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Home , Hydrazine sulfate, Tiazofurin

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 (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 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 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 Tripdiolide Eremantholides Maytanisine Eriofertopin Mitomycin Sangivamycin Eudesmanolides Pentamethylmelamine Eupacunin " 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 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 - Vepesid BMY 11/10/83 Porfironycin - Zanosar Upjohn 7/7/82 Pseudoguaianolides 10 estramustine - Emcyt Roche 12/24/81 Puromycin - Cerubidine Ives 12/19/79 Pyrazomycin cisplatin - Platinol BMY 2A19/78 Quadrone tamoxifen - Nolvadex CI 2/30/77 Quassimarin (antiestrogen) Roridin BiCNU 3/7/77 Sanadierine 15 Sangivamycin lonustine - CEENU BMY 8/4/76 Eudesmanolide - DTIC-Dome Miles 5/27/75 Showdomysin - Adriamycin Farmitalia 8/7/74 Sikkimototoxin - 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 - Lysodren BMY 7/8/70 Streptonigrin - Mithracin Pfizer 5/5/70 Taxodione - Matulane Roche 7/22/69 Tenulin - Cytosar U Upjohn 6/17/69 Tetrandrine - Teslac Squibb 6/3/69 Thalicarpine 25 hydroxyurea - Hydrea Squibb 2/7/67 Trichodermin - Vercyte Abbott 7/1/66 Undulatone - 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 Roche 4/25/62 Withaferin dronostanolone - Droban Lilly 10/26/61 Withanolide - Velban Lilly 3/6/6 Phosphonoacetic acid cyclophosphamide - Cytoxan BMY 11/16/59 - Thio-Tepa Lederle 3/9/59 Deazaguanine chlorambuci - Leukeran BW 3/18/57 Tiazofurin 35 - Myleran BW 6/26/54 Ocodazole - 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 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 ) 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 tumor progression patients in order to establish a most effective non-toxic (tumor energy gain) and cancer cachexia (host energy dose. loss); this has been taught in the scientific literature Hydrazine sulfate therapy can advantageously be since 1974 (J. Gold, Cancer Cachexia and Gluconeo combined with other modalities for cancer treatment genesis, Ann. N.Y. Acad. Sci., 230, 103-110 (1974). 15 like , immunotherapy, radiation and sur Thus, while it is true that any antitumor agent may have gery. anticachexia potential, if curative, it is also true that a Hydrazine sulfate is most effective when adminis specific anticachexia agent may have potential for in tered usually by itself one or two hours before meals in creased patient survival. However, it is not obvious, nor the form of a gelatin capsule. If desired, the sulfate can predictable, from the prior art that hydrazine sulfate 20 be dissolved or suspended in sterile, aqueous, isotonic would possess this potential. saline solution and given orally and parenterally. Like In 1978, the present inventor was issued U.S. Pat. No. wise, hydrazine sulfate can be formulated with solid 4,110,437 for the treatment of cancer cachexia with carriers such as talc, corn starch or stearic acid and hydrazine sulfate. Investigations were also undertaken compressed into tablets for oral administration. Such to ascertain whether hydrazine sulfate could retard 25 tablets can be enteric coated with shellac or cellulose tumor growth in humans. However, these early studies acetate phthalate in a manner well known to those were inadequate and failed to statistically demonstrate skilled in the pharmaceutical art. antitumor activity. The efficacy of hydrazine sulfate in prelonging sur A group at Sloan-Kettering concluded after a trial vival in early-stage human cancer patients has now been that: "The clinical observations recorded in this report 30 demonstrated for the first time in a placebo-controlled, fail to support a role for hydrazine sulfate as an antican double-blind experiment with a statistically significant cer agent. We conclude that its clinical utilization is not number of subjects. warranted at present and do not plan further trials.'O- Early-stage human cancer patients are distinguished choa et al., Cancer Chemotherapy Reports, Part 1, Vo. from late-stage human cancer patients on the basis of 59, No. 6, Nov./Dec. 1975; pp. 1151-1154). 35 the nature of their symptoms. These symptoms have In addition, a group at the University of Virginia been quantitatively correlated by two recognized meth repoted that: "Hydrazine sulfate as administered in this ods of categorization: the Eastern Cooperative Oncol series failed to demonstrate any objective or subjective ogy Group (ECOG) Performance Status Score (also antitumor activity and no further trials are currently known as Zubrod's) and the Karnofsky Rating Scale. planned.'(Lerner and Regelson, Cancer Treatment The relationship between these two methods and the Reports, Vol. 60, No. 7, July 1976, pp. 959-966). An resulting division of human cancer patients into early other later publication by Regelson et al. stated: "In stage and late-stage, as recognized by ECOG and Kar conclusion, we feel that hydrazine sulfate as given in nofsky rating criteria, is set forth as follows: this study is an inactive compound."(Cancer Chemother. Pharmacol., 3, 121-124, 1979). 45 Thus, the prior art taught that hydrazine sulfate ap Stage of ECOG Performance Karnofsky Nature of peared to be inactive against primary tumor growth in Cancer Status Score Rating Symptoms 3. Early O 100 Asymptomatic without SUMMARY OF THE INVENTION physical 50 limitation This invention is based on the discovery that hydra Early 1 80-90 Symptomatic, but fully zine sulfate, when administered parenterally or orally in ambulatory effective, non-toxic amounts to humans with tumors of Late 2 60-70 Symptomatic, the lung, prostate, breast, ovaries, thyroid, pancreas, but in bed lymph, cervix, gastrointestinal tract and other sites will 55 less than 50% of day significantly prolong survival of early-stage human Late 3 40-50 Symptomatic, cancer patients, while improving the patient's quality of in bed more life. than 50% of day, but not DETAILED DESCRIPTION OF THE bedridden NVENTION Late 4. 20-30 Bedridden The dosages of hydrazine sulfate employed in the present invention can vary from 1 to 5 mg/kg daily, In the placebo-controlled, double-blind experiemnt which is well below the LD50 and has been found to be referred to above, to determine whether hydrazine sul well tolerated in the majority of early-stage patients so 65 fate treatment is associated with a survival benefit (R.T. treated for periods of up to four years. Chlebowski et al., "Influence of Hydrazine Sulfate on Preferably, the regimen followed is one 60 mg cap Survival in Non-Small Cell : A Random sule of hydrazine sulfate daily for the first three days, ized Placebo-Controlled Trial', presented at the An 4,867,978 7 8 nual Meeting of the American Society for Clinical On creased patient survival in early-stage patients with cology, May 17-19, 1987, Atlanta, Georgia), sixty-five non-small cell lung cancer. patients with unresectable, non-small cell lung cancer Specifically, this increased survival time occurred in and no prior chemotherapy were randomized to receive early-stage human cancer patients with Performance combination chemotherapy with either hydrazine sul Status 0 or 1 (PS0-1), whereas late-stage patients (PS2) fate or placebo addition for a period of up to four years. did not exhibit prolonged survival. All received Platinol/Velban/Blenoxane (PVB) che Several patients with tumors of the prostate, lung, motherapy every 28 days, consisting of Platinol 100 breast, ovary, lymph, cervix, thyroid, pancreas and mg/m2; Velban 4 mg/m2, days 1 and 2; and Blenoxane other tumor sites were treated with hydrazine sulfate 10 units every 8 hours for three doses. After the initial 10 according to the preferred regimen previously set forth. three cycles, the Blenoxane was discontinued and the I claim: Platinol dose was reduced to 50 mg/m2. 1. A method for prolonging patient survival in an Pre-chemotherapy factors including age, sex, perfor early-stage human cancer patient which comprises in mance status (PS), prior weight loss and disease extent ternally administering to said human hydrazine sulfate were comparable in the two groups, with pre-chemoth 5 in an effective dosage sufficient in amount and for a erapy performance status (0-vs. 2) and prior weight loss duration of from fourteen weeks to four years to pro (>10%) subsequently influencing overall survival long patient survival without treating a cancerous (p<0.05). Toxicity was that expected from PVB with tumor per se. three patients not continuing hydrazine sulfate because 2. The method of claim 1 wherein the hydrazine of additional nausea. Survival by hydrazine sulfate or sulfate is administered orally in dosage form. placebo were: 3. The method of claim 2 wherein the dosage form is a gelatin capsule or tablet. 4. The method of claim 1 wherein the hydrazine Median Survival bv. Patient Group sulfate is administered parenterally. Treatment Group All Patients PSO-1 Patients 25 5. The method of claim 1 wherein the dosage of hy Hydrazine Sulfate 292 days 328 days' drazine sulfate is 1 to 5 mg/kg of body weight daily. Placebo 173 days 209 days 6. The method of claim 1 wherein the hydrazine Statistical analysis of the data was by the generalized sulfate is administered in a daily regimen of one 60 Wilcoxon (Breslau) method. Comparison of the hydra milligram capsule for three days, then two 60 milligram zine sulfate and placebo groups showed statistical sig 30 capsules for the next three days, and three 60 milligram nificance at the PC0.01 level. All of the survival bene capsules each day thereafter for up to four years. fit of hydrazine sulfate was in the performance status 0-1 7. The method of claim 1 wherein the hydrazine group. For the performance status (PS) 2 patients, sulfate is administered to patients weighing less than 100 whose condition was poor, survivals were short (me pounds in a daily regimen of one 30 milligram capsule dian 132 days) and closely comparable whether on pla 35 for three days, then two 30 milligram capsules for the cebo or hydrazine sulfate. Thus, hydrazine sulfate addi next three days, then two or three 30 milligram capsules tion, as an anti-cachexia agent directed primarily at each day thereafter for up to four years. correcting abnormal host mechanism, significantly in it is is

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