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
  • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
• • 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
  • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
  • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents

Definitions

• griseofulvin for inhibiting the growth of cancers
• This invention is a pharmaceutical composition that is useful for the treatment of cancers and tumors, particularly in human and warm blooded animals.
• the composition contains griseofulvin. It can be used in combination with other chemotherapeutic agents also.
• the exact cause of leukemia is not known, but links between certain activities such as smoking or exposure to carcinogens and the incidence of certain types of leukemia and tumors has been shown by a number of researchers.
• Many types of chemotherapeutic agents have been shown to be effective against cancers, tumors and leukemia, but not all types of cancer and tumor cells respond to these agents. Unfortunately, many of these agents also destroy normal cells. The exact mechanism for the action of these chemotherapeutic agents are not always known.
• cytocidal or cytostatic agents work best on cancers with large growth factors, i.e., ones whose cells are rapidly dividing.
• hormones in particular estrogen, progesterone and testosterone, and some antibiotics produced by a variety of microbes, alkylating agents, and anti-metabolites form the bulk of therapies available to oncologists.
• cytotoxic agents that have specificity for leukemia, cancer and tumor cells while not affecting normal cells would be extremely desirable. Unfortunately, none have been found and instead agents which target especially rapidly dividing cells (both diseased and normal) have been used.
• i' is an object of this invention to provide a pharmaceutical composition that is effective in treating leukemia with mild or no effects on normal blood cells
• a composition comprising a pharmaceutical carrier and a griseofulvin as defined herein along with a method for treating cancer, leukemia and tumors.
• griseofulvin in combination with other chemotherapeutic agents which are effective in destroying the tumor is a novel method of treatment.
• Griseofulvin can also be used to treat viral infections in the presence of a potentiator.
• a pharmaceutical composition for treatment of mammals, and in particular, warm blooded animals and humans, which are affected by leukemia comprising a pharmaceutical carrier and an effective amount of griseofulvin.
• Griseofulvin has the formula:
• compositions can be used to inhibit the growth of leukemia, tumors and cancer cells in humans or animals by administration of an effective amount either orally, rectally, topically or parenterally, or intravenously. These compositions do not significantly affect healthy cells.
• Potentiators can also be used in combination with griseofulvin as can chemotherapeutic agents.
• the term “comprising” means various components can be conjointly employed in the pharmaceutical composition of this invention. Accordingly, the terms “consisting essentially o and “consisting o are embodied in the term comprising.
• a "pharmaceutically acceptable” component is one that is suitable for use with humans and or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit/risk ratio.
• safe and effective amount refers to the quantity of a component which is sufficient to yield a desired therapeutic response without undue adverse side effects (such as toxicity, irritation, or allergic response) commensurate with a reasonable benefit/risk ratio when used in the manner of this invention.
• the specific "safe and effective amount” will, obviously, vary with such factors as the particular condition being treated, the physical condition of the patient, the type of mammal being treated, the duration of the treatment, the nature of concurrent therapy (if any), and the specific formulations employed and the structure of the compounds or its derivatives.
• a "pharmaceutical addition salts” is salt of the anti-leukemia compound with an organic or inorganic acid.
• These preferred acid addition salts are chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, malates, citrates, benzoates, salicylates, ascorbates, and the like.
• a “pharmaceutical carrier” is a pharmaceutically acceptable solvent, suspending agent or vehicle for delivering the anti-leukemia agent to the animal or human.
• the carrier may be liquid or solid and is selected with the planned manner of administration in mind.
• cancer or “leukemia” refers to all types of cancers or neoplasm or malignant disease which attack normal healthy blood cells or bone marrow which produces blood cells which are found in mammals.
• virus includes viruses which cause diseases in warm blooded animals including HIV, influenza, rhinoviruses, herpes and the like.
• grisofulvin means 7-Chloro-2',4,6-trimethoxy-6-methylspiro
• potentiators are materials such as triprolidine and its cis-isomer which are used in combination with griseofulvin. Potentiators can suppress the immune system or enhance the effectiveness of the drugs.
• chemotherapeutic agents includes DNA-interactive Agents, Antime- tabolites, Tubulin-Interactive Agents, Hormonal agents and others, such as Asparaginase or hydroxyurea.
• GRISEOFULVIN Griseofulvin has the following structure:
• the chemotherapeutic agents are generally grouped as DNA-interactive Agents, Antimetabolites, Tubulin-Interactive Agents, Hormonal agents and others such as Asparaginase or hydroxyurea. Each of the groups of chemotherapeutic agents can be further divided by type of activity or compound.
• the chemotherapeutic agents used in combination with griseofulvin include members of all of these groups.
• DNA-interactive Agents include the alkylating agents, e.g. Cisplatin, Cyclophosphamide, Altretamine; the DNA strand-breakage agents, such as Bleomycin; the intercalating topoisomerase II inhibitors, e.g., Dactinomycin and Doxorubicin); the nonintercalating topoisomerase II inhibitors such as, Etoposide and Teniposde; and the DNA minor groove binder
• the alkylating agents form covalent chemical adducts with cellular DNA, RNA, and protein molecules and with smaller amino acids, glutathione and similar chemicals. Generally, these alkylating agents react with a nucleophilic atom in a cellular constituent, such as an amino, carboxyl, phosphate, sulfhydryl group in nucleic acids, proteins, amino acids, or glutathione. The mechanism and the role of these alkylating agents in cancer therapy is not well understood.
• Typical alkylating agents include: Nitrogen mustards, such as Chlorambucil, Cyclophosphamide, Isofamide,
• Mechlorethamine, Melphalan, Uracil mustard such as Thiotepa methanesulphonate esters such as Busulfan; nitroso ureas, such as Carmustine, Lomustine, Streptozocin; platinum complexes, such as Cisplatin, Carboplatin; bioreductive alkylator, such as Mitomycin, and Procarbazine, dacarbazine and Altretamine;
• DNA strand breaking agents include Bleomycin; DNA topoisomerase II inhibitors include the following: Intercalators, such as Amsacrine, Dactinomycin, Daunorubicin, Doxorubicin,
• the DNA minor groove binder is Plicamycin.
• the antimetabolites interfere with the production of nucleic acids by one or the other of two major mechanisms. Some of the drugs inhibit production of the deoxyribonucleoside triphosphates that are the immediate precursors for DNA synthesis, thus inhibiting DNA replication. Some of the compounds are sufficiently like purines or pyrimidines to be able to substitute for them in the anabolic nucleotide pathways. These analogs can then be substituted into the DNA and RNA instead of their normal counterparts.
• the antimetabolites useful herein include: folate antagonists such as Methotrexate and trimetrexate pyrimidine antagonists, such as Fluorouracil, Fluorodeoxyuridine, CB3717, Azacitidine,
• Cytarabine, and Floxuridine purine antagonists include Mercaptopurine, 6-Thioguanine, Fludarabine, Pentostatin; sugar modified analogs include Cyctrabine, Fludarabine; ribonucleotide reductase inhibitors include hydroxyurea.
• Tubulin Interactive agents act by binding to specific sites on tubulin, a protein that polymerizes to form cellular microtubules. Microtubules are critical cell structure units. When the interactive agents bind on the protein, the cell can not form microtubules
• Tubulin Interactive agents include Vincristine and Vinblasune, both alkaloids and Paclitaxel.
• Hormonal agents are also useful in the treatment of cancers and tumors. They are used in hormonally susceptible tumors and are usually derived from natural sources. These include: estrogens, conjugated estrogens and Ethinyl Estradiol and Diethylsulbesterol, Chlortrianisen and Idenestrol; progestins such as Hydroxyprogesterone caproate, Medroxyprogesterone, and Megestrol; androgens such as testosterone, testosterone propionate; fluoxymesterone, methyltestosterone;
• Adrenal corticosteroids are derived from natural adrenal cortisol or hydrocortisone. They are used because of their anti inflammatory benefits as well as the ability of some to inhibit mitotic divisions and to halt DNA synthesis. These compounds include, Prednisone, Dexamethasone, Methylprednisolone, and Prednisolone. Leutinizing hormone releasing hormone agents or gonadotropin-releasing hormone antagonists are used primarily the treatment of prostate cancer. These include leuprolide acetate and goserelin acetate. They prevent the biosynthesis of steroids in the testes.
• Antihormonal antigens include: antiestrogenic agents such as Tamosifen, antiandrogen agents such as Flutamide ; and antiadrenal agents such as Mitotane and Aminoglutethimide.
• Hydroxyurea appears to act primarily through inhibition of the enzyme ribonucleotide reductase.
• Asparaginase is an enzyme which converts asparagine to nonfunctional aspartic acid and thus blocks protein synthesis in the tumor.
• D. POTENTIATORS are enzymes which converts asparagine to nonfunctional aspartic acid and thus blocks protein synthesis in the tumor.
• potentiators can be any material which improves or increase the efficacy of the pharmaceutical composition or acts as an immunosuppressor.
• One such potentiator is triprolidine and its cis-isomer which are used in combination with the chemotherapeutic agents and the griseofulvin.
• Triprolidine is described in US 5,114,951 (1992).
• Another potentiator is procodazole, lH-Benzimidazole-2-propanoic acid; [ ⁇ -(2-benzimidazole) propionic acid; 2-(2- carboxyethyl)benzimidazole; propazol].
• Procodazole is a non-specific active immunoprotective agent against viral and bacterial infections and can be used with the compositions claimed herein. It is effective with griseofulvin alone in treating cancers, tumors, leukemia and viral infections or combined with chemotherapeutic agents.
• Propionic acid and its salts and esters can also be used in combination with the pharmaceutical compositions claimed herein.
• Antioxidant vitamins such as vitamins A, C and E and beta-carotene can be added to these compositions.
• any suitable dosage may be given in the method ofthe invention.
• the type of compound and the carrier and the amount will vary widely depending on the species of the warm blooded animal or human, body weight, and the type of cancer or tumor or viral infection being treated.
• a dosage of between about 1 milligram (mg) per kilogram (kg) of body weight and about 8000 mg per kg of body weight is suitable for either the griseofulvin or the chemotherapeutic agent.
• Preferably from 15 mg to about 5000 mg/kg of body weight is used.
• the dosage in man is lower than for small warm blooded mammals such as mice.
• a dosage unit may comprise a single compound or mixtures thereof with other compounds or other cancer inhibiting compounds.
• the dosage unit can also comprise diluents, extenders, carriers, liposomes and the » like.
• the unit may be in solid or gel form such as pills, tablets, capsules and the like or in liquid form suitable for oral, rectal, topical, intravenous injection or parenteral administration or injection into or around the bone marrow.
• the range and ratio of griseofulvin to chemotherapeutic agent will depend on the type of cancer or tumor being treated and the particular chemotherapeutic agent.
• the chemotherapeutic agents, griseofulvin and, optionally, the potentiators are typically mixed with a pharmaceutically acceptable carrier.
• This carrier can be a solid or liquid and the type is generally chosen based on the type of administration being used.
• the active agent can be coadministered in the form of a tablet or capsule, liposome, as an agglomerated powder or in a liquid form.
• suitable solid carriers include lactose, sucrose, gelatin and agar. Capsule or tablets can be easily formulated and can be made easy to swallow or chew; other solid forms include granules, and bulk powders.
• Tablets may contain suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents.
• suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules.
• Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents.
• Oral dosage forms optionally contain flavorants and coloring agents.
• Parenteral and intravenous forms would also include minerals and other materials to make them compatible with the type of injection or delivery system chosen.
• the method of treatment can be any suitable method which is effective in the treatment of the particular cancer or tumor type being treated.
• Treatment may be oral, rectal, topical, parenteral or intravenous administration or by injection into the tumor or cancer.
• the method of applying an effective amount also varies depending on the leukemia, cancer, tumor or virus being treated. It is believed that parenteral treatment by intravenous, subcutaneous, or intramuscular application ofthe griseofulvin, formulated with an appropriate carrier, additional cancer inhibiting compound or compounds or diluent to facilitate application will be the preferred method of administering the compounds to warm blooded animals.
• griseofulvin can be combined with fungicides, herbicides or other antiviral agents.
• Preferred herbicides and fungicides include carbendazim, fluoconazole, benomyl, glyphosate and propicodazole.
• griseofulvin inhibited viral replication by 98% at lO ⁇ g ml with a therapeutic index of 5.3.
• AZT a known HIV drug
• the therapeutic index is the ratio of toxic dose of drug to efficacious dose of drug.
• griseofulvin showed an increase in the survival time relative to a non treated control of 156% at 4000 mg/kg dose; 188% at 5000 mg/kg dose; and 218% at 6000 mg/kg dose.
• griseofulvin showed an increase in the survival time relative to a nontreated control of 165% at 4000 mg/kg dose; 179% at 5000 mg/kg dose; and 201% at 6000 mg/kg dose. Cytoxan at 300 mg/kg showed an increased survival rate of 192%.
• Rhinovirus type A-l, cell line WI-38
• griseofulvin was effective at 100 ⁇ g/ml.
• the positive control was A-36683 of Abbot Company, (S,S)-l,2-bis(5- methoxy-2-benzimidazolyl)-l,2-ethanediol.
• A-36683 has a therapeutic index of 1000-3200.
• Griseofulvin has a therapeutic index of 1-2. (See Schleicher et al, Applied Microbiology, 23, No. 1, 113-116 (1972).
• Solid tumors removed by patients are minced into 2 to 5 mm fragments and immediately placed in McCoy's Medium 5A plus 10% heat inactivated newborn calf serum plus 1% penicillin streptomycin. Within 4 hours, these solid tumors are mechanically disassociated with scissors, forced through No. 100 stainless steel mesh, through 25 gauge needles, and then washed with McCoy's medium as described above. Ascitic, pleural, pericardial fluids and bone marrow are obtained by standard techniques. The fluid or marrow is placed in sterile containers containing 10 units of preservative free heparin per ml. of malignant fluid or marrow. After centrifugation at 150 x g for 10 minutes, the cells are harvested and washed with McCoy's medium plus 10% heat inactivated calf serum. The viability of cell suspensions is determined on a hemocytometer with trypan blue.
• Cells to be cloned are suspended in 0.3% agar in enriched CMRL1066 supplemented with 15% heat inactivated horse serum, penicillin (100 units/ml), streptomycin (2mg ml), glutamine (2mM), insulin (3 units/ml), asparagine (0.6 mg/ml), and HEPES buffer (2mM).
• penicillin 100 units/ml
• streptomycin 2mg ml
• insulin 3 units/ml
• asparagine 0.6 mg/ml
• HEPES buffer HEPES buffer
• the number of colonies (defined as 50 cells) formed in the 3 compound treated plates is compared to the number of colonies formed in the 3 control plates, and the percent colonies surviving at the concentration of compound can be estimated.
• Three positive control plates are used to determine survival rate. Orthosodium vanadate at 200 ⁇ g/ml is used as the positive control. If there is ⁇ 30% colonies in the positive control when compared to the untreated control, the test is evaluated.

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