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
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
• • 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
  • A61K31/66—Phosphorus compounds
  • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
• • 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
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
• • 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
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4164—1,3-Diazoles
  • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
• • 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
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4196—1,2,4-Triazoles
• • 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
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/425—Thiazoles
  • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • 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
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
  • A61P31/18—Antivirals for RNA viruses for HIV
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents

Definitions

• This invention is a method of inhibiting the growth of viruses, particularly HIV, cancers and tumors in human and warm blooded animals, involving the administration of herbicidal and fungicidal agents. Tumor size is decreased, the growth of the cancer is slowed, and the replication of viruses is inhibited.
• This treatment is particularly effective when the virus or cancer is the result of a mutated cell, i.e. an animal cell which has been mutated by incorporating therein genetic material from plants, fungi or molds.
• HIV and other viral infections are one leading cause of death. HIV is a disease in which a virus is replicated in the body which attacks the body's immune system. The HIV virus is not easily destroyed nor is there a good mechanism for keeping the host cells from replicating the virus. Herpes Simplex is another viral infection which is difficult, if not impossible, to cure. A method of treating these diseases and other viral infections is highly desirable.
• fungicides, herbicides, mold inhibitors and their derivatives can inhibit the replication of viruses.
• the fungicides or herbicides can be used in conjunction with other treatments, e.g. with AZT, 3TC or protease inhibitors for the treatment of HIV.
• This HIV treatment is uniquely effective in the treatment of chronically infected cells and the cells do not appear to develop resistance to the treatment.
• thiabendazole and chloropropham have been shown to quickly reduce the level of virus production from cell populations chronically infected with HIV-1 and the antiviral effect is maintained with continued compound exposure (up to one year).
• Cancers are a leading cause of death in animals and humans.
• the exact cause of cancer is not known, but links between certain activities such as smoking or exposure to carcinogens and the incidence of certain types of cancers and tumors has been shown by a number of researchers.
• cancer cells are abnormal cells and can be dormant for a time and then rapidly grow. Many cancers cells are considered immortal because they do not die off like normal animal or human cells, but continue to replicate themselves.
• plant and animal cells can be genetically altered by insertion of genetic material from a different cell type. These genetically altered cells have the DNA or portions of the genes or genetic material of one cell incorporated within the new cell. These new cells have the characteristics of both types of cells, but are no longer identified as wholly a plant or an animal cell. Such mutated or abnormal animal cells can be fast growing and do not respond as normal cells to the "aging" mechanisms.
• the body has certain mechanisms for filtering out or eliminating molds, fungi and pollen materials. If they are ingested, the body's digestive system can eliminate or detoxify the materials in reasonable quantities.
• the nose, lungs and skin have active mechanisms for filtering foreign materials.
• fungal and mold materials which penetrate the body's defense mechanisms and get into the blood stream, lymph system or penetrate the lung and skin membranes. These materials can penetrate animal cells and mutate them.
• the mutated cells can be made by the combination of plant cells with animal cells created by pollen combining with the animal cell. Pollen can be absorbed either through.respiration wherein pollen is constantly bathing the lung tissues and other cells in the nose, mouth and throat with plant material.
• Other cells can be created by fungal materials or molds combining with the genetic material of the animal cells in the same way.
• Abnormal or mutated cells which contain the genetic materials of both plant and animal or fungal and animal cells are environmentally altered cells.
• the body normally rejects these materials by creating antibodies, but when the cells have the characteristics of both the animal cell and the plant or fungal materials, including molds, the antibodies may not function in the same way. This allows the cells to grow and since they are not normal, they can be called a "cancer” or tumor growth; including so-called “liquid tumors” such as leukemia.
• Viruses also have the ability to invade cells and to replicate themselves within the cell matrix. These new cells are different from the two starting cells. Viruses themselves mutate and change based upon interactions with fungi, molds and plant material, particularly pollen. These viruses can also be destroyed or their replication inhibited by treatment with fungicides, mold inhibitors and herbicides. It is interesting that some of these compounds also act as anthelmintics.
• This method comprises the administration of a safe and effective amount of a herbicide or fungicide alone or in conjunction with other HIV drugs, e.g. AZT or 3TC.
• It is a further object of this invention to provide an anti-viral therapy comprising administering a safe and effective amount of a viral growth inhibiting agent which has the ability to destroy viruses, particularly environmentally altered or mutated cells.
• the materials are herbicides which can destroy plant cells or fungicides which are effective against fungal materials, including molds.
• the agents may also be administered in conjunction with a potentiator, an anti inflammatory agent or vitamins, including antioxidant vitamins.
• It is another object of this invention to provide an anti-cancer therapy comprising administering a safe and effective amount of a tumor reducing agent which has the ability to destroy cancer cells, particularly, environmentally altered cells.
• the materials are herbicides which can destroy plant cells or fungicides which are effective against fungal materials, including molds.
• the agents may also be administered with a chemotherapeutic agent either concurrently or in sequence and/or in conjunction with a potentiator.
• a method of treating HIV and other viral infections and cancers in mammals, and in particular, warm blooded animals and humans comprises administering a safe and effective amount of a herbicide or a fungicide or derivative thereof which significantly reduces the mass of the tumor or cancer or inhibits the replication of viruses and cancer cells.
• the herbicidal agent and its derivatives are effective for treatment of cancers or viruses which are genetically altered animal cells made by combining a plant cell with an animal cell and the fungicidal agents and their derivatives are effective when the cancer or virus is an animal cell which contains genetic materials derived from a fungus or mold.
• compositions can be used to inhibit the growth of cancers and other tumors in humans or animals by administration of an effective amount either orally, rectally, topically or parenterally, intravenously or by injection into the tumor. Potentiators can also be used with this composition.
• the compositions can be used in conjunction with other therapies either sequentially or concurrently.
• the term “comprising” means various components can be conjointly employed in the pharmaceutical composition of this invention. Accordingly, the terms “consisting essentially of and “consisting of” are embodied in the term comprising.
• mutated cell or "environmentally altered cell” is an animal cell which has been genetically altered by combining genetic material, e.g. DNA or RNA fragments, from a plant or fungus cell with the genetic material of the animal cell to produce a new genetically modified cell which is neither a plant or fungus or animal cell but which is a viable parasite and remains in the host animal. Such a cell, when it grows and multiples, becomes a cancer cell in the host animal.
• genetic material e.g. DNA or RNA fragments
• 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 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 herbicidal or fungicidal agents and their derivatives 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 "derivative” is a chemically modified derivative of the fungicide or herbicide compound which is more soluble or more easily metabolized but which has not had its efficacy as a herbicide or fungicide altered significantly.
• addition of a hydroxyl group or other hydrophilic group will enhance the solubility and absorption by the body, and in most cases, not significantly affect the functionality of the compound.
• One skilled in the art can easily ascertain such compounds.
• a "pharmaceutical carrier” is a pharmaceutically acceptable solvent, suspending agent or vehicle, including liposomes, for delivering the anti- cancer 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 refers to all types of cancers or neoplasm or malignant tumors found in mammals, including tumors and leukemia.
• chemotherapeutic agents includes DNA-interactive Agents, Antimetabolites, Tubulin-Interactive Agents, Hormonal agents and others, such as Asparaginase or hydroxyurea.
• virus includes viruses which cause diseases (viral infection) in man and other warm blooded animals such as HIV virus, herpes, influenza and rhinoviruses.
• fungicides means a material which is effective in inhibiting the growth of fungi or killing a fungus. Mold inhibitors are included in the term “fungicide” since molds can be considered a fungus.
• herbicide means a material which is effective in inhibiting the growth of plants, particularly those which kill the plant cells.
• fungicides and their derivatives and pharmaceutically acceptable salts can be used.
• the particular fungicide will be chosen for safety as well as its effectiveness in preventing the growth of the fungus. Broader spectrum fungicides are preferred. Some fungicides which have been shown to be effective are listed below.
• the benzimidazole derivatives are known for their antifungal activities. Surprisingly it has been found that these compounds can also cause apoptosis in cancer cell lines. Apoptosis is specific cell death which differs from necrosis. Most cancer cells can live indefinitely; cancer cells are often referred to as immortalized cell lines. Therefore the ability to induce apoptosis is very important.
• the compounds have the following structure:
• X is hydrogen, halogen, alkyl of less than 7 carbon atoms or alkoxy of less than 7 carbon atoms; n is a positive integer of less than 4; Y is hydrogen, chlorine, nitro, methyl or ethyl; and R is hydrogen, CONHR3 and R3 is alkyl of less than 7 carbons, preferably butyl or isobutyl or an alkyl group having from 1 to 8 carbons, and R2 is NHCOORj wherein R ⁇ is aliphatic hydrocarbon of less than 7 carbon atoms, and preferably and alkyl group of less than 7 carbon atoms.
• the compositions are:
• Thiabendazole has been found to be particularly effective in the treatment of Chronic HIV where it has been shown to suppress viral production without the cells developing resistance to it.
• R is hydrogen and R2 is 4-thiazolyl or non-toxic, pharmaceutically acceptable acid addition salts with both organic and inorganic acids.
• the most preferred compounds are 2-(4-thiazolyl)benzimidazole.
• Thiabendazole is also an anthelmintic.
• thiazolyl derivatives are prepared according to the method described in Brown et al., J. Am. Chem. Soc, 83, 1764 (1961) and Grenda et al., J. Ore. Chem., 30, 259 (1965). 3. Substituted benzimidazole derivatives.
• More soluble benzimidazole compounds are also useful in this invention. While these compounds are not known for herbicidal or fungicidal use, it is believed that they will be effective against HIV, cancer and other viral infections. These derivatives have the formula:
• R is selected from the group consisting of H, carboxyl (-CO2H), hydroxyl, amino or esters (-CO2R ) wherein R is selected from the group consisting of alkoxy, haloalkyl, alkenyl, and cycloalkyl wherein the alkyl groups have from 1 - 8 carbons or CH 3 CH2(OCH2CH2)n— or CH3CH2CH2(OCH2CH 2 CH2) n — or (CH 3 ) 2 CH- and
• the preferred alkyl groups are straight chain.
• the halogen is substituted on the terminal carbon, and the halogen is chlorine.
• the preferred cycloalkyl groups are those having 3-6 carbon atoms.
• the cycloalkyl groups also include those which are substituted on an alkyl chain, 2-cyclopropylethyl, cyclopropylmethyl, 2-cyclopropyl propyl or 2- cyclopropylpropyl or cyclohexylmethyl.
• Preferred compounds are those having the formulas:
• lH-l,2,4-triazole derivatives are known for their anti f ungal activities. They are systemic materials used to prevent and eradicate fungi. The compounds have the following structure:
• Z is an alkylene selected from the group consisting of CH2-CH 2 -,-CH 2 -CH2-CH2-, -CH(CH 3 )-CH(CH 3 )- and -CH 2 -CH(alkyl) wherein said alkyl has from 1 to about 10 carbon atoms; and Ar is a member selected from the group consisting of phenyl, substituted phenyl, thienyl, halothienyl, naphthyl and fluorenyl, wherein "substituted phenyl” has the meaning of a phenyl radical having thereon from 1 to 3 substituents selected independently from the group consisting of halo, lower alkyl, lower polyalkoxy, cyano and nitro.
• alkyl is meant to include straight and branch chained hydrocarbon radicals having from 1 to about 10 carbon atoms, such as, for example, methyl, ethyl, 1-methylethyl, propyl, 1,1- dimethylethyl, butyl, pentyl, hexyl, heptyl, octyl, decyl and the like; as used herein "lower alkyl” may be straight or branch chained saturated hydrocarbons having from 1 to 6 carbon atoms, such as, for example, methyl, ethyl, propyl, 1-methylethyl, butyl, 1,1-dimethylethyl, pentyl, hexyl and the like alkyls; and the term "halo" is generic to halogen atoms of atomic weight
• Preferred derivatives include: l-[2-(2,4-dichlorophenyl)-l,3-dioxolan-2-ylmethyl]-lH-l,2,4-triazole; l-[2-(2,4-dichlorophenyl)-4-methyl-l,3-dioxolan-2-ylmethyl]-lH-l,2,4-triazole, 1 -[2-(2,4-dichlorophenyl)-4-ethyl- 1 ,3-dioxolan-2-ylmethyl]- 1 H- 1 ,2,4-triazole, 1 -[2-(2,4-dichlorophenyl)-4-propyl- 1 ,3-dioxolan-2-ylmethyl]- 1 H- 1 ,2,4-triazole, 1 -[2-(2,4-dichlorophenyl)-4-pentyl- 1 ,3-dioxolan-2-ylmethyl]-
• R! c is an op-tio C na H ll 2 y ⁇ sub0stituted alkyl, cycloalkyl (e.g. cyclopentyl or cyclohexyl), aryl or haloaryl (e.g. phenyl or 2,4-dichlorophenyl) or aralkyl (e.g., benzyl); and salts and metal complexes and ethers or esters thereof, and the nontoxic, pharmaceutically acceptable acid addition salts with both organic and inorganic acids.
• cycloalkyl e.g. cyclopentyl or cyclohexyl
• aryl or haloaryl e.g. phenyl or 2,4-dichlorophenyl
• aralkyl e.g., benzyl
• such bis triazole derivatives as 2-(2,4- dichlorophenyl)-l,3-bis(lH-l,2,4-triazole-l-yl)propan-2-ol and its corresponding 2- and 4- chlorophenyl analogs and 2,4-diflourophenyl analogs are useful herein.
• the composition is 2-(2,4-difluorophenyl)-l,3-bis(lH-l,2,4-triazol-l- yl)propan-2-ol and its pharmaceutically acceptable acid addition salts with both organic and inorganic acids.
• Griseofulvin has the following structure:
• herbicides and their derivatives and the pharmaceutically acceptable salts can be used in the practice of this invention.
• Preferred herbicides are those described below.
• N-chlorophenylcarbamates and N-chlorophenylthiocarbamates are known for their herbicidal activities. They are systemic herbicides used to prevent and eradicate certain plants or weeds. Systemic herbicides are differentiated from other herbicides by their ability to be absorbed by the plant and to move through the plant. This systemic ability is not a necessary requirement of the compounds of this invention.
• Chloropropham isopropyl N-(3-chlorophenyl)carbamate, has been shown to be particularly effective in the treatment of HIV.
• the compounds have the following structure
• n is from 1 to 3
• X is oxygen or sulfur and R is selected from the group consisting of hydrogen, lower alkyl and lower alkenyl, cyclohexyl, phenalkyl of up to 8 carbon atoms and phenyl, and the pharmaceutically acceptable salts of these compounds.
• Preferred compounds are those in which R is alkyl with 1 to 4 carbons, preferably, isopropyl and X is oxygen, n is 1 and the chloro group is in the 3 position on the phenyl group. N-3-chlorophenylcarbamate is a most preferred compound.
• N-phosphonoglycine derivatives are known for their herbicidal activities.
• the compounds have the following structure
• OZ wherein X is selected from the group consisting of hydroxy, thioyl, alkoxy or chloroxy up to 12 carbon atoms; lower alkenoxy, cyclohexyloxy, morpholino, pyrrlidinyl, piperidino and NHR; Y and Z each independently selected from hydrogen and lower alkyl; and R is selected from the group consisting of hydrogen, formyl, acetyl, benzoyl, nitrobenzoyl and chlorinated benzoyl; and R' is selected from the group consisting of hydrogen, lower alkyl and lower alkenyl, cyclohexyl, phenalkyl of up to 8 carbon atoms, phenyl, chlorinated phenyl and anisyl; and certain salts of these compounds, which salts are selected from the group consisting of the Group I and II metals having an atomic number of up to 30, hydrochloride, pyridine, ammonium, lower aliphatic hydrocarbon amine, lower alkan
• the lower alkylamine salts in particular the isopropyl amine salts, are preferred.
• HIV is treated with two general classes of drugs, reverse transcriptase inhibitors and protease inhibitors.
• AZT and 3TC are widely used to treat acute HIV.
• the herbicidal and fungicidal agents and their derivatives can be used in conjunction with AZTor 3TC for the treatment of acute HIV. They do not interfere with the activity of the AZT.
• HIV and antiviral agents can be used in conjunction with the therapy provided by this invention. These would include reverse transcriptase inhibitors and protease inhibitors.
• the drugs can be used concurrently or given in sequence with the herbicidal or fungicidal agents and their derivatives.
• the fungicides and herbicides can be administered with chemotherapeutic agents. This can be in sequence, where the chemotherapeutic agent is used to debulk the tumor and then the treatment with the herbicide, fungicide, or their derivatives begins, or the two materials can be administered together.
• 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 the sequential method in combination herbicidal or fungicidal agents primarily include members of the DNA-interactive Agents, Antimetabolites, Tubulin-Interactive Agents groups.
• the chemotherapeutic agent In order to reduce the mass of the tumor or stop the growth of the cancer cells, the chemotherapeutic agent must prevent the cells from replicating and also must interfere with the cell's ability to maintain itself.
• the agents which do this are primarily the DNA-interactive agentsuch as Cisplatin, and tubulin interactive agents.
• 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 Teniposide; and the DNA minor groove binder Plicamycin.
• the alkylating agents form covalent chemical adducts with cellular DNA, RNA. and protein molecules and with smaller amino acids, glutathione and similar chemicals.
• 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.
• a nucleophilic atom such as an amino, carboxyl, phosphate, sulfhydryl group in nucleic acids, proteins, amino acids, or glutathione.
• Typical alkylating agents include:
• Nitrogen mustards such as Chlorambucil, Cyclophosphamide, Isofamide, Mechlorethamine, Melphalan, Uracil mustard; aziridines such as Thiotepa; methanesulfonate 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;
• Nitrogen mustards such as Chlorambucil, Cyclophosphamide, Isofamide, Mechlorethamine, Melphalan, Uracil mustard
• aziridines such as Thiotepa
• methanesulfonate esters such as Busulfan
• nitroso ureas such as Carmustine, Lomustine, Streptozocin
• platinum complexes such as Cis
• DNA strand breaking agents include Bleomycin
• DNA topoisomerase II inhibitors include the following:
• Intercalators such as Amsacrine, Dactinomycin, Daunorubicin, Doxorubicin, Idarubicin, and Mitoxantrone
• nonintercalators such as Etoposide and Teniposide.
• 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, Azacytidine, Cytarabine, and Floxuridine purine antagonists include Mercaptopurine, 6-Thioguanine, Fludarabine, Pentostatin; sugar modified analogs include Cyctrabine, Fludarabine; ribonucleotide reductase inhibitors include hydroxyurea.
• folate antagonists such as Methotrexate and trimetrexate pyrimidine antagonists, such as Fluorouracil, Fluorodeoxyuridine, CB3717, Azacytidine, Cytarabine, and Floxuridine purine antagonists include Mercaptopurine, 6-Thioguanine, Fludarabine, Pentostatin
• sugar modified analogs include Cyctrabine, Fludarabine
• 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 Vinblastine, both alkaloids and Paclitaxel.
• 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.
• Hydroxyurea appears to act primarily through inhibition of the enzyme ribonucleotide reductase.
• Asparagenase is an enzyme which converts asparagine to nonfunctional aspartic acid and thus blocks protein synthesis in the tumor.
• the hormonal agents and leutinizing hormones are not usually used to substantially reduce the tumor mass. However, they can be used in conjunction with the chemotherapeutic agents or the herbicidal or fungicidal agents or their derivatives.
• Hormonal blocking 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 Diethylstilbesterol, Chlorotrianisene and Idenestrol; progestins such as Hydroxyprogesterone caproate, Medroxyprogesterone, and Megestrol; androgens such as testosterone, testosterone propionate; fluoxymesterone, methyltestosterone;
• 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 agentsuch as Tamosifen, antiandrogen agentsuch as Flutamide ; and antiaformatal agentsuch as Mitotane and Aminoglutethimide.
• Antihormonal antigens include: antiestrogenic agentsuch as Tamosifen, antiandrogen agentsuch as Flutamide ; and antiaformatal agentsuch as Mitotane and Aminoglutethimide.
• potentiators can be any material which improves or increases the efficacy of the pharmaceutical composition and/or act on the immune system.
• One such potentiator is triprolidine and its cis-isomer which are used in combination with the chemotherapeutic agents and the fungicide or herbicide.
• Triprolidine is described in US 5,1 14,951 (1992).
• Another potentiator is procodazole, 1H- 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.
• the potentiators can improve the efficacy of the herbicidal or fungicidal compounds and can be used in a safe and effective amount. These combinations can be administered to the patient or animal by oral, rectal, topical or parenteral administration.
• Antioxidant vitamins such as ascorbic acid, beta-carotene, vitamin A and vitamin E can be administered with the compositions of this invention.
• any suitable dosage can be given in the method of the invention.
• the type of compounds and the carriers and the amount will vary widely depending on the species of the warm blooded animal or human, body weight, and the virus or cancer, or tumor being treated.
• the range and ratio of the fungicidal or herbicidal agents and their derivatives and/or the chemotherapeutic agent used will depend on the type of agent and the cancer being treated.
• a dosage of 2 milligrams (mg) per kilogram (kg) of body weight and as high as 4000 mg per kg of body weight is suitable. Higher dosages, up to 6000 mg/kg can also be used.
• a lower dosage may be appropriate, i.e., from as little as about 0.01 mg/kg of body weight to as much as about 400 mg/kg body weight, although amounts up to 1500 mg/kg can be 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.
• any suitable dosage can be given in the method of the invention for treating HIV.
• the types of compounds and the carriers and the amount will vary widely depending on the species and the warm blooded animal or human body weight.
• the range and ratio of the fungicidal or herbicidal agents and their derivatives and the HIV treating agent used will depend on the type of agent.
• a dosage of as little as about 0.2 milligrams (mg) per kilogram (kg) of body weight to as much as about 4000 mg per kg of body weight is suitable. Higher dosages, up to 6000 mg/kg can also be used.
• a dosage unit may comprise a single compound or mixtures thereof with other compounds or other HIV treating compound.
• the dosage unit can also comprise diluents, extenders, carriers and the like.
• the unit may be in solid or gel form such as pills, tablets, capsules, liposomes and the like or in liquid form suitable for oral, rectal, topical, intravenous injection or parenteral administration or injection into or around the tumor.
• the herbicide or fungicide and their derivatives are typically mixed with a pharmaceutically acceptable carrier.
• This carrier can be a solid or liquid or a liposome 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, or 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 virus, cancer or tumor type that is being treated.
• Treatment may be oral, rectal, topical, parenteral or intravenous administration or by injection into the tumor and the like.
• the method of applying or administering an effective amount also varies depending on the tumor or virus being treated. It is believed that parenteral treatment by intravenous, subcutaneous, or intramuscular application of the herbicidal or fungicidal compounds, formulated with an appropriate carrier. Additional anti-viral materials can be used along with the herbicide or fungicide as well as additional cancer inhibiting compound(s) can be combined in the treatment. Diluents can be used to facilitate application or administration is the preferred method of administering the compounds to warm blooded animals.
• the herbicidal or fungicidal agent is administered in doses for 7 to about 21 days or longer if needed to inhibit the growth or to kill the virus. In the case of chronic infections, these agents may need to be given for extended periods of time, up to years.
• the herbicidal or fungicidal agent can be administered after an AZT treatment or in conjunction with other HIV therapies. These drugs can be also administered in a sequential regimen in which the HIV virus is first reduced in the body and then the herbicidal or fungicidal agent is administered to keep the virus from continuing to replicate. AZT therapy can be continued during the treatment with the herbicidal or fungicidal treatment. If the disease is in the early stages, the herbicidal or fungicidal agent can be administered to keep the virus from replicating or growing and thus slow the progress of the disease.
• the herbicidal or fungicidal agent is administered first to significantly reduce the size of the cancer or tumor mass. Usually this will take 3 to about 14 days. The reduction in the tumor or level of cancer cells will be to less than 50% of the original level. Radiation therapy may be used in conjunction with the herbicidal or fungicidal agent treatment.
• the herbicidal or fungicidal is administered. Because of the relative safety of this material, it can be administered for from 14 days to 365 days as needed to maintain its effectiveness in reducing the regrowth of the cancer.
• Chlorpropham and thiabendazole were tested in chronically infected HIV virus. These cell populations contain integrated copies of the HIV genome and constitutively produce HIV at relatively high levels (CEM-SK1, U937-SK1 and H9- SK1 from Frederick Research Center, Maryland) or are latently infected and only produce virus after stimulation with phorbol esters, tumor necrosis factor or IL6 (Ul and ACH2). Virus products was reduced in all cell lines tested and the compounds did not stimulate virus production form the latently infected cells. Reductions in virus production were observed when quantifying supernatant reverse transcriptase activity, supernatant p24 as well as intracellular p24, indicating the compounds inhibit virus production at a step of replication prior to production of intracellular proteins.
• Quantification of the infectivity of virions produced from the infected cells demonstrates reductions in the number of infectious virions in parallel with reductions in supernatant RT or p24, indicating that the compounds reduce the amount of virus produced, but not the quality of the virions.
• Inhibition of virus production from the chronically infected cells was observed at concentrations which were nontoxic to the target class.
• Thiabendazole inhibited virus production at concentrations great than l-10 ⁇ g/ml while chloropropham inhibited virus production at concentrations greater than 0.25 ⁇ g/ml.
• Toxicity to the chronically infected cells was similar to that observed with the uninfected cells.
• Evaluation of chloropropham and thiabendazole on chronically infected cells was performed by evaluation of thymidine (DNA), uridine (RNA) and leucine (protein) incorporation into cellular macromolecules. Inhibition of cellular macromolecule synthesis paralleled the toxicity of the two compounds as would be expected and did not occur at lower nontoxic concentrations found to inhibit virus production from the chronically infected cells.
• chloropropham and thiabendazole can quickly reduce the level of virus production from cell populations chronically infected with HIV-1 and the antiviral effect is maintained with prolonged compound exposure. This reduction of virus production occurs at concentrations which are nontoxic to the host cell and which have no effect on the synthesis of cellular DNA, RNA and protein.
• Chronically infected HIV cells were cultured in the presence of thiabendazole at 1 ⁇ g/ml for the first month, 5 ⁇ g/ml for the second month, 10 ⁇ g/ml for the third month, 20 and 40 ⁇ g/ml for the fourth month and 80 ⁇ g/ml for the fifth , n >d sixth months.
• Chloropropham was used at 1, 2, 4, 8 and 16 ⁇ g/ml for each of the six months.
• the cells were evaluated for virus production compared to chronically infected cells not treated with the compounds. For each of the six months of treatment experience, no change in the antiviral effect of the compounds was noticed and the toxicity of the compounds remains identical.
• the compounds remain active against HIV and that resistance was not rapidly achieved via the selection of resistant viruses or adaptation of the cells to prevent compound induced toxicity. Virus production remains totally suppressed from cultures treated with thiabendazole at 40 and 80 ⁇ g/ml and chloropropham at 8 and 16 ⁇ g/ml.
• Chronic HIV-1 infected cells Ul were derived from an acute HIV-1 infection of the promonocytic cell line, U937.
• the chronic HIV-1 infected cells, ACH-2 were derived from an acute HIV-1 infection of the T cell line, A3.01.
• PMA phorbol ester
• Both cell lines constituitively produce a small amount of HIV- 1.
• ACH-2 cell lines tend to produce more HIV-1 than Ul cells as shown by p-24 ELISA.
• either cell line is cultured in the presence of PMA there is an increase in the quantity of HIV- 1 produced as measured by the p-24 antigen ELISA.
• griseofulvin inhibited viral replication by 98% at lO ⁇ g/ml with a therapeutic index of 5.3.
• AZT a known HIV drug, also inhibited viral replication by 98% at 1 ⁇ g/ml with a therapeutic index of 12,500.
• the therapeutic index is the ratio of toxic dose of drug to efficacious dose of drug.
• MTT 3-[4,5-dimethylthiazol-2- yl] -2,5-diphenyltetrazolium bromide
• the colon tumor cells (HT29 from American Type Culture Collection (ATCC) and the breast cells (MX1 from cell lines from ATCC) were cultured in Eagle's Miminal Essential Medium with 10% fetal bovine serum.
• the lung tumor cells (A549 from ATCC cell lines) were cultured in Ham's F12 medium with 10% fetal bovine serum.
• the tumor cells were passaged and seeded into culture flasks at the desired cell densities.
• the culture medium was decanted and the cell sheets were washed twice with phosphate buffered saline (PBS).
• PBS phosphate buffered saline
• the cells were trypsinized and triturated prior to seeding the flasks. Unless otherwise indicated the cultures were incubated at 37 + 1° C in a humidified atmosphere of 5+ 1% carbon dioxide in air. The cultures were incubated until they were 50-80% confluent.
• the cells were subcultured when the flasks were subconfluent.
• the medium was aspirated from the flasks and the cell sheets rinsed twice with PBS.
• the Trypsin Solution was added to each flask to cover the cell sheet.
• the Trypsin Solution was removed after 30-60 seconds and the flasks were incubated at room temperature for two to six minutes. W en 90% of the cells became dislodged, growth medium was added.
• the cells were removed by trituration and transferred to a sterile centrifuge tube.
• the concentration of cells in the suspension was determined, and an appropriate dilution was made to obtain a density of 5000 cells/ml.
• the cells were subcultured into the designated wells of the 96-well bioassay plates (200 microliter cell suspension per well). PBS was added to all the remaining wells to maintain humidity. The plates were then incubated overnight before test article treatment.
• the absorbance at 550 nm (OD550) of each well was measured with a Molecular Devices (Menlo Park, CA) VMax plate reader.
• the mean OD550 of the solvent control wells and that of each test article dilution, and that of each of the blank wells and the positive control were calculated.
• the mean OD550 of the blank wells was subtracted from the mean of the solvent control wells, and test article wells, respectively to give the corresponding mean
• % of Control corrected mean OD550 of Test Article Dilution ⁇ j QQ corrected mean of OD550 of Solvent Control
• Dose response curves were prepared as semi-log plots with % of control on the ordinate (linear) and the test article concentration on the abscissa (logarithmic). The EC50 was interpolated from the plots for each test article.
• Adriamycin was used as a positive control. In all cases, it was more toxic than any of the test materials by one or two logs. Adriamycin is one of the more potent agents in current use and one with significant side effects. The peak plasma concentration of other, quite effective chemotherapeutic agents may be 10 to 50 times higher than that of Adriamycin.
• the EC50 is the concentration at which one half of the cells are killed.
• Test Material EC-50 Broncheal Kerotinoyle Cells Cells Fibroblasts chloropropham 0.002 >15.2 3.9 13.0 >152 64.2 glyphosate 1.59 3.54 3.09 3.21 86.1 35.8 1 : 1 mixture* 0.001 0.497 0.242 0.286 129 5.95 Adriamycin 0.015 0.0020 0.0035 0.0093 0.065 0.10
• mice are randomly selected and divided into groups for treatment. Five groups are infected with leukemia. The diseased animals are dosed for five days, off two days and then dosed for another five days and then three days off, then dosed for five days and off for two days. This dosing on and off in an irregular pattern was not an ideal regimen, but the results do show a positive benefit for the Carbendazim TM.
• mice One group of mice was treated with CytoxanTM, 2-[bis(2-chloroethyl)-amino-l- oxo-2-aza-5-oxophosphoridin, a control was dosed with canola oil and three groups were treated with various levels of CarbendazimTM, methyl -(butylcarbamoyl)-2- benzimidazole-carbamate. A control with no treatment was also used. The CarbendazimTM was dosed at three levels 4000 mg/kg, 2500 mg/kg and 1000 mg/kg. The CytoxanTM was dosed at 125 mg/kg.
• mice in the CytoxanTM group survived more than 21 days.
• the higher dose CarbendazimTM group had one mouse die on day 14, two died on days 15,16 and 17 and one each died on days 20, 21, and 22.
• the mean number of days for this group is 17.3.
• the intermediate dosage group had 2 mice die on day 14. 4 on day 15, 1 on day 16, 2 on day 19 and 1 on day 21.
• the mean number of days for this group is 16.50.
• the lowest dosage group had 2 mice die on day 12, 13, 14, and 15; and 1 died on each of days 16 and 17.
• the mean number of days for this group is 14.1.
• Carbendazim slowed tumor growth.
• MXI breast cancer tumors implanted subcutaneously under the mice skin were treated with 500 mg/kg of Carbendazim. Tumor growth was slowed by 42%.
• Carbendazim slowed tumor growth in lung A549 tumors implanted subcutaneously under the mice skin by 57% at the same dose.
• tumor growth was slowed 54% at 2500 mg/kg dose of Carbendazim.
• cytoxan In a mouse model for breast cancer cytoxan is administered to the animal reduce the tumor mass significantly.
• Carbendazim is administered to the mice at 4000, 5000, and 6000 mg/kg of body weight in a separate leg.
• the tumor continued to decrease in size and its regrowth was limited even after 180 days with the carbendazim treatment. The growth was dose dependent.
• the cytoxan treated control had tumor regrowth after 100 days; and when stimulated with estrogen at day 115 had a rapid regrowth. Even with estrogen stimulation, the carbendazim treated animals had no significant change in tumor mass.
• carbendazim is administered to the mice (at 4000, 5000, and 6000 mg/kg of body weight) that had been treated with Cytoxan. The tumor continued to decrease in size and its regrowth was limited even after 180 days.
• the effective dose of the Carbendazin is lowered in an in vivo mouse model for melanoma.
• 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%.
• mice Female CD (mice Charles River Breeding Laboratories, Portage, MI) 5 to 7 weeks old of age at the time of receipt are used. Mice are approximately 6 to 9 weeks old and weigh approximately 20 to 28 grams at the time test initiation. All mice used in the study do not vary in age by more than 10 days. The mice are housed 6 per cage with bedding. The mice are fed rodent diet 5002 (PMI, St. Louis Missouri) ad libitum. Fresh water is supplied to the mice ad libitum.
• PMI rodent diet
• Human influenza virus strain AT2/Tai wan/ 1/64 is used to challenge the mice.
• the organism is stored at approximately -70°C.
• Prior to infectious challenge a vial of frozen stock is thawed and diluted to the appropriate concentration in buffered saline solution.
• the mice are anesthetized with Halothane and the virus challenge dose is administered intra-nasally in volume of 50 microlitres.
• Test materials are administered at the concentration and volume as provided below.
• 10 mice per group receive the test articles by oral lavage.
• Saline control animals 10 receive a comparable volume of saline as compared to the test article-dosed mice.
• Test article dosing is accomplished at approximately 24 hour intervals.
• day 0 approximately 4 hours after the second dosing of test articles or saline, all mice are challenged intra-nasally with an infective dose of virus calculated to produce approximately 90% lethality. Animals are observed daily for 21 days after infectious challenge for mortality or moribundity.
• propiconazole was effective at 32 ⁇ 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.
• Propiconazole has a therapeutic index of 1 -3. (See Schleicher et al, Applied Microbiology, 23, No. 1, 113-1 16 (1972).
• 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 5 A 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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