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United States Patent (19) 11 Patent Number: 4,867,978 Gold (45)

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United States Patent (19) 11 Patent Number: 4,867,978 Gold (45) United States Patent (19) 11 Patent Number: 4,867,978 Gold (45) . Date of Patent: Sep. 19, 1989 54 METHOD OF PROLONGING CANCEROUS 52 U.S. Cl. ..................................... 424/719; 424/709 PATIENTSURVIVAL IN HUMANS WITH 58 Field of Search ......................................... 424/166 HYDRAZINE SULFATE (56) References Cited 76) Inventor: Joseph Gold, 127 Edgemont Dr., U.S. PATENT DOCUMENTS Syracuse, N.Y. 13214 4,110,437 8/1978 Gold .................................... 424/66 21 Appl. No.: 276,059 Primary Examiner-Jerome D. Goldberg 22 Filed: Nov. 25, 1988 57 ABSTRACT Related U.S. Application Data Hydrazine sulfate, alone or formulated with liquid or solid carriers, will prolong patient survival when ad 63 Continuation-in-part of Ser. No. 201,083, Jun. 1, 1988, ministered to early-stage human cancer patients paren abandoned, which is a continuation of Ser. No. 32,051, terally or orally. Mar. 27, 1987, abandoned. (51) Int. Cl.".............................................. A61K 33/02 7 Claims, No Drawings 4,867,978 1. 2 TABLE I-continued METHOD OF PROLONGING CANCEROUS PATENT SURVIVAL IN HUMANS WITH New Chemotypes evaluated against cancer 1960-1985 HYDRAZINE SULFATE Succeeded Failed Acylagmatine Allamandicin This application is a continuation-in-part of pending Allamandin Ser. No. 201,083, filed June 1, 1988, now abandoned, Agolosamine which is a continuation of Ser. No. 032,051, filed Mar. Anguidine 27, 1987, now abandoned. Angustmycin 10 Ansamycin BACKGROUND OF THE INVENTION Aureolic acid Baccharin Many different types of chemical compounds have Bakkenolide Baumycin been used in the past to retard or inhibit various tumors Bisnorditerpene in man. More than thirty compounds are approved for Bouvardin use in cancer therapy in various countries, but the 15 Brederine achievement of therapeutic benefit has reached a pla Bruceolide Bryogenin teau, and the search for antitumor agents continues in Bufadienolide various directions. Cardenoides In 1967, Weitzel and co-workers reported in the Catharanthus Zeitschrift fuer Physiologische Chemie, 348, 433-442 20 Cephalotaxine Chapparinone that hydrazine acetate and sulfate inhibit in vivo the Coformycin growth of ascites carcinoma and sarcoma 180 in the Colcemid mouse and Walker carcinosarcoma in the rat. It is well Colchicine known that the results from lower animals cannot be Colubrinol extrapolated in humans. Indeed, the experience at the 25 Coralyne Cucurbitacin U.S. National Institutes of Health has been that more Daphnetoxin than 200 new chemotypes having anticancer activity in Datiscacin animals have failed to show clinically useful anticancer Cecoyinine activity in humans, as shown in the following table Angustmycin 30 Scirpenol (Table I was compiled from various reports of the U.S. Isobruceine National Cancer Institute): Nitidine TABLE I Duborimycin Elemanolide New Chemotypes evaluated against cancer 1960-1985 Elephantopin Succeeded Failed Ellipticine 35 Elephantopin Adriamycin Enteromycin Cisplatin Tripdiolide Eremantholides Bleomycin Maytanisine Eriofertopin Mitomycin Sangivamycin Eudesmanolides Vincristine Pentamethylmelamine Eupacunin Cyclophosphamide" Taxo Euparotin Etopside Bactobolin Fabacein Alanosine Fagaronine PALA Acivicin Fusarenon Germacranolide Methyl GAG Glaucarubinone Menogarol 45 Triciribine Guaianolide Disuccinimide Helenolin Flavoneacetic acid Homoerythrina Teroxirone Hycanthone Acodazole Picrasin Iridoid actone Benzisoquinolinedione 50 Didemnin B Isobruceine Phyllanthoside Isocucurbitacin Ellipticine Isoplumericin Emetime Iatrophone Indicine-N-oxide Lapachol Bouvardin leurosidine Thalicarpine 55 Leurosine Tetrandrine Liatrin Acronycine Masine Tylocrebrine Maysenine Lapachol Maytanbutacine Nitidine Maytanbutine Neocarzinostatin Maytanprine Macromomycin Maytanvaline Largomycin Miracil D Streptimidone Mitrymicin Valinomycin Mycophenolic acid Piperazinedione Neosolaneol Fagaronine 65 Nitidine Coralyne Nivalenol Benzophenanthridine Normaysine Camptothecin Oxazinomycin Acosamine Peltatin 4,867,978 3 4. TABLE I-continued Administration. Table IV shows that the last new New Chenotypes evaluated against cancer 1960-1985 chemotype which succeeded in the clinic was discov Succeeded Failed ered more than 20 years ago. Penstenide TABLE I Phleomycin Anticancer Drugs Approved in U.S. in Order of Approval by FDA Picrasane Picropodophyllin leuprolide - Lupron Takeda-Abbott 4/9/85 Piptocarphins (gonadotropin releasing hormone) Pumericin etoposide - Vepesid BMY 11/10/83 Porfironycin streptozotocin - Zanosar Upjohn 7/7/82 Pseudoguaianolides 10 estramustine - Emcyt Roche 12/24/81 Puromycin daunorubicin - Cerubidine Ives 12/19/79 Pyrazomycin cisplatin - Platinol BMY 2A19/78 Quadrone tamoxifen - Nolvadex CI 2/30/77 Quassimarin (antiestrogen) Roridin carmustine BiCNU 3/7/77 Sanadierine 15 Sangivamycin lonustine - CEENU BMY 8/4/76 Eudesmanolide dacarbazine - DTIC-Dome Miles 5/27/75 Showdomysin doxorubicin - Adriamycin Farmitalia 8/7/74 Sikkimototoxin mitomycin C - Mutamycin BMY 5/28/74 Simalikalactone bleomycin - Blenoxane BMY 7/31/73 Sinarouboide megestrol acetate - Megace BMY 8/18/7 Stachybotrytoxin foxuridine - FUDR Roche 12/8/70 Steganacin mitotane - Lysodren BMY 7/8/70 Streptonigrin plicamycin - Mithracin Pfizer 5/5/70 Taxodione procarbazine - Matulane Roche 7/22/69 Tenulin cytarabine - Cytosar U Upjohn 6/17/69 Tetrandrine testolactone - Teslac Squibb 6/3/69 Thalicarpine 25 hydroxyurea - Hydrea Squibb 2/7/67 Trichodermin pipobroman - Vercyte Abbott 7/1/66 Undulatone melphalan - Alkeran BW /17/64 Vernolepin wincristine - Oncovin Lilly 7/10/63 Verrucarin Vincadioline uracil Enustard - Uracil Mustard Upjohn 9/13/62 Vindoline 30 5-fluorouracil - Fluorouracil Roche 4/25/62 Withaferin dronostanolone - Droban Lilly 10/26/61 Withanolide vinblastine - Velban Lilly 3/6/6 Phosphonoacetic acid cyclophosphamide - Cytoxan BMY 11/16/59 Pentostatin thiotepa - Thio-Tepa Lederle 3/9/59 Deazaguanine chlorambuci - Leukeran BW 3/18/57 Tiazofurin 35 busulfan - Myleran BW 6/26/54 Ocodazole methotrexate - Methotrexate Lederie 12/7/53 Bisbenzinidazole ICRF JB-11 A review of the FDA's New Drug Evaluation - Sta Dihydrotriazine benzene sulfonyl fluorid Glyoxylic acid sulfonylhydrazone tistical Report (March 1986) shows that no novel anti N-Methylformamide cancer drug is pending approval at the FDA. Caracemide Isopropylpyrrolizine deriv. TABLE II Phyllanthoside The following are the dispositions of antineoplastics Aphidicolin fied in 980 to 1984: Largomycin 45 Filed in 1980 Not approvable NDA No. 18-348 Antineoplastic Analog of nitrogen mustard Not approvable NDA No. 18-529 Antineoplastic Analog of podophyllotoxin Not approvable NDA No. 18-554 Antineoplastic Filed in 1981. Not approvable NDA No. 18-641 Antineoplastic In addition, hundreds of analogs of the new and old Not approvable NDA No. 18-653 Antineoplastic chemotypes have failed to show anticancer activity in Filed in 1982. Not approvable NDA No. 50-569 Antineoplastic man, in spite of good antitumor activity in animals. In 50 Filed in 1984. Not approvable NDA No. 50-595 Antineoplastic contrast to the above, only about five new chemotype anticancer drugs have reached the market in the last 25 Table IV lists the anticancer drugs approved in the years. Hence, early reports that hydrazine sulfate had United States. The last non-hormonal anticancer agent antitumor activity in animals did not serve to predict to be approved in the U.S. was etoposide in 1983. that it might have anticancer activity in humans. 55 The following are the years of discovery of the major Because of this poor predictability of animal models, anticancer drugs on the U.S. market (arbitrarily as the National Cancer Institute of the U.S. National Insti sumed to be one year before.the first publication): tutes of Health has now abandoned the mouse model after 25 years of unproductive trial and is instituting a TABLE IV new in vitro program for discovering new antitumor Etoposide 1966 Adriamycin 1966 drugs (E. Eckholm, New York Times, Dec. 23, 1986, p. Bleomycin 1966 C1). Cisplatin 1965 A total inventory of cancer drugs approved for sale Mitomycin C 1965 in the United States is set forth in Table II, and it will be Vincristine 1961 seen that most of these are analogs of other drugs. Table 65 5-Fluorouracil 1957 III shows that, with one exception, all of the recent Cyclophosphamide 1957 New Drug Applications filed for anticancer drugs led Methotrexate 949 to unapprovable ratings by the U.S. Food and Drug 4,867,978 5 6 Thus, there have been no new chemotype cytotoxic then two such capsules daily for the next three days, anticancer drugs discovered in the past twenty years. and then three 60 mg capsules each day thereafter. In Consequently, there remains an unfulfilled need for actual practice, patients weighing over 130 pounds do additional cancer drugs for clinical use against tumors well on three or four 60 mg capsules daily. For patients in humans. weighing less than 100 pounds, the regimen followed is Up the present time, it has been generally unrecog preferably one 30 mg capsule of hydrazine sulfate daily nized that a specific anticachexia agent (by virtue of its for the first three days, then two such capsules daily for ability to interrupt those specific thermodynamic meta the next three days, and then two or three 30 mg cap bolic processes leading to cancer cachexia) possesses sules each day thereafter. For best results blood levels antitumor potential, by virtue of a systematic thermody 10 of hydrazine sulfate should be determined on these namic interrelationship between
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