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(12) Patent Application Publication (10) Pub. No.: US 2008/0045610 A1 Michallow (43) Pub US 20080045610A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0045610 A1 Michallow (43) Pub. Date: Feb. 21, 2008 (54) METHODS FOR REGULATING filed on Feb. 27, 2006. Provisional application No. NEUROTRANSMITTER SYSTEMIS BY 60/858,186, filed on Nov. 9, 2006. INDUCING COUNTERADAPTATIONS Publication Classification (76) Inventor: Alexander Michalow, Bourbonnais, IL (US) (51) Int. Cl. A6II 45/00 (2006.01) Correspondence Address: A6IP 25/00 (2006.01) MCDONNELL BOEHNEN HULBERT & A6IP 3/00 (2006.01) BERGHOFF LLP A6IP 9/00 (2006.01) 3OO S. WACKER DRIVE (52) U.S. Cl. .............................................................. 514/789 32ND FLOOR CHICAGO, IL 60606 (US) (57) ABSTRACT (21) Appl. No.: 11/711,487 The present invention relates to methods for regulating neurotransmitter systems by inducing a counteradaptation (22) Filed: Feb. 27, 2007 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 (63) Continuation-in-part of application No. 1 1/234,850, neurotransmitter system, with a ratio of administration half filed on Sep. 23, 2005. life to period between administrations of no greater than /2. The methods of the present invention may be used to address (60) Provisional application No. 60/612,155, filed on Sep. a whole host of undesirable mental, neurological and physi 23, 2004. Provisional application No. 60/777,190, ological conditions. a) first time Second period time period -1N ax /2max base line Nl-administration half-life administration next administration Period between administrations time Patent Application Publication Feb. 21, 2008 Sheet 1 of 4 US 2008/004561.0 A1 a) first time Second period time period -1N ax 9 t C CD C 8 % max C 2 SS S base line NPll-administration half-life administration next administration Period between administrations time b) first time Second period time period -- (-1^- good i bad N 1-administration half-life administration next administration Period between administrations F.G. 1 time Patent Application Publication Feb. 21, 2008 Sheet 2 of 4 US 2008/004561.0 A1 gOOd bad admin, admin admin admin, admin admins admins time FIG. 2 time FIG. 3 time FIG. 4 Patent Application Publication Feb. 21, 2008 Sheet 3 of 4 US 2008/004561.0 A1 41 Patch removed time FIG. 5 Patent Application Publication Feb. 21, 2008 Sheet 4 of 4 US 2008/004561.0 A1 a) induction of maintenance through repeated Counteradaptation administration of ligand -N- -1- time b) induction of maintenance through repeated Counteradaptation administration of ligand -1- -1N good o O O S bad time F.G. 6 US 2008/004561.0 A1 Feb. 21, 2008 METHODS FOR REGULATING chloride), NRIs, SNRIs, CRF modulating agents, serotonin NEUROTRANSMITTER SYSTEMIS BY INDUCING pre-synaptic autoreceptor antagonists, 5HT agonist, COUNTERADAPTATIONS GABA-A modulating agents, serotonin 5H2 and/or 5HP modulating agents, beta-3 adrenoceptor agonists, NMDA CROSS-REFERENCE TO RELATED antagonists, V1B antagonists, GPCR modulating agents, APPLICATIONS dynorphin antagonists, and Substance Pantagonists. 0001. This application is a continuation-in-part under 35 0007 Conventional therapeutic agents and methods, U.S.C. S 120 of U.S. patent application Ser. No. 1 1/234,850, while somewhat effective, suffer from a few disadvantages. filed on Sep. 23, 2006, which in turn claims the benefit under For example, use of many conventional therapeutic agents is 35 U.S.C. S 119(e) of U.S. Provisional Patent Application attended by side effects, such as sexual dysfunction, nausea Ser. No. 60/612,155 entitled “COUNTER-ADAPTATION nervousness, fatigue, dry mouth, blurred vision and weight THERAPY FOR TREATMENT OF DEPRESSION AND gain. Further, patients can adapt or build up a resistance to OTHER MENTAL CONDITIONS, and filed on Sep. 23, conventional therapeutic agents with repeated use, making 2004. This application also claims priority to U.S. Provi them lose efficacy over time. sional Patent Application Ser. No. 60/777,190, entitled METHOD OF REGULATING THE CRF AND AVP SYS SUMMARY OF THE INVENTION TEMS BY INDUCING COUNTERADAPTATIONS, and 0008 One aspect of the present invention relates to a filed on Feb. 27, 2006; and to U.S. Provisional Patent method of regulating a neurotransmitter system by inducing Application Ser. No. 60/858,186, entitled “OPIATE a counteradaptation in a patient, the neurotransmitter system ANTAGONISTS FOR COUNTERADAPTATION including a type of receptor, the method comprising: repeat THERAPY,” and filed on Nov. 9, 2006. The above-refer edly administering to the patient a ligand for the type of enced provisional application is hereby incorporated herein receptor, each administration having an administration half by reference in its entirety. life, thereby causing the ligand to bind receptors of that type during a first time period associated with each administra BACKGROUND OF THE INVENTION tion, thereby inducing, maintaining or improving a counter adaptation, wherein the counteradaptation causes the regu 0002) 1. Field of the Invention lation of the neurotransmitter system, and wherein the ratio 0003) The present invention relates generally to neu of the administration half-life to the period between admin rotransmitter systems. The present invention relates more istrations is no greater than /2. particularly to methods for regulating these neurotransmitter 0009. In one aspect of the invention, the neurotransmitter systems by inducing counteradaptative responses. system is the SP system; the type of receptor is SP receptors; 0004 2. Technical Background the ligand is an SP receptor agonist; and the counteradaption 0005 Mood, mood disorders and related conditions are a causes a down-regulation of the SP system. result of a complex web of central nervous system events 0010. In another aspect of the invention, the neurotrans that interrelate many neurotransmitter systems. A most com mitter system is the endogenous endorphin System; the type mon mood disorder is depression. Depression is a clinical of receptor is mu and/or delta opiate receptors; the ligand is diagnosis with numerous somatic and mental symptoms, a mu and/or delta opiate receptor agonist; and the counter which is due to an alteration of numerous neurotransmitter adaption causes an up-regulation of the endogenous endor systems. While the neurotransmitter systems most com phin system. monly related with depression are the norepinephrine and serotonin systems, current research indicates that other sys 0011. In yet another aspect of the invention, the neu tems, such as the Substance P system, the dynorphin system rotransmitter system is the dynorphin system; the type of (kappa receptors), the endogenous endorphin system (mu receptor is kappa receptors; the ligand is a kappa receptor and delta opiate receptors), the corticotropin releasing factor agonist; and the counteradaption causes a down-regulation system, and the arginine vasopressin Systems are also of the dynorphin system. involved in depression. Further, these neurotransmitter sys 0012. In still yet another aspect of the invention, the tems are also related to a whole host of other undesirable neurotransmitter system is the serotonin system; and the mental, neurological and physiological conditions, including counteradaption causes an up-regulation of the serotonin bipolar disorders, obsessive-compulsive disorders, anxiety, system. Thus, in one embodiment of this aspect of the phobias, stress disorders, Substance abuse, sexual disorders, invention, the type of receptor is serotonin pre-synaptic eating disorders, motivational disorders, pain disorders, car autoreceptors; and the ligand is a serotonin pre-synaptic diovascular disorders, aging-related disorders, and immune autoreceptor agonist. In another embodiment of this aspect system related disorders. of the invention the type of receptor is serotonin post synaptic receptors; and the ligand is a serotonin post 0006 Conventional strategies for treating neurotransmit synaptic autoreceptor antagonist. ter-linked conditions are centered on improving abnormally high or low levels of synaptic neurotransmitters. Conven 0013 In still yet another aspect of the invention, the tional therapeutic agents work to directly regulate the func neurotransmitter system is the norepinephrine system; and tioning of the neurotransmitter systems. Such agents may be the counteradaption causes an up-regulation of the norepi anxiolytic agents, hypnotic agents, or selective reuptake nephrine system. Thus, in one embodiment of this aspect of inhibitors, and include benzodiazepines (e.g., diazepam, the invention, the type of receptor is norepinephrine pre lorazepam, alprazolam, temazepam, flurazepam, and chlo synaptic alpha-2 adrenergic receptors; and the ligand is a diazepoxide), TCAS, MAOIs, SSRIs (e.g., fluoxetine hydro norepinephrine pre-synaptic alpha-2 adrenergic receptor US 2008/004561.0 A1 Feb. 21, 2008 agonist. In another embodiment of this aspect of the inven 0023. In yet another aspect of the present invention, the tion the type of receptor is norepinephrine post-synaptic methods described herein are used to address or treat an adrenergic receptors; and the ligand is a norepinephrine undesirable condition linked to the Sirt1 pathway. post-synaptic adrenergic receptor antagonist. 0024. The methods of the present invention result in a 0014. In still yet another aspect of the invention, the number of advantages over prior art methods. For example,
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