Hydrazine sulfate

Hydrazine sulfate, more properly hydrazinium hydrogensulfate, is a salt of the cation hydrazinium and the anion bisulfate (hydrogensulfate), with the formula N2H6SO4 or more properly [N2H5]+[HSO4]−. It is a white, water-soluble solid at room temperature.

Hydrazine sulfate
Names
IUPAC name
Hydrazinium hydrogen sulfate
Other names
  • Hydrazinium sulfate
  • Hydrazinium hydrogensulfate
Identifiers
3D model (JSmol)
ChemSpider
ECHA InfoCard 100.030.088
EC Number
  • 233-110-4
UNII
  • InChI=1S/H4N2.H2O4S/c1-2;1-5(2,3)4/h1-2H2;(H2,1,2,3,4) checkY
    Key: ZGCHATBSUIJLRL-UHFFFAOYSA-N checkY
  • InChI=1/H4N2.H2O4S/c1-2;1-5(2,3)4/h1-2H2;(H2,1,2,3,4)
    Key: ZGCHATBSUIJLRL-UHFFFAOYAL
  • O=S(=O)(O)O.NN
Properties
[N2H5]+[HSO4]−
Molar mass 130.12 g·mol−1
Appearance colourless crystals or white powder
Density 1.37 g/cm3
Melting point 254°C
Boiling point decomposes
30 g/L (20°C)
Hazards
GHS labelling:
GHS06: ToxicGHS09: Environmental hazardGHS05: Corrosive
NFPA 704 (fire diamond)
NFPA 704 four-colored diamond
3
1
0
Safety data sheet (SDS) External MSDS
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
checkY verify (what is checkY☒N ?)
Infobox references

Hydrazine sulfate has a number of uses in chemical laboratories and in the chemical industry, including analytical chemistry and the synthesis of organic compounds. In those uses it is usually preferred to pure hydrazine, because it is not volatile and is less susceptible to atmospheric oxidation on storage.

Preparation

The compound can be prepared by treating an aqueous solution of hydrazine (N2H4) with sulfuric acid (H2SO4).[1]

Laboratory and industrial uses

Besides its general use as a safe source of hydrazine, the compound is used as a catalyst in making fibers out of acetate, in the analysis and synthesis of minerals, and testing for arsenic in metals.[2]

Medical uses

Hydrazine sulfate can be used as a fungicide and antiseptic.[2]

Hydrazine sulfate has been used as an alternative medical treatment for the loss of appetite (anorexia) and rapid weight loss (cachexia), which are often associated with cancer.[3][4][5]

Although it has been marketed as a dietary supplement,[6][7] hydrazine sulfate has never been approved in the United States as safe and effective in treating any medical condition.

History

Hydrazine sulfate was first proposed as an anti-cancer agent by U.S. physician Joseph Gold in the mid-1970s.[8] Gold's arguments were based on the fact that cancer cells are often unusually dependent on glycolysis for energy (the Warburg effect). Gold proposed that the body might offset this increased glycolysis using gluconeogenesis, which is the pathway that is the reverse of glycolysis. Since this process would require a great deal of energy, Gold thought that inhibiting gluconeogenesis might reverse this energy requirement and be an effective treatment for cancer cachexia.[9] Hydrazine is a reactive chemical that in the test tube can inactivate one of the enzymes needed for gluconeogenesis, phosphoenolpyruvate carboxykinase (PEP-CK). It was also postulated that if tumor energy gain (glycolysis) and host-energy loss (gluconeogenesis) were functionally interrelated, inhibition of gluconeogenesis at PEP CK could result in actual tumor regression in addition to reversal or arrest of cancer cachexia.[10] In this model, hydrazine sulfate is therefore thought to act by irreversibly inhibiting the enzyme phosphoenolpyruvate carboxykinase.

The use of hydrazine sulfate as a cancer remedy was popularized by the magazine Penthouse in the mid-1990s, when Kathy Keeton, wife and business partner of the magazine's publisher Bob Guccione, used it in an attempt to treat her metastatic breast cancer.[11] Alternative medicine nutritionist Gary Null wrote three of the articles about alternative cancer treatments, including one titled "The Great Cancer Fraud."[12] Keeton (until her death in 1997) and other supporters of hydrazine sulfate treatment accused the U.S. National Cancer Institute (NCI) of deliberately hiding the beneficial effects of the compound, and threatened to launch a class action lawsuit.[13][14] The NCI denied the claims,[15] and says that there is little to no evidence that hydrazine sulfate has any beneficial effects whatsoever.[6] The position of the NCI was supported by an inquiry held by the General Accounting Office.[16]

Clinical evaluation

A review of the clinical research concluded that hydrazine sulfate has never been shown to act as an anticancer agent; patients do not experience remissions or regressions of their cancer, and patients do not live longer than non-treated patients.[6][17][18] Some academic reviews of alternative cancer treatments have described the compound as a "disproved and ineffective treatment for cancer".[19][20]

Joseph Gold's claims[8] have been questioned by the American Cancer Society, and other investigators have been unable to repeat or confirm these results.[17][21] Gold is reported not to trust the motives or results of other investigators, with CNN quoting him as stating that "they've been out to get hydrazine sulfate, and I don't know why".[22]

In response to these results, an uncontrolled clinical trial was carried out at the Petrov Research Institute of Oncology in St. Petersburg over a period of 17 years,[17][23] and a controlled trial was carried out at the Harbor-UCLA Medical Center in California over period of 10 years, respectively. The Russian trial reported complete tumor regression in about 1% of cases, a partial response in about 3% of cases and some subjective improvement of symptoms in about half of the patients.[23] The National Cancer Institute analysis of this trial notes that interpretation of these data is difficult, due to the absence of controls, the lack of information on prior treatment and the study's reliance on subjective assessments of symptoms (i.e. asking patients if the drug had made them feel any better).[24] Overall, the trials in California saw no statistically significant effect on survival from hydrazine sulfate treatment, but noted increased calorie intake in treated patients versus controls.[25] The authors also performed a post-hoc analysis on one or more subgroups of these patients, which they reported as suggesting a beneficial effect from treatment. The design and interpretation of this trial, and in particular the validity of this subgroup analysis, was criticized in detail in an editorial in the Journal of Clinical Oncology.[26]

Later randomized controlled trials failed to find any improvement in survival,[27][28] For example, in a trial of the treatment of advanced lung cancer, with either cisplatin and vinblastine or these drugs plus hydrazine sulfate, saw complete tumor regression in 4% of the hydrazine group, versus 3% in the control group, and tumor progression in 36% of the hydrazine group, versus 30% of the control group; however, none of these differences were statistically significant.[29] Some trials even found both significantly decreased survival and significantly poorer quality of life in those patients receiving hydrazine sulfate.[30] These consistently negative results have resulted in hydrazine sulfate being described as a "disproven cancer therapy" in a recent medical review.[20] Similarly, other reviews have concluded that there is "strong evidence" against the use of hydrazine sulfate to treat anorexia or weight loss in cancer patients.[31][32]

Side effects

Hydrazine sulfate is toxic and potentially carcinogenic.[33][34] Nevertheless, the short-term side effects reported in various clinical trials are relatively mild:[7] minor nausea and vomiting, dizziness and excitement, polyneuritis (inflammation of the nerves) and difficulties in fine muscle control (such as writing). However, more serious, even fatal side effects have been reported in rare cases: one patient developed fatal liver and kidney failure,[35] and another developed serious symptoms of neurotoxicity.[36] These side effects and other reports of hydrazine toxicity[25][26] are consistent with the hypothesis that hydrazine may play a role in the toxicity of the antibiotic isoniazid, which is thought to be metabolized to hydrazine in the body.[7]

Hydrazine sulfate is also a monoamine oxidase inhibitor (MAOI),[37] and is incompatible with alcohol, tranquilizers and sleeping pills (benzodiazepines and barbiturates), and other psycho-active drugs, with pethidine (meperidine, Demerol), and with foods containing significant amounts of the amino acid breakdown product tyramine, such as aged cheeses, raisins, avocados, processed and cured fish and meats, fermented products, and others.

References
  1. Adams, Roger; Brown, B. K. (1922). "Hydrazine Sulfate". Organic Syntheses. 2: 37.; Collective Volume, vol. 1, p. 309
  2. Milne, George W. A. (2005). Gardner's commercially important chemicals: synonyms, trade names, and properties. New York: Wiley-Interscience. pp. 325. ISBN 978-0-471-73518-2.
  3. Chlebowski, R. T.; Bulcavage, L.; Grosvenor, M.; et al. (1987), "Hydrazine Sulfate in Cancer Patients With Weight Loss. A Placebo-Controlled Clinical Experience", Cancer, 59 (3): 406–10, doi:10.1002/1097-0142(19870201)59:3<406::AID-CNCR2820590309>3.0.CO;2-W, PMID 3791153, archived from the original on 2014-11-30, retrieved 2009-05-31.
  4. Chlebowski, R. T.; Bulcavage, L.; Grosvenor, M.; Oktay, E.; Block, J. B.; Chlebowski, J. S.; Ali, I.; Elashoff, R. (1990), "Hydrazine Sulfate Influence on Nutritional Status and Survival in Non-Small-Cell Lung Cancer", Journal of Clinical Oncology, 8 (1): 9–15, doi:10.1200/jco.1990.8.1.9, PMID 1688616, archived from the original on 2014-09-28, retrieved 2009-05-31.
  5. Gold, J. (1999), "Long term complete response in patient with advanced, localized NSCLC with hydrazine sulfate, radiation and Carboplatin, refractory to combination chemotherapy", Proceedings of the American Association for Cancer Research (40): 642. Abstract. Archived 2016-03-03 at the Wayback Machine
  6. Questions and answers about hydrazine sulfate, National Cancer Institute, March 12, 2009
  7. Black, M.; Hussain, H. (2000), "Hydrazine, Cancer, the Internet, Isoniazid, and the Liver", Annals of Internal Medicine, 133 (11): 911–13, doi:10.7326/0003-4819-133-11-200012050-00016, PMID 11103062, S2CID 41415415.
  8. Gold J (1987), "Hydrazine sulfate: a current perspective", Nutr Cancer, 9 (2–3): 59–66, doi:10.1080/01635588709513912, PMID 3104888
  9. Gold, J. (1968), "Proposed Treatment of Cancer by Inhibition of Gluconeogenesis", Oncology, 22 (2): 185–207, doi:10.1159/000224450, PMID 5688432.
  10. Gold, J. (1974), "Cancer Cachexia and Gluconeogenesis", Annals of the New York Academy of Sciences, 230 (1 Paraneoplasti): 103–10, Bibcode:1974NYASA.230..103G, doi:10.1111/j.1749-6632.1974.tb14440.x, PMID 4522864, S2CID 8572475.
  11. London, William M. (July 23, 2006), Penthouse's promotion of hydrazine sulfate
  12. Null's articles on alternative cancer therapies in Penthouse include:
    • Null, Gary; Robert Houston (1979). "The Great Cancer Fraud". Penthouse: 76–78, 82, 268, 270, 272, 274, 276–278.
    • Null, Gary; A. Pitrone (1980). "Suppression of new cancer therapies: Dr. Joseph Gold and hydrazine sulfate". Penthouse: 97–98, 160, 162–163.
    • Null, Gary; L. Steinman (1980). "The politics of cancer. Part five. Suppression of new cancer therapies: Dr. Lawrence Burton". Penthouse: 75–76, 188–194, 196–197.
  13. Goldberg, Burton (June 12, 2000), Holding the National Cancer Institute Accountable for Cancer Deaths, archived from the original on May 15, 2009, retrieved May 30, 2009
  14. Goldberg, Burton; Trivieri, Larry; Anderson, John W., eds. (2002), Alternative medicine: the definitive guide (2nd ed.), Celestial Arts, pp. 50–51, 598, ISBN 978-1-58761-141-4.
  15. Jenks, S. (1993), "Hydrazine Sulfate Ad Is "Offensive"", Journal of the National Cancer Institute, 85 (7): 528–29, doi:10.1093/jnci/85.7.528, PMID 8455198, archived from the original on 2012-07-11.
  16. Nadel, M. V. (September 1995), "Cancer Drug Research—Contrary to Allegations, Hydrazine Sulfate Studies Were Not Flawed", Report to the Chairman and Ranking Minority Member, Human Resources and Intergovernmental Relations Subcommittee, House Committee on Government Reform and Oversight, Washington, D.C.: General Accounting Office, Document No. HEHS-95-141.
  17. Kaegi, Elizabeth (1998), "Unconventional therapies for cancer: 4. Hydrazine sulfate. Task Force on Alternative Therapies of the Canadian Breast Cancer Research Initiative", Canadian Medical Association Journal, 158 (10): 1327–30, PMC 1229327, PMID 9614826.
  18. Green, Saul (1997), "Hydrazine sulfate: is it an anticancer agent?", Scientific Review of Alternative Medicine, 1: 19–21
  19. Hydrazine sulfate / Hydrazine sulphate Archived 2009-09-19 at the Wayback Machine from the British Columbia Cancer Agency
  20. Vickers A (2004), "Alternative cancer cures: "unproven" or "disproven"?", CA Cancer J Clin, 54 (2): 110–8, CiteSeerX 10.1.1.521.2180, doi:10.3322/canjclin.54.2.110, PMID 15061600, S2CID 35124492
  21. "Editorial: Unproven methods of cancer management: hydrazine sulfate", CA Cancer J Clin, 26 (2): 108–10, 1976, doi:10.3322/canjclin.26.2.108, PMID 816429, S2CID 221547391
  22. Elizabeth Cohen Regulators warn about online cancer 'cures' Archived 2007-01-08 at the Wayback Machine CNN December 5, 2000
  23. Filov, V. A.; Gershanovich, M. L.; Danova, L. A.; Ivin, B. A. (1995), "Experience of the Treatment with Sehydrin (Hydrazine Sulfate, HS) in the Advanced Cancer Patients", Investigational New Drugs, 13 (1): 89–97, doi:10.1007/BF02614227, PMID 7499115, S2CID 24465375.
  24. Hydrazine sulfate:Human/Clinical Studies National Cancer Institute
  25. Chlebowski RT, Bulcavage L, Grosvenor M, et al. (January 1990), "Hydrazine sulfate influence on nutritional status and survival in non-small-cell lung cancer", J. Clin. Oncol., 8 (1): 9–15, doi:10.1200/jco.1990.8.1.9, PMID 1688616
  26. Piantadosi, S. (1990), "Hazards of small clinical trials" (PDF), Journal of Clinical Oncology, 8 (1): 1–3, doi:10.1200/JCO.1990.8.1.1, PMID 2295901, retrieved 2009-06-03
  27. Loprinzi CL, Goldberg RM, Su JQ, et al. (June 1994), "Placebo-controlled trial of hydrazine sulfate in patients with newly diagnosed non-small-cell lung cancer", J. Clin. Oncol., 12 (6): 1126–9, doi:10.1200/JCO.1994.12.6.1126, PMID 8201374
  28. Kosty MP, Fleishman SB, Herndon JE, et al. (June 1994), "Cisplatin, vinblastine, and hydrazine sulfate in advanced, non-small-cell lung cancer: a randomized placebo-controlled, double-blind phase III study of the Cancer and Leukemia Group B", J. Clin. Oncol., 12 (6): 1113–20, doi:10.1200/JCO.1994.12.6.1113, PMID 8201372
  29. Herndon JE, Fleishman S, Kosty MP, Green MR (August 1997), "A longitudinal study of quality of life in advanced non-small cell lung cancer: Cancer and Leukemia Group B (CALGB) 8931", Controlled Clinical Trials, 18 (4): 286–300, doi:10.1016/0197-2456(96)00116-X, PMID 9257067
  30. Loprinzi CL, Kuross SA, O'Fallon JR, et al. (June 1994), "Randomized placebo-controlled evaluation of hydrazine sulfate in patients with advanced colorectal cancer", J. Clin. Oncol., 12 (6): 1121–5, doi:10.1200/JCO.1994.12.6.1121, PMID 8201373
  31. Yavuzsen T, Davis MP, Walsh D, LeGrand S, Lagman R (November 2005), "Systematic review of the treatment of cancer-associated anorexia and weight loss", J. Clin. Oncol., 23 (33): 8500–11, doi:10.1200/JCO.2005.01.8010, PMID 16293879
  32. Gagnon B, Bruera E (May 1998), "A review of the drug treatment of cachexia associated with cancer", Drugs, 55 (5): 675–88, doi:10.2165/00003495-199855050-00005, PMID 9585863, S2CID 22180434
  33. Hydrazine Hazard Summary, U.S. Environmental Protection Agency, January 2000.
  34. Section 9.2.1, Environmental Health Criteria for Hydrazine, International Programme on Chemical Safety, 1987.
  35. Hainer, M. I.; et al. (2000), "Fatal hepatorenal failure associated with hydrazine sulfate", Annals of Internal Medicine, 133 (11): 877–80, doi:10.7326/0003-4819-133-11-200012050-00011, PMID 11103057, S2CID 25672540.
  36. Nagappan, R.; Riddell, T. (2000), "Pyridoxine therapy in a patient with severe hydrazine sulfate toxicity", Critical Care Medicine, 28 (6): 2116–18, doi:10.1097/00003246-200006000-00076, PMID 10890675, S2CID 12935478.
  37. National Cancer Institute (October 1999), "Hydrazine Sulfate", PDQ Complementary/Alternative Medicine
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