Human Corticotropin-Releasing Factor (hCRF)
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Human Corticotropin-Releasing Factor (hCRF)
in Peritumoral Brain Edema



By Lisa U. Carr, MD, PhD
Senior Vice President and Chief Medical Officer
Neurobiological Technologies, Inc.
Emeryville, CA
Phone: 510-595-6000   Fax: 510-595-60060
E-mail: carrl@ntii.com   web site: http://www.ntii.com
Last Updated: 1/11/2006

A common and serious complication of malignant brain tumors is cerebral edema, swelling in the brain. In brain tumor patients, the tumor promotes increased permeability of small blood vessels in the brain, resulting in fluid flow into the brain, swelling of brain tissue and consequent loss of neurological function. For more than 30 years corticosteroids have been used to treat the symptoms of peritumoral brain edema despite the detrimental side effects associated with chronic use.

Human corticotropin-releasing factor (hCRF) is a naturally occurring 41 residue neuropeptide produced in the hypothalamus and mainly responsible for stimulating the hypothalamic-pituitary-adrenal (HPA) axis. However, this neurohormone also appears to possess strong anti-edema properties independent of adrenal gland function, perhaps acting directly on brain and tumor blood vessels or surrounding epithelial tissue. Therefore, hCRF has been proposed as an alternative treatment for peritumoral brain edema that might provide substantial benefits with fewer side effects than corticosteroids.
CRF Anti-Edema Activity In Rats With Brain Tumors
  hCRF 100mcg/kg BID Saline BID (Placebo)
Before Treatment Mouse Brain on CRF Mouse Brain On Placebo
After 3 Days
Of Treatment

Observations from several animal and human studies of hCRF's effects on brain edema lend support to this proposal. Animal studies have provided evidence that hCRF-treated animals perform similarly to dexamethasone-treated animals in models of vasogenic peritumoral brain edema. In one animal study, hCRF appeared to enhance the anti-edema effect of dexamethasone. Human studies have demonstrated clinical improvement in neurologic symptoms such as seizures, muscle weakness, loss of coordination and double vision.

A synthetic hCRF, delivered by a single daily subcutaneous injection, is currently being tested in a double blind, positive-controlled study of malignant brain tumor patients (primary or metastatic) for the control of neurological symptoms of peritumoral brain edema. Each participant receives one of the following: 0.5 mg hCRF, 1.0 mg hCRF, or 4.0 mg dexamethasone (in addition to current medication) per day for 15 days.

Human and sheep CRF have been safely used for several years as diagnostic agents to evaluate the HPA axis in patients with a variety of endocrine disorders. The biologic effects and safety of intravenous administration of human and sheep CRF to human volunteers (including children and pregnant women) have been extensively studied. The most frequently reported adverse events following 0.3 to 1.2 mg/day subcutaneous hCRF treatment have been flushing (vasodilatation) of the face and mild subcutaneous injection site reactions. Though the longest duration of hCRF administration in clinical trials in humans is 2 weeks of daily subcutaneous administration, in normal pregnant women circulating levels of hCRF rise dramatically from the normal range (2-26 picograms/mL) at 26-28 weeks gestation to approximately 1500 picograms/mL at full term. Thus, elevated levels of hCRF without any known deleterious effects persist in the normal pregnant female for about 10 weeks.


Editor's Note: 1/11/2006: Neurobiological Technologies, Inc. (NTI) is currently conducting 3 Phase III trials with XERECEPT®. To find them, click here




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