WO2000016794A1 - Neuro-immunophillines pour radioprotection neuronale selective - Google Patents

Neuro-immunophillines pour radioprotection neuronale selective Download PDF

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Publication number
WO2000016794A1
WO2000016794A1 PCT/US1998/020040 US9820040W WO0016794A1 WO 2000016794 A1 WO2000016794 A1 WO 2000016794A1 US 9820040 W US9820040 W US 9820040W WO 0016794 A1 WO0016794 A1 WO 0016794A1
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WIPO (PCT)
Prior art keywords
neuroimmunophilin
ionizing radiation
radiation
neurons
brain
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PCT/US1998/020040
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English (en)
Inventor
Marcus Keep
Eskil Elmer
Original Assignee
Marcus Keep
Eskil Elmer
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Filing date
Publication date
Priority to APAP/P/2001/002113A priority Critical patent/AP2001002113A0/en
Priority to NZ510739A priority patent/NZ510739A/en
Priority to BR9816047-8A priority patent/BR9816047A/pt
Priority to CA002345378A priority patent/CA2345378A1/fr
Priority to IL14212098A priority patent/IL142120A0/xx
Priority to EP98948530A priority patent/EP1115412A4/fr
Application filed by Marcus Keep, Eskil Elmer filed Critical Marcus Keep
Priority to AU95081/98A priority patent/AU766095B2/en
Priority to CN98814297A priority patent/CN1322136A/zh
Priority to PCT/US1998/020040 priority patent/WO2000016794A1/fr
Priority to JP2000573755A priority patent/JP2002526453A/ja
Publication of WO2000016794A1 publication Critical patent/WO2000016794A1/fr
Priority to HK02101925.6A priority patent/HK1040617A1/zh

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A61K38/13—Cyclosporins
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0038—Radiosensitizing, i.e. administration of pharmaceutical agents that enhance the effect of radiotherapy
    • 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
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • 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

Definitions

  • Both cyclosporin and FK506 are neuroimmunophilin ligands, that is they bind specifically to neuroimmunophilins.
  • the neuroimmunophilins were previously named after their respective binding ligand i.e. they were defined as cyclophilins and FK- binding proteins. Because the effect of cyclosporin and FK506 on the immune system is so robust and well known in clinical transplantation, the cyclophilin and FK-binding protein families together became known as immunophilins. When it was discovered that neurons were 20 times more enriched in immunophilins than immune cells, the name became neuroimmunophilins. In addition, it was realized that neuroimmunophilin ligands were neuroprotective.
  • neuroimmunophilins could be exploited to improve the safety and efficacy of radiation treatments of the brain, or radiation fields or rays that pass through the brain.
  • the crucial realization is that neurons are highly enriched in neuroimmunophilins and that the glia or support cells of the brain contain little or no neuroimmunophilin protein.
  • Neuroimmunophilin ligands are herein defined as all compounds that bind to the neuroimmunophilins.
  • Neuroimmunophilin ligands include but are not limited to the immunosuppressants cyclosporin A, cyclosporins, FK506, all their immunosuppressant and non-immunosuppressant analogs, derivatives and variants, as well as small molecule immunophilin ligands developed by the companies Guilford Pharmaceuticals Inc. and Vertex Pharmaceuticals Inc. and described in other patent applications.
  • Treatment medication or treatment medications will be defined as a medicament comprising as its active ingredients not less than one neuroimmunophilin ligand, and may contain a mixture of two or more similar or different neuroimmunophilin ligands.
  • neuroimmunophilin ligands include cyclosporins, FK506 and the small FK-binding protein neuroimmunophilins ligands ("FKBP-neuroimmunophilin ligands") of Guilford Pharmaceuticals Inc. and Vertex Pharmaceuticals Inc.
  • Cyclosporin A is an immunosuppressive drug.
  • the above mentioned treatment medication has already been described, in United States Pat. No. 4,117,118 and numerous patents since, which relate to its production, formulation and immunosuppressive properties.
  • Cyclosporin A is a product of the fungus Tolypocladium Inflatum Gams. It is a cyclic poly-amino acid molecule, consisting of 11 amino acids. One of the amino acids is unique for cyclosporin A, a ⁇ -hydroxyamino acid called butenyl-methyl-threonin (MeBmt). The molecular weight is 1202.6 and the chemical composition is C 62 H ⁇ nN ⁇ O 12 .
  • the molecule is highly lipophilic, and therefore virtually insoluble in water.
  • the bioavailability after an oral dose varies between 8 and 60% depending in part on the bile flow.
  • the drug is absorbed mainly in the small intestine.
  • the drug is transported in the blood within red blood cells to about 58%, and the remaining approximately 10-20% in leukocytes, and 33% bound to plasma proteins.
  • cyclosporin A is bound to high-density lipoprotein, low-density lipoproteins, very-low density lipoproteins and a small fraction to albumin. A very small fraction is free in plasma.
  • the drug undergoes extensive metabolism, mainly in the liver by the cytochrome P450 system.
  • cyclosporin A There are at least 30 known metabolites of cyclosporin A, with various chemical modifications, such as hydroxylation, demethylation, oxidation and epoxide formations.
  • variants of cyclosporin A differing for example in one amino acid, which have similar pharmacological properties.
  • cyclosporin A and its metabolites do not pass the blood-brain barrier.
  • the glycoprotein-p transporter is poisoned, or the blood-brain barrier is disrupted, cyclosporin is able to cross it and come into contact with neurons.
  • Several analogs of cyclosporin are able to readily cross the blood-brain barrier.
  • analogs of cyclosporin are not imrnunosuppressants.
  • analogs of cyclosporin that both readily cross the blood-brain barrier and are not imrnunosuppressants.
  • cyclosporins This entire family of cyclosporins, all derivatives, variants, amino acid variants, metabolites, including variations of mono-, di- and trihydroxylates, N-demethylates, aldehydes, carboxylates, conjugates, sulphates, glucuronides, intramolecular cyclizations and those without a cyclic structure as well as shorter peptides and amino acids and their derivatives and salts with or without immunosuppressive properties and whether able to cross the blood brain barrier or not will hereinafter be referred to as cyclosporins. Cyclosporins will hereinafter be referred to as "neuroimmunophilin ligand or ligands" based on their affinity and binding to the group of neuroimmunophilins called cyclophilins.
  • the present invention also discloses treatment medications of the family of cyclosporins and all known salts, variants, amino acid variants, derivatives, metabolites and their salts and derivatives for use in treatments of the conditions listed below, as well as the use of such treatment medications for the treatment of such conditions.
  • This includes cyclosporin A, cyclosporin C, cyclosporin D, cyclosporin G.
  • this includes all products of the fungus Tolypocladium Inflatum Gams.
  • Some known metabolites of cyclosporin A include the following : (according to Hawk's Cay nomenclature) AMI, AM9, AMlc, AM4N, AM19, AMlc9, AMlc4N9, AM1A, AM1A4N, AMlAc, AM1AL, AMI Id, AM69, AM4N9, AM14N, AM14N9, AM4N69, AM99N, Dihydro- CsA, Dihydro-CsC, Dihydro-CsD, Dihydro-CsG, Ml 7, A lc-GLC, sulphate conjugate of cyclosporin, BH1 la, BH15a, B, G, E, (and with come overlap with the Hawk's above, according to Maurer's nomenclature) Ml, M2, M3, M4, M5, M6, M7, M8, M9, M10, Mi l, M12, M13, M14, M15, M16, M17, M18
  • metabolites of cyclosporin G include GM1, GM9, GM4N, GMlc, GMlc9, and GM19.
  • Modified cyclosporins include modified C-9 amino acid analogs, modified 8-amino acid analogs, modified 6-position analogs containing Me Ala or MeAbu residue, and SDZ 209-313, SDZ-205-549, SDZ-033-243, SDZ IMM 125 and SDZ-PSC-833.
  • FK506 is a macrolide compound, known and disclosed in European Patent Publication No. 0184162 and other documents.
  • the known macrolide compounds include FR- 900506, FR-900520, FR-900523 and FR-900525 isolated from microorganisms of the genus Streptomyces like Streptomyces tsukubensis No. 9993 and their related compounds.
  • Derivatives include ascomycin (C21-ethyl-FK506), C18-OH-ascomycin, 9-deoxo-31-o-demethylFK506, 31-o-demethylFK506, C32-indolyl-ascomycin, A- 119435, L-683,590, L-685,818, and L-688,617. These compounds were indicated as useful in treating rejection in transplantation, autoimmune diseases, and in US Patent 5,648,351 as useful for preventing or treating cerebral ischemic disease. FK506 and its derivative macrolide compounds and salts with or without immunosuppressive properties will hereinafter be referred to as FKs.
  • FKs will hereinafter be referred to as a "neuroimmunophilin ligand or ligands" based on their affinity and binding to the group of neuroimmunophilins called FK-binding proteins, especially FKBP12, or other FKBPs.
  • FKBP-type neuroimmunophilin ligands will hereinafter be refereed to as a "neuroimmunophilin ligand or ligands" based on their affinity and binding to the group of neuroimmunophilins called FK-binding proteins, especially FKBP12, or other FKBPs.
  • cyclophilin-type neuroimmunophilin ligands will hereinafter be referred to as "neuroimmunophilin ligand or ligands" based on their affinity and binding to the group of neuroimmunophilins called cyclophilins.
  • a dose of ionizing radiation causes damage and kills cells primarily by ionizing water or oxygen into toxic hydroxyl, oxygen and/or other species of free radicals. These radicals then damage or kill the cell by their high reactivity against cell proteins, membranes and DNA.
  • the free radicals themselves can induce a mitochondrial permeability transition which incapacitates a cells ability to make ATP to carry out its normal functions and causes the mitochondria to release mitochondrial enzymes which activate nuclear caspases and other enzymes that cause apoptosis, or programmed cell death.
  • Cyclosporins but not FK506, nor the FKBP-type neuroimmunophilin ligands, blocks the formation of this mitochondrial transition and thereby blocks apoptosis. This will make cyclosporins most likely the most effective of the neuroimmunophilin ligands, though a mixture with one or more other ligands may have a synergistic effect.
  • Ionizing radiation is frequently used in the medical field to treat disease.
  • Primary brain rumors are often treated with radiotherapy, and are radiated with a wide field including much or all of the brain with an X-ray source such as a linear accellerator over one or many daily sessions typically over eight weeks.
  • the radiation is from gamma rays or proton and particle beam. This radiation slows the growth of the brain tumor, but also kills normal neurons. Cystic brain tumors sometimes have radioactive liquids instilled into them. Sometimes radioactive pellets are temporarily or permanently implanted.
  • tumors of the head that are adjacent to brain such as pituitary tumors, meningiomas and craniopharyngiomas.
  • radiosensitive vascular malformations in the brain There are disorders of the brain which can be helped with partial or complete lesions of small brain structures including Parkinson's disease, epilepsy, obsessive compulsive disorder and trigeminal neuralgia, in which radiation passes through normal brain.
  • Radiosurgery uses either gamma rays or X-rays usually administering a high dose precisely localized in one session, with radiation passing through normal brain enroute and beyond the target structure.
  • Tumors in the body such as squamous cell, laryngeal, lung, breast, renal, or prostate cancers are often treated with radiation by linear accellerator, or implantation of radioactive pellets.
  • the radiation fields treating these cancers sometimes include neural structures of the brain, spinal cord or peripheral nerves.
  • Administration of the treatment medication may be by any suitable route including oral, sublingual, buccal, nasal, inhalation, parenteral (including intraperitoneal, intraorgan, subcutaneous, intradermal, intramuscular, intra-articular, venous (central, hepatic or peripheral), lymphatic, cardiac, arterial, including selective or superselective cerebral arterial approach, retrograde perfusion through cerebral venous system, via catheter into the brain parenchyma or ventricles), direct exposure or under pressure onto or through the brain or spinal tissue, or any of the cerebrospinal fluid ventricles, injections into the subarachnoid, brain cisternal, subdural or epidural spaces, via brain cisterns or lumbar puncture, intra and peri-ocular instillation including application by injection around the eye, within the eyeball, its structures and layers, as well as via enteral, bowel, rectal, vaginal, urethral or bladder cisternal.
  • parenteral including intraperitoneal, intraorgan, subcutaneous
  • the preferred route may vary depending on the condition of the patient.
  • the invention is administration of the treatment medication via any means with purposeful disruption of brain or spinal parenchyma, or disrupting the blood-brain barrier via mechanical, thermal, cryogenic, chemical, toxic, receptor inhibitor or augmentor, p- glycoprotein transporter poisoning, inhibition or saturation, osmotic, charge altering, radiation, photon, electrical or other energy or process.
  • This invention includes all methods of administering treatment medications along with all methods of opening, bypassing or disrupting the blood-brain barrier in combination, simultaneously or in sequence to get the treatment medication in contact with nervous tissues in order for it to exert neuro-radioprotection.
  • This invention includes the possibility of the timing and sequence of delivery of treatment medications to include pre-treatment and post-treatment, as well as simultaneous with treatment.
  • the treatment medication While it is possible for the treatment medication to be administered alone, it is preferred to present it as part of a pharmaceutical formulary drug.
  • the formulary drug of this invention comprise at least one administered treatment medication as defined above together with one or several appropriate carriers thereof and possibly other pharmaceutical treatment medications.
  • the carriers must be appropriate in that they can readily coexist with the other agents of the formulary drug and are not detrimental to the receiver thereof.
  • This treatment medication combined, as described in this paragraph, with other appropriate agents common to the art, is defined herein as the formulary drug.
  • the formulary drug includes those suitable for administration by the routes including oral, sublingual, buccal, nasal, inhalation, parenteral (including intraperitoneal, intraorgan, subcutaneous, intradermal, intramuscular, intra-articular, venous (central, hepatic or peripheral), lymphatic, cardiac, arterial, including selective or superselective cerebral arterial approach, retrograde perfusion through cerebral venous system, via catheter into the brain parenchyma or ventricles), direct exposure or under pressure onto or through the brain or spinal tissue, or any of the cerebrospinal fluid ventricles, injections into the subarachnoid, brain cisternal, subdural or epidural spaces, via brain cisterns or lumbar puncture, intra and peri-ocular instillation including application by injection around the eye, within the eyeball, its structures and layers, as well as via enteral, bowel, rectal, vaginal, urethral or bladder cisternal.
  • parenteral including intraperitoneal, intraorgan, sub
  • the formulary drug may be distributed and made available in convenient unit dose form such as capsules and ampoules, containing the treatment medication of the invention, and may be manufactured and distributed by any of the methods known to the pharmaceutical arts.
  • the formulary drug can also contain other usual agents of the art relating to the type of formulary drug produced.
  • the formulary drug may, by example, take the configuration of suspensions, solutions and emulsions of the treatment medication in lipid, non-aqueous or aqueous dilutents, solvents, dissolving agents, emulsifiers, syrups, granulates or powders, or mixtures of these.
  • the formulary drug can also contain coloring agents, preservatives, perfumes, flavoring additions and sweetening agents.
  • the formulary drug can also contain other pharmaceutically active medications.
  • manufacture and distribution of the formulary drug is carried out by techniques known to the art, such as, evenly and intimately bringing together the treatment medication with liquids or fine solids or both, and then if needed, forming the formulary drug into a dose unit form.
  • the discrete dose, portion and carrier vehicle constituting the formulary drug will generally be adapted by virtue of shape or packaging for medical administration and distributed for this purpose.
  • the formulary drug acceptable for oral administration may be manufactured and distributed as individual dosage units such as capsules, pills, tablets, dragees, dissolvable powders, or cachets, each containing a known dose of the treatment medication; as powder or granules; as solution or suspension in syrups, elixirs as a lipid, aqueous liquid or a non- aqueous liquid; or as an oil-in-water emulsion or as a water-in-oil emulsion.
  • individual dosage units such as capsules, pills, tablets, dragees, dissolvable powders, or cachets, each containing a known dose of the treatment medication; as powder or granules; as solution or suspension in syrups, elixirs as a lipid, aqueous liquid or a non- aqueous liquid; or as an oil-in-water emulsion or as a water-in-oil emulsion.
  • Tablets can be manufactured and distributed by compression or mould, from treatment medication possibly with one or more additional pharmaceutically active compound.
  • Compressed tablets can be manufactured and distributed through compression in a machine typical to the art a known quantity of the treatment medication in a dispersible configuration such as powder or granules, possibly mixed with other agents including binders, lubricants, inert dilutents, preservatives, and dispersing agents.
  • Moulded tablets can be manufactured and distributed by moulding in a machine typical to the art a mix of known quantity of treatment medication addition pharmaceutically active compounds and other additives moistened with a liquid dilutent.
  • the tablets can possibly be coated, enveloped or covered, with substances including protective matrices, which can contain opacifiers or sweeteners and can be formulated to allow slow or controlled release, or also release within a certain part of the digestive system of the contained treatment medications.
  • Capsules can be manufactured and distributed by placement of a known quantity of treatment medication, additional pharmaceutically active compounds and additives within a two part or sealed capsule of gelatin or other aqueous dissolvable substance.
  • the treatment medication can also be manufactured and distributed as formulary drug in microencapsulated, microsomal, micellar and microemulsion forms.
  • the formulary drug containing the treatment medication acceptable for parenteral administration can be manufactured and distributed from aqueous and non-aqueous sterile injection solutions, other pharmaceutically active compounds, additives including anti- oxidants, bacteriostats and solutes and sugars such as mannitol to make the formulary drug isotonic, hypotonic or hypertonic with the blood of the recipient; and also aqueous and non-aqueous sterile suspensions which can include suspenders and thickeners.
  • the formulary drug can be manufactured and distributed in unit-dose or multi-dose containers, such as sealed glass or plastic ampoules, vials, bottles and bags as a liquid, and in a dry state requiring only the addition of sterile liquid, for example water, saline or dextrose solutions, immediately prior to use.
  • sterile liquid for example water, saline or dextrose solutions
  • Extemporaneous solutions and suspensions for injection can be prepared from powders and tablets of the kind above described.
  • the formulary drug containing the treatment medication acceptable for administration into the brain and related structures, spinal cord and related structures, ventricular system and cerebrospinal fluid spaces can be manufactured and distributed from aqueous and non- aqueous sterile injection solutions, other pharmaceutically active compounds, additives including anti-oxidants, bacteriostats and solutes and sugars such as mannitol to make the formulary drug isotonic, hypotonic or hypertonic with the cerebrospinal fluid; and also aqueous and non-aqueous sterile suspensions including solvents which can include suspenders and thickeners.
  • the formulary drug can be manufactured and distributed in unit-dose or multi-dose containers, such as sealed glass or plastic ampoules, vials, bottles and bags as a liquid, and in a dry state requiring only the addition of sterile liquid, for example water, saline or dextrose solutions, immediately prior to use.
  • sterile liquid for example water, saline or dextrose solutions
  • Extemporaneous solutions and suspensions for injection can be prepared from powders and tablets of the kind above described.
  • the desired unit dose of formulary drug are those containing a daily dose or ionizing radiation treatment dose or an appropriate fraction thereof, of the administered treatment medication.
  • Unit dose forms of the invention may also include more complex systems such as double barrelled syringes, syringes with sequential compartments one of which may contain the treatment medication, and the other any necessary dilutents or vehicles, or agents for opening the blood-brain barrier.
  • the agents in the syringes would be released sequentially or as a mixture or combination of the two after the triggering of the syringe plunger.
  • Such systems are known in the art.
  • the formulary drug generally contains from 0.1 to 90% of the treatment medication by weight of the total composition. Amounts of from 0.0001 mg to 200 mg/kg, or preferably 0.001 to 50 mg/kg, of body weight per day for parenteral administration and 0.001 to 150 mg/kg, preferably 0.01 to 60mg/kg, of body weight per day for enteral administration, can be given to improve neuro-radioprotection. Nevertheless, it could be necessary to alter those dosage rates, depending on the condition, weight, and individual reaction of the subject to the treatment, the type of formulary drug in which the treatment medication is administered and the mode in which the administration is carried out, and the stage of the disease process or interval of administration. It may thus be sometimes adequate to use less than the before stated minimum dose, while in other instances the upper limit must be surpassed to obtain therapeutic results.
  • the invention is for the use of the treatment medication in the conditions described throughout the application.
  • the invention thus also includes all advertising, labelling, packaging, informational materials, inserts, product descriptions, advertising materials, the written word, including letter, pamphlet, brochures, magazines and books, as well as other media of communication including the spoken word, fax, phone, photos, radio, video, television, film, internet, e-mail or computer based, and proposals for clinical trials and study protocols for clinical trials using the treatment medication for its selective neuronal protection from ionizing radiation.
  • Examples 1-14 demonstrate typical situations where neuro- radioprotection could be used.
  • Examples 15-27 demonstrate possible neuroimmunophilin ligand formulations for administering as neuro-radioprotective drugs.
  • a patient has a primary brain tumor, such as an astrocytoma, oligodendroglioma or ependymoma and is a candidate for clinical radiation therapy, radiosurgery or brachy therapy.
  • a primary brain tumor such as an astrocytoma, oligodendroglioma or ependymoma and is a candidate for clinical radiation therapy, radiosurgery or brachy therapy.
  • the patient has an injection of an neuroimmunophilin ligand into the vein, artery, thecal sac (via lumbar puncture) or ventricular catheter.
  • the patient then has a session of clinical radiation treatment. Because the neuroimmunophilins are concentrated in neurons, but not glial tumors, the drug is concentrated in the neurons but not the tumor. Fewer neurons die compared to tumor at a given radiation dose compared to untreated patients, increasing the safety of higher radiation doses to kill tumor, and reducing the loss of neurons.
  • a patient with a primary brain tumor such as an astrocytoma, anaplastic astrocytoma or glioblastoma multiforme receives X-radiation therapy to the brain for a series of daily treatments over two months.
  • This radiation field is wide and include large areas of normal brain in addition to the normal neurons adjacent to tumor.
  • the patient is given a series of doses of neuroimmunophilin ligand. This reduces side effects of cognitive decline, brain swelling, nausea, headaches and radiation necrosis. This increases the chances for cure or control of tumor growth.
  • a patient with a pituitary tumor is going to have radiation therapy or radiosurgery.
  • Part of the radiation field includes the optic chiasm, optic nerve and optic tract.
  • the patient is given a dose of neuroimmunophilin ligand prior to each session.
  • a patient with a craniopharyngioma is going to have radiation therapy or radiosurgery.
  • Part of the radiation field includes the hypothalamus of the brain.
  • the patient is given a dose of neuroimmunophilin ligand prior to each session. This reduces the side effects of endocrine abnormalities or insufficiencies, diabetes insipidus, retardation or mental decline and radiation necrosis.
  • An infant or child with a medulloblastoma brain tumor requires whole brain radiation, including the forebrain, midbrain, cerebellum, brain stem and spinal cord.
  • the infant or child is given a dose of neuroimmunophilin ligand prior to each session. This reduces the common side effects of mental retardation, cognitive and functional decline, endocrine abnormalities and radiation necrosis. This allows the treatment to be given at an earlier age than without neuroradioprotection. This allows a higher radiation dose be given than would be allowed without neuroradioprotection.
  • a patient with one or more metastatic tumors from a lung, breast or other primary cancer to the brain has Gamma Knife, particle beam or Linear accellerator based stereotactic radiosurgery, with the gamma, particle beam or X-radiation fields including normal brain neurons.
  • the patient is given a dose of neuroimmunophilin ligand. This reduces the side effects of radiation necrosis and cognitive decline.
  • a patient with a lung tumor is going to have lung radiation therapy.
  • Part of the radiation field includes the spinal cord.
  • the patient is given a dose of neuroimmunophilin ligand prior to each session.
  • a patient with a kidney cancer is going to have kidney radiation therapy.
  • Part of the radiation field includes the small and large bowel.
  • the patient is given a dose of neuroimmunophilin ligand prior to each session.
  • a patient with prostate cancer is going to have radiation therapy or brachytherapy radioactive prostate implants.
  • Part of the radiation field includes the pudendal nerves controlling penile sensation, erection and ejaculation.
  • the patient is given a dose or doses of neuroimmunophilin ligand. This reduces impotence.
  • a patient with a breast tumor is going to have radiation therapy.
  • Part of the radiation field includes the brachial plexus nerves.
  • the patient is given a dose of neuroimmunophilin ligand prior to each session. This reduces the side effect of loss of sensorimotor function to the arm.
  • a person is in an occupation or situation with high likelihood of radiation exposure, or has just received whole body radiation.
  • the person is administered or self-administers a dose of neuroimmunophilin ligand to protect all the neurons in his or her body and increases chances for survival.
  • a person is in earth orbit or space travel and receives cosmic radiation.
  • the person is administered dose or doses of neuroimmunophilin ligand to protect all neurons in his or her body and increase chances for survival.
  • Example 15 A person is pregnant and the fetus is exposed to radiation. To reduce the damage to developing fetal neurons and brain, and reduce brain damage and mental retardation of the surviving child, a dose of neuroimmunophilin ligand is administered.
  • Example 15 A person is pregnant and the fetus is exposed to radiation. To reduce the damage to developing fetal neurons and brain, and reduce brain damage and mental retardation of the surviving child, a dose of neuroimmunophilin ligand is administered.
  • the formulary drug is sterilized by heat or radiation and then placed in a sealed container such as glass in doses of 1 or 5 ml.
  • Sterile injectable concentrate formulary drug is diluted 1 ml in 20 ml saline so that it may be administered by infusion or by injection into artery, vein, brain, spine or cerebrospinal fluid spaces.
  • the formulary drug is sterilized by heat or radiation and then placed in a sealed container such as glass in doses of 1 or 5 ml.
  • Sterile injectable concentrate formulary drug is diluted 1 ml in 10 ml saline so that it may be administered by infusion or by injection into artery, vein, brain, spine or cerebrospinal fluid spaces.
  • a one or two part capsule is prepared by placing the formulary drug in a one or two part gelatine capsule.
  • the formulary drug is sterilized by heat or radiation and then placed in a sealed container such as glass in doses of 1 or 5 ml.
  • Sterile injectable concentrate formulary drug is diluted 1 ml in 10 ml saline so that it may be administered by infusion or by injection into artery, vein, brain, spine or cerebrospinal fluid spaces.
  • a one or two part capsule is prepared by placing the formulary drug in a one or two part gelatine capsule.
  • the formulary drug is sterilized by heat or radiation and then placed in a sealed container such as glass in doses of 1 or 5 ml.
  • Sterile injectable concentrate formulary drug is diluted 1 ml in 10 ml saline so that it may be administered by infusion or by injection into artery, vein, brain, spine or cerebrospinal fluid spaces.
  • a one or two part capsule is prepared by placing the formulary drug in a one or two part gelatine capsule.
  • the formulary drug is sterilized by heat or radiation and then placed in a sealed container such as glass in doses of 1 or 5 ml.
  • Sterile injectable concentrate formulary drug is diluted 1 ml in 10 ml saline so that it may be administered by infusion or by injection into artery, vein, brain, spine or cerebrospinal fluid spaces.
  • the formulary drug is sterilized by heat or radiation & then placed in a sealed container such as glass in doses of 1 or 5 ml.
  • Sterile injectable concentrate formulary drug is diluted 1 ml in 10 ml saline so that it may be administered by infusion or by injection into artery, vein, brain, spine or cerebrospinal fluid spaces.
  • Example 25
  • a one or two part capsule is prepared by placing the formulary drug in a one or two part gelatine capsule.
  • the formulary drug is sterilized by heat or radiation & then placed in a sealed container such as glass in doses of 1 or 5 ml.
  • Sterile injectable concentrate formulary drug is diluted 1 ml in 10 ml saline so that it may be administered by infusion or by injection into artery, vein, brain, spine or cerebrospinal fluid spaces.
  • a one or two part capsule is prepared by placing the formulary drug in a one or two part gelatine capsule.

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  • Health & Medical Sciences (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
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  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

L'invention concerne un procédé et des produits pharmaceutiques permettant de protéger sélectivement les neurones contre les dégâts provoqués par le rayonnement ionisant, indépendamment de la source d'irradiation. Ce procédé est particulièrement utile pour protéger sélectivement les neurones normaux, mais non les cellules cérébrales tumorales, contre les effets dommageables du rayonnement ionisant.
PCT/US1998/020040 1998-09-23 1998-09-23 Neuro-immunophillines pour radioprotection neuronale selective WO2000016794A1 (fr)

Priority Applications (11)

Application Number Priority Date Filing Date Title
NZ510739A NZ510739A (en) 1998-09-23 1998-09-23 Neuroimmunophilins for selective neuronal radioprotection
BR9816047-8A BR9816047A (pt) 1998-09-23 1998-09-23 Método de utilização de neuroimunofilinas para radioproteção neuronal seletiva; método aperfeiçoado; uso de ligantes de neuroimunofilinas e artigo fabricado
CA002345378A CA2345378A1 (fr) 1998-09-23 1998-09-23 Neuro-immunophillines pour radioprotection neuronale selective
IL14212098A IL142120A0 (en) 1998-09-23 1998-09-23 Neuroimmunophilins for selective neuronal radioprotection
EP98948530A EP1115412A4 (fr) 1998-09-23 1998-09-23 Neuro-immunophillines pour radioprotection neuronale selective
APAP/P/2001/002113A AP2001002113A0 (en) 1998-09-23 1998-09-23 Neuroimmunophilins for selective neuronal radioprotection.
AU95081/98A AU766095B2 (en) 1998-09-23 1998-09-23 Neuroimmunophilins for selective neuronal radioprotection
CN98814297A CN1322136A (zh) 1998-09-23 1998-09-23 用于选择性神经元辐射防护的神经亲免素类物质
PCT/US1998/020040 WO2000016794A1 (fr) 1998-09-23 1998-09-23 Neuro-immunophillines pour radioprotection neuronale selective
JP2000573755A JP2002526453A (ja) 1998-09-23 1998-09-23 選択的なニューロンの放射線保護のためのニューロイムノフィリン類
HK02101925.6A HK1040617A1 (zh) 1998-09-23 2002-03-13 用於選擇性神經元輻射防護的神經親免素類物質

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US1998/020040 WO2000016794A1 (fr) 1998-09-23 1998-09-23 Neuro-immunophillines pour radioprotection neuronale selective

Related Child Applications (2)

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US09787861 A-371-Of-International 2001-06-14
US10/757,533 Continuation US20040147433A1 (en) 2001-06-14 2004-01-15 Neuroimmunophilins for selective neuronal radioprotection

Publications (1)

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WO2000016794A1 true WO2000016794A1 (fr) 2000-03-30

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PCT/US1998/020040 WO2000016794A1 (fr) 1998-09-23 1998-09-23 Neuro-immunophillines pour radioprotection neuronale selective

Country Status (10)

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EP (1) EP1115412A4 (fr)
JP (1) JP2002526453A (fr)
CN (1) CN1322136A (fr)
AP (1) AP2001002113A0 (fr)
AU (1) AU766095B2 (fr)
BR (1) BR9816047A (fr)
CA (1) CA2345378A1 (fr)
HK (1) HK1040617A1 (fr)
IL (1) IL142120A0 (fr)
WO (1) WO2000016794A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005103255A1 (fr) * 2004-03-25 2005-11-03 The Government Of The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Recepteur formylpeptide (fpr) utilise en tant que cible pour une therapie anti-gliome malin
US7473681B2 (en) 2000-10-31 2009-01-06 Pharma Mar, S.A. Kahalalide F
CN112218683A (zh) * 2018-05-30 2021-01-12 睿谱外科系统股份有限公司 靠近关键结构的辐射外科手术神经调节

Citations (1)

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Publication number Priority date Publication date Assignee Title
WO1997018828A1 (fr) * 1995-11-20 1997-05-29 Guilford Pharmaceuticals Inc. Inhibiteurs d'activite de cyclophiline rotamase

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Publication number Priority date Publication date Assignee Title
SE520730C2 (sv) * 1995-01-20 2003-08-19 Eskil Elmer Behandling av hjärnischemi och hjärnskador med ett neuroprotektivt läkemedel

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Publication number Priority date Publication date Assignee Title
WO1997018828A1 (fr) * 1995-11-20 1997-05-29 Guilford Pharmaceuticals Inc. Inhibiteurs d'activite de cyclophiline rotamase

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Title
BRADLEY W.G. ET AL: "Post-Radiation Motor Neuron Syndromes", ADVANCES IN NEUROLOGY, vol. 56, 1991, USA, pages 341 - 353, XP002916357 *
FRIBERG H. ET AL: "Cyclosporin A, But not FK 506, Protects Mitochondria and Neurons Against Hypoglycemic Damage and Implicates the Mitochondrial Permeability Transition in Cell Death", THE JOURNAL OF NEUROSCIENCE, vol. 18, no. 14, 15 July 1998 (1998-07-15), pages 5151 - 5159, XP002916359 *
PELLMAR T. ET AL: "Radiation-Induced Impairment of Neuronal Excitability", COMMENTS TOXICOLOGY, vol. 2, no. 4, 1988, GREAT BRITAIN, pages 253 - 263, XP002916356 *
See also references of EP1115412A4 *
TATTON W.G. ET AL: "Mitochondria in Neurodegenerative Apoptosis: An Opportunity for Therapy?", ANN NEUROL, vol. 44, no. 1, September 1998 (1998-09-01), USA, pages S134 - S141, XP002916358 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7473681B2 (en) 2000-10-31 2009-01-06 Pharma Mar, S.A. Kahalalide F
JP2010047601A (ja) * 2000-10-31 2010-03-04 Pharma Mar Sa カハラリドｆ
WO2005103255A1 (fr) * 2004-03-25 2005-11-03 The Government Of The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Recepteur formylpeptide (fpr) utilise en tant que cible pour une therapie anti-gliome malin
CN112218683A (zh) * 2018-05-30 2021-01-12 睿谱外科系统股份有限公司 靠近关键结构的辐射外科手术神经调节
EP3801217A4 (fr) * 2018-05-30 2022-07-20 Zap Surgical Systems, Inc. Neuromodlation radiochirurgicale proche de structures critiques
US11745029B2 (en) 2018-05-30 2023-09-05 Zap Surgical Systems, Inc. Radiosurgical neuromodulation close to critical structures

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AU766095B2 (en) 2003-10-09
AP2001002113A0 (en) 2001-06-30
BR9816047A (pt) 2003-01-07
JP2002526453A (ja) 2002-08-20
CA2345378A1 (fr) 2000-03-30
AU9508198A (en) 2000-04-10
EP1115412A4 (fr) 2004-12-15
CN1322136A (zh) 2001-11-14
HK1040617A1 (zh) 2002-06-21
EP1115412A1 (fr) 2001-07-18
IL142120A0 (en) 2002-03-10

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