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Preclinical Studies Support Use of Subcutaneous Amifostine Prior to Radiation Therapy to Protect Against Mucositis

Preclinical Studies Support Use of Subcutaneous Amifostine Prior to Radiation Therapy to Protect Against Mucositis

GAITHERSBURG, Maryland-Animal studies of amifostine (Ethyol) are
being used to explore optimal subcutaneous (SC) treatment and to refine
approaches to dosing and scheduling of the radioprotectant. David R. Cassatt,
PhD, of MedImmune, Inc., Gaithersburg, Maryland, described current
preclinical work with amifostine.

"There are several unresolved issues regarding amifostine use,"
he said. "First we need to protect normal tissues and not protect
tumors from radiotherapy or chemotherapy. Second we need to reduce the
severity of amifostine side effects such as hypotension. We also need to
improve the ease of administration. The IV formulation is effective but
difficult, especially in the radiotherapy setting. Finally, we want to
expand the indications for amifostine beyond xerostomia and nephrotoxicity.
Currently amifostine is approved for intravenous administration, to prevent
nephrotoxicity associated with cisplatin (Platinol) and xerostomia
associated with radiotherapy."

Also being studied are effects of amifostine on mucositis, esophagitis,
pneumonitis, protection of bone-marrow cells, and myelodysplastic syndrome.
"The approved indication for radiotherapy is for prevention of
xerostomia only. Mucositis would be an important additional
indication," Dr. Cassatt said.

IV vs SC Routes

One limitation to amifostine use is the need for intravenous
administration. Dr. Cassatt said that the initial intravenous bolus dose
spike is sometimes associated with hypotension.

The goals of Dr. Cassatt’s preclinical studies are to determine whether
SC administration is equivalent to IV administration, to explore mucositis
as an endpoint, and to define markers that predict protection against
radiation injury. Radioprotection against salivary gland damage is being
studied in rats. Protection against mucositis is being studied in mice and
dogs.

"We give rats amifostine intra-enously or subcutaneously, and at
certain periods after the administration, we anesthetize and restrain the
rats, put a shield around everything except the head and the neck to get
exposure only to the local area, and give 15.3 Gy of gamma irradiation. Over
a period of 10 days or so we examine the rats daily using the Parkins
mucositis scale, looking at erythema and looking at edema," Dr. Cassatt
said. Differences in degree of mucositis are readily apparent in this model.
The main questions being asked are whether subcutaneous amifostine can
protect against radiation-induced mucositis and how long the effective
pretreatment interval is.

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