Safety of DR-HC for adrenal insufficiency

Posted on October 22, 2014 by MaryO

Conventional treatment of adrenal insufficiency involves cortisol replacement therapy with twice- or thrice-daily oral hydrocortisone. Recently dual-release hydrocortisone (DR-HC) administered once daily to provide high levels of cortisol during the morning, followed by a gradual decrease throughout the day is being used. This results in considerably lower cortisol exposure during the afternoon and evening compared with immediate-release thrice-daily hydrocortisone, thereby mimicking normal cortisol secretion more closely than conventional therapy.

Nilsson et al. conducted a study to evaluate the long-term safety of DR-HC and whether the difference in the incidence of adverse events persisted over time and if it was related to different levels of exposure to cortisol. They conducted a randomised, open-label, crossover trial of DR-HC or thrice-daily hydrocortisone for 3 months each (stage 1) followed by two consecutive, prospective, open-label studies of DR-HC for 6 months (stage 2) and 18 months (stage 3) at five university clinics in Sweden. The results of the study of the newly developed DR-HC showed that long-term maintenance treatment and rescue therapy was well tolerated up to 27 months of continuous treatment.

Read full article titled ‘Prospective evaluation of long-term safety of dual-release hydrocortisone replacement administered once daily in patients with adrenal insufficiency’ by Nilsson et al., European Journal of Endocrinology 171 pp 369 – 377, DOI: 10.1530/EJE-14-0327

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Mutation of ARMC5 gene characterized as the cause of meningeal tumour growth

Posted on October 13, 2014 by MaryO

Scientists at the Luxembourg Centre for Systems Biomedicine (LCSB) of the University of Luxembourg have published their findings that mutations in a gene known as “ARMC5” promote the growth of benign tumours in the adrenal glands and on the meninges: ARMC5 appears to belong to the group of so-called tumour suppressor genes. It is the first time in years that scientists have characterized such a gene.

The ARMC5 gene was discovered by independent workgroups studying – so-called adrenal adenomas – in connection with Cushing’s syndrome. In this disease, the body produces too much of the . Now, for the first time, a mutation of ARMC5 has been characterized as the cause behind the growth of meningeal tumours. The results on this tumour syndrome, obtained by the group of Dr. Patrick May and PD. Dr. Jochen Schneider together with colleagues from Charité Berlin (Dr. Ulf Elbelt) and the Universities of Würzburg (Prof. Dr. Bruno Allolio) and Cologne (Dr. Michael Kloth), have been published recently in the Journal of Clinical Endocrinology Metabolism.

Cortisol is an important hormone. It influences many metabolic pathways in the body and has a suppressing effect on the immune system. Accordingly, it is commonly employed as an anti-inflammatory medication. Prolonged, elevated levels of cortisol in the body can lead to obesity, muscular dystrophy, depression and other symptoms. To maintain the correct concentration in the blood, the body has a refined regulation system: Certain areas of the brain produce the hormone corticotropin as a stimulator of cortisol release; the actual formation of cortisol takes place in the . As the concentration of cortisol in the blood rises, the brain reduces the production of corticotropin.

In search of the causes of Cushing’s syndrome, scientists recently encountered certain genetic causes of benign tumours of the adrenal cortex. Growth of these adrenal cortex adenomas is based on a combination of hereditary and spontaneous mutations: It affects people in whom one of two “alternative copies” – one of the so-called alleles – of the ARMC5 gene is mutated from birth. If the second allele of ARMC5 later also undergoes a spontaneous mutation in the adrenal cortex, then the gene no longer functions. “What is interesting is that the failure of ARMC5 has no direct influence on cortisol production. However, because the tumour cells multiply faster than other body cells, and the number of cells in the tumour increases, the blood cortisol level rises in the course of the disease”, says Dr Schneider. Then, the level in the body rises and ultimately results in the onset of Cushing’s syndrome.

When other scientific workgroups discovered that further benign tumours – in this case meningeal tumours – occur more often in ARMC5-Cushing families, the group of Patrick May and Jochen Schneider sequenced the ARMC5 gene and studied it using bioinformatic techniques. “We demonstrated for the first time, in a patient with an adrenal cortex tumour and simultaneously a meningeal tumour, that somatic, that is non-hereditary, ARMC5 mutations are present in both tumours. This observation suggests that ARMC5 is a true tumour-suppressor gene.”

It must now be explored, Schneider continues, to what extent patients with adrenal cortex tumours ought to be screened for simultaneous presence of meningioma, and in which other types of tumour ARMC5 mutations are responsible for tumour growth: “Building upon that, we can learn whether the gene and the metabolic pathways it influences offer new approaches for treating the tumour syndrome.”

Explore further: Are you carrying adrenal Cushing’s syndrome without knowing it?

More information: “Molecular and Clinical Evidence for an ARMC5 Tumor Syndrome: Concurrent Inactivating Germline and Somatic Mutations are Associated with both Primary Macronodular Adrenal Hyperplasia and Meningioma.” Journal of Clinical Endocrinology Metabolism, October 2014. DOI: 10.1210/jc.2014-2648

Journal reference: Journal of Clinical Endocrinology & Metabolism search and more info website

Provided by University of Luxembourg search and more info

From http://medicalxpress.com/news/2014-10-mutation-armc5-gene-characterized-meningeal.html

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EU Looks to Okay Ketoconazole for Use in Cushing’s Syndrome

Posted on September 27, 2014 by MaryO

The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has recommended granting a marketing authorization for ketoconazole (Ketoconazole HRA; Laboratoire HRA Pharma) for the treatment of Cushing’s syndrome, a rare hormonal disorder sometimes called hypercortisolism.

Cushing’s syndrome is characterized by an excess of the hormone cortisol in the blood, which may be caused by a tumor. Treatment options currently available in the European Union include surgery to remove the tumor responsible for the high cortisol levels and radiotherapy, as well as several medicines that reduce the production of cortisol.

But pharmacological options remain very limited, and there is an unmet medical need for additional treatments, especially when surgery fails or for patients who cannot undergo surgery or take other medications. For this reason, the EMA’s CHMP evaluated the medicine under expedited review.

The opinion adopted by the CHMP at its September 2014 meeting is an intermediary step on Ketoconazole HRA’s path to patient access.

The CHMP opinion will now be sent to the European Commission for the adoption of a decision on an EU-wide marketing authorization. Once a marketing authorization has been granted, decisions about price and reimbursement will then take place at the level of each member state considering the potential role/use of this medicine in the context of the national health system of that country.

The recommendation is that Ketoconazole HRA is to be prescribed only by physicians specialized in treating Cushing’s syndrome, as the dosing needs to be individualized for each patient.

This is because oral ketoconazole was previously suspended in the European Union for the indication it was first approved for, fungal infections, due to risk for liver injury. The US Food and Drug Administration (FDA) also decreed, at the same time, that doctors should no longer prescribe ketoconazole tablets as a first-line therapy for any fungal infection, for the same reason.

Information will be sent to healthcare professionals to allow them to advise patients and prescribe the medicine safely and effectively.

A Medicine Used Off-Label for More than 30 Years

Doctors have used ketoconazole to treat Cushing’s syndrome for more than 30 years, although it has never been authorized for this indication in the European Union. The drug is also frequently used off-label in the United States and elsewhere for this purpose.

The CHMP’s recommendation builds on information from published literature and documented off-label use in clinical practice.

At the time of the suspension of ketoconazole for fungal infections, healthcare professionals and patients were concerned that ketoconazole would no longer be available for patients with Cushing’s syndrome.

The CHMP therefore reviewed Ketoconazole HRA through accelerated assessment to facilitate patients’ access to a fully authorized medicine as soon as possible with evidence-based information for patients and doctors.

When assessing Ketoconazole HRA for the treatment of Cushing’s syndrome, the CHMP considered that “in this rare and potentially life-threatening condition, the medicine’s benefits are greater than its risks, which can be manageable in clinical practice by specific measures mitigating the risk of liver toxicity, including close monitoring of the patients’ liver function.”

In 2012, it was estimated that the disease affected approximately 46,000 people in the European Union. Cushing’s syndrome is a long-lasting condition that can be life-threatening because of its complications, including diabetes, high blood pressure, and depression.

From http://www.medscape.com/viewarticle/832399?src=rss

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Clinical effectiveness of metyrapone monotherapy in 195 patients with Cushing’s syndrome

Posted on June 21, 2014 by MaryO

From Day 1 of the 16th International Congress of Endocrinology and the Endocrine Society’s 96th Annual Meeting and Expo »

Chicago, IL – June 21, 2014

E Daniel, SJB Aylwin, SG Ball, K Boelaert, D Cuthbertson, C Daousi, JR Davis, W Drake, AB Grossman, M Gurnell, N Karavitaki, T Kearney, K Meeran, A Rees, PJ Trainer, JDC Newell-Price

Summary: Metyrapone is widely used in the UK for the control of cortisol excess in Cushing’s syndrome, but its use is not standardised. The few published reports on metyrapone use pertain to limited patient numbers. In this report, the largest report on metyrapone use, metyrapone was effective in achieving eucortisolemia in over 70% of patients without any other cortisol-lowering intervention, with a satisfactory safety profile. A variety of monitoring regimens were used, but greater standardisation of practice and more active dose titration is needed.

Methods:

  • A retrospective survey was conducted across 13 tertiary centres in England and Wales.
  • Using a standardised proforma, extensive data including monitoring and safety information were collected for patients with Cushing’s syndrome on metyrapone therapy between 1997 and 2013.
  • Eucortisolemia was defined according to the monitoring test used as a mean cortisol ‘day curve’ value ≤300 nmol/l, a urinary free cortisol bellow the upper limit of normal (ULN) or a 9am serum cortisol

Results:

  • A total of 195 patients received metyrapone (160 as monotherapy). Average age was 49.6 +/-15.7 years: 87.2% had metyrapone in conjunction with other interventions (surgery, radiotherapy or chemotherapy) while 12.8% had cortisol-lowering treatment alone.
  • Dose-titration was used in 81% of patients, whereas 19% had a block-and-replace regimen.
  • A total of 138 patients received metyrapone monotherapy for a mean duration of 162 days before any other intervention took place.
  • The etiology of Cushing’s syndrome in this subgroup was: pituitary-dependent disease [CD, 59% (macroadenoma 32% of CD)], ectopic ACTH syndrome (EAS, 17%), adrenocortical carcinoma (ACC, 4%), adrenal adenoma (AA, 17%) and other benign adrenal disease (3%).
  • Hypokalemia was actively managed with potassium levels increasing during metyrapone therapy (3.90 mmol/L vs 3.68 mmol/L, P=0.0026).
  • In this subgroup, 74% achieved eucortisolemia on varying doses: CD 1370 mg, EAS 2080 mg, AA 1170 mg, ACC 750 mg daily in divided doses.
  • The preferred monitoring method was by cortisol ‘day-curves’, followed by 9am cortisol and urinary free cortisol.
  • Overall, 25.3% of patients developed side effects, most commonly gastrointestinal upset and hypoadrenalism.
  • 88% of adverse events were managed as outpatients; 36% of patients treated for more than one month had ≤2 monitoring assessments and insufficient dose titration.

From MDLinx

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Diagnosing and Treating Cortisol Excess and Deficiency

Posted on June 21, 2014 by MaryO

From Day 1 of the 16th International Congress of Endocrinology and the Endocrine Society’s 96th Annual Meeting and Expo »

Chicago, IL – June 21, 2014

A phase 2 study of Chronocort®, a modified release formulation of hydrocortisone, in the treatment of adults with classic congenital adrenal hyperplasia

A Mallappa, L-A Daley, N Sinaii, C Van Ryzin, H Huatan, D Digweed, D Eckland, M Whitaker, LK Nieman, RJ Ross, DP Merke

Summary: Classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is characterized by cortisol and aldosterone deficiency and androgen excess. Current conventional glucocorticoid therapy is suboptimal as it cannot replace the normal cortisol circadian rhythm and inadequate or inappropriate suppression of adrenal androgens are common. In the preliminary results of a phase 2 study of Chronocort®, a modified release hydrocortisone capsule formulation, researchers found that Chronocort®, a novel modified release hydrocortisone capsule formulation, approximates physiological cortisol secretion, and improves biochemical control of CAH. Further analyses are underway.

Methods:

  • The study objectives were to characterize pharmacokinetics and examine disease control following 6 months dose titration.
  • Serial profiling was obtained at baseline (conventional glucocorticoid) and every 2 months.
  • Twice-daily Chronocort® was initiated: 20 mg at 2300 h, 10 mg at 0700 h.
  • Dose titration was based on clinical status and optimal hormonal ranges (17OHP 300-1200 ng/dL, normal androstenedione (males: 40-150, females: 30-200 ng/dL), with androstenedione prioritized.
  • Chronocort® cortisol pharmacokinetic profile was the primary endpoint.
  • Secondary endpoints included biomarkers of disease control.

Results:

  • A total of 16 adults (8 females; age 29 ±13 years) with classic CAH (12 salt-wasting, 4 simple virilizing) participated.
  • Conventional therapy varied (5 dexamethasone, 7 prednisone, 4 hydrocortisone).
  • Chronocort® cortisol pharmacokinetic profile approximated physiological cortisol secretion.
  • Ten patients required Chronocort® dose adjustments (decrease in 8, increase in 2; mean hydrocortisone equivalent dose conventional vs 6 months: 16.1 ± 6.4 vs 14.7 ± 6.4 mg/m2).
  • Serial androstenedione levels were in the normal range in 8 (50%) of patients on conventional therapy compared with 12 (75%) on Chronocort® at 6 months.
  • The majority of patients on Chronocort® achieved 17O HP levels within the normal range, rather than within the mildly elevated range currently used for management.
  • At 6 months, Chronocort® resulted in lower 24-hr (P=0.02), morning (0700-1500; P=0.008), and afternoon (1500-2300; P=0.03) area-under-the-curve androstenedione compared with conventional therapy.
  • No serious adverse events occurred.
  • Common adverse events were headache, fatigue, early awakening, and anemia.
  • Three patients had unexpected carpal tunnel syndrome, which resolved with wrist splints.

From http://www.mdlinx.com/endocrinology/conference-abstract.cfm/ZZ5BA369FDE9DE4CED82CB6A7CD5BFD1BE/16521/?utm_source=confcoveragenl&utm_medium=newsletter&utm_content=abstract-list&utm_campaign=abstract-ICE/EN2014&nonus=0#

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