Topical administration of amifostine and related compounds

Details Topical administration of amifostine and related compounds Topical administration of amifostine and related compounds

2001-03-28

2004-06-22

Kim, Vickie (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Phosphorus containing other than solely as part of an...

C514S665000

Reexamination Certificate

active

06753323

ABSTRACT:

1. FIELD OF THE INVENTION
The invention relates to topical use of aminothiols and compositions containing them for the protection from and treatment of radiation and/or chemotherapeutic damage to tissue.
2. INTRODUCTION
The present invention is directed to novel methods of using amifostine and structurally related aminothiols, including aminophosphorothioates, and their metabolites for the topical treatment of tissue. In particular, the invention relates to protecting mucosal, skin or hair tissue from damage by radiation and chemotherapeutic agents, as well as to the treatment of such damaged tissue. In one aspect, the invention encompasses methods of protection of mucosal tissue, and especially mucosal tissue of the head and neck regions, from chemical, radiation, and radio/chemo induced mucositis and conditions related to mucositis, associated with the treatment of cancers. The methods are achieved by the topical application of amifostine, structurally related compounds or their metabolites. The invention also encompasses treatment and prevention of infections associated with mucositis in mucosa of the head and neck region by topical application of amifostine and related compounds. Topical application of these radiochemical protectants allows the use of more aggressive radiochemical treatment schedules while avoiding the toxic effects of systemically administered amifostine.
3. BACKGROUND OF THE INVENTION
3.1 Systemically Administered Amifostine
The compound S-2-(3-aminopropylamino)ethyl dihydrogen phosphorothioate (also known as amifostine, ethiofos, Ethyol®, NSC 296961, and WR-2721, and which will hereinafter be referred to as “amifostine” has been known for over thirty years, and was originally developed by the Walter Reed Institute of Research as an antiradiation agent (radioprotectant) In particular, amifostine was developed for military use against x-ray or nuclear radiation which may be encountered during military conflicts. Bulk amifostine and other aminoalkyl dihydrogen phosphorothioates, and methods to obtain them, are disclosed in U.S. Pat. No. 3,892,824, which is incorporated herein by reference.
In addition to its utility as a military antiradiation agent, amifostine has demonstrated excellent utility as a non-military radioprotectant and chemoprotectant when administered systemically prior to chemotherapy and/or radiation therapy. Amifostine acts to protect normal tissue against the adverse effects which accompany the use of radiochemical therapies for the treatment of various cancers, while largely leaving the target cancerous tissues unprotected. This protective effect is observed in radiation and chemotherapeutic treatments by, for example, alkylating agents such as cyclophosphamide, cisplatin, carboplatin, doxorubicin and its derivatives, and mitomycin and its derivatives. For representative studies, see, e.g., Constine et al.,
Int. J. Radia. Oncol. Biol. Phys.,
12, 1505-1508 (1986); Liu et al.,
Cancer,
69(11), 2820-2825 (1992); Wadler et al.,
J. Clin. Oncol.,
11(8), 1511-1516 (1993); and Buntzel et al.,
Ann. Oncol.
7 (
Suppl.
5), 81, 381P (1996).
Similarly, it has been reported that amifostine may be used to protect against the harmful side effects of 3′-azido-3′-deoxythymidine (AZT) therapy. In addition, amifostine and its derivatives appear to exert their protective effects without significantly affecting the beneficial properties of the administered therapeutic agents.
Amifostine is approved in the United States for treatment to reduce the cumulative renal toxicity associated with repeated administration of cisplatin in patients with advanced ovarian or non-small cell lung cancer.
Physicians' Desk Reference,
51st ed. (1997).
Amifostine is a pro-drug that is dephosphorylated at the tissue site by alkaline phosphatase to the free thiol, which is the active metabolite (WR-1065). Without wishing to be bound by theory, it is believed that once inside the cell, the active free thiol can protect against the toxicities associated with radiation by acting as a scavenger for oxygen free-radicals. (See, Yuhas, in
Radiation-Drug Interactions in Cancer Management
, pp. 303-352 (1977); Yuhas,
J. Natl. Cancer Inst.,
50, 69-78 (1973); Philips et al.,
Cancer Treat. Rep.,
68, 291-302 (1984)).
Amifostine shows these favorable radioprotective effects when administered systemically prior to radiation treatment. Systemic administration, however, suffers from numerous disadvantages. The typical systemic route of administration is intravenously, but administering compounds intravenously is extremely inconvenient, particularly when a daily dosing schedule for several weeks is necessary. In addition, when amifostine is administered systemically, patients suffer from dose-dependent undesirable side-effects such as nausea, vomiting, emesis and hypotension, as well as flushing or feeling of warmth, chills or feeling of coldness, dizziness, somnolence, hiccups and sneezing. At high enough doses, systemic amifostine is toxic.
3.2 Topically Administered Amifostine
Topical administration of amifostine, if feasible, would be advantageous for a number of reasons. The therapeutic effect of radiation is dose-dependent, so that it would be desirable in many cases to increase the radiation dosage, or use an accelerated radiation schedule, in order to increase the cure rate. Such increased doses of radiation, however, require corresponding increases in amifostine doses in order to counteract the damage to normal tissue accompanying the increased or accelerated radiation schedule. The protective effect of the compound is said to be dependent upon the concentration of amifostine or its active metabolite present in the normal tissue. Because of the adverse side effects of systemic amifostine, however, the amount that can be administered systemically is severely limited. Topical administration would allow greater local control of the amifostine concentration, allowing higher local concentrations without delivery of the higher doses to unaffected tissues and organs. To date, however, topical administration of amifostine has not been shown to be feasible.
The need for an effective topical radiation and chemotherapy (“radio/chemo”) protectant is especially acute in patients suffering from radiation or chemically induced damage to mucosal tissue, such as mucositis and conditions associated with mucositis. As a specific example, cancers of the head and neck are often highly localized, and would benefit from aggressive radio/chemo treatment. The normal mucosal tissues of the head and neck region, such as the oral mucosa, are susceptible to chemical and radiation damage. Chemical, radiation, and combined radiation and chemical treatment act to deplete the mucosal basal epithelium, thinning the tissue and causing inflammation, swelling, erythema and ultimately ulceration.
Ulceration of the mucosa leads to additional complications, as the exposed underlying tissue is vulnerable to infection. For example, Bourhis et al. evaluated an accelerated radiation schedule in patients suffering from locally advanced head and neck cancers. Bourhis et al.,
Int. J. Radiat. Oncol. Biol. Phys.,
32(3), 747-752 (1995). In all of the patients treated with the accelerated schedule, confluent mucositis was observed, and more than half of the patients required hospitalization to treat the mucositis. Similar results were reported by Delaney et al. (96% showed confluent mucositis), following a different aggressive radiotherapy schedule. Delaney et al.,
Int. J. Radiat. Oncol. Biol. Phys.,
32(3), 763-768 (1995). But for the sensitivity to head and neck mucosal tissue to radio/chemo damage, more aggressive therapeutic treatments including increased radiation doses and accelerated radiation schedules could be particularly effective at treating cancers in these regions. Thus, protection of mucosal tissue of the head and neck regions would be especially advantageous.
3.2.1 Topical Application to Non-Mucosal Tissue
Although much is known about the radioprotective effects of systemically administere

Affiliated with

Also associated with

Rating

Topical administration of amifostine and related compounds does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Topical administration of amifostine and related compounds, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Topical administration of amifostine and related compounds will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3318326