US 20090023705A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0023705 A1 Roberts et al. (43) Pub. Date: Jan. 22, 2009

(54) DROXIDOPA AND PHARMACEUTICAL Publication Classification COMPOSITION THEREOF FOR THE (51) Int. Cl. TREATMENT OF MOOD DISORDERS, SLEEP A 6LX 3/553 (2006.01) DSORDERS ORATTENTION DEFICT A 6LX 3L/95 (2006.01) DSORDERS A 6LX 3L/275 (2006.01) A6II 3/12 (2006.01) A6II 3/445 (2006.01) A6IP 25/20 (2006.01) A6IP 25/24 (2006.01) (75) Inventors: Michael J. Roberts, Charlotte, NC A6IP 25/22 (2006.01) (US); Simon Pedder, Fort Mill, SC A63L/35 (2006.01) (US) A6II 3/44 (2006.01) A 6LX 3/5.375 (2006.01) A63/37 (2006.01) (52) U.S. Cl...... 514/211.13: 514/567; 514/565; Correspondence Address: 514/619; 514/676; 514/319; 514/354; 514/239.2: ALSTON & BRD LLP 514/651: 514/646 BANK OF AMERICA PLAZA, 101 SOUTH TRYON STREET, SUITE 4000 (57) ABSTRACT CHARLOTTE, NC 28280-4000 (US) The present invention provides pharmaceutical compositions comprising droxidopa alone, or in combination with one or more further active ingredients, for the treatment of condi tions, such as mood disorders, sleep disorders, or attention deficit disorders. In certain embodiments, the compositions (73) Assignee: Chelsea Therapeutics, Inc. useful in the methods of the invention comprise droxidopa and a compound selected from the group consisting of DOPA decarboxylase inhibiting compounds, catechol-O-methyl (21) Appl. No.: 12/116,560 transferase inhibiting compounds, cholinesterase inhibiting compounds, monoamine oxidase inhibiting compounds, norepinephrine reuptake inhibiting compounds, selective serotonin reuptake inhibiting compounds, tricyclic antide (22) Filed: May 7, 2008 pressant compounds, serotonin norepinephrine reuptake inhibiting compounds, norepinephrine dopamine reuptake inhibiting compound, noradrenergic and specific serotoner Related U.S. Application Data gic antidepressants, and combinations thereof. The inventive compositions are particularly useful in the treatment of (60) Provisional application No. 60/916,497, filed on May depression, narcolepsy, insomnia, and Attention Deficit/Hy 7, 2007. peractivity Disorder (AD/HD). Patent Application Publication Jan. 22, 2009 Sheet 1 of 2 US 2009/0023705 A1

250 -

200

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50 Patent Application Publication Jan. 22, 2009 Sheet 2 of 2 US 2009/0023705 A1

O 50 100 150 200 250 300 350

Vehicle

Despiramine

Entacapone

Fluoxetine

Wenlafaxine

Amitriptyline

Droxidopa -- Carbidopa

Droxidopa + Carbidopa it Entacapone

Droxidopa + Carbidopa -- Fluoxetine Droxidopa + Carbidopa + Venlafaxine

Droxidopa + Carbidopa + Amitriptyline

FIG. 2 US 2009/0023705 A1 Jan. 22, 2009

DROXDOPA AND PHARMACEUTICAL decisions; Suicidal thoughts or attempts; frequent physical COMPOSITION THEREOF FOR THE complaints (i.e., headache, stomach ache, fatigue); running TREATMENT OF MOOD DISORDERS, SLEEP away or threats of running away from home; hypersensitivity DISORDERS ORATTENTON DEFCIT to failure or rejection; and irritability, hostility, or aggression. DISORDERS In mood disorders, these feelings appear more intense than what a person may normally feel from time to time, and these CROSS-REFERENCE TO RELATED feelings tend to continue over a period of time or interfere APPLICATIONS with an individual’s interest in family, friends, community, or work. 0001. The present application claims priority to U.S. Pro 0006 Various treatments are currently available for mood visional Patent Application No. 60/916,497, filed May 7, disorders. Examples of current treatments include antidepres 2007, which is incorporated herein by reference in its entirety. sant medications, psychotherapy, and family therapy. Three major types of medication are typically used to treat depres FIELD OF THE INVENTION sion: tricyclics, selective serotonin re-uptake inhibitors (SS 0002 The present application is directed to methods of RIs), and monoamine oxidase inhibitors (MAO inhibitors). treatment of various conditions. In particular, the application All three classes of medications are known to have varying is directed to the use of droxidopa, alone or in combination degrees of effectiveness from patient to patient. Moreover, all with one or more additional components, for the treatment of three classes of medications are known to cause varying, various conditions, such as mood disorders, sleep disorders, undesirable side effects. It is estimated that approximately 44 or attention deficit disorders. million Americans experience a mental disorder each year, and mental illnesses are among the most common conditions BACKGROUND affecting health today. Accordingly, there remains a need in 0003 Droxidopa is a known synthetic amino acid precur the art for further pharmaceutical compositions useful in the sor of norepinephrine that is converted directly to norepi treatment of mood disorders, particularly depression. nephrine via the action of dopa decarboxylase (DDC). Droxi 0007 Sleep disorder encompasses a broad range of con dopa is generally used to treat orthostatic hypotension (OH) ditions, including sleep apnea (brief periods while sleeping and can be categorized as an antiparkinsonian agent; how during which breathing stops), insomnia (which includes dif ever, multiple pharmacological activities have been observed ficulty falling asleep or staying asleep, waking too early, or with droxidopa, including the following: (1) it is directly Sleep State Misperception), narcolepsy (an irresistible need converted to 1-norepinephrine by the action of the aromatic to sleep, where sleep attacks lasting from about 30 seconds to L-amino acid decarboxylase which is widely distributed in a about 30 minutes occur during waking hours), and restless leg living body, and thus has an effect of replenishing norepi syndrome (a discomfort in the legs, often sensed while trying nephrine; (2) it has limited permeability through the blood to sleep, which can include crawling, tingling, or prickling brain barrier into the brain; (3) it specifically recovers nore sensation, that can be relieved by moving or stimulating the pinephrine activated nerve functions which have decreased in legs). Sleep disorders are often comorbid with other condi the central and peripheral nervous system; and (4) it shows tions, such as depression, fibromyalgia, and chronic fatigue various actions, as norepinephrine, via the adrenaline recep syndrome. tors in various tissues. 0008 Narcolepsy, in particular, is known to adversely 0004 Mood disorders form a category of mental health affect an individual’s ability to function in daily life. This problems that include all types of depression and are some condition may be classified under the broader term of hyper times called affective disorders. The most common types of Somnia, which encompasses additional sleep attack condi mood disorders include: major depressive disorder, which is tions, such as idiopathic hypersomnia, recurrent hyperSom defined as an at least two-week period of a depressed or nia, and hypersomnia resulting from a medical condition. The irritable mood or a noticeable decrease in interest or pleasure 'sleep attacks' common with narcolepsy can occur at any in usual activities, along with other signs of a mood disorder; time. Such as while working, carrying on a conversation, or dysthymia (dysthymic disorder), which is defined as a even driving a car. The four classic symptoms of narcolepsy chronic, low-grade, depressed or irritable mood for at least are excessive daytime sleepiness; cataplexy (Sudden, brief one year, manic depression (bipolar disorder), which is episodes of muscle weakness or paralysis brought on by defined as at least one episode of a depressed or irritable mood strong emotions such as laughter, anger, Surprise, or antici and at least one period of a manic (persistently elevated) pation); sleep paralysis (paralysis upon falling asleep or wak mood; mood disorder due to a general medical condition ing up); and hypnagogic hallucinations (vivid dreamlike (such as cancer, injuries, infections, and chronic medical images that occur at sleep onset). Disturbed nighttime sleep, illnesses), which can trigger symptoms of depression; and including tossing and turning in bed, leg jerks, nightmares, Substance induced mood disorder, wherein symptoms of and frequent awakenings, may also occur. depression are present due to the effects of medication, drug 0009. There is no known cure for narcolepsy, but some abuse, exposure to toxins, or other forms of treatment. evidence Suggests the condition may be linked to abnormali 0005 Depending upon age and the type of mood disorder ties in cerebral perfusion. See Joo et al., Neuroimage (2005), present, a person may exhibit different symptoms of depres 28(2): p. 410-416, which is incorporated herein by reference. Sion. The following are the most common symptoms of a Excessive daytime sleepiness is typically treated with stimu mood disorder; however, each individual may experience lant drugs, such as methylphenidate (e.g., RITALINR), dex symptoms differently. Symptoms may include: persistent troamphetamine (e.g., DEXTROSTATCR) O feelings of sadness; feeling hopeless or helpless; having low DEXEDRINE(R), methamphetamine (DESOXYNR), pemo self-esteem; feeling inadequate; excessive guilt; feelings of line (CYLERTR), mazindol (SANOREX(R), as well as the wanting to die; loss of interest in usual activities or activities “non-stimulant stimulant modafinil (PROVIGIL(R). Cata once enjoyed; difficulty with relationships; sleep distur plexy and other REM-sleep symptoms are often treated with bances; changes in appetite or weight; decreased energy; antidepressant medications, such as Venlafaxine (EF difficulty concentrating; a decrease in the ability to make FEXORR), fluoxetine (PROZAC(R), reboxetine US 2009/0023705 A1 Jan. 22, 2009

(EDRONAX(R), imipramine (TOFRANIL(R), desipramine genetically transmitted in many cases and results from a (NORPRAMINR) or PERTOFRANR), protriptyline (TRIP chemical imbalance or deficiency in certain neurotransmit TIL(R) or VIVACTIL(R), and atomoxetine (STRATERRAR). ters. Other evidence suggests that AD/HD is partially a result At best, known medications reduce the symptoms, but do not of hypoperfusion of specific regions of the brain (e.g., a result eliminate them entirely. Moreover, such pharmaceutical oflow regional cerebral blood flow). See Lou, Henriksen, and treatments often have undesirable side effects. Thus, there Bruhn, Archives of Neurology (1984), 41 (8), which is incor remains a need in the art for further pharmaceutical compo porated herein by reference. Professionals who diagnose sitions useful in the treatment of sleep disorders, particularly AD/HD use the diagnostic criteria set forth by the American narcolepsy. Psychiatric Association (1994) in the Diagnostic and Statis 0010 Insomnia is typically described as difficulty in ini tical Manual of Mental Disorders; the fourth edition of this tiating and/or maintaining sleep, but the term is sometimes manual, known as the DSM-IV, was released in May 1994. used to indicate any and all stages and types of sleep loss. The The criteria in the DSM-IV. and other essential diagnostic condition described by the term insomnia can actually features, are the signs of AD/HD. The primary features asso encompass multiple types of sleep loss. Sleep onset insomnia ciated with the disability are inattention, hyperactivity, and (also known as delayed sleep phase syndrome) is a disorderin impulsivity. which the major sleep episode is delayed in relation to the 0015. A patient with AD/HD is usually described as hav desired clock time of sleep that results in Symptoms of sleep ing a short attention span and as being distractible, distract onset insomnia or difficulty in awakening at the desired time. ibility and inattentiveness being non-synonymous. Distract Idiopathic insomnia is a long-term (often lifelong) inability to ibility refers to the short attention span and the ease with obtain adequate sleep that is presumably due to an abnormal which some patients can be pulled off-task. Attention, on the ity of the neurological control of the sleep-wake system. In other hand, is a process that has different parts, including Such conditions, the insomnia is long-standing, commonly focus (picking something on which to pay attention), selec beginning in early childhood, and sometimes existing since tion (picking something that needs attention at that moment), birth. Psychophysiological insomnia is a disorder of Soma and Sustaining (paying attention for as long as needed). Atten tized tension (i.e., conversion of anxiety into physical Symp tion also includes resistance (avoiding things that remove toms) and learned sleep-preventing association that results in attention from where it needs to be) and shifting (moving a complaint of insomnia and associated decreased function attention to something else when needed). Symptoms of inat ing during wakefulness. tention, as listed in the DSM-IV, include: often failing to give 0011 Treatment for insomnia can vary depending upon close attention to details or making careless mistakes in the particular patient's needs. Most medications for treating schoolwork, work, or other activities; often having difficulty insomnia are sedatives (i.e., hypnotics) or other sleep-induc Sustaining attention in tasks or play activities; often not seem ing drugs, such as muscle relaxers and CNS depressants. ing to listen when spoken to directly; often not following Over-the-counter sleep aids typically include antihistamines through on instructions and failing to finish Schoolwork, (e.g., diphenhydramine or doxylamine), which have the side chores, or duties in the workplace (not due to oppositional effect of causing sleepiness. Examples of prescription sleep behavior or failure to understand instructions); often having aids include Zolpidem (AMBIENR), Zalepon (SONATAR), difficulty organizing tasks and activities; often avoiding, dis and eszopiclone (LUNESTAR). Such medications are gen liking, or being reluctant to engage in tasks that require Sus erally prescribed (or suggested in relation to OTC drugs) for tained mental effort (such as schoolwork or homework); often short term use only. In the absence of drug treatment, several losing things necessary for tasks or activities (e.g., toys, methods for inducing sleep have also been suggested. Meth School assignments, pencils, books, or tools); often being ods used for treatment include behavioral modification, fol easily distracted by extraneous stimuli; and often being for lowing good sleep hygiene practices, and light therapy. getful in daily activities. 0012 Attention deficit disorder is officially recognized by 0016 Excessive activity is the most visible sign of the American Psychiatric Association as Attention-Deficit/ AD/HD. Symptoms of hyperactivity, as listed in the DSM-IV. Hyperactivity Disorder, or AD/HD, although most lay include: often fidgeting with hands or feet or Squirming in people, and even some professionals, still use the separate seat; often leaving seat in classroom or in other situations in terms Attention Deficit Disorder (ADD) or Attention Deficit which remaining seated is expected; often running about or Hyperactivity Disorder (ADHD). Many researchers believe climbing excessively in situations in which it is inappropriate AD/HD is properly divided into three subtypes according to (inadolescents or adults, may be limited to Subjective feelings the main features associated with the disorder: inattentive of restlessness); often having difficulty playing or engaging in ness, impulsivity, and hyperactivity. The three subtypes are: leisure activities quietly; often being “on the go” or often AD/HD Predominantly Combined Type: AD/HD Predomi acting as if “driven by a motor,” and often talking excessively. nantly Inattentive Type; and AD/HD Predominantly Hyper (0017. Impulsivity of patients with AD/HD typically active-Impulsive Type. encompasses acting before thinking, because they have diffi 0013 The three subtypes take into account that some culty waiting or delaying gratification. The impulsivity leads patients with AD/HD have little or no trouble sitting still or these patients to speak out of turn, interrupt others, and inhibiting behavior, but may be predominantly inattentive engage in what looks like risk-taking behavior. A child may and, as a result, have great difficulty getting or staying run across the street without looking or climb to the top of focused on a task or activity. Others with AD/HD may be able very tall trees. Although such behavior is risky, the patient is to pay attention to a task but lose focus because they may be not really a risk-taker but, rather, has great difficulty control predominantly hyperactive-impulsive and, thus, have trouble ling impulse. Symptoms of impulsivity, as listed in the DSM controlling impulse and activity. The most prevalent Subtype IV, include: often blurting out answers before questions have is the Combined Type, and patients with this subtype have been completed; often having difficulty awaiting turn; and significant symptoms of all three characteristics often interrupting or intruding on others. 0014 AD/HD is a neurobiologically-based developmen 0018 Many medications are approved for use in the treat tal disability, but there is currently no known specific cause ment of AD/HD; however, stimulants, such as methylpheni for the condition. Some evidence Suggests that the disorder is date (e.g., RITALINR) and dextroamphetamine (e.g., DEX US 2009/0023705 A1 Jan. 22, 2009

TROSTATR or DEXEDRINE(R), are generally recognized as of the invention may particularly be characterized as being being the most effective pharmaceutical treatment. Other effective in relation to a specific symptom of the attention pharmaceutical treatments include atomoxetine (STRAT deficit disorder. For example, when the attention deficit dis TERAR), bupropion (WELLBUTRINR), and alpha-2-ago order is AD/HD and the subject is suffering from at least one nists, such as clonidine (CATAPRES(R). AD/HD is most symptom of AD/HD, the invention can be characterized as prevalent in children, and many parents find it undesirable to eliminating the symptom, reducing the severity of the Symp treat their children through administering stimulants. More tom, or reducing the frequency of occurrence of the symptom. over, there can be undesirable side effects, such as decreased Moreover, administration of an effective amount of a phar appetite, insomnia, increased anxiety, and/or irritability. maceutical combination according to the invention may be Accordingly, there remains a need in the art for further phar characterized as an amount effective to achieve the same goal maceutical compositions useful in the treatment of AD/HD. of eliminating or reducing the severity or frequency of a SUMMARY OF THE INVENTION symptom. 0024. The methods of the invention can include adminis 0019. The present invention provides pharmaceutical tration of droxidopa alone or can include administration of compositions useful in the treatment of various conditions or droxidopa in combination with one or more further active disorders. The pharmaceutical compositions generally com agents. Accordingly, the invention provides for the adminis prise droxidopa alone or in combination with one or more tration of a variety of pharmaceutical compositions. In certain further pharmaceutically active compounds. The invention embodiments, the additional active agents useful in combi further provides methods of treating a variety of conditions or nation with droxidopa can be selected from the group con disorders. For example, in one aspect, the invention is sisting of DOPA decarboxylase inhibiting compounds, cat directed to a method of treating a condition comprising echol-O-methyltransferase inhibiting compounds, administering to a subject in need of treatment of the condi cholinesterase inhibiting compounds, monoamine oxidase tion a pharmaceutical composition comprising a therapeuti inhibiting compounds, norepinephrine reuptake inhibiting cally effective amount of droxidopa or a pharmaceutically compounds, selective serotonin reuptake inhibiting com acceptable ester, amide, salt, Solvate, prodrug, or isomer pounds, tricyclic antidepressant compounds, serotonin nore thereof, wherein the condition is selected from the group pinephrine reuptake inhibiting compounds, norepinephrine consisting of a mood disorder, a sleep disorder, oran attention dopamine reuptake inhibiting compound, noradrenergic and deficit disorder. specific serotonergic antidepressants, and combinations 0020. In one embodiment, the method of the invention thereof. comprises treating a mood disorder, particularly depression. 0025. In one embodiment, a pharmaceutical composition Although the word depression alone may be used herein to for use according to the invention comprises droxidopa and a describe a condition treated by the invention, it is understood DOPA decarboxylase inhibiting compound. In particular, the that depression is intended to refer to the diagnosed condition DOPA decarboxylase inhibiting compound may selected ofmajor depressive disorder, such as defined above. In further from the group consisting of benserazide, carbidopa, difluo embodiments, other mood disorders may also be treated. Such romethyldopa, C.-methyldopa, and combinations thereof. as dysthymia (dysthymic disorder), manic depression (bipo 0026. In another embodiment, a pharmaceutical composi lar disorder), mood disorder due to a general medical condi tion for use according to the invention comprises droxidopa tion (such as cancer, injuries, infections, and chronic medical and a catechol-O-methyltransferase inhibiting compound. In illnesses), and Substance induced mood disorder. 0021. The methods of the invention may particularly be particular, the catechol-O-methyltransferase inhibiting com characterized as being effective in relation to a specific symp pound may be selected from the group consisting of entaca tom of the mood disorder. For example, when the mood pone, tolcapone, nitecapone, and combinations thereof. disorder is depression and the Subject is Suffering from at least 0027. In yet another embodiment, a pharmaceutical com one symptom of depression, the invention can be character position for use according to the invention comprises droxi ized as eliminating the symptom, reducing the severity of the dopa and a cholinesterase inhibiting compound. In particular, symptom, or reducing the frequency of occurrence of the the cholinesterase inhibiting compound may be selected from symptom. Moreover, administration of an effective amount of the group consisting of pyridostigmine, donepezil, rivastig a pharmaceutical composition according to the invention may mine, galantamine, tacrine, neostigmine, metrifonate, phys be characterized as an amount effective to achieve the same ostigmine, ambenonium, demarcarium, thiaphySovenine, goal of eliminating or reducing the severity or frequency of a phenserine, edrophonium, cymserine and combinations symptom. thereof. 0022. In other embodiments, the method of the invention 0028. In still another embodiment, a pharmaceutical com comprises treating a sleep disorder. For example, the method position for use according to the invention comprises droxi can comprise treating a condition of hypersomnia, particu dopa and a monoamine oxidase inhibiting compound. In par larly narcolepsy. In further embodiments, the sleep disorder ticular, the monoamine oxidase inhibiting compound may be treated according to the invention may include insomnia. In selected from the group consisting of isocarboxazid, particular embodiments, administration of an effective moclobemide, phenelzine, tranylcypromine, selegiline, amount of a pharmaceutical composition according to the nialamide, iproniazid, iproclozide, toloxatone, harmala, bro invention may be characterized as an amount effective to faromine, benmoxin, 5-methoxy-N,N-dimethyltryptamine, prevent the evident symptom of the sleep disorder (e.g., to 5-methoxy-O-methyltryptamine, and combinations thereof. prevent narcoleptic events, or related events, during waking 0029. In a further embodiment, a pharmaceutical compo hours or prevent insomnia during sleeping hours). sition for use according to the invention comprises droxidopa 0023. In still further embodiments, the method of the and a norepinephrine reuptake inhibiting compound. In par invention comprises treating an attention deficit disorder. In ticular, the norepinephrine reuptake inhibiting compound specific embodiments, the attention deficit disorder com may be selected from the group consisting of atomoxetine, prises a condition classified under the title of Attention-Defi reboxetine, Viloxazine, maprotiline, bupropion, radafaxine, cit/Hyperactivity Disorder (AD/HD). As before, the methods and combinations thereof. US 2009/0023705 A1 Jan. 22, 2009

0030. In yet a further embodiment, a pharmaceutical com additional active agent may be selected from the group con position for use according to the invention comprises droxi sisting of DOPA decarboxylase inhibiting compounds, cat dopa and a selective serotonin reuptake inhibiting compound. echol-O-methyltransferase inhibiting compounds, cholinest In particular, the selective serotonin reuptake inhibiting com erase inhibiting compounds, monoamine oxidase inhibiting pound may be selected from the group consisting of fluoxet compounds, norepinephrine reuptake inhibiting compounds, ine, paroxetine, citalopram, escitalopram, fluvoxamine, Ser selective serotonin reuptake inhibiting compounds, tricyclic traline, and combinations thereof. antidepressant compounds, serotonin norepinephrine 0031. In still another embodiment, a pharmaceutical com reuptake inhibiting compounds, norepinephrine dopamine position for use according to the invention comprises droxi reuptake inhibiting compound, noradrenergic and specific dopa and a tricyclic antidepressant compound. In particular, serotonergic antidepressants, and combinations thereof. the tricyclic antidepressant compound may selected from the group consisting of amitriptyline, amoxapine, butriptyline, BRIEF DESCRIPTION OF THE DRAWINGS clomipramine, desipramine, dibenzepin, doSulepin, doxepin, 0038 Having thus described the invention in general imipramine, lofepramine, nortriptyline, protriptyline, trimi terms, reference will now be made to the accompanying pramine, and combinations thereof. drawings wherein: 0032. In a particular embodiment, a pharmaceutical com 0039 FIG. 1 is a graph illustrating average time immobile position for use according to the invention comprises droxi for 11 groups of mice (10 in each group) treated with 11 dopa, a tricyclic antidepressant, and a DOPA decarboxylase different compositions and evaluated in a murine Forced inhibiting compound. Swim Test, to determine the antidepressive effects of the 0033. When the droxidopa is combined with one or more compositions; and additional active agents, the co-administration can be via a 0040 FIG. 2 is a chart illustrating the actual data points on variety of methods. For example, the droxidopa and the addi the time immobile scale for all mice evaluated in the murine tional active agent can be in the same pharmaceutical com Forced Swim Test. position. In other embodiments, the droxidopa and the addi tional active agent can be administered in separate DETAILED DESCRIPTION compositions. In Such embodiments, the separated composi tions can be administered at the same time or within close 0041. The invention now will be described more fully proximity to one another. Alternatively, the separate compo hereinafter through reference to various embodiments. These sitions can be administered as different times, which may be embodiments are provided so that this disclosure will be desirable to optimize the effects of the co-administered active thorough and complete, and will fully convey the scope of the agents. invention to those skilled in the art. Indeed, the invention may 0034. In another aspect, the invention is specifically be embodied in many different forms and should not be directed to pharmaceutical compositions comprising novel construed as limited to the embodiments set forth herein; combinations of active agents. In certain embodiments, a rather, these embodiments are provided so that this disclosure pharmaceutical composition according to the invention com will satisfy applicable legal requirements. As used in the prises droxidopa and a tricyclic antidepressant compound. In specification, and in the appended claims, the singular forms further embodiments, the composition may further comprise “a”, “an”, “the’, include plural referents unless the context a compound selected from the group consisting of DOPA clearly dictates otherwise. decarboxylase inhibiting compounds, catechol-O-methyl 0042. The present invention provides pharmaceutical transferase inhibiting compounds, cholinesterase inhibiting compositions and methods that can be used in the treatment of compounds, monoamine oxidase inhibiting compounds, a variety of disorders that can find a basis in regulating CNS norepinephrine reuptake inhibiting compounds, selective activity and, thus, may include a certain level of interconnec serotonin reuptake inhibiting compounds, tricyclic antide tivity. In particular, the compositions and methods can be pressant compounds, serotonin norepinephrine reuptake used in the treatment of mood disorders, sleep disorders, and inhibiting compounds, norepinephrine dopamine reuptake attention deficit disorders. Treatment can comprise the use of inhibiting compound, noradrenergic and specific serotoner droxidopa as a single active agent. In other embodiments, gic antidepressants, and combinations thereof. In a particular treatment can comprise the use of droxidopa in combination embodiment, a pharmaceutical composition according to the with one or more further active agents. Examples of Such invention comprises: droxidopa; a tricyclic antidepressant combinations are disclosed in U.S. Patent Application Publi compound; and a DOPA decarboxylase inhibiting compound. cation 2008/0015181, which is incorporated herein by refer 0035. In still another aspect, the present invention is ence in its entirety. The specific pharmaceutical composition directed to methods of treating conditions that have at least (or compositions) used in the invention, and the methods of one underlying cause related to hypoperfusion of the brain treatment provided by the invention, are further described (i.e., reduced blood flow to an area of the brain). One example below. of hypoperfusion is reduced cerebral blood flow. 0036. In one embodiment, the invention is directed to a I. DEFINITIONS method of treating a patient Suffering from a condition at least 0043. The term “alkyl as used herein means saturated partially arising from reduced blood flow in the brain, the straight, branched, or cyclic hydrocarbon groups. In particu method comprising administering to the patient an amount of lar embodiments, alkyl refers to groups comprising 1 to 10 droxidopa that is therapeutically effective to increase brain carbon atoms (“Clio alkyl). In further embodiments, alkyl blood flow and thus treat the condition. In specific embodi refers to groups comprising 1 to 8 carbon atoms ("Cs ments, the condition may particularly be selected from the alkyl”), 1 to 6 carbon atoms ("C. alkyl”), or 1 to 4 carbon group of mood disorders, sleep disorders, and attention deficit atoms (“C alkyl). In specific embodiments, alkyl refers to disorders. methyl, trifluoromethyl, ethyl, propyl, isopropyl, cyclopro 0037. In carrying the method according to this aspect of pyl, butyl, isobutyl, t-butyl, pentyl, cyclopentyl, isopentyl, the invention, the droxidopa may be combined with one or neopentyl, hexyl, isohexyl, cyclohexyl, cyclohexylmethyl, more additional active agents. In some embodiments, the 3-methylpenty1, 2,2-dimethylbutyl, and 2,3-dimethylbutyl. US 2009/0023705 A1 Jan. 22, 2009

Substituted alkyl refers to alkyl substituted with one or more alkyl; alkoxyalkyl including methoxymethyl, aralkyl includ moieties selected from the group consisting of halo (e.g., Cl, ing benzyl, aryloxyalkyl Such as phenoxymethyl, aryl includ F. Br, and I); halogenated alkyl (e.g., CF, 2-Br-ethyl, CHF, ing phenyl optionally Substituted with halogen, C-C alkyl or CHCl, CHCF, or CFCF); hydroxyl; amino; carboxylate: C-C alkoxy, Sulfonate esters such as alkyl or aralkyl Sul carboxamido; alkylamino: arylamino; alkoxy, aryloxy; nitro: phonyl including methanesulfonyl: mono-, di-, or triphos azido: cyano; thio; Sulfonic acid; Sulfate; phosphonic acid; phate ester; trity1 or monomethoxytrityl; substituted benzyl: phosphate; and phosphonate. trialkylsilyl such as dimethyl-t-butylsilyl or diphenylmethyl 0044) The term "heteroalkyl as used herein means alkyl silyl. Aryl groups in the esters optimally comprise a phenyl moieties wherein at least one C atom is replaced with a group. non-carbon atom, such as N, O, or S. 0055. The term “amino” as used herein means a moiety 0045. The term “alkenyl' as used herein means alkyl moi represented by the structure NR, and includes primary eties wherein at least one saturated C-C bond is replaced by amines, and secondary and tertiary amines Substituted by a double bond. In particular embodiments, alkenyl refers to alkyl (i.e., alkylamino). Thus, R may represent two hydrogen groups comprising 1 to 10 carbon atoms (“Coalkenyl). In atoms, two alkyl moieties, or one hydrogen atom and one further embodiments, alkyl refers to groups comprising 1 to 8 alkyl moiety. carbon atoms (“Cs alkenyl), 1 to 6 carbon atoms (“C. 0056. The terms “alkylamino” and “arylamino” as used alkenyl), or 1 to 4 carbon atoms (“Calkenyl). In specific herein mean an amino group that has one or two alkyl or aryl embodiments, alkenyl can be vinyl, allyl, 1-propenyl, 2-pro Substituents, respectively. penyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pente 0057 The term “hydroxyalkyl as used herein means an nyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, alkyl group as described above including one or more 4-hexenyl, or 5-hexenyl. hydroxy groups thereon. 0046. The term "heteroalkenyl as used herein means alk 0058. The term “analogue' as used herein means a com enyl moieties wherein at least one C atom is replaced with a pound in which one or more individual atoms or functional non-carbon atom, such as N, O, or S. groups have been replaced, either with a different atom or a 0047. The term “alkynyl as used herein means alkyl moi different functional, generally giving rise to a compound with eties wherein at least one saturated C-C bond is replaced by similar properties. a triple bond. In particular embodiments, alkynyl refers to 0059. The term "derivative' as used herein means a com groups comprising 1 to 10 carbonatoms (“Clio alkynyl). In pound that is formed from a similar, beginning compound by further embodiments, alkyl refers to groups comprising 1 to 8 attaching another molecule or atom to the beginning com carbon atoms (“Cs alkynyl), 1 to 6 carbon atoms (“C. pound. Further, derivatives, according to the invention, alkynyl), or 1 to 4 carbonatoms (“C alkynyl). In specific encompass one or more compounds formed from a precursor embodiments, alkynyl can be ethynyl, 1-propynyl, 2-propy compound through addition of one or more atoms or mol nyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, ecules or through combining two or more precursor com 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, pounds. 4-hexynyl, or 5-hexynyl. 0060. The term “prodrug” as used herein means any com 0048. The term "heteroalkynyl as used herein means pound which, when administered to a mammal, is converted alkynyl moieties wherein at least one C atom is replaced with in whole or in part to a compound of the invention. a non-carbon atom, Such as N, O, or S. 0061. The term “active metabolite' as used herein means a 0049. The term “alkoxy” as used herein means straight or physiologically active compound which results from the branched chain alkyl groups linked by an oxygen atom (i.e., metabolism of a compound of the invention, or a prodrug —O-alkyl), wherein alkyl is as described above. In particular thereof, when such compound or prodrug is administered to a embodiments, alkoxy refers to oxygen-linked groups com mammal. prising 1 to 10 carbon atoms ("Clo alkoxy”). In further 0062. The terms “therapeutically effective amount’ or embodiments, alkoxy refers to oxygen-linked groups com “therapeutically effective dose' as used herein are inter prising 1 to 8 carbon atoms (“Cs alkoxy), 1 to 6 carbon changeable and mean a concentration of a compound accord atoms ("Calkoxy'), or 1 to 4 carbonatoms ("Calkoxy”). ing to the invention, or a biologically active variant thereof, 0050. The term “halo' or “halogen' as used herein means sufficient to elicit the desired therapeutic effect according to fluorine, chlorine, bromine, or iodine. the methods of treatment described herein. 0051. The term “arylas used herein means a stable mono 0063. The term “pharmaceutically acceptable carrier as cyclic, bicyclic, or tricyclic carbon ring of up to 8 members in used herein means a carrier that is conventionally used in the each ring, wherein at least one ring is aromatic as defined by art to facilitate the storage, administration, and/or the healing the Hickel 4n+2 rule. Exemplary aryl groups according to the effect of a biologically active agent. invention include phenyl, naphthyl, tetrahydronaphthyl, and 0064. The term “intermittent administration” as used biphenyl. The aryl group can be substituted with one or more herein means administration of a therapeutically effective moieties selected from the group consisting of hydroxyl, dose of a composition according to the invention, followed by amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, a time period of discontinuance, which is then followed by Sulfonic acid, Sulfate, phosphonic acid, phosphate, or phos another administration of a therapeutically effective dose, phonate. and so forth. 0052. The terms “aralkyl and “arylalkyl as used herein mean an aryl group as defined above linked to the molecule II. ACTIVE AGENTS through an alkyl group as defined above. 0065. The present invention provides pharmaceutical 0053. The terms “alkaryland “alkylaryl” as used herein compositions and methods of treatment of various conditions means an alkyl group as defined above linked to the molecule using such pharmaceutical compositions. The pharmaceuti through an aryl group as defined above. cal compositions of the invention generally comprise droxi 0054 The term “acyl as used herein means a carboxylic dopa as an active agent. In certain embodiments, the pharma acid esterin which the non-carbonyl moiety of the ester group ceutical compositions can comprise one or more further is selected from straight, branched, or cyclic alkyl or lower active agents. US 2009/0023705 A1 Jan. 22, 2009

0066 A. Droxidopa dopa. Various preferred active agents that can be combined 0067. The compositions for use in the methods of the with droxidopa for treatment of the conditions noted herein invention generally comprise, as an active ingredient, threo are described below. Of course, such disclosure should not be 3-(3,4-dihydroxyphenyl)serine, which is commonly known viewed as limiting the scope of further active agents that may as droxidopa and has the structure provided below in Formula be combined with droxidopa. Rather, further active com (1). pounds, particularly compounds identified as useful for treat ing mood disorders, sleep disorders, or attention deficit dis orders, or for treating, preventing, or ameliorating symptoms (1) associated with Such disorders, may be used in addition to the OH compounds specifically disclosed herein. 0072. In one particular embodiment, an active agent used HO COOH in combination with droxidopa comprises one or more DOPA decarboxylase (DDC) inhibiting compounds. DDC catalyzes NH2 the decarboxylation of levodopa (L-DOPA or 3,4-dihydroxy HO L-phenylalanine) and 5-hydroxytryptophan (5-HTP) to yield dopamine and serotonin, respectively. Similarly, DDC cata Droxidopa is also known as threo-3,3-dihydroxy-L-tyrosine, lyzes the conversion of droxidopa to norepinephrine. DDC (-)-(2S,3R)-2-amino-3-hydroxy-3-(3,4-dihydroxyphenyl) inhibiting compounds prevent the above-noted conversions and are useful in combination with precursor drugs (such as propionic acid, and threo-dopaserine, as well as the common droxidopa) to focus conversion within the central nervous terms DOPS, threo-DOPS, and L-DOPS. The compound can system and thus increase the concentration of droxidopa in is optically active and can be provided in various forms, the CNS. including L-threo-DOPS, D-threo-DOPS, L-erythro-DOPS, 0073. Any compound typically recognized as inhibiting or and D-erythro-DOPS. The compounds can also exist in the decreasing the activity of DDC can be used according to the racemic form. The L-threo isomer is generally preferred present invention. Non-limiting examples of DDC inhibiting according to the present invention; however, the invention compounds useful according to the invention comprise also encompasses compositions and methods of use incorpo benserazide, carbidopa, difluoromethyldopa, C.-methyldopa, rating the other forms of droxidopa. Accordingly, as used and combinations thereof. throughout the present disclosure, the term “droxidopa” is 0074. In further embodiments, an active agent used in intended to encompass any isolated or purified isomer (e.g., combination with droxidopa comprises one or more com the L-threo isomer), as well as the racemic forms of droxi pounds that at least partially inhibit the function of catechol dopa. O-methyltransferase (such compounds being generally 0068 Droxidopa useful according to the invention can be referred to as “COMT inhibiting compounds’). Catechol-O- prepared by a variety of conventional methods, including methyltransferase catalyzes the transfer of the methyl group methods particularly useful for isolating the L-isomer of from S-adenosyl-L-methionine to various catechol com droxidopa. See, for example, U.S. Pat. No. 3,920,728; U.S. pounds (e.g., catecholamines), including dopamine, epineph Pat. No. 4,319,040; U.S. Pat. No. 4,480,109; U.S. Pat. No. rine, norepinephrine, and droxidopa. The COMT enzyme is 4,562,263: U.S. Pat. No. 4,699,879; U.S. Pat. No. 5,739,387: important in the extraneuronal inactivation of catecholamines and U.S. Pat. No. 5,864.041, which are incorporated herein and drugs with catechol structures, and is generally one of the by reference. most important enzymes involved in the metabolism of cat 0069. The present invention also encompasses composi echolamines and their metabolites. It is present in most tis tions comprising one or more pharmaceutically acceptable Sues, including the peripheral and the central nervous system. esters, amides, salts, Solvates, prodrugs, or isomers of droxi 0075. Inhibitors of COMT slow metabolism and elimina dopa. In one embodiment, the invention involves use of droxi tion of catechol compounds by increasing their half-life. dopa esters that allow for slowed or delayed decarboxylation Accordingly, COMT inhibiting compounds can function to of droxidopa resulting from hydrolytic or enzymatic degra increase levels of naturally occurring catechol compounds, as dation of the ester linkage. As would be recognized by one of well as alter the pharmacokinetics of administered catechol skill in the art, an ester of droxidopa can be formed by replac compounds (such as L-B-3,4-dihydroxyphenylalanine ing the hydrogen on the carboxylic ester group with any (L-DOPA), an immediate precursor of dopamine, generally suitable ester-forming group. For example, U.S. Pat. No. used for symptomatic treatment of Parkinson's disease). 5,288,898, which is incorporated herein by reference, dis Inhibitors of COMT can act peripherally (such as the com closes various esters of N-methylphenylserine, including pound entacapone), while others (such as tolcapone) are methyl esters, ethyl esters, n-propyl esters, isopropyl esters, capable of crossing the blood-brain barrier and thus acting n-butyl esters, isobutyl esters, tert-butyl esters, n-pentyl centrally and peripherally. esters, isopentyl esters, n-hexyl esters, and the like, and the 0076 Any compound generally recognized as being a present invention encompasses such esters, as well as other COMT inhibitor can be used as an additional active agent esters. Further examples of ester-forming groups that could according to the invention. Non-limiting examples of COMT be used according to the invention are disclosed in U.S. Pat. inhibiting compounds useful in combination with droxidopa No. 5,864.041, which is incorporated herein by reference in according to the invention include the following: (E)-2-cy its entirety. Accordingly, the compounds of the present inven ano-N,N-diethyl-3-(3,4-dihydroxy-5-nitrophenyl)propena tion particularly encompass a droxidopa ester, including mide, also called entacapone (COMTANR): 4-dihydroxy esters that are N-substituted and esters that are not N-substi 4'-methyl-5-nitrobenzophenone, also called tolcapone tuted. (TASMAR(R); and 3-(3,4-dihydroxy-5-nitrophenyl)methyl 0070 B. Additional Active Agents ene-2,4-pentanedione, also called nitecapone. In addition to 0071. As noted above, in certain embodiments, the com the above examples, U.S. Pat. No. 6.512,136 (the disclosure positions for use according to the methods of the invention of which is incorporated herein by reference) describes vari can comprise one or more active agents in addition to droxi ous substituted 2-phenyl-1-(3,4-dihydroxy-5-nitrophenyl)- US 2009/0023705 A1 Jan. 22, 2009

1-ethanone compounds that may also be useful as COMT I0081. The above groups of compounds, and specific com inhibitors according to the present invention. Likewise, U.S. pounds, are provided to exemplify the types of cholinesterase Pat. No. 4,963,590; GB 2200 109; U.S. Pat. No. 6,150,412: inhibiting compounds that are useful according to the inven and EP 237929, each describes groups of COMT inhibiting tion and should not be viewed as limiting the scope of the compounds that could be useful according to the present invention. In fact, the invention can incorporate various fur invention, and the disclosure of each of the above-noted docu ther cholinesterase inhibitors, including compounds ments is incorporated herein by reference. described in the following documents, the disclosures of which are incorporated herein by reference: Brzostowska, 0077 According to another embodiment of the invention, Malgorzata, et al. “Phenylcarbamates of (-)-Eseroline, (-)- an active agent used in combination with droxidopa com N1-Noreseroline and (-)-Physovenol: Selective Inhibitors of prises one or more compounds that at least partially inhibit the Acetyl and, or Butyrylcholinesterase.” Medical Chemistry function of cholinesterase. Such cholinesterase inhibiting Research. (1992) Vol. 2, 238-246; Flippen-Anderson, Judith compounds may also be referred to as anticholinesterase L., et al. “Thiaphysovenol Phenylcarbamates: X-ray Struc compounds. Cholinesterase inhibiting compounds can be tures of Biologically Active and Inactive Anticholinesterase reversible or non-reversible. The present invention preferably Agents.” Heterocycles. (1993) Vol. 36, No. 1: Greig, Nigel H., encompasses any compounds that may be considered revers et al. “Phenserine and Ring C Hetero-Analogues: Drug Can ible cholinesterase inhibiting compounds (either competitive didates for the Treatment of Alzheimer's Disease.” Medicinal or non-competitive inhibitors). Non-reversible cholinesterase Research Reviews. (1995) Vol. 15, No. 1,3-31; He, Xiao-shu, inhibitors generally find use as pesticides (such as diazinon et al. “Thiaphysovenine and Carbamate Analogues: A New and Sevin) and chemical weapons (such as tabin and Sarin) Class of Potent Inhibitors of Cholinesterases.” Medical and are not preferred according to the present invention. Chemistry Research. (1992) Vol. 2, 229-237: Lahiri, D. K., et al. “Cholinesterase Inhibitors, B-Amyloid Precursor Protein 0078 Cholinesterase inhibitors are understood to include and Amyloid B-Peptides in Alzheimer's Disease.” Acta Neu compounds that increase levels of acetylcholine (or a cholin rologica Scandinavia. (December 2000) Vol. 102 (s176), ergic agonist), generally by reducing or preventing the activ 60-67; Pei, Xue-Feng, et al. “Total Synthesis of Racemic and ity of chemicals involved in the breakdown of acetylcholine, Optically Active Compounds Related to Physostigimine and Such as acetylcholinesterase. Cholinesterase inhibitors may Ring-C Heteroanalogues from 3-I-2'- also include compounds having other mechanisms of action, (Dimethylamino0ethyl-2,3-dihydro-5-methoxy-1,3-dim Such as stimulating release of acetylcholine, enhancing ethyl-1H-indol-2-ol.” Helvetica Chimica ACTA. (1994) Vol. response of acetylcholine receptors, or potentiating gonadot 77:Yu, Qian-sheng, et al. “Total Syntheses and Anticholinest ropin releasing hormone (GNRH)-induced growth hormone erase Activities of (3aS)—N (8)-Norphysostigmine, release. Moreover, cholinesterase inhibiting compounds may (3aS) N (8)-Norphenserine. Their Antipodal Isomers, and act by enhancing ganglionic transmission. Other N (8)-Substituted Analogues.” J. Med. Chem., (1997) 0079 Any compound generally recognized as being a Vol. 40,2895-2901; and Yu, Q. S., et al. “Novel Phenserine cholinesterase inhibitor (or an anticholinesterase compound) Based-Selective Inhibitors of Butyrylcholinesterase for may be useful according to the present invention. Non-limit Alzheimer's Disease.” Reprinted with permission from J. ing examples of cholinesterase inhibiting compounds useful Med. Chem., May 20, 1999, 42, 1855-1861. in combination with droxidopa for preparing compositions according to the invention include the following: 3-dimeth I0082 An active agent used in combination with droxidopa ylcarbamoyloxy-1-methylpyridinium, also called pyridostig according to the invention can particularly be chosen from the mine (MESTINONR) or Regonol); (+)-2,3-dihydro-5,6- group of compounds recognized as antidepressant com dimethoxy-2-1-(phenylmethyl)-4-piperidinyl)methyl)-1H pounds. As used herein, an antidepressant can refer to any inden-1-one, also called donepezil (ARICEPTR): (S) N psychiatric medication or other Substance (including nutri ethyl-3-((1-dimethyl-amino)ethyl)-N-methylphenyl ents and herbs) used for treating a mood disorder, particularly carbamate, also called rivastigmine (Exelon); (4aS,6R,8aS)- depression and/or dysthymia. Non-limiting examples of anti 4a,5.9,10,11,12-hexahydro-3-methoxy-11-methyl-6H depressants according to the invention include monoamine benzofuro3a,3.2efI2)benzazepin-6-ol. also called oxidase inhibitors (MAOIs), norepinephrine reuptake inhibi galantamine (REMINYL(R) or RAZADYNE(R): 9-amino-1,2, tors (NRIs), selective serotonin reuptake inhibitors (SSRIs), 3,4-tetrahydroacridine, also called tacrine (COGNEXR): tricyclic antidepressant compounds, serotonin norepineph (m-hydroxyphenyl) trimethylammonium methylsulfate dim rine reuptake inhibitors (SNRIs, also known as 5-HT-NE dual ethylcarbamate, also called neostigmine: 1-hydroxy-2.2.2- reuptake inhibitors), norepinephrine dopamine reuptake trichloroethylphosphonic acid dimethyl ester, also called inhibitors (NDRIs), and noradrenergic and specific seroton metrifonate or trichlorofon; 1.2.3,3A,8.8A-hexahydro-1,3a, ergic antidepressants (NASSAs). 8-trimethylpyrrolo-2,3-b-indole-5-ol methylcarbamate ester, also called physostigmine; Oxalylbis(iminoethyl I0083. According to yet another embodiment of the inven ene)-bis-(o-chlorobenzyl)diethylammoniumdichloride, tion, an active agent used in combination with droxidopa also called ambenonium (MYTELASER): ethyl (m-hydrox comprises one or more compounds that at least partially yphenyl) dimethylammonium, also called edrophonium (EN inhibit the function of monoamine oxidase. Monoamine oxi LONGR); demarcarium; thiaphysovenine; phenserine; and dase inhibitors (MAOIs) comprise a class of compounds cymserine. understood to act by inhibiting the activity of monoamine 0080 More generally, compounds useful as cholinest oxidase, an enzyme generally found in the brain and liver of erase inhibitors according to the invention can comprise car the human body, which functions to break down monoamine bamate compounds, particularly phenylcarbamates, ogano compounds, typically through deamination. phosphate compounds, piperidines, and phenanthrine 0084. There are two isoforms of monoamine oxidase derivatives. The invention further comprises cholinesterase inhibiting compounds, MAO-A and MAO-B. The MAO-A inhibitors that are carbamoyl esters, as disclosed in U.S. Pub isoform preferentially deaminates monoamines typically lished Patent Application No. 2005/0096387, which is incor occurring as neurotransmitters (e.g., serotonin, melatonin, porated herein by reference. epinephrine, norepinephrine, and dopamine). Thus, MAOIs US 2009/0023705 A1 Jan. 22, 2009 have been historically prescribed as antidepressants and for treatment of other social disorders, such as agoraphobia and social anxiety. The MAO-B isoform preferentially deami (2) nates phenylethylamine and trace amines. Dopamine is equally deaminated by both isoforms. MAOIs may by revers ible or non-reversible and may be selective for a specific isoform. For example, the MAOI moclobemide (also known as Manerix or Aurorix) is known to be approximately three times more selective for MAO-A than MAO-B. wherein X is C, N, O, or S.; R is a substituent present on one, 0085 Any compound generally recognized as being an two, or all three non-fused atoms of the central ring (each MAOI may be useful according to the present invention. substituent being independent of the other) and is selected Non-limiting examples of MAOIs useful in combination with from the group of H. carbonyl, halo, amino, optionally Sub droxidopa for preparing compositions according to the inven stituted alkyl or heteroalkyl, optionally substituted alkenyl or tion include the following: isocarboxazid (MARPLANR): heteroalkenyl, optionally substituted alkynyl or heteroalky moclobemide (Aurorix, Manerix, or Moclodura); phenelzine nyl, or optionally substituted alkaryl or aralkyl, wherein the (NARDIL(R); tranylcypromine (PARNATE(R); selegiline optional Substituent is selected from alkyl, alkenyl, alkynyl, (ELDEPRYL(R), EMSAMR, or 1-deprenyl); lazabemide: nialamide; iproniazid (marsilid, iprozid, ipronid, rivivol, or hydroxyalkyl, and optionally substituted aryl; and n is an propilniaZida); iproclozide; toloxatone; harmala; brofarom integer from 0 to 6. ine (Consonar); benmoxin (Neuralex); and certain 0090. In certain embodiments, a tricyclic antidepressant tryptamines, such as 5-MeO-DMT (5-Methoxy-N,N-dimeth for use according to the present invention is selected from the yltryptamine) or 5-MeO-AMT (5-methoxy-C.-methyl group consisting of amitriptyline (ELAVIL(R), amoxapine, tryptamine). butriptyline, clomipramine (ANAFRANILR), desipramine I0086 According to still another embodiment of the inven (NORPRAMINR), dibenzepin, dosulepin, doxepin (SINE tion, an active agent used in combination with droxidopa QUANR), imipramine (TOFRANILR), lofepramine, comprises one or more norepinephrine reuptake inhibiting nortriptyline (PAMELOR(R) or AVENTYL(R), protriptyline compounds (NRI). NRIs are also known or noradrenalin (VIVACTYL(R), trimipramine (SURMONTIL(R), and com reuptake inhibitors (NARI) and generally function to elevate binations thereof. the level of norepinephrine in the central nervous system 0091. In specific embodiments, a tricyclic antidepressant (CNS) by inhibiting reuptake of norepinephrine from the used according to the present invention is selected from the synaptic cleft into the presynaptic neuronal terminal. Nore group consisting of amitriptyline, butriptyline, clomi pinephrine is a catecholamine and phenylethylamine that pramine, desipramine, do Sulepin, doxepin, imipramine, functions as a neurotransmitter and is known to affect many lofepramine, nortriptyline, protriptyline, trimipramine, and conditions. combinations thereof. 0087 Any compound typically recognized as inhibiting 0092. In a particularly preferred embodiment, a tricyclic the reuptake of norepinephrine in the CNS can be used antidepressant used according tot the present invention is according to the present invention. Non-limiting examples of selected from the group consisting of amitriptyline, butrip NRIs useful according to the invention comprise atomoxetine tyline, nortriptyline, protriptyline, and combinations thereof. (STRATTERAR), reboxetine (EDRONAX(R), VESTRAR, or 0093 Tricyclic antidepressants can be a particularly use NOREBOX(R), viloxazine (EMOVITR), VIVALANR), ful active agent according to the invention in combination VIVARINTR, or VIVILANR), maprotiline (DEPRILEPTR), with droxidopa and optionally one or more further active LUDIOMILR), or PSYMIONR), bupropion (WELL agents as described herein. In particular, tricyclic antidepres BUTRINR) or ZYBANR), and radafaxine. Note that bupro sants are one class of compounds according to the invention pion may also be classified as a norepinephrine dopamine that have broad applicability across the various conditions reuptake inhibitor, as described below. that may be treated using the invention combinations. 0088. In yet another embodiment, an active agent used in 0094. Of course, it is well recognized that the tricyclic combination with droxidopa comprises one or more selective compounds of the invention can be used in the treatment of serotonin reuptake inhibiting compounds (SSRIs). Non-lim depression. Tricyclic antidepressants have also been shown iting examples of specific SSRIs useful according to the useful in the treatment of several sleep disorders. For invention comprise fluoxetine (PROZAC(R), paroxetine example, protriptyline, clomipramine, and imipramine can (PAXIL(R), citalopram (CELEXAR), escitalopram (LEX Suppress REM sleep, thus making them useful in preventing APROR), fluvoxamine (LUVOX(R), and sertraline narcolepsy. Moreover, as provided in a 2007 report from the (ZOLOFTR). American Academy of Sleep Medicine (AASM), tricyclic 0089. In certain embodiments of the invention, droxidopa antidepressants are useful for treating other hypersomnias of may be combined with one or more compounds recognized as central origin, including cataplexy, hypnagogic hallucina being a tricyclic antidepressant. Tricyclic antidepressants tions, and sleep paralysis (see Morgenthaler et al., Sleep (TCA) are a class of antidepressant compounds that can be (2007), 30(12): 1705-1727). described as including any compound exhibiting antidepres 0095. Furthermore, tricyclic antidepressants can by useful Santactivity and having a chemical formula including a fused in the treatment of AD/HD conditions, which are thought to three ring structure. In certain embodiments, a tricyclic anti be at least partially caused by dopamine and norepinephrine depressant for combination with droxidopa (and optionally shortages in the brain's prefrontal cortex. Tricyclic antide one or more further compounds) comprises a compound hav pressants block the reuptake of these neurotransmitters and ing the structure of Formula (2), are commonly used in patients for whom psychoStimulants US 2009/0023705 A1 Jan. 22, 2009

are ineffective or contraindicated. TCAS are particularly use one or more further classes of compounds. Accordingly, the ful to help limit hyperactivity and impulsivity in AD/HD above classifications should not be viewed as limiting the patients. Scope of the types of compounds useful in combination with 0096. In further embodiments of the invention, an active droxidopa for treating the conditions described herein. agent used in combination with droxidopa comprises one or 0102 Although several specific examples of active agents more serotonin norepinephrine reuptake inhibiting com for use in combination with droxidopa have been disclosed pounds (SNRIs). As the name implies, SNRIs affect levels of above, Such compounds should not be viewed as limiting the both serotonin and norepinephrine in the CNS. Any com invention. Rather, any drug generally recognized as being an pound typically recognized as an SNRI can be used according antidepressant, antinarcoleptic, anti-insomniac, or AD/HD to the present invention. Non-limiting examples of SNRIs treatment can be used in combination with droxidopa accord useful according to the invention comprise Venlafaxine (EF ing to the invention. Moreover, it is possible according to the FEXORR), desvenlafaxine (PRISTIQR), milnacipran invention to combine two or more additional active agents (DALCIPRANR), and dulloxetine (CYMBALTAR). with droxidopa for the treatment of the noted conditions. 0097. According to additional embodiments, an active 0103) In specific embodiments, the active agents agent used in combination with droxidopa comprises one or described above may be combined such that droxidopa is more norepinephrine dopamine reuptake inhibiting com combined with at least one further active agent for use in the pounds (NDRIs). One example of such compounds is bupro treatment of mood disorders, sleep disorders, or attention pion (WELLBUTRINR). As previously noted, this com deficit disorders. In some embodiments, droxidopa may be pound may also be classified as simply an NRI. Both combined with only one further active agent. In other embodi bupropion and its metabolite, radafaxine, may exhibit inhibi ments, droxidopa may be combined with two or more further tion of both norepinephrine and dopamine. active agents. Moreover, when two or more further active 0098. In still further embodiments, an active agent used in agents are combined with droxidopa, the further active agents combination with droxidopa comprises one or more noradr may be selected from the same or different groups of com energic and specific serotonergic antidepressant (NaSSA) pounds (e.g., two tricyclic antidepressants or a tricyclic anti compounds. Specific, non-limiting examples of Such com depressant and a DDC inhibitor). Non-limiting examples of pounds include mirtazapine (REMERONR) andmaprotoline specific combinations encompasses encompassed by the (LUDIOMILCR). invention include the following: 0099. Another group of compounds having antidepressant 0.104) a) droxidopa--a DDC inhibiting compound; properties that may be combined with droxidopa according to 0105 b) droxidopa--a COMT inhibiting compound; the invention is benzoxazocine compounds, such as nefopam 0106 c) droxidopa--a cholinesterase inhibiting com (including (+)-nefopam). For example, U.S. Patent Applica pound; tion Publication No. 2006/0019940, which is incorporated 0.107 d) droxidopa--an antidepressant selected from the herein by reference in its entirety, discloses benzoxazocine group of MAOS, NRIs, SSRIs, tricyclics, SNRIs, compounds that may exhibit reuptake inhibition for seroto NDRIs, and NASSAs; nin, norepinephrine, and dopamine, and Such compounds are 0.108 e) droxidopa--a DDC inhibiting compound+an useful according to the present invention. antidepressant selected from the group of MAOS, NRIs, 0100. In addition to the above compounds, even further SSRIs, tricyclics, SNRIs, NDRIs, and NASSAs; types of compounds may be combined with droxidopa 0.109 f) droxidopa+a COMT inhibiting compound+an according to the invention. Non-limiting examples of further antidepressant selected from the group of MAOS, NRIs, active agents that can be combined with droxidopa include: SSRIs, tricyclics, SNRIs, NDRIs, and NASSAs; mood stabilizers (such as lithium, olanzipine, Verapamil, que 0110 g) droxidopa--a cholinesterase inhibiting com tiapine, lamotrigine, carbamazepine, Valproate, oXcarba pound+an antidepressant selected from the group of Zepine, risperidone, aripiprazole, and Ziprasidone); antipsy MAOS, NRIs, SSRIs, tricyclics, SNRIs, NDRIs, and chotics (such as haloperidol and other butyrophenones, NASSAs; chlorpromazine, fluphenazine, perphenazine, prochlorpera 0.111 h) droxidopa--a DDC inhibiting compound+a tri Zine, and other phenothiazines, and clozapine); serotonin cyclic antidepressant; receptor antagonists (5-HT2 and 5-HT3 antagonists) (Such as 0112 i) droxidopa--a COMT inhibiting compound+a traZodone, ondansetron, tropisetron, katenserin, methyser tricyclic antidepressant; gide, cyproheptadine, and pizotifen); serotonin receptorago 0113 j) droxidopa--a cholinesterase inhibiting com nists (5-HT1A receptoragonists) (such as buspirone or BUS pound+a tricyclic antidepressant; PARR); stimulants such as caffeine, ADDERALL(R), 0114 k) droxidopa--an MAOI+a tricyclic antidepres methylphenidate (METADATE(R), RITALINR, or CON Sant, CERTAR), pemoline (CYLERTR), dextroamphetamine 0115 l) droxidopa--an NRI--a tricyclic antidepressant; (DEXEDRINER, DEXTROSTATR, or FOCALINR), meth 0116 m) droxidopa+an SSRI--a tricyclic antidepres amphetamines (DESOXYNR), mazindol (SANOREX(R), or Sant, modafinil (PROVIGIL(R); and gamma-hydroxybutyrate 0.117 in) droxidopa--one or more of benserazide, carbi (GHB) (XYREMR). dopa, difluoromethyldopa, and C.-methyldopa+one or 0101 Although the above compounds are described in more of amitriptyline, butriptyline, nortriptyline, and terms of classes of compounds and specific compounds, it is protriptyline; understood that there is substantial overlap between certain 0118 o) droxidopa--one or more of entacapone, tolca classes of compounds (such as between mood Stabilizers, pone, and nitecapone+one or more of amitriptyline, antipsychotics, antidepressants, and serotonin receptor butriptyline, nortriptyline, and protriptyline; antagonists). Thus, specific compounds exemplifying a spe 0119 p) droxidopa--one or more of pyridostigmine, cific class of compounds may also properly be identified with donepezil, rivastigmine, galantamine, tacrine, neostig US 2009/0023705 A1 Jan. 22, 2009 10

mine, metrifonate, physostigmine, ambenonium, edro fatigue); running away or threats of running away from home; phonium, demarcarium, thiaphySovenine, phenserine, hypersensitivity to failure or rejection; and irritability, hostil and cymserine--one or more of amitriptyline, butrip ity, or aggression. Accordingly, treatment of a mood disorder tyline, nortriptyline, protriptyline; according to the present invention may include eliminating or I0120 q) droxidopa+one or more of isocarboxazid, reducing the frequency or severity of any of the noted Symp moclobemide, phenelzine, tranylcypromine, selegiline, toms or other symptoms relied upon by a medical profes lazabemide, nialamide, iproniazid, iproclozide, sional in making a diagnosis of a mood disorder. Accordingly, toloxatone, harmala, brofaromine, and benmoxin--one in some embodiments, the present invention comprises treat or more of amitriptyline, butriptyline, nortriptyline, pro ing a patient exhibiting at least one symptoms of a mood triptyline; disorder by administering to the patient droxidopa alone, or in I0121 r) droxidopa--one or more of atomoxetine, rebox combination with one or more further active agents as etine, Viloxazine, maprotiline, bupropion, and radafax described herein, in an amount effective to eliminate or ine+one or more of amitriptyline, butriptyline, nortrip reduce the frequency or severity of the symptom. In particular tyline, protriptyline; embodiments, the mood disorder is depression. In other 0.122 s) droxidopa+one or more of fluoxetine, paroxet embodiments, the invention may specifically be described as ine, citalopram, escitalopram, fluvoxamine, and Sertra eliminating or reducing the frequency or severity of any one line--one or more of amitriptyline, butriptyline, nortrip of the specific symptoms of a mood disorder as provided tyline, protriptyline; above. In one embodiment, the method comprises eliminat I0123 t) droxidopa+a DDC inhibiting compound+one ing or reducing the frequency or severity of a specific symp or more of a COMT inhibiting compound, a cholinest tom of depression. In Such embodiments, the method may erase inhibiting compound, and an antidepressant; comprise administering droxidopa alone or in combination 0.124 u) droxidopa+a DDC inhibiting compound+a with one or more further active agents as described herein. COMT inhibiting compound; and Effectiveness of the inventive methods may be established 0.125 V) droxidopa--one or more of benserazide, carbi through analysis of a treated patient, through self-reporting of dopa, difluoromethyldopa, and C.-methyldopa+one or the treated patient, or through a diagnosis of effective treat more of entacapone, tolcapone, and nitecapone. ment provided by a medical professional after evaluating the treated patient. III. METHODS OF TREATMENT 0.130. In further embodiments, the invention provides a 0.126 The present invention, in one embodiment, provides method for the treatment of sleep disorders. Specifically, the a method for the treatment of mood disorders. Specifically, invention provides a method for the treatment of any condi the invention provides a method for the treatment of depres tion classified as hypersomnia (including narcolepsy, with or Sion. The methods of the invention generally comprise without cataplexy, idiopathic hypersomnia, recurrent hyper administering droxidopa to a patient Suffering from depres Somnia, and hypersomnia resulting from a medical condi Sion. In a specific embodiment, the invention comprises tion). In another specific embodiment, the invention provides administering droxidopa to a patient exhibiting symptoms of a method for the treatment of insomnia. The methods of the or having been diagnosed as Suffering from, depression. invention generally comprise administering droxidopa to a 0127 Depression is typically associated with reduced lev patient Suffering from a condition of hypersomnia or Suffer els of the neurotransmitters serotonin and norepinephrine, ing from insomnia. and avenues for increasing neurotransmitter levels within the I0131 Although the method of treatment may be described brain can be effective in treating depression. Interventions for as follows in terms of the specific hypersomnia condition of depression thus have included neurotransmitter reuptake narcolepsy, it is understood that the inventive method also inhibitors; however, many reuptake inhibitors also cause encompasses treatment of other conditions of hypersomnia, undesirable side effects (e.g., weight changes, sleep disrup as provided above. As previously pointed out, narcolepsy is tion, and sexual dysfunction). typically treated with stimulants and antidepressants (i.e., 0128 Droxidopa is converted to norepinephrine by the compositions useful for increasing alertness and reducing action of the aromatic L-amino acid decarboxylase known as fatigue). Accordingly, narcolepsy (and particularly Symp DDC. Droxidopa is believed to be useful for treating mood toms thereof. Such as cataplexy) can be associated with disorders, and particularly depression, because of its ability to reduced levels of neurotransmitters, such as norepinephrine, increase norepinephrine levels via the noted conversion pro and avenues for increasing neurotransmitter levels within the cess. Since depression (and other mood disorders) can be brain can be effective in treating narcolepsy. As droxidopa is linked to reduced norepinephrine levels, treatments that converted directly to norepinephrine, it is believed to be use increase the available amount of norepinephrine, particularly ful for treating sleep disorders, and particularly narcolepsy, in the CNS, are beneficial for treating such conditions. because of its ability to increase norepinephrine levels via the 0129. Mood disorders, such as depression, may be diag noted conversion process. nosed when a patient exhibits certain symptoms of such dis 0.132. Insomnia may be associated with abnormally orders. As previously noted, symptoms of a mood disorder elevated norepinephrine levels. Accordingly, the use of one or may include: persistent feelings of sadness; feeling hopeless more drugs that normalize norepinephrine levels may be use or helpless; having low self-esteem; feeling inadequate; ful to treat insomnia. excessive guilt, feelings of wanting to die; loss of interest in 0.133 Treatment of a sleep disorder according to the usual activities or activities once enjoyed; difficulty with rela present invention may include a complete cessation of the tionships; sleep disturbances; changes in appetite or weight; sleeping disorder or may include reducing the frequency or decreased energy; difficulty concentrating; a decrease in the severity of the sleep disorder. For example, treatment of nar ability to make decisions; Suicidal thoughts or attempts; fre colepsy according to the invention may be evidenced by a quent physical complaints (i.e., headache, stomach ache, complete absence of any narcoleptic events for a specific US 2009/0023705 A1 Jan. 22, 2009 period of time, a reduction in the frequency of narcoleptic tive to reduce the severity of any one or more of the symptoms events, or a reduction in the severity of a narcoleptic event. As of narcolepsy previously exhibited by the patient. used herein, a “narcoleptic event' or a “narcoleptic episode' 0.137 Treatment of insomnia according to the invention is meant to mean the occurrence of any one or more of the may similarly be evidenced by a complete absence of any following known symptoms of narcolepsy: excessive day symptoms of insomnia for a specific period of time, a reduc time sleepiness; cataplexy, sleep paralysis; and hypnagogic tion in the frequency of episodes of insomnia, or a reduction hallucinations. in the severity of an episode of insomnia. As previously pointed out, insomnia may be evidenced by various symp 0134. In preferred embodiments, treatment of narcolepsy toms. In some patients, insomnia presents as the inability to according to the invention is effective to achieve the complete fall asleep for up to several hours after retiring to sleep at a absence of any narcoleptic events for a time of at least 1 day, usual time for the patient. For example, in a patient that at least 2 days, at least 3 days, at least 4 days, at least 5 days, normally retires to sleep at 10 p.m., an episode of insomnia at least 6 days, at least 7 days, at least 2 weeks, at least 3 may present as the inability to fall asleep until 30 minutes, 1 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at hour, 2 hours, 3 hours, or even longer after initially retiring to least 2 months, at least 3 months, at least 6 months, or at least sleep. Episodes of insomnia may typically be present for 2 or 1 year. In specific embodiments, the present invention thus more consecutive days, 3 or more consecutive days, 4 or more comprises treating a patient suffering from recurrent narco consecutive days, 5 or more consecutive days, 6 or more leptic episodes, wherein the method comprises administering consecutive days, 7 or more consecutive days, or even longer. to the patient droxidopa alone, or in combination with one or In other cases, insomnia may present as being able to initially more further active agents as described herein, in an amount fall asleep, but the sleep may be interrupted by one or more effective to achieve the complete absence of a narcoleptic awakenings during the sleep period, often accompanied by event for a time as described above. Thus, treatment may be the inability to fallback asleep for 30 minutes, 1 hour, 2 hours, effective to achieve the complete absence of any one or more 3 hours, or even longer. of the symptoms of narcolepsy previously exhibited by the 0.138. In preferred embodiments, treatment of insomnia patient. according to the invention is effective to achieve the complete 0135) In other embodiments, the treatment may be effec absence of any episode of insomnia. Specifically, episodes of tive to reduce the frequency of narcoleptic events. In particu insomnia may be prevented for at least 1 week, at least 2 lar, the treatment may be effective to reduce the frequency of weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at narcoleptic events to no more than 1 event over the course of least 6 weeks, at least 2 months, at least 3 months, at least 6 a 24-hour day, no more than 1 event over the course of 2 days, months, or at least 1 year. The present invention thus com no more than 1 event over the course of 3 days, no more than prises treating a patient Suffering from recurrent episodes of 1 event over the course of 4 days, no more than 1 event over insomnia, wherein the method comprises administering to the the course of 5 days, no more than one event over the course patient droxidopa alone, or in combination with one or more of 6 days, no more than 1 event over the course of 7 days, no further active agents as described herein, in an amount effec more than 1 event over the course of 2 weeks, no more than tive to achieve the complete absence of an episode of insom one event over the course of 3 weeks, no more than 1 event nia for a time as described above. Thus, treatment may be over the course of 4 weeks, no more than 1 event over the effective to achieve the complete absence of difficulty falling course of 5 weeks, no more than 1 event over the course of 6 asleep or recurrent awakenings during sleep as previously weeks, no more than 1 event over the course of 2 months, no exhibited by the patient. more than 1 event over the course of 3 months, no more than 0.139. In other embodiments, the treatment may be effec one event over the course of 6 months, or no more than 1 event tive to reduce the frequency of episodes of insomnia. In over the course of 1 year. In specific embodiments, the present particular, the treatment may be effective to reduce the fre invention thus comprises treating a patient Suffering from quency of episodes of insomnia to no more than 1 episode recurrent narcoleptic episodes, wherein the method com over the course of 1 week, no more than 1 episode over the prises administering to the patient droxidopa alone, or in course of 2 weeks, no more than 1 episode over the course of combination with one or more further active agents as 3 weeks, no more than 1 episode over the course of 4 weeks, described herein, in an amount effective to reduce the fre no more than 1 episode over the course of 5 weeks, no more quency of a narcoleptic event for a time as described above. than 1 episode over the course of 6 weeks, no more than 1 Thus, the treatment may be effective to reduce the frequency episode over the course of 2 months, no more than 1 episode of occurrence of any one or more of the symptoms of narco over the course of 3 months, no more than one episode over lepsy previously exhibited by the patient. the course of 6 months, or no more than 1 episode over the 0136. In yet further embodiments, treatment may be effec course of 1 year. In specific embodiments, the present inven tive to reduce the severity of a narcoleptic event. For example, tion thus comprises treating a patient Suffering from recurrent the treatment may be effective such that, if the patient does episodes of insomnia, wherein the method comprises admin Suffer a narcoleptic event, the symptoms of the event do not istering to the patient droxidopaalone, or in combination with include complete unconsciousness, do not include complete one or more further active agents as described herein, in an paralysis, do not include any paralysis, or do not include any amount effective to reduce the frequency of an episode of hallucinations. In specific embodiments, the present inven insomnia for a time as described above. Thus, the treatment tion thus comprises treating a patient Suffering from recurrent may be effective to reduce the frequency of occurrence of narcoleptic episodes, wherein the method comprises admin difficulty falling asleep or recurrent awakenings during sleep istering to the patient droxidopaalone, or in combination with as previously exhibited by the patient. one or more further active agents as described herein, in an 0140. In yet further embodiments, treatment may be effec amount effective to reduce the severity of the narcoleptic tive to reduce the severity of an episode of insomnia. For event as described above. Thus, the treatment may be effec example, the treatment may be effective such that, if the US 2009/0023705 A1 Jan. 22, 2009 patient does suffer an episode of insomnia, the symptoms of pointed out previously, droxidopa is useful for increasing the episode are less severe than previously suffered. For norepinephrine levels, particularly in the CNS. Such an example, difficulty infalling asleep may be reduced in sever increase in norepinephrine levels, in addition to the direct ity such that the patient is able to achieve sleep in less than 1 effect of the neurotransmitter, can also have indirect effects hour, less than 45 minutes, less than 30 minutes, less than 20 that may be beneficial according to the present invention. minutes, or less than 15 minutes. Likewise, frequent awaken While not wishing to be bound by theory, increased blood ings may be reduced in severity so that a patient awakens less pressure resulting from increased norepinephrine levels (par than 5 times, less than 4 times, less than 3 times, or less than ticularly in the CNS through conversion of droxidopa) can 2 times during an 8 hour period of sleep. Moreover, is a patient lead to increased blood flow in the brain. This can have a Suffering from frequent awakenings during sleep does con significant effect on a variety of conditions. For example, tinue to awaken, the severity of the condition is reduced such depression, narcolepsy, and AD/HD have all been linked to that the patient is able to re-attain sleep in a time of less than reduced cerebral blood flow (rCBF). Although focusing on 1 hour, less than 45 minutes, less than 30 minutes, less than 20 narcolepsy, a recent study by Joo et al., Neuroimage (2005), minutes, or less than 15 minutes. In specific embodiments, the 28(2): p. 410-416 (incorporated herein by reference) dis present invention thus comprises treating a patient suffering closed that abnormal cerebral perfusion may explain the char from recurrent episodes of insomnia, wherein the method acteristic features of narcolepsy, including cataplexy, emo comprises administering to the patient droxidopa alone, or in tional lability (i.e., depression), and attention deficit. Other combination with one or more further active agents as clinical studies with compounds, such as methylphenidate, described herein, in an amount effective to reduce the severity that increase regional cerebral blood flow (perfusion) were of the episodes of insomnia as described above. Thus, the found to improve AD/HD. See Lee, et al., Hum. Brain Mapp., treatment may be effective to reduce the severity of any one or (2005), 24(3): 157-164, and Kim, et al., Yonsei Med J., more of the symptoms of insomnia previously exhibited by (2001), 42(1): 19-29, both of which are incorporated herein the patient. by reference. Surprisingly, the present invention has found 0141. In still another embodiment, the invention provides that a single drug, such as droxidopa, can form a link to a method for the treatment of attention deficit disorders (AD/ provide Successful treatment of a variety of conditions HD). The methods of the invention thus comprise adminis wherein reduced cerebral blood flow may be an underlying tering droxidopa to a patient suffering from AD/HD. factor. 0142. Historically, stimulants (which affect CNS dopam 0145 The present invention may thus particularly encom ine levels) have been the drug of choice for treatment of pass methods of treating patients suffering from conditions AD/HD; however, recent research indicates other classes of that at least partially arise from reduced blood flow in one or pharmaceuticals can also be effective. For example, the U.S. more portions of the brain, such as the cerebrum. The method Food and Drug Administration (FDA) recently approved the can particularly comprise administering to the patient droxi use of the NRISTRATTERAR) (atomoxetine) for the treat dopa alone, or in combination with one or more additional ment of AD/HD, which indicates compounds capable of active agents, as described herein. Preferably, the adminis increasing levels of available norepinephrine in the CNS may tered agent (e.g., droxidopa) or agents (e.g., droxidopa--at be effective for treating AD/HD. Again, as droxidopa is con least one additional agent) is a therapeutically effective verted directly to norepinephrine, it is believed to be useful amount that will function to increase brain blood flow (e.g., for treating AD/HD because of its ability to increase norepi cerebral blood flow) and thus treat the condition. nephrine levels via the noted conversion process. 0146 The various combinations of one or more further 0143. As with mood disorders, AD/HD may be diagnosed active ingredients with droxidopa, in certain embodiments, when a patient exhibits certain symptoms of the disorder. are also beneficial for treating the conditions described Accordingly, treatment of AD/HD according to the present herein. In certain embodiments, the one or more further active invention may include eliminating or reducing the frequency agents provide a conserving effect on the droxidopa. In fur or severity of any of the noted symptoms or other symptoms ther embodiments, the one or more further active agents pro relied upon by a medical professional in making a diagnosis vide a complimentary effect to the action of the droxidopa, of AD/HD. Accordingly, in some embodiments, the present preferably eliminating or reducing the frequency or severity invention comprises treating a patient exhibiting at least one of one or more of the symptoms associated with the condi symptoms of AD/HD by administering to the patient droxi tions described herein. dopa alone, or in combination with one or more further active 0.147. In particular embodiments, droxidopa is combined agents as described herein, in an amount effective to eliminate with one or more DDC inhibitors. Such a combination is or reduce the frequency or severity of the symptom. In other particularly beneficial for focusing the effect of the droxidopa embodiments, the invention may specifically be described as in increasing norepinephrine levels. Many DDC inhibitors, eliminating or reducing the frequency or severity of any one Such as benserazide and carbidopa, do not enter the central of the specific symptoms of AD/HD as described herein. In nervous system. Rather, they remain within the periphery Such embodiments, the method may comprise administering where they prevent decarboxylation of compounds (such as droxidopa alone or in combination with one or more further levodopa or droxidopa) into the active metabolites (such as active agents as described herein. Effectiveness of the inven norepinephrine). Thus, when a non-CNS DDC inhibitor is tive methods may be established through analysis of a treated administered in combination with droxidopa, the DDC patient, through self-reporting of the treated patient, or inhibitor prevents decarboxylation of the droxidopa in the through a diagnosis of effective treatment provided by a periphery and therefore allows more droxidopa to enter the medical professional after evaluating the treated patient. CNS intact. Once within the CNS (and thus segregated from 0144. It is Surprising that a single drug, Such as droxidopa, the DDC inhibitor), the droxidopa can be converted to nore could find use intreating a variety of conditions, such as mood pinephrine. Accordingly, the combination of a DDC inhibitor disorders, sleep disorders, and attention deficit disorders. As with droxidopa can increase the effective ability of the droxi US 2009/0023705 A1 Jan. 22, 2009 dopa to provide norepinephrine within the CNS and the more further active agents described herein to be particularly reduce the necessary doses of droxidopa to be effective in effective in treating depression is illustrated in the Example treating the conditions described herein. provided below. 0148. As previously noted, catechol-O-methyltransferase 0153. In light of the clear synergistic effect resulting from is directly involved in the metabolism of catecholamines, the combination of a tricyclic antidepressant and droxidopa, including dopamine, epinephrine, norepinephrine, and droxi the present invention also includes a method of enhancing the dopa. Accordingly, by providing droxidopa in combination therapeutic effectiveness of a tricycle antidepressant in treat ing any condition for which Such compounds are used. For with a COMT inhibitor, the effect of the droxidopa to affect example, the combination of droxidopa and tricyclic antide the conditions described herein is conserved. Specifically, by pressants could be used to enhance the therapeutic effective inhibiting the action of COMT, the COMT inhibiting com ness of Such antidepressants to treat mood disorders, sleep pound slows or delays the metabolism of droxidopa (as well disorders, and attention deficit disorders as noted herein, but as norepinephrine itself). This influences the overall plasma also to enhance treatment of neuropathic pain, nocturnal concentration of the droxidopa by increasing both the peak enuresis, headaches (including migraines), anxiety, bulimia plasma concentration (C) and the half-life of the admin nervosa, irritable bowel syndrome, persistent hiccups, and istered droxidopa. This is particularly beneficial in that it interstitial cystitis. allows for reduced dosages of droxidopa without limiting effective treatment of the conditions described herein. Fur ther, the combination of the COMT inhibitor with droxidopa IV. BIOLOGICALLY ACTIVE VARIANTS may be effective for increasing the duration of the droxidopa 0154 Biologically active variants of the various com activity (i.e., increasing the duration of norepinephrine activ pounds disclosed herein as active agents are particularly also ity), which may allow for a reduction in dosing frequency of encompassed by the invention. Such variants should retain the droxidopa. See, for example, U.S. Patent Application the general biological activity of the original compounds; Publication 2008/0015181, which is incorporated herein by however, the presence of additional activities would not nec reference in its entirety. essarily limit the use thereof in the present invention. Such 014.9 The combination of droxidopa with an MAOI has a activity may be evaluated using standard testing methods and similar effect of conserving bodily norepinephrine levels. In bioassays recognizable by the skilled artisan in the field as particular embodiments, the MAOI inhibits the action of generally being useful for identifying such activity. monoamine oxidase in breaking down norepinephrine, 01:55 According to one embodiment of the invention, Suit including that formed from the conversion of droxidopa. able biologically active variants comprise analogues and Accordingly, droxidopa plasma concentrations are positively derivatives of the compounds described herein. Indeed, a influenced as the half-life of the droxidopa is increase. This is single compound, Such as those described herein, may give again particularly beneficial in allowing for reduced droxi rise to an entire family of analogues or derivatives having dopa dosages without limiting effective treatment of the con similar activity and, therefore, usefulness according to the ditions described herein. Moreover, the combination of the present invention. Likewise, a single compound. Such as MAOI with droxidopa is also effective for increasing droxi those described herein, may represent a single family member dopaactivity duration, which again may allow for a reduction of a greater class of compounds useful according to the in dosing frequency of the droxidopa. present invention. Accordingly, the present invention fully 0150. In certain embodiments, the combination of droxi encompasses not only the compounds described herein, but dopa with cholinesterase inhibitors can be particularly effec analogues and derivatives of Such compounds, particularly tive. For example, in a specific embodiment, pyridostigmine those identifiable by methods commonly known in the art and could be combined with droxidopa, the pyridostigmine recognizable to the skilled artisan. enhancing ganglionic neurotransmission while the droxidopa 0156 The compounds disclosed herein as active agents acts to load the postganglionic neuron with norepinephrine. may contain chiral centers, which may be either of the (R) or 0151. In still further embodiments, it is particularly useful (S) configuration, or may comprise a mixture thereof. to combine droxidopa with one or more compounds known to Accordingly, the present invention also includes stereoiso directly increase the availability of norepinephrine in the mers of the compounds described herein, where applicable, CNS. As noted above, droxidopa has the effect of being either individually or admixed in any proportions. Stereoiso directly converted into norepinephrine; however, the produc mers may include, but are not limited to, enantiomers, dias tion of norepinephrine can be ineffective if it is undergoing tereomers, racemic mixtures, and combinations thereof. Such excessive presynaptic reuptake. The combination of droxi Stereoisomers can be prepared and separated using conven dopa with a NRI functions to conserve CNS norepinephrine tional techniques, either by reacting enantiomeric starting levels. materials, or by separating isomers of compounds of the 0152 The combination of droxidopa with the further present invention. Isomers may include geometric isomers. active ingredients is also particularly useful in the treatment Examples of geometric isomers include, but are not limited of the conditions described herein. For example, combining to, cis isomers or trans isomers across a double bond. Other droxidopa with one or more antidepressants can provide an isomers are contemplated among the compounds of the additive effect. Moreover, treatments that affect neurotrans present invention. The isomers may be used either in pure mitter levels are known to require a “build-up' phase of one to form or in admixture with other isomers of the compounds three weeks to reach maximum effectiveness. Thus, it can be described herein. useful to combine droxidopa with one or more further active 0157 Various methods are known in the art for preparing agents that can provide immediate relief to symptoms asso optically active forms and determining activity. Such meth ciated with the conditions described herein. This ability of a ods include standard tests described herein other similar tests combination of droxidopa with an antidepressant and one or which are will known in the art. Examples of methods that can US 2009/0023705 A1 Jan. 22, 2009 be used to obtain optical isomers of the compounds according 0170 xiii) transport across chiral membranes whereby a to the present invention include the following: racemate is placed in contact with a thin membrane barrier. 0158 i) physical separation of crystals whereby macro The barrier typically separates two miscible fluids, one con scopic crystals of the individual enantiomers are manually taining the racemate, and a driving force Such as concentra separated. This technique may particularly be used when tion or pressure differential causes preferential transport crystals of the separate enantiomers exist (i.e., the material is across the membrane barrier. Separation occurs as a result of a conglomerate), and the crystals are visually distinct; the non-racemic chiral nature of the membrane which allows 0159) ii) simultaneous crystallization whereby the indi only one enantiomer of the racemate to pass through. vidual enantiomers are separately crystallized from a solution 0171 The compound optionally may be provided in a of the racemate, possible only if the latteris a conglomerate in composition that is enantiomerically enriched, such as a mix the solid state; ture of enantiomers in which one enantiomer is present in 0160 iii) enzymatic resolutions whereby partial or com excess, in particular to the extent of 95% or more, or 98% or plete separation of a racemate by virtue of differing rates of more, including 100%. reaction for the enantiomers with an enzyme; 0172. The compounds described herein as active agents 0161 iv) enzymatic asymmetric synthesis, a synthetic can also be in the form of an ester, amide, salt, Solvate, technique whereby at least one step of the synthesis uses an prodrug, or metabolite provided they maintain pharmacologi enzymatic reaction to obtain an enantiomerically pure or cal activity according to the present invention. Esters, amides, enriched synthetic precursor of the desired enantiomer; salts, Solvates, prodrugs, and other derivatives of the com 0162 v) chemical asymmetric synthesis whereby the pounds of the present invention may be prepared according to desired enantiomer is synthesized from an achiral precursor methods generally known in the art, such as, for example, under conditions that produce asymmetry (i.e., chirality) in those methods described by J. March, Advanced Organic the product, which may be achieved using chiral catalysts or Chemistry: Reactions, Mechanisms and Structure, 4' Ed. chiral auxiliaries; (New York: Wiley-Interscience, 1992), which is incorporated 0163 vi) diastereomer separations whereby a racemic herein by reference. compound is reacted with an enantiomerically pure reagent 0173 Examples of pharmaceutically acceptable salts of (the chiral auxiliary) that converts the individual enantiomers the compounds useful according to the invention include acid to diastereomers. The resulting diastereomers are then sepa addition salts. Salts of non-pharmaceutically acceptable rated by chromatography or crystallization by virtue of their acids, however, may be useful, for example, in the preparation now more distinct structural differences and the chiral auxil and purification of the compounds. Suitable acid addition salts according to the present invention include organic and iary later removed to obtain the desired enantiomer; inorganic acids. Preferred salts include those formed from 0164 vii) first- and second-order asymmetric transforma hydrochloric, hydrobromic, Sulfuric, phosphoric, citric, tar tions whereby diastereomers from the racemate equilibrate to taric, lactic, pyruvic, acetic, Succinic, fumaric, maleic, oxalo yield a preponderance in Solution of the diastereomer from acetic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, the desired enantiomer or where preferential crystallization benzesulfonic, and isethionic acids. Other useful acid addi of the diastereomer from the desired enantiomer perturbs the tion salts include propionic acid, glycolic acid, oxalic acid, equilibrium such that eventually in principle all the material is malic acid, malonic acid, benzoic acid, cinnamic acid, man converted to the crystalline diastereomer from the desired delic acid, salicylic acid, and the like. Particular example of enantiomer. The desired enantiomer is then released from the pharmaceutically acceptable salts include, but are not limited diastereomers; to, Sulfates, pyrosulfates, bisulfates, Sulfites, bisulfites, phos 0.165 viii) kinetic resolutions comprising partial or com phates, monohydrogenphosphates, dihydrogenphosphates, plete resolution of a racemate (or of a further resolution of a metaphosphates, pyrophosphates, chlorides, bromides, partially resolved compound) by virtue of unequal reaction iodides, acetates, propionates, decanoates, caprylates, acry rates of the enantiomers with a chiral, non-racemic reagent or lates, formates, isobutyrates, caproates, heptanoates, propi catalyst under kinetic conditions; olates, oxalates, malonates, succinates, Suberates, sebacates, 0166 ix) enantiospecific synthesis from non-racemic pre fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, cursors whereby the desired enantiomer is obtained from benzoates, chlorobenzoates, methylbenzoates, dinitroben non-chiral starting materials and where the stereochemical Zoates, hydroxybenzoates, methoxyenzoates, phthalates, Sul integrity is not or is only minimally compromised over the fonates, Xylenesulfonates, phenylacetates, phenylpropi course of the synthesis; Onates, phenylbutyrates, citrates, lactates, 0167 x) chiral liquid chromatography whereby the enan Y-hydroxybutyrates, glycolates, tartrates, methanesulfonates, tiomers of a racemate are separated in a liquid mobile phase propanesulfonates, naphthalene-1-sulfonates, naphthalene by virtue of their differing interactions with a stationary 2-sulfonates, and mandelates. phase. The stationary phase can be made of chiral material or 0.174. An acid addition salt may be reconverted to the free the mobile phase can contain an additional chiral material to base by treatment with a suitable base. Preparation of basic provoke the differing interactions; salts of acid moieties which may be present on a compound 0168 xi) chiral gas chromatography whereby the race useful according to the present invention may be prepared in mate is volatilized and enantiomers are separated by virtue of a similar manner using a pharmaceutically acceptable base, their differing interactions in the gaseous mobile phase with a Such as sodium hydroxide, potassium hydroxide, ammonium column containing a fixed non-racemic chiral adsorbent hydroxide, calcium hydroxide, triethylamine, or the like. phase; 0.175 Esters of the active agent compounds according to 0169 xii) extraction with chiral solvents whereby the the present invention may be prepared through functionaliza enantiomers are separated by virtue of preferential dissolu tion of hydroxyl and/or carboxyl groups that may be present tion of one enantiomer into a particular chiral solvent; and within the molecular structure of the compound. Amides and US 2009/0023705 A1 Jan. 22, 2009 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 0180 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 ethylamine, potassium carbonate) in a Suitable organic Sol boxylic acid moiety include, but are not limited to, the fol vent (e.g., tetrahydrofuran, acetone, methanol, pyridine, N.N- lowing: aryl; Steroids; carbohydrates (including Sugars); 1.2- dimethylformamide) at a temperature of 0° C. to 60° C. diacylglycerol; alcohols; acyl (including lower acyl); alkyl Prodrugs are typically prepared by covalent attachment of a (including lower alkyl); Sulfonate ester (including alkyl or moiety, which results in a compound that is therapeutically arylalkyl Sulfonyl. Such as methanesulfonyl and benzyl, inactive until modified by an individual's metabolic system. wherein the phenyl group is optionally substituted with one or Examples of pharmaceutically acceptable Solvates include, more Substituents as provided in the definition of an aryl given but are not limited to, compounds according to the invention herein); optionally Substituted arylsulfonyl: lipids (including in combination with water, isopropanol, ethanol, methanol, phospholipids); phosphotidylcholine; phosphocholine; DMSO, ethyl acetate, acetic acid, or ethanolamine. amino acid residues or derivatives; amino acid acyl residues 0176). In the case of solid compositions, it is understood or derivatives; peptides; cholesterols; or other pharmaceuti that the compounds used in the methods of the invention may cally acceptable leaving groups which, when administered in exist in different forms. For example, the compounds may vivo, provide the free amine and/or carboxylic acid moiety. exist in stable and metastable crystalline forms and isotropic Any of these can be used in combination with the disclosed and amorphous forms, all of which are intended to be within active agents to achieve a desired effect. the scope of the present invention. 0177. If a compound useful as an active agent according to V. PHARMACEUTICAL COMPOSITIONS the invention is a base, the desired salt may be prepared by any 0181. While it is possible for individual active agent com suitable method known to the art, including treatment of the pounds used in the methods of the present invention to be free base with an inorganic acid, such as hydrochloric acid, administered in the raw chemical form, it is preferred for the hydrobromic acid, Sulfuric acid, nitric acid, phosphoric acid compounds to be delivered as a pharmaceutical composition. and the like, or with an organic acid, such as acetic acid, Accordingly, there are provided by the present invention maleic acid, Succinic acid, mandelic acid, fumaric acid, mal pharmaceutical compositions comprising one or more com onic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic pounds described herein as active agents. As such, the com acid, pyranosidyl acids Such as glucuronic acid and galactu positions used in the methods of the present invention com ronic acid, alpha-hydroxy acids such as citric acid and tartaric prise the pharmaceutically active compounds, as described acid, amino acids such as aspartic acid and glutamic acid, above, or pharmaceutically acceptable esters, amides, salts, aromatic acids such as benzoic acid and cinnamic acid, Sul Solvates, analogs, derivatives, or prodrugs thereof. Further, fonic acids such a p-toluenesulfonic acid or ethanesulfonic the compositions can be prepared and delivered in a variety of acid, or the like. combinations. For example, the composition can comprise a 0.178 If a compound described herein as an active agent is single composition containing all of the active ingredients. an acid, the desired salt may be prepared by any Suitable Alternately, the composition can comprise multiple compo method known to the art, including treatment of the free acid sitions comprising separate active ingredients but intended to with an inorganic or organic base. Such as an amine (primary, be administered simultaneously, in Succession, or in other secondary or tertiary), an alkali metal or alkaline earth metal wise close proximity of time. hydroxide or the like. Illustrative examples of suitable salts 0182. The active agent compounds described herein can include organic salts derived from amino acids Such as gly be prepared and delivered together with one or more pharma cine and arginine, ammonia, primary, secondary and tertiary ceutically acceptable carriers therefore, and optionally, other amines, and cyclic amines such as piperidine, morpholine and therapeutic ingredients. Carriers should be acceptable in that piperazine, and inorganic salts derived from Sodium, calcium, they are compatible with any other ingredients of the compo potassium, magnesium, manganese, iron, copper, Zinc, alu sition and not harmful to the recipient thereof. A carrier may minum and lithium. also reduce any undesirable side effects of the agent. Such 0179 The present invention further includes prodrugs and carriers are known in the art. See, Wang etal. (1980).J. Parent. active metabolites of the active agent compounds described Drug Assn. 34(6):452-462, herein incorporated by reference herein. Any of the compounds described herein can be admin in its entirety. istered as a prodrug to increase the activity, bioavailability, or 0183 Compositions may include short-term, rapid-onset, stability of the compound or to otherwise alter the properties rapid-offset, controlled release, Sustained release, delayed of the compound. Typical examples of prodrugs include com release, and pulsatile release compositions, providing the pounds that have biologically labile protecting groups on a compositions achieve administration of a compound as functional moiety of the active compound. Prodrugs include described herein. See Remington's Pharmaceutical Sciences compounds that can be oxidized, reduced, aminated, deami (18" ed.: Mack Publishing Company, Eaton, Pa., 1990), nated, hydroxylated, dehydroxylated, hydrolyzed, dehydro herein incorporated by reference in its entirety. lyzed, alkylated, dealkylated, acylated, deacylated, phospho 0.184 Pharmaceutical compositions for use in the methods rylated, and/or dephosphorylated to produce the active of the invention are suitable for various modes of delivery, US 2009/0023705 A1 Jan. 22, 2009

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, intrasternal, 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. administration can vary, especially depending upon the con 0.190 Powdered and granular compositions of a pharma dition of the recipient and the disorder being treated. ceutical preparation may be prepared using known methods. 0185. The pharmaceutical compositions may be conve Such compositions may be administered directly to a patient niently made available in a unit dosage form, whereby Such or used in the preparation of further dosage forms, such as to compositions may be prepared by any of the methods gener form tablets, fill capsules, or prepare an aqueous or oily ally known in the pharmaceutical arts. Generally speaking, Suspension or solution by addition of an aqueous or oily Such methods of preparation comprise combining (by various vehicle thereto. Each of these compositions may further com methods) the active compounds of the invention with a suit prise one or more additives, such as dispersing or wetting able carrier or other adjuvant, which may consist of one or agents, Suspending agents, and preservatives. Additional more ingredients. The combination of the active ingredients excipients (e.g., fillers, Sweeteners, flavoring, or coloring with the one or more adjuvants is then physically treated to agents) may also be included in these compositions. present the composition in a suitable form for delivery (e.g., 0191 Liquid compositions of pharmaceutical composi shaping into a tablet or forming an aqueous Suspension). tions which are suitable for oral administration may be pre 0186 Pharmaceutical compositions suitable for oral dos pared, packaged, and sold either in liquid form or in the form age may take various forms, such as tablets, capsules, caplets, of a dry product intended for reconstitution with water or and wafers (including rapidly dissolving or effervescing), another suitable vehicle prior to use. each containing a predetermined amount of the active agent. 0.192 A tablet containing one or more active agent com The compositions may also be in the form of a powder or pounds described herein may be manufactured by any stan granules, a Solution or Suspension in an aqueous or non dard process readily known to one of skill in the art, such as, aqueous liquid, and as a liquid emulsion (oil-in-water and for example, by compression or molding, optionally with one water-in-oil). The active agents may also be delivered as a or more adjuvant or accessory ingredient. The tablets may bolus, electuary, or paste. It is generally understood that optionally be coated or scored and may be formulated so as to methods of preparations of the above dosage forms are gen provide slow or controlled release of the active agents. erally known in the art, and any such method would be Suit 0193 Adjuvants or accessory ingredients for use in the able for the preparation of the respective dosage forms for use compositions can include any pharmaceutical ingredient in delivery of the compositions according to the present commonly deemed acceptable in the art, Such as binders, invention. fillers, lubricants, disintegrants, diluents, Surfactants, stabi 0187. In one embodiment, an active agent compound may lizers, preservatives, flavoring and coloring agents, and the be administered orally in combination with a pharmaceuti like. Binders are generally used to facilitate cohesiveness of cally acceptable vehicle such as an inert diluent or an edible the tablet and ensure the tablet remains intact after compres carrier. Oral compositions may be enclosed in hard or soft sion. Suitable binders include, but are not limited to: starch, shell gelatin capsules, may be compressed into tablets or may polysaccharides, gelatin, polyethylene glycol, propylene gly be incorporated directly with the food of the patient's diet. col, waxes, and natural and synthetic gums. Acceptable fillers The percentage of the composition and preparations may be include silicon dioxide, titanium dioxide, alumina, talc, varied; however, the amount of Substance in Such therapeuti kaolin, powdered cellulose, and microcrystalline cellulose, as cally useful compositions is preferably such that an effective well as soluble materials, such as mannitol, urea, Sucrose, dosage level will be obtained. lactose, dextrose, Sodium chloride, and Sorbitol. Lubricants 0188 Hard capsules containing the active agent com are useful for facilitating tablet manufacture and include Veg pounds may be made using a physiologically degradable etable oils, glycerin, magnesium Stearate, calcium Stearate, composition, such as gelatin. Such hard capsules comprise and Stearic acid. Disintegrants, which are useful for facilitat the compound, and may further comprise additional ingredi ing disintegration of the tablet, generally include starches, ents including, for example, an inert Solid diluent such as clays, celluloses, algins, gums, and crosslinked polymers. calcium carbonate, calcium phosphate, or kaolin. Softgelatin Diluents, which are generally included to provide bulk to the capsules containing the compound may be made using a tablet, may include dicalcium phosphate, calcium sulfate, physiologically degradable composition, Such as gelatin. lactose, cellulose, kaolin, mannitol, Sodium chloride, dry Such soft capsules comprise the compound, which may be starch, and powdered Sugar. Surfactants Suitable for use in the mixed with water or an oil medium such as peanut oil, liquid composition according to the present invention may be paraffin, or olive oil. anionic, cationic, amphoteric, or nonionic Surface active 0189 Sublingual tablets are designed to dissolve very rap agents. Stabilizers may be included in the compositions to idly. Examples of such compositions include ergotamine tar inhibit or lessen reactions leading to decomposition of the trate, isosorbide dinitrate, and isoproterenol HCL. The com active agents, such as oxidative reactions. positions of these tablets contain, in addition to the drug, 0194 Solid dosage forms may be formulated so as to various soluble excipients, such as lactose, powdered provide a delayed release of the active agents, such as by Sucrose, dextrose, and mannitol. The Solid dosage forms of application of a coating. Delayed release coatings are known the present invention may optionally be coated, and examples in the art, and dosage forms containing such may be prepared US 2009/0023705 A1 Jan. 22, 2009

by any known Suitable method. Such methods generally creams, gels, pastes, and solutions. Compositions for admin include that, after preparation of the Solid dosage form (e.g., istration in the mouth include lozenges. a tablet or caplet), a delayed release coating composition is 0200. In certain embodiments, the compounds and com applied. Application can be by methods, such as airless spray positions disclosed herein can be delivered via a medical ing, fluidized bed coating, use of a coating pan, or the like. device. Such delivery can generally be via any insertable or Materials for use as a delayed release coating can be poly implantable medical device, including, but not limited to meric in nature, such as cellulosic material (e.g., cellulose stents, catheters, balloon catheters, shunts, or coils. In one butyrate phthalate, hydroxypropyl methylcellulosephthalate, embodiment, the present invention provides medical devices, and carboxymethyl ethylcellulose), and polymers and Such as stents, the Surface of which is coated with a compound copolymers of acrylic acid, methacrylic acid, and esters or composition as described herein. The medical device of thereof. this invention can be used, for example, in any application for 0.195 Solid dosage forms according to the present inven treating, preventing, or otherwise affecting the course of a tion may also be sustained release (i.e., releasing the active disease or condition, such as those disclosed herein. agents over a prolonged period of time), and may or may not 0201 In another embodiment of the invention, pharma also be delayed release. Sustained release compositions are ceutical compositions comprising one or more active agents known in the art and are generally prepared by dispersing a described herein are administered intermittently. Administra drug within a matrix of a gradually degradable or hydrolyZ tion of the therapeutically effective dose may be achieved in able material. Such as an insoluble plastic, a hydrophilic poly a continuous manner, as for example with a Sustained-release mer, or a fatty compound. Alternatively, a Solid dosage form composition, or it may be achieved according to a desired may be coated with Such a material. daily dosage regimen, as for example with one, two, three, or 0196) Compositions for parenteral administration include more administrations per day. By “time period of discontinu aqueous and non-aqueous sterile injection solutions, which ance' is intended a discontinuing of the continuous Sustained may further contain additional agents, such as anti-oxidants, released or daily administration of the composition. The time buffers, bacteriostats, and solutes, which render the compo period of discontinuance may be longer or shorter than the sitions isotonic with the blood of the intended recipient. The period of continuous Sustained-release or daily administra compositions may include aqueous and non-aqueous sterile tion. During the time period of discontinuance, the level of the Suspensions, which contain Suspending agents and thicken components of the composition in the relevant tissue is Sub ing agents. Such compositions for parenteral administration stantially below the maximum level obtained during the treat may be presented in unit-dose or multi-dose containers, such ment. The preferred length of the discontinuance period as, for example, sealed ampoules and vials, and may be stores depends on the concentration of the effective dose and the in a freeze-dried (lyophilized) condition requiring only the form of composition used. The discontinuance period can be addition of the sterile liquid carrier, for example, water (for at least 2 days, at least 4 days or at least 1 week. In other injection), immediately prior to use. Extemporaneous injec embodiments, the period of discontinuance is at least 1 tion solutions and Suspensions may be prepared from sterile month, 2 months, 3 months, 4 months or greater. When a powders, granules, and tablets of the kind previously Sustained-release composition is used, the discontinuance described. period must be extended to account for the greater residence 0197) The compositions for use in the methods of the time of the composition in the body. Alternatively, the fre invention may also be administered transdermally, wherein quency of administration of the effective dose of the sus the active agents are incorporated into a laminated structure tained-release composition can be decreased accordingly. An (generally referred to as a "patch') that is adapted to remainin intermittent schedule of administration of an inventive com intimate contact with the epidermis of the recipient for a position can continue until the desired therapeutic effect, and prolonged period of time. Typically, Such patches are avail ultimately treatment of the disease or disorder, is achieved. able as single layer "drug-in-adhesive' patches or as multi 0202 Administration of the composition comprises layer patches where the active agents are contained in a layer administering a pharmaceutically active agent as described separate from the adhesive layer. Both types of patches also herein or administering one or more pharmaceutically active generally contain a backing layer and a liner that is removed agents described herein in combination with one or more prior to attachment to the recipient's skin. Transdermal drug further pharmaceutically active agents (i.e., co-administra delivery patches may also be comprised of a reservoir under tion). Accordingly, it is recognized that the pharmaceutically lying the backing layer that is separated from the skin of the active agents described herein can be administered in a fixed recipient by a semi-permeable membrane and adhesive layer. combination (i.e., a single pharmaceutical composition that Transdermal drug delivery may occur through passive diffu contains both active agents). Alternatively, the pharmaceuti Sion, electrotransport, or iontophoresis. cally active agents may be administered simultaneously (i.e., 0198 Compositions for rectal delivery include rectal Sup separate compositions administered at the same time). In positories, creams, ointments, and liquids. Suppositories may another embodiment, the pharmaceutically active agents are be presented as the active agents in combination with a carrier administered sequentially (i.e., administration of one or more generally known in the art, such as polyethylene glycol. Such pharmaceutically active agents followed by separate admin dosage forms may be designed to disintegrate rapidly or over istration or one or more pharmaceutically active agents). One an extended period of time, and the time to complete disinte of skill in the art will recognized that the most preferred gration can range from a short time, such as about 10 minutes, method of administration will allow the desired therapeutic to an extended period of time. Such as about 6 hours. effect. 0199 Topical compositions may be in any form suitable 0203 Delivery of a therapeutically effective amount of a and readily known in the art for delivery of active agents to the composition according to the invention may be obtained via body Surface, including dermally, buccally, and Sublingually. administration of a therapeutically effective dose of the com Typical examples of topical compositions include ointments, position. Accordingly, in one embodiment, a therapeutically US 2009/0023705 A1 Jan. 22, 2009

effective amount is an amount effective to treat depression. In undesired symptoms and the clinical signs associated with the another embodiment, a therapeutically effective amount is an condition being treated. Methods to determine efficacy and amount effective to treat a narcolepsy. In yet another embodi dosage are known to those skilled in the art. See, for example, ment, a therapeutically effective amount is an amount effec Isselbacher et al. (1996) Harrison's Principles of Internal tive to treat AD/HD. In further embodiments, a therapeuti Medicine 13 ed., 1814-1882, herein incorporated by refer cally effective amount is an amount effective to treat a CCC. symptom of depression. In still another embodiment, a thera 0207. In certain embodiments, the therapeutically effec peutically effective amount is an amount effective to treat a tive amount of droxidopa can encompass varying ranges, and symptom of narcolepsy. In yet another embodiment, a thera the appropriate range could be determined based upon the peutically effective amount is an amount effective to treat a severity of the condition being treated and the presence of one symptom of AD/HD. or more additional compounds with which the droxidopa is 0204 The active agents included in the pharmaceutical combined. In specific embodiments, a therapeutically effec composition are present in an amount Sufficient to deliver to tive amount of droxidopa comprises about 10 mg to about 2 g, a patient a therapeutic amount of an active ingredient in vivo about 10 mg to about 1 g, about 20 mg to about 900 mg, about in the absence of serious toxic effects. The concentration of 30 mg to about 850 mg, about 40 mg to about 800 mg, about active agent in the drug composition will depend on absorp 50 mg to about 750 mg, about 60 mg to about 700 mg, about tion, inactivation, and excretion rates of the drug as well as 70 mg to about 650 mg, about 80 mg to about 600 mg, about other factors known to those of skill in the art. It is to be noted 90 mg to about 550 mg, about 100 mg to about 500 mg, about that dosage values will also vary with the severity of the 100 mg to about 400 mg. or about 100 mg to about 300 mg. condition being treated. It is further understood that for any 0208. A therapeutically effective amount of the one or particular subject, specific dosage regimens should be more additional compounds that can be combined with droxi adjusted according to the individual need and the professional dopa according to the invention can be determined in relation judgment of the person administering or Supervising the to the amount of droxidopa included in the dosage form and administration of the compositions, and that the dosage the desired ratio of droxidopa to the additional compound(s). ranges set forth herein are exemplary only and are not Advantageously, the present invention allows for great flex intended to limit the scope or practice of the claimed compo ibility in formulating combinations. For example, the con sition. The active ingredient may be administered at once, or serving effects provided by the one or more additional com may be divided into a number of smaller doses to be admin pounds can allow for using droxidopa in a lesser amount and istered at varying intervals of time still achieve the same, or better, therapeutic effects achieved 0205 Atherapeutically effective amount according to the using droxidopa alone. Likewise, it is possible to increase the invention can be determined based on the bodyweight of the therapeutic effects of droxidopa by using an amount of the recipient. Alternatively, a therapeutically effective amount one or more additional compounds that is less than the typi can be described in terms of a fixed dose. In still further cally recommended dosage for the one or more additional embodiments, a therapeutically effective amount of one or compounds. The one or more additional compounds com more active agents disclosed herein can be described in terms bined with droxidopa according to the invention can be of the peak plasma concentration achieved by administration included in amount typically recommended for use of the of the active agents. Of course, it is understood that the compounds alone. therapeutic amount could be divided into a number of frac 0209. In one embodiment, the ratio of droxidopa to the one tional dosages administered throughout the day. The effective or more additional compounds is in the range of about 500:1 dosage range of pharmaceutically acceptable salts and pro to about 1:10. In further embodiments, the ratio of droxidopa drugs can be calculated based on the weight of the parent to the additional compound(s) is in the range of about 250:1 to nucleoside to be delivered. If a salt or prodrug exhibits activ about 1:5, about 100:1 to about 1:2, about 8.0:1 to about 1:1, ity in itself, the effective dosage can be estimated as above about 50:1 to about 2:1, or about 20:1 to about 3:1. using the weight of the salt or prodrug, or by other means known to those skilled in the art. VI. ARTICLES OF MANUFACTURE 0206. It is contemplated that compositions of the invention comprising one or more active agents described herein will be 0210. The present invention also includes an article of administered in therapeutically effective amounts to a mam manufacture providing a composition comprising one or mal, preferably a human. An effective dose of a compound or more active agents described herein. The article of manufac composition for treatment of any of the conditions or diseases ture can include a vial or other container that contains a described herein can be readily determined by the use of composition Suitable for use according to the present inven conventional techniques and by observing results obtained tion together with any carrier, either dried or in liquid form. In under analogous circumstances. The effective amount of the particular, the article of manufacture can comprise a kit compositions would be expected to vary according to the including a container with a composition according to the weight, sex, age, and medical history of the Subject. Of invention. In Such a kit, the composition can be delivered in a course, other factors could also influence the effective amount variety of combinations. For example, the composition can of the composition to be delivered, including, but not limited comprise a single dosage comprising all of the active ingre to, the specific disease involved, the degree of involvement or dients. Alternately, where more than one active ingredient is the severity of the disease, the response of the individual provided, the composition can comprise multiple dosages, patient, the particular compound administered, the mode of each comprising one or more active ingredients, the dosages administration, the bioavailability characteristics of the being intended for administration in combination, in Succes preparation administered, the dose regimen selected, and the Sion, or in other close proximity of time. For example, the use of concomitant medication. The compound is preferen dosages could be solid forms (e.g., tablets, caplets, capsules, tially administered for a sufficient time period to alleviate the or the like) or liquid forms (e.g., vials), each comprising a US 2009/0023705 A1 Jan. 22, 2009 single active ingredient, but being provided in blister packs, bile when it ceased struggling and remained floating in the bags, or the like, for administration in combination. water making only those movements necessary to keep its 0211. The article of manufacture further includes instruc head above water. Data were analyzed by ANOVA for sig tions in the form of a label on the container and/or in the form nificant differences in group means, followed by T-test to of an insert included in a box in which the container is pack distinguish statistically significant groups as appropriate. aged, for carrying out the inventive method. The instructions 0215. As illustrated in FIG. 1 and FIG. 2, test mice treated can also be printed on the box in which the vial is packaged. with the vehicle alone displayed a pattern of immobility that The instructions contain information such as Sufficient dos was slightly depressed relative to the historical control values age and administration information to allow the Subject or a (i.e., an average time immobile of 138.3+20.4 sec versus worker in the field to administer the pharmaceutical compo historical control values of 190+30 sec). The lower than nor sition. A worker in the field encompasses any doctor, nurse, mal value for the control group was likely due to 2 outlying technician, spouse, or other caregiver that might administer animals (as seen in FIG. 2). Treatment with desipramine, the composition. The pharmaceutical composition can also be entacapone, fluoxetine, or Venlafaxine alone also did not sig self-administered by the subject. nificantly decrease the length of time that the mice spent 0212. The present invention will now be described with immobile (136.4 sec for desipramine, 129.9 sec for entaca specific reference to various examples. The following pone, 158.2 sec for fluoxetine, and 117.5 sec for Venlafaxine). examples are not intended to be limiting of the invention and Further, the time spent immobile was not decreased by are rather provided as exemplary embodiments. administration of droxidopa--carbidopa (191.8 sec), droxi dopa+carbidopa--entacapone (161.1 sec), or droxidopa+car EXAMPLE bidopa+fluoxetine (139.3 sec). Treatment with amitriptyline alone caused a significant decrease in the length of time the Treatment of Depression test mice spent immobile (60.0 sec). Surprisingly, treatment 0213. The effect of droxidopa, alone or in combination with droxidopa+carbidopa--amitriptyline resulted in a sig with other drugs, in the treatment of depression was evaluated nificant decrease in the length of time animals spent immobile using the murine Forced Swim Test (FST), a mouse model of (20.0 sec, p<0.005). Moreover, the addition of droxidopa-- depression commonly used to evaluate antidepressive drugs. carbidopa to amitriptyline resulted in a significant decrease in Depression (i.e., “learned helplessness” as evaluated by the the depression score of mice over that seen with amitriptyline FST model) was measured using the method of Porsolt et al., alone (p<0.05). Arch. Int. Pharmacodyn. (1977), 229: 327-336. Briefly, male 0216. As seen in FIG. 1, treatment with desipramine, flu CD-1 mice weighing 22 g (t2g) were fasted overnight prior oxetine, or Venlafaxine failed to decrease depression even to testing. The mice were randomized into 11 groups of 10 though these compounds have been reported to be active in mice each. Mice in each group were treated with the vehicle this model (see Dablehet al., Eur: J. Pharmacol. (2005), 507: alone, a drug, or a drug composition as outlined in Table 1 and 99-105, and Dhir et al., Pharmacol. (2007), 80: 239-43). returned to their respective groups. However the validity of the model was confirmed by the finding that 10 mg/kg of amitriptyline induced a significant TABLE 1. decrease in the length of time the test mice spent immobile. Further, the degree of reduction in the time spent immobile Test Conc. Dosage induced by amitriptyline is similar to that previously reported in the literature (see Lambertietal. Br. J. Pharmacol. (1998), Group Composition Route mg/ml ml/kg mg/kg 123: 1331-1336). By contrast, the addition of droxidopa+ 1 Vehicle intraperitonea NA O NA carbidopa to amitriptyline resulted in significantly lower 2 Desipramine intraperitonea 5 O 10 3 Entacapone intraperitonea O 30 immobility times, indicating that droxidopa acted synergisti 4 Fluoxetine intraperitonea O 18 cally with amitriptyline. Although not wishing to be bound by 5 Venlafaxine intraperitonea O 10 theory, it is believed that the synergistic effect seen with this 6 Amitriptyline intraperitonea O 10 specific combination may arise because from the specific 7 Droxidopa + intraperitonea O 400 action of tricyclic antidepressants (amitriptyline being one Carbidopa 2O 8 Droxidopa + intraperitonea O 400 example) on the noradrenergic system and the augmenting Carbidopa + 2O effect of droxidopa on the action of tricyclic antidepressants. Entacapone 30 0217 Many modifications and other embodiments of the 9 Droxidopa + intraperitonea O 400 inventions set forth herein will come to mind to one skilled in Carbidopa + 2O Fluoxetine 18 the art to which these inventions pertain having the benefit of 10 Droxidopa + intraperitonea O 400 the teachings presented in the foregoing descriptions. There Carbidopa + 2O fore, it is to be understood that the inventions are not to be Venlafaxine 10 11 Droxidopa + intraperitonea O 400 limited to the specific embodiments disclosed and that modi Carbidopa + 2O fications and other embodiments are intended to be included Amitriptyline 10 within the scope of the appended claims. Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation. 0214. In Table 1, the vehicle 2% TWEENR 80 (i.e., polysorbate 80) was included in all test compositions. One That which is claimed: hour after dosing, the test mice were placed in a 1 liter Volume 1. A method of treating a condition selected from the group glass beaker (height: 14.5 cm, diameter: 10.5 cm) containing consisting of a mood disorder, a sleep disorder, and an atten water 6 cm in height at room temperature (22 to 24°C.) for 6 tion deficit disorder, the method comprising administering a minutes. The duration of animal immobility within the last 4 pharmaceutical composition comprising a therapeutically minutes was then recorded. A mouse was judged to be immo effective amount of droxidopa, or a pharmaceutically accept US 2009/0023705 A1 Jan. 22, 2009 20 able ester, amide, salt, Solvate, or prodrug thereof, to a subject 20. The method of claim 15, wherein the one or more in need of treatment of the condition. additional active agents comprises a cholinesterase inhibiting 2. The method of claim 1, wherein the method comprises compound. treating a mood disorder. 21. The method of claim 20, wherein the cholinesterase 3. The method of claim 2, wherein the mood disorder is inhibiting compound is selected from the group consisting of depression. pyridostigmine, donepezil, rivastigmine, galantamine, 4. The method of claim 3, wherein the subject is suffering tacrine, neostigmine, metrifonate, physostigmine, from at least one symptom of depression, and the method ambenonium, demarcarium, thiaphySovenine, phenserine, comprises eliminating the symptom, reducing the severity of edrophonium, cymserine, and combinations thereof. the symptom, or reducing the frequency of occurrence of the 22. The method of claim 15, wherein the one or more symptom. additional active agents comprises a monoamine oxidase 5. The method of claim 1, wherein the method comprises inhibiting compound. treating a sleep disorder. 6. The method of claim 5, wherein the sleep disorder is a 23. The method of claim 22, wherein the monoamine oxi condition of hypersomnia. dase inhibiting compound is selected from the group consist 7. The method of claim 6, wherein the condition of hyper ing of isocarboxazid, moclobemide, phenelzine, tranyl Somnia is narcolepsy. cypromine, selegiline, nialamide, iproniazid, iproclozide, 8. The method of claim 5, wherein the sleep disorder is toloxatone, harmala, brofaromine, benmoxin, 5-methoxy-N, insomnia. N-dimethyltryptamine, 5-methoxy-y-methyltryptamine, and 9. The method of claim 1, wherein the method comprises combinations thereof. treating an attention deficit disorder. 24. The method of claim 15, wherein the one or more 10. The method of claim 9, wherein the attention deficit additional active agents comprises a norepinephrine reuptake disorder is Attention-Deficit/Hyperactivity Disorder (AD/ inhibiting compound. HD). 25. The method of claim 24, wherein the norepinephrine 11. The method of claim 10, wherein the subject is suffer reuptake inhibiting compound is selected from the group ing from at least one symptom of AD/HD, and the method consisting of atomoxetine, reboxetine, Viloxazine, mapro comprises eliminating the symptom, reducing the severity of tiline, bupropion, radafaxine, and combinations thereof. the symptom, or reducing the frequency of occurrence of the 26. The method of claim 15, wherein the one or more symptom. additional active agents comprises a selective serotonin 12. The method of claim 1, wherein the method further reuptake inhibiting compound. comprises administering one or more additional active 27. The method of claim 26, wherein the selective seroto agents. nin reuptake inhibiting compound is selected from the group 13. The method of claim 12, wherein the one or more consisting of fluoxetine, paroxetine, citalopram, escitalo additional active agents are formulated in the same pharma pram, fluvoxamine, Sertraline, and combinations thereof. ceutical composition with droxidopa. 28. The method of claim 15, wherein the one or more 14. The method of claim 12, wherein the one or more additional active agents comprises a tricyclic antidepressant additional active agents are administered in a pharmaceutical compound. composition separate from droxidopa. 29. The method of claim 28, wherein the tricyclic antide 15. The method of claim 12, wherein the one or more pressant compound is selected from the group consisting of additional active agents comprise a compound selected from amitriptyline, amoxapine, butriptyline, clomipramine, the group consisting of DOPA decarboxylase inhibiting com desipramine, dibenzepin, doSulepin, doxepin, imipramine, pounds, catechol-O-methyltransferase inhibiting com lofepramine, nortriptyline, protriptyline, trimipramine, and pounds, cholinesterase inhibiting compounds, monoamine oxidase inhibiting compounds, norepinephrine reuptake combinations thereof. inhibiting compounds, selective serotonin reuptake inhibiting 30. The method of claim 28, wherein the tricyclic antide compounds, tricyclic antidepressant compounds, serotonin pressant compound is selected from the group consisting of norepinephrine reuptake inhibiting compounds, norepineph amitriptyline, butriptyline, nortriptyline, protriptyline, and rine dopamine reuptake inhibiting compound, noradrenergic combinations thereof. and specific serotonergic antidepressants, and combinations 31. The method of claim 15, wherein the one or more thereof. additional active agents comprises a tricyclic antidepressant 16. The method of claim 15, wherein the one or more compound and a third active agent selected from the group additional active agents comprises a DOPA decarboxylase consisting of DOPA decarboxylase inhibiting compounds, inhibiting compound. catechol-O-methyltransferase inhibiting compounds, cho 17. The method of claim 16, wherein the DOPA decar linesterase inhibiting compounds, monoamine oxidase inhib boxylase inhibiting compound is selected from the group iting compounds, norepinephrine reuptake inhibiting com consisting of benserazide, carbidopa, difluoromethyldopa, pounds, selective serotonin reuptake inhibiting compounds, C.-methyldopa, and combinations thereof. serotonin norepinephrine reuptake inhibiting compounds, 18. The method of claim 15, wherein the one or more norepinephrine dopamine reuptake inhibiting compound, additional active agents comprises a catechol-O-methyltrans noradrenergic and specific serotonergic antidepressants, and ferase inhibiting compound. combinations thereof. 19. The method of claim 18, wherein the catechol-O-me 32. The method of claim 31, wherein the third active agent thyltransferase inhibiting compound is selected from the is a DOPA decarboxylase inhibiting compound. group consisting of entacapone, tolcapone, nitecapone, and 33. The method of claim 32, wherein the DOPA decar combinations thereof. boxylase inhibiting compound is carbidopa. US 2009/0023705 A1 Jan. 22, 2009

34. The method of claim 31, wherein the tricyclic antide inhibiting compound, noradrenergic and specific sero pressant is amitriptyline, and the third active agent is a DOPA tonergic antidepressants, and combinations thereof. decarboxylase inhibiting compound. 42. The pharmaceutical composition of claim 41, wherein 35. The method of claim 15, wherein the one or more the group c) compound is a DOPA decarboxylase inhibiting additional active agents comprises a DOPA decarboxylase compound. inhibiting compound and a third active agent selected from 43. The pharmaceutical composition of claim 42, wherein the group consisting of catechol-O-methyltransferase inhib the DOPA decarboxylase inhibiting compound is selected iting compounds, cholinesterase inhibiting compounds, from the group consisting of benserazide, carbidopa, difluo monoamine oxidase inhibiting compounds, norepinephrine romethyldopa, C.-methyldopa, and combinations thereof. reuptake inhibiting compounds, selective serotonin reuptake 44. The pharmaceutical composition of claim 42, compris inhibiting compounds, tricyclic antidepressant compounds, 1ng: serotonin norepinephrine reuptake inhibiting compounds, a) droxidopa, or a pharmaceutically acceptable ester, norepinephrine dopamine reuptake inhibiting compound, amide, salt, Solvate, or prodrug thereof, noradrenergic and specific serotonergic antidepressants, and b) a tricyclic antidepressant compound selected from the combinations thereof. group consisting of amitriptyline, butriptyline, nortrip 36. The method of claim 35, wherein the third active agent tyline, protriptyline, and combinations thereof, and is a catechol-O-methyltransferase inhibiting compound. c) a DOPA decarboxylase inhibiting compound selected 37. The method of claim 1, wherein droxidopa is adminis from the group consisting of benserazide, carbidopa, tered in the form of a mixture enantiomerically enriched in the difluoromethyldopa, C.-methyldopa, and combinations L-threo isomer. thereof. 38. A pharmaceutical composition comprising: 45. The pharmaceutical composition of claim 44, compris a) droxidopa, or a pharmaceutically acceptable ester, ing droxidopa, amitriptyline, and carbidopa. amide, salt, Solvate, or prodrug thereof, and 46. A method of treating a patient Suffering from a condi b) a tricyclic antidepressant compound. tion at least partially arising from reduced blood flow in the 39. The pharmaceutical composition of claim 38, wherein brain, the method comprising administering to the patient an the tricyclic antidepressant compound is selected from the amount of droxidopa that is therapeutically effective to group consisting of amitriptyline, amoxapine, butriptyline, increase brain blood flow. clomipramine, desipramine, dibenzepin, doSulepin, doxepin, 47. The method of claim 46, wherein the condition is imipramine, lofepramine, nortriptyline, protriptyline, trimi selected from the group consisting of a mood disorder, a sleep pramine, and combinations thereof. disorder, and an attention deficit disorder. 40. The pharmaceutical composition of claim 39, wherein 48. The method of claim 46, further comprising adminis the tricyclic antidepressant compound is selected from the tering one or more additional active agents selected from the group consisting of amitriptyline, butriptyline, nortriptyline, group consisting of DOPA decarboxylase inhibiting com protriptyline, and combinations thereof. pounds, catechol-O-methyltransferase inhibiting com 41. The pharmaceutical composition of claim 38, further pounds, cholinesterase inhibiting compounds, monoamine comprising: oxidase inhibiting compounds, norepinephrine reuptake c) a compound selected from the group consisting of inhibiting compounds, selective serotonin reuptake inhibiting DOPA decarboxylase inhibiting compounds, catechol compounds, tricyclic antidepressant compounds, serotonin O-methyltransferase inhibiting compounds, cholinest norepinephrine reuptake inhibiting compounds, norepineph erase inhibiting compounds, monoamine oxidase inhib rine dopamine reuptake inhibiting compound, noradrenergic iting compounds, norepinephrine reuptake inhibiting and specific serotonergic antidepressants, and combinations compounds, selective serotonin reuptake inhibiting thereof. compounds, serotonin norepinephrine reuptake inhibit ing compounds, norepinephrine dopamine reuptake