US20070117091A1 - Anti-candida agents for the treatment of prion diseases - Google Patents

Anti-candida agents for the treatment of prion diseases Download PDF

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US20070117091A1
US20070117091A1 US10/544,748 US54474804A US2007117091A1 US 20070117091 A1 US20070117091 A1 US 20070117091A1 US 54474804 A US54474804 A US 54474804A US 2007117091 A1 US2007117091 A1 US 2007117091A1
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candida
individual
cancer
biological sample
susceptibility
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Zine Mahboubi
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MAHBOUBI HAFID
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    • 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
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • 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
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0002—Fungal antigens, e.g. Trichophyton, Aspergillus, Candida
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0005—Vertebrate antigens
    • A61K39/0007—Nervous system antigens; Prions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • 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
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
    • G01N33/56961—Plant cells or fungi
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • G01N33/6896—Neurological disorders, e.g. Alzheimer's disease
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/37—Assays involving biological materials from specific organisms or of a specific nature from fungi
    • G01N2333/39—Assays involving biological materials from specific organisms or of a specific nature from fungi from yeasts
    • G01N2333/40—Assays involving biological materials from specific organisms or of a specific nature from fungi from yeasts from Candida
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/28—Neurological disorders
    • G01N2800/2814—Dementia; Cognitive disorders
    • G01N2800/2828—Prion diseases

Definitions

  • the present invention relates to methods of treatment and diagnosis and compositions for use in such therapy.
  • the present invention relates to methods of diagnosing and treatment of prion related conditions and methods of diagnosing and treatment of cancer.
  • Prion diseases are believed to occur in most mammals. They include diseases such as scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle, transmissible mink encephalopathy (TME) in mink and chronic wasting disease (CWD) in deer and elk.
  • Prion disease of humans include sporadic and familial Creutzfeldt-Jakob disease (CJD), kuru, Fatal Familial Insomnia (FFI), Gerstmann Straussler Scheinker syndrome (GSS) and Alpers syndrome.
  • PrPsc abnormal isoform
  • PrPc normal protein
  • PrPc normal protein
  • PrPc the safe form of the protein, PrPc, is normally adopted but rarely switches to the infective prion (PrPsc). Mutations are believed to favour the switch to PrPsc with PrPsc believed to be transdominant, causing switching from PrPc to molecular aggregates of PrPsc in an exponential fashion.
  • Creutzfeldt-Jakob disease Early stages of variant Creutzfeldt-Jakob disease are dominated by psychiatric symptoms, such as dysphoria, withdrawal, anxiety, and insomnia. A significant proportion of patients also exhibit neurological symptoms within four months of clinical onset, including poor memory, pain, sensory symptoms, and unsteadiness of gait.
  • vCJD ulcerative colitis
  • Diagnosis typically involves magnetic resonance imaging to exclude other problems such as tumour.
  • a characteristic abnormality can be seen in 80 percent or more of cases which may be very useful in arriving at a diagnosis.
  • Blood and other biochemical tests are usually normal.
  • the presence of certain proteins within the cerebrospinal fluid may be helpful.
  • a brain biopsy (sampling of brain tissue) may be carried out to detect signs of spongiform change. Tonsil biopsy may also be useful.
  • TSEs such as nvCJD in humans are believed to be caused predominantly by exposure to infected meat products.
  • certain other factors may increase or decrease the likelihood of an individual becoming infected with a TSE.
  • Polymorphisms in the prion protein gene are known to affect incubation duration in humans and other animals. However, large differences in incubation times still occur even with the same amino acid sequence of the prion protein, suggesting that other genes are also involved.
  • Some genotypes of sheep often develop scrapie, e.g.
  • mice have been identified in mice (Lloyd et al, Proc Natl Acad Sci USA 2001, 98:6279-6283).
  • Mouse and human genomes are very similar, making it highly likely that human prion susceptibility alleles will be identified.
  • mice exposed to prolonged administration of Candida exhibit neurological symptoms similar to those associated with sheep scrapie.
  • subsequent analysis of the brain tissue of affected mice demonstrated the presence of prion proteins in capillary walls and intracellular spaces as well as conspicuous microcavitation in intracellular spaces especially in the frontal lobe area, suggesting that, contrary to conventional wisdom, prion related disease in mammals may be induced by exposure to Candida infection.
  • Candida may induce or accelerate the induction of the conformational change from host proteins PrPc to the prion form (PrPsc).
  • the prion proteins may be produced by Candida toxins. Therefore, in either case, by reducing the presence of Candida in a mammal, the development of prion related disease may be inhibited.
  • a method of reducing the susceptibility of an individual to prion disease comprising administering an anti-Candida agent to said individual.
  • prion disease is interchangeable with “prion related encephalopathy” and “transmissible spongiform encephalopathy” and include any disease caused by a prion agent.
  • diseases include Creutzfeldt-Jakob disease (CJD), kuru, Fatal Familial Insomnia (FFI), Gerstmann Straussler Scheinker syndrome (GSS), Alpers syndrome, scrapie, bovine spongiform encephalopathy (BSE), transmissible mink encephalopathy (TME) and chronic wasting disease (CWD).
  • the expression of infective prion proteins in the tissues of the mammal may be reduced and the likelihood of development of prion related encephalopathies reduced accordingly.
  • the presence of Candida apparently facilitates the conversion of non infective PrPc proteins to infective PrPsc prions. Therefore, as well as enabling reduction of the likelihood of a patient developing a TSE, the present invention enables treatment of a patient with a pre-existing TSE to ameliorate or cure the condition by reducing or eliminating PrPsc.
  • a method of treatment of prion disease in an individual in need thereof comprising administering an anti-Candida agent to said individual.
  • anti-Candida agents in the preparation of a medicament for the treatment of prion disease.
  • an anti- Candida agent in the preparation of a medicament to reduce the susceptibility of a mammal to prion disease.
  • the suitability of treatment with an anti-Candida agent may be assessed by screening the patient for systemic Candida infection, in particular systemic candidiasis.
  • systemic candidiasis in particular systemic candidiasis.
  • the presence of systemic candidiasis in the patient may be indicative that the patient is more likely to respond to the treatment according to the invention.
  • Tests to determine the presence of candidiasis are routine in the art and may include culture of blood or tissue, examining samples of infected tissue under the microscope, identification of circulating anti-Candida antibody, passive hemagglutination assays (PHA), counterimmunoelectrophoresis assay (CIE), or the Cand-tec test (Fung et al, (1986) J. Clin. Microbiol. 24:542-547).
  • the present invention provides a method of screening an individual for susceptibility or predisposition to prion disease comprising:
  • any suitable biological sample may be used, for example, sputum, urine, stools, cerebrospinal fluid (CSF) or blood.
  • the biological sample is a blood or CSF sample.
  • the concentration of Candida in the biological sample may thus be used to assess the likelihood of developing prion related disease.
  • a high concentration of Candida in the sample especially a systemic sample e.g. a blood or CSF sample, may be indicative of a predisposition to prion related disease compared with individuals in which Candida is not present.
  • a systemic sample e.g. a blood or CSF sample
  • the presence of agglutination at a serum dilution of 1:160 when assessed by serological agglutination tests may indicate a medium risk.
  • the presence of agglutination at a serum dilution of 1:320-1:640 may indicate a high risk.
  • agglutination at a serum dilution of 1:1280 to 1:2560 or greater dilution indicates very high susceptibility to prion disease compared with individuals in which agglutination does not occur at that dilution.
  • Such factors may include a family history of prion related disease and/or the presence or absence of a genotype conferring increased susceptibility to prion disease.
  • the present invention may be used as an aid to diagnosis of prion related disease.
  • the invention therefore provides a method of diagnosis of prion disease in an individual, the method comprising providing a biological sample from said individual and determining the presence of Candida in said sample.
  • the method may comprise the additional step of correlating the concentration of Candida detected with other symptoms which may be indicative of prion disease. This aspect of the invention may be particularly useful in assessing prion infection at an early stage.
  • a biological sample e.g. a blood or CSF sample from a patient
  • the detection of Candida in such samples obtained from patients exhibiting neurological and/or psychiatric symptoms characteristic of prion related disease may be used in a preliminary diagnosis or final diagnosis of prion related disease depending on the number and severity of other symptoms exhibited by the patient and the severity of the Candida infection detected.
  • Candida is present systemically in a patient exhibiting one or more psychiatric symptoms such as dysphoria, withdrawal, anxiety, or insomnia and/or neurological symptoms such as poor memory, pain, sensory symptoms, and unsteadiness of gait may be used in a preliminary diagnosis which optionally may be subsequently confirmed by biopsy.
  • one or more psychiatric symptoms such as dysphoria, withdrawal, anxiety, or insomnia
  • neurological symptoms such as poor memory, pain, sensory symptoms, and unsteadiness of gait
  • kits for diagnosing prion disease or susceptibility to prion disease comprising means for the determination of the presence of Candida in a biological sample.
  • the kit is a kit for use in the method of diagnosis of prion disease according to the fourth aspect of the invention.
  • the present invention may be used in the diagnosis and treatment of prion related disease.
  • Treatment may be of an existing condition or may be prophylactic.
  • treatment may be by means of vaccination.
  • a vaccine for prion disease comprising Candida antigenic material as the immunising agent.
  • the antigenic material may comprise any suitable antigenic material, natural or synthetic.
  • the antigenic material may be inactivated yeast blastospores and/or yeast blastospores that are in a swollen condition or an antigenic portion thereof.
  • a method of vaccination against prion disease comprising administering a vaccine according to the invention to a mammmal.
  • Candida antigenic material in the preparation of a vaccine for immunisation against prion disease.
  • a further aspect of the invention is an anti-Candida agent for use in the treatment of prion disease.
  • Candida infection may be associated with a number of further pathological conditions and that treatment with anti-Candida agents may diminish or cure these pathological conditions.
  • the inventor has surprisingly found that Candida infection was significant in patients with a variety of cancers. Moreover, when the patients were treated with anti-Candida agents, the cancers were cured.
  • a method of treatment of cancer in an individual in need thereof comprising administering an anti-Candida agent to said individual.
  • the cancer is uterine cancer, prostate cancer or ovarian cancer.
  • a method of reducing the susceptibility of an individual to cancer comprising administering an anti-Candida agent to said individual.
  • the invention further provides the use of anti- Candida agents in the preparation of a medicament for the treatment of cancer.
  • the invention further provides the use of an anti- Candida agent in the preparation of a medicament to reduce the susceptibility of a mammal to cancer.
  • the present invention provides a method of diagnosis of cancer in an individual, the method comprising providing a biological sample from said individual and determining the presence of Candida in said sample.
  • the method may comprise the additional step of correlating the concentration of Candida detected with other symptoms which may be indicative of cancer.
  • the present invention provides a method of screening an individual for susceptibility or predisposition to cancer comprising:
  • a method of vaccination against cancer comprising administering a vaccine according to the invention to a mammal.
  • kits for diagnosing cancer or susceptibility to cancer comprising means for the determination of the presence of Candida in a biological sample.
  • Candida antigenic material in the preparation of a vaccine for immunisation against cancer.
  • a further aspect of the invention is an anti-Candida agent for use in the treatment of cancer.
  • the invention further provides a method of treatment of a condition in an individual in need thereof comprising administering an anti-Candida agent to said individual, wherein said condition is independently one of the following: inflammatory bowel disease; multiple sclerosis; ulcerative colitis; allergy; chronic dermatological disease; hair loss; chronic dandruff; thick, whitish deposits on the tongue; chronic inflammation of the eyes; dry eyes; rapid deterioration of vision; chronic fatigue; drowsiness; exaggerated craving for sweet food; insomnia; snoring; depression; melancholy; anxiety; memory problems; weight increase or loss; constipation; diarrhea; flatulence; burning in the oesophagus and the stomach; hepatic and biliary problems; menstrual problems; inflammation of the ovaries; metritis vaginitis; frequent headaches of unknown origin which do not respond to treatment; recurrent cystitis; chronic
  • Treatment includes any regime that can benefit a human or non-human animal.
  • the treatment may be in respect of an existing condition or may be prophylactic (preventative treatment). Treatment may thus include curative, alleviation or prophylactic effects.
  • tumour of cancer includes treatment of conditions caused by cancerous growth and includes the treatment of neoplastic growths or tumours.
  • tumours that can be treated by the invention are, for instance, sarcomas, including osteogenic and soft tissue sarcomas, carcinomas, e.g., breast-, lung-, bladder-, thyroid-, prostate-, colon-, rectum-, pancreas-, stomach-, liver-, uterine-, cervical and ovarian carcinoma, lymphomas, including Hodgkin and non-Hodgkin lymphomas, neuroblastoma, melanoma, myeloma, Wilms tumor, and leukemias, including acute lymphoblastic leukaemia and acute myeloblastic leukaemia, gliomas and retinoblastomas.
  • the anti-Candida agent for use in aspects of the invention is a polyene antifungal agent or a vaccine.
  • Antifungals such as Amphotericin B, fluconazole, ketoconazole, and nystatin are the drugs most commonly used to treat candidiasis and may be used in the present invention.
  • Fluconazole is as effective as amphotericin B.
  • infections caused by C. cruzii do not respond to fluconazole and should be treated with amphotericin B; some other species of Candida are less sensitive to fluconazole than are C. albicans , particularly C. glabrata .
  • high doses of oral, or if necessary, IV fluconazole 600 mg/day or more) can be used pending species identification and results of in vitro susceptibility tests.
  • Anti-Candida agents of and for use in the present invention may be administered alone but will preferably be administered as a pharmaceutical composition, which will generally comprise a suitable pharmaceutical excipient, diluent or carrier selected dependent on the intended route of administration.
  • the present invention extends to a pharmaceutical composition for the treatment of prion disease, wherein the composition comprises at least one anti-Candida agent.
  • the present invention also extends to a pharmaceutical composition for the treatment of cancer, wherein the composition comprises at least one anti-Candida agent.
  • Anti-Candida agents of and for use in the present invention may be administered to a patient in need of treatment via any suitable route.
  • the precise dose will depend upon a number of factors, including the precise nature of the agent.
  • Some suitable routes of administration include (but are not limited to) oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) administration.
  • the active ingredient will be in the form of a parenterally acceptable aqueous solution which is pyrogen-free and has suitable pH, isotonicity and stability.
  • a parenterally acceptable aqueous solution which is pyrogen-free and has suitable pH, isotonicity and stability.
  • isotonic vehicles such as Sodium Chloride Injection, Ringer's Injection, Lactated Ringer's Injection.
  • Preservatives, stabilisers, buffers, antioxidants and/or other additives may be included, as required.
  • compositions for oral administration may be in tablet, capsule, powder or liquid form.
  • a tablet may comprise a solid carrier such as gelatin or an adjuvant.
  • Liquid pharmaceutical compositions generally comprise a liquid carrier such as water, petroleum, animal or vegetable oils, mineral oil or synthetic oil. Physiological saline solution, dextrose or other saccharide solution or glycols such as ethylene glycol, propylene glycol or polyethylene glycol may be included.
  • composition may also be administered via microspheres, liposomes, other microparticulate delivery systems or sustained release formulations placed in certain tissues including blood.
  • sustained release carriers include semipermeable polymer matrices in the form of shared articles, e.g. suppositories or microcapsules.
  • Implantable or microcapsular sustained release matrices include polylactides (U.S. Pat. No.
  • Liposomes containing the polypeptides are prepared by well-known methods: DE 3,218, 121A; Epstein et al, PNAS USA, 82: 3688-3692, 1985; Hwang et al, PNAS USA, 77: 4030-4034, 1980; EP-A-0052522; E-A-0036676; EP-A-0088046; EP-A-0143949; EP-A-0142541; JP-A-83-11808; U.S. Pat. Nos. 4,485,045 and 4,544,545. ordinarily, the liposomes are of the small (about 200-800 Angstroms) unilamellar type in which the lipid content is greater than about 30 mol. % cholesterol, the selected proportion being adjusted for the optimal rate of the polypeptide leakage.
  • compositions are preferably administered to an individual in a “therapeutically effective amount”, this being sufficient to show benefit to the individual.
  • the actual amount administered, and rate and time-course of administration, will depend on the nature and severity of what is being treated. Prescription of treatment, e.g. decisions on dosage etc, is ultimately within the responsibility and at the discretion of general practitioners and other medical doctors, and typically takes account of the disorder to be treated, the age, sex, weight and condition of the individual patient, the active ingredient being administered, the site of delivery, the method of administration and other factors known to practitioners.
  • the anti- Candida agent is fluconazole, 400 to 800 mg/day (po, or if necessary, IV) may be used.
  • Vaccines of and for use in the present invention may be prepared using any suitable Candida antigenic material.
  • the antigenic material may be natural, recombinant or synthetic.
  • the antigenic material is or is derivable from inactivated yeast blastospores and/or yeast blastospores that are in a swollen condition or an antigenic portion thereof.
  • vaccines which contain Candida antigenic material as active ingredient(s)
  • Such vaccines may be prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for solution in, or suspension in, liquid prior to injection may also be prepared.
  • the preparation may also be emulsified, or the protein encapsulated in liposomes.
  • the active immunogenic ingredients are often mixed with excipients which are pharmaceutically acceptable and compatible with the active ingredient. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol, or the like and combinations thereof.
  • the vaccine may contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, and/or adjuvants which enhance the effectiveness of the vaccine.
  • auxiliary substances such as wetting or emulsifying agents, pH buffering agents, and/or adjuvants which enhance the effectiveness of the vaccine.
  • adjuvants which may be effective include but are not limited to: aluminium hydroxide, N-acetyl-muramyl-L-threonyl-D-isoglutamine (thr-MDP), N-acetyl-nor-muramyl-L-alanyl-D-isoglutamine (CGP 11637, referred to as nor-MDP),N-acetylmuramyl-L-alanyl-D-isoglutaminyl-L-alanine-2-(1′-2′-dipalmitoyl-sn-glycero-3-hydroxyphosphoryloxy)-ethylamine (CGP 19835A,
  • adjuvants and other agents include aluminium hydroxide, aluminium phosphate, aluminium potassium sulphate (alum), beryllium sulphate, silica, kaolin, carbon, water-in-oil emulsions, oil-in-water emulsions, muramyl dipeptide, bacterial endotoxin, lipid X, Corynebacterium parvum (Propionobacterium acnes), Bordetella pertussis , polyribonucleotides, sodium alginate, lanolin, lysolecithin, vitamin A, saponin, liposomes, levamisole, DEAE-dextran, blocked copolymers or other synthetic adjuvants.
  • Such adjuvants are available commercially from various sources, for example, Merck Adjuvant 65 (Merck and Company, Inc., Rahway, N.J.) or Freund's Incomplete Adjuvant and Complete Adjuvant (Difco Laboratories, Detroit, Mich.).
  • adjuvants such as Amphigen (oil-in-water), Alhydrogel (aluminium hydroxide), or a mixture of Amphigen and Alhydrogel are used. Only aluminium hydroxide is approved for human use.
  • the proportion of immunogen and adjuvant can be varied over a broad range so long as both are present in effective amounts.
  • aluminium hydroxide can be present in an amount of about 0.5% of the vaccine mixture (Al 2 O 3 basis).
  • the vaccines are formulated to contain a final concentration of immunogen in the range of from 0.2 to 200 mu g/ml, preferably 5 to 50 mu g/ml, most preferably 15 mu g/ml.
  • the vaccine may be incorporated into a sterile container which is then sealed and stored at a low temperature, for example 4° C. or it may be freeze-dried. Lyophilisation permits long-term storage in a stabilised form.
  • the vaccines are conventionally administered parenterally, by injection, for example, either subcutaneously or intramuscularly.
  • Additional formulations which are suitable for other modes of administration include suppositories and, in some cases, oral formulations.
  • suppositories traditional binders and carriers may include, for example, polyalkylene glycols or triglycerides; such suppositories may be formed from mixtures containing the active ingredient in the range of 0.5% to 10%, preferably 1% to 2%.
  • Oral formulations include such normally employed excipients as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, and the like.
  • compositions take the form of solutions, suspensions, tablets, pills, capsules, sustained release formulations or powders and contain 10% to 95% of active ingredient, preferably 25% to 70%.
  • the lyophilised material may be reconstituted prior to administration, e.g. as a suspension. Reconstitution is preferably effected in buffer.
  • Capsules, tablets and pills for oral administration to a patient may be provided with an enteric coating comprising, for example, Eudragit “S”, Eudragit “L”, cellulose acetate, cellulose acetate phthalate or hydroxypropylmethyl cellulose.
  • FIG. 1 shows a treatment mouse brain section stained with Hematoxylin-Eosin, magnified 20 ⁇ . Arrows indicate microcavitations.
  • FIG. 2 shows a treatment mouse brain section stained with Hematoxylin-Eosin, magnified 40 ⁇ . Arrows indicate microcavitations.
  • FIG. 3 shows a treatment mouse brain section stained with Hematoxylin-Eosin, magnified 40 ⁇ . Arrows indicate microcavitations.
  • FIG. 4 shows a treatment mouse brain section stained with Hematoxylin-Eosin, magnified 40 ⁇ . Arrows indicate lipofuscin (pink colouration).
  • FIG. 5 shows a treatment mouse brain section stained with Hematoxylin-Eosin, magnified 40 ⁇ .
  • FIG. 6 shows a treatment mouse brain section stained with Hematoxylin-Eosin, magnified 20 ⁇ .
  • FIG. 7 shows immunhistochemistry results from a treatment mouse brain section using the 3F4 antibody to identify prion protein. Magnification 20 ⁇ . Arrows indicate prions (pinkish colouration).
  • FIG. 8 shows immunohistochemistry results from a treatment mouse brain section using the 3F4 antibody to identify prion protein. Magnification 40 ⁇ .
  • FIG. 9 shows immunohistochemistry results from a treatment mouse brain section using the 3F4 antibody to identify prion protein. Magnification 40 ⁇ . Arrows indicate prions (pinkish colouration).
  • FIG. 10 shows immunohistochemistry results from a treatment mouse brain section using the 3F4 antibody to identify prion protein. Magnification 20 ⁇ .
  • FIG. 11 shows immunohistochemistry results from a treatment mouse brain section using the method antibody to identify GFAP. Magnification 10 ⁇ . Arrows indicate degenerated nerve cells.
  • FIG. 12 shows a treatment mouse brain section stained with Cresyl, Magnification 20 ⁇ .
  • FIGS. 13 to 19 show slides of brain sections stained with PAS.
  • the sections correspond to those stained with Hematoxylin-Eosin and used for immunohistochemistry as shown in FIGS. 1 to 11 (Magnification ⁇ 20).
  • the PAS colouration clearly identifies Candida in the brain sections.
  • FIG. 20 shows immunohistochemistry results from a treatment mouse brain section (white matter) using the BE 12 monoclonal antibody to identify prion protein. Magnification 40 ⁇ .
  • FIG. 21 shows immunohistochemistry results from a treatment mouse brain section (hippocampus) using the BE 12 monoclonal antibody to identify prion protein. Magnification 40 ⁇ .
  • FIG. 22 shows immunohistochemistry results from a treatment mouse brain section (GLIA) using the BE 12 monoclonal antibody to identify prion protein. Magnification 40 ⁇ .
  • FIG. 23 shows immunohistochemistry results from a treatment mouse brain section (truncus cerebri) using the BE 12 monoclonal antibody to identify prion protein. Magnification 20 ⁇ .
  • FIG. 24 shows immunohistochemistry results from a treatment mouse brain section (truncus cerebri) using the BE 12 monoclonal antibody to identify prion protein. Magnification 40 ⁇ .
  • FIG. 25 shows immunohistochemistry results from a treatment mouse brain section (truncus cerebri) using the BE 12 monoclonal antibody to identify prion protein. Magnification 40 ⁇ .
  • FIG. 26 shows a goose oesophagus section stained with Hematoxylin-Eosin.
  • FIG. 27 shows a goose ovary section stained with Hematoxylin-Eosin.
  • FIG. 28 shows a goose ovary section stained with Hematoxylin-Eosin.
  • FIG. 29 shows a rabbit lung section stained with Hematoxylin-Eosin.
  • FIG. 30 shows a rabbit oesophagus section stained with Hematoxylin-Eosin.
  • FIG. 31 shows a rabbit ovary section stained with Hematoxylin-Eosin.
  • FIG. 32 shows a rabbit ovary section stained with Hematoxylin-Eosin.
  • FIG. 33 shows a rabbit tongue section stained with Hematoxylin-Eosin.
  • FIG. 34 shows a pig brain section stained with Hematoxylin-Eosin.
  • FIG. 35 shows a pig kidney section stained with Hematoxylin-Eosin.
  • FIG. 36 shows a pig ovary section stained with Hematoxylin-Eosin.
  • mice 5 females and 3 males, one of which was used as control
  • All mice were White lab specific pathogen free mice from the National Institute of Animal Health, Department of Virology, Budapest, Hungary. Normal lab nutrition for mice was administered ad-libitum.
  • Hungarian and Argentinian strains of Candida parapsillosis and Candida guilliermondii were individually cultured in culture medium (Sabouraud Dextrose agar with penicillin 30 iu, Streptomycin 40 mg. per litre, sterilised in autoclave.
  • the cultured cells were cultivated at 37° C. for a period of 72 hrs, then gathered by washing the plates with physiological solution, centrifuged and resuspended in physiological solution.
  • the Candida strains were administered to the treatment mice orally. The frequency of administration was once a week. 51 ⁇ 10 4 of cells per ml per Kg. of each animal's net weight was added to its drinking water. The strain of Candida used was alternated every two weeks starting with the Hungarian C . parapsillosis followed by Hungarian C. guillermondii , followed by Argentinian C. parapsillosis followed by C. quillermondii etc. A control mouse received no Candida.
  • mice Following mating, white mice delivered offspring of different colour (brown). The inventors believe that this indicates that the Candida may have some mutagenic effect on the DNA of the mice.
  • mice After 15 months, the last surviving mice showed serious symptoms of sheep scrapie with lesion of the skin in addition to symptoms already described in other mice used throughout the same study.
  • mice were sacrificed (one male, one female) for preparation of samples for histological analysis.
  • FIGS. 7, 8 , 9 and 10 Marked presence of prion proteins in the capillary walls was observed in every section analysed using the 3F4 antibody (see FIGS. 7, 8 , 9 and 10 . Arrows indicate examples of prion proteins in FIGS. 7 and 9 ). Besides these findings, conspicuous microcavitation can be observed in the intracellular space especially in the frontal lobe area which does not seem to be an artefact (see FIGS. 1, 2 , 3 , 4 , 5 , 6 . Arrows indicating microcavitations are shown in FIGS. 1, 2 and 3 ).
  • mice treated with Candida according to the schedule described above showed signs of neurological symptoms consistent with scrapie.
  • Post mortem brain sections demonstrated cavitation characteristic of prion related disease.
  • the presence of prion proteins was confirmed by immunofluorescence using the prion protein specific monoclonal antibody 3F4.
  • the preparation begins with a four week fermentation technique using a 10 litre fermentor of (New Brunswick).
  • the culture medium used is: sabouraudextrose bouillon (SDB) pepton 10 gr. distilled water 100 ml; sterilised in autoclave.
  • Candida strain for example C. albicans, C. parpsilosis, C. tropicalis, C. guillermondii, C. glabrata, C. torulopsis, C. keyfir etc.
  • Fermentation conditions should be a culture temperature of 37° C. with a mixture of filtered air (4 litres per minute for a period of 10 minutes), stirred three times a day at the rate of 50 rounds per minute followed with an addition of 250 ml SDB once a day. The duration of the whole fermentation procedure lasts for four weeks.
  • the medium is then centrifuged and the cell mass recovered.
  • the cell mass is then washed in physiological solution and centrifuged three times and utilised for the production of metabolic antigens.
  • antigens are then used for the fabrication of diagnostic tests, ELISA as well as for vaccination and treatment.
  • the Supernatant is discarded and the pellet is resuspended in 10 ml of ethanol prior to further centrifugation at 3000 ⁇ g for 5 minutes.
  • the supernatant is again discarded and the pellet resuspended in 5 ml of distilled water and kept at a constant 4° C. for 10 to 12 hrs.
  • the solution is then sonicated in a Branson cell disrupter in an ice bath for 2 hrs at 150 w with 15 min bursts.
  • the sonicated material is then centrifuged at 4° C. at 20000 g for 60 nm.
  • the supernatant material is used as the antigen.
  • the concentration of proteins is analysed by photometric absorption at 280/260 nm.
  • the antigen is lyophilised.
  • Serum samples Before starting the test, Serum samples have to be diluted 1:200 dilution
  • the plate is incubated in a humid chamber at 37° C. for 30 min.
  • the bottom of the cavities should not be in touch with materials that conduct temperature well (ie—metal or wet paper).
  • the ELISA plate should not be placed in a cold moist chamber which is heated to 37° C. during the incubation.
  • the chamber must already be adapted to 37° C. prior to the incubation
  • Decant or aspirate all microwells into a waste container with disinfectant Ensure complete removal of the liquid from the microwells by tapping the inverted plate onto absorbent paper, then wash all wells 4 times with 300 ⁇ l of washing buffer. Be sure to remove residual washing solution by firmly tapping the inverted microwells on absorbent paper after single washing steps.
  • DAKO Horseradish peroxide-coupled polyvalent anti-human goat immunglobulin
  • Tetramethybenzidine 10 mg Tetramethybenzidine in 200 ml Citrate buffer
  • Perhydrole 30% H 2 O
  • the reaction is stopped by adding 100 ⁇ l of stopping solution (1.5 N sulphuric acid solution) to each well.
  • stopping solution 1.5 N sulphuric acid solution
  • Candidiasis is detected serologically using the agglutination test developed by Hasenclever and Mitchell J. Bacteriol 0.82:570-573. This test detects antibodies primarily to the mannan component of Candida cell wall. Alternatively, candidiasis may be diagnosed using the precipitin test (Taschdjian, et al 1972. Am.J. Clin.Path.57:195-205; Taschdjian, et al, 1969-70 Sabouraudia 0.7:110-117).
  • the antigens commonly used to detect Candida Precipitin are derived from the Cytoplasm of sonically or mechanically disrupted Candida cells. It has been claimed that antibodies to the Cytoplasmic Antigens occur only in systemic disease.
  • the preparation begins with the fermentation technique using a 10 litre fermentor Type New Brunswick for 48 hours.
  • the culture media consists of:
  • the culture media is the inoculated with Candida strain.
  • the fermentation parameter is at a culture temperature of 37° C. with addition of filtered air (4 litres per min. for 10 min.) three times a day. Stir three times a day at the rate of 50 round per min. Then addition of 250 ml of SDB twice daily.
  • the duration of the whole fermentation procedure lasts for 48 hrs.
  • centrifugation is performed, followed by recuperation of cell mass, which is then washed in physiological water and centrifuged (2000 g 30 min), three times and utilised for the production of the Immunisation Vaccine.
  • Protein concentration 0.7% LOWRY 1 mg pr dose The judicious use of adjuvants is preferable to induce a strong antibody response to soluble Antigens.
  • Most adjuvants incorporate two components. One is a substance designed to form a deposit protecting the Antigen from rapid catabolism. The two traditional methods of forming a deposit are: the use mineral oils or Aluminum hydroxide precipitates (Glennyetal) with mineral oils, such as those used in Frund's adjuvant, the immunogen is prepared in water-in-oil emulsion.
  • the experiment lasted 6 months, during which the animals received a solution of a Candida albicans, Candida parapsilosis and Candida guilliermondii culture broth under the following conditions:
  • FIGS. 34, 35 and 36 show pig brain, kidney and ovary sections and demonstrate the presence of Candida (pink colourations) as well as agglomeration of Granuloma.
  • FIGS. 29, 30 , 31 , 32 and 33 show rabbit lung, oesophagus, ovary, ovary and tongue sections and demonstrate the presence of Candida (pink colourations) as well as agglomeration of Granuloma.
  • FIGS. 26, 27 and 28 show oesophagus, ovary and ovary sections respectively, and demonstrate the presence of Candida (pink colourations) as well as agglomeration of Granuloma.
  • the inventor has performed many serological tests on patients suffering from various illnesses and particularly from different types of cancer.
  • the inventor has shown that, in many of the patients who tested positive for Candida in the serological tests, after antimycotic treatments, a full recovery was observed, with complete disappearance of the tumours in the case of the patients affected by cancer.
  • the patient was treated with Nizoral (1 tablet 2 ⁇ day for two weeks, then 1 tablet a day for 30 days).
  • the patient was treated with Orungal, 100 mg capsules, 1 ⁇ 1 caps a day for 1 month.
  • the patient was treated with Orungal, capsule 100 mg, 1 ⁇ 1 caps a day for 60 days.
  • the patient was treated with Diflucan, 100 mg 1 ⁇ 1 capsule a day. For 1 month.
  • the patient was treated with Orungal, 100 mg 1 ⁇ 1 caps a day, for 28 days.
  • Patient 6 Female with cancer of the ovary with liver metastasis.
  • the patient was treated with Diflucan, 100 mg 1 capsule a day. For 30 days
  • Patient 7 Male with prostate cancer
  • the patient was treated with Nizoral (1 tablet 2 ⁇ day for two weeks, then 1 tablet a day for 30 days.
  • the inventor has also demonstrated successful treatment of the following Candida related symptoms with anti-Candida agents:

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US9180173B2 (en) * 2013-12-09 2015-11-10 Stephanie D. Neider Methods of treating psoriasis using candida antigen

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US10772903B2 (en) * 2016-09-12 2020-09-15 Cedars-Sinai Medical Center Targeting fungi in combination with cancer therapy

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US5372935A (en) * 1993-06-29 1994-12-13 Pearl Medical Science, Inc. Detection of candida
US5578309A (en) * 1994-05-23 1996-11-26 The Research And Development Institute, Inc. Candida albicans phosphomannoprotein adhesion as a vaccine
US5707816A (en) * 1997-02-06 1998-01-13 Immunosciences Lab, Inc. Immunological cross reactivity between Candida and human tissue or food antigens
US6488929B2 (en) * 1994-05-23 2002-12-03 Montana State University Candida albicans phosphomannan complex as a vaccine
US6875422B2 (en) * 2000-10-20 2005-04-05 Yuusuke Nonomura Oral treatment/care agent

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US5908855A (en) * 1996-07-16 1999-06-01 The Procter & Gamble Company Compositions for treating viral infections

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US5372935A (en) * 1993-06-29 1994-12-13 Pearl Medical Science, Inc. Detection of candida
US5578309A (en) * 1994-05-23 1996-11-26 The Research And Development Institute, Inc. Candida albicans phosphomannoprotein adhesion as a vaccine
US6488929B2 (en) * 1994-05-23 2002-12-03 Montana State University Candida albicans phosphomannan complex as a vaccine
US5707816A (en) * 1997-02-06 1998-01-13 Immunosciences Lab, Inc. Immunological cross reactivity between Candida and human tissue or food antigens
US6875422B2 (en) * 2000-10-20 2005-04-05 Yuusuke Nonomura Oral treatment/care agent

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9180173B2 (en) * 2013-12-09 2015-11-10 Stephanie D. Neider Methods of treating psoriasis using candida antigen

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