Fluconazole Found to Be Safe Alternative for Patient with Recurrent Cushing’s

Posted on September 28, 2018 by MaryO

Treatment with fluconazole after cabergoline eased symptoms and normalized cortisol levels in a patient with recurrent Cushing’s disease who failed to respond to ketoconazole, a case study reports.

The case report, “Fluconazole as a Safe and Effective Alternative to Ketoconazole in Controlling Hypercortisolism of Recurrent Cushing’s Disease: A Case Report,” was published in the International Journal of Endocrinology Metabolism.

Ketoconazole, (brand name Nizoral, among others) is an anti-fungal treatment used off-label for Cushing’s disease to prevent excess cortisol production, a distinct symptom of the disease. However, severe side effects associated with its use often result in treatment discontinuation and have led to its unavailability or restriction in many countries.

Consequently, there is a need for alternative medications that help manage disease activity and clinical symptoms without causing adverse reactions, and that could be given to patients who do not respond to ketoconazole treatment.

In this case report, researchers in Malaysia reported on a 50-year-old woman who fared well with fluconazole treatment after experiencing severe side effects with ketoconazole.

The woman had been in remission for 16 years after a transsphenoidal surgery — a minimally invasive brain surgery to remove a pituitary tumor — but went to the clinic with a three-year history of high blood pressure and gradual weight gain.

She also showed classic symptoms of Cushing’s disease: moon face, fragile skin that bruised easily, and purple stretch marks on her thighs.

Blood and urine analysis confirmed high cortisol levels, consistent with a relapse of the pituitary tumor. Accordingly, magnetic resonance imaging (MRI) of her brain showed the presence of a small tumor on the right side of the pituitary gland, confirming the diagnosis of recurrent Cushing’s disease.

Doctors performed another transsphenoidal surgery to remove the tumor, and a brain MRI then confirmed the success of the surgery. However, her blood and urine cortisol levels remained markedly high, indicating persistent disease activity.

The patient refused radiation therapy or adrenal gland removal surgery, and was thus prescribed ketoconazole twice daily for managing the disease. But after one month on ketoconazole, she experienced low cortisol levels.

Hydrocortisone — a synthetic cortisol hormone — was administered to maintain steady cortisol levels. However, she developed severe skin itching and peeling, which are known side effects of ketoconazole. She also suffered a brain bleeding episode, for which she had to have a craniotomy to remove the blood clot.

Since she experienced adverse effects on ketoconazole, which also hadn’t decreased her disease activity, the doctors switched her to cabergoline. Cabergoline (marketed as Dostinex, among others) is a dopamine receptor agonist that has been shown to be effective in managing Cushing’s disease.

But cabergoline treatment also did not lower the disease activity, and her symptoms persisted.

The doctors then added fluconazole (marketed as Diflucan, among others), an anti-fungal medication, based on studies that showed promising results in managing Cushing’s syndrome. Three months after the addition of fluconazole to her treatment plan, the patient’s clinical symptoms and cortisol levels had responded favorably.

At her next clinical visit 15 months later, her condition remained stable with no adverse events.

“This case demonstrates the long-term efficacy of fluconazole in tandem with cabergoline for the control of recurrent Cushing’s disease,” the researchers wrote.

The favorable outcome in this case also “supports the notion that fluconazole is a viable substitute for ketoconazole in the medical management of this rare but serious condition,” they concluded.

From https://cushingsdiseasenews.com/2018/09/27/fluconazole-safe-effective-alternative-recurrent-cushings-patient-case-report/

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ACTH-producing Lung Tumors Hard to Detect, But May Be Cured with Surgery

Posted on December 13, 2017 by MaryO

Ectopic Cushing’s syndrome can be challenging to diagnose, especially when it comes identifying the problem source. But appropriate hormone management protocols, used in combination with advanced imaging methods, may help physicians identify ectopic ACTH-producing tumors.

The findings in a case report of a young man with ectopic Cushing’s syndrome were published in the International Journal of Surgery Case Reports, under the title “Case report: Ectopic Cushing’s syndrome in a young male with hidden lung carcinoid tumor.”

Cushing’s syndrome is caused by high amounts of glucocoticosteroids in the blood. The most common cause is a malfunction of the glands that produce these hormones. In some cases, however, the disease may be caused by tumors elsewhere in the body that have the ability to produce adrenocorticotropic hormone (ACTH).

In half of all Cushing’s patients, ectopic ACTH is produced by small lung cell carcinomas or lung carcinoids (a type of slow-growing lung cancer). But some tumors in the thymus and pancreas also have been found to produce ACTH.

Researchers at Damascus University Hospital in Syria presented the case of a 26-year-old man who had ectopic Cushing’s syndrome due to lung carcinoids.

The patient presented with increased appetite and rapid weight gain for more than a year. These were associated with headache, fatigue, proximal muscle weakness, and easy bruising. He had no family history of hormonal disorder.

Based on the initial physical and symptom evaluation, the clinical team suspected Cushing’s syndrome. Blood analysis revealed high levels of cortisol and ACTH hormones, which supported the diagnosis.

Administration of dexamethasone, a treatment used to inhibit the production of glucocoticosteroids by the pituitary gland, reduced cortisol levels within normal range, but not ACTH levels. This led to the diagnosis of ectopic Cushing’s syndrome.

The next step was to identify the tumor causing the syndrome. The team conducted imaging studies of the brain, chest, and abdomen, but found no tumor.

Because ectopic ACTH is commonly produced by lung cancers, the team then analyzed the patient’s lungs. Again, they failed to detect a tumor.

The patient was discharged with prescription of 200 mg of Nizoral (ketoconazole) once-daily, calcium, and vitamin D. After three months of treatment, he remained stable, with no evidence of symptom improvement.

At this point, the team decided to surgically remove both adrenal glands in an attempt to reduce the hormone levels. Treatment with prednisolone 5 mg and fludrocortisone 0.1 mg once daily was initiated, along with calcium and vitamin D.

Eighteen months later, the patient’s condition worsened and he required hospitalization.

Imaging tests targeting the neck, chest, and abdomen were conducted again. This time, physicians detected a 2 cm mass in the middle lobe of the right lung, which was removed surgically. Detailed analysis of the small tumor confirmed that it was the source of the excessive ACTH.

“ACTH secreting tumors can be very hard to detect,” the researchers stated. “Initial failed localization is common in ectopic ACTH syndrome and it is usually due to carcinoid.”

Cases where the ectopic ACTH production is caused by a carcinoid tumor can be challenging to diagnose because tumors are small and relatively slow-growing. Imaging data is often hard to analyze and the tumors can be confused with pulmonary vessels, the researchers explained.

“In such cases we should first aim to lower blood cortisol medically or through bilateral adrenalectomy to avoid Cushing’s complications,” which should then “be followed up through imaging studies (CT, MRI, scintigraphy or PET) to detect the tumor and resect it, which is the definitive treatment of these patients,” the researchers concluded.

From https://cushingsdiseasenews.com/2017/12/12/case-report-ectopic-acth-producing-lung-tumors-can-hard-detect/

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FDA Puts Strict Limits on Oral Ketoconazole Use

Posted on August 3, 2013 by MaryO

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

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