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  Pharmaceutical compositions comprising amifostine and related compoundsUSPTO Application #: 20080027030Title: Pharmaceutical compositions comprising amifostine and related compounds Abstract: The present invention is directed to pharmaceutical compositions comprising amifostine or a related compound and a compound which may be selected from the group consisting of an anesthetic, a corticosteroid, an antihistamine and an anti-inflammatory. The present invention is also directed to methods of treating or protecting tissue of a human from damage associated with radiation and/or chemotherapeutic treatment of cancers by the application of the pharmaceutical compositions. (end of abstract) Agent: Jones Day - New York, NY, US Inventors: Martin Stogniew, Jean Bourthis USPTO Applicaton #: 20080027030 - Class: 514114000 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Phosphorus Containing Other Than Solely As Part Of An Inorganic Ion In An Addition Salt Doai, Nitrogen, Other Than Nitro Or Nitroso, Bonded Indirectly To Phosphorus The Patent Description & Claims data below is from USPTO Patent Application 20080027030. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] This application is a continuation of U.S. patent application Ser. No. 10/872,870, filed Jun. 22, 2004, which is a divisional of U.S. patent application Ser. No. 09/818,555, filed Mar. 28, 2001, now U.S. Pat. No. 6,753,323, issued Jun. 22, 2004, which is a continuation of U.S. patent application Ser. No. 09/298,824, filed Apr. 26, 1999, now U.S. Pat. No. 6,239,119, issued May 29, 2001, which claims the benefit of U.S. provisional patent application No. 60/083,071, filed Apr. 27, 1998, all of which are incorporated by reference in their entirety. 1. FIELD OF THE INVENTION [0002] 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 [0003] 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 [0004] 3.1 Systemically Administered Amifostine [0005] The compound S-2-(3-aminopropylamino)ethyl dihydrogen phosphorothioate (also known as amifostine, ethiofos, ETHYOL.RTM., 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. [0006] 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). [0007] 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. [0008] 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, 51 st ed. (1997). [0009] 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)). [0010] 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. [0011] 3.2 Topically Administered Amifostine [0012] 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. [0013] 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. [0014] 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. [0015] 3.2.1 Topical Application to Non-Mucosal Tissue [0016] Although much is known about the radioprotective effects of systemically administered amifostine and related compounds, relatively little is known about the effects of these compounds when administered topically. The few studies which have addressed topical administration have produced inconclusive results. [0017] In an early study, Utley et al. found that topical administration of amifostine in carbowax to the oral mucosa of mice subjected to whole head irradiation prevented oral radiation death syndrome (LD50/8-10) by a factor of 1.4, with no toxicity observed at the dosages tested. Utley et al., Int. J. Radiat. Oncol. Biol. Phys., 1, Supp. 1, No. 154 (1976). Systemically administered amifostine was found to be more effective in preventing oral radiation death, although some deaths due to drug toxicity were reported. The study did not address protection of other tissues or of the oral mucosa per se from mucositis. [0018] Several studies have looked at the radioprotective effects of topical amifostine on radiation-induced damage to non-mucosal tissue, particularly to rat and mouse skin. [0019] In an early pre-clinical study, Lowy et al. studied the radioprotective effects of systemically and topically administered amifostine in mice. Lowy et al., Radiation Biology, 105, 425-428 (1972). The amifostine was administered to mouse skin as a paste formed from an aqueous sodium bicarbonate solution (pH 7) and Unibase. Although the study found systemically administered amifostine to be effective in reducing the severity of radiation damage, topically applied amifostine was found to provide no radioprotective effect at any dose studied. [0020] Similarly, Verhey et al. found amifostine to be ineffective to protect mouse skin from radiation-induced damage when applied topically. Verhey et al., Radiation Research, 93, 175-183 (1983). A gauze saturated with a 10% solution of amifostine in saline was applied to murine skin for 15 to 60 minutes, followed by .sup.137Cs irradiation. The study found no significant radioprotective effects for topically-applied amifostine. [0021] More recently, Geng et al. compared the effects of topically and systemically administered 16, 16 dm prostaglandin E.sub.2 (PGE.sub.2) and amifostine on radiation-induced alopecia in mice. Geng et al., Int. J. Radiat. Biol., 61(4), 533-537 (1992); see also Malkinson et al., J. Invest. Dermatol., 101(suppl), 135S-137S (1993), reporting similar results. In the topical studies, a 0.3 mg sample of the dephosphorylated form of amifostine, WR-1065, in 0.2 mL Ringer's solution was administered to the depilated mouse skin prior to fractionated irradiation treatment, then the rate of hair regrowth was studied as a function of radiation dosage. Although topically administered WR-1065 showed some effectiveness in protecting hair matrix cells from radiation-induced injury, the Geng study found systemically administered amifostine to be more effective at all radiation doses studied. Continue reading... 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