# US 2008/0188480 A1 · Use of Sildenafil, Vardenafil and Other 5-Phosphodiesterase Inhibitors to Enhance Permeability of the Abnormal Blood-Brain Barrier > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 2008/0188480 A1 - Document ID: US20080188480A1 - Status: Published application - Kind: A1 - Application number: 11/813,494 - Filed: 2006-02-22 - Published: 2008-08-07 - Earliest claimed: 2005-02-22 - Assignees: Cedars-Sinai Medical Center - Inventors: Keith L. Black - Web page: https://patentgrep.com/patent/US20080188480A1 ## CPC - A61K 31/415: 1,2-Diazoles - A61K 31/22: of acyclic acids, e.g. pravastatin - A61K 31/519: ortho- or peri-condensed with heterocyclic rings - A61P 7/00: Drugs for disorders of the blood or the extracellular fluid - A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## Abstract This invention relates to compositions, methods and kits for enhancing the permeability of the blood-brain barrier. Particularly, compositions comprising 5-phosphodiesterase inhibitors, such as sildenafil, vardenafil, or tadalafil, when administered to a mammal, will selectively enhance the permeability of the blood-brain barrier in abnormal brain tissue. This selective enhancement allows for selective delivery of therapeutic agents to treat the abnormal brain tissue; for example, a brain tumor. ## Claims ### Claim 1 A method to selectively enhance the permeability of the blood-brain barrier in abnormal brain tissue of a mammal, comprising: providing a 5-phosphodiesterase (“PDE-5”) inhibitor; and administering the PDE-5 inhibitor in an amount sufficient to selectively enhance the permeability of the blood-brain barrier of the mammal. ### Claim 2 (depends on 1) The method of claim 1, wherein the PDE-5 inhibitor is selected from the group consisting of sildenafil, vardenafil, tadalafil, salts thereof, analogs thereof and combinations thereof. ### Claim 3 (depends on 1) The method of claim 1, wherein the permeability of the blood-brain barrier is enhanced for a duration of at least about 30 minutes. ### Claim 4 (depends on 1) The method of claim 1, wherein the permeability of the blood-brain barrier is enhanced for a duration of from about 30 to about 360 minutes. ### Claim 5 (depends on 1) The method of claim 1, wherein administering the PDE-5 inhibitor comprises: administering the PDE-5 inhibitor via a route of administration selected from the group consisting of oral, intravenous, intraarterial, intracarotid and combinations thereof. ### Claim 6 (depends on 1) The method of claim 1, wherein the administering the PDE-5 inhibitor comprises: administering the PDE-5 inhibitor prior to administering a therapeutic agent. ### Claim 7 (depends on 1) The method of claim 1, wherein the administering the PDE-5 inhibitor comprises: administering the PDE-5 inhibitor from about 30 to about 45 minutes prior to administering a therapeutic agent. ### Claim 8 (depends on 6) The method of claim 6, wherein the therapeutic agent is selected from the group consisting of an anti-cancer drug, therapeutic viral particle, antiproliferative agent, antimicrobial, mood-stabilizing agent, anticonvulsant, anti-neurodegenerative agent, anti-stroke agent, cytokine, therapeutic protein, immunotoxin, immunosuppressant, gene therapeutic, and combinations thereof. ### Claim 9 (depends on 6) The method of claim 6, wherein the therapeutic agent is an anti-cancer drug selected from the group consisting of a cytotoxic agent, cytotoxic alkylating agent, alkylating agent, antimitotic agent, topoisomerase I inhibitor, topoisomerase II inhibitor, androgen inhibitor, antiestrogen and combinations thereof. ### Claim 10 (depends on 6) The method of claim 6, wherein the therapeutic agent is an anti-cancer drug selected from the group consisting of 5-fluorouracil, actinomycin D, allocolchicine, all-trans retinoic acid, alpha interferon, altretamine, amonafide, anthrapyrazole derivatives, asaley, AZQ, BCG, bisantrene HCL, bisulphan, bleomycin, busulfan, camptothecin, camptothecin derivatives, carboplatin, carboxyphthalatoplatinum, carmustine (BCNU), CBDCA, CBDCA, CHIP, chlorambucil, chlorozotocin, cis-diamminedichloroplatimun, cisplatin, cis-platinum, clomesone, colchicine, colchicine derivatives, cyanomorpholinodoxorubicin, cyclodisone, cyclophosphamide, cytarabine USP, dacarbazine, daunorubicin, deoxydoxorubicin, dianhydrogalactitol, dolastatin 10, doxorubicin, droloxifene, estramucine phosphate sodium, ethylesulfonic acid, exrazoxane, filgrastim, fluorodopan, flutamide leuprolide acetate, gallium nitrate, G-CSF, gliadel, GM-CSF, granisetron, Halichondrin M, hepsulfam, hexamethylmelamine, hycanthone, hydroxyurea, idarubicin, ifosfamide, interferon alfa-2a recombinant, interleukin-2, iphosphamide, L-asparaginase, levamisole, lomustine (CCNU), m-AMSA, maytansine, melphalan, menogaril, methotrexate, methyl CCNU, mitomycin C, mitomycin, mitoxantron, mitoxantrone, mithramycin, morpholinodoxorubicin, N,N-dibenzyl daunomycin, Navelbine, nitrogen mustard, o,p'-DDD, ondansetron, oxanthrazole, oxorubicin, paclitaxel, paclitaxel derivatives, PCNU, pilocarpine, piperazine, piperazinedione, pipobroman, porfimer sodium, porfiromycin, procarbazine, pyrazoloacridine, rhizoxin, roloxifene, rubidazone, sargramostim strontium-89 chloride, spirohydantoin mustard, streptozoci, streptozotocin, taxotere, teniposide, teroxirone, tetraplatin, thiocolchicine, thiotepa, toremifene, triethylenemelamine, trityl cysteine, uracil nitrogen mustard, vinblastine, vinblastine sulfate, vincristine, vincristine sulfate, VM-26, VP-16, VP-16-213, Yoshi-864, and combinations thereof. ### Claim 11 (depends on 1) The method of claim 1, further comprising: administering an additional agent that enhances the permeability of the blood-brain barrier. ### Claim 12 (depends on 11) The method of claim 11, wherein the additional agent that enhances the permeability of the blood-brain barrier is selected from the group consisting of a bradykinin, a nitrogen oxide donor drug, a potassium channel agonist, analogs thereof, salts thereof and combinations thereof. ### Claim 13 (depends on 11) The method of claim 11, wherein the administering the PDE-5 inhibitor and the administering the additional agent that increases the permeability of the blood-brain barrier occur prior to administering a therapeutic agent. ### Claim 14 A method for treating abnormal brain tissue present in a mammal, comprising: providing a 5-phosphodiesterase (“PDE-5”) inhibitor; administering the PDE-5 inhibitor in an amount sufficient to selectively enhance the permeability of the blood-brain barrier in the mammal; and administering a therapeutic agent to the mammal. ### Claim 15 (depends on 14) The method of claim 14, wherein the abnormal brain tissue is selected from the group consisting of a tumor, a tissue affected by a disease, a tissue affected by a physical injury, and combinations thereof. ### Claim 16 (depends on 15) The method of claim 15, wherein the disease is selected from the group consisting of degenerative brain disease, cerebrovascular disease, cerebral ischemia, infection, migraine, convulsion, bacterial infection, viral infection, schizophrenia, Parkinson's disease, Alzheimer's disease, hypoxia, cerebral palsy, dyspnea, encephalopathy, meningitis, cerebral abscess, multiple sclerosis, subarachnoid hemorrhage and combinations thereof. ### Claim 17 (depends on 14) The method of claim 14, wherein the abnormal brain tissue is selected from the group consisting of glioma, glioblastoma, glioblastoma multiforme, oligodendroglioma, primitive neuroectodermal tumor, astrocytoma, ependymoma, oligodendroglioma, medulloblastoma, meningioma, pituitary adenomas, neuroblastoma, craniopharyngioma and combinations thereof ### Claim 18 (depends on 14) The method of claim 14, wherein the PDE-5 inhibitor is selected from the group consisting of sildenafil, vardenafil, tadalafil, salts thereof, analogs thereof and combinations thereof. ### Claim 19 (depends on 14) The method of claim 14, wherein the permeability of the blood-brain barrier is enhanced for a duration of at least about 30 minutes. ### Claim 20 (depends on 14) The method of claim 14, wherein the permeability of the blood-brain barrier is enhanced for a duration of from about 30 to about 360 minutes. ### Claim 21 (depends on 14) The method of claim 14, wherein administering the PDE-5 inhibitor comprises: administering the PDE-5 inhibitor via a route of administration selected from the group consisting of oral, intravenous, intraarterial, intracarotid and combinations thereof. ### Claim 22 (depends on 14) The method of claim 14, further comprising: administering an additional agent that enhances the permeability of the blood-brain barrier. ### Claim 23 (depends on 22) The method of claim 22, wherein the additional agent that enhances the permeability of the blood-brain barrier is selected from the group consisting of a bradykinin, a nitrogen oxide donor drug, a potassium channel agonist, salts thereof, analogs thereof and combinations thereof. ### Claim 24 (depends on 14) The method of claim 14, wherein the administering the PDE-5 inhibitor to the mammal comprises: administering the PDE-5 inhibitor to the mammal prior to administering the therapeutic agent to the mammal. ### Claim 25 (depends on 14) The method of claim 14, wherein administering the PDE-5 inhibitor to the mammal comprises: administering the PDE-5 inhibitor to the mammal from about 30 to about 45 minutes prior to administering the therapeutic agent to the mammal. ### Claim 26 (depends on 22) The method of claim 22, wherein the administering the PDE-5 inhibitor and the administering the additional agent that enhances the permeability of the blood-brain barrier occur prior to administering a therapeutic agent. ### Claim 27 A kit for selective enhancement of the permeability of the blood-brain barrier in a mammal, comprising: a quantity of a PDE-5 inhibitor; and instructions for using the kit to selectively enhance the permeability of the blood-brain barrier. ### Claim 28 (depends on 27) The kit of claim 27, wherein the PDE-5 inhibitor is selected from the group consisting of sildenafil, vardenafil, tadalafil, salts thereof, analogs thereof and combinations thereof. ### Claim 29 (depends on 27) The kit of claim 27, wherein the permeability of the blood-brain barrier is enhanced for a duration of at least about 30 minutes. ### Claim 30 (depends on 27) The kit of claim 27, wherein the permeability of the blood-brain barrier is enhanced for a duration of about 30 to about 360 minutes. ### Claim 31 (depends on 27) The kit of claim 27, further comprising a bradykinin, a nitrogen oxide donor drug, a potassium channel agonist, salts thereof, or analogs thereof. ### Claim 32 (depends on 27) The kit of claim 27, wherein the instructions for using the kit comprise: instructions to administer the PDE-5 inhibitor in an amount sufficient to selectively enhance the permeability of the blood-brain barrier. ### Claim 33 (depends on 31) The kit from claim 31, wherein the instructions for using the kit comprise: instructions to administer a therapeutically effective amount of the bradykinin, the nitrogen oxide donor drug, the potassium channel agonist, salts thereof or analogs thereof to the mammal. ### Claim 34 (depends on 32) The kit of claim 32, wherein the instructions to administer the PDE-5 inhibitor to the mammal comprise: instructions to administer the PDE-5 inhibitor prior to administering a therapeutic agent. ### Claim 35 (depends on 32) The kit of claim 32, wherein the instructions to administer the PDE-5 inhibitor to the mammal comprise: instructions to administer the PDE-5 inhibitor about 30 to about 45 minutes prior to administering a therapeutic agent. ### Claim 36 (depends on 33) The kit of claim 33, wherein the instructions to administer the PDE-5 inhibitor to the mammal comprise: instructions to administer the PDE-5 inhibitor via a route of administration selected from the group consisting of oral, intravenous, intraarterial, intracarotid and combinations thereof.