US 20110259786A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0259786 A1 Roberts et al. (43) Pub. Date: Oct. 27, 2011

(54) DROXDOPA AND PHARMACEUTICAL Publication Classification COMPOSITION THEREOF FOR THE TREATMENT OF FIBROMYALGA (51) Int. Cl. B65D 69/00 (2006.01) (76) Inventors: Michael J. Roberts, Charlotte, NC (52) U.S. Cl...... 2O6/570 (US); Simon Pedder, Fort Mill, SC (US) (57) ABSTRACT (21) Appl. No.: 13/174,827 The present invention provides methods of treating fibromy algia or other diseases or conditions causing widespread pain (22) Filed: Jul. 1, 2011 and/or fatigue. In particular, the invention provides pharma ceutical compositions comprising droxidopa alone, or in Related U.S. Application Data combination with one or more further active agents, that can be used in the inventive methods. The methods of treatment (62) Division of application No. 12/044,680, filed on Mar. can comprise treating, preventing, reducing, or eliminating a 7, 2008, now Pat. No. 8,008,285. variety of symptoms recognized as indicative of fibromyal (60) Provisional application No. 60/894,030, filed on Mar. gia. Such as chronic pain, allodynia, hyperalgesia, fatigue, 9, 2007. sleep disturbance, and depression.

Patent Application Publication Oct. 27, 2011 Sheet 2 of 2 US 2011/0259786 A1

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DROXDOPA AND PHARMACEUTICAL physically. Many fibromyalgia patients also have an associ COMPOSITION THEREOF FOR THE ated sleep disorder that prevents deep, restful, restorative TREATMENT OF FIBROMYALGA sleep. Studies have documented specific and distinctive abnormalities in the stage 4 deep sleep of fibromyalgia CROSS-REFERENCE TO RELATED patients. During sleep, individuals with fibromyalgia are con APPLICATION stantly interrupted by bursts of awake-like brain activity lim iting the amount of time they spend in deep sleep. Additional 0001. The present application is a division of U.S. Patent symptoms associated with fibromyalgia can include the fol application Ser. No. 12/044,680, filed Mar. 7, 2008, which lowing: irritable bowel and bladder, headaches and claims priority to U.S. Provisional Patent Application No. migraines, restless legs syndrome (periodic limb movement 607894,030, filed Mar. 9, 2007, the disclosures of which are disorder), impaired memory and concentration, skin sensi incorporated herein by reference in their entireties. tivities and rashes, dry eyes and mouth, anxiety, depression, ringing in the ears, dizziness, hypotension, vision problems, FIELD OF THE INVENTION Raynaud's Syndrome, neurological symptoms, and impaired 0002 The present application is directed to the use of coordination, as well as other symptoms. droxidopa, alone or in combination with one or more addi 0007 Currently there are no known diagnostic tests spe tional components, for the treatment of Central Sensitivity cific to fibromyalgia. Accordingly, diagnosis generally arises Syndromes, such as fibromyalgia. from evaluation of patient histories, self-reported symptoms, physical examination, and an accurate manual “tender point' BACKGROUND examination based on the standardized criteria from the 0003 Droxidopa is a known synthetic amino acid precur American College of Rheumatology (ACR). As defined by sor of norepinephrine that is converted directly to norepi ACR guidelines, FMS involves the presence of pain for over nephrine via the action of dopa decarboxylase (DDC). Droxi three months duration in all four quadrants of the body, as dopa is generally used to treat orthostatic hypotension (OH) well as along the spine. In addition, pain is elicited by palpa and can be categorized as an antiparkinsonian agent; how tion in at least 11 out of 18 “tender points'. It is estimated that ever, multiple pharmacological activities have been observed it takes an average of five years for a fibromyalgia patient to with droxidopa, including the following: (1) it is directly get an accurate diagnosis, and many fibromyalgia symptoms converted to 1-norepinephrine by the action of the aromatic overlap with those of other conditions. Moreover, the pres L-amino acid decarboxylase which is widely distributed in a ence of comorbidities (such as rheumatoid arthritis or lupus) living body, and thus has an effect of replenishing norepi does not rule out a fibromyalgia diagnosis. nephrine; (2) it has limited permeability through the blood 0008. The etiology and pathophysiology of fibromyalgia brain barrier into the brain; (3) it specifically recovers nore are unknown; however, it is generally believed to include pinephrine activated nerve functions which have decreased in central nervous system involvement. Most researchers agree the central and peripheral nervous system; and (4) it shows fibromyalgia is a disorder of central processing with neuroen various actions, as norepinephrine, via the adrenaline recep docrine/neurotransmitter dysregulation. Fibromyalgia tors in various tissues. patients often experience pain amplification due to abnormal 0004 Fibromyalgia—also referred to as fibromyalgia sensory processing in the central nervous system. Further syndrome (FMS)—is a chronic pain illness or condition char more, studies show multiple physiological abnormalities in acterized by a generalized heightened perception of sensory fibromyalgia patients, including: increased levels of Sub stimuli and manifested by widespreadaches, pain, and stiff stance P in the spinal cord; low levels of blood flow to the ness in muscles, fascia, and joints, as well as Soft tissue thalamus region of the brain; HPA axis hypofunction; low tenderness. The most common sites of pain include the neck, levels of serotonin and tryptophan; and abnormalities in back, shoulders, pelvic girdle, and hands, but any body part cytokine function. Recent studies indicate the possibility of a can be affected. Patients with fibromyalgia display abnor genetic susceptibility to fibromyalgia. malities in pain perception in the form of both allodynia (pain 0009 Treatment of fibromyalgia is often multi-faceted with innocuous stimulation) and hyperalgesia (increased sen and typically seeks to alleviate the associated symptoms sitivity to painful stimuli). Other symptoms typically include rather than treat the condition itself. Medications, such as general fatigue, sleep disturbances, and depression. analgesics, anti-inflammatories, and muscle relaxants can be 0005 Fibromyalgia is characterized by the presence of beneficial in reducing pain. Antidepressants may also be pre multiple tender points and a constellation of symptoms. The scribed. Complementary therapies include: physical therapy, pain of fibromyalgia is profound, widespread, and chronic therapeutic massage, myofascial release therapy, water and is known to migrate to all parts of the body with varying therapy, light aerobics, diet adjustments, acupressure, appli intensity. Fibromyalgia pain has been described as deep mus cation of heat or cold, acupuncture, yoga, relaxation exer cular aching, throbbing, twitching, stabbing and shooting cises, breathing techniques, aromatherapy, cognitive therapy, pain. Neurological complaints such as numbness, tingling, biofeedback, herbs, nutritional Supplements, and osteopathic and burning are often present and add to the discomfort of the or chiropractic manipulation. One or more of these may be patient. Pain severity and stiffness is often worse in the morn used. ing, and aggravating factors include cold/humid weather, 0010 Despite all of the above approaches for management non-restorative sleep, physical and mental fatigue, excessive offibromyalgia, there remains an ongoing search for effective physical activity, physical inactivity, anxiety, and stress. drug treatment of fibromyalgia. Multiple studies have been 0006 Fatigue associated with fibromyalgia can itself be performed around a wide variety of compounds, and Such debilitating, interfering with even the simplest daily activi studies are further referenced in U.S. Pat. No. 6,610,324, ties. At times, fibromyalgia-associated fatigue can leave the which is incorporated herein by reference. None of the pre patient with a limited ability to function both mentally and viously evaluated drugs have shown particularly useful for US 2011/0259786 A1 Oct. 27, 2011 long-term treatment of fibromyalgia beyond symptomatic tyline, nortriptyline, desipramine, traZodone, Venlafaxine, alleviation, and the need for effective drug treatment offibro dulloxetine, milnacipran, nefopam, bupropion, and combina myalgia persists. tions thereof. 0018. The invention also comprises methods of treating SUMMARY OF THE INVENTION fibromyalgia comprising administering droxidopa in combi 0011. The present invention provides pharmaceutical nation with one or more additional active agents having a compositions useful in the treatment of fibromyalgia or other complimentary activity to the activity of droxidopa. In one conditions falling under the umbrella of Central Sensitivity particular embodiment, the invention provides a method of Syndrome (CSS). The pharmaceutical compositions gener treating fibromyalgia comprising administering a pharma ally comprise droxidopa alone or in combination with one or ceutical composition comprising droxidopa and one or more more further pharmaceutically active compounds. DOPA decarboxylase inhibiting compounds. Preferably, the 0012. In one aspect, the invention provides a method of DOPA decarboxylase inhibiting compounds are selected treating fibromyalgia. In one embodiment, the method of the invention comprises administering to a subject suffering from from the group consisting of benserazide and carbidopa. fibromyalgia a pharmaceutical composition comprising a 0019. In a further embodiment, the invention provides a therapeutically effective amount of droxidopa. method of treating fibromyalgia comprising administering a 0013. In certain embodiments, treatment can be indicated pharmaceutical composition comprising droxidopa and one in a Subject that is suffering from fibromyalgia and exhibiting or more catechol-O-methyltransferase inhibiting com a symptom known to be indicative of fibromyalgia, such as pounds. Preferentially, the catechol-O-methyltransferase chronic pain, allodynia, hyperalgesia, fatigue, sleep distur inhibiting compounds are selected from a specified group of bance, and depression. In such embodiments, the method of compounds, such as entacapone, tolcapone, and nitecapone. treatment can comprise reducing or eliminating the symptom. 0020. In another embodiment, the invention provides a 0014. In further embodiments, treatment can be indicated method of treating fibromyalgia comprising administering a in a Subject that is Suffering from fibromyalgia and is know to pharmaceutical composition comprising droxidopa and one have previously exhibited a symptom known to be indicative or more cholinesterase inhibiting compounds. Preferentially, of fibromyalgia, Such as chronic pain, allodynia, hyperalge the cholinesterase inhibiting compounds are selected from a sia, fatigue, sleep disturbance, and depression. In Such specified group of compounds, such as pyridostigmine, done embodiments, the method of treatment can comprise prevent pezil, rivastigmine, galantamine, tacrine, neostigmine, met ing re-occurrence of the Symptom. rifonate, physostigmine, ambenonium, demarcarium, thia 0015. In specific embodiments, the method of the inven phySovenine, phenserine, edrophonium, cymserine, and tion comprises treating a patient Suffering from fibromyalgia combinations thereof. to reduce or eliminate pain associated with the fibromyalgia. 0021. In yet another embodiment, the invention provides a Preferably, such fibromyalgia-associated pain is reduced by method of treating fibromyalgia comprising administering a at least 40%. The effective treatment offibromyalgia canthus pharmaceutical composition comprising droxidopa and one be evidenced by the effective reduction in the fibromyalgia or more monoamine oxidase inhibiting compounds. Prefer associated pain. entially, the monoamine oxidase inhibiting compounds are 0016. In other embodiments, the method of the invention comprises treating a patient Suffering from fibromyalgia to selected from a specified group of compounds, Such as sel reduce or eliminate depression associated with the fibromy egiline, moclobemide, and lazabemide. algia. 0022. When the droxidopa is combined with one or more 0017. The present invention also provides a variety of additional active agents, the co-administration can be via a combinations of active agents, which combinations can be variety of methods. For example, the droxidopa and the addi particularly useful in the treatment of CSS, and particularly tional active agent can be in the same pharmaceutical com fibromyalgia. Thus, the invention provides combinations of position. In other embodiments, the droxidopa and the addi droxidopa and one or more further pharmaceutically active tional active agent can be administered in separate compounds, which combinations can be used in methods for compositions. In such embodiments, the separated composi treating CSS, particularly fibromyalgia. In certain embodi tions can be administered at the same time or within close ments, the one or more further pharmaceutically active com proximity to one another. Alternatively, the separate compo pounds comprise compounds useful for treatment or preven sitions can be administered as different times, which may be tion of symptoms associated with fibromyalgia. For example, desirable to optimize the effects of the co-administered active Such further pharmaceutically active compounds can com agents. prise antidepressants (such as selective serotonin reuptake 0023. In another embodiment, the invention is directed to inhibitors, tricyclics, serotonin norepinephrine reuptake a method of reducing, eliminating, or preventing pain asso inhibitors, norepinephrine reuptake inhibitors, and norepi ciated with fibromyalgia. The method can particularly com nephrine and dopamine reuptake inhibitors), anti-inflamma prise administering to a patient diagnosed as Suffering from tories, muscle relaxants, antibiotics, mood Stabilizers, antip fibromyalgia a pharmaceutical composition comprising a sychotics, serotonin receptor antagonists, serotonin receptor therapeutically effective amount of droxidopa. As above, the agonists, pain relievers, stimulants, NMDA receptor ligands, method can further comprise administering one or more addi S-adenosyl-methionine, Zopiclone, chlormeZanone, proglu tional active agents, such as described herein. metacin, 5-OH-L-tryptophan, gabapentin, pregabalin, and 0024. The invention also includes kits useful for practicing tamoxefin. In specific embodiments, the invention is directed the methods of the invention, Such as a kit comprising a to a composition comprising droxidopa in combination with container containing one or more therapeutically effective one or more antidepressants, such as fluoxetine, paroxetine, doses of droxidopa, and an instruction set describing a citalopram, escitalopram, fluvoxamine, Sertraline, amitrip method for administering a therapeutically effective amount US 2011/0259786 A1 Oct. 27, 2011 of droxidopa to a subject suffering from a Central Sensitivity Droxidopa is also known as threo-B3-dihydroxy-L-tyrosine, Syndrome, Such as fibromyalgia. (-)-(2S,3R)-2-amino-3-hydroxy-3-(3,4-dihydroxyphenyl) propionic acid, and threo-dopaserine, as well as the common BRIEF DESCRIPTION OF THE DRAWINGS terms DOPS, threo-DOPS, and L-DOPS. The compound can is optically active and can be provided in various forms, 0025 Having thus described the invention in general including L-threo-DOPS, D-threo-DOPS, L-erythro-DOPS, terms, reference will now be made to the accompanying and D-erythro-DOPS. The compounds can also exist in the drawings wherein: racemic form. The L-threo isomer is generally preferred 0026 FIG. 1 is a graph illustrating the average percentage according to the present invention; however, the invention inhibition of allodynia in rats following a Chronic Constric also encompasses compositions and methods of use incorpo tion Injury (CCI) and treated with a pharmaceutical vehicle, rating the other forms of droxidopa. Accordingly, as used fluoxetine, or a combination of droxidopa and carbidopa throughout the present disclosure, the term “droxidopa” is according to one embodiment of the invention; and intended to encompass any isolated or purified isomer (e.g., 0027 FIG. 2 is a graphical representation of the half-life of the L-threo isomer), as well as the racemic forms of droxi droxidopa in a mammal when administered alone or in com dopa. bination with various further active agents according to cer 0034 Droxidopa useful according to the invention can be tain embodiments of the invention. prepared by conventional methods, including methods par DETAILED DESCRIPTION ticularly useful for isolating the L-isomer of droxidopa. See, for example, U.S. Pat. No. 3,920,728; U.S. Pat. No. 4.319, 0028. The invention now will be described more fully 040; U.S. Pat. No. 4,480,109; U.S. Pat. No. 4,562,263: U.S. hereinafter through reference to various embodiments. These Pat. No. 4,699,879; U.S. Pat. No. 5,739,387; and U.S. Pat. embodiments are provided so that this disclosure will be No. 5,864.041, which are incorporated herein by reference. thorough and complete, and will fully convey the scope of the 0035. The present invention also encompasses composi invention to those skilled in the art. Indeed, the invention may tions comprising one or more pharmaceutically acceptable be embodied in many different forms and should not be esters, amides, salts, Solvates, or prodrugs of droxidopa. In construed as limited to the embodiments set forth herein; one embodiment, the invention involves use of droxidopa rather, these embodiments are provided so that this disclosure esters that allow for slowed or delayed decarboxylation of will satisfy applicable legal requirements. As used in the droxidopa resulting from hydrolytic or enzymatic degrada specification, and in the appended claims, the singular forms tion of the ester linkage. As would be recognized by one of “a”, “an”, “the’, include plural referents unless the context skill in the art, an ester of droxidopa can be formed by replac clearly dictates otherwise. ing the hydrogen on the carboxylic ester group with any 0029. The present invention provides pharmaceutical suitable ester-forming group. For example, U.S. Pat. No. compositions and methods that can be used in the treatment of 5,288.898, which is incorporated herein by reference, dis Central Sensitivity Syndrome (CCS), and particularly fibro closes various esters of N-methylphenylserine, including myalgia. Treatment can comprise the use of droxidopa as a methyl esters, ethyl esters, n-propyl esters, isopropyl esters, single active agent. In other embodiments, treatment can n-butyl esters, isobutyl esters, tert-butyl esters, n-pentyl comprise the use of droxidopa in combination with one or esters, isopentyl esters, n-hexyl esters, and the like, and the more further active agents. Such combinations are disclosed present invention encompasses such esters, as well as other in U.S. Patent Application Publication 2008/0015181, which esters. Further examples of ester-forming groups that could is incorporated herein by reference in its entirety. The specific be used according to the invention are disclosed in U.S. Pat. pharmaceutical composition (or compositions) used in the No. 5,864.041, which is incorporated herein by reference in invention, and the methods of treatment provided by the its entirety. invention, are further described below. 0036 B. Additional Active Agents 0030. I. Active Agents 0037. As noted above, in certain embodiments, the com 0031. The pharmaceutical compositions of the invention positions for use according to the methods of the invention generally comprise droxidopa as an active agent. In certain can comprise one or more active agents in addition to droxi embodiments, the pharmaceutical compositions can com dopa. Various preferred active agents that can be combined prise one or more further active agents. with droxidopa for treatment of fibromyalgia are described 0032 A. Droxidopa below. Of course, such disclosure should not be viewed as 0033. The compositions for use in the methods of the limiting the scope of further active agents that may be com invention generally comprise, as an active agent, threo-3-(3. bined with droxidopa. Rather, further active compounds, par 4-dihydroxyphenyl) serine, which is commonly known as ticularly compounds identified as useful for treating fibromy droxidopa and has the structure provided below in Formula algia, or for treating or preventing symptoms associated with (1). fibromyalgia, may be used in addition to the compounds specifically disclosed herein. 0038. In one particular embodiment, an active agent used (1) in combination with droxidopa comprises one or more DOPA OH decarboxylase (DDC) inhibitors. DDC catalyzes the decar HO COOH boxylation of levodopa (L-DOPA or 3,4-dihydroxy-L-pheny lalanine) and 5-hydroxytryptophan (5-HTP) to yield dopam NH2 ine and serotonin, respectively. Similarly, DDC catalyzes the HO conversion of droxidopa to norepinephrine. DDC inhibitors prevent the above-noted conversions and are useful in com bination with precursor drugs (such as droxidopa) to focus US 2011/0259786 A1 Oct. 27, 2011

conversion within the central nervous system and thus generally find use as pesticides (such as diazinon and Sevin) increase the concentration of droxidopa in the CNS. and chemical weapons (such as tabin and Sarin) and are not 0039. Any compound typically recognized as inhibiting or preferred according to the present invention. decreasing the activity of DDC can be used according to the 0044 Cholinesterase inhibitors are understood to include present invention. Non-limiting examples of DDC inhibitors compounds that increase levels of acetylcholine (or a cholin useful according to the invention comprise benserazide, car ergic agonist), generally by reducing or preventing the activ bidopa, difluoromethyldopa, C.-methyldopa, and combina ity of chemicals involved in the breakdown of acetylcholine, tions thereof. Such as acetylcholinesterase. Cholinesterase inhibitors may 0040. In further embodiments, an active agent used in also include compounds having other mechanisms of action, combination with droxidopa comprises one or more com Such as stimulating release of acetylcholine, enhancing pounds that at least partially inhibit the function of catechol response of acetylcholine receptors, or potentiating gonadot O-methyltransferase (such compounds being generally ropin releasing hormone (GNRH)-induced growth hormone referred to as “COMT inhibitors'). Catechol-O-methyltrans release. Moreover, cholinesterase inhibitors may act by ferase catalyzes the transfer of the methyl group from S-ad enhancing ganglionic transmission. enosyl-L-methionine to various catechol compounds (e.g., 0045 Any compound generally recognized as being a catecholamines), including dopamine, epinephrine, norepi cholinesterase inhibitor (or an anticholinesterase compound) nephrine, and droxidopa. The COMT enzyme is important in may be useful according to the present invention. Non-limit the extraneuronal inactivation of catecholamines and drugs ing examples of cholinesterase inhibitors useful in combina with catechol structures, and is generally one of the most tion with droxidopa for preparing compositions according to important enzymes involved in the metabolism of catechola the invention include the following: 3-dimethylcarbamoy mines and their metabolites. It is present in most tissues, loxy-1-methylpyridinium, also called pyridostigmine (MES including the peripheral and the central nervous system. TINONR) or Regonol); (+)-2,3-dihydro-5,6-dimethoxy-2- 0041. Inhibitors of COMT slow metabolism and elimina 1-(phenylmethyl)-4-piperidinyl)methyl)-1H-inden-1-one, tion of catechol compounds by increasing their half-life. also called donepezil (ARICEPTR): (S)-N-ethyl-3-((1-dim Accordingly, COMT inhibitors can function to increase lev ethyl-amino)ethyl)-N-methylphenyl-carbamate, also called els of naturally occurring catechol compounds, as well as rivastigmine (Exelon); (4aS,6R,8aS)-4a,5.9,10,11,12 alter the pharmacokinetics of administered catechol com hexahydro-3-methoxy-11-methyl-6H-benzofuro3a, 3, 2ef pounds (such as L-B-3,4-dihydroxyphenylalanine 2)benzazepin-6-ol, also called galantamine (REMINYL(R) or (L-DOPA), an immediate precursor of dopamine, generally RAZADYNER): 9-amino-1,2,3,4-tetrahydroacridine, also used for symptomatic treatment of Parkinson's disease) called tacrine (COGNEXR); (m-hydroxyphenyl)trimethy Inhibitors of COMT can act peripherally (such as the com lammonium methylsulfate dimethylcarbamate, also called pound entacapone), while others (such as tolcapone) are neostigmine; 1-hydroxy-2.2.2-trichloroethylphosphonic capable of crossing the blood-brain barrier and thus acting acid dimethyl ester, also called metrifonate or trichlorofon; centrally and peripherally. 1.2.3,3A,8.8A-hexahydro-13a,8-trimethylpyrrolo-2,3-N- 0.042 Any compound generally recognized as being a indole-5-ol methylcarbamate ester, also called physostig COMT inhibitor can be used as an additional active agent mine: Oxalylbis(iminoethylene)-bis-(o-chlorobenzyl)di according to the invention. Non-limiting examples of COMT ethylammoniumdichloride, also called ambenonium inhibitors useful in combination with droxidopa for treatment (MYTELASER): ethyl (m-hydroxyphenyl)dimethylammo offibromyalgia according to the invention include the follow nium, also called edrophonium (ENLONR); demarcarium; ing: (E)-2-cyano-N,N-diethyl-3-(3,4-dihydroxy-5-nitro thiaphySovenine; phenserine; and cymserine. phenyl)propenamide, also called entacapone (COMTANR): 0046 More generally, compounds useful as cholinest 4-dihydroxy-4-methyl-5-nitrobenzophenone, also called tol erase inhibitors according to the invention can comprise car capone (TASMAR(R); and 3-(3,4-dihydroxy-5-nitrophenyl) bamate compounds, particularly phenylcarbamates, ogano methylene-2,4-pentanedione, also called nitecapone. In addi phosphate compounds, piperidines, and phenanthrine tion to the above examples, U.S. Pat. No. 6.512,136 (the derivatives. The invention further comprises cholinesterase disclosure of which is incorporated herein by reference) inhibitors that are carbamoyl esters, as disclosed in U.S. Pub describes various substituted 2-phenyl-1-(3,4-dihydroxy-5- lished Patent Application No. 2005/0096387, which is incor nitrophenyl)-1-ethanone compounds that may also be useful porated herein by reference. as COMT inhibitors according to the present invention. Like 0047. The above groups of compounds, and specific com wise, U.S. Pat. No. 4,963,590; GB 2 200 109; U.S. Pat. No. pounds, are provided to exemplify the types of cholinesterase 6,150,412; and EP237929, each describes groups of COMT inhibitors that are useful according to the invention and inhibiting compounds that could be useful according to the should not be viewed as limiting the scope of the invention. In present invention, and the disclosure of each of the above fact, the invention can incorporate various further cholinest noted documents is incorporated herein by reference. erase inhibitors, including compounds described in the fol 0043. According to another embodiment of the invention, lowing documents, the disclosures of which are incorporated an active agent used in combination with droxidopa com herein by reference: Brzostowska, Malgorzata, et al. “Phe prises one or more compounds that at least partially inhibit the nylcarbamates of (-)-Eseroline, (-)-N1-Noreseroline and function of cholinesterase. Such cholinesterase inhibiting (-)-Physovenol: Selective Inhibitors of Acetyl and, or compounds may also be referred to as anticholinesterase Butyrylcholinesterase.” Medical Chemistry Research. (1992) compounds. Cholinesterase inhibiting compounds can be Vol. 2, 238-246; Flippen-Anderson, Judith L., et al. “Thia reversible or non-reversible. The present invention preferably physovenol Phenylcarbamates: X-ray Structures of Biologi encompasses any compounds that may be considered revers cally Active and Inactive Anticholinesterase Agents.” Hetero ible cholinesterase inhibitors (either competitive or non-com cycles. (1993) Vol. 36, No. 1: Greig, Nigel H., et al. petitive inhibitors). Non-reversible cholinesterase inhibitors “Phenserine and Ring C Hetero-Analogues: Drug Candidates US 2011/0259786 A1 Oct. 27, 2011

for the Treatment of Alzheimer's Disease.” Medicinal fascia, fatigue, sleep disturbance, and depression. Accord Research Reviews. (1995) Vol. 15, No. 1,3-31; He, Xiao-shu, ingly, the additional active agents of the invention can com et al. “Thiaphysovenine and Carbamate Analogues: A New prise compounds useful for treating, reducing, or preventing Class of Potent Inhibitors of Cholinesterases.” Medical any of the above-noted symptoms that present with fibromy Chemistry Research. (1992) Vol. 2, 229-237: Lahiri, D. K., et algia. al. “Cholinesterase Inhibitors, B-Amyloid Precursor Protein 0053. In certain embodiments, the present invention pro and Amyloid B-Peptides in Alzheimer's Disease.” Acta Neu vides a method for treating fibromyalgia comprising admin rologica Scandinavia. (December 2000) Vol. 102 (s176), istering a combination of droxidopa and one or more antide 60-67; Pei, Xue-Feng, et al. “Total Synthesis of Racemic and pressants (in addition to MAOIs already noted above). Optically Active Compounds Related to Physostigimine and Antidepressants useful according to the invention comprise Ring-C Heteroanalogues from 3-2-(Dimethylamino0ethyl selective serotonin reuptake inhibitors (SSRIs), tricyclics, 2,3-dihydro-5-methoxy-1, 3-dimentyl-1H-indol-2-ol.' Hel serotonin norepinephrine reuptake inhibitors (5-HT-NE dual vetica Chimica ACTA. (1994) Vol. 77; Yu, Qian-sheng, et al. reuptake inhibitors), norepinephrine reuptake inhibitors “Total Syntheses and Anticholinesterase Activities of (NRIs), and norepinephrine and dopamine reuptake inhibi (3aS)-N (8)-Norphysostigmine, (3aS)-N (8)-Norphenserine, tors (NDRIs). Non-limiting examples of specific antidepres Their Antipodal Isomers, and Other N (8)-Substituted Ana sants useful according to the invention comprise fluoxetine, logues.”.J.Med. Chem. (1997) Vol. 40,2895-2901; andYu, Q. paroxetine, citalopram, escitalopram, fluvoxamine, Sertra S., et al. “Novel Phenserine-Based-Selective Inhibitors of line, amitriptyline, nortriptyline, desipramine, traZodone, Butyrylcholinesterase for Alzheimer's Venlafaxine, dulloxetine, milnacipran, nefopam (including 0048 Disease.” Reprinted with permission from J. Med. (+)-nefopam), and bupropion. For example, U.S. Patent Chem., May 20, 1999, 42, 1855-1861. Application Publication No. 2006/0019940, which is incor 0049 According to yet another embodiment of the inven porated herein by reference in its entirety, discloses benzox tion, an active agent used in combination with droxidopa azocine compounds useful as noradrenaline and serotonin comprises one or more compounds that at least partially reuptake inhibitors, and Such compounds are useful accord inhibit the function of monoamine oxidase. Monoamine oxi ing to the present invention. dase inhibitors (MAOIs) comprise a class of compounds 0054. In further embodiments, the present invention pro understood to act by inhibiting the activity of monoamine vides a method for treating fibromyalgia comprising admin oxidase, an enzyme generally found in the brain and liver of istering a combination of droxidopa and one or more anti the human body, which functions to break down monoamine inflammatories. Anti-inflammatories useful according to the compounds, typically through deamination. invention comprise steroidal anti-inflammatories and non 0050. There are two isoforms of monoamine oxidase steroidal anti-inflammatory drugs (NSAIDs). Non-limiting inhibitors, MAO-A and MAO-B. The MAO-A isoform pref examples of specific anti-inflammatories useful according to erentially deaminates monoamines typically occurring as the invention comprise prednisone, cortisone, dexametha neurotransmitters (e.g., serotonin, melatonin, epinephrine, Sone, methylprednisone, ibuprofen, ketoprofen, aspirin, norepinephrine, and dopamine). Thus, MAOIs have been his naproxen, and Cox-II inhibitors, such as celebrex. torically prescribed as antidepressants and for treatment of 0055. In additional embodiments, the present invention other Social disorders, such as agoraphobia and Social anxi provides a method for treating fibromyalgia comprising ety. The MAO-B isoform preferentially deaminates phenyl administering a combination of droxidopa and one or more ethylamine and trace amines. Dopamine is equally deami muscle relaxants. Muscle relaxants useful according to the nated by both isoforms. MAOIs may by reversible or non invention comprise both benzodiazepines and non-benzodi reversible and may be selective for a specific isoform. For azepines. Non-limiting examples of specific muscle relaxants example, the MAOI moclobemide (also known as Manerix or useful according to the invention comprise diazepam, alpra Aurorix) is known to be approximately three times more Zolam, lorazepam, triazolam, baclofen, carisoprodol, chlor Selective for MAO-A than MAO-B. ZOxazone, cyclobenzaprine, dantrolene, metaxalone, 0051. Any compound generally recognized as being an orphenadrine, pancurion, and tizanidine. MAOI may be useful according to the present invention. 0056. The above compounds and classes of compounds Non-limiting examples of MAOIs useful in combination with are only examples of the types of active agents that can be droxidopa for preparing compositions according to the inven used in combination with droxidopa for the treatment of tion include the following: isocarboxazid (MARPLANR): fibromyalgia and are not intended to be limiting of the inven moclobemide (Aurorix, Manerix, or Moclodura); phenelzine tion. Rather, various further active agents can be combined (NARDIL(R); tranylcypromine (PARNATE(R); selegiline with droxidopa according to the invention. Moreover, it is (ELDEPRYL(R), EMSAM , or 1-deprenyl); lazabemide: possible according to the invention to combine two or more nialamide; iproniazid (marsilid, iprozid, ipronid, rivivol, or additional active agents with droxidopa for the treatment of propilniaZida); iproclozide; toloxatone; harmala; brofarom fibromyalgia. Non-limiting examples of further active agents ine (Consonar); benmoxin (Neuralex); and certain that can be combined with droxidopa include: antibiotics tryptamines, such as 5-MeO-DMT (5-Methoxy-N,N-dimeth (such as those specific for lyme disease); mood stabilizers yltryptamine) or 5-MeO-AMT (5-methoxy-C.-methyl (such as lithium, olanzipine, Verapamil, quetiapine, lamot tryptamine). rigine, carbamazepine, Valproate, oXcarbazepine, risperi 0052. In specific embodiments, active agents used in com done, aripiprazole, and Ziprasidone); antipsychotics (Such as bination with droxidopa comprise one or more compounds haloperidol and other butyrophenones, chlorpromazine, useful for treating fibromyalgia or for reducing or preventing fluphenazine, perphenazine, prochlorperazine, and other phe occurrence of symptoms associated with fibromyalgia. As nothiazines, and clozapine); serotonin receptor antagonists previously discussed, fibromyalgia manifests itself by a vari (5-HT2 and 5-HT3 antagonists) (such as ondansetron, tro ety of symptoms including pain of the joints, muscles, and pisetron, katenserin, methysergide, cyproheptadine, and US 2011/0259786 A1 Oct. 27, 2011 pizotifen); serotonin receptor agonists (5-HT1A receptor reducing or eliminating the symptom. Likewise, the patient agonists) (Such as buspirone); pain relievers (such as acetami can be a patient that has previously suffered from a symptom nophen, flupirtine, and tramadol); Stimulants (such as caf of fibromyalgia, and the treatment can comprise preventing feine or modafinil); NMDA (glutamate) receptor ligands re-occurrence of the symptom or reducing the severity of the (such as ketamine); S-adenosyl-methionine; Zopiclone; chlo symptom upon re-occurrence. rmeZanone; proglumetacin, 5-OH-L-tryptophan; gabapentin, 0061 Although the exact underlying cause of fibromyal pregabalin, and tamoxefin. Although the above compounds gia is not completely understood, most researchers agree are described in terms of classes of compounds and specific fibromyalgia involves a processing disorder in the central compounds, it is understood that there is substantial overlap nervous system including neuroendocrine/neurotransmitter between certain classes of compounds (such as between dysregulation. In particular, fibromyalgia has been associated mood stabilizers, antipsychotics, antidepressants, and sero with reduced levels of the neurotransmitters serotonin and tonin receptor antagonists). Thus, specific compounds exem norepinephrine, and avenues for increasing neurotransmitter plifying a specific class of compounds may also properly be levels within the brain can be effective in treating fibromyal identified with one or more further classes of compounds. gia. Because serotonin and norepinephrine are thought to be Accordingly, the above classifications should not be viewed key mediators of descending pain pathways, increasing levels as limiting the Scope of the types of compounds useful in of these neurotransmitters can particularly be useful for combination with droxidopa for treating fibromyalgia. reducing pain associated with fibromyalgia. Interventions for fibromyalgia thus have included neurotransmitter reuptake II. Methods of Treatment inhibitors; however, many reuptake inhibitors also cause 0057 The present invention, in a specific embodiment, undesirable side effects (e.g., weight changes, sleep disrup provides a method for the treatment of fibromyalgia. In fur tion, and sexual dysfunction). ther embodiments, the invention more generally provides 0062 Droxidopa is converted to norepinephrine by the methods of treating conditions having the pathophysiology of action of the aromatic L-amino acid decarboxylase DDC. central sensitization, typically causing widespread pain and/ Droxidopa is believed to be useful for treating conditions of or fatigue. Such conditions may be grouped into the category central sensitization, and particularly fibromyalgia, because of Central Sensitivity Syndromes (CSS) and include disor of its ability to increase norepinephrine levels via the noted derS Such as fibromyalgia, chronic myofascial pain, chronic conversion process. Since fibromyalgia (and other conditions fatigue syndrome, restless leg syndrome, and irritable bowel categorized under the heading of CSS) are linked to reduced Syndrome. norepinephrine levels, treatments that increase the available 0058. Throughout the present specification, the method of amount of norepinephrine, particularly in the CNS, are ben treatment of the invention may be referenced in terms of eficial for treating such conditions. For example, Some pub treatment offibromyalgia. While treatment offibromyalgia is lished research indicates a possible link between autonomic a preferred embodiment of the invention, disclosure in terms dysfunction (i.e., orthostatic hypotension) and fibromyalgia. thereof is not intended to limit the scope of the invention. Such research confirms the relationship between reduced Rather, as further described below, the present invention can norepinephrine levels and fibromyalgia, and increasing nore provide methods of treating a variety of diseases or conditions pinephrine levels would thus be indicated for treating fibro characterized by widespread pain and/or fatigue, particularly myalgia. See Lowe, P., (1998) Cardiol. Rev. 6(3): 125-134, those conditions typically recognized under the CSS cat and Lowe, P. (1995), Lancet 345(8950): 623-624. egory. 0063 As previously noted, fibromyalgia is a chronic pain 0059. The methods of the invention generally comprise condition characterized by a generalized heightened percep administering droxidopa to a patient Suffering from a condi tion of sensory stimuli and manifested by widespreadaches, tion of central sensitization or a condition generally causing pain, and stiffness in muscles, fascia, and joints, as well as soft widespread pain and/or fatigue. In a specific embodiment, the tissue tenderness. Patients with fibromyalgia display abnor invention comprises administering droxidopa to a patient malities in pain perception in the form of both allodynia (pain exhibiting symptoms of, or having been diagnosed as Suffer with innocuous stimulation) and hyperalgesia (increased sen ing from, fibromyalgia. In further embodiments, the inven sitivity to painful stimuli). Thus, there is a clear connection tion comprises administering droxidopa to a patient suffering between pain alleviation and effective fibromyalgia treat from one or more further conditions included in the category ment, and this connection is well documented in the litera of Central Sensitivity Syndromes. Accordingly, the present ture. A 1998 study by I. J. Russell (Am. J. Med. Sci., 315(6): invention can be described as providing methods for treating 377–384) noted that the term allodynia is properly associated a condition categorized as a Central Sensitivity Syndrome. In with fibromyalgia because people with fibromyalgia experi certain embodiments, the invention provides methods of ence pain from pressure stimuli that are not normally painful. treating fibromyalgia. In other embodiments, the invention Thus, Russell determined that the nociceptive neurotransmit can be described as providing methods for treating, reducing, ters of animal studies are relevant to the human model of or preventing a symptom associated with fibromyalgia. In chronic, widespread pain that is common with fibromyalgia. particular, the invention provides methods for treating, reduc The association between pain and fibromyalgia and the effi ing, or preventing chronic pain, allodynia, hyperalgesia, cacy for treatment of fibromyalgia as evidenced by effective fatigue, sleep disturbance, and depression associated with treatment of chronic pain is further supported in the literature. fibromyalgia or another condition categorized as CSS. A 2005 study by Bomholt et al. (Brain Res., 1044(2): 216 0060 Thus, in specific embodiments, the inventive 226) illustrated that chronic pain conditions, such as fibro method can comprise treating a patient Suffering from fibro myalgia, are associated with profound hypothalamo-pitu myalgia. In particular, the patient can be a patient suffering itary-adrenal (HPA) axis dysfunction which can exacerbate from a symptom, Such as described above, typically associ symptoms of chronic pain. Another 2005 study by Pedersenet ated with fibromyalgia, and the treatment can comprise al. (Psychopharmacology (Berl), 18204): 551-561) deter US 2011/0259786 A1 Oct. 27, 2011 mined that anti-nociception is selectively enhanced by paral in increasing norepinephrine levels. Many DDC inhibitors, lel inhibition of multiple subtypes of monoamine transporters Such as benserazide and carbidopa, do not enter the central in rat models of persistent and neuropathic pain. A 2002 study nervous system. Rather, they remain within the periphery by Gracely et al. (Arthritis & Rheumatism, 46(5): 1333-1343) where they prevent decarboxylation of compounds (such as used functional magnetic resonance imaging (fMRI) to pro levodopa or droxidopa) into the active metabolites (such as vide evidence that fibromyalgia is characterized by cortical norepinephrine). Thus, when a non-CNS DDC inhibitor is and Subcortical augmentation of pain processing in the administered in combination with droxidopa, the DDC human brain. A 1988 study by Bennett, G. J. and Xie, Y. K. inhibitor prevents decarboxylation of the droxidopa in the (Pain, 33(1): 87-107) indicated that a rat model of peripheral periphery and therefore allows more droxidopa to enter the mononeuropathy produced through chronic constrictive CNS intact. Once within the CNS (and thus segregated from injury (CCI) was an effective model of pain sensation disor the DDC inhibitor), the droxidopa can be converted to nore ders like those experienced by humans. Example 1 below uses pinephrine. Accordingly, the combination of a DDC inhibitor such a model to illustrate the effectiveness of the invention for with droxidopa can increase the effective ability of the droxi treating fibromyalgia through reduction of chronic pain. dopa to provide norepinephrine within the CNS and thereby 0064. The invention is thus particularly characterized by reduce the dose of droxidopa necessary to be effective in the ability to treat fibromyalgia through reducing or eliminat treating fibromyalgia. ing pain associated with the fibromyalgia. Such pain can be 0068. As previously noted, catechol-O-methyltransferase chronic pain, allodynia, or hyperalgesia, all of which are is directly involved in the metabolism of catecholamines, commonly associated with fibromyalgia and are recognized including dopamine, epinephrine, norepinephrine, and droxi as clear indicators that a patient is suffering from fibromyal dopa. Accordingly, by providing droxidopa in combination gia. In specific embodiments, the methods of the present with a COMT inhibitor, the ability of the droxidopa to affect invention are useful for reducing pain by at least about 30%. fibromyalgia is conserved. Specifically, by inhibiting the Such reduction in pain can be determined by objective testing, action of COMT, the COMT inhibiting compound slows or Such as measuring a patient's response palpation of known delays the metabolism of droxidopa (as well as norepineph pain sites. Likewise, pain reduction can be evaluated as a rine itself). This influences the overall plasma concentration subjective report from the patient describing the patient's of the droxidopa by increasing both the peak plasma concen overall pain level in light of the treatment. Preferably, the tration (C.) and the half-life of the administered droxidopa. methods of the invention are useful for reducing pain by at This is particularly beneficial in that it allows for reduced least about 40%, at least about 50%, at least about 60%, at dosages of droxidopa without limiting effective treatment of least about 70%, at least about 80%, or at least about 90%. In fibromyalgia. Further, the combination of the COMT inhibi specific embodiments, pain can be completely eliminated by tor with droxidopa may be effective for increasing the dura treatment according to the invention. tion of the droxidopa activity (i.e., increasing the duration of 0065. In other specific embodiments, the methods of the norepinephrine activity), which may allow for a reduction in invention are particularly useful for reducing or eliminating dosing frequency of the droxidopa. depression associated with fibromyalgia. It is readily recog 0069. The combination of droxidopa with an MAOI has a nized that depression and fibromyalgia often coincide. The similar effect of conserving bodily norepinephrine levels. In chronic pain offibromyalgia, as well as the dearth of effective particular embodiments, the MAOI inhibits the action of treatments, can often lead to depression. There may also be a monoamine oxidase in breaking down norepinephrine, common underlying cause, however, in the link between neu including that formed from the conversion of droxidopa. rotransmitter levels and depression and fibromyalgia. Thus, it Accordingly, droxidopa plasma concentrations are positively has been found according to the present invention that treat influenced as the half-life of the droxidopa is increase. This is ment offibromyalgia can be evidenced by the effective reduc again particularly beneficial in allowing for reduced droxi tion or elimination of the depressive state often associated dopa dosages without limiting effective treatment of fibro with fibromyalgia. A reduction in depression can be indicated myalgia. Moreover, the combination of the MAOI with droxi as a self-reported improvement by the patient. Further, dopa is also effective for increasing droxidopa activity reduced depression (and thus effective treatment of fibromy duration, which again may allow for a reduction in dosing algia) can also be indicated by objective evaluation of a pre frequency of the droxidopa. viously depressed Subject and noting certain indicators of 0070. In certain embodiments, the combination of droxi reduced depression, Such as increased activity, increased dopa with cholinesterase inhibitors is particularly effective interest in various stimuli, and the like. arising from Synergistic properties. As previously noted, cer 0066. The methods of treatment provided by the present tain cholinesterase inhibitors (such as pyridostigmine) have invention comprise administering, to a Subject suffering from been found to enhance ganglionic transmission, thereby fibromyalgia, droxidopa or droxidopa in combination with directly affecting fibromyalgia and providing some degree of one or more further active agents, as described herein. In treatment for fibromyalgia and its associated symptom. The certain embodiments, the one or more further active agents synergistic effect of the cholinesterase inhibitor with droxi provide a conserving effect on the droxidopa. In further dopa can therefore be envisioned. For example, in a specific embodiments, the one or more further active agents provide a embodiment, pyridostigmine could be combined with droxi complimentary effect to the action of the droxidopa, prefer dopa, the pyridostigmine enhancing ganglionic neurotrans ably treating or reducing one or more of the symptoms asso mission while the droxidopa acts to load the postganglionic ciated with fibromyalgia, Such as pain, depression, fatigue, neuron with norepinephrine. hypotension, or sleep disturbance. 0071. The combination of droxidopa with the further 0067. In particular embodiments, droxidopa is combined active agents is also particularly useful in the treatment of with one or more DDC inhibitors. Such a combination is fibromyalgia. For example, combining droxidopa with one or particularly beneficial for focusing the effect of the droxidopa more antidepressants can lead to a synergistic effect. More US 2011/0259786 A1 Oct. 27, 2011

over, treatments that affect neurotransmitter levels are known 0078 iii) enzymatic resolutions whereby partial or com to require a “build-up' phase of one to three weeks to reach plete separation of a racemate by virtue of differing rates of maximum effectiveness. Thus, combining droxidopa with reaction for the enantiomers with an enzyme; one or more further active agents that can provide immediate 0079 iv) enzymatic asymmetric synthesis, a synthetic relief to symptoms associated with fibromyalgia, such as technique whereby at least one step of the synthesis uses an inflammation or sleep disorders, can be particularly useful. enzymatic reaction to obtain an enantiomerically pure or III. Biologically Active Variants enriched synthetic precursor of the desired enantiomer; 0080 V) chemical asymmetric synthesis whereby the 0072 Biologically active variants of the various com desired enantiomer is synthesized from an achiral precursor pounds disclosed herein as active agents are particularly also under conditions that produce asymmetry (i.e., chirality) in encompassed by the invention. Such variants should retain the product, which may be achieved using chiral catalysts or the general biological activity of the original compounds; chiral auxiliaries; however, the presence of additional activities would not nec I0081 vi) diastereomer separations whereby a racemic essarily limit the use thereof in the present invention. Such compound is reacted with an enantiomerically pure reagent activity may be evaluated using standard testing methods and (the chiral auxiliary) that converts the individual enantiomers bioassays recognizable by the skilled artisan in the field as to diastereomers. The resulting diastereomers are then sepa generally being useful for identifying Such activity. rated by chromatography or crystallization by virtue of their 0073. According to one embodiment of the invention, suit now more distinct structural differences and the chiral auxil able biologically active variants comprise analogues and iary later removed to obtain the desired enantiomer; derivatives of the compounds described herein. Indeed, a I0082 vii) first- and second-order asymmetric transforma single compound, such as those described herein, may give tions whereby diastereomers from the racemate equilibrate to rise to an entire family of analogues or derivatives having yield a preponderance in Solution of the diastereomer from similar activity and, therefore, usefulness according to the the desired enantiomer or where preferential crystallization present invention. Likewise, a single compound. Such as of the diastereomer from the desired enantiomer perturbs the those described herein, may represent a single family member equilibrium such that eventually in principle all the material is of a greater class of compounds useful according to the converted to the crystalline diastereomer from the desired present invention. Accordingly, the present invention fully enantiomer. The desired enantiomer is then released from the encompasses not only the compounds described herein, but diastereomers; analogues and derivatives of Such compounds, particularly I0083 viii) kinetic resolutions comprising partial or com those identifiable by methods commonly known in the art and plete resolution of a racemate (or of a further resolution of a recognizable to the skilled artisan. partially resolved compound) by virtue of unequal reaction 0074 The compounds disclosed herein as active agents may contain chiral centers, which may be either of the (R) or rates of the enantiomers with a chiral, non-racemic reagent or (S) configuration, or may comprise a mixture thereof Accord catalyst under kinetic conditions; ingly, the present invention also includes Stereoisomers of the I0084 ix) enantiospecific synthesis from non-racemic pre compounds described herein, where applicable, either indi cursors whereby the desired enantiomer is obtained from vidually or admixed in any proportions. Stereoisomers may non-chiral starting materials and where the stereochemical include, but are not limited to, enantiomers, diastereomers, integrity is not or is only minimally compromised over the racemic mixtures, and combinations thereof. Such stereoiso course of the synthesis; mers can be prepared and separated using conventional tech I0085 x) chiral liquid chromatography whereby the enan niques, either by reacting enantiomeric starting materials, or tiomers of a racemate are separated in a liquid mobile phase by separating isomers of compounds of the present invention. by virtue of their differing interactions with a stationary Isomers may include geometric isomers. Examples of geo phase. The stationary phase can be made of chiral material or metric isomers include, but are not limited to, cis isomers or the mobile phase can contain an additional chiral material to trans isomers across a double bond. Other isomers are con provoke the differing interactions; templated among the compounds of the present invention. I0086 xi) chiral gas chromatography whereby the race The isomers may be used either in pure form or in admixture mate is volatilized and enantiomers are separated by virtue of with other isomers of the compounds described herein. their differing interactions in the gaseous mobile phase with a 0075 Various methods are known in the art for preparing column containing a fixed non-racemic chiral adsorbent optically active forms and determining activity. Such meth phase; ods include standard tests described herein other similar tests I008.7 xii) extraction with chiral solvents whereby the which are will known in the art. Examples of methods that can enantiomers are separated by virtue of preferential dissolu be used to obtain optical isomers of the compounds according tion of one enantiomer into a particular chiral solvent; and to the present invention include the following: I0088 xiii) transport across chiral membranes whereby a 0076 i) physical separation of crystals whereby macro racemate is placed in contact with a thin membrane barrier. scopic crystals of the individual enantiomers are manually The barrier typically separates two miscible fluids, one con separated. This technique may particularly be used when taining the racemate, and a driving force Such as concentra crystals of the separate enantiomers exist (i.e., the material is tion or pressure differential causes preferential transport a conglomerate), and the crystals are visually distinct; across the membrane barrier. Separation occurs as a result of 0077 ii) simultaneous crystallization whereby the indi the non-racemic chiral nature of the membrane which allows vidual enantiomers are separately crystallized from a solution only one enantiomer of the racemate to pass through. of the racemate, possible only if the latteris a conglomerate in I0089. The compound optionally may be provided in a the solid state; composition that is enantiomerically enriched, such as a mix US 2011/0259786 A1 Oct. 27, 2011

ture of enantiomers in which one enantiomer is present in ethylamine, potassium carbonate) in a suitable organic Sol excess, in particular to the extent of 95% or more, or 98% or vent (e.g., tetrahydrofuran, acetone, methanol, pyridine, N.N- more, including 100%. dimethylformamide) at a temperature of 0° C. to 60° C. 0090 The compounds described herein as active agents Prodrugs are typically prepared by covalent attachment of a can also be in the form of an ester, amide, salt, Solvate, moiety, which results in a compound that is therapeutically prodrug, or metabolite provided they maintain pharmacologi inactive until modified by an individual's metabolic system. cal activity according to the present invention. Esters, amides, Examples of pharmaceutically acceptable Solvates include, salts, Solvates, prodrugs, and other derivatives of the com but are not limited to, compounds according to the invention pounds of the present invention may be prepared according to in combination with water, isopropanol, ethanol, methanol, methods generally known in the art, such as, for example, DMSO, ethyl acetate, acetic acid, or ethanolamine. those methods described by J. March, Advanced Organic 0094. In the case of solid compositions, it is understood Chemistry: Reactions, Mechanisms and Structure, 4" Ed. that the compounds used in the methods of the invention may (New York: Wiley-Interscience, 1992), which is incorporated exist in different forms. For example, the compounds may herein by reference. exist in stable and metastable crystalline forms and isotropic 0091 Examples of pharmaceutically acceptable salts of and amorphous forms, all of which are intended to be within the compounds useful according to the invention include acid the scope of the present invention. addition salts. Salts of non-pharmaceutically acceptable 0.095 Ifa compound useful as an active agent according to acids, however, may be useful, for example, in the preparation the invention is a base, the desired salt may be prepared by any and purification of the compounds. Suitable acid addition suitable method known to the art, including treatment of the salts according to the present invention include organic and free base with an inorganic acid, such as hydrochloric acid, inorganic acids. Preferred salts include those formed from hydrobromic acid, Sulfuric acid, nitric acid, phosphoric acid hydrochloric, hydrobromic, Sulfuric, phosphoric, citric, tar and the like, or with an organic acid, such as acetic acid, taric, lactic, pyruvic, acetic, Succinic, fumaric, maleic, oxalo maleic acid, Succinic acid, mandelic acid, fumaric acid, mal acetic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, onic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic benzesulfonic, and isethionic acids. Other useful acid addi acid, pyranosidyl acids Such as glucuronic acid and galactu tion salts include propionic acid, glycolic acid, oxalic acid, ronic acid, alpha-hydroxy acids such as citric acid and tartaric malic acid, malonic acid, benzoic acid, cinnamic acid, man acid, amino acids such as aspartic acid and glutamic acid, delic acid, salicylic acid, and the like. Particular example of aromatic acids such as benzoic acid and cinnamic acid, Sul pharmaceutically acceptable salts include, but are not limited fonic acids such a p-toluenesulfonic acid or ethanesulfonic to, Sulfates, pyrosulfates, bisulfates, Sulfites, bisulfites, phos acid, or the like. phates, monohydrogenphosphates, dihydrogenphosphates, 0096. If a compound described herein as an active agent is metaphosphates, pyrophosphates, chlorides, bromides, an acid, the desired salt may be prepared by any Suitable iodides, acetates, propionates, decanoates, caprylates, acry method known to the art, including treatment of the free acid lates, formates, isobutyrates, caproates, heptanoates, propi with an inorganic or organic base. Such as an amine (primary, olates, oxalates, malonates. Succinates, Suberates, sebacates, secondary or tertiary), an alkali metal or alkaline earth metal fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, hydroxide or the like. Illustrative examples of suitable salts benzoates, chlorobenzoates, methylbenzoates, dinitroben include organic salts derived from amino acids Such as gly Zoates, hydroxybenzoates, methoxyenzoates, phthalates, Sul cine and arginine, ammonia, primary, secondary and tertiary fonates, Xylenesulfonates, phenylacetates, phenylpropi amines, and cyclic amines such as piperidine, morpholine and Onates, phenylbutyrates, citrates, lactates, piperazine, and inorganic salts derived from Sodium, calcium, Y-hydroxybutyrates, glycolates, tartrates, methanesulfonates, potassium, magnesium, manganese, iron, copper, Zinc, alu propanesulfonates, naphthalene-1-sulfonates, naphthalene minum and lithium. 2-sulfonates, and mandelates. 0097. The present invention further includes prodrugs and 0092 An acid addition salt may be reconverted to the free active metabolites of the active agent compounds described base by treatment with a suitable base. Preparation of basic herein. Any of the compounds described herein can be admin salts of acid moieties which may be present on a compound istered as a prodrug to increase the activity, bioavailability, or useful according to the present invention may be prepared in stability of the compound or to otherwise alter the properties a similar manner using a pharmaceutically acceptable base, of the compound. Typical examples of prodrugs include com Such as Sodium hydroxide, potassium hydroxide, ammonium pounds that have biologically labile protecting groups on a hydroxide, calcium hydroxide, triethylamine, or the like. functional moiety of the active compound. Prodrugs include 0093 Esters of the active agent compounds according to compounds that can be oxidized, reduced, aminated, deami the present invention may be prepared through functionaliza nated, hydroxylated, dehydroxylated, hydrolyzed, dehydro tion of hydroxyl and/or carboxyl groups that may be present lyzed, alkylated, dealkylated, acylated, deacylated, phospho within the molecular structure of the compound. Amides and rylated, and/or dephosphorylated to produce the active prodrugs may also be prepared using techniques known to compound. In preferred embodiments, the compounds of this those skilled in the art. For example, amides may be prepared invention possess anti-proliferative activity against abnor from esters, using Suitable amine reactants, or they may be mally proliferating cells, or are metabolized to a compound prepared from anhydride or an acid chloride by reaction with that exhibits such activity. ammonia or a lower alkylamine. Moreover, esters and amides 0098. A number of prodrug ligands are known. In general, of compounds of the invention can be made by reaction with alkylation, acylation, or other lipophilic modification of one a carbonylating agent (e.g., ethyl formate, acetic anhydride, or more heteroatoms of the compound. Such as a free amine or methoxyacetyl chloride, benzoyl chloride, methyl isocyan carboxylic acid residue, reduces polarity and allows passage ate, ethyl chloroformate, methanesulfonyl chloride) and a into cells. Examples of Substituent groups that can replace Suitable base (e.g., 4-dimethylaminopyridine, pyridine, tri one or more hydrogen atoms on the free amine and/or car US 2011/0259786 A1 Oct. 27, 2011

boxylic acid moiety include, but are not limited to, the fol administration can vary, especially depending upon the con lowing: aryl; Steroids; carbohydrates (including Sugars); 1.2- dition of the recipient and the disorder being treated. diacylglycerol; alcohols; acyl (including lower acyl); alkyl 0103) The pharmaceutical compositions may be conve (including lower alkyl); Sulfonate ester (including alkyl or niently made available in a unit dosage form, whereby Such arylalkyl Sulfonyl. Such as methanesulfonyl and benzyl, compositions may be prepared by any of the methods gener wherein the phenyl group is optionally substituted with one or ally known in the pharmaceutical arts. Generally speaking, more Substituents as provided in the definition of an aryl given Such methods of preparation comprise combining (by various herein); optionally Substituted arylsulfonyl: lipids (including methods) the active compounds of the invention with a suit phospholipids); phosphotidylcholine; phosphocholine; able carrier or other adjuvant, which may consist of one or amino acid residues or derivatives; amino acid acyl residues more ingredients. The combination of the active agents with or derivatives; peptides; cholesterols; or other pharmaceuti the one or more adjuvants is then physically treated to present cally acceptable leaving groups which, when administered in the composition in a suitable form for delivery (e.g., shaping vivo, provide the free amine and/or carboxylic acid moiety. into a tablet or forming an aqueous Suspension). Any of these can be used in combination with the disclosed 0104 Pharmaceutical compositions suitable for oral dos active agents to achieve a desired effect. age may take various forms, such as tablets, capsules, caplets, and wafers (including rapidly dissolving or effervescing), IV. Pharmaceutical Compositions each containing a predetermined amount of the active agent. The compositions may also be in the form of a powder or 0099 While it is possible for individual active agent com granules, a solution or Suspension in an aqueous or non pounds used in the methods of the present invention to be aqueous liquid, and as a liquid emulsion (oil-in-water and administered in the raw chemical form, it is preferred for the water-in-oil). The active agents may also be delivered as a compounds to be delivered as a pharmaceutical composition. bolus, electuary, or paste. It is generally understood that Accordingly, there are provided by the present invention methods of preparations of the above dosage forms are gen pharmaceutical compositions comprising one or more com erally known in the art, and any such method would be Suit pounds described herein as active agents. As such, the com able for the preparation of the respective dosage forms for use positions used in the methods of the present invention com in delivery of the compositions according to the present prise the pharmaceutically active compounds, as described invention. above, or pharmaceutically acceptable esters, amides, salts, 0105. In one embodiment, an active agent compound may Solvates, analogs, derivatives, or prodrugs thereof. Further, be administered orally in combination with a pharmaceuti the compositions can be prepared and delivered in a variety of cally acceptable vehicle such as an inert diluent or an edible combinations. For example, the composition can comprise a carrier. Oral compositions may be enclosed in hard or soft single composition containing all of the active agents. Alter shell gelatin capsules, may be compressed into tablets or may nately, the composition can comprise multiple compositions be incorporated directly with the food of the patient's diet. comprising separate active agents but intended to be admin The percentage of the composition and preparations may be istered simultaneously, in Succession, or in otherwise close varied; however, the amount of Substance in Such therapeuti proximity of time. cally useful compositions is preferably such that an effective 0100. The active agent compounds described herein can dosage level will be obtained. be prepared and delivered together with one or more pharma 0106 Hard capsules containing the active agent com ceutically acceptable carriers therefore, and optionally, other pounds may be made using a physiologically degradable therapeutic agents. Carriers should be acceptable in that they composition, Such as gelatin. Such hard capsules comprise are compatible with any other agents of the composition and the compound, and may further comprise additional ingredi not harmful to the recipient thereof. A carrier may also reduce ents including, for example, an inert Solid diluent such as any undesirable side effects of the agent. Such carriers are calcium carbonate, calcium phosphate, or kaolin. Softgelatin known in the art. See, Wang etal. (1980).J. Parent. Drug Assn. capsules containing the compound may be made using a 34(6):452-462, herein incorporated by reference in its physiologically degradable composition, Such as gelatin. entirety. Such soft capsules comprise the compound, which may be 0101 Compositions may include short-term, rapid-onset, mixed with water or an oil medium such as peanut oil, liquid rapid-offset, controlled release, Sustained release, delayed paraffin, or olive oil. release, and pulsatile release compositions, providing the 0107 Sublingual tablets are designed to dissolve very rap compositions achieve administration of a compound as idly. Examples of such compositions include ergotamine tar described herein. See Remington's Pharmaceutical Sciences trate, isosorbide dinitrate, and isoproterenol HCL. The com (18" ed.: Mack Publishing Company, Eaton, Pa., 1990), positions of these tablets contain, in addition to the drug, herein incorporated by reference in its entirety. various soluble excipients, such as lactose, powdered 0102 Pharmaceutical compositions for use in the methods Sucrose, dextrose, and mannitol. The solid dosage forms of of the invention are suitable for various modes of delivery, the present invention may optionally be coated, and examples including oral, parenteral (including intravenous, intramus of Suitable coating materials include, but are not limited to, cular, Subcutaneous, intradermal, intra-articular, intra-syn cellulose polymers (such as cellulose acetate phthalate, ovial, intrathecal, intra-arterial, intracardiac, Subcutaneous, hydroxypropyl cellulose, hydroxypropyl methylcellulose, intraorbital, intracapsular, intraspinal, intrastemal, and trans hydroxypropyl methylcellulose phthalate, and hydroxypro dermal), topical (including dermal, buccal, and Sublingual), pyl methylcellulose acetate Succinate), polyvinyl acetate vaginal, urethral, and rectal administration. Administration phthalate, acrylic acid polymers and copolymers, and meth can also be via nasal spray, Surgical implant, internal Surgical acrylic resins (such as those commercially available under the paint, infusion pump, or via catheter, stent, balloon or other trade name EUDRAGITR), Zein, shellac, and polysaccha delivery device. The most useful and/or beneficial mode of rides. US 2011/0259786 A1 Oct. 27, 2011

0108 Powdered and granular compositions of a pharma and carboxymethyl ethylcellulose), and polymers and ceutical preparation may be prepared using known methods. copolymers of acrylic acid, methacrylic acid, and esters Such compositions may be administered directly to a patient thereof. or used in the preparation of further dosage forms, such as to 0113 Solid dosage forms according to the present inven form tablets, fill capsules, or prepare an aqueous or oily tion may also be Sustained release (i.e., releasing the active Suspension or solution by addition of an aqueous or oily agents over a prolonged period of time), and may or may not vehicle thereto. Each of these compositions may further com also be delayed release. Sustained release compositions are prise one or more additives, such as dispersing or wetting known in the art and are generally prepared by dispersing a agents, Suspending agents, and preservatives. Additional drug within a matrix of a gradually degradable or hydrolyZ excipients (e.g., fillers, Sweeteners, flavoring, or coloring able material. Such as an insoluble plastic, a hydrophilic poly agents) may also be included in these compositions. mer, or a fatty compound. Alternatively, a Solid dosage form may be coated with Such a material. 0109 Liquid compositions of pharmaceutical composi 0114 Compositions for parenteral administration include tions which are suitable for oral administration may be pre aqueous and non-aqueous sterile injection solutions, which pared, packaged, and sold either in liquid form or in the form may further contain additional agents, such as anti-oxidants, of a dry product intended for reconstitution with water or buffers, bacteriostats, and solutes, which render the compo another suitable vehicle prior to use. sitions isotonic with the blood of the intended recipient. The 0110. A tablet containing one or more active agent com compositions may include aqueous and non-aqueous sterile pounds described herein may be manufactured by any stan Suspensions, which contain Suspending agents and thicken dard process readily known to one of skill in the art, Such as, ing agents. Such compositions for parenteral administration for example, by compression or molding, optionally with one may be presented in unit-dose or multi-dose containers. Such or more adjuvant or accessory ingredient. The tablets may as, for example, sealed ampoules and vials, and may be stores optionally be coated or scored and may be formulated so as to in a freeze-dried (lyophilized) condition requiring only the provide slow or controlled release of the active agents. addition of the sterile liquid carrier, for example, water (for 0111 Adjuvants or accessory ingredients for use in the injection), immediately prior to use. Extemporaneous injec compositions can include any pharmaceutical ingredient tion Solutions and Suspensions may be prepared from sterile commonly deemed acceptable in the art, Such as binders, powders, granules, and tablets of the kind previously fillers, lubricants, disintegrants, diluents, Surfactants, stabi described. lizers, preservatives, flavoring and coloring agents, and the 0115 The compositions for use in the methods of the like. Binders are generally used to facilitate cohesiveness of present invention may also be administered transdermally, the tablet and ensure the tablet remains intact after compres wherein the active agents are incorporated into a laminated sion. Suitable binders include, but are not limited to: starch, structure (generally referred to as a “patch') that is adapted to polysaccharides, gelatin, polyethylene glycol, propylene gly remain in intimate contact with the epidermis of the recipient col, waxes, and natural and synthetic gums. Acceptable fillers for a prolonged period of time. Typically, such patches are include silicon dioxide, titanium dioxide, alumina, talc, available as single layer "drug-in-adhesive' patches or as kaolin, powdered cellulose, and microcrystalline cellulose, as multi-layer patches where the active agents are contained in a well as soluble materials, such as mannitol, urea, Sucrose, layer separate from the adhesive layer. Both types of patches lactose, dextrose, sodium chloride, and Sorbitol. Lubricants also generally contain a backing layer and a liner that is are useful for facilitating tablet manufacture and include Veg removed prior to attachment to the skin of the recipient. etable oils, glycerin, magnesium Stearate, calcium Stearate, Transdermal drug delivery patches may also be comprised of and Stearic acid. Disintegrants, which are useful for facilitat a reservoir underlying the backing layer that is separated from ing disintegration of the tablet, generally include starches, the skin of the recipient by a semi-permeable membrane and clays, celluloses, algins, gums, and crosslinked polymers. adhesive layer. Transdermal drug delivery may occur through Diluents, which are generally included to provide bulk to the passive diffusion or may be facilitated using electrotransport tablet, may include dicalcium phosphate, calcium Sulfate, or iontophoresis. lactose, cellulose, kaolin, mannitol, Sodium chloride, dry 0116 Compositions for rectal delivery include rectal Sup starch, and powdered Sugar. Surfactants Suitable for use in the positories, creams, ointments, and liquids. Suppositories may composition according to the present invention may be be presented as the active agents in combination with a carrier anionic, cationic, amphoteric, or nonionic Surface active generally known in the art, such as polyethylene glycol. Such agents. Stabilizers may be included in the compositions to dosage forms may be designed to disintegrate rapidly or over inhibit or lessen reactions leading to decomposition of the an extended period of time, and the time to complete disinte active agents, such as oxidative reactions. gration can range from a short time. Such as about 10 minutes, 0112 Solid dosage forms may be formulated so as to to an extended period of time, Such as about 6 hours. provide a delayed release of the active agents, such as by 0117 Topical compositions may be in any form suitable application of a coating. Delayed release coatings are known and readily known in the art for delivery of active agents to the in the art, and dosage forms containing such may be prepared body Surface, including dermally, buccally, and Sublingually. by any known Suitable method. Such methods generally Typical examples of topical compositions include ointments, include that, after preparation of the Solid dosage form (e.g., creams, gels, pastes, and solutions. Compositions for topical a tablet or caplet), a delayed release coating composition is administration in the mouth also include lozenges. applied. Application can be by methods, such as airless spray 0118. In certain embodiments, the compounds and com ing, fluidized bed coating, use of a coating pan, or the like. positions disclosed herein can be delivered via a medical Materials for use as a delayed release coating can be poly device. Such delivery can generally be via any insertable or meric in nature, such as cellulosic material (e.g., cellulose implantable medical device, including, but not limited to butyrate phthalate, hydroxypropyl methylcellulosephthalate, stents, catheters, balloon catheters, shunts, or coils. In one US 2011/0259786 A1 Oct. 27, 2011

embodiment, the present invention provides medical devices, amount effective to treat muscle pain, joint pain, or neuro Such as stents, the Surface of which is coated with a compound logic pain. In still another embodiment, a therapeutically or composition as described herein. The medical device of effective amount is an amount effective to treat fatigue. this invention can be used, for example, in any application for 0.122 The active agents included in the pharmaceutical treating, preventing, or otherwise affecting the course of a composition are present in an amount Sufficient to deliver to disease or condition, such as those disclosed herein. a patientatherapeutic amount of an active agent in vivo in the 0119. In another embodiment of the invention, pharma absence of serious toxic effects. The concentration of active ceutical compositions comprising one or more active agents agent in the drug composition will depend on absorption, described herein are administered intermittently. Administra inactivation, and excretion rates of the drug as well as other tion of the therapeutically effective dose may be achieved in factors known to those of skill in the art. It is to be noted that a continuous manner, as for example with a Sustained-release dosage values will also vary with the severity of the condition composition, or it may be achieved according to a desired to be alleviated. It is to be further understood that for any daily dosage regimen, as for example with one, two, three, or particular subject, specific dosage regimens should be more administrations per day. By “time period of discontinu adjusted over time according to the individual need and the ance' is intended a discontinuing of the continuous Sustained professional judgment of the person administering or Super released or daily administration of the composition. The time vising the administration of the compositions, and that the period of discontinuance may be longer or shorter than the dosage ranges set forth herein are exemplary only and are not period of continuous Sustained-release or daily administra intended to limit the scope or practice of the claimed compo tion. During the time period of discontinuance, the level of the sition. The active agent may be administered at once, or may components of the composition in the relevant tissue is Sub be divided into a number of smaller doses to be administered stantially below the maximum level obtained during the treat at varying intervals of time ment. The preferred length of the discontinuance period I0123. A therapeutically effective amount according to the depends on the concentration of the effective dose and the invention can be determined based on the bodyweight of the form of composition used. The discontinuance period can be recipient. Alternatively, a therapeutically effective amount at least 2 days, at least 4 days or at least 1 week. In other can be described in terms of a fixed dose. In still further embodiments, the period of discontinuance is at least 1 embodiments, a therapeutically effective amount of one or month, 2 months, 3 months, 4 months or greater. When a more active agents disclosed herein can be described in terms Sustained-release composition is used, the discontinuance of the peak plasma concentration achieved by administration period must be extended to account for the greater residence of the active agents. Of course, it is understood that the time of the composition in the body. Alternatively, the fre therapeutic amount could be divided into a number of frac quency of administration of the effective dose of the sus tional dosages administered throughout the day. The effective tained-release composition can be decreased accordingly. An dosage range of pharmaceutically acceptable salts and pro intermittent schedule of administration of a composition of drugs can be calculated based on the weight of the parent the invention can continue until the desired therapeutic effect, nucleoside to be delivered. If a salt or prodrug exhibits activ and ultimately treatment of the disease or disorder, is ity in itself, the effective dosage can be estimated as above achieved. using the weight of the salt or prodrug, or by other means 0120 Administration of the composition comprises known to those skilled in the art. administering a pharmaceutically active agent as described 0.124. It is contemplated that compositions of the invention herein or administering one or more pharmaceutically active comprising one or more active agents described herein will be agents described herein in combination with one or more administered in therapeutically effective amounts to a mam further pharmaceutically active agents (i.e., co-administra mal, preferably a human. An effective dose of a compound or tion). Accordingly, it is recognized that the pharmaceutically composition for treatment of any of the conditions or diseases active agents described herein can be administered in a fixed described herein can be readily determined by the use of combination (i.e., a single pharmaceutical composition that conventional techniques and by observing results obtained contains both active agents). Alternatively, the pharmaceuti under analogous circumstances. The effective amount of the cally active agents may be administered simultaneously (i.e., compositions would be expected to vary according to the separate compositions administered at the same time). In weight, sex, age, and medical history of the Subject. Of another embodiment, the pharmaceutically active agents are course, other factors could also influence the effective amount administered sequentially (i.e., administration of one or more of the composition to be delivered, including, but not limited pharmaceutically active agents followed by separate admin to, the specific disease involved, the degree of involvement or istration or one or more pharmaceutically active agents). One the severity of the disease, the response of the individual of skill in the art will recognized that the most preferred patient, the particular compound administered, the mode of method of administration will allow the desired therapeutic administration, the bioavailability characteristics of the effect. preparation administered, the dose regimen selected, and the 0121 Delivery of a therapeutically effective amount of a use of concomitant medication. The compound is preferen composition according to the invention may be obtained via tially administered for a sufficient time period to alleviate the administration of a therapeutically effective dose of the com undesired symptoms and the clinical signs associated with the position. Accordingly, in one embodiment, a therapeutically condition being treated. Methods to determine efficacy and effective amount is an amount effective to treat fibromyalgia. dosage are known to those skilled in the art. See, for example, In another embodiment, a therapeutically effective amount is Isselbacher et al. (1996) Harrison's Principles of Internal an amount effective to treat a symptom offibromyalgia. In yet Medicine 13 ed., 1814-1882, herein incorporated by refer another embodiment, a therapeutically effective amount is an CCC. amount effective to treat chronic pain generally. In further 0.125. In certain embodiments, a therapeutically effective embodiments, a therapeutically effective amount is an amount of droxidopa comprises about 10 mg to about 3 g. US 2011/0259786 A1 Oct. 27, 2011

Such therapeutically effective amount represents an amount mended, particularly in relation to DDC inhibitors, COMT of droxidopa that would be provided in a single dose when inhibitors, cholinesterase inhibitors, and MAO inhibitors. In used as part of a combination according to the invention. It is certain embodiments, a therapeutically effective amount of a understood that when the droxidopa is provided as a salt, DDC inhibitor, COMT inhibitor, cholinesterase inhibitor, or ester, amide, or other pharmaceutically acceptable form, the MAO inhibitor to be combined with droxidopa is in the range amount of the pharmaceutical form of droxidopa can vary to of about 1 mg to about 200 mg. Of course, this range is the extent necessary to deliver a therapeutically effective exemplary and could vary depending upon the amount of amount of droxidopa. Further, as the therapeutically effective droxidopa included in the combination and the desired ratio of the compounds in the combination, as described above. amount of droxidopa is provided as an amount for a single I0131. As noted above, droxidopa may also be combined dose, the dosage amounts indicated herein do not necessarily with other active agents that can provide complimentary represent the maximum amount of droxidopa that may be effects for the treatment of fibromyalgia (e.g., antidepres administered over the course of a 24 hour period since it is sants, anti-inflammatories, muscle relaxants, antibiotics, possible that multiple doses of the combination may be indi mood stabilizers, antipsychotics, 5-HT2 and 5-HT3 antago cated for treatment of various conditions. nists, 5-HT1A receptor agonists, pain relievers, caffeine; 0126. In further embodiments, the therapeutically effec NMDA receptor ligands, S-adenosyl-methionine; Zopiclone; tive amount of droxidopa can encompass varying ranges, and chlormeZanone; proglumetacin, 5-OH-L-tryptophan; gabap the appropriate range could be determined based upon the entin, pregabalin, and tamoxefin). When Such complimentary severity of the condition being treated and the one or more active agents are used, they can be included in amounts typi additional compounds with which the droxidopa is com cally prescribed for their respective uses. bined. In specific embodiments, a therapeutically effective V. Articles of Manufacture amount of droxidopa comprises about 10 mg to about 2 g, 0.132. The present invention also includes an article of about 10 mg to about 1 g, about 20 mg to about 900 mg, about manufacture providing a composition comprising one or 30 mg to about 850 mg, about 40 mg to about 800 mg, about more active agents described herein. The article of manufac 50 mg to about 750 mg, about 60 mg to about 700 mg, about ture can include a vial or other container that contains a 70 mg to about 650 mg, about 80 mg to about 600 mg, about composition Suitable for use according to the present inven 90 mg to about 550 mg, about 100 mg to about 500 mg, about tion together with any carrier, either dried or in liquid form. In 100 mg to about 400 mg. or about 100 mg to about 300 mg. particular, the article of manufacture can comprise a kit 0127. In yet other embodiments, a therapeutically effec including a container with a composition according to the tive amount of droxidopa can be even greater, such as when invention. In Such a kit, the composition can be delivered in a provided as a Sustained-, extended-, or continuous-release variety of combinations. For example, the composition can formulation. As understood in the art, such formulations pro comprise a single dosage comprising all of the active agents. vide an increased drug amount in a single dosage form that Alternately, where more than one active agentis provided, the slowly releases the drug over time. Atherapeutically effective composition can comprise multiple dosages, each comprising amount of droxidopa for use in Such a formulation can be one or more active agents, the dosages being intended for calculated in light of the effective amounts described above administration in combination, in Succession, or in other and the determined frequency of dosing that would otherwise close proximity of time. For example, the dosages could be Solid forms (e.g., tablets, caplets, capsules, or the like) or be necessary to treat a given condition. liquid forms (e.g., vials), each comprising a single active 0128. A therapeutically effective amount of the one or agent, but being provided in blisterpacks, bags, or the like, for more additional compounds that are combined with droxi administration in combination. dopa according to the invention can be determined in relation 0133. The article of manufacture further includes instruc to the amount of droxidopa included in the dosage form and tions in the form of a label on the container and/or in the form the desired ratio of droxidopa to the additional compound(s). of an insert included in a box in which the container is pack Advantageously, the present invention allows for great flex aged, for the carrying out the method of the invention. The ibility in formulating combinations. For example, the con instructions can also be printed on the box in which the vial is serving effects provided by the one or more additional com packaged. The instructions contain information Such as Suf pounds can allow for using droxidopa in a lesser amount and ficient dosage and administration information so as to allow still achieve the same, or better, therapeutic effects achieved the subject or a worker in the field to administer the pharma using droxidopa alone. Likewise, it is possible to increase the ceutical composition. It is anticipated that a worker in the field therapeutic effects of droxidopa by using an amount of the encompasses any doctor, nurse, technician, spouse, or other one or more additional compounds that is less than the typi caregiver that might administer the composition. The phar cally recommended dosage for the one or more additional maceutical composition can also be self-administered by the compounds. Subject. 0129. In one embodiment, the ratio of droxidopa to the one Experimental or more additional compounds is in the range of about 500:1 I0134. The present invention will now be described with to about 1:10. In further embodiments, the ratio of droxidopa specific reference to various examples. The following to the additional compound(s) is in the range of about 250:1 to examples are not intended to be limiting of the invention and about 1:5, about 100:1 to about 1:2, about 8.0:1 to about 1:1, are rather provided as exemplary embodiments. about 50:1 to about 2:1, or about 20:1 to about 3:1. 0130. The one or more additional compounds combined EXAMPLE 1. with droxidopa according to the invention can be included in Effective Treatment of Chronic Pain Through amount typically recommended for use of the compounds Administration of Droxidopa in Combination with alone for other indications. However, as noted above, it is Carbidopa possible according to the invention to use the additional com 0.135 Treatment of fibromyalgia through reducing sensi pound(s) in amounts that are less than typically recom tivity to chronic pain using droxidopa in combination with US 2011/0259786 A1 Oct. 27, 2011 14 carbidopa was investigated using the Chronic Constriction carbidopa, or 3) 18 mg/kg of fluoxetine. The treatments were Injury (CCI) model. Male Wistar rats weighing 160 to 200 administered by IP injection to groups of 10 animals and the grams were used, and CCI was induced using the methods level of allodynia was determined at 60 minutes post dosing. described in Bennett and Xie (Pain, 33(1): 87-107). Specifi 0.138 Allodynia was calculated according to the following cally, after anesthetization using pentobarbital (50 mg/kg, 5 formula: ml/kg, i.p.), the Sciatic nerve was exposed at mid-thigh level. %. Inhibition=A Treatment A Blankx100%. and three ligatures (4-0 silk Suture), about 1 mm apart, were where A Treatment is the change in tactile pressure threshold loosely tied around the nerve. The animals were then housed over pre-treatment after ligation (Post-Treatment)-(Pre individually in cages with soft bedding for seven days before Treatment), and A Blank is change in tactile pressure thresh testing for mechanical allodynia. old over pre-ligation but before treatment (Pre-Ligation)- 0136. On the test day, rats were placed under inverted (Pre-Treatment). A one-way ANOVA followed by t-test was Plexiglas cages on a wire mesh rack and allowed to acclimate applied for comparison between test Substance treated groups for 20 to 30 minutes. Mechanical allodynia was evaluated by and the vehicle control group. Activity was considered sig responsiveness to a #12 Supertip (IITC, USA) applied nificant at PKO.05. through the mesh floor perpendicular to the central plantar 0.139. Rats from all groups developed marked allodynia surface of the left hind paw. The tip was gradually applied following the CCI procedure with an average change intactile with sufficient force to cause slight buckling of the filament response of greater than 20 for each group (range=12.7-26.3), against the paw. A positive response to the applied tactile as illustrated in Table 1. Animals in the vehicle treatment pressure, noted by sharp withdrawal of the paw, was recorded group had no change in the level of allodynia observed pre automatically by an Electronic Von Frey Anesthesiometer and post-treatment (p-0.7). The percent inhibition of allo (2290CE ELECTROVONFREYR, IITC, USA). dynia was significantly different between the three groups by 0.137 Rats were pre-selected (clear presence of allodynia) ANOVA (p<0.0001). Animals treated with fluoxetine were for experimentation only if the nociceptive response seven not significantly different from vehicle-treated rats. In con days after nerve ligation (pre-treatment) was reduced by 10 trast, animals treated with 400 mg/kg of Droxidopa plus 20 grams of force relative to the response of the individual paw mg/kg. Carbidopa had significantly decreased levels of allo before nerve ligation (pre-ligation. Treatment was with 1) 5 dynia when compared with vehicle treated animals (p<0. ml/kg of a pharmaceutical vehicle (2% TWEENR 80 and 0001). The percent inhibition of allodynia in the three groups 0.9% NaCl), 2) 400 mg/kg of droxidopa and 20 mg/kg of is illustrated in FIG. 1. TABLE 1. (1) Pre- (2) Pre- (3) Post- Inhibition Treatment N B.W. Ligation Treatment (1) - (2) Treatment (3) - (2) (%) Vehicle - 1 199 24.7 7.8 6.9 8.6 O.8 4.7 2% TWEEN (R) 80, 2 191 25.1 12.4 2.7 9.1 -3.3 -26.0 O.9% NaCl 3 187 27.4 S.6 21.8 6.6 1 4.6 4 203 34.4 12.1 22.3 8.5 -3.6 -16.1 5 205 31.6 6.3 25.3 1O.S 4.2 16.6 6 215 24.4 11 3.4 5.2 -58 -43.3 7 201 29.4 1O.S 8.9 7.6 -2.9 -153 8 208 30.6 7 23.6 7.4 0.4 1.7 9 184 29.4 9.7 9.7 10.1 0.4 2.0 10 205 32.9 7.7 25.2 13 5.3 21.0 Ave. 29.0 9.0 2O.O 8.7 -0.4 -50 SEM 1.1 O.8 1.4 0.7 1.1 6.3 Droxidopa 1 218 25.6 10.1 5.5 26.3 16.2 104.5 2 178 28.8 7.7 21.1 32.1 24.4 115.6 3 190 31.9 6.7 25.2 23.4 16.7 66.3 4 184 30.8 11.8 9 26.2 14.4 75.8 5 178 28.5 6.6 21.9 22.9 16.3 744 6 211 32.9 8.6 24.3 11.4 2.8 11.5 7 212 25.3 6.3 9 20.1 13.8 72.6 8, 18O 29.6 6.6 23 12.6 6 26.1 9 196 28.9 11.4 7.5 22.3 10.9 62.3 10 197 31.5 8.8 22.7 19.7 10.9 48.0 Ave. 29.4 8.5 20.9 21.7 13.2 65.7 SEM O.8 O6 1.O 2.0 1.9 1O.O Fluoxetine 1 77 30.3 9.1 21.2 14.4 5.3 2SO 2 204 31.5 11.2 20.3 12.4 1.2 5.9 3 86 25.5 8.2 17.3 11.2 3 17.3 4 201 24.7 9.1 15.6 9.7 O6 3.8 S 210 31.7 5.4 26.3 7 1.6 6.1 6 198 32.O 7.4 24.6 10.4 3 12.2 7 176 25.7 12 13.7 6.5 -SS -40.1 8, 190 24.2 8.2 16 8.8 O6 3.8 9 225 31.1 8.7 22.4 6 -2.7 -12.1 10 191 34.1 9.5 24.6 5.9 -3.6 -14.6 Ave. 29.1 8.9 2O2 9.2 0.4 0.7 SEM 1.2 O6 1.4 O.9 1.1 5.9 US 2011/0259786 A1 Oct. 27, 2011

0140. As seen in Table 1 and illustrated in FIG. 1, treat ment according to the invention resulted in total allodynia TABLE 3-continued inhibition in several test Subjects. The average percentage inhibition using the inventive method was almost 66%. By Formulation Components - concentration (mg/g contrast, treatment using the control vehicle resulted in an Formulation Droxidopa Entacapone Pyridostigmine Nialamide average increase in allodynia of 5%. Two test subjects treated with the vehicle showed 16.6% and 21% inhibition, but other 5 20.20 mg/g 4.042 mgg test subjects treated with the vehicle exhibited increases in 6 20.15 mg/g 0.202 mgg allodynia of 15.3%, 16.1%, 26.0%, and even 43.3%. Simi 7 20.04 mg/g 5.985 mg/g larly, treatment with fluoxetine resulted in an average allo dynia inhibition of less than 1%. Again, one test Subject 0.143 Rats in each group were given a single gavage dose treated with fluoxetine exhibited allodynia inhibition of 25%; of droxidopa alone or the droxidopa combination, the time of however, other fluoxetine-treated subjects exhibited dosing being recorded as time–0. Dosing was based upon the increases in allodynia of as much as 40.1%. weight of the subject and was adjusted to provide all test Subjects a droxidopa dose of approximately 100 mg per kg of EXAMPLE 2 body weight. Blood samples (approximately 100 uL) were Pharmacokinetic Properties of Droxidopa Combina collected at approximately 5, 15, and 30 minutes, and at tions approximately 1, 2, 4, 8, and 24 hours after dosing. Dosing and blood collection were via an indwelling jugular vein 0141. The pharmacokinetic properties of droxidopa com cannula. Blood samples were drawn into a heparinized 1 mL binations useful in the methods of the invention were evalu syringe (charged with 5uIL of heparin solution 1000 U/mL) ated in male Sprague Dawley rats. Four test groups with four and then transferred to a microcentrifuge. Acetonitrile (100 rats in each group were established. Group 1 was adminis LL) containing 0.2% formic acid was added to 25 LL of each tered droxidopa alone as a baseline group. Group 2 was plasma sample in a microcentrifuge tube. Internal standard (5 administered droxidopa in combination with the COMT uL of 4 ug/mL 3,4-dihydroxybenzylamine (DHBA) in aceto inhibitorentacapone. Group 3 was administered droxidopa in nitrile) was added, and the samples were Vortexed and cen combination with the cholinesterase inhibitor pyridostig trifuged to precipitate protein. The Supernatant was trans mine. Group 4 was administered droxidopa in combination ferred to an autosample vial with insert and injected on an with the MAOInialamide. For each group, the droxidopa or Applied Biosystems API 4000 Liquid Chromatography droxidopa combination was formulated with a vehicle Mass Spectrometer (LC-MS) apparatus interfaced with an formed of a water solution containing 1% carboxymethylcel Agilent 100 High Pressure Liquid Chromatography (HPLC) lulose with 0.2% TWEENR 80 emulsifier. apparatus. Data was collected and processed using Analyst 0142. The weights and of the droxidopa, entacapone, pyri software. The autosampler was cooled to 4° C., and the dostigmine, nialamide, and the vehicle provided in the vari sample injection Volume 5 uL. Chromatography was con ous formulations are shown in Table 2. The calculated con ducted on a Waters Atlantis dC18 column (25 cmx4.6 mm, 5 centrations for each component are separately provided in um) with guard column. The solvent was water containing Table 3. The amounts of entacapone, pyridostigmine, and 0.2% formic acid, and the flow rate was set at 0.8 mL/min. nialamide used in formulations 2-7 were provided as “low” 0144 Plasma droxidopa concentration in the rat test sub doses and “high doses based upon disclosure in the literature jects following administration of droxidopa alone or droxi of generally accepted dosage ranges for their respective dopa combinations according to the invention is provided in known indications. Table 4. As a standard, plasma droxidopa concentration in rats administered the drug vehicle with no droxidopa or droxi TABLE 2 dopa combinations present was also evaluated, and no droxi dopa was detected over a 24 hour period in plasma from the Formu- Formulation Components - weight (g rats administered the vehicle alone. Likewise, no droxidopa lation Vehicle Droxidopa Entacapone Pyridostigmine Nialamide was detected in any Subjects prior to dosing of the droxidopa or droxidopa combinations. As seen in Table 4, plasma droxi 1 13.87 g 0.280 g 2 13.65 g 0.280 g 0.0084g dopa concentration reached a maximum concentration for all 3 13.60 g 0.280 g 0.0842g formulations in a time of approximately 1-2 hours following 4 13.53 g 0.280 g 0.0028 g dosing. 5 13.60 g 0.280 g 0.0563g TABLE 4 6 13.61 g 0.280 g 0.0028 g 7 13.70 g 0.280 g 0.0842 g Mean Plasma Droxidopa Concentration Ig/mL) at Time Post-Dosage

For- O.O83 0.25 TABLE 3 mulation hir hr 0.5 hr 1 hr 2hr 4 hr 8 hr 24 hr Formulation Components - concentration (mg/g O401 3.996 7.869 11.336 10.548 3.391 0.61O O.OO1 O.328 3.245 8.641 12.OSO 8.772 4.795 3.054 O.OOS Formulation Droxidopa Entacapone Pyridostigmine Nialamide O.189 2.799 6.77S 8.440 9.27O 3425 1853 0.010 O.459 3.570 7.941 10.054 8.6SO 2.976 1.795 O.OOS 1 19.81 mg/g O456 4.033 7.341 8.380 5.989 2.429 O.431 O.OO2 2 20.11 mgg 0.603 mgg O493 2.867 6.807 8.579 6.06S 1.829 O.297 O.OOO 3 20.08 mgig 6.031 mgg O.311 3.017 6.506 7.886 6.381 2.380 1535 0.113 4 20.30 mg/g 0.203 mgg US 2011/0259786 A1 Oct. 27, 2011

0145 Administration of droxidopa combinations was 0.148. As seen above, when droxidopa is combined with seen to affect plasma norepinephrine concentration in com certain additional active agents, the combination can increase parison to administration of droxidopa alone. Mean plasma the half-life of droxidopa, and Such increase can be seen in a norepinephrine concentration at 2 hours post-dosing with the variety of pathways, Such as through an effect on drug various formulations tested is provided in Table 5. Formula metabolism, volume of distribution of the drug, or a combi tion 0 indicates administration of the vehicle alone without nation of the two. For example, the increase in half-life aris droxidopa or a droxidopa combination of the invention and ing from the combination with entacapone indicates periph provides a baseline comparative of plasma norepinephrine eral activity to block the metabolism of droxidopa to 3-OM droxidopa (the major metabolite of droxidopa), thus levels in an untreated Subject. increasing residence time of droxidopa in the body. Similarly, an increase in the Volume of distribution indicates a decrease TABLE 5 in the amount of drug available to organs of elimination, Plasma Norepinephrine which can further affect half-life. The increase in half-life Formulation Concentration (pg. IL) associated with the relatively high dose of nialamide is sur O O.711 prising since MAOIs are not typically considered to be a 1 3.32O major metabolic pathway for droxidopa, and is likely the 2 3.358 result of the unexpected increase in the apparent Volume of 3 6.359 distribution. Similarly, the combination with pyridostigmine 4 4.OOO 5 2.290 also surprisingly led to an increase in droxidopa half-life even 6 2.182 though cholinesterase compounds would generally not be 7 2.674 expected to affect droxidopa metabolism. Droxidopa half-life when administered alone or in combination with entacapone, pyridostigmine, or nialamide is graphically illustrated in FIG. 0146. As seen in Table 5, administration of droxidopa 2. alone caused an approximate 5-fold increase in plasmanore 0149 Many modifications and other embodiments of the pinephrine concentration. Treatment with droxidopa in com inventions set forth herein will come to mind to one skilled in bination with the COMT inhibiting compound caused an even the art to which these inventions pertain having the benefit of greater increase in plasma norepinephrine concentration. the teachings presented in the foregoing descriptions. There Treatment with droxidopa in combination with a relatively fore, it is to be understood that the inventions are not to be low dose of the cholinesterase inhibiting compound similarly limited to the specific embodiments disclosed and that modi caused an increase in plasmanorepinephrine concentration in fications and other embodiments are intended to be included relation to treatment with droxidopa alone; however, the within the scope of the appended claims. Although specific plasmanorepinephrine concentration was reduced in relation terms are employed herein, they are used in a generic and to treatment with droxidopa alone when a combination of descriptive sense only and not for purposes of limitation. droxidopa with a relatively high dose of the cholinesterase inhibiting compound was used. Plasma norepinephrine con 1. A kit comprising a container including one or more centration after treatment with both combinations of droxi therapeutically effective doses of a pharmaceutical composi dopa with the MAOI compound was reduced relative to treat tion comprising droxidopa, and an instruction set describing ment with droxidopa alone. a method for administering the pharmaceutical composition 0147 Mean values for various pharmacokinetic properties to a Subject Suffering from fibromyalgia in a therapeutically of the inventive combinations used in the above study are effective amount to treat the fibromyalgia. provided in Table 6. Specifically, Table 6 provides the termi 2. The kit according to claim 1, wherein the instruction set nal elimination half-life (T) of the administered formula describes a method for administering the pharmaceutical tions, the maximum observed concentration (C) of the composition to the subject in a therapeutically effective active agents in each formulation, the time to reach the maxi amount to treat a symptom associated with the fibromyalgia. mum observed concentration (T,), the area under the 3. The kit according to claim 2, wherein the symptom is plasma concentration-time curve from time Zero to the last pain associated with fibromyalgia. measured time point (AUC), and the observed Volume of 4. The kit according to claim 2, whereintreating comprises distribution at steady state (VZ F obs). Note that for reducing the severity of the symptom. extravascular models, the fraction of dose absorbed cannot be 5. The kit according to claim 2, wherein the instruction set estimated. Therefore, VZ F obs for such models is actually describes a method for administering the pharmaceutical Volume/F where F is the fraction of dose absorbed. composition to the subject in a therapeutically effective amount to reduce pain associated with the fibromyalgia. TABLE 6 6. The kit according to claim 1, wherein the pharmaceutical composition is in a solid form. T1/2 Cmax Tmax AUC, Vz F obs Formulation (hr) (ugmL) (hir) (hrug?mL) (mL/kg) 7. The kit according to claim 6, wherein the solid form is a tablet, caplet, capsule, or wafer. 1 1.4 11.4 1.25 44.4 S270.4 2 1.86 12.4 1.125 71.1 SO16.4 8. The kit according to claim 1, wherein the pharmaceutical 3 2.64 102 1.38 52.3 8854.1 composition is in a delayed release form. 4 1.93 10.1 1.25 51.2 S900.8 9. The kit according to claim 1, wherein the pharmaceutical 5 1.79 8.4 1 3O.S 8763.6 6 1.41 8.6 1 27.2 8O3O.O composition is in a Sustained release form. 7 3.77 8.1 0.875 42.O 16404.1 10. The kit according to claim 1, wherein the pharmaceu tical composition comprises about 10 mg to about 2 g of droxidopa. US 2011/0259786 A1 Oct. 27, 2011

11. The kit according to claim 10, wherein the pharmaceu amitriptyline, nortriptyline, desipramine, traZodone, Ven tical composition comprises about 50 mg to about 750 mg of lafaxine, dulloxetine, milnacipran, nefopam, bupropion, and droxidopa. combinations thereof. 12. The kit according to claim 10, wherein the pharmaceu 22. The kit according to claim 14, wherein the pharmaceu tical composition comprises about 80 mg to about 600 mg of tical composition comprises the droxidopa and the one or droxidopa. more additional compounds in a ratio of about 500:1 to about 1:10. 13. The kit according to claim 10, wherein the pharmaceu 23. The kit according to claim 22, wherein the pharmaceu tical composition comprises about 100 mg to about 500 mg of tical composition comprises the droxidopa and the one or droxidopa. more additional compounds in a ratio of about 80:1 to about 14. The kit according to claim 1, wherein the pharmaceu 1:1. tical composition comprises one or more additional active 24. The kit according to claim 22, wherein the pharmaceu agents selected from the group consisting of DOPA decar tical composition comprises the droxidopa and the one or boxylase inhibiting compounds, catechol-O-methyltrans more additional compounds in a ratio of about 50:1 to about ferase inhibitors, cholinesterase inhibitors, antidepressants, 2:1. anti-inflammatories, muscle relaxants, antibiotics, mood sta 25. The kit according to claim 22, wherein the pharmaceu bilizers, antipsychotics, serotonin receptor antagonists, sero tical composition comprises the droxidopa and the one or tonin receptor agonists, pain relievers, stimulants, NMDA more additional compounds in a ratio of about 20:1 to about receptor ligands, S-adenosyl-methionine, Zopiclone, chlo 3:1. rmeZanone, proglumetacin, 5-OH-L-tryptophan, gabapentin, 26. The kit according to claim 14, wherein the one or more pregabalin, tamoxefin, and combinations thereof. additional active agents is a DOPA decarboxylase inhibiting 15. The kit according to claim 14, wherein the one or more compound. additional active agents comprise one or more DOPA decar 27. The kit according to claim 26, wherein the DOPA boxylase inhibiting compounds selected from the group con decarboxylase inhibiting compound is carbidopa. sisting of benserazide, carbidopa, difluoromethyldopa, a-me 28. The kit according to claim 26, wherein the pharmaceu thyldopa, and combinations thereof. tical composition comprises about 50 mg to about 750 mg of 16. The kit according to claim 14, wherein the one or more droxidopa, and wherein the droxidopa and the DOPA decar additional active agents comprise one or more catechol-O- boxylase inhibiting compound are in a ratio of about 8.0:1 to methyltransferase inhibitors selected from the group consist about 1:1. ing of entacapone, tolcapone, nitecapone, and combinations 29. The kit according to claim 28, wherein the droxidopa thereof and the DOPA decarboxylase inhibiting compound are in a ratio of about 50:1 to about 2:1. 17. The kit according to claim 14, wherein the one or more 30. The kit according to claim 26, wherein the pharmaceu additional active agents comprise one or more cholinesterase tical composition comprises a further active agent. inhibitors selected from the group consisting of pyridostig 31. The kit according to claim 30, wherein the further mine, donepezil, rivastigmine, galantamine, tacrine, neostig active agent is selected from the group consisting of catechol mine, metrifonate, physostigmine, ambenonium, edropho O-methyltransferase inhibitors, cholinesterase inhibitors, nium, demarcarium, thiaphySovenine, phenserine, antidepressants, anti-inflammatories, muscle relaxants, anti cymserine, and combinations thereof biotics, mood stabilizers, antipsychotics, serotonin receptor 18. The kit according to claim 14, wherein the one or more antagonists, serotonin receptor agonists, pain relievers, additional active agents comprise one or more antidepres stimulants, NMDA receptor ligands, S-adenosyl-methionine, SantS. Zopiclone, chlormeZanone, proglumetacin, 5-OH-L-tryp 19. The kit according to claim 14, wherein the antidepres tophan, gabapentin, pregabalin, tamoxefin, and combinations sant is a monoamine oxidase inhibitor selected from the thereof. group consisting of isocarboxazid, moclobemide, 32. The kit according to claim 31, wherein the further phenelZine, tranylcypromine, selegiline, lazabemide, niala active agent is a serotonin norepinephrine reuptake inhibitor mide, iproniazid, iproclozide, toloxatone, harmala, brofar or pregabalin. omine, benmoxin, 5-Methoxy-N,N-dimethyltryptamine, 33. The kit according to claim 1, wherein the instruction set 5-methoxy-O-methyltryptamine, and combinations thereof describes administering the pharmaceutical composition 20. The kit according to claim 19, wherein the antidepres once daily. sant is selected from the group consisting of selective seroto 34. The kit according to claim 1, wherein the instruction set nin reuptake inhibitors, tricyclics, serotonin norepinephrine describes administering the pharmaceutical composition reuptake inhibitors, norepinephrine reuptake inhibitors, nore twice daily. pinephrine and dopamine reuptake inhibitors, and combina 35. The kit according to claim 1, wherein the instruction set tions thereof describes administering the pharmaceutical composition 21. The kit according to claim 19, wherein the antidepres three times daily. sant is selected from the group consisting of fluoxetine, par oxetine, citalopram, escitalopram, fluvoxamine, Sertraline,