorice; Dietary Supplement: Grapefruit Juice	Not Applicable

Detailed 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).

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 17 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Supportive Care
• Official Title: Use of Liquorice and Grapefruit in Patients With Addison's Disease
• Study Start Date: April 2008
• Actual Primary Completion Date: January 2009
• Actual Study Completion Date: January 2009

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Liquorice; Liquorice eq to 150 mg glycyrrhizinic acid. Results are compared to a baseline assessment without liquorice/grapefruit juice ingestion.	Dietary Supplement: Liquorice; 24 gram liquorice eq. to 150 mg glycyrrhizinic acid, taken orally, for three days.
Active Comparator: Grapefruit juice; 200 ml pink grapefruit juice three times a day. Results are compared to a baseline assessment without liquorice/grapefruit juice ingestion.	Dietary Supplement: Grapefruit Juice; 200 ml pink grapefruit juice three times a day, taken orally, for three days.
No Intervention: Baseline; Baseline assessment without intake of liquorice or grapefruit juice

Outcome Measures

Primary Outcome Measures :

1. AUC Serum Cortisol - Levels of cortisol in serum during the first 2.6 hours after oral administration of cortisone acetate. [ Time Frame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. ]
   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.

Secondary Outcome Measures :

1. Serum Cortisol levels at the end of time-series sampling (t=160min) [ Time Frame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. ]
   At the end of time series sampling (160 minutes after orally administered cortisone acetate) on all three assessments
2. Serum Cortisone levels at the end of time-series sampling (t=160min) [ Time Frame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. ]
   At the end of time series sampling (160 minutes after orally administered cortisone acetate) on all three assessments
3. Saliva Cortisol levels at the end of time-series sampling (t=160min) [ Time Frame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. ]
   At the end of time series sampling (160 minutes after orally administered cortisone acetate) on all three assessments
4. Saliva Cortisone levels at the end of time-series sampling (t=160min) [ Time Frame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. ]
   At the end of time series sampling (160 minutes after orally administered cortisone acetate) on all three assessments
5. Time of maximum concentration of serum Cortisol [ Time Frame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. ]
   Based on time-series sampling at each of the three assessments
6. Time of maximum concentration of serum Cortisone [ Time Frame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. ]
   Based on time-series sampling at each of the three assessments
7. Time of maximum concentration of Saliva Cortisol [ Time Frame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. ]
   Based on time-series sampling at each of the three assessments
8. Time of maximum concentration of Saliva Cortisone [ Time Frame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. ]
   Based on time-series sampling at each of the three assessments
9. Half life of serum cortisol [ Time Frame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. ]
   Based on time-series sampling at each of the three assessments
10. Half life of serum cortisone [ Time Frame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. ]
    Based on time-series sampling at each of the three assessments
11. Urinary aTHF/THF-ratio [ Time Frame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. ]

    Measured in 24h urine obtained at the three assessments.

    aTHF = allo-tetrahydrocortisol, THF = tetrahydrocortisol

12. AUC Serum Cortisone [ Time Frame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. ]
    Similar to primary outcome Serum AUC Cortisol
13. Urine total metabolites (Urinary cortisol+cortisone+6OHF+aTHF+THF+THE) [ Time Frame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. ]

    24-hour urine collected on each of the three assessments

    aTHF = allo-tetrahydrocortisol, THF = tetrahydrocortisol, THE = tetrahydrocortisone, 6OHF = 6beta-hydroxycortisol

14. Urinary ratio (aTHF+THF)/THE [ Time Frame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. ]

    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

15. Urinary Ratio Cortisol/6beta-OH-Cortisol [ Time Frame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. ]

    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

16. Urine total metabolites (Urinary cortisol+cortisone+6OHF+aTHF+THF+THE) [ Time Frame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. ]

    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

17. AUC Saliva cortisone [ Time Frame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. ]
    Similar to primary outcome Saliva AUC Cortisol, but for cortisone.
18. AUC Serum Cortisone [ Time Frame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. ]
    Similar to primary outcome Serum AUC Cortisol, but for cortisone.
19. AUC Saliva Cortisol [ Time Frame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. ]
    Similar to AUC Serum Cortisol, but measurements are on saliva.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 80 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

Norway

Haukeland University Hospital, Helse-Bergen HF

Bergen, Norway, 5020

Sponsors and Collaborators

Haukeland University Hospital

Investigators

• Principal Investigator: Paal Methlie, MD; University of Bergen. Helse-Bergen HF
• Principal Investigator: Kristian Løvås, MD, PhD; University of Bergen. Helse-Bergen HF.
• Principal Investigator: Eystein S Husebye, Prof, MD; University of Bergen. Helse-Bergen HF.
• Principal Investigator: Ernst A Lien, Prof. MD.; University of Bergen

More Information

• Responsible Party: Lars Birger Nesje, Head of Department of Medicine, Haukeland University Hospital, Helse-Bergen HF, Haukeland University Hospital
• ClinicalTrials.gov Identifier: NCT01271296
• Other Study ID Numbers: 3.2007.2620 (REK); 17775 (NSD) ( Other Identifier: Norwegian Social Science Data Services (registry for approval of data protection) ); 07/5829 (SHdir) ( Other Identifier: The Norwegian Directorate of Health and Social Affairs (Approval of research biobank) ); 3.2007.2620 ( Other Identifier: West Regional Committee of Research Ethics )
• First Posted: January 6, 2011
• Last Update Posted: January 17, 2011
• Last Verified: December 2010

Keywords provided by Haukeland University Hospital:

Addison Disease; Pharmacokinetics; Hormone Replacement Therapy; cortisone acetate; Quality of Life

Additional relevant MeSH terms:

Addison Disease; Adrenal Insufficiency; Adrenal Gland Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases