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US008729070B2

(12) United States Patent (10) Patent N0.: US 8,729,070 B2 Glozman (45) Date of Patent: May 20, 2014

(54) CNS PHARMACEUTICAL COMPOSITIONS FOREIGN PATENT DOCUMENTS AND METHODS OF USE GB 2 I66 651 5/1986 (75) Inventor: Sabina Glozman, Naharya (IL) OTHER PUBLICATIONS

(73) Assignee: Targia Pharmaceuticals, Jerusalem (IL) Ashton H, Toxicity and adverse consequences of use, ( * ) Notice: Subject to any disclaimer, the term of this Psychiatric Annals, 1995;25: 15 8-65 .* Eccles, Substitution of for as a nasal patent is extended or adjusted under 35 decongestant. An illogical way to control metamphetamine abuse. U.S.C. 154(b) by 468 days. British Journal ofClinical , 63:1, pp. 10-14, published online Nov. 20, 2006* (21) Appl.No.: 12/860,846 European Search Report for corresponding European Patent Appli cation No. 097115679 dated Jan. 18,2012. (22) Filed: Aug. 20, 2010 International Search Report for corresponding PCT Application No. PCT/IB2009/000309 dated Jul. 27, 2009. (65) Prior Publication Data Written Opinion of the International Searching Authority for corre US 2011/0054038 A1 Mar. 3, 2011 sponding PCT Application No. PCT/IB2009/000309 dated Jul. 27, 2009. International Preliminary Report on Patentability for corresponding Related US. Application Data PCT Application No. PCT/IB2009/000309 dated Aug. 24, 2010. (63) Continuation-in-part of application No. PCT/IB2009/000309, ?led on Feb. 20, 2009. * cited by examiner (60) Provisional application No. 61/030,141, ?led on Feb. 20,2008. Primary Examiner * Sreeni Padmanabhan Assistant Examiner * Svetlana M Ivanova (51) Int. Cl. (74) Attorney, Agent, or Firm * Rodney J. Fuller; Booth A61K31/55 (2006.01) Udall Fuller, PLC A61K31/155 (2006.01) A61K33/30 (2006.01) (57) ABSTRACT A61K31/19 (2006.01) (52) U.S.Cl. The present invention is directed to CNS pharmaceutical USPC ...... 514/220;514/221;514/635;514/718; compositions and methods of use. The pharmaceutical com 5 14/5 68 positions comprise a CNS active agent and preferably at least (58) Field of Classi?cation Search two vagal neuromodulators, one of which is a mechanorecep None tor stimulator. The vagal neuromodulators are preferably in See application ?le for complete search history. an amount su?icient to reduce a somnolence side-effect of the CNS active agent without changing its therapeutic ef?cacy/ (56) References Cited activity. The invention further encompasses a method of reducing CNS active agent side-effects. The method typically U.S. PATENT DOCUMENTS comprises oral administration of at least one CNS active agent to a patient at the conventionally accepted dose; and 6,833,377 B2 * 12/2004 Serdyuk ...... 514/327 administration of at least two vagal neuromodulators to the 2002/0015713 A1 2/2002 Murdock et a1. 2004/0063628 A1 4/2004 Piccariello et al. patient so that at least one neuromodulator is administered or 2005/0008690 A1 1/2005 Miller released from dosage form after the CNS active agent is 2005/0031651 A1 2/2005 Gervais et al. administered and/or released. 2005/0267009 A1 12/2005 Deagle 2008/0020018 A1 1/2008 Moodley et al. 2009/0197958 A1 * 8/2009 Sastry et al...... 514/563 4 Claims, 7 Drawing Sheets

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w. :3; ‘daagsv Qua; {moi US. Patent May 20, 2014 Sheet 7 0f 7 US 8,729,070 B2 US 8,729,070 B2 1 2 CNS PHARMACEUTICAL COMPOSITIONS Such combinations, however, are not without their prob AND METHODS OF USE lems. Thus, there still exists a need for novel combinations of CNS active agents and neuromodulators to potentiate the CROSS-REFERENCE TO RELATED pharmacological effect of the CNS active agent, reduce dose APPLICATION dependent side-effects, avoid tolerance/tachyphylaxis prob lems, and overcome the resistance and noncompliance issues. This patent application is a continuation-in-part of Inter More speci?cally, there is a clinical need to develop “non national Application No. PCT/ 1 B2009/ 000309, ?led Feb. 20, sedating” GABA for therapeutic activities where 2009, which is based on and claims the bene?t of US. Pro sedation-related side effect damages the quality of life and visional Patent Application Ser. No. 61/030,141 ?led on Feb. cognitive functioning of the patient, causing the patient to live 20, 2008, the contents of each of which are hereby incorpo most of the day in a daze and making it dangerous to drive rated herein by reference for all that it discloses. vehicles and operate machinery. However, attempts to develop these “non-” have failed as FIELD OF THE INVENTION the prior art teaches that sedation effects of benzodiazepine The present invention is directed to pharmaceutical com treatment are linked to the GABA-inhibiting therapeutic positions in general, and more particularly to vagal afferent activity. In addition, attempts have been made to develop neuromodulators used in combination with a central nervous non-sedating by chemical modi?cation of system (CNS) active agent as an adjunctive to reduce side the active agent, but no benzodiazepine partial ago effects associated with CNS agent without affecting its thera 20 nist has emerged as a viable alternative. peutic e?icacy. The optimal anxiolytic product will be capable of producing a robust anxiolytic action by having a more rapid BACKGROUND onset of action than current therapies while potentially reduc ing the number of side effects. This drug would be compa Various pharmaceuticals, such as CNS active agents cause 25 rable to benzodiazepines, but lacking their limiting side severe side-effects that generally worsen with increasing effects at therapeutic doses. This new drug would represent an doses. Some classes of CNS active agents that require important advancement in the treatment of anxiety disorders. increasing doses include pain reducing drugs, selective sero Even if it is possible that a new, chemically-modi?ed non tonin re-uptake inhibitors, , anti-convulsants, sedative GABA may be ?nally developed, there is an , anesthetics, sedative agents, angiolytics, NSAIDs, 30 advantage in the utilization of a drug product combination , , appetite suppressants, sleep from known, approved, and available pharmaceutical ingre agents, antibiotics, antivirals, insulin resistance drugs, anti dients. Such an approach reduces the risk of potential hypertensives, and anti-asthma drugs. At high doses, many unknown toxicity, and the long term development investment CNS active agents rapidly lose their effectiveness, induce required of new pharmaceutical ingredients. pharmacologic tolerance, and cause increasingly severe side 35 In light of the prior art, the inventors surprisingly discov effects. Lowering the dose of the CNS active agent, however, ered that (1) the reduction of sedation-associated side effects does not address the problem because reducing the dose to of CNS active agents is possible using the conventional dos prior levels results in signi?cantly lower therapeutic ef?cacy. age of the CNS drug; (2) chemoreceptor stimulators (i.e. Combinations of centrally active agents have been used in pseudoephedrine (PSE) and other andrenergic receptor ago an effort to overcome the current disadvantages of single 40 nists) optimally reduce the side effects associated with a CNS agent use. In local anesthetic formulations, locally acting agent when a mechanoreceptor stimulator (i.e. agonists, such as epinephrine, are known to (GUA)) is administered approximately 15 minutes after enhance the local activity of analgesic drugs and improve administration of the CNS agent and PSE; and (3) adminis therapeutic ef?cacy. For example, it has been demonstrated tration of GUA eliminates the need to use a very high dose of that a higher dosage of epinephrine potentiated the effects of osmoactive polymers (or other osmoactive agents) which can local anesthesia. (Morganroth et al. 2009). Furthermore, sev complicate formulation preparation and disturb the subject’ s eral selective (12 agonist drugs have been used in anesthesia, physiological osmotic balance. either alone or in combination, with various opiate or inhala tional anesthetics, and have been found to reduce the dose SUMMARY OF THE INVENTION requirement for opiates, , or (Verstegen 50 1989; Nevalainen et al. 1989; Moens and Fargetton 1990). The present invention is directed to pharmaceutical com Additionally, US. Pat. No. 5,605,911 discloses the use of an positions comprising a central nervous system (CNS) active (12 agonist to block the neurotoxic effects, such as hallucina agent and method of use. The compositions and method tions and neuronal damage, of an NMDA antagonist. Simi advantageously reduce a side effect of the CNS active agent. larly, US. Pat. No. 6,562,855 teaches that co-administration 55 In a preferred embodiment, the compositions further com of an NMDA and an (12 adrenergic ago prise at least two vagal neuromodulators; and a pharmaceu nist both potentiates the effects of anesthesia and diminishes tically-acceptable vehicle, carrier or diluent. The vagal neu the side effects compared to administration of anesthesia romodulators are in an amount suf?cient to reduce a side alone. effect of the CNS active agent. Preferably, at least one of the US. Pat. No. 6,833,377 teaches that the activity of systemi 60 vagal neuromodulators is a mechanoreceptor stimulator. Suit cally administered CNS drugs may be signi?cantly potenti able mechanoreceptor stimulator may be selected from the ated by the co-administration of a compound which affects group consisting of: mucomodulators and surfactants, e.g., peripheral chemoreceptors (i.e. pseudoephedrine (PSE)) and guaifenesin (GUA). a stimulator of osmoreceptors (osmoactive polymers or sor In addition, preferably that the vagal neuromodulators fur bitol). This potentiation results in a reduction of the minimal 65 ther comprise at least one chemoreceptor stimulator, and effective dose of a variety of CNS active agents, which in turn more preferably, at least one chemoreceptor stimulator reduces the associated side effects. selected from the group consisting of: pH modulators, secre US 8,729,070 B2 3 4 tagouges, adrinomimetics, xanthines, cholecystokinins and In an alternative embodiment, the invention is directed to a gastric agonists, e.g., pseudoephedrine (aka PSE, PED, PSD, method for reducing dependency or toxicity of an addictive and NMl). central nervous system (CNS) active agent. The method com Advantageously, the present composition may further prises: administering to a patient between about 5 to about 80 comprise a GABA modulator and/or a nociceptor stimulator. percent, more preferably less than about 60%, and most pref In an exemplary embodiment, the vagal neuromodulator erably less than about 50% of the conventionally accepted comprises a vasoactive agent and the mechanoreceptor com effective dosage of the addictive CNS active agent for the prises a mucomodulator. desired treatment. The method further comprises administer In certain embodiments the mechanoreceptor stimulator is ing to the patient at least two vagal neuromodulators in an in a delayed form for co-synchronization with the CNS active amount suf?cient to reduce the dosage of the addictive CNS agent. For example, in one formulation, the CNS active agent active agent without reduction of ef?cacy. Preferably the at has a time to maximum concentration (Tmax) and the mecha least two vagal neuromodulators comprises a mechanorecep noreceptor stimulator has a Tmax, the delay in the release of tor stimulator and a chemoreceptor stimulator. Typically, in mechanoreceptor stimulator is equal to the Tmax of the CNS this embodiment, the mechanoreceptor is released or admin active agent minus the Tmax of the mechanoreceptor stimu istered after the CNS active agent. For example, the CNS lator plus about 5 to about 30 minutes, more preferably plus active agent the mechanoreceptor stimulator is administered about 10 to 20 minutes. or released at a time equal to the Tmax of the CNS active agent In a preferred embodiment, at least one side-effect is minus the Tmax of the mechanoreceptor stimulator plus reduced selected from the group consisting of: sedation, som about 5 to about 30 minutes, more preferably about 10 to nolence, sleepnece, memory impairment, amnesia, impair 20 about 20 minutes. ment of cognitive and learning function, ataxia, impaired The invention is further directed to a pharmaceutical kit. night sleep/day alertness, impaired memory, impaired con The kit preferably comprises a central nervous system (CNS) centration, impaired appetite, drowsiness, hypotension, active agent; and at least two vagal neuromodulators, wherein fatigue, kinetic disorders, catalepsy, movement disorders, the vagal neuromodulators are in an amount suf?cient to bowel irritation and impaired reaction. Preferably the side 25 reduce a side-effect of the CNS active agent and at least one effect that is reduced is sedation. of the vagal neuromodulators is a mechanoreceptor stimula In an exemplary embodiment, the invention is direct to a tor. The vagal neuromodulators may be in separate dosage composition comprising a central nervous system (CNS) forms to be administrated separately or together. active agent and at least two vagal neuromodulators, wherein the CNS active agent has a time to maximum concentration 30 BRIEF DESCRIPTION OF THE DRAWINGS (Tmax) and the at least two vagal neuromodulators each have a Tmax, wherein the Tmax of the CNS active agent is greater FIG. 1 illustrates a dosage form presented as a ?xed kit, than the Tmax of at least one vagal neuromodulator and the wherein the kit allows for the simple administration of day release of at least one vagal neuromodulator is delayed, the time and night time dosage forms; delay being equal to the Tmax of the CNS active agent minus 35 FIG. 2 illustrates another dosage form presented as a ?xed the Tmax of the neuromodulator plus about 5 to about 30 kit, wherein the kit allows for the simple administration of day minutes. Preferably, in this embodiment the at least two vagal time and night time dosage forms; neuromodulators comprise at least one mechanoreceptor FIG. 3 illustrates yet another dosage form presented as a stimulator and the mechanoreceptor stimulator is in a delayed ?xed kit, wherein the kit allows for the simple administration release form. For example, the formulation of this embodi 40 of day time and night time dosage forms; ment may comprise GUA and PSE, wherein the GUA is FIG. 4 illustrates a dosage form presented as a ?xed kit, released between about 10 and about 20 minutes after the comprising a single package with a double dual reservoir that CNS active agent. does not require the dosage forms to be in contact with each The invention is further directed to a method of reducing a other before opening by the patient or caregiver; side-effect of a CNS active agent. Preferably, the method 45 FIG. 5 illustrates the study scheme used in Examples 7 and comprises: administering the CNS active agent to a patient; 9; consisted of 1 mg “ALP” (Xanax), and administering at least two vagal neuromodulators to the 1 mg LRZ “LRZ” (Activan), neuromodulors patient in an amount suf?cient to reduce a side-effect of the “NM”, and a placebo “PLZ”; subjects were monitored over CNS active agent. Particularly, at least one neuromodulator the course of six hours; may be administered or released at least about 5 minutes after 50 FIG. 6 shows a bar graph and corresponding table indicat the CNS active agent is administered or released. In a speci?c ing the time spent sleeping by subjects in Examples 7 (sub embodiment, the neuromodulator is administered or released jects 101-104; alprazolam “ALP”) and 9 (subjects 105-108; after the CNS active agent is administered or released, pref lorazepam “LRZ”); and erably within 30 minutes. In this embodiment the CNS agent FIG. 7 illustrates the study scheme used in Example 10; maybe in an amount that is substantially the same as the 55 medications consisted of active pharmaceutical ingredients conventionally accepted effective dosage, yet still have a “API” (alprazolam [Xanax] or lorazepam [Activan]), pseu reduction in at least one side-effect of the CNS. The at least doephedrine “NMl”, guaifenesin “NM2”, or a placebo two vagal neuromodulators may also comprise at least one “PLAC”. mechanoreceptor stimulator as stated above, wherein the at least two vagal neuromodulators are in an amount suf?cient to 60 DETAILED DESCRIPTION OF THE INVENTION reduce the side-effect associated with the CNS active agent. Speci?cally, the release or the administration of the mechan The present invention comprises pharmaceutical composi oreceptor stimulator may be delayed. In this embodiment, the tions and methods for administering the pharmaceutical com delay in the administration or release of mechanoreceptor positions by combining at least two, preferably three, thera stimulator is typically equal to the Tmax of the CNS active 65 peutic agents, at least one of which is the CNS active agent. agent minus the Tmax of the mechanoreceptor stimulator The other therapeutic agent comprises at least one vagal plus about 5 to about 30 minutes. neuromodulator, which is a neuromodulator of the efferent or US 8,729,070 B2 5 6 afferent vagal nerve. In general, the advantage of the pharma eases. It should be recognized that some CNS active agents ceutical composition of the present invention is that the dis may fall into more than one category. The CNS active agent of closed combination reduces a side-effect associated with the the present invention may contain one or more chiral centers CNS active agent and/or that the therapeutically effective and/or double bonds and, therefore, includes all stereoiso amount of CNS active agent used in conjunction with the mers, such as double-bond isomers (i.e., geometric isomers), combination of neuromodulators of present invention is 1.2 , and diastereomers. In addition, the CNS active 100 folds lower than the conventionally accepted effective agents discussed herein also include all pharmaceutically dosage of same CNS active agent when used alone. acceptable salts, complexes (e.g., hydrates, solvates, and The pharmaceutical composition of the present invention clathrates) and prodrugs thereof. In a preferable embodiment, will now be described in more detail. Broadly described, such compounds are GABA agonists (i.e. benzodiazepine “CNS active agent” refers to any active pharmaceutical/thera peutic ingredient/compound/agent (drug substance or prod receptor agonists), or any other compound that performs uct) that induces sedation-related effects. “Sedation-related CNS-inhibiting neuronal activity as the desired therapeutic effects” are side effects of the compound (when therapeutic mechanism (somnolence drugs, anesthetics, hypnotics). The effect is tranquiliZing, anexielytic, analgetic, spasmolytic, CNS active agents of the present invention will now be neuroprotective, etc.). Sometimes, a CNS drug with sedative described in greater detail. activity may be used in the treatment of sleeping disorders, “” means any compound or composition such as (benzodiazepines and non-benzodiazepines that, when tested according to standard in vivo or in vitro such as , , , , etc.), assays, displays receptor-binding properties or other mecha hypnosis (Rohypnol-?unitrazepam, opiods, etc.), and narco 20 nistic properties associated with the clinically approved anti lepsy Qiyrem--GHB). However, these same or any compound or composition known or to be drugs are often used therapeutically to treat other conditions, discovered that has demonstrated clinical e?icacy in treating in which case sedation is a side effect. For example, ORG depression in mammals including those compounds and com 50081 , the (S)-(+)- of , positions that have been approved for treating depression in developed by Schering-Plough, has been used in the treat 25 humans. Classes of antidepressants include ment of insomnia and menopausal symptoms (i.e. hot ?ashes) reuptake inhibitors (N RIs), selective--reuptake . Expansion in the use of other CNS drugs is possible through inhibitors (SSRIs), monoamine-oxidase inhibitors (MAOIs), a reduction in sedation-related effects. For example, in the serotonin-and-noradrenaline-reuptake inhibitors (SNRIs); areas of: corticotropin-releasing factor (CRF) antagonists, (x-adreno Anti-pain: opiates, ?unariZine, , , 30 receptor antagonists; NKl-receptor antagonists, 5-HTlA-re and methotrimepraZine (NoZinan®) ceptor agonist, antagonists, and partial agonists, atypical anti Muscle relaxants to treat pain (MRs): robaxin, , depressants, and other antidepressants. ?exeril (), soma (), chlor Starting with norepinephrine-reuptake inhibitors, each of Zoxazone, benzodiazepines, , metaxa these classes of antidepressants will now be described in lone, and 35 greater detail. “Norepinephrine-reuptake inhibitors” are Anti-convulsants: , benzodiazepines, gaba compounds that when administered systemically in a mam pentin (Neurontin®), (), mal, inhibit norepinephrine-reuptake or that display receptor , hydantoins, sodium valproate, , binding properties or other mechanistic properties associated levetiracetam, and lamotrigine with norepinephrine-reuptake inhibitors when tested accord Anti-Psychotics: (anti-) , olanzap 40 ing to standard in vivo or in vitro assays, such as are described ine, (marketed by AstraZeneca as Seroquel in Wong et al., 61 J. Pharm. Exp. Therap. 222 (1982); P. and by Orion Pharma as Ketipinor), , and Skolnick et al., 86 BR. J. Pharmacology 637-644 (1985), ; (anti-bipolar) depakote, tegretol, and tri which are incorporated herein by reference. Norepinephrine leptal; and (anti-mania) reuptake inhibitors comprise amitriptyline, desmethylami Anti-Depressants: mirtazapine (Remeron, Avanza, Zispin, 45 triptyline, , , , imipramine Re?ex) elavil (amitriptyline), tofranil (imipramine), oxide, , , amiltriptylinoxide, norpramin (), pamelor (nortripyline), sine , desipramine, , , protrip quan (doxepin), anafranil, lomipramine, , and tyline, , , , , nefazadone , dothiepin, ?uaciZine, , , Sedation-inducing drugs used in Neurodegenerative dis 50 , , norclolipramine, noxiptilin, eases: (anti-parkinsonian) , , , , pizotyline, , , , , , , pramipex , and . Other norepinephrine-reuptake ole, , and ; anti-Alzheimer inhibitors include the compounds encompassed by The CNS active agent of the present invention may be the generic formula disclosed in US. Pat. No. 6,211,171, described according to various classi?cations and categories, 55 which is incorporated herein by reference. including antidepressants, such as norephrine-reuptake Serotonin-reuptake inhibitors will now be described. inhibitors, serotonin-reuptake inhibitors, monoamine-oxi “Serotonin reuptake inhibitors” are compounds that inhibit dase inhibitors, serotonin- and noradrenalin-reuptake inhibi reuptake of serotonin when systemically administered in tors, corticotrop-releasing-factor antagonists, (x-adrenore mammals or that display receptor-binding properties or other ceptor antagonists, 5-HT1A receptor antagonists and partial 60 mechanistic properties associated with serotonin-reuptake agonists, N-methyl-D-aspartate receptor antagonists, and inhibitors when tested according to standard in vivo or in vitro GABA analogues, intermediates and modulators, and NK-l - assays such as are described in Wong, et al., 8 Neuropsychop receptor antagonists. Other categories of CNS agents include harmacology 337 (1993); US. Pat. Nos. 6,225,324; and benzodiazepines, barbiturates, and other addictive 5,648,396, which are incorporated herein by reference. drugs, analgesics, antipsychotics and antidepressants, muscle 65 Examples of serotonin-reuptake inhibitors comprise bineda relaxants and , antispasmolytics, antihis line, m-chloropiperZine, , , , tamines and drugs for treatment of neurodegenerative dis , , ?uoxetine, ?uvoxamine, indal US 8,729,070 B2 7 8 pine, indelovaine, , , oxa?azone, which is incorporated by reference. Examples of (x-adreno , , , , , receptor antagonists comprise and those and Zimeldine. described in US. Pat. No. 6,150,389, which is incorporated Turning now to monoamine-oxidase inhibitors (MAOIs), by reference. MAOIs are compounds that when administered systemically 5-HTlA-receptor agonist, antagonists, and partial agonists in a mammal, act as monoamine-oxidase inhibitors or that (5-HT1A agents) will now be described. 5-HT1A agents are inhibit monoamine oxidase when tested according to stan compounds that when administered systemically in a mam dard in vivo or in vitro assays, such as may be adapted from mal, act as 5-HTlA-receptor agonist, antagonists, and partial the monoamine-oxidase inhibitory assay described in 12 Bio agonists or that act as 5-HTlA-receptor agonist, antagonists, chem. Pharrnacol. 1439 (1963) and Kinemuchi et al., 35 J. and partial agonists, when tested according to standard in vivo Neurochem. 109 (1980); US. Pat. No. 6,096,771, which are or in vitro assays, such as might be adapted from the 5-HT1A incorporated by reference. Examples of non-selective MAOIs receptor binding assays described in US. Pat. Nos. 6,255,302 comprise ami?amine, boxepraZine, AGN 2253 and 6,239,194, are expressly incorporated by reference. (Nicholas Kiwi), , isocarbovaid, M-3-PPC Examples of 5-HT1A agents comprise , ?esinoxan, (Draxis), nialamid, , pargyline, and tranylcyprom , and , and those disclosed in US. Pat. ine and pharmaceutically acceptable salts thereof. Examples Nos. 6,255,302; 6,245,781 and 6,242,448. An example ofa of selective MAOIs comprise clorgyline, cimoxatone, compound with 5-HT1A receptor antagonist/ be?oxatone, brofaromine, baZinaprine, BW-616U (Bur activity is . roughs Wellcome), BW-1370U87 (Burroughs Wellcome), N-methyl-D-aspartate receptor antagonists (NMDAs) rep CS-722 (RS-722) (Sankyo), E-2011 (Eisai), harmine, harma 20 resent another CNS active agent. The NMDA receptor is a line, , PharmaProjects 3975 (Hoechst), RO cell-surface protein complex in the class of ionotropic 41-1049 (Roche), RS-8359 (Sankyo), T-794 (Tanabe Seiy glutamate receptors, with a structure comprising a ligand aku), , K-Y 1349 (Kalir and Youdim), LY-51641 gated/voltage-sensitive ion channel. The NMDA receptor is (Lilly), LY-121768 (Lilly), M&B 9303 (May & Baker), MDL believed to contain at least ?ve distinct binding (activation) 72394 (Marion Merrell), MDL 72392 (Marion Merrell), ser 25 sites: a glycine-binding site, a glutamate-binding site cloremine, and MO 1671. Other MAOIs comprise , (N MDA-binding site); a (PCP)-binding site, a , D-1711 (Biocodex), , FLA-334 polyamine-binding site, and a -binding site. In general, a (RAN-1 13) (Astra), FLA-289 (FLA-299, FLA-365, FLA receptor antagonist is a molecule that blocks or reduces the 384, FLA-463, FLA-727) (Astra), K-1 1566 (Pharmacia ability of an agonist to activate the receptor. NMDA-receptor Upjohn, Farmitalia), K-1 1829 (Pharmacia Upjohn, Farmita 30 antagonist is any compound or composition that, when con lia), , MPCPAM (Yissum), PharmaProjects 227 tacted with the NMDA receptor in vivo or in vitro, inhibits the (Syntex/Roche), PharmaProjects 2806 (Fournier), Phar ?ow of ions through the NMDA-receptor ion channel. maProjects 1122, PharmaProjects 3311 (Roche), Phar NMDA-receptor antagonist suitable for use in the invention maProjects 4433 (Roche), RS-2232 (Sankyo), and UP-614 can be identi?ed by testing NMDA-receptor antagonist for 04 (Bristol-Myers). Still other MAOIs comprise , 35 local-anesthetic and peripheral antinociceptive properties brofaromide, hypericin, , , niala according to standardpain models. See e.g., J. Sawynok et al., mide, , phenoxypropaaZine, pivalyl benZhydra 82 Pain 149 (1999); J. Sawynok et al., 80 Pain 45 (1999). Zine, prodipine, , and benmoxine. In one embodiment, the NMDA-receptor antagonist is a CNS active agents of the present invention also include non-competitive NMDA-receptor antagonist, preferably, ket “serotonin- and noradrenalin-reuptake inhibitors” (SNRIs). 40 amine and/or ketamine hydrochloride. In addition, NMDA SNRIs are compounds that, when administered systemically receptor antagonist further comprises any compound or com in a mammal, act as serotonin- and noradrenaline-reuptake position that antagonizes the NMDA receptor by binding at inhibitors or that display receptor-binding properties or other the glycine site. These NMDA-receptor antagonists can be mechanistic properties associated with serotonin- and nora identi?ed by standard in vitro and in vivo assays, such as are drenalin-reuptake inhibitors when tested according to stan 45 described in US. Pat. No. 6,251,903; US. Pat. No. 6,191, dard in vivo or in vitro assays, such as are described in US. 165; Grimwood et al. 4 Molecular Pharmacology 923 (1992); Pat. No. 6,172,097, which is incorporated by reference. Yoneda et al 62 J. Neurochem. 102 (1994); and Mayer et al. J. Examples of SNRIs comprise mirtazapine, and venlafaxine. Neurophysiol. 645 (1988), which are incorporated by refer Corticotropin-releasing-factor antagonists (CRF antago ence. Glycine-site NMDA-receptor antagonists comprise nists) are also CNS active agents. CRF antagonists are com 50 glycinamide, threonine, D-serine, , 5,7-dichlo pounds that, when administered systemically in a mammal, rokynurenic acid, and 3-amino-1-hydroxy-2-pyrrolidone act as corticotropin-releasing factor antagonists or that dis (HA-966), diethylenetriamine, 1,10-diaminodecane, 1,12-di play receptor-binding properties or other mechanistic prop aminododecane, and ifenprodil and those described in US. erties associated with CRF antagonists, when tested accord Pat. Nos. 6,251,903; 5,914,403; 5,863,916; 5,783,700; and ing to standard in vivo or in vitro assays, such as are described 55 5,708,168, which are incorporated by reference. in US. Pat. No. 6,218,391, which is incorporated by refer In yet another embodiment, the NMDA-receptor antago ence. Examples of CRF antagonists comprise those described nist comprises any compound or composition that antago in US. Pat. Nos. 6,191,131; 6,174,192; 6,133,282; PCT nizes the NMDA receptor by binding at the glutamate site, Patent Application Publication Nos. W0 94/ 13643, WO also known as “competitive NMDA-receptor antagonists.” 94/13644, WO 94/13661, WO 94/13676 and WO 94/13677, 60 Competitive NMDA receptor antagonists comprise 3-(2-car which are incorporated by reference. boxypiperaZin-4-yl)propyl-1-phosphonic acid (CPP); (x-Adrenoreceptor antagonists will now be described in 3 -[(R)-2-carboxypiperZin-4-yl)-prop-2-enyl-1-phosphonic greater detail. (x-Adrenoreceptor antagonists are compounds acid (CPP-ene); 1-(cis-2-carboxypiperidine-4-yl)methyl-1 that, when administered systemically in a mammal, act as phosphonic acid (CGS 19755), D-2-Amino-5-phosphono (x-adrenoreceptor antagonists or that act as (x-adrenoreceptor 65 pentanoic acid (AP5); 2-amino-phosphonoheptanoate (AP7); antagonists when tested according to standard in vivo or in D,L-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid vitro assays, such as are described in US. Pat. No. 6,150,389, carboxyethyl ester (CGP39551); 2-amino-4-methyl-5 US 8,729,070 B2 9 10 phosphono-pent-3-enoic acid (CGP 40116); (4-phosphono ceptor antagonists comprise , eliprodil, iamot but-2-enylamino)-acetic acid (PD 132477); 2-amino-4-oxo rigine, riluzole, aptiganel, ?upirtine, celfotel, and 5 -phosphono-pentanoic acid (MDL 100,453); levemopamil. 3 -((phosphonylmethyl)-sul?nyl)-D,L-alanine; amino The NMDA receptor also comprises pyroloquinolin (4phosphonomethyl-phenyl)-acetic acid (PD 12963 5); quinone, cis-4-(phosphonomethyl)-2- carboxylic 2-amino -3 -(5 -chloro-1phosphonomethyl-1H-benzoimida acid, MK801, , and D-. zol-2-yl)-propionic acid; 2-amino-3-(3-phosphonomethyl The amount of NMDA-receptor antagonist in composi quinoxalin-2-yl)-propionic acid; 2-amino-3-(5-phospho tions of the invention will vary according to the type and nomethyl-biphenyl-3-yl)-propionic acid (SDZ EAB 515); identity of the NMDA-receptor antagonist, the concentration 2-amino -3 -&1sqb; 2-(2-pho sphono -ethyl) -cyclohexyl] -pro and identity of the antidepressant, and the painful indiction treated. Dosages and concentrations for a particular NMDA pionic acid (NPC 17742); 4-(3 -phosphono-propyl)-pipera receptor antagonist can be optimized according to routine Zine-2-carboxylic acid (D-CPP); 4-(3-phosphono-allyl)-pip experiments using well-known pain models, for example, eraZine-2-carboxylic acid (D-CPP-ene); those described in J. Sawynok et al., 82 Pain 149 (1999) and 4-phosphonomethyl-piperidine-2-carboxylic acid (CGS J. Sawynok et al., 80 Pain 45 (1999). In general, the amount of 1975 5); 3 -(2 -phosphono-acetyl) -piperidine-2 -carboxylic NMDA-receptor antagonist in the pharmaceutical composi acid (MDL 100,925); 5-phosphono-1,2,3,4-tetrahydro-iso tion of the present invention ranges from about 0.1 percent to quinoline-3-carboxylic acid (SC 48981); 5-(2-phosphono about 5 percent of the total weight of the composition, pref ethyl)-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid erably, from about 0.3 percent to about 0.5 percent of the total (PD 145950); 6phosphonomethyl-decahydro-isoquinoline 20 weight of the composition. When combined with the neuro 3-carboxylic acid (LY 274614); 4-(1H-tetrazol-5-ylmethyl) modulators of the present invention, the therapeutically effec piperidine-2-carboxylic acid (LY 233053 and 235723); tive amounts of NMDA receptor antagonist are approxi 6-(1H-Tetrazol-5-ylmethyl)-decahydro-isoquinoline-3 -car mately 1.2-100 folds lower than conventionally accepted boxylic acid (LY 233536). References that disclose other effective dosage when the NMDA-receptor antagonist is used competitive NMDA-receptor antagonists as well as assays for 25 alone. identifying competitive NMDA-receptor antagonists include Turning now to a different category, GABA analogues, Jia-He Li, et al., 38 J. Med. Chem. 1955 (1995); Steinberg et intermediates and modulators will now be described. Gamma al, 133 Neurosci. Left 225 (1991); Meldrum et al., 11 Trends vinyl GABA (GVG) is a selective and irreversible inhibitor of Pharmacol. Sci., 379 (1990); Willetts et al., 11 Trends Phar GABA-transaminase (GABA-T) known to potentiate macol. Sci. 423 (1990); Faden et al., 13 Trends Pharmacol. 30 GABAergic inhibition. It is also known that GVG alters Sci. 29 (1992); Rogawski 14 Trends Pharmacol. Sci. 325 ’s biochemical effects by causing a dose-dependent (1993); Albers et al, 15 Clinical Neuropharm. 509 (1992); and prolonged elevation of extracellular endogenous brain Wolfe et al., 13 Am. J. Emerg. Med., 174 (1995); and Bigge, GABA levels. Another selective GABA modulator is zolpi 45 Biochem. Pharmacol. 1547 (1993), which are incorpo dom. rated by reference. 35 Another CNS active agent is g-Hydroxybutyric acid Still another NMDA receptor antagonist comprises any (GHB). GHB is also known as sodium oxybate, sodium oxy compound or composition that antagonizes the NMDA recep butyrate, and others. GHB has been used for intravenous tor by binding at the PCP binding site, also known as “non induction of anesthesia, treatment of dependence and competitive NMDA-receptor antagonists.” Non-competitive opiate withdrawal. GHB is a schedule 1 controlled substance NMDA-receptor antagonists can be identi?ed using routine 40 in the US. The drug is rapidly absorbed orally with an onset assays, such as those described in US. Pat. Nos. 6,251,948; of action within 15 minutes. At lower doses of 25 mg/kg, the 5,985,586; and 6,025,369; Jacobson et al., 110 J. Pharmacol. Tmax of GHB is approximately 30 minutes.After higher doses Exp. Ther. 243 (1987); and Thurkaufet al., 31 J. Med. Chem. of 50 mg/kg, the Tmax occurs around 45 minutes. Oral inges 2257 (1988), which are incorporated by reference. Examples tion of GHB 75-100 mg/kg in humans results in peak blood of non-competitive NMDA-receptor antagonists that bind at 45 levels of approximately 90-100 ug/ml at 1-2 hours after inges the PCP site comprise ketamine, phencyclidine, dex tion. GHB at 50 mg/kg/day has been given orally to treat the tromethorphan, , dexoxadrol, (MK symptoms of acute alcohol withdrawal and to facilitate both 801), remacemide, thienylcyclohexylpiperidine (TCP), N-al short- and long-term abstinence from alcohol. It also was lylnormetazocine (SKF 10,047), cyclazocine, etoxadrol, given to treat opiate withdrawal, often in higher dosages of (1,2,3,4,9,9a-hexahydro-?uoren-4a-yl)-methyl-amine (PD 50 50-300 mg/kg/day. 137889); (1,3,4,9,10,10a-hexahydro-2H-phenanthren-4a CNS active agents also include NKl-receptor antagonists, yl)-methyl-amine (PD 138289); PD 138558, , which are compounds that when administered systemically in kynurenic acid, 7-chloro-kynurenic acid, and memantine; a mammal, act as NK1 -receptor antagonists (N eurokinn sub and quinoxalinediones, such as 6-cyano-7-nitroquinoxaline stance P receptor antagonists) or that acts as NKl-receptor 2,3-dione (CNQX) and 6,7-dinitro-quinoxaline-2,3-dione 55 antagonists, when tested according to standard in vivo or in (DNQX). vitro assays, such as may be adapted from the NK1 -receptor In yet another embodiment, the NMDA-receptor antago binding assay described in US. Pat. No. 6,117,855, which is nist comprises compounds that block the NMDA receptor at incorporated by reference. Examples of NK1 -receptor the polyamine binding site, the Zinc-binding site, and other antagonists comprise those described in PCT Patent Applica NMDA-receptor antagonists that are either not classi?ed tion Publication Nos. WO 95/16679, WO 95/18124, WO according to a particular binding site or that block the NMDA 95/23798, and European Patent Speci?cation No. 0 577 394. receptor by another mechanism. Examples of NMDA-recep Antidepressants comprise tricyclic antidepressants, such tor antagonists that bind at the polyamine site comprise sper as amitryptyline, clomipramine, desipramine, dothiepin, mine, spermidine, putrescine, and arcaine. Assays useful to doxepin, imipramine, nortriptyline, opipramol, identify NMDA-receptor antagonists that act at the Zinc or 65 and trimipramine; antidepressants, such as polyamine binding site are disclosed in US. Pat. No. 5,834, ; MOAls such as isocarbovaid, pheneliZine, tra 465, which is incorporated by reference. Other NMDA-re nylcypromine and moclobemide; and selective serotonin re US 8,729,070 B2 11 12 uptake inhibitors such as ?uoxetine, paroxetine, citalopram, pramine, cimoxatone, clemeprol, , dazepinil, ?uvoxamine and sertraline. In an embodiment of the present deanol, enefexine, , fezolamine, ?uotracen, ida invention, preferably, the antidepressant is a norepinephrine Zoxan, levoprotiline, , montirelin, nebracetam, nor , a , amitriptyline, ?uoxetine, orotirelin, oxa?ozane, , pirlindone, set or, more preferably, amitriptyline hydrochloride. iptiline, sulbutiamine, , tenilovaine, thymoliberin, CNS active agents also include atypical antidepressants, ti?ucarbine, to?sopam, tomoxetine, , viqualine, such as , , , , and zometapine, and St. John’s wort herb or levophacetoperance, metralindone, mianserin, , roli hypericum perforatum, or extracts thereof. cyprine, rolipram, , , trazodone, vilovaine, The amount of antidepressant in compositions of the inven and and pharmaceutically acceptable salts 10 tion will vary according to the type and identity of the anti thereof. , the concentration and identity of the NMDA Antidepressants also include selective serotonin reuptake receptor antagonist, and the painful indiction treated. inhibitors (SSRIs) and tricyclic antidepressants (). Dosages and concentrations for a particular antidepressants Tricyclics include amitriptyline (Elavil), desipramine (Nor- can be optimized according to routine experiments using pramin), imipramine (Tofranil) and nortriptyline (Aventyl, 15 well-known pain models, for example, those described in J. Pamelor). Other antidepressants have mechanisms than are Sawynok et al., 82 Pain 149 (1999) and J. Sawynok et al., 80 markedly different from SSRIs and tricylics. Common anti- Pain 45 (1 999). In general, the amount of antidepressant in the depressants are venlafaxine (Effexor), nefazadone (Serzone), pharmaceutical composition of the present invention ranges bupropion (Wellbutrin), mirtazapine (Remeron) and traZ- from about 0.1 percent to about 10 percent of the total weight odone (Desyrel). Less commonly used are the monomine 20 of the pharmaceutical, preferably from about 1 percent to oxidase inhibitors (MAOIs), such as phenelZine (Nardil) and about 5 percent of the total weight of the composition. In (Pamate). Mirtazapine may be used in com- another embodiment, the amount of antidepressant ranges bination with SSRIs to boost antidepressive effect, improve from about 0.5 percent to about 8 percent. sleep and avoid sexual side-effects. The conventionally Benzodiazepines of the present invention will now be accepted effective dose is 15-45 mg/day. 25 described. Benzodiazepines are anxiolytic, Speci?cally, mirtazapine is a tetracyclic antidepressant and sedative- drugs that can also act as antidepres used primarily in the treatment of depression. It is also some- sants, muscle relaxants, amnesties and antipsychotics. When times used as a hypnotic, antiemetic, and appetite , administered orally, they become widely distributed through and for the treatment of anxiety. Along with its close ana- out the body, particularly in lipid-rich tissues such as adipose logues mianserin and , mirtazapine is one of the few 30 cells and the brain. While high doses of benzopiaepines are noradrenergic and speci?c antidepressants. often required to obtain therapeutic bene?ts, such high dos Potential non-sedating applications of mirtazapine include: ages may produce severe sedative and hypnotic effects. Other monotherapy of panic/generalized Anxiety disorder (GAD); problems associated with benzodiazepine use are physical adjunctive treatment to gap the delayed onsent of SSRI anxi- withdrawal symptoms after abrupt cessation of moderate to olytic activity in ?rst diagnosed or acute stress patients; pre- 35 high doses and interaction with other CNS depressants, espe vention of acute anxiety induced by local anesthesia-related cially alcohol. Long-term use can be problematic due to the surgery (dental, plastic, ophthalmology, etc.); on-demand use development of tolerance and physiological and psychologi for prevention of panic attacks; improved and more reliable cal dependency. for GAD/panic disorder sufferers; and improved Benzodiazepines are commonly divided into three groups: patient compliance due to reduced benzodiazepine (BDZ)- 40 Short-acting compounds which act for less than six hours and induced side effects, especially for GAD/panic disorder have few residual effects if taken before bedtime such as the patients. possibility of inducing rebound insomnia or wake-time anxi Further, CNS active agents comprise a wide variety of ety. Intermediate-acting compounds have an effect for 6-10 other drugs that are thought to have antidepressant activity hours and may have mild residual effects. Long-acting com including, , oxitriptan, , thiazesim, 45 pounds have strong sedative effects that persist. Accumula adra?nil, benactyZine, butacetin, dioxadrol, , tion of the compounds in the body may occur. The elimination hematoporphyrin, , , pyrisuccideanol, half-life may vary greatly between individuals, especially the , , sulpride, , tofena- elderly. cin, 1-, , amitriptyline-chlordiazep- Various benzodiazepines and their respective trade names, oxide combination, , azamianserin, baZinaprine, 50 half-lives, and primary uses, and conventionally accepted , binodaline, bipenamol, , ciano- effective doses are listed in TABLE 1 below. TABLE 1

Brief description of various benzodiazepines.

Elimination Common Half—Life Conventionally Brand [active Primary Accepted Drug Name Names metabolite] Effects Effective Dose

Alprazolam Xanax, 6—12 hours anxiolytic 0.5 mg Xanor, Ta?l, Alprox Lexotan, 10—20 hours anxiolytic 5—6 mg Lexomil, Somalium, Bromam US 8,729,070 B2 13 14 TABLE l-continued

Brief description of various benzodiazepines.

Elimination Common Half—Life Conventionally Brand [active Primary Accepted Drug Name Names metabolite] Effects Effective Dose Librium, 5—30 hours anxiolytic 25 mg Tropium, [36—200 hours] Risolid, Klopoxid Gerodorm 9 h sedative 40 mg Frisium, 12—60 hours anxiolytic, 5—20 mg Urbanol anticonvulsant Klonopin, 18—50 hours anxiolytic, 0.5 mg Klonapin, anticonvulsant Rivotril Tranxene [36—100 hours] anxiolytic, 15 mg anticonvulsant Valium, 20—100 hours anxiolytic, 10 mg Apzepam, [36—200] hypnotic, Stesolid, anticonvulsant, Apozepam, Hexalid, Valaxona Estazolam ProSom 10—24 h hypnotic 1—2 mg Rohypnol, 18—26 hours hypnotic 1 mg Fluscand, [36—200 hours] Flunipam, Ronal Dalmane [40—250 hours] hypnotic 15—30 mg Paxipam [30—100 hours] anxiolytic 20 mg Anxon 2 hours anxiolytic 15—30 mg Dormonoct 6—12 hours hypnotic 1—2 mg Lorazepam Ativan, 10—20 hours anxiolytic 1 mg Temesta, LorabenZ Noctamid, 10—12 hours hypnotic 1—2 mg Pronoctan Nobrium 36—200 hours anxiolytic 10 mg Dormicum, 3 hours hypnotic 5—15 mg Versed, (1.8—6 hours) Hypnovel Mogadon, 15—38 hours hypnotic 10 mg Apodorm, Pacisyn, Dumolid Madar, 50—120 hours anxiolytic 10 mg Stilny Serax, 4-15 hours anxiolytic 20 mg Serenid, Serepax, Sobril, Oxascand, Alopam, Oxabenz, Oxapax Pinazepam Domar [40—100 hours] sedative 5—20 mg Centrax [36—200 hours] anxiolytic 10—20 mg Doral 25—100 hours hypnotic 20 mg Restoril, 8—22 hours hypnotic 15 mg Normison, Euhypnos Mylostan 3—26 hours Skeletal muscle 50 mg relaxant Halcion, 2 hours hypnotic 0.5 mg Rilamir

of less than ~10 mg/mL, and preferably of less than ~1 Benzodiazepines may also include , demox 60 azepam, ?umazenil, and midazepam. Preferred mg/mL. As noted above, the solubility of lorazepam in water benzodiazepines are alprazolam, diazepam, midazolam, is 0.08 mg/mL. Benzodiazepines can additionally comprise clonazepam, lorazepam, and triazolam. Benzodiazepines, one or more compounds useful in the condition to be treated, such as lorazepam, are preferably present in an essentially such as antidepressants, steroids, antiemetics, antinauseants, pure form, are poorly soluble, and are dispersible in at least 65 spasmolytics, antipsychotics, opioids, /levodopa or one liquid media. By “poorly soluble,” it is meant that the agoni sts, GABA modulators, anesthetics, and nar benzodiazepines have a solubility in liquid dispersion media cotics. US 8,729,070 B2 15 16 Another CNS active agent is zonisamide, which is a sul extracts, powdered opium, granulated opium, raw opium, fonamide anticonylusant used as therapeutically to prevent tincture of opium, oxycodone, oxymorphone, , migraines. Zonisamide has also been demonstrated to be phenazocine, piminodine, racemethorphan, , effective in some cases of neuropathic pain and has been cocaine, heroinand thebaine. Other opioids are described in studied in cases of obesity. Furthermore, zonisamide is further detail below. Addictive drugs also include hypnotics approved for use as an adjunctive therapy in adults with and , such as barbiturates, chlordiazepoxide, amy partial-onset seizures for adults; infantile spasm, mixed sei lobarbitone, butobarbitone, pentobarbitone, choral hydrate, zure types of Lennox-Gastaut syndrome, myoclonic, and chlormethiazole, and , and alco generalized tonic clonic seizure. The most common side hols, such as , and . effect of zonisamide is drowsiness. Examples of psychostimulants include , dextro Barbituates are yet another known CNS active agent. Bar amphetamine, , , diethyl bituric acid and its derivatives are known to act mainly as propion, , cocaine, phencyclidine, and meth sedatives, hypnotics and anesthetics. Certain derivatives, ylenedioxymethamphetamine. such as 5-ethyl-5-phenyl barbituric acid (Phenobarbital), for Addictive drugs may further comprise antianxiety agents example, have an anticonvulsive effect and are therefore such as the benzodiazepines, alprazolam, bromazepam, chlo employed in the treatment of epilepsy. However, like other rdiazepoxide, clobazam, chlorazepate, diazepam, ?uni barbituric acid derivatives, phenobarbital has also sedative trazepam, ?urazepam, lorazepam, nitrazepam, oxazepam, and hypnotic effects that are disadvantageous in the treatment temazepam and triazolam, and neuroleptic and of epilepsy (TABLE 2). drugs, such as the , , ?uphena TABLE 2

Psychiatric side—effects of anti—epileptics including sedation.

Drug Psychiatric side—effects Phenobarbital Depression, sedation, sleep disturbances, psychosis, cognitive impairment, paradoxical agitation, delirium Primidone Sedation, mood lability, psychotic symptoms, delirium Benzodiazepines Agitation, sedation, hallucinations, psychosis, cognitive impairment, delirium, withdrawal syndrome Hydantoins Similar to Phenobarbital Sodium valproate Sedation, hallucinations, depressive symptoms, delirium Carbamazepine Depression, agitation, sedation, psychosis, cognitive impairment, delirium Tiagabine Psychosis (0.8% of treated patients), depressive symptoms, sedation Levetiracetam Irritability, sedation and psychosis Sedation, agitation, fatigue Lamotrigine Sedation, depression, agitation, psychosis (0.3% of treated patients)

Barbiturates in high concentrations may also prove neuro Zine, pericyaZine, , , , protective; however, the dosages necessary to confer neuro and tri?uoperaZine and the , dro protection are toxic and cause lethargy, stupor, coma, or are 40 peridol and and the other antipsychotic drugs lethal, making accepted dosages of barbiturates unsuitable such as , thiothixene and lithium. CNS , for treatment of ischemia and other neurodegenerative dis such as , may also be included. eases. When used along with the neuromodulators of the Cessation of addictive drugs brings with it numerous and present invention, lower therapeutically effective dosages 45 unpleasant withdrawal symptoms. For , withdrawal may be achieved. symptoms include irritability, anxiety, restlessness, lack of Opioids and other addictive drugs will now be discussed. concentration, lightheadedness, insomnia, tremors, increased As used herein, “” means all agonists and antagonists hunger and weight gain, and of course, an intense craving for of opioid receptors, such as mu (which can be denoted by mu tobacco. Withdrawal symptoms from the cessation of opioid or u), kappa (which can be denoted by kappa or K), and delta 50 use include craving, anxiety, dysphoria, yawning, perspira (which can be denoted by delta or A) opioid receptors and tion, lacrimation, rhinorrhoea, restless and broken sleep, irri subtypes thereof. “Addictive drugs” are any substance that is tability, dilated pupils, aching of bones, back and muscles, consumed by a mammal and causes addiction related behav piloerection, hot and cold ?ashes, nausea, vomiting, diarrhea, ior, cravings for the substance, rewarding/incentive effects, weight loss, fever, increased blood pressure, pulse and respi dependency characteristics, or any combination thereof. 55 ratory rate, twitching of muscles and kicking movements of Addictive drugs comprise psychostimulants, narcotic analge the lower extremities. Medical complications associated with sics, and addictive alkaloids, such as nicotine, or injection of opioids include a variety of pathological changes combinations thereof. Examples of psychostimulants include in the CNS including degenerative changes in globus palli amphetamine, , methamphetamine, dus, necrosis of spinal gray matter, transverse myelitis, phenmetraZine, diethylpropion, methylphenidate, cocaine, 60 amblyopia, plexitis, peripheral neuropathy, Parkinsonian phencyclidine, and methylenedioxymethamphetamine. syndromes, intellectual impairment, personality changes, and Examples of narcotic analgesics comprise opioids and pathological changes in muscles and peripheral nerves. Infec include alfentanyl, alphaprodine, anileridine, beZitramide, tions of skin and systemic organs are also quite common codeine, diazepam, dihydrocodeine, diphenoxylate, ethyh including staphylococcal pneumonitis, tuberculosis, norphine, fentanyl, heroin, hydrocodone, hydromorphone, 65 endocarditis, septicemia, viral hepatitis, human immunode isomethadone, , , metazocine, ?ciency virus (HIV), malaria, tetanus and osteomyelitis. methadone, metopon, , opium extracts, opium ?uid Pharmaceutical agents used in treating opioid dependence, US 8,729,070 B2 17 18 including methadone, naloxone, naltrexone, and , hormone activity and, unlike 3a,5a-P, cannot be converted to are not without their drawbacks, frequently causing their own metabolites with such activity. As with 3a,5a-P, set of side-effects. The present invention of combining the potentiation of the GABAA receptor occurs at a site distinct CNS active agent, in this embodiment, addictive drugs, with from the benzodiazepine site. Acute ganaxolone treatment is the neuromodulators of the present invention can be used to associated with reversible, dose-related sedation reduce dosages of addictive drugs during the period of Asenapine is described in US. Pat. No. 4,145,434. Cloza therapy for withdrawal. pine, 8-chloro-1 I-(4-methyl-i-piperazinyl)-5H-dibenzo[be] CNS active agents of the present invention may also com [1,4]diazepine, is used to treat schizophrenia. , prise analgesics, including opioids and opiates, such as oral 3 -[2-[4-(6-?uoro-1,2-benzisoxazol-3 -yl)piperidino] ethyl] - anileridine (Leritine®ianalogs of meperidine), Meperidine 2-methyl-6,7,8, 9-tetrahydro-4H-pyrido- [1 ,2-a]pyrimidin-4 (Demerol®), Normeperidine, Morphine and congeners, codeine, Tylenol, anti-in?ammatory agents, narcotics, anti one, is used to treat various psychotic diseases. , pyretics including the opioid analgesics-such as buprenor I-[2-[4-[5-chloro-1-(4-?uorophenyl)-1H-indol-3-yl 1-1-10 phine, dextromoramide, , fentanyl, piperidinyl]ethyl]imidazolidin-2-one, is also used to treat alfentanil, sufentanil, hydromorphone, methadone, mor schizophrenia. Quetiapine, 5-[2-(4-dibenzo[be][1,4]thiaz phine, oxycodone, papaveretum, pentazocine, pethidine, epin-1 I-yl-1 -piperazinyl)ethoxy] ethanol, is used to treat and phenoperidine, codeine and dihydrocodeine. Others include its activity in assays which demonstrate utility in the treat acetylsalicylic acid (aspirin), paracetamol, and phenazone. ment of schizophrenia are described in US. Pat. No. 4,879, Analgesics have wide-ranging side-effects from mild to 288. Quetiapine is typically administered as its (E)-2- severe, including sedation, psychic slowing, dysphoria, mood 20 dioate (2:1) salt. Aripiprazole, 7-{4-[4-(2,3-dichlorophenyl) changes, psychosis, convulsions, constipation, nausea, men 1-piperazinyl]-butoxy}-3,4-dihydro carbostyril or 7-{4-[4 tal clouding and delirium. The conventionally accepted effec (2,3 -dichlorophenyl)-1-piperazinylj-butoxy}-3,4-dihydro tive dosage of codeine ranges from doses of 15-30 mg, 1-3 2(1 H)-quinolinone, is an agent used times daily. for the treatment of schizophrenia. , a selective The CNS active agent of the present invention also includes 25 , is an atypical antipsychotic agent, antipsychotics. Conventional antipsychotics are antagonists higher doses of which block the postsynaptic dopamine of dopamine (02) receptors; atypical antipsychotics also have receptors resulting in an improvement in psychoses. Amisul 02 antagonistic properties, but with different binding kinet pride is not approved by the Food and Drug Administration ics, as well as, and activity at other receptors, particularly for use in the United States. Amisulpride (in 50 mg doses) is 5-HT2A, 5-HT2c and 5-HT1 D. Examples of antipsychotics 30 marketed as a treatment for dysthymia in Italy (as Deniban). for use in the present invention are clozapine (Clozaril®), Antidepressants may be used as analgesics at low doses to risperidone (Risperdal®), (Zyprexa®), quetiap manage chronic back pain. Tricyclic antidepressants (TCAs), ine (Seroquel®), ziprasidone (Geodon®), sertindole, such as amitriptyline, nortriptyline, and imipramine, and amisuipride and aripiprazole (Abilify®). selected tetracyclic agents are believed to control pain, due to Structurally similar to the benzodiazepine family, olanza the blockade of neurotransmitters, norepinephrine and sero pine (2-methyl-4-(4-methyl-1-piperazinyl)-1 OH-thieno[2, tonin. Side-effects of tricyclic antidepressants (TCAs) 3-bJ ii,5]benzo) is used to treat schizophrenia and biopolar include side-effects (dry mouth, cardiac mania, but has the signi?cant side-effects of increased appe arrhythmias, orthostatic hypotension), sedation, and a low tite and subsequent weight gain and sedation. ered seizure threshold. SEROQUEL® sustained release formulation (quetiapine 40 Other analgesics will now be described. Methotrimepra fumarate sustained release) and SEROQUEL® (original for zine (N ozinan®) is a with analgesic properties, mulation quetiapine) are used to treat schizophrenia, bipolar but it also has prominent sedative, anticholinergic, and disorder, major depressive disorder, dementia, and general hypotensive effects, which may preclude its use in most long ized anxiety disorder, in conventionally accepted therapeutic terrn therapy. Carbamazepine is widely used for chronic neu doses of 400-700 mg daily. While less likely to induce extra ropathic pain, such as trigeminal neuralgia, but has adverse pyramidal symptoms and long term tardive dyskinesia, one of effects (mainly drowsiness, dizziness and gait disturbance) SEROQUEL®’s prominent side-effects is sedation. Other over two weeks. Conventially accepted effected doses have side-effects include headache and dry mouth. been mostly 400-1000 mg/day. Carbamazepine risks many SEROQUEL XR is supplied for oral administration as 200 interactions and toxicities of particular signi?cance in the mg (yellow), 300 mg (pale yellow), and 400 mg (white). Each elderly (sedation, ataxia, hyponatremia, leukopenia). Its 200 mg tablet contains 230 mg of quetiapine fumarate equiva elimination half-life is about 12 hours. Gabapentin Gabapen lent to 200 mg quetiapine. Each 300 mg tablet contains 345 tin (N eurontin®), a well-known alpha-2-delta ligand, 1 -(ami mg of quetiapine fumarate equivalent to 300 mg quetiapine. nomethyl)cyclohexylacetic acid, is an antiepileptic agent that Each 400 mg tablet contains 461 mg of quetiapine fumarate is also approved to help alleviate neuropathic pain. Its mecha equivalent to 400 mg quetiapine. All tablets are capsule 55 nism of action is unknown. A second alpha-2-delta ligand, shaped and ?lm coated. Inactive ingredients for SEROQUEL , (S)-(+)-4-’amino-3~(2-methylpropyl)butanoic XR are lactose monohydrate, microcrystalline cellulose, acid, has been used for anti-convulsant and pain treatment. sodium citrate, hypromellose, and stearate. The Additional alpha-2-delta ligands are also known. Conven ?lm coating for all SEROQUEL XR tablets contain tionally accepted effective Gabapentin dosing should be ini hypromellose, polyethylene glycol 400 and titanium dioxide. tiated low and titrated 100 to 300 mg every three to ?ve days In addition, yellow iron oxide (200 and 300 mg tablets) are until pain relief is achieved or side-effects, such as dizziness included in the ?lm coating of speci?c strengths. or somnolence, become intolerable. Ganaxolone (3a-hydroxy-3b-methyl-5a-pregnan-20-one) Other suitable CNS active agents of the present invention is the 3b-methylated synthetic analog of the also include muscle relaxants (MRs) such as nonbenzodiaz (3a,5a-P), a metabolite of , epines generally and baclofen, diazepam, cyclobenzaprine and used to treat epilepsy in adults and children. Importantly, hydrochloride, dantrolene, methocarbamol, orphenadrine ganaxolone does not have signi?cant classical nuclear steroid and quinine. US 8,729,070 B2 19 20 Nonbenzodiazepines include a variety of drugs that can act dent, psychiatric side-effects, speci?cally sedation, particu at the brain stem or spinal cord level. Cyclobenzaprine is larly in the elderly (TABLE 4). structurally related to the tricycle antidepressant amitrip tyline but is not clinically used as an antidepressant. TABLE 4 Cyclobenzaprine relieves muscle spasms, but is not effective Psychiatric side—effects of antiparkinsonian for the treatment of muscle spasms due to CNS diseases, such drugs, including sedation. as cerebral palsy or spinal cord disease. Cyclobenzaprine possesses anticholinergic activity unlike that of carisoprodol, Drug(s) Psychiatric side—effects due to the structural similarity to amitriptyline. A 5-mg dose Apomorphine, bromocriptine, Sedation, psychomotor agitation, anxiety, has been found to be as effective as a lO-mg dose and has the cabergoline, lisuride, akathisia, sleep disturbance, advantage of less sedation. Cyclobenzaprine should be initi pergolide, ropinirole, hallucinations, psychosis, cognitive impairment, delirium ated with the lowest dose (5 mg) and titrated up slowly. Benzatropine Sedation, anxiety, psychosis, delirium, Elimination half-life is 1-3 days, and hence it can be given as visual hallucinations, potential for misuse a single bedtime dose. Possible side-effects include drowsi Biperiden Sedation, anxiety, psychosis, delirium, ness, diZZiness, and anticholinergic effects. visual hallucinations Carisoprodol and have moderate antispas modic effects and are mildly sedative. Similar to Carisopro Included in this category of CNS active agents are: Anti dol, most of Metaxalone’ s bene?cial effects are thought to be parkinson agents such as amantadine, , carbi due to its sedative properties. Principal advantages over other 20 dopa, levodopa, benZtropine, biperiden, benZhexyl, procycli commonly used MRs include lack of abuse, limited accumu dine and dopamine-2 agonists such as S(—)-2-(N-propyl-N lation due to relatively short elimination half-life, and rela 2-thienylethylamino)-5-hydroxytetralin (N -0923); tively low degree of sedation. A disadvantage of metaxalone such as phenyloin, valproic acid, primidone, may be its duration of four to six hours. The conventionally phenobarbitone, methylphenobarbitone and carbamazepine, accepted effective dose of metaxalone is 400 to 800 mg, three 25 ethosuximide, methsuximide, phensuximide, sulthiame and to four times daily. In some cases, metaxalone should be clonazepam. avoided in elderly patients, due to its anticholinergic and Antiemetics, antinauseants such as the phenothiaZines, sedative side-effects. prochloperaZine, and 5HT-3 receptor Methocarbamol (Robaxin®) including various formula antagonists such as and and others 30 such as , , , tions combined with acetaminophen, ASA, and codeine (e.g. , hyoscine, hyoscine hydrobromide, hyoscine Robaxacet-8®, Robaxisal-C®) has long been available to treat non-neuropathic pain. It also has a sedative effect. hydrochloride, and brompride. CNS agents generally are prescribed according to their The use of MRs for lower back pain (LBP) remains con conventionally accepted effective dosage. Conventionally troversional, mainly because of their side-effects. In addition 35 accepted effective dosages for some CNS agents are listed to sedation, potential adverse effects include drowsiness, below: headache, blurred vision, nausea, and vomiting, potential to Antipsychotics: abuse. Muscle relaxants and their conventionally accepted Clozapine: Adults: Initial: 12.5 mg qd-bid. Titrate: effective dosages are listed in TABLE 3 below. Increase by 25-50 mg/day, up to 300-450 mg/day by end 40 of 2nd week, then increase weekly or bi-weekly by up to TABLE 3 100 mg. Usual: 100-900 mg/day given tid. Max: 900 mg/day Conventionally accepted dosaoed of various muscle relaxant . Olanzapine: Usual DoseiOral olanzapine should be Muscle Relaxants Usual Dosage Range administered on a once-a-day schedule without regard to 45 meals, generally beginning with 5 to 10 mg initially, Carisoprodol 350 mg, 4 times daily Chlorzoxazone 250—500 mg, 3—4 times daily with a target dose of 10 mg/day within several days. Cyclobenzaprine 5—10 mg, 3—4 times daily Quetiapine (Seroquel): Bipolar Disorder: Depressive Epi Diazepam 2—10 mg, 3—4 times daily sodes: Give once daily hs. Day 1: 50 mg/day. Day 2: 100 Methocarbamol 4,000—4,500 mg/day in divided doses mg/day. Day 3: 200 mg/ day. Day 4: 300 mg/day. Bipolar Metaxalone 400—800 mg, 3—4 times daily 50 Mania: Monotherapy/Adjunctive: Give bid. Initial: 100 mg/day on Day 1. Titrate: Increase to 400 mg/day on In addition, Baclofen and are indicated for spas Day 4 in increments of up to 100 mg/day in bid divided ticity and muscle spasms associated with multiple sclerosis doses. Adjust doses up to 800 mg/day by Day 6 in and spinal cord trauma. All agents in this drug class appear to incrementss200 mg/day. Max: 800 mg/day. Mainte have a similar onset of action but vary in their elimination 55 nance for BipolarI Disorder: Give bid. 400-800 mg/day. half-lives, duration of activity, pharrnacokinetics, and phar Schizophrenia: Initial: 25 mg bid. Titrate: Increase by macodynamics. 25-50 mg bid-tid on the 2nd and 3rd day to 300-400 CNS active agents also include sedating . mg/day given bid-tid by the 4th day. Adjust doses by Diphenhydramine and are oral, sedating antihis 25-50 mg bid at intervals of at least 2 days. Maint: tamines that may be used for insomnia and nocturnal pain. 60 Lowest effective dose. Max: 800 mg/day. Other CNS active agents also comprise zaleplon, zolpi Ziprasidone (Geodon): Ef?cacy in schizophrenia was dem dem, eszopiclone and trazodone, which induce sleep. onstrated in a dose range of 20 to 100 mg BID in short Drugs for treatment of Neurodegenerative diseases will term now be described. Many of the drugs used to treat agitation Aripiprazole: The recommended starting and target dose accompanying neurodegenerative diseases, such as anti-Par 65 for ABILIFY is 10 mg/day or 15 mg/day administered kinsonian-PD and Anti-Alzheimer disease-AD drugs like on a once-a-day schedule without regard to meals. Arricept, Exelon, Memantine, and tacrine illicit does-depen ABILIFY has been systematically evaluated and shown US 8,729,070 B2 21 22 to be effective in a dose range of 10 mg/day to 30 Ropinirole: The recommended starting dose for Parkin mg/day, when administered as the tablet formulation son’s disease is 0.25 mg 3 times daily; based on indi Depakote: Initial: 10-15 mg/kg/ day. Titrate: Increase by vidual patient response, dosage should then be titrated 5-10 mg/kg/week. Max: 60 mg/kg/ day. with weekly increments as described in Table 5. After Tegretol: Initial: (Immediate- or Extended-Release Tabs) week 4, if necessary, daily dosage may be increased by 200 mg bid or (Sus) 100 mg qid, Titrate: (Immediate 1.5 mg/day on a weekly basis up to a dose of9 mg/day, Release Tabs/Sus) Increase weekly by 200 mg/ day given and then by up to 3 mg/day weekly to a total dose of 24 tid-qid. (Extended-Release Tabs) Increase weekly by mg/day. 200 mg/day given bid. Maint: 800-1200 mg/day. Max: Benzatropine-Initial: 0.5-1 mg PO/IV/IM qhs. Titrate: 1200 mg/day. May increase every 5-6 days by 0.5 mg. Usual: 1-2 mg Trileptal-Monotherapy: Initial: 4-5 mg/kg bid. Titrate: PO/IV/IM qhs. Max: 6 mg/day. Increase by 5 mg/kg/ day every 3rd day. Maint (mg/day): Anti-Convulsants: 20 kg: Initial: 600 mg. Max: 900 mg. 25-30 kg: Initial: Carbamazepine-Initial: 200 mg bid. Titrate: May increase 900 mg. Max: 1200 mg. 35-40 kg: Initial: 900 mg. Max: weekly by 200 mg/ day. Maint: 800-1200 mg/day. Max: 1500 mg. 45 kg: Initial: 1200 mg. Max: 1500 mg. 50-55 15 1200 mg/day. kg: Initial: 1200 mg. Max: 1800 mg. 60-65 kg: Initial: Gabapentin (N eurontin®): Initial: 300 mg tid. Titrate: 1200 mg. Max: 2100 mg. 70 kg: Initial: 1500 mg. Max: Increase up to 1800 mg/day. Max: 3600 mg/day. 2100 mg. Adjunct Therapy: Initial: 4-5 mg/kg bid. Max: Barbiturates (Phenobarbital): 60-200 mg/day 600 mg/ day. Titrate: Increase over 2 weeks. Maint (mg/ Primidone: Day 1-3: 100-125 mg qhs. Day 4-6: 100-125 day): 20-29 kg: 900 mg. 29.1-39 kg: 1200 mg.>39 kg: 20 mg bid. Day 7-9: 100-125 mg tid. Day 10-Maint: 250 mg 1800 mg. tid. Max: 500 mg qid. Analgesics: Tiagabine: Initial: 4 mg qd. Titrate: May increase weekly Amitriptyline-Initial: (Outpatient) 75 mg/day in divided by 4-brag until clinical response. Max: 56 mg/day given doses or 50-100 mg qhs. (Inpatient) 100 mg/ day. Titrate: bid-qid (Outpatient) Increase by 25-50 mg qhs. (Inpatient) 25 Anti-Depressants Increase to 200 mg/day. Maint: 50-100 mg qhs. Max: Remeron (mirtazapine): Initial: 15 mg qhs. Titrate: May (Outpatient) 150 mg/ day. (Inpatient) 300 mg/day increase every 1-2 weeks. Max: 45 mg/day. MethotrimepraZine (N oZinan®): Minor conditions in Elavil (Amitriptyline): Initial: (Outpatient) 75 mg/day in which NoZinan may be given in low doses as a tranquil divided doses or 50-100 mg qhs. (Inpatient) 100 mg/day. izer, anxiolytic, analgesic or sedative: begin treatment 30 Titrate: (Outpatient) Increase by 25-50 mg qhs. (Inpa with 6 to 25 mg/day in 3 divided doses at mealtimes. tient) Increase to 200 mg/day. Maint: 50-100 mg qhs. Increase the dosage until the optimum level has been Max: (Outpatient) 150 mg/day. reached. As a sedative, a single night time dose of 10 to Tofranil (Imipramine): Depression: Initial: (Inpatient) 100 25 mg is usually suf?cient. Severe conditions: Such as mg/day in divided doses. Titrate: Increase to 200 psychoses or intense pain in which NoZinan is employed 35 mg/day, up to 250-300 mg/ day after 2 weeks if needed. at higher doses: Begin treatment with 50 to 75 mg/day (Outpatient) 75 mg/ day. Titrate: Increase to 150 mg/day. divided into 2 or 3 daily doses; increase the dosage until Maint: 50-150 mg/ day. Max: 200 mg/ day. the desired effect is obtained. In certain psychotics, Norpramin (Desipramine): 100-200 mg/day given qd or in doses may reach 1 g or more/ day. If it is necessary to start divided doses. Max: 300 mg/day. therapy with higher doses, i.e., 100 to 200 mg/day, 40 Pamelor (Nortripyline): 25 mg tid-qid. Max: 150 mg/day. administer the drug in divided daily doses and keep the Sinequan (Doxepin): Very Mild Illness: Usual: 25-50 patient in bed for the ?rst few days. mg/day. Mild to Moderate Severity: Initial: 75 mg/day. Muscle Relaxants (MRs): Usual: 75-150 mg/day. Severely Ill: May increase up to Robaxin: Initial: (500 mg tab) 1500 mg qid for 2-3 days. 300 mg/day. Maint: 1000 mg qid. Initial: (750 mg tab) 1500 mg qid 45 Anafranil (Clomipramine): 25 mg/day with meals. Titrate: for 2-3 days. Maint: 750 mg q4h or 1500 mg tid. Max: 6 Increase within 2 weeks to 100 mg/ day. Increase further g/d for 2-3 days; 8 g/d if severe over several weeks. Max: 250 mg/day. Baclofen: Initial: 5 mg tid for 3 days. Titrate: May increase Trazodone: 150 mg/day in divided doses pc. Titrate: May dose by 5 mg tid every 3 days. Usual: 40-80 mg/day. increase by 50 mg/day every 3-4 days. Max: (Outpa Max: 80 mg/day (20 mg qid). tient) 400 mg/day, (Inpatient) 600 mg/day. Flexeril (cyclobenzaprine): Usual: 5 mg tid. Titrate: May Nefazodone: 100 mg bid. Usual: 300-600 mg/day. increase to 10 mg tid Conventionally accepted effective dosages may also be Soma (Carisoprodol): 250 mg to 350 mg three times a day found in the 2009 edition of Physicians’Desk Reference (Th and at bedtime omson 2009), which is incorporated herein for its convention Cyclobenzaprine: 15 mg qd. Titrate: May increase to 30 mg 55 ally accepted effective dosages of CNS active agents. qd if needed, As mentioned above, another element of the pharmaceuti Metaxalone: one 800 mg tablet three to four times a day cal composition of the present invention is the combination of Orphenadrine: 100 mg bid, in the am and pm neuromodulators, (NMS) which may be referred to herein as Neurodegenerative Diseases: Anti-Parkinsonian “vagal neuromodulators.” Neuromodulators of the present Apomorphine: 2 mg SC; closely monitor BP. Titrate: 60 invention will now be described in greater detail. Increase by 1 mg every few days; assess e?icacy/toler Neuromodulators modulate sensory receptors. Several ability. Max: 6 mg/day. types of sensory receptors are present on enteric neurons, Bromocriptine: 25 mg bid. Titrate: if needed, increase by including mechanoreceptors, chemoreceptors, thermal 2.5 mg/day every 2-4 weeks. Max: 100 mg/day. receptors, and possibly nociceptors (pain receptors). Low Cabergoline: 0.25 mg twice weekly. Titrate: May increase 65 and high-threshold mechanoreceptors are also present. The by 0.25 mg twice weekly at 4 week intervals. Max: 1 mg low-threshold receptors process normal input from the gut. twice weekly. The high-threshold receptors only respond to higher pres US 8,729,070 B2 23 24 sures and distention and may be important in mediating pain Mucomodulators include N-acetyl-cysteine are thiols with in patients with irritable bowel syndrome (IBS). Psychologi a free-sulfhydryl group. They are assumed to break disul?de cal factors are also important in the patient who develops IBS. bonds between gel-forming mucins and thus reduce mucus Serotonin, cholecystokinin (CCK), neurokinins, and other viscosity. Mucokinetic agents are thiols with a blocked sulf chemicals stimulate chemoreceptors. Mechanoreceptors also hydryl group. Expectorants such as guaifenesin (GUA) contain chemoreceptors. As a result, serotonin and other increase mucus secretion. They may act as irritants to gastric chemoreceptor stimulators serve a paracrine function and vagal receptors, and recruit efferent parasympathetic re?exes modify the response of mechanoreceptors in the gut. that cause glandular exocytosis of a less viscous mucus mix As used herein the “modulate, “neuromodulate,” and ture. “stimulate” mean the ability to regulate positively or nega Furthermore, the pharmaceutical compositions may com tively neuronal activity, preferably the activity of vagal nerve. prise mucomodulators that reduce the viscosity of the gastric mucosa, thereby accelerating the exposure of gastric mucosa These terms can be used to refer to an increase, decrease, to chemoreceptor neuromodulator, such as vasoactive agent masking, altering, overriding or restoring neuronal activity. or neurotransmitter. Such mucomodulators are, for example, Modulation, neuromodulation, or stimulation of neuronal reducing agents such as N-acetyl cysteine, dithiothreitol, activity affects psychological and/or psychiatric activity of a GUA, citric acid or mannitol. subject. Suitable mucomodulators also comprise expectorants, “Neuromodulator(s)” (NM) or “stimulating”, or “potenti including ambroxol, ammonium bicarbonate, ammonium ating” agents comprise medications, neurotransmitters and/ carbonate, bromhexine, iodide, carbocysteine, guai or mimetics thereof, synthetic or natural peptides or hor 20 acol, guaiacol benzoate, guaiacolcarbonate, guaiacol phos mones, neurotransmitters, cytokines and other intracellular phate, guaifenesin, guaithylline, hydriodic acid, iodinated and intercellular chemical signals and messengers, and the glycerol, potassium guaiacolsulfonate, potassium iodide, like. In addition, certain neurotransmitters, hormones, and sodium citrate, sodium iodide, storax, terebene, terpin, and other drugs are excitatory for some tissues, yet are inhibitory trifolium. to other tissues. NM may be endogenous, natural or pharma 25 Additional mechanoreceptor modulators are surfactants. ceutical agents that exert central nervous system (CNS) Surfactants modulate surface tension providing hypotension effects by interfering with one or more of neurotransmitter wherein the surface tension is less than 10; or hypertension systems. In particular case the neuromodulator agent is (the surface tension of about 10 to 70 dynes/ cm). Surfactants referred to as an “excitatory” drug, this means that the drug is in this invention may be selected from the following groups: acting in an excitatory manner, although it may act in an 30 PEGS (Polyethylene glycols); Sodium Lauryl Sulfates; Sor inhibitory manner in other circumstances and/or locations. bitan esters; Polysorbates and Benzalkonium Chlorides. Similarly, where an “inhibitory” drug is mentioned, this drug Polysorbate is selected from the group consisting of: Polysor is acting in an inhibitory manner, although in other circum bate 20 (polyoxethylene (20) sorbitan monolaurate), Polysor stances and/or locations, it may be an “excitatory” drug. In bate 40 (polyoxethylene (20) sorbitan monopalmitate), and addition, stimulation of an area herein includes stimulation of 35 Polysorbate 60 (polyoxyethylene (20) sorbitan monostear cell bodies and axons in the area, especially receptors of said ate). Other surfactants can be selected from such groups as neuromodulators localized on afferent or efferent vagal nerve dispersing agents, solubiliZing agents, emulsifying agents, ?bers. thickening and spreading agents. “Combination of” or “In combination with” a neuromodu Neuromodulators of the present invention also comprise lator of the present invention refers to co-administration of 40 chemoreceptor stimulators which will now be described. the two agents. Co-administration may occur either concur Chemoreceptor stimulators may be pH modulators, secreta rently or sequentially. gouges, adrinomimetics, xanthines, cholecystokinins and In the context of the present invention, neuromodulation of gastric agonists. Chemoreceptors are sensitive to biochemical centrally active agents refers to pharmaceutical stimulation of neurotransmitters, hormones, ATP-receptor modulators and vagal afferent and/or vagal efferent receptors by the admin 45 pH and generator information on nutrient concentration, istration of combinations of neuromodulators in the formula osmolarity and pH in the luminal contents. The actions of tions provided below. The vagal neuromodulator of the extracellular ATP are known to be mediated by speci?c cell present invention stimulates the vagal afferent and/or vaagal surface receptors, P2-purinoceptors. These receptors are sub efferent receptors when administered as part of the pharma divided into two families: P2x and P2y. Vaso-active, oxygen, ceutical composition. The vagal neuromodulator comprises 50 ATP-modulators, hypertensive, including succinic acid and mechanoreceptor stimulators, chemoreceptor stimulators, a other Krebs cycle intermediates, are also putative ATP modu vagal efferent stimulator, a vagal afferent stimulator and a lators, and therefore neuromodulators of chemoreceptors. nociceptor stimulator. Neuromodulators may also be used in Chemoreceptor stimulators of the present invention are neu combination with electrical stimulation. rotransmitters, neuropeptides and other agents that stimulate Mechanoreceptors sense mechanical events in the mucosa, 55 chemoreceptors localized in afferent nerves. musculature, serosal surface, and mesentery. They supply Chemoreceptor stimulators of the present invention com both the enteric minibrain and the CNS with information on prise adrenomimetics (ADR), (e.g. , noradrena stretch-related tension and muscle length in the wall and on line, adrianol, phenylephrine/metazone (PHE), , the movement of luminal contents as they brush the mucosal ethylephrine, etc.) and polypeptides (e.g. glucogon, angio surface. Whether the neuronal cell bodies of intramuscular 60 tensin, octapressin, etc.) that are most often used to affect and mucosal mechanoreceptors belong to dorsal root ganglia, arterial blood pressure by either stimulating alpha-adrenergic enteric ganglia, or both, is uncertain. Mechanoreceptor receptors or directly on the visceral muscles of the vascular stimulator(s) of the present invention stimulate the mechan wall. PHE may be classi?ed functionally as “Vasoactive” or oreceptors and comprise mucomodulators, surfactants and “Vasoconstricting” agent and/ or “Hypertensive agent” (refers vasoactive agents. 65 to any of a class of pharmacological agents which increase Preferable mechanoreceptors stimulators comprise muco blood pressure), examples of appropriate hypertensive agents modulators and vaso-active agents. include, without limitation, phenylephrine and sodium chlo