Research Study: An Open Label Study to Assess the Safety and Efficacy of COR-003 (2S, 4R-ketoconazole) in the Treatment of Endogenous Cushing’s Syndrome

Objectives:         

The purpose of this study is to test the effects of different doses of COR-003 on people with Cushing’s syndrome (CS) primarily by measuring the cortisol levels in urine and secondarily by measuring other health parameters such as blood pressure, weight, and liver function. This study is also being conducted to see if there is any harm caused when using COR-003.

This study is an open label study. That means both the health providers and the participants in the study are aware of the drug or treatment being given.

Eligibility:

Adult Subjects (18 years or older) with elevated levels of cortisol due to endogenous CS.

Confirmed diagnosis of persistent or recurrent CS (with or without therapy) or newly diagnosed disease, if subjects are not candidates for surgery. CS will be defined according to the criteria in the guidelines for diagnosis of CS (Nieman 2008).

Women who are pregnant or lactating are not eligible for this study.

Individuals with other health conditions or diagnoses may not be eligible for this study.

These and other eligibility criteria are best reviewed with a doctor who is participating in the study. You can also get more detailed eligibility information about the study by clicking here to visithttp://www.clinicaltrials.gov.

Study Design:

• The study will begin with a screening period to make sure subjects are eligible to participate in the study.
• After the screening period, subjects who are eligible for participation will each be given several different doses of COR-003, to be taken orally in tablet form.
• After an individualized dose has been selected, participants will take COR-003 for six months.
• Finally, participants will continue in the study for an additional six months at doses to be determined by the study doctor.

Throughout the study, participants will meet regularly with a study doctor and will take part in a variety of medical tests to make sure they are doing well and to see if COR-003 is working.

Participants in the study should be sure they have the time to participate. Participants will generally be followed for over a year:

Study Locations

The study is currently taking place in several places around the world (United States, Belgium, France, Israel, Netherlands, Spain, and Sweden).
Additional information on the study can be found at clinicaltrials.gov throughthis link.

Study sponsor: Cortendo AB

For more information, please contact:

Jim Ellis at Cortendo AB tel: +1 (610) 254-9245 or jellis@cortendo.com

FDA Puts Strict Limits on Oral Ketoconazole Use

By John Gever, Deputy Managing Editor, MedPage Today

SILVER SPRING, Md. -- Oral ketoconazole (Nizoral) should never be used as first-line therapy for any type of fungal infection because of the risk of liver toxicity and interactions with other drugs, the FDA said Friday.

The agency ordered a series of label changes and a new medication guide for patients that emphasize the risks, which also include adrenal insufficiency. It noted that the restrictions apply only to the oral formulation, not topical versions.

Late Thursday, the chief advisory body for the FDA's European counterpart went further. The EU's Committee on Medicinal Products for Human Use (CHMP) recommended that member nations pull oral ketoconazole from their markets entirely.

Both the FDA and the CHMP cited studies indicating high risks of severe, acute liver injury in patients taking the drug. Studies using the FDA's adverse event reporting system and a similar database in the U.K. indicated that liver toxicity was more common with oral ketoconazole than with other anti-fungals in the azole class.

The FDA also said that oral ketoconazole "is one of the most potent inhibitors" of the CYP3A4 enzyme. This effect can lead to sometimes life-threatening interactions with other drugs metabolized by CYP3A4, and also to adrenal insufficiency, since the enzyme also catalyzes release of adrenal steroid hormones.

"This accounts for clinically important endocrinologic abnormalities observed in some patients (particularly when the drug is administered at high dosages), including gynecomastia in men and menstrual irregularities in women," the FDA said.

The only indication for oral ketoconazole still supported by the FDA is for use in life-threatening mycoses in patients who cannot tolerate other anti-fungal medications or when such medications are unavailable.

In such instances, the FDA said, physicians should assess liver function before starting the drug. It is contraindicated in patients with pre-existing liver disease, and patients should be instructed not to drink alcohol or use other potentially hepatotoxic drugs.

Adrenal function should also be monitored in patients using the drug.

The CHMP also indicated the topical formulations of ketoconazole should stay on the market, but it found no basis for keeping the oral form available for any purpose.

"Taking into account the increased rate of liver injury and the availability of alternative anti-fungal treatments, the CHMP concluded that the benefits did not outweigh the risks," the panel indicated in a statement.

It recommended that physicians stop prescribing oral ketoconazole and that they should review alternatives in patients currently receiving the drug. The committee also said that patients now taking oral ketoconazole "make a non-urgent appointment" with their physicians to discuss their treatment.

From MedPage Today

Cushing's Disease - Rare Disease Quick Facts

Cushing's disease is a rare condition due to excess cortisol levels that result from a pituitary tumor secreting adrenocorticotropic hormone (ACTH), which stimulates cortisol secretion.  Cushing’s disease should not be confused with Cushing’s syndrome which is increased cortisol levels but that increase can be due to any number of factors. However, Cushing’s disease is the most common form of Cushing’s syndrome.

Symptoms

The symptoms related to Cushing's disease and Cushing's syndrome are the same, since both are related to an excess of cortisol. Also, symptoms vary extensively among patients and that, with the inherent fluctuation in hormone levels make it difficult to diagnosis both conditions.

Changes in physical characteristics of the body

• Fullness and rounding of the face
• Added fat on back of neck (so-called "buffalo hump")
• Easy bruising
• Purplish stretch marks on the abdomen (abdominal striae)
• Excessive weight gain, especially in abdominal region
• Red cheeks
• Excess hair growth on the face, neck, chest, abdomen and thighs

Changes in physiology/psychology

• Generalized weakness and fatigue
• Menstrual disorder
• Decreased fertility and/or sex drive
• High blood pressure that is often difficult to treat
• Diabetes mellitus
• Mood and behavior disorders

Diagnosis

The early stages of Cushing's disease may be difficult to recognize. However, if it is suspected, diagnosis is generally a 2 stage process. First to determine if cortisol levels are high, and if so, why they are high.

Tests to confirm high cortisol levels:

• 24-hour urine cortisol
• Dexamethasone suppression test (low dose)

Tests to determine cause:

• Blood ACTH level
• Brain MRI
• Corticotropin-releasing hormone test
• Dexamethasone suppression test (high dose)
• Petrosal sinus sampling

Treatment

Surgery

• Most patients with Cushing’s disease undergo surgery to remove the pituitary adenoma offers.
• If the tumor is isolated to the pituitary, cure rates of 80-85% are common.
• If the tumor has spread to nearby organs, cure rates of 50-55% are common.

Medicine (approved orphan drugs)

Signifor (pasireotide)

• Approved for patients with Cushing’s disease for whom pituitary is not an option or surgery has been ineffective.
• Signifor is a somatostatin receptor agonist that leads to inhibition of ACTY secretion (and subsequently decreased cortisol levels).

Korlym (mifepristone)

• Approved for patients with Cushing’s syndrome who have type 2 diabetes or glucose intolerance and have failed surgery (or not candidates for surgery).
• Korlym is a glucocorticoid receptor antagonist which in turn blocks the effects of the high levels of cortisol in the body. Korlym is used to treat high glucose levels due to elevated cortisol.

Medicines used but not indicated for Cushing’s disease include

Mitoden

ketoconazole

Metyrapone

Etomidate

Radiation

• Radiation therapy may be used in some patients and can be very effective in controlling the growth of these tumors.

Prognosis

In most cases, treatment can cure Cushing’s disease. If not treated properly, the chronic hypercortisolism can lead to excess morbidity and mortality due to increased cardiovascular and other risk factors.

For more information

National Library of Medicine, National Institute of Health

Cushing’s Disease Information (provided by Novartis Pharmaceuticals)

Images courtesy of the open access journal Orhanet Journal for Rare Diseases.  Castinetti et al. Orphanet J Rare Dis. 2012 7:41   doi:10.1186/1750-1172-7-41

- See more at: http://www.raredr.com/front-page-medicine/articles/cushings-disease-rare-disease-quick-facts-0

Research and Markets: Pituitary ACTH Hypersecretion (Cushing's Disease) - Pipeline Review Report, H1 2013 Edition

Research and Markets (http://www.researchandmarkets.com/
research/rdf6gm/pituitary_acth) has announced the addition of the "Pituitary ACTH Hypersecretion (Cushing's Disease) - Pipeline Review, H1 2013" report to their offering.

'Pituitary ACTH Hypersecretion (Cushing's Disease) - Pipeline Review, H2 2013', provides an overview of the indication's therapeutic pipeline. This report provides information on the therapeutic development for Pituitary ACTH Hypersecretion (Cushing's Disease), complete with latest updates, and special features on late-stage and discontinued projects. It also reviews key players involved in the therapeutic development for Pituitary ACTH Hypersecretion (Cushing's Disease).

Scope

- A snapshot of the global therapeutic scenario for Pituitary ACTH Hypersecretion (Cushing's Disease).

- A review of the Pituitary ACTH Hypersecretion (Cushing's Disease) products under development by companies and universities/research institutes based on information derived from company and industry-specific sources.

- Coverage of products based on various stages of development ranging from discovery till registration stages.

- A feature on pipeline projects on the basis of monotherapy and combined therapeutics.

- Coverage of the Pituitary ACTH Hypersecretion (Cushing's Disease) pipeline on the basis of route of administration and molecule type.

- Key discontinued pipeline projects.

- Latest news and deals relating to the products.

Companies Involved in Pituitary ACTH Hypersecretion (Cushing's Disease) Therapeutics Development

• Isis Pharmaceuticals, Inc.
• Ipsen S.A.
• Novartis AG
• HRA Pharma, SA
• Cortendo Invest AB

Drug Profiles: Product Description, Mechanism of Action and R&D Progress

• LCI-699
• mifepristone
• ISIS-GCCRRx
• Inhibitors of ACTH receptor
• ketoconazole
• Next Generation Cortisol Inhibitor
• pasireotide Long Acting Release

For more information visit http://www.researchandmarkets.com/research/rdf6gm/pituitary_acth

Read more here: http://www.heraldonline.com/2013/06/17/4952623/research-and-markets-pituitary.html#storylink=cpy

Read more here: http://www.heraldonline.com/2013/06/17/4952623/research-and-markets-pituitary.html#storylink=cpy

Salk scientists find potential therapeutic target for Cushing's disease

LA JOLLA, CA---Scientists at the Salk Institute for Biological Studies have identified a protein that drives the formation of pituitary tumors in Cushing's disease, a development that may give clinicians a therapeutic target to treat this potentially life-threatening disorder.

The protein, called TR4 (testicular orphan nuclear receptor 4), is one of the human body's 48 nuclear receptors, a class of proteins found in cells that are responsible for sensing hormones and, in response, regulating the expression of specific genes. Using a genome scan, the Salk team discovered that TR4 regulates a gene that produces adrenocorticotropic hormone (ACTH), which is overproduced by pituitary tumors in Cushing's disease (CD). The findings were published in the May 6 early online edition of Proceedings of the National Academy of Sciences.

"We were surprised by the scan, as TR4 and ACTH were not known to be functionally linked," says senior author Ronald M. Evans, a professor in Salk's Gene Expression Laboratory and a lead researcher in the Institute's Helmsley Center for Genomic Medicine. "TR4 is driving the growth and overexpression of ACTH. Targeting this pathway could therapeutically benefit treatment of CD."

In their study, Evans and his colleagues discovered that forced overexpression of TR4 in both human and mouse cells increased production of ACTH, cellular proliferation and tumor invasion rates. All of these events were reversed when TR4 expression was reduced.

First described more than 80 years ago, Cushing's disease is a rare disorder that is caused by pituitary tumors or excess growth of the pituitary gland located at the base of the brain. People with CD have too much ACTH, which stimulates the production and release of cortisol, a hormone that is normally produced during stressful situations.

While these pituitary tumors are almost always benign, they result in excess ACTH and cortisol secretion, which can result in various disabling symptoms, including diabetes, hypertension, osteoporosis, obesity and psychological disturbances. Surgical removal of the tumors is the first-line therapy, with remission rates of approximately 80 percent; however, the disease recurs in up to 25 percent of cases.

Drugs such as cabergoline, which is used to treat certain pituitary tumors, alone or in combination with ketoconazole, a drug normally used to treat fungal infections, have been shown to be effective in some patients with Cushing's disease. More recently, mefipristone-best known as the abortion pill RU-486-was approved by the FDA to treat CD. Despite these advances in medical therapy, the Salk scientists say additional therapeutic approaches are needed for CD.

"Pituitary tumors are extremely difficult to control," says Michael Downes, a senior staff scientist in the Gene Expression Laboratory and a co-author of the study. "To control them, you have to kill cells in the pituitary gland that are proliferating, which could prevent the production of a vital hormone."

Previous studies have found that, by itself, TR4 is a natural target for other signaling molecules in the pituitary. Small-molecule inhibitors that have been developed for other cancers could be potentially applied to disrupt this signaling cascade. "Our discovery," says Evans, a Howard Hughes Medical Institute investigator and holder of the March of Dimes Chair in Molecular and Developmental Biology, "might lead clinicians to an existing drug that could be used to treat Cushing's disease."

Source: Salk Institute

The Latest Cushing's News Items ~ 3/18/2013

News:

• Cushing's Awareness Blogging Challenge 2013
• Signifor® (Pasireotide) is now Commercially Available
• Cushing’s Syndrome, Prostate Cancer and Adrenocortical Carcinoma
• Predictors of Mortality, CVD Risk in Cushing's Disease ID'd
• Early Detection, Treatment Needed To Reduce Risk Of Death, Cardiovascular Disease In Cushing's Disease Patients
• Dr Oz covered Cushing's on Thursday, December 20
• Cushing Syndrome Overview
• Mifepristone: is there a place in the treatment of Cushing's disease?
• Cushing's Syndrome after Hemodialysis for 21 Years
• Novartis drug Signifor® recommended by FDA advisory committee for approval to treat patients with Cushing's disease
• Evaluation of depression, quality of life and body image in patients with Cushing's disease
• Robotic versus laparoscopic adrenalectomy in obese patients
• A Quarter of a Century
• Use of ketoconazole in the treatment of Cushing's syndrome
• Surgical Versus Medical Treatment for Cushing Disease, the New and the Old
• Novartis launches pasireotide for Cushing’s disease
• Transsphenoidal Microsurgery for Cushing’s Disease: Initial Outcome and Long-Term Results More info
• Efficacy and Safety of Pasireotide Administered Monthly in Patients With Cushing's Disease
• We have started the Non-Profit Paperwork
• Notes on the Magic Foundation Cushing's Conference, 2012
• Cushing's syndrome
• Body composition and cardiovascular risk markers after remission of Cushing's disease: a prospective study using whole-body MRI
• Genetic variant is linked to obesity and insulin resistance
• Cortendo Receives Positive Orphan Drug Opinion from EMA for NormoCort for Cushing’s Disease
• Clinicopathological Correlations in Pituitary Adenomas
• Comment has been added: Can stress cause Cushing's syndrome?
• Medical management of Cushing's disease: what is the future?
• New! Cushie Readers book club on goodreads.com Please join us!
• Magic Foundation Cushing's Conference http://cushie.info
• Stand Up and Be Counted!
• Archived! Interview with Dr. Theodore Friedman April 2, 2012 http://BlogTalkRadio.com/CushingsHelp
• We Have Lost Another Cushie.http://cushings.posterous.com
• Cushie warriors: men, women & children who battle Cushing’s numerous times in hopes of winning the war  http://cushie.info
• We're on Pinterest http://pinterest.com/cushingshelp
• Google+ page for Cushings http://cushie.info
• Tweeting about Cushing's? Use this hashtag: #cushingshttp://tagdef.com/cushings

More at http://www.cushie.info/

Use of ketoconazole in the treatment of Cushing's syndrome

An older, but still useful, abstract:

J Clin Endocrinol Metab. 1986 Dec;63(6):1365-71.

 

Loli P, Berselli ME, Tagliaferri M.

Abstract

The therapeutic value of ketoconazole for long term treatment of patients with Cushing's syndrome was studied. Seven patients with Cushing's disease and one with an adrenal adenoma received 600-800 mg/day ketoconazole for 3-13 months. Plasma ACTH, cortisol, and dehydroepiandrosterone sulfate levels and urinary cortisol, 17-ketosteroid, and tetrahydro-11-deoxycortisol excretion were determined periodically during the treatment period.

Plasma ACTH and cortisol responses to CRH stimulation were determined before and during treatment. Rapid and subsequently persistent clinical improvement occurred in each patient; plasma dehydroepiandrosterone sulfate and urinary 17-ketosteroid and cortisol excretion decreased soon after the initiation of treatment, subsequently remaining normal or nearly so throughout the treatment period. Urinary tetrahydro-11-deoxycortisol excretion increased significantly. Plasma cortisol levels decreased. Plasma ACTH levels did not change, and individual plasma ACTH and cortisol increments in response to CRH were comparable before and during treatment. The cortisol response to insulin-induced hypoglycemia improved in one patient and was restored to normal in another.

The seven patients tested recovered normal adrenal suppressibility in response to a low dose of dexamethasone during ketoconazole treatment. Ketoconazole is effective for long term control of hypercortisolism of either pituitary or adrenal origin. Its effect appears to be mediated by inhibition of adrenal 11 beta-hydroxylase and 17,20-lyase, and it, in some unknown way, prevents the expected rise in ACTH secretion in patients with Cushing's disease.

From http://www.ncbi.nlm.nih.gov/pubmed/3023421

 

Surgical Versus Medical Treatment for Cushing Disease, the New and the Old

Surgical Versus Medical Treatment for Cushing Disease the New and the Old

Cortendo Receives Positive Orphan Drug Opinion from EMA for NormoCort for Cushing’s Disease

Cortendo AB with support from their preclinical development partner, PharmaDirections, Inc. received a positive opinion from the European Medicines Agency for NormoCort.

Radnor, PA (PRWEB) June 26, 2012

Cortendo AB [ticker: CORT on the Norwegian NOTC-A], a biopharmaceutical Corporation focused on the development of new therapies in the field of Metabolic Diseases, obtained a positive opinion by the European Medicines Agency's Committee for Orphan Medicinal Products, on its application for orphan drug designation for NormoCort (COR-003) for the treatment of hypercortisolism (Cushing’s Syndrome). The positive opinion of the COMP for NormoCort has now been forwarded to the EU commission for final approval and publication in the EU community register. With orphan drug designation granted in the US by the FDA in March and now with this positive opinion from the EU’s COMP, Cortendo is well positioned to move NormoCort into pivotal global clinical trials in Cushing’s Syndrome.

Cortendo is a biopharmaceutical company that relies in part on quality consultants and CRO’s to support the research and development of its pipeline. For the past year, Cortendo has contracted with PharmaDirections for a number of key services ranging from CMC to US and European Regulatory support. PharmaDirections’ regulatory services have ranged from the successful preparation and support to orphan drug designation applications in both the US and Europe to support with both IND and CTA preparation. “Cortendo has appreciated the high quality of support particularly in the areas of regulatory, CMC, and project management services offered by PharmaDirections”, said Dr. Ted Koziol, COO of Cortendo.

“Our Cortendo relationship is a great example of a virtual company using outsourced resources to their maximum advantage” said Dr. Richard Soltero, President of PharmaDirections.

About Cortendo:

Cortendo is a pioneer in the field of cortisol inhibition. The development of the lead drug candidate NormoCort (COR-003), the 2S,4R-enantiomer of ketoconazole, has been directed to Cushing’s Syndrome. The company’s strategy is to focus its resources to opportunities where the path to commercialization or partnership is clear and relatively near-term. Strategically, Cortendo’s business model is to commercialize relevant opportunities in the United States while partnering its assets ex-US. Backed by a highly experienced leadership team Cortendo has plans to continue to implement its pipeline expansion efforts in osteoarthritis and diabetes, as well as other near term revenue opportunities.

About PharmaDirections:

PharmaDirections, Inc. provides pharmaceutical consulting and project management services with a focus on preclinical development, formulation development and CMC, and regulatory affairs. The company was founded in 2003 and is based in Cary, North Carolina.

From PRWeb

Medical management of Cushing's disease: what is the future?

Fleseriu M, Petersenn S.

Source

Departments of Medicine and Neurological Surgery, Northwest Pituitary Center, Oregon Health & Science University, Portland, OR, USA.

Abstract

Cushing's disease (CD) is caused by a corticotroph, adrenocorticotropic-hormone (ACTH)-secreting pituitary adenoma resulting in significant morbidity and mortality. Transsphenoidal surgery is the initial treatment of choice in almost all cases.

Remission rates for microadenomas are good at 65-90 % (with an experienced neurosurgeon) but remission rates are much lower for macroadenomas. However, even after postoperative remission, recurrence rates are high and can be seen up to decades after an initial diagnosis. Repeat surgery or radiation can be useful in these cases, although both have clear limitations with respect to efficacy and/or side effects.

Hence, there is a clear unmet need for an effective medical treatment. Currently, most drugs act by inhibiting steroidogenesis in the adrenal glands. Most is known about the effects of ketoconazole and metyrapone. While effective, access to ketoconazole and metyrapone is limited in many countries, experience with long-term use is limited, and side effects can be significant. Recent studies have suggested a role for a pituitary-directed therapy with new multireceptor ligand somatostatin analogs (e.g., pasireotide, recently approved in Europe for treatment of CD), second-generation dopamine agonists, or a combination of both.

Mifepristone (a glucocorticoid receptor antagonist) is another promising drug, recently approved by the FDA for treatment of hyperglycemia associated with Cushing's syndrome. We review available medical treatments for CD with a focus on the two most recent compounds referenced above.

Our aim is to expand awareness of current research, and the possibilities afforded by available medical treatments for this mesmerizing, but often frightful disease.

PMID: 22674211 [PubMed - as supplied by publisher]

From http://www.ncbi.nlm.nih.gov/pubmed/22674211

Course of pregnancies in women with Cushing’s disease treated by gamma-knife

(doi:10.3109/09513590.2012.683057)

Francesco Ferraù1, Marco Losa2, Oana Ruxandra Cotta1, Maria Luisa Torre1, Marta Ragonese1, Francesco Trimarchi1, Salvatore Cannavò1

1Department of Medicine and Pharmacology, Section of Endocrinology, University of Messina, Messina, Italy

2Department of Neurosurgery, Istituto Scientifico San Raffaele, Milan, Italy

Correspondence: Francesco Ferraù, MD, Department of Medicine and Pharmacology, Section of Endocrinology, University of Messina, AOU Policlinico “G. Martino” (Pad. H, floor 4), Via Consolare Valeria 1, 98125 Messina, Italy. Tel: +39 090 2213507. Fax: +39 090 2213945. E-mail: ferrau1@interfree.it

 

Data concerning pregnancy in women with Cushing’s disease treated by gamma-knife (GK) are scanty. We present and discuss the course and outcome of five pregnancies in two women with Cushing’s disease (CD), the first of whom was treated only by GK, and the second one treated by surgery, GK and ketoconazole.

In the first patient, pregnancy was uneventful and full-term. During gestation, plasma ACTH, serum cortisol and 24-h urinary free cortisol (UFC) levels were steady, and always in the normal range for healthy non-pregnant individuals. The newborn was healthy and normal-weight.

In the second woman, two pregnancies, occurring 3 years after GK and few months after ketoconazole withdrawal, were interrupted by spontaneous abortion or placental disruption despite normal cortisol levels. This patient became again pregnant 3 years later and delivered vaginally a healthy full-term infant.

Seven months after the delivery, the patient became pregnant again and at the 39th week of gestation delivered vaginally a healthy male. Hypoprolactinemia and/or central hypothyroidism occurred in both cases. In women with CD treated by GK, pregnancy can occur. However, pregnancy is at risk even when ACTH and cortisol levels are normalized by treatment. After GK, evaluation of pituitary function is mandatory due to the risk of hypopituitarism.

Read More: http://informahealthcare.com/doi/abs/10.3109/09513590.2012.683057

Dr. Theodore Friedman Returns to Answer Our Questions

Have questions about the new Korlym? How about Korlym vs ketoconazole? About medical vs surgical treatment for Cushing's.

Ask Dr. Theodore Friedman.

 

 

Theodore C. Friedman, M.D., Ph.D. has opened a private practice, specializing in treating patients with adrenal, pituitary, thyroid and fatigue disorders. Dr. Friedman has privileges at Cedars-Sinai Medical Center and Martin Luther King Medical Center. His practice includes detecting and treating hormone imbalances, including hormone replacement therapy. Dr. Friedman is also an expert in diagnosing and treating pituitary disorders, including Cushings disease and syndrome.

Dr. Friedman's career reflects his ongoing quest to better understand and treat endocrine problems. With both medical and research doctoral degrees, he has conducted studies and cared for patients at some of the country's most prestigious institutions, including the University of Michigan, the National Institutes of Health, Cedars-Sinai Medical Center, and UCLA's Charles Drew University of Medicine and Science.

Read Dr. Friedman's First Guest Chat, November 11, 2003. 
Read Dr. Friedman's Second Guest Chat, March 2, 2004. 

Listen to Dr. Friedman First Live Voice Interview, January 29, 2009. 
Listen to Dr. Friedman Second Live Voice Interview, March 12, 2009. 
Listen to Dr. Friedman Third Live Voice Interview, February 13, 2011.

 

 

Listen live at http://www.blogtalkradio.com/cushingshelp/2012/03/13/questions-about-medical-therapies-for-cushings

Call in to ask your question at 

(646) 200-0162

This interview will be archived afterwards at the same link and on iTunes Cushie Podcasts 

Dr. Theodore Friedman Returns to Answer Our Questions

Have questions about the new Korlym? How about Korlym vs ketoconazole? About medical vs surgical treatment for Cushing's.

Ask Dr. Theodore Friedman.

Theodore C. Friedman, M.D., Ph.D. has opened a private practice, specializing in treating patients with adrenal, pituitary, thyroid and fatigue disorders. Dr. Friedman has privileges at Cedars-Sinai Medical Center and Martin Luther King Medical Center. His practice includes detecting and treating hormone imbalances, including hormone replacement therapy. Dr. Friedman is also an expert in diagnosing and treating pituitary disorders, including Cushings disease and syndrome.

Dr. Friedman's career reflects his ongoing quest to better understand and treat endocrine problems. With both medical and research doctoral degrees, he has conducted studies and cared for patients at some of the country's most prestigious institutions, including the University of Michigan, the National Institutes of Health, Cedars-Sinai Medical Center, and UCLA's Charles Drew University of Medicine and Science.

Read Dr. Friedman's First Guest Chat, November 11, 2003. 
Read Dr. Friedman's Second Guest Chat, March 2, 2004. 

Listen to Dr. Friedman First Live Voice Interview, January 29, 2009. 
Listen to Dr. Friedman Second Live Voice Interview, March 12, 2009. 
Listen to Dr. Friedman Third Live Voice Interview, February 13, 2011.

 

Listen live at http://www.blogtalkradio.com/cushingshelp/2012/03/13/questions-about-medical-therapies-for-cushings

Call in to ask your question at 

(646) 200-0162

This interview will be archived afterwards at the same link and on iTunes Cushie Podcasts 

First potential Prader-Willi treatment among EMA’s orphan recommendations

Ferring’s carbetocin, potentially the first treatment for Prader-Willi syndrome, is among 16 new medicines recommended to receive orphan drug designation in Europe.

The European Medicines Agency’s (EMA) Committee for Orphan Medicinal Products (COMP) said work on carbetocin’s use to treat the rare genetic disorder should be granted development incentives.

Prader-Willi syndrome, which is estimated to affect less than 1 in 5,000 people in the EU, causes a variety of symptoms, including a constant desire to eat food, leading to obesity, impaired function of the gonads, learning difficulties and behavioural problems.

Patients with the disease often have a significantly reduced life span and require lifelong care.

Carbetocin’s recommendation was supported by the European Organisation for Rare Diseases (Eurordis), a European alliance of patient organisations and individuals involved in the promotion of research for rare diseases and development of orphan drugs.

Other treatments to be recommended by the COMP for orphan drug designation, which is granted to products for life-threatening or very serious conditions that affect no more than 5 in 10,000 people in the EU, included Nexus Oncology’s diamidophosphate.

The drug, which is being investigated as a treatment for soft tissue sarcoma, was joined on the list by TMC Pharma Service’s chlormethine for treatment of cutaneous T-cell lymphoma and Laboratoire HRA Pharma’s ketoconazole for treatment of Cushing's syndrome.

Therapies for neglected tropical diseases also featured in the COMP’s recommendations, with Dafra Pharma’s oleylphosphocholine intended to treat leishmaniasis – a disease caused by sand fly parasites that is estimated to cause as many as 50,000 deaths per year.

The EMA said that orphan medicine incentives can be also used to support the development of treatments for similar neglected diseases, which would not be developed under normal market conditions.

All the COMP’s recommendations are now with the European Commission, which will make the final decision on each drug.

The full list of EMA orphan drug recommendations

From http://www.pmlive.com/pharma_news/potential_first_prader-willi_treatment_ema_orphan_recommendation_357835

Cushing’s syndrome in pregnancy

    BMJ Case Reports   2011;  doi:10.1136/bcr.01.2011.3720

    * Rare disease

   1. Margarita Victoria B Holgado-Galicia1,
   2. Jose Donato Magno2,
   3. Czarlota Acelajado-Valdenor3,
   4. Iris Thiele Isip-Tan1,
   5. Mary Anne Lim-Abrahan1

   1. Correspondence to Dr Margarita Victoria B Holgado-Galicia, marvi.holgado@gmail.com

Summary

A 22-year-old G1P0 was admitted at 26 weeks gestation for preeclampsia, hyperglycaemia and cushingoid features. Elevated 24-h urine free cortisol (UFC) and suppressed plasma adrenocorticotrophic hormone (ACTH) suggested ACTH-independent Cushing’s syndrome. Ultrasound showed left adrenal mass. She delivered preterm at 28 weeks due to severe preeclampsia and fetal distress. The infant expired after 4 days. Blood pressure was controlled after delivery and the patient was discharged on ketoconazole. Adrenalectomy was planned postpartum; however, she withdrew consent and was lost to follow-up.

A 33-year-old G1P1 presented with gestational diabetes. Pregnancy was complicated by premature delivery at 31 weeks for fetal distress. The baby improved and survived. Three months postpartum, she was evaluated for osteoporosis after sustaining a fracture from a fall. Cushingoid facies, elevated 24-h UFC, suppressed ACTH and a right adrenal mass on MRI confirmed an ACTH-independent Cushing’s syndrome. She underwent adrenalectomy and improved.

From http://casereports.bmj.com/content/2011/bcr.01.2011.3720.abstract

Pasireotide Alone or with Cabergoline and Ketoconazole in Cushing's Disease

To the Editor:

 

Cushing's disease, which is caused by an adrenocorticotropin-secreting pituitary adenoma, is associated with increased morbidity and mortality.1 Currently, there is no effective medical therapy for Cushing's disease. However, recent studies identified the somatostatin-receptor subtype 5 and dopamine-receptor subtype 2 as potential therapeutic targets in Cushing's disease.2

Pasireotide is a new somatostatin analogue that binds with high affinity to somatostatin-receptor subtypes 1, 2, and 3, and it especially has high-affinity binding to somatostatin-receptor subtype 5.3 In a recent 15-day pilot study, pasireotide normalized the excretion of urinary free cortisol in 17% of patients with Cushing's disease.4 Cabergoline, a dopamine-receptor subtype 2 agonist, can also normalize levels of urinary free cortisol in Cushing's disease, but this effect is often not maintained during prolonged treatment.5 Because the majority of adrenocorticotropin-secreting adenomas simultaneously express somatostatin-receptor subtype 5 and dopamine-receptor subtype 2,2 we hypothesized that pasireotide and dopamine-receptor subtype 2 agonists may have synergistic effects in the treatment of Cushing's disease. Finally, ketoconazole suppresses cortisol production at the adrenal level through inhibition of steroidogenic enzymes.1 In a prospective, open-label, multicenter trial, we used a stepwise approach for the medical treatment of Cushing's disease, with pasireotide as the initial form of treatment and the sequential addition of cabergoline and low-dose ketoconazole.

Seventeen patients with Cushing's disease (mean age, 45.7 years; 13 women) were included in an 80-day trial with normalization of levels of urinary free cortisol as the main outcome measure. All patients began treatment with 100 μg of pasireotide subcutaneously three times daily; this dose was increased to 250 μg subcutaneously three times daily at day 15 if the level of urinary free cortisol had not normalized. At day 28, cabergoline was added to pasireotide at a dose of 0.5 mg every other day (this dose was increased to 1.0 mg every other day after 5 days and 1.5 mg every other day after 10 days) if the level of urinary free cortisol remained elevated. If the level of urinary free cortisol had not normalized at day 60, ketoconazole was added at a dose of 200 mg thrice daily.

Pasireotide monotherapy induced sustained normalization of the level of urinary free cortisol in 5 of 17 patients (29%) (Figure 1A  
(Figure 1A Levels of Urinary Free Cortisol after Treatment for Cushing's Disease.).

 

The addition of cabergoline normalized urinary free cortisol values in an additional 4 of 17 patients (24%). At day 60, a total of 8 of 17 patients (47%) still had elevated urinary free cortisol levels with pasireotide–cabergoline combination therapy, although a trend toward normalization of levels of urinary free cortisol was observed in all but one patient, with a mean (±SE) decrease of 48±6% in the level of urinary free cortisol. The addition of low-dose ketoconazole induced biochemical remission in six of these eight patients at day 80, increasing the number of patients with a complete response to 88%.

Figure 1B shows the effects of 28 days of pasireotide monotherapy in relation to the severity of hypercortisolism at baseline. In patients with mild hypercortisolism and those with severe hypercortisolism, significant reductions in the level of urinary free cortisol of up to 67% of the baseline value were observed.

Along with the normalization of the level of urinary free cortisol, the clinical features of Cushing's disease improved, including a decrease in body weight (−2.4±0.9 kg), waist circumference (−4.2±1.3 cm), systolic blood pressure (−12±4 mm Hg), and diastolic blood pressure (−8±3 mm Hg). Adverse events included disturbance of glucose homeostasis (glycated hemoglobin level, 5.8±0.2% to 6.7±0.3%; P<0.01) and a decrease in levels of serum type I insulin-like growth factor to below the lower limit of the normal range in 9 of 17 patients.

Thus, stepwise medical therapy for Cushing's disease with the use of three drugs that differentially target somatostatin-receptor subtype 5 and dopamine-receptor subtype 2 receptors in the adrenocorticotropin-secreting adenoma and steroidogenic enzymes in the adrenal cortex resulted in biochemical control in nearly 90% of patients.

Richard A. Feelders, M.D., Ph.D.
Christiaan de Bruin, M.D., Ph.D.
Erasmus Medical Center, Rotterdam, the Netherlands
r.feelders@erasmusmc.nl

Alberto M. Pereira, M.D., Ph.D.
Johannes A. Romijn, M.D., Ph.D.
Leiden University Medical Center, Leiden, the Netherlands

Romana T. Netea-Maier, M.D., Ph.D.
Ad R. Hermus, M.D., Ph.D.
Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands

Pierre M. Zelissen, M.D., Ph.D.
University Medical Center Utrecht, Utrecht, the Netherlands

Ramona van Heerebeek
Frank H. de Jong, Ph.D.
Aart-Jan van der Lely, M.D., Ph.D.
Wouter W. de Herder, M.D., Ph.D.
Leo J. Hofland, Ph.D.
Steven W. Lamberts, M.D., Ph.D.
Erasmus Medical Center, Rotterdam, the Netherlands

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

5 References

From http://www.nejm.org/doi/full/10.1056/NEJMc1000094

Cushing's Syndrome due to a Pancreatic Neuroendocrine Tumor Metastatic to the Ovaries

Summary

We report the case of a 36-year-old woman with Cushing's syndrome caused by a malignant unresectable neuroendocrine carcinoma of the pancreas that developed bilateral ovarian metastases 7 years after diagnosis.

In November 2001, because of abdominal pain and jaundice, the patient underwent radiological investigations and exploratory laparotomy that demonstrated the presence of a 3-cm mass of the head of the pancreas, infiltrating the superior mesenteric vein, associated with enlargement of multiple abdominal lymph nodes and with a liver nodule. Histological examination of one lymph node and of the liver nodule demonstrated the presence of metastases from a well-differentiated neuroendocrine carcinoma showing corticotropin immunoreactivity.

A few months later, the patient started to show the clinical symptoms of Cushing's syndrome and underwent steroid-blocking ketoconazole therapy. The clinical endocrine picture was controlled until the end of 2008, when the endocrine symptoms of the Cushing's syndrome worsened and bilateral ovarian tumors appeared. Hysteroannexectomy was performed and ovarian tumors were found to be metastases from a well-differentiated neuroendocrine carcinoma with morphological and immunohistochemical features overlapping those observed in 2002.

The clinical situation worsened and the patient died in November 2009. The clinical aspects and the problems in the differential diagnosis are discussed.

Affiliation

Department of Pathology, Ospedale di Circolo, Viale Borri 57, 21100, Varese, Italy, stefano.larosa@ospedale.varese.it.

Journal Details

Name: Endocrine pathology
ISSN: 1559-0097
Pages:

Links

• PubMed Source
• DOI Link

From http://www.bioportfolio.com/resources/pmarticle/155008/Cushing-s-Syndrome-Due-To-A-Pancreatic-Neuroendocrine-Tumor-Metastatic-To-The.html

Pancreatic islet cell carcinoma presenting with concurrent Cushing's and Zollinger-Ellison syndromes: case series and literature review

European Journal of Gastroenterology & Hepatology:

February 2010 - Volume 22 - Issue 2 - pp 246-252

doi: 10.1097/MEG.0b013e3283314827

Case Reports

Said, Rabih

Cushing's syndrome and Zollinger–Ellison syndrome occur occasionally as a result of neuroendocrine cancers. The concurrence of the two syndromes has been considered to confer a poor clinical and therapeutic outcome.

In this study, we are reviewing two patients with pancreatic islet cell carcinomas and with both Zollinger–Ellison and Cushing's syndromes, one followed up for more than 5 years, and the other still receiving therapy, 5 years since diagnosis. A literature review showed that surgery has limited utility as the majority of these patients had metastases at the time of diagnosis.

Proton-pump inhibitors, ketoconazole, and somatostatin antagonists have a major role in controlling symptoms. Interferon and systemic chemotherapeutic agents play a role in the management of metastatic and fast-growing cases. Chemoembolization and bland embolization show encouraging results in controlling liver metastases. The latter was used effectively and more than once in the two patients presented herein.

On the basis of recent molecular genetics studies, target therapy may be helpful, however, ongoing trials will define it's utility. As the data confers a worse prognosis versus other pancreatic neuroendocrine tumors, the relatively favorable outcome of the two patients reported herein may reflect the impact of multiple therapeutic modalities.

From http://journals.lww.com/eurojgh/Abstract/2010/02000/Pancreatic_islet_cell_carcinoma_presenting_with.20.aspx

Treatment of Cushing disease: overview and recent findings

Authors: Tatiana Mancini, Teresa Porcelli, Andrea Giustina

Published Date October 2010 , Volume 2010:6 Pages 505 - 516 DOI 10.2147/TCRM.S12952

Tatiana Mancini¹, Teresa Porcelli², Andrea Giustina^2
1Department of Internal Medicine and Medical Specialties, San Marino Hospital, San Marino, Republic of San Marino, ²Department of Medical and Surgical Sciences, University of Brescia, Brescia, Italy

Abstract:

Endogenous Cushing syndrome is an endocrine disease caused by excessive secretion of adrenocorticotropin hormone in approximately 80% of cases, usually by a pituitary corticotroph adenoma (Cushing disease [CD]). It is a heterogeneous disorder requiring a multidisciplinary and individualized approach to patient management.

The goals of treatment of CD include the reversal of clinical features, the normalization of biochemical changes with minimal morbidity, and long-term control without recurrence. Generally, the treatment of choice is the surgical removal of the pituitary tumor by transsphenoidal approach, performed by an experienced surgeon. Considering the high recurrence rate, other treatments should be considered.

Second-line treatments include more radical surgery, radiation therapy, medical therapy, and bilateral adrenalectomy. Drug treatment has been targeted at the hypothalamic or pituitary level, at the adrenal gland, and also at the glucocorticoid receptor level. Frequently, medical therapy is performed before surgery to reduce the complications of the procedure, reducing the effects of severe hypercortisolism.

Commonly, in patients in whom surgery has failed, medical management is often essential to reduce or normalize the hypercortisolemia, and should be attempted before bilateral adrenalectomy is considered. Medical therapy can be also useful in patients with CD while waiting for pituitary radiotherapy to take effect, which can take up to 10 years or more.

So far, results of medical treatment of CD have not been particularly relevant; however, newer tools promise to change this scenario. The aim of this review is to analyze the results and experiences with old and new medical treatments of CD and to reevaluate medical therapies for complications of CD and hypopituitarism in patients with cured CD.

Keywords: ketoconazole, somatostatin analogs, dopamine agonists, rosiglitazone, Cushing disease, glucocorticoids, hypopituitarism

From http://www.dovepress.com/treatment-of-cushing-disease-overview-and-recent-findings-peer-reviewed-article-TCRM