Methods and compositions for treating acute stress disorder

Abstract

The present disclosure relates to the treatment of disorders associated with noradrenergic hyperarousal in a human subject. The present disclosure also provides a method of treating acute stress disorder (ASD) comprising administering a therapeutically effective amount of latrepirdine or dexmedetomidine or pharmaceutically acceptable salts thereof. The present disclosure also provides a method of treating autism spectrum disorders in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of latrepirdine or dexmedetomidine alone or a combination thereof. The present disclosure provides oromucosal dosage forms comprising effective amounts of latrepirdine either alone or in combination with dexmedetomidine or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable carriers and / excipients. Methods of their use are also provided. The present disclosure also provides a method of treating depression by administering oromucosally a therapeutically effective amount of dexmedetomidine alone or in combination with latrepirdine.

Description

Attorney Docket No. BXTI-052 / 01WO 332712-2374 METHODS AND COMPOSITIONS FOR TREATING ACUTE STRESS DISORDER Cross-Reference to Related Applications

[0001] This application claims priority to and benefit of U.S. Provisional Application No. 63 / 402,855, filed August 31, 2022, the contents of which are hereby incorporated in their entirety as set forth herein. Incorporation by Reference

[0002] The contents of PCT / US2022 / 017963, filed February 25, 2022, and the contents of PCT / US2019 / 039268, filed June 26, 2019, are hereby incorporated in their entirety as if set forth herein. FIELD

[0003] The present disclosure also relates to the treatment of agitation in a subject in need thereof by administering an oromucosal dosage form comprising an effective amount of latrepirdine either alone or in combination with an effective amount of dexmedetomidine or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable carriers and / excipients. The present disclosure also provides a method of treating depression in a subject in need thereof, the method comprising administering oromucosally a therapeutically effective amount of dexmedetomidine alone or in combination with latrepirdine. BACKGROUND

[0004] Noradrenergic hyperarousal is a subclinical state in which there is excess noradrenergic signaling that causes hemodynamic and motor changes. The excessive noradrenergic signaling, being norepinephrine-dependent, may further result in heightened sympathetic tone and other stress-related psychiatric symptoms.

[0005] Acute stress disorder (ASD) is a mental health condition that results from the experience of a traumatic event. According to DSM IV (Disorder class: Anxiety disorder) and DSM 5 (Disorder class: Trauma- and Stressor-Related Disorders), symptoms of ASD may include: a) increased anxiety, b) having trouble in sleeping, c) exaggerated startle response, d) 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 lack of motivation, e) being irritable, and f) being unable to stop moving or sit still. Symptoms of ASD typically begin no less than 3 days following a traumatic event and no more than 4 weeks after. ASD can also be a precursor to the development of post-traumatic stress disorder (PTSD). Symptoms of ASD such as anxiety, irritability, being unable to stop moving etc. are related to stress-mediated sympathetic hyperarousal and therefore should be treatable with pharmacological agents suitable for treatment of agitation. Similarly, one other symptom of ASD is lack of motivation or helplessness.

[0006] Therefore, there is a need to develop treatments with pharmacological agents having efficacy in both depression and agitation for the effective treatment of ASD. Although a number of existing pharmacological treatment agents such as selective serotonin reuptake inhibitors, tricyclic antidepressants or monoamine oxidase inhibitors) are available and have shown equivocal response rates, these treatments require multiple doses or are associated with adverse effects such as memory impairment for a traumatic event. Thus, there is a major need for development of strategies that offer a sufficient solution for ASD patients.

[0007] Autism spectrum disorder is a neurological and developmental disorder that affects how people interact with others, communicate, learn, and behave. Although autism can be diagnosed at any age, it is described as a “developmental disorder” because symptoms generally appear in the first 2 years of life. According to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), a guide created by the American Psychiatric Association that health care providers use to diagnose mental disorders, people with autism often have: difficulty with communication and interaction with other people, Restricted interests and repetitive behaviors, Symptoms that affect their ability to function in school, work, and other areas of life. Autism is known as a “spectrum” disorder because there is wide variation in the type and severity of symptoms people experience. Currently, there are only few treatment options for children and adults suffering from autism, thus there is a need for more effective therapies to treat autistic patients.

[0008] The pathology of ASD is not well understood but may be associated with genetic disease that causes changes in the neurocircuitry of newborn infants. Children with ASD have difficulty in establishing and maintaining social relationships. As a consequence of this, children with ASD often suffer from panic disorders and exhibit aggressive behaviors. Children with ASD often experience hyper-arousal, or heightened noradrenergic 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 signaling, that may contribute to the panic and aggressive behaviors (Patriquin MA, Hartwig EM, Friedman BH, Porges SW, Scarpa A. Autonomic response in autism spectrum disorder: Relationship to social and cognitive functioning. Biol Psychol.2019 Jul;145:185-197).

[0009] Agitation is a complex biological phenomenon that represents a loss of behavioral control. A single drug is not effective against all types of agitation. Many neural pathways and associated receptors mediate aspects of agitation. These pathways include amygdala, frontal cortex, nucleus acumbens and locus coeruleus. Drugs and associated drug targets to treat agitation work in these brain areas include antipsychotics and dopamine D2 receptors, benzodiazepines and GABA receptors, ketamine and glutamate receptors, and serotonin uptake inhibitors (Miller CW, Hodzic V, Weintraub E. Current Understanding of the Neurobiology of Agitation. Western Journal of Emergency Medicine. 2020 Jul;21(4):841). Depression is a mood disease that causes a persistent feeling of sadness and loss of interest that results from a complex interaction of social, psychological, and biological factors. During a depressive episode, the person experiences a depressed mood (e.g. feeling sad, irritable, or empty) or a loss of pleasure or interest in activities, for most of the day, nearly every day, for at least two weeks. A depressive episode can be categorized as mild, moderate, or severe depending on the number and severity of symptoms, as well as the impact on the individual’s functioning. Increasingly there is a large scientific and medical effort to develop drugs that target specific pathways and therefore treat specific aspects of depression). SUMMARY

[0010] Trauma induces changes in brain neurochemistry that can result in ASD which may ultimately become PTSD. The consolidation of fear memories occurs in the 12 to 24 hours following the experience of a traumatic event. During this time, new connections are made among neurons in the brain that associate the memory of the trauma with emotional responses.

[0011] Without being bound by theory it is thought that compositions may be more effective when administered sooner after the trauma incident than later, ideally as soon as practical. For example, the compositions may be administered within about 30 minutes, 1 hour, about 2 hours, about 4 hours, about 8 hours, about 12 hours, about 1 day, or about 2 days. In aspects, the compositions are administered within about 1 hour to 1 day after the trauma. Chronic treatment is typically not required. Typically, administration may be one or more times daily for a period of up to 1 week, up to 2 weeks, up to 3 weeks, up to 4 weeks, or up to 6 weeks. 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374

[0012] The present disclosure provides oromucosal dosage forms comprising effective amounts of latrepirdine either alone or in combination with dexmedetomidine or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable carriers and / or excipients. In embodiments, the present disclosure provides methods of treating stress- mediated neuropsychiatric disorders such as ASD mediated by noradrenergic hyperarousal in a subject in need thereof, comprising: administering to the subject a therapeutically effective amount of Dexmedetomidine, an alpha 2 adrenergic receptor agonist; wherein the therapeutic intervention has a remedial effect on the stress-mediated neuropsychiatric disorders such as ASD mediated by noradrenergic hyperarousal.

[0013] The present disclosure provides methods of treating a disorder of a human subject associated with noradrenergic mediated hyperarousal, comprising administering to the human subject a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof, optionally in combination with a therapeutically effective amount of dexmedetomidine or pharmaceutically acceptable salt thereof. The disclosure also provides methods of treating a disorder of a human subject associated with noradrenergic mediated hyperarousal, comprising administering orally to the human subject a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof, optionally in combination with a therapeutically effective amount of dexmedetomidine or pharmaceutically acceptable salt thereof. The present disclosure provides methods of treating disorders associated with noradrenergic mediated hyperarousal in a human subject, comprising oromucosally administering to the human subject a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof, optionally in combination with a therapeutically effective amount of dexmedetomidine or pharmaceutically acceptable salt thereof.

[0014] The present disclosure provides methods of treating acute stress disorder (ASD) in a subject in need thereof, comprising administering a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof. The present disclosure also provides methods of treating ASD in a subject in need thereof, comprising administering a therapeutically effective amount of dexmedetomidine alone or in combination with latrepirdine or pharmaceutically acceptable salts thereof.

[0015] The disclosure provides a method of preventing PTSD in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of latrepirdine or a 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 pharmaceutically acceptable salt thereof. The disclosure further relates to a method of treating autism spectrum disorders in a subject in need thereof, the method comprising administering a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof. The disclosure further relates to a method of treating autism spectrum disorders in a subject in need thereof, the method comprising administering a therapeutically effective amount of dexmedetomidine alone or in combination with latrepirdine or pharmaceutically acceptable salts thereof.

[0016] In embodiments, the disorder is acute stress disorder.

[0017] In embodiments, the human subject has one or more symptoms associated with acute stress disorder selected from the group consisting of: anxiety, a sleep disorder, exaggerated startle response, irritability, inability to stop moving or sit still, lack of motivation, and agitation.

[0018] In embodiments, the symptom is anxiety.

[0019] In embodiments, the symptom is a sleep disorder.

[0020] In embodiments, the symptom is an exaggerated startle response.

[0021] In embodiments, the symptom is irritability.

[0022] In embodiments, the symptom is inability to stop moving or sit still.

[0023] In embodiments, the symptom is a lack of motivation. In embodiments, the symptom is agitation.

[0024] In embodiments, disorder of the human subject is autism spectrum disorder.

[0025] In embodiments, the method prevents the disorder from developing into post-traumatic stress disorder. In embodiments, the disorder is caused by a traumatic event experienced by the human subject.

[0026] In embodiments, latrepirdine is administered within 1 week, 2 weeks or 4 weeks of the traumatic event. 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374

[0027] In embodiments, latrepirdine is administered within 3 days of the traumatic event. In embodiments, latrepirdine is administered within 1 day of the traumatic event. In embodiments, latrepirdine is administered within 4 hours of the traumatic event. In embodiments, latrepirdine is administered within 6 hours of the traumatic event. In embodiments, latrepirdine is administered within 12 hours of the traumatic event. In embodiments, latrepirdine is administered once a day, twice a day or thrice a day.

[0028] In embodiments, the present disclosure provides a method of treating stress-mediated neuropsychiatric disorders mediated by noradrenergic hyperarousal in a human subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof, optionally in combination with a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0029] In embodiments, the present disclosure provides a method of treating stress-mediated neuropsychiatric disorders mediated by noradrenergic hyperarousal in a human subject in need thereof, the method comprising: administering orally to the subject a dosage form comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof, optionally in combination with a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0030] In embodiments, the therapeutically effective amount of latrepirdine is in the range from about 5 mg to about 300 mg daily. In embodiments, the therapeutically effective amount of latrepirdine is in the range from about 10 mg to about 200 mg daily. In embodiments, the therapeutically effective amount of latrepirdine is in the range from about 10 mg to about 100 mg daily. In embodiments, the therapeutically effective amount of latrepirdine is in the range from about 10 mg to about 80 mg daily. In embodiments, the therapeutically effective amount of latrepirdine is in the range from about 15 mg to about 60 mg daily. In embodiments, the therapeutically effective amount of latrepirdine is in the range from about 30 mg to about 45 mg daily.

[0031] In embodiments, the therapeutically effective amount of latrepirdine is divided evenly for administration either twice daily or three times daily. 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374

[0032] In embodiments, the latrepirdine or a pharmaceutically acceptable salt thereof is administered in combination with a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof simultaneously, sequentially, or intermittently.

[0033] In embodiments, the present disclosure provides preclinical animal models established to correlate noradrenergic signaling with psychiatric conditions such as acute stress disorder, PTSD, depression, substance withdrawal, substance use craving, agitation, panic disorders, and anxiety.

[0034] In embodiments, the preclinical animal models include the resident intruder assay, a forced swim test, yohimbine-induced anxiety models, and CCK-induced panic models.

[0035] In embodiments, the preclinical animal models surprisingly demonstrated that latrepirdine unexpectedly reduced the magnitude of the symptoms in stress-related psychiatric conditions including acute stress disorder, PTSD, depression, substance withdrawal, substance use craving, agitation, panic disorders, and anxiety.

[0036] In embodiments, the preclinical models correlated noradrenergic signaling with ADHD.

[0037] In embodiments, the methods of the present disclosure reduce the magnitude of the symptoms patients experience and improve their clinical outcomes due to enhanced compliance with underlying therapeutic treatments, including adhering to medication regimens and participating in therapy.

[0038] In embodiments, the improved clinical outcomes can arise because patients with reduced symptoms interact more effectively in social settings, mitigating aggressive and panic symptoms that might result from lack of social interaction, as seen in conditions like autism spectrum disorder.

[0039] In embodiments, the present disclosure provides that effective symptom management prevents conditions from deteriorating, as might be the case when acute stress disorder progresses to PTSD. 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374

[0040] In embodiments, the present disclosure provides that latrepirdine treats and prevents the exacerbation of disorders such as acute stress disorder and autism spectrum disorder over time.

[0041] In embodiments, the present disclosure provides methods of treating noradrenergic mediated hyperarousal in a subject, comprising administering oromucosally to the subject a dosage form comprising: (i) a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof and (ii) a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g. hydrochloride).

[0042] In embodiments, the oromucosal administration includes sublingual, buccal, or gingival administration.

[0043] In embodiments, the present disclosure provides a method of treating ASD in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0044] In embodiments, the present disclosure provides a method of treating ASD in a subject in need thereof, comprising administering to the subject as a monotherapy a dosage form comprising therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0045] In embodiments, the present disclosure provides a method of treating ASD in a subject in need thereof, comprising administering orally to the subject as a monotherapy a dosage form comprising therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0046] In embodiments, the present disclosure provides a method of treating ASD in a subject in need thereof, comprising, administering orally to the subject a dosage form comprising about 10 mg to about 100 mg of latrepirdine or a pharmaceutically acceptable salt thereof.

[0047] In embodiments, the present disclosure provides a method of treating ASD in a subject in need thereof, comprising administering oromucosally (e.g. sublingually, buccally, or 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 gingivally) to the subject a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0048] In embodiments, the present disclosure provides a method of treating ASD in a subject in need thereof, comprising, administering to the subject a dosage form comprising about 10 mg to about 100 mg of latrepirdine or a pharmaceutically acceptable salt thereof. In embodiments, the present disclosure provides a method of treating ASD in a subject in need thereof, comprising administering to the subject a dosage form comprising about 20 mg to about 40 mg of latrepirdine or a pharmaceutically acceptable salt thereof.

[0049] In embodiments, the present disclosure provides a method of treating the worsening of ASD in a subject after a traumatic event, comprising administering to the subject about 10 mg to about 100 mg of latrepirdine or a pharmaceutically acceptable salt thereof and continuing for a period of about 2 to about 4 weeks.

[0050] In embodiments, the present disclosure provides a method of treating the worsening of ASD in a subject after a traumatic event, comprising administering to the subject about 20 mg to about 40 mg of latrepirdine or a pharmaceutically acceptable salt thereof and continuing for a period of about 2 to about 4 weeks.

[0051] In embodiments, latrepirdine or a pharmaceutically acceptable salt thereof is administered orally as a tablet.

[0052] In embodiments, the present disclosure provides a method of increasing the resilience against development of PTSD in a subject after a traumatic event, comprising administering to the subject a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0053] In embodiments, the present disclosure provides a method of preventing PTSD in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0054] In embodiments, a total daily dose of about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered to the subject. In embodiments, a total daily dose of about 40 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered to the 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 subject. In embodiments, a total daily dose of about 60 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered to the subject. In embodiments, the target plasma concentration of latrepirdine is about 1 to 5 ng / ml.

[0055] In embodiments, a dosage form comprising latrepirdine or a pharmaceutically acceptable salt thereof is administered just after the traumatic event. In embodiments, a dosage form comprising latrepirdine or a pharmaceutically acceptable salt thereof is administered within 1 minute to 48 hours (including all ranges and values in between) post traumatic event. In embodiments, a dosage form comprising latrepirdine or a pharmaceutically acceptable salt thereof is administered within 48 hours of the traumatic event. In embodiments, a dosage form comprising latrepirdine or a pharmaceutically acceptable salt thereof is administered within 24 hours of the traumatic event. In embodiments, a dosage form comprising latrepirdine or a pharmaceutically acceptable salt thereof is administered within 1 hour of the traumatic event (or before the onset of ASD). In embodiments, the traumatic event is directly and personally experienced by the subject. In embodiments, the traumatic event is witnessed by the subject. In embodiments, a dosage form comprising latrepirdine or a pharmaceutically acceptable salt thereof is administered in a single or multiple units.

[0056] In embodiments, the present disclosure provides a method of treating ASD in a subject in need thereof, comprising, administering to the subject a dosage form comprising about 10 mg to about 100 mg of latrepirdine or a pharmaceutically acceptable salt thereof within 24 hours of the traumatic event and continuing for a period of about 2 to about 4 weeks of traumatic event.

[0057] In embodiments, the present disclosure provides a method of treating ASD in a subject in need thereof, comprising, administering to the subject a dosage form comprising about 10 mg to about 100 mg of latrepirdine or a pharmaceutically acceptable salt thereof within 24 hours of the traumatic event to up to 4 weeks of traumatic event.

[0058] In embodiments, the present disclosure provides a method of preventing PTSD in a subject in need thereof, comprising administering to the subject a dosage form comprising about 10 mg to about 100 mg of latrepirdine or a pharmaceutically acceptable salt thereof. 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374

[0059] In embodiments, latrepirdine or a pharmaceutically acceptable salt thereof is administered orally. In embodiments, latrepirdine or a pharmaceutically acceptable salt thereof is administered as a tablet, capsule, solution, suspension or so on.

[0060] In embodiments, latrepirdine or a pharmaceutically acceptable salt thereof is administered sublingually. In embodiments, latrepirdine or a pharmaceutically acceptable salt thereof is administered buccally. In embodiments, latrepirdine or a pharmaceutically acceptable salt thereof is administered sublingually or buccally as a tablet. In embodiments, the tablet is lyophilized (or freeze-dried).

[0061] In embodiments, latrepirdine or a pharmaceutically acceptable salt thereof is administered oromucosally (sublingually or buccally or gingivally) as a wafer, a patch or a film.

[0062] In embodiments, the present disclosure provides a method of treating ASD in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0063] In embodiments, the present disclosure provides a method of treating ASD in a subject in need thereof, comprising administering oromucosally (e.g. sublingually, buccally, or gingivally) to the subject a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0064] In embodiments, a dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof is administered just after the traumatic event. In embodiments, a dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof is administered within 1 minute to 48 hours (including all ranges and values in between) post traumatic event. In embodiments, a dosage form comprising latrepirdine or a pharmaceutically acceptable salt thereof is administered within 24 hours of the event. In embodiments, a dosage form comprising latrepirdine or a pharmaceutically acceptable salt thereof is administered within 48 hours of the event. In embodiments, a dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof is administered within 1 hour of the traumatic event (or before the onset of ASD). In embodiments, a dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in a single or multiple units. 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374

[0065] In embodiments, about 10 micrograms to about 300 micrograms (including all ranges and values in between) of dexmedetomidine or a pharmaceutically acceptable salt thereof is administered to the subject. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in an amount of about 20 micrograms, about 30 micrograms, about 40 micrograms, about 60 micrograms, about 80 micrograms, about 120 micrograms, about 150 micrograms, about 180 micrograms or more. In embodiments, about 60 micrograms to about 80 micrograms (including all ranges and values in between) of dexmedetomidine or a pharmaceutically acceptable salt thereof is administered to the subject. In embodiments, about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof is administered to the subject. In embodiments, the target plasma concentration of dexmedetomidine is about 50 to 200 pg / ml.

[0066] In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered once or multiple times a day (e.g. once daily, twice daily, thrice daily or four times, five times, six times a day), preferably once, twice or thrice daily.

[0067] In embodiments, the present disclosure provides a method of treating ASD in a subject in need thereof, comprising orally, administering to the subject a dosage form comprising about 20 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof within 24 hour of the traumatic event to up to 4 weeks of traumatic event.

[0068] In embodiments, the present disclosure provides a method of treating ASD in a subject in need thereof, comprising oromucosally (e.g. sublingually, buccally, or gingivally), administering to the subject a dosage form comprising about 20 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof within 24 hour of the traumatic event to up to 4 weeks of traumatic event.

[0069] In embodiments, the present disclosure provides a method of treating ASD in a subject in need thereof, comprising oromucosally (e.g. sublingually, buccally, or gingivally), administering to the subject a dosage form comprising about 60 micrograms to about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof within 24 hour of the traumatic event to up to 4 weeks of traumatic event.

[0070] In embodiments, the present disclosure provides a method of preventing PTSD in a subject in need thereof, comprising orally administering to the subject a dosage form 12 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 comprising 20 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0071] In embodiments, the present disclosure provides a method of preventing PTSD in a subject in need thereof, comprising oromucosally (e.g. sublingually, buccally, or gingivally), administering to the subject a dosage form comprising 20 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0072] In embodiments, the present disclosure provides a method of preventing PTSD in a subject in need thereof, comprising oromucosally (e.g. sublingually, buccally, or gingivally), administering to the subject a dosage form comprising 60 micrograms to about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0073] In embodiments, the present disclosure provides a method of increasing the resilience against development of PTSD in a subject after a traumatic event, comprising administering orally to the subject a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0074] In embodiments, the present disclosure provides a method of increasing the resilience against development of PTSD in a subject after a traumatic event, comprising administering oromucosally (e.g. sublingually, buccally, or gingivally) to the subject a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0075] In embodiments, the subject is experiencing aggressive, reckless, or self-destructive behaviour, sleep disturbances, hypervigilance, or related problems for more than a month.

[0076] In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered orally. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered buccally. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually or buccally as a tablet. In embodiments, the tablet is lyophilized (or freeze-dried). In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually or buccally or gingivally as a wafer, a patch or a film. 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374

[0077] In embodiments, the present disclosure provides a method of treating ASD in a subject in need thereof, comprising administering to the subject a therapeutically effective amounts of latrepirdine and dexmedetomidine or pharmaceutically acceptable salts thereof. In embodiments, the present disclosure provides a therapeutically effective amount of latrepirdine or pharmaceutically acceptable salt thereof from about 20 mg to 40 mg and therapeutically effective amount of dexmedetomidine or pharmaceutically acceptable salt thereof from about 60 micrograms to about 80 micrograms.

[0078] In embodiments, the present disclosure provides a method of preventing PTSD in a subject in need thereof, comprising administering to the subject a therapeutically effective amounts of latrepirdine and dexmedetomidine or pharmaceutically acceptable salts thereof.

[0079] In embodiments, the dosage form is administered just prior to an anticipated event that may lead to development of PTSD. In embodiments, the dosage form is continued through the PTSD-inducing event and / or for a period of time following the PTSD-inducing event.

[0080] In embodiments, the present disclosure provides a method of treating autism spectrum disorders in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0081] In embodiments, the present disclosure provides a method of treating autism spectrum disorders in a subject in need thereof, comprising administering orally to the subject a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0082] In embodiments, the present disclosure provides a method of treating autism spectrum disorders in a subject, comprising administering to the subject a dosage form comprising about 10 mg to about 60 mg of latrepirdine or a pharmaceutically acceptable salt thereof, e.g. about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, or about 60mg, including all ranges and values in between. 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374

[0083] In embodiments, about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered once a day. In embodiments, about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered twice a day. In embodiments, about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered thrice a day. In embodiments, about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered once a day. In embodiments, about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered twice a day. In embodiments, about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered thrice a day. In embodiments, about 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered once a day. In embodiments, about 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered twice a day. In embodiments, about 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered thrice a day. In embodiments, a total daily dose of about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered to the subject. In embodiments, a total daily dose of about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered to the subject. In embodiments, a total daily dose of about 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered to the subject. In embodiments, a total daily dose of about 40 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered to the subject. In embodiments, a total daily dose of about 60 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered to the subject.

[0084] In embodiments, the present disclosure provides a method of treating autism spectrum disorders in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of dexmedetomidine alone or in combination with latrepirdine or a pharmaceutically acceptable salt thereof.

[0085] In embodiments, the present disclosure provides a method of treating autism spectrum disorders in a subject in need thereof, comprising administering orally to the subject a therapeutically effective amount of dexmedetomidine alone or in combination with latrepirdine or pharmaceutically acceptable salts thereof.

[0086] In embodiments, latrepirdine or a pharmaceutically acceptable salt thereof is administered orally. In embodiments, latrepirdine or a pharmaceutically acceptable salt thereof is administered orally as a tablet. In embodiments, latrepirdine or a pharmaceutically 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 acceptable salt thereof is administered sublingually or buccally. In embodiments, latrepirdine or a pharmaceutically acceptable salt thereof is administered sublingually or buccally as a tablet. In embodiments, the tablet is lyophilized (or freeze-dried).

[0087] In embodiments, latrepirdine or a pharmaceutically acceptable salt thereof is administered oromucosally (sublingually or buccally or gingivally) as a wafer, a patch or a film.

[0088] In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually / buccally. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually or buccally as a tablet. In embodiments, the tablet is lyophilized (or freeze-dried). In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually or buccally or gingivally as a wafer, a patch or a film.

[0089] In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in a single or multiple unit dosage form.

[0090] In embodiments, latrepirdine or a pharmaceutically acceptable salt thereof is administered in a single or multiple unit dosage form.

[0091] In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered once or multiple times a day (e.g. once daily, twice daily, thrice daily or four times, five times, six times a day), preferably once, twice or thrice daily.

[0092] In embodiments, latrepirdine or a pharmaceutically acceptable salt thereof is administered once or multiple times a day (e.g. once daily, twice daily, thrice daily or four times, five times, six times a day), preferably once, twice or thrice daily.

[0093] In embodiments, the dexmedetomidine and latrepirdine are provided as two separate dosage forms for the treatment of autism spectrum disorder in a subject, one comprising a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, and the other comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof. In embodiments, the active agents dexmedetomidine and latrepirdine or pharmaceutically acceptable salts thereof are administered concurrently to 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 the subject in need thereof. In embodiments, the active agents dexmedetomidine and latrepirdine or pharmaceutically acceptable salts thereof are administered sequentially to the subject in need thereof.

[0094] In embodiments, the dexmedetomidine and latrepirdine are provided as a single dosage form for the treatment of autism spectrum disorder, comprising a therapeutically effective amounts of dexmedetomidine and latrepirdine or pharmaceutically acceptable salts thereof.

[0095] In embodiments, the combination comprising latrepirdine and dexmedetomidine or pharmaceutically acceptable salts thereof is administered for at least 7 days, at least 10 days, at least 30 days, at least 60 days, at least 180 days, at least 365 days or longer.

[0096] In embodiments, the severity of autism spectrum disorder symptoms is assessed by Childhood Autism Rating Scale (CARS). In embodiments, the severity of autism spectrum disorder symptoms is assessed by Childhood Autism Rating Scale 2—Standard Form (CARS2- ST). In embodiments, the severity of autism spectrum disorder symptoms is assessed by Childhood Autism Rating Scale 2—High Functioning (CARS2-HF). In embodiments, the severity of autism spectrum disorder symptoms is assessed by Aberrant Behavior Checklist (ABC). In embodiments, the severity of autism spectrum disorder symptoms is assessed by Social Responsiveness Scale (SRS). In embodiments, the severity of autism spectrum disorder symptoms is assessed by Vineland Adaptive Behavior Scale II (VABS-II).

[0097] In embodiments, the present disclosure provides a method of reducing score on childhood Autism Rating Scale (CARS) in a human subject suffering from autism spectrum disorder comprising administering effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0098] In embodiments, the present disclosure provides a method of reducing score on childhood Autism Rating Scale (CARS) in a human subject suffering from autism spectrum disorder comprising administering orally effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0099] In embodiments, the present disclosure provides a method of reducing score on childhood Autism Rating Scale (CARS) in a human subject suffering from autism spectrum 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 disorder comprising administering oromucosally effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0100] In embodiments, the present disclosure provides a method of reducing score on childhood Autism Rating Scale (CARS) in a human subject suffering from autism spectrum disorder comprising administering orally effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0101] In embodiments, the present disclosure provides a method of reducing score on childhood Autism Rating Scale (CARS) in a human subject suffering from autism spectrum disorder comprising administering effective amounts of dexmedetomidine in combination with latrepirdine or pharmaceutically acceptable salts thereof.

[0102] In embodiments, the present disclosure provides a method of reducing score on childhood Autism Rating Scale 2—Standard Form (CARS2-ST) in a human subject suffering from autism spectrum disorder comprising administering effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0103] In embodiments, the present disclosure provides a method of reducing score on childhood Autism Rating Scale 2—Standard Form (CARS2-ST) in a human subject suffering from autism spectrum disorder comprising administering orally effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0104] In embodiments, the present disclosure provides a method of reducing score on childhood Autism Rating Scale 2—Standard Form (CARS2-ST) in a human subject suffering from autism spectrum disorder comprising administering orally effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0105] In embodiments, the present disclosure provides a method of reducing score on childhood Autism Rating Scale 2—Standard Form (CARS2-ST) in a human subject suffering from autism spectrum disorder comprising administering oromucosally effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0106] In embodiments, the present disclosure provides a method of reducing score on childhood Autism Rating Scale 2—Standard Form (CARS2-ST) in a human subject suffering 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 from autism spectrum disorder comprising administering effective amounts of dexmedetomidine in combination with latrepirdine or pharmaceutically acceptable salts thereof.

[0107] In embodiments, the present disclosure provides a method of reducing score on childhood Autism Rating Scale 2—Standard Form (CARS2-HF) in a human subject suffering from autism spectrum disorder comprising administering effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0108] In embodiments, the present disclosure provides a method of reducing score on childhood Autism Rating Scale 2—Standard Form (CARS2-HF) in a human subject suffering from autism spectrum disorder comprising administering orally effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0109] In embodiments, the present disclosure provides a method of reducing score on childhood Autism Rating Scale 2—Standard Form (CARS2-HF) in a human subject suffering from autism spectrum disorder comprising administering orally effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0110] In embodiments, the present disclosure provides a method of reducing score on childhood Autism Rating Scale 2—Standard Form (CARS2-HF) in a human subject suffering from autism spectrum disorder comprising administering oromucosally effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0111] In embodiments, the present disclosure provides a method of reducing score on childhood Autism Rating Scale 2—Standard Form (CARS2-HF) in a human subject suffering from autism spectrum disorder comprising administering effective amounts of dexmedetomidine in combination with latrepirdine or pharmaceutically acceptable salts thereof.

[0112] In embodiments, the present disclosure provides a method of reducing score on Aberrant Behavior Checklist (ABC) in a human subject suffering from autism spectrum disorder comprising administering effective amount of latrepirdine or a pharmaceutically acceptable salt thereof. 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374

[0113] In embodiments, the present disclosure provides a method of reducing score on Aberrant Behavior Checklist (ABC) in a human subject suffering from autism spectrum disorder comprising administering orally effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0114] In embodiments, the present disclosure provides a method of reducing score on Aberrant Behavior Checklist (ABC) in a human subject suffering from autism spectrum disorder comprising administering orally effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0115] In embodiments, the present disclosure provides a method of reducing score on Aberrant Behavior Checklist (ABC) in a human subject suffering from autism spectrum disorder comprising administering oromucosally effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0116] In embodiments, the present disclosure provides a method of reducing score on Aberrant Behavior Checklist (ABC) in a human subject suffering from autism spectrum disorder comprising administering effective amounts of dexmedetomidine in combination with latrepirdine or pharmaceutically acceptable salts thereof.

[0117] In embodiments, the present disclosure provides a method of reducing score on Social Responsiveness Scale (SRS) in a human subject suffering from autism spectrum disorder comprising administering effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0118] In embodiments, the present disclosure provides a method of reducing score on Social Responsiveness Scale (SRS) in a human subject suffering from autism spectrum disorder comprising administering orally effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0119] In embodiments, the present disclosure provides a method of reducing score on Social Responsiveness Scale (SRS) in a human subject suffering from autism spectrum disorder comprising administering orally effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof. 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374

[0120] In embodiments, the present disclosure provides a method of reducing score on Social Responsiveness Scale (SRS) in a human subject suffering from autism spectrum disorder comprising administering oromucosally effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0121] In embodiments, the present disclosure provides a method of reducing score on Social Responsiveness Scale (SRS) in a human subject suffering from autism spectrum disorder comprising administering effective amounts of dexmedetomidine in combination with latrepirdine or pharmaceutically acceptable salts thereof.

[0122] In embodiments, the present disclosure provides a method of reducing score on Vineland Adaptive Behavior Scale II (VABS-II) in a human subject suffering from autism spectrum disorder comprising administering effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0123] In embodiments, the present disclosure provides a method of reducing score on Vineland Adaptive Behavior Scale II (VABS-II) in a human subject suffering from autism spectrum disorder comprising administering orally effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0124] In embodiments, the present disclosure provides a method of reducing score on Vineland Adaptive Behavior Scale II (VABS-II) in a human subject suffering from autism spectrum disorder comprising administering orally effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0125] In embodiments, the present disclosure provides a method of reducing score on Vineland Adaptive Behavior Scale II (VABS-II) in a human subject suffering from autism spectrum disorder comprising administering oromucosally effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0126] In embodiments, the present disclosure provides a method of reducing score on Vineland Adaptive Behavior Scale II (VABS-II) in a human subject suffering from autism spectrum disorder comprising administering oromucosally effective amounts of dexmedetomidine in combination with latrepirdine or pharmaceutically acceptable salts thereof. 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374

[0127] In embodiments, the treatment results in reduction in score of at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% compared to score prior to the treatment, wherein the symptoms of autism spectrum severity are assessed based on CARS, CARS2-ST, CARS2-HF, ABC, SRS, and VABS-II scales. In embodiments, the reduction in score is achieved after at least 4, 8 , 12, 16, 24 or more weeks of treatment.

[0128] In embodiments, the treatment inhibits the progression of or reduces the severity of one or more symptoms of autistic disorder. In embodiments, the treatment inhibits the progression of or reduces the severity of one or more symptoms of Asperger’s disorder. In embodiments, the treatment inhibits the progression of or reduces the severity of one or more symptoms of child disintegrative disorder. In embodiments, the treatment inhibits the progression of or reduces the severity of one or more symptoms of Rett’s disorder. In embodiments, the treatment inhibits the progression of or reduces the severity of one or more symptoms of pervasive developmental disorder-not otherwise specified (PDD-NOS).

[0129] The present disclosure provides methods of treating agitation in a subject, comprising administering to the subject a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0130] The present disclosure also provides methods of treating agitation in an agitated subject, comprising administering to the subject a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof. The present disclosure also provides methods of treating acute agitation in a subject, comprising administering to the subject a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof. The present disclosure also provides methods of treating acute agitation in an agitated subject, comprising administering to the subject a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof. The present disclosure also provides methods of treating or preventing chronic agitation in a subject, comprising administering to the subject a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof. The present disclosure also provides methods of treating or preventing chronic agitation in an agitated subject, comprising administering to the subject a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof. 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374

[0131] The present disclosure also provides a method of treating agitation in an agitated subject, the method comprising administering to the subject a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof. In embodiments, the agitation is caused by noradrenergic hyperarousal. In embodiments, the agitated subject also exhibits aggression. In embodiments, the agitation is treated without inducing significant sedation. The present disclosure also provides a method of treating acute agitation in an agitated subject, the method comprising administering to the subject a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof. The present disclosure also provides a method of treating chronic agitation in a subject, the method comprising administering to the subject a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0132] In embodiments, the present disclosure provides a method of treating agitation in an agitated subject, comprising administering orally to the subject a dosage form comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof. In embodiments, the present disclosure provides a method of treating agitation in an agitated subject, comprising administering oromucosally (e.g. sublingually, buccally, or gingivally), to the subject a dosage form comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof. In embodiments, the present disclosure provides a method of treating agitation in an agitated subject, comprising administering oromucosally (e.g., sublingually, buccally, or gingivally) to the subject a dosage form comprising about 1 mg to about 100 mg of latrepirdine or a pharmaceutically acceptable salt thereof. In embodiments, the present disclosure provides a method of treating agitation in an agitated subject, comprising administering oromucosally (e.g., sublingually, buccally, or gingivally) to the subject a dosage form comprising about 10 mg to about 60 mg of latrepirdine or a pharmaceutically acceptable salt thereof, e.g. about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 29 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, or about 60mg, including all ranges and values in between.

[0133] In embodiments, about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered once a day. In embodiments, about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered twice a day. In embodiments, about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered thrice a day. In embodiments, about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered once a day. In embodiments, about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered twice a day. In embodiments, about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered thrice a day. In embodiments, about 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered once a day. In embodiments, about 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered twice a day. In embodiments, about 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered thrice a day. In embodiments, a total daily dose of about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered to the subject. In embodiments, a total daily dose of about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered to the subject. In embodiments, a total daily dose of about 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered to the subject. In embodiments, a total daily dose of about 40 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered to the subject. In embodiments, a total daily dose of about 60 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered to the subject.

[0134] In embodiments, the present disclosure provides a method of treating agitation in an agitated subject, comprising administering oromucosally to the subject a dosage form comprising: (i) a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof, and (ii) a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride).

[0135] In embodiments, the present disclosure provides a method of treating agitation in an agitated subject, comprising administering about 1 mg to about 500 mg of latrepirdine or a 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 pharmaceutically acceptable salt thereof and about 5 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof to the subject. In embodiments, the present disclosure provides a method of treating agitation in an agitated subject, comprising administering oromucosally about 1 mg to about 100 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 10 micrograms to about 300 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof to the subject. In embodiments, the present disclosure provides a method of treating agitation in an agitated subject, comprising oromucosally administering about 5 mg to about 100 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 20 micrograms to about 300 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof to the subject. In embodiments, the present disclosure provides a method of treating agitation in an agitated subject, comprising administering oromucosally about 5 mg to about 60 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 10 micrograms to about 200 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof to the subject.

[0136] In embodiments, the present disclosure provides a method of treating agitation in an agitated subject, comprising administering about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 30 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof to the subject.

[0137] In embodiments, the present disclosure provides a method of treating agitation in an agitated subject, comprising administering about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 30 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof to the subject, wherein the agitation is caused by noradrenergic hyperarousal.

[0138] In embodiments, the present disclosure provides a method of treating agitation in an agitated subject, comprising administering about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 30 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof to the subject.

[0139] In embodiments, the present disclosure provides a method of treating agitation in an agitated subject, comprising administering about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 30 micrograms of dexmedetomidine or a pharmaceutically 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 acceptable salt thereof to the subject, wherein the agitation is caused by noradrenergic hyperarousal.

[0140] In embodiments, the present disclosure provides a method of treating agitation in an agitated subject, comprising administering about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 40 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof to the subject,

[0141] In embodiments, the present disclosure provides a method of treating agitation in an agitated subject, comprising administering about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 40 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof to the subject, wherein the agitation is caused by noradrenergic hyperarousal.

[0142] In embodiments, the present disclosure provides a method of treating agitation in an agitated subject, comprising administering about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 40 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof to the subject.

[0143] In embodiments, the present disclosure provides a method of treating agitation in an agitated subject, comprising administering about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 40 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof to the subject, wherein the agitation is caused by noradrenergic hyperarousal.

[0144] In embodiments, the present disclosure provides a method of treating agitation in an agitated subject, comprising administering about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof to the subject.

[0145] In embodiments, the present disclosure provides a method of treating agitation in an agitated subject, comprising administering about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof to the subject, wherein the agitation is caused by noradrenergic hyperarousal. 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374

[0146] In embodiments, the present disclosure provides a method of treating agitation in an agitated subject, comprising administering about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof to the subject.

[0147] In embodiments, the present disclosure provides a method of treating agitation in an agitated subject, comprising administering about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof to the subject, wherein the agitation is caused by noradrenergic hyperarousal.

[0148] In embodiments, the present disclosure provides a method of treating agitation in an agitated subject, comprising administering about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof to the subject.

[0149] In embodiments, the present disclosure provides a method of treating agitation in an agitated subject, comprising administering about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof to the subject, wherein the agitation is caused by noradrenergic hyperarousal.

[0150] In embodiments, the present disclosure provides a method of treating agitation in an agitated subject, comprising administering about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof to the subject.

[0151] In embodiments, the present disclosure provides a method of treating agitation in an agitated subject, comprising administering about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof to the subject, wherein the agitation is caused by noradrenergic hyperarousal.

[0152] In embodiments, the present disclosure provides a method of treating agitation in an agitated subject, comprising administering about 10 mg of latrepirdine or a pharmaceutically 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 acceptable salt thereof and about 120 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof to the subject.

[0153] In embodiments, the present disclosure provides a method of treating agitation in an agitated subject, comprising administering about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 120 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof to the subject, wherein the agitation is caused by noradrenergic hyperarousal.

[0154] In embodiments, the present disclosure provides a method of treating agitation in an agitated subject, comprising administering about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 120 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof to the subject.

[0155] In embodiments, the present disclosure provides a method of treating agitation in an agitated subject, comprising administering about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 120 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof to the subject, wherein the agitation is caused by noradrenergic hyperarousal.

[0156] In embodiments, the present disclosure provides a method of treating agitation in an agitated subject, comprising administering about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof to the subject.

[0157] In embodiments, the present disclosure provides a method of treating agitation in an agitated subject, comprising administering about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof to the subject, wherein the agitation is caused by noradrenergic hyperarousal.

[0158] In embodiments, the present disclosure provides a method of treating agitation in an agitated subject, comprising administering about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof to the subject. 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374

[0159] In embodiments, the present disclosure provides a method of treating agitation in an agitated subject, comprising administering about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof to the subject, wherein the agitation is caused by noradrenergic hyperarousal.

[0160] In embodiments, the present disclosure provides a method of treatment comprising administering dexmedetomidine or a pharmaceutically acceptable salt to a subject in an oral dosage form that provides rapid relief of agitation and then continuing treatment with latrepirdine or a pharmaceutically acceptable salt for an effective period of time. In embodiments, the present disclosure provides a method of treatment comprising administering dexmedetomidine or a pharmaceutically acceptable salt to a subject in an oromucosal dosage form that provides rapid relief of agitation and then continuing treatment with latrepirdine or a pharmaceutically acceptable salt for an effective period of time. In embodiments, latrepirdine and dexmedetomidine or pharmaceutically acceptable salts thereof are administered sublingually. In embodiments, latrepirdine and dexmedetomidine or pharmaceutically acceptable salts thereof are administered buccally. In embodiments, latrepirdine and dexmedetomidine or pharmaceutically acceptable salts thereof are administered sublingually or buccally as a tablet. In embodiments, the tablet is lyophilized. In embodiments, latrepirdine and dexmedetomidine or pharmaceutically acceptable salts thereof are administered sublingually or buccally or gingivally as a wafer. In embodiments, latrepirdine and dexmedetomidine or pharmaceutically acceptable salts thereof are administered sublingually or buccally or gingivally as a patch. In embodiments, latrepirdine and dexmedetomidine or pharmaceutically acceptable salts thereof are administered sublingually or buccally or gingivally as a film.

[0161] In embodiments, the present disclosure provides a synergistic combination comprising: (i) a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof and (ii) a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, for the treatment of agitation in a subject in need thereof. 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374

[0162] In embodiments, the agitation is associated with a neurodegenerative disorder selected from the group consisting of Alzheimer’s disease, frontotemporal dementia (FTD), dementia, dementia with Lewy bodies (DLB), post-traumatic stress disorder (PTSD), Parkinson's disease, vascular dementia, vascular cognitive impairment, Huntington's disease, multiple sclerosis, Creutzfeldt-Jakob disease, multiple system atrophy, progressive supranuclear palsy and other related neurodegenerative disorders. In embodiments, the agitation is associated with sundown syndrome in Alzheimer’s disease or dementia. In embodiments, the agitation is chronic and is associated with dementia.

[0163] In embodiments, the agitation is associated with a neuropsychiatric disease selected from the group consisting of schizophrenia, bipolar disorder, bipolar mania, delirium, and depression. In embodiments, the agitation is associated with an alcohol and substance abuse withdrawal including opioid withdrawal. In embodiments, the agitation is associated with an OPD / IPD procedure (e.g. MRI, CT or CAT scan, lumbar puncture, bone marrow aspiration / biopsy, tooth extraction or other dental procedures).

[0164] In embodiments, the agitation is caused by noradrenergic hyperarousal.

[0165] In embodiments, the agitation is treated without inducing significant sedation.

[0166] In embodiments, the agitation is a result of administration of alpha-2 adrenergic receptors antagonist such as yohimbine. In embodiments, the agitation is caused as a result of administration of cocaine. In embodiments, the agitation is caused as a result of administration of lurasidone. In embodiments, the agitation is caused as a result of administration of mirtazapine. In embodiments, the agitation is caused as a result of administration of esmirtazapine. In embodiments, the agitation is caused as a result of administration of atipamezole. In embodiments, the agitation is caused as a result of administration of trazodone. In embodiments, the present disclosure provides a method of treating agitation in a subject in need thereof, comprising oromucosally administering to the subject a dosage form comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof wherein said agitation is caused due to the administration of yohimbine.

[0167] In embodiments, the agitation may be acute or chronic. In embodiments, the agitation may be severe or mild. In embodiments, the agitation may be acute or chronic. In embodiments, the agitation may be severe or mild. 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374

[0168] In embodiments, the present disclosure provides a method of treating depression in a subject in need thereof, comprising administering oromucosally to the subject a dosage form comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0169] The present disclosure provides a method of treating depression in a subject in need thereof, the method comprising administering oromucosally to the subject a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0170] The present disclosure provides a method of treating depression in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof. The present disclosure provides a method of treating depression in a subject in need thereof, the method comprising administering oromucosally to the subject a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0171] In embodiments, the present disclosure provides a method of treating depression in a subject in need thereof, the method comprising administering oromucosally to the subject about 1 mg to about 100 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 10 micrograms to about 300 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof. In embodiments, the improvement in depressive symptoms is observed as measured by HAM-D-17 depression subscale. In embodiments, the subject has a HAM-D-17 total score ≥18 at the start of treatment.

[0172] In embodiments, the present disclosure provides a method of reducing score on HDRS scale in a human subject suffering from depression comprising administering oromucosally effective amount of latrepirdine or a pharmaceutically acceptable salt thereof. In embodiments, the present disclosure provides a method of reducing score on HDRS scale in a human subject suffering from depression comprising administering oromucosally effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0173] In embodiments, the present disclosure provides a method of reducing score on HDRS scale in a human subject suffering from depression comprising administering oromucosally 31 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 effective amounts of dexmedetomidine in combination with latrepirdine or pharmaceutically acceptable salts thereof.

[0174] In embodiments, the present disclosure provides a method of reducing score on MADRS scale in a human subject suffering from depression comprising administering oromucosally effective amount of latrepirdine or a pharmaceutically acceptable salt thereof. In embodiments, the present disclosure provides a method of reducing score on MADRS scale in a human subject suffering from depression comprising administering oromucosally effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof. In embodiments, the present disclosure provides a method of reducing score on MADRS scale in a human subject suffering from depression comprising administering oromucosally effective amounts of dexmedetomidine in combination with latrepirdine or pharmaceutically acceptable salts thereof.

[0175] In embodiments, the depression is moderate or severe. In embodiments, the depression is major depression, bipolar disorder or mixed depression.

[0176] In embodiments, the combination comprising latrepirdine and dexmedetomidine or salts thereof is administered once daily, twice daily, thrice daily or four times, five times, six times a day, preferably once, twice or thrice daily.

[0177] In embodiments, the combination comprising latrepirdine and dexmedetomidine or salts thereof is administered for at least 3 days, at least 5 days, at least 7 days, at least 10 days, at least 15 days, at least 30 days, at least 60 days, at least 90 days, at least 180 days, at least 365 days, or longer.

[0178] In embodiments, the present disclosure provides a synergistic combination comprising: (i) a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof and (ii) a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, for the treatment of depression in a subject in need thereof.

[0179] In embodiments, the present disclosure provides a method of treating psychosis in a subject in need thereof, comprising administering a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof to the subject. 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374

[0180] In embodiments, the present disclosure provides a method of treating psychosis in a subject in need thereof, comprising administering oromucosally (e.g. sublingually, buccally, or gingivally) a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof to the subject.

[0181] In embodiments, the present disclosure provides a method of treating psychosis in a subject in need thereof, the method comprising administering oromucosally e.g. sublingually, buccally, or gingivally) to the subject a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0182] In embodiments, the treatment is effective without causing significant sedation.

[0183] In embodiments, the treatment is effective without experiencing clinically significant cardiovascular effects. In embodiments, the severity of psychosis in the subject is assessed using PANSS scale.

[0184] In embodiments, the present disclosure provides a method of achieving a PANSS score reduction in psychosis for a sustained period of time in a subject comprising administering to the subject a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0185] In embodiments, the present disclosure provides a method of achieving a PANSS score reduction in psychosis for a sustained period of time in a subject comprising administering oromucosally to the subject a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0186] In embodiments, the present disclosure provides a method of achieving a PANSS score reduction in psychosis for a sustained period of time in a subject comprising administering to the subject a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0187] In embodiments, the present disclosure provides a method of achieving a PANSS score reduction in psychosis for a sustained period of time in a subject comprising administering 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 oromucosally to the subject a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0188] In embodiments, the PANSS score reduction is at least about 20% to about 50% from baseline score. In embodiments, the PANSS score reduction is about 25% from baseline score. In embodiments, the PANSS total score reduction is about 30% from baseline score. In embodiments, the PANSS total score reduction is about 35% points from baseline score. In embodiments, the PANSS total score reduction is about 40% points from baseline score. In embodiments, the PANSS total score reduction is about 45% points from baseline score. In embodiments, the PANSS total score reduction is about 50% points from baseline score.

[0189] In embodiments, the psychosis is acute. In embodiments, the psychosis is chronic. In embodiments, the subject is agitated. In embodiments, the subject is non-agitated.

[0190] In embodiments, the psychosis is associated with a neuropsychiatric disorder selected from the group consisting of schizophrenia, schizoaffective disorder, depression, dementia and bipolar disorder or another related neuropsychiatric disorder. In embodiments, the psychosis is associated with neurodegenerative disorders.

[0191] In embodiments, the psychosis is associated with diseased condition such as substance abuse disorders (e.g., alcohol, opioid and other substance withdrawal).

[0192] In embodiments, the psychosis is acute. In embodiments, the psychosis is chronic. In embodiments, the psychosis is a single episode. In embodiments, the psychosis is recurring or includes recurrent episodes. In embodiments, the acute psychosis is associated with acute psychotic episodes and / or mixed episodes.

[0193] In embodiments, the dosage form disintegrates within about 1 second to about 10 minutes upon contact with an oral mucosa. In embodiments, the dosage form disintegrates in more than 1 minute upon contact with an oral mucosa. In embodiments, the dosage form disintegrates within about 5 seconds to about 2 minutes upon contact with an oral mucosa. In embodiments, the dosage form disintegrates within about 5 seconds to about 5 minutes upon contact with an oral mucosa. In embodiments, the dosage form disintegrates within about 5 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 seconds to about 10 minutes upon contact with an oral mucosa. In embodiments, the dosage form disintegrates in less than 60 seconds.

[0194] In embodiments, the dosage form is an oral dosage form comprising: (i) a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof and (ii) one or more pharmaceutically acceptable excipients or carriers.

[0195] In embodiments, the dosage form is an oromucosal dosage form comprising: (i) a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof; (ii) one or more mucoadhesive agents; and (iii) one or more pharmaceutically acceptable excipients or carriers; wherein the dosage form disintegrates within about 5 seconds to about 10 minutes upon contact with an oral mucosa.

[0196] In embodiments, the dosage form is an oral dosage form comprising: (i) a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof and (ii) one or more pharmaceutically acceptable excipients or carriers.

[0197] In embodiments, the dosage form is an oromucosal dosage form comprising: (i) a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof; (ii) one or more mucoadhesive agents; and (iii) one or more pharmaceutically acceptable excipients or carriers; wherein the dosage form disintegrates within about 5 seconds to about 10 minutes upon contact with an oral mucosa.

[0198] In embodiments, the dosage form is an oromucosal dosage form comprising: (i) a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof; 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 (ii) a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof; (iii) one or more mucoadhesive agents; and (iv) one or more pharmaceutically acceptable excipients or carriers; wherein the dosage form disintegrates within about 5 seconds to about 10 minutes upon contact with an oral mucosa.

[0199] In embodiments, the oromucosal dosage form is a tablet, capsules, patch, film, sachet, wafer, powder, minitablet, pellet, paste, gel, ointment, cream, drops, liquid (e.g., solution, suspension or emulsion), spray, microspheres or nanospheres which can be formulated in accordance with methods that are standard in the art.

[0200] In embodiments, the dosage form is an oromucosal tablet for sublingual or buccal, or gingival administration. In embodiments, the dosage form is lyophilized (or freeze-dried).

[0201] In embodiments, the dosage form is a lyophilized sublingual or buccal or gingival tablet comprising: (i) a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof; (ii) sodium alginate; (iii) croscarmellose sodium or sodium starch glycolate; (iv) sucralose; (v) magnesium stearate and / or silicon dioxide; (vi) lactose or mannitol; and (vii) optionally other pharmaceutical acceptable excipients; wherein the dosage form disintegrates within about 5 seconds to about 10 minutes upon contact with an oral mucosa.

[0202] In embodiments, the dosage form is a lyophilized sublingual or buccal or gingival tablet comprising: (i) a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof; (ii) carbomer; 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 (iii) croscarmellose sodium or sodium starch glycolate; (iv) sucralose; (v) magnesium stearate and / or silicon dioxide; (vi) lactose or mannitol; and (vii) optionally other pharmaceutical acceptable excipients; wherein the dosage form disintegrates within about 5 seconds to about 10 minutes upon contact with an oral mucosa.

[0203] In embodiments, the dosage form is a lyophilized sublingual or buccal or gingival tablet comprising: (i) a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof; (ii) xanthan gum; (iii) croscarmellose sodium or sodium starch glycolate; (iv) sucralose; (v) magnesium stearate and / or silicon dioxide; (vi) lactose or mannitol; and (vii) optionally other pharmaceutical acceptable excipients; wherein the dosage form disintegrates within about 5 seconds to about 10 minutes upon contact with an oral mucosa.

[0204] In embodiments, the dosage form is a lyophilized sublingual or buccal or gingival tablet comprising: (i) a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof; (ii) a therapeutically effective amount of dexmedetomidine or a salt thereof; (iii) sodium alginate, xanthan gum, carbomer, hydroxypropyl cellulose, hydroxypropyl methylcellulose or polyethylene oxide; (iv) croscarmellose sodium or sodium starch glycolate; (v) sucralose; (vi) magnesium stearate and / or silicon dioxide; (vii) lactose or mannitol; and (viii) optionally other pharmaceutical acceptable excipients; 37 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 wherein the dosage form disintegrates within about 5 seconds to about 10 minutes upon contact with an oral mucosa.

[0205] In embodiments, the dexmedetomidine and latrepirdine are provided as a single dosage form as an oromucosal tablet for the treatment of agitation comprising a therapeutically effective amounts of dexmedetomidine and latrepirdine or pharmaceutically acceptable salts thereof. In embodiments, the agitation is caused by noradrenergic hyperarousal. In embodiments, the agitation is treated without also inducing significant sedation.

[0206] In embodiments, the dexmedetomidine and latrepirdine are provided as a single dosage form as an oromucosal tablet for the treatment of depression, comprising a therapeutically effective amounts of dexmedetomidine and latrepirdine or pharmaceutically acceptable salts thereof.

[0207] In embodiments, the dexmedetomidine and latrepirdine are provided as two separate dosage forms as oromucosal tablets for treatment of agitation, one comprising a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, and the other comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof. In embodiments, the active agents dexmedetomidine and latrepirdine are administered concurrently to the subject in need thereof. In embodiments, the active agents dexmedetomidine and latrepirdine are administered sequentially to the subject in need thereof. In embodiments, the agitation is caused by noradrenergic hyperarousal. In embodiments, the agitation is treated without also inducing significant sedation.

[0208] In embodiments, the dexmedetomidine and latrepirdine are provided as two separate dosage forms as oromucosal tablets for the treatment of depression in a subject, one comprising a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, and the other comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof. In embodiments, the active agents dexmedetomidine and latrepirdine are administered concurrently to the subject in need thereof. In embodiments, the active agents dexmedetomidine and latrepirdine are administered sequentially to the subject in need thereof. 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374

[0209] In embodiments, the active agents, dexmedetomidine and latrepirdine, or pharmaceutically acceptable salt thereof, are administered concurrently (e.g. single dosage form or two separate dosage forms) to the subject for a specific period of time (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 days or so on) followed by single agent administration of latrepirdine to the subject for a specific period of time (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months or so on). In embodiments, dexmedetomidine or salt thereof is administered at least 1 hour before administration of latrepirdine so that symptoms are relieved as early as possible. In embodiments, dexmedetomidine is administered at least 0.5 hour before the administration of latrepirdine so that symptoms are relieved as early as possible. In embodiments, dexmedetomidine is administered at least 0.25 hours before the administration of latrepirdine so that symptoms are relieved as early as possible. In embodiments, dexmedetomidine is administered simultaneously with latrepirdine so that symptoms are relieved as early as possible.

[0210] In embodiments, the active agents, dexmedetomidine and latrepirdine, or pharmaceutically acceptable salt thereof, are administered intermittently (e.g. single dosage form or two separate dosage forms) to the subject for a specific period of time (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 days, 1 month, 2 months, 3 months or so on) followed by a rest period ((e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 days or so on) and then dosing period (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 days, 1 month, 2 months, 3 months or so on).

[0211] In embodiments, the active agents are sequentially administered separated by an appropriate period of time such as about 1 minute, about 2 minutes, about 3 minutes, about 4 minutes, about 5 minutes, about 6 minutes, about 7 minutes, about 8 minutes, about 9 minutes, about 10 minutes, about 11 minutes, about 12 minutes, about 13 minutes, about 14 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 60 minutes (1 hour), about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about 24 hours, including all ranges and values in between. In embodiments, the active agents are administered simultaneously at the same time or within a short period of time, usually less than about 60 minutes (i.e., about 1 hour), preferably about 45 minutes, more preferably about 15 minutes. In embodiments, the active agents are administered simultaneously at the same time or within a short period of time, usually less than about 60 minutes (i.e., about 1 hour), preferably about 45 minutes, more preferably about 15 minutes.

[0212] In embodiments, the present disclosure provides an individual unit oral tablet dosage form provided as a kit comprising: (i) a therapeutic effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof; (ii) a therapeutic effective amount of latrepirdine or a pharmaceutically acceptable salt thereof; and (iii) instructions for the administration of (i) and (ii) to a subject in need thereof.

[0213] In embodiments, the present disclosure provides an individual unit oromucosal lyophilized tablet dosage form provided as a kit comprising: (i) a therapeutic effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof; (ii) a therapeutic effective amount of latrepirdine or a pharmaceutically acceptable salt thereof; and (iii) instructions for the administration of (i) and (ii) to a subject in need thereof.

[0214] In embodiments, the present disclosure provides a two-unit oral dosage form provided as a kit comprising: (i) a first oral tablet dosage form comprising a therapeutic amount of dexmedetomidine or a pharmaceutically acceptable salt thereof; (ii) a second oral tablet dosage form comprising a therapeutic amount of latrepirdine or a pharmaceutically acceptable salt thereof; and (iii) instructions for the simultaneous, sequential or separate administration of (i) and (ii) to a subject in need thereof. 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374

[0215] In embodiments, the present disclosure provides a two-unit dosage form provided as a kit comprising: (i) a first oromucosal lyophilized tablet dosage form comprising a therapeutic amount of dexmedetomidine or a pharmaceutically acceptable salt thereof; (ii) a second oromucosal lyophilized tablet dosage form comprising a therapeutic amount of latrepirdine or a pharmaceutically acceptable salt thereof; and (iii) instructions for the simultaneous, sequential or separate administration of (i) and (ii) to a subject in need thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0216] FIG.1: depicts an elevated plus maze apparatus. The maze consists of two closed arms and two open arms forming a cross, with a square central platform according to Example 2.

[0217] FIG. 2: depicts the study design and administration time points of various drugs according to Example 2.

[0218] FIG.3: depicts the time (in seconds) Wistar rats spent in the open arms of the elevated plus maze after administration of latrepirdine dihydrochloride hydrate (3 mg / kg and 10 mg / kg) as compared to dextromethorphan (10 mg / kg) and fluvoxamine maleate (10 mg / kg) to the yohimbine hydrochloride (2.5 mg / kg) administered rats according to Example 2.

[0219] FIG.4: depicts the number of times Wistar rats entered the open arms of the elevated plus maze after administration of latrepirdine (3 mg / kg and 10 mg / kg) as compared to dextromethorphan hydrobromide (10 mg / kg) and fluvoxamine maleate (10 mg / kg) to the yohimbine hydrochloride (2.5 mg / kg) administered rats according to Example 2.

[0220] FIG.5: depicts the time (in seconds) Wistar rats spent in the open arms of the elevated plus maze after administration of latrepirdine dihydrochloride hydrate (0.1 mg / kg, 0.3 mg / kg, 1 mg / kg and 3 mg / kg) to the yohimbine hydrochloride (2.5 mg / kg) administered rats with latrepirdine dihydrochloride hydrate (3 mg / kg + saline) as per se treatment according to Example 3. 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374

[0221] FIG.6: depicts the number of times Wistar rats entered the open arms of the elevated plus maze after administration of latrepirdine dihydrochloride hydrate (0.1 mg / kg, 0.3 mg / kg, 1 mg / kg and 3 mg / kg) to the yohimbine hydrochloride (2.5 mg / kg) administered rats with latrepirdine dihydrochloride hydrate (3 mg / kg + saline) as per se treatment according to Example 3.

[0222] FIG.7: depicts the effects on immobility (7A), swimming (7B), climbing (7C) and total active (7D) behaviors (in seconds) during the 5-minutes FST test in Sprague–Dawley (SD) rats in dark phase after administration of dexmedetomidine hydrochloride (1 μg / kg and 5 μg / kg), latrepirdine dihydrochloride hydrate (1 mg / kg) and combination of dexmedetomidine hydrochloride and latrepirdine dihydrochloride hydrate (1 μg / kg + 1 mg / kg and 5 μg / kg + 1 mg / kg, respectively) according to Example 4.

[0223] FIGs.8A & 8B: depicts the effect of dexmedetomidine hydrochloride (4 μg / kg and 10 μg / kg) and latrepirdine dihydrochloride hydrate (0.3 mg / kg, 1 mg / kg, 3 mg / kg and 10 mg / kg) on duration of attack (in seconds) in Swiss albino mice in resident intruder task according to Example 5.

[0224] FIGs.9A & 9B: depicts the effect of combinations of dexmedetomidine hydrochloride and latrepirdine dihydrochloride hydrate (4 μg / kg + 0.3 mg / kg, 4 μg / kg + 1 mg / kg, 4 μg / kg + 3 mg / kg, 4 μg / kg + 10 mg / kg and 10 μg / kg + 1 mg / kg, respectively) on duration of attack (in seconds) in Swiss albino mice in resident intruder task according to Example 5.

[0225] FIG.10: depicts the effect of dexmedetomidine hydrochloride (4 μg / kg and 10 μg / kg), latrepirdine dihydrochloride hydrate (0.3 mg / kg, 1 mg / kg, 3 mg / kg and 10 mg / kg) and combinations of dexmedetomidine hydrochloride and latrepirdine dihydrochloride hydrate (4 μg / kg + 0.3 mg / kg, 4 μg / kg + 1 mg / kg, 4 μg / kg + 3 mg / kg, 4 μg / kg + 10 mg / kg and 10 μg / kg + 1 mg / kg, respectively) on duration of attack (in seconds) in Swiss albino mice in resident intruder task according to Example 5.

[0226] FIG. 11: shows the SMARTCUBE signatures of dexmedetomidine hydrochloride, latrepirdine and combination of dexmedetomidine hydrochloride and latrepirdine for antipsychotic behavior according to Example 6. 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374

[0227] FIG.12: depicts the effect of dexmedetomidine hydrochloride (4 μg / kg, 10 μg / kg, 20 μg / kg and 30 μg / kg), latrepirdine dihydrochloride hydrate (1 mg / kg, 3 mg / kg and 10 mg / kg) and combinations of dexmedetomidine hydrochloride and latrepirdine dihydrochloride hydrate (4 μg / kg + 10 mg / kg and 10 μg / kg + 1 mg / kg, respectively) on distance traveled (in centimeters) in Swiss albino mice in open field test according to Example 7.

[0228] FIG. 13: depicts the number of entries in the open arms after administration of latrepirdine dihydrochloride hydrate (1, 3, 10 and 15 mg / kg) to the CCK-4 administered rats according to Example 8.

[0229] FIG. 14: depicts the time spent in the open arms after administration of latrepirdine dihydrochloride hydrate (1, 3, 10 and 15 mg / kg) to the CCK-4 administered rats according to Example 8. DETAILED DESCRIPTION

[0230] Yohimbine is an alpha-2 adrenergic antagonist and is useful to test the norepinephrine- mediated hyper-arousal pathway. As described herein, yohimbine was used to induce sympathetic hyper-arousal in rodents and three different classes of drugs were tested to determine their ability to reduce hyper-arousal. Surprisingly, only latrepirdine (Dimebon), a drug with complex pharmacology, was able to reduce hyper-arousal. Latrepirdine is an orally active, small molecule compound that operates through multiple mechanisms of action and works through complex mechanisms.

[0231] Administration of an alpha-2 adrenergic receptor agonist or a pharmaceutically acceptable salt thereof is a particularly effective and safe intervention for the treatment of agitation. Dexmedetomidine is an alpha-2 adrenergic agonist and is reported to have anti- agitational effects when administered intravenously during surgical procedures and intensive care unit (ICU) setups.

[0232] The inventors of the present application have found that administration of latrepirdine either alone or in combination with dexmedetomidine provides a significantly improved outcomes in anti-agitation response along with other benefits over conventional treatment. 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374

[0233] In a forced swim model in rodents, it was discovered that the administration of a combination comprising latrepirdine and dexmedetomidine provided significant increase in swimming behavior (correlated to improvement in lack of motivation or helplessness behavior, which are symptoms of depression as well as ASD) as compared to dexmedetomidine and latrepirdine administered individually, as described below in Example 4.

[0234] The inventors of the present application have found that administration of latrepirdine or / and dexmedetomidine individually or in combination have a beneficial role in alleviating symptoms of stress-mediated sympathetic hyperarousal such as anxiety, agitation, irritability etc., thus treating symptoms associated with ASD as well as preventing possible occurrence of PTSD.

[0235] These symptoms are present in psychiatric disorders including acute stress disorder, PTSD, depression, withdrawal, substance use craving, agitation, panic, anxiety, ADHD and panic disorder. The inventors of the present application discovered that the active agents (i.e. latrepirdine and / or dexmedetomidine or pharmaceutically acceptable salts thereof) reduce magnitude of symptoms in stress-induced psychiatric indications that are norepinephrine- dependent. By treating these symptoms, patients are able to improve their clinical outcomes because (1) they are better able to comply with underlying therapeutic treatment, including taking prescribed drugs and participating in therapy; (2) they are better able to interact socially, allowing them to mitigate aggressive and panic symptoms that arise from lack of social interaction as occurs in autism spectrum disorder; (3) patients are better able to manage their symptoms and prevent them from worsening, as occurs when acute stress disorder develops into PTSD. It was also found that latrepirdine may not only treat symptoms of disorders such as acute stress disorder or autism spectrum disorder, but may also prevent worsening of the disorders over time.

[0236] The inventors of the present application have also found that administration of latrepirdine or / and dexmedetomidine individually or in combination have a beneficial role in treating autism spectrum disorder. Abbreviations AD: Alzheimer's disease 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 AMPA: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid ANOVA: Analysis of variance ASD: acute stress disorder CNS: Central nervous system CT / CAT scan: Computed tomography scan EPM: Elevated Plus Maze FTD: Frontotemporal dementia GABA: Gamma-aminobutyric Acid 5-HT: 5-Hydroxytryptamine HDRS or (HAM-D): Hamilton Depression Rating Scale ICU: Intensive care unit IPD: In-Patient department IM: Intramuscular IP: Intraperitoneal LC: locus coeruleus MRI: Magnetic resonance imaging µg: Microgram mg: Milligram MADRS: Montgomery-Asberg Depression Rating Scale MW: Molecular weight NE: Nor-epinephrine NMDA: N-methyl-D-aspartate OPD: Out-patient department PANSS: Positive and Negative Syndrome Scale PTSD: Post-traumatic stress disorders wt%: Weight percentage Definitions

[0237] It will be understood that the terminology used herein is for the purpose of describing embodiments only and is not intended to be limiting. As used in this specification, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374

[0238] Unless otherwise indicated, any reference to a compound herein, such as latrepirdine, dexmedetomidine by structure, name, or any other means, includes pharmaceutically acceptable salts; alternate solid forms, such as polymorphs, solvates, hydrates, etc.; tautomers; deuterium-modified compounds, such as deuterium modified latrepirdine or dexmedetomidine; or any chemical species that may rapidly convert to a compound described herein under conditions in which the compounds are used as described herein.

[0239] As used herein, “about” or “approximately,” when used in connection with a numerical variable, generally refers to the value of the variable and to all values of the variable that are within the experimental error (e.g., within the 95% confidence interval for the mean) or within ±10% of the indicated value, whichever is greater.

[0240] Throughout the present specification, numerical ranges are provided for certain quantities. It is to be understood that these ranges comprise all subranges therein. Thus, the range “from 50 to 80” includes all possible ranges therein (e.g., 51-79, 52-78, 53-77, 54-76, 55-75, 60-70, etc.). Furthermore, all values within a given range may be an endpoint for the range encompassed thereby (e.g., the range 50-80 includes the ranges with endpoints such as 55-80, 50-75, etc.).

[0241] The term “a” or “an” refers to one or more of that entity. In addition, reference to “an agent” by the indefinite article “a” or “an” does not necessarily exclude the possibility that more than one of the agents are present.

[0242] As used herein, the term “comprise” as is used in this description and in the claims and its conjugations are used in its non-limiting sense to mean that items following the word are included, but items not specifically mentioned are not excluded. The present disclosure may suitably “comprise”, “consist of”, or “consist essentially of”, the steps, elements, and / or reagents described in the claims.

[0243] As used herein, the term “subject” preferably refers to a human patient. In embodiments, the subject can be any animal, including non-human mammals, such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates.

[0244] As used herein, unless indicated otherwise, the terms “dosage form” "pharmaceutical composition", "composition", "formulation" and "composition of the disclosure," are used 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 interchangeably. Unless stated otherwise, the terms are meant to encompass, and are not limited to, dosage form containing drug substance i.e. dexmedetomidine or latrepirdine or both.

[0245] As used herein, the term "an effective amount" is interchangeable with "therapeutically effective dose," or "therapeutically effective amount," and refers to an amount sufficient to produce the desired effect. An effective amount is sufficient to cause an improvement in a clinically significant condition of the subject. An effective amount can be administered in one or more administrations, applications, or dosages.

[0246] As used herein, "pharmaceutically acceptable salt" refers to a salt known to be non- toxic and commonly used in the pharmaceutical literature. Typical inorganic acids used to form such salts include hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric, and the like. Salts derived from organic acids, such as aliphatic mono and dicarboxylic acids, phenyl substituted alkanoic acids, hydroxyalkanoic and hydroxyl alkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids may also be used. A preferred salt is hydrochloride (or dihydrochloride) salt.

[0247] The term “treatment” is used herein to mean to relieve or alleviate at least one symptom of a disease in a subject. For example, in relation to behavioral disorders, the term “treatment” may mean to relieve or alleviate agitation and any combination of its manifestations in an agitated subject (e.g. pacing, rocking, gesturing, pointing fingers, restlessness, performing repetitious mannerisms, yelling, speaking in an excessively loud voice, using profanity, screaming, shouting, grabbing, shoving, pushing, resisting, hitting others, kicking objects or people, scratching, biting, throwing objects, hitting self, slamming doors, tearing things, destroying property, etc.). Treatment may be measured as a reduction level by at least 10% or higher, preferably 20% or higher, more preferably 40% or higher, even more preferably 60% or higher, still more preferably 80% or higher, and 90% or higher, as compared to a control. For example, in the context of agitation, the skilled artisan will understand that treatment can be measured in terms of well-known agitation scales, such as PEC score, CGI-I, and ACES (each of which is described in detail in WO / 2020 / 006119, which is incorporated by reference in its entirety for all purposes). As an example, when agitation is treated in a patient, the patient may experience at least a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% or greater reduction in PEC total score from baseline (e.g. measured at 2 hours post-dose). Similarly, a treated patient may be measured on the CGI-I scale and may refer to a patient that 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 has a score of 1 or 2 (e.g. measured at 1, 2, or 4 hours post-dose) or the Agitation-Calmness Evaluation Scale (ACES) scale and may refer to a patient that has a score of 3, 4, 5, 6, or 7.

[0248] The term "prevention" means preventing the occurrence of a disease, condition, or associated symptoms or preventing the recurrence of the same, for example after a period of improvement.

[0249] The term “oromucosal delivery” or “oromucosal administration” and the like means administration to the oral mucosa. It includes delivery across any tissue of the mouth, pharynx, larynx, trachea, or upper gastrointestinal tract, particularly including the sublingual, buccal, gingival and palatal mucosal tissues.

[0250] The term "sublingual" means "under the tongue" and refers to a method of administering substances via the mouth in such a way that the substances are rapidly absorbed via the blood vessels under the tongue rather than via the digestive tract. Sublingual absorption occurs through the highly vascularized sublingual mucosa, which allows a substance direct access to the blood circulation, thereby providing for direct systemic administration independent of gastrointestinal influences and avoiding undesirable first-pass hepatic metabolism. Accordingly, by administering the dosage forms of the present disclosure sublingually, the total amount of latrepirdine and / or dexmedetomidine may be reduced, thereby reducing the likelihood of deleterious side effects and providing a cost benefit to the manufacturer.

[0251] The term “buccal” means administration of the dosage form against the gum and the inner lip or cheek. Oromucosal absorption occurs through the highly vascularized transmucosal mucosa, which allows a substance direct access to the blood circulation, thereby providing for direct systemic administration independent of gastrointestinal influences and avoiding undesirable first-pass hepatic metabolism.

[0252] The term "disintegrate" refers to the breaking up of or loss of structural cohesion of the constituent particles comprising a solid formulation. This can occur in a number of different ways including breaking into smaller pieces and ultimately, fine and large particulates or, alternatively, eroding from the outside in until the dosage form has disappeared. 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374

[0253] The terms “oral dosage form”, “oromucosal dosage form,” and “oral transmucosal dosage form,” may be used interchangeably herein and refer to a dosage form for use in practicing the present disclosure, which comprises a drug formulation as described herein. The oral dosage form is typically a sublingual or buccal dosage form, but in some cases other oral transmucosal routes may be employed. The disclosure relies upon such oral dosage forms to provide sustained delivery of drugs across the oral mucosa; by controlling the formulation design immediate, intermediate and sustained release of drugs can be achieved, as described below. The dosage form comprises active ingredients (dexmedetomidine and / or latrepirdine) and one or more mucoadhesives that provide for adherence to the mucosa of the mouth of a patient, and other carriers and excipients described in more detail herein.

[0254] The term “orally disintegrating tablet” (ODT) refers to an oral dosage form composed of a tablet that is designed to disintegrate in the oral cavity without need for chewing or swallowing with liquids. Orally disintegrating tablets may have the characteristics set forth by the U.S. Food & Drug Administration in Guidance for Industry: Orally Disintegrating Tablets (Dept. of Health and Human Services, U.S. FDA Center for Drug Evaluation and Research, December 2008). The rate of disintegration of the solid pharmaceutical compositions of the present disclosure can be measured using various in vitro test methods, for example the USP <701> Disintegration Test. As explained in the foregoing section of the U.S Pharmacopoeia, the USP Disintegration Test is conducted by placing the dosage form to be tested in a basket rack assembly, immersing the assembly in a specified fluid at a temperature between 35° C. and 39° C. for a given time period, and raising and lowering the basket in the immersion fluid through a distance of about 5.5 cm at a frequency of about 30 cycles per minute. The dosage forms are visually inspected at specified times for complete disintegration, defined in Section 701 of USP 24-NF 19 as the state in which any residue of the dosage form remaining in the basket rack of the test apparatus is a “soft mass having no palpably firm core.” As such, it will be appreciated that the present dosage forms are optimal for disintegration in the mouth without the need to drink additional water. Adsorption may be through the oral mucosa.

[0255] The term “film” herein includes thin films, sheets and wafers, in any shape, including rectangular, square, or other desired shape. The film may be of any desired thickness and size, such that it can be conveniently placed sub-lingually in the patient. For example, the film may 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 be a relatively thin film having a thickness of from about 20 micrometers to about 200 micrometers or may be a somewhat thicker film having a thickness of from about 20 micrometers to about 1000 micrometers. In embodiments, the film may be even thicker, e.g., having a thickness greater than about 30 millimeters.

[0256] The term “mucoadhesion” is used herein to refer to adhesion to mucosal membranes, such as those in the oral cavity. Mucoadhesion may be measured in “mucoadhesive strength” or “mucoadhesive peak force”. The term “mucoadhesive” is a material that adheres to a mucosal tissue surface in-vivo. Such adhesion adherently localizes the dosage form onto the mucus membrane and requires the application of a force to separate the mucoadhesive material from the mucus membrane.

[0257] “Therapeutic” as used herein, may mean treatment and / or prophylaxis, depending on context.

[0258] The term “hyperarousal” refers herein a subclinical state in which there is excess noradrenergic signaling that causes hemodynamic and motor changes Stress-related psychiatric symptoms may results from heightened sympathetic tone (excessive noradrenergic signaling).

[0259] The term “acute stress disorder” or “ASD” refers to a mental health condition that results from the experience of a traumatic event. Symptoms of ASD typically begin no less than 3 days following a traumatic event and no more than 4 weeks after.

[0260] The term “trauma” or “traumatic events” that may lead to ASD include, but are not limited to, spontaneous abortion, military combat, violent personal assault (sexual assault, physical attack, robbery, mugging), being kidnapped, being taken hostage, terrorist attack, torture, incarceration as a prisoner of war or in a concentration camp, natural or manmade disasters, automobile accidents (including, but not limited severe automobile accidents), or being diagnosed with a life-threatening illness. For children, sexually traumatic events may include developmentally inappropriate sexual experiences without being threatened or actual violence or injury. Witnessed events include, but are not limited to, observing the serious injury or unnatural death of another person due to violent assault, accident, war, or disaster or unexpectedly witnessing a dead body or body parts. Events experienced by others that are learned about include, but are not limited to, violent personal assault, serious accident, or serious injury experienced by a family member or a close friend; learning about the sudden, 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 unexpected death of a family member or a close friend; or leaning that one's child has a life- threatening disease.

[0261] The term “ post-traumatic stress disorder” is also referred as PTSD. As per DSM-5, behavioural symptoms that accompany PTSD includes four distinct diagnostic clusters. They are described as re-experiencing, avoidance, negative cognitions and mood, and arousal. Re- experiencing covers spontaneous memories of the traumatic event, recurrent dreams related to it, flashbacks, or other intense or prolonged psycho-logical distress. Avoidance refers to distressing memories, thoughts, feelings, or external reminders of the event. Negative cognitions and mood represent myriad feelings, from a persistent and distorted sense of blame of self or others to estrangement from others or markedly diminished interest in activities, to an inability to remember key aspects of the event. The arousal aspect of PTSD is marked by aggressive, reckless, or self-destructive behaviour, sleep disturbances, hypervigilance, or related problems. According to DSM-5, PTSD is characterized by disturbance(s) that continues for more than a month. (It eliminates the distinction between acute and chronic phases of PTSD.) With respect to arousal and reactivity associated with PTSD, there has to be marked alterations in two (or more) of the following aspects: a) Irritable behaviour and angry outbursts (with little or no provocation) typically expressed as verbal or physical aggression toward people or objects; b) Reckless or self-destructive behaviour; c) Hypervigilance; d) Exaggerated startle response; e) Problems with concentration; f) Sleep disturbance (e.g. difficulty falling or staying asleep or restless sleep).

[0262] The term “autism spectrum disorder” used interchangeably with “autism” refers to a complex developmental condition involving persistent challenges with social communication, restricted interests, and repetitive behavior. The term “spectrum” here refers to the wide range of symptoms and severity. The symptoms may include behavioral symptom that include (i) insistence on sameness or resistance to change; (ii) difficulty in expressing needs; (iii) repeating words or phrases in place of normal, responsive language; (iv) laughing, crying, showing distress for reasons not apparent to others; (v) prefers to be alone or aloof manner; (vi) tantrums; (vii) difficulty in mixing with others; (viii) may not want to cuddle or be cuddled; (ix) little or no eye contact; (x) unresponsive to normal teaching methods; (xi) sustained odd play; (xii) apparent over-sensitivity or under- sensitivity to pain; (xiii) little or no real fears of danger; (xiv) noticeable physical overactivity or extreme under-activity; (xv) 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 uneven gross / fine motor skills; and / or (xvi) non- responsiveness to verbal cues. In embodiments, the behavioral symptom is selected from the group consisting of compulsive behavior, ritualistic behavior, restricted behavior, stereotypy, sameness, or self-injury. Autism spectrum disorder includes autistic disorder (classic autism), Asperger’s syndrome, childhood disintegrative disorder (CDD), Rett’s disorder (Rett’s syndrome) and pervasive developmental disorder not otherwise specified (usually referred as PDD-NOS). This disorder begins in early childhood and eventually causes problems functioning in society — socially, in school and at work, for example. The term “Asperger syndrome” refers to an autism spectrum disorder, which is milder than autism but shares some of its symptoms, such as problems with language and communication, and repetitive or restrictive patterns of thoughts and behavior. An obsessive interest in a single subject is one of the major symptom of Asperger syndrome. The term “pervasive developmental disorder” refers to a group of disorders characterized by delays in the development of socialization and communication skills. Symptoms may include problems with using and understanding language, difficulty relating to people or objects, difficulty with changes in routine or familiar surroundings, and repetitive body movements or behavior patterns. The term “Rett Disorder”, as used herein, refers to neurodevelopmental disorder that is classified as an autism spectrum disorder by the DSM-IV. It most often affects girls and clinical features include a deceleration of the rate of head growth (including microcephaly in some) and small hands and feet. Behavioral symptoms include stereotypic, repetitive hand movements such as mouthing or wringing.

[0263] The term “agitation”, as used herein, means a disorder characterized by symptoms of irritability, emotional outburst, impaired thinking, or excess motor and verbal activity that may occur due to either dysfunction of specific brain regions such as frontal lobes or due to dysfunction of neurotransmitter systems such as the noradrenergic system. In embodiments, the agitation may be caused by noradrenergic hyperarousal. In the present disclosure, an agitated subject may also exhibit aggression. The agitation may be acute or chronic. The agitation may be severe.

[0264] The term “acute agitation” means agitation that occurs rapidly and is severe and sudden in onset. Acute agitation may be associated with, for example, neurodegenerative disorders and neuropsychiatric disorders, although it may particularly exist in neuropsychiatric conditions. Acute agitation may lead to chronic agitation if it remains untreated. 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374

[0265] The term “chronic agitation” means agitation developed over a long period of time and is less severe than acute agitation. Chronic agitation may be associated with, for example, neurodegenerative disorder and neuropsychiatric disorders, although it may particularly exist in neurodegenerative disorders.

[0266] The term “without significant sedation” or “without inducing significant sedation” and the like means that the patient experiences a level of sedation not greater than Level 3 on the Ramsay Sedation Scale. Level 3 means sedated but responds to commands. In embodiments, the dexmedetomidine may be dosed to achieve a Richmond Agitation Sedation Scale (RASS) of -1 (“light sedation”).

[0267] The term “neurodegenerative disorder” includes, but is not limited to, Alzheimer’s disease, frontotemporal dementia (or Pick’s disease), Dementia (e.g., Dementia with Lewy bodies, vascular dementia), posttraumatic stress disorder (PTSD), Parkinson’s disease, vascular cognitive impairment, Huntington’s disease, multiple sclerosis, Creutzfeldt- Jakob disease, multiple system atrophy, progressive supranuclear palsy.

[0268] The term “neuropsychiatric disorder” includes, but is not limited to, schizophrenia, bipolar illness (bipolar disorder, bipolar mania), depression, delirium.

[0269] The term “sundown syndrome” refers to a late-day circadian syndrome of increased confusion, agitation, and / or restlessness, generally in a patient with some form of dementia. Some subjects affected with sundown syndrome may have more than one disease or disorders. For example, a patient with sundown syndrome may suffer from dementia, Alzheimer’s disease, or both. About 20-45% of Alzheimer type patients will experience some sort of sundowning confusion. Sundown syndrome also refers to confusion and / or agitation worsening in the late afternoon, evening, or as the sun goes down.

[0270] The term “behavioral and psychological symptoms” refer to agitation / aggression, delusions and / or hallucinations, aberrant motor behavior, aberrant vocalizations, anxiety, euphoria / elation, irritability, depression / dysphoria, apathy, disinhibition, sleep and night-time behavior change, and appetite and eating change.

[0271] The term “freeze-drying” or “lyophilization” refers to a process used in the creation of a stable preparation of a substance by freezing a fluid formulation containing the substance and 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 substantially remove the frozen liquid under vacuum. The term “lyophilization” refers to the conventional, art-recognized procedure freeze-drying a composition. “Lyophilized” and “freeze-dried” are used herein as synonyms.

[0272] The term “pharmaceutically acceptable carrier” refers to a pharmacologically inert substance to be used as a carrier. As used herein, the phrase “carrier” and “excipients” are used interchangeably, except where otherwise clearly intended to have different meanings.

[0273] The term “unit dosage form” as used herein refers to a physically discrete units, suitable as unit dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.

[0274] It will be understood, however, that the total daily usage of the compositions of the present disclosure will be decided by the attending physician within the scope of sound medical judgment.

[0275] Within the meaning of the present disclosure, the term “conjoint administration” or “simultaneous administration” is used to refer to administration of dexmedetomidine or a pharmaceutically acceptable salt thereof and latrepirdine or a pharmaceutically acceptable salt thereof at the same time in separate formulations or as a combination formulation, i.e. in a single dosage form.

[0276] . The term “sequential administration” refers to administration of the latrepirdine and dexmedetomidine one after the other, i.e. not at the same time, in two or more separate dosage forms. If the disclosed drug substances are administered sequentially, then typically administration of the last drug substance is begun an hour or less, generally 30 minutes or less, after administration of the first drug substance is begun.

[0277] As used herein “nanonization” means the process of reducing the particles to be in a range such that the average particle size is less than 1000 nanometers in size preferably less than 100 nanometers in size.

[0278] The phrase “spray drying” refers to processes involved in breaking up liquid mixtures into small droplets (atomization) and rapidly removing solvent from the mixture in a spray drying apparatus where there is a strong driving force for evaporation of solvent from the 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 droplets. The phrase spray drying is used conventionally and broadly. Spray drying processes and spray drying equipment are described generally in Perry, Robert H., and Don W. Green (eds.), Perry’s Chemical Engineers’ Handbook, New York: McGraw-Hill, 2007 (8thedition).

[0279] The term “sublimation” refers to the physical phase transition from a solid state directly to a vapor state. More specifically, sublimation is a process in which a substance goes from a solid to a gas without going through a liquid phase. Sublimation of a solution may be obtained through the freeze-drying process.

[0280] As used herein, the term “granulation” refers to the process of agglomerating powder particles into larger agglomerates (i.e. granules) that contain the active agent. The term “granulation” includes dry and wet granulation techniques. The term “wet granulation” refers to any process comprising the steps of addition of a water comprising liquid, preferably water to the powder starting materials, preferably kneading, and drying to yield a solid dosage form. The term “dry granulation” refers to any process that comprises compacting the powder, usually either by slugging or with a roller compactor, and preferably milling the compacted powder to obtain the granules. No liquid is employed for the dry granulation. The compacted granulate or compacted granules as disclosed herein are preferably prepared by dry granulation.

[0281] “Direct compression” refers to a process which involves blending the ingredients and then compressing into tablets. I. Active agents

[0282] Dexmedetomidine has the IUPAC name (+) 4-(S)-[1-(2,3-dimethylphenyl) ethyl]-1H- imidazole. As the monohydrochloride salt, it is predominantly used as a medication for the sedation of patients during treatment in an intensive care setting or to sedate patients prior to and / or during surgical and other procedures. Such medication is currently sold under the registered trade name “PRECEDEX®”.

[0283] Pharmaceutically acceptable salts of dexmedetomidine that may be used herein include generally any suitable salt that has been or may be approved by the US FDA or other appropriate foreign or domestic agency for administration to a human. Non-limiting examples of suitable pharmaceutically acceptable salts include salts of inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, monohydrocarbonic, phosphoric, monohydrogen 55 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 phosphoric, dihydrogen phosphoric, sulfuric, hydrogen sulfuric, and hydroiodic acid. Other examples include salts derived from non-toxic organic acids, including acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, and methanesulfonic acids, or combinations of these acid salts. Exemplary salts include dexmedetomidine hydrochloride, dexmedetomidine hydrobromide, dexmedetomidine sulfate, dexmedetomidine sulfonate, dexmedetomidine phosphate, dexmedetomidine nitrate, dexmedetomidine formate, dexmedetomidine citrate, dexmedetomidine tartrate, dexmedetomidine malate, dexmedetomidine benzoate, dexmedetomidine salicylate, dexmedetomidine ascorbate or the like. In embodiments, deuterated forms of dexmedetomidine or a pharmaceutically acceptable salt thereof may be included.

[0284] Latrepirdine (also known as Dimebon) has the IUPAC name of 2,8-dimethyl-5-[2-(6- methylpyridin-3-yl)ethyl]-3,4-dihydro-1H-pyrido[4,3-b]indole and should be understood herein to include any pharmaceutically acceptable form. By “pharmaceutically acceptable form” is meant any pharmaceutically acceptable form, including, solvates, hydrates, isomorphs, polymorphs, co-crystals, pseudomorphs, neutral forms, acid addition salt forms, and prodrugs. It may be present in a form of salts with pharmaceutically acceptable acids and in a form of quarternized derivatives. Pharmaceutically acceptable base addition salts can be prepared from inorganic and / or organic bases.

[0285] The pharmaceutically acceptable acid addition salts of latrepirdine are prepared in a conventional manner by treating a solution or suspension of the free base with, for example, one or two chemical equivalents of a pharmaceutically acceptable acid. Illustrative of suitable acids are acetic, lactic, succinic, maleic, tartaric, citric, gluconic, ascorbic, mesylic, tosylic, benzoic, cinnamic, fumaric, nitric, sulfuric, phosphoric, hydrochloric, dihydrochloric, hydrobromic, hydroiodic, sulfamic, sulfonic such as methanesulfonic, benzenesulfonic, and related acids. In embodiments, latrepirdine is present as a free base. In embodiments, latrepirdine is present as latrepirdine dihydrochloride. In embodiments, latrepirdine is present as latrepirdine hydrochloride. In embodiments, latrepirdine is present as latrepirdine dihydrochloride dihydrate. In embodiments, latrepirdine is present as latrepirdine dihydrochloride hydrate. 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 II. Dosages

[0286] In embodiments, the dosage of dexmedetomidine or a pharmaceutically acceptable salt thereof administered may conveniently be in the range of between about 0.5 micrograms to about 300 micrograms. Examples of suitable dosages include: about 0.5 micrograms to about 280 micrograms, about 1 microgram to about 270 micrograms about 1 microgram to about 260 micrograms, about 1 microgram to about 250 micrograms, about 1 microgram to about 240 micrograms, about 1 microgram to about 230 micrograms, about 1 microgram to about 220 micrograms, about 1 microgram to about 210 micrograms, about 1 microgram to about 200 micrograms, about 1 microgram to about 190 micrograms, about 1 microgram to about 180 micrograms, about 1 microgram to about 170 micrograms, about 1 microgram to about 160 micrograms, about 1 microgram to about 150 micrograms, about 1 microgram to about 140 micrograms, about 1 microgram to about 130 micrograms, about 1 microgram to about 120 micrograms, about 1 microgram to about 110 micrograms, about 1 microgram to about 100 micrograms, about 3 micrograms to about 90 micrograms, about 3 micrograms to about 80 micrograms, about 3 micrograms to 70 micrograms, about 3 micrograms to about 60 micrograms, about 3 micrograms to 50 micrograms, about 3 micrograms to about 40 micrograms, about 3 micrograms to about 35 micrograms, about 5 micrograms to about 35 micrograms, about 10 micrograms to about 50 micrograms, about 10 micrograms to about 40 micrograms, about 10 micrograms to about 35 micrograms or about 15 micrograms to 35 micrograms. The dose may be administered one or more times a day, e.g. two times, three times, four times, five times or six times per day.

[0287] In embodiments, the per unit dose of dexmedetomidine or a pharmaceutically acceptable salt thereof is about 10 micrograms, about 15 micrograms, about 20 micrograms, about 25 micrograms, about 30 micrograms, about 35 micrograms, about 40 micrograms, about 45 micrograms, about 50 micrograms, about 55 micrograms, about 60 micrograms, about 65 micrograms, about 70 micrograms, about 75 micrograms, about 80 micrograms, about 85 micrograms, about 90 micrograms, about 95 micrograms, about 100 micrograms, about 105 micrograms, about 110 micrograms, about 115 micrograms, about 120 micrograms, about 125 micrograms, about 130 micrograms, about 135 micrograms, about 140 micrograms, about 145 micrograms, about 150 micrograms, about 155 micrograms, about 160 micrograms, about 165 micrograms, about 170 micrograms, about 175 micrograms, about 180 micrograms, about 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 185 micrograms, about 190 micrograms, about 195 micrograms, about 200 micrograms, about 205 micrograms, about 210 micrograms, about 215 micrograms, about 220 micrograms, about 225 micrograms, about 230 micrograms, about 235 micrograms, about 240 micrograms, about 245 micrograms about 250 micrograms, about 255 micrograms, about 260 micrograms, about 265 micrograms, about 270 micrograms, about 275 micrograms, about 280 micrograms, about 285 micrograms, about 290 micrograms, about 295 micrograms or about 300 micrograms, including all values and ranges in between.

[0288] Each unit may be administered to the subject one or more times per day, e.g.1, 2, 3, 4, 5, or 6 times per day. In embodiments, each unit may be administered at an appropriate dosing interval (e.g. about 1 hour between doses) or can be administered concurrently.

[0289] An effective total daily dose may, for example, include one or more-unit doses, up to a total daily dose of about 1 mg of dexmedetomidine or a pharmaceutically acceptable salt thereof. In embodiments, the total daily dose of dexmedetomidine or a pharmaceutically acceptable salt thereof is about 0.5 micrograms to about 500 micrograms, e.g. a total daily dose of about 20 micrograms, about 25 micrograms, about 30 micrograms, about 35 micrograms, about 40 micrograms, about 45 micrograms, about 50 micrograms, about 55 micrograms, about 60 micrograms, about 65 micrograms, about 70 micrograms, about 75 micrograms, about 80 micrograms, about 85 micrograms, about 90 micrograms, about 95 micrograms, about 100 micrograms, about 110 micrograms, about 120 micrograms, about 130 micrograms, about 140 micrograms, about 150 micrograms, about 160 micrograms, about 170 micrograms, about 180 micrograms, about 190 micrograms, about 200 micrograms, about 210 micrograms, about 220 micrograms, about 230 micrograms, about 240 micrograms, about 250 micrograms, about 260 micrograms, about 270 micrograms, about 280 micrograms, about 290 micrograms, about 300 micrograms, about 310 micrograms, about 320 micrograms, about 330 micrograms, about 340 micrograms, about 350 micrograms, about 360 micrograms, about 370 micrograms, about 380 micrograms, about 390 micrograms, about 400 micrograms, about 410 micrograms, about 420 micrograms, about 430 micrograms, about 440 micrograms, about 450 micrograms, about 460 micrograms, about 470 micrograms, about 480 micrograms, about 490 micrograms or about 500 micrograms, including all ranges and values in between.

[0290] In embodiments, the daily dose of latrepirdine or a pharmaceutically acceptable salt thereof administered may conveniently be in the range of between about 0.5 mg to about 500 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 mg. Examples of suitable dosages include: about 0.5 mg to about 450 mg, about 0.5 mg to about 400 mg, about 0.5 mg to about 350 mg, about 0.5 mg to about 300 mg, about 0.5 mg to about 250 mg, about 0.5 mg to about 200 mg, about 0.5 mg to about 150 mg, about 0.5 mg to about 100 mg, about 1 mg to about 500 mg, about 1 mg to about 450 mg, about 1 mg to about 400 mg, about 1 mg to about 350 mg, about 1 mg to about 300 mg, about 1 mg to about 200 mg, about 1mg to about 150 mg, about 1 mg to about 100 mg, about 2 mg to about 500 mg, about 2 mg to about 450 mg, about 2 mg to about 400 mg, about 2 mg to about 350 mg, about 2 mg to about 300 mg, about 2 mg to about 250 mg, about 2 mg to about 200 mg, about 2 mg to about 150 mg, about 2 mg to about 100 mg, about 3 mg to about 500 mg, about 3 mg to about 450 mg, about 3 mg to about 400 mg, about 3 mg to about 350 mg, about 3 mg to about 300 mg, about 3 mg to about 250 mg, about 3 mg to about 200 mg, about 3 mg to about 150 mg, about 3 mg to about 100 mg, about 4 mg to about 500 mg, about 4 mg to about 450 mg, about 4 mg to about 400 mg, about 4 mg to about 350 mg, about 4 mg to about 300 mg, about 4 mg to about 250 mg, about 4 mg to about 200 mg, about 4 mg to about 150 mg, about 4 mg to about 100 mg, about 5 mg to about 500 mg, about 5 mg to about 450 mg, about 5 mg to about 400 mg, about 5 mg to about 350 mg, about 5 mg to about 300 mg, about 5 mg to about 250 mg, about 5 mg to about 200 mg, about 5 mg to about 150 mg, about 5 mg to about 100 mg, about 5 mg to about 90 mg, about 5 mg to about 80 mg, about 5 mg to about 70 mg, about 5 mg to about 60 mg, about 5 mg to about 50 mg, about 5 mg to about 40 mg, about 5 mg to about 30 mg, about 5 mg to about 20 mg or about 5 mg to about 10 mg. In embodiments, the daily dose of latrepirdine or a pharmaceutically acceptable salt thereof administered may conveniently be in the range of about 10 mg to about 200 mg. In embodiments, the daily dose of latrepirdine or a pharmaceutically acceptable salt thereof administered may conveniently be in the range of about 10 mg to about 100 mg. In embodiments, the daily dose of latrepirdine or a pharmaceutically acceptable salt thereof administered may conveniently be in the range of about 10 mg to about 80 mg. In embodiments, the daily dose of latrepirdine or a pharmaceutically acceptable salt thereof administered may conveniently be in the range of about 15 mg to about 6 In embodiments, the daily dose of latrepirdine or a pharmaceutically acceptable salt thereof administered may conveniently be in the range of about 15 mg to about 45 mg. In embodiments, the daily dose of latrepirdine or a pharmaceutically acceptable salt thereof administered may conveniently be in the range of about 5 mg to about 60 mg, for example about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 59 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, about 55 mg, about 56 mg, about 57 mg, about 58 mg, about 59 mg, or about 60 mg, including all values and ranges in between.

[0291] In embodiments, the per unit dose of latrepirdine is about 100 mg, about 95mg, about 90 mg, about 85 mg, about 80 mg, about 75 mg, about 70 mg, about 65 mg, about 60 mg, about 55 mg, about 50 mg, about 45 mg, about 40 mg, about 35 mg, about 30 mg, about 25 mg, about 20 mg, about 15 mg, about 10 mg, about 8 mg, about 7 mg, about 6 mg, about 5 mg, about 4 mg, about 3 mg, about 2 mg, about 1 mg, about 0.5 mg or about 0.1 mg, including all ranges and values in between.

[0292] In embodiments, the therapeutically effective amount of latrepirdine is divided evenly for administration either twice daily or three times daily.

[0293] The exemplary dosages of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g. hydrochloride salt) and latrepirdine or a pharmaceutically acceptable salt thereof (e.g. dihydrochloride salt) to be administered to a particular patient, will depend on the type and extent of the condition, the overall health status of the particular patient, the particular form of dexmedetomidine and latrepirdine or pharmaceutically acceptable salts thereof being administered, and the particular formulation used to treat the patient. III. Dosage Forms

[0294] Oral dosage forms:

[0295] In embodiments, the present disclosure provides an oral dosage form comprising effective amount of latrepirdine or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. In embodiments, the present disclosure provides an oral dosage form comprising effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. In embodiments, the oral 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374

[0296] In embodiments, the oral dosage form comprising latrepirdine or dexmedetomidine or pharmaceutically acceptable salts thereof is administered in the form of tablets, orally disintegrating tablets (ODTs), effervescent tablets, capsules, pellets, pills, lozenges or troches, powders, dispersible granules, catchets, aqueous solutions, syrups, emulsions, suspensions, solutions, soft gels, dispersions and the like. Tablets

[0297] In embodiments, the present disclosure provides an oral tablet dosage form comprising effective amount of latrepirdine or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. In embodiments, the present disclosure provides an oral tablet dosage form comprising effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient The dosage forms of the disclosure comprise additives conventional in the dosage form in question. Tabletting aids, commonly used in tablet formulation can be used and reference is made to the extensive literature on the subject, see in particular Fiedler's “Lexikon der Hilfsstoffe”, 4th Edition, ECV Aulendorf, 1996, which is incorporated herein by reference. These include but are not limited to diluents, binders, disintegrants, glidants, lubricants, pH modifying agents and combinations thereof.

[0298] Diluents: one or more diluents comprise, but are not limited to dibasic calcium phosphate, pullulan, maltodextrin, isomalt, sugar pellets, mannitol, spray-dried mannitol, microcrystalline cellulose, dibasic calcium phosphate dihydrate, lactose, sugars, sorbitol, mixture of microcrystalline cellulose and guar gum (Avicel CE-15), mixture of mannitol, polyplasdone and syloid (Pharmaburst), mixture of mannitol, crospovidone and polyvinyl acetate (Ludiflash), isomalt, Panexcea, F-Melt, sucrose, calcium salts and similar inorganic salts, heavy magnesium carbonate and the like, and the mixtures thereof.

[0299] Binders: one or more binders comprise, but are not limited to, low- substituted hydroxypropyl cellulose, xanthan gum, polyvinylpyrrolidone (povidone), gelatin, sugars, glucose, natural gums, gums, synthetic celluloses, polymethacrylate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose, methyl cellulose, and other cellulose derivatives and the like, and the mixtures thereof. 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374

[0300] Disintegrants: one or more binders comprise, but are not limited to, at least one or a mixture of sodium starch glycolate, croscarmellose sodium, crospovidone, sodium alginate, gums, starch, and magnesium aluminium silicate.

[0301] Lubricants: one or lubricants comprise, but are not limited to sodium stearyl fumarate, sodium lauryl sulphate, magnesium stearate, polyethylene glycol, metal stearates, hydrogenated castor oil and the like, and the mixtures thereof.

[0302] Glidant: one or glidants comprise, but are not limited to, stearic acid, colloidal silicon dioxide, talc, aluminium silicate and the like, and the mixtures thereof.

[0303] pH modifying agents: one or more pH modifying agents comprises, but are not limited to organic acid or its salts like phosphoric acid, citric acid and the like.

[0304] Oral suspensions:

[0305] In embodiments, the present disclosure provides an oral liquid suspension comprising effective amount of latrepirdine or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. In embodiments, the present disclosure provides an oral liquid suspension comprising effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient,

[0306] A liquid pharmaceutical suspension of the present disclosure for oral administration contains at least one particulate drug as active ingredient wherein active ingredient is latrepirdine or dexmedetomidine or pharmaceutically acceptable salts thereof. The particulate drug (latrepirdine or dexmedetomidine) may be partially dissolved in the liquid phase, but preferably more than about 50 percent should be particulates. The suspension of the present disclosure contains at least one suspending polymer exhibiting plastic flow that imparts a yield value of about 0.2 to about 15 Pa, preferably from about 0.5 to about 10 Pa Polymers exhibiting Bingham plastic and shear-thinning plastic flow are preferred. Polymers exhibiting thixotropic plastic flow can be used only if the lag time to recover 50% of the yield value is fast, less than about an hour, preferably less than about five minutes, most preferably less than about a minute. The polymer exhibiting plastic flow may be selected from but are not limited to xanthan gum, carbomer, microcrystalline cellulose, 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 carboxymethylcellulose, sodium carboxymethylcellulose, and combinations thereof. The final yield value of the suspension must be less than about 15 Pa, preferably less than about 10 Pa to ensure that the product is pourable without shaking.

[0307] In addition to a yield value, the rheology of the final suspension should have an apparent viscosity of at least about 50 cps, preferably at least about 100 cps, most preferably at least about 200 cps, at a shear rate of 100 sec−1 to retard particle motion when the shear rate exceeds the yield value such as when shaking or pouring. For thixotropic plastic fluid, the high viscosity retards particle motion while the yield value is recovering after application of shear. When the suspending polymer(s) added to impart the yield value is not adequate to achieve the desired apparent viscosity of at least about 50 cps at a shear rate of 100 sec−1, viscosity-building agents with no yield value can be added. These viscosity-building agents may be selected from but are not limited to hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, guar gum, locust bean gum, and combinations thereof.

[0308] The liquid suspension of the present disclosure may contain additional ingredients used in the drug industry, herein referred to as additives. Additives include well-known components, but are not limited to sweetening agents, flavors, colorants, antioxidants, chelating agents, surfactants, wetting agents, antifoaming agents, pH modifiers, acidifiers, preservatives, cosolvents, and mixtures thereof.

[0309] Oral solutions:

[0310] The present disclosure relates to a homogeneous and stable pharmaceutical solution of latrepirdine or a pharmaceutically acceptable salt thereof suitable for oral administration. It also relates to a homogeneous and stable pharmaceutical solution of dexmedetomidine or a pharmaceutically acceptable salt thereof suitable for oral administration.

[0311] The oral liquid pharmaceutical solution of this disclosure comprises one or more pharmaceutically acceptable excipient which is selected from the group comprising co- solvents, solvents, antioxidants, microbial preservatives, buffering agents, aromatic agents, sweeteners and diluents. 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374

[0312] Co-solvents and solvents may include but are not limited to glycerine, alcohols, propylene glycol, polyethylene glycol, benzyl alcohol, water, ethanol, isopropyl alcohol or their mixtures thereof.

[0313] Suitable antioxidants may include but are not limited to butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ascorbic acid, beta-carotene, alpha-tocopherol, propyl gallate, gentisic acid sodium ascorbate, sodium bisulfite, sodium metabisulfite, monothioglycero, cysteine, thioglycolate sodium, acetone sodium bisulfite, ascorbate (sodium / acid), bisulfite sodium, cystein / cysteinate HCl, dithionite sodium (Na hydrosulfite, Na sulfoxylate), gentisic acid, gentisic acid ethanolamine, glutamate monosodium, formaldehyde sulfoxylate sodium, metabisulfite potassium, metabisulfite sodium, monothioglycerol (thioglycerol), propyl gallate, sulfite sodium, tocopherol alpha, thioglycolate sodium, EDTA in calcium and sodium compounds or the mixtures thereof.

[0314] Buffering agents may include but are not limited to ascorbic acid, acetic acid, tartaric acid, citric acid monohydrate, trisodium citrate dehydrate, sodium citrate, potassium citrate, sodium phosphate, tricalcium phosphate, calcium carbonate, sodium bicarbonate, calcium phosphate, carbonated calcium phosphate, magnesium hydroxide, hydrochloric acid, sodium hydroxide or their mixtures thereof.

[0315] Diluents may include but are not limited to maltitol solution, glucose syrup, glycerin, sorbitol and mannitol solutions, sucrose, sorbitol, xylitol, dextrose, fructose, sugar potassium, aspartame, saccharine, saccharine sodium, spray dried or anhydrase lactose, mannitol, starch or their mixtures thereof.

[0316] Sweeteners may include but are not limited to sucralose, aspartame, acesulfame-K, thaumatin, mogroside, saccharin and salts thereof, sodium cyclamate, glucose, sucrose, lactose, fructose, mannitol, sorbitol, lactitol, xylitol, erythritol, glycyrrhizin, monosodium glycyrrhizinate, monoamonium glycyrrhizinate, isomalt, glycerine, dextrose or their mixtures thereof.

[0317] Aromatic agents may include but are not limited to fruit aromas such as orange, banana, strawberry, cherry, wild cherry, lemon and the like, and other aromas such as cardamom, anis, mint, menthol, vanillin or their mixtures thereof. 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374

[0318] Microbial preservatives may include but are not limited to sodium benzoate, benzoic acid, boric acid, sorbic acid and their salts thereof, benzyl alcohol, benzalkonium chloride, parahydroxybenzoic acids and their alkyl esters, methyl and propyl parabens or their mixtures thereof.

[0319] Oromucosal

[0320] In embodiments, the present disclosure provides an oromucosal dosage form comprising latrepirdine or a pharmaceutically acceptable salt thereof, one or more mucoadhesive agents and one or more pharmaceutically acceptable excipients or carriers. In embodiments, the present disclosure provides an oromucosal dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof, one or more mucoadhesive agents and one or more pharmaceutically acceptable excipients or carriers. In embodiments, the dosage forms described herein disintegrate within about 5 second to about 10 minutes upon contact with an oral mucosa, e.g. about 5 seconds to about 10 minutes, about 5 seconds to about 5 minutes, about 5 seconds to about 1 minute, about 5 seconds to about 30 seconds, about 5 seconds to about 10 seconds, about 30 seconds to about 10 minutes, about 30 seconds to about 5 minutes, about 30 seconds to about 1 minute, about 1 minute to about 10 minutes, about 1 minute to about 5 minutes, about 1 minute to about 2 minutes, about 2 minutes to about 10 minutes, about 2 minutes to about 5 minutes, about 2 minutes to about 3 minutes, about 3 minutes to about 10 minutes, about 3 minutes to about 5 minutes, about 4 minutes to about 10 minutes, about 4 minutes to about 5 minutes, about 5 minutes to about 10 minutes, about 5 minutes to about 7 minutes, or about 7 minutes to about 10 minutes upon contact with an oral mucosa. In embodiments, the dosage form disintegrates in less than about 1 minute upon contact with an oral mucosa, e.g. about 5 seconds, about 10 seconds, about 15 seconds, about 20 seconds, about 25 seconds, about 30 seconds, about 35 seconds, about 40 seconds, about 45 seconds, about 50 seconds, about 55 seconds, or about 60 seconds, including all ranges and values in between. In embodiments, the dosage form does not disintegrate within 1 minute upon contact with an oral mucosa. In embodiments, the dosage form disintegrates in more than 1 minute upon contact with an oral mucosa, e.g. about 1 minute, about 2 minutes, about 3 minutes, about 4 minutes, about 5 minutes, about 6 minutes, about 7 minutes, about 8 minutes, about 9 minutes, or about 10 minutes. Thus, dosage forms produced in 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 accordance with one of the embodiments of the present disclosure meet the disintegration time criteria of disintegration within about 5 seconds to about 10 minutes when tested by the <701> disintegration test method (see Guidance to Industry, herein incorporated by reference).

[0321] In embodiments, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98% or at least about 99% of the drug in a dosage form comprising a formulation of the disclosure is absorbed via the oral mucosa.

[0322] In embodiments, the dosage forms of the present disclosure possess sufficient mechanical strength to resist attrition / chipping during packaging in blisters and bottles, storage and transportation for commercial distribution and end use.

[0323] In embodiments, the dosage forms described herein effectively treat disorders related to noradrenergic hyperarousal. In embodiments, the dosage forms described herein effectively reduces noradrenergic hyperarousal. In embodiments, the dosage forms described herein effectively treat acute stress disorder (ASD). In embodiments, the dosage forms described herein effectively prevents post traumatic stress disorder (PTSD). In embodiments, the dosage forms described herein effectively treat autism spectrum disorders.

[0324] In embodiments, the dosage forms described herein effectively treat agitation in an agitated subject. For example, the dosage forms described herein effectively treat agitation in a subject as measured by PEC, CGI-I, and / or ACES. In embodiments, the dosage form effectively treats agitation in a subject without also inducing significant sedation. In embodiments, the subject is treated without experiencing clinically significant cardiovascular effects. In embodiments, the agitation is caused by noradrenergic hyperarousal. 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374

[0325] In embodiments, the dosage forms described herein effectively treat depression in a subject. For example, the dosage forms described herein effectively treat depression in a subject as measured by HAM-D scale or MADRS scale. In embodiments, the present disclosure provides an oromucosal dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g. hydrochloride salt), one or more mucoadhesive agents and one or more pharmaceutically acceptable excipients or carriers to treat agitation. In embodiments, the dosage form disintegrates in less than about 1 minute upon contact with an oral mucosa. For example, the dosage form may disintegrate in about 5 seconds, about 10 seconds, about 15 seconds, about 20 seconds, about 25 seconds, about 30 seconds, about 35 seconds, about 40 seconds, about 45 seconds, about 50 seconds, about 55 seconds, or about 60 seconds, including all ranges and values in between. In embodiments, the dosage form disintegrates more than about 1 minute upon contact with an oral mucosa. In embodiments, the dosage form disintegrates in not less than about 1 minute upon contact with an oral mucosa, e.g. about 1 minute, about 2 minutes, about 3 minutes, about 4 minutes, about 5 minutes, about 6 minutes, about 7 minutes, about 8 minutes, about 9 minutes, or about 10 minutes. In embodiments, the dosage form effectively treats agitation in a subject. In embodiments, the dosage form effectively treats agitation in a subject without also inducing significant sedation. In embodiments, the agitation is caused by noradrenergic hyperarousal. In embodiments, the dosage forms described herein effectively treats depression in a subject.

[0326] In embodiments, the present disclosure provides dosage forms comprising dexmedetomidine or a pharmaceutically acceptable salt thereof and latrepirdine or a pharmaceutically acceptable salt thereof, one or more mucoadhesive agents and one or more pharmaceutically acceptable excipients or carriers to treat disorders associated with noradrenergic hyperarousal. In embodiments, latrepirdine or a pharmaceutically acceptable salt thereof is administered in combination with a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof simultaneously, sequentially, or intermittently. 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374

[0327] In embodiments, the present disclosure provides an oromucosal dosage form comprising latrepirdine or a pharmaceutically acceptable salt thereof, one or more mucoadhesive agents and one or more pharmaceutically acceptable excipients or carriers to treat ASD in a subject. In embodiments, the present disclosure provides an oromucosal dosage form comprising latrepirdine or a pharmaceutically acceptable salt thereof, one or more mucoadhesive agents and one or more pharmaceutically acceptable excipients or carriers to prevent PTSD in a subject.

[0328] In embodiments, the present disclosure provides an oromucosal dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof, one or more mucoadhesive agents and one or more pharmaceutically acceptable excipients or carriers to treat autism spectrum disorder in a subject. In embodiments, the present disclosure provides an oromucosal dosage form comprising latrepirdine or a pharmaceutically acceptable salt thereof, one or more mucoadhesive agents and one or more pharmaceutically acceptable excipients or carriers to treat autism spectrum disorder in a subject.

[0329] In embodiments, the present disclosure provides an oromucosal dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof, one or more mucoadhesive agents and one or more pharmaceutically acceptable excipients or carriers to treat ASD in a subject. In embodiments, the present disclosure provides an oromucosal dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof, one or more mucoadhesive agents and one or more pharmaceutically acceptable excipients or carriers to prevent PTSD in a subject. In embodiments, the present disclosure provides an oromucosal dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof and latrepirdine or a pharmaceutically acceptable salt thereof, one or more mucoadhesive agents and one or more pharmaceutically acceptable excipients or carriers to treat agitation. In embodiments, the dosage form disintegrates in less than about 1 minute upon contact with an oral mucosa. For example, the dosage form may disintegrate in about 5 seconds, about 10 seconds, about 15 seconds, about 20 seconds, about 25 seconds, about 30 seconds, about 35 seconds, about 40 seconds, about 45 seconds, about 50 seconds, about 55 seconds, or about 60 seconds upon contact with an oral mucosa. In embodiments, the dosage form disintegrates in not less than about 1 minute upon contact with an oral 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 mucosa. For example, the dosage form may disintegrate in about 1 minute, about 2 minutes, about 3 minutes, about 4 minutes, about 5 minutes, about 6 minutes, about 7 minutes, about 8 minutes, about 9 minutes, or about 10 minutes. In embodiments, the dosage form effectively treats agitation in a subject. In embodiments, the dosage form effectively treats agitation in a subject without also inducing significant sedation. In embodiments, the agitation is caused by noradrenergic hyperarousal. In embodiments, the dosage forms described herein effectively treats depression in a subject.

[0330] In embodiments, the present disclosure provides a first oromucosal dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof and a second oromucosal dosage form comprising latrepirdine or a pharmaceutically acceptable salt thereof for conjoint administration either concurrently or sequentially to treat agitation.

[0331] In embodiments, the dosage form is administered for the treatment of agitation associated with neurodegenerative disorders, neuropsychiatric disorders and alcohol withdrawal or substance abuse withdrawal, including opioid withdrawal. In embodiments, the dosage form is administered for the treatment of agitation associated with an OPD / IPD procedure (e.g. MRI, CT or CAT scan, lumbar puncture, bone marrow aspiration / biopsy, tooth extraction or other dental procedures).

[0332] In embodiments, the present disclosure provides a first oromucosal dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof and a second oromucosal dosage form comprising latrepirdine or a pharmaceutically acceptable salt thereof for conjoint administration either concurrently or sequentially to treat depression in a subject.

[0333] In embodiments, the dosage form disintegrates in less than about 1 minute upon contact with an oral mucosa. For example, the dosage form may disintegrate in about 5 seconds, about 10 seconds, about 15 seconds, about 20 seconds, about 25 seconds, about 30 seconds, about 35 seconds, about 40 seconds, about 45 seconds, about 50 seconds, about 55 seconds, or about 60 seconds upon contact with an oral mucosa. In embodiments, the dosage form disintegrates in not less than about 1 minute upon contact with an oral mucosa. For example, the dosage form may disintegrate in about 1 minute, about 2 minutes, about 3 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 minutes, about 4 minutes, about 5 minutes, about 6 minutes, about 7 minutes, about 8 minutes, about 9 minutes, or about 10 minutes.

[0334] In embodiments, the oromucosal (e.g. sublingual or buccal) dosage form of the disclosure is a tablet, capsule, disc, patch or film, sachet, wafer, powder, minitablet, pellet, paste, gel, ointment, cream, drops, liquid (solution, suspension or emulsion), spray, microspheres or nanospheres which can be formulated in accordance with methods that are standard in the art.

[0335] In embodiments, the dosage form is an oromucosal wafer. In embodiments, the wafer is lyophilized. In embodiments, the wafer disintegrates in less than about 1 minute upon contact with an oral mucosa. In embodiments, the wafer disintegrates in more than about 1 minute upon contact with an oral mucosa. In embodiments, the wafer comprises excipients such as hydroxypropyl cellulose, lactose, mannitol, glycine, and the like.

[0336] In embodiments, the dosage form is an oromucosal mini-tablet. In embodiments, the mini-tablet disintegrates in less than about 1 minute upon contact with an oral mucosa. In embodiments, the mini-tablet disintegrates in more than about 1 minute upon contact with an oral mucosa. In embodiments, the minitablet comprises excipients based on co- processed mannitol. In embodiments, the mini-tablet contains directly compressible excipients. In embodiments, the compressible excipient is in the form of a hydrate, and may be selected from organic compounds such as dextrose monohydrate, maltodextrin, lactose monohydrate, and dextrin, as well as inorganic compounds including dibasic calcium phosphate dihydrate, dibasic sodium phosphate dihydrate, dibasic sodium phosphate heptahydrate, dibasic sodium phosphate dodecahydrate, monobasic sodium phosphate monohydrate and monobasic sodium phosphate dihydrate. In embodiments, the rapidly disintegrating tablet portion includes a compressible excipient selected from the group consisting of isomalt, dextrose monohydrate, hydrogenated starch hydrolysate base, maltodextrin, lactose monohydrate, dextrin, mannitol, lactitol, sorbitol, xylitol, erythritol, sucrose, and lactose.

[0337] In embodiments, the oromucosal dosage form is in the form of a tablet or disc or packed powder. 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374

[0338] In embodiments, the dosage form is a hard or compressed powdered sublingual or buccal tablet having a low grit component for an organoleptically pleasant mouth feel. In embodiments, the tablet (or particles thereof containing the active agent which can be compressed to form the tablet) comprises a protective outer coating e.g. any polymer conventionally used in the formation of microparticles and microcapsules. In embodiments, the dosage form is a sublingual (or buccal) tablet containing an effervescent agent. Sublingual compositions comprising effervescent agents are disclosed in US Patent No. 6,200,604, which is herein incorporated by reference in its entirety, for all purposes.

[0339] In embodiments, the oromucosal tablet conveniently includes the active ingredient within a matrix. In embodiments, the matrix is composed of, for example, at least one filler and / or a lubricant. Fillers include, for example, lactose or mannitol, and suitable lubricants include, but are not limited to, magnesium stearate, silicon dioxide and talc. The matrix may also include one or more of: a binder (e.g. povidone, a sugar or carboxymethylcellulose), a disintegrant (e.g. croscarmellose sodium, crospovidone or sodium starch glycolate), a sweetening agent (e.g. sucralose) and the like. The tablet may conveniently have a friability of about 2% or less and a hardness of about 15 to about 50 Newtons.

[0340] In embodiments, the oromucosal dosage form is in the form of a patch or film (e.g. thin film). The patch may have adhesive qualities to prevent movement or swallowing of the patch. Suitable film compositions comprising dexmedetomidine are disclosed in US Patent No.10,792,246, which is incorporated herein by reference in its entirety for all purposes.

[0341] In embodiments, the oromucosal dosage form is in the form of a paste, gel or ointment. The viscosity of the paste, gel or ointment can be adjusted to allow for retention under the tongue or near gums or cheeks or upper lip.

[0342] In embodiments, the oromucosal dosage form is in a liquid form (e.g. as a solution, suspension or emulsion), and may be, for example, presented as a spray or as drops. In a particular embodiment of the disclosure, Latrepirdine and / or dexmedetomidine or pharmaceutically acceptable salts thereof are oromucosally administered in liquid form, e.g. in a flavored or unflavored physiological saline solution. The liquid dosage form may conveniently be administered under the tongue or near the gums or cheeks or upper lip as 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 drops or as a spray. The solutions include the active ingredient together with a diluent such as water, normal saline, sodium chloride solution, or any other suitable solvent such as propylene glycol, glycerol, ethyl alcohol and so on. The diluent for the solution may particularly be physiological saline solution or water.

[0343] The spray dosage form of the present disclosure for oromucosal administration may include one or more pharmaceutically acceptable liquids (e.g. present in the amount of about 30% to about 99.99% by weight of the composition). Such liquids may be solvents, co-solvents, or non-solvents for dexmedetomidine and latrepirdine or pharmaceutically acceptable salts thereof. Examples of pharmaceutically acceptable liquids include water, ethanol, dimethyl sulfoxide, propylene glycol, polyethylene glycol, propylene carbonate, pharmaceutically acceptable oils (e.g., soybean, sunflower, peanut, peppermint etc.) and the like. The pharmaceutically acceptable liquid is selected either to dissolve the active pharmaceutical ingredient, to produce a stable, homogenous suspension or solution of it, or to form any combination of a suspension or solution. In addition to these ingredients, spray formulations may include one or more excipients such as viscosity modulating materials (e.g. polymers, sugars, sugar alcohols, gums, clays, silicas, and the like, such as polyvinylpyrrolidone (PVP); preservatives (e.g., ethanol, benzyl alcohol, propylparaben and methylparaben); flavoring agents (e.g. peppermint oil), sweeteners (e.g., sugars such as sucrose, glucose, dextrose, maltose, fructose, etc.), artificial sweeteners (e.g. saccharin, aspartame, acesulfame, sucralose), or sugar alcohols (e.g. mannitol, xylitol, lactitol, maltitol syrup); buffers and pH-adjusting agent (e.g., sodium hydroxide, citrate, and citric acid); coloring agents; fragrances, chelating agents (e.g., EDTA); UV absorbers and antifoam agents (e.g., low molecular weight alcohols, dimethicone). In addition to one or more of the aforementioned ingredients suitable for sublingual or buccal administration, sprays may include one or more excipients such as viscosity modulating materials (e.g. water soluble or water swellable polymers such as carbopol, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose).

[0344] Sprays may be made by mixing appropriate quantities of the foregoing ingredients in accordance with standard good manufacturing practices. Such excipients may be included in the formulation to improve patient or subject acceptance or taste, to improve bioavailability, to increase shelf-life, to reduce manufacturing and packaging costs, to 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 comply with requirements of governmental regulatory agencies, and for other purposes. The relative amounts of each ingredient should not interfere with the desirable pharmacological and pharmacokinetic properties of the resulting formulation.

[0345] A patient may, in one embodiment, be treated by administering sublingually or buccally 1 to 2 actuations from a spray pump. An advantage of spray delivery is the ability to easily titrate patients by 1 or 2 doses as required by a single actuation.

[0346] Pump action sprays are characterized in requiring the application of external pressure for actuation, for example, external manual, mechanical or electrically initiated pressure. This is in contrast to pressurized systems, e.g., propellant-driven aerosol sprays, where actuation is typically achieved by controlled release of pressure e.g., by controlled opening of a valve.

[0347] The non-solid dosage forms of the disclosure may conveniently be administered by spraying, dripping, painting or squirting the composition under the tongue or near the gums or cheeks or upper lip.

[0348] In embodiments, the oromucosal tablet dosage form is prepared by lyophilization (or freeze-drying). A suspension comprising active agent(s) may be prepared with appropriate excipients and the active agent (latrepirdine / dexmedetomidine) suspension may be dispensed into blister packs and freeze-dried. An exemplary freeze-dried preparation platform that could be used for a latrepirdine and / or dexmedetomidine orally disintegrating table (ODT) is the ZYDIS®(Catalent, Somerset, NJ, USA) formulation. In particular, the excipients are blended and the active agents are separately milled to size and then mixed with the excipients. The solution / suspension then undergoes lyophilization by flash freezing and freeze drying. This aqueous solution / suspension must be chemically and morphologically stable throughout the dosing process. Gelatin may be used to give sufficient strength to the dosage form to prevent breakage during removal from packaging, but once placed in the mouth, the gelatin allows for immediate disintegration of the dosage form. Other alternatives such as fish gelatin and modified starches may be used. During processing, dosed solution / suspension is preferably frozen by passing through a gaseous medium. This serves to immobilize the solution / suspension rapidly, thereby improving the manufacture efficiency. Examples of oromucosal dosage forms includes orally 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 disintegrating tablets disclosed in US Patent No.6,509,040, US Patent No.7,972,621, US Patent No.1,054,8839, US Patent No.9,775,819, US Patent No.5,188,825, US Patent No. 5,631,023, US Patent No.6,297,240, US Patent No.6,413,549, US Patent No.5,976,577, US Patent No.6, 156,339, US Patent No.5,827,541, US Patent No.5,729,958, US Patent No.6,726,928, US Patent No.9,192,580, US Patent No.6,709,669, US Appl. Publication No. 20200138721, US Appl. Publication No. 20190276707, US Appl. Publication No. 20190314274, US Appl. Publication No.20040156894, PCT Publication No.1999038496, PCT Publication No.2000044351, and US Appl. Publication No.20090226522 and related patents / patent applications, which are herein incorporated by reference in their entirety, for all purposes.

[0349] Other methods of preparing oromucosal dosage forms such as ODTs may be used without limitation, and detailed description of general methods thereof have been disclosed, for example, in US Patent No 5,837,287; US Patent No 6,149,938; US Patent No 6,212,791; US Patent No 6,284,270; US Patent No 6,316,029; US Patent No 6,465,010; US Patent No 6,471,992; US Patent No 6,471,992; US Patent No 6,814,978; US Patent No 6,908,626; US Patent No 6,908,626; US Patent No 6,982,251; US Patent No 7,282,217; US Patent No 7,425,341; US Patent No 7,939,105; US Patent No.7,993.674; US Patent No.8,048,449; US Patent No.8,127,516; US Patent No.8,158,152; US Patent No.8,221,480; US Patent No. 8,256,233; US Patent No. 8,313,768, US Patent No. 5,039,540; US Patent No. 5,120,549; US Patent No.5,330,763; US Patent No.4,760,093; US Patent No.4,760,094; and US Patent No.4,767,789, which are herein incorporated by reference in their entirety, for all purposes.

[0350] Different technologies that may be used to prepare oromucosal dosage forms of the disclosure include but not limited to Flash Dose, Orasolv, durasolv, wowtab technology, Flash Tab Technology, Oraquick Technology, Quick–Dis Technology, Nanocrystal Technology, Shearform Technology, Ceform Technology, Pharmaburst technology, Frosta technology, Ziplet technology, Humidity treatment, Sintering, Lyoc Technolog, Quicksolv Technology, Nanocrystal technology, Pharmafreeze, AdvaTab Technology, cotton-candy technology and the like.

[0351] In embodiments, the oromucosal dosage forms (e.g., sublingual or buccal or gingival tablet) of the present disclosure may be prepared by sublimation, nanonization, spray 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 drying, granulation including wet granulation, dry granulation or direct compression and the like. U.S. Pat. Nos.5,178,878, 6,269,615 and 6,221,392 disclose manufacturing friable orally disintegrating tablets by direct compression and packaging in specially designed dome-shaped blister package using a robot-controlled integrated tableting-packaging system, which are herein incorporated by reference in their entirety, for all purposes.

[0352] In embodiments, the oromucosal tablet dosage forms as used herein may be prepared by direct compression comprising mixing the active agents (latrepirdine and / or dexmedetomidine) with one or more pharmaceutically acceptable excipients, lubricating the blend and directly compressing into a tablet.

[0353] In embodiments, there is provided a process of preparing oromucosal tablet dosage form by dry granulation comprising the steps of: (i) preparing a mixture containing active agent (latrepirdine and / or dexmedetomidine) and one or more pharmaceutically acceptable excipients; (ii) compacting the mixture obtained in step (i) to form a granulate; (iii) optionally mixing the granulate obtained in step (ii) with remaining excipients; and (iv) subjecting the granulate to compression to obtain the tablet.

[0336] In embodiments, the compaction in step (ii) is carried out by roller compaction or slugging techniques.

[0337] In embodiments, there is provided a process of preparing oromucosal tablet dosage form by wet granulation comprising the steps of: (i) preparing a mixture containing active agent (latrepirdine and / or dexmedetomidine) and one or more pharmaceutically acceptable excipients; (ii) granulating the mixture obtained in step (i) with a suitable granulation liquid to form a wet granulate; (iii) drying the wet granulate obtained in step (ii); (iv) optionally mixing the dried granulate obtained in step (iii) with one or more excipients; and (iv) subjecting the granulate obtained in step (iii) or the mixture obtained in step (iv) to compression to obtain the tablet. 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374

[0338] In embodiments, the mixture of step (i) is granulated with any suitable solvent including but not limited to water, an alcohol such as ethanol or isopropyl alcohol, or mixtures thereof.

[0339] The dosage form of the present disclosure may be administered to mammals, including humans, as well as non-mammals (e.g., rats, cats and dogs) in need thereof.

[0340] In embodiments, latrepirdine or a pharmaceutically acceptable salt thereof and dexmedetomidine or a pharmaceutically acceptable salt thereof are formulated as a sublingual tablet or buccal tablet.

[0341] In embodiments, the dosage form comprises a mucoadhesive agent to make the active agent or agents adhere to the oral mucosa. The mucoadhesive agent may possess properties to swell and expand in contact with water thus making tablet disintegrate when wetted with saliva. In embodiments, the dosage form comprises one or more mucoadhesive agents in an amount of about 0.5% to about 30 % w / w. For example, the one or more mucoadhesive agents are present in an amount ranging from about 0.5% w / w to about 30 % w / w, about 0.5% w / w to about 25 % w / w, about 0.5% w / w to about 20 % w / w, about 0.5% w / w to about 10 % w / w, about 0.5% w / w to about 5 % w / w, about 1% w / w to about 30 % w / w, about 1% w / w to about 20 % w / w, about 1 % w / w to about 10 % w / w, about 1% w / w to about 5 % w / w, about 1 % w / w to about 3 % w / w, about 1 % w / w to about 2 % w / w, about 3 % w / w to about 30 % w / w, about 3 % w / w to about 20 % w / w, about 3% w / w to about 10 % w / w, about 3 % w / w to about 5 % w / w, about 5 % w / w to about 30 % w / w, about 5% w / w to about 20 % w / w, about 5 % w / w to about 10 % w / w, about 10% w / w to about 30 % w / w, about 10 % w / w to about 20 % w / w, about 10% w / w to about 15 % w / w, about 15% w / w to about 30 % w / w, about 15% w / w to about 20 % w / w, about 20% w / w to about 30 % w / w, about 20% w / w to about 25 % w / w, or about 25% w / w to about 30 % w / w. In embodiments, the mucoadhesive agent is present in an amount of about 1% w / w to about 5% w / w. In embodiments, the mucoadhesive agent is present in an amount of about 0.5% w / w, about 0.6% w / w, about 0.7% w / w, about 0.8% w / w, about 0.9% w / w, about 1% w / w, about 2% w / w, about 3% w / w, about 4% w / w, about 5% w / w, about 6% w / w, about 7% w / w, about 8% w / w, about 9% w / w, about 10% w / w, about 11% w / w, about 12% w / w, about 13% w / w, about 14% w / w, about 15% w / w, about 16% w / w, about 17% w / w, about 18% w / w, about 19% w / w, about 20% w / w, about 21% w / w, about 22% w / w, about 23% w / w, about 24% w / w, about 25% w / w, about 26% w / w, about 27% w / w, about 28% w / w, about 29% w / w, or about 30% w / w, including all ranges and values in between. 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374

[0342] In embodiments, the mucoadhesive dosage forms have a mucoadhesive strength of at least about 50 dynes / cm2, e.g. about 50 dynes / cm2, about 75 dynes / cm2, about 100 dynes / cm2, about 150 dynes / cm2, about 200 dynes / cm2, about 250 dynes / cm2, about 300 dynes / cm2, about 350 dynes / cm2, about 400 dynes / cm2, about 450 dynes / cm2, about 500 dynes / cm2, about 550 dynes / cm2, about 600 dynes / cm2, about 650 dynes / cm2, about 700 dynes / cm2, about 750 dynes / cm2, about 800 dynes / cm2, about 850 dynes / cm2, about 900 dynes / cm2, about 950 dynes / cm2, or about 1000 dynes / cm2, including all ranges and values in between. In embodiments, the mucoadhesive dosage forms have a mucoadhesive strength greater than about 1000 dynes / cm2. In embodiments, the dosage form has a mucoadhesive peak force greater than about 50 g, about 100 g, about 200 g, about 300 g, about 400 g, about 500g, about 600g, about 700 g, about 800 g, about 900 g, about 1000 g, about 1100 g, about 1200 g, about 1300 g, about 1400 g or about 1500 g. In embodiments, the dosage form has a mucoadhesive peak force of about 50 g, about 100 g, about 200 g, about 300 g, about 400 g, about 500g, about 600g, about 700 g, about 800 g, about 900 g, about 1000 g, about 1100 g, about 1200 g, about 1300 g, about 1400 g or about 1500 g, including all ranges and values in between.

[0343] In embodiments, suitable mucoadhesive agents as used in the present disclosure include but are not limited to polyacrylic acid polymers (such as carbomers (e.g. with low viscosity), polycarbophil etc), methacrylic acid polymers, cellulose derivatives such as hydroxyethyl cellulose, (HEC), hydroxypropyl cellulose (HPC-such as lower viscosity grades of MW <150K daltons), ethyl hydroxyethyl cellulose, hydroxypropyl methylcellulose (HPMC-such as grades with lower viscosity like K100L or 4000cps or less), methyl cellulose, sodium carboxymethyl cellulose, thiolated carboxymethyl cellulose; polysaccharides (such as chitosan, pectin etc); xanthan gum, karaya gum, tragacanth gum; propylene glycol, propylene glycol alginate, sodium alginate, polyethylene oxide (PEO), microcrystalline cellulose (Avicel), croscarmellose, poloxamers (i.e. nonionic triblock copolymers composed of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene; e.g. Poloxamer 407) and mixtures thereof.

[0344] In embodiments, the excipients or carriers for inclusion in oromucosal dosage forms are selected from the group consisting of disintegrants, fillers / diluents (matrix forming agents), binders, glidants, lubricants, plasticizers, pH regulators, coloring agents, flavoring agents, taste 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 masking agents, viscosity enhancers, sweetening agents and combinations thereof. Carriers which readily dissolve in saliva are preferred.

[0345] In embodiments, examples of suitable disintegrants as used in the present disclosure include but are not limited to cross-linked polyvinyl pyrrolidone, low-substituted hydroxypropyl cellulose, carboxymethyl starch, natural starch, carboxymethyl starch, sodium starch glycolate, pregelatinized starch, dextrins, and other modified starches (starches whose hydroxyl groups have been esterified, hydroxypropyl di-starch phosphate, an enzymatically modified starch, a pregelatinized di-starch phosphate, hydroxyethyl starch, hydroxypropyl starch, a pregelatinized acetylated di-starch phosphate and a pregelatinized purified starch); carboxymethylcellulose calcium, carboxymethylcellulose sodium (or croscarmellose sodium), microcrystalline cellulose, cellulose gum and mixtures thereof. In embodiments, the amount of disintegrant present in the dosage form may range from about 1% w / w to about 5% w / w. For example, the amount of disintegrant present in the dosage form may range from about 1% w / w to about 5% w / w, about 1% w / w to about 4% w / w, about 1% w / w to about 3% w / w, about 1% w / w to about 2% w / w, about 2% w / w to about 5% w / w, about 2% w / w to about 4% w / w, about 2% w / w to about 3% w / w, about 3% w / w to about 5% w / w, about 3% w / w to about 4% w / w or about 4% w / w to about 5% w / w. In embodiments, the disintegrant is present in an amount of about 1% w / w, about 2% w / w, about 3% w / w, about 4% w / w, or about 5% w / w. In embodiments, the disintegrant is present in an amount of about 1% w / w. In embodiments, the disintegrant is present in an amount of about 2% w / w. In embodiments, the disintegrant is present in an amount of about 3% w / w. In embodiments, the disintegrant is present in an amount of about 4% w / w. In embodiments, the disintegrant is present in an amount of about 5% w / w.

[0346] In embodiments, examples of suitable diluents / fillers (also called as matrix forming agents) include but are not limited to materials derived from animal or vegetable proteins, such as mammalian gelatin, non-mammalian gelatins, fish gelatin (e.g. high molecular weight gelatin in which more than 50%, more than 60%, or more than 70% of the molecular weight distribution of the gelatin is greater than 30,000 daltons); a standard molecular weight gelatin in which more than substantially 50%, preferably more than 60% and most preferably more than 70% of the molecular weight distribution of the gelatin is below than 30,000 daltons and combinations may be formed wherein the ratio of high molecular weight gelatin to standard 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 molecular weight gelatin (HMW:SMW) ranges substantially from 1:1 to 1:9), dextrins and soy, wheat and psyllium seed proteins; gums such as acacia, guar, agar, and xanthan; polysaccharides; alginates; carboxymethylcelluloses; carrageenans; dextrans; pectins; synthetic polymers such as polyvinylpyrrolidone; and polypeptide / protein or polysaccharide complexes such as gelatin-acacia complexes, starch, mannitol, dicalcium phosphate, potassium sulfate, microcrystalline cellulose, dextrose, lactose, galactose and trehalose; cyclic sugars such as cyclodextrin; inorganic salts such as sodium phosphate, sodium chloride and aluminum silicates; and amino acids having from 2 to 12 carbon atoms such as a glycine, L-alanine, L- aspartic acid, L-glutamic acid, L-hydroxyproline, L-isoleucine, L-leucine and L-phenylalanine and mixtures thereof. In embodiments, the diluents / fillers (or matrix forming agent) are present in a range from about 1% to about 50% w / w of the dosage form. For example, the amount of diluents / fillers present in the dosage form may range from about 1% w / w to about 50% w / w, about 1% w / w to about 20% w / w, about 1% w / w to about 10% w / w, about 1% w / w to about 5% w / w, about 5% w / w to about 50% w / w, about 5% w / w to about 25% w / w, about 5% w / w to about 15% w / w, about 5% w / w to about 10% w / w, about 10% w / w to about 50% w / w, about 10% w / w to about 40% w / w, about 10% w / w to about 30% w / w, about 10% w / w to about 20% w / w, about 10% w / w to about 15% w / w, about 20% w / w to about 50% w / w, about 20% w / w to about 40% w / w, about 20% w / w to about 30% w / w, about 20% w / w to about 25% w / w, about 30% w / w to about 50% w / w, about 30% w / w to about 40% w / w, about 30% w / w to about 35% w / w, about 40% w / w to about 50% w / w, or about 40% w / w to about 45% w / w. In embodiments, the diluents / fillers are present in an amount of about 1% w / w, about 2% w / w, about 3% w / w, about 4% w / w, about 5% w / w, about 6% w / w, about 7% w / w, about 8% w / w, about 9% w / w, about 10% w / w, about 15% w / w, about 20% w / w, about 25% w / w, about 30% w / w, about 35% w / w, about 40% w / w, about 45% w / w, or about 50% w / w, including all ranges and values in between.

[0347] In embodiments, examples of suitable binders include but are not limited to starch, pregelatinized starch, PVP (polyvinylpyrrolidone), polyethylene oxide, polyethylene glycol, acacia, alginic acid, tragacanth, sucrose, guar gum, bentonite, cellulose derivatives, such as hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC) and carboxymethyl cellulose (CMC) and their salts; and mixtures thereof. In embodiments, the binder is present in a range from about 0% to about 20% w / w of the dosage form. For example, the amount of binder present in the dosage form may range from about 1% w / w to 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 about 20% w / w, about 1% w / w to about 10% w / w, about 1% w / w to about 5% w / w, about 5% w / w to about 20% w / w, about 5% w / w to about 15% w / w, about 5% w / w to about 10% w / w, about 10% w / w to about 20% w / w, or about 10% w / w to about 15% w / w. In embodiments, the binder is present in an amount of about 1% w / w, about 2% w / w, about 3% w / w, about 4% w / w, about 5% w / w, about 6% w / w, about 7% w / w, about 8% w / w, about 9% w / w, about 10% w / w, about 11% w / w, about 12% w / w, about 13% w / w, about 14% w / w, about 15% w / w, about 16% w / w, about 17% w / w, about 18% w / w, about 19% w / w, or about 20% w / w, including all ranges and values in between.

[0348] In embodiments, examples of suitable glidants are selected from group comprising calcium phosphate, calcium silicate, powdered cellulose, magnesium silicate, magnesium trisilicate, talc, colloidal silicon dioxide, silica gel, precipitated silica and mixtures thereof. In embodiments, the glidant is present in a range from about 0% to about 5% w / w of the dosage form. For example, the amount of glidant present in the dosage form may range from about 0.1% w / w to about 5% w / w, about 0.1% w / w to about 3% w / w, about 0.1% w / w to about 1% w / w, about 0.5% w / w to about 5% w / w, about 0.5% w / w to about 3% w / w, about 0.5% w / w to about 1% w / w, about 1% w / w to about 5% w / w, about 1% w / w to about 4% w / w, about 1% w / w to about 3% w / w, about 1% w / w to about 2% w / w, about 2% w / w to about 5% w / w, about 2% w / w to about 4% w / w, about 2% w / w to about 3% w / w, about 3% w / w to about 5% w / w, about 3% w / w to about 4% w / w or about 4% w / w to about 5% w / w. In embodiments, the glidant is present in an amount of about 0% w / w, about 0.1% w / w, about 0.2% w / w, about 0.3% w / w, about 0.4% w / w, about 0.5% w / w, about 0.6% w / w, about 0.7% w / w, about 0.8% w / w, about 0.9% w / w, about 1% w / w, about 2% w / w, about 3% w / w, about 4% w / w, or about 5% w / w, including all ranges and values in between.

[0349] In embodiments, examples of suitable lubricants include but are not limited to magnesium stearate, calcium stearate, stearic acid, talc, sodium fumarate stearate, sucrose fatty acid esters, aluminum stearate, potassium sodium tartrate, light silicic anhydride, carnauba wax, carmellose calcium, carmellose sodium, hydrated silicon dioxide, hydrogenated oil, hydrogenated rapeseed oil, and mixtures thereof. In embodiments, the lubricant is present in a range from about 0% to about 3% w / w of the dosage form. For example, the amount of lubricant present in the dosage form may range from about 0.1% w / w to about 3% w / w, about 0.1% w / w to about 2% w / w, about 0.1% w / w to about 1% w / w, about 0.5% w / w to about 3% 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 w / w, about 0.5% w / w to about 2% w / w, about 0.5% w / w to about 1% w / w, about 1% w / w to about 3% w / w, about 1% w / w to about 2% w / w, or about 2% w / w to about 3% w / w. In embodiments, the lubricant is present in an amount of about 0% w / w, about 0.1% w / w, about 0.2% w / w, about 0.3% w / w, about 0.4% w / w, about 0.5% w / w, about 0.6% w / w, about 0.7% w / w, about 0.8% w / w, about 0.9% w / w, about 1% w / w, about 2% w / w, or about 3% w / w, including all ranges and values in between.

[0350] In embodiments, examples of suitable plasticizers include but are not limited to macrogol, triethyl citrate, acetylated monoglyceride, glycerin, monoacetin, diacetin triacetin, phthalate derivatives like dimethyl, diethyl and dibutyl phthalate polysorbate 80, and propylene glycol, 1,2,3-propanetiol triacetate, hydrogenated starch hydrolysates, corn syrups, distilled acetylated monoglycerides, castor oil derivatives thereof sucrose acetate isobutyrate, and mixtures thereof. In embodiments, the plasticizer is present in a range from about 0% to about 10% w / w of the dosage form. For example, the amount of glidant present in the dosage form may range from about 0.1% w / w to about 10% w / w, about 0.1% w / w to about 5% w / w, about 0.1% w / w to about 3% w / w, about 0.1% w / w to about 1% w / w, about 0.5% w / w to about 10% w / w, about 0.5% w / w to about 5% w / w, about 0.5% w / w to about 3% w / w, about 0.5% w / w to about 1% w / w, about 1% w / w to about 10% w / w, about 1% w / w to about 5% w / w, about 1% w / w to about 4% w / w, about 1% w / w to about 3% w / w, about 1% w / w to about 2% w / w, about 2% w / w to about 10% w / w, about 2% w / w to about 5% w / w, about 2% w / w to about 4% w / w, about 2% w / w to about 3% w / w, about 3% w / w to about 10% w / w, about 3% w / w to about 5% w / w, about 3% w / w to about 4% w / w, about 4% w / w to about 10% w / w, about 4% w / w to about 5% w / w, or about 5% w / w to about 10% w / w. In embodiments, the plasticizer is present in an amount of about 0% w / w, about 0.1% w / w, about 0.2% w / w, about 0.3% w / w, about 0.4% w / w, about 0.5% w / w, about 0.6% w / w, about 0.7% w / w, about 0.8% w / w, about 0.9% w / w, about 1% w / w, about 2% w / w, about 3% w / w, about 4% w / w, about 5% w / w, about 6% w / w, about 7% w / w, about 8% w / w, about 9% w / w, or about 10% w / w, including all ranges and values in between.

[0351] In embodiments, examples of suitable pH regulators include but are not limited to inorganic acid (e.g., hydrochloric acid, sulfuric acid, phosphoric acid), an inorganic base (e.g., sodium hydroxide, potassium hydroxide, calcium hydroxide), an organic acid (e.g., citric acid, acetic acid, tartaric acid, succinic acid, boric acid, edetic acid, glucuronic acid, glutaric acid, 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 malic acid, formic acid, gluconic acid, ascorbic acid or fatty acids), and / or an organic base (e.g., ethanolamine, triethanolamine) or mixtures thereof. In embodiments, the pH regulator is present in a range from about 0% to about 2% w / w of the dosage form. For example, the amount of pH regulator present in the dosage form may range from about 0.1% w / w to about 2% w / w, about 0.1% w / w to about 1% w / w, about 0.5% w / w to about 2% w / w, about 0.5% w / w to about 1% w / w, or about 1% w / w to about 2% w / w. In embodiments, pH regulator is present in an amount of about 0% w / w, about 0.1% w / w, about 0.2% w / w, about 0.3% w / w, about 0.4% w / w, about 0.5% w / w, about 0.6% w / w, about 0.7% w / w, about 0.8% w / w, about 0.9% w / w, about 1% w / w, or about 2% w / w, including all ranges and values in between.

[0352] In embodiments, examples of suitable coloring agents include but are not limited to food, drug, and cosmetic (FD&C) dyes (FD&C blue, FD&C green, FD&C red, FD&C yellow, FD&C lake), ponceau, indigo drug & cosmetic (D&C) blue, indigo Carmine; iron oxides (e.g. red iron oxide, yellow, black), quinoline yellow, flame red, brilliant red (carmine), carmoisine, sunset yellow and mixtures thereof. In embodiments, the amount of coloring used ranges from about 0% to about 3 % w / w of the dosage form. For example, the amount of coloring agent present in the dosage form may range from about 0.1% w / w to about 3% w / w, about 0.1% w / w to about 2% w / w, about 0.1% w / w to about 1% w / w, about 0.5% w / w to about 3% w / w, about 0.5% w / w to about 2% w / w, about 0.5% w / w to about 1% w / w, about 1% w / w to about 3% w / w, about 1% w / w to about 2% w / w, or about 2% w / w to about 3% w / w. In embodiments, the coloring agent is present in an amount of about 0% w / w, about 0.1% w / w, about 0.2% w / w, about 0.3% w / w, about 0.4% w / w, about 0.5% w / w, about 0.6% w / w, about 0.7% w / w, about 0.8% w / w, about 0.9% w / w, about 1% w / w, about 2% w / w, or about 3% w / w, including all ranges and values in between.

[0353] In embodiments, examples of suitable flavoring agents include but are not limited to strawberry, apple, pear, peach, plum, orange, pineapple, apricot, lemon, peppermint, black currant, banana, raspberry, raspberry aroma, wild berries, caramel, mint, licorice, grapefruit, caramel, vanilla, cherry and grape flavor, flavoring oils such as cinnamon oil, wintergreen oil, peppermint oil, clove oil, bay oil, anise oil, eucalyptus oil, thyme oil, cedar leave oil, nutmeg oil, sage oil, bitter almond oil and cassia oil and mixtures thereof. In embodiments, the amount of flavoring agent used ranges from about 0% to about 3 % w / w of the dosage form. For example, the amount of flavoring agent present in the dosage form may range from about 0.1% 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 w / w to about 3% w / w, about 0.1% w / w to about 2% w / w, about 0.1% w / w to about 1% w / w, about 0.5% w / w to about 3% w / w, about 0.5% w / w to about 2% w / w, about 0.5% w / w to about 1% w / w, about 1% w / w to about 3% w / w, about 1% w / w to about 2% w / w, or about 2% w / w to about 3% w / w. In embodiments, the flavoring agent is present in an amount of about 0% w / w, about 0.1% w / w, about 0.2% w / w, about 0.3% w / w, about 0.4% w / w, about 0.5% w / w, about 0.6% w / w, about 0.7% w / w, about 0.8% w / w, about 0.9% w / w, about 1% w / w, about 2% w / w, or about 3% w / w, including all ranges and values in between.

[0354] In embodiments, suitable taste-masking agents include sodium bicarbonate, ion- exchange resins, cyclodextrin inclusion compounds, adsorbates or microencapsulated actives. In embodiments, the amount of taste-masking agent used ranges from about 0% to about 10 % w / w of the dosage form. For example, the amount of taste-masking agent present in the dosage form may range from about 0.1% w / w to about 10% w / w, about 0.1% w / w to about 5% w / w, about 0.1% w / w to about 3% w / w, about 0.1% w / w to about 1% w / w, about 0.5% w / w to about 10% w / w, about 0.5% w / w to about 5% w / w, about 0.5% w / w to about 3% w / w, about 0.5% w / w to about 1% w / w, about 1% w / w to about 10% w / w, about 1% w / w to about 5% w / w, about 1% w / w to about 4% w / w, about 1% w / w to about 3% w / w, about 1% w / w to about 2% w / w, about 2% w / w to about 10% w / w, about 2% w / w to about 5% w / w, about 2% w / w to about 4% w / w, about 2% w / w to about 3% w / w, about 3% w / w to about 10% w / w, about 3% w / w to about 5% w / w, about 3% w / w to about 4% w / w, about 4% w / w to about 10% w / w, about 4% w / w to about 5% w / w, or about 5% w / w to about 10% w / w. In embodiments, the taste-masking agent is present in an amount of about 0% w / w, about 0.1% w / w, about 0.2% w / w, about 0.3% w / w, about 0.4% w / w, about 0.5% w / w, about 0.6% w / w, about 0.7% w / w, about 0.8% w / w, about 0.9% w / w, about 1% w / w, about 2% w / w, about 3% w / w, about 4% w / w, about 5% w / w, about 6% w / w, about 7% w / w, about 8% w / w, about 9% w / w, or about 10% w / w, including all ranges and values in between.

[0355] In embodiments, suitable viscosity enhancers include but are not limited to polymers, sugars, sugar alcohols, gums, clays, silicas, and the like. In embodiments, the amount of viscosity enhancers used ranges from about 0% to about 65% w / w of the dosage form. For example, the amount of viscosity enhancers present in the dosage form may range from about 0.1% w / w to about 65% w / w, about 0.1% w / w to about 50% w / w, about 0.1% w / w to about 20% w / w, about 0.1% w / w to about 10% w / w, about 0.1% w / w to about 5% w / w, about 5% 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 w / w to about 65% w / w, about 5% w / w to about 50% w / w, about 5% w / w to about 25% w / w, about 5% w / w to about 15% w / w, about 5% w / w to about 10% w / w, about 10% w / w to about 65% w / w, about 10% w / w to about 50% w / w, about 10% w / w to about 40% w / w, about 10% w / w to about 30% w / w, about 10% w / w to about 20% w / w, about 10% w / w to about 15% w / w, about 20% w / w to about 65% w / w, about 20% w / w to about 50% w / w, about 20% w / w to about 40% w / w, about 20% w / w to about 30% w / w, about 20% w / w to about 25% w / w, about 30% w / w to about 65% w / w, about 30% w / w to about 50% w / w, about 30% w / w to about 40% w / w, about 30% w / w to about 35% w / w, about 40% w / w to about 65% w / w, about 40% w / w to about 50% w / w, about 40% w / w to about 45% w / w, about 50% w / w to about 65% w / w, about 50% w / w to about 60% w / w, or about 50% w / w to about 55% w / w. In embodiments, the viscosity enhancer is present in an amount of about 0% w / w, about 0.1% w / w, about 0.2% w / w, about 0.3% w / w, about 0.4% w / w, about 0.5% w / w, about 0.6% w / w, about 0.7% w / w, about 0.8% w / w, about 0.9% w / w, about 1% w / w, about 2% w / w, about 3% w / w, about 4% w / w, about 5% w / w, about 6% w / w, about 7% w / w, about 8% w / w, about 9% w / w, about 10% w / w, about 15% w / w, about 20% w / w, about 25% w / w, about 30% w / w, about 35% w / w, about 40% w / w, about 45% w / w, about 50% w / w, about 55% w / w, about 60% w / w, or about 65% w / w, including all ranges and values in between.

[0356] In embodiments, examples of suitable sweetening agents include but are not limited to fructose, sucrose, glucose, maltose, sorbitol, erythritol, xylitol, aspartame, stevia extract, glycyrrhiza, mogroside, sodium cyclamate, saccharine, saccharine sodium, acesulfame, dextrose, sucralose, monosodium glycyrrhizinate, monoamonium glycyrrhizinate, isomalt, glycerine, dipotassium glycyrrhizinate, thaumatin and mixtures thereof. In embodiments, the amount of sweetening agent ranges from about 0.5 to about 2 % w / w of the dosage form. For example, the amount of sweetening agents present in the dosage form may range from about 0.5% w / w to about 2% w / w, about 0.5% w / w to about 1% w / w, or about 1% w / w to about 2% w / w. In embodiments, the sweetening agents are present in an amount of about 0.5% w / w, about 0.6% w / w, about 0.7% w / w, about 0.8% w / w, about 0.9% w / w, about 1% w / w, or about 2% w / w, including all ranges and values in between.

[0357] In embodiments, the present disclosure provides an oromucosal dosage form comprising: 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 (i) therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof; (ii) one or more mucoadhesive agents; and (iii) one or more pharmaceutically acceptable excipients or carriers, wherein the dosage form disintegrates in not less than about 1 minute upon contact with an oral mucosa. In embodiments, the dosage form is lyophilized (freeze-dried).

[0358] In embodiments, the mucoadhesive is sodium alginate. In embodiments, the mucoadhesive is a carbomer.

[0359] In embodiments, there is provided an oromucosal (e.g., sublingual or buccal or gingival) lyophilized tablet comprising: (i) therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof; (ii) sodium alginate; (iii) croscarmellose sodium or sodium starch glycolate; (iv) sucralose; (v) magnesium stearate; (vi) lactose monohydrate and (vii) optionally other pharmaceutical acceptable excipients. In embodiments, the tablet disintegrates in more than about 1 minute upon contact with an oral mucosa.

[0360] In embodiments, there is provided an oromucosal (e.g., sublingual or buccal or gingival) lyophilized tablet comprising: (i) therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof; (ii) sodium alginate (iii) croscarmellose sodium or sodium starch glycolate; (iv) sucralose; (v) silicon dioxide; (vi) mannitol and (vii) optionally other pharmaceutical acceptable excipients. In embodiments, the tablet disintegrates in more than about 1 minute upon contact with an oral mucosa.

[0361] In embodiments, there is provided an oromucosal (e.g., sublingual or buccal or gingival) lyophilized tablet comprising: (i) therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof; (ii) carbomer; (iii) croscarmellose sodium or sodium starch glycolate; (iv) sucralose; (v) magnesium stearate; (vi) mannitol and (vii) optionally other pharmaceutical acceptable excipients. In embodiments, the tablet disintegrates in not less than about 1 minute upon contact with an oral mucosa.

[0362] In embodiments, there is provided an oromucosal (e.g., sublingual or buccal) lyophilized tablet comprising: (i) therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof; (ii) carbomer; (iii) croscarmellose sodium or sodium 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 starch glycolate; (iv) sucralose; (v) silicon dioxide; (vi) lactose monohydrate and (vii) optionally other pharmaceutical acceptable excipients. In embodiments, the tablet disintegrates in not less than about 1 minute upon contact with an oral mucosa.

[0363] In embodiments, the mucoadhesive is xanthan gum.

[0364] In embodiments, there is provided an oromucosal (e.g., sublingual or buccal) lyophilized tablet comprising: (i) therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof; (ii) xanthan gum; (iii) croscarmellose sodium or sodium starch glycolate; (iv) sucralose; (v) magnesium stearate; (vi) lactose monohydrate and (vii) optionally other pharmaceutical acceptable excipients. In embodiments, the tablet disintegrates in not less than about 1 minute upon contact with an oral mucosa.

[0365] In embodiments, there is provided an oromucosal (e.g., sublingual or buccal) lyophilized tablet comprising: (i) therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof; (ii) xanthan gum; (iii) croscarmellose sodium or sodium starch glycolate; (iv) sucralose; (v) silicon dioxide; (vi) mannitol and (vii) optionally other pharmaceutical acceptable excipients. In embodiments, the tablet disintegrates in not less than about 1 minute upon contact with an oral mucosa.

[0366] In embodiments, the dosage form is a sublingual tablet and is elliptical or oval. In embodiments, the dosage form is a buccal tablet and is oval in shape. In embodiments, the dosage form is used for the treatment of agitation. In embodiments, the dosage form is used in reducing noradrenergic hyperarousal. In embodiments, the dosage form is used for the treatment of depression.

[0367] In embodiments, the present disclosure provides an oromucosal tablet dosage form comprising: (i) a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof; (ii) one or more mucoadhesive agents; and (iii) one or more pharmaceutically acceptable excipients or carriers.

[0368] In embodiments, the tablet disintegrates in not less than about 1 minute upon contact with an oral mucosa. 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374

[0369] In embodiments, the present disclosure provides an oromucosal tablet dosage form comprising: (i) a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof; (ii) one or more mucoadhesive agents; and (iii) one or more pharmaceutically acceptable excipients or carriers.

[0370] In embodiments, the tablet disintegrates in not less than about 1 minute upon contact with an oral mucosa.

[0371] In embodiments, the present disclosure provides an oromucosal dosage form comprising: (i) a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof; (ii) a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof; (iii) one or more mucoadhesive agents; and (iv) one or more pharmaceutically acceptable excipients or carriers.

[0372] In embodiments, the tablet disintegrates within about 5 seconds to about 10 minutes upon contact with an oral mucosa.

[0373] In embodiments, the dosage form is lyophilized (freeze dried).

[0374] In embodiments, the dosage form is used for the treatment of disorders associated with noradrenergic hyperarousal. In embodiments, the dosage form is used for the treatment of ASD. In embodiments, the dosage form is used for the prevention of PTSD thereof. In embodiments, the dosage form is used for the treatment of autism spectrum disorders. In embodiments, the dosage form is used for the treatment of agitation caused by noradrenergic hyperarousal. In embodiments, the agitation is treated in a subject without causing significant sedation. In embodiments, the dosage form is used for the treatment of depression in a subject. In embodiments, the present disclosure provides an oromucosal (sublingual or buccal) lyophilized tablet comprising (i) a therapeutically effective amount of latrepirdine or a pharmaceutically 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 acceptable salt thereof; (ii) a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof; (iii) sodium alginate, xanthan gum, carbomer, hydroxypropyl cellulose, hydroxypropyl methylcellulose, or polyethylene oxide; (iv) croscarmellose sodium or sodium starch glycolate; (v) sucralose; (vi) magnesium stearate and / or silicon dioxide; (vii) lactose or mannitol; and (viii) optionally other pharmaceutical acceptable excipients. In embodiments, the tablet disintegrates in not less than about 1 minute upon contact with an oral mucosa.

[0375] In embodiments, the oromucosal tablet comprises about 5 micrograms to about 300 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof and about 0.1 mg to about 100 mg of latrepirdine per unit. In embodiments, the oromucosal tablet comprises about 10 micrograms to 240 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g. about 30 micrograms, about 60 micrograms, about 90 micrograms, about 120 micrograms, 180 micrograms, about 210 micrograms or about 240 micrograms, including all ranges and values in between) and about 1 mg to about 50 mg of latrepirdine or a pharmaceutically acceptable salt thereof per unit (e.g. about 5mg, about 10mg, about 15mg, about 20 mg, about 25mg, about 30 mg, about 35mg, about 40 mg, about 45 mg or about 50 mg, including all ranges and values in between).

[0376] In embodiments, the tablet is administered sublingually, buccally or gingivally. In embodiments, the dosage form is administered via a single dosage form or via multiple dosage forms. IV. Methods and Administration

[0377] In embodiments, the present disclosure provides a method of reducing noradrenergic hyperarousal in a human subject, comprising administering to the subject a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof, optionally in combination with a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0378] In embodiments, the present disclosure provides a method of reducing noradrenergic hyperarousal in a human subject, comprising administering orally to the subject a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof, 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 optionally in combination with a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0379] In embodiments, the present disclosure provides a method of treating a disorder associated with noradrenergic hyperarousal in a human subject, comprising administering to the human subject a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof, optionally in combination with a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0380] In embodiments, the disorder is acute stress disorder.

[0381] In embodiments, the human subject has one or more symptoms associated with acute stress disorder selected from the group consisting of: anxiety, a sleep disorder, exaggerated startle response, irritability, inability to stop moving or sit still, lack of motivation, or agitation.

[0382] In embodiments, the symptom is anxiety.

[0383] In embodiments, the symptom is a sleep disorder.

[0384] In embodiments, the symptom is exaggerated startle response.

[0385] In embodiments, the symptom is irritability.

[0386] In embodiments, the symptom is an inability to stop moving or sit still.

[0387] In embodiments, the symptom is a lack of motivation.

[0388] In embodiments, the symptom is agitation.

[0389] In embodiments, disorder of the human subject is autism spectrum disorder.

[0390] In embodiments, the method prevents the disorder from developing into post-traumatic stress disorder.

[0391] In embodiments, the disorder is caused by a traumatic event experienced by the human subject. 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374

[0392] In embodiments, latrepirdine is administered within 1 week, 2 weeks or 4 weeks of the traumatic event.

[0393] In embodiments, latrepirdine is administered within 3 days of the traumatic event. In embodiments, latrepirdine is administered within 1 day of the traumatic event. In embodiments, latrepirdine is administered within 4 hours of the traumatic event. In embodiments, latrepirdine is administered within 6 hours of the traumatic event. In embodiments, latrepirdine is administered within 12 hours of the traumatic event.

[0394] In embodiments, latrepirdine is administered once a day, twice a day or thrice a day.

[0395] In embodiments, the therapeutically effective amount of latrepirdine is in the range from about 5 mg to about 300 mg daily. In embodiments, the therapeutically effective amount of latrepirdine is in the range from about 10 mg to about 200 mg daily. In embodiments, the therapeutically effective amount of latrepirdine is in the range from about 10 mg to about 100 mg daily. In embodiments, the therapeutically effective amount of latrepirdine is in the range from about 10 mg to about 80 mg daily. In embodiments, the therapeutically effective amount of latrepirdine is in the range from about 15 mg to about 60 mg daily. In embodiments, the therapeutically effective amount of latrepirdine is in the range from about 30 mg to about 45 mg daily.

[0396] In embodiments, the therapeutically effective amount of latrepirdine is divided evenly for administration either twice daily or three times daily.

[0397] In embodiments, the latrepirdine or a pharmaceutically acceptable salt thereof is administered in combination with a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof simultaneously, sequentially, or intermittently.

[0398] In embodiments, the present disclosure provides preclinical animal models established to correlate noradrenergic signaling with psychiatric conditions such as acute stress disorder, PTSD, depression, substance withdrawal, substance use craving, agitation, panic disorders, and anxiety.

[0399] In embodiments, the preclinical animal models include the resident intruder assay, a forced swim test, yohimbine-induced anxiety models, and CCK-induced panic models. 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374

[0400] In embodiments, the preclinical animal model is resident intruder assay and latrepirdine treatment reduces the aggression in response to social intrusion.

[0401] In embodiments, the preclinical animal model is CCK-induced panic model wherein when rodents are administered CCK, they become panicky, or anxious, and will avoid leaving the closed arms of a maze. In embodiments, on latrepirdine administration the rodents leave the closed arms and explore the open arms, indicating they are less anxious. In embodiments, CCK also induces panic in healthy human volunteers as well indicating this is a translatable model.

[0402] In embodiments, the preclinical animal models surprisingly demonstrated that latrepirdine unexpectedly reduced the magnitude of the symptoms in stress-related psychiatric conditions including acute stress disorder, PTSD, depression, substance withdrawal, substance use craving, agitation, panic disorders, and anxiety.

[0403] In embodiments, the preclinical models correlated noradrenergic signaling with ADHD.

[0404] In embodiments, the methods described herein reduce the magnitude of symptoms the patients experience and improves their clinical outcomes due to enhanced compliance with underlying therapeutic treatments, including adhering to medication regimens and participating in therapy.

[0405] In embodiments, the improved clinical outcomes arise because patients with reduced symptoms interact more effectively in social settings, mitigating aggressive and panic symptoms that might result from lack of social interaction, as seen in conditions like autism spectrum disorder.

[0406] In embodiments, that the methods described herein provide effective symptom management to prevent conditions from deteriorating, as might be the case when acute stress disorder progresses to PTSD.

[0407] In embodiments, the present disclosure provides that latrepirdine treats and prevents the exacerbation of disorders such as acute stress disorder and autism spectrum disorder over time. 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374

[0408] In embodiments, the present disclosure provides a method of treating ASD in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0409] In embodiments, the present disclosure provides a method of treating ASD in a subject in need thereof, comprising administering to the subject as a monotherapy a dosage form comprising therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0410] In embodiments, the present disclosure provides a method of treating ASD in a subject in need thereof, comprising administering orally to the subject as a monotherapy a dosage form comprising therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0411] In embodiments, the present disclosure provides a method of preventing PTSD in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof. In embodiments, the present disclosure provides a method of preventing PTSD in a subject in need thereof, comprising administering orally to the subject a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0412] In embodiments, the present disclosure provides a method of treating ASD after traumatic event in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0413] In embodiments, the present disclosure provides a method of treating ASD in a subject in need thereof, comprising administering oromucosally (e.g. sublingually, buccally, or gingivally) to the subject a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0414] In embodiments, the present disclosure provides a method of increasing the resilience against development of PTSD in a subject after a traumatic event, comprising administering oromucosally (e.g. sublingually, buccally, or gingivally) to the subject a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374

[0415] In embodiments, the present disclosure provides a method of treating ASD in a subject in need thereof, comprising administering to the subject a dosage form comprising about 10 mg to about 100 mg (including all ranges and values in between) of latrepirdine or a pharmaceutically acceptable salt thereof.

[0416] In embodiments, about 10 mg to about 40 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered once, twice or thrice a day. In embodiments, about 20 mg to about 80 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered once, twice or thrice a day.

[0417] In embodiments, a total daily dose of about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered to the subject. In embodiments, a total daily dose of about 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered to the subject. In embodiments, a total daily dose of about 40 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered to the subject. In embodiments, a total daily dose of about 60 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered to the subject.

[0418] In embodiments, a dosage form comprising latrepirdine or a pharmaceutically acceptable salt thereof is administered just after the traumatic event. In embodiments, a dosage form comprising latrepirdine or a pharmaceutically acceptable salt thereof is administered within 1 minute to 48 hours (including all ranges and values in between) post traumatic event. In embodiments, a dosage form comprising latrepirdine or a pharmaceutically acceptable salt thereof is administered within 24 hours of the traumatic event. In embodiments, a dosage form comprising latrepirdine or a pharmaceutically acceptable salt thereof is administered within 48 hours of the traumatic event. In embodiments, a dosage form comprising latrepirdine or a pharmaceutically acceptable salt thereof is administered within 1 hour of the traumatic event (or before the onset of ASD). In embodiments, the administration of latrepirdine is continued for up to 4 weeks. In embodiments, a dosage form comprising latrepirdine or a pharmaceutically acceptable salt thereof is administered in a single or multiple units.

[0419] In embodiments, the present disclosure provides a method of treating ASD in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof. In embodiments, the present 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 disclosure provides a method of treating ASD in a subject in need thereof, comprising administering orally to the subject a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0420] In embodiments, the present disclosure provides a method of preventing PTSD in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof. In embodiments, the present disclosure provides a method of preventing PTSD in a subject in need thereof, comprising administering orally to the subject a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0421] In embodiments, the present disclosure provides a method of treating ASD in a subject in need thereof, comprising administering oromucosally (e.g. sublingually, buccally, or gingivally) to the subject a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0422] In embodiments, the present disclosure provides a method of treating ASD after traumatic event in a subject in need thereof, comprising administering oromucosally (e.g. sublingually, buccally, or gingivally) to the subject a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0423] In embodiments, the present disclosure provides a method of increasing the resilience against development of PTSD in a subject after a traumatic event, comprising administering oromucosally (e.g. sublingually, buccally, or gingivally) to the subject a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0424] In embodiments, a dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof is administered just after the traumatic event. In embodiments, a dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof is administered within 1 minute to 48 hours (including all ranges and values in between) post traumatic event. In embodiments, a dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof is administered within 1 hour of the traumatic event (or before the onset of ASD). In embodiments, a dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof is administered within 24 hours of the traumatic event (or before the onset of ASD). In embodiments, the administration of dexmedetomidine 94 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 is continued for up to 4 weeks. In embodiments, a dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in a single or multiple units.

[0425] In embodiments, about 10 micrograms to about 300 micrograms (including all ranges and values in between) of dexmedetomidine or a pharmaceutically acceptable salt thereof is administered to the subject. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in an amount of about 20 micrograms, about 30 micrograms, about 40 micrograms, about 60 micrograms, about 80 micrograms, about 120 micrograms, about 150 micrograms, about 180 micrograms or more.

[0426] In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered once or multiple times a day (e.g. once daily, twice daily, thrice daily or four times, five times, six times a day), preferably once, twice or thrice daily.

[0427] In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered orally. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered buccally. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually or buccally as a tablet. In embodiments, the tablet is lyophilized (or freeze-dried). In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually or buccally or gingivally as a wafer, a patch or a film.

[0428] In embodiments, the present disclosure provides a method of treating ASD in a subject in need thereof, comprising administering to the subject a therapeutically effective amounts of latrepirdine and dexmedetomidine or pharmaceutically acceptable salts thereof within 24 hours of the traumatic event and continuing for a period up to 4 weeks.

[0429] In embodiments, the present disclosure provides a method of treating ASD in a subject in need thereof, comprising administering orally to the subject a therapeutically effective amounts of latrepirdine and dexmedetomidine or pharmaceutically acceptable salts thereof within 24 hours of the traumatic event and continuing for a period up to 4 weeks.

[0430] In embodiments, the present disclosure provides a method of preventing PTSD in a subject in need thereof, comprising administering a therapeutically effective amounts of 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 latrepirdine and dexmedetomidine or pharmaceutically acceptable salts thereof within 24 hours of the traumatic event and continuing for a period up to 4 weeks.

[0431] In embodiments, the present disclosure provides a method of preventing PTSD in a subject in need thereof, comprising administering orally a therapeutically effective amounts of latrepirdine and dexmedetomidine or pharmaceutically acceptable salts thereof within 24 hours of the traumatic event and continuing for a period up to 4 weeks.

[0432] In embodiments, the present disclosure provides a method of treating autism spectrum disorders in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0433] In embodiments, the present disclosure provides a method of treating autism spectrum disorders in a subject in need thereof, comprising administering to the subject as a monotherapy a dosage form comprising therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0434] In embodiments, the present disclosure provides a method of treating autism spectrum disorders in a subject in need thereof, comprising administering orally to the subject as a monotherapy a dosage form comprising therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0435] In embodiments, the present disclosure provides a method of treating autism spectrum disorders in subject, comprising administering to the subject a dosage form comprising about 1 mg to about 100 mg of latrepirdine or a pharmaceutically acceptable salt thereof.

[0436] In embodiments, the dosage form comprises about 10 mg to about 60 mg of latrepirdine or a pharmaceutically acceptable salt thereof, e.g. about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, or about 60mg, including all ranges and values in between. 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374

[0437] In embodiments, about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered once a day. In embodiments, about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered twice a day. In embodiments, about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered thrice a day. In embodiments, about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered once a day. In embodiments, about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered twice a day. In embodiments, about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered thrice a day. In embodiments, about 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered once a day. In embodiments, about 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered twice a day. In embodiments, about 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered thrice a day. In embodiments, a total daily dose of about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered to the subject. In embodiments, a total daily dose of about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered to the subject. In embodiments, a total daily dose of about 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered to the subject. In embodiments, a total daily dose of about 40 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered to the subject. In embodiments, a total daily dose of about 60 mg of latrepirdine or a pharmaceutically acceptable salt thereof is administered to the subject.

[0438] In embodiments, latrepirdine or a pharmaceutically acceptable salt thereof is administered orally. In embodiments, latrepirdine or a pharmaceutically acceptable salt thereof is administered sublingually or buccally. In embodiments, latrepirdine or a pharmaceutically acceptable salt thereof is administered sublingually or buccally as a tablet. In embodiments, the tablet is lyophilized (or freeze-dried).

[0439] In embodiments, latrepirdine or a pharmaceutically acceptable salt thereof is administered oromucosally (sublingually or buccally or gingivally) as a wafer, a patch or a film.

[0440] In embodiments, latrepirdine or a pharmaceutically acceptable salt thereof is administered in a single or multiple unit dosage form. 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374

[0441] In embodiments, latrepirdine or a pharmaceutically acceptable salt thereof is administered once or multiple times a day (e.g. once daily, twice daily, thrice daily or four times, five times, six times a day), preferably once, twice or thrice daily.

[0442] In embodiments, the present disclosure provides a method of treating autism spectrum disorders in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of dexmedetomidine alone or in combination with latrepirdine or pharmaceutically acceptable salts thereof.

[0443] In embodiments, the present disclosure provides a method of treating autism spectrum disorders in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of dexmedetomidine alone or in combination with latrepirdine or pharmaceutically acceptable salts thereof.

[0444] In embodiments, the present disclosure provides a method of treating autism spectrum disorders in a subject in need thereof, comprising administering orally to the subject a therapeutically effective amount of dexmedetomidine alone or in combination with latrepirdine or pharmaceutically acceptable salts thereof.

[0445] In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually / buccally. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually or buccally as a tablet. In embodiments, the tablet is lyophilized (or freeze-dried). In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually or buccally or gingivally as a wafer, a patch or a film.

[0446] In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in a single or multiple unit dosage form.

[0447] In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered once or multiple times a day (e.g. once daily, twice daily, thrice daily or four times, five times, six times a day), preferably once, twice or thrice daily.

[0448] In embodiments, the unit dosage forms comprising dexmedetomidine or a pharmaceutically acceptable salt thereof and latrepirdine are administered simultaneously at 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 the same time or within a short period of time, usually less than 1 hour, preferably 0.5 hours, more preferably 0.25 hours.

[0449] In embodiments, the unit dosage forms comprising dexmedetomidine or a pharmaceutically acceptable salt thereof and latrepirdine are administered sequentially separated by a time-period anywhere within about 24 hours, e.g., about 12 hours, about 11 hours, about 10 hours, about 9 hours, about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours or about 1 hour of each other.

[0450] In embodiments, the dexmedetomidine and latrepirdine are provided as two separate dosage forms for the treatment of autism spectrum disorder in a subject, one comprising a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, and the other comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof. In embodiments, the active agents dexmedetomidine and latrepirdine are administered concurrently to the subject in need thereof. In embodiments, the active agents dexmedetomidine and latrepirdine are administered sequentially to the subject in need thereof.

[0451] In embodiments, the dexmedetomidine and latrepirdine are provided as a single dosage form for the treatment of autism spectrum disorder, comprising a therapeutically effective amounts of dexmedetomidine and latrepirdine or pharmaceutically acceptable salts thereof.

[0452] In embodiments, the combination comprising latrepirdine and dexmedetomidine or salts thereof is administered for at least 7 days, at least 10 days, at least 30 days, at least 60 days, at least 180 days, at least 365 days or longer.

[0453] In embodiments, the severity of autism spectrum disorder symptoms is assessed by Childhood Autism Rating Scale (CARS). In embodiments, the severity of autism spectrum disorder symptoms is assessed by Childhood Autism Rating Scale 2—Standard Form (CARS2- ST). In embodiments, the severity of autism spectrum disorder symptoms is assessed by Childhood Autism Rating Scale 2—High Functioning (CARS2-HF). In embodiments, the severity of autism spectrum disorder symptoms is assessed by Aberrant Behavior Checklist (ABC). In embodiments, the severity of autism spectrum disorder symptoms is assessed by Social Responsiveness Scale (SRS). In embodiments, the severity of autism spectrum disorder symptoms is assessed by Vineland Adaptive Behavior Scale II (VABS-II). 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374

[0454] In embodiments, the score improvement is measured after at least 8, 16, 24, 32, 40, 50, 60, or 80 weeks of treatment and compared to a score prior to the treatment.

[0455] In embodiments, the improvement in symptoms is measured after discontinuing treatment for at least 2, 4, 6, 8, 10 or more weeks and compared to a measurement prior to the treatment.

[0456] In embodiments, the present disclosure provides a method of reducing score on childhood Autism Rating Scale (CARS) in a human subject suffering from autism spectrum disorder comprising administering effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0457] In embodiments, the present disclosure provides a method of reducing score on childhood Autism Rating Scale (CARS) in a human subject suffering from autism spectrum disorder comprising administering orally effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0458] In embodiments, the present disclosure provides a method of reducing score on childhood Autism Rating Scale (CARS) in a human subject suffering from autism spectrum disorder comprising administering oromucosally effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0459] In embodiments, the present disclosure provides a method of reducing score on childhood Autism Rating Scale (CARS) in a human subject suffering from autism spectrum disorder comprising administering oromucosally effective amounts of dexmedetomidine in combination with latrepirdine or pharmaceutically acceptable salts thereof.

[0460] In embodiments, the present disclosure provides a method of reducing score on childhood Autism Rating Scale 2—Standard Form (CARS2-ST) in a human subject suffering from autism spectrum disorder comprising administering effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0461] In embodiments, the present disclosure provides a method of reducing score on childhood Autism Rating Scale 2—Standard Form (CARS2-ST) in a human subject suffering 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 from autism spectrum disorder comprising administering orally effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0462] In embodiments, the present disclosure provides a method of reducing score on childhood Autism Rating Scale 2—Standard Form (CARS2-ST) in a human subject suffering from autism spectrum disorder comprising administering oromucosally effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0463] In embodiments, the present disclosure provides a method of reducing score on childhood Autism Rating Scale 2—Standard Form (CARS2-ST) in a human subject suffering from autism spectrum disorder comprising administering effective amounts of dexmedetomidine in combination with latrepirdine or pharmaceutically acceptable salts thereof.

[0464] In embodiments, the present disclosure provides a method of reducing score on childhood Autism Rating Scale 2—Standard Form (CARS2-HF) in a human subject suffering from autism spectrum disorder comprising administering effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0465] In embodiments, the present disclosure provides a method of reducing score on childhood Autism Rating Scale 2—Standard Form (CARS2-HF) in a human subject suffering from autism spectrum disorder comprising administering orally effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0466] In embodiments, the present disclosure provides a method of reducing score on childhood Autism Rating Scale 2—Standard Form (CARS2-HF) in a human subject suffering from autism spectrum disorder comprising administering oromucosally effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0467] In embodiments, the present disclosure provides a method of reducing score on childhood Autism Rating Scale 2—Standard Form (CARS2-HF) in a human subject suffering from autism spectrum disorder comprising administering effective amounts of dexmedetomidine in combination with latrepirdine or pharmaceutically acceptable salts thereof. 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374

[0468] In embodiments, the present disclosure provides a method of reducing score on Aberrant Behavior Checklist (ABC) in a human subject suffering from autism spectrum disorder comprising administering effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0469] In embodiments, the present disclosure provides a method of reducing score on Aberrant Behavior Checklist (ABC) in a human subject suffering from autism spectrum disorder comprising administering orally effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0470] In embodiments, the present disclosure provides a method of reducing score on Aberrant Behavior Checklist (ABC) in a human subject suffering from autism spectrum disorder comprising administering oromucosally effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0471] In embodiments, the present disclosure provides a method of reducing score on Aberrant Behavior Checklist (ABC) in a human subject suffering from autism spectrum disorder comprising administering effective amounts of dexmedetomidine in combination with latrepirdine or pharmaceutically acceptable salts thereof.

[0472] In embodiments, the present disclosure provides a method of reducing score on Social Responsiveness Scale (SRS) in a human subject suffering from autism spectrum disorder comprising administering effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0473] In embodiments, the present disclosure provides a method of reducing score on Social Responsiveness Scale (SRS) in a human subject suffering from autism spectrum disorder comprising administering orally effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0474] In embodiments, the present disclosure provides a method of reducing score on Social Responsiveness Scale (SRS) in a human subject suffering from autism spectrum disorder comprising administering oromucosally effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof. 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374

[0475] In embodiments, the present disclosure provides a method of reducing score on Social Responsiveness Scale (SRS) in a human subject suffering from autism spectrum disorder comprising administering effective amounts of dexmedetomidine in combination with latrepirdine or pharmaceutically acceptable salts thereof.

[0476] In embodiments, the present disclosure provides a method of reducing score on Vineland Adaptive Behavior Scale II (VABS-II) in a human subject suffering from autism spectrum disorder comprising administering effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0477] In embodiments, the present disclosure provides a method of reducing score on Vineland Adaptive Behavior Scale II (VABS-II) in a human subject suffering from autism spectrum disorder comprising administering orally effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0478] In embodiments, the present disclosure provides a method of reducing score on Vineland Adaptive Behavior Scale II (VABS-II) in a human subject suffering from autism spectrum disorder comprising administering oromucosally effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0479] In embodiments, the present disclosure provides a method of reducing score on Vineland Adaptive Behavior Scale II (VABS-II) in a human subject suffering from autism spectrum disorder comprising administering effective amounts of dexmedetomidine in combination with latrepirdine or pharmaceutically acceptable salts thereof.

[0480] In embodiments, the treatment results in reduction in score of at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% compared to score prior to the treatment, wherein the symptoms of autism spectrum severity are assessed based on CARS, CARS2-ST, CARS2-HF, ABC, SRS, and VABS-II scales. In embodiments, the reduction in score is achieved after at least 4, 8 , 12, 16, 24 or more weeks of treatment.

[0481] In embodiments, the treatment achieves between 10% and 20%, between 10% and 30%, between 10% and 40%, between 10% and 50%, between 10% and 60%, between 10% and 70%, between 10% and 80%, between 10% and 90%, between 20% and 30%, between 20% and 40%, between 20% and 50%, between 20% and 60%, between 20% and 70%, between 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 20% and 80%, between 20% and 90%, between 30% and 40%, between 30% and 50%, between 30% and 60%, between 30% and 70%, between 30% and 80%, between 30% and 90%, between 40% and 50%, between 40% and 60%, between 40% and 70%, between 40% and 80%, between 40% and 90%, between 50% and 60%, between 50% and 70%, between 50% and 80%, or between 50% and 90% reduction in autism symptom severity after 8 or more weeks of treatment as compared to before initiating the treatment, where the autism symptom severity is assessed by a method selected from the group consisting of CARS, CARS2-ST, CARS2-HF, ABC, SRS, and VABS-II. In embodiments, a treatment achieves between 10% and 90%, between 20% and 80%, between 30% and 70%, or between 40% and 60% reduction in autism symptom severity after 8 or more weeks of treatment as compared to before initiating the treatment, where the autism symptom severity is assessed by a method selected from the group consisting of CARS, CARS2-ST, CARS2-HF, ABC, SRS, and VABS-II. In embodiments, the treatment achieves between 10% and 90%, between 20% and 80%, between 30% and 70%, or between 40% and 60% reduction in autism symptom severity after 12 or more weeks of treatment as compared to before initiating the treatment, where the autism symptom severity is assessed by a method selected from the group consisting of CARS, CARS2-ST, CARS2-HF, ABC, SRS, and VABS-II. In embodiments, the treatment achieves between 10% and 90%, between 20% and 80%, between 30% and 70%, or between 40% and 60% reduction in ASD symptom severity after 18 or more weeks of treatment as compared to before initiating the treatment, where the autism symptom severity is assessed by a method selected from the group consisting of CARS, CARS2-ST, CARS2-HF, ABC, SRS, and VABS-II. In embodiments, the treatment achieves between 10% and 90%, between 20% and 80%, between 30% and 70%, or between 40% and 60% reduction in autism symptom severity after 24 or more weeks of treatment as compared to before initiating the treatment, where the autism symptom severity is assessed by a method selected from the group consisting of CARS, CARS2-ST, CARS2-HF, ABC, SRS, and VABS-II.

[0482] In embodiments, the subject is a young child, an adolescent, a pediatric patient or a geriatric patient. In embodiments, the subject is a child below about 18, 15, 12, 10, 8, 6, 4, 3, 2, or 1 year old. In embodiments, the subject is an adult patient. In embodiments, the subject is an elderly patient. In embodiments, the subject is above about 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95 years old 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374

[0483] In embodiments, the treatment inhibits the progression of or reduces the severity of one or more symptoms of autistic disorder. In embodiments, the treatment inhibits the progression of or reduces the severity of one or more symptoms of Asperger’s disorder. In embodiments, the treatment inhibits the progression of or reduces the severity of one or more symptoms of child disintegrative disorder. In embodiments, the treatment inhibits the progression of or reduces the severity of one or more symptoms of Rett’s disorder.

[0484] In embodiments, the severity of autism spectrum disorder symptoms is assessed by Childhood Autism Rating Scale (CARS). In embodiments, the severity of autism spectrum disorder symptoms is assessed by Childhood Autism Rating Scale 2—Standard Form (CARS2- ST). In embodiments, the severity of autism spectrum disorder symptoms is assessed by Childhood Autism Rating Scale 2—High Functioning (CARS2-HF). In embodiments, the severity of autism spectrum disorder symptoms is assessed by Aberrant Behavior Checklist (ABC). In embodiments, the severity of autism spectrum disorder symptoms is assessed by Social Responsiveness Scale (SRS). In embodiments, the severity of autism spectrum disorder symptoms is assessed by Vineland Adaptive Behavior Scale II (VABS-II).

[0485] Childhood Autism Rating Scale (CARS) is a 15-item scale: Relating to People; Imitation; Emotional Response; Body Use; Object Use; Adaptation to Change; Visual Response; Listening Response; Taste, Smell, and Touch Response and Use; Fear; Verbal Communication; Nonverbal Communication; Activity; Level and Consistency of Intellectual Response; and General Impressions. It can be used to both diagnose autism and ASD and to assess the overall severity of symptoms. The CARS assessment is done subsequent to the ADIR assessment by the same evaluator.

[0486] A second edition of CARS, known as the Childhood Autism Rating Scale—2 or CARS- 2, was developed by Schopler et al. (Childhood Autism Rating Scale—Second edition (CARS2): Manual. Los Angeles: Western Psychological Services, 2010). The original CARS was developed primarily with individuals with co-morbid intellectual functioning and was criticized for not accurately identifying higher functioning individuals with ASD. CARS-2 retained the original CARS form for use with younger or lower functioning individuals (now renamed the CARS2-ST for “Standard Form”), but also includes a separate rating scale for use with higher functioning individuals (named the CARS2-HF for “High Functioning”) and an 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 unscored information-gathering scale (“Questionnaire for Parents or Caregivers” or CARS2- QPC) that has utility for making CARS2ST and CARS2-HF ratings.

[0487] Aberrant Behavior Checklist (ABC) is a symptom rating checklist used to assess and classify problem behaviors of children and adults in a variety of settings. The ABC includes 58 items that resolve onto five subscales: (1) irritability / agitation, (2) lethargy / social withdrawal, (3) stereotypic behavior, (4) hyperactivity / noncompliance, and (5) inappropriate speech.

[0488] Social Responsiveness Scale (SRS) is a 65-item scale that assesses social impairments, a core issue in autism, including social awareness, social information processing, capacity for reciprocal social communication, social anxiety / avoidance, and autistic preoccupations and traits. See Constantino et al., Validation of a brief quantitative measure of autistic traits: comparison of the social responsiveness scale with the autism diagnostic interview-revised. J Autism Dev Disord.2003 August; 33(4):427-33.

[0489] The Repetitive Behavior Scale-Revised (RBS-R) (Bodfish et al, The Repetitive Behavior Scale: A test manual (1998)) is an empirically derived clinical rating scale for measuring the presence and severity of a variety of forms of restricted, repetitive behavior that are characteristic of individuals with autism. The RBS-R consists of 6 subscales: stereotyped behavior, self-injurious behavior, compulsive behavior, routine behavior, sameness behavior, and restricted behavior. The scale provides an overall raw score for severity of repetitive behaviors and separate measures of severity for each subtype of repetitive behavior. High scores indicate more severe behavioral symptoms.

[0490] Vineland Adaptive Behavior Scale II (VABS-II) is a measure of the functioning level in four different domains: Communication, Daily Living Skills, Socialization, and Motor Skills, and 11 sub-domains. The raw scores were converted into an age equivalent score. It complements the ABC, which assesses problem behaviors. See Sara et al., Vineland Adaptive Behavior Scales, Second Edition (Vineland™-II), Pearson Publishing, 2005.

[0491] Other scales that may be used to assess improvement in autism spectrum disorder include Clinical Global Impression Scale (CGI), Pervasive Developmental Disorder Behavior Inventory (PDDBI), Expressive One-Word Picture Vocabulary Test-4 (EOWPVT-4), Behavior Assessment for Children-Social Skills subscale, Sensory Experiences Questionnaire, Intelligence Scales (Mullen Scales of Early Learning or Stanford-Binet), Language 106 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 Environment Analysis, Preschool Age Psychiatric Assessment, Pre-Linguistic Autism Diagnostic Observation Schedule (PL-ADOS), Autism diagnostic Interview-Revised (ADI-R), ATN GI Symptoms Inventory, and Parenting Stress Index.

[0492] In embodiments, the present disclosure provides methods of treating agitation in an agitated subject, comprising administering a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof to the subject. In embodiments, the therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof is present in a dosage form as described herein.

[0493] In embodiments, the present disclosure provides a method of treating agitation in an agitated subject, comprising oromucosally administering a therapeutic effective amount of latrepirdine or a pharmaceutically acceptable salt thereof to the subject. In embodiments, latrepirdine or a pharmaceutically acceptable salt thereof is administered (e.g. daily) for at least one week, at least two weeks, at least three weeks, at least four weeks, at least one month, at least two months, at least three months, at least four months, at least five months, at least six months or at least one year.

[0494] In embodiments, the present disclosure provides a method of treating agitation in an agitated subject, comprising administering a therapeutic effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with a therapeutic effective amount of dexmedetomidine or a pharmaceutically acceptable salt (e.g. dexmedetomidine hydrochloride) thereof to the subject. In embodiments, the treatment is effective with reduced or no side effects (e. g. cardiac or respiratory side effects). In embodiments, the therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof is present in a dosage form as described herein. In embodiments, the therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof is present in a dosage form as described herein. In embodiments, the therapeutically effective amount of latrepirdine and dexmedetomidine or a pharmaceutically acceptable salt thereof are present in the same dosage form or in separate dosage forms as described herein.

[0495] In embodiments, the active agents dexmedetomidine and latrepirdine are administered concurrently (same dosage form or separate dosage form) to the subject for a specific period of time (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 25, 26, 27, 28, 29, 30 days or so on) followed by single agent administration of latrepirdine to the subject for a specific period of time (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months or so on).

[0496] The present disclosure provides a method of treating agitation in an agitated subject, comprising oromucosally administering a therapeutic effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with a therapeutic effective amount of dexmedetomidine or a pharmaceutically acceptable salt (e.g. hydrochloride salt) thereof to the subject. In embodiments, the treatment is effective with reduced or no side effects (e. g. cardiac or respiratory side effects). In embodiments, the single administration of the combination treats agitation and maintains calming effect for at least 12 hours. In embodiments, the therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof is present in a dosage form as described herein. In embodiments, the therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof is present in a dosage form as described herein. In embodiments, the therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof and dexmedetomidine or a pharmaceutically acceptable salt thereof are present in the same dosage form or in separate dosage forms as described herein.

[0497] In embodiments, the agitation can be acute agitation, chronic agitation or both.

[0498] In embodiments, the agitation is caused by noradrenergic hyperarousal.

[0499] In embodiments, the agitation is treated without causing any significant sedation.

[0500] In embodiments, the agitation is associated with neuropsychiatric disorders selected from schizophrenia, bipolar disorder, bipolar mania, delirium, depression or other related neuropsychiatric disorders.

[0501] In embodiments, the agitation is associated with neurodegenerative disorders selected from Alzheimer’s disease, frontotemporal dementia (or Pick's disease), dementia, dementia with Lewy bodies, post-traumatic stress disorder, Parkinson's disease, vascular dementia, vascular cognitive impairment, Huntington's disease, multiple sclerosis, Creutzfeldt-Jakob disease, multiple system atrophy, progressive supranuclear palsy or other related neurodegenerative disorders. 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374

[0502] In embodiments, the agitation is associated with alcohol withdrawal or substance abuse withdrawal including opioid withdrawal.

[0503] The present disclosure provides a method of treating chronic agitation in a subject, comprising oromucosally administering a therapeutic effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with a therapeutic effective amount of dexmedetomidine or a pharmaceutically acceptable salt (e.g. dexmedetomidine hydrochloride) thereof to the subject. In embodiments, the subject is suffering from dementia. In embodiments, dementia include Alzheimer's disease dementia (AD), Fronto-temporal dementia (FTD), Vascular dementia, Lewy body disease (LBD), and Down dementia.

[0504] In embodiments, the disclosure provides a method of treating chronic agitation in a subject, comprising oromucosally administering to the subject a dosage form comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof. In embodiments, the disclosure provides a method of treating chronic agitation in a subject, comprising oromucosally administering to the subject a dosage form comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with therapeutic effective amount of dexmedetomidine or a pharmaceutically acceptable salt. In embodiments, the subject is suffering from dementia. In embodiments, dementia includes Alzheimer's disease dementia (AD), Fronto-temporal dementia (FTD), Vascular dementia, Lewy body disease (LBD), and Down dementia.

[0505] In embodiments, the disclosure provides a method of treating agitation in an agitated subject, comprising oromucosally administering to the subject a dosage form comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof. In embodiments, the agitation is caused by noradrenergic hyperarousal. In embodiments, the therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof is present in a dosage form as described herein. In embodiments, the therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof is present in a dosage form as described herein.

[0506] In embodiments, the agitation is severe. In embodiments, the agitation is mild.

[0507] In embodiments, the disclosure provides a method of treatment of agitation in a subject comprising oromucosally administering a therapeutically effective amount of latrepirdine or a 109 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 pharmaceutically acceptable salt thereof, wherein the subject has a concomitant Alzheimer’s disease.

[0508] In embodiments, the disclosure provides a method of treatment of agitation in a subject comprising oromucosally administering a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with a therapeutic effective amount of dexmedetomidine or a pharmaceutically acceptable salt, wherein the subject has a concomitant Alzheimer’s disease.

[0509] In embodiments, the disclosure provides a method of treatment of agitation in a subject comprising oromucosally administering a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof, wherein the subject has a concomitant dementia.

[0510] In embodiments, the disclosure provides a method of treatment of agitation in a subject comprising oromucosally administering a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with a therapeutic effective amount of dexmedetomidine or a pharmaceutically acceptable salt, wherein the subject has a concomitant Dementia.

[0511] In embodiments, the disclosure provides a method of treatment of agitation in a subject comprising oromucosally administering a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof, wherein the subject has a concomitant Parkinson’s disease.

[0512] In embodiments, the disclosure provides a method of treatment of agitation in a subject comprising oromucosally administering a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with a therapeutic effective amount of dexmedetomidine or a pharmaceutically acceptable salt, wherein the subject has a concomitant Parkinson’s disease.

[0513] In embodiments, the disclosure provides a method of treatment of agitation in a subject comprising oromucosally administering a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof, wherein the subject has a concomitant PTSD. 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374

[0514] In embodiments, the disclosure provides a method of treatment of agitation in a subject comprising oromucosally administering a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with a therapeutic effective amount of dexmedetomidine or a pharmaceutically acceptable salt, wherein the subject has a concomitant PTSD.

[0515] In embodiments, the disclosure provides a method of treatment of agitation in a subject comprising oromucosally administering a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof, wherein the subject has a concomitant vascular cognitive impairment.

[0516] In embodiments, the disclosure provides a method of treatment of agitation in a subject comprising oromucosally administering a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with a therapeutic effective amount of dexmedetomidine or a pharmaceutically acceptable salt, wherein the subject has a concomitant vascular cognitive impairment.

[0517] In embodiments, the disclosure provides a method of treatment of agitation in a subject comprising oromucosally administering a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof, wherein the subject has a concomitant Huntington’s disease.

[0518] In embodiments, the disclosure provides a method of treatment of agitation in a subject comprising oromucosally administering a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with a therapeutic effective amount of dexmedetomidine or a pharmaceutically acceptable salt, wherein the subject has a concomitant Huntington’s disease.

[0519] In embodiments, the disclosure provides a method of treatment of agitation in a subject comprising oromucosally administering a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof, wherein the subject has a concomitant schizophrenia.

[0520] In embodiments, the disclosure provides a method of treatment of agitation in a subject comprising oromucosally administering a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with a therapeutic effective amount of 111 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 dexmedetomidine or a pharmaceutically acceptable salt, wherein the subject has a concomitant schizophrenia

[0521] In embodiments, the disclosure provides a method of treatment of agitation in a subject comprising oromucosally administering a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof, wherein the subject has a concomitant bipolar disorder.

[0522] In embodiments, the disclosure provides a method of treatment of agitation in a subject comprising oromucosally administering a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with a therapeutic effective amount of dexmedetomidine or a pharmaceutically acceptable salt, wherein the subject has a concomitant bipolar disorder.

[0523] In embodiments, the disclosure provides a method of treatment of agitation in a subject comprising oromucosally administering a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof, wherein the subject has a concomitant depression.

[0524] In embodiments, the disclosure provides a method of treatment of agitation in a subject comprising oromucosally administering a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with a therapeutic effective amount of dexmedetomidine or a pharmaceutically acceptable salt, wherein the subject has a concomitant depression

[0525] In embodiments, the disclosure provides a method of treatment of agitation in a subject comprising oromucosally administering a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof, wherein the subject has a concomitant delirium.

[0526] In embodiments, the disclosure provides a method of treatment of agitation in a subject comprising oromucosally administering a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with a therapeutic effective amount of dexmedetomidine or a pharmaceutically acceptable salt, wherein the subject has a concomitant delirium. 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374

[0527] In embodiments, the present disclosure provides a method of treating agitation in an agitated subject, comprising oromucosally administering to the subject: (i) about 5 micrograms to about 300 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g. dexmedetomidine hydrochloride); and (ii) about 0.1 mg to about 100 mg of latrepirdine or a pharmaceutically acceptable salt thereof.

[0528] In embodiments, the agitation is treated without also inducing significant sedation. In embodiments, the agitation is caused by noradrenergic hyperarousal. In embodiments, the therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof and dexmedetomidine or a pharmaceutically acceptable salt thereof are present in the same dosage form or in separate dosage forms as described herein.

[0529] In embodiments, the present disclosure provides a method of treating agitation in an agitated subject, comprising oromucosally administering to the subject: (i) about 5 micrograms to about 200 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g. dexmedetomidine hydrochloride); and (ii) about 5 mg to about 50 mg of latrepirdine or a pharmaceutically acceptable salt thereof.

[0530] In embodiments, the agitation is treated without also inducing significant sedation. In embodiments, the agitation is caused by noradrenergic hyperarousal. In embodiments, the therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof and dexmedetomidine or a pharmaceutically acceptable salt thereof are present in the same dosage form or in separate dosage forms as described herein.

[0531] In embodiments, the present disclosure provides a method of reducing noradrenergic hyperarousal comprising orally administering a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof to a subject. In embodiments, the present disclosure provides a method of reducing noradrenergic hyperarousal comprising oromucosally administering a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof to a subject. 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374

[0532] In embodiments, the present disclosure provides a method of reducing noradrenergic hyperarousal comprising orally administering a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) to a subject.

[0533] In embodiments, the present disclosure provides a method of reducing noradrenergic hyperarousal comprising oromucosally administering a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) to a subject.

[0534] In embodiments, dexmedetomidine and latrepirdine are administered together in a single dosage form. In embodiments, dexmedetomidine and latrepirdine are administered conjointly in separate dosage forms. In embodiments, dexmedetomidine and latrepirdine or pharmaceutically acceptable salts thereof are administered as a single dose via single unit dosage form or multiple unit dosage forms administered simultaneously. In embodiments, dexmedetomidine or a salt thereof is administered in one or more-unit doses up to a total daily dose of about 0.5 micrograms to about 500 micrograms. In embodiments, latrepirdine or a salt thereof is administered in one or more-unit doses up to a total daily dose of about 1 mg to about 100 mg.

[0535] In embodiments, the present disclosure provides a method of treatment comprising administering dexmedetomidine or a pharmaceutically acceptable salt to a subject in an oral dosage form that provides rapid relief of agitation and then continuing treatment with latrepirdine or a pharmaceutically acceptable salt for an effective period of time. In embodiments, the present disclosure provides a method of treatment comprising administering dexmedetomidine or a pharmaceutically acceptable salt to a subject in an oromucosal dosage form that provides rapid relief of agitation and then continuing treatment with latrepirdine or a pharmaceutically acceptable salt for an effective period of time.

[0536] In embodiments, the present disclosure provides a method of treatment of behavioral and psychological symptoms in subjects with neurodegenerative disorder, comprising oromucosally administering a therapeutically effective amount of latrepirdine or a 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 pharmaceutically acceptable salt thereof. In embodiment, the behavioral and psychological symptom includes agitation or aggression.

[0537] In embodiments, the present disclosure provides a method of treatment of behavioral and psychological symptoms in subjects with neurodegenerative disorder, comprising oromucosally administering a therapeutically effective amounts of latrepirdine and dexmedetomidine or pharmaceutically acceptable salts thereof. In embodiment, the behavioral and psychological symptom includes agitation or aggression.

[0538] In embodiments, the present disclosure provides a method of treatment of behavioral and psychological symptoms in subjects with a neuropsychiatric disorder, comprising oromucosally administering a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof. In embodiment, the behavioral and psychological symptom includes agitation or aggression.

[0539] In embodiments, the present disclosure provides a method of treatment of behavioral and psychological symptoms in subjects with a neuropsychiatric disorder, comprising oromucosally administering a therapeutically effective amounts of latrepirdine and dexmedetomidine or pharmaceutically acceptable salts thereof. In embodiment, the behavioral and psychological symptom includes agitation or aggression.

[0540] In embodiments, the present disclosure provides use of therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof for the treatment of behavioral and psychological symptoms in subjects with a neurodegenerative disorder.

[0541] In embodiments, the present disclosure provides use of therapeutically effective amounts of latrepirdine and dexmedetomidine or pharmaceutically acceptable salts thereof for the treatment of behavioral and psychological symptoms in subjects with a neurodegenerative disorder.

[0542] In embodiments, the present disclosure provides use of therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof for the treatment of behavioral and psychological symptoms in subjects with a neuropsychiatric disorder. 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374

[0543] In embodiments, the present disclosure provides use of therapeutically effective amounts of latrepirdine and dexmedetomidine or pharmaceutically acceptable salts thereof for the treatment of behavioral and psychological symptoms in subjects with a neuropsychiatric disorder.

[0544] In embodiments, the present disclosure provides a method of treatment of depression in a subject in need thereof, comprising administering oromucosally to the subject a dosage form comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof. In embodiments, latrepirdine is administered in a dosage amount of about 1 mg to about 100 mg once a day. In embodiments, latrepirdine is administered in a dosage amount of about 10 mg once a day. In embodiments, latrepirdine is administered in a dosage amount of about 20 mg once a day. In embodiments, latrepirdine is administered in a dosage amount of about 30 mg once a day. In embodiments, latrepirdine is administered in a dosage amount of about 20 mg twice a day. In embodiments, latrepirdine is administered in a dosage amount of about 20 mg thrice a day. In embodiments, latrepirdine is administered in a dosage amount of about 30 mg once a day. In embodiments, latrepirdine is administered in a dosage amount of about 30 mg twice a day. In embodiments, latrepirdine is administered to the subject in a total daily dose of about 60 mg

[0545] The present disclosure provides a method of treating depression in a subject in need thereof, the method comprising administering oromucosally to the subject a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0546] The present disclosure provides a method of treating depression in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof. The present disclosure provides a method of treating depression in a subject in need thereof, the method comprising administering oromucosally to the subject a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0547] In embodiments, the present disclosure provides a method of treating depression in a subject in need thereof, the method comprising administering oromucosally to the subject about 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 1 mg to about 100 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 5 micrograms to about 300 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0548] In embodiments, the present disclosure provides a method of treating depression in a subject in need thereof, the method comprising administering oromucosally to the subject about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 30 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0549] In embodiments, the present disclosure provides a method of treating depression in a subject in need thereof, the method comprising administering oromucosally to the subject about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 40 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0550] In embodiments, the present disclosure provides a method of treating depression in a subject in need thereof, the method comprising administering oromucosally to the subject about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0551] In embodiments, the present disclosure provides a method of treating depression in a subject in need thereof, the method comprising administering oromucosally to the subject about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0552] In embodiments, the present disclosure provides a method of treating depression in a subject in need thereof, the method comprising administering oromucosally to the subject about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 30 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof

[0553] In embodiments, the present disclosure provides a method of treating depression in a subject in need thereof, the method comprising administering oromucosally to the subject about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 40 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof. 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374

[0554] In embodiments, the present disclosure provides a method of treating depression in a subject in need thereof, the method comprising administering oromucosally to the subject about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0555] In embodiments, the present disclosure provides a method of treating depression in a subject in need thereof, the method comprising administering oromucosally to the subject about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0556] In embodiments, the improvement in depressive symptoms is observed as measured by HAM-D-17 depression subscale.

[0557] In embodiments, the subject has a HAM-D-17 total score ≥18 at the start of treatment.

[0558] In embodiments, there is provided a method of reducing score on HDRS scale in a human subject suffering from depression comprising administering oromucosally effective amounts of dexmedetomidine either alone or in combination with latrepirdine or pharmaceutically acceptable salts thereof.

[0559] In embodiments, there is provided a method of reducing score on MADRS scale in a human subject suffering from depression comprising administering oromucosally effective amounts of dexmedetomidine either alone or in combination with latrepirdine or pharmaceutically acceptable salts thereof.

[0560] HAM-D or HDRS is used as an instrument for assessing the symptoms of depression. The instrument is administered by clinicians after a structured or unstructured interview of the patient to determine their symptoms. A total score is calculated by summing the individual scores from each question. Scores below 7 generally represent the absence or remission of depression. Scores between 7-17 represent mild depression. Scores between 18-24 represent moderate depression. Scores 25 and above represent severe depression. Most of the studies of depression consider a patient to have experienced 'response' to treatment if the score decreases by more than 50%. Remission' is commonly understood to be a score below 7. 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374

[0561] The Montgomery–Åsberg Depression Rating Scale (MADRS) is a ten-item diagnostic questionnaire which psychiatrists use to measure the severity of depressive episodes in patients with mood disorders. Higher MADRS score indicates more severe depression, and each item yields a score of 0 to 6. The overall score ranges from 0 to 60. The questionnaire includes questions on the following symptoms 1. Apparent sadness 2. Reported sadness 3. Inner tension 4. Reduced sleep 5. Reduced appetite 6. Concentration difficulties 7. Lassitude 8. Inability to feel 9. Pessimistic thoughts 10. Suicidal thoughts.

[0562] In embodiments, the unit dosage forms comprising dexmedetomidine or a pharmaceutically acceptable salt thereof and latrepirdine are administered simultaneously at the same time or within a short period of time, usually less than 1 hour, preferably 0.5 hours, more preferably 0.25 hours.

[0563] In embodiments, the unit dosage forms comprising dexmedetomidine or a pharmaceutically acceptable salt thereof and latrepirdine are administered sequentially separated by a time-period anywhere within about 24 hours, e.g., about 12 hours, about 11 hours, about 10 hours, about 9 hours, about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours or about 1 hour of each other.

[0564] In embodiments, the combination comprising latrepirdine and dexmedetomidine or salts thereof is administered once daily, twice daily, thrice daily or four times, five times, six times a day, preferably once, twice or thrice daily.

[0565] In embodiments, the combination comprising latrepirdine and dexmedetomidine or salts thereof is administered for at least 3 days, at least 5 days, at least 7 days, at least 10 days, at least 15 days, at least 30 days, at least 60 days, at least 90 days, at least 180 days, at least 365 days, or longer.

[0566] In embodiments, the depression is moderate or severe. In embodiments, the depression is major depression, bipolar disorder or mixed depression.

[0567] In embodiments, the present disclosure provides a synergistic combination comprising: (i) a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof; and 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 (ii) a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, for the treatment of depression in a subject in need thereof.

[0568] In embodiments, the present disclosure provides a method of treating psychosis in a subject in need thereof, comprising administering a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof to the subject. In embodiments, latrepirdine is administered in a dosage amount of about 1 mg to about 100 mg once a day. In embodiments, latrepirdine is administered in a dosage amount of about 10 mg once a day. In embodiments, latrepirdine is administered in a dosage amount of about 20 mg once a day. In embodiments, latrepirdine is administered in a dosage amount of about 30 mg once a day. In embodiments, latrepirdine is administered in a dosage amount of about 10 mg twice a day. In embodiments, latrepirdine is administered in a dosage amount of about 20 mg twice a day. In embodiments, latrepirdine is administered in a dosage amount of about 30 mg twice a day. In embodiments, latrepirdine is administered in a dosage amount of about 10 mg thrice a day. In embodiments, latrepirdine is administered in a dosage amount of about 20 mg thrice a day. In embodiments, latrepirdine is administered in a dosage amount of about 30 mg thrice a day. In embodiments, latrepirdine is administered to the subject in a total daily dose of about 60 mg

[0569] In embodiments, the present disclosure provides a method of treating psychosis in a subject in need thereof, comprising administering oromucosally a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof to the subject.

[0570] The present disclosure provides a method of treating psychosis in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0571] The present disclosure provides a method of treating psychosis in a subject in need thereof, the method comprising administering oromucosally (e.g. sublingually, buccally or gingivally) to the subject a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof. 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374

[0572] In embodiments, the treatment is effective without causing significant sedation.

[0573] In embodiments, the treatment is effective without experiencing clinically significant cardiovascular effects. In embodiments, the severity of psychosis in the subject is assessed using PANSS scale.

[0574] The Positive and Negative Syndrome Scale (PANSS) standard has been widely used in clinical trials and is considered the “gold standard” for assessment of antipsychotic treatment efficacy. To assess a patient using PANSS, an approximately 45-minute clinical interview is conducted. The patient is rated from 1 to 7 on 30 different symptoms based on the interview as well as reports of family members or primary care hospital workers. Scores are often given separately for the positive items, negative items, and general psychopathology

[0575] In embodiments, the present disclosure provides a method of achieving a PANSS score reduction in psychosis for a sustained period of time in a subject comprising administering to the subject a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0576] In embodiments, the present disclosure provides a method of achieving a PANSS score reduction in psychosis for a sustained period of time in a subject comprising administering oromucosally to the subject a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0577] In embodiments, the present disclosure provides a method of achieving a PANSS score reduction in psychosis for a sustained period of time in a subject comprising administering to the subject a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0578] In embodiments, the present disclosure provides a method of achieving a PANSS score reduction in psychosis for a sustained period of time in a subject comprising administering oromucosally to the subject a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof. 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374

[0579] In embodiments, the PANSS score reduction is at least about 20% to about 50% from baseline score. In embodiments, the PANSS score reduction is about 25% from baseline score. In embodiments, the PANSS total score reduction is about 30% from baseline score. In embodiments, the PANSS total score reduction is about 35% points from baseline score. In embodiments, the PANSS total score reduction is about 40% points from baseline score. In embodiments, the PANSS total score reduction is about 45% points from baseline score. In embodiments, the PANSS total score reduction is about 50% points from baseline score.

[0580] In embodiments, the psychosis is acute. In embodiments, the psychosis is chronic. In embodiments, the subject is agitated. In embodiments, the subject is non-agitated.

[0581] In embodiments, the psychosis is associated with a neuropsychiatric disorder selected from the group consisting of schizophrenia, schizoaffective disorder, depression, dementia and bipolar disorder or another related neuropsychiatric disorder. In embodiments, the psychosis is associated with neurodegenerative disorders.

[0582] In embodiments, the psychosis is associated with diseased condition such as substance abuse disorders (e.g., alcohol, opioid and other substance withdrawal).

[0583] In embodiments, the psychosis is acute. In embodiments, the psychosis is chronic. In embodiments, the psychosis is a single episode. In embodiments, the psychosis is recurring or includes recurrent episodes. In embodiments, the acute psychosis is associated with acute psychotic episodes and / or mixed episodes. In embodiments, dexmedetomidine and latrepirdine or pharmaceutically acceptable salts thereof are administered by the buccal route. In embodiments, dexmedetomidine and latrepirdine or pharmaceutically acceptable salts thereof are administered by the sublingual route. In embodiments, dexmedetomidine and latrepirdine or pharmaceutically acceptable salts thereof are administered sublingually or buccally in the form of a tablet or disc.

[0584] The combinations disclosed herein may be administered for as long as needed to treat agitation. In embodiments, said combination is administered at least once a day, such as once daily or twice daily, for at least 3 days, at least 5 days, at least 7 days, at least 10 days, at least 15 days, at least 30 days, at least 60 days, at least 90 days, at least 180 days, at least 365 days, or longer. The combinations disclosed herein may be administered for as long as needed to treat depression. 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374

[0585] The unit doses may be administered once daily, twice daily, thrice daily or four times, five times, six times a day, preferably once, twice or thrice daily. The daily dose depends on the frequency of administration, preferably once or twice, or thrice or five times a day. The daily doses can be split into two, three, four, five or six times.

[0586] In embodiments, the present disclosure provides a combination comprising: (i) a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof; and (ii) a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, for the treatment of behavioral and psychological symptoms in a subject in need thereof.

[0587] In embodiments, the present disclosure provides a synergistic combination comprising: (i) a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof and (ii) a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, for the treatment of agitation in a subject in need thereof.

[0588] In embodiments the therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof is dexmedetomidine hydrochloride.

[0589] In embodiments the therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof is latrepirdine hydrochloride or dihydrochloride.

[0590] In embodiments, the agitated subject has a baseline score in PEC scale of about 14 or higher.

[0591] In embodiments, the agitated subject experiences a PEC score reduction following administration of dosage forms of the present disclosure in accordance with the methods described herein. In embodiments, the patient achieves a change in PEC score of greater than -2 relative to baseline within 2 hours of administering the composition. For example, the PEC score reduction is about -1, about, about -2, about -3, about -4, about -5, about -6, about -7, about -8, about -9, or about -10 relative to baseline. In embodiments, the dosage form 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 comprises dexmedetomidine or a pharmaceutically acceptable salt thereof. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is present at a dose of about 0.5 micrograms to about 500 micrograms (e.g. about 30, about 60, about 80, about 90, about 120, about 180 or about 240 micrograms). In embodiments, the dosage form comprises latrepirdine or a pharmaceutically acceptable salt thereof. In embodiments, latrepirdine or a pharmaceutically acceptable salt thereof is present at a dose of about 0.5 mg to about 100 mg. In embodiments, the dosage form comprises dexmedetomidine or a pharmaceutically acceptable salt thereof and latrepirdine or a pharmaceutically acceptable salt thereof. In embodiments, the PEC score reduction is sustained for about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about 24 hours following administration of the composition.

[0592] In embodiments, the agitated subject has a baseline score in ACES score of about 3 or below.

[0593] In embodiments, the agitated subject experiences an Agitation-Calmness Evaluation Scale (ACES) score improvement following administration of dosage forms of the present disclosure in accordance with the methods described herein. In embodiments, the agitation is reduced to a 2 (moderate agitation), 3 (mild agitation) or 4 (normal behavior) 2 hours after administering the composition, as measured by the Agitation-Calmness Evaluation Scale (ACES). For example, the ACES score is improved to about a 3 (mild agitation) or 4 (normal behavior). In embodiments, the dosage form comprises dexmedetomidine or a pharmaceutically acceptable salt thereof. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is present at a dose of about 0.5 micrograms to about 500 micrograms (e.g. about 30, about 60, about 90, about 120, about 180 or about 240 micrograms). In embodiments, the dosage form comprises latrepirdine or a pharmaceutically acceptable salt thereof. In embodiments, latrepirdine or a pharmaceutically acceptable salt thereof is present at a dose of about 0.5 mg to about 500 mg. In embodiments, the dosage form comprises dexmedetomidine or a pharmaceutically acceptable salt thereof and latrepirdine or a pharmaceutically acceptable salt thereof. In embodiments, the ACES score improvement is sustained for about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about 24 hours following administration of the composition. In embodiments, the ACES score after treatment is preferably between 3 and 7; for example, 3, 4, 5, 6, or 7. Advantageously, the improved ACES score is obtained shortly after latrepirdine (alone or, preferably, with dexmedetomidine) is administered; for example the improved ACES score may be obtained within about 2 hours of administering the composition. For example, the improved ACES score may be obtained within about 5 minutes, about 10 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 60 minutes, about 70 minutes, about 80 minutes, about 90 minutes, about 100 minutes, about 110 minutes, or about 120 minutes. The improved ACES score may be obtained within about 5 minutes to about 120 minutes, about 5 minutes to about 60 minutes, about 5 minutes to about 30 minutes, about 30 minutes to about 120 minutes, about 30 minutes to about 90 minutes, about 30 minutes to about 60 minutes, about 60 minutes to about 120 minutes, about 60 minutes to about 90 minutes, or about 90 minutes to about 120 minutes following administration of the composition.

[0594] In embodiments, the agitated subject h...

Claims

Attorney Docket No. BXTI-052 / 01WO 332712-2374 Claims:

1. A method of treating a disorder associated with noradrenergic hyperarousal in a human subject, comprising administering to the human subject a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof, optionally in combination with a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein the disorder is acute stress disorder.

3. The method of claim 2, wherein the human subject has one or more symptoms associated with acute stress disorder selected from the group consisting of: anxiety, a sleep disorder, exaggerated startle response, irritability, inability to stop moving or sit still, lack of motivation, and agitation.

4. The method of claim 3, wherein the symptom is anxiety.

5. The method of claim 3, wherein the symptom is a sleep disorder.

6. The method of claim 3, wherein the symptom is exaggerated startle response.

7. The method of claim 3, wherein the symptom is irritability.

8. The method of claim 3, wherein the symptom is inability to stop moving or sit still.

9. The method of claim 3, wherein the symptom is a lack of motivation.

10. The method of claim 3, wherein the symptom is agitation.

11. The method of any one of claims 1 to 10, wherein the method prevents the disorder from developing into post-traumatic stress disorder.

12. The method of claim 1, wherein the disorder is autism spectrum disorder.

13. The method of any one of claims 1 to 12, wherein the disorder is caused by a traumatic event experienced by the human subject.

14. The method of any one of claims 1 to 13, wherein the latrepirdine is administered once a day.

15. The method of any one of claims 1 to 13, wherein the latrepirdine is administered twice a day.

16. The method of any one of claims 1 to 13, wherein the latrepirdine is administered three times a day.

17. The method of claim 13, wherein the latrepirdine is administered within 4 weeks of the traumatic event.

18. The method of claim 13, wherein the latrepirdine is administered within 2 weeks of the traumatic event. 290369642 v2Attorney Docket No. BXTI-052 / 01WO 332712-2374 19. The method of claim 13, wherein the latrepirdine is administered within 1 week of the traumatic event.

20. The method of claim 13, wherein the latrepirdine is administered within 3 days of the traumatic event.

21. The method of claim 13, wherein the latrepirdine is administered within 1 day of the traumatic event.

22. The method of claim 13, wherein the latrepirdine is administered within 12 hours of the traumatic event.

23. The method of claim 13, wherein the latrepirdine is administered within 6 hours of the traumatic event.

24. The method of claim 13, wherein the latrepirdine is administered within 4 hours of the traumatic event.

25. The method according to any of the preceding claims, wherein the therapeutically effective amount of latrepirdine is in the range from about 5 mg to about 300 mg daily.

26. The method according to any of the preceding claims, wherein the therapeutically effective amount of latrepirdine is in the range from about 10 mg to about 200 mg daily.

27. The method according to any of the preceding claims, wherein the therapeutically effective amount of latrepirdine is in the range from about 10 mg to about 100 mg daily.

28. The method according to any of the preceding claims, wherein the therapeutically effective amount of latrepirdine is in the range from about 10 mg to about 80 mg daily.

29. The method according to any of the preceding claims, wherein the therapeutically effective amount of latrepirdine is in the range from about 15 mg to about 60 mg daily.

30. The method according to any of the preceding claims, wherein the therapeutically effective amount of latrepirdine is in the range from about 30 mg to about 45 mg daily.

31. The method according to any of the preceding claims, wherein the therapeutically effective amount of latrepirdine is divided evenly for administration either twice daily or three times daily.

32. The method according to any of the preceding claims, wherein the latrepirdine or a pharmaceutically acceptable salt thereof is administered in combination with a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof simultaneously, sequentially, or intermittently. 290369642 v2

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