Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
1999-10-28
2003-07-01
Travers, Russell (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S114000, C514S649000, C514S608000, C514S706000
Reexamination Certificate
active
06586476
ABSTRACT:
1. FIELD OF THE INVENTION
The present invention relates to new uses for S-2-(3-aminopropylamino)ethyl dihydrogen phosphorothioate, also known as amifostine, its salts, hydrates, esters, metabolites, functional derivatives, functional analogues, and related aminothiol compounds, to treat and reverse certain toxicities, including toxicities caused by drugs and/or radiation therapy, and to treat certain disorders, particularly neuro- and nephro-disorders.
2. BACKGROUND OF THE INVENTION
2.1. Aminothiol Compounds
The compound S-2-(3-aminopropylamino)ethyl dihydrogen phosphorothioate (which is also known as amifostine, ethiofos, Ethyol®, NSC 296961, and WR-2721 and which will hereinafter be referred to as “amifostine”) and other aminothiol compounds are disclosed in U.S. Pat. No. 3,892,824 to Piper et al. These compounds were originally developed as antiradiation agents (radio-protectants), in particular to be used prior to exposure to x-ray or nuclear radiation, to protect against the harmful effects of such exposure which may be encountered during military conflicts.
In addition to its utility as a military antiradiation agent, amifostine has demonstrated excellent utility as a non-military radioprotectant and chemoprotectant, i.e., as a protectant administered prior to therapy to reduce the undesirable adverse effects which arise during the use of chemotherapy and radiation therapy in the treatment of cancer. Nygaard et al., eds., 1983,
Radioprotectors and Anticarcinogens,
Academic Press, Inc., New York, pp. 73-85; Grdina et al., 1985, “Radioprotector WR-1065 Reduces Radiation-Induced Mutations of the HGPRT Locus in V79 Cells,”
Carcinogenesis
(London) 6:929-931. In addition, these compounds have been reported to afford protection against the adverse effects of chemotherapeutic agents, for example, alkylating agents such as cisplatin and carboplatin, when administered before or concurrently with the chemotherapeutic agent. Jordan et al., 1982, “Modulation of cis-platinum renal toxicity by the Radioprotective agent WR-2721”
, Exp. Mol. Pathol.
36:297; Doz et al., 1991, “Experimental Basis for Increasing the Therapeutic Index of Carboplatin in Brain Tumor Therapy by Pretreatment With WR-Compounds”,
Cancer Chemother. Pharmacol.
28:308. Similarly, it has been reported that amifostine has been used experimentally prior to therapy to protect HIV-infected patients (AIDS) from the harmful side effects of 3′-azido-3′-deoxythymidine (AZT) therapy. International Published Application WO 90/14007, published Nov. 29, 1990. Amifostine and its derivatives have been shown to exert these reported protective effects without affecting the beneficial properties of the administered therapeutic agents. This is, in the case of chemotherapy, believed to be due to the selective uptake of the protective thiol and other metabolites into normal tissue. Yuhas, 1980, “Active versus Passive Absorption Kinetics as the basis for Selective Protection of Normal Tissues by WR-2721”,
Cancer Res.
40:1519-1524;
Yuhas, 1979, “Differential Protection of Normal and Malignant Tissues Against the Cytotoxic Effects of Mechlorethamine”
Cancer Treat. Rep.
63:971-976.
Amifostine and related aminothiol compounds have also been shown to stimulate bone marrow growth. See U.S. patent application Ser. No. 08/390,713; International Published Application WO 96/25045 published Aug. 22, 1996; List et al., “Amifostine Stimulated Formation of Multipotent Progenitor and Generated Macroscopic Colonies in Normal and Myelodysplastic Bone Marrow,”
Proc. Am. Soc. Clin. Oncol.
15:449 [1403] [Abstract]. Currently, amifostine is in Phase II clinical trials as a bone marrow stimulant in patients suffering from myelodysplastic syndrome. List et al., 1996, “Amifostine Promotes Multilineage Hematopoiesis in Patients with Myelodysplastic.Syndrome (MDS): Results of a Phase I/II Clinical Trial,”
Am. J. Hem.
1 (Abstract); List et al., 1996, “Amifostine Promotes in vitro and in vivo Hematopoiesis in Myelodysplastic Syndromes,”
Chem. Found Sympos.
(Abstract); List et al., 1996, “Amifostine Promotes Multilineage Hematopoiesis in Patients with Myelodysplastic Syndrome (MDS): Results of a Phase I/II Clinical Trial,” Abstract, 8th Annual Meeting, American Society of Hematology, Orlando, Fla. Pre-exposure with aminothiol compounds is capable of causing the bone marrow function to more rapidly recover following chemotherapy. List et al., 1996, “Amifostine Protects Primitive Hematopoietic Progenitors Against Chemotherapy Cytotoxicity,”
Semin. Oncol.
23 (4) Supp. 8:58-63.
Presently, amifostine is indicated 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, p. 485-486. The recommended starting dosage for adults in an FDA-approved indication is 910 mg/m
2
administered once daily as a 15-minute intravenous (i.v.) infusion, starting 30 minutes prior to chemotherapy. However, clinical trials have used doses as low as 100 mg.
U.S. Pat. Nos. 5,567,686 and 5,488,042, both to Grdina, allege that the administration of an aminothiol compound before irradiation of a mammal affords protection against genotoxic mutagenesis. Although the U.S. Pat. No. 5,488,042 patent discloses administering an aminothiol up to about three hours after irradiation, both patents focus solely on prevention of mutations, rather than the treatment or reversal of radiation- or chemotherapy-induced damage. Further, the Grdina patents are silent as to the use of any aminothiol compound in humans to treat chemotherapy- or radiation-induced disorders and toxicities including neuro-, nephro-, hematological or mucosal disorders.
Nagy et al., 1986, “Protection Against cis-Diamminedichloroplatinum Cytotoxicity and Mutagenicity in V79 Cells by 2-[(Aminopropyl)amino]ethanthiol,”
Cancer Research
46:1132-1135, disclose that the free thiol metabolite of amifostine, also known as WR-1065, protects against cytotoxicity in V79-B310H Chinese hamster cells when administered before, during and immediately after treatment of the cells with cis-diamminedichloroplatinum (cis-DDP, “cisplatin”). Although some protection against cell death was observed under all conditions, Nagy et al. report that maximum protection was obtained when WR-1065 was present in the cell growth medium for 30 minutes prior to exposure of cells to cisplatin. In addition, Nagy et al. state that little if any difference in the magnitude of protection against cell killing was seen whether the WR-1065 was present either during or immediately following cisplatin exposure.
Treskes et al., 1992, “Effects of the Modulating Agent WR-2721 and its Main Metabolites on the Formation and Stability of Cisplatin-DNA Adducts in Vitro in Comparison to the Effects of Thiosulphate and Diethyldithiocarbonate,”
Biochemical Pharmacology
43(5):1013-1019 investigated the ability of amifostine and its main metabolites, WR-1065 and WR-33278, to prevent formation of adducts of cisplatin with the DNA of salmon sperm. They found that amifostine, WR-1065 and WR-33278 caused a decrease in the platination of salmon sperm in vitro when the compounds were present concomitantly with cisplatin. It was also observed that part of the already formed cisplatin-DNA adducts is disrupted during post-incubation with subject compounds, but this decrease in adduct levels was small compared to those obtained during co-incubations. Treskes et al. speculated that conformational changes in DNA induced by the WR-1065 metabolite of amifostine observed by other researchers might provide a rational for applying amifostine after cisplatin administration.
However, Treskes et al. later reported in 1993, “WR2721 as a Modulator of Cisplatin- and Carboplatin-induced Side Effects in Comparison with Other Chemoprotective Agents: A Molecular Approach,”
Cancer Chemother. Pharmacol.
33:93-106, that neither WR-1065 nor WR-2721 (amifostine) could protect cells from the cytostatic effect of cispl
Alberts David S.
Kaplan Edward H.
Stogniew Martin
MedImmune Oncology Inc.
Pennie & Edmonds LLP
Travers Russell
LandOfFree
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