MXPA01003029A - Neuroimmunophilins for selective neuronal radioprotection - Google Patents

Abstract

A method and pharmaceuticals for selectively protecting neurons against ionizing radiation induced damage, irrespective of the source of radiation insult. This method is particularly useful in selectively protecting normal neurons, but not brain tumor cells, against the damaging effects of ionizing radiation.

Description

NEUROINMUNOPHYLINS FOR SELECTIVE NEURONAL RADIOPROTECTION Neuroimmunofilin ligands. Both cyclosporin and FK506 are neuroimmunophilic ligands that bind specifically to neuroimmunophilins. Neuroimmunoflins were previously named after their respective binding ligand, ie they were defined as cyclophilins and FK-binding proteins. Because the effect of cyclosporins and FK506 on the immune system is so strong and well known in clinical transplantation, the families of the cyclosyphins and the FK-binding proteins together are known as immunophilins. When it was discovered that neurons were 20 times richer in immunophilins than immune cells, they were named neuroimmunophilins. In addition, they realized that neuroimmunophilic ligands were neuroprotective. However, it has never been proposed or considered that the differential distribution of neuroimmunophilins could be exploited to improve the safety and efficacy of brain radiation treatments, or radiation fields or rays passing through the brain. The crucial understanding is that neurons are greatly enriched in neuroimmunophilins and that glia or brain support cells contain little or no neuroimmunophilinic protein.

The neuroimmunophilinic ligands are defined herein as all compounds that bind to neuroimmunophilins. Neuroimmunophilinic ligands include but are not limited to immunosuppressive cyclosporin A, cyclosporins, FK506, all their analogues, derivatives and immunosuppressant and non-immunosuppressant variants, as well as the small molecule immunophilin ligands developed by the companies Guilford Pharmaceuticals Inc. and Vértex Pharmaceuticals. Inc. and described in other patent applications. Treatment medication or treatment medications will be defined as a medicament that comprises as its active ingredients no less than a neuroimmunophilinic ligand, and may contain a mixture of two or more similar or different neuroimmunophilinic ligands. The three major classes of neuroimmunophilinic ligands will be discussed below, including the cyclosporins, FK506 and the small neuroinmunophilic ligands of FK-binding protein ("neuroimmunophilinic ligands-FKBP") of Guilford Pharmaceuticals Inc. and Vértex Pharmaceuticals Inc. Cyclosporin A and derivatives . It is already known that cyclosporin A is an immunosuppressant drug. The aforementioned treatment medication has already been described in Pat. of the United States No. 4,117,118 and in numerous patents, which refer to its production, formulation and immunosuppressive properties. Cyclosporin A is a product of the fungus Tolypocladium Inflatum Gams. It is a polycyclic amino acid molecule consisting of 11 amino acids. One of the amino acids is unique to cyclosporin A, a β-hydroxyamino acid called butenyl-methyl-threonine (MeBmt). The molecular weight is 1202.6 and the chemical composition is C6H ??? Nn012. The molecule is highly lipophilic and therefore virtually insoluble in water. Bioavailability after an oral dose varies between 8 and 60% depending in part on bile flow. The drug is absorbed mainly in the small intestine. The drug is transported in the blood within the red blood cells to approximately 58%, and the rest approximately 10-20% in the leukocytes, and 33% bound to the plasma proteins. In plasma, cyclosporin A binds to high density lipoproteins, low density lipoproteins, very low density lipoproteins and to small fractions of albumin. A very small fraction is free in the plasma. The drugs undergo extensive metabolism, mainly in the liver by the cytochrome P450 system. There are at least 30 known metabolites of cyclosporin A with various chemical modifications, such as hydroxylation, demethylation, oxidation and epoxide formations. There are numerous variants of cyclosporin A, which differ for example in an amino acid, which has similar pharmacological properties. Under normal conditions, cyclosporin A and its metabolites do not pass the blood-brain barrier. When the glycopyrin-p transporter is weakened, or the blood-brain barrier breaks down, cyclosporine is able to cross it and come into contact with the neurons. Several analogs of cyclosporine are able to easily cross the blood-brain barrier. Several analogues of cyclosporin are not immunosuppressants. There is a subset of cyclosporin analogues that easily cross the blood-brain barrier and are not immunosuppressive. This complete family of cyclosporins, all derivatives, variants, amino acid variants, metabolites, including variations of mono-, di- and trihydroxylates, N-demethylates, aldehydes, carboxylates, conjugates, sulfates, glucuronides, intramolecular cyclizations and those without a structure cyclic as well as peptides and shorter amino acids and their derivatives and salts with or without immunosuppressive properties and whether or not able to cross the blood-brain barrier, in the present will be referred to as cyclosporins. Cyclosporins will be referred to below as "neuroimmunophilinic ligands or ligands" based on their affinity and binding to the group of neuroimmunophilins called cyclophilins.

The present invention also describes treatment medications of the cyclosporin family and all salts, variants, amino acid variants, derivatives, metabolites and their known 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. In addition, this includes all the products of the fungi Tolypocladium Inflatum Gams. Some known metabolites of cyclosporin A include the following: (according to "the Hawk Cay nomenclature) AM1, AM9, AMlc, AM4N, AM19, AMlc9, aAMlc4N9, AMIA, AM1A4N, AMIAc, AM1AL, AMlld, AM69, AM4N9, AM14N, AM14N9, AM4N69, AM99N, Dihydro-CsA, Dihydro-CsC, Dihydro-CsD, Dihydro-CsG, M17, AMlc-GLC, conjugated sulfate of cyclosporin, BHlla, BH15a, B, G, E, (and with which overlap with the previous Hawk, according to the nomenclature of aurer) Ml, M2, M3, M4, M5, Mß, M7, M8, M9, Mio, Mil, M12, M13, M14, M15, M16, M17, M18, M19, M20, M21, M22, M23, M24, M25, M26, MUNDF1, and MeBM Some metabolites of cyclosporin G include GMl, GM9, GM4N, GMlc, GMlc9, and GM19 Modified cyclosporins include amino acid analogs Modified C-9, analogues of modified amino acid-8, analogs of modified position 6 containing residues of MeAla or MeAbu and SDZ 209-313, SDZ-205- 549, SDZ-033-243, SDZ IMM 125 and SDZ-PSC-833. FK506 and its derivatives. FK506 is a macrolide compound, known and described in European Patent Publication No. 0184162 and other documents. Known macrolide compounds include FR-900506, FR-900520, FR-900523 and FR-900525 isolated from microorganisms of the genus Streptomyces such as Streptomyces tsukubensis No. 9993 and their related compounds. Derivatives include ascomycin (C21-ethyl-FK506), C18-0H-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 the treatment of rejection in transplants, autoimmune diseases, and in the U.S. Patent. 5,648,351 as useful to prevent or treat cerebral ischemic disease. FK506 and its derivatives of compounds and macrolide salts with or without the immunosuppressive properties will be referred to hereinafter as FKs. The FKs will now be referred to as a "neuroimmunophilinic ligand or ligands" based on their affinity and binding to the group of neuroimmunophilins called FK-binding proteins, especially FKBP12, or other FKBPs. Guilford and Vértex have discovered a series of small molecules that easily enter the brain and have been found to be neurotrophic and neuroprotective, by virtue of their ability to bind as ligands to FKBP12 and FKBPs, for which they have a variety of patents including the U.S. Patent. 5,780,484 and 5,614,547. . However, they do not claim protection from damage by ionizing radiation. Furthermore, they do not claim that using these small molecule FKBP-type neuroimmunophilic ligands could be an improvement over current ionizing radiation treatment techniques, or protection from exposure to ionizing radiation. Small-molecule FKBP-like neuroimmunophilinic ligands will now be referred to as "neuroimmunophilinic ligands or ligands" based on their affinity and binding to the group of neuroimmunophilins called FK-binding proteins, especially FKBP12, or other FKBPs. Currently, small molecules that easily enter the brain are under development, which have neurotrophic and neuroprotective properties by virtue of their ability to bind to the cyclophilin of neuroimmunophilins. It has not been claimed that using these small molecule cyclophilin-like neuroimmunophilin ligands the current techniques of ionizing radiation or ionizing radiation treatment can be improved. Cyclophilin-like neuroimmunophilin ligands will be referred to below as "neuroimmunophilinic ligands or ligands" based on their affinity and binding to the group of neuroimmunophilins called cyclophilins.

A dose of ionizing radiation causes damage and destroys cells mainly by ionizing water or oxygen into toxic hydroxyl, oxygen and / or other free radical species. These radicals then damage or destroy the cells due to their high reactivity against cellular proteins, membranes and DNA. In addition, free radicals by themselves can induce a mitochondrial permeability transition that disables the cellular ability to cause ATP to carry out its normal functions and cause the mitochondria to release the mitochondrial enzymes that activate the nuclear caspases and other enzymes that cause apoptosis, or programmed cell death. The cyclosporins, but not the neuroinmunophilic ligands type FK506, nor the FKBP, block the formation of this mitochondrial transition and therefore block apoptosis. This will make cyclosporins more likely, the most effective of the neuroimmunophilic ligands, although a mixture with one or more other ligands may have a synergistic effect. Radiation therapy Following is a description of the radiation treatment technique for cancer and other conditions. It has never been suggested before that radiation therapy could be improved by the use of a selective neuronal protection drug. Never before has proposed that by administering a drug of the class of neuroimmunophilic ligands the resistance of normal neurons which are rich in neuroimmunophilins in the brain, spinal cord and peripheral nerves to the toxic effects of ionizing radiation could be selectively improved, compared to all other cell types that are poor in neuroimmunophilins. Never before has it been considered that most primary brain cancers originate from glial cells poor in neuroimmunophilins (gliomas) or astrocytes (astrocytomas) or oligodendrocytes (oligodendrogliomas) and therefore would not be protected from the toxic effects of ionizing radiation, while normal neurons rich in neuroimmunophilins would be protected from ionizing radiation by means of a neurouimmunofilinic ligand. Thus, the person who is treated systemically with a radioprotective neuroimmunophilic ligand would have selective and improved protection of the neurons, improving the technique of radiation treatment in a novel and not obvious way. Ionizing radiation is frequently used in the medical field to treat diseases. Primary brain tumors are often treated with radiation therapy, and they radiate in a wide field including most or all of the brain with an X-ray source such as a linear accelerator during one or many sessions daily typically for eight weeks. Sometimes the radiation is gamma rays or proton and particle beam. This radiation decreases brain tumor growth, but also destroys normal neurons. Cystic brain tumors sometimes have radioactive fluids installed in them. Sometimes radioactive pellets are temporarily or permanently implanted. Metastatic tumors of the lung, breast, colon, skin and other organs often leave the brain. There are tumors of the head that are adjacent to the brain, such as tumors of the pituitary, memingiomas and crareofarinfiomas. There are radiosensible vascular maldormations in the brain. There are disorders of the brain that can be helped by partial or complete lesions of small brain structures including Parkinson's disease, epilepsy, obsessive compulsive disorder and trigeminal neuralgia, in which radiation passes through the normal brain. These tumors and conditions are often treated either with radiation therapy as described above or with radiosurgery. Radiosurgery uses either gamma rays or X-rays that are usually administered at high doses located precisely in a session, with radiation passing through the normal brain in and beyond the target structure. Tumors in the body, such as cancers of Squamous, laryngeal, lung, breast, renal or prostate cells are often treated with radiation by linear accelerator or implantation of radioactive pellets. The radiation fields that treat these cancers sometimes include neural structures of the brain, spinal cord or peripheral nerves. In addition to therapeutic medical uses for radiation, there are no medical cases of radiation exposure. They include the dose or accidental overdose by radioactive substances, and suparterapeutic doses that use a medical radiation device. Occasionally there is inadvertent exposure of a pregnant person's fetus and thus its developing nervous system, to X-ray radiation. Occupational or accidental situations of exposure to radiation such as nuclear reactor radiation leakage, cause brain radiation in addition of the rest of the body. The Present Invention There are side effects of radiation. It causes normal neurons to die, causing nausea and vomiting, lethargy, permanent diminished perception, decreased intelligence, loss of endocrine control, necrosis and loss of function due to radiation, spinal cord dysfunction and necrosis with resultant paralysis. The concern about these resulting side effects reduces the radiation dose that can be given by the radiation oncologist producing few cures or recurrence faster than would be possible if higher doses were given. In addition, the pediatric population is more susceptible to the effects of radiation on the nervous system, which causes mental retardation. If the neurons could be protected, these side effects could be lessened or avoided by leading to more cured cancers or more effectively treated cancers. There is a need for a treatment that protects normal neurons from radiation, while leaving them susceptible to tumor cells. Treating a person exposed to radiation with neuroimmunophilic ligands would be a significant improvement over current radiation treatment. By being available to administer such a compound to patients, it will have industrial applicability. The simultaneous realization of three factors leads to the novel and non-obvious inventive step that by giving neuroimmunophilinic ligands to radiation therapy patients, normal neurons would be selectively protected on tumor cells and especially tumor brain cells, and thus would improve radiation therapy - (1) these neurons are more enriched in neuroimmunophilins than any other tissue (especially compared to brain cancer or other cancer cells), (2) those drugs from the class of neuroimmunophilic ligands, notably cyclosporin and FK506, protect cells containing neuronmunofilins against free radicals, and (3) that ionizing radiation destroys cells through the production of free radicals. This also leads to the inventive and not obvious step that those exposed to toxic non-medical radiation doses of the whole body could survive better or survive longer if their neurons were selectively protected compared to those that were not fully protected. . Medication and administration. The administration of the treatment medication can be by any suitable route including oral, sublingual, buccal, nasal, inhalation, parenteral (including intraperitoneal, intraorganic, subcutaneous, intradermal, intramuscular, intra-articular, venous (central, hepatic or peripheral) lymphatic , cardiac, arterial, including selective or superselective cerebral arterial focus, retrograde perfusion through the cerebral venous system, through catheter in the parenchyma or cerebral ventricles), direct exposure or under pressure in or through the brain or spinal cord, or any of the cerebrospinal fluid ventricles, injections in the subarachnoid spaces, cranial cerebral, subdural or epidural, through lumbar puncture or in the cerebral cisterns, intra and peri-ocular instillation including the application by injection around the eye, inside the eyeball, its structures and layers, as well as enteral, intestinal , rectal, vaginal, urethral or cisternal bladder. Also for in utero and perinatal indications, injections into the maternal vasculature, or through or into the maternal organs, and into the embryo, fetus, neonate and related tissues and spaces such as the amniotic sac, umbilical cord, umbilical artery or vein and the placenta, parenteral being the most preferred route. The preferred route may vary depending on the conditions of the patient. Included in the invention is the administration of the treatment medication through any means with the intentional disruption of the brain or spinal parenchyma, or by breaking the blood-brain barrier via mechanical, thermal, cryogenic, chemical, toxic, inhibitor or receptor enhancer, weakening the p-glycoprotein transporter, inhibition or saturation, osmotic, alteration of change, radiation, photon, electrical or other energy process. This invention includes all methods of administering treatment medications along with all methods of opening, deviating or breaking the blood barrier. brain in simultaneous or sequential combination to put the treatment medication in contact with the nervous tissues in order to exercise the neuronal radioprotection. This invention includes the possibility of synchronization and sequencing of the delivery of the treatment medications to include pre-treatment and post-treatment, as well as simultaneous to the treatment. Although it is possible to administer the treatment medication alone, it is preferred to present it as part of a drug in the pharmaceutical form. The drug of the form of this invention comprises at least one medication of the treatment administered as described above together with one or more appropriate vehicles thereof and possibly other pharmaceutical treatment medications. Vehicles should be appropriate in that they can easily coexist with the other agents of the drug in the form and that are not harmful to the recipient of the same. This combined treatment medication, as described in this paragraph, with other appropriate agents common to the art, is defined herein as the drug of the form. The form drug includes those suitable for administration by routes including oral, sublingual, buccal, nasal, inhalation, parenteral (including intraperitoneal, intraoral, subcutaneous, intradermal, intramuscular, intra-articular, venous (central, hepatic or peripheral) lymphatic, cardiac, arterial, including the selective or superselective cerebral arterial approach, retrograde perfusion through the cerebral venous system, through catheter in the parenchyma or cerebral ventricles), direct exposure or under pressure in or Through the brain or spinal tissue, or any of the cerebrospinal fluid ventricles, injections in the subarachnoid, cerebral, subdural or epidural spaces, through lumbar puncture or in the cerebral cisterns, intra and peri-ocular instillation including application through the injection around the eye, inside the eyeball, its structures and layers, as well as the enteral, intestinal, rectal, vaginal, urethral or cisternal route of the bladder. Also for indications in utero and perinatal, injections in the maternal vasculature, or through or in the maternal organs including the uterus, cervix and vagina, and in the embryo, fetus, neonate and related tissues and spaces such as the amniotic sac, umbilical cord umbilical artery or vein and the placenta, the most preferred route being parenteral. The drug of the form can be distributed and made available in a convenient unit dosage form such as capsules or ampoule, containing the treatment medication of the invention, and can be made and distributed by any of the methods known by the pharmaceutical techniques. In addition to the treatment medication, the drug of the form may also contain other usual agents of the technique related to the type of drug of the form produced. The drug form can, for example, take the configuration of suspensions, solutions and emulsions of the treatment medication in lipid, non-aqueous or aqueous diluents, solvents, dissolving agents, emulsifiers, syrups, granules or powders or mixtures of these . The drug in the form may also contain coloring agents, preservatives, perfumes, flavorings, additional agents and sweeteners. In addition to the treatment medication, the formulary drug may also contain other pharmaceutically active medications. The manufacture and distribution of the drug of the form is carried out by techniques known in the art, such as putting uniformly and intimately together the treatment medication with liquids or fine solids or both, and then it is necessary to formulate the drug of the form in a dosage unit form. The separate dose, portion and carrier vehicle constitute the drug form that will generally be adapted by virtue of the form or packaging for medical administration and distributed for this purpose. The form drug acceptable for oral administration can be made and distributed as single dose units, such as capsules, pills, tablets, dragees, soluble powders, or capsule, each containing a known dose of the treatment medication; as powder or granules; as a solution or suspension in syrups, elixirs as a lipid, aqueous or non-aqueous liquid; or as an oil-in-water emulsion or water-in-oil emulsion. The tablets can be made and distributed by compression or molding, of the treatment medication possibly with one or more additional pharmaceutically active compounds. The compressed tablets can be made and distributed through compression in a typical machine in the art of a known amount of the treatment medication in a dispersible configuration such as powder or granules, possibly mixed with other agents including binding agents, lubricants, inert diluents. conservatives and dispersants. The molded tablets can be made and distributed by molding in a typical machine in the art, a mixture of the known amount of the treatment medication, the addition of pharmaceutically active compounds and other additives wetted with a liquid diluent. The tablets can possibly be coated, wrapped or covered, with substances including protective matrices, which may contain opacifiers or sweeteners and can be formulated to allow slow or controlled release, or also to be released within a certain part of the digestive system from the contained treatment medications. The capsules can be made and distributed by placing a known amount of the treatment medication, additional pharmaceutically active compounds and additives, into a sealed or two-part gelatin capsule or other aqueous soluble substance. Treatment medication can also be made and distributed as the form drug in microencapsulated, microsomal, micellar, and microemulsion forms. The drug form containing the acceptable treatment medication for parenteral administration can be made and distributed from sterile aqueous and non-aqueous injection solutions, other pharmaceutically active compounds, additives including antioxidants, bacteriolates and solutes and sugars such as mannitol to make the drug of the isotonic, hypotonic or hypertonic form with the recipient's blood; and also sterile aqueous and non-aqueous suspensions which may include suspenders and thickeners. The drug in the form can be made and distributed in unit-dose or multiple-dose containers, such as sealed glass or plastic ampoules, vials, bottles and bags, as a liquid, and in the dry state that requires only the addition of sterile liquid, for example water, saline or dextrose solutions, immediately before use. Extemporaneous solutions and suspensions for injection can be prepared from powders and tablets of the type described above. The drug form containing the treatment medication acceptable for administration to the brain and related structures, spinal cord and related structures, ventricular system and cerebrospinal fluid spaces can be elaborated and distributed from sterile aqueous and non-aqueous injection solutions, other compounds pharmaceutically active additives including antioxidants, bacteriolates and solutes and sugars such as mannitol to make the drug form isotonic, hypotonic or hypertonic with cerebrospinal fluid; and also sterile aqueous and non-aqueous suspensions including solvents which may include suspenders and thickeners. The drug in the form can be made and distributed in single-dose or multi-dose containers, such as sealed glass or plastic ampoules, vials, bottles and bags, as a liquid, and in a dry state that requires the addition of sterile liquid only. example, water, saline or dextrose solutions, immediately before use. Extemporaneous solutions and suspensions for injection can be prepared from powders and tablets of the type previously described. The desired unit doses of the drug of the form are those containing a daily dose or dose of ionizing radiation treatment or an appropriate fraction thereof of the administered treatment medication. Dosage forms per unit of the invention may also include more complex systems such as double-barreled syringes, syringe with sequential compartments one of which may contain the treatment medication, and the other any diluent or necessary vehicle, or agent to open the blood-brain barrier. The agents in the syringe can be released sequentially or as a mixture or combination of the two after activation of the plunger of the syringe. Such systems are known in the art. The drug in the form generally contains 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 60 mg / kg, of body weight per day for enteral administration, can be given to improve neuro-radioprotection. However, it may be necessary to alter these dose proportions, depending on the condition, weight and individual reaction of the subject to the treatment, the type of drug in the form in which the treatment medication is administered and the manner in which the administration is carried out, and the stage of the disease process or administration interval. Thus, it may sometimes be appropriate to use less than the minimum dose established above, while in other cases the upper limit must be exceeded in order to obtain therapeutic results. The invention is for the use of the treatment medicament in the conditions described through the application. Thus, the invention also includes all advertising, labeling, packaging, information materials, inserts, product descriptions, advertising materials, the written word, including letters, brochures, manuals, magazines and books as well as other means of communication including word spoken, fax, telephone, photos, radio, video, television, film, internet, email or computer based and proposal for clinical analysis and study protocols for clinical analysis using treatment medication for selective neuronal protection of ionizing radiation. Examples: Examples 1-14 demonstrate the typical situations where neuro-radioprotection can be used. Examples 15-27 demonstrate the possible formulations of Neuroimmunophilinic ligands for administration as neuro-radioprotective drugs. Example 1 A patient has a primary brain tumor, such as an astrocytoma, oligodendroglioma or ependymoma and is a candidate for clinical radiation therapy, radiosurgery or brachytherapy. Four hours before the radiation treatment, the patient has an injection of a neuroimmunophilic ligand into the vein, artery, thecal sac (via lumbar puncture) or ventricular catheter. The patient then has a clinical radiation treatment session. Because neuroimmunophilins are concentrated in neurons, but not in glial tumors, the drug is concentrated in the neurons but not in the tumor. Few neurons die compared to the tumor at a given dose of radiation compared to untreated patients, increasing the safety of high doses of radiation to destroy the tumor, and reduce the loss of neurons. Example 2 A patient has a primary brain tumor, such as an astrocytoma, anaplastic astrocytoma or glioblastoma multiforme receives X-radiation therapy for the brain by a series of daily treatments for two months. This radiation field is broad and includes large areas of the normal brain in addition to normal neurons adjacent to the brain. tumor. During the period of radiation therapy, to protect neurons in the brain from radiation damage, or allow the administration of large doses of radiation that are otherwise tolerated, the patient is given a series of doses of neuroimmunophilic ligands. This reduces the side effects of knowledge decline, brain dilation, nausea, headache and radiation necrosis. This increases the chance to cure or control the growth of the tumor. Example 3 A patient with a pituitary tumor will have a radiation or radiosurgery therapy. Part of the radiation field includes the optic chiasm, optic nerve and optic tract. To protect neurons of the optic chiasm, nerve and tract from radiation damage, and the patient from loss of vision, or blindness, the patient is given a dose of neuroimmunifilinic ligands before each session. Example 4 A patient with a craniopharyngioma will have a radiation or radiosurgery therapy. Part of the radiation field includes the hypothalamus of the brain. To protect the neurons of the hypothalamus from radiation damage, the patient is given a dose of neuroimmunifilic ligands before each session. This reduces the side effects of abnormalities or endocrine deficiencies, diabetes insipid, mental retardation or decline and radiation necrosis. Example 5 An infant or child with a medulloblastoma brain tumor requires complete radiation of the brain including the anterior brain, cerebellum, brainstem and spinal cord. To protect all neurons in these locations, the infant or child is given a dose of neuroimmunifilinic ligands before 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 done at a younger age than without the neuroradioprotection. This allows a higher dose of radiation than could be allowed without neuroradioprotection. Example 6 A patient with one or more metastatic tumors of the lung, breast or other primary cancer to the brain has Linear accelerator or particle beam, Gamma Knife based on stereotactic radiosurgery, with the beam of gamma particles or X-radiation fields that They include normal brain neurons. To protect normal brain neurons in the path of radiation, the patient is given a dose of neuroimmunophilic ligands. This reduces the side effects of radiation necrosis and cognitive decline. Example 7 A patient with a lung tumor will have lung radiation therapy. Part of the radiation field includes the spinal cord. To protect neurons in the spinal cord from radiation damage by "spectator", the patient is given a dose of neuroimmunophilic ligands before each session. Example 8 A patient with kidney cancer will have kidney radiation therapy. Part of the radiation field includes the small and large intestines. In order to protect the autonomic neurons in the intestine from radiation damage "bystander", the patient is given a dose of neuroimmunophilic ligands before each session. Example 9 A patient with prostate cancer will have radiation therapy or radioactive prostate implants by brachytherapy. Part of the radiation field includes the pudendal nerves that control penile sensation, erection and ejaculation. To protect the penile nerves that pass adjacent to the prostate against the damage of the "spectator" radiation, the patient is given one or several doses of the neuroimmunophilic ligand. This reduces impotence.

Example 10 A patient with a breast tumor is going to have radiation therapy. Part of the radiation field includes the nerves of the brachial plexus. To protect the nerves of the brachial plexus that innervate the muscles and skin of the arm against the damage of the "spectator" radiation, the patient is given a dose of the neuroimmunophilinic ligand before each session. This reduces the side effect of loss of sensory-motor function in the arm. Example 11 The personnel of a uranium processing plant is exposed to radiation. In order to protect the neurons of exposed persons, they are given an intravenous dose of cyclosporin A and / or FK506. This reduces radiation poisoning and increases the chances of survival. Example 12 A person is in an occupation or situation with a high probability of exposure to radiation or has already received full body radiation. The person is given or by himself a dose of neuroimmunophilic ligand is administered to protect all the neurons in his body and increases the chances of survival. Example 13 A person is in Earth orbit or travel through space and receive cosmic radiation. The person is given one or several doses of the neuroimmunophilic ligand to protect all the neurons in his body and increase the chances of survival. Example 14 A person is pregnant and the fetus is exposed to radiation. A dose of the neuroimmunophilic ligand is administered to reduce the development damage to the fetus' neurons and brain and reduce brain damage and mental retardation of the surviving child. Example 15 Drug Sterile Injectable Concentrate Form Containing per ml: Cyclosporine A 100 mg Spiritus fortis 280 mg Polyoxyethylated castor oil 600 mg The form drug is sterilized by heat or radiation and then placed in a sealed container such as glass in doses of 1 or 5 ml. The drug in the sterile injectable concentrate form is diluted 1 ml in 20 ml of saline so that it can be administered by infusion or by injection into the artery, vein, brain, spine or spaces of the cerebrospinal fluid. Example 16 Drug Formulary Sterile Injectable Concentrate Containing per ml: Cyclosporine A 200 mg Tween 80 800 mg The form drug is sterilized by heat or radiation and then placed in a sealed container such as glass in a dose of 1 or 5 ml. The drug in the sterile injectable concentrate form is diluted 1 ml in 10 ml of saline so that it can be administered by infusion or by injection into the artery, vein, brain, spine or cerebrospinal fluid spaces. Example 17 Capsule Formula Drug Cyclosporine A 200 mg Iron oxide E172 1 mg Titanium dioxide 3 mg Ethanol 100 mg Corn oil 415 mg Gelatin 280 mg Labrafil 300 mg Andrisorb 105 mg 85% glycerol 3 mg A single or two-part capsule was prepared by placing the Form drug in a gelatin capsule one or two parts. Example 18 Form Drug in Oral Fluid Containing 1 ml: Cyclosporine A 200 mg Ethanol 100 mg Corn oil 430 mg Labrafil 200 mg Example 19 Sterile Injectable Concentrated Drug Formula Containing per ml: FK506 anhydride 5 mg Polyoxyl 60 beaver oil 200 mg hydrogenated USP 80% dehydrated alcohol v / v The form drug is sterilized by heat or radiation and then placed in a container sealed such as glass in doses of 1 or 5 ml. The drug in the sterile injectable concentrate form is diluted 1 ml in 10 ml of saline so that it can be administered by infusion or by injection into the artery, vein, brain, spine or cerebrospinal fluid spaces. Example 20 Capsule Formula Drug FK506 anhydride 5 mg Lactose 100 mg Hydroxypropyl methylcellulose 100 mg Croscarmellose sodium 10 mg Magnesium stearate 10 mg A single- or two-part capsule was prepared by placing the drug form in a one- or two-part gelatin capsule. Example 21 Drug of the Sterile Injectable Concentrated Form Containing per ml: Ligand neuroinmunofilinic type FKBP of 5 mg small molecule Hydrogenated castor oil 200 mg Polyoxyl 60 Dehydrated alcohol USP, 80% v / v. The drug in the form is sterilized by heat or radiation and then placed in a sealed container such as glass in a dose of 1 or 5 ml. The drug in the sterile injectable concentrate form is diluted 1 ml in 10 ml of saline so that it can be administered by infusion or by injection into the artery, vein, brain, spine or cerebrospinal fluid spaces. Example 22 Capsule Formula Drug Neuroimmunophilic ligand type FKBP 5 mg small molecule Lactose 100 mg Hydroxypropyl methylcellulose 100 mg Croscarmellose sodium 10 mg Magnesium stearate 10 mg A single or two-part capsule was prepared by placing the drug form in a one or two gelatin capsule parts. Example 23 Sterile Injectable Concentrated Drug Formula Containing per ml: Cyclosporine A 200 mg FK506 anhydride 5 mg Neuroimmunophilic ligand type FKBP 5 mg small molecule Tween 80 v / v The form drug is sterilized by heat or radiation and then placed in a container sealed such as glass in doses of 1 or 5 ml. The drug in the sterile injectable concentrate form is diluted 1 ml in 10 ml of saline so that it can be administered by infusion or by injection into the artery, vein, brain, spine or cerebrospinal fluid spaces.

Example 24 Drug of the Sterile Injectable Concentrated Form Containing per ml: Ligand neuroinmunophilinic type small molecular molecule m9 Hydrogenated castor oil 200 mg Polyoxyl 60 Dehydrated alcohol USP, 80% v / v. The drug in the form is sterilized by heat or radiation and then placed in a sealed container such as glass in a dose of 1 or 5 ml. The drug in the sterile injectable concentrate form is diluted 1 ml in 10 ml of saline so that it can be administered by infusion or by injection into the artery, vein, brain, spine or cerebrospinal fluid spaces. Example 25 Capsule Formula Drug Ligand neuroimmunophilinic type 5 mg small molecule cyclophilin Lactose 100 mg Hydroxypropyl methylcellulose 100 mg Croscarmellose sodium 10 mg Magnesium stearate 10 mg A one or two-part capsule was prepared Place the drug of the form in a gelatin capsule of one or two parts. Example 26 Drug of the Sterile Injectable Concentrated Form Containing per ml: Cyclosporine A 200 mg FK506 anhydride 5 mg Neuroimmunofilinic ligand type FKBP of 5 mg small molecule Ligand neuroimmunofilinic type 5 mg small molecule cyclophilin Tween 80 v / v. The drug in the form is sterilized by heat or radiation and then placed in a sealed container such as glass in a dose of 1 or 5 ml. The drug in the sterile injectable concentrate form is diluted 1 ml in 10 ml of saline so that it can be administered by infusion or by injection into the artery, vein, brain, spine or cerebrospinal fluid spaces. Example 27 Capsule Formula Drug Ciclosporin A 200 mg FK506 anhydride 5 mg Ligand neuroimmunophilinic type FKBP 5 mg small molecule Neuroimmunophilic ligand type 5 mg small molecule cyclophilin Iron oxide E172 1 mg Titanium dioxide 3 mg Ethanol 100 mg Corn oil 415 mg Gelatin 280 mg Labrafil 300 mg Andrisorb 105 mg Glycerol 85% 3 mg One capsule was prepared or two parts by placing the drug of the form in a gelatin capsule of one or two parts.

Claims (16)

1. CLAIMS 1. A method to selectively reduce in mammals neuronal damage or death in normal neurons rich in neuroimmunophilins of the central, peripheral and autonomic nervous system while offering reduced or no protection to tumor cells of the glial or glia-derived poor in neuroimmunophilins , tumor cells derived from abnormal neurons, body tissue from non-brain tumors and without neurons from ionizing radiation, said method comprises the steps of: (a) preparing a dose of a chemical compound selected from the group of neuroimmunophilic lingcripts, said dose of an effective amount less than 1 g / kg of body weight of the mammal; and (b) administering the dose to the mammal before, during or after the ionizing radiation of the mammal.
2. 2. A method of selective radioprotection to radiating neurons comprising: a. administering to the mammal a pharmaceutical composition in an amount sufficient to produce radioprotection of the neurons, the pharmaceutical composition comprising a neuro-radioprotective dose of neuroimmunophilinic ligand b. subject the mammal to different doses of radiation; Y c. repeat the stages a. and b. such that the mammal receives a plurality of doses of the pharmaceutical composition and radiation over a prolonged period of time.
3. 3. An improved method for the treatment of ionizing radiation of a patient with a disease or condition requiring the treatment of ionizing radiation, employing a selective neuronal protector of ionizing radiation, wherein the improvement comprises treating the patient with an effective amount of ligand neuroimmunophilinic as the selective neuronal protector of ionizing radiation.
4. The method of claims 1, 2 and 3 wherein the ionizing radiation includes an alpha, beta, X, gamma, cosmic, proton or particle fast neutron.
5. The method of claims 1, 2 and 3 wherein the exposure to ionizing radiation is therapeutic or non-therapeutic from medical, industrial, natural, man-made or nuclear sources.
6. The method of claims 1, 2 and 3 wherein the neuroimmunophilic ligand is administered by a method selected from the group consisting of injection including intravenous, intra-arterial, parenteral, intra-parenchymal, into or adjacent to the brain, tumor, in spinal cord or via spaces of cerebrospinal fluid including intraventricular, intrathecal, or through application in the digestive, respiratory, genito-urinary or skin systems or a combination of these routes so that it comes in contact with the neurons.
7. The method of claims 1, 2 and 3 wherein the neuroimmunophilic ligand is cyclosporin A, cyclosporins or functional derivatives, metabolites, variants or salts thereof.
8. The method of claims 1, 2 and 3 wherein the neuroimmunophilic ligand is FK506 or functional derivatives, metabolites, variants or salts thereof.
9. The method of claims 1, 2 and 3 wherein the neuroimmunophilic ligand is small molecule FKBP type neuroimmunophilic ligands or functional derivatives, metabolites, variants or salts thereof.
10. The method of claims 1, 2 and 3 wherein the neuroimmunophilic ligand is small molecule cyclophilin-like neuroimmunophilinic ligands or functional derivatives, metabolites, variants or salts thereof.
11. The method of claims 1, 2 and 3 wherein the neuroimmunophilinic ligand is a mixture of neuroimmunophilic ligands of cyclosporin A, cyclosporins, FK506, FKBP type, or cyclophilin type of small molecule or functional derivatives, metabolites, variants or salts thereof.
12. The method of claims 1, 2 and 3 wherein the mammal is a cancer patient with a primary brain tumor composed of tumor cells of glial origin poor in neuroimmunofilin, mixed with or surrounded by neurons rich in neuroinmunofilin that are found in the field or trajectory of ionizing radiation.
13. The method of claims 1, 2 and 3 wherein the mammal is a cancer patient with a metastatic brain tumor composed of tumor cells poor in neuroimmunophilin, mixed with or surrounded by neurons rich in neuroimmunophilin found in the field or trajectory of ionizing radiation.
14. 14. The method of claims 1, 2 and 3 wherein the mammal is a patient with a lesion treatable by ionizing radiation in proximity to neurons rich in neuroimmunophilin that are in the field or path of ionizing radiation.
15. 15. A method for using an effective amount of radiation protection treatment to cyclosporin neurons A, or a compound of the class of cyclosporins, or FK506, or a compound of the class of neuroimmunophilic ligands FK506, or FKBP type or cyclophilin type of small molecule or functional derivatives, metabolites, variants or salts thereof, or a mixture of the above for the preparation of a medicine for the improved treatment of a human with neurons and other tissues subjected to ionizing radiation.
16. 16. A manufacturing article comprising packaging material and a pharmaceutical agent contained within the packaging material, wherein the pharmaceutical agent is therapeutically effective to reduce or prevent selective neuronal damage or death by ionizing radiation when administered in an amount therapeutically effective and wherein the packaging material comprises a label indicating that the pharmaceutical agent can be used to reduce or prevent selective neuronal damage caused by ionizing radiation and wherein the pharmaceutical agent comprises a neuroimmunophilinic ligand such as cyclosporin A or a compound of the class of cyclosporins, or FK506 or a compound of the FK506 class or neuroimmunophilinic ligands type FKBP or small molecule cyclophilin type, or functional derivatives, metabolites, variants or salts thereof, or the combination of the above, either alone or in a mixture with diluents or additives.