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

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

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

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.

Detailed Summary:

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).

Current Primary Outcome: 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. ]

Original Primary Outcome: Same as current

Current Secondary Outcome:

• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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

• 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
• 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

• 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

• Urinary Ratio Cortisol/6beta-OH-Cortisol [ Time&nbs
  
  

  Original Secondary Outcome: Same as current
  
  Information By: Haukeland University Hospital
  

  Dates:
  Date Received: December 22, 2010
  Date Started: April 2008
  Date Completion:
  Last Updated: January 13, 2011
  Last Verified: December 2010