Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/365—Lactones
  • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof

Definitions

• This invention relates to novel selected mixtures of anthracycline antitumor agents with L-ascorbic acid and their employment as antitumor agents.
• L-ascorbic acid or Vitamin C is a well known physiologically active agent originally isolated by Szent- Gyorgyi. It has many and well known pharmaceutical activities.
• the anthracyclines are a well known class of antitumor agents that have been employed in the clinical treatment of various tumors in humans since at least 1970.
• the best known of the class is doxorubicin (Andriamycin) . It has a wide spectrum of antitumor activity, such activity encompasing a broad range of solic tumors that prior to its isolation from Streptomyces peucetius caesium had been relatively insensitive to chromatherapy, especially the soft tissue and bone sarcomas and bladder cancer.
• the anthracyclines are further characterized by falling into two classes based on their mode of inhibition of DNA synthesis.
• Type I anthracyclines such as aclacinomycin-A and marcellomycin, inhibit whole cellular RNA synthesis at six-seven fold lower concentrations and nucleolar preribosomal synthesis at 170-1250 fold lower concentrations than those required for inhibition of DNA synthesis.
• Structural differences between type I and type II anthracyclines include the presence of 10-carbomethoxy group and a greater number of sugar residues in the Type II compounds. If the 10-carbomethoxy group is removed, the ability to inhibit nucleolar RNA synthesis is decreased and their is a loss of antitumor activity. Removal of sugar residues can also cause a loss of selectivity of the anthracyclines.
• This invention is concerned with Type I anthracyclines exemplified by doxorubicin, carminomycin and dihydroxy anthracenedione (Mitoxantrone) or its diacetate (DHAQ diacetate) .
• the anthracyclines are unique amongst clinical antitumor agents in that many of them including those presently believed to be the most active, have toxic effects which are dose related.
• the major toxicities are myelosuppression including cardiotoxicity in approximately 60 to 80% of the patients, stomatitis in as many as 80%, nausea and/or vomiting in 20 to 55%, and alopecia in virtually all cases.
• the art has attempted to circumscribe the toxicity of doxorubicin and other anthracyclines by limiting the dose. Such efforts have included coadministration with other chemotherapeutic agents, preparation of homologs, and intermittent administration of the drug. Some degree of success has been achieved with these procedures, but there is room for improvement. The art has sought methods for increasing the efficacy of a particular doses or for making possible the administration of the same or larger doses over longer periods of time without triggering a toxic response.
• SUBSTITUTE SHEET tested combinations of adriamycin, ascorbic acid and dimethyl sulfoxide and concluded that the combinations did not alter the effectiveness of adriamycin.
• anthracycline Type I antitumor agents together with anthracycline Type I antitumor agents are effective to improve the efficacy of the selected antitumor agent provided that the correct amounts of each component of the mixture are selected.
• compositions of this invention not only reduce the toxicity of anthracycline Type I antitumor agents, but also increase the antitumor activity of the therapeutic agent.
• the parts by weight ratio of ascorbic acid to antitumor agent will vary with the selected antitumor agents in the
• compositions of the invention Generally it will vary from about 20:1 to 440:1 in compositions having antitumor activity which is greater than that of the same amount of antitumor agent alone.
• the observation which forms the basis of this selective invention is the recognition that
• the effective ratio of L-ascorbic acid to antitumor agent v depends upon the selected antitumor agent.
• doxorubicin With doxorubicin the ratio for improved activity is about 20:1 to 175:1, the preferred ratio being 85:1 to 90:1.
• DHAQ-diacetate dihydroxy anthracenedione diacetate
• SUBSTITUTE SHEET respective ratios are about 55:1 to 440:1 and 220:1 to 230:1. Below these ratios the desired effect is not achieved. Above these ratios the toxicity of the antitumor agent is unacceptably high even in the presence of L- ascorbic acid.
• P-388 is an ascites tumor administered at a concentration of 1,000,000 cells via the intraperitoneal
• the drugs were given via the NCI's recommended intermittent schedule by I.P. injection of P-388 or L-1210 ascites tumor cells on day zero.
• mice were treated with a mixture of L-ascorbic (200 mM) and doxorubicin.
• the doxorubicin powder was reconstituted in 200 mM of the L-ascorbic acid in 0.85% saline to an equivalent concentration of 10 mg/kg body weight, calculated for 22 gram mice.
• the positive control for P-388 was the known antitumor agent 5-fluorouracil (60 mg/kg) in 200 mM of the acid.
• the doses of doxorubicin were prepared fresh daily.
• L-ascorbic acid in 0.85% saline, doxorubicin in 0.85% saline and 0.85% saline served as further controls.
• L-ascorbic acid can be used in the form of its metal salts, preferably an alkali metal salt such as sodium ascorbate, as will be recognized by those skilled in the art.
• the pH of the mixtures employed in the invention is preferably about 7, but any pH, e.g., 6 to 8, which is neither so high or so low as to be toxic is acceptable.

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• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Molecular Biology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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• 1986
  • 1986-12-05 AU AU68466/87A patent/AU6846687A/en not_active Abandoned
  • 1986-12-05 WO PCT/US1986/002646 patent/WO1987003481A1/en not_active Application Discontinuation
  • 1986-12-05 EP EP19870900499 patent/EP0249632A4/de not_active Withdrawn

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