Claims for Patent: 6,187,756

Summary for Patent: 6,187,756

Title:	Composition and methods for treatment of neurological disorders and neurodegenerative diseases
Abstract:	It has been discovered that the stimulation of .beta.-adrenergic receptors, which activate cAMP formation, give rise to increased APP and GFAP synthesis in astrocytes. Hence, the in vitro or in vivo exposure of neuronal cells to certain compositions comprising .beta.-adrenergic receptor ligands or agonists, including, e.g., norepinephrine, isoproterenol and the like, increases APP mRNA transcription and consequent APP overproduction. These increases are blocked by .beta.-adrenergic receptor antagonists, such as propranolol. The in vitro or in vivo treatment of these cells with 8Br-cAMP, prostaglandin E.sub.2 (PG E.sub.2), forskolin, and nicotine ditartrate also increased APP synthesis, including an increase in mRNA and holoprotein levels, as well as an increase in the expression of glial fibrillary acidic protein (GFAP). Compositions and methods are disclosed of regulating APP overexpression and mediating reactive astrogliosis through cAMP signaling or the activation of .beta.-adrenergic receptors. It has further been found that the increase in APP synthesis caused by 8Br-cAMP, PG E.sub.2, forskolin, or nicotine ditartrate is inhibited by immunosuppressants or anti-inflammatory agents, such as cyclosporin A, and FK-506 (tacrolimus), as well as ion-channel modulators, including ion chelating agents such as EGTA, or calcium/calmodulin kinase inhibitors, such as KN93. The present invention has broad implications in the alleviation, treatment, or prevention of neurological disorders and neurodegenerative diseases, including Alzheimer\'s Disease.
Inventor(s):	Lee; Robert K. K. (Boston, MA), Wurtman; Richard J. (Boston, MA)
Assignee:	The Massachusetts Institute of Technology (Cambridge, MA)
Application Number:	09/493,228
Patent Claims:	1. A method of alleviating the negative effects of a neurological disorder or neurodegenerative disease stemming from the aberrant expression, production, or formation of amyloid precursor protein (APP) in a subject comprising administering to a subject suffering from said disorder or disease an effective amount of an antagonist of a .beta.-adrenergic receptor that is coupled to the cellular levels of cAMP. 2. The method of claim 1 in which said antagonist a receptor antagonist of a neurotransmitter, a modulator of signal transduction or ion channels, an immunosuppressant, an anti-inflammatory agent, or combinations thereof, provided that said modulator does not activate protein kinase C. 3. The method of claim 1 in which the administering occurs at least once per day. 4. The method of claim 1 in which the effective amount is between about 0.01 and about 25 mg/kg body weight. 5. The method of claim 4 in which the effective amount is between about 0.1 and about 15 mg/kg body weight. 6. The method of claim 1 in which the effective amount is administered orally, transdermally, topically, parenterally, rectally, opthalmically, or aurally. 7. The method of claim 6 in which the parenteral administration is intramuscular or subcutaneous and the duration of the effect is prolonged by delayed absorption. 8. The method of claim 1 in which the neurological disorder or neurodegenerative disease is Alzheimer's disease, Parkinson's disease, Lou Gehrig's disease, or multiple sclerosis. 9. The method of claim 2 in which the anti-inflammatory agent is a steroidal anti-inflammatory agent, non-steroidal anti-inflammatory agent, salicylate, steroid, receptor site blocker, inhibitor of complement activation, or combinations thereof. 10. The method of claim 2, in which the anti-inflammatory agent is a 5-lipoxygenase inhibitor, phosphodiesterase inhibitor, cyclooxygenase inhibitor, cyclosalicylazosulfapyridine, azulfasalazine, Asacol, Disalcid, Pentesa, Salflex, Trilisate, leukotriene, B.sub.4 receptor antagonist, C.sub.4 receptor antagonist, D.sub.4 receptor antagonist and E.sub.4 receptor antagonist, Aerobid, Aristocort, Azmacort, Beclovent, Beconase, Celestone, Cortenema, Cortifoam, Decadron, Delalone, Depo-Medrol, Dexacort, Epifoam, Hydeltra, Hydrocortone, Hydeltrasol, Medrol, Nasacort, Plaquenil, Pediapred, Rhinocort, Solu-Cortef, Vancenase, Vanceril, prostanoid receptor antagonist, prostaglandin receptor antagonist, neurokinin receptor anatagonist, endothelin receptor antagonist, antihistamine, cytokine receptor anatagonist, interleukin receptor anatagonist, or interferon receptor antagonist. 11. The method of claim 2 in which the immunosuppressant is an immunomodulator. 12. The method of claim 11 in which the immunomodulator is Ergamisol, Leukine, Neupogen, cyclophosphamide, colony-stimulating factors, or combinations thereof. 13. The method of claim 2 in which the immunosuppressant is Atgam, Azathioprine, 15-Deoxyspergualine, HypRho, Imuran, Methotrexate, 6-Mercaptopurine, Mycophenolate mefotil, MICRhoGAM, Misoprostol, Methylprednisolone, Orthoclone, Prograf, Rapamycin, ThoGAM, Sandimmune, antithymocyte globulin, antilymphocyte globulin, monoclonal pan-T cell antibody, or combinations thereof. 14. The method of claim 2 in which the ion channel modulator is N-acetylprocainamide HCl, amiloride HCl, 5-(N,N-dimethyl)-amiloride HCl, 5-(N-ethyl-N-isopropyl)-amiloride, 5-(N,N-hexamethylene)-amiloride, 5-(N-methyl-N-isobutyl)-amiloride, 4-aminopyridine, amiodarone HCl, apamin, benzamil HCl, bepridil HCl, .beta.-bungarotoxin, 2,3-butanedione monoxime, calciseptine, charybdotoxin, .mu.-conotoxin GIIIA, .omega.-conotoxin GVIA, .omega.-conotoxin MVIIC, cyclic ADP ribose, cyclopiazonic acid, cyproheptadine HCl, dantrolene sodium salt, dendrotoxin, diltiazem HCl, efaroxan HCl, flunarizine HCl, fluspirilene, glibenclamide, glipizide, 5-hydroxydecanoic acid sodium salt, iberiotoxin, kaliotoxin, lidocaine N-ethyl bromide, loperamide HCl, manoalide, MCD peptide, nicardipine HCl, nifedipine, nifedipine metabolite, (.+-.)-niguldipine HCl, S(+)-niguldipine HCl, R(-)-niguldipine HCl, nimodipine, nitrendipine, 5-nitro-2-(3-phenylpropylamino)benzoic acid, phenamil methanesulfonate, N-phenylanthranylic acid, phentolamine mesylate, pimozide, procainamide HCl, quinidine sulfate, quinine sulfate, ruthenium red, ryanodine, saxitoxin, tetraethylammonium chloride, tetrodotoxin, tetrodotoxin citrate, thapsigargin, tityustoxin-K.alpha., tolbutamide, triamterene, (.+-.)-verapmil HCl, S(-)-verapmil HCl, R(+)-verapamil HCl, S(-)-methoxyl-verapamil HCl, or R(+)-methoxy-verapamil. 15. The method of claim 2 in which the neurotransmitter antagonist is an antagonist of at least one beta-adrenergic, serotonergic, dopaminergic, adenosine, adrenoreceptors, angiotensin, atrial natriuretic peptide, bombesin, bradykinin, cholecystokinin, gastrin, dopamine, endothelin, GABA, glutamate, interleukin-1, serotonin, leukotriene, vasoactive intestinal polypeptide, pituitary adenylate cyclase activating peptide, prostaglandin E.sub.2, histamine, muscarinic acetylcholine, neuropeptide Y, nicotinic acetylcholine, opioid, PAF, prostanoid, purinoceptors, somatostatin, tachykinin, thrombin, vasopressin, oxytocin, VIP, and combinations thereof. 16. A method of alleviating the negative effects of a neurological disorder or neurodegenerative disease stemming from aberrant expression, production, or formation of amyloid precursor protein, in a subject in need thereof, comprising administering a protein kinase A or protein kinase C signaling agent. 17. The method of claim 16 in which the agent is phorbol ester, indolactam, mezerin, diacylglycerol, cAMP, cGMP, related analogs, forskolin, activators of adenylate guanylate cyclase, inhibitors of adenylate guanylate cyclase, modulators of calcium channels, modulators of potassium channels, G-proteins, or combinations thereof. 18. The method of claim 16 in which administration of the signaling agent reduces cyclic AMP levels. 19. A method of stimulating the processing of amyloid precursor protein comprising administering a phorbol ester, a diacylglycerol or a combination thereof, wherein said administration stimulates the processing of amyloid precursor protein.

Details for Patent 6,187,756

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Amgen, Inc.	NEUPOGEN	filgrastim	Injection	103353	02/20/1991		2016-09-05
Amgen, Inc.	NEUPOGEN	filgrastim	Injection	103353	06/28/2000		2016-09-05
Partner Therapeutics, Inc.	LEUKINE	sargramostim	For Injection	103362	03/05/1991		2016-09-05
Partner Therapeutics, Inc.	LEUKINE	sargramostim	Injection	103362	03/05/1991		2016-09-05
Pharmacia & Upjohn Company Llc	ATGAM	lymphocyte immune globulin, anti-thymocyte globulin (equine)	Injection	103676	12/04/1996		2016-09-05
Jubilant Hollisterstier Llc	N/A	positive skin test control-histamine	Injection	103891	03/13/1924		2016-09-05