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 |
 |
 |
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
