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(12) Patent Application Publication (10) Pub. No.: US 2010/0234360 A1 Michallow (43) Pub

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US 2010O234360A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0234360 A1 Michallow (43) Pub. Date: Sep. 16, 2010 (54) METHODS FOR REGULATING Publication Classification NEUROTRANSMITTER SYSTEMIS BY INDUCING COUNTERADAPTATIONS (51) Int. Cl. A6II 3/55 (2006.01) Inventor: Alexander Michalow, A63L/485 (2006.01) (76) A6IP 25/22 (2006.01) Bourbonnais, IL (US) A6IP 25/24 (2006.01) Correspondence Address: A 6LX 3/553 (2006.01) MCDONNELL BOEHNEN HULBERT & BERG HOFF LLP (52) U.S. Cl. .......................... 514/220; 514/282; 514/221 300 S. WACKER DRIVE, 32ND FLOOR CHICAGO, IL 60606 (US) (57) ABSTRACT (21) Appl. No.: 12/708,240 The present invention relates to methods for regulating neu rotransmitter systems by inducing a counteradaptation (22) Filed: Feb. 18, 2010 response. According to one embodiment of the invention, a method for regulating a neurotransmitter includes the step of Related U.S. Application Data repeatedly administering a ligand for a receptor in the neu rotransmitter system, with a ratio of administration half-life (63) Continuation of application No. 1 1/234.850, filed on to period between administrations of no greater than /2. The Sep. 23, 2005, now abandoned. methods of the present invention may be used to address a (60) Provisional application No. 60/612,155, filed on Sep. whole host of undesirable mental and neurological condi 23, 2004. tions. Patent Application Publication Sep. 16, 2010 Sheet 1 of 4 US 2010/0234360 A1 a) first time second period time period -N- 2X % m a.X base line N-administration half-life administration next administration Period between administrations time b) first time Second period time period N-administration half-life administration next administration Period between administrations F.G. 1 time Patent Application Publication Sep. 16, 2010 Sheet 2 of 4 US 2010/0234360 A1 good bad admin admin admin admins admin admins admins time F.G. 2 time F.G. 3 time FG. 4 Patent Application Publication Sep. 16, 2010 Sheet 3 of 4 US 2010/0234360 A1 41 Patch renoved time F.G. 5 Patent Application Publication Sep. 16, 2010 Sheet 4 of 4 US 2010/0234360 A1 a) induction of maintenance through repeated counteradaptation administration of ligand -1N- -1- time b) induction of maintenance through repeated Counteradaptation administration of ligand good o d O E bad time F.G. 6 US 2010/0234360 A1 Sep. 16, 2010 METHODS FOR REGULATING gain. Further, patients can adapt or build up a resistance to NEUROTRANSMITTER SYSTEMIS BY conventional therapeutic agents with repeated use, making INDUCING COUNTERADAPTATIONS them lose efficacy over time. CROSS-REFERENCE TO RELATED SUMMARY OF THE INVENTION APPLICATIONS 0008. One embodiment of the present invention relates to 0001. This application claims the benefit under 35 U.S.C. a methodofregulating a neurotransmitter system by inducing S119(e) of U.S. Provisional Patent Application Ser. No. a counteradaptation in a patient, the neurotransmitter system 60/612,155 entitled “COUNTER-ADAPTATION including a type of receptor linked to an undesirable mental or THERAPY FOR TREATMENT OF DEPRESSION AND neurological condition. The method comprises the step of OTHER MENTAL CONDITIONS, and filed on Sep. 23, repeatedly administering to the patient a ligand for the type of 2004. The above-referenced provisional application is hereby receptor, each administration having an administration half incorporated herein by reference in its entirety. life, thereby causing the ligand to bind receptors of that type during a first time period associated with each administration, thereby inducing a counteradaptation, wherein the counter BACKGROUND OF THE INVENTION adaptation causes the regulation of the neurotransmitter sys tem, and wherein the ratio of the administration half-life to 0002 1. Field of the Invention the period between administrations is no greater than /2. 0003. The present invention relates generally to neu 0009. In another embodiment of the invention, a method is rotransmitter systems associated with undesirable mental and provided for inducing a regulation of a neurotransmitter sys neurological conditions. The present invention relates more tem in a patient, the neurotransmitter system including a type particularly to methods for regulating these neurotransmitter of receptor linked to an undesirable mental or neurological systems by inducing counteradaptative responses. condition. The method comprising the steps of inducing a 0004 2. Technical Background counteradaptation by giving the patient a ligand for the type 0005 Mood, mood disorders and related conditions are a of receptor, then repeatedly administering to the patient a result of a complex web of central nervous system events that ligand for the type of receptor, each administration having an interrelate many neurotransmitter systems. A most common administration half-life, thereby causing the ligand to bind mood disorder is depression. Depression is a clinical diagno receptors of that type during a first time period associated sis with numerous somatic and mental symptoms, which is with each administration, thereby maintaining or improving due to an alteration of numerous neurotransmitter systems. the counteradaptation, wherein the counteradaptation causes While the neurotransmitter systems most commonly related the regulation of the neurotransmitter system, and wherein with depression are the norepinephrine and serotonin sys the ratio of the administration half-life to the period between tems, current research indicates that other systems, such as administrations is no greater than /2. the Substance P system, the dynorphin system (kappa recep 0010. In one aspect of the invention, the neurotransmitter tors), and the endogenous endorphin system (mu and delta system is the SP system; the type of receptor is SP receptors; opiate receptors) are also involved in depression. Further, the ligand is an SP receptoragonist; the undesirable mental or these neurotransmitter systems are also related to a whole neurological condition is positively linked to the receptors; host of other undesirable mental and neurological conditions, and the counteradaption causes a down-regulation of the SP including bipolar disorders, obsessive-compulsive disorders, system. anxiety, phobias, stress disorders, Substance abuse, sexual 0011. In another aspect of the invention, the neurotrans disorders, eating disorders, motivational disorders and pain mitter system is the endogenous endorphin System; the type disorders. of receptor is mu and/or delta opiate receptors; the ligand is a 0006 Conventional strategies for treating neurotransmit mu and/or delta opiate receptoragonist; the undesirable men ter-linked conditions are centered on improving abnormally tal or neurological condition is negatively linked to the recep high or low levels of synaptic neurotransmitters. Conven tors; and the counteradaption causes an up-regulation of the tional therapeutic agents work to directly regulate the func endogenous endorphin system. tioning of the neurotransmitter systems. Such agents may be 0012. In yet another aspect of the invention, the neu anxiolytic agents, hypnotic agents, or selective reuptake rotransmitter system is the dynorphin system; the type of inhibitors, and include benzodiazepines (e.g., diazepam, receptor is kappa receptors; the ligand is a kappa receptor lorazepam, alprazolam, temazepam, flurazepam, and chlodi agonist; the undesirable mental or neurological condition is azepoxide), TCAS, MAOIs, SSRIs (e.g., fluoxetine hydro positively linked to the receptors; and the counteradaption chloride), NRIs, SNRIs, CRF modulating agents, serotonin causes a down-regulation of the dynorphin system. pre-synaptic autoreceptor antagonists, 5HT agonist, 0013. In still yet another aspect of the invention, the neu GABA-A modulating agents, serotonin 5H, and/or 5H2 rotransmitter system is the serotonin system; and the coun modulating agents, beta-3 adrenoceptor agonists, NMDA teradaption causes an up-regulation of the serotonin system. antagonists, V1B antagonists, GPCR modulating agents, Thus, in one embodiment of this aspect of the invention, the dynorphin antagonists, and Substance Pantagonists. type of receptor is serotonin pre-synaptic autoreceptors; the 0007 Conventional therapeutic agents and methods, ligand is a serotonin pre-synaptic autoreceptor agonist; and while somewhat effective, suffer from a few disadvantages. the undesirable mental or neurological condition is positively For example, use of many conventional therapeutic agents is linked to the receptors. In another embodiment of this aspect attended by side effects, such as sexual dysfunction, nausea of the invention the type of receptor is serotonin post-synaptic nervousness, fatigue, dry mouth, blurred vision and weight receptors; the ligand is a serotonin post-synaptic autoreceptor US 2010/0234360 A1 Sep. 16, 2010 antagonist; and the undesirable mental or neurological con 0021 FIG. 2 is a graph of mood vs. time for several admin dition is negatively linked to the serotonin post-synaptic istrations of a ligand according to another embodiment of the autoreceptors. invention; 0014. In still yet another aspect of the invention, the neu 0022 FIG. 3 is a graph of in vivo ligand concentration vs. rotransmitter system is the norepinephrine system; and the time for the administration via a single injection of a ligand counteradaption causes an up-regulation of the norepineph with a relatively long compound half-life; rine system. Thus, in one embodiment of this aspect
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