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Completed

NCT Number: NCT01271296

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

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.

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Key information

Conditions

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

Age range

18 year–80 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

Haukeland University Hospital, Helse-Bergen HF

Bergen, 5020, Norway

About this study

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).

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

Liquorice

Dietary Supplement

24 gram liquorice eq. to 150 mg glycyrrhizinic acid, taken orally, for three days.

Grapefruit Juice

Dietary Supplement

200 ml pink grapefruit juice three times a day, taken orally, for three days.

Primary outcomes

  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 outcomes

  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.

Sponsors and collaborators

Lead sponsor

Haukeland University Hospital

Other

Registry information

Official study title

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

Important dates

Study start
2008
Primary completion
2009
Study completion
2009
First posted
Jan 6, 2011
Registry last updated
Jan 17, 2011

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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